• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention provides a novel cyclization process useful for the production of the peptide moiety of an ergotalkaloid.
    公开号:SU725565A3
    申请号:SU772439829
    申请日:1977-01-12
    公开日:1980-03-30
    发明作者:Штадлер Пауль
    申请人:Сандос Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a new method for producing derivatives of octahydrox zol o [3,2 - a] p and rorol o [2,1-c] pyrazine of the formula I where Rj R 5 R 4
    - denotes a carbobeneoxy group; , - alkyl with 1-4 carbon atoms;
    - a hydrogen atom or alkyl with
    1-4 carbon atoms;
    - ^ hydrogen volume, alkyl with 1-4 carbon atoms, phenyl, benzyl or benzyl monosubstituted with alkoxy group with 1-4 carbon atoms;
    - hydrogen atom or alkyd with
    1-4 carbon atoms with biologically active properties (
    A multi-stage process is known for the preparation of octahydrooxazolo [3,2-a] pyrrolo [2,1-e] pyrazine derivatives containing a carbobenzoxy amino group in position 2 by successive conversion of the corresponding compound with a 2-carboethoxy group to a compound with a 2-carboxy group, a compound with a 2-carboxy group in a compound with a 2-halocarbonyl group; and then a compound with a 2-halocarbonyl group in a target product.
    The starting 2-carboethoxy derivatives are obtained by cyclization of the corresponding 2- (<A-ethoxycarbonyl-EX-benzyloxybutyryl) -1,4-dioxoctahydro-pyrrolo [1,2-a) pyrazines [1].
    The disadvantage of this method is its multi-stage.
    The purpose of the invention is to simplify the process. . ''
    This goal is achieved by the present method, which is that the compound of formula II
    Ri rs
    where R is R, have the above meanings;
    R & is N-succinimidoxy, phenoxy-, phenylthio-, methylphenoxy-, methylphenylTHO-, nitrophenylthio, pentafluorophenoxy-, pentachlorophenoxy-, p-chlorophenylthio, or unsubstituted or washed with a nitro group and / or chloroform or methyl nitrocarbonyl radicals aqueous organic plant. ' yoritel at a pH of 7.3-10 and a temperature of 0-30 about C.
    As the aqueous organic solvent, aqueous acetone, damethyl sulfoxide ~, dimethoxyethane are preferably used; dyoxane, tetrahydro- * rofurats, dimethylformamide or dimethylacetamide.
    The compound of formula .11 can be used in any steric form *. So, the compound of formula 11a. '
    YbKzPP V th ί I Ea '0 ^ b <. v I * 'H is cyclized to the compound of formula 1a ·
    $ 3 8.4
    T. y. ' The ’natural’ form, where the absolute configurations of asymmetric carbon movs are the same as for dihydroergotaminescyclol.
    The compound of formula Hb
    I
    7 1 ¾ ρ · 4 is cycled to the compound Formula
    a
    FROM
    0 ’“ A
    Hi
    Ib ;
    • vG '· * I. Cz ”4 is also an aci form that can be divided.
    The compounds of formula II are mainly unstable and can be used as raw materials, which is about. is formed by exchanging the group R l0 for * hydroxyl under oxidizing or mild. Hydrolytic conditions from compounds of the formula III
    ΤΊ · '. 15 th -'ch * 'W L *' / R IQ znacheniya- minutes means a group tseplyaemuyu'pri The relative oxidizing or soft
    .... hydrolytic conditions., '• ja R © means, for example, halogen, chlorine, bromine or iodine, isocyanate, the group' pu "CH {CH 3 } OH, or preferably the CHgOH group. Under basic hydrolytic conditions, the compounds of the formula III. directly translate into.
    compounds of formula I. Compounds of formula .. !! are obtained predominantly by oxidation. For example, oxidation can be carried out using lead tetra-acetate ’, in this case, during
    thirty'. A number of reactions in the carbon to which Rg is bound are racemization. Therefore, based on the sterile mixture of the Compounds of Formula III, they are obtained but used to produce natural. , th ’acyi-forms’ compounds ’of formula I.
    Compounds of formula III can be obtained by esterification of compounds of formula IV. · ..
    diastereoisomer mixture / which can 35
    I.
    which R, -R 5 and 3R ) 0 have the above values. The esterification can be carried out with the help of the compound H in 'H; in ”the direct solution of imide. /; ·. ·.
    Compounds of formula IV can be prepared by cleavage under acidic conditions of the protecting group R H : from compounds of formula V _ '55. 'Th which R, -R to carry out using, compounds with
    I c = o
    Rj R.4
    those,. into a known ami form.
    Aci ^ form and natural form under: mild acidic conditions can bring ¢ 0 ty to equilibrium with each other.
