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    • 专利摘要:
    (I) compound having a strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria and exhibiting a strong antibacterial activity against various? -Lactamase-acid live bacteria, MRSA, and resistant P. aeruginosa and extremely stable against DHP- Lt; / RTI >
    公开号:KR19990081972A
    申请号:KR1019980705690
    申请日:1997-11-25
    公开日:1999-11-15
    发明作者:가주히로 아이하라；토시로 사사키；유미코 토유카；유코 가노；구니오 아츠미；가츠요시 이와마츠；타카시 이다
    申请人:이치로 키타사토；메이지 세이카 가부시키가이샤；
    IPC主号:
    专利说明:

    Carbapenem derivatives and antimicrobial agents
    Carbapenem derivatives have been actively studied as highly potent β-lactam agents because of their strong antibacterial activity against a wide range of bacteria, and Imipenem, Panipenem and Meropenem have been used clinically .
    At present, in the case of imipenem, due to the instability of the dehydropeptidase-I (DHP-I) (nephropathy), in the case of panifenem, All of the phenem is used as a mixture. On the other hand, recently, meropenem, which is commercially available, has increased stability to DHP-I due to the presence of a methyl group at the 1 -Position, and thus can be used as a single active ingredient in a drug.
    However, the stability against DHP-I is not yet sufficient. In addition, methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococcus pneumoniae (PRSP), and resistant Pseudomonas aeruginosa, which have severe clinical problems, The antimicrobial activity against the bacteria is not always sufficient. There is thus a strong need for new carbapenem antibiotics with improved antibacterial activity against these bacteria.
    WO 96/028455 discloses that carbapenem derivatives having an aromatic heterocyclic imidazo [5,1-b] thiazolium-6-ylmethyl group at the 2-position of the carbapenem ring have antibacterial activity .
    Japanese Patent Laid-Open Nos. 239058/1993 and 291973/1995, WO 95/10520, and WO / 93/21186 disclose that position 5 of pyrrolidinylthio bonded to position 2 of the carbapenem ring is suitable Carbapenem derivatives which bind to the carbon atom of an aromatic heterocycle through a spacer are described.
    The present invention relates to carbapenem derivatives having strong antibacterial activity against a wide range of bacteria. In particular, the present invention relates to imidazo [5,1-b] thiazole or imidazo [5,1-b] thiazolidine substituted or unsubstituted pyrrolidinyl thio groups at position 2 of the carbapenem ring Lt; RTI ID = 0.0 > carbapenem < / RTI >
    The inventors of the present invention have found that imidazo [5,1-b] thiazole substituted at the 2-position of the carbapenem ring via a pyrrolidinyl thio group (via a pyrrolidinyl thio optionally having a spacer) or unsubstituted And succeeded in synthesizing a novel carbapenem derivative having a substituted imidazo [5,1-b] thiazolium group.
    According to one aspect of the present invention there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
    here
    A is a bond, - (CH 2) m-, -CHR 8 -, - (CH 2) n-CH = CH- (CH 2) n'-, -C (= O) N (-R 9) CH 2 -, wherein R 8 represents a hydroxyl group, a methoxy group, a halogen atom, or an amino group, R 9 represents a hydrogen atom or - (CH 2 ) p CH 3 wherein p is an integer of 0 to 3 and m is an integer of 1 to 3 And n and n 'each represent an integer of 0 to 3;
    R 1 represents a hydrogen atom or a lower alkyl group;
    R 2 represents a hydrogen atom, sodium, or potassium; And any one of R 3 , R 4 , R 5 and R 6 represents a bond and is bonded to A, and the remaining three substituents may be the same or different and are a hydrogen atom, a halogen atom, a nitro group, a cyano group, , A lower cycloalkyl group, a lower alkylthio group, a C 2-4 alkenyl group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group or an aryl group (the lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group, At least one hydrogen atom is replaced by a halogen atom, a nitro group, a cyano group, a lower cycloalkyl group, a lower alkylthio group, a lower alkoxy group, a hydroxyl group, an amino group, , A lower alkoxycarbonyl group, a formylamino group, a lower alkylcarbonylamino group, a carbamoyl group, (N-lower alkylamino) carbonyl group, an aminosulfonyl group, (Lower alkylamino) sulfonyl group, aminosulfonylamino group, (N-lower alkylamino) sulfonylamino group, and aryl group;
    Or any two of R 3 , R 4 , R 5 , and R 6 together may form a pentagonal heterocyclic saturated ring comprising one oxygen atom and one nitrogen atom, O), or any two of R 3 , R 4 , R 5 , and R 6 may form C 3-6 alkylene, wherein one or more of the methylene groups of the alkylene group may be replaced by -NH- , -O-, -S-, or -CO-.
    According to a further aspect of the present invention there is provided a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:
    here
    A is a bond, - (CH 2) m-, -CHR 8 -, - (CH 2) n-CH = CH- (CH 2) n'-, -C (= O) N (-R 9) CH 2 -, wherein R 8 represents a hydroxyl group, a methoxy group, a halogen atom, or an amino group, R 9 represents a hydrogen atom or - (CH 2 ) p CH 3 wherein p is an integer of 0 to 3 and m is an integer of 1 to 3 and n and n 'each represent an integer of 0 to 3;
    R 1 represents a hydrogen atom or a lower alkyl group;
    R 2 represents a hydrogen atom, sodium, or potassium;
    Any one of R 3 , R 4 , R 5 and R 6 represents a bond and is bonded to A, and the remaining three substituents may be the same or different and are a hydrogen atom, a halogen atom, a nitro group, a cyano group, , A lower cycloalkyl group, a lower alkylthio group, a C 2-4 alkenyl group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, or an aryl group;
    R 7 represents a lower alkyl group, a lower cycloalkyl group, or an aryl group; And
    At least one hydrogen atom in said lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group, and aryl group as a part of each group or group represented by R 3 , R 4 , R 5 , R 6 and R 7 is A lower alkoxy group, a hydroxyl group, an amino group, an N-lower alkylamino group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a nitro group, a cyano group, (N-lower alkylamino) carbonyl group, aminosulfonyl group, (N-lower alkylamino) sulfonyl group, aminosulfonylamino group, (N- A sulfonylamino group, a sulfonylamino group, a sulfonylamino group, a sulfonylamino group, a sulfonylamino group, a sulfonylamino group, a sulfonylamino group, And
    Or any two of R 3 , R 4 , R 5 , and R 6 together may form a pentagonal heterocyclic saturated ring comprising one oxygen atom and one nitrogen atom, O), or any two of R 3 , R 4 , R 5 , and R 6 may together form C 3-6 alkylene, wherein at least one of the methylene groups of the alkylene group is replaced by -NH -, -O-, -S-, or -CO-.
    The carbapenem derivatives represented by the formulas (I) and (II) have not only a strong antibacterial activity against various -Lactamase-acid live bacteria, MRSA and resistant P. aeruginosa, but also a broad spectrum including Gram-positive bacteria and Gram- It has a strong antibacterial activity against bacteria. They are also very stable against DHP-I. Therefore, the compound of the present invention is useful as an antimicrobial agent.
    As used herein, the term "lower alkyl" or "lower alkoxy" as a group or part of a group refers to straight or branched C 1-6 alkyl or alkoxy, preferably straight or branched C 1-4 alkyl and alkoxy . The term " lower cycloalkyl " means a C 3-6 monocyclic alkyl.
    The term " halogen " means a fluorine, chlorine, bromine, or iodine atom.
    Examples of lower alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl.
    Examples of lower alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.
    compound
    - (CH 2 ) m - represented by A is preferably - (CH 2 ) - (that is, m = 1).
    -CHR < 8 > is preferably -CHOH-.
    - (CH 2 ) n -CH═CH- (CH 2 ) n'- represented by A is preferably -CH═CH- (ie, n = n '= 0).
    -C (═O) N (-R 9 ) CH 2 - represented by A is preferably -C (═O) N (-CH 3 ) CH 2 - or -C (═O) NH-CH 2 - .
    R 1 preferably represents a hydrogen atom or a methyl group.
    R 2 preferably represents a hydrogen atom.
    R 3, R 4, R 5 , and R 6 is preferably hydrogen atom, a halogen atom, a lower alkyl group, a lower cyclo alkyl group, a lower alkylthio import, C 2-4 alkenyl, formyl, lower alkyl carbonyl group , Or an aryl group, and more preferably a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group, or a lower alkylthio group.
    At least one hydrogen atom in the lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group, and aryl group as a part of the group or group which may be represented by R 3 , R 4 , R 5 , and R 6 is a halogen atom A lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a carbamoyl group or an (N-lower alkylamino) carbonyl group (for example, a fluorine atom), a hydroxyl group, an amino group, a lower cycloalkyl group (e.g., cyclopropyl), a lower alkylcarbonyl group, (For example, dimethylaminocarbonyl).
    R 3 , R 4 , R 5 , and R 6 , and examples of the substituted group include an aminomethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, a carbamoylmethyl group, a carbamoylmethyl group, A benzoylethyl group, a 2-fluoroethyl group, a cyclopropylmethyl group, an N, N-dimethylcarbamoylmethyl group, a methoxymethyl group, an ethoxycarbonylmethyl group, and a formylaminomethyl group.
    The arylcarbonyl group which may be represented by R 3 , R 4 , R 5 , and R 6 is preferably a phenylcarbonyl group or a naphthylcarbonyl group.
    The aryl group which may be represented by R 3 , R 4 , R 5 , and R 6 is preferably a phenyl group or a naphthyl group.
    One or more hydrogen in the lower alkyl group, the lower cycloalkyl group, and the aryl group as part of each group or group which may be represented by R 7 may be substituted. Examples of preferred substituents and examples of preferred substituted alkyl groups include those described above in connection with R 3 , R 4 , R 5 , and R 6 . R 7 is preferably a lower alkyl group or a lower cycloalkyl group.
    According to a preferred embodiment of the present invention, any two of R 3 , R 4 , R 5 , and R 6 together may form a pentagonal heterocyclic saturated ring comprising one oxygen atom and one nitrogen atom , Wherein the ring may be substituted with oxo (= O), or any two of R 3 , R 4 , R 5 , and R 6 may together form C 3-6 alkylene, One or more of the methylene groups may be replaced by -NH-, -O-, -S-, or -CO-. Examples of compounds having such a cyclic structure include compounds wherein R 3 or R 4 represents 1-oxo-2-azapropano.
    When A represents a bond, it is preferable that R 4 and R 5 represent a bond.
    A preferred group of compounds represented by formula (I)
    A is a bond, -CH 2 -, -CH (OH ) -, -CH = CH-, -C (O) NHCH 2 - or -C (= O) N (-CH 3) CH 2 - represents;
    R 1 represents a hydrogen atom or a methyl group;
    R 2 represents a hydrogen atom;
    R 3 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower cycloalkyl group, a lower alkylthio group, a C 2 -4 alkenyl group, formyl group, lower alkylcarbonyl group, or aryl group, wherein at least one hydrogen atom in the lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group, and aryl group may be optionally substituted by the above-mentioned substituent More preferably a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group, or a lower alkylthio group in which at least one hydrogen atom of the lower alkyl group and lower cycloalkyl group may be optionally substituted by the substituent described above) ≪ / RTI >
    A preferred group of compounds represented by formula (II)
    A is a bond, -CH 2 -, -CH (OH ) -, -CH = CH-, -C (O) NHCH 2 - or -C (= O) N (-CH 3) CH 2 - represents;
    R 1 represents a hydrogen atom or a methyl group;
    R 2 represents a hydrogen atom;
    R 3 , R 4 , R 5 and R 6 may be the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower cycloalkyl group, a lower alkylthio group, a C 2 -4 alkenyl group, formyl group, lower alkylcarbonyl group, or aryl group, wherein at least one hydrogen atom in the lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group, and aryl group may be optionally substituted by the above-mentioned substituent More preferably a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group, or a lower alkylthio group in which at least one hydrogen atom of the lower alkyl group and lower cycloalkyl group may be optionally substituted by the substituent described above) Lt; / RTI > And
    R 7 is a lower cycloalkyl group or a lower alkyl group, wherein at least one hydrogen atom in the lower alkyl group and lower cycloalkyl group may be optionally substituted by the above-mentioned substituents.
    Specific examples of preferred carbapenem derivatives represented by formula (I) and formula (II) according to the present invention include the following compounds:
    1. Synthesis of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5 - [(imidazo [5,1- b] thiazol- Yl) methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-3-carboxylic acid;
    2. Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5 - [(6-methylimidazo [ , L-b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    3. Synthesis of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [N- (imidazo [5,1- b] thiazole -5-yl) methyl-N-methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate;
    4. Synthesis of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) Methylimidazo [5,1-b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    5. Synthesis of (lR, 5S, 6S) -2 - [(3S, 5S) -5- [N-methyl- N- (5-aminomethyl-6-methylimidazo [ Yl) methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    6. Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ 1-b] thiazol-3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    7. Synthesis of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl [5,1-b] thiazolium-3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    8. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ -b] thiazol-3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    9. Preparation of perchloric acid (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl [5,1-b] thiazolium-3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    10. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [5,1- b] thiazol- Yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    11. Synthesis of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) 1-b] thiazolium-5-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    12. (1R, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ -b] thiazol-5-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    13. Preparation of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- Yl [5,1-b] thiazolium-5-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    14. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ -b] thiazol-7-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    15-1. (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ 5,1-b] thiazolium-7-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    15-2. (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ 5,1-b] thiazolium-7-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    16. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ -b] thiazol-2-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    17. (1R, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ -b] thiazol-2-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    18. Preparation of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl [5,1-b] thiazolium-2-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    19. Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl [5,1-b] thiazolium-2-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    20. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [ Yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    21. Iodine (1R, 5S, 6S) -6 - [(1R) -1-hydroxyethyl) , L-b] thiazolium-3-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    22. Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5R) -5- [6- (2-hydroxyethyl) imidazo [ , 1-b] thiazolium-3-yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    23. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- (imidazo [ Yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    24. Iodine (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- 1-b] thiazolium-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    25. Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [6- (2-hydroxyethyl) imidazo [ , 1-b] thiazolium-2-yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    26. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    27. Chloride (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    28. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- (3-methylimidazo [ -b] thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    29. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- (3,6-dimethylimidazo [5,1- b] thiazolium 2-yl) methylpyrrolidine 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    30. Preparation of iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6-carbamoylmethyl-3-methylimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    31. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- (5-methylimidazo [ -b] thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    32. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- (5,6-dimethylimidazo [5,1- b] thiazolium 2-yl) methylpyrrolidine 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    33. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6- carbamoylmethyl- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    34. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [5,1- b] thiazol- Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    35. Iodine (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) 1-b] thiazolium-7-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    36. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -1-methyl-2 - [(3S) -5- (6-methylimidazo [ b] thiazolium-5-yl) pyrrolidin-3-yl] thiocarbazol-2-yl) -3-carboxylic acid;
    37. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S) -5- [6- (2-hydroxyethyl) imidazo [ -b] thiazolium-5-yl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-3-carboxylic acid;
    38. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [ ] Thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    39. A mixture of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- [ Imidazo [5,1-b] thiazolium-3-yl) ethyl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    40. A mixture of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- [ Imidazo [5,1-b] thiazolium-3-yl) ethyl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2- cyclopropylmethyl) -5- methylimidazo [5,1- b] thiazolium- Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    42. Trifluoromethanesulfonic acid (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2-fluoroethyl) Thiazol-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    43. Trifluoromethanesulfonic acid (1R, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl) -2- [(3S, 5S) -5- [6- (2- -5-methylimidazo [5,1-b] thiazolium-2-yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-3-carboxylic acid;
    44. (lR, 5S, 6S) -2 - [(3S, 5S) -5- [6-N, N-Dimethylcarbamoylmethyl-5-methylimidazo [5,1- b] thiazolium Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate;
    45. (lR, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [6- methoxymethyl-5-methylimidazo [ , 1-b] thiazolium-2-yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate;
    46. (lR, 5S, 6S) -2 - [(3S, 5S) -5- [6-ethoxycarbonylmethyl-5-methylimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate;
    47. A mixture of (1R, 5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2- (Z) , 1-b] thiazol-2-yl) vinyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    48. A mixture of (1R, 5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2- (E) , 1-b] thiazol-2-yl) vinyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid;
    49. A mixture of (5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2- (Z) -b] thiazol-2-yl) vinyl] pyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    50. A mixture of (5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2- (E) -b] thiazol-2-yl) vinyl] pyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    51. (lR, 5S, 6S) -2 - [(3S, 5S) -5- [imidazo [5,1- b] thiazol-3- yl] pyrrolidin- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    52. A mixture of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5 - [(6-methylimidazo [ , 1-b] thiazolidium) -3-yl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid;
    53. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5 - [(6-carbamoylmethylimidazo [5,1- b] thiazolidium) 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    54. A pharmaceutical composition comprising (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    55. A process for the preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) 2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    56. Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- 2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    57. A process for the preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5 - [[2- (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    58. A process for the preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) - (6- (carbamoylmethyl) imidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    59. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    60. A process for preparing (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) imidazo [ 5-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    61. Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- 7-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    62. Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) ] Thiazolyl-2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- mountain;
    63. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) ] Thiazolyl-2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- mountain;
    64. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) Thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- mountain;
    65. Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (Z) Thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- mountain;
    66. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- (5-methylthioimidazo [ -b] thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl] -3-carboxylic acid;
    67. (lR, 5S, 6S) -6 - (((1R) -1-Hydroxyethyl) Diazo [5,1-b] thiazolid-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-yl) -3-carboxylate;
    68. Iodine (1R, 5S, 6S) -2 - [(3S, 5S) -5- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    69. A process for the preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (5-chloro- imidazo [5,1- b] thiazol- 2- yl) methylpyrrolidin- Thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    70. A process for the preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (5-chloro-6-methylimidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    71. A mixture of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6- (carbamoylmethyl-5-chloroimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    72. Preparation of (lR, 5S, 6S) -2 - [(3S, 5S) -5- (6- (2- carbamoylethyl) -5- methylimidazo [5,1- b] thiazolium Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid;
    73. A mixture of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6-carbamoylmethyl-5-methylimidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    74. A mixture of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) - (6-carbamoylmethyl-5-methylimidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    75. A mixture of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [ 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate;
    76. Trifluoromethanesulfonic acid (1R, 5S, 6S) -6 - (((1R) -1-Hydroxyethyl) -2- [ (2-hydroxyethyl) imidazo [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin-3- yl] thio- 1 -methylcarbapen- Bicic acid;
    77. (lR, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (2- carbamoylethyl) imidazo [5,1- b] thiazolium Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate;
    78. A mixture of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (2- fluoroethyl) imidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid;
    79. (lR, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (2- carbamoylethyl) imidazo [5,1- b] thiazolium Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate;
    80. (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl-2 - [(3S, 5S) -5- [ Imidazo [5,1-b] thiazolium-2-yl) ethenyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate;
    81. Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid;
    82. A mixture of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (2- fluoroethyl) imidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylic acid; And
    83. (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate.
    The compounds of formula (I) and formula (II) may exist in the form of their pharmaceutically acceptable salts. Examples of such salts include pharmaceutically acceptable non-toxic salts. Examples of salts formed with amino and / or imidazothiazolium groups include hydrohalide hydrohalides such as hydrofluoroacid, hydrochloride, hydrobromide and hydroiodide; Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates and carbonates; Methanesulfonic acid salts, trifluoromethanesulfonic acid salts, and ethanesulfonic acid salts; Arylsulfonic acid salts such as benzenesulfonic acid salt and p-toluenesulfonic acid salt; But are not limited to, trichloroacetate, trifluoroacetate, hydroxyacetate, benzoate, mandelate, butyrate, propionate, formate, fumarate, succinate, citrate, tartrate, oxalate, maleate, Organic acid salts such as hydrochloric acid, sulfuric acid, and ascorbic acid; And acidic amino acid salts such as glutamic acid and aspartic acid salts. Examples of the salt formed in the carboxyl group include alkali metal salts such as sodium, potassium and lithium salts; Alkaline earth metal salts such as calcium and magnesium salts; Ammonium salts; Organic solvents such as triethylamine, trimethylamine, diethylamine, pyridine, ethanolamine, triethanolamine, dicyclohexylamine, procaine, benzylamine, N-methylpiperidine, N-methylmorpholine, Amine salts; And basic amino acid salts such as lysine, arginine, and histidine.
    The compound represented by the formula (II) can form a salt in a molecule. Such salts are also included in the pharmaceutically acceptable salts of the compounds according to the invention.
    In the compounds represented by the formulas (I) and (II), isomers exist. Any of the isomers and mixtures thereof are included in the scope of the present invention.
    Compound manufacturing
    Preferably, the compound represented by the compound (I) according to the present invention is produced according to the following reaction path.

    In the reaction pathway, A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I) and R 10 is hydrogen or a hydroxy protecting group R 11 is a carboxyl protecting group (for example, allyl, di (methoxycarbonyl), p-nitrobenzyloxycarbonyl Phenylmethyl, p-methoxybenzyl or p-nitrobenzyl), R 12 represents an amino protecting group (for example, allyloxycarbonyl, p-methoxybenzyloxycarbonyl, or p-nitrobenzyloxycarbonyl And W represents a eliminator group (preferably, diphenylphosphoryloxy, or trifluoromethanesulfonyloxy).
    In the first step, the compound of formula (III) can be prepared by a conventional method, for example, as described in WO 96/28455. In addition, the compound represented by the formula (IV) can be produced by the method described below.
    In the first step, compound (III) can be converted to compound (V) by the following method. Particularly, the compound (III) can be used in an amount of 1 equivalent or excess of the compound (IV) relative to the compound (III) and 1 equivalent or excess of diisopropylethylamine, triethylamine, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, toluene or hexane in the presence of a base such as pyridine, (V) can be obtained by a usual post-treatment after allowing the compound to react in a solvent such as tetrahydrofuran, methylenephosphoric triamide, methylphosphoric triamide or a mixed solvent of the above solvents at -80 ° C to + 60 ° C for 15 minutes to 72 hours.
    Finally, in the second step, the protecting groups R 10, R 11 and R 12 of the compound (V) are removed in one or more stages depending on the kind of protecting group to obtain the compound represented by the formula (I) according to the present invention.
    The deprotection reaction for removing R 10, R 11 , and R 12 can be carried out according to a conventional method generally known in the art, although the method is different depending on the kind of the protecting group used. If some or all of the protecting groups can be removed under acidic conditions, mineral acids such as hydrochloric acid, or organic acids such as formic acid, acetic acid, or citric acid, or Lewis acids such as aluminum chloride may be used . On the other hand, if it can be removed under reducing conditions, catalytic reduction using various catalysts or metal reducing agents such as zinc or iron may be used. When R 10 represents a silyl protecting group (for example, t-butyldimethylsilyl, trimethylsilyl, or triethylsilyl), a fluoroion reagent (for example, tetrabutylammonium fluoride) may be used. When R 10 represents allyloxycarbonyl and R 11 represents allyl, the protecting group can be easily removed using various palladium complexes.
    Among the compounds represented by the formula (I), a compound in which A represents -CH (OH) -, that is, the compound (I-1) can be produced according to the following reaction path:
    In the reaction path, M represents lithium, MgCl, MgBr, or MgI, R 1 and R 2 are as defined in formula (I), and any of R 3 ' , R 4' , R 5 ' and R 6' One represents M and the remaining three substituents may be the same or different and are hydrogen; halogen; Nitro; Cyano; Lower alkyl; Lower cycloalkyl lower alkylthio; C 2-4 alkenyl; Or aryl, and R 10 ' represents a hydroxy protecting group (for example, t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, allyloxycarbonyl, p-methoxybenzyloxycarbonyl, or p-nitrobenzyloxy Carbonyl), R 11 , R 12 , and W are as defined in formula (III).
    In the first step, compound (III) can be converted to compound (VII) by the following method. The compound (III) is reacted with 1 equivalent or excess of the compound (VI) to the compound (III) and 1 equivalent or excess of the compound (VI) with diisopropylethylamine, triethylamine, N, N-dimethylaminopyridine N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, toluene or hexamethylphosphoric acid in the presence of a base such as pyridine or acetonitrile, Triamide and the like or a mixed solvent of the above solvent at -50 ° C to + 50 ° C for 15 minutes to 24 hours, and then the compound (VII) can be obtained by a usual post-treatment.
    Then, in a second step, compound (VII) can be converted to compound (VIII) by conventional alcohol oxidation (e.g. Swern oxidation, DMSO oxidation, or chromic acid oxidation). Preferably, however, the conversion is carried out in an inert solvent such as dichloromethane in the presence of a catalytic amount of tetra-n-propylammonium perruthenate in the presence of Molecular Sieves 4A and a slight excess of N-methylmorpholine N- Can be performed using a seed.
    The organometallic compound of imidazo [5,1-b] thiazole represented by the formula (IX) can be synthesized by the method described below.
    In the third step, compound (VIII) can be converted to compound (X) by the following method. Compound (X) is prepared by adding 0.5 to 1 equivalent of compound (VIII) to a solution of compound (IX) in an inert solvent (e.g. tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, toluene or benzene) At -80 [deg.] C to + 50 [deg.] C for 15 minutes to 24 hours, and then carrying out conventional post-treatment.
    In the fourth step, the protecting groups R 10 ' , R 11 , and R 12 of the compound (X) are removed in one step or a plurality of steps depending on the kind of the protecting group to obtain the compound represented by the formula (I- .
    R10 ', R11, And R12May be carried out by a conventional method generally known in the art although the method is different depending on the kind of the protecting group used. If some or all of the protecting groups can be removed under acidic conditions, a mineral acid such as hydrochloric acid, or an organic acid such as formic acid, acetic acid, or citric acid, or a Lewis acid such as aluminum chloride may be used. On the other hand, when removed under reducing conditions, catalytic reduction using various catalysts or metal reducing agents such as zinc or iron may be used. R10 '(Such as t-butyldimethylsilyl, trimethylsilyl, or triethylsilyl), a fluoroion reagent (for example, tetrabutylammonium fluoride) may be used. R10 'Represents allyloxycarbonyl and R11Represents an allyl, the protecting group can be easily removed using various palladium complexes.
    Thus, the compounds represented by the formulas (I) and (I-1) obtained may be subjected to chromatography using a macro high porous resin, gel filtration using Sephadex or the like, reverse phase silica gel column chromatography, ≪ / RTI >
    The compound represented by the formula (II) according to the present invention is preferably prepared according to the following reaction path:

    In the reaction path, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in formula (II) and R 11 and R 12 are as defined in formula And Y represents a leaving group (preferably a halogen atom, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, trifluoromethanesulfonyloxy, and the like), and X - represents a pharmaceutically acceptable halogen ion, an organic acid anion or an inorganic acid anion. Sulfonyloxy, or methanesulfonyloxy).
    The starting compound (XI) in the first step is a compound wherein R 10 of the compound (V) or R 10 ' of the compound (X) is t-butyldimethylsilyl. This compound can be synthesized by the method described above in the production method of the compound represented by the formula (I) and the formula (I-1).
    In a first step, the compound (XI) is reacted with a fluoride anion reagent (preferably, tetrabutylammonium fluoride or the like) in an inert solvent such as tetrahydrofuran at -20 ° C to + 50 ° C for 1 hour to one week, , Followed by deprotection of the t-butyldimethylsilyl group, followed by the ordinary post-treatment to obtain the compound (XII).
    The compound (XII) is a compound in which R 10 ' of the compound (V) is hydrogen. This compound can also be synthesized from a compound represented by the formula (III) in which R 10 ' represents t-butyldimethylsilyl according to the method described above in the process for producing the compound represented by the formula (I).
    In the second step, conversion of compound (XII) to compound (XIII) can be carried out as follows. Particularly, the compound (XII) is reacted with the electrophilic reagent R (XII) in the absence of a solution or under an inert solvent (for example, benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, N, N-dimethylformamide or acetonitrile) 7- Y with 1 to 100 equivalents at -80 ° C to + 60 ° C for 15 minutes to one week, and then the compound (XIII) is obtained by conventional post-treatment.
    In the third and last step, the deprotection reaction for the removal of the protecting groups R 11 and R 12 of formula (XIII) can be carried out according to the usual methods known in the art, depending on the kind of protecting group used, . Accordingly, the compound represented by the formula (II) according to the present invention can be produced.
    If some or all of the protecting groups can be removed under acidic conditions, a mineral acid such as hydrochloric acid, or an organic acid such as formic acid, acetic acid, or citric acid, or a Lewis acid such as aluminum chloride may be used. When R < 11 > represents allyl, the protecting group can be easily removed using various palladium complexes.
    Thus, in the case of deprotection under reducing conditions or deprotection using a palladium complex, X - represents anion of the leaving group Y, whereas in the case of deprotection using an acid, the anion of the organic or inorganic acid used for X - Lt; RTI ID = 0.0 > (II) < / RTI >
    Thus, the obtained compound represented by the formula (II) can be isolated by chromatography using a non-ionic macroporous resin, gel filtration using Sephadex or the like, reverse phase silica gel column chromatography, or using an ion exchange resin or the like Can be purified.
    The compound represented by the formula (IV) can be produced according to a method which varies according to A.
    Compound (IV-1) wherein A of formula (IV) represents -C (= O) N (-R 9 ) CH 2 - is preferably prepared according to the following reaction path:

    In this reaction path, R 3 , R 4 , R 5 , R 6 and R 9 are as defined in formula (I) and R 12 is as defined above in relation to formula (IV).
    In the first step, the compound represented by the formula (XIV) can be produced by a conventional method described in Japanese Patent Laid-Open No. 104088/1985, and the compound represented by the formula (XV) And can be prepared by a conventional method as described in EP-A-311071/1996.
    In the first step, the compound (XIV) can be obtained by using a condensing agent (for example, dicyclohexylcarbodiimide or carbonyldiimidazo), a halogenated acid such as thionyl chloride or phosphorus oxychloride (XV) in the presence of a base. Alternatively, the use of the following method is preferred.
    To a solution of the compound (XIV) in an inert solvent (for example dichloromethane, chloroform, benzene, toluene or diethyl ether) is added 1 to 5 equivalents of a Vilsmeier reagent prepared by a conventional method. The reaction is then carried out at -50 ° C to + 50 ° C for 15 minutes to 1 hour. 1 to 10 equivalents of a compound (XV) and a base (for example, triethylamine, diisopropylethylamine, or pyridine) are added thereto. The reaction is further allowed to proceed at the same temperature for 30 minutes to 24 hours, and then the compound (XVI) is obtained by conventional post-treatment.
    Compound XVI is then dissolved in a suitable solvent (e.g. methanol, ethanol, distilled water, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide or dichloromethane) Is added to a solution of one equivalent of an alkali (for example, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium methoxide, sodium ethoxide or ammonia) to the compound (XVI) To + 50 < 0 > C for 10 minutes to 24 hours, followed by conventional post treatment to obtain compound (IV-1).
    Compound (IV-2) wherein A of formula (IV) represents a compound represented by -CH (OH) - is preferably prepared according to the following reaction path.


    In the above reaction scheme, M, R 3 ', R 4', R 5 ', and R 6' are as defined in formula (Ⅸ), R 12 are as defined in formula (Ⅴ), R 13 is Lower alkyl (preferably ethyl) or aryl (preferably phenyl).
    The organometallic compound of imidazo [5,1-b] thiazole represented by the formula (IX) in the first step can be synthesized by the method described below.
    In the first step, the compound (XVII) can be converted to the compound (XVIII) by the following method. To the solution obtained by dissolving the compound (XVII) in an inert solvent (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, toluene or benzene), 0.5 to 2 equivalents of the compound (XVII) After the reaction is carried out at -80 ° C to + 50 ° C for 15 minutes to 24 hours, the compound (XVIII) is obtained by conventional post-treatment.
    In the second step, the t-butyldimethylsilyl group is removed using an acid or fluoride anion reagent as a protecting group for the compound (XVII) to obtain the compound (XIX).
    When an acid is used, the compound (XVII) is dissolved in a solvent (for example, acetonitrile, methanol or ethanol or an aqueous solution of the solvent), 1 to 10 equivalents of a mineral acid (preferably hydrochloric acid) , At -20 ° C to + 50 ° C for 15 minutes to 24 hours, neutralizing the reaction mixture, and then subjecting to a usual post-treatment to prepare compound (XIX).
    On the other hand, when a fluoride anion reagent is used, the compound (XVIII) is dissolved in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dioxane, acetonitrile or dichloromethane) The reaction is carried out at -50 ° C to + 50 ° C for 30 minutes to 24 hours, and then the usual post-treatment is carried out to obtain the compound ((2-methyl-2-pyrrolidone) XIX).
    In the third and fourth steps, compound (XIX) is converted to the acid thio compound (XXI) in one step by the Mitsunobu reaction, or alternatively the two Step < / RTI >
    The method of synthesis in one step by the mineral reaction is as follows.
    A solution of Compound (XIX) dissolved in an inert solvent (for example, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, toluene, dichloromethane or N, N-dimethylformamide) Triphenylphosphine is added in one equivalent or excess. Then, at the same time or 1 for the proper sequence of the compound (XⅨ) equivalent or an excess amount of the thiol acids (R 13 C (= O) SH wherein R 13 represents a preferably methyl or phenyl) and a carboxylic acid dialkyl (preferably Diisopropyl azodicarboxylate or diisopropyl azocarboxylate) is added to the mixture and reacted at -80 ° C to + 50 ° C for 15 minutes to 24 hours and then reacted with the compound XXI).
    On the other hand, the synthesis in two steps via the mesylate compound (XX) is carried out as follows. Particularly, Compound (XIX) is added to a solution prepared by dissolving Compound (XIX) in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dioxane, acetonitrile, toluene, dichloromethane or N, N- dimethylformamide) In the presence of one equivalent or excess of an organic base (preferably diisopropylethylamine, triethylamine, 2,6-lutidine, pyridine, etc.) at a temperature of -80 ° C to + 50 ° C for 15 minutes to 12 hours (XX) < / RTI > is obtained by conventional post-treatment. In some cases, the post-treatment is omitted and the reaction proceeds to the next step. Compound (XX) is treated with a salt of a thiol acid to convert to an acidic thio compound (XXI). Compound (XX) is dissolved in an inert solvent (preferably a mixed solvent of N, N-dimethylformamide or N, N-dimethylformamide and toluene, xylene, dioxane or the like). If no post-treatment is performed, the reaction solvent is exchanged for the inert solvent. Subsequently, 1 equivalent or excess of a thiolate salt (preferably potassium thioacetate) is added to the solution for the compound (XX), and the reaction is carried out at a temperature ranging from room temperature to reflux temperature for 30 minutes to 48 hours, (XXI). ≪ / RTI >
    In the last fifth step, the thiol compound represented by the formula (IV-2) can be derived from the compound (XXI) in the same manner as described above in connection with the conversion of the compound (XVI) into the compound (IV-1) .
    Compound (IV-3) wherein A of formula (IV) is a compound that represents -CH 2 - can be preferably prepared according to the following reaction path:

    In this reaction path, Z is OC (S) SR 14 , wherein R 14 is lower alkyl or aryl, -OC (S) OR 14 , wherein R 14 is as defined above, Cl, Br, I or -OSO 2 R 14 wherein R 14 is as defined above, preferably OC (S) SCH 3 or Cl, R 3 ' , R 4' , R 5 ' and R 6' (IX), R 12 is as defined in formula (V), and R 13 is as defined in formula (XXI).
    In the first and second processes, the conversion of the compound (XVII) to the compound (XXII) and further to the compound (XXIII) can be carried out per process or continuously. This can be done via the above Z. [
    For example, the compound (XXII) wherein Z represents -OC (S) SCH 3 can be prepared by the following method. Compound (XIII) is dissolved in a solution of compound (XVIII) dissolved in an inert solvent (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, toluene, benzene, dichloromethane, or hexamethylphosphoric triamide) (E.g., a metal hydride (preferably NaH), or an alkali lithium), carbon disulfide, and a catalytic amount of an amidazole are added to the reaction mixture at a temperature of from -50 ° C to +50 ° C Deg.] C for 15 minutes to 6 hours, adding 1 equivalent to an excess amount of iodomethane to the compound (XVIII) and further reacting at -20 DEG C to + 30 DEG C for 30 minutes to 24 hours, After phosphorus treatment, compound (XXII) is obtained.
    Subsequently, an excess of hydrogenated tributyltin and a catalytic amount of azobisisobutyronitrile are added to a solution of the compound (XXII) dissolved in an inert solvent (for example, toluene, xylene, or benzene) For 15 minutes to 24 hours, and the compound (XXIII) is obtained by conventional post-treatment.
    Further, for example, compound (XXII) in which Z represents Cl can be prepared by a conventional method in which the hydroxyl group is exchanged with Cl. Alternatively, a method using thionyl chloride is preferred. Compound (XIII) is dissolved in a solution of compound (XVIII) dissolved in an inert solvent (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, toluene, benzene, dichloromethane, or hexamethylphosphoric triamide) And an excess amount of thionyl chloride and a catalytic amount of N, N-dimethylformamide are added, and the reaction is carried out at -50 ° C to + 50 ° C for 10 minutes to 6 hours. Accordingly, the compound (XXII) can be prepared.
    Subsequently, the compound (XXII) is dissolved in an excess amount in an acidic solvent (preferably a mixed solution of an aqueous acetic acid solution or an aqueous acetic acid solution and an inert solvent (for example, N, N-dimethylformamide, tetrahydrofuran, or dioxane) Is added and the reaction is carried out at an ice-cooling temperature of + 80 ° C for 30 minutes to 24 hours to obtain the compound (XXIII) by conventional post-treatment.
    In the third step, the conversion of the compound (XXIII) to the alcohol compound represented by the formula (XXIV) is carried out in the same manner in which the above-mentioned compound (XVIII) is converted into the compound (XIX).
    Thus, in the fourth and fifth steps, the compound (XXIV) can be converted to the compound (XXI) in the same manner as in the conversion of the compound (XIX) to the compound (XXI) in one step or alternatively via the mesylate compound (XXVI). ≪ / RTI >
    In the last sixth step, the thiol compound represented by the formula (IV-3) can be derived from the compound (XXVI) in the same manner as the above-mentioned compound (XVI) is converted into the compound (IV-1).
    Compound (IV-4) wherein A of formula (IV) is a compound representing -CH = CH- can be preferably prepared according to the following reaction path:

    Wherein R 3 , R 4 , R 5 and R 6 are as defined in formula (II), R 12 is as defined in formula (V), and R 13 is lower alkyl Represents methyl) or aryl (preferably phenyl), X - is as defined in the above reaction path, R 15 represents methanesulfonyl or t-butyldimethylsilyl, and X 'represents halogen.
    In the first step, the compound represented by the formula (XXVII) can be prepared by the method disclosed in Japanese Patent Laid-Open Publication No. 311071/1996 proposed by the present inventor.
    In the first step, the compound (XXVII) can be converted to the compound (XXVIII) by the following method. The compound (XXVII) can be obtained by reacting the compound (XXVII) in the presence or absence of an inert solvent (for example, tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, toluene, or benzene or a mixed solvent of at least two of the above solvents) (Preferably, thionyl chloride, phosphorus oxychloride, etc.) is added under an inert atmosphere. The reaction is completed under cooling or heating, and the compound (XXVIII) is obtained by conventional post-treatment.
    In a second step, compound (XXVIII) can be converted to compound (IXXX) by the following method. The compound (XXVIII) can be reacted with the compound (XXVIII) in an inert solvent (for example, N, N-dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, acetonitrile, tetrahydrofuran, dioxane, methanol, Mixed solvent consisting of two or more solvents). An equivalent or excess of triphenylphosphine is added to the solution. The reaction is completed in a temperature range of room temperature to reflux temperature, and compound (IXXX) is obtained by conventional post-treatment.
    In the third step, compound (IXXX) can be converted to compound (XXXI) by the following method. Compound (IXXX) is dissolved or suspended in an inert solvent (dimethylsulfoxide, N, N-dimethylformamide, tetrahydrofuran, dioxane or a mixed solvent comprising at least two solvents selected from the above solvents). To the solution is added two equivalents of a base (for example, t-butoxy potassium, n-butyl lithium, lithium diisopropyl amide, lithium hexamethyldisilazide, or sodium hydride). (Yl) at a temperature of from -78 째 C to room temperature and reacting the compound of the formula (XXX) with a compound of the formula (XXX) in an inert solvent (dimethylsulfoxide, N, N-dimethylformamide, tetrahydrofuran, dioxane, Mixed solvent consisting of at least two solvents) at an appropriate concentration and added to the solution. This reaction is completed at a temperature of from -78 째 C to room temperature to obtain compound (XXXI) by conventional post-treatment.
    For compounds of formula (XXXI), there are cis (Z) and trans (E) geometric isomers in connection with the double bond. In this reaction, one of these isomers can be selectively or preferentially prepared by appropriately selecting the solvent, the reaction temperature, the base, and the like.
    In the fourth, fifth, and sixth steps, the compound (XXXI) can be converted to the acyl thio compound (XXXIII) according to the following method according to R 15 in the formula (XXXI).
