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    expression Wherein a carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure is represented by [wherein, R 1 represents a C 1 -C 3 alkyl group, and R 2 and R 3 each independently represent a hydrogen atom or the like] (4 ) Or a method for preparing the salt thereof, compound (1) or a salt thereof, and a method for producing the same, which is a useful synthetic intermediate.
    公开号:KR20030097793A
    申请号:KR10-2003-7006797
    申请日:2001-11-19
    公开日:2003-12-31
    发明作者:후지모또가쯔히꼬；가사이다까시
    申请人:상꾜 가부시키가이샤；
    IPC主号:
    专利说明:

    Production method of carbapenem type antibacterial agent {PROCESS FOR PRODUCING CARBAPENEM-TYPE ANTIBACTERIAL AGENTS}
    [2] Carbapenem-based antimicrobial agents having a 1-alkylpyrrolidine structure having excellent antimicrobial activity are known in the art. For example, Japanese Patent Laid-Open No. 11-71277 discloses a carbapenem type antibacterial agent having a 1-alkylpyrrolidine structure and a method for producing the same. However, the production method described in the above publication is a carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure according to the present invention, whereas the three substructures of the carbapenem-based antimicrobial agent, which is a compound for manufacture, are being stepwise bound. The manufacturing method of is different in that three substructures are continuously combined in one step by so-called one-port synthesis.
    [3] Heterocycles, Vol. 41, p. 147 (1995), describes a carbapenem-based antimicrobial agent (meropenem) having a pyrrolidine structure having no substituent on a nitrogen atom and a method for producing the same. The starting materials for the production method described in the above document and the method for producing the carbapenem type antimicrobial agent having the 1-alkylpyrrolidine structure according to the present invention are all 2-thia-5-azabicyclo [2.2.1] heptane. It is common in that it is a 3-one derivative. However, the starting material of the production method described in the above document, due to the presence of p-nitrobenzyloxycarbonyl group, which is a carbonyl protecting group on the nitrogen atom in its structure, decreases the nucleophilicity of the nitrogen atom and suppresses side reactions. In the starting material of the production method of the present invention, since the nitrogen atom in the structure has nucleophilicity and its chemical properties are different, there is a concern about side reactions and a decrease in yield. In addition, since the synthesis example described in the said literature is a thing of very small scale (an example which produced the product 315 mg in 69% yield from the starting material), the manufacturing method of the carbapenem type antimicrobial agent described in the said literature is based on this invention. It is not known whether it is applicable to the mass synthesis of carbapenem type antimicrobial agents having the described 1-alkylpyrrolidine structure.
    [4] There are also various known methods for producing 2-thia-5-azabicyclo [2.2.1] heptan-3-one derivatives. For example, compounds in which the nitrogen atom of 2-thia-5-azabicyclo [2.2.1] heptan-3-one is protected with an acetyl group and the preparation thereof are described in J. Org. Chem., Vol. 46, p. 4182 (1981) and Chem. Pharm. Bull., Vol. 20, p. 543 (1972). However, the method described in the above document is not suitable for mass synthesis because condensing agents such as N, N'-dicyclohexylcarbodiimide are used in the post-molecular cyclization step, which is very difficult for post-treatment.
    [5] Carbapenem-based antimicrobial agents have excellent antimicrobial activity, but their chemical structures are generally complex. Therefore, the carbapenem type antimicrobial agent having the 1-alkylpyrrolidine structure described in the present invention has also been required to construct a synthetic route that is cheaper, easier and safer, and is suitable for mass synthesis.
    [6] In addition, the 5-alkyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one of the present invention is a synthetic route of a carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure capable of achieving the above object. Although a very important intermediate compound in, there is a need for a low cost, easy, safe and mass production method for this compound.
    [1] The present invention provides a method for preparing a carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure having excellent antimicrobial activity, and 5-alkyl-2-thia-5-azabicyclo [2.2.1] heptan-3, a useful synthetic intermediate thereof. -On, its salts, and a method for producing the same.
    [7] In order to solve the above problems, the present inventors have variously studied the synthetic route of the carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure. As a result, 5-alkyl-2-thia-5-azabicyclo [2.2.1] It has been found that the synthetic route of the present invention using heptane-3-one and its salt as the synthetic intermediate is an excellent synthetic route for solving the above problems.
    [8] In addition, the present inventors have conducted various studies on the production method of 5-alkyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one and salts thereof, and cis-2-carboxy-4-mercapto- The present invention has found that a method for intramolecular dehydration of 1-alkylpyrrolidine or a salt thereof in the presence of an acid anhydride is an excellent synthetic route for solving the above problems.
    [9] The present invention,
    [10] A method for preparing a carbapenem-based antimicrobial agent or a salt thereof by reacting a compound of Formula 1 or a salt thereof, a compound of Formula 2 or a salt thereof, and a compound of Formula 3 or a salt thereof:
    [11]
    [12] [Wherein, R 1 represents a C 1 -C 3 alkyl group],
    [13]
    [14] [Wherein, R 2 and R 3 each independently represent a hydrogen atom or an organic residue, or R 2 and R 3 may be integrated with the nitrogen element to which they are bonded to form a ring],
    [15]
    [16] [Wherein L represents a leaving group and the hydroxyl and carboxyl groups may each independently be protected with a protecting group],
    [17]
    [18] [In formula, R <1> , R <2> and R <3> have the same meaning as mentioned above, A hydroxyl group and a carboxyl group may each independently be protected by a protecting group.
    [19] Herein, the "alkyl group" in R 1 is a linear or branched saturated hydrocarbon group, and the C 1 -C 3 alkyl group in R 1 is a methyl, ethyl, propyl or isopropyl group, preferably C 1 -C It is a 2 alkyl group, More preferably, it is a methyl group.
    [20] R 2 and "organic residue" for R 3 in the formula -N (R 2) (R 3 ) has a nitrogen atom of the nucleophilic group represented by the further formula -N (R 2) (R 3 ) represented by the The carbapenem type antimicrobial agent (4) having a structure or salt thereof is not particularly limited as long as it has excellent antimicrobial action, for example, a hydrogen atom; Substituted or unsubstituted lower alkyl group, lower alkenyl group or lower alkynyl group; A substituted or unsubstituted cycloalkyl group, cycloalkylalkyl group, cycloalkylalkenyl group or cycloalkylalkynyl group; Substituted or unsubstituted aralkyl group, arkenyl group or aralkylyl group; And a substituted or unsubstituted heteroaralkyl group, heteroaralkenyl group, heteroaralkynyl group, heterocyclyl group, heterocyclylalkyl group, heterocyclylalkenyl group or heterocyclylalkynyl group. The "substituted or unsubstituted, lower alkyl, lower alkenyl or lower alkynyl group" in R 2 and R 3 has 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, 2- Propenyl, 2-butenyl, ethynyl, 2-butynyl, 2-hydroxyethyl, 2-chloroethyl, 2-methoxyethyl, 3-pentenyl and 4-hexynyl groups. The "substituted or unsubstituted cycloalkyl group, cycloalkylalkyl group, cycloalkylalkenyl group or cycloalkylalkynyl group" in R 2 and R 3 has 3 to 6 carbon atoms in the cycloalkyl ring, and also alkyl or alkenyl. Or having 1 to 6 carbon atoms in the alkynyl moiety, for example cyclopentyl, cyclohexyl, 2-cyclobutylethyl, 6-cyclohexylhexyl, 2- (4-methoxycyclohexyl) ethyl, 5- (3 -Bromocyclopentyl) pentyl, 5-cyclopentyl-4-pentenyl and 6-cyclohexyl-3-hexynyl groups. The "substituted or unsubstituted aralkyl group, alkenyl group or aralkylyl group" in R 2 and R 3 is an aryl moiety substituted or an unsubstituted phenyl group, and also has 1 to 3 alkyl, alkenyl or alkynyl moieties. Having 3 carbon atoms, for example, benzyl, p-nitrobenzyl, p-chlorobenzyl, 2-phenylethyl, cinnamil and 3-cyclopentyl-2-propynyl group. The substituted or unsubstituted heteroaralkyl group, heteroarralkenyl group, heteroaralkynyl group, heterocyclyl group, heterocyclylalkyl group, heterocyclylalkenyl group or heterocyclylalkynyl group in R 2 and R 3 is , Having 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms in the heterocyclic moiety, and 1 to 6 carbon atoms in the alkyl, alkenyl or alkynyl moiety bonded to the heterocyclic moiety, For example 2-, 3- or 4-pyridyl lower alkyl, 2-, 4- or 5-pyridyl lower alkyl, 3- (2-pyridyl) -2-propenyl, 4- (3-pyridyl ) -2-butynyl, N-methyl-2-, 3- or 4-piperidino, N-propyl-2- or 3-morpholino lower alkyl, N-methyl-2- or 3-thiomorpholi And a lower lower alkyl, 6- (N-methyl-2-piperidino) -3-hexenyl or 6- (N-methyl-2-piperidino) -3-hexynyl group.