    It is advisable to use the compound of formula II in the form of a diastereoisomeric mixture of compounds of the formulas Na lib, ___, ____________ „ r „ ...________, moreover, they form as natural, ° 65 current, for example ^ tert-butyl
    in which R ^ -Rg and R | 0 have the above meanings, and Rh means the remainder cleavable under acidic conditions
    Compounds of formula V can be prepared by condensation of a compound of formula VI ___
    Ό "η" -ί And O C = 0
    V s
    B »4 in which R 5 -R 5 and R (( have the above meanings, with the compound of Formula VI
    have vyshenazin in which R,, R 2 and R, o bath values.
    The reaction can be carried out by a method known for linking two amino acids, for example in the presence of dicyclohexylcarbodiimide. The compounds of formula VII may be in activated form, for example, after reaction with N-oxysuccinimide.
    If the compounds of formula VII are in recomic form, then the compounds of formula V are obtained in the form of their diastrereoysomeric mixture, which! can be divided. Since, upon receipt of the compounds of formula II from compounds of the formula III, racemization still takes place, it is impractical to carry out the separation at this stage.
    Compounds of formula Vi can be prepared by hydrogenolytic cleavage of residue R (2 from compounds of formula VIII Ό
    II e = o o /, • »3 * 4 in which R, -R 5 are named values, tatoe, cleaved under tic conditions, benzoxy radical.
    'Come to the compounds of the formula by condensation of the formula IX and R „
    And R, z with hydrogenoline, for example, have a carbohydrate;
    I> i
    I and 0-C
    P, 0 in which R 5 and R 1f are numerical values, with compounds of the formula X _
    R „NAN - s - COOH have the above named Ζ χ Bj B 4 in which Rj, Rj, and R | 2 are named values.
    Compounds of Formula X. Natural Amino Acids. In this case, the compounds obtained above may be the case, and formulas VII exist as a mixture of steric isomers.
    Compounds of formula IX can be prepared as described in Examples 1a and 1b. ·
    In the following Examples, temperatures are given in degrees Celsius. The commonly used high vacuum is 0.01 mmHg.
    The individual optical isomers of the compounds of formulas III, IV and V are characterized * with the help of tripeptides or esters of tripeptides I and II.
    Example 1. The aci-form (2S, 5S, 10aS, 10bS) and the natural form (2R, 5S, 10aS, 10bS) 2-carbobenzoxyamino-2-methyl-5-benzyl-10b-hydroxy-3, b-dioxooctagid-6O -oxaz0lo [3,2-a] pyrrolo [2,1 ~ s] pyrazine.
    The compounds of formula 1, where R, -car20benzoxy, R 2 -methyl, R } -hydrogen,; is benzyl, R g is hydrogen.
    6.1 g of crude N- (N-Kap6o6eH3pKCH-DL- (X-oKCHalanyl) -b-phenylalanyl-b-proline crude p-nitrophenyl ether is dissolved in 300 ml of acetone and added to 300 ml of a 10% solution potassium tartrate (pH 7.9).
    The reaction mixture was stirred for 18 h at room temperature, placed in a separatory funnel, adjusted with a 10% solution of tartaric acid to pH 5.0 and then extracted three times with methylene chloride. The partially crystallized crude compound is warmly suspended with ethyl acetate. Leave for about 2 hours to cool and crystallize, then filtered off and further washed with ethyl ether. Acetic acid. After drying in high vacuum at 90 ° C, the aci-form of the compound remains pure according to thin layer chromatography (mp 206-208 ° C; decomp.) [<X] u = -28 ° (c = 0.5- , in methanol). The mother liquor is diluted with 0.5 l of methyl enchloride, shaken well three times, each time with 400 ml of 0.5 N. soda solution and soda extracts two more times extra! extracted with methylene chloride. The methylene chloride phases are dried, evaporated and chromatographed on. silica gel. Head fractions eluted with a mixture of methylene chloride with 4-6% acetonitrile are discarded. Then elute with a mixture of methylene chloride with 10-14% acetonitrile of the target compound in its natural form. The natural form is purified by chromatography on alumina (ΊΙ-ΙΙΙ activity), and it is eluted with a methyl: nchloride-acetone mixture (1: 1). The first fractions crystallize from a mixture of wet ethyl acetate and a small amount of 65 diisopropyl ether. According to the data of thin layer chromatography, the compound (natural form) is obtained as a prism (mp 170-172 ° С; [<Л] р = + 9.8 ° (с = 1.6 in ethanol).
    Another aci-form of the target compound can be obtained in that the soda extracts are adjusted to pH 4-9 with tartaric acid and extracted twice with methylene chloride. The extracts are dried, concentrated and chromatographed on a 10-fold amount of silica gel 0.06-0.2. First of all, nitrophenol and undefined by-products elute with a mixture of methylene chloride with 6% acetonitrile. A mixture of methylene chloride and 20% acetonitrile was then eluted with the acyl form of the compound, which crystallized from ethyl acetate.
    Then elute in the above chromatography with a mixture of methylene chloride with 14-20% acetonitrile, the fractions are washed with 0.5 N. soda solution and crystallize from ethyl ester of acetic acid, whereby an acid form is obtained
    The starting compounds can be prepared as follows.