    The compound represented by the formula (XXXI) wherein R 15 represents methanesulfonyl can be converted by the following method. Compound (XXXI) is dissolved in an inert solvent (N, N-dimethylformamide or N, N-dimethylformamide and mixed solvent of toluene, xylene, dioxane and the like). To this solution is added an equivalent or excess of thiolate salt (preferably potassium thioacetate). This reaction is completed in a temperature range of room temperature to reflux temperature, and compound (XXXIII) is obtained by conventional post-treatment.
    The compound of the formula (XXXI) wherein R 15 represents t-butyldimethylsilyl in the compound (XXXI) can be converted by the following method. In the fourth step, t-butyldimethylsilyl as a protecting group represented by R 15 in the compound (XXXI) can be removed using an acid or a fluoride anion reagent. In a fifth step, the methanesulfonation is carried out using methanesulfonyl chloride and a suitable base; In the sixth step, the thiolate salt is used to obtain the acid thio compound (XXXIII).
    When an acid is used in the fourth step, the compound (XXXI) is first dissolved in a solvent (for example, acetonitrile, methanol, or ethanol or an aqueous solution of the solvent). A mineral (preferably hydrochloric acid) is added to the solution. The reaction is carried out at -20 ° C to + 50 ° C for 15 minutes to 24 hours. After neutralizing the reaction mixture, the compound (XXXII) is obtained by conventional post-treatment. On the other hand, when a fluoride anion reagent is used, firstly compound (XXXI) is dissolved in an inert solvent (for example, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, or dichloromethane). A fluoride anion reagent (preferably tetra-n-butylammonium fluoride) is added to the solution. At -50 ° C to + 50 ° C for 30 minutes to 24 hours, and the compound (XXXII) is obtained by conventional post-treatment.
    In a fifth step, the compound (XXXII) is dissolved in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dioxane, acetonitrile, dichloromethane or N, N-dimethylformamide) Excess organic base (preferably diisopropylethylamine, triethylamine, 2,6-lutidine or pyridine, etc.) is added to the solution. One equivalent or excess of methanesulfonyl chloride is added to the solution. At -50 ° C to + 50 ° C for 15 minutes to 24 hours, and the compound (XXXIV) is obtained by conventional post-treatment. In this case, the post-treatment is omitted, and the reaction proceeds to the next step.
    In the sixth step, the compound (XXXIV) is added to an inert solvent (N, N-dimethylformamide or N, N-dimethylformamide and mixed solvent such as toluene, xylene or dioxane). An equivalent or excess of a thiolate salt (preferably potassium thioacetate) is added to the solution. The reaction is completed in the range of room temperature to reflux temperature, and the compound (XXXIII) is obtained by conventional post-treatment.
    In the seventh step, the thiol compound represented by the formula (IV-4) is derived from the compound (XXXVI) in the same manner as the above-mentioned compound (XVI) is converted into the compound (IV-1).
    When the 5-position of the pyrrolidine ring is not directly bonded to the 5-position of the imidazo [5, 1-b] thiazole, because A of the formula (IV) does not exist and - (CH 2 ) m- (IV-5) can be preferably prepared according to the following reaction pathway:

    In this reaction path, R 3 , R 4 , and R 6 are as defined in formula (II) and R 12 is as defined in formula (V).
    In the first step, the compound (XXXVI) can be synthesized from the compound (XIV) and the compound (XXXV) by the following method and the like. Compound (XIV) is dissolved in an inert solvent (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, dichloromethane, chloroform, toluene, or benzene). One equivalent of an additive (preferably 1-hydroxybenzotriazole) and one equivalent of a condensing agent (preferably dichlorohexylcarbodiimide) is added to the solution. The reaction is carried out at 0 ° C to room temperature for 30 minutes to 12 hours, and if necessary, the compound (s) is / are reacted with an acid chloride in the presence of a suitable base such as triethylamine, (XXXV) is diluted to an appropriate concentration, added to the above solution, reacted at 0 ° C to room temperature for 30 minutes to 12 hours, and compound (XXXVI) is obtained by conventional post-treatment.
    In the second step, the compound (XXXVII) can be synthesized from the compound (XXXVI) by the following method. Compound (XXXVIII) is added to an inert solvent (e.g., benzene, toluene, xylene, dichloromethane, chloroform, tetrahydrofuran, or dioxane). In some cases, a dehydrating agent (preferably phosphorus oxychloride) is added in an equivalent or excess without addition of a solvent. The reaction is carried out at -20 ° C to reflux temperature for 10 minutes to 48 minutes, and the compound (XXXVII) is obtained by conventional post-treatment.
    In the third step, the thiol compound represented by the formula (IV-5) can be derived from the compound (XXXVI) in the same manner as the above-mentioned compound (XVI) is converted into the compound (IV-1). When the 5-position of the pyrrolidine ring of formula (IV) is absent and (- (CH 2 ) m-, where m = 0) is directly attached to the 3-position of the imidazo [5,1- b] thiazole (IV-6) can be preferably prepared according to the following reaction route:

    In this reaction path, R 12 is as defined in formula (V).
    In the first step, the compound (XLI) can be synthesized from the compound (IXL) and the compound (XL) by the following method and the like. Compound (IXL) is dissolved in an inert solvent (preferably tetrahydrofuran). The reaction is carried out in the presence of 2 equivalents of iodochloromethane at -100 DEG C to room temperature using 2 equivalents of methyl lithium for 30 minutes to 12 hours, followed by post treatment by a conventional method. The residue obtained and one equivalent of compound (XL) are dissolved in an inert solvent (preferably N, N-dimethylformamide). In the presence of 1 equivalent of sodium bromide at 100 占 폚 for 30 minutes to 12 hours to obtain the compound (XLI) by conventional post-treatment. In the second step, the compound (XLII) can be synthesized from the compound (XLI) by the following method. As the protecting group of the compound (XLI), t-butylcarbonyl is removed by using trifluoroacetic acid, and the deprotecting compound is dissolved in a mixed solvent of methylene chloride and water. (XLII) in the presence of an inorganic base such as sodium hydrogencarbonate or potassium carbonate using a mixed acid anhydride prepared from formic acid and acetic acid. In the third step, the compound (XLIII) can be prepared from the compound (XLII) by the following method. The compound (XLII) is dissolved in an inert solvent (for example, benzene, toluene, xylene, or dioxane or a mixed solvent composed of at least two of the above solvents). One equivalent or excess dehydrating agent (preferably phosphorus oxychloride) can be added without the addition of a solvent. At -20 占 폚 to reflux temperature for 10 minutes to 48 hours, and the compound (XLIII) is obtained by conventional post-treatment.
    In the fourth step, the compound (XLIII) can be converted to the thiol compound represented by the compound (IV-6) in the same manner as the compound (XXXI) described above is converted into the compound (IV-4).
    The organometallic compound of the imidazo [5,1-b] thiazole compound represented by the formula (IX) can be preferably prepared according to the following reaction path.

    In the above reaction path, M represents lithium, MgCl, MgBr, or MgI, and any one of R 3 ' , R 4' , R 5 ' and R 6' represents a hydrogen, chlorine, bromine or iodine atom, The three substituents may be the same or different and are hydrogen; halogen; Nitro; Cyano; Lower alkyl; Lower cycloalkyl; Lower alkylthio; C 2-4 alkenyl; (Lower alkyl, lower cycloalkyl, C 2-4 alkenyl, and at least one hydrogen atom of the aryl is optionally substituted by one or more substituents selected from the group consisting of halogen, nitro, lower cycloalkyl, lower alkylthio, lower alkoxy, (N-lower alkylamino) sulfonyl, and aryl; or a pharmaceutically acceptable salt thereof.
    The compound (IX) wherein M is lithium is a compound represented by the formula (XXXIII) wherein R 3 ' , R 4' , R 5 ' and R 6' represent hydrogen (see Japanese Patent Laid-Open Publication No. 311071/1996 ) With a lithium reagent in the following manner. Compound (XXXIII) is dissolved in an inert solvent (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, toluene, benzene, or hexamethylphosphoric triamide). A lithium reagent (e.g., alkyl lithium or aryl lithium, preferably n-butyl lithium, or methyl lithium, etc.) is added to the solution. And reacted at -100 ° C to + 50 ° C for 10 minutes to 24 hours. Thus, a solution containing Compound (IX) in which M represents lithium is obtained.
    Compound (IX) wherein M is MgCl, MgBr or MgI is a compound represented by formula (XXXIII) in which any one of R 3 ' , R 4' , R 5 ' and R 6' represents a chlorine, bromine or iodine atom (See Japanese Patent Laid-Open No. 311071/1996) can be prepared by treating with a Grignard reagent in the following manner. The compound (XXXVIII) is dissolved in an inert solvent (for example, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, toluene, benzene, dichloromethane or hexamethylphosphoric triamide). Grignard reagent (alkyl magnesium chloride, alkyl magnesium bromide, alkyl magnesium iodide, or magnesium aryl bromide, preferably methyl magnesium iodide, or magnesium ethyl bromide) is added to the solution. And reacted at -100 DEG C to + 70 DEG C for 10 minutes to 24 hours. Thus, a solution containing compound (IX) in which M represents MgCl, MgBr, and MgI is obtained.
    Use of compounds and pharmaceutical compositions
    The carbapenem derivatives represented by the formulas (I) and (II) have strong antibacterial activity against a wide range of bacteria including Gram-positive bacteria and Gram-negative bacteria. In particular, they have a strong antibacterial activity against various -Lactamase-acid live bacteria, resistant pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). In addition, they are highly stable against neodihydropeptidase-I (DHP-I). Accordingly, the carbapenem derivatives represented by formulas (I) and (II) are useful for the treatment of infectious diseases. The term " treatment ", as used herein, is taken to mean " prevention ".
    According to the present invention, there is provided a pharmaceutical composition comprising a carbapenem derivative represented by formula (I) and formula (II). The above pharmaceutical composition can be used as an antimicrobial agent. The pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be administered orally or parenterally (for example, intravenously, intramuscularly, subcutaneously, rectally, or percutaneously) ) Can be administered to humans or animals other than humans.
    The pharmaceutical composition comprising the compound of the present invention as an active ingredient can be produced as a formulation suitable for the administration route of administration. In particular, injections such as intravenous or intramuscular injection; Oral preparations such as capsules, tablets, granules, powders, pills, granules, or troche; Rectal administration agents; An oleaginous suppository, and the like. The above-mentioned various formulations may be formulated using excipients, fillers, binders, wetting agents, disintegrators, surface active agents, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives, flavoring agents, soothing agents, Can be prepared by conventional methods. Examples of the non-toxic additives which can be used in the formulation include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, mica, magnesium stearate, salts of methylcellulose or methylcellulose, gum arabic, polyethylene glycol, , Vaseline, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite and sodium phosphate.
    The dosage of the compound of the present invention is appropriately determined in consideration of the usage, the age and sex of the patient, and the degree of the disease. However, in order to treat infectious diseases, a dose of about 100 mg to 2000 mg, preferably 200 mg to 1000 mg per adult per day is preferably administered once or several times a day, preferably once a day.
    The following examples further illustrate the invention, but the invention is not limited thereto.
    [Example 1]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5 - [(imidazo [5,1- b] thiazol- ) Methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] thio-6 - [(1 R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen-
    2N sodium hydroxide solution (0.38 ml) was added to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5 [ -Yl) methylaminocarbonyl] pyrrolidine (293 mg), and the mixture was stirred for 20 minutes. Saturated saline (2 ml) and 1N hydrochloric acid were added to the mixture to adjust the pH to 7 and the mixture was extracted twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by filtration under reduced pressure to obtain 260 mg of a mercaptan compound as a milky white amorphous substance. N, N-diisopropylethylamine (0.15 ml) was added to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -6- [ -3-carboxylate (352 mg) obtained in the same manner as in Example 1, and this mixture was added dropwise to a solution of 1 (1-tert-butyldimethylsilyloxy) ethyl] -2- (diphenylphosphono) oxy- Lt; / RTI > 1 / 15M phosphate buffer solution (pH 7) was added, and the mixture was extracted successively with 30 ml of ethyl acetate and 15 ml of ethyl acetate. The combined organic layers were dried over a 1: 1 mixture of anhydrous magnesium sulfate and potassium carbonate, filtered and the solvent was evaporated to remove from the filtrate to give a light yellow viscous material. This viscous substance was purified by column chromatography successively by column chromatography using silica gel (ethyl acetate: methanol = 97: 3) and Sephadex LH-20 (chloroform: methanol = 1: 1) to obtain allyl (1R, 5S , 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5 - [(imidazo [5,1- b] thiazol- 5- yl) methylaminocarbonyl] pyrrolidin- Ethyl] -1-methylcarbapen-2-yl) -3-carboxylate (241 mg) was obtained in the form of a white solid.
    NMR (CDCl 3) δ: 0.07 (6H, s), 0.88 (9H, s), 1.20 (3H, d, J = 7.2 Hz), 1,23 (3H, d, J = 5.8Hz), 1.9-2.4 (2H, br), 2.7 (1H, br.s), 3.15 (1H, dd, J1 = 5.8Hz, J2 = 2.7Hz), 3.38 (2H, m), 5.53 (1H, br.s), 5.87-6.00 (1H, m), 4.00 (1H, br.s), 4.16-4.27 ), 6.78 (1H, d, J = 4.3 Hz), 6.95 (1H, s), 7.56
    MS (SIMS): 730 (M < + & gt ; + H)
    b) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5 - [(imidazo [5,1- b] thiazol- 3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    1.65 mL of acetic acid (0.285 mL) and 1M tetra-n-butylammonium fluoride / THF solution was added to a solution of allyl (1S, 5R, 6S) -2- [(3S, 5S) Yl] thio-6 - [(1R) -1- (t-butyl) -5-methyl- Dimethyl] silyloxy) ethyl] -1-methylcarbapen-2-yl] -3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 47 hours. Subsequently, the solution was diluted with 50 ml of ethyl acetate and washed with 10 ml of a 5% aqueous solution of sodium hydrogencarbonate to obtain an organic layer. The aqueous layer was re-extracted with 20 ml of acetic acid, and the obtained organic layer was combined with the organic layer. The solution was then dried over a mixture of anhydrous magnesium sulfate and potassium carbonate 1: 1, filtered and the solvent removed by filtration under reduced pressure to give a yellow oil. The oil was sequentially purified by column chromatography using silica gel (ethyl acetate: methanol = 9: 1) and Sephadex LH-20 (chloroform: methanol = 1: 1) to obtain allyl (1R, (3S, 5S) -1-allyloxycarbonyl-5 - [(imidazo [5,1- b] thiazol-5-yl) methylaminocarbonyl] pyrrolidin- (1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate was obtained.
    NMR (CDCl 3) δ: 1.23 (3H, d, J = 7.2 Hz), 1.33 (3H, d, J = 5.8 Hz), 1.6-2.4 (3H, br), 2.7 (1H, br.s), 3.21 (2H, br), 3.60 (1H, br), 4.10 (1H, br.s), 4.25-4.60 (6H, br) (2H, m), 5.50 (1H, br.s), 5.92-6.40 (1H, m), 6.80 (1H, d, J = 4.2 Hz), 6.95 (1H, s), 7.4 (1H, br.s), 7.73
    MS (SIMS): 616 (M < + & gt ; + H)
    c) (1R, 5S, 6S) -2 - [(3S, 5S) -6 - ((1R) -1- Hydroxyethyl) -5 - [(imidazo [5,1- b] thiazol- Yl) methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-
    Tetrakis (triphenylphosphine) palladium (0) (8.1 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methyl-1 H-pyrrolo [2,3- -3-carboxylate and 0.038 ml of aniline, and the mixture was stirred at room temperature for 60 minutes under an argon atmosphere. Distilled water (2 ml) was added and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was filtered, concentrated under reduced pressure, and the concentrate was lyophilized to give a colorless solid. The solid was purified by column chromatography using Sephadex LH-20 (water: methanol = 1: 1) to give the title compound (13.2 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.09 (3H, d, J = 6.6Hz), 1.28 (3H, d, J = 6.3HZ), 1.95-2.05 (1H, m), 2.79-2.89 (1H, m), 3.20-3.43 (3H, m), 3.62-3.75 (1H, m), 3.92-4.00 (1H, m), 4.15-4.28 , 4.67 (1H, d, J = 13.2 Hz), 4.80 (1H, d, J = 13.2 Hz), 7.04 J = 4.3 Hz)
    MS (SIMS): 492 (M < + & gt ; + H)
    [Example 2]
    Methyl-2 - [(3S, 5S) -5 - [(6-methylimidazo [5,1 -b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thiocarbazol-2-
    a) Preparation of allyl iodide (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) 5,1-b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thiocarbazol-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5 - [(imidazo [5,1- b] thiazol- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- And the mixture was shielded from light under an argon atmosphere and left at room temperature for 19 hours. The excess reagent was removed under reduced pressure to obtain allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- -b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) Carboxylate (52.6 mg).
    (CD 3 COCD 3 ) : 1.26 (3H, d, J = 6.9 Hz), 1.27 (3H, d, J = 6.0 Hz), 2.00 (3H, m, br s), 4.28-4.37 (3H, m, 2H) (2H, br s), 4.52 (1H, br.s), 4.61 (1H, ddt), 4.79 (1H, ddt), 4.95-5.35 (1H, br.s), 8.50 (1H, br.s), 8.87 & 9.03 (total 1H) , br.s each)
    MS (SIMS): 630 (M + ) (except for I - )
    b) Preparation of (lR, 5S, 6S) -6- (lR) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5 - [(6-methylimidazo [ , 1-b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thiocarbazol-
    Tetrakis (triphenylphosphine) palladium (0) (7.6 mg) was added to a solution of allyl iodide (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) thiophene-2-carboxylic acid ) -1-methylcarbapen-2-3-carboxylate and 0.036 ml of aniline, and the mixture was stirred at room temperature for 70 minutes under an argon atmosphere. Distilled water (2 ml) was added and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was filtered and concentrated under reduced pressure to obtain an orange oil. The oil was dissolved in saturated saline and purified sequentially by column chromatography using Sephadex LH-20 (water: methanol = 1: 1) and Diaion CHP-20P (2% THF aqueous solution) 5.3 mg of the title compound was obtained as a material.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.05 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.3 Hz), 1.77 (1H, m), 2.57 (1H, m ), 2.88 (1H, dd, J1 = 11.3 Hz, J2 = 3.6 Hz), 3.25-3.40 (3H, m), 3.65-3.74 (1H, d, J = 16.3 Hz), 4.12-4.28 (2H, m), 4.89 s), 8.04 (1 H, d, J = 4.3 Hz)
    MS (SIMS): 506 (M + ) (except for Cl - )
    [Example 3]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [N- (imidazo [5,1- b] thiazol- Methyl) -N-methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-6 - [(1R) -1- (tert- butyldimethylsilyloxy) ethyl] Ylmethyl] -N-methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen- Carboxylate
    2N sodium hydroxide solution (0.24 ml) was added to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [N- (imidazo [ 5-yl) methyl-N-methylaminocarbonyl] pyrrolidine in 20 ml of tetrahydrofuran and the mixture was stirred for 20 minutes. Saturated brine (2 mL) and 1 N hydrochloric acid were added to the mixture to adjust the pH to 8, and the mixture was extracted twice with 10 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain 168.6 mg of mercaptan compound as a yellow viscous substance. N, N-Diisopropylethylamine (0.094 ml) was added to a solution of allyl (lR, 5S, 6S) -6- [(lR) -1- (tert- butyldimethylsilyl Methyl-1-methylcarbapen-2-yl) oxy) ethyl] -2- (diphenylphosphino) oxy- Lt; / RTI > 1 / 15M phosphate buffer solution (pH 7.0) (3 ml) was added, and the mixture was extracted twice with 20 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the solution was then removed by filtration under reduced pressure to yield a yellowish orange amorphous material. The material was successively purified by column chromatography successively using silica gel (ethyl acetate: methanol = 97: 3) and Sephadex LH-20 (chloroform: methanol = 1: 1) to give allyl Ethyl] -5- [N- (1, < / RTI > 5) Methyl] -N-methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate 114.4 Mg.
    NMR (CDCl 3) (mixture of conformers body) δ: 0.09 (6H, s ), 0.88 (9H, s), 1.22-1.26 (6H, m), 1.80-2.1.97 (1H, m), 2.66 (1H, m), 3.07 & 3.09 (total 3H, s each), 3.19-3.32 (2H, m), 3.47-3.55 (1H, m), 3.57-3.70 m), 4.58-4.84 (5H, m), 4.94-5.07 (2H, m), 5.22-5.48 (1 + 2H, m), 5.48-5.61 & 5.88-6.02 J = 4.3 Hz), 6.98 & 7.00 (total 1H, s each), 7.69 & 7.78 (total 1H, d each, J = 4.3 Hz each)
    MS (SIMS): 743 (M < + & gt ; + H)
    b) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [N- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    0.77 ml of acetic acid (0.132 ml) and 1M tetra-n-butylammonium fluoride / THF solution was added dropwise to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) 3-yl] thio-6 - [(1R) - (2-methoxyphenyl) Was added to a solution of 114 mg of 1- (t-butyldimethylsilyloxy) ethyl) -1-methylcarbapen-2-yl-3-carboxylate and the mixture was stirred at room temperature under argon atmosphere for 22.5 hours. 1 / 15M phosphate buffer (pH 7.0) (3 ml) was added, and the mixture was extracted twice with 15 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed by filtration under reduced pressure to give a yellowish orange oil. The oil was successively purified by column chromatography using silica gel (ethyl acetate: methanol = 9: 1) to give allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxy Yl) thio-6 - ((1 R) -methoxycarbonylpyrrolidin-3-yl] -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate (78.3 mg).
    NMR (CDCl 3) (mixture of conformers body) δ: 1.23-1.28 (3H, m ), 1.34-1.38 (3H, m), 1.8-2.3 (2H, m + br.s), 2.64-2.85 (1H, m ), 3.07 & 3.09 (total 3H, s each), 3.23-3.29 (1H, m), 3.31-3.44 (1H, m), 3.46-3.57 M), 4.57-5.08 (total 7H, m), 5.22-5.51 (3H, m), 5.51-5.61 & 5.88-6.04 (total 2H, m each), 6.79-6.82 ), 6.98 & 7.00 (total 1H, s each), 7.69 & 7.78 (total 1H, br.d each)
    c) (1R, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [N- (imidazo [5,1- b] thiazole Methyl-N-methylaminocarbonyl] pyrrolidin-3-yl] thio-1-methylcarbapen-
    Tetrakis (triphenylphosphine) palladium (0) (7.0 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- Methyl] -N-methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-heptyl- Hydroxy-1-methylcarbapen-2-yl) -3-carboxylate and 0.033 ml of aniline, and the mixture was stirred at room temperature for 60 minutes under an argon atmosphere. Distilled water (2 ml) was added and the mixture was washed three times with 4 ml of ethyl acetate. The aqueous layer was concentrated under reduced pressure to obtain a yellow amorphous solid. The solution obtained by dissolving the amorphous substance in an aqueous 5% sodium hydrogencarbonate solution has a pH of 8. Subsequently, the solution was purified by column chromatography using dianion CHP-20P (2% aqueous THF solution) to obtain the title compound (13.4 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80ppm): 1.13 (3H, d, J = 7.5Hz), 1,28 (3H, d, J = 6.3 Hz), 1.46-1.55 (1H, m), 2.65 (2H, m), 3.73-3.81 (1H, m), 4.08 (1H, dd, J1 = D, J = 15.4 Hz), 7.02 (1H, s), 7.11 (1H, d, J = 6.8 Hz), 4.15-4.27 (1H, d, J = 4.2Hz), 7.59 (1H, d, J = 4.2Hz)
    MS (SIMS): 506 (M < + & gt ; + H) (with COOH)
    [Example 4]
    (3R, 5S) -6- (1R) -1-hydroxyethyl) 5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [N-methyl- N- (6-methylimidazo [ ] Thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3-yl] thio-6 ((1R) -1-hydroxyethyl) Decylate
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [N- (imidazo [5,1- b] thiazole Yl) methyl-N- methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) Carboxylate, and the mixture was shaded under an argon atmosphere and stirred at room temperature for 18 hours. The excess reagent was evaporated under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (chloroform: methanol = 1: 1) to give allyl iodide as a white light amorphous substance (1R, 5S, 6S) - 5 - [(3S, 5S) -1-allyloxycarbonyl-5- [N-methyl-N- (6-methylimidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate.
    NMR (CD 3 COCD 3 ) (mixture of stereoisomers) : 1.25-1.28 (6H, m), 1.77-1.88 (1H, m), 2.80 ), 3.30 (1H, dd, J1 = 6.8 Hz, J2 = 2.6 Hz), 3.34 & 3.43 & 3.47 (total 3H, M), 4.60-4.65 (2H, m), 4.33-4.36 (1H, m), 4.76 (2H, m each), 7.78 (1H, m), 4.85-3.53 (2H, (1H, m), 8.30-8.36 (1H, m), 7.82 (total 1H,
    MS (SIMS): 644 (M < + & gt ; ) (part excluding I-)
    b) Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) Methylimidazo [5,1-b] thiazolium-5-yl) methylaminocarbonyl] pyrrolidin-3- yl] thiocarbazol-
    (1R, 5S, 6S) -2 - [(3S, 5S) - l- (4-methylphenyl) 5-yl) methylaminocarbonyl] pyrrolidin-3-yl] -methanone [0251] -3-carboxylate (35.3 mg) and aniline (0.025 mL), and the mixture was stirred at room temperature under an argon atmosphere Lt; / RTI > for 60 minutes. Distilled water (2 ml) was added and the mixture was washed three times with 4 ml of ethyl acetate. The aqueous layer was concentrated under reduced pressure, and the concentrate was lyophilized to obtain a bright orange fluorescent substance. This material was dissolved in saturated saline and then purified by column chromatography using dianion CHP-20P (distilled water) to obtain 4.1 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 0) (conformers material mixture) δ: 1.23-1.31 (6H, m ), 1.8-2.1 (1H, m), 2.2-2.65 (total 1H, m), 2.85-3.12 (1H, m), (1H, m), 3.14-3.25 (total 4H, m), 3.35-3.90 (total 4H, m), 4.10 & 4.12 & 4.13 (2H, m), 7.58 (1H, d, J = 4.1 Hz), 7.66-7.
    [Example 5]
    (5S, 5S) -5- [N-methyl-N- (5-aminomethyl-6-methylimidazo [5,1- b] thiazolium- 3-yl) methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- 5- [N- [5- (allyloxycarbonylaminomethyl) imidazo [ yl] thio-6 - [(1R) -1-t-butyldimethylsilyloxy) ethyl] -1-methylcarbamoyl] pyrrolidin- 3-carboxylate
    2N sodium hydroxide aqueous solution (0.315 ml) was added to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [N- [5- (allyloxycarbonylaminomethyl) Imidazo [5,1-b] thiazol-3-yl) methyl-N-methylaminocarbonyl] pyrrolidine in 20 ml of dichloromethane and the mixture was stirred for 20 minutes. Saturated brine (3 ml) and 1N hydrochloric acid were added to the mixture to adjust the pH to 7 and the mixture was extracted twice with 15 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by filtration under reduced pressure to obtain 286 mg of a mercaptan compound as a colorless powdery substance. N, N-diisopropylethylamine (0.12 ml) was added to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -6- -3-carboxylate (354 mg) was added dropwise to a solution of [(1R) -1- (t-butyldimethylsilyloxy) ethyl] -2- (diphenylphosphono) oxy- , And the mixture was stirred for 3.5 hours in this state. 1 / 15M phosphate buffer solution (pH 7.0) (10 ml) was added, and the mixture was extracted twice with 20 ml of ethyl acetate. The combined organic layers were dried over a 1: 1 mixture of anhydrous magnesium sulfate and potassium carbonate, filtered and the solvent was removed by filtration under reduced pressure to give a pale yellow viscous material by filtration. This viscous substance was purified in succession by column chromatography using silica gel (ethyl acetate) and Sephadex LH-20 (chloroform: methanol = 1: 1) to obtain allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [N- [5- (allyloxycarbonylaminomethyl) imidazo [5,1- b] thiazol- Methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - [(1R) -1- (t- butyldimethylsilyloxy) ethyl] -1- methylcarbapen- 305 mg.
    NMR (CDCl 3) δ: 0.07-0.09 (6H, m), 0.87-0.91 (9H, m), 1.19-1.29 (. 6H m), 1.95-2.15 (1H, m), 2.6-2.9 (1H, br ), 3.1-3.35 (5H, m), 3.45-3.55 (1H, m), 3.6-3.8 (1H, br), 3.95-4.1 (6H, m), 5.6-5.75 (1H, br), 5.8-6.05 (3H, m), 6.83 & 6.95 (total 1H, br s), 6.99 & 7.14 total 1H, s each)
    MS (FD): 857 (M < + & gt ; + H)
    b) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [N- [ yl] methyl-N-methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) - M-3-carboxylate
    1.75 ml of acetic acid (0.30 ml) and 1M tetra-n-butylammonium fluoride / THF solution was added to a solution of allyl (1S, 5R, 6S) -2- [(3S, 5S) Yl] methyl-N-methylaminocarbonyl] pyrrolidin-3-yl} -5- [N- [5- (allyloxycarbonylaminomethyl) imidazo [5,1- b] thiazol- ] -3 - [(1R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen- 2- 3-carboxylate in tetrahydrofuran And the mixture was stirred at room temperature for 27.5 hours. 1 / 15M phosphate buffer solution (pH 7.0) (10 ml) was added, and the mixture was extracted twice with 30 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and potassium carbonate 1: 1 mixture, filtered and the solvent removed by filtration under reduced pressure to give a colorless viscous material. The viscous material was purified sequentially by column chromatography using silica gel (ethyl acetate: methanol = 97: 3 to 95: 5) and Sephadex LH-20 (chloroform: methanol = 1: 1) to give allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [N- [5- (allyloxycarbonylaminomethyl) imidazo [ Yl] methyl-N-methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -Carboxylate (212.6 mg).
    NMR (CDCl 3) δ: 1.27-1.37 (6H, m), 1.95-2.15 (1H, m + br), 2.6-2.9 (1H, m + br) 3.12-3.75 (7H, m), 3.98-4.07 ( (1H, m), 4.15-4.3 (3H, m), 4.5-4.85 (10H, m), 4.9-5.5 (7H, m), 5.75 6.53 & 6.84 & 6.95 (total 1H, br.s each), 6.98 & 7.01 & 7.03 & 7.06 (total 1H, s each)
    MS (FD): 743 (M < + & gt ; + H)
    c) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [N- [5- (allyloxycarbonylaminomethyl- Yl] methyl-N-methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- Methylcarbapen-2-yl) -3-carboxylate
    Iodomethane (2.14 g) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- 5- [N- [ Methyl] -N-methylaminocarbonyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- Methylcarbapen-2-yl) -3-carboxylate (111 mg), and the mixture was shaded under an argon atmosphere and stirred at room temperature for 18 hours. The excess reagent was removed under reduced pressure to give allyl iodide (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [N- (5-allyloxycarbonylamino Yl) thio-6 - ((1R) -1, 5-dihydro- -Hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate (132 mg).
    NMR (CD 3 COCD 3) δ : 1.25-1.29 (6H, m), 1.65-1.975 (1H, m), 2.95-3.15 (2H, m), 3.20-3.40 (4H, m), 3.63-3.75 (1H m), 3.85-4.40 (8H, m), 4.55-4.75 (5H, m), 4.75-4.85 (1H, m), 4.95-5.65 & 7.48 & 7.55 & 7.67 & 7.80 & 7.97 & 8.03 (total 3H, s or br.s each)
    MS (SIMS): 757 (M + ) (part excluding I - )
    d) Preparation of iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [N- (5-Aminomethyl-6-methylimidazo [5,1- b] thiazolium- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    To a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- (4-fluorophenyl) Allyloxycarbonyl-5- [N- (5-allyloxycarbonylaminomethyl-6-methylimidazo [5,1- b] thiazolium-3-yl] methyl- ] Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate and 0.125 ml aniline The mixture was stirred at room temperature under argon atmosphere for 4 hours. Distilled water (5 ml) was added and the mixture was washed four times with 4 ml of ethyl acetate. The aqueous layer was concentrated under reduced pressure, and the concentrate was lyophilized The above material was dissolved in distilled water and the solution was purified by column chromatography using Sephadex LH-20 (water: methanol = 1: 1) to obtain 27.9 mg of the title compound as a milky white fluorescent substance To It was.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.0 Hz), 1.97-2.07 (1H, m), 2.4-3.0 (4H, m), 4.80-5.25 (4H, m), 4.07 (4H, br.s), 4.18-4.40 (3H, m), 3.05-3.25 , 7.25 & 7.30 & 7.34 (total 1H, s each), 7.64 (3H, s)
    [Example 6]
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazole- 3-yl) methyl] pyrrolidin-3-yl] thio-6 - [(1 R) -1- (t- butyldimethylsilyloxy) ethyl] -1- methylcarbapen- The ratio (stereoisomer A)
    2N sodium hydroxide aqueous solution (0.30 ml) was added dropwise to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [ Yl] methyl] pyrrolidine (stereoisomer A), and the mixture was stirred for 25 minutes. Saturated brine (10 ml) and 1N hydrochloric acid were added to the mixture to adjust the pH to 7 and the mixture was extracted twice with 15 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by filtration under reduced pressure to obtain 187.5 mg of a mercaptan compound as a pale red solid. N, N-Diisopropylethylamine (0.11 ml) was added to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -6- -3,4-dihydroxy-1 - [(1R) -1- (t-butyldimethylsilyloxy) ethyl] -2- (diphenylphosphino) oxy-1-methylcarbapen- , And the mixture was stirred in this state for 35 minutes. 1 / 15M phosphate buffer solution (pH 7.0) (10 ml) was added, and the mixture was extracted twice with 20 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure and removed by filtration to obtain a red viscous substance. This viscous substance was purified by column chromatography using silica gel (ethyl acetate: methanol = 97: 3) to give allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycar Yl] methyl] pyrrolidin-3-yl] thio-6 - [(1R) -1- ethyl] -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A).
    NMR (CDCl 3) δ: 0.08 (6H, s), 0.88 (9H, s), 1.21-1.25 (6H, s) 1.75 (1H, br.s), 2.3 (2H, br), 3.20 (1H, dd M), 4.60 (2H, br.s), 4.65-4. 4H, m, J = 5.6 Hz, J2 = 2.5 Hz), 3.29 (2H, m, br), 6.74 (1H, s), 7.03 (1H, s), 8.07 & , br.s each)
    MS (FAB < + & gt ; ): 703 (M <
    b) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-aryloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ 3-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1 R) -1-
    1.8 mL of acetic acid (0.31 mL) and 1 M tetra-n-butylammonium fluoride / THF solution was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) Yl] methyl} pyrrolidin-3-yl] thio-6 - [(1R) -1- (1-hydroxy- (tert-butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A) and the mixture was stirred at room temperature under an argon atmosphere for 35 hours Lt; / RTI > This solution was diluted with 100 ml of ethyl acetate, and the diluted solution was sequentially washed with 50 ml of 1 / 15M phosphate buffer (pH 7.0) and 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by evaporation to give 244 mg of light brown oil. The oil was purified sequentially by column chromatography using silica gel (ethyl acetate: methanol = 9: 1) and Sephadex LH-20 (chloroform: methanol = 1: 1) to give allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A).
    NMR (CDCl 3 ) : 1.23 (3H, d, J = 7.2 Hz), 1.35 (3H, d, J = 6.2 Hz), 1.8-2.5 (3H, dr), 3.2-3.4 (2H, m), 5.2-5.6 (6H, m), 5.70 (1H, m) (1H, s), 7.05 (1H, s), 8.07 & 8.25 (total 1H, br.s each)
    MS (FAB < + & gt ; ): 589 (M &
    c) (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ 3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbophen- 2- 3-carboxylic acid (stereoisomer A)
    Tetrakis (triphenylphosphine) palladium (0) (13.8 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxy 3-yl] thio-6 - ((1R) -1, 1 -dimethyl- -Hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A) and 0.077 ml of N-methyl aniline, and the mixture was stirred at room temperature Stir for 45 min. Distilled water (3 ml) was added and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was filtered, concentrated under reduced pressure and lyophilized to obtain a colorless fluorescent substance. This fluorescent substance was purified by column chromatography (water-methanol) using Cosmosil 40C18-PREP to give the title compound (11.5 mg) as a colorless fluorescent substance.
    NMR (D 2 0) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.5 Hz), 1.96-2.07 (1H, m), 2.65-2 (1H, m), 3.77 (1H, d, J = 6.2 Hz, J2 = 2.8 Hz), 77 (1H, m), 3.29-3.40 ), 4.15-4.28 (3H, m), 5.27 (1H, d, J = 6.6 Hz), 7.13 (1H, s), 7.19
    MS (FAB + ): 465 (M < + & gt ; + H)
    [Example 7]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer A)
    a) Preparation of allyl iodide (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate The ratio (stereoisomer A)
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ yl] methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1-methylcarbapen- (Stereoisomer A), and the mixture was shaded under an argon atmosphere and stirred at room temperature for 14 hours. The excess reagent was removed under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (chloroform: methanol = 1: 1) to give allyl iodide as a pale yellow amorphous substance (1R, 5S, 6S) (1R) -1-hydroxyethyl) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [ ] Thiazolium-3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A).
    NMR (CD 3 COCD 3) δ : 1.25-1.29 (6H, m), 2.18-2.28 (1H, m), 2.75 (1H, br.s), 3.31 (2H, br + dd, J1 = 6.8 Hz, J2 = 2.7 Hz), 3.62 (1H, m), 3.98 (1H, br.t), 4.13 (1H, m), 4.22-4.30 (2H, m), 4.33 3H, br), 4.63 (1H, m), 4.80 (1H, m), 5.05-5.30 (2 + 1H, br + m), 5.35-5.52 Br s), 8.02 (1H, br.s), 9.82 & 9.93 (total 1H, br.s each)
    MS (FAB + ): 603 (M + ) (part excluding I - )
    b) Preparation of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl] methyl} pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer A)
    (1R, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl (4-methoxyphenyl) ethyl) amide in 0.9 ml of dry dichloromethane and 0.4 ml of dry DMF was added tetrakis (triphenylphosphine) palladium ) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [5,1- b] thiazolium- Methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A) and 0.074 ml of N-methyl aniline, Was stirred at room temperature under an argon atmosphere for 35 minutes. Distilled water (5 ml) was added and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was concentrated under reduced pressure and the concentrate was lyophilized to give a milky white fluorescent substance. This milky white fluorescent substance was sequentially purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) and Sephadex LH-20 (water: methanol = 1: 1) to obtain the title compound 8.2 Mg.
    NMR (D 2 0) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.78 (1H, m), 2.62 (1H, dt J1 = 12.0 Hz, J2 = 6.1 Hz), 3.33-3.44 (1H, d, J = (2H, m), 3.73-3.88 (2H, m), 4.10 (3H, s), 4.16-4.27 (2H, m), 5.05 (1H, d, J = 7.7 Hz), 7.50 (1H, s), 9.36 (exchange to 1H, s, gradually D 2 0)
    MS (FAB + ): 479 (M + ) (part excluding I - )
    [Example 8]
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer B)
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazole- 3-yl) methyl] pyrrolidin-3-yl] thio-6 - [(1 R) -1- (t- butyldimethylsilyloxy) ethyl] -1- methylcarbapen- (Stereoisomer B)
    2N aqueous sodium hydroxide solution (0.30 ml) was added to a solution of (3R, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [ Was added to a solution of 138 mg of 2-hydroxy-1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer B) and the mixture was stirred for 25 minutes The temperature was gradually increased while stirring for 10 minutes. Semi-saturated saline (10 ml) and 1N hydrochloric acid were added to the mixture to adjust the pH to 7, then the mixture was extracted twice with 15 ml of ethyl acetate, dried over anhydrous magnesium sulfate and filtered , And the solvent was removed by evaporation to obtain 123.5 mg of a mercaptan compound as a light red solid. N, N-Diisopropylethylamine (0.11 ml) was added to a solution of the above mercaptan compound and allyl (1R, 5R, 6S) -6- [ -3-carboxylate (273 mg) obtained in the same manner as in Example 1, and the mixture was added dropwise to a solution of 1- Lt; / RTI > for 30 minutes. 1 / 15M phosphate buffer solution (pH 7.0) (10 ml) was added, and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by evaporation to obtain 347 mg of an orange-brown oil. This oil was purified by column chromatography using silica gel (ethyl acetate: methanol = 96: 4) to give allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl Yl] thio-6 - [(1R) -1- (t-butylamino) Ethyl] -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer B).