    [21] R 2 and "R 2 and R 3 ring is formed in one body with the nitrogen atom to which they bind," in R 3 is the formula -N (R 2) having a nitrogen atom of the nucleophilic group represented by (R 3) And carbapenem-based antimicrobial agents (4) having a structure represented by formula -N (R 2 ) (R 3 ) or salts thereof are not particularly limited as long as they have excellent antimicrobial activity.
    [22]
    [23] [Wherein n represents 0, 1 or 2,
    [24] p represents 0, 1 or 2,
    [25] R a represents a hydrogen atom or a C 1 -C 4 alkyl group,
    [26] B is phenylene, phenylenealkyl (this alkyl moiety is C 1 -C 3 alkyl), cyclohexylene, cyclohexylenealkyl (this alkyl moiety is C 1 -C 3 alkyl) or 1 to 3 substituents A C 1 -C 5 alkylene group which may have (this substituent is an amino, hydroxyl, cyclohexylalkyl (this alkyl moiety is C 1 -C 3 alkyl), C 1 -C 4 alkyl, phenyl or benzyl group),
    [27] R b represents a hydrogen atom or a C 1 -C 4 alkyl group,
    [28] R c is a group represented by the formula -C (= NH) R d wherein R d is a hydrogen atom, a C 1 -C 4 alkyl group or a group represented by the formula -NR e R f (where R e and R f represents a hydrogen atom or a C 1 -C 4 alkyl group independently of one another;
    [29] Preferably
    [30] n is 0 or 1,
    [31] p is 0 or 1,
    [32] R a is a hydrogen atom, a methyl or an ethyl group,
    [33] B is 1,4-phenylene, 1,4-cyclohexylenemethyl, methylene, methylmethylene (-CH (CH 3 )-), ethylene, trimethylene or 2-hydroxypropylene group,
    [34] R b is a hydrogen atom, a methyl or an ethyl group,
    [35] R c is formimidoyl, acetimidoyl or amidino group,
    [36] More preferably
    [37] n is 0 or 1,
    [38] p is 0,
    [39] R a is a hydrogen atom or a methyl group,
    [40] B is methylene, methylmethylene (-CH (CH 3 )-), ethylene, trimethylene or 2-hydroxypropylene group,
    [41] R b is a hydrogen atom or a methyl group,
    [42] R c is an amidino group,
    [43] Most preferably
    [44] n is 0 or 1,
    [45] p is 0,
    [46] R a is a hydrogen atom,
    [47] B is methylene, methylmethylene (-CH (CH 3 )-) or an ethylene group,
    [48] R b is a hydrogen atom,
    [49] R c is an amidino group]
    [50] Such that R 2 and R 3 together with the nitrogen atom form a heterocyclic ring which may have a substituent, preferably R 2 and R 3 together with the nitrogen atom form a pyrrolidino group which may have a substituent will be.
    [51] The "leaving group" in L is not particularly limited as long as it is a group detached as a normal nucleophilic residue, as described in JP-A-11-71277, for example, chlorine, bromine and iodine Halogen atoms such as; Trihalogenomethyloxy groups such as trichloromethyloxy; Lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; Halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; Arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy; Or a diarylphosphoryloxy group such as diphenylphosphoryloxy; Preferably it is a diaryl phosphoryloxy group, More preferably, it is a diphenylphosphoryloxy group (OP (= O) (OPh) 2 ).
    [52] Compound (I) has a tertiary amine moiety and can form a salt with an acidic compound. The acidic compound may be, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid; Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; Or organic technical acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; Preferably they are inorganic acids, More preferably, they are hydrochloric acid or sulfuric acid.
    [53] Since compound (2) is an amine compound, it can form a salt with an acidic compound. The acidic compound may be, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; Or an organic technical acid such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Preferably they are inorganic acids.
    [54] Compound (3) has a carboxyl group and can form a salt with a basic substance. Such salts include, for example, alkali metal salts such as sodium salts, potassium salts and lithium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; Or inorganic salts such as ammonium salts; Preferably it is lithium salt, sodium salt, potassium salt, or magnesium salt.
    [55] When the carbapenem-based antimicrobial agent (4) can form salts with acidic compounds, such acidic compounds are, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid. Inorganic acids; Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; Or organic technical acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Preferably they are inorganic acids, More preferably, they are hydrochloric acid, sulfuric acid, or a carbonic acid.
    [56] In addition, the carbapenem type antimicrobial agent (4) has a carboxyl group and can form a salt with a basic substance. Such salts include, for example, alkali metal salts such as sodium salts, potassium salts and lithium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; Or ammonium salts; Preferably it is lithium salt, sodium salt, potassium salt, or magnesium salt.
    [57] When either or both of the hydroxyl and carboxyl groups of the compound (3) are protected with a protecting group, the compound (2) or salts thereof and the compound (3) or salts thereof are sequentially reacted with the compound (1) or salts thereof. Compound (4) or its salt can be obtained by removing the said protecting group after making it carry out.
    [58] In addition, the present invention
    [59] A compound of formula 1 or a salt thereof and
    [60] [Formula 1]
    [61]
    [62] [Wherein, R 1 represents a C 1 -C 3 alkyl group]
    [63] A method of preparing a compound of Formula 1 or a salt thereof by reacting a compound of Formula 5 or a salt thereof with an acid anhydride:
    [64] [Formula 1]
    [65]
    [66] [Wherein, R 1 represents the same meaning as described above]
    [67] [Formula 5]
    [68]
    [69] [Wherein, R 1 represents a C 1 -C 3 alkyl group].
    [70] When compound (5) forms a salt, such a salt may be any of the salt of a tertiary amine part and an acidic compound, the salt of a carboxyl group and a basic compound, or the metal salt of a carboxyl group.
    [71] When compound (5) forms a salt with an acidic compound, the acidic compound may be, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; Or organic technical acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Preferably they are inorganic acids, More preferably, they are hydrochloric acid or sulfuric acid.
    [72] When compound (5) forms a salt with a basic compound, a basic compound is ammonia; Or methylamine, ethylamine, propylamine, dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine, morpholine, triethylamine, diisopropylethylamine, pyridine, picoline, lutidine , 4-dimethylaminopyridine, N, N-dimethylaniline, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholino, imidazole, 1-methylimidazole, 1,5-dia Xavicyclo [4.3.0] -5-nonene (DBN), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), ethylenediamine, piperazine, 1,4-diazabicyclo [ 2.2.2] may be an organic amine such as octane; Preferably they are organic amines, More preferably, they are triethylamine, diisopropylethylamine, or N-methylmorpholine.