    A.. N-carbobenzoxy-E-proline tertiary butyl ether.
    To a solution of 200 ml of abs. Dimethylformamide in 500 ml of abs. with stirring at -20 ° C, 126.9 g (1 mol) of oxalyl chloride are added dropwise over 15 minutes. Then the solution was stirred for another 15 min at -20 ° C and 249 g (1 mol) of N-carbobenzoxy-E-proline were added to it. After stirring again for 15 minutes, a mixture of 250 ml of abs was added dropwise to the resulting clear yellow solution. tre.t-butanol and 200 ml abs. pyridine so that the temperature of the mixture does not exceed -15 ° C. After cooling was removed, the reaction mixture gradually turning red was allowed to react for 3 hours at room temperature. For separation, distribute between 1200 ml of 2 N. soda solution and methylene chloride and from the methylene chloride phase, a compound is obtained in the form of oil Pr 5- g 1,5015, which slowly transforms into crystals.
    B. Tertiary butyl ether of B-proline (compound of formula. IX). 2.6 7 g cheese "of the product obtained in stage A ^ are hydrogenated in 1.5 L of ethanol using a palladium-activated carbon catalyst (5% P <3) under normal pressure and room temperature. The title compound is obtained in the form of a colorless oil; t.kip. 43-46 ° C (0.01 mmHg); ηξ ° 1.4435; = -41.7 ° (s-2, in ethanol).
    B. N-carbobe'nz · oxy-E-phenylalanyl-E-proline tert-butyl ester (compound of formula VIII). ''
    To a solution consisting of 157 g of N-carbobenzoxy-B-phenylalanine in 500 ml of methylene chloride and 300 ml of abs. diethyl ether, 85.5 g of L-proline tert-butyl ether in 100 ml of diethyl ether are added at 15-18 ° C for 5 minutes and then 114 g of Ν, Ν 1 - '-dicyclohexylcarbodiimide in 150 ml of diethyl ether are added over 15. min so that the temperature of the reaction mixture does not exceed 18 ° C. ι The mixture is stirred for 1. h at room temperature, filtered and the residue washed with ether. After this, the filtrate is treated in turn with 2 N. hydrochloric acid, water, potassium bicarbonate and water, the aqueous phases are additionally extracted twice with diethyl ether. The organic phases are dried with sodium sulfate and concentrated. The remaining oil is dissolved in methylene chloride 'and filtered until transparent. The filtrate for drying was concentrated and dried under high vacuum, whereby the title compound was obtained as a yellowish oil.
    G. T-Butyl ester of B-phenylalanyl-B-proline (compound of formula VI), '
    223 g of карб-carbobenzoxy-B-phenylalanyl-B-proline tert-butyl ester is hydrogenated in a similar manner to step B, with 2100 ml of abs, tetrahydrofuran, instead of ethanol being used as a solvent. The title compound is obtained as a colorless oil.
    D. N- (N-Kapbobenzoxy-D- and B-gC-methylserine) -B-phenylalanyl-B-proline tert-butyl esters (tripeptides I and II esters; compound of formula V).
    7.2 g of M-carbobenzoxy-0B- <X-methyl ~ serine are reacted with
    9.5 g of B-phenylalanyl-E-proline tert-butyl ether in the presence of 6.8 g of Ν, Ν 1- dicyclohexylcarbodiimide and treated as described in step B. The oil obtained is chromatographed on silica gel using methylene chloride 1 mixture as an eluting means % methanol. First, the tripeptide ester 1 elutes. This compound is obtained in amorphous form; [<L] 2 ° = -28.2 ° (in methylene chloride).
    Further elution with methylene chloride with an increasing methanol content (1-4% v / v) leads to the tripeptide II ester, which crystallizes from a mixture of ethyl ether, acetic acid and hexane (1: 3) and has a melting point of 120-121 °; [<L] p = -48.4 ° (c = 2, in methylene chloride).
    . . E. Diasteroisomers of Ν- (N’-carbobenzoxy-D- and Ε ^ -Λ-methylseryl) -b-phenylalanyl-E-proline (tripeptides I and II, compounds of formula IV).
    Tripeptide I. 2.2 g of amorphous hydrochloride ester of stage I tripeptide I is dissolved in 3 ml of trifluoroacetic acid and left to stand 3/4 h at room temperature. Part of trifluoroacetic acid is suctioned off at room temperature under high vacuum, the remaining resin is dissolved in methylene chloride, and the solution is made alkaline with a potassium bicarbonate solution. It is extracted three times with a mixture of methylene chloride with a certain amount of ethanol, the organic phases are washed twice with a dilute potassium bicarbonate solution, the aqueous phases are acidified with 16% hydrochloric acid and then they are extracted three times with methylene chloride. The organic phases are washed once more with water, dried with sodium sulfate and concentrated. By crystallizing the white foam thus obtained