    NMR (CDCl 3) δ: 0.08 (6H, s), 0.89 (9H, s), 1.19-1.25 (6H, m), 1.7 (1H, br.s), 2.22 (1H, br), 3.15-3.23 ( (1H, m), 4.05 (1H, m), 4.19-4.29 (1H, m) , 4.49-4.83 (6H, m), 4.98 (1H, d, 8.3 Hz), 5.23-5.48 (4H, m), 5.88-6.02 & ), 7.07 (1H, s), 8.26 (1H, br.s)
    MS (FAB < + & gt ; ): 703 (M <
    b) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ 3-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl)
    1.52 mL of acetic acid (0.26 mL) and 1M tetra-n-butylammonium fluoride / THF solution was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) Yl] methyl] pyrrolidin-3-yl] thio-6 - [(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer B) and the mixture was stirred at room temperature under an argon atmosphere for 38 hours Respectively. The reaction solution was diluted with 80 ml of ethyl acetate, and the diluted solution was sequentially washed with 40 ml of 1 / 15M phosphate buffer solution (pH 7.0) and saturated brine. The washed solution was dried over anhydrous magnesium sulfate, The solvent was removed by evaporation to obtain 193 mg of a pale yellow oil. The oil was purified sequentially by column chromatography using silica gel (ethyl acetate: methanol = 95: 5 -> 9: 1) and Sephadex LH-20 (chloroform: methanol = 1: 1) to yield a white amorphous Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- .
    NMR (CDCl 3) δ: 1.22 (3H, d, J = 7.1 Hz), 1.36 (3H, d, J = 6.2 Hz), 1.67 (1H, m), 2.25 (1 + 1H, br + m), 3.20 J = 7.4 Hz), 4.06 (1H, br.t), 4.20-4.29 (2H, m), 3.40 (1H, dd + ), 4.57 (1H, dd, J1 = 14.5 Hz, J2 = 7.7 Hz), 4.64-4.73 (1 + 2H, m + br.s), 4.83 Hz), 5.25-5.49 (4H, m), 5.90-6.04 & 6.30 (total 3H, m + br), 6.76
    MS (FAB < + & gt ; ): 589 (M &
    c) (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ 3-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer B)
    (1R, 5S, 6S) -2 - [(3S, 5S) - (2-hydroxyphenyl) Yl] methyl} pyrrolidin-3-yl] thio-6 - (((2-hydroxy-1- 1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A) and 0.072 ml of N-methyl aniline, And stirred at room temperature for 70 minutes. Distilled water (3 ml) was added, and the mixture was washed three times with 3 ml of ethyl acetate. The aqueous layer was filtered, concentrated under reduced pressure and lyophilized to obtain 23 mg of a colorless fluorescent substance. This colorless fluorescent substance was sequentially purified by column chromatography using dianion CHP-20P (4% aqueous THF solution) and cosmosil 5C18-MS (water: methanol = 2: 1) to obtain the title compound 5.8 Mg.
    NMR (D 2 0) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.2 Hz), 1.28 (3H, J = 6.0 Hz), 1.81 (1H, m), 2.60 (1H, m), (1H, d, J = 8.5 Hz), 7.12 (1H, m), 3.33-3.47 (3H, m), 3.67 s), 7.20 (1 H, s), 8.34 (1 H, s)
    MS (FAB + ): 465 (M < + & gt ; + H)
    [Example 9]
    (1R, 5S, 6S) -6 - [(1R) -1-hydroxyethyl] -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer B)
    a) Perlylic acid allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [ yl] methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1-methylcarbapen- (Stereoisomer B)
    Iodomethane (0.71 g) was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [ Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1 R) -1- hydroxyethyl) 3-carboxylate (stereoisomer B), and the mixture was shaded under an argon atmosphere and stirred at room temperature for 24 hours. The excess reagent was removed under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (chloroform: methanol = 1: 1) to give allyl iodide (1R, 5S, 6S) -2- [ (3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy-1- (6-methylimidazo [5,1- b] thiazolium- -3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (stereoisomer B). Perchloric acid (31 mg) was added to the oil solution in a mixture of 2 ml of dry dichloromethane and 2 ml of acetonitrile, and the mixture was stirred. The solvent was removed by evaporation, and then acetonitrile was added thereto to suspend, followed by filtration, and the solvent was removed by evaporation to obtain oil. Subsequently, the oil was purified by column chromatography using Sephadex LH-20 (chloroform: methanol = 1: 1) to obtain allyl (1R, 5S, 6S) -2 - [(3S, 5S) Yl] methyl] pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin- 55 mg of thio-6 ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-m-3-carboxylate (stereoisomer B) was obtained.
    NMR (CDCl 3) δ: 1.18 (3H, d, J = 6.9 Hz), 1.31 (3H, d, J = 6.3 Hz), 1.62 (1H, m), 1.82 & 2.03 (total 1H, br.s each) , 2.31 & 2.55 (total 1H, m each), 3.17-3.65 (5H, m), 3.95-4.30 (total 6H, br.sup. + M), 4.35-4.85 (1H, br.s), 7.40 (1H, br.s), 9.64 (1H, br.s)
    MS (FAB +): 603 ( M +) ( except for the ClO 4)
    b) Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer B)
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5 Yl] methyl] pyrrolidin-3-yl] thio-6 - ((1R) - (2-methyl-pyridin- To a solution of 55 mg of 1-hydroxyethyl) -1-methylcarbapen-2-m-3-carboxylate (stereoisomer B) and 0.7 ml of N-methyl aniline, the mixture was stirred at room temperature Stir for 45 min. Distilled water (3 ml) was added, and the mixture was washed three times with 3 ml of ethyl acetate. The aqueous layer was filtered, concentrated under reduced pressure, and lyophilized to obtain 31 mg of a bright orange fluorescent substance. This bright orange fluorescent substance was purified by column chromatography using Cosmosil 5C18-MS (water: methanol = 10: 1) to obtain 3.9 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80ppm): 1.14 (3H, J = 7.4 Hz), 1.22 (3H, d, J = 6.3 Hz), 1.70 (1H, m), 2.52 (1H, m), 3.31 (2H, m), 3.40 (1H, dd, J1 = 6.3 Hz, J2 = 2.5 Hz), 3.56 (1H, m), 3.95 (1H, br.s), 4.02-4.12 m), 4.14-4.21 (2H, m ), 5.20 (1H, d, J = 9.2 Hz), 7.54 (1H, s), 7.61 (1H, s), 9.38 (1H, br.s, gradually D 2 O)
    [Example 10]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [5,1- b] thiazol- Methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    2N sodium hydroxide aqueous solution (0.145 ml) was added to a solution of (3S, 5R) -1-allyloxycarbonyl-3-benzoylthio-5- (imidazo [5,1- b] thiazol- Ylmethyl) pyrrolidine, and the mixture was stirred for 20 minutes. Saturated brine (10 ml) was added, and the mixture was extracted twice with 10 ml of dichloromethane. The extract was dried over anhydrous magnesium sulfate and filtered to remove the solvent by evaporation to obtain 120 mg of mercaptan compound as yellow oil ≪ / RTI > N, N-Diisopropylethylamine (0.061 ml) was added to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -2- (diphenylphosphono) oxy- Was added dropwise to a solution of 148 mg of 6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-m-3-carboxylate and the mixture was stirred for 150 minutes. Saturated brine (10 ml) was added, and the mixture was extracted twice with 20 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation to obtain 245 mg of yellow oil . This oil was sequentially purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) and Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl (1R, 5S , 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- 5- yl) methylpyrrolidin- 6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate.
    NMR (CDCl 3) δ: 1.24 (3H, d, J = 7.1 Hz), 1.35 (3H, d, J = 6.3 Hz), 1.92 (1H, br.s), 2.14 (1H, br.s), 2.45 (2H, m), 3.87-4.47 (4H, m), 4.55-4.72 (2H, m), 3.15-3.35 (4H, dd + (1H, m), 6.77 (1H, br.s), 7.37 & 7.55 (total 1H, br .s each)
    MS (FAB < + & gt ; ): 573 (M <
    b) (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [5,1- b] thiazol- Yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    To a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxy (triphenylphosphine) palladium Yl) thio - ((1R) -1-hydroxyethyl-1-methylcarbapen- 3-carboxylic acid and 0.040 ml of N-methyl aniline, and the mixture was stirred at room temperature for 60 minutes under an argon atmosphere. Distilled water (3 ml) was added, and the mixture After washing three times with 6 ml of ethyl acetate, the aqueous layer was filtered, concentrated under reduced pressure and lyophilized to obtain 16.7 mg of a colorless fluorescent substance. The colorless fluorescent substance was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) To obtain 9.8 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.0 Hz), 1.77 (1H, m), 2.77 (1H, m (1H, m), 3.31-3.50 (5H, m), 3.65-3.70 (1H, m), 4.01 (1H, m), 4.10-4.26 = 4.2 Hz), 7.66 (1H, d, J = 4.2 Hz)
    MS (FAB < + & gt ; ): 499 (M <
    [Example 11]
    (1S, 5R) -5- (6-methylimidazo [5, < RTI ID = 0.0 & b] thiazolium-5-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (6-methylimidazo [5,1- b] thiazolium- Yl) thio-6 - ((1R) -1-hydroxyethyl-1-methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- Was shaded under argon atmosphere and stirred at room temperature for 3 days. The excess reagent was removed under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide (1R, 5S, 6S) -2- [ (3S, 5R) -1-allyloxycarbonyl-5- (6-methylimidazo [5,1- b] thiazolium-5-yl) methylpyrrolidin- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate.
    NMR (CD 3 OD) δ: 1.28 (3H, d, J = 7.2 Hz), 1.29 (3H, J = 6.2 Hz), 1.40 (1H, m), 1.95-2.15 (1H, m), 2.60-3.00 ( (1H, br.s), 3.40-3.95 (6H, m), 3.98-4.23H, m), 4.35 (3H, br), 4.72-4.87 , m), 5.70-6.15 (2H, br), 7.62 (1H, br.s), 7.67
    MS (FAB < + & gt ; ): 587 (M + ) (parts excluding I - )
    b) iodide (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) 1-b] thiazolium-5-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    Tetrakis (triphenylphosphine) palladium (0) (10.7 mg) was added to a solution of (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl- 6-methylimidazo [5,1-b] thiazolium-5-yl) methylpyrrolidin-3- yl] 3-carboxylate and 0.061 mL of N-methylaniline, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Distilled water (4 ml) was added and the mixture was washed three times with a mixed solution consisting of 3 ml of ethyl acetate and 1 ml of dichloromethane. The aqueous layer was filtered, concentrated under reduced pressure and lyophilized to give 54 mg of a bright orange fluorescent substance. This bright orange fluorescent substance was purified by column chromatography using Cosmosil 40C18-PREP (water: methanol = 20: 1) to obtain 6.7 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80ppm): 1.20 (3H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.80 (1H, m), 2.74 (1H, m ), 3.34 (1H, m), 3.43 (2H, m), 3.67 D, J = 4.2 Hz), 7.66 (1H, s), 8.04 (1H,
    [Example 12]
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (hydroxymethyl) pyrrolidin- -1- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-yl) -3-carboxylate
    2N sodium hydroxide aqueous solution (6.3 ml) was added to a solution of 3.122 g of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (hydroxymethyl) pyrrolidine in 36 ml of methanol under ice- And the mixture was stirred for 15 minutes. The mixture was adjusted to pH 7 by the addition of semi-saturated brine (100 ml) and 2N hydrochloric acid, and the mixture was extracted twice with 150 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered to evaporate the solvent To obtain 2.820 g of a mercaptan compound as a light yellow liquid. N, N-Diisopropylethylamine (2.3 ml) was added to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -6- [ methyl-carbapen-2-yl) -3-carboxylate in tetrahydrofuran, and the mixture was stirred at 4 to 6 DEG C Lt; / RTI > for 110 minutes. The mixture was diluted with 300 ml of ethyl acetate, and the diluted solution was washed with 100 ml of semi-saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by evaporation to obtain yellow oil. The oil was successively purified by column chromatography using silica gel (n-hexane: ethyl acetate = 1: 1) and Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl (1R, Yl] thio-6 - [(1R) -1- (t-butoxycarbonyl) pyrrolidin- Butyl] dimethyl] silyloxy) ethyl] -1-methylcarbapen-2-yl) -3-carboxylate.
    NMR (CDCl 3) δ: 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H, s), 1.23-1.27 (6H, m), 1.80-2.10 (1H, m), 2.49 (1H, m), 3.62 (2H, m), 4.68 (1H, m), 3.20-3.45 m), 4.78 (1H, m), 5.18-5.47 (4H, m), 5.95 (2H, m)
    b) Synthesis of allyl (1R, 5S, 6S) -2 - ((3S, 5S) -1-allyloxycarbonyl-5-formylpyrrolidin- t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-yl) -3-carboxylate
    (45 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycar Yl] thio-6 - [(1 R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen- -Carboxylate, 272 mg of N-methylmorpholine N-oxide, and 4A active molecular sieves (powder), and the mixture was stirred at room temperature for 10 minutes under an argon atmosphere. The reaction solution was directly purified by column chromatography using silica gel (n-hexane: ethyl acetate = 1: 1) to obtain allyl (1R, 5S, 6S) -2 - ((3S, 5S) -1- Yl) thio-6 - [(1 R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen- Carboxylate (719 mg).
    NMR (CDCl 3) δ: 0.09 (6H, s), 0.89 (9H, s), 1.22-1.25 (6H, m), 2.10 (1H, m), 2.95 (1H, m), 3.13-3.26 (2H, m), 3.52 (1H, m), 3.91 (2H, m), 4.20-4.32 (3H, m), 4.60-4.83 , 9.64 (1 H, m)
    MS (FAB + ): 579 (M < + & gt ; + H)
    c) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ Yl) methyl] pyrrolidin-3-yl] thio-6 - [(1 R) -1- (tert- butyldimethylsilyloxy) ethyl] -1- methylcarbapen-
    A solution of 214 mg of 5-bromoimidazo [5,1-b] thiazole in 4.2 ml of anhydrous THF was diluted with 4.2 ml of 1.0 M anhydrous THF in a 1.0 M solution of magnesium bromide / THF in an argon atmosphere under ice- Was added dropwise over 5 minutes to the prepared solution, and the solution was stirred at 4 to 7 DEG C for 15 minutes in this state. After cooling the internal temperature to -3 ° C, the solution was added to a solution of allyl (1R, 5S, 6S) -2 - ((3S, 5S) -1- allyloxycarbonyl-5-formylpyrrolidine -3-ylthio) -6 - [(1R) -1 (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen- . The mixture was stirred at -3 to + 5 < 0 > C for another 53 minutes. The mixture was extracted with ethyl acetate (40 ml) twice, and the combined organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation to yield yellow I got oil. The oil was sequentially purified by column chromatography using silica gel (n-hexane: ethyl acetate = 1: 1) and Sephadex LH-20 (dichloromethane: methanol = 1: 1) to obtain allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- -3-yl] thio-6 - [(1R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen- 2- 3-carboxylate (stereoisomer A) was obtained as yellow amorphous material (158 mg) and low polar component (stereoisomer B) as yellow oil.
    (Stereoisomer A)
    NMR (CDCl 3 ) : 0.08 (6H, s), 0.88 (9H, s), 1.20 (3H, d, J = 7.2 Hz), 1.24 (1H, br s), 2.27 (1H, br s), 3.17-3.35 (1 + 2H, dd + br, J1 = 5.9 Hz, J2 = 2.7 Hz) M), 6.80 (1 H, d, J = 8 Hz), 4.75 (2H, m), 4.45-4.82 4.1 Hz), 7.01 (1H, s), 7.74 (1H, br.s)
    MS (FAB < + & gt ; ): 703 (M <
    (Stereoisomer B)
    NMR (CDCl 3) δ: 0.08 (6H, s), 0.89 (9H, s), 1.22-1.26 (6H, m), 1.60 (1H, br.s), 2.42 (2H, br.s), 3.20 ( (2H, m), 3.52 (1H, m), 3.95-4.30 (3H, m), 4.40-4.82 (5H, m), 5.20-5.50 (1H, m), 5.80-6.02 (2H, m), 6.77 (1H, br.d), 6.99
    MS (FAB < + & gt ; ): 703 (M <
    d) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    1.1 ml of acetic acid (0.19 ml) and 1M tetra-n-butylammonium fluoride / THF solution were added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) Yl] methyl] pyrrolidin-3-yl] thio-6 - [(1R) -1- (1-hydroxy- (stereoisomer A) of the high polarity component (stereoisomer A) of 2-amino-3- (t-butyldimethylsilyloxy) ethyl] -1-methylcarbapen- Lt; / RTI > for 39 h. The reaction solution was diluted with 30 ml of ethyl acetate, and the diluted solution was washed with semi-saturated brine, dried over magnesium sulfate, and filtered to remove the solvent by evaporation to obtain a pale yellow oil. The oil was sequentially purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) and Sephadex LH-20 (dichloromethane: methanol = 1: 1) to obtain allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- 3-yl] thio-6 - [(1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (stereoisomer A).
    NMR (CDCl 3) δ: 1.22 (3H, d, J = 7.2 Hz), 1.35 (3H, d, J = 6.3 Hz), 1.60-2.00 (3H, br + m), 2.28 (1H, br.s) , 3.17-3.35 (1 + 2H, dd + br, J1 = 7.0 Hz, J2 = 2.6 Hz), 3.54 (1H, br.t), 4.08 (1H, br.s), 4.18-4.27 , 4.45-4.72 (4H, m + br), 4.82 (1H, m), 5.15-5.48 (5H, m), 5.95 , < / RTI > s), 7.73 (1H, br.s)
    MS (TS): 589 (M < + & gt ; + H)
    e) (lR, 5S, 6S) -6- (lR) -1-Hydroxyethyl-2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    6.5 mg of morpholine (0.026 ml) and tetrakis (triphenylphosphine) palladium (0) were added to a solution of allyl (lR, 5S, 6S) -2- [ Yl) methyl] pyrrolidin-3-yl] thio-6- (4-fluorobenzyl) Was added to a solution of 65.6 mg ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-M-3-carboxylate (stereoisomer A) and 12 mg of triphenylphosphine, Was stirred under argon atmosphere at room temperature for 30 minutes. Ethyl acetate (5 ml) and dichloromethane (1 ml) were added to the solution and the resulting precipitate was further washed with ethyl acetate (5 ml) and dichloromethane (5 ml) and dried in vacuo to give 48.4 mg of colorless powder. This colorless powder was sequentially purified by column chromatography using Cosmosil 40C18-PREP (water: methanol = 5: 1 to 3: 1) and cosmosil 5C18-MS (water: methanol = 3: 1) 3.3 mg of the title compound was obtained as a material.
    (Stereoisomer A)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.70 (1H, m), 2.59 (1H, m ), 3.37 (1H, br.t), 3.44-3.50 (2H, m), 3.73 (1H, m), 4.05 (1H, m), 4.20-4.40 D, J = 4.1 Hz), 7.09 (1H, s), 7.17
    [Example 13]
    (1S, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1- [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer A)
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -l-allylcarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [ ] Thiazolium-5-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- (Stereoisomer A)
    Iodomethane (0.76 g) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ - (imidazo [5,1, -b] thiazol-5-yl) methyl] pyrrolidin-3- yl] -2-methyl-3-carboxylate (stereoisomer A), and the mixture was shaken under an argon atmosphere and stirred at room temperature for 19.5 hours. The excess reagent was removed under reduced pressure, and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide as a milky, glass- 1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [5,1- b] thiazolium Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- 2- 3-carboxylate (stereoisomer A ).
    (CD 3 COCD 3 ) : 1.20-1.24 (6H, m), 1.77-2.31 (total 2H, m), 2.70-3.95 (8H, m + br + dd, J1 = 7.0 Hz, J2 = 2.5 Hz) (1H, m), 4.00-4.30 (6H, m + s), 4.40-4.80 (3H, m + br), 5.05-5.30 (3H, m), 5.40-5.50 (1H, br s), 7.85 (1H, br.s), 8.14 (br.d, J = 4.2 Hz)
    MS (TS): 603 (M + ) (parts excluding I - )
    b) Synthesis of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl-2 - [(3S, 5S) -5- [1 -hydroxy- 1- Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer A)
    4.5 g of morpholine (0.018) and tetrakis (triphenylphosphine) palladium (0) were dissolved in a mixture of 0.38 ml of anhydrous THF and 0.38 ml of dry methanol to give (1R, 5S, 6S) -2- [ ) -1-allyloxycarbonyl-5- [1 -hydroxy-1- (6-methylimidazo [5,1- b] thiazolium-5-yl) methyl] pyrrolidin- (56 mg) and triphenylphosphine (8 mg) was added sequentially to a solution of 2-amino-thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- And the mixture was stirred at room temperature for 30 minutes under argon atmosphere. Ethyl acetate (5 ml) and dichloromethane (1 ml) were added to the solution and the resulting precipitate was washed with additional 5 ml of ethyl acetate and 5 ml of dichloromethane and dried in vacuo to give 53.5 mg of a colorless powder. This colorless powder was purified by column chromatography using Cosmosil 40C18-PREP (water: methanol = 20: 1) to give the title compound (1.9 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 7.4 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.79 (1H, m), 2.62 (1H, m ), 3.37 (1H, m), 3.48 (1H, dd, J1 = 6.4 Hz, J2 = 2.8 Hz), 3.55 (1H, dd, J1 = 12.6 Hz, J2 = (1H, d, J = 8.8H), 4.17 (3H, s), 4.25 (1H, s), 7.64 (1H, d, J = 4.3 Hz)
    [Example 14]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- (1 -hydroxy- 1- (imidazo [ ] Thiazol-7-yl) methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazole- Yl) methyl] pyrrolidin-3-yl] thio-6 - [(1 R) -1- (tert- butyldimethylsilyloxy) ethyl] -1- methylcarbapen- The rate (diastereomer mixture)
    A 2M solution of methylmagnesium iodide / diethyl ether (1.3 ml) was diluted with 10 ml of anhydrous THF and a solution of 650 mg of 7-iodoimidazo [5,1-b] thiazole in 10 ml of anhydrous THF was diluted Was added dropwise to the solution over 4 minutes. The mixture was stirred at this room temperature for an additional 30 minutes. The internal temperature was lowered to -48 ° C and the solution was added to a solution of allyl (1R, 5S, 6S) -2 - ((3S, 5S) -1-allyloxycarbonyl- -Yl) -1-methylcarbapen-2-yl] -3-carboxylate in 5 ml of tetrahydrofuran was added dropwise over 5 minutes to a solution of 1.003 g of thio-6 - [(1R) -1- (tert- butyldimethylsilyloxy) ethyl] Respectively. The mixture was stirred at -45 to -40 < 0 > C for 40 minutes in the above state, and then the temperature was raised to -25 < 0 > C over 50 minutes. An aqueous solution of semi-saturated ammonium chloride (50 ml) was added to the solution, and the mixture was extracted with ethyl acetate (90 ml). The organic layer was dried over anhydrous magnesium sulfate and then filtered and the solvent was removed by evaporation to obtain yellow viscous substance ≪ / RTI > This viscous substance was purified by column chromatography sequentially using a column of silica gel (toluene: ethyl acetate = 1: 9) using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to obtain allyl (1R , 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ] Pyrrolidin-3-yl] thio-6 - [(1 R) -1- (t- butyldimethylsilyl) ethyl] -1- methylcarbapen- 2- 3-carboxylate (diastereomer) 491.3 mg was obtained.
    NMR (CDCl 3) (diastereomer mixture) δ: 0.08 (6H, s ), 0.88 (9H, s), 1.20-1.25 (6H, m), 1.62 (1H, br.s), 1.95-3.00 (4H m), 4.57-5.10 (4H, m), 3.17-3.35 (1 + 1H, dd + m, J1 = 5.8 Hz, J2 = 2.4 Hz), 3.47 , m + br), 5.18-5.46 (4H, m), 5.57 & 5.94 (total 2H, br.sup. + m), 6.82 (1H, d, J = 4.1 Hz), 7.36 & , J = 4.1 Hz), 7.92 & 7.94 (total 1H, br.s each)
    MS (FAB < + & gt ; ): 703 (M <
    b) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- )
    3.5 ml of acetic acid (0.61 ml) and 1M tetra-n-butylammonium fluoride / THF solution were added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) Yl] methyl] pyrrolidin-3-yl] thio-6 - [(1R) -1- (1-hydroxy- 1- (imidazo [5,1- b] thiazol- (di-tert-butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-3-carboxylate (diastereomeric mixture) and the mixture was stirred at room temperature under argon atmosphere for 16 Lt; / RTI > The reaction solution was diluted with 100 ml of ethyl acetate and the diluted solution was washed sequentially with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation to give a dark yellow I got oil. The oil was purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) to give allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl Yl] methyl] pyrrolidin-3-yl] thio-6 - [(1R) -1-heptyl] -5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- 3-carboxylate (diastereomer mixture) (353 mg).
    NMR (CDCl 3) (diastereomer mixture) δ: 1.22 (3H, d , J = 7.2 Hz), 1.35 (3H, d, J = 6.3 Hz), 1.85 (3H, br), 2.35 (1H, br) , 2.95 (1H, br), 3.22 (1H, dd, J1 = 7.4 Hz, J2 = 2.2 Hz), 3.40 (2H, m), 3.90-4.30 (3H, m), 4.32-4.75 4.81 (1H, m), 4.90-5.48 (5H, br + m), 5.60 & 5.95 (total 2H, br + d each J = 4.2 Hz), 7.93 & 7.95 (total 1H, br.s each)
    MS (FAB < + & gt ; ): 589 (M &
    c) (lR, 5S, 6S) -6- (1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-carboxylic acid (diastereomeric mixture)
    34.1 mg of aniline (0.15 ml) and tetrakis (triphenylphosphine) palladium (0) were added to a solution of allyl (lR, 5S, 6S) -2- [(3S, 5S) -1- allyloxycar Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- Was added to a solution of 160 mg of hydroxyethyl-1-methylcarbapen-2-M-3-carboxylate (diastereomer mixture) and the mixture was stirred at room temperature for 45 minutes under argon atmosphere. The resulting precipitate was further washed with 20 ml of ethyl acetate and dried in vacuo to give 126 mg of a white light solid as a milky white powder. The powder (46.8 mg) was dissolved in methanol-water, The residue was purified by column chromatography using 5C18-MS (water: methanol = 5: 1) to obtain the title compound (15.0 mg) as a pale white fluorescent substance.
    1 H NMR (D 2 O) (diastereomeric mixture) δ (HOD = 4.80 ppm): 1.17 (3H, d, J = 7.1 Hz), 1.27 M, 2H), 2.57 (1H, m), 3.27-3.46 (3H, m), 3.70 (1H, d, J = 8.0 Hz), 5.23 (0.5H, d, J = 4.9 Hz), 7.80 + 0.5H, s each)
    MS (FAB +): 465 (M < + & gt ; + H)
    [Example 15]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methyl-carbapen- 2- 3-carboxylic acid (stereoisomer A) The material (stereoisomer B)
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -l-allyloxycarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [ b] thiazolium-7-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- The rate (diastereomer mixture)
    Iodomethane (2.13 g) was added to allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) Carboxylate (177 mg), and the mixture was shaded under an argon atmosphere and stirred at room temperature for 12 hours. Excess reagent was removed under reduced pressure. The residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give the allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) Yl] methyl] pyrrolidin-3-yl] thio- [alpha] -methoxy] To obtain 206 mg of 6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-2-m -3-carboxylate (diastereomeric mixture).
    (CD 3 COCD 3 ) (diastereomeric mixture) : 1.21-1.28 (6H, m), 1.42 (1H, m), 1.88 and 2.10 (0.5 + 0.5H, m each), 2.27 & M), 2.87 (1H, br shoulder), 3.15-3.35 (2H, m), 3.48-3.70 (1H, m), 3.90 (1H, br.t), 4.14 & m), 7.70 (0.5H, m), 5.30 (m, 2H) d, J = 4.2 Hz), 7.76 (0.5H, d, J = 4.2 Hz), 8.26 (0.5H, d, J = 4.2 Hz), 8.32 H, br, s), 9.77 (0.5H, br.s)
    MS (FAB + ): 603 (M + ) (part excluding I - )
    b) Synthesis of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl-2 - [(3S, 5S) -5- [1 -hydroxy- 1- Yl] methyl] pyrrolidin-3-yl] thio-1-methyl-1 -carben- And homogeneous materials (stereoisomers B)
    31.6 mg of aniline (0.15 ml) and tetrakis (triphenylphosphine) palladium (0) were added to a solution of allyl iodide (1R, 5S, 6S) -2- [ , 5S) -1-allyloxycarbonyl-5- [1 -hydroxy-1- (6-methylimidazo [5,1- b] thiazolium-7-yl) methyl] pyrrolidin- (200 mg) was added successively to a solution of 200 mg of 2-thio-6 - ((1 R) -1-hydroxyethyl-1-methylcarbapen- Ethyl acetate (30 ml) was added, and the resulting precipitate was further washed with 30 ml of ethyl acetate and dried under vacuum to obtain 151 mg of a white powdery milky white powder. The powder (21.1 mg) was dissolved in methanol The resulting solution was purified by column chromatography using Cosmosil 5C18-MS (water: methanol = 5: 1) to give the title compound iodide (1R, 5S, 5S) -6- ( 1R) -l-Hydro 5-yl) methyl] pyrrolidine (2-hydroxyethyl) -2 - [(3S, 5S) -5- (Stereoisomer A: high polarity component) and 3.6 mg of a homogeneous material (stereoisomer B: low polarity substance) were mixed with a solution of milky white 2.8 g of the title compound was obtained as a white fluorescent substance.
    (Stereoisomer A: high polarity component)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.4 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.75 (1H, m), 2.68 (1H, m ), 3.31-3.48 (3H, m), 3.64 (1H, m), 4.03 (1H, br.s), 4.12 (3H, s), 4.10-4.27 = 7.5 Hz), 7.56 (1H , d, J = 4.2 Hz), 7.95 (1H, d, J = 4.2 Hz), 9.31 (1H, br.s, gradually exchanged with d 2 O)
    (Stereoisomer B: low polarity component)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.5 Hz), 2.06 (1H, m), 2.44 (1H, m ), 3.36 (2H, m), 3.44 (1H, dd), 3.71 (1H, m), 3.94 (1H, m), 4.06 (3H, s), 4.13-4.27 d, J = 3.5 Hz), 7.55 ( exchange with 1H, d, J = 4.3 Hz ), 7.93 (1H, d, J = 4.3 Hz), 9.27 (1H, br.s, gradually d 2 O)
    [Example 16]
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazole- Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl- And B)
    1N aqueous sodium hydroxide solution (0.55 ml) was added to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [ Imidazo [5,1-b] thiazol-2-yl) methyl] pyrrolidine (diastereomer mixture), and the mixture was stirred for 15 minutes. The mixture was adjusted to pH 7 by the addition of 1N hydrochloric acid and the methanol was removed under reduced pressure. Semi-saturated brine (10 ml) was added to the residue and the mixture was extracted three times with 10 ml of dichloromethane, then dried over anhydrous magnesium sulfate and filtered to remove the solvent by evaporation to give a brown viscous material (159 mg). N, N-diisopropylethylamine (0.12 ml) was added to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -2- (diphenylphosphono) oxy- To a mixed solution of 6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylate in 263 ml, the mixture was stirred for 1 hour in this state. Water (10 ml) was added to the solution, and the mixture was extracted three times with 5 ml of dichloromethane, washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation to give brown I got oil. Subsequently, this oil was purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) to give allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxy Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1 (3S, 5S) -2-methyl-1-methylcarbapen-2-carboxylate (high polarity component; stereoisomer A) Yl] methyl] pyrrolidin-3-yl] thio-6- ((1-benzyloxycarbonylamino) (1R) -1-hydroxyethyl) -1-methylcarbapen-2-3-carboxylate (low polarity substance; stereoisomer B).
    (Stereoisomer A)
    NMR (CDCl 3) δ: 1.20 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.1 Hz), 1.62-1.73 (1H, m), 2.30-2.43 (1H, m), 3.10 (2H, m), 3.31 (3H, m), 3.40-3.52 (1H, m), 3.95-4.28 (5H, m), 4.50-4.80 m), 6.97 (1H, s), 7.33 (1H, s), 7.90
    MS (FAB < + & gt ; ): 589 (M &
    (Stereoisomer B)
    NMR (CDCl 3) δ: 1.20 (3H, d, J = 7.2 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.64-1.75 (1H, m), 2.30-2.41 (1H, m), 3.16 (1H, m), 5.19-5.40 (4H, m), 3.50-4.30 (4H, m) m), 5.81-5.97 (2H, m), 6.99 (1H, s), 7.38
    MS (FAB < + & gt ; ): 589 (M &
    b) (1R, 5S, 6S) -6 - ((1R) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    Tetrakis (triphenylphosphine) palladium (0) (8.4 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1 -Methylcarbapen-2-yl) -3-carboxylate (stereoisomer A) and 0.045 ml of N-methyl aniline, and the mixture was stirred at room temperature for 35 minutes under an argon atmosphere. DMF was removed under reduced pressure, 3 ml of distilled water was added to the residue, and the mixture was washed three times with 5 ml of ethyl acetate while removing insoluble matter. The aqueous layer was concentrated under reduced pressure, the ethyl acetate was distilled off, and the concentrate was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to obtain 3.5 mg of the title compound as a colorless fluorescent substance ≪ / RTI >
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.96-2.06 (1H, m), 2.65-2.74 (1H, m), 3.31-3.48 (3H, m), 3.62-3.70 (1H, m), 3.97-4.05 6.6 Hz), 7.09 (1H, s), 7.83 (1H, s), 8.20
    [Example 17]
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (imidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer B)
    (1R, 5S, 6S) -2 - [(4-Chloro-pyridin-2-yl) (3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy-1- (imidazo [5,1- b] thiazol-2- yl) methyl] pyrrolidin- Was added to a solution of 51.6 mg of thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer B) , And the mixture was stirred at room temperature under an argon atmosphere for 1.5 hours. Ethyl acetate (10 ml) was added to the solution and the resulting precipitate was washed twice with additional 5 ml of ethyl acetate and dried in vacuo to give a yellow powder. Subsequently, the powder was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to obtain 0.83 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.18 (3H, d, J = 7.4 Hz), 1.27 (3H, d, J = 6.2 Hz), 1.16-1.73 (1H, m), 2.48-2.57 (1H, m), 3.33-3.43 (3H, m), 3.45-4.02 (1H, m), 3.75-3.93 9.0 Hz), 7.01 (1H, s), 7.82 (1H, s), 8.15
    [Example 18]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    a) Preparation of allyl iodide (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate The ratio (stereoisomer A)
    Iodomethane (0.6 ml) was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [ Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -2-methyl-3-carboxylate (stereoisomer A) (54.0 mg), the mixture was shaded under an argon atmosphere and stirred at room temperature for 5 hours. (1R, 5S, 6S) -2 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -1-allyloxycarbonyl Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbazole (5-hydroxyimidazo [5,1-b] thiazolium- -2-methyl-3-carboxylate (stereoisomer A).
    NMR (CD 3 OD) : 1.23 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 2.02-2.15 (1H, m), 2.35-2.46 (2H, m), 4.13 (3H, s), 4.57-4.75 (5H, m), 3.18-3.31 (4H, m), 3.53-3.60 ), 5.21-5.50 (5H, m), 5.90-6.01 (2H, m), 7.74 (1H, s), 8.03
    MS (FAB < + & gt ; ): 603 (M &
    b) Preparation of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [1 -hydroxy- Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer A)
    Tetrakis (triphenylphosphine) palladium (0) (21.9 mg) was added to a solution of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1, 6-methylimidazo [5,1-b] thiazolium- -3-carboxylate (stereoisomer A) and 0.061 ml of N-methylaniline, and the mixture was stirred at room temperature for 40 minutes under an argon atmosphere. Lt; / RTI > DMF was removed under reduced pressure, 5 ml of distilled water was added to the residue, and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was concentrated under reduced pressure and then purified by chromatography using Cosmosil 40C18-PREP (water-methanol) to obtain the title compound (11.9 mg) as a white powder.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.5 Hz), 2.01-2.11 (1H, m), 2.58-2.68 (1H, m), 3.35-3.48 (3H, m), 3.74-3.81 (1H, m), 3.99-4.10 (1H, d, J = 4.8 Hz), 7.62 (1H, s), 8.05
    [Example 19]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl-2 - [(3S, 5S) -5- [1 -hydroxy- 1- (6-methylimidazo [ Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-carboxylic acid (stereoisomer B)
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -l-allyloxycarbonyl-5- [1 -hydroxy- 1- (6-methylimidazo [ yl] methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1-methylcarbapen- (Stereoisomer B)
    Iodomethane (0.65 ml) was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [ Yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -2-methyl-3-carboxylate (stereoisomer B), and the mixture was shaded under an argon atmosphere and stirred at room temperature for 8 hours. The excess reagent was removed under reduced pressure, and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide (1R, 5S, 6S) -2- [ (3S, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy-1- (6-methylimidazo [5,1- b] thiazolium 2-yl) methyl] pyrrolidine -3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (stereoisomer B).
    NMR (CD 3 OD) : 1.21 (3H, d, J = 7.1 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.88-1.98 (1H, m), 2.65-2.74 (2H, m), 4.13 (3H, s), 4.58-4.72 (5H, m), 3.23-3.35 (4H, m), 3.45-3.53 ), 5.20-5.50 (5H, m), 5.89-6.05 (2H, m), 7.72 (1H, s), 7.93
    MS (FAB < + & gt ; ): 603 (M &
    b) Synthesis of (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -1 - [(3S, 5S) -5- [1 -hydroxy- Yl] methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid (stereoisomer B)
    Tetrakis (triphenylphosphine) palladium (0) (8.2 mg) was added to a solution of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl] methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- Methylcarbapen-2-yl) -3-carboxylate and 0.046 ml of N-methyl aniline, and the mixture was stirred at room temperature for 45 minutes under an argon atmosphere. DMF was removed under reduced pressure, 5 ml of distilled water was added to the solution, and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was filtered and concentrated under reduced pressure. The concentrate was sequentially purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) and Sephadex LH-20 (dichloromethane: methanol = 1: 1) , 1.7 mg of the title compound was obtained.
    NMR (D 2 O) (HOD = 4.80 ppm): 1.20 (3H, d, J = 6.9 Hz), 1.32 (3H, d, J = 6.7 Hz), 1.82-1.90 (1H, m), 3.33-3.49 (3H, m), 3.69-3.78 (1H, m), 4.06-4.21 (1H, d, J = 9.0 Hz), 7.63 (1H, s), 8.10
    Example 20
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [5,1- b] thiazol- Pyrrolidin-3-yl] thio-1-methylcarbapen-2-3-carboxylic acid
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Yl] thio-6 - [(1 R) -1- (t-butyldimethylsilyloxy) ethyl] -1- methylcarbapen-
    1N sodium hydroxide aqueous solution (0.75 ml) was added to a solution of (3S, 5R) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [ ] Thiazol-3-yl) methyl] pyrrolidine, and the mixture was stirred for 15 minutes. The mixture was adjusted to pH 7 by the addition of 1N hydrochloric acid and the methanol was removed under reduced pressure. Semi-saturated brine (10 ml) was added to the residue and the mixture was extracted three times with 10 ml of dichloromethane, then dried over anhydrous magnesium sulfate and filtered to remove the solvent by evaporation to give a brown viscous material 215 mg. N, N-diisopropylethylamine (0.18 ml) was added dropwise to a solution of the mercaptan compound and allyl (1R, 5R, 6S) -6 - [(1R) -1- 3-carboxylate (517 mg) obtained in the same manner as in Example 1, and the mixture was added dropwise to a solution of 2 (tert-butyldimethylsilyloxy) ethyl] -2- (diphenylphosphono) oxy- Lt; / RTI > Water (10 ml) was added to the solution and the mixture was extracted three times with 5 ml of dichloromethane and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by evaporation to obtain a red viscous material. This viscous substance was purified by column chromatography using silica gel (n-hexane: ethyl acetate = 2: 1) to obtain allyl (1R, 5S, 6S) -2- [ Yl] thio-6 - [(1R) -1- (t (2-benzyloxycarbonyl-5- -Butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-yl) -3-carboxylate (332 mg).
    NMR (CDCl 3) δ: 0.02 (6H, s), 0.80 (9H, s), 1.12-1.20 (6H, m), 1.48-1.62 (1H, m), 1.66-1.80 (1H, m), 2.34- (1H, m), 2.85-3.00 (1H, m), 3.10-3.18 (2H, m), 3.27-3.41 ), 4.55-4.74 (4H, m), 5.17-5.40 (4H, m), 5.82-5.97 (2H, m), 6.45 (1H, br.s), 7.01 ), 8.20 (1 H, s)
    MS (ES): (M < + & gt ; + H)
    b) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    1.7 ml of acetic acid (0.30 ml) and 1 M tetra-n-butylammonium fluoride / THF solution was added dropwise to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl (Imidazo [5,1-b] thiazol-3-yl) methylpyrrolidin-3-yl] thio-6 - [(1R) -1- (tert- butyldimethylsilyloxy) ethyl] -1-methylcarbapen-2-M-3-carboxylate anhydride, and the mixture was stirred at room temperature under an argon atmosphere for 21 hours. The reaction solution was diluted with 50 ml of ethyl acetate, and 20 ml of water was added to the solution. The mixture was extracted with ethyl acetate three times, washed with 20 ml of saturated brine, dried over anhydrous magnesium sulfate and filtered to remove the solvent by evaporation to obtain 87 mg of a crude product (crude product) as an oil. This oil was purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) to give allyl (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycar 5- (imidazo [5,1-b] thiazol-3-yl] methylpyrrolidin-3- yl] thio-6 - ((1R) -1- hydroxyethyl) -2-methyl-3-carboxylate (189 mg).