    [73] When compound (5) forms a metal salt with a carboxyl group, such metals include, for example, alkali metals such as lithium, sodium, potassium and cesium; And alkaline earth metals such as magnesium, calcium and barium, preferably lithium, sodium, potassium or magnesium.
    [74] When compound (5) forms a salt, such a salt is preferably a salt of a tertiary amine moiety and an acidic compound, more preferably a hydrochloride of compound (5) or a sulfate of compound (5). .
    [75] Compound (1) of the present invention has two sub-carbons in the molecule, and stereoisomers exist in the (2S, 4S) configuration or the (2R, 4R) configuration, but the present invention provides the respective isomers and their arbitrary ratios. Any mixture of is included. In compound (1), it is preferably a (2S, 4S) configuration.
    [76] [Formula 1]
    [77]
    [78] In addition, the compound (5) of the present invention also has two sub-carbons in the molecule and four stereoisomers exist, but is preferably an optical isomer of (2S, 4S) configuration or (2R, 4R) configuration. Preferably it is a (2S, 4S) arrangement.
    [79] [Formula 5]
    [80]
    [81] The compound of the present invention may be left in the air or recrystallized, whereby water may be absorbed and adsorbed water may be attached or become a hydrate. Compounds (1) to (5) and salts thereof of the present invention shall each contain such a hydrate.
    [82] Moreover, the compound of this invention may become a solvate by absorbing another kind of solvent. Compounds (1) to (5) of the present invention and salts thereof shall each contain such solvates.
    [83] The method for producing a carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure of the present invention is accomplished as shown below.
    [84] [A method]
    [85]
    [86] In said formula, R <1> , R <2> , R <3> and L show the same meaning as the above-mentioned.
    [87] Method A is achieved by reacting compound (1) or a salt thereof with compound (2) or a salt thereof and compound (3) or a salt thereof in the same reaction vessel in the presence of a base in an inert solvent, preferably compound ( 2) or a salt thereof and compound (3) or a salt thereof.
    [88] Moreover, if necessary, the functional group in R <2> and R <3> of compound (2), and the hydroxyl group and carboxyl group of compound (3) may be protected by a protecting group.
    [89] The protecting group of the hydroxyl group of compound (3) is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, deca Noyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, Hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nona Alkylcarbonyl groups such as decanoyl, aicosanoyl and henaicosanoyl; Carboxylated alkylcarbonyl groups such as succinoyl, glutaroyl and adipoyl; Halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl; Lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl; And aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl;
    [90] Arylcarbonyl groups such as benzoyl, α-naphthoyl and β-naphthoyl; Halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; Lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl; Lower alkoxylated arylcarbonyl groups such as 4-anisoyl; Carboxylated arylcarbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl; Nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl; Aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl and arylated arylcarbonyl groups such as 4-phenylbenzoyl;
    [91] Tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran- Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 4-yl;
    [92] Tetrahydrofuranyl or tetrahydrothiofuranyl groups such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl;
    [93] Tri (lower alkyl) silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl and triisopropylsilyl; And silyl groups such as tri (lower alkyl) silyl groups substituted with one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl;
    [94] Lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl; Lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl; And alkoxymethyl groups such as halogeno lower alkoxymethyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl;
    [95] Lower alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl; And substituted ethyl groups such as halogenated ethyl groups such as 2,2,2-trichloroethyl;
    [96] Lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl; And 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4 Aralkyl groups, such as lower alkyl groups substituted by 1-3 aryl groups substituted by lower alkyl, lower alkoxy, halogen, cyano groups, such as -chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, and piperonyl;
    [97] Lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl; And alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri (lower alkyl) silyl groups such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;
    [98] Alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl; or
    [99] 1 or 2 lower alkoxy, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl It is an aralkyloxycarbonyl group in which the aryl ring may be substituted by the nitro group, Preferably it is an aliphatic acyl group.
    [100] The protecting group of the carboxyl group of the compound (3) may be, for example, a benzyl group which may have substituents such as benzyl, p-nitrobenzyl and trimethylbenzyl; or
    [101] May be an allyl group which may have a substituent at the 2 position such as an allyl group, 2-chloroallyl and 2-methylallyl;
    [102] Preferably it is a benzyl group which may have a substituent, More preferably, it is a p-nitrobenzyl group.
    [103] Bases used in the process are, for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, picoline, lutidine, 4-dimethylaminopyridine, 1- Organic bases such as methylimidazole and 1,2-dimethylimidazole; Or inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate; Preferred is diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydrogen carbonate.
    [104] The solvent that can be used in the present method is not particularly limited as long as the raw material is dissolved to some extent without inhibiting the reaction. For example, nitriles such as acetonitrile; Alcohols such as methanol, ethanol, propanol and isopropanol; Esters such as methyl acetate and ethyl acetate; Halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; Ethers such as diethyl ether, tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Amides such as dimethylformamide and dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Water; Or combinations of any of the solvents described above, preferably nitriles, amides, sulfoxides, hydrous amides and hydrous sulfoxides; More preferably amides, sulfoxides and hydrous sulfoxides; Even more preferred are dimethylformamide, dimethylacetamide, dimethyl sulfoxide and hydrous dimethyl sulfoxide.
    [105] Although the reaction temperature of the said method mainly depends on a reaction solvent, it is -50 degreeC-100 degreeC normally, Preferably it is 10 degreeC-50 degreeC.
    [106] The reaction time of the method varies depending on the reaction solvent and the reaction temperature, but is usually 1 hour to 60 hours, preferably 4 hours to 30 hours.
    [107] When the functional groups in R 2 and R 3 of compound (2) and the hydroxyl group and / or carboxyl group of compound (3) are protected by a protecting group, the carbapenem-based system may be removed by removing the protecting group by a method known to those skilled in the art after completion of the reaction. The compound (4) which is an antibacterial agent can be obtained. For example, when the protecting group of the hydroxyl group of compound (3) is a silyl group, it is treated with a compound that produces fluorine anions such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride; Or protecting groups can be removed by treatment with organic acids such as acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid or inorganic acids such as hydrochloric acid.
    [108] When the protecting group of the hydroxyl group of the compound (3) is an aralkyl group or an aralkyloxycarbonyl group, the protecting group can be removed by treatment with a reducing agent (preferably by catalytic reduction at room temperature under a catalyst) or by oxidizing agent in a solvent. have.
    [109] When the protecting group of the hydroxyl group of compound (3) is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group, the protecting group can be removed by treating with a base in a solvent.
    [110] When the protecting group of the hydroxyl group of compound (3) is an alkoxymethyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, tetrahydrofuranyl group, tetrahydrothiofuranyl group or substituted ethyl group, the protecting group is removed by treating with acid in a solvent. can do.
    [111] When the protecting group of the hydroxyl group of the compound (3) is an alkenyloxycarbonyl group, the protecting group can be removed by treating with a base in the same manner as the deprotection conditions when the protecting group of the hydroxyl group is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. have. When the protecting group of the hydroxyl group of compound (3) is a benzyl group which may have a substituent, the protecting group can be removed by treating with water, methanol, ethanol, tetrahydrofuran or a mixed solvent with hydrogen under palladium carbon or platinum catalyst. In addition, when the protecting group of the carboxyl group of the compound (3) is an allyl group which may have a substituent at the 2-position, bis (triphenylphosphine) palladium chloride and tetra in water, methanol, ethanol, tetrahydrofuran, acetone or a mixed solvent thereof. In the presence of a palladium catalyst such as kiss (triphenylphosphine) palladium, the protecting group can be removed by treating with trialkyl tin hydrides such as tributyltin hydride or organic carboxylic acid alkali metal salts such as sodium 2-ethylhexanoate. Can be.
    [112] After completion of the reaction, the target compound of the present method can be obtained from the reaction mixture according to the conventional method. For example, it is obtained by adding a solvent in which the product does not dissolve to the reaction mixture to precipitate the product, or removing the reaction solvent by distillation under reduced pressure, and then further refining by recrystallization, reprecipitation or chromatography.
    [113] Synthetic intermediate compound (1) and its salt of the method for producing a carbapenem-based antimicrobial agent having a 1-alkylpyrrolidine structure according to the present invention are compound (5) or salts thereof and acid anhydrides as shown below. It can manufacture by making it react.
    [114] [B method]
    [115]
    [116] In said formula, R <1> represents the same meaning as the above-mentioned.
    [117] Method B is a method for producing compound (1) and its salt by carrying out an intramolecular cyclization reaction by reacting compound (5) or a salt thereof with an acid anhydride.
    [118] The reaction can be carried out in the presence or absence of a solvent.
    [119] The solvent used in the present method is not particularly limited as long as it dissolves the compound (5), which is a starting material, to some extent without inhibiting the reaction, and includes, for example, nitriles such as acetonitrile; Esters such as methyl acetate, ethyl acetate and t-butyl acetate; Alcohols such as methanol, ethanol, propanol, isopropanol and butanol; Ketones such as acetone and methyl ethyl ketone; Aliphatic hydrocarbons such as hexane, heptane and petroleum ethers; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Amides such as dimethylformamide and dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid; Or a combination of any ratio of the solvents, preferably organic acids, and more preferably acetic acid.
    [120] The acid anhydride used in this method is, for example, anhydrides of phosphoric acids; Anhydrides of organic carboxylic acids such as acetic anhydride, propionic anhydride, trifluoroacetic anhydride and phthalic anhydride; And anhydrides of organic technical acids such as methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, p-toluenesulfonic anhydride; Preferably it is anhydride of organic carboxylic acids, More preferably, it is acetic anhydride.
    [121] The amount of the acid anhydride to be used is usually 1.0 to 100.0 molar equivalents, and preferably 1.0 to 10.0 molar equivalents, relative to compound (5) or its salt.
    [122] Although the reaction temperature of this method mainly depends on the reagent used, it is 0 degreeC-120 degreeC normally, Preferably it is 30 degreeC-80 degreeC.
    [123] Although the reaction time of this method mainly changes with reaction temperature and a solvent, it is 0.5 to 20 hours normally, Preferably it is 1.5 to 5.0 hours.
    [124] After completion of the reaction, the target compound of the method can be obtained from the reaction mixture according to a conventional method. For example, after neutralizing the reaction mixture, an organic solvent which is not mixed with water is added, washed with water, and then obtained by distilling off the solvent. If desired, the desired compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
    [125] The compound (5) and its salt used by this invention can be manufactured by the C method shown next.
    [126] [C way]
    [127]
    [128] In the above formula, R 1 represents the same meaning as described above, R 4 represents a C 1 -C 6 alkyl group, R 5 and R 6 are C 6 -C which may have a C 1 -C 6 alkyl group or a substituent. 10 aryl group.
    [129] Herein, the "alkyl group" in R 4 , R 5 and R 6 is a linear or branched saturated hydrocarbon group, and the C 1 -C 6 alkyl group in R 4 , R 5 and R 6 is, for example, methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl ), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, It may be 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably a C 1 -C 4 alkyl group, more preferably a C 1 -C 2 alkyl group, even more preferably Methyl group.
    [130] The "aryl group" in R 5 and R 6 is an aromatic hydrocarbon group, and the C 6 -C 10 aryl group in R 5 and R 6 may be, for example, phenyl, 1-naphthyl or 2-naphthyl, Preferably phenyl.
    [131] When the aryl group has a substituent, the number of substituents is preferably 1 to 3, more preferably 1, and the substituent is an alkyl group such as methyl, ethyl and propyl; Aliphatic acyl groups such as formyl, acetyl and propionyl groups; Aliphatic acyloxy groups such as acetoxy and propionyloxy groups; Alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl group; Halogenated alkyl groups such as monofluoromethyl, difluoromethyl and trifluoromethyl groups; Alkoxy groups such as methoxy, ethoxy and propoxy groups; Halogen atoms such as fluorine, chlorine, bromine and iodine atoms; Alkylsulfonyl groups such as methylsulfonyl and ethylsulfonyl groups; Nitro group; And cyano groups; Preferably they are an alkyl group, a halogenated alkyl group, a halogen atom, a nitro group, or a cyano group, More preferably, they are a methyl group, a trifluoromethyl group, a fluorine atom, a chlorine atom, a nitro group, or a cyano group.
    [132] In said formula, compound (6)-(10) may form a salt with an acidic compound in an amine part. The acidic compound may be, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; May be eutectic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Preferably they are inorganic acids, More preferably, they are hydrochloric acid and sulfuric acid.
    [133] The C1 step is an esterification reaction of the compound (6), which can be carried out with reference to methods known in the art. For example, compound (7) can be manufactured by performing esterification of compound (6) in the corresponding alcohol in presence of an acid.
    [134] The acid used in this process may be, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and hydrogen bromide, or organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid. Preferably they are inorganic acids.
    [135] The alcohol which can be used in this step is a compound in which the above-mentioned C 1 -C 6 alkyl group is substituted with a hydroxyl group, for example, methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, pentanol, s-pentyl alcohol, isopentyl alcohol, 2-methylbutanol, neopentyl alcohol, 1-ethylpropanol, hexanol, 4-methylpentanol, 3-methylpentanol, 2-methylpentane Ol, 1-methylpentanol, 3,3-dimethylbutanol, 2,2-dimethylbutanol, 1,1-dimethylbutanol, 1,2-dimethylbutanol, 1,3-dimethylbutanol, 2,3-dimethylbutanol and 2-ethylbutanol, preferably methanol.
    [136] Although the reaction temperature of this process changes mainly with the solvent used, it is 0 degreeC-150 degreeC normally, Preferably it is 20 degreeC-100 degreeC.
    [137] Although the reaction time of this process mainly changes with reaction temperature and a solvent, it is 1 hour-40 hours normally, Preferably it is 1 hour-7 hours.
    [138] After completion of the reaction, the target compound of the present process can be obtained from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent of the reaction mixture. If necessary, it may be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography, but may be used in the next reaction step without purification.
    [139] The C2 step is an alkylation reaction of the compound (7), and can be carried out with reference to the method known in the art. For example the corresponding C 1 -C 3 aldehyde or derivative thereof (for example formamide) or an aqueous solution thereof and a combination of a reducing agent; Or compound (8) by carrying out alkylation of compound (7) by combining a corresponding C 1 -C 3 alkyl halide and a base in water, methanol, ethanol, tetrahydrofuran, or a mixed solvent thereof. can do.
    [140] The reducing agent used in this process can be, for example, hydrogen in the presence of formic acid or palladium; Preferably hydrogen in the presence of palladium.
    [141] Examples of the base used in the present step include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate; Or triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4- (dimethylamino) pyridine, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), 1 And organic amines such as 8-diazabicyclo [5.4.0] -7-undecene (DBU), preferably alkali metal carbonates, and more preferably sodium carbonate.
    [142] Although the reaction temperature of this process mainly depends on the reagent used, it is -20 degreeC-120 degreeC normally, Preferably it is 10 degreeC-80 degreeC.
    [143] Although the reaction time of this process mainly depends on reaction temperature and a solvent, it is 0.5 hour-15 hours normally, Preferably it is 1 hour-5 hours.
    [144] After completion of the reaction, the target compound of the present process can be obtained from the reaction mixture according to a conventional method. For example, it is obtained by distilling off the solvent of the reaction mixture or by adding a solvent (for example, propanol, isopropyl ether, etc.) in which the target compound is not dissolved in the reaction mixture to precipitate the target compound and to separate it by filtration. The obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography, if necessary, but can also be used in the next reaction step without purification.