    NMR (CDCl 3) δ: 1.25 (3H, d, J = 7.1 Hz), 1.36 (3H, d, J = 6.3 Hz), 1.79-1.88 (1H, m), 2.45-2.58 (1H, m), 2.59 (3H, m), 3.81-4.88 (1H, m), 3.81-4.40 (5H, m) s), 8.03 (1H, s), 8.31 (1H, s), 8.42
    MS (ES): 573 (M < + & gt ; + H)
    c) (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [ Yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    Tetrakis (triphenylphosphine) palladium (0) (14.3 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5R) -1- allyloxycarbonyl- (1 R) -1-hydroxyethyl) -1-methylcarbapen-2- -3-carboxylate and 0.08 ml of N-methylaniline, and the mixture was stirred at room temperature for 40 minutes under an argon atmosphere. Distilled water (3 ml) and ethyl acetate (5 ml) were added to the solution to remove insoluble matter, followed by washing twice with 5 ml of ethyl acetate and concentration under reduced pressure. The concentrate was then lyophilized to give a colorless fluorescent substance. Subsequently, the material was purified by column chromatography using Cosmosil 40C18-PREP (water: methanol) to obtain the title compound (6.12 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.4 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.80-1.90 (1H, m), 2.80-2.90 (1H, m), 3.33-3.47 (5H, m), 3.62-3.68 (1H, m), 4.01-4.26 (4H, m), 7.01 , s)
    [Example 21]
    (1S, 5R) -5- (6-methylimidazo [5, < RTI ID = 0.0 & b] thiazolium-3-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (6-methylimidazo [5,1- b] thiazolium- Yl) thio-6 - ((1R) -1-hydroxyethyl-1-methylcarbapen-
    Iodomethane (2.13 g) was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- (imidazo [ yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- And the mixture was shaded under an argon atmosphere and stirred at room temperature for 16 hours. The excess reagent was removed under reduced pressure and the residue was purified using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide (1R, 5S, 6S) -2- [ Yl) thio-6 - ((1 R) -methoxypyrrolidin-3-yl) ) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate.
    NMR (CDCl 3) δ: 1.27 (3H, d, J = 7.5 Hz), 1.36 (3H, d, J = 6.4 Hz), 1.69-1.81 (1H, m), 2.89-2.99 (1H, m), 3.28 (1H, m), 4.65-4.88 (2H, m), 3.61 (3H, m), 3.71-3.88 m), 5.24-5.52 (6H, m), 5.87-6.07 (2H, m), 6.99
    MS (ES): 587 (M < + & gt ; + H)
    b) iodide (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) 1-b] thiazolium-3-yl) methylpyrrolidin-3-yl] thiocarbazol-
    Tetrakis (triphenylphosphine) palladium (0) (14.3 mg) was added to a solution of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl- - (6-methylimidazo [5,1-b] thiazolium-3-yl) methylpyrrolidin-3- yl] thio- Methylcarbapen-2-yl) -3-carboxylate and 0.084 ml of N-methylaniline, and the mixture was stirred at room temperature for 75 minutes under an argon atmosphere. Distilled water (2 ml) was added to the solution and the mixture was washed three times with 5 ml of ethyl acetate. The aqueous layer was then concentrated under reduced pressure, and the concentrate was lyophilized to give a milky white fluorescent substance. This material was then purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to obtain the title compound 8.5 Mg.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.23 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.87-1.97 (1H, m), 2.86-2.97 (1H, m), 7.41 (1H, s), 7.67 (1H, , < / RTI > s), 9.40 (1H, s)
    [Example 22]
    (3R, 5R) -5- [6- (2-hydroxyethyl) imidazo [5, l -b] thiazolidin-3-yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-
    (3R, 5S, 6S) -2 - [(3S, 6S) -3- (trifluoromethanesulfonyloxy) ethyl trifluoromethanesulfonate (63.5 mg) was added to a solution of allyl 5R) -1-allyloxycarbonyl-5- (imidazo [5,1-b] thiazol-3-yl) methylpyrrolidin- Carboxylate (98.3 mg), and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. The excess reagent was removed under reduced pressure to obtain a brown (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- [6- (2-t-butyldimethylsilyloxyethyl) imidazolium trifluoromethanesulfonate Yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-one -3-carboxylate. Acetic acid (0.01 ml) and 0.18 ml of 1M tetra-n-butylammonium fluoride / THF solution were added to a solution of the above compound in 1 ml of anhydrous THF and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. Dry ethanol (1 ml) was added to the solution. Thereafter, 9.3 mg of triphenylphosphine, 0.038 ml of morpholine, and 11.3 mg of tetrakis (triphenylphosphine) palladium (0) were sequentially added to the mixture, and then the mixture was stirred at room temperature for 1 hour Lt; / RTI > THF (10 mL) was added to the solution and the resulting precipitate was washed with additional 5 mL of THF and dried in vacuo to give a yellow powder. And then an anion exchange resin amber list (Amberlyst) A-26 was purified by column chromatography using a - then the yellow powder course carry 40C18-PREP (methanol water) was passed through a (Cl form) to give the title compound 13.3 as a colorless fluorescent substance Mg.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.1 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.48-1.58 (1H, m), 2.59-2.69 (1H, m), 3.03-3.07 (1H, m), 3.22-3.42 (5H, m), 3.72 (1H, (2H, m), 4.51 (2H, t, J = 3.6 Hz), 7.31 (1H, s), 7.73
    [Example 23]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- (imidazo [5,1- b] thiazol- Methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    1N sodium hydroxide aqueous solution (0.87 ml) was added to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [ ] Thiazol-2-yl) methylpyrrolidine, and the mixture was stirred for 15 minutes. A 1N aqueous sodium hydroxide solution (0.75 ml) was added to the solution under ice cooling and stirred for 15 minutes. To this mixture was added 1N hydrochloric acid to adjust the pH to 7, then the methanol was removed under reduced pressure, 10 ml of semi-saturated brine was added to the solution, the mixture was extracted three times with 10 ml of dichloromethane and then anhydrous magnesium sulfate Dried over filtration, and the solvent was removed by evaporation to obtain 244 mg of mercaptan compound as yellow oil. N, N-diisopropylethylamine (0.115 ml) was added to a solution of 143 mg of the mercaptan compound and 1.5 g of allyl (1R, 5R, 6S) -2- (diphenylphosphono) 1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate in tetrahydrofuran, and the mixture was stirred for 2 hours in an argon atmosphere under ice-cooling. Water (10 ml) was added to the solution, and the mixture was extracted three times with 10 ml of chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation to obtain 423 mg of yellow oil . The oil was then purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) to give allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxy Yl) thio] -6- (1R) -1-hydroxyethyl) -1-methylcarbamoyl-5- 3-carboxylate (153.4 mg).
    NMR (CDCl 3) δ: 1.25 (3H, d, J = 7.2 Hz), 1.36 (3H, d, J = 6.3 Hz), 1.80-1.88 (1H, m), 2.45-2.56 (1H, m), 3.21 M), 5.90-6.15 (2H, m), 3.60-4.62 (4H, m) m), 7.03 (1 H, s), 7.27 (1 H, s), 7.94 (1 H, s)
    MS (ES): 573 (M < + & gt ; + H)
    b) (lS, 5S, 6S) -6- (lR) -1-Hydroxyethyl) -2 - [(3S, 5S) -5- (imidazo [ Yl) methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    Tetrakis (triphenylphosphine) palladium (0) (16.4 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- (Imidazo [5,1-b] thiazol-2-yl) methylpyrrolidin-3- yl] thio- -3-carboxylate and 0.092 ml of N-methylaniline, and the mixture was stirred at room temperature for 45 minutes under an argon atmosphere. Distilled water (3 ml) and ethyl acetate (10 ml) were added to the solution to remove insoluble matter. The aqueous layer was washed twice with 3 ml of ethyl acetate and concentrated under reduced pressure. The concentrate was lyophilized, and the concentrate was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to give the title compound 10.3 mg.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 7.3 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.72-1.82 (1H, m), 2.74-2.83 (2H, m), 3.33-3.39 (2H, m), 3.44-3.47 (1H, m), 3.23-3.27 , 4.20-4.28 (2H, m), 7.04 (1H, s), 7.68 (1H, s), 8.13
    [Example 24]
    Methyl-2 - [(3S, 5S) -5- (6-methylimidazo [5,1-b ] Thiazolium-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6-methylimidazo [5,1- b] thiazolium- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    Iodomethane (1.2 ml) was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl-5- (imidazo [ yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 113.3 mg, and the mixture was shaded under an argon atmosphere and stirred overnight at room temperature. The excess reagent was removed under reduced pressure, and the residue was purified by using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide as a yellow viscous substance (1R, 5S, 6S) -2- [ , 5S) -1-allyloxycarbonyl-5- (6-methylimidazo [5,1-b] thiazolium- 1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate.
    NMR (CDCl 3) δ: 1.28 (3H, d, J = 7.1 Hz), 1.39 (3H, d, J = 6.1 Hz), 1.73-1.83 (1H, m), 2.62-2.72 (1H, m), 3.29 M), 4.24-4.35 (1H, m), 4.25 (3H, s), 4.65-4.85 (4H, m), 5.26-5.49 (6H, m), 5.90-6.02 , 7.42 (1 H, s), 8.41 (1 H, s)
    b) Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) 1-b] thiazolium-2-yl) methylpyrrolidin-3-yl] thiocarbazol-
    Tetrakis (triphenylphosphine) palladium (0) (13.6 mg) was added to a solution of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methyl-pyridin- -3-carboxylate and 0.077 ml of N-methyl aniline, and the mixture was stirred at room temperature for 40 minutes under an argon atmosphere. DMF was removed by evaporation in vacuo, 5 ml of distilled water was added to the solution, the mixture was washed three times with 5 ml of ethyl acetate and concentrated under reduced pressure. The concentrate was lyophilized to give 74.7 mg as a yellow fluorescent substance. The yellow fluorescent substance was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to obtain 21.2 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.81-1.91 (1H, m), 2.80-2.90 (1H, m), 3.38-3.50 (5H, m), 3.70-3.77 (1H, m), 4.05-4.11 (1H, s), 7.95 (1H, s), 9.71 (1H, s)
    [Example 25]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [6- (2-hydroxyethyl) imidazo [ -b] thiazolidin-2-yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-
    2- (t-butyldimethylsilyloxy) ethyl trifluoromethanesulfonate (20.9 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [((3S , 5S) -1-allyloxycarbonyl-5- (imidazo [5,1-b] thiazol-2-yl) methylpyrrolidin- 3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. Excess reagent was removed under reduced pressure to obtain a brown viscous (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2-t- butyldimethylsilyloxyethyl) imidazole Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- 3-carboxylate.
    Acetic acid (0.0034 ml) and 0.057 ml of 1M tetra-n-butylammonium fluoride / THF solution were added to a solution of the above compound in 0.5 ml of anhydrous THF and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Dry ethanol (0.5 ml) was added to the solution and 5.9 mg of triphenylphosphine, 0.012 ml of morpholine and 3.6 mg of tetrakis (triphenylphosphine) palladium (0) were added sequentially to the solution, Was stirred at room temperature under an argon atmosphere for 1 hour. THF (10 mL) was added to the solution and the resulting precipitate was washed twice with 3 mL of THF and dried in vacuo to give a yellow powder which was then purified by using Cosmosil 40C18-PREP (water-methanol) The product was purified by column chromatography and then passed through anion exchange resin amberlist A-26 (Cl - form) to obtain 4.4 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.81-1.91 (1H, m), 2.69-2.84 (1H, m), 4.49 (2H, t, J = 8.4 Hz, 4.5 Hz), 7.70 (1H, s), 7.97 (1H, s), 9.27
    [Example 26]
    Iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (carbamoylmethyl) imidazo [5,1- b] thiazolium 2-yl] methylpyrrolidine Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (carbamoylmethyl) imidazo [5,1- b] Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    2-iodoacetamide (96.1 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2 -M-3-carboxylate in 50 ml of tetrahydrofuran, and the mixture was stirred at room temperature under an argon atmosphere for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide as a light yellow solid (1R, 5S, 6S) 3S, 5S) -1-allyloxycarbonyl-5- [6- (carbamoylmethyl) imidazo [5,1- b] thiazolium-2- yl] methylpyrrolidin- -6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate.
    NMR (CD 3 OD) : 0.85-0.98 (1H, m), 1.23 (3H, d, J = 7.4 Hz), 1.28 (2H, m), 2.60-2.70 (1H, m), 3.23-3.56 (4H, m), 3.85-3.93 (1H, m), 4.09-4.38 m), 5.89-6.04 (2H, m), 7.20-7.42 (1H, m), 7.76
    MS (FAB < + & gt ; ): 630 (M &
    b) iodide (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen- 2-
    Acetic acid (0.01 ml) and 0.18 ml of 1M tetra-n-butylammonium fluoride / THF solution were added to a solution of allyl iodide (1R, 5S, 6S) -2- [(3S, 5S) Yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-ylmethyl] pyrimidin- -3-chlorobenzyl chloride in 30 ml of tetrahydrofuran, and the mixture was stirred at room temperature under an argon atmosphere for 1.5 hours. Dry ethanol (1 ml) was added to the solution and 9.3 mg of triphenylphosphine, 0.038 ml of morpholine and 11.3 mg of tetrakis (triphenylphosphine) palladium (0) were added sequentially to the solution, The mixture was stirred at room temperature under argon atmosphere for 1 hour. THF (10 ml) was added to the solution and the resulting precipitate was washed twice with 5 ml of additional THF and dried in vacuo to give a yellow powder which was then purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) To obtain 3.5 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 7.5 Hz), 1.28 (3H, d, J = 6.2 Hz), 1.82-1.93 (1H, m), 2.80-2.90 (1H, m), 3.30-3.50 (5H, m), 3.65-3.68 (1H, m), 3.96-4.27 (4H, m), 5.27 , s), 9.31 (1 H, s)
    [Example 27]
    Yl] methylpyrrole (5R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Synthesis of allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2- fluoroethyl) imidazo [ yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- Rate
    Fluoroethyl trifluoromethylsulfonate (76.4 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- (Imidazo [5,1-b] thiazol-2-yl) methylpyrrolidin-3- yl] thio- -3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- - yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate.
    NMR (CDCl 3) δ: 1.22-1.40 (6H, m), 1.82-1.95 (2H, m), 2.05-2.08 (1H, m), 2.52-2.55 (1H, m), 3.20-3.35 (5H, m ), 3.62-3.70 (1H, m), 4.20-4.30 (4H, m), 4.63-4.98 (6H, m), 5.33-5.48 (1H, s), 7.95 (1H, s), 9.78 (1H, s)
    MS (FAB < + & gt ; ): 619 (M &
    b) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2- fluoroethyl) imidazole Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) Carboxylate, and 7.9 mg of triphenylphosphine, 0.016 ml of morpholine and 4.2 mg of tetrakis (triphenylphosphine) palladium (0) were sequentially added to the solution, And the mixture was stirred at room temperature under an argon atmosphere for 55 minutes. THF (10 mL) was added to the solution and the resulting precipitate was washed twice with additional 3 mL of THF and dried in vacuo to give a yellow powder which was purified by column chromatography using COSMOSIL 40C18-PREP (water-methanol) And then passed through anion exchange resin amberlly A-26 (Cl - form) to obtain 4.1 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) (HOD = 4.80 ppm): 1.21 (3H, d, J = 7.3Hz), 1.28 (3H, d, J = 6.3Hz), 1.82-1.92 (1H, m), 3.72-3.75 (1H, m), 3.68-3.75 (1H, m), 4.04-4.28 (4H, m), 4.70-4.98 (1 H, s), 9.31 (1 H, s)
    [Example 28]
    Methyl-2 - [(3S, 5S) -5- (3-methylimidazo [5, 1-b ] Thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (3-methylimidazo [ Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (3-methylimidazo [5,1-b] Thiazol-2-yl) methylpyrrolidine, 362.4 mg of mercaptan compound was prepared as yellow oil. Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (3- methylimidazo [5,1- b] thiazol- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 544.2 mg of the title compound was obtained as a colorless, clear, colorless oil from 1R, 5S, 6S) -2- (diphenylphosphino) oxy- Of amorphous material.
    NMR (CDCl 3) δ: 1.27 (3H, d, J = 7.1 Hz), 1.36 (3H, d, J = 6.2 Hz), 1.65-1.82 (1H, m), 2.40 (3H, s), 2.45-2.58 (1H, m), 2.90-3.01 (1H, m), 3.25-3.40 (5H, m), 3.60-3.67 (1H, m), 4.15-4.28 , 5.23-5.48 (4H, m), 5.91-6.03 (2H, m), 7.06 (1H, s), 7.86
    MS (FAB < + & gt ; ): 587 (M + )
    b) (lR, 5S, 6S) -6- (lR) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- (3-methylimidazo [ -b] thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    The procedure of Example 23-b) was repeated to give allyl (lR, 5S, 6S) -2 - [(3S, 5S) -l-allylcarbonyl-5- (3-methylimidazo [ Thiazol-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- To give the title compound (5.8 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.4 Hz), 1.27 (3H, d, J = 6.2 Hz), 1.72-1.82 (1H, m), 2.41 (3H (2H, m), 7.06 (1H, m), 2.71-2.81 (1H, m), 3.18-3.46 (5H, m), 3.62-3.68 (1 H, s), 8.12 (1 H, s)
    [Example 29]
    (3S, 5S) -5- (3,6-dimethylimidazo [5,1-b] thiazolium-3-yl) methylpyrrolidin- - yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- 5- (3,6- dimethylimidazo [5,1- b] thiazolium- 2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    The procedure of Example 24-a) was repeated to give the allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- (3S, 5S) -1-allyloxycarbonyl) -5- (3,6-dimethylpyridin-2-yl) Yl) thio-6 - ((1 R) -2-hydroxyethyl) -1-methylcarbapen- 2- -3-carboxylate (66.7 mg).
    NMR (CD 3 COCD 3) δ : 1.10-1.15 (6H, m), 1.59-1.68 (1H, m), 2.45-2.63 (1H, m), 2.50 (3H, s), 3.12-3.54 (5H, m ), 3.83-3.71 (5H, m), 4.35-4.65 (4H, m), 5.01-5.33 (4H, m), 5.72-5.88 )
    MS (FAB < + & gt ; ): 601 (M + )
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (3,6-dimethylimidazo [5,1- b] thiazolium 2-yl) methylpyrrolidine Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    The procedure of Example 24-b) was repeated to give allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (3,6-dimethylimidazo [ Yl] thiophen-2-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- Carboxylate (66.7 mg), the title compound (5.9 mg) was obtained as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 7.1 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.76-1.86 (1H, m), 2.50 (3H (2H, m), 4.08 (3H, s), 4.20-4.26 (1H, m), 2.73-2.84 (1H, m), 3.30-3.48 (2H, m), 7.59 (1H, s), 9.21 (1H, s)
    [Example 30]
    Methyl-3-methylimidazo [5, l- b] thiazolium-2-yl) thiophene was obtained in the same manner as in (1R, 5S, Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- (6-carbamoylmethyl-3-methylimidazo [ ] Thiazolium-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    The procedure of Example 26-a) was repeated to give the allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (57.6 mg) was added to a solution of allyl iodide of yellow oil (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl-5- Methylimidazo [5,1-b] thiazolium-2-yl) methylpyrrolidin-3- yl] thio-6- ((1R) -1- hydroxyethyl) -2-methyl-3-carboxylate (70.9 mg).
    NMR (CD 3 COCD 3) δ : 1.14-1.22 (6H, m), 1.72-1.86 (1H, m), 2.57-2.62 (3H, m), 2.62 (3H, m), 3.10-3.60 (5H, m ), 3.80-4.32 (5H, m), 4.52-4.78 (4H, m), 5.12-5.45 (6H, m), 5.87-5.98 , br.s), 7.95 (1H, s), 9.70 (1H, s)
    MS (FAB < + & gt ; ): 644 (M &
    b) Preparation of iodide (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6-carbamoylmethyl-3-methylimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    The procedure of Example 26-b) was repeated to give allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2 -M-3-carboxylate (70.9 mg) was prepared 11.6 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) (HOD = 4.80 ppm): 1.20 (3H, d, J = 7.1 Hz), 1.27 (3H, d, J = 6.9 Hz), 1.62-1.71 (2H, m), 5.26-2.73 (1H, m), 3.27-3.40 (5H, m), 3.44-3.56 (2 H, s), 7.64 (1 H, s)
    [Example 31]
    Methyl-2 - [(3S, 5S) -5- (5-methylimidazo [5, 1-b ] Thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-methylimidazo [ Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (5-methylimidazo [5,1-b] Thiazol-2-yl) methylpyrrolidine (766.4 mg), 653.0 mg of mercaptan compound as yellow oil was prepared. Allyl (5R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-methylimidazo [ 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- (1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate from 891.6 mg of colorless Of amorphous material.
    NMR (CDCl 3) δ: 1.18 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.3 Hz), 1.76-1.83 (1H, m), 2.40-2.50 (1H, m), 2.48 (3H, s), 2.96-3.08 (1H, m), 3.19-3.28 (4H, m), 3.52-3.58 (1H, m), 4.04-4.21 , 4.75-4.80 (1H, m), 5.18-5.42 (4H, m), 5.83-5.89 (2H, m), 6.81
    MS (TS): 587 (M < + & gt ; + H)
    b) (lR, 5S, 6S) -6- (lR) -1-Hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- (5-methylimidazo [ -b] thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    The procedure of Example 23-b) was repeated to give allyl (lR, 5S, 6S) -2 - [(3S, 5S) -l-allyloxycarbonyl-5- (5-methylimidazo [ b] thiazol-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- Mg of the title compound as a white powder.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.17-1.81 (1H, m), 2.52 (3H (2H, m), 2.71-2.81 (1H, m), 3.24 (2H, d, J = 7.2 Hz), 3.32-3.46 (3H, m), 3.60-3.67 ), 4.20-4.28 (2H, m), 6.93 (1H, s), 7.54
    [Example 32]
    (5S, 5S) -5- (5,6-dimethylimidazo [5,1-b] thiazolium-2-yl) methylpyrrolidin- - yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5,6-dimethylimidazo [5,1- b] thiazolium- 2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    The procedure of Example 24-a) was repeated to give the allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate from 71.2 mg of (3S, 5S) -1-allyloxycarbonyl-5- (5,6-dimethylimidazo Yl] methyl} pyridin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) Carboxylate (88.4 mg).
    NMR (CDCl 3) δ: 1.18-1.33 (6H, m), 1.65-1.83 (1H, m), 2.63-2.74 (1H, m), 3.05 (3H, s), 3.20-3.35 (3H, m), (1H, m), 3.55-3.67 (1H, m), 4.05 (3H, s), 4.15-4.26 (2H, m), 4.55-4.64 (3H, m), 4.70-4.76 ), 5.84-5.96 (2H, m), 7.55 (1H, s), 8.60 (1H, s)
    MS (TS): 601 (M < + & gt ; ).
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (5,6-dimethylimidazo [5,1- b] thiazolium 2-yl) methylpyrrolidine Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    The procedure of Example 24-b) was repeated to give allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5,6-dimethylimidazo [ Yl] thiophen-2-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- Carboxylate (88.4 mg) to give the title compound (11.0 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.8 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.5 Hz), 1.80-1.85 (1H, m), 2.78 (3H , < / RTI > s), 2.79-2.89 (1H, m). 3.36-3.50 (5H, m), 3.70-3.77 (1H, m), 3.93 (3H, s), 4.02-4.11 (2H, m). 4.21-4.27 (2 H, m), 7.47 (1 H, s). 7.86 (1H, s)
    [Example 33]
    Methyl iodide (5R, 5S, 6S) -2 - [(3S, 5S) -5- (6-Carbamoyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -l-allyloxycarbonyl-5- (6-carbamoylmethyl-5-methylimidazo [ ] Thiazolium-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    The procedure of Example 26-a) was repeated to give the title compound as a light yellow solid in the same manner as in Example 31-a) except that the allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl- Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- 3-carboxylate from 45.2 mg, there was thus obtained allyl iodide of yellow oil (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6- carbamoylmethyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2 -M-3-carboxylate (83.4 mg).
    NMR (CD 3 OD) : 1.23 (3H, d, J = 7.4 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.78-1.89 (1H, m), 2.62-2.75 (1H, m), 2.82 (3H, s), 3.20-3.40 (4H, m), 3.49-3.59 (1H, m), 3.83-3.93 ), 4.61-4.76 (4H, m), 5.17-5.42 (6H, m), 5.89-6.03 (2H, m), 7.65
    MS (Ts-Pos): 644 (M <+> )
    b) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6-carbamoylmethyl-5-methylimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    The procedure of Example 26-b) was repeated to give allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- (6- carbamoylmethyl- Yl) thio-6 - ((1 R) b-1-hydroxyethyl) -1-methylcarbapen- 3-carboxylate (83.4 mg), 6.3 mg of the title compound was obtained as a pale yellow fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.80-1.90 (1H, m), 2.77 (3H m), 4.02-4.13 (2H, m), 4.02-4.28 (2H, m), 5.19 (1H, m), 2.77-2.88 (2H, s), 7.55 (1H, s), 7.92 (1H, s)
    [Example 34]
    (LS, 5R) -5- (imidazo [5,1-b] thiazol-7-yl) -6- ((1R) Methyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylic acid
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (3S, 5R) -1-allyloxycarbonyl-3-benzoylthio-5- (imidazo [5,1-b] thiazol-7 (1R) -1-methylcarbapen-2-yl) methyl] pyrrolidine and 169 mg of allyl (1R, 5R, 6S) -2- (diphenylphosphono) (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazole -7-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate .
    NMR (CDCl 3) δ: 1.23 (3H, d, J = 7.4 Hz), 1.34 (3H, d, J = 6.3 Hz), 1.96 (1H, m), 2.45 (1H, m), 3.00-3.60 (6H m), 3.90-4.35 (4H, m), 4.55-4.97 (4H, m), 5.20-5.48 7.37 (1H, d, J = 4.1 Hz), 7.95 (1H, s)
    b) (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -2 - [(3S, 5R) -5- (imidazo [5,1- b] thiazol- Yl) -methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yne-3-carboxylic acid
    The procedure of Example 10-b) was repeated to give allyl (lR, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazole 3-carboxylate (43.2 mg) was obtained as a colorless oil from the titled compound 11.1 mg.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.17 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.75 (1H, m), 2.71 (1H, m (2H, m), 7.05 (1H, d, J = 4.1 Hz), 7.64 (2H, (1H, d, J = 4.1 Hz), 8.15 (1H, s)
    [Example 35]
    (1S, 5R) -5- (6-methylimidazo [5, &lt; RTI ID = 0.0 & b] thiazolium-7-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    Iodomethane (0.468 ml) was added to a solution of allyl (1R, 5S, 6S) -2- [(3S, 5R) -1- allyloxycarbonyl-5- (imidazo [ yl) thiazol-7-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- And the mixture was shaded under an argon atmosphere and stirred at room temperature for 19 hours. Excess reagent was removed under reduced pressure to obtain allyl iodide (1R, 5S, 6S) -2 - [(3S, 5R) -1-allyloxycarbonyl-5- (6- Yl) thio] -6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The product was obtained. The procedure of Example 11-b) was repeated except that only the total amount of the crude product prepared above was used. Thus, 3.2 mg of the title compound was obtained.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 6.92 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.86 (1H, m), 2.80 (1H, m ), 3.39 (1H, m), 3.46-3.58 (4H, m). 3.78 (1H, m), 4.06 (3H, s), 4.05-4.28 (4H, m). (1H, s), 7.56 (1H, d, J = 4.4 Hz), 7.94
    [Example 36]
    Methyl-2 - [(3S) -5- (6-methylimidazo [5,1-b] Yl] pyrrolidin-3-yl] thiocarbazol-2-yl) -3-carboxylic acid (stereoisomer A)
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- (Stereoisomer A) was obtained in the same manner as in (1)
    1N sodium hydroxide aqueous solution (0.78 ml) was added to a solution of (3S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1-b] thia 5-yl) pyrrolidine (stereoisomer A), and the mixture was stirred at the same temperature for 15 minutes. The mixture was adjusted to pH 7 with 1 N hydrochloric acid solution, dichloromethane was added to the solution, and the mixture was washed successively with water and saturated brine successively. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain a mercaptan compound. (1R, 5S, 6S) -2- (Diphenylphosphono) oxy-6 - ((1R) -1-hydroxyethyl) piperidine in 4 ml of acetonitrile under ice- -1-methylcarbapen-2-yl) -3-carboxylate in 20 ml of tetrahydrofuran. Ethyl acetate was added to the reaction mixture and stirred for 30 minutes. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel to give allyl (1R, 5S, 6S) -2- [(3S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazole- Yl) pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- .
    b) Preparation of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S) -5- (6-methylimidazo [ ] Thiazolium-5-yl) pyrrolidin-3-yl] thiocarbazol-2-
    Methyl triflate (0.022 ml) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S) -1-allyloxycarbonyl-5- (imidazo [ ] Thiazol-5-yl) pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- A), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. 0.055 mL of DMF (2 mL), N-methyl aniline, and 40 mg of tetrakis (triphenylphosphine) palladium (0) were added to the concentrate and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and water was added to the concentrate. The mixture was washed with dichloromethane. The aqueous layer was purified by column chromatography using Cosmosil 40C18-PREP and Amberlyst A-26 (Cl - form) to give the title compound (12.6 mg).
    [Example 37]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S) -5- [6- (2-hydroxyethyl) imidazo [ ] Thiazolium-5-yl] pyrrolidin-3-yl] thio-1-methylcarbapen- 2- 3-carboxylic acid (stereoisomer A)
    (58 mg) was added to a solution of allyl (1R, 5S, 6S) - (2-trifluoromethylsulfonyloxyethoxy) -2-trifluoromethanesulfonyloxyethane (58 mg) in 1 mL of dichloromethane under ice- Yl) pyrrolidin-3-yl] thio-6 - ((1R) - (3S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (stereoisomer A), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 1.5 ml of THF, 0.0095 ml of acetic acid, and 0.156 ml of 1 M tetrabutylammonium fluoride / THF solution were added to the solution. The mixture was stirred at room temperature for 2 hours. Ethyl alcohol (1.5 ml), triphenylphosphine 16 mg, morpholine 0.034 ml, and tetrakis (triphenylphosphine) palladium (0) 60 mg were added to the solution. The mixture was stirred at room temperature under an argon atmosphere for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the concentrate, and the mixture was washed with dichloromethane. The aqueous layer was purified by column chromatography using Cosmosil 40C18-PREP and Amberlyst A-26 (Cl - form) to obtain 22.5 mg of the title compound.
    NMR (D 2 O) δ ( HOD = 4.80ppm): 1.22 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.5 Hz), 1.90-2.00 (1H, m), 2.75-2.87 (1H, m), 3.40-3.55 (3H, m), 3.87-4.00 (3H, m), 4.20-4.28 (2H, m), 4.45-4.53 , 7.54 (1H, d, J = 4.3 Hz), 7.66 (1H, s), 8.33
    [Example 38]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [ 3-yl) ethenyl] pyrrolidin-3-yl] thio-1-methylcarbapen-
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl) thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen- , 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2 (Z) - (imidazo [5,1- b] thiazol- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    1N sodium hydroxide aqueous solution (0.69 ml) was added dropwise to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [ 1-b] thiazol-3-yl) pyrrolidine (mixture of geometric isomers), and the mixture was stirred at this temperature for 15 minutes. The mixture was adjusted to pH 7 with a 1N hydrochloric acid solution, dichloromethane was added to the solution, the mixture was washed sequentially with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain a mercaptan compound. (1R, 5S, 6S) -2- (diphenylphosphino) oxy-6 - ((1R) -1 -Hydroxyethyl) -1-methylcarbapen-2-3-carboxylate in 10 ml of dimethylformamide and the mixture was stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was purified by column chromatography using silica gel to give allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- E) - (imidazo [5,1-b] thiazol-3-yl) ethenyl] pyrrolidin-3- yl] thio- Carboxylate and 78 mg of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [ Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- Carboxylate (147 mg).
    b) Synthesis of (1R, 5S, 6S) -6- (1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [ ] Thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio- 1-methylcarbapen-
    Allyloxycarbonyl-5- [2 (Z) - (imidazo [5,1-b] thiazol-3-yl) Ethyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (80 mg) And 1 ml of DMF. 40 mg of N-methylaniline (0.060 ml) and tetrakis (triphenylphosphine) palladium (0) were added to the solution, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrate and the resulting precipitate was collected by filtration and then purified by column chromatography using Cosmosil 40C18-PREP and Amberlyst A-26 (Cl - form) to give the title compound (11.9 mg).
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.3 Hz), 1.86-2.00 (1H, m), 2.82-2.94 (1H, m), 3.30-3.48 (3H, m), 3.62-3.70 (1H, m), 4.00-4.10 (1H, m), 4.18-4.30 (2H, m). 6.22-6.30 (1 H, m). S), 7.12 (1H, s), 8.17 (1H, s), 6.74 (1H, d, J =
    [Example 39]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- [ Tri [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin-3- yl] thiocarbazol-
    Methyl triflate (0.0155 ml) was added dropwise to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) - [2 (Z) - (imidazo [5,1- b] thiazol- -1-methylcarbapen-2-yl) -3-carboxylate, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the concentrate was added dichloromethane (1 ml), DMF (1 ml), N-methyl aniline (0.050 ml) and tetrakis (triphenylphosphine) palladium Lt; / RTI &gt; The reaction mixture was concentrated under reduced pressure, and the mixture was washed with dichloromethane. The aqueous layer was purified by column chromatography using Cosmosil 40C18-PREP and Amberlyst A-26 (Cl - form) to obtain 6.0 mg of the title compound.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.5 Hz), 1.94-2.03 (1H, m), 2.87-3.03 (1H, m), 3.03-3.42 (1H, m), 3.45-3.53 (1H, m), 3.67-3.76 S), 7.68 (1H, s), 9.29 (1H, s), 6.84 (1H,
    [Example 40]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- [ Tri [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin-3- yl] thiocarbazol-
    Methyl triflate (0.0225 ml) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) - [2 (E) - (imidazo [5,1- b] thiazol- 3-carboxylate, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To this concentrate, dichloromethane (1 ml), DMF (1 ml), N-methyl aniline (0.071 ml) and tetrakis (triphenylphosphine) palladium (0) were added to the concentrate. Lt; / RTI &gt; The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was washed with dichloromethane. The aqueous layer was purified by column chromatography using Cosmosil 40C18-PREP and Amberlyst A-26 (Cl - form) to give the title compound (5.7 mg).
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.5 Hz), 1.96-2.06 (1H, m), 2.80-3.05 (2H, m), 3.35-3.52 (2H, m), 3.68-3.80 (2H, m), 4.10 (3H, s), 4.10-4.18 (2H, m), 9.45 (1H, s), 6.65 (1H,
    [Example 41]
    (5S, 5S) -5- [6- (2-cyclopropylmethyl) -5-methylimidazo [5,1- b] thiazolium- ] Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl)
    a) Synthesis of allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2-cyclopropylmethyl) Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- Carboxylate
    56 mg of cyclopropylmethyl bromide (0.044 ml) and sodium iodide were added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1-allyloxy Yl) thio-6 - ((1R) -1-hydroxyethyl) thiophene- -1-methylcarbapen-2-yl) -3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 27 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - (3S, 5S) -1-allyloxycarbonyl-5- [6- (2-cyclomethyl) -5-methylimidazo [5,1- b] thiazolium- Pyridin-3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-2-m -3-carboxylate.
    NMR (CDCl 3) δ: 0.50-0.56 (2H, m), 0.71-0.76 (2H, m), 1.18 (3H, d, J = 6.0 Hz), 1.27 (3H, d, J = 6.1 Hz), 1.68 (2H, m), 3.40 (s, 3H), 3.50-3.68 (1H, m), 3.89 M), 4.59-4.78 (4H, m), 5.15-5.40 (4H, m), 5.80-5.95 (2H, m), 7.59 (1H, br. s), 8.19,8.34 (total 1H, each s)
    MS (ES): 641 (M &lt; + & gt ; ).
    b) (lR, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2- cyclopropylmethyl) -5- methylimidazo [5,1- b] thiazolium- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (intramolecular salt)
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) thiophene- -1-methylcarbapen-2-yl) -3-carboxylate. 4.3 mg of triphenylphosphine (7.8 mg), morpholine (0.016 ml) and tetrakis (triphenylphosphine) palladium (0) were successively added to the solution, and the mixture was stirred at room temperature for 1 hour Lt; / RTI &gt; THF (10 ml) was added to the solution and the resulting precipitate was washed twice with 3 ml of additional THF, dried in vacuo and purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to give the title 2.0 mg of the compound was obtained.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 0.46-0.48 (2H, m), 0.70-0.7 6 (2H, m), 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d (3H, s), 3.05-3.20 (3H, m), 3.26-3.44 (3H, m), 2.54-2.66 (2H, m), 7.59 (1H, s), 3.54-3.63 (1H, m), 4.80-4.89 (1H, m), 4.11 (2H, d, J = 7.4Hz). 7.75 (1 H, s)
    [Example 42]
    (5S, 6S) -2 - [(3S, 5S) -5- [6- (2-fluoroethyl) -5- methylimidazo [5,1- b] thiazo Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    a) Synthesis of allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2-fluoroethyl) Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- Carboxylate
    Fluoroethyl trifluoromethanesulfonate (40.6 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- (5-methylimidazo [5,1-b] thiazol-2-yl) methylpyrrolidin-3- yl] -3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 3.5 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl trifluoromethanesulfonate (1R, 5S, 6S) -2- [ Yl] methylpyrrolidin-3-yl) -1- (4-fluorobenzyl) (36 mg) of thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate was obtained.
    NMR (CD 3 OD) δ: 1.23 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.17-1.90 (1H, m), 2.60-2.73 (1H, m), M), 4.06-4.38 (4H, m), 4.62-4.80 (4H, m), 3.82-3.41 ), 4.81-4.91 (4H, m), 5.20-5.42 (4H, m), 5.89-6.03 (2H, m), 7.68
    MS (ES): 633 (M &lt; + & gt ; ).
    b) Trifluoromethanesulfonic acid (1R, 5S, 6S) -2 - [(3S, 5S) -5- [6- (2- fluoroethyl) Yl)] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    To a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [6- (2- fluoroethyl) Methylimidazo [5,1-b] thiazol-2-yl] methylpyrrolidin-3- yl] thio-6 - ((1R) -1- hydroxyethyl) -2-methyl-3-carboxylate (36.4 mg). (5.5 mg), morpholine (0.011 ml) and tetrakis (triphenylphosphine) palladium (0) (3.0 mg) were successively added to the above solution, and the mixture was stirred at room temperature for 1 hour Lt; / RTI &gt; THF (10 ml) was added to the solution, and the resulting precipitate was further washed twice with 3 ml of THF and dried in vacuo to obtain a yellow powder. The powder was then subjected to column chromatography using Cosmosil 40C18-PREP (water-methanol) To obtain 3.1 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.81-1.92 (1H, m), 2.79-2.89 (3H, m), 2.82 (3H, s), 3.33-3.49 (4H, m), 3.69-3.85 (2H, m), 4.05-4.28 (1 H, s), 7.89 (1 H, s)
    [Example 43]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [6- (2-hydroxyethyl) -5 Methylimidazo [5,1-b] thiazolium-2-yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-
    2- (t-butyldimethylsilyloxy) ethyl trifluoromethanesulfonate (20.4 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [((3S , 5S) -1-allyloxycarbonyl-5- (5-methylimidazo [5,1- b] thiazol-2-yl) methylpyrrolidin- ) -1-methylcarbapen-2-yl] -3-carboxylate in 10 ml of dichloromethane, and the mixture was stirred for 2 hours at room temperature under an argon atmosphere. The filtrate was evaporated under reduced pressure to give allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [6- (2-t-butyldimethylsilyloxy Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) - ethyll-5-methylimidazo [5,1- b] thiazolium- Carboxylate was obtained. 0.056 ml of acetic acid (0.0033 ml) and 1M tetra-n-butylammonium fluoride / THF solution was added to a solution of the above compound in 0.5 ml of anhydrous THF (0.5 ml) was added to the solution. Triphenylphosphine (5.8 mg), morpholine (0.012 ml) and tetrakis (triphenylphosphine) were added to the solution and the mixture was stirred at room temperature for 1 hour. 3.2 mg of triphenylphosphine palladium (0) was added sequentially to the solution, and the mixture was stirred at room temperature under argon atmosphere for 1 hour. THF (10 ml) was added to the solution and the resulting precipitate was added Washed twice with 3 ml of THF and dried in vacuo to obtain yellow powder. The powder was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) to give the title compound (4.62 mg) as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.18-1.91 (1H, m), 2.79-2.90 (1H, m), 2.82 (3H, s), 3.31-3.49 (5H, m), 3.68-3.76 ), 4.21-4.28 (1H, m), 4.41 (2H, t, J = 4.5 Hz), 7.57 (1H, s), 7.89
    MS (ES): 507 (M &lt; + & gt ; ).