    [145] In addition, you may perform a C1 process and a C2 process first. That is, the C2 process (alkylation reaction of nitrogen atom) may be performed first, and then the C1 process (esterification reaction) may be performed instead of the reaction path.
    [146] The C3 step is a sulfonylation reaction of the hydroxyl group in the compound (8), and can be carried out with reference to the method known in the art. For example, compound (9) can be manufactured by performing the sulfonylation reaction of compound (8) using a sulfonylating agent in presence of a base in an inert solvent.
    [147] The solvent used in the present step is not particularly limited as long as it does not inhibit the reaction, and examples thereof include hydrocarbons such as hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; Esters such as methyl acetate and ethyl acetate; Nitriles such as acetonitrile; Ketones such as acetone and methyl ethyl ketone; Ethers such as diethyl ether, dioxane and tetrahydrofuran; Sulfoxides such as dimethyl sulfoxide; Or amides such as dimethylformamide and dimethylacetamide; Preferably they are esters.
    [148] Bases used in this step include, for example, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Or organic bases such as triethylamine, diisopropylethylamine, 4-methylmorpholine, 1-methylimidazole, pyridine, lutidine and 4-dimethylaminopyridine; Preferably it is organic base.
    [149] The sulfonylating agents used in this process are, for example, methanesulfonylchloride, chloromethylsulfonylchloride, benzenesulfonylchloride, p-toluenesulfonylchloride, p-chlorobenzenesulfonylchloride and p-nitrobenzenesulfonyl Halogenated sulfonyls such as chlorides; Or sulfonic anhydrides such as methanesulfonic anhydride, p-toluenesulfonic anhydride and trifluoromethanesulfonic anhydride; Preferred are halogenated sulfonyls.
    [150] The amount of the sulfonylating agent to be used is usually 1 to 10 molar equivalents, and preferably 1 to 2 molar equivalents, relative to compound (8).
    [151] Although the reaction temperature of this process mainly depends on the reagent used, it is -50 degreeC-100 degreeC normally, Preferably it is -10 degreeC-50 degreeC.
    [152] Although the reaction time of this process changes with reaction temperature and a solvent, it is 0.1 to 10 hours normally, Preferably it is 0.1 to 4 hours.
    [153] After completion of the reaction, the target compound of the process can be obtained from the reaction mixture according to a conventional method. For example, it is obtained by adding an organic solvent which is not mixed with water to the reaction mixture, and distilling off the solvent after washing with water. If desired, the desired compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
    [154] The C4th step is a reaction in which the sulfonyloxy group in the compound (9) is substituted with a thiocarboxylic acid carboxylate anion, and can be carried out with reference to the method known in the art. For example, compound (10) can be manufactured by performing substitution reaction of compound (9) using the metal salt of thiocarboxylic acid, or the combination of thiocarboxylic acid and a base in an inert solvent.
    [155] The solvent used in this step is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; Esters such as methyl acetate and ethyl acetate; Alcohols such as methanol, ethanol and propanol; Nitriles such as acetonitrile; Ketones such as acetone and methyl ethyl ketone; Ethers such as diethyl ether, dioxane and tetrahydrofuran; Sulfoxides such as dimethyl sulfoxide; Amides such as dimethylformamide and dimethylacetamide; Water; Or a combination of any proportion of the solvents; Preferred are alcohols, amides, water and combinations thereof.
    [156] The metal salt of thiocarboxylic acid used in this process may be, for example, sodium thioacetate, potassium thioacetate, cesium thioacetate, sodium thiobenzoate, potassium thiobenzoate or cesium thiobenzoate, preferably potassium thioacetate. .
    [157] This process can be reacted even if it uses the combination of thiocarboxylic acid and a base. The thiocarboxylic acid used in this process may be, for example, thioacetic acid or thiobenzoic acid, preferably thioacetic acid. Bases used in combination include, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium hydrogen carbonate; Alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium t-butoxide; Metal hydrides such as sodium hydride and potassium hydride; Or triethylamine, diisopropylethylamine, 4-methylmorpholine, 1-methylimidazole, pyridine, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN) and 1,8- Organic bases of diazabicyclo [5.4.0] -7-undecene (DBU); Preferably it is an inorganic base.
    [158] The amount of the metal salt or thiocarboxylic acid of thiocarboxylic acid to be used is usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents relative to compound (9).
    [159] Although the reaction temperature of this process changes mainly with the reagent used, it is 0 degreeC-150 degreeC normally, Preferably it is 40 degreeC-100 degreeC.
    [160] Although the reaction time of this process mainly changes with reaction temperature and a solvent, it is 1 hour-20 hours normally, Preferably it is 1 hour-10 hours.
    [161] After completion of the reaction, the target compound of the present process can be obtained from the reaction mixture according to a conventional method. For example, it is obtained by adding an organic solvent which is not mixed with water to the reaction mixture, and distilling off the solvent after washing with water. If desired, the desired compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
    [162] The fifth C5 step is a hydrolysis reaction of the compound (10), which is carried out with reference to methods known in the art. For example, compound (5) can be manufactured by carrying out the hydrolysis reaction of compound (10) in either acidic or basic conditions.
    [163] When hydrolysis is performed under acidic conditions, the acid used in the present process may be, for example, an inorganic acid such as hydrochloric acid or sulfuric acid, preferably hydrochloric acid or sulfuric acid.
    [164] When hydrolysis is carried out under basic conditions, the base used in the present process may be, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide, preferably sodium hydroxide or potassium hydroxide.
    [165] Although the reaction temperature of this process changes mainly with the reagent used, it is -20 degreeC-150 degreeC normally, Preferably it is 0 degreeC-110 degreeC.
    [166] Although the reaction time of this process mainly changes with reaction temperature and a solvent, it is 0.1 to 20 hours normally, Preferably it is 0.1 to 10 hours.
    [167] After completion of the reaction, the target compound of the process can be obtained from the reaction mixture according to the conventional method. For example, it is obtained by distilling off the solvent of the reaction mixture. If desired, the desired compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
    [168] Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.
    [169] (Example 1)
    [170]
    [171] In the formula, PNB represents a p-nitrobenzyl group which is a protecting group of a carboxyl group, and PNZ represents a p-nitrobenzyloxycarbonyl group which is a protecting group of a guanidino group. The same meanings apply to the PNB and the PNZ.
    [172] (1R, 5S, 6S) -6 [(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-[(3S) -3- [2- [3- ( 4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbafen-2-m-3- Carboxylic acid 4-nitrobenzyl ester (method A)
    [173] (2S, 4S) -5-methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one (250 mg) and (S) -3- [2- [3- (4-nitrobenzyl Diisopropylethylamine (1.49 mL) was added to a methanol / methylene chloride (1: 2) suspension (7.5 mL) of oxycarbonyl) guanidino] acetylamino] pyrrolidine disulfate (979 mg). It stirred by heating at 7 degreeC for 7 hours. The solvent of the reaction solution was distilled off under reduced pressure, and then dimethylformamide (7 mL), (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -2-[(diphenylforce) under ice-cooling. Pino) oxy] -1-methyl-carbafen-2-m-3-carboxylic acid 4-nitrobenzyl ester (934 mg) and diisopropylethylamine (0.6 mL) were added sequentially, overnight at the same temperature. It was left. The reaction solution was poured into 1% sodium bicarbonate water (70 mL), and the precipitated solid was collected by filtration to obtain the title compound (1.4 g, purity 79%, yield: 83%).
    [174] Infrared Absorption Spectrum (KBr) (max cm -1 : 3384, 3113, 3080, 2970, 2875, 2789, 1770, 1643, 1609, 1522, 1450, 1379, 1346, 1322, 1287, 1209, 1181, 1136, 1109.
    [175] Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl 3 ) δ (ppm): 1.08-2.22 (m, 6H), 1.75-2.26 (m, 6H), 2.44-2.76 (m, 2H), 2.89-3.00 (m, 1H ), 3.03-3.15 (m, 1H), 3.18-3.65 (m, 6H), 3.68-3.90 (m, 3H), 3.93-4.06 (m, 1H), 4.13-4.35 (m, 2H), 5.05-5.15 (m, 2H), 5.30 (d, J = 14.1 Hz, 1H), 5.45 (d, J = 14.1 Hz, 1H), 7.58 (dd, J = 8.8 and 2.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 8.18-8.33 (m, 4H).
    [176] (Example 2)
    [177]
    [178] (1R, 5S, 6S) -6 [(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-[(3S) -3- [2- [3- ( 4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carbafen-2-m-3- Carboxylic acid 4-nitrobenzyl ester (method A)
    [179] (2S, 4S) -5-methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one hydrochloride (89.8 g) and (S) -3- [2- [3- (4- Sodium hydrogen carbonate (209.2 g) was added to a dimethyl sulfoxide (2.65 L) solution of nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidine disulfate (265.0 g, purity 95.8%) to give 45-50 It stirred by heating for 3 hours at ℃. (1R, 5R, 6S) -6-[(1R) -1-hydroxyethyl] -2-[(diphenylphosphino) oxy] -1-methyl-carbafen-2-m- in the reaction solution at room temperature 3-carboxylic acid 4-nitrobenzyl ester (269.2 g) and sodium hydrogencarbonate (42.0 g) were added sequentially and left overnight. The reaction solution was poured into water (7.95 L) and heated and stirred at 20 to 35 ° C for 1 hour, after which the precipitated solid was collected by filtration to obtain the title compound (400.3 g, purity 85.6%, yield: 85%). The spectral data were consistent with the compound of Example 1.
    [180] (Example 3)
    [181]
    [182] (2S, 4S) -5-methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one (method B)
    [183] 2 mol / L aqueous hydrochloric acid solution (2 ml) was added to (2S, 4S) -4-acetylthio-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (200 mg), and the mixture was heated at 70 ° C for 12 hours. By stirring, the acetyl group which is a protecting group of a mercapto group, and the methyl group which is a protecting group of a carboxylic acid were removed. After distilling off the water of reaction liquid under reduced pressure, acetic anhydride (1 ml) was added to the obtained residue, and it stirred for 1 hour by heating at 60 degreeC. Ethyl acetate (20 mL) and saturated sodium bicarbonate water (20 mL) were added to the reaction mixture, and the mixture was extracted. After separating the aqueous layer, the solvent of the organic layer was distilled off under reduced pressure to obtain the title compound (73.4 mg, yield: 52%).
    [184] Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl 3 ) δ (ppm): 2.10 (s, 2H), 2.47 (s, 3H), 2.55 (d, J = 10.0 Hz, 1H), 3.59 (s, 1H), 3.74 (dd, J = 10.0 and 2.9 Hz, 1H), 3.86-3.89 (m, 1H).
    [185] Mass spectrum m / z: 144 (M + l) + .
    [186] (Example 4)
    [187]
    [188] (2S, 4S) -5-methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one (method B)
    [189] 2 mol / L aqueous hydrochloric acid (2 ml) was added to (2S, 4S) -4-acetylthio-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (204 mg), and the mixture was heated at 80 ° C for 7 hours. By stirring, the acetyl group which is a protecting group of a mercapto group, and the methyl group which is a protecting group of a carboxylic acid were removed. After distilling off the water of the reaction solution under reduced pressure, acetic acid (1 ml) and acetic anhydride (0.6 ml) were added to the obtained residue, and the mixture was heated and stirred at 60 ° C for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate water (20 mL) were added to the reaction mixture, and the mixture was extracted. After separating the aqueous layer, the solvent of the organic layer was distilled off under reduced pressure to obtain the title compound (77.8 mg, yield: 54%). The spectral data were consistent with the compound of Example 3.
    [190] (Example 5)
    [191]
    [192] (2S, 4S) -5-methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one hydrochloride (method B)
    [193] Acetic anhydride (8.6 ml) was added dropwise at 15 ° C. or lower to a mixed solution of (2S, 4S) -4-mercapto-1-methyl-2-pyrrolidinecarboxylic acid hydrochloride (6 g) and acetic acid (24 ml). Thereafter, the mixture was heated and stirred at 55 to 60 ° C for 2 hours. The acetic acid of the reaction solution was distilled off under reduced pressure, ethyl acetate (72 mL) and water (36 mL) were added, and the aqueous layer was adjusted to pH = 8-9 with aqueous sodium hydroxide solution and then extracted. After separating an organic layer, the aqueous layer was extracted with ethyl acetate (36 mL) again, the ethyl acetate layers were combined, and the solvent was distilled off under reduced pressure. A 4 mol / lHCl / ethyl acetate (7.6 ml) solution was added dropwise to the obtained residue of ethyl acetate (35 ml) at 25 ° C. or lower, and the mixture was heated and stirred for 1 hour at the same temperature. The precipitated solid was collected by filtration to obtain the title compound (4.4 g, yield: 80%).
    [194] Melting Point 191-192 ℃
    [195] Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl 3 ) δ (ppm): 2.54 (d, J = 12.5 Hz, 1H), 2.90 (d, J = 12.5 Hz, 1H), 2.95 (s, 3H), 3.14 (d , J = 11.2 Hz, 1H), 4.32 (s, 1H), 4.35 (s, 1H), 4.40 (d, J = 11.2 Hz, 1H).
    [196] Elemental Analysis:
    [197] Calc .: C, 40.11%; H, 5.61%; N, 7.80%; S, 17.85%; Cl, 19.73%
    [198] Found: C, 39.93%; H, 5.52%; N, 7.75%; S, 17.93%; Cl, 19.76%.
    [199] (Example 6)
    [200]
    [201] (2S, 4S) -5-methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one hydrochloride (Steps C3 to C5 and Method B)
    [202] Triethylamine (8.2 mL) was added to an ethyl acetate (50 mL) suspension of (2S, 4R) -4-hydroxy-1-methylpyrrolidinecarboxylic acid methyl ester hydrochloride (5 g, purity 92%). After refluxing for 3 hours, an ethyl acetate (10 ml) solution of methanesulfonyl chloride (2 ml) was added dropwise under ice-cooling, and the mixture was heated and stirred for 1 hour at the same temperature. Saturated brine (25 ml) was added to the reaction mixture, and the mixture was extracted. After separating an organic layer, the aqueous layer was extracted with ethyl acetate (50 mL) again, the ethyl acetate layers were combined, and the solvent was distilled off under reduced pressure. Dimethylformamide (50 ml) and potassium thioacetate (4.0 g) were sequentially added to the residue, followed by heating and stirring at 70 to 75 ° C. for 2 hours. After cooling the reaction solution to room temperature, toluene (50 mL) and saturated brine (25 mL) were added and extracted. After separating an organic layer, the aqueous layer was extracted again with toluene (50 mL), the toluene layers were combined, and the solvent was distilled off under reduced pressure. Water (15 mL) and concentrated hydrochloric acid (4.2 mL) were added sequentially to the residue, followed by heating and stirring at 80 to 85 ° C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water was distilled off under reduced pressure. Acetic acid (15 mL) and acetic anhydride (6.65 mL) were sequentially added to the obtained residue, and the mixture was heated and stirred at 55 to 60 ° C for 2 hours. The acetic acid of the reaction solution was distilled off under reduced pressure, ethyl acetate (50 mL) and saturated brine (25 mL) were added to the residue, and the pH of the aqueous layer was adjusted to 8-9 with aqueous sodium hydroxide solution, followed by extraction. After separating an organic layer, the aqueous layer was extracted again with ethyl acetate (50 mL), the ethyl acetate layers were combined, and the solvent was distilled off under reduced pressure. 4 mol / L HCl / ethyl acetate (4.7 mL) solution was dripped at the obtained residue of ethyl acetate (25 mL) at 25 degreeC or less, and it heat-stirred for 1 hour at the same temperature. The precipitated solid was collected by filtration to obtain the title compound (3.1 g, purity 94%, yield yield: 69%). The spectral data were consistent with the compound of Example 5.