    [Example 44]
    (5S, 5S) -5- [6-N, N-dimethylcarbamoylmethyl-5-methylimidazo [5,1- b] thiazolium- (Methyl) pyrrolidin-3-yl] thio-6 - ((1R) -1-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -l-allyloxycarbonyl- 5- [6-N, N- dimethylcarbamoylmethyl-5-methylimidazo [ Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- - carboxylate
    N, N-dimethyl chloroacetamide (0.03 ml) and 41.5 mg of sodium iodide were added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1 Yl) thio-6 - ((1R) -1-heptyl-5-methylimidazo [5,1-b] thiazol- Methyl-carbapen-2-yl) -3-carboxylate in 10 ml of dichloromethane, and the mixture was stirred at room temperature under an argon atmosphere for 27 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) [5,1-b] thiazolium-2-yl] methylpyrrolidin-3-yl] -methanone [ -6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate.
    NMR (CDCl 3 ) : 1.16 (3H, d, J = 7.4 Hz), 1.23 (3H, d, J = 6.1 Hz), 1.63-1.76 (1H, m), 2.46-2.59 (3H, s), 2.90 (3H, s), 3.15 (3H, s), 3.12-3.41 (4H, m), 3.58-3.68 (1H, m), 3.91-4.02 (4H, m), 5.70 (1H, br.s), 5.80-5.95 (2H, m), 4.53-4.65 (3H, m), 4.61-4.78 , 7.72 (1H, br.s), 8.78 (1H, s)
    MS (TS): 672 (M &lt; + & gt ; ).
    b) (lR, 5S, 6S) -2 - [(3S, 5S) -5- [6-N, N-Dimethylcarbamoylmethyl-5-methylimidazo [5,1- b] thiazolium -2-yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    To a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [ Methyl] imidazo [5,1-b] thiazolium-2-yl] methylpyrrolidin- Methylcarbapen-2-yl) -3-carboxylate. 3.1 mg of triphenylphosphine (5.8 mg), morpholine (0.012 ml) and tetrakis (triphenylphosphine) palladium (0) were sequentially added to the solution, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere . THF (10 ml) was added to the mixture and the resulting precipitate was washed twice with 3 ml of additional THF and dried in vacuo to give a yellow powder which was purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) To give the title compound (10.4 mg) as a white powder.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.42-1.15 (1H, m), 2.51-2.66 (1H, m), 2.71 (3H, s), 3.00 (3H, m), 3.03-3.44 (6H, m), 3.15 (3H, s), 3.50-3.60 m), 4.18-4.28 (2H, m), 5.37 (2H, s), 7.43 (1H, s), 7.79
    [Example 45]
    (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [6-methoxymethyl-5-methylimidazo [ yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate (intramolecular salt)
    a) Preparation of allyl iodide (1S, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- 5- [6- methoxymethyl) ] Thiazolium-2-yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    Iodomethyl methyl ether (0.01 ml) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl) -5 - (5-methylimidazo [5,1-b] thiazol-2-yl) methylpyrrolidin-3- yl] Carboxylate (34.0 mg), and the mixture was stirred at room temperature under an argon atmosphere for 10 minutes. The solvent was removed under reduced pressure. The residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) Yl] methylpyrrolidin-3-yl] thio-6 - (((2-methoxyphenyl) thiazolyl) 1R) -1-hydroxyethyl) -1-methylcarbapen-2-m-3-carboxylate (42.3 mg).
    NMR (CDCl 3) δ: 1.18-1.32 (6H, m), 1.68-1.80 (1H, m), 2.58-2.70 (1H, m), 3.03 (3H, s), 3.12-3.28 (2H, m), (3H, s), 3.91-4.02 (1H, m), 4.08-4.27 (4H, m), 3.90-4.36 (3H, m), 4.52-4.72 ), 5.71 (1H, br.s), 5.80-5.97 (2H, m), 7.88
    MS (TS): 631 (M &lt; + & gt ; ).
    b) (lR, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [6- methoxymethyl-5-methylimidazo [ Yl] methylpyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3-carboxylate (intramolecular salt)
    To a solution of the allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [6-methoxymethyl-5-methyl Yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- -M-3-carboxylate &lt; / RTI &gt; Triphenylphosphine (5.8 mg), morpholine (0.012 ml) and tetrakis (triphenylphosphine) palladium (0) (3.2 mg) were sequentially added, and the mixture was stirred at room temperature for 75 minutes under argon atmosphere. THF (10 mL) was added to the solution and the resulting precipitate was washed twice with additional 3 mL of THF and dried in vacuo to give a yellow powder which was purified by column chromatography using COSMOSIL 40C18-PREP (water-methanol) To obtain 2.2 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.3 Hz), 1.42-1.55 (1H, m), 2.54-2.66 (1H, m), 2.85 (3H, m), 3.03-3.43 (6H, m), 3.42 (3H, s), 3.54-3.61 (1H, m), 3.79-3.87 (2H, m), 5.64 (2H, s), 7.65 (1H, s), 7.80
    [Example 46]
    (5S, 6S) -2 - [(3S, 5S) -5- [6-ethoxycarbonylmethyl-5-methylimidazo [5,1- b] thiazolium- Pyrrolidin-3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1- methylcarbapen- 2- 3-carboxylate
    a) bromo allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- b] thiazolium-2-yl] methylpyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    (0.04 ml) was added to a solution of allyl (lR, 5S, 6S) -3 - [(3S, 5S) -1-allyloxycarbonyl-5- Methylimidazo [5,1-b] thiazol-2-yl) methylpyrrolidin-3- yl] thio-6 - ((1R) -1-hydroxyethyl) -3-carboxylate, and the mixture was stirred at room temperature under argon atmosphere for 1 hour. The solvent was removed under reduced pressure. The residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give allyl (1R, 5S, 6S) -2- [(3S, 5S) Yl] methylpyrrolidin-3-yl] thio-6- (2-methoxyphenyl) -5-methyl- (1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate.
    NMR (CDCl 3) δ: 1.18 (3H, d, J = 7.1 Hz), 1.27 (3H, d, J = 6.0 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.66-1.76 (1H, m ), 2.40-2.68 (2H, m), 2.52 (3H, s), 3.10-3.45 (4H, m), 3.52-3.68 (1H, m), 3.90-4.02 m), 4.53-4.67 (3H, m), 4.70-4.79 (1H, m), 5.16-5.45 (4H, m), 5.50 (1H, br.s), 5.81-5.96 (1H, s), 8.00 (1H, br.s)
    MS (TS): 673 (M &lt; + & gt ; ).
    b) Synthesis of (lS, 5S, 6S) -2 - [(3S, 5S) -5- [6-ethoxycarbonylmethyl-5-methylimidazo [5,1- b] thiazolium- ] Methylpyrrolidin-3-yl] thio-6 ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    To a solution of allyl bromide (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [ -Methylimidazo [5,1-b] thiazolium-2-yl] methylpyrrolidin-3- yl] thio-6 - ((1R) -1- hydroxyethyl) -2-methyl-3-carboxylate. 3.8 mg of triphenylphosphine (6.9 mg), morpholine (0.014 ml) and tetrakis (triphenylphosphine) palladium (0) were successively added to the solution, and the mixture was stirred at room temperature for 55 minutes under an argon atmosphere . THF (10 mL) was added and the resulting precipitate was washed twice with additional 3 mL of THF and dried in vacuo to yield a yellow powder which was then purified by column chromatography using Cosmosil 40C18-PREP (water-methanol) To obtain 1.6 mg of the title compound as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.29 (3H, t, J = 7.1 Hz), (1H, m), 2.50-2.67 (1H, m), 2.77 (3H, s), 3.01-3.47 (5H, m), 3.50-3.87 ), 4.30 (2H, q, J = 7.1Hz), 5.64 (2H, s), 7.52
    [Example 47]
    (1R, 5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [ yl] vinyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-carboxylic acid and (1R, 5S, 6S) -6- 1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2 (E) Pyrrolidin-3-yl] thio-1-methylcarbapen-2-3-carboxylic acid
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- Yl] thio-6- (1 (R) -hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (mixture of geometric isomers)
    1N sodium hydroxide aqueous solution (1.2 ml) was added to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [ 1-b] thiazol-2-yl) vinyl] pyrrolidine in 50 ml of tetrahydrofuran and the mixture was stirred at the same temperature for 15 minutes. The mixture was adjusted to pH 7 with 1N hydrochloric acid solution, dichloromethane was added to the above additive, and the mixture was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain a mercaptan compound. Diisopropylethylamine (0.29 ml) was added to a solution of the mercaptan compound and allyl (1R, 5S, 6S) -6- (1 (R) -hydroxyethyl) -2- Phosphono) oxy-1-methylcarbapen-2-3-carboxylate in 30 ml of tetrahydrofuran and the compound was stirred for 30 minutes. Ethyl acetate was added to the reaction mixture. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel to give allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [ yl] vinyl] pyrrolidin-3-yl] thio-6- (1 (R) -hydroxyethyl) -1-methylcarbapen- (Mixture of geometric isomers).
    b) Preparation of (1R, 5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2- (Z) Yl] vinyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-carboxylic acid and (1R, 5S, 6S) -6 - (6-methylimidazo [5,1-b] thiazol-2-yl) - (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [ Vinyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-M-3-
    Methyl triflate (0.017 ml) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [2- (imidazo [ 5,1-b] thiazol-2-yl) vinyl] pyrrolidin-3- yl] thio-6- (1 (R) 3-carboxylate (mixture of geometric isomers), and the mixture was stirred at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the concentrate was added the ethyl alcohol (1 ml), THF 1 ml, N-methylmorpholine 0.033 ml, triphenylphosphine 16 mg, and tetrakis (triphenylphosphine) palladium (0) The mixture was stirred at room temperature under an argon atmosphere for 30 minutes. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was washed with dichloromethane. The course carry 40C18-PREP and ember list A-26 water column (Cl - form) was purified by column chromatography using a chloride (1R, 5S, 6S) -6- (1 (R) - hydroxyethyl) -2 Yl] vinyl] pyrrolidin-3-yl] thio-1- (2-methylpiperazin-1- Carboxylic acid (12.0 mg) and (1R, 5S, 6S) -6- (1R) -hydroxyethyl) -2 - [(3S, 5S) -5- [ Yl] vinyl] pyrrolidin-3-yl] thio-1-methylcarbapen-2-yl) -3- Carboxylic acid 5.4 mg &lt; tb &gt;&lt; / TABLE &gt;
    (Z) type
    NMR (D 2 O) : 1.19 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.55-1.65 (1H, m), 2.65-2.80 M), 3.30-3.45 (3H, m), 3.80-3.95 (1H, m), 4.07 (3H, s), 4.15-4.30 ), 6.08 (1H, dd, J = 11.6, 9.7 Hz), 6.62 (1H, d, J = 11.6 Hz), 7.60
    (E) type
    NMR (D 2 O) : 1.22 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.70-1.80 (1H, m), 2.70-2.80 (3H, m), 3.29 (1H, dd, J), 3.20-3.30 (1H, m), 3.30-3.55 (1H, d, J = 15.7 Hz, 7.7 Hz), 6.92
    [Example 48]
    (5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [ ] Thiazol-2-yl) vinyl] pyrrolidin-3-yl] thiocarbazol-2- carboxylic acid and (5S, 6S) -6- (1 (R) Yl) vinyl] pyrrolidin-3-yl] propan-2-ol, Thiocarbazol-2-yl) -3-carboxylic acid
    a) Preparation of allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- 3-yl] thio-6- (1 (R) -hydroxyethyl) carbapen- 2- 3-carboxylate (mixture of geometric isomers)
    1N sodium hydroxide aqueous solution (0.67 ml) was added dropwise to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [ 1-b] thiazol-2-yl) vinyl] pyrrolidine (mixture of geometric isomers). The mixture was stirred at the same temperature for 15 minutes. The mixture was adjusted to pH 7 with 1N hydrochloric acid solution, dichloromethane was added, and the mixture was successively washed with water and saturated brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain a mercaptan compound. Diisopropylethylamine (0.16 ml) was added to a solution of the mercaptan compound and allyl (5S, 6S) -6- (1 (R) -hydroxyethyl) -2- (diphenylphosphino ) Oxycarbapen-2-yl) -3-carboxylate, and the compound was stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, followed by drying over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel to obtain (5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [ Yl) vinyl] pyrrolidin-3-yl] thio-6- (1 (R) -hydroxyethyl) carbapen- 2- 3-carboxylate (mixture of geometric isomers) 0.18 g.
    b) Preparation of (5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [2- (Z) yl) vinyl] pyrrolidin-3-yl] thiocarben-2-yl) -3-carboxylic acid and (5S, 6S) -6- (1 (R) Yl) vinyl] pyrrolidine-3-carboxamide was prepared in the same manner as in Example 1, Yl] thiocarbazol-2-yl} -3-carboxylic acid
    (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [ yl] vinyl] pyrrolidin-3-yl] thio-6- (1 (R) -hydroxyethyl) carbapen- ) 91 mg, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the concentrate, ethanol (1 ml), 1 ml of THF, 0.033 ml of N-methylmorpholine, 16 mg of triphenylphosphine and 40 mg of tetrakis (triphenylphosphine) palladium (0) Was stirred under argon atmosphere at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with dichloromethane. 40C18-PREP carry the water layer course and ember list A-26 (Cl - form) chloride (5S, 6S) was purified by column chromatography using -6- (1 (R) - hydroxyethyl) -2 - [( Yl) vinyl] pyrrolidin-3-yl] thiocarbazol-2-yl) Carboxylic acid (6.7 mg) and (5S, 6S) -6- (1 (R) -hydroxyethyl) -2 - [(3S, 5S) -5- [ Yl] vinyl] pyrrolidin-3-yl] thiocarbazol-2-yl} -3-carboxylic acid was obtained in the form of a white solid.
    (Z) type
    NMR (D 2 O) : 1.27 (3H, d, J = 6.3 Hz), 1.55-1.75 (1H, m), 2.65-2.80 (1H, m), 3.10-3.30 (1H, m), 3.45-3.55 (1H, m), 3.60-3.80 (1H, m), 3.85-3.95 D, J = 11.6 Hz, 9.7 Hz), 6.63 (1H, d, J = 11.6 Hz), 7.60 (1H, s), 7.92
    (E) type
    NMR (D 2 O) δ: 1.27 (3H, d, J = 6.4 Hz), 1.80-1.95 (1H, m), 2.65-2.85 (1H, m), 3.15-3.25 (2H, m), 3.25-3.35 (1H, m), 3.35-3.40 (1H, m), 3.60-3.80 (2H, m), 3.95-4.05 (1H, d, J = 15.6 Hz, 7.5 Hz), 6.94 (1H, d, J = 15.6 Hz), 7.57
    [Example 49]
    Yl) thio-6 - (((1R, 5S, 6S) -2 - [(3S, 5S) -5- [imidazo [5,1- b] thiazol- 1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylic acid
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    1N sodium hydroxide aqueous solution (0.76 ml) was added dropwise to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [ ] Thiazol-3-yl) pyrrolidine (mixture of geometric isomers), and the mixture was stirred at this temperature for 15 minutes. The mixture was neutralized with 1N hydrochloric acid solution, dichloromethane was added, and the mixture was washed sequentially with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain a mercaptan compound. (1R, 5S, 6S) -2- (Diphenylphosphono) oxy-6 - ((1R) -1, 2-diisopropylethylamine (0.14 ml) was added dropwise to a solution of the mercaptan compound and allyl -Hydroxyethyl) -1-methylcarbapen-2-yl carboxylate, and the compound was stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, followed by drying over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel (methanol: ethyl acetate = 12: 88) to give allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- (Imidazo [5,1-b] thiazol-3-yl) pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -3-carboxylate (0.24 g).
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [imidazo [5,1- b] thiazol-3-yl] pyrrolidin- ((1 R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylic acid
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Carboxylate (65 mg) was dissolved in 0.75 ml of ethanol and 0.75 ml of THF. To a solution of triphenylphosphine Phosphine (12 mg) and 0.025 ml of morpholine were added to the solution and 40 mg of tetrakis (triphenylphosphine) palladium (0) was further added and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Was powdered using ethyl acetate, and then this powder was purified by column chromatography using Cosmosil 40C18-PREP (30% methanol aqueous solution) to obtain 10 mg of the title compound.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 2.00-2.01 (1H, m), 2.85-3.00 (1H, m), 3.05-3.10 (1H, m), 3.40-3.55 (2H, m), 3.65-3.85 (2H, m), 4.15-4.30 , 7.13 (1H, s), 7.15 (1H, s), 8.28 (1H, s)
    [Example 50]
    Methyl-2 - [(3S, 5S) -5 - [(6-methylimidazo [5,1 -b] thiazolidium) -3-yl] pyrrolidin-3-yl] thiocarbazol-2-
    Methyl triflate (19 μl) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- -3-carboxylate, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 0.75 ml of ethanol and 0.75 ml of THF. Triphenylphosphine (12 mg) and 0.025 ml of morpholine were added to the solution, and 40 mg of tetrakis (triphenylphosphine) palladium (0) was further added to the solution and the mixture was stirred at room temperature And stirred for 30 minutes. The reaction mixture was triturated with ethyl acetate and then purified by column chromatography using Cosmosil 40C18-PREP (30% aqueous methanol solution) and Amberlyst A-26 (Cl - form) (water) to give the title compound 8.9 mg.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3Hz), 1.30 (3H, d, J = 6.3 Hz), 1.90-2.00 (1H, m), 2.80-2.90 (1H, m), 2.98 (1H, dd, J = 5.3,11.9 Hz), 3.40-3.50 (3H, m), 3.85-3.95 (1H, m), 4.63 (1H, t, J = 7.7 Hz), 7.48 (1H, s), 7.62
    [Example 51]
    (5S, 6S) -2 - [(3S, 5S) -5 - [(6-carbamoylmethylimidazo [5,1- b] thiazolidin- 3- yl] pyrrolidine Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    Iodoacetamide (258 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- -Carboxylate, and the mixture was shaken at room temperature under argon atmosphere and stirred for 20 hours. The mixture was evaporated under reduced pressure. The obtained residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1), and then dissolved in 0.75 ml of ethanol and 0.75 ml of THF. Triphenylphosphine (12 mg) and 0.025 ml of morpholine were added to the solution, followed by addition of 40 mg of tetrakis (triphenylphosphine) palladium (0) and the mixture was stirred at room temperature for 30 minutes Lt; / RTI &gt; The reaction mixture was pulverized using ethyl acetate and the powder was purified by column chromatography using Cosmosil 40C18-PREP (15% aqueous methanol solution) to give the title compound (17.9 mg).
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.90-2.00 (1H, m), 2.80-2.90 (1H, m), 2.97 (1H, dd, J = 5.2 Hz, 11.8 Hz), 3.35-3.50 (3H, m), 3.85-3.90 (1H, s, J = 7.7 Hz), 5.30 (2H, s), 7.51
    [Example 52]
    (3S, 5S) -5- [2- (imidazo [5,1-b] thiazol-2-yl) ethenyl] pyrrolidin- Thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    Synthesis of (3S, 5S) -3-acetylthio-1-aryloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- The procedure of Example 49-a) was repeated except that 0.42 g of dian (mixture of geometric isomers) was used. Thus, the synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Ethyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- .
    b) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5 - [[2- imidazo [5,1- b] thiazol- 2- yl] ethenyl] pyrrolidin- Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    Allyloxycarbonyl-5 - [[2- (imidazo [5,1-b] thiazol-2-yl) ethenyl] ] Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (mixture of geometric isomers) The procedure of Example 49-b) was repeated. Thus, 86 mg of the title compound (mixture of geometric isomers) was prepared.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.90-2.00 (1H, m), 2.80-2.90 (1H, m), 3.35-3.50 (3H, m), 3.65-3.80 (1H, m), 4.00-4.10 S, each), 7.76 (1H, s), 8.14, 8.18 (1H, s, each)
    [Example 53]
    (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl) thio] -6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- ) And iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5 - [[2- (imidazo [5,1- b] thia Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1 R) -1- hydroxyethyl) -1- methylcarbapen- Lt; / RTI &gt; mixture of isomers) was used as the starting material. Thus, the title compound (E type 11.0 mg; Z type 9.2 mg) was prepared.
    (E type)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.55-2.70 (2H, m), 4.15-4.30 (2H, m), 5.25 (2H, m), 3.03 (1H, dd, J = 3.6,11.9 Hz), 3.25-3.45 (1H, s), 6.30 (1H, dd, J = 7.1,15.9 Hz), 6.80 (1H, d, J = 15.9 Hz), 7.62
    (Z type)
    NMR (D 2 O) (HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.90-2.00 (1H, m). (2H, m), 3.85-3.95 (2H, m), 2.80-2.90 (1H, m), 3.05 (1H, dd, J = 3.6,11.9Hz) (1H, m), 4.20-4.35 (3H, m), 5.28 (2H, s), 6.11 (1H, t, J = 11.4 Hz), 6.58 s), 7.95 (1 H, s)
    [Example 54]
    (1R, 5S, 6S) -2 - [(3S, 5S) -5 - [[2 (Z) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl) thienyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5 - [[2 (Z) - (imidazo [ thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- The procedure of Example 51 was repeated except that the rate was 57 mg. Thus, 2.3 mg of the title compound was prepared.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (2H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.55-2.70 (1H, m), 3.03 (1H, dd, J = 3.6,12.1 Hz), 3.26 (1H, dd, J = 6.3,12.1 Hz), 3.30-3.45 ), 4.15-4.30 (3H, m), 5.28 (2H, s), 6.31 (1H, t, J = 11.5 Hz), 6.50 (1H, d, J = 11.5 Hz), 7.43 (1H, s)
    [Example 55]
    Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    Iodoacetamide (703 mg) was added to a solution of allyl (lR, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl- - (imidazo [5,1, -b] thiazol-3-yl) ethenyl] pyrrolidin-3- yl] thio-6 - ((1R) -1-hydroxyethyl) 3-carboxylate (218 mg), and the mixture was shaded under an argon atmosphere and stirred at room temperature for 20 hours. The mixture was evaporated under reduced pressure. The obtained residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) and Amberlyst A-26 (Cl - form). The procedure of Example 49-b) was repeated except that the purified product prepared above was used. Thus, 40.5 mg of the title compound was prepared.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.55-2.70 (1H, m), 3.22 (1H, dd, J = 3.6,12.1 Hz), 3.35-3.50 (3H, m), 3.90-4.00 (1H, d, J = 7.5, 16.2 Hz), 6.80
    [Example 56]
    Iodide (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    71 mg of sodium iodide (70 mg) and brominated propionamide were added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- Yl] thio-6 - ((1R) -1 (3H) -thienyl] pyrrolidin- -Hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate in 50 ml of tetrahydrofuran was added, and the solution was shaken at room temperature and stirred for 36 hours. The solvent was removed under reduced pressure, and the residue was purified using Sephadex LH-20 (dichloromethane: methanol = 1: 1). The procedure of Example 49-a) was repeated except that the purified product prepared above was used. Thus, 2 mg of the title compound was prepared.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.55-2.70 (1H, m), 3.00 (2H, t, J = 6.3 Hz), 3.07 (1H, dd, J = 6.4, 11.6 Hz), 3.25-2.45 (1H, d, J = 7.4, 15.9 Hz), 7.51 (1H, d, J = , &lt; / RTI &gt; s), 7.72 (1H, s)
    [Example 57]
    Iodide (1R.5S.6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl) ethyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl) -5- [2- (imidazo [5,1- b] thiazol- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1-b] thiazol-5-yl) pyrrolidine (mixture of geometric isomers ) Was used as the starting material in Example 49-a). Thus, the reaction of (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (mixture of geometric isomers) .
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl) thienyl] pyrrolidin-5-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- Pyrrolidin-5-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate The procedure of Example 51 was repeated. Thus, 12.3 mg of the title compound was prepared.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.55-2.70 (3H, m), 5.28 (2H, s), 5.28 (2H, s), 3.20-3.30 ), 6.83 (2H, m), 7.68 (1H, d, J = 4.4 Hz)
    [Example 58]
    (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1-b] thiazol-7-yl) pyrrolidine (mixture of geometric isomers ) Was used as the starting material in Example 49-a). Thus, the reaction of allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl- Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (mixture of geometric isomers) .
    b) Preparation of iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (60 (carbamoylmethyl) imidazo [5,1- b] thiazolium- Yl) thienyl] pyrrolidin-5-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- ] Pyrrolidin-7-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylic acid The procedure of Example 51 was repeated. Thus 28.6 mg of the title compound was prepared.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.55-2.70 (2H, s), 6.29 (1H, m), 3.00-3.10 (1H, m), 3.35-3.45 (3H, m), 3.75-4.00 (1H, d, J = 4.4 Hz), 6.60 (1H, d, J =
    [Example 59]
    (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (carbamoylmethyl) -3-methylimidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- E type) and iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) -3-methylimidazo [ yl] ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Carboxylic acid (Z type)
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (3-methylimidazo [5,1- b] thiazol-2-yl) pyrrolidine Mixture of diastereoisomeric &lt; / RTI &gt; diastereoisomeric &lt; RTI ID = 0.0 &gt; diastereoisomers). &Lt; / RTI &gt; Thus, allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- Mixture).
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) ] Thiazolyl-2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- (E) and iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) -3-methylimidazo [ Yl] thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- 3-carboxylic acid (Z-form)
    Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (3-methylimidazo [5,1- b] thiazol- ] Pyrrolidin-3-yl) ethenyl] thio-6- ((1R) -1-hydroxyethyl) -1-methylcarbapen- g was used as the starting material. Thus, the title compound (E type 10.5 mg, Z type 6.2 mg) was prepared.
    (E type)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.51 (3H (2H, m), 4.20-4.30 (2H, m), 2.55-2.70 (1H, m), 3.03 (1H, dd, J = 3.6, 12.1 Hz), 3.25-3.45 d, J = 7.4, 15.1 Hz), 6.82 (1H, d, J = 15.1 Hz), 7.60 (1H, s)
    (Z) type
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 7.3 Hz), 1.25-1.30 (3H, m), 1.45-1.55 (1H, m), 2.45 (3H, s) , 2.95-3.05 (2H, m), 3.20-3.45 (2H, m), 3.65-3.90 (3H, m), 4.10-4.25 J = 11.1 Hz), 6.55 (1H, d, J = 11.1 Hz), 7.65 (1H, s)
    [Example 60]
    (5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (carbamoylmethyl) -2-methylimidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- E-type) and iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) -2-methylimidazo [ yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Carboxylic acid (Z type)
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [2- Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (2-methylimidazo [5,1- b] thiazol-3-yl) pyrrolidine Mixture of diastereoisomeric &lt; / RTI &gt; diastereoisomeric &lt; RTI ID = 0.0 &gt; diastereoisomers). &Lt; / RTI &gt; Thus, allyl (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-5- [2- Yl) thienyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (mixture of geometric isomers ).
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) Thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- (E) and iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (carbamoylmethyl) -2-methylimidazo [ Yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-M.piperazin- 3-carboxylic acid (Z-form)
    Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- Yl) thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate (mixture of geometric isomers) The procedure of Example 51 was repeated except that 0.15 g was used. Thus, the title compound (E type 10.2 mg, Z type 7.4 mg) was prepared.
    (E type)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.24 (3H, d, J = 7.3 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.50-1.60 (1H, m), 2.48 (3H (2H, m), 4.15-4.30 (2H, m), 2.55-2.70 (1H, m), 3.03 (1H, dd, J = 3.3,11.9 Hz), 3.25-3.45 d, J = 7.4, 16.4 Hz), 6.66 (1H, d, J = 16.4 Hz), 7.63 (1H, s)
    (Z type)
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.18 (3H, d, J = 7.3 Hz), 1.25 (3H, d, J = 6.4 Hz), 1.45-1.55 (1H, m), 2.40 (3H , 2H), 2.40-2.50 (1H, m), 2.92 (1H, dd, J = 3.5,11.8 Hz), 3.13 (1H, dd, J = 6.2,11.9 Hz), 3.40-3.50 (2H, m), 6.22 (2H, s), 6.29 (1H, d, J = 10.7 Hz), 6.38 (1H, t, J = 10.7 Hz), 7.60 (1H, s)
    [Example 61]
    Methyl-2 - [(3S, 5S) -5- (5-methylthioimidazo [5,1-b ] Thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allylcarbonyl-5- (5-methylthioimidazo [5,1- b] thiazol- Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (3S, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (5-methylimidazo [5,1- b] thiazol- 2- yl) methylpyrrolidine The procedure of Example 23-a) was repeated except that 671.9 mg was used. Thus, 677.3 mg of the mercaptan compound was prepared as yellow oil. Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- -3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (344.2 mg) was added to the above mercaptan and allyl (1R , 5R, 6S) -2- (diphenylphosphino) oxy-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- Lt; / RTI &gt;
    NMR (CDCl 3) δ: 1.19 (3H, d, J = 7.0 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.71-1.82 (1H, m), 2.40-2.54 (1H, m), 2.46 (4H, m), 5.18-5.41 (4H, m), 5.84-5.96 (2H, m) , 7.01 (1 H, s), 7.17 (1 H, s)
    b) (1R, 5S, 6S) -6- ((1R) -1-Hydroxyethyl) -1-methyl-2 - [(3S, 5S) -5- (5-methylthioimidazo [ -b] thiazol-2-yl) methylpyrrolidin-3-yl] thiocarbazol-2-
    Allyl (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 23-b) was repeated. Thus, 5.7 mg of the title compound was prepared as a white powder.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.5 Hz), 1.74-1.89 (1H, m), 2.45 (3H (2H, m), 7.12 (2H, m), 2.75-2.86 (1H, m), 3.27-3.98 (5H, m), 3.62-3.74 (1 H, s), 7.73 (1 H, s)
    [Example 62]
    Methyl-2 - [(3S, 5S) -5- (6-methyl-5-methylthioimidazo [5R, 5S, 6S) Yl] methylpyrrolidin-3-yl] thiocarbazol-2-yl) -3-carboxylate (intramolecular salt)
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6-methyl-5-methylthioimidazo [5,1- b] thiazo Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-methylthioimidazo [5,1- b] thia 2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The procedure of Example 24-a) was repeated. Thus, as the yellow oil, allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6-methyl-5-methylthioimidazo [ ] Thiazolium-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) Mg.
    NMR (CDCl 3) δ: 1.21 (3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.82-1.97 (1H, m), 2.61 (3H, s), 2.70-2.81 (1H, m), 3.26-3.41 (5H, m), 3.86-4.22 (5H, m), 4.15 (3H, s), 4.52-4.75 (2H, m), 7.91 (1H, s), 8.18 (1H, s)
    MS (FAB &lt; + & gt ; ): 633 (M &
    b) Synthesis of (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) [5,1-b] thiazolium-2-yl) methylpyrrolidin-3-yl] thiocarbazol-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6-methyl-5-methylthioimidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate The procedure of Example 24-b) was repeated except that. Thus, 10.0 mg of the title compound was prepared as a white fluorescent substance.
    NMR (D 2 O) (HOD = 4.80 ppm): 1.20 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3Hz), 1.43-1.53 , 2.50-2.64 (1H, m), 3.00-3.46 6H, m), 3.50-3.61 (1H, m), 3.75-3.88 (1H, m), 4.10 (3H, s), 4.13-4.28 2H, m), 7.74 (1H, s), 7.99 (1H, s)
    [Example 63]
    a) Preparation of iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6-carbamoylmethyl-5-methylthioimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-methylthioimidazo [5,1- b] thia 2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The procedure of Example 26-a) was repeated. Thus, the synthesis of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6- carbamoylmethyl- ] Thiazolium-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) Mg &lt; / RTI &gt; as yellow oil.
    (CD 3 OD) : 1.22 (3H, d, J = 7.3 Hz), 1.28 (3H, d, J = 6.2Hz), 1.81-1.97 (1H, m), 2.95 M), 5.32 (2H, s), 2.32 (2H, s), 2.79 (2H, 5.89-6.06 (2H, m), 7.96 (1H, s), 8.24 (1H, s)
    b) Preparation of iodinated (1R, 5S, 6S) -2 - [(3S, 5S) -5- (6-carbamoylmethyl-5-methylthioimidazo [5,1- b] thiazolium- ) Methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    Allyloxycarbonyl-5- (6-carbamoylmethyl-5-methylthioimidazo [5,1-b] thia 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The procedure of Example 26-b) was repeated. Thus, 9.3 mg of the title compound was prepared as a white fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.20 (3H, d, J = 6.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.45-1.57 (1H, m), 2.51 (3H (1H, m), 4.17 (1H, m), 2.52-2.69 (1H, m), 3.02-3.10 (2H, s), 7.83 (1H, s), 8.07 (1H, s)
    [Example 64]
    (5S, 5S) -6- (3S, 5S) -5- (5-Chloroimidazo [5,1- b] thiazol-2-yl) methylpyrrolidin- 6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-2-M-3-
    a) Synthesis of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-chloroimidazo [5,1- b] thiazol- Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (5S, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (5-chloroimidazo [5,1- b] thiazol-2- yl) methylpyrrolidine 303.0 The procedure of Example 23-a) was repeated except that &lt; RTI ID = 0.0 &gt; mg &lt; / RTI &gt; Thus, 261.0 mg of the mercaptan compound was prepared as yellow oil. (5R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate (186.7 mg) was treated with 9.3 mg of the title compound And (1R, 5S, 6S) -2- (diphenylphosphino) oxy-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- Mg of the title compound as a colorless amorphous substance.
    NMR (CDCl 3) δ: 1.21-1.38 (6H, m), 1.77-1.87 (1H, m), 2.45-2.57 (1H, m), 3.03-3.40 (4H, m), 3.58-3.67 (1H, m ), 3.95-4.25 (5H, m), 4.10-4.84 (4H, m), 5.22-5.47 (4H, m), 5.88-6.02 )
    MS (FAB &lt; + & gt ; ): 607 (M + )
    b) Synthesis of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (5-Chloroimidazo [5,1- b] thiazol-2-yl) methylpyrrolidin- Thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    (5R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- -b) was repeated. Thus, 2.2 mg of the title compound was prepared as a white powder.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 6.8 Hz), 1.28 (3H, d, J = 6.1 Hz), 1.63-1.76 (1H, m), 2.69-2.80 (1H, s), 7.55 (1H, m), 3.19-3.40 (5H, m), 3.42-3.60 (2H, m), 3.80-4.02 (1H, s)
    [Example 65]
    (5R, 5S, 6S) -2 - [(3S, 5S) -5- (5-Chloro-6-methylimidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl iodide (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-chloro-6-methylimidazo [ Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-chloroimidazo [5,1- b] thiazole -2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate The procedure of Example 24-a) was repeated. Thus, the iodinated allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- (6-methyl-5-chloro- imidazo [ -2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- .
    NMR (CDCl 3) δ: 1.20-1.30 (6H, m), 1.55-1.65 (1H, m), 2.52-2.62 (1H, m), 3.20-3.50 (5H, m), 3.60-3.71 (1H, m ), 4.06-4.25 (4H, m), 4.12 (3H, s), 4.50-4.77 (4H, m), 5.18-5.40 (4H, m), 5.82-5.98 ), 8.30 (1 H, s)
    MS (FAB &lt; + & gt ; ): 623 (M &lt;
    b) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- (5-chloro-6-methylimidazo [5,1- b] thiazolium- Yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    (5R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (5-chloro-6-methylimidazo [5,1- b] thiazolium- -2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The procedure of Example 24-b) was repeated except that. Thus, 4.4 mg of the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.22 (3H, d, J = 7.4 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.81-1.91 (1H, m), 2.80-2.90 (1H, m), 3.30-3.50 (6H, m), 3.69-3.75 (1H, m), 4.01 (3H, s), 4.02-4.15 (1 H, s), 7.94 (1 H, s)
    [Example 66]
    (5S, 6S) -2 - [(3S, 5S) -5- (6-Carbamoylmethyl-5-chloroimidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen 2 -
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -l-allyloxycarbonyl-5- (6- carbamoylmethyl- Yl) thio] -6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    2-iodoacetamide (198.0 mg) and 221.9 mg of aluminum perchlorate were added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- Yl] thio-6 - ((1R) -1-hydroxyethyl) -5- (5-chloroimidazo [5,1-b] thiazol- ) -1-methylcarbapen-2-yl) -3-carboxylate in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature under argon atmosphere for 48 hours. The mixture was then filtered to remove insoluble material and the filtrate was evaporated. Sepharose and the residue obtained dex LH-20 (dichloromethane: methanol = 1: 1) a using purified by column chromatography and then ember list A-26 (Cl - form) ion are used (water) - exchanges as yellow oil (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6-carbamoylmethyl-5-chloro- imidazo [ -3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- .
    NMR (CD 3 OD) δ: 1.30-1.45 (6H, m), 1.86-1.95 (1H, m), 2.58-2.65 (1H, m), 3.35-3.45 (4H, m), 3.60-3.70 (5H, m), 4.40-4.65 (6H, m), 5.20-5.35 (5H, m), 5.90-6.05
    MS (ES): 665 (M &lt; + & gt ; ).
    b) Preparation of (lR, 5S, 6S) -2 - [(3S, 5S) -5- (6-carbamoylmethyl-5-chloroimidazo [5,1- b] thiazolium- Yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6-carbamoylmethyl-5-chloroimidazo [5,1- b] thiazo -3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate The procedure of Example 26-b) was repeated. Thus, 1.0 mg of the title compound was prepared as a white fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.27 (3H, d, J = 7.1 Hz), 1.35 (3H, d, J = 6.4 Hz), 1.70-1.85 (1H, m), 2.55-2.70 (1H, m), 3.20-3.50 (5H, m), 3.82-3.92 (3H, m), 4.20-4.40 (2H, m), 5.10 , s)
    [Example 67]
    (5S, 5S) -5- (6- (2-carbamoylethyl) -5-methylimidazo [5,1- b] thiazolium- Yl) methylpyrrolidin-3-yl] thio-6- (1R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- (6- (2-carbamoylethyl) -5-methylimidazo [ Yl] thiophen-2-yl) methyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- Carboxylate
    3-bromopropionamide (409.6 mg) and 403.8 mg of sodium iodide were added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- Yl] thio-6 - ((1R) -1-hydroxyethyl) -5-methyl- imidazo [5,1-b] thiazol- ) -1-methylcarbapen-2-yl) -3-carboxylate in 5 ml of dichloromethane, and the mixture was stirred at room temperature under argon atmosphere for 4 days. Then, it evaporated and the mixture under reduced pressure, and Sephadex LH-20 and the residue (dichloromethane: methanol = 1: 1) a using purified by column chromatography and then ember list A-26 (Cl - form) with an ion- (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6- (2- carbamoylethyl) -5-methylimidazole Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-ylmethyl] pyrrolidin- -3-carboxylate (47.5 mg).
    NMR (CD 3 OD) : 1.23 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.78-1.85 (1H, m), 2.52-2.70 M), 4.08-4.25 (5H, m), 4.52-4.70 (5H, m), 3.90-3.90 (3H, s), 2.91-3.00 ), 5.20-5.42 (4H, m), 5.87-6.02 (2H, m), 7.66
    b) Preparation of (lR, 5S, 6S) -2 - [(3S, 5S) -5- (6- (2- carbamoylethyl) -5- methylimidazo [5,1- b] thiazolium Yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- (6- (2-carbamoylethyl) -5-methylimidazo [ -b] thiazolium-2-yl) methylpyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- The procedure of Example 26-b) was repeated except that the rate was 47.5 mg. Thus, 7.9 mg of the title compound was prepared as a slightly yellow fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.40-1.50 (1H, m), 2.52-2.60 (1H, m), 2.80 (3H, s), 2.90 (2H, t, J = 6.4Hz), 3.00-3.05 ), 3.32-3.42 (2H, m), 3.48-3.57 (1H, m), 4.17-4.28 (2H, m), 4.54 (2H, t, J = 6.3Hz), 7.50 1H, s)
    [Example 68]
    (5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6-carbamoylmethyl-5-methylimidazo [5,1- b] thiazolium Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Methylimidazo [5,1-b] thiazol-3-yl] pyrrolidin-3-yl] thio- 1 -methylcarbapen- 2- 3-carboxylate and allyl (1R5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-6 - ((1R) -1-hydroxyethyl) -5- [ , 1-b] thiazol-3-yl) ethenyl] pyrrolidin-3- yl] thio- 1-methylcarbapen-
    1N sodium hydroxide aqueous solution (1.83 ml) was added dropwise to a solution of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- 5,1-b] thiazol-3-yl) ethenyl] pyrrolidine in 50 ml of tetrahydrofuran and the mixture was stirred at the same temperature for 40 minutes. The mixture was adjusted to pH 7 by the addition of 1N hydrochloric acid solution, and dichloromethane was added to the solution and extracted three times. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain a mercaptan compound. (1R, 5S, 6S) -2- (diphenylphosphono) oxy-6 - ((1R) -1, 2-diisopropylethylamine) (0.43 ml) was added dropwise to a solution of the above mercaptan compound and allyl -Hydroxyethyl) -1-methylcarbapen-2-3-carboxylate in 10 ml of dimethylformamide and the compound was stirred for 3.6 hours. Dichloromethane was added to the reaction mixture and then extracted three times. The extract was washed with saturated brine and then dried over magnesium sulfate. The solvent was removed by evaporation. The resulting residue was purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) to give allyl (1R, 5S, 6S) -2- [(3S, 5S) -1- allyloxycarbonyl- (1R) -1hydroxyethyl) -5- [2 (E) - (5-methylimidazo [5,1- b] thiazol-3- yl) ethenyl] pyrrolidin- (1R, 5S, 6S) -2- [(3S, 5S) -1-allyloxycarbonyl-6 - ((1R Yl) thio] pyrrolidin-3-yl] thio (2-methylpiperazin-1- -1-methylcarbapen-2-yl) -3-carboxylate.