    [203] (Reference Example 1)
    [204]
    [205] (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester hydrochloride (Steps C1 and C2)
    [206] (2S, 4R) -trans-4-hydroxyproline (100 g) was added to a methanol (1 L) solution in which hydrogen chloride gas (127 g) was blown, followed by stirring under reflux for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 3-4 using a 28% sodium methoxide / methanol solution, and the solvent was distilled off under reduced pressure. Methanol (200 mL), 37% formamide aqueous solution (93 g), and 7.5% Pd / C (1.1 g) were added to the obtained residue, and the mixture was heated and stirred at room temperature for 5 hours under hydrogen pressure. After removal of Pd / C by filtration, propanol (200 mL) and isopropyl ether (1 L) were added to the residue obtained by distilling off the solvent of the filtrate under reduced pressure, and heating and stirring was carried out at 20 to 25 ° C for 2 hours. Precipitated crystals were collected by filtration to obtain the title compound (156 g, purity 92%, yield: 96%).
    [207] Nuclear Magnetic Resonance Spectrum (400 MHz, CD 3 OD) δ (ppm): 2.26-2.34 (m, 1H), 2.44-2.51 (m, 1H), 3.11 (s, 3H), 3.21 (d, J = 12.4 Hz , 1H), 3.87 (s, 3H), 3.87-3.92 (m, 1H), 4.53-4.64 (m, 2H).
    [208] (Reference Example 2)
    [209]
    [210] (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid (Step C2)
    [211] A suspension of water (15 ml) of (2S, 4R) -trans-4-hydroxyproline (5 g), 37% aqueous formamide solution (4.6 g) and 7.5% Pd / C (53% water content: 3.2 g) was added with hydrogen. The mixture was heated and stirred for 10 hours at room temperature under pressurized conditions. After Pd / C was removed by filtration, the water of the filtrate was distilled off under reduced pressure. The obtained solid residue was suspended and stirred by ethanol (25 ml), and then the precipitated crystals were collected by filtration to obtain the title compound (5.1 g, yield: 92%).
    [212] Nuclear Magnetic Resonance Spectrum (400 MHz, CD 3 OD) δ (ppm): 2.12-2.21 (m, 1H), 2.40-2.47 (m, 1H), 3.01 (s, 3H), 3.09 (d, J = 12.4 Hz , 1H), 3.85 (dd, J = 12.4 and 4.6 Hz, 1H), 4.06 (dd, J = 10.8 and 7.6 Hz, 1H), 4.48-4.52 (m, 1H).
    [213] (Reference Example 3)
    [214]
    [215] (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester hydrochloride (Steps C1 and C2)
    [216] Concentrated hydrochloric acid (3 ml) was added to the methanol (15 ml) suspension of (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid (3 g), and the mixture was refluxed for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (4.0 g, yield: 100%). The spectral data were consistent with the compound of Reference Example 1.
    [217] (Reference Example 4)
    [218]
    [219] (2S, 4R) -4-methylsulfonyloxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (Step C3)
    [220] Triethylamine in a tetrahydrofuran (10 ml) suspension of (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester hydrochloride (1 g) obtained in Reference Example 1 or 3. (1.53 ml) was added thereto, and the mixture was heated and stirred at 40 ° C. for 3 hours, and then methyl chloride was added under ice cooling, followed by further stirring for 2 hours. Ethyl acetate (20 mL) and 5% sodium bicarbonate water (10 mL) were added to the reaction solution, and the mixture was extracted. After the aqueous layer was separated, the solvent of the organic layer was distilled off under reduced pressure to obtain the title compound (1.0 g, yield: 83%).
    [221] Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl 3 ) δ (ppm): 2.41 (d, J = 7.8 Hz, 1H), 2.43 (dd, J = 7.8 and 1.7 Hz, 1H), 2.47 (s, 3H), 2.74 (dd, J = 11.2 and 3.9 Hz, 1H), 3.04 (s, 3H), 3.42 (dd, J = 7.8 and 7.8 Hz, 1H), 3.59 (dd, J = 11.2 and 6.1 Hz, 1H), 3.76 ( s, 3H), 5.20-5.5.26 (m, 1H).
    [222] (Reference Example 5)
    [223]
    [224] (2S, 4S) -4-acetylthio-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (C4 process)
    [225] To ethanol / water (9: 1) mixture (6 ml) of (2S, 4R) -4-methylsulfonyloxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (609 mg) obtained in Reference Example 4. After addition of potassium thioacetate (677 mg), the mixture was heated and stirred at 80 ° C for 3 hours, and left at room temperature overnight. Ethyl acetate (20 mL) and 10% brine (10 mL) were added to the reaction solution, and the mixture was extracted. The organic layer was separated and washed with water (10 ml), and then the solvent was distilled off under reduced pressure to obtain the title compound (543 mg, yield: 97%).
    [226] Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl 3 ) δ (ppm): 1.96-2.03 (m, 1H), 2.30 (s, 3H), 2.43 (s, 3H), 2.65-2.74 (m, 1H), 2.82- 2.87 (m, 1 H), 3.05-3.10 (m, 2 H), 3.76 (s, 3 H), 3.93-4.00 (m, 1 H).
    [227] (Reference Example 6)
    [228]
    [229] (2S, 4S) -4-mercapto-1-methyl-2-pyrrolidinecarboxylic acid hydrochloride (Step C5)
    [230] A mixture of (2S, 4S) -4-acetylthio-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (10.7 g), concentrated hydrochloric acid (14.9 g), and water (16 mL) at 75 to 85 ° C It stirred by heating for 5 hours. After completion of the reaction, water in the reaction solution was distilled off under reduced pressure, acetic acid (10 mL) and ethyl acetate (20 mL) were added to the residue, and the mixture was stirred under heating at 0 5 占 폚 for 1 hour. The precipitated crystals were collected by filtration to obtain the title compound (9.2 g, yield: 95%).
    [231] Nuclear magnetic resonance spectrum (400 MHz, CDCl 3 ) δ (ppm): 2.11-2.20 (m, 1H), 2.97-3.05 (m, 1H), 3.02 (s, 3H), 3.56-3.68 (m, 2H), 3.80-3.88 (m, 1 H), 4.35-4.41 (m, 1 H).
    [232] (Reference Example 7)
    [233]
    [234] (S) -3- [2- [3- (4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidine disulfate
    [235] To a solution of concentrated sulfuric acid (234 g) and methanol (2.45 L) (S) -1- (t-butyloxycarbonyl) -3- [2- [3- (4-nitrobenzyloxycarbonyl) guanidino] Acetylamino] pyrrolidine 1/2 sulfate (350 g, purity 86%) was added, and the mixture was heated and stirred at 40 to 45 ° C for 2.5 hours. After cooling the reaction liquid to 20-30 degreeC and heating-stirring for 0.5 hour at the same temperature, diisopropyl ether (3.5 L) was added and heat-stirring for 1 hour at the same temperature again. Precipitated crystals were collected by filtration to obtain the title compound (328 g, purity 95.8%, yield: 95.4%).
    [236] Nuclear Magnetic Resonance Spectrum (400 MHz, D 2 O) δ (ppm): 1.85-1.96 (m, 1H), 2.10-2.25 (m, 1H), 3.13-3.44 (m, 4H), 4.01 (s, 2H) , 4.31-4.39 (m, 1H), 5.25 (s, 2H), 7.48 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.6 Hz, 2H).