    (E) type
    NMR (CDCl 3) δ: 1.29 (3H, d, J = 7.1 Hz), 1.37 (3H, d, J = 6.3 Hz), 1.84-1.96 (1H, m), 2.63-2.74 (2H, m), 2.67 (3H, s), 3.23-3.46 (4H, m), 3.68-3.78 (1H, m), 4.20-4.28 (2H, m), 4.10-4.35 (5H, m), 5.20-5.64 , 5.88-6.01 (2H, m), 6.18-6.27 (1H, m), 6.69 (1H, s), 6.89
    MS (TS): 599 (M &lt; + & gt ; + H)
    (Z) type
    NMR (CDCl 3) δ: 1.27 (3H, d, J = 7.2 Hz), 1.36 (3H, d, J = 6.3 Hz), 1.75-1.90 (1H, m), 2.64 (3H, s), 2.58-2.70 (1H, m), 3.25-3.48 (3H, m), 3.63-3.70 (1H, m), 4.20-4.28 (2H, m), 4.55-4.95 (6H, m), 5.28-5.50 , 5.93-6.08 (2H, m), 6.45 (1H, s), 6.49 (1H, s), 6.90
    MS (TS): 599 (M &lt; + & gt ; + H)
    b) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin-3- yl] thio-6 - ((1 R) -1- hydroxyethyl) - M-3-carboxylate
    2-iodoacetamide (246.4 mg) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- Ethyl] -5- [2 (Z) - (5-methylimidazo [5,1-b] thiazol-3- yl) ethenyl] methylpyrrolidin- -3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 18 hours. The mixture was then evaporated under reduced pressure. Residues of sephadex LH-20 (dichloromethane: methanol = 1: 1) was purified by column chromatography using the following ember list A-26 (Cl - form) to an ion-exchange to a yellow oil, allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 104.2 mg.
    NMR (CD 3 OD) δ: 1.23-1.35 (6H, m), 1.84-1.98 (1H, m), 2.18 (3H, s), 2.60-2.90 (3H, m), 3.38-3.57 (3H, m) , 3.90-4.15 (3H, m), 4.20-4.24 (1H, m), 4.50-4.85 (4H, m), 5.18-5.28 (4H, m), 5.40 & 5.46 S, each), 7.55 & 7.71 (total 1H, s, 1H), 6.63 (1H, each)
    MS (TS): 656 (M &lt; + & gt ; + H)
    c) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 (4-methoxyphenyl) -2-methylpyridine in 0.8 ml of THF and 0.8 ml of dry ethanol was treated with triphenylphosphine (14.2 mg), 0.029 ml of morpholine and 8.8 mg of tetrakis - [(3S, 5S) -1-allyloxycarbonyl-5- [2 (Z) - (6-carbamoylmethyl) -5-methylimidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate And the mixture was stirred at room temperature under argon atmosphere for 1 hour. THF (10 ml) was added, and the obtained precipitate was further washed twice with 5 ml of THF and dried under vacuum to prepare yellow powder. The powder was then purified by column chromatography using Cosmosil 40C18-PREP (aqueous methanol solution) To give the title compound (5.7 mg) as a colorless fluorescent substance.
    NMR (D 2 O) (HOD = 4.80 ppm): 1.20 (3H, d, J = 7.4 Hz), 1.28 (3H, d, J = 6.6 Hz), 1.54-1. (1H, m), 2.83 (3H, s), 3.01-3.06 (1H, m), 3.20-3.28 (1H, m), 3.35-3.45 (2H, s), 6.31 (1H, t, J = 10.4 Hz), 6.65 (1H, d, J = 11.0 Hz), 7.27 s)
    [Example 69]
    (3R, 5S) -5- [2 (E) - (6-carbamoylmethyl-5-methylimidazo [5,1-b] thiazolium chloride Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (E) - (6-carbamoylmethyl- [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin- M-3-carboxylate
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (E) Yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen- The procedure of Example 68 was repeated except that 67.1 mg of 3-carboxylate was used. Thus, a solution of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [2 (E) - (6-carbamoylmethyl- [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin- -3-carboxylate (90.9 mg) as a yellow oil.
    NMR (CD 3 OD) δ: 1.25-1.31 (6H, m), 1.95-2.04 (1H, m), 2.18 (3H, s), 2.60-2.67 (2H, m), 2.75-2.92 (1H, m) (3H, m), 3.94-4.25 (3H, m), 4.60-4.75 (4H, m), 4.85-4.90 S), 7.50 (1H, s), 7.69 (1H, s), 6.69 (1H,
    MS (TS): 656 (M &lt; + & gt ; + H)
    b) Preparation of (lR, 5S, 6S) -2 - [(3S, 5S) -5- [2- (E) - (6-carbamoylmethyl-5-methylimidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6- (1R) -1-hydroxyethyl) -1-methylcarbapen-
    (2R) - (6-carbamoylmethyl-5-methylimidazo [5 Yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-M.piperazin- The procedure of Example 68-c) was repeated except that 90.9 mg of 3-carboxylate was used. Thus, 6.9 mg of the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.23 (3H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.3 Hz), 1.98-2.09 (1H, m), 2.87 (3H (1H, s), 2.88-2.97 (1H, m), 3.36-3.50 (3H, m), 3.75-3.81 (1H, m), 4.10-4.28 ), 5.22 (2H, s), 6.58 (1H, dd, J1 = 15.5 Hz, J2 = 8.0 Hz), 7.06 (1H, d, J = 15.7 Hz), 7.54 )
    [Example 70]
    (5R, 5S, 6S) -2 - [(3S, 5S) -5- [ Pyrrolidin-3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1- methylcarbapen- 2- 3-carboxylate
    a) Preparation of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    1-iodoethane (1.1 ml) was added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl- Yl] thio-6 - ((1 R) -1-hydroxyethyl) - (2-methylpyrrolidin- Methylcarbapen-2-yl) -3-carboxylate, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. The mixture was evaporated under reduced pressure. Sepharose residue dex LH-20-Use (type Cl) ion (dichloromethane: methanol = 1: 1) was separated by chromatography using the following ember list A-26 exchange as a yellow oil, allyl chloride (1R , 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) ) Ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate.
    NMR (CD 3 OD) δ: 1.22-1.30 (6H, m), 1.64 (3H, t, J = 7.1 Hz), 1.80-1.98 (1H, m), 2.15-2.18 (3H, m), 2.60-2.62 (2H, m), 2.80-3.05 (1H, m), 3.40-3.65 (3H, m), 3.82-4.28 (3H, m), 4.62-4.80 (4H, m), 5.18-5.48 , 5.86-6.02 (1H, m), 6.30-6.58 (2H, m), 7.56 & 7.70 (total 1H, s, each), 7.89 & 7.91 ), 9.60 & 9.70 (total 1H, s, each)
    MS (FAB &lt; + & gt ; ): 613 (M &lt;
    b) Synthesis of (lR, 5S, 6S) -2 - [(3S, 5S) -5-2 (Z) ] Pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2 (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The procedure of example 68-c) was followed except that &lt; RTI ID = 0.0 &gt; Accordingly, the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80ppm): 1.19 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.57 (3H, t, J = 7.4 Hz), (1H, m), 3.78-3.85 (1H, m), 3.00-3.05 (1H, m) (m, 2H), 4.15-4.28 (2H, m), 4.38-4.44 (2H, q, J = 7.4 Hz), 6.29 (1H, t, J = 9.4 Hz), 6.47 (1 H, s), 7.69 (1 H, s)
    [Example 71]
    (Trifluoromethanesulfonic acid) (1R, 5S, 6S) -6 - ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [ Yl] thio] -1-methylcarbapen-2-yl} -3-carboxylic acid (hereinafter referred to as &quot; hydroxyethyl) imidazo [5,1-b] thiazolium-
    (1R, 5S, 6S) -2 - [(3S, 5S, 6S) -2- (t-butyldimethylsilyloxy) ethyl trifluoromethanesulfonate (42.2 mg) 5S) -1-allyloxycarbonyl-5- [2 (Z) - (imidazo [5,1- b] thiazol-3- yl) ethenyl] pyrrolidin- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 hours under argon atmosphere. The excess reagent was removed under reduced pressure to give allyl trifluoromethanesulfonate (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 ((1R) - (2-tert- butyldimethylsilyloxycarbonyl) imidazo [5,1- b] thiazolium- 1-hydroxyethyl) -1-methylcarbapen-2-yl] -3-carboxylate. 0.09 ml of acetic acid (0.0054 ml) and 1 M tetra-n-butylammonium fluoride / THF solution were added and the mixture was stirred at room temperature for 2.5 hours under argon atmosphere. Dry ethanol (0.5 ml) was added to the solution. 512 mg of triphenylphosphine (10.4 ml), morpholine (0.02 ml) and tetrakis (triphenylphosphine) palladium (0) were successively added to the solution, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere . THF (10 mL) was added and the resulting precipitate was washed twice with 3 mL of additional THF and dried in vacuo to give a yellow powder which was then purified by column chromatography using COSMOSIL 40C18-PREP (aqueous methanol solution) To obtain 0.9 mg of the title compound.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.94-2.06 (1H, m), 2.88-2.98 (1H, m), 3.33-3.54 (3H, m), 3.70-3.80 (1H, m), 4.00-4.04 (2H, m), 4.08-4.19 , 4.48-4.54 (2H, m), 6.44 (1H, t, J = 10.7 Hz), 6.76 (1H, d, J = 11.0 Hz), 7.52 1H, s)
    [Example 72]
    (5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) Yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl- Yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-M.piperazin- 3-carboxylate
    (273.4 mg) and sodium iodide (274.8 mg) were added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1- allyloxycarbonyl-5- [ Yl) thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbamoyl- 3-carboxylate in 50 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature under an argon atmosphere for 5 days. The mixture was evaporated under reduced pressure. The obtained residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) and ion exchange was carried out using Amberlly A-26 (Cl - form) (water) Allyl (5R, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [ yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Carboxylate (51.0 mg).
    NMR (CD 3 OD) δ: 1.24-1.30 (6H, m), 1.80-1.95 (1H, m), 2.85-2.90 (4H, m), 2.95-3.00 (6H, m), 3.40-3.58 (1H, m), 5.40-5.48 (2H, m), 5.90-5.27 (2H, m), 3.94-4.15 (2H, m), 4.23-4.26 (2H, m), 6.30-6.54 (1H, m), 7.08-7.10 (1H, s), 7.70
    MS (TSP): 656 (M &lt; + & gt ; + H)
    b) (lR, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (2- carbamoylethyl) imidazo [5,1- b] thiazolium 3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1 R) -1- hydroxyethyl) -1- methylcarbapen- salt)
    (2R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [ 3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1-methylcarbapen- -Carboxylate &lt; / RTI &gt; was used as the starting material. Thus, 9.2 mg of the title compound was prepared as a colorless tin material.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.19 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.52-1.62 (1H, m), 2.58-2.68 (3H, m), 6.30 (1H, t, J = 8Hz) 9.4 Hz), 6.48 (1H, d, J = 11.5Hz), 7.40 (1H, s), 7.71
    [Example 73]
    (2R) - (6-2-fluoroethyl) imidazo [5,1-b] thiazolium-3- Yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) Yl] thio] -6- ((1R) -1-hydroxyethyl) -1-methylcarbapen-2-M.piperazin- 3-carboxylate
    2-fluoroethyl trifluoromethylsulfonate (198.9 mg) was added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) Yl] thio-6 - ((1R) -1 (3H) -imidazo [5,1-b] thiazol- -Hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate in tetrahydrofuran, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. Under reduced pressure of the solvent, and Sephadex LH-20 (dichloromethane: methanol = 1: 1) of the residue by using purified by column chromatography and ember list A-26 (Cl - form) ion exchange with a (water) (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin- -3-carboxylate (63.7 mg).
    NMR (CD 3 OD) δ: 1.51-1.35 (6H, m), 1.88-1.95 (1H, m), 2.70-2.85 (1H, m), 3.30-3.60 (2H, m), 3.95-4.15 (4H, (2H, m), 6.63-6.68 (1H, m), 7.60-7.05 (4H, m) 7.75 (total 1H, s, each), 7.86 & 7.94 (total 1H, s, each), 9.65 & 9.72
    MS (TSP): 631 (M &lt; + & gt ; + H)
    b) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5 [2 (Z) - (6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- Yl) thienyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- The procedure of Example 68-c) was repeated except that 63.7 mg of the carboxylate was used. Thus, 5.1 mg of the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) (HOD = 4.80 ppm): 1.22 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.3Hz), 1.96-2.04 (1H, m), 3.32-3.40 (1H, m), 3.48-3.54 (2H, m), 3.70-3.76 , 4.70-4.75 (1H, m), 4.90-4.98 (3H, m), 6.44 (1H, t, J = 9.9 Hz), 6.76 7.79 (1H, s), 9.44 (1H, s)
    [Example 74]
    (5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) Yl) thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-aryloxycarbonyl-5- [2- (Z) -6-cyclopropylmethylimidazo [ Thiazol-3-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Rate
    (124.2 mg) and sodium iodide (63.9 mg) were added to a solution of allyl (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxy Yl] thio-6 - ((1 R) -1- (2-fluoropyridin-2-yl) Hydroxyethyl) -1-methylcarbapen-2-yl) -3-carboxylate in 50 ml of tetrahydrofuran and the mixture was stirred at room temperature under argon atmosphere for 4 days. Evaporation of the mixture under reduced pressure, and Sephadex LH-20 (dichloromethane metal: methanol = 1: 1) and the residue obtained was purified by column chromatography using the following ember list A-26 - a (Cl form) (water) To give (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) -6-cyclopropylmethylimidazole [5,1-b] thiazolium-3-yl) ethenyl] pyrrolidin- -3-carboxylate (52.3 mg).
    NMR (CD 3 OD) δ: 0.57 (2H, d, J = 4.5 Hz), 0.77 (2H, d, J = 7.4 Hz), 1.24-1.35 (6H, m), 1.38-1.40 (1H, m), (2H, m), 3.92-4.17 (2H, m), 4.21-4.30 (2H, m), 1.80-1.98 (1H, m), 2.76-2.95 m), 4.62-4.80 (2H, m), 4.90-5.08 (4H, m), 5.10-5.32 (3H, m), 5.40-5.50 S, each), 7.60 & 7.70 (total 1H, s, each)
    b) Synthesis of (lS, 5S, 6S) -2 - [(3S, 5S) -5- [2- (Z) -6- 3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3 -carboxylate (intramolecular salt)
    Synthesis of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (Z) -6-cyclopropylmethylimidazo [ Yl) thienyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- The same procedure as in Example 68-c) was repeated except that. Thus, 8.4 mg of the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 0.50 (2H, d, J = 4.7 Hz), 0.75 (2H, d, J = 7.9 Hz), 1.20 (3H, d, J = 6.9 Hz), (1H, m), 3.22 (1H, m), 1.28 (3H, d, J = 6.3 Hz), 1.33-1.44 (1H, m), 1.53-1.63 (2H, m), 3.80 (1H, m), 3.30 (1H, m), 3.35-3.42 t, J = 10.5Hz), 7.38 (1H, s), 7.74 (1H, s)
    [Example 75]
    (1R, 5S, 6S) -6- ((1R) -1-hydroxyethyl) -2 - [(3S, 5S) -5- [ Yl] thio] -1-methylcarbapen-2-yl) -3-carboxylate (intramolecular salt)
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazole Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- &Lt; / RTI &gt; was used as the starting material). The resulting yellow powder was purified by column chromatography using Cosmosil 40C18-PREP (aqueous methanol solution) to isolate the geometric isomers. Thus, 6.8 mg of the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.21 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.3 Hz), 1.10-1.18 (1H, m), 2.68-2.78 (1H, m), 3.11-3.14 (1H, m), 3.36-3.45 (1H, m), 4.20-4.40 (3H, m), 4.08-4.19 , 4.42-4.52 (3H, m), 4.75-4.85 (2H, m), 6.10 (1H, t, J = 10.2 Hz), 6.61 (1H, d, J = 7.83 (1 H, s)
    [Example 76]
    (5R, 5S, 6S) -2 - [(3S, 5S) -2 (Z) Yl) thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen-
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (6- (2-carbamoylethyl) imidazo [ yl] ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Carboxylate (mixture of geometric isomers)
    (523.7 mg) and sodium iodide (574.8 mg) were added to a solution of allyl (lR, 5S, 6S) -2 - [(3S, 5S) -1-allyl Yl] thio] -6- ((1R) -1-hydroxy-2-oxo- Ethyl) -1-methylcarbapen-2-yl] -3-carboxylate in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 day under an argon atmosphere. The solvent was removed under reduced pressure and Sepharose residue dex LH-20 (dichloromethane: methanol = 1: 1) was purified by column chromatography using: Amber list A-26 (Cl - form) ion with - exchange (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (6- (2- carbamoylethyl) imidazo [ Yl] thio] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Carboxylate (112.1 mg).
    NMR (CD 3 OD) δ: 1.25-1.30 (6H, m), 1.80-1.95 (1H, m), 2.85-3.00 (5H, m), 3.30-3.60 (3H, m), 3.95-4.15 (3H, m), 4.22-4.28 (1H, m), 4.50-4.75 (5H, m), 5.15-5.45 (4H, m), 5.87-6.00 (1H, d, J = 18 Hz), 7.79 & 7.82 (total 1H, s, each), 7.98 & 8.03
    MS (TSP): 656 (M &lt; + & gt ; ).
    b) Preparation of (1R, 5S, 6S) -2 - [(3S, 5S) -5- [2- (Z) Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen-
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (6- (2-carbamoylethyl) imidazo [ ] Thiazolyl-2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- The procedure of Example 68-c) was repeated but using 112.1 mg of the compound of formula (II) (geometric isomer mixture). The resulting yellow powder was purified by column chromatography using Cosmosil 40C18-PREP (aqueous methanol solution) to isolate the geometric isomers. Thus, 6.9 mg of the title compound was prepared as a colorless fluorescent substance.
    NMR (D 2 O) δ ( HOD = 4.80 ppm): 1.23 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.92-2.04 (1H, m), 2.90-3.02 (1H, m), 3.37-3.40 (1H, m), 3.46-4.05 (2H, m), 3.72-3.80 (2H, m), 6.21 (1H, t, J = 11.8 Hz), 6.80 (1H, d, J = 11.3 Hz), 7.71 (1H, s), 7.99 1H, s)
    [Example 77]
    (1S, 5S) -5- [2 (Z) - (6- (2-fluoroethyl) imidazo [5,1- b] thiazolium- Yl) thio] pyrrolidin-3-yl] thio-6- (1 (R) -hydroxyethyl) (5S, 5S) -5- [2 (E) - (6- (2- fluoroethyl) 3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3-carboxylate )
    a) Preparation of allyl chloride (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2-6- (2- fluoroethyl) imidazo [ ] Thiazolyl-2-yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- Rate (mixture of geometric isomers)
    (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazole Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1- hydroxyethyl) -1- methylcarbapen- 2- 3-carboxylate (geometric isomer &Lt; / RTI &gt; was used as the starting material). Thus, as a yellow oil, (1R, 5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (6- (2- fluoroethyl) imidazo [ Yl] ethenyl] pyrrolidin-3-yl] thio-6- ((1R) -1- hydroxyethyl) -1- methylcarbapen- Carboxylate (108.6 mg).
    NMR (CD 3 OD) δ: 1.04-1.15 (6H, m), 1.60-1.75 (1H, m), 2.50-2.71 (1H, m), 3.10-3.27 5H, m), 3.74-3.98 2H, m) , 4.02-4.08 1H, m), 4.40-4.80 8H, m), 4.95-5.25 4H, m), 5.70-5.80 1H, m), 6.08-6.30 1H, m), 6.59 Hz), 7.61 & 7.65 (total 1H, s, each), 7.85-8.00 (1H, m), 9.24 &
    MS (FAB &lt; + & gt ; ): 631 (M &
    b) Preparation of (lR, 5S, 6S) -2 - [(3S, 5S) -5- [2 (Z) - (6- (2- fluoroethyl) imidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- , 5S, 6S) -2 - [(3S, 5S) -5- [2 (E) - (6- (2- fluoroethyl) imidazo [5,1- b] thiazolium- 3-yl] thio-6 - ((1 R) -1-hydroxyethyl) -1-methylcarbapen- 2- 3 -carboxylate (intramolecular salt)
    (5S, 6S) -2 - [(3S, 5S) -1-allyloxycarbonyl-5- [2- (6- (2- fluoroethyl) imidazo [ Yl) ethenyl] pyrrolidin-3-yl] thio-6 - ((1R) -1-hydroxyethyl) -1- methylcarbapen- The procedure of Example 68-c) was repeated except that 108.6 mg of the compound (mixture of geometric isomers) was used. The resulting yellow powder was purified by column chromatography using Cosmosil 40C18-PREP (aqueous methanol solution) to isolate the geometric isomers. Thus, the title compound (7.9 mg of a (Z) -form and 3.2 mg of (E) -form as a colorless fluorescent substance) was prepared.
    (Z) type
    NMR (D 2 O) (HOD = 4.80 ppm): 1.22 (3H, d, J = 7.1 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.90-2.01 (3H, m), 3.70-3.85 (2H, m), 4.08-4.12 (1H, m), 4.21-4.30 , 4.93-4.98 (1H, m), 6.22 (1H, t, J = 11.3 Hz), 6.80 (1H, d, J = 11.6 Hz), 7.75 (1H, s), 8.01 1H, s)
    (E type)
    (1H, m), 2.59-2.68 (1H, d, J = 7.1 Hz), 1.29 (3H, d, J = 6.3 Hz) m), 3.03-3.09 (1H, m), 3.06 (1H, dd, J1 = 11.9 Hz, J2 = 3.4 Hz), 3.29-3.43 (3H, m), 3.82-3.98 (2H, m), 4.67-4.69 (1H, m), 4.72-4.81 (3H, m), 4.94-4.97 (1H, m), 6.30 (1H, dd, J1 = , 6.82 (1H, d, J = 16.1Hz), 7.67 (1H, s), 7.91
    [Synthesis Example 1]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5 - [(imidazo [5,1- b] thiazol- 5- yl) methylaminocarbonyl] pyrrolidine
    A 1.1 M Vilsmeier reagent / dichloromethane solution (1.5 mL) prepared from DMF and phosphorus oxychloride by conventional methods was added to a solution of (3S, 5S) -3-acetylthio-pyrrolidine in 1.5 mL of dry dichloromethane at &lt; Oxycarbonylpyrrolidine-5-carboxylic acid, and the mixture was stirred at the temperature of 3-8 占 폚 for 75 minutes in the above state. A solution of 265 mg of 5-aminomethylimidazo [5,1-b] thiazole in dry dichloromethane was added dropwise to the mixture over 5 minutes, then the mixture was stirred at 5-8 ° C for 5 minutes. The mixture was neutralized with a sodium hydroxide dilution solution, adjusted to pH 9 with 5% aqueous sodium hydrogencarbonate solution, salted out and extracted twice with 50 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate + potassium carbonate and filtered, and the solvent was removed under reduced pressure to give 514 mg of yellow oil. This oil was sequentially purified by column chromatography using Sephadex LH-20 (chloroform: methanol = 1: 1) and silica gel (ethyl acetate: methanol = 95: 5) to obtain 293 mg of the title compound as a pale yellow oil.
    NMR (CDCl 3) δ: 2.22 (3H, s), 2.3 (1H, br.s), 2.6 (1H, br.s), 3.33-3.37 (1H, m), 3.91-4.05 (2H, m), (2H, br s), 4.66 (1H, dd, J1 = 15.3 Hz, J2 = 5.9 Hz), 4.84 (1H, dd, J1 = 15.3 Hz, J2 = 6.6 Hz, ), 5.2 (1H, br.s), 5.85 (1H, br.s), 6.77 (1H, d, J = 4.2 Hz), 6.98 1H, &lt; / RTI &gt; d, J = 4.2 Hz)
    MS (EI): 408 (M &lt; + & gt ; ).
    [Synthesis Example 2]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [N- (imidazo [5,1- b] thiazol- Loridine
    A solution of 260 mg of (3S, 5S) -3-acetylthio-1-allyloxycarbonylpyrrolidine-5-carboxylic acid, 0.95 ml of a 1.1 M solution of Vilsmeier reagent / dichloromethane and 0.95 ml of 5- (N- The procedure of Synthesis Example 1 was repeated except that 159 mg of imidazo [5,1-b] thiazole was used. Thus, 190.6 mg of the title compound was obtained as a pale yellow amorphous substance.
    NMR (CDCl 3) (about 3: 2 mixture of conformers body) δ: 1.78-1.88 (1H, m ), 2.31 (3H, s), 2.66-2.81 (1H, m), 3.07 (1H × 3/5, s ), 3.10 (1H x 2.5, s), 3.46 (1H, dd, J1 = 10.2 Hz, J2 = 8.7 Hz), 3.99 (1H, quintet, J = 8.1 Hz), 4.07-4.15 (1H x 2/5, dd, J 1 = 13.3 Hz, J 2 = 5.4 Hz), 4.47 (1H x 2/5, dd, J 1 = 13.3 Hz, J 2 = 5.7 Hz), 4.57-4.60 d, J = 15.0 Hz), 4.69 (1H, d, J = 15.4, J2 = 7.4 Hz), 4.82 ), 4.73-5.03 (2H x 2/5, m), 5.09-5.36 (2H, m), 5.50 (1H x 2/5, (1H x 3/5, s), 7.72 (1H x 3/5, d, J = 4.3 Hz), 7.81 (1H x 3/5, 2/5, d, J = 4.3 Hz)
    MS (EI): 422 (M &lt; + & gt ; ).
    [Synthesis Example 3]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [N- [5- (allyloxycarbonylaminomethyl) imidazo [5,1- b] thiazol- Methyl-N-methylaminocarbonyl] pyrrolidine
    (3S, 5S) -3-acetylthio-1-allyloxycarbonylpyrrolidine-5-carboxylic acid, 0.93 ml of a 1.1 M solution of Vilsmeier reagent / dichloromethane and 0.95 ml of a solution of 5-allyloxycarbonylaminomethyl- Except that 262 mg of 3- (N-methylaminomethyl) imidazo [5,1-b] thiazole was used and finally 0.145 mg of triethylamine was added at 4 ° C, followed by stirring at room temperature for 50 minutes The procedure of Synthesis Example 1 was repeated. Thus, 327.5 mg of the title compound was prepared as a colorless amorphous substance.
    NMR (CDCl 3 ) (mixture of stereoisomers) : 1.9-2.0 (1H, m), 2.32 (3H 1/3, m), 3.12 & 3.18 & 3.27 (total 3H, s, 3: 1: 6 each), 3.37-3.40 (1H, m), 3.90-4.15 (2H, m), 4.50-4.95 D, J = 4.2 Hz), 6.82 & 6.95 (total 1H, s, 3: 1 each), 5.15-5.35 (4H, m), 5.8-6.1 , 6.95 & 7.02 (total 1H, s, 3: 1 each)
    MS (EI): 535 (M &lt; + & gt ; ).
    [Synthesis Example 4]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol-3- yl) methyl] pyrrolidine (Stereoisomer A)
    a) Synthesis of (3R, 5S) -3-acetylthio-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [ Yl) methyl] pyrrolidine (stereoisomer A) and homologous material (stereoisomer B)
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1-hydroxy- 1- (imidazo [ (Silica gel 60, No. 9385, 360 g, manufactured by Merck; dichloromethane: ethanol = 20: 1) was used as a starting material The residue was purified by flash column chromatography to give (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- 1 -hydroxy- 1- (imidazo [ Yl) methyl] pyrrolidine (stereoisomer A, high polarity component) as a pale yellow amorphous solid and (3R, 5S) -1-allyloxycarbonyl- (trimethylsilyloxy) -5- [1-hydroxy-1- (imidazo [5,1-b] thiazol-3- yl) methyl] pyrrolidine (stereoisomer B, ).
    (Stereoisomer A)
    NMR (CD 3 COCD 3) δ : 0.07 (3H, s), 0.08 (3H, s), 0.86 (9H, s), 1.70-1.90 (1H, m), 2.33-2.45 (1H, m), 3.47 ( (1H, dt, J1 = 10.7 Hz, J2 = 3.9 Hz), 3.57 (1H, dt, J1 = 10.7 Hz, J2 = 5.0 Hz), 4.35-4.51 (1H, m), 4.55-4.70 5.15-5.50 (4H, m, 1H is exchangeable with D 2 O), 5.90-6.05 (1H , m), 6.96 (1H, s), 7.03 (1H, s), 8.10 & 8.37 (total 1H, s , 1: 3 each)
    MS (FAB + ): 438 (M &lt; + & gt ; + H)
    (Stereoisomer B)
    NMR (CDCl 3) δ: -0.01 (3H, s), 0.01 (3H, s), 0.82 (9H, s), 1.66-1.73 (1H, m), 3.40 (1H, dd, J1 = 11.6 Hz, J2 (1H, m), 3.64 (1H, d, J = S), 6.26 (1H, s), 8.26 (1H, s), 6.63 (1H,
    MS (FAB + ): 438 (M &lt; + & gt ; + H)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Lt; / RTI &gt; (stereoisomer A)
    To a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- Was added dropwise to a solution of 525 mg of 4-hydroxy-1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer A). The mixture was stirred for 5 minutes in the above state, and then the temperature was raised to 15 DEG C over 20 minutes. The instantaneous reaction solution was concentrated under reduced pressure to about 20 ml, and the concentrate was adjusted to pH 8.5 by adding 40 ml of a 5% sodium hydrogencarbonate aqueous solution. The mixture was then extracted three times with 100 ml of ethyl acetate. The combined organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give the crude (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [1 -hydroxy- To obtain 457 mg of 1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer A).
    (Stereoisomer A)
    NMR (CD 3 COCD 3 ) : 1.73-1.88 (1H, m), 2.36-2.45 (1H, m), 3.42-3.65 (1H, s), 7.01 (1H, m), 5.17-5.55 (4H, m), 5.90-6.05 each)
    MS (EI): 323 (M &lt; + & gt ; ).
    c) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Oxipyrrolidine (stereoisomer A)
    (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [1- Was added sequentially to a solution of 457 mg of hydroxy-1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer A) Lt; / RTI &gt; A 5% sodium hydrogencarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give a slightly cloudy orange brown oil. This oil was purified by flash column chromatography using silica gel (ethyl acetate: methanol = 92: 8) to give the crude (3R, 5S) -1-allyloxycarbonyl- (Imidazo [5,1-b] thiazol-3-yl) methyl] -3-methanesulfonyloxypyrrolidine (344 mg).
    (Stereoisomer A)
    NMR (CD 3 COCD 3) δ : 2.12-2.30 (1H, m), 2.62-2.71 (1H, m), 3.14 (3H, s), 3.67-3.97 (2H, m), 4.44-4.67 (3H, m ), 5.19-5.57 (5H, m, it is possible to exchange 1H in D 2 0), 5.92-6.07 (1H , m), 7.01 (1H, s), 7.04 (1H, s), 8.09 & 8.34 (total 1H , s 1: 2 each)
    MS (EI): 401 (M &lt; + & gt ; ).
    d) (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Lt; / RTI &gt; (stereoisomer A)
    Potassium thioacetate (134 mg) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ -b] thiazol-3-yl) methyl] -3-methanesulfonyloxypyrrolidine (stereoisomer A), and the mixture was stirred under an argon atmosphere at 70 DEG C for 22 hours Respectively. The mixture was diluted with 60 mL of ethyl acetate, washed twice with half-saturated brine, and the organic layer was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure, and the residue was dried under reduced pressure by means of a vacuum pump. The dark red oil was purified by flash column chromatography using silica gel (ethyl acetate) to obtain the title compound (217 mg) as a slightly red amorphous substance.
    (Stereoisomer A)
    NMR (CDCl 3) δ: 2.17-2.35 (3H, br + m), 2.33 (3H, s), 3.20 (1H, br.t), 3.84 (2H, quintet, J = 8.4 Hz), 4.19 (1H, m), 5.19-5.35 (2H, m), 5.54 & 5.75 (total 1H, br.s), 4.32 (1H, dt, J1 = 7.8 Hz, J2 = 2.6 Hz). s), 6.99 (1H, s), 8.06 & 8.24 (total 1H, br.s, 1: 2 each), 5.85-5.95 (1H,
    MS (EI): 381 (M &lt; + & gt ; ).
    [Synthesis Example 5]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol-3- yl) methyl] pyrrolidine (Stereoisomer B)
    a) Preparation of (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Lt; / RTI &gt; (stereoisomer B)
    (3R, 5S) -l-allyloxycarbonyl-3-t-butyldimethylsilyl (3R, 5S) Was added dropwise to a solution of 327 mg of 4-hydroxy-5- [1-hydroxy-1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer B). The mixture was stirred for 20 minutes under the above conditions, diluted to 50 ml with ethyl acetate, and the diluted solution was adjusted to pH 9.2 by adding 5% sodium hydrogencarbonate and then shaken. The organic layer was separated. The aqueous layer was extracted twice with 50 ml of ethyl acetate while adjusting the pH to 9.2 by adding a 5% aqueous solution of sodium hydrogencarbonate. The organic layer was combined with the organic layer, and the combined organic layer was dried over magnesium sulfate and then filtered. The solvent was removed under reduced pressure to obtain (3R, 5S) -1-allyloxycarbonyl- 313 mg of 5- [1-hydroxy-1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer B) was obtained.
    (Stereoisomer B)
    NMR (CDCl 3) δ: 1.65-1.85 (3H, m), 3,42-3.50 (1H, m), 3.79 (1H, br.d, J = 12.1 Hz), 4.33 (1H, br.s), (2H, m), 6.62 (1H, s), 6.65 (1H, m), 4.60-4.70 (3H, m), 4.80 (1H, br.d, J = 7.9 Hz), 5.25-5.38 1H, br.s), 6.97 (1H, s), 8.21 (1H, br.s)
    MS (EI): 323 (M &lt; + & gt ; ).
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Lt; / RTI &gt; (stereoisomer B)
    (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [l, 2-dihydroxy- Was added to the solution in succession to a solution of 3-hydroxy-1- (imidazo [5,1-b] thiazol-3-yl) methyl] pyrrolidine (stereoisomer B) Lt; / RTI &gt; for 40 minutes. In addition, 0.008 ml of methanesulfonyl chloride was added and the mixture was stirred for 20 minutes. A 5% aqueous solution of sodium hydrogencarbonate (20 ml) was added to the mixture and the mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and then filtered. The solvent was removed under reduced pressure to obtain the crude (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ) Methyl] -3-methanesulfonyloxypyrrolidine (stereoisomer B).
    (Stereoisomer B)
    NMR (CDCl 3) δ: 1.75 (1H, br.s), 1.90-2.15 (2H, m), 3.01 (3H, s), 3.60 (1H, dd, J1 = 13.4 Hz, J2 = 3.8 Hz), 4.10 M), 4.85 (1H, br.d, J = 7.5 Hz), 5.15 (1H, br.s), 5.25-5.40 (2H, m), 5.88 M), 6.69 (1H, s), 7.09 (1H, s), 8.26
    MS (EI): 401 (M &lt; + & gt ; ).
    c) (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Lt; / RTI &gt; (stereoisomer B)
    Potassium thioacetate (149 mg) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [ 1-b] thiazol-3-yl) methyl] -3-methanesulfonyloxypyrrolidine (stereoisomer B), and the mixture was stirred under an argon atmosphere at a reactor temperature of 80 ° C for 12 hours Respectively. The mixture was diluted with 100 mL of ethyl acetate and washed twice with 40 mL of 5% aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was dried under reduced pressure by vacuum pump means for 2 hours. The obtained brown oil was purified by column chromatography sequentially using silica gel (ethyl acetate) and Sephadex LH-20 (chloroform: methanol = 1: 1) to obtain 139.1 mg of the title compound as a red amorphous substance.
    (Stereoisomer B)
    NMR (CDCl 3) δ: 1.70 (1H, m), 2.29 (1H, m), 2.33 (3H, s), 3.22 (1H, br.t), 3.84 (1H, quintet, J = 7.7 Hz), 4.17 (1H, br.t), 4.53 (1H, dd, J1 = 14.5 Hz, J2 = 7.7 Hz), 4.60-4.80 (2H, m), 4.92 (2H, m), 5.85-6.00 (1H, m), 6.50 (1H, br.s), 6.68 (1H, s), 7.04
    MS (EI): 381 (M &lt; + & gt ; ).
    [Synthesis Example 6]
    (3R, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (imidazo [5,1- b] thiazol- 5- yl) methylpyrrolidine
    a) 5-bromoimidazo [5,1-b] thiazole, 7-bromoimidazo [5,1-b] thiazole, and 5,7-dibromoimidazo [ ] Thiazole
    N-Bromosuccinimide (8.900 g) was added to a solution of 6.208 g of imidazo [5,1-b] thiazole in 250 ml of dry dichloroethane and the mixture was stirred at -7 to -4 ° C for 40 minutes Lt; / RTI &gt; The reaction solution was concentrated under reduced pressure to about 50 ml. The concentrate was diluted with 500 ml of ethyl acetate, and the diluted solution was washed twice with 250 ml of distilled water and twice with 250 ml of semi-saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain an oil. The resulting oil was purified by flash column chromatography using silica gel (n-hexane: ethyl acetate = 2: 1 to 1: 1) to obtain a milky white powder Bromoimidazo [5,1-b] thiazole as colorless powder, 4.443 g of 7-bromoimidazo [5,1-b] thiazole as a milky white powder, To obtain 1.174 g of 7-dibromoimidazo [5,1-b] thiazole.
    5-bromoimidazo [5,1-b] thiazole
    NMR (CDCl 3) δ: 6.89 (1H, d, J = 4.3 Hz), 7.09 (1H, s), 7.29 (1H, d, J = 4.3 Hz)
    MS (TSP): 205 (M &lt; + &gt; + H + 2), 203 (M &
    7-Bromoimidazo [5,1-b] thiazole
    NMR (CDCl 3) δ: 6.88 (1H, d, J = 4.2 Hz), 7.43 (1H, d, J = 4.2 Hz), 7.91 (1H, s)
    MS (TSP): 205 (M &lt; + &gt; + H + 2), 203 (M &
    5,7-dibromoimidazole [5,1-b] thiazole
    NMR (CDCl 3) δ: 6.94 (1H, d, J = 4.3 Hz), 7.31 (1H, d, J = 4.3 Hz)
    MS (TSP): 285 (M + + H + 4), 283 (M + + H + 2), 281 (M + + H)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ) Methyl] pyrrolidine (stereoisomer A) and homogeneous material (stereoisomer B)
    A solution of 15.0 mL of 0.99 M ethylmagnesium bromide / THF solution (15.2 mL) was diluted with 60 mL of dry THF. A solution of 3.046 g of 5-bromoimidazo [5,1-b] thiazole in 60 mL of dry THF (4 to 8 DEG C), and the mixture was stirred for 5 minutes in this state. The mixture was then cooled to -3 DEG C over 10 minutes. Then, 60 mL of anhydrous THF A solution of 4.702 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine was added dropwise to the mixture over 20 minutes (-3 to -1 DEG C) . This mixture was stirred under the above conditions at -1 to 1 DEG C for 80 minutes. A semi-saturated aqueous ammonium chloride solution (180 mL) was added to the mixture and the mixture was extracted twice with 360 mL of ethyl acetate. Dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain yellow oil. Purification by flash column chromatography using a gel (n-hexane: ethyl acetate = 1: 1 to 1: 2) gave (3R, 5S) -1- allyloxycarbonyl-3-t- butyldimethylsilyl (Stereoisomer A, high polarity component) and 4.934 g of a slightly yellow solid of the title compound as a colorless oil. (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Yl) methyl] pyrrolidine (stereoisomer B, low polarity component).
    (Stereoisomer A)
    NMR (CDCl 3) δ: -0.02 (3H, s), 0.01 (3H, s), 0.81 (9H, s), 1.53-1.63 (1H, m), 1.94-2.15 (1H, m), 3.37 (1H (d, J = 11.5 Hz, J2 = 3.9 Hz), 3.60 (1H, br.d, J = 11.5 Hz), 4.18 M), 6.05 (1H, br.s), 6.77 (1H, d, J = 7.7 Hz), 5.23-5.37 (d, J = 4.3 Hz), 6.97 (1H, s), 7.80
    MS (TSP): 438 (M &lt; + & gt ; + H)
    (Stereoisomer B)
    NMR (CDCl 3) δ: 0.00 (3H, s), 0.02 (3H, s), 0.83 (9H, s), 1.87-1.97 (1H, m), 2.09 (1H, s), 2.33-2.43 (1H, J1 = 11.3 Hz, J2 = 3.2 Hz), 4.04 (1H, quintet, J = 4.5 Hz), 4.49 (1H, dd, J = (1H, br, J = 7.5 Hz), 4.62-4.65 (2H, m), 5.20-5.37 4.1 Hz), 6.98 (1H, s), 7.71 (1H, d, J = 4.1 Hz)
    MS (ES): 438 (M &lt; + & gt ; + H)
    c) Preparation of (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [5,1- b] thiazol- 5- yl) methylpyrrolidine
    Thionyl chloride (0.39 ml) was added dropwise to a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy- Yl) methyl] pyrrolidine (stereoisomer A), and the mixture was stirred for 25 minutes in this state . The solvent and excess reagent were removed under reduced pressure, and the residue was dried under reduced pressure by means of a vacuum pump to obtain a light yellow amorphous substance, which was then dissolved in 17.7 ml of 90% acetic acid. Zinc (1.156 g) was added to the solution under ice cooling, and the mixture was stirred for 20 minutes in this state. The ice bath was also removed and stirring was continued for an additional 10 minutes. Distilled water and ethyl acetate were added and the mixture was adjusted to pH 6 with stirring by addition of sodium hydrocarbons. The organic layer was separated, and the remaining aqueous layer was adjusted to pH 8 by adding sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic layers were washed twice with 5% sodium hydrogencarbonate, dried over magnesium sulfate and potassium carbonate and filtered. The solvent was removed under reduced pressure. The residue was azeotropically evaporated once with acetonitrile and the residue was redissolved in 17.7 ml of acetonitrile and 0.70 ml of concentrated hydrochloric acid was added to the solution under ice cooling, Stir for 15 min. The mixture was diluted with 200 ml of ethyl acetate and the diluted solution was washed with 50 ml of 5% aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give an orange- Material was obtained. The amorphous material was subjected to column chromatography using silica gel (first, ethyl acetate: methanol = 9: 1; second, chloroform: methanol = 9: 1) and Sephadex LH-20 (chloroform: methanol = 1: 1) To thereby obtain (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [5,1- b] thiazol-5-yl) methylpyrrolidone as a colorless amorphous substance &Lt; / RTI &gt;
    NMR (CDCl 3) δ: 1.96-2.10 (1H, m), 2.15-2.30 (1H, m), 3.08-3.16 (1H, m), 3.25-3.60 (3H, m), 4.00 (1H, br.s ), 4.17-4.40 (2H, m), 4.45-4.66 (2H, m), 5.20-5.40 (2H, m), 5.86-6.00 6.90 (1H, s), 7.22 (1H, br.s), 7.62 (1H, d, J = 4.1 Hz)
    MS (ES): 308 (M &lt; + & gt ; + H)
    d) Synthesis of (3S, 5R) -1-allyloxycarbonyl-3-benzoylthio-5- (imidazo [5,1- b] thiazol-
    Diethyl azodicarboxylate (0.105 ml) was added to a solution of (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [ Yl) methylpyrrolidine and 174 mg of triphenylphosphine, and the mixture was stirred for 15 minutes under the above conditions, and then treated with tribenzoic acid (90%) 0.130 And the mixture was stirred for 14 hours while raising the temperature from the above state to room temperature. The solvent and an excess of the reagent were removed under reduced pressure to obtain yellow oil, which was then subjected to column chromatography using Sephadex LH-20 (chloroform: methanol = 1: 1) and silica gel (first, n-hexane: ethyl acetate = 1: 1) To obtain 87 mg of the title compound as a yellow oil.
    NMR (CDCl 3) δ: 2.13-2.35 (1H, m), 2.50-2.65 (1H, m), 3.17-3.30 (2H, m), 3.45-3.62 (1H, m), 4.15-4.35 (3H, m (2H, m), 5.62-6.02 (1H, m), 6.76 (1H, d, J = 4.2 Hz), 6.97 7.48 (2H, m), 7.56-7.61 (2H, m), 7.91-7.94 (2H, m)
    MS (EI): 427 (M &lt; + & gt ; ).
    [Synthesis Example 7]
    (3R, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol-2- yl) methyl] pyrrolidine (Diastereomer mixture)
    a) Preparation of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ) Methyl] pyrrolidine (diastereomeric mixture) and (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [ , L-b] thiazol-3-yl) methyl] pyrrolidine (diastereomeric mixture)
    A solution of 1.69 M n-butyllithium-hexane (7.2 ml) in 2.0 ml of dry imidazo [5,1-b] thiazole in 40 ml of dry THF was added over 10 minutes while maintaining the temperature at or below- The mixture was added dropwise and the mixture was stirred at the same temperature for 2 hours. 5.32 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 20 ml of THF was gradually added dropwise to the above mixed solution, Lt; / RTI &gt; for 1.5 hours. The temperature was raised to 0 &lt; 0 &gt; C over 1 hour and the mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and further at room temperature for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography sequentially using a column of Sephadex LH-20 (dichloromethane: methanol = 1: 1) and silica gel (hexane: ethyl acetate = 1: 1) to give (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy-1- (imidazo [5,1- b] thiazol-2- yl) methyl] pyrrolidine (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [ Thiazol-3-yl) methyl] pyrrolidine (diastereomer mixture).
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ] Pyrrolidine (diastereomer mixture)
    NMR (CDCl 3) δ: 0.01 , 0.02 (total 6H, s each), 0.82, 0.83 (total 9H, s, each), 1.66-1.75 (1H, m), 1.83-1.95 (1H, m), 3.30- (2H, m), 5.87 (1H, m), 3.41 (1H, m), 4.20-4.35 6.00 (1H, m), 7.01, 7.03 (total 1H, s, each), 7.34 (1H, s), 7.90
    MS (ES): 437 (M &lt; + & gt ; ).
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ] Pyrrolidine (diastereomer mixture)
    NMR (CDCl 3) δ: 0.02 , 0.03 (total 6H, s, each), 0.82, 0.84 (total 9H, s, each), 1.63-1.76 (2H, m), 3.36-3.51 (1H, m), 3.65 (2H, m), 5.91-6.03 (1H, m), 6.64,6.66 (1H, m) , s, each), 7.08 (1H, s), 8.26, 8.29 (total 1H, s, each)
    MS (ES): 437 (M &lt; + & gt ; ).
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Oxipyrrolidine (diastereomer mixture)
    (0.85 ml) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [ Diazo [5,1-b] thiazol-2-yl) methyl] pyrrolidine in 10 ml of tetrahydrofuran and the mixture was stirred for 20 minutes in this state. The reaction solution was diluted with 50 ml of ethyl acetate, water was added to the reaction solution, and the mixture was made into a weak alkali by adding a saturated aqueous solution of sodium hydrogencarbonate. The mixture was then extracted three times with ethyl acetate, and the organic layer was washed twice with saturated brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Methyl] pyrrolidine. &Lt; / RTI &gt; Triethylamine (0.46 ml) and methanesulfonyl chloride (0.24 ml) were successively added to the above solution of the compound in 20 ml of THF, and the mixture was stirred at -14 캜 under an argon stream for 50 minutes. Water was added to the reaction solution, and the mixture was extracted four times with ethyl acetate. The organic layer was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain a crude product. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol = 9: 1) (3R, 5S) -1-allyloxycarbonyl-5- [1 -hydroxy-1- (imidazo [5,1- b] thiazol-2- yl) methyl] -3- methanesulfonyloxy Pyrrolidine (mixture of diastereomers).
    NMR (CDCl 3) δ: 1.53-1.72 (2H, m), 2.25-2.45 (1H, m), 2.50-2.75 (1H, m), 3.02, 3.03 (total 3H, s, each), 3.57-3.67 ( (1H, m), 4.00-4.15 (1H, m), 4.38-4.48 (1H, m), 4.65-4.75 (2H, m), 5.15-5.36 7.05 (1H, s), 7.39 (1H, s), 7.93 (1H, s)
    MS (FAB + ): 402 (M &lt; + & gt ; + H)
    c) (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- Lt; / RTI &gt; (diastereomer mixture)
    Potassium thioacetate (204 mg) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-3- methanesulfonyloxy-5- [1 -hydroxy- 1- (imidazo [ b] thiazol-2-yl) methyl] pyrrolidine (diastereomer mixture), and the mixture was stirred at 70 ° C for 5 hours in an argon atmosphere. The mixture was cooled, water was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and then the solvent was removed under reduced pressure. The obtained product was purified by column chromatography using silica gel (hexane: acetone = 1: 1) to obtain 136.4 mg of the title compound (diastereomeric mixture) as a brown oil.
    NMR (CDCl 3) δ: 1.60-1.69 (1H, m), 1.72-1.88 (1H, m), 2.25, 2.26 (total 3H, s, each), 2.95-3.05 (1H, m), 3.13-3.21 ( (1H, m), 3.69-3.81 (1H, m), 4.09-4.28 (2H, m), 4.54-4.60 (2H, m), 4.86-4.90 (1H, s), 7.86 (1H, s), 7.86 (1H,
    MS (FAB &lt; + & gt ; ): 382 (M &lt;
    [Synthesis Example 8]
    (3S, 5R) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-3- yl) methylpyrrolidine
    a) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol- Methylthiocarbonyloxy) methyl] pyrrolidine (diastereomer mixture)
    (2.7 g), 0.53 ml of carbon disulfide and 128 mg of sodium hydride were successively added to a solution of (3R, 5S) -1-allyloxycarbonyl-3 yl) methyl] pyrrolidine (diastereomeric mixture) in tetrahydrofuran was added dropwise to a solution of 1-butyldimethylsilyloxy-5- [1-hydroxy-1-imidazo [5,1- b] thiazol- And the mixture was stirred at the same temperature for 20 minutes. Methyl iodide (0.19 ml) was added dropwise to the mixed solution, and the mixture was gradually warmed and stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the obtained crude product was purified by column chromatography using silica gel (hexane: ethyl acetate = 1: 1) to obtain (3R, 5R) -allyloxycarbonyl- (Diastereomeric mixture) was obtained in the same manner as in Example 1, except that the amount of the diastereomeric mixture of dihydroxy-5- [1- (imidazo [5,1-b] thiazol-3-yl) -1- (methylthiocarbonyloxy) methyl] pyrrolidine
    NMR (CDCl 3 ) : 0.02, 0.03 (total 6H, s, each), 0.85 (9H, s), 2.07-2.11 , 4.20-4.45 (2H, m), 4.58-4.78 (3H, m), 5.21-5.31 (2H, m), 5.79-5.98 , 8.12, 8.19 (total 1H, s, each)
    MS (FAB + ): 528 (M &lt; + & gt ; + H)
    b) Synthesis of (3R, 5R) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1- b] thiazol-
    143 mg of hydrogenated tri-n-butyltin (1.34 ml) and 2,2'-azobisisobutyronitrile were added to a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethyl To 143 mg of silyloxy-5- [1- (imidazo [5,1-b] thiazol-3-yl) -1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomeric mixture) , And the mixture was degassed under an argon stream for 20 minutes and heated under reflux for 5 hours. The solvent in the reaction solution was removed under reduced pressure to obtain a crude product which was purified sequentially by column chromatography using silica gel (dichloromethane: methanol = 50: 1) and Sephadex LH-20 (chloroform: methanol = 1: 1) (3R, 5R) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1- b] thiazol-3- yl) methylpyrrolidine 732 Mg.
    NMR (CDCl 3) δ: 0.01 (6H, s), 0.82 (9H, s), 1.75-1.86 (1H, m), 1.91-2.04 (1H, m), 2.72-2.91 (1H, m), 3.25- (1H, s), 3.53 (3H, m), 4.22-4.38 (2H, m), 4.58-4.69 (2H, m), 5.20-5.33 7.07 (1H, s), 8.00, 8.17 (total 1H, s each)
    MS (FAB + ): 422 (M &lt; + & gt ; + H)
    c) Preparation of (3R, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-3-yl) methyl- 3- methanesulfonyloxypyrrolidine
    (0.75 ml) was added to a solution of (3R, 5R) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [ 3-yl) thiazol-3-yl) methylpyrrolidine, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with 50 ml of ethyl acetate, water was added to the reaction solution, and the mixture was made into a weak alkali by adding a saturated aqueous solution of sodium hydrogencarbonate and extracted three times with ethyl acetate. The organic layer was washed once with saturated brine, dried over magnesium sulfate and filtered to remove the solvent under reduced pressure to give (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [ -b] thiazol-3-yl) methylpyrrolidine. Triethylamine (0.41 ml) and methanesulfonyl chloride (0.23 ml) were successively added to the above solution of the compound in 3 ml of dichloromethane under ice-cooling under an argon atmosphere, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel (ethyl acetate) to give (3R, 5R ) -1-allyloxycarbonyl-5- (imidazo [5,1-b] thiazol-3-yl) methyl-3-methanesulfonyloxypyrrolidine.
    NMR (CDCl 3) δ: 1.85-2.08 (1H, m), 2.31-2.50 (1H, m), 2.71-2.93 (1H, m), 2.95 (3H, s), 3.31-3.63 (2H, m), (1H, m), 6.42 (1H, s), 4.42-4.41 (1H, ), 7.04 (1H, s), 7.94, 8.14 (total 1H, s, each)
    MS (EI): 385 (M &lt; + & gt ; ).
    d) (3S, 5R) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-
    Potassium thioacetate (365 mg) was added to a solution of (3R, 5R) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Sulfonyloxypyrrolidine and the mixture was stirred at 70 ° C under an argon atmosphere for 8.5 hours. The reaction solution was cooled, water was added to the reaction solution, and the mixture was extracted four times with ethyl acetate. The organic layer was washed once with saturated brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel (hexane: ethyl acetate = 1: 1) to obtain 374.7 mg of the title compound as a brown viscous substance.
    NMR (CDCl 3) δ: 1.62-1.79 (1H, m), 2.30 (3H, s), 2.35-2.53 (1H, m), 2.79-2.88 (1H, m), 3.22-3.56 (2H, m), M), 6.40 (1H, s), 3.85-4.09 (2H, m), 4.18-4.28 (1H, m), 4.53-4.61 ), 7.03 (1H, s), 7.95, 8.18 (total 1H, s, each)
    MS (TSP): 366 (M &lt; + & gt ; + H)
    [Synthesis Example 9]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-2- yl) methylpyrrolidine
    a) Synthesis of (3R, 5R) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol-
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1-hydroxy- 1- (imidazo [ Thiazol-2-yl) methyl] pyrrolidine (diastereomeric mixture) was used as the starting material. Thus, as a yellow oil, (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol- 1.24 g of 1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomeric mixture) was prepared.
    NMR (CDCl 3) δ: 0.01 , 0.02 (total 6H, s, each), 0.82, 0.87 (total 9H, s, each), 1.71-1.79 (1H, m), 2.05-2.19 (1H, m), 2.61 (3H, s), 3.30-3.36 (1H, m), 3.42-3.62 (2H, m), 4.21-4.29 (1H, m), 4.50-4.70 m), 5.88-6.01 (1H, m), 7.04 (1H, s), 7.26
    MS (FAB + ): 528 (M &lt; + & gt ; + H)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1- b] thiazol-
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol- Carbonyloxy) methyl] pyrrolidine was used as the starting material, the procedure of Synthetic Example 8-b) was repeated, and purification was carried out by column chromatography using silica gel (ethyl acetate: methanol = 9: 1) Respectively. Thus, as colorless oil, (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1- b] thiazol- 656.2 mg.
    NMR (CDCl 3) δ: 0.02 (6H, s), 0.81 (9H, s), 1.87-1.98 (1H, m), 2.93-3.04 (1H, m), 3.00-3.18 (2H, m), 3.36- (1H, s), 3.58 (2H, m), 4.21-4.30 (2H, m), 4.61-4.67 (2H, m), 5.20-5.34 7.16 (1H, s), 7.89 (1H, s)
    MS (FAB + ): 422 (M &lt; + & gt ; + H)
    c) (3R, 5S) -1-Allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-2-yl) methyl-3-methanesulfonylpyrrolidine
    656.2 mg of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1-b] thiazol-2- yl) methylpyrrolidine was used The procedure of Synthesis Example 8-c) was repeated except that the methanesulfonation was carried out under ice-cooling. Thus, 349.1 mg of (3R, 5S) -1-allyloxycarbonyl-3-mesyloxy-5- (imidazo [5,1-b] thiazol-2- yl) methylpyrrolidine was prepared as colorless oil Respectively.
    NMR (CDCl 3) δ: 1.90-2.06 (1H, m), 2.32-2.45 (1H, m), 2.95 (3H, s), 2.98-3.23 (2H, m), 3.40-3.52 (1H, m), (1H, m), 5.17-5.31 (2H, m), 5.83-5.98 (1H, m), 6.95 (1H, s), 7.14 (1H, s), 7.85
    MS (FAB &lt; + & gt ; ): 386 (M &lt;
    d) (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-
    Except that 326.8 mg of (3R, 5S) -1-allyloxycarbonyl-3-mesyloxy-5- (imidazo [5,1-b] thiazol-2- yl) methylpyrrolidine was used The procedure of Synthesis Example 8-d) was repeated. Thus, 289.4 mg of the title compound was obtained as a brown viscous substance.
    NMR (CDCl 3) δ: 1.66-1.78 (1H, m), 2.24 (3H, s), 2.34-2.50 (1H, m), 2.91-3.22 (3H, m), 3.76-3.87 (1H, m), (1H, s), 7.14 (1H, s), 7.14 (1H, m) 7.84 (1H, s)
    MS (FAB &lt; + & gt ; ): 366 (M &lt;
    [Synthesis Example 10]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (3-methylimidazo [5,1- b] thiazol-2- yl) methylpyrrolidine
    a) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (3-methylimidazo [5,1- b] thiazole Yl) methyl] pyrrolidine (diastereomer mixture)
    1.69 M n-butyllithium / n-hexane solution (7.4 ml) was added to a solution of 1.56 g of 3-methylimidazo [5,1-b] thiazole in 25 ml of dry THF while maintaining the temperature at- Was added dropwise over 10 minutes and the mixture was stirred at this temperature for 2 hours. A solution of 3.54 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 15 ml of THF was dropwise added dropwise to the mixed solution, At -70 &lt; 0 &gt; C to 0 &lt; 0 &gt; C, and the mixture was stirred at 0 &lt; 0 &gt; C for 2 hours and then at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate and filtered to remove the solvent under reduced pressure. The resulting crude product was purified by silica gel (ethyl acetate) and Sephadex LH-20 (dichloromethane: methanol = 1 : 1) to give (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1-hydroxy- Methyl imidazo [5,1-b] thiazol-2-yl) methyl] pyrrolidine (diastereomer mixture).
    NMR (CDCl 3 ) : 0.01, 0.02 (total 6H, s, each), 0.80, 0.81 (total 9H, s, each), 1.63-2.06 ), 3.35-3.61 (2H, m), 4.17-4.38 (2H, m), 4.58-4.88 (2H, m), 5.02-5.31 (total 1H, s, each), 7.79 (1H, s)
    MS (EI): 451 (M &lt; + & gt ; ).
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- -1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomer mixture)
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- (3-methylimidazo [5,1- b] thiazol- ) Methyl] pyrrolidine (1.40 g) was used as the starting material. Thus, a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- -Yl) -1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomer mixture).
    NMR (CDCl 3) δ: 0.07 (6H, s), 0.80, 0.88 (total 9H, s, each), 1.70-2,28 (3H, m), 2.35, 2.19 (total 3H, s, each), 2.65 (2H, m), 5.81-5.99 (1H, m), 7.01-7.10 (1H, m), 4.20-4.66 (3H, m) , 7.81-7.91 (1 H, m)
    MS (ESI): 542 (M &lt; + & gt ; + H)
    c) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5 - [(3-methylimidazo [5,1- b] thiazol- Pyrrolidine
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- - (methylthiocarbonyloxy) methyl] pyrrolidine was used as a starting material. Thus, as a yellow oil, (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5 - [(3-methylimidazo [5,1- b] thiazol- ) Methylpyrrolidine (660.9 mg).
    NMR (CDCl 3) δ: 0.01 (6H, s), 0.82 (9H, s), 1.70-2.01 (2H, m), 2.36 (3H, s), 2.75-2.84 (1H, m), 3.03-3.22 ( (1H, m), 3.39-3.42 (2H, m), 4.14-4.27 (2H, m), 4.61-4.66 7.03 (1 H, s), 7.82 (1 H, s)
    MS (ESI): 436 (M &lt; + & gt ; + H)
    d) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5 - [(3-methylimidazo [5,1- b] thiazol- Dean
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5 - [(3- methylimidazo [5,1- b] thiazol- The procedure of Synthesis Example 9-c) was repeated except that 660.9 mg of the compound of Example 9 was used. Thus, as colorless oil, methyl (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5 - [(3-methylimidazo [5,1- b] thiazol- ] Pyrrolidine (596.5 mg).
    NMR (CDCl 3) δ: 1.91-2.18 (2H, m), 2.45 (3H, s), 2.45-2.60 (1H, m), 3.10 (3H, s), 3.30-3.39 (1H, m), 3.58- (1H, m), 3.68 (2H, m), 3.68 (1H, ), 5.98-6.12 (1H, m), 7.12 (1H, s), 7.93 (1H, s)
    MS (FAB + ): 400 (M &lt; + & gt ; + H)
    e) Synthesis of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5 - [(3- methylimidazo [5,1- b] thiazol-2- yl) methyl] pyrrolidine
    (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5 - [(3-methylimidazo [5,1- b] thiazol-2- yl) methyl] pyrrolidine 596.5 The procedure of Synthesis Example 8-d) was repeated except that &lt; RTI ID = 0.0 &gt; Thus, 474.5 mg of the title compound was prepared as a yellow oil.
    NMR (CDCl 3) δ: 1.69-1.88 (1H, m), 2.34 (3H, s), 2.39 (3H, s), 2.40-2.60 (1H, m), 2.81-2.90 (1H, m), 3.20- (2H, m), 3.41 (2H, m), 3.05-3.96 (1H, m), 4.01-4.18 (2H, m), 4.62-4.64 ), 7.05 (1H, s), 7.84 (1H, s)
    MS (FAB &lt; + & gt ; ): 380 (M &lt; + &
    [Synthesis Example 11]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (5-methylimidazo [5,1- b] thiazol-2- yl) methylpyrrolidine
    a) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (5-methylimidazo [5,1- b] thiazole Yl)] methylpyrrolidine
    1.53 g of 5-methylimidazo [5,1-b] thiazole and 3.46 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine The procedure of Example 10-a was repeated except that the residue was purified by column chromatography using silica gel (ethyl acetate: methanol = 9: 1) and Sephadex LH-20 (dichloromethane: methanol = 1: 1) Followed by purification to obtain (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1-hydroxy- Yl] methyl] pyrrolidine (diastereomeric mixture) as a colorless oil.
    NMR (CDCl 3) δ: 0.00 , 0.01 (total 6H, s, each), 0.81, 0.82 (total 9H, s, each), 1.60-2.04 (3H, m), 2.51 (3H, s), 3.31-3.68 (2H, m), 4.20-4.48 (2H, m), 4.60-4.75 (2H, m), 4.98 (1H, m), 5.21-5.34 , 6.88 (total 1H, s, each), 7.16, 7.17 (total 1H, s, each)
    MS (FAB + ): 452 (M &lt; + & gt ; + H)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- -1- (methylthiothiocarbonyloxy) methyl] pyrrolidine
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (5-methylimidazo [5,1- b] thiazol- -Yl) methyl] pyrrolidine was used as a starting material in Example 8-a). Thus, as a yellow oil, (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- -Yl) -1- (methylthiothiocarbonyloxy) methyl] pyrrolidine (diastereomer mixture).
    NMR (CDCl 3) δ: 0.06 (6H, s), 0.81, 0.87 (total 9H, s, each), 1.69-1.88 (1H, m), 2.01-2.18 (1H, m), 2.31-2.38 (1H, m), 2.51 (3H, s), 2.60,2.61 (total 3H, s, each), 3.30-3.55 (2H, m), 4.22-4.67 (4H, m), 5.19-5.33 , 5.87-6.03 (1H, m), 6.88-6.93 (1H, m), 7.10-7.21 (1H, m)
    MS (FAB &lt; + & gt ; ): 542 (M &lt;
    c) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-methylimidazo [5,1- b] thiazol- Dean
    (5R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- - (methylthiothiocarbonyloxy) methyl] pyrrolidine (2.19 g) was used as the starting material. Thus, a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-methylimidazo [5,1- b] thiazol- Methylpyrrolidine (1.10 g).
    NMR (CDCl 3 ) : 0.05 (6H, s), 0.81 (9H, s), 1.79-1.88 (1H, m), 1.93-2.05 (2H, m), 3.37-3.45 (2H, m), 4.19-4.28 (2H, m), 4.59-4.68 (2H, m), 5.19-5.33 6.84 (1H, s), 6.97 (1H, s)
    MS (FAB &lt; + & gt ; ): 436 (M &lt;
    d) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5- (5-methylimidazo [5,1- b] thiazol-
    (5R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-methylimidazo [5,1- b] thiazol-2-yl) methylpyrrolidine 1.15 g was used in the same manner as in Synthesis Example 9-c). Thus, as colorless oil, (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5- (5-methylimidazo [5,1- b] thiazol- Lt; / RTI &gt;
    NMR (CDCl 3) δ: 2.10-2.21 (1H, m), 2.48-2.62 (1H, m), 2.60 (3H, s), 3.10 (3H, s), 3.11-3.38 (2H, m), 3.58- (1H, m), 3.69 (1H, m), 4.01-4.15 (1H, m), 4.34-4.43 (1H, m), 4.71-4.80 ), 5.98-6.10 (1H, m), 6.93 (1H, s), 7.10 (1H, s)
    MS (TS): 400 (M &lt; + & gt ; + H)
    e) Synthesis of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (5-methylimidazo [5,1- b] thiazol-
    1.04 g of (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5- (5-methylimidazo [5,1- b] thiazol- The procedure of Synthesis Example 8-d) was repeated. Thus, 766.4 mg of the title compound was prepared as brown oil.
    NMR (CDCl 3) δ: 1.60-1.79 (2H, m), 2.27 (3H, s), 2.47 (3H, s), 2.40-2.51 (1H, m), 2.90-3.00 (1H, m), 3.02- M), 5.15-5.30 (2H, m), 5.81-5.96 (1H, m), 3.23 (2H, m), 3.78-3.89 ), 6.80 (1H, s), 6.94 (1H, s)
    MS (TS): 380 (M &lt; + & gt ; ).
    [Synthesis Example 12]
    (3S, 5R) -1-allyloxycarbonyl-3-benzoylthio-5- (imidazo [5,1- b] thiazol-7-yl) methylpyrrolidine
    a) 5,7-diiodoimidazo [5,1-b] thiazole, 5-iodoimidazo [5,1-b] thiazole and 7-iodoimidazo [5,1-b ] Thiazole
    A solution of 5.95 g of imidazo [5,1-b] thiazole and 150 ml of 1,2-dichloroethane was cooled to -38 ° C and 10.80 g of N-iodosuccinimide was added to the solution, The temperature was raised to room temperature over 3 hours. In addition, the mixture was stirred for 5 hours, 250 ml of dichloromethane was added to the solution, and the mixture was washed twice with 250 ml of water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by evaporation. The residue was purified by column chromatography using silica gel (toluene: ethyl acetate = 10: 1 - &gt; 3: 1 -> ethyl acetate alone). Thus, 1.65 g of 5,7-diiodoimidazo [5,1-b] thiazole, 1.59 g of 5-iodoimidazo [5,1- b] thiazole, and 7-iodoimidazo [ , 1-b] thiazole was prepared.
    5,7-diiodoimidazo [5,1-b] thiazole
    NMR (CDCl 3) δ: 6.97 (1H, d, J = 4.3 Hz), 7.36 (1H, d, J = 4.3 Hz)
    MS (EI): 376 (M &lt; + & gt ; ).
    5-iodoimidazo [5,1-b] thiazole
    NMR (CDCl 3 ) : 6.91 (1H, d, J = 4.3 Hz), 7.17 (1H, s), 7.28
    MS (EI): 250 (M &lt; + & gt ; ).
    7-iodoimidazo [5,1-b] thiazole
    NMR (CDCl 3) δ: 6.89 (1H, d, J = 4.3 Hz), 7.50 (1H, d, J = 4.3 Hz), 7.96 (1H, s)
    MS (EI): 250 (M &lt; + & gt ; ).
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ) Methyl] pyrrolidine (stereoisomer A) and homogeneous material (stereoisomer B)
    A 2M solution of methylmagnesium iodide / ether diethyl (4.6 ml) was diluted with 50 ml of anhydrous THF and a solution of 2.0 g of 7-iodoimidazo [5,1-b] thiazole in 50 ml of THF was added with argon Was added dropwise to the diluted solution in an atmosphere. The mixture was stirred at the same temperature for 10 minutes, stirred at room temperature for 1.5 hours, then cooled to -50 ° C and a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyl Oxo-5-formylpyrrolidine in 100 ml of tetrahydrofuran was added dropwise. The reaction was carried out over 3 hours while raising the temperature to 10 ° C, 200 ml of a semi-saturated ammonium chloride aqueous solution was added to the solution, and the mixture was extracted twice with 250 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation. The residue was purified by column chromatography using silica gel (ethyl acetate alone → ethyl acetate: methanol = 20: 1 → 10: 1). Thus, (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- 1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ) Methyl] pyrrolidine (stereoisomer A: a high polar component) and 450 mg of (3R, 5S) -1-allyloxycarbonyl-3- (Imidazo [5,1-b] thiazol-7-yl) methyl] pyrrolidine (stereoisomer B: low polar component).
    (Stereoisomer A)
    NMR (CDCl 3) δ: 0.01 (6H, s), 0.82 (9H, s), 1.78 (1H, m), 2.18 (1H, m), 3.40 (1H, m), 3.60 (1H, m), 4.20 (2H, m), 4.82 (2H, m), 4.82 (2H, m) J = 4.2 Hz), 7.36 (1H, d, J = 4.2 Hz), 7.91 (1H, s)
    (Stereoisomer B)
    NMR (CDCl 3) δ: 0.02 (6H, s), 0.84 (9H, s), 1.70 (1H, m), 2.00 (1H, m), 2.46 (1H, m), 3.03 (1H, m), 3.40 (2H, m), 6.80 (1H, m), 4.11 (1H, m), 4.45-4.70 (3H, m), 5.00-5.40 ), 7.35 (1H, d, J = 4.2 Hz), 7.88 (1H, s)
    c) Preparation of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol- Methylthiocarbonyloxy) methyl] pyrrolidine (stereoisomer A)
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (imidazo [5,1- b] thiazol- ] Pyrrolidine (stereoisomer A) was used as the starting material. The procedure of Synthesis Example 8-a) was repeated. Thus, a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol- Methylthiocarbonyloxy) methyl] pyrrolidine (stereoisomer) was prepared.
    NMR (CDCl 3) δ: 0.01 (6H, s), 0.85 (9H, s), 2.08 (1H, m), 2.43 (3H, s), 2.50 (1H, m), 2.98 (1H, m), 3.20 (2H, m), 5.50-5.78 (1H, m), 4.54-4.76 (2H, m), 5.13-5.50 (1H, s), 5.88-6.20 (1H, m), 6.82 (1H, d, J = 4.3 Hz), 7.34
    d) Synthesis of (3R, 5R) -1-aryloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1- b] thiazol-
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (imidazo [5,1- b] thiazol- Yl) thiocarbonyloxy) methyl] pyrrolidine (stereoisomer A) was used as the starting material. Thus, as colorless oil, (3R, 5R) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [5,1- b] thiazol-7-yl) methylpyrrolidine 206 mg.
    NMR (CDCl 3) δ: 0.01 (6H, s), 0.83 (9H, s), 1.82-2.25 (2H, m), 3.00-3.45 (4H, m), 4.05 (1H, m), 4.30 (1H, (1H, m), 4.67 (2H, m), 5.18-5.40 (2H, m), 6.00 7.92 (1 H, s)
    e) Preparation of (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [5,1- b] thiazol-7-yl) methylpyrrolidine
    (0.204 ml) was added to a solution of (3R, 5R) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (imidazo [ Thiazol-7-yl) methylpyrrolidine, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was diluted with 20 ml of ethyl acetate, and saline was added to the diluted solution. The mixture was adjusted to pH 9 by adding a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered to remove the solvent under reduced pressure. The residue was purified by column chromatography using silica gel (chloroform: methanol = 10: 1) to obtain (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [ ] Thiazol-7-yl) methylpyrrolidine.
    NMR (CDCl 3) δ: 1.90-2.40 (2H, m), 3.00-3.60 (5H, m), 4.25 (1H, m), 4.33 (1H, m), 4.64 (2H, m), 5.16-5.40 ( (2H, m), 5.98 (1H, m), 6.79 (1H, d, J = 4.5 Hz), 7.34
    f) (3S, 5R) -1-Allyloxycarbonyl-3-benzoylthio-5- (imidazo [5,1- b] thiazol-
    A solution of 134 mg of (3R, 5R) -1-allyloxycarbonyl-3-hydroxy-5- (imidazo [5,1- b] thiazol- And ice-cooled. Triphenylphosphine (228 mg) and 0.139 ml of diethyl azocarboxylate were added in an argon atmosphere. The mixture was stirred at the same temperature for 1.5 hours, 0.104 ml of thiobenzoic acid was added, and the mixture was stirred at the same temperature for 20 minutes and then at room temperature for 3 hours. The reaction solution was diluted with 30 ml of ethyl acetate, and saline was added to this solution. The mixture was adjusted to pH 9 by adding a saturated aqueous sodium hydrogencarbonate solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using silica gel (toluene: ethyl acetate = 1: 1 -> chloroform: ethyl acetate = 2: 1) to obtain 147 mg of the title compound.
    NMR (CDCl 3) δ: 2.10 (1H, m), 2.54 (1H, m), 3.00-3.35 (3H, m), 4.05 (1H, m), 4.18 (1H, m), 4.30 (1H, m) (1H, d, J = 4.2 Hz), 4.65 (2H, m), 5.20-5.42 7.60 (3H, m), 7.90 (1H, s), 7.93 (2H, m)
    [Synthesis Example 13]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol-3- yl) ethenyl] pyrrolidine mixture)
    a) (imidazo [5,1-b] thiazol-3-yl) methyltriphenylphosphonium chloride hydrochloride
    Thionyl chloride (12.7 ml) was added to 6.67 g of 3-hydroxymethylimidazo [5,1-b] thiazole hydrochloride, and the mixture was stirred at 60 ° C for 30 minutes. The temperature was lowered to room temperature, isopropyl ether was added to the solution, the supernatant was poured gently, and the residue was dried under reduced pressure to obtain 3-chloromethylimidazo [5,1-b] thiazole hydrochloride. This compound was dissolved in 35 ml of DMF, 10.11 g of triphenylphosphine was added to the solution, and the mixture was stirred at 100 ° C for 12 hours. The resulting precipitate was collected by filtration to obtain 8.86 g of (imidazo [5,1-b] thiazol-3-yl) methyltriphenylphosphonium chloride hydrochloride.
    NMR (CDCl 3) δ: 5.99 (2H, d, J = 14.8 Hz), 7.41 (1H, s), 7.60-7.70 (6H, m), 7.80-7.90 (9H, m), 9.59 (1H, s)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [2- (imidazo [5,1- b] thiazol-3- yl) ethenyl] pyrrolidine Mixture of isomers)
    Potassium t-butoxide (1.95 g) was added to 15 ml of THF and 15 ml of DMSO under ice cooling and 4.09 g of (imidazo [5,1-b] thiazol-3-yl) methyltriphenylphosphonium chloride hydrochloride Lt; / RTI &gt; The mixture was stirred for 2 hours and a solution of 2.9 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 15 ml of THF was added, The mixture was stirred under ice-cooling for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was successively washed with diluted hydrochloric acid and saturated brine, then dried over magnesium sulfate. The solvent was removed by evaporation, the residue was dissolved in 80 mL of methanol, 3.5 mL of 5N hydrochloric acid aqueous solution was added to the solution, and the mixture was stirred at room temperature for 12 hours. The mixture was neutralized with a 5N aqueous sodium hydroxide solution, dichloromethane was added to the mixture, the mixture was washed sequentially with water and brine, and then dried over magnesium sulfate. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel to give (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [2- -b] thiazol-3-yl) ethenyl] pyrrolidine.
    NMR (CDCl 3) δ: 1.75-2.00 (1H, m), 2.05-2.30 (1H, m), 3.40-3.55 (2H, m), 4.75-5.35 (3H, m), 5.80-6.00 (1H, m ), 6.35-6.64 (2H, m), 7.05-7.15 (1H, m), 7.20-7.30 (1H, m), 8.20-8.50
    c) Synthesis of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol-3- yl) ethenyl] pyrrolidine Mixture of isomers)
    0.43 ml of triethylamine and 0.43 ml of methanesulfonyl chloride were added to a solution of (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- [2- (imidazo [ -b] thiazol-3-yl) ethenyl] pyrrolidine, and the mixture was stirred for 2 hours under ice-cooling. Dichloromethane was added to the reaction mixture, and the reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over magnesium sulfate. The solvent was removed by evaporation to give the methanesulfonyloxy derivative. Potassium thioacetate (0.77 g) was added to a solution of the above compound in 15 ml DMF and the mixture was stirred at 70 &lt; 0 &gt; C for 4 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography using silica gel to obtain 1.44 g of the title compound.
    NMR (CDCl 3) δ: 1.75-1.95 (1H, m), 2.34 (3H, m), 2.56-2.80 (1H, m), 3.33-3.48 (1H, m), 3.90-4.15 (2H, m), (2H, m), 6.40-6.65 (2H, m), 4.85-5.35 (3H, m), 5.60-6.05 ), 7.92-8.20 (1 H, m)
    [Synthesis Example 14]
    (Stereoisomer A) and a homologue (stereoisomer B (3S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- )
    a) (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5 - [(thiazol-2- yl) methylaminocarbonyl] pyrrolidine
    0.66 g of 1-hydroxybenzotriazole and 0.66 g of dicyclohexylcarbodiimide were added to a solution of (3S.5S) -3-acetothio-1-oxycarbonylpyrrolidine-5-carboxylic acid Was added to a solution of 0.83 g and the mixture was stirred at room temperature for 12 hours. The reaction mixture was ice-cooled, a solution of 0.37 g of 2-aminomethylthiazole in 1 ml of THF was added to the mixture, and the mixture was stirred for 12 hours. The insoluble material was removed by filtration and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel to give (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5 - [(thiazol-2- yl) methylaminocarbonyl] pyrrolidine 1.00 g.
    NMR (CDCl 3) δ: 2.30 (3H, s), 2.30-2.80 (2H, m), 3.30-3.40 (1H, m), 3.90-4.00 (1H, m), 4.10-4.15 (1H, m), M), 7.25 (2H, m), 4.40-5.50 (1H, m), 4.45-4.55 D, J = 3.3 Hz), 7.55 (1H, s), 7.72 (1H,
    b) Synthesis of (3S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-5-yl) pyrrolidine (stereoisomer A) Isomer B)
    (1.2 ml) was added to a solution of 1.00 g of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5 - [(thiazol-2- yl) methylaminocarbonyl] pyrrolidine And the mixture was stirred at 100 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated under reduced pressure, and dichloromethane was added to the residue. The mixture was successively washed successively with an aqueous solution of potassium carbonate and saturated brine, followed by drying over magnesium sulfate. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel to give 0.27 g of the title compound (stereoisomer A: high polarity component) and 0.07 g of the title compound (stereoisomer B: low polarity component).
    (Stereoisomer A)
    NMR (CDCl 3) δ: 2.32 (3H, s), 2.70-2.83 (2H, m), 3.30-3.40 (1H, m), 3.91-4.05 (1H, m), 4.19-4.26 (1H, m), (1H, m), 4.70-4.60 (2H, m), 4.90-5.30 (3H, m), 5.80-5.95 (1H, m), 6.75-6.80 )
    (Stereoisomer B)
    NMR (CDCl 3) δ: 2.22-2.40 (4H, m), 2.98-3.07 (1H, m), 3.55-3.63 (1H, m), 3.95-4.05 (1H, m), 4.44-5.62 (3H, m ), 5.17-5.32 (3H, m), 5.82-5.96 (1H, m), 6.75-6.82
    [Synthesis Example 15]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol-2- yl) vinyl] pyrrolidine
    a) (imidazo [5,1-b] thiazol-2-yl) methyltriphenylphosphonium chloride hydrochloride
    Hydroxymethylimidazo [5,1-b] thiazole hydrochloride (1.40 g) was suspended in 15 ml of THF, 0.8 ml of thionyl chloride was added, and the mixture was stirred at 60 ° C for 1.5 hours . The solvent was removed by evaporation to give 2-chloromethylimidazo [5,1-b] thiazole hydrochloride. This compound was dissolved in 7 ml of DMF, 1.78 g of triphenylphosphine was added to the solution, and the mixture was stirred at 100 ° C for 12 hours. The resulting precipitate was collected by filtration to obtain 2.14 g of (imidazo [5,1-b] thiazol-2-yl) methyltriphenylphosphonium chloride hydrochloride.