    [237] The preparation method of the carbapenem type antimicrobial agent having the 1-alkylpyrrolidine structure of the present invention is low cost, easy and high in safety, and is suitable for mass synthesis. 5-alkyl-2-thia-5-azabicyclo [2.2.1] Heptane-3-one is useful as an intermediate compound which is very important in the preparation method.
    [238] Moreover, the manufacturing method of 5-alkyl- 2-thia-5-azabicyclo [2.2.1] heptane-3-one of this invention is also the 5-alkyl- 2-thia-5- azabicyclo [2.2.1] heptane- The 3-on has the effect of being inexpensive, easy, safe and mass produced.
    权利要求:
    Claims (19)
    [1" claim-type="Currently amended] Carbapenem-based antimicrobial agents of the formula (4) or the salt thereof, by reacting a compound of the formula (1) or a salt thereof, a compound of the formula (2) or a salt thereof, and a compound of the formula (3) or a salt thereof Method of preparation of salts:
    [Formula 1]
    [Wherein, R 1 represents a C 1 -C 3 alkyl group],
    [Formula 2]
    [Wherein, R 2 and R 3 each independently represent a hydrogen atom or an organic residue, or R 2 and R 3 may be integrated with the nitrogen element to which they are bonded to form a ring] [Formula 3]
    [Wherein L represents a leaving group and the hydroxyl and carboxyl groups may each independently be protected with a protecting group] [Formula 4]
    [In formula, R <1> , R <2> and R <3> have the same meaning as mentioned above, A hydroxyl group and a carboxyl group may each independently be protected by a protecting group.
    [2" claim-type="Currently amended] 2. The compound of formula (1) according to claim 1, wherein the compound of formula (1) or a salt thereof and a compound of formula (2) or a salt of formula (3) or a salt thereof are reacted in an inert solvent in the same reaction vessel in the presence of a base. Carbapenem type antibacterial agent or its salt manufacturing method.
    [3" claim-type="Currently amended] The method according to claim 1 or 2, wherein the compound of formula (2) or a salt thereof and the compound of formula (3) or a salt thereof are reacted sequentially.
    [4" claim-type="Currently amended] The method for producing a carbapenem type antimicrobial agent or a salt thereof according to any one of claims 1 to 3, wherein R 1 is a methyl group.
    [5" claim-type="Currently amended] The method according to any one of claims 1 to 4, wherein R 2 and R 3 are integrated with the nitrogen atom to which they are bonded to form a ring.
    [6" claim-type="Currently amended] The carbapenem type antimicrobial agent according to any one of claims 1 to 4, wherein R 2 and R 3 are integrated with the nitrogen atom to which they are bonded to form a ring represented by the following formula. Or a method for preparing the salt thereof:

    [Wherein n represents 0, 1 or 2,
    p represents 0, 1 or 2,
    R a represents a hydrogen atom or a C 1 -C 4 alkyl group,
    B is phenylene, phenylenealkyl (this alkyl moiety is C 1 -C 3 alkyl), cyclohexylene, cyclohexylenealkyl (this alkyl moiety is C 1 -C 3 alkyl) or 1 to 3 substituents A C 1 -C 5 alkylene group which may have {this substituent being an amino, hydroxyl, cyclohexylalkyl (this alkyl moiety is C 1 -C 3 alkyl), C 1 -C 4 alkyl, phenyl or benzyl group},
    R b represents a hydrogen atom or a C 1 -C 4 alkyl group,
    R c is a group represented by the formula -C (= NH) R d wherein R d is a hydrogen atom, a C 1 -C 4 alkyl group or a group represented by the formula -NR e R f (where R e and R f represents independently of each other a hydrogen atom or a C 1 -C 4 alkyl group.
    [7" claim-type="Currently amended] The method of claim 6,
    n is 0 or 1,
    p is 0 or 1,
    R a is a hydrogen atom, a methyl or an ethyl group,
    B is 1,4-phenylene, 1,4-cyclohexylenemethyl, methylene, methylmethylene (-CH (CH 3 )-), ethylene, trimethylene or 2-hydroxypropylene group,
    R b is a hydrogen atom, a methyl or an ethyl group,
    R c is a formimidoyl, acetimidoyl or amidino group, characterized in that the carbapenem-based antimicrobial agent of formula (4) or a method for producing a salt thereof.
    [8" claim-type="Currently amended] The method of claim 6,
    n is 0 or 1,
    p is 0,
    R a is a hydrogen atom or a methyl group,
    B is methylene, methylmethylene (-CH (CH 3 )-), ethylene, trimethylene or 2-hydroxypropylene group,
    R b is a hydrogen atom or a methyl group,
    R c is an amidino group, wherein the carbapenem-based antimicrobial agent of formula (4) or a method for producing the salt thereof.
    [9" claim-type="Currently amended] The method of claim 6,
    n is 0 or 1,
    p is 0,
    R a is a hydrogen atom,
    B is methylene, methylmethylene (-CH (CH 3 )-) or an ethylene group,
    R b is a hydrogen atom,
    R c is an amidino group, wherein the carbapenem-based antimicrobial agent of formula (4) or a method for producing the salt thereof.
    [10" claim-type="Currently amended] The method for producing a carbapenem-based antimicrobial agent or a salt thereof according to any one of claims 1 to 9, wherein L is a diarylphosphoryloxy group.
    [11" claim-type="Currently amended] The method for producing a carbapenem-based antimicrobial agent or salt thereof according to any one of claims 1 to 9, wherein L is a diphenylphosphoryloxy group.
    [12" claim-type="Currently amended] The method according to any one of claims 1 to 11, wherein the compound of formula (1) is in a (2S, 4S) configuration.
    [13" claim-type="Currently amended] A compound of formula (1) or a salt thereof:
    [Formula 1]
    [Wherein, R 1 represents a C 1 -C 3 alkyl group].
    [14" claim-type="Currently amended] The compound of formula 1 or a salt thereof according to claim 13, wherein R 1 is a methyl group.
    [15" claim-type="Currently amended] The compound of formula 1 or a salt thereof according to claim 13 or 14, wherein the compound of formula 1 is in a (2S, 4S) configuration.
    [16" claim-type="Currently amended] A process for preparing a compound of formula (1) or a salt thereof, by reacting a compound of formula (5) or a salt thereof with an acid anhydride:
    [Formula 5]
    [Wherein, R 1 represents a C 1 -C 3 alkyl group],
    [Formula 1]
    [Wherein, R 1 represents the same meaning as described above].
    [17" claim-type="Currently amended] The process for producing a compound of formula (1) or a salt thereof according to claim 16, wherein R 1 is a methyl group.
    [18" claim-type="Currently amended] 18. The process according to claim 16 or 17, wherein the compound of formula 5 is in a (2S, 4S) configuration or a (2R, 4R) configuration.
    [19" claim-type="Currently amended] 18. The process of claim 16 or 17, wherein the compound of formula 5 is in a (2S, 4S) configuration.
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    CN1486316A|2004-03-31|
    TWI290925B|2007-12-11|
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    HK1054745A1|2006-04-21|
    ES2256311T3|2006-07-16|
    DK1338596T3|2006-04-18|
    WO2002040482A1|2002-05-23|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-11-20|Priority to JPJP-P-2000-00352178
    2000-11-20|Priority to JP2000352178
    2001-11-19|Application filed by 상꾜 가부시키가이샤
    2001-11-19|Priority to PCT/JP2001/010096
    2003-12-31|Publication of KR20030097793A
    2008-04-25|Application granted
    2008-04-25|Publication of KR100825243B1
    优先权:
    申请号 | 申请日 | 专利标题
    JPJP-P-2000-00352178|2000-11-20|
    JP2000352178|2000-11-20|
    PCT/JP2001/010096|WO2002040482A1|2000-11-20|2001-11-19|Process for producing carbapenem-type antibacterial|
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