    NMR (CDCl 3) δ: 5.89 (2H, d, J = 15.4 Hz), 7.57 (1H, s), 7.75-8.05 (16H, m), 9.40 (1H, s)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3- methanesulfonyloxy-5- [2- (imidazo [5,1- b] thiazol-
    Potassium t-butoxide (1.06 g) was added to a solution of (imidazo [5,1-b] thiazol-2-yl) methyltriphenylphosphonium chloride hydrochloride Was added to a solution of 2.24 g. The mixture was stirred under ice cooling for 2 hours and a solution of 1.32 g of (3R, 5S) -1-allyloxycarbonyl-3-methanesulfonyloxy-5-formylpyrrolidine in 5 ml of THF was added, This solution was stirred under ice-cooling for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with dilute hydrochloric acid and brine, followed by drying over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography on silica gel to give (3R, 5S) -1-allyloxycarbonyl-3- methanesulfonyloxy-5- [2- (imidazo [5,1- b] thiazole- Yl) vinyl] pyrrolidine (mixture of geometric isomers).
    NMR (CDCl 3) δ: 1.90-2.15 (1H, m), 2.55-2.70 (1H, m), 3.05-3.10 (3H, m), 3.65-3.75 (1H, m), 3.95-4.05 (1H, m ), 4.05-4.70 (2H, m), 5.05-5.35 (4H, m), 5.65-6.00 (2H, m), 6.30-6.70 (1H, m), 7.00-7.05 , &lt; / RTI &gt; s), 7.84-7.95 (1H, m)
    c) Synthesis of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2-imidazo [5,1- b] thiazol-2-yl) vinyl] pyrrolidine mixture)
    Potassium thioacetate (0.22 g) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-3- methanesulfonyloxy-5- [2- (imidazo [5,1- b] thiazol- Yl) vinyl] pyrrolidine (mixture of geometric isomers), and the mixture was stirred at 70 ° C under argon atmosphere for 4 hours. Ethyl acetate was added to the reaction solution, and the mixture was successively washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel to obtain 0.42 g of the title compound.
    NMR (CDCl 3) δ: 2.32-2.38 (3H, m), 2.55-2.80 (1H, m), 3.30-3.40 (1H, m), 3.90-4.15 (2H, m), 4.50-4.70 (3H, m ), 4.90-5.35 (3H, m), 5.70-6.00 (2H, m), 6.25-6.60 (1H, m), 7.00-7.05 , m)
    [Synthesis Example 16]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-
    a) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- [2- (t-butoxyaminomethyl) thiazol-4-yl] -3-t-butyldimethyloxypyrrolidine
    A solution of 0.72 g of (3S, 5R) -1-allyloxycarbonyl-3-t-butyldimethyloxyproline ethyl ester and 0.35 g of lithium bromide in 5 ml of dry THF was dried with a dry ice / acetone solution, Lithium / diethyl ether was added dropwise to the solution. The mixture was stirred at the same temperature for 30 minutes and the reaction was quenched with saturated aqueous ammonium chloride solution. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine. The solvent was concentrated under reduced pressure. To the obtained residue was added DMF (2 ml), sodium bromide (0.02 g), calcium carbonate (0.02 g) and t- (butoxycarbonylamino) acetothioamide (0.38 g), and the mixture was stirred at 45 ° C for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (hexane: ethyl acetate = 3: 1) to give (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethyloxy-5- [2- -Butoxyaminomethyl) thiazol-4-yl] pyrrolidine (0.08 g).
    NMR (CDCl 3) δ: 0.07 (6H, s), 0.88 (9H, s), 1.47 (9H, s), 2.20-2.30 (2H, m), 3.45-3.60 (1H, m), 3.65-3.75 ( (1H, m), 4.45-4.60 (5H, m), 5.05-5.30 (4H, m), 5.70-5.95
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- [2- (t-butoxyaminomethyl) thiazol-4-yl] -3- methanesulfonyloxypyrrolidine
    1M tetrabutylammonium fluoride / THF solution (4 ml) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethyloxy-5- [2- Aminomethyl) thiazol-4-yl] pyrrolidine in 100 ml of tetrahydrofuran and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with brine. Dichloromethane (20 mL), triethylamine (0.78 mL), and methanesulfonyl chloride (0.39 mL) were added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed sequentially with water, an aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by column chromatography using silica gel (hexane: ethyl acetate = 1: 1) to give (3R, 5S) -1-allyloxycarbonyl-5- [2- -Butoxyaminomethyl) thiazol-4-yl] -3-methanesulfonyloxypyrrolidine (1.26 g).
    NMR (CDCl 3) δ: 1.45 (9H, s), 2.55-2.65 (2H, m), 3.05 (3H, m), 3.85-4.05 (2H, m), 4.45-4.60 (4H, m), 5.05- 5.50 (5H, m), 5.70-5.95 (1H, m), 7.00-7.15 (1H, m)
    c) Preparation of (3R, 5S) -1-allyloxycarbonyl-5- (2-formylaminoethylthiazol-4-yl) -3- methanesulfonyloxypyrrolidine
    Trifluoroacetic acid (4 ml) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-5- [2- (tert- butoxyaminomethyl) thiazol- Lt; / RTI &gt; and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrocarbons (30 ml) and 20 ml of dichloromethane were added to the residue, mixed acid anhydride prepared from 1.0 ml of formic acid and 0.75 ml of acetic acid was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour . The reaction mixture was separated, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography using silica gel (methanol: ethyl acetate = 5: 95) to give (3R, 5S) -1-allyloxycarbonyl-5- (2-formylaminomethylthiazol- ) -3-methanesulfonyloxypyrrolidine (0.81 g).
    NMR (CDCl 3) δ: 2.50-2.70 (2H, m), 3.05 (3H, s), 3.85-4.00 (2H, m), 4.45-4.60 (2H, m), 4.75 (2H, dd, J = 1.0 , 5.8 Hz), 5.05-5.35 (3H, m), 5.40-5.50 (1H, m), 5.70-6.00 (1H, m), 6.35 (1H, br s), 7.05-7.15 (1H, s)
    d) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-3-yl) -3- methanesulfonyloxypyrrolidine
    Toluene (20 ml) and 0.95 ml of phosphorus oxychloride were added to a solution of (3R, 5S) -1-allyloxycarbonyl-5- (2-formylaminomethylthiazol-4-yl) -3- methanesulfonyloxypyrrole And the mixture was heated at 120 &lt; 0 &gt; C for 45 minutes under reflux. The mixture was concentrated under reduced pressure. Dichloromethane was added to the residue and the mixture was washed sequentially with water, aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel (methanol: ethyl acetate = 5: 95) to give (3R, 5S) -1- allyloxycarbonyl-5- (imidazo [5,1- b] thiazole - (3R, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1-b] thiazol-3-yl) -3-methanesulfonyloxypyrrolidine.
    NMR (CDCl 3) δ: 2.40-2.50 (1H, m), 2.70-2.90 (1H, m), 3.10 (3H, s), 3.80-3.90 (1H, m), 4.10-4.25 (1H, m), (2H, m), 5.05-5.35 (4H, m), 5.60-5.95 (1H, m), 6.63 (1H, s), 7.11
    e) (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol-
    Potassium thioacetate (0.24 g) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-5- (imidazo [5,1- b] thiazol- Oxypyrrolidine in 100 ml of dichloromethane, and the mixture was stirred at 70 캜 for 2 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed successively with water, aqueous sodium hydrogencarbonate solution and brine, and then dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by column chromatography using silica gel (methanol: ethyl acetate = 2: 98) to obtain 0.46 g of the title compound.
    NMR (CDCl 3) δ: 2.33 (3H, s), 2.10-2.20 (1H, m), 2.80-2.90 (1H, s), 3.45-3.55 (1H, m), 4.05-4.15 (1H, m), (2H, m), 5.05-5.35 (3H, m), 5.70-5.95 (1H, m), 6.60 (1H, s), 7.11 7.84 (1H, s)
    [Synthesis Example 17]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- 5- yl) ethenyl] pyrrolidine mixture)
    a) Chloride (imidazo [5,1-b] thiazol-5-yl) methyltriphenylphosphonium
    Triphenylphosphine (2.51 g) was added to a solution of 1.23 g of 5-hydroxymethylimidazo [5,1-b] thiazole hydrochloride in 20 ml of DMF, and the mixture was stirred at 100 ° C for 12 hours . The solvent was removed by evaporation, and the residue was purified by column chromatography using silica gel (methanol: dichloromethane = 5: 95) to give a chlorinated (imidazo [5,1- b] thiazol- 2.1 g of phosphinium was obtained.
    (1H, s), 7.12 (1H, d, J = 4.3 Hz), 7.65-7.90 (16H, m)
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- 5- yl) ethenyl] -3-methanesulfonyloxypyrrolidine
    T-Butoxide (1.11 g) was added to a solution of 0.44 g of (imidazo [5,1-b] thiazol-5-yl) methyltriphenylphosphonium chloride in 2 ml of THF and 2 ml of DMSO under ice- Lt; / RTI &gt; The mixture was stirred at the same temperature for 1 hour and a solution of 0.28 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 2 ml of THF was added , And the solution was stirred at the same temperature for 2 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over magnesium sulfate. The solvent was removed by evaporation and the residue was purified by column chromatography using silica gel (methanol: ethyl acetate = 5: 95) to give (3R, 5S) -1-allyloxycarbonyl-5- [2- [5,1-b] thiazol-5-yl) ethenyl] -3-methanesulfonyloxypyrrolidine (mixture of geometric isomers).
    NMR (CDCl 3) δ: 2.15-2.25 (1H, m), 2.55-2.65 (1H, m), 3.06 (3H, s), 3.65-3.75 (1H, m), 3.95-4.10 (1H, m), (2H, m), 4.75 (1H, m), 5.10-5.35 (3H, m), 5.85-6.00 (1H, m), 6.35-6.40 (1H, dd, J = 7.3,15.6 Hz) 6.70 (1H, s), 7.40-7.50 (1H, m)
    c) Synthesis of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol- 5- yl) ethenyl] pyrrolidine
    (3S, 5S) -1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol-5-yl) ethenyl] -3-methanesulfonyloxypyrrolidine , The procedure of Synthesis Example 16-e) was repeated. Thus, 0.25 g of the title compound was obtained.
    NMR (CDCl 3) δ: 1.85-1.95 (1H, m), 2.32 (3H, s), 2.60-2.75 (1H, m), 3.30-3.40 (1H, m), 3.95-4.05 (1H, m), (2H, m), 6.85-6.90 (1H, m), 4.05-4.15 (1H, m), 4.55-4.65 (3H, m), 5.10-5.35 , m), 7.10 (1 H, s), 7.45 (1 H, dd, J = 4.1 Hz)
    [Synthesis Example 18]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (imidazo [5,1- b] thiazol-7-yl) ethenyl] pyrrolidine mixture)
    The procedure of Synthesis Example 15 was repeated except that 0.44 g of 7-hydroxymethylimidazo [5,1-b] thiazole hydrochloride was used. Thus, 0.25 g of the title compound was prepared.
    NMR (CDCl 3) δ: 1.85-1.95 (1H, m), 2.33, 2.35 (3H, s each), 2.60-2.75 (1H, m), 3.30-3.40 (1H, m), 3.95-4.05 (1H, m), 6.50-6.60 (2H, m), 6.75-7.30 (2H, m), 4.10-4.15 6.90 (1H, m), 7.30-7.40 (1H, m), 7.90,9.95 (1H, s each)
    [Synthesis Example 19]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (3-methylimidazo [5,1- b] thiazol-2-yl) ethenyl] pyrrolidine (Mixture of geometric isomers)
    The procedure of Synthesis Example 15 was repeated except that 1.0 g of 3-methyl-2-hydroxymethylimidazo [5,1-b] hydrochloride was used. Thus, 0.92 g of the title compound was prepared.
    NMR (CDCl 3) δ: 2.05-2.20 (1H, m), 2.42 (3H, s), 2.55-2.70 (1H, m), 3.07 (3H, s), 3.65-3.75 (1H, m), 3.95- (1H, m), 4.55-4.70 (3H, m), 5.00-5.35 (3H, m), 5.60-5.75 (1H, m), 5.80-6.00 ), 7.00-7.10 (1H, m), 7.85-7.90 (1H, m)
    [Synthesis Example 20]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (2-methylimidazo [5,1- b] thiazol- (Mixture of geometric isomers)
    The procedure of Synthesis Example 15 was repeated except that 0.80 g of 2-methyl-3-hydroxymethylimidazo [5,1-b] thiazole hydrochloride was used. Thus, 1.20 g of the title compound was prepared.
    NMR (CDCl 3) δ: 1.85-2.00 (1H, m), 2.35-2.40 (6H, m), 2.70-2.85 (1H, m), 3.40-3.50 (1H, m), 4.00-4.15 (2H, m ), 4.55-4.65 (3H, m), 5.15-5.35 (2H, m), 5.85-6.00 (1H, m), 6.15-6.25 (1H, m), 6.40-6.60 (1 H, m), 8.00 (1 H, s)
    [Synthesis Example 21]
    (3S, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (5-methylthioimidazo [5,1- b] thiazol-
    a) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (5-methylthioimidazo [5,1- b] thiazole 2-yl)] methylpyrrolidine (diastereomer)
    1.60 g of 5-methylthioimidazo [5,1-b] thiazole and 2.97 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy- , The procedure of Synthesis Example 10-a) was repeated and column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) and silica gel (hexane: ethyl acetate = 1: 2) To give (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (5-methylthioimidazo [ 1-b] thiazol-2-yl) methyl] pyrrolidine (diastereomer mixture).
    NMR (CDCl 3) δ: 0.02 (6H, s), 0.83 (9H, s), 1.66-2.07 (2H, m), 2.51 (3H, s), 3.32-3.70 (3H, m), 4.24-4.37 ( (2H, m), 4.37-4.81 (2H, m), 5.24-5.38 (2H, m), 5.90-6.01 each)
    MS (FAB &lt; + & gt ; ): 484 (M &lt;
    b) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (5-methylthioimidazo [ -1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomer)
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1 -hydroxy- 1- (5-methylthioimidazo [5,1- b] thiazol- -Yl) methyl] pyrrolidine (diastereomer) (2.10 g) was used as the starting material. Thus, (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- -1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomeric mixture) as yellow oil.
    NMR (CDCl 3) δ: 0.01 & 0.06 (total 6H, s, each), 0.80 & 0,84 (total 9H, s, each), 1.81-1.87 (1H, m), 2.02-2.12 (1H, m) , 2.49 (3H, s), 2.59 (3H, s), 3.42-3.53 (1H, m), 3.70-3.75 (2H, m), 4.22-4.66 (4H, m), 5.18-5.32 , 5.86-6.00 (1H, m), 7.08 (1H, s), 7.31 (1H, br, s)
    MS (FAB + ): 574 (M &lt; + & gt ; + H)
    c) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-methylthioimidazo [5,1- b] thiazol- Dean
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (5-methylthioimidazo [5,1- b] thiazol- - (methylthiothiocarbonyloxy) methyl] pyrrolidine (diastereomeric mixture) was used in place of diethyl azodicarboxylate. The procedure of Synthesis Example 9-b) was repeated. Thus, (3R, 5S) -allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-methylthioimidazo [5,1- b] thiazol-2- yl) methylpyrrolidine 1.37 g &lt; / RTI &gt; as yellow oil.
    NMR (CDCl 3) δ: 0.03 (6H, s), 0.84 (9H, s), 1.78-1.91 (1H, m), 1.96-2.08 (1H, m), 2.51 (3H, s), 3.03-3.19 ( (2H, m), 3.38-3.58 (2H, m), 4.22-4.31 (2H, m), 4.64-4.68 (2H, m), 5.22-5.38 ), 7.07 (1H, s), 7.20 (1H, br.s)
    MS (TS): 468 (M &lt; + & gt ; + H)
    d) Synthesis of (3S, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (5-methylthioimidazo [5,1- b] thiazol-
    (1.3 ml) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-methylthioimidazo [ 1-b] thiazol-2-yl) methylpyrrolidine in 50 ml of tetrahydrofuran, and the mixture was stirred for 30 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, ethyl acetate was added, and then extracted three times. The extract was washed three times with half-saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain (3R, 5S) -1-allyloxycarbonyl-3-hydroxy-5- (5-methylthioimidazo [5,1- b] thiazol- Of 1.30 g. The compound was dissolved in 18 ml of THF, 1.53 g of triphenylphosphine and 0.92 ml of diethyl azodicarboxylate were added to the solution at -17 ° C and the mixture was stirred for 30 minutes. In addition, 0.7 ml of thiobenzoic acid was added and the mixture was stirred at -20 <0> C for 40 min. The solvent was removed by evaporation and the residue was purified by column chromatography using Sephadex LH-20 (dichloromethane: methanol = 1: 1) to give 1.06 g of the title compound as a yellow oil.
    NMR (CDCl 3) δ: 1.79-1.80 (1H, m), 1.91-2.10 (1H, m), 2.42 (3H, s), 2.49-2.61 (1H, m), 3.00-3.12 (1H, m), 3.19-3.30 (1H, m), 4.00-4.18 (3H, m), 5.15-5.30 (2H, m), 5.81-5.96 ), 7.35-7.41 (2H, m), 7.49-7.62 (1H, m), 7.80-7.83 (2H, m)
    MS (TS): 474 (M &lt; + & gt ; + H)
    [Synthesis Example 22]
    (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (5-methylimidazo [5,1- b] thiazol-3- yl) ethenyl] pyrrolidine
    a) Synthesis of (5-methylimidazo [5,1-b] thiazol-3-yl) methyltriphenylphosphonium chloride hydrochloride
    5-methylimidazo [5,1-b] thiazole hydrochloride (1.10 g) was suspended in 20 ml of THF, 0.7 ml of thionyl chloride was added to the solution, and this mixture was added to 85 Lt; 0 &gt; C for 3.5 hours. The solvent was removed by evaporation to give 1.10 g of 3-chloromethyl-5-methylimidazo [5,1-b] thiazohydrochloride. The compound was dissolved in 7 ml of DMF and triphenylphosphine (1.36 g) was added to the solution, and the mixture was stirred at 83 캜 for 15 hours and at 90 캜 for 4 hours. The obtained precipitate was collected by filtration and washed with diethyl ether to obtain 1.87 g of (5-methylimidazo [5, 1 - b] thiazol-3-yl) methyltriphenylphosphonium chloride hydrochloride.
    NMR (CD 3 OD) δ: 2.68 (3H, s), 5.59 (2H, m), 7.16 (1H, s), 7.58 (1H, s), 7.75-8.05 (15H, m)
    MS (TS) 413 (M &lt; + & gt ; )
    b) Preparation of (3R, 5S) -1-allyloxycarbonyl-4-methanesulfonyloxy-2- [2- ] Pyrrolidine
    (0.45 g) was added to a solution of (5-methylimidazo [5,1-b] thiazol-3-yl) methyltriphenylphosphonium Was added to a solution of 0.91 g of hydrochloride hydrochloride. The mixture was stirred under ice cooling for 2 hours and added to a solution of 0.60 g of (3R, 5S) -1-allyloxycarbonyl-5-formyl-3-methanesulfonyloxypyrrolidine in 2 ml of THF , And the solution was stirred for 1 hour under ice cooling. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with dilute hydrochloric acid and brine, followed by drying over magnesium sulfate. The solvent was removed by evaporation and the residue was purified by column chromatography using silica gel (ethyl acetate: methanol = 95: 5) to give (3R, 5S) -1-allyloxycarbonyl-4-methanesulfonyloxy- To obtain 0.49 g of 2- [2- (5-methylimidazo [5,1-b] thiazol-3-yl) ethenyl] pyrrolidine (mixture of geometric isomers).
    NMR (CD 3 OD) δ: 2.38-2.50 (1H, m), 2.57 (3H, s), 2.98 (3H, s), 3.60-3.68 (1H, m), 3.89-3.98 (1H, m), 4.38 (2H, m), 6.43 (1H, d, J = 11.3Hz), 4.55-5.28 6.80 (1H, s), 7.10 (1H, s)
    MS (TS): 412 (M &lt; + & gt ; + H)
    c) Preparation of (3S, 5S) -3-acetylthio-1-allyloxycarbonyl-5- [2- (5-methylimidazo [5,1- b] thiazol- Lt; / RTI &gt; (mixture of geometric isomers)
    Potassium thioacetate (0.33 g) was added to a solution of (3R, 5S) -1-allyloxycarbonyl-4-methanesulfonyloxy-2- [2- ] Thiazol-3-yl) ethenyl] pyrrolidine (mixture of geometric isomers), and the mixture was stirred at 70 ° C for 6.5 hours. Water and ethyl acetate were added to the reaction mixture and then extracted three times. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography using silica gel (ethyl acetate) to obtain 0.65 g of the title compound.
    NMR (CDCl 3) δ: 2.36 (3H, s), 2.58-2.73 (3H, m), 3.32-3.43 (1H, m), 3.89-4.10 (2H, m), 4.50-4.65 (2H, m), (1H, s), 6.89 (1H, s), 6.83 (1H, s)
    MS (TS): 392 (M &lt; + & gt ; + H)
    [Synthesis Example 23]
    (3S, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (5-chloroimidazo [5,1- b] thiazol-2- yl) methylpyrrolidine
    a) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [1- (5-chloroimidazo [5,1- b] thiazol- 1-hydroxymethyl] pyrrolidine (diastereomeric mixture)
    A 1.4 M methyl lithium / diethyl ether solution (7.9 ml) was diluted with 20 ml dry THF, the diluted solution was replaced with argon and cooled to -69 캜. A solution of 1.586 g of 5-chloroimidazo [5,1-b] thiazole in 20 ml of anhydrous THF was stirred into the solution over 17 minutes with stirring while maintaining the solution at -65 占 폚 or below, Was stirred in this state for an additional 37 min. 3.135 g of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 20 ml of anhydrous THF was added to the mixed solution while keeping the solution at -65 캜 or lower Was added dropwise over 23 minutes, and the mixture was stirred for an additional 52 minutes in this state. Semi-saturated saline (100 ml) was added to the reaction solution, and the mixture was extracted with 200 ml of ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel (hexane: ethyl acetate = 2: 1) to obtain (3R, 5S) -1-allyloxycarbonyl- yl) -1-hydroxymethyl] pyrrolidine (diastereomeric mixture) 2.351 &lt; tb &gt; ______________________________________ &lt; tb &gt; ______________________________________ &lt; g.
    NMR (CDCl 3) δ: 0.02-0.04 (6H, m), 0.83 & 0.85 (total 9H, s, each), 1.67-2.07 (2H, m), 3.30-3.45 (1H, m), 3.55-3.70 ( (2H, m), 4.60-4.75 (2H, m), 4.80-5.05 (total 1H, d, each), 5.22-5.37 (1H, s), 7.24 (1H, s), 6.95-6.97 (1H,
    MS (FAB + ): 474 (M + + 3H), 472 (M &lt;
    b) Preparation of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [ 1- (methylthiocarbonyloxy) methyl] pyrrolidine (diastereomeric mixture)
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- [ Hydroxymethyl] pyrrolidine (diastereomeric mixture) (2.300 g) and imidazo [3.3 mg] were dissolved in 24.5 ml of anhydrous THF. Carbon disulfide (0.44 ml) and 292 mg of 60% sodium hydride were successively added to the above solution in an ice bath under an argon atmosphere, and the mixture was stirred for 20 minutes in this state. Methyl iodide (0.32 ml) was added dropwise, and the mixture was stirred for 1 hour under the above conditions. The reaction solution was diluted with 250 ml of ethyl acetate, washed with half-saturated brine, and dried over anhydrous magnesium sulfate. The crude product was purified by column chromatography using silica gel (hexane: ethyl acetate = 3: 1) to give (3R, 5S) -1-allyloxycarbonyl- (Di-tert-butyldimethylsilyloxy) -5- [1- (5-chloroimidazo [5,1- b] thiazol- Mixture).
    NMR (CDCl 3) δ: 0.02 & 0.03 & 0.08 (total 6H, s, each), 0.83 & 0.87 (total 9H, s, each), 1.62 (1H, s), 2.08 (1H, m), 2.61 & 2.62 (3H, s), 3.25-3.70 (total 3H, m), 4.25 (1H, m), 4.50-4.80 (3H, br), 5.20-5.35 m), 6.96 & 6.98 (total 1H, s, each), 7.15-7.35
    MS (FAB + ): 564 (M + + 3H), 562 (M +
    c) Synthesis of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-chloroimidazo [5,1- b] thiazol-
    Hydrogenated tri-n-butyltin (1.8 ml) and 147 mg of 2,2'-azobisisobutyronitrile were added to a solution of (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethyl Yl) -1- (methylthiothiocarbonyloxy) methyl] pyrrolidine (diastereomeric mixture) in the presence of a base, And the mixture was stirred under an argon atmosphere at an external temperature of 80 DEG C for 90 minutes. The reaction solution was diluted with 200 ml of ethyl acetate, washed with half-saturated brine, and dried over anhydrous magnesium sulfate. The crude solution was then removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel (hexane: ethyl acetate = 2: 1) to obtain (3R, 5S) -1-allyloxycarbonyl- To obtain 1.467 g of butyl dimethylsilyloxy-5- (5-chloroimidazo [5,1-b] thiazol-2-yl) methylpyrrolidine.
    NMR (CDCl 3) δ: 0.01 & 0.06 & 0.07 (total 6H, s, each), 0.82 & 0.87 (total 9H, s, each), 1.75-1.88 (1H, m), 1.93-2.15 (1H, m) , 2.97-3.25 (2H, m), 3.35-3.60 (2H, m), 4.24 (2H, br.s), 4.60-4.67 (2H, m), 5.19-5.35 1H, &lt; / RTI &gt; m), 6.92 (1H, s), 7.05
    MS (TSP): 458 (M & lt ; + & gt ; + 3H), 456 (M &
    d) Preparation of (3R, 5S) -1-allyloxycarbonyl-5- (5-chloroimidazo [5,1- b] thiazol-
    (3R, 5S) -1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5- (5-chloroimidazo [5,1- b] thiazol- A solution of 1.430 g of methyl pyrrolidine was cooled to 3 DEG C and 1.3 mL of concentrated hydrochloric acid was added dropwise to the solution while keeping the internal temperature at 4 DEG C or lower and the mixture was stirred for 15 minutes in this state. The reaction solution was diluted with 200 ml of ethyl acetate, washed with 40 ml of 5% aqueous sodium hydrogencarbonate solution (pH 9 in water), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel (ethyl acetate) to obtain (3R, 5S) -1-allyloxycarbonyl-5- (5- , 1-b] thiazole) methyl-3-hydroxypyrrolidine (1.020 g).
    NMR (CDCl 3) δ: 1.80-1.95 (1H, m), 2.06-2.25 (1H, m), 2.55-2.80 (1H, m), 3.05-3.25 (2H, m), 3.40-3.47 (1H, m ), 3.60-3.75 (1H, m), 4.25-4.35 (1H, m), 4.38 (1H, br.s), 4.55-4.70 (1H, m), 6.92 (1H, s), 7.08 (1H, s)
    MS (FAB + ): 344 (M & lt ; + & gt ; + 3H), 342 (M &
    e) Synthesis of (3S, 5S) -1-allyloxycarbonyl-3-benzoylthio-5- (5-chloroimidazo [5,1- b] thiazol-
    (3R, 5S) -1-allyloxycarbonyl-5- (5-chloroimidazo [5,1-b] thiazol-2-yl) methyl-3-hydroxypyrrolidine 438 And 672 mg of triphenylphosphine was cooled to -10 &lt; 0 &gt; C under an argon atmosphere. Diethyl azodicarboxylate (0.40 ml) was added dropwise to the mixture over 7 minutes while keeping the solution at -5 [deg.] C or below. Thiobenzoic acid (90%) (0.34 ml) was added to the mixed solution over 5 minutes at -10 DEG C, and the mixture was stirred for an additional 25 minutes in this state. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using silica gel (hexane: ethyl acetate = 1: 1) to obtain 505 mg of the title compound as a light yellow viscous substance.
    NMR (CDCl 3) δ: 1.83-1.96 (1H, m), 2.55-2.70 (1H, m), 3.05-3.45 (3H, m), 4.15-4.35 (3H, m), 4.62-4.68 (2H, m ), 5.22-5.38 (2H, m), 5.88-6.02 (1H, m), 6.93 & 6.95 (total 1H, s), 7.10 (1H, br.s), 7.40-7.50 7.63 (1H, m), 7.89 & 8.15 (total 2H, d, each)
    MS (FAB + ): 464 (M & lt ; + & gt ; + 3H), 462 (M &
    The structures of the compounds prepared in the above examples are summarized in Table 1.
    Table 1

    [Pharmacological Test Example 1]
    For the representative compounds among the novel carbapenem derivatives of the present invention, the minimum development inhibitory concentration for various pathogens was measured according to the method described in CHEMOTHERAPY, Vol. 16, No. 1, 99 (1968). The results are summarized in Tables 2 to 5.
    Table 2
    *: Highly Meticillin-resistant strain
    Table 3
    *: Methicillin height tolerance
    Table 4
    *: Methicillin height tolerance
    Table 5
    *: Methicillin height tolerance
    Compound A: Imipenem
    Compound B: pannifenem
    [Pharmacological Test Example 2]
    Stability for DHP-I
    The stability of a representative compound between the novel carbapenem derivatives of the present invention against the new dihydropeptidase-I (DHP-I) in pigs and mice was measured, and the residual amount (%) of the carbapenem derivative after 3 hours was measured 6.
    The stability to DHP-I was measured according to the following method.
    1. Preparation of DHP-1 from kidney acetone powder of various animals
    1.5 g of Porcine Type II (Lot. 33H7225) was suspended in 100 ml of 50 mM Tris-HCl buffer (pH 7.0) containing 20% butanol and the suspension was incubated at 5 캜 for 48 hours Lt; / RTI &gt; The suspension was then dialyzed against 50 mM Tris-HCl buffer (cellulose tube 30/32 Viskase Sales Corp.) until the butanol odor disappeared. The dialysate was centrifuged for 20 minutes at 1000 x g (KUBOTA 6800) and the supernatant was obtained as partially purified DHP-I. The partially purified DHP-I was subdivided and stored at -80 &lt; 0 &gt; C. The same procedure was repeated except that 1.5 g of a mouse (Lot. 23F8105) was used. Thus, partially purified DHP-I was prepared and stored.
    2. Stability measurement for various DHP-I
    For carbapenem as a matrix drug, a solution (2000 μg (effective amount) / ml) was prepared using sterile purified water. For the sample solution, a carbapenem solution (2000 μg (effective amount) / ml) was added to a partial purified DHP-I of various animals at a final concentration of 100 μg (effective amount) / ml. For the blank, 50 mM Tris-HCl buffer (pH 7.0) was used in place of the partially purified DHP-I of the various animals. The reaction was allowed to proceed at 37 DEG C for 3 hours, and a certain amount of the reaction mixture was collected. The reaction was terminated by the addition of methanol in the same amount as the reaction mixture taken under ice cooling. The reaction mixture was filtered with a filter (Sanprep LCR 13-LH manufactured by MILLIPORE) and purified by HPLC (column: CAPCELL PACK C 18 SG120 manufactured by Shiseido Co., Ltd. Detection: UV; mobile layer: acetonitrile / 10 mM Acetic acid aqueous solution).
    Remaining amount (%) = (sample peak area / blank peak area) x 100
    Table 6
    [Pharmacological Test Example 3]
    Acute toxicity test in intravenous administration
    In experiments using mice (ICR, male) (3 mice per group), the compound prepared in Example 53 was administered at a dose of 1,000 mg / kg. As a result, all the mice survived.
    [Formulation Example 1]
    Injectable preparation
    The pharmaceutical composition comprising the compound according to the invention is aseptically filled into vials so that each vial contains 1000 mg (effective amount) of a compound according to the invention.
    250 parts of the compound prepared in Example 53 (effective amount)
    Lactose 60 parts
    Magnesium stearate 5 parts
    [Formulation Example 2]
    Preparation of soft capsules for rectal administration
    Olive oil 160 parts
    10 parts of polyoxyethylene lauryl ether
    Sodium hexametaphosphate 5 parts
    Twenty-five parts (effective amount) of the compound prepared in Example 53 were added to a base composed of the components described above, uniformly mixed, and the mixture was filled into rectal capsules for rectal administration. Each capsule was filled with 250 Mg.
    权利要求:
    Claims (15)
    [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof:
    Formula I

    here
    A is a bond, - (CH 2) m-, -CHR 8 -, - (CH 2) n-CH = CH- (CH 2) n'-, -C (= O) N (-R 9) CH 2 -, wherein R 8 represents a hydroxyl group, a methoxy group, a halogen atom, or an amino group, R 9 represents a hydrogen atom and - (CH 2 ) p CH 3 wherein p is an integer of 0 to 3 and m is an integer of 1 To 3, and n and n 'each represent an integer 0 to 3;
    R 1 represents a hydrogen atom or a lower alkyl group;
    R 2 represents a hydrogen atom, sodium, or potassium; And
    Any one of R 3 , R 4 , R 5 and R 6 represents a bond and is bonded to A and the remaining three substituents are the same or different and are a hydrogen atom, a halogen atom, a nitro group, an anion group, a lower alkyl group, An alkyl group, a lower alkylthio group, a C 2-4 alkenyl group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, or aryl;
    When at least one hydrogen atom in the lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group, and aryl group represented by R 3 , R 4 , R 5 , and R 6 is a halogen atom, a nitro group A lower alkoxy group, a hydroxyl group, an amino group, a lower cycloalkyl group, an N-lower alkylamino group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, (N-lower alkylamino) carbonyl group, an aminosulfonyl group, an (N-lower alkylamino) sulfonyl group, an aminosulfonylamino group, (N-lower alkylamino) sulfonylamino group, Lt; / RTI &gt;group;
    Or any two of R 3 , R 4 , R 5 , and R 6 together may form a pentagonal heterocyclic saturated ring comprising one oxygen atom and one nitrogen atom, O), or any two of R 3 , R 4 , R 5 , and R 6 may form C 3-6 alkylene, wherein one or more of the methylene groups may be replaced by -NH -, -O-, -S-, or -CO-.
    [2" claim-type="Currently amended] The compound of formula (I) according to claim 1, wherein R 1 is a hydrogen atom or a methyl group and R 2 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
    [3" claim-type="Currently amended] The compound according to claim 1, wherein R 3 , R 4 , R 5 , and R 6 are the same or different from each other and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower cycloalkyl group, Import, C 2-4 alkenyl group, a formyl group, a lower alkyl group, or may represent an aryl group, wherein the lower alkyl group, a lower cyclo alkyl group, a C 2-4 alkenyl group, an aryl group and one or more hydrogen atoms may be substituted on the Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
    [4" claim-type="Currently amended] The method of claim 1 wherein, A is a bond, -CH 2 -, -CH (OH ) -, -CH = CH-, -C (O) -NHCH 2 -, or -C (= O) N (-CH 3 ) CH 2 -;
    R 1 represents a hydrogen atom and a methyl group;
    R 2 represents a hydrogen atom; And
    R 3 , R 4 , R 5 and R 6 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group or a lower alkylthio group, and the lower alkyl group, lower cycloalkyl group And the lower alkylthio group is selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a lower cycloalkyl group, a lower alkylcarbonyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a carbamoyl group and an (N- A compound of formula (I) or a pharmaceutically acceptable salt thereof, which may be substituted with a selected group.
    [5" claim-type="Currently amended] The compound of formula (I) according to any one of claims 1 to 4, wherein A represents a bond and R 4 or R 5 represents a bond, or a pharmaceutically acceptable salt thereof.
    [6" claim-type="Currently amended] A compound represented by the formula (II) or a pharmaceutically acceptable salt thereof:
    (II)

    here
    A is a bond, - (CH 2) m-, -CHR 8 -, - (CH 2) n-CH = CH- (CH 2) n'-, -C (= O) N (-R 9) CH 2 -, wherein R 8 represents a hydroxyl group, a methoxy group, a halogen atom, or an amino group, R 9 represents a hydrogen atom and - (CH 2 ) p CH 3 wherein p is an integer of 0 to 3 and m is an integer of 1 To 3, and n and n 'each represent an integer of 0 to 3
    R 1 represents a hydrogen atom or a lower alkyl group;
    R 2 represents a hydrogen atom, sodium, or potassium;
    Any one of R 3 , R 4 , R 5 and R 6 represents a bond and is bonded to A and the remaining three substituents are the same or different and are a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group, An alkyl group, a lower alkylthio group, a C 2-4 alkenyl group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, or an aryl group;
    R 7 represents a lower alkyl group, a lower cycloalkyl group, or an aryl group;
    At least one hydrogen atom of said lower alkyl group, lower cycloalkyl group, C 2-4 alkenyl group and aryl group as a part of the group or group represented by R 3 , R 4 , R 5 , R 6 and R 7 is a halogen atom, A nitro group, a cyano group, a lower alkylthio group, a lower alkoxy group, a hydroxyl group, an amino group, a lower cycloalkyl group, an N-lower alkylamino group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, (N-lower alkylamino) carbonyl group, an aminosulfonyl group, (N-lower alkylamino) sulfonyl group, aminosulfonylamino group, (N-lower alkylamino) sulfonylamino group, And an aryl group;
    Or any two of R 3 , R 4 , R 5 , and R 6 together may form a pentagonal heterocyclic saturated ring comprising one oxygen atom and one nitrogen atom, = O), or any two of R 3 , R 4 , R 5 , and R 6 may form C 3-6 alkylene, wherein one or more of the methylene groups of the alkylene group may be replaced by -NH -, -O-, -S-, or -CO-.
    [7" claim-type="Currently amended] The compound or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein R 1 is a hydrogen atom or a methyl group and R 2 is a hydrogen atom.
    [8" claim-type="Currently amended] 7. The compound according to claim 6, wherein R 3 , R 4 , R 5 and R 6 are the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower cycloalkyl group, Import, C 2-4 alkenyl group, a formyl group, a lower alkyl represents a carbonyl group, or an aryl group can be optionally substituted with a lower alkyl group, a lower cyclo alkyl group, a C 2-4 alkenyl group, and at least one hydrogen atom in the aryl group, R 7 Is a lower alkyl group or a lower cycloalkyl group, and at least one hydrogen of the lower alkyl group and lower cycloalkyl group may be substituted, or a pharmaceutically acceptable salt thereof.
    [9" claim-type="Currently amended] The method of claim 6, wherein, A is a bond, -CH 2 -, -CH (OH ) -, -CH = CH-, -C (O) -NHCH 2 -, or -C (= O) N (-CH 3 ) CH 2 - represents;
    R 1 represents a hydrogen atom and a methyl group;
    R 2 represents a hydrogen atom;
    R 3 , R 4 , R 5 and R 6 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group or a lower alkylthio group, and the lower alkyl group, The alkyl group and the lower alkylthio group may be the same or different and each is a group consisting of a halogen atom, a hydroxyl group, an amino group, a lower cycloalkyl group, a lower alkylcarbonyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a carbamoyl group, &Lt; / RTI &gt; And
    R 7 represents a lower alkyl group or a lower cycloalkyl group and the lower alkyl group is a halogen atom, a hydroxyl group, an amino group, a lower cycloalkyl group, a lower alkylcarbonyl group, a lower alkoxyl group, a lower alkoxycarbonyl group, And (N-lower alkylamino) carbonyl group, or a pharmaceutically acceptable salt thereof.
    [10" claim-type="Currently amended] 10. The compound of formula (II) as claimed in any one of claims 6 to 9, wherein A represents a bond and R 4 or R 5 represents a bond, or a pharmaceutically acceptable salt thereof.
    [11" claim-type="Currently amended] 10. A pharmaceutical composition comprising a pharmacologically acceptable carrier together with a compound according to any one of claims 1 to 10.
    [12" claim-type="Currently amended] 12. The pharmaceutical composition according to claim 11, which is used as an antimicrobial agent.
    [13" claim-type="Currently amended] 10. A method of treating an infectious disease comprising administering a compound according to any one of claims 1 to 10 to an animal comprising a human.
    [14" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 10 for the preparation of an antibacterial agent.
    [15" claim-type="Currently amended] 11. Use of a compound according to any one of claims 1 to 10 as an antimicrobial agent.
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    同族专利:
    公开号 | 公开日
    EP0887352A4|1999-12-29|
    ID21039A|1999-04-08|
    CN1081641C|2002-03-27|
    TW445265B|2001-07-11|
    US6180622B1|2001-01-30|
    EP0887352A1|1998-12-30|
    CN1209810A|1999-03-03|
    WO1998023623A1|1998-06-04|
    CA2244123A1|1998-06-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-11-25|Priority to JP313922/1996
    1996-11-25|Priority to JP31392296
    1997-11-25|Application filed by 이치로 키타사토, 메이지 세이카 가부시키가이샤
    1999-11-15|Publication of KR19990081972A
    优先权:
    申请号 | 申请日 | 专利标题
    JP313922/1996|1996-11-25|
    JP31392296|1996-11-25|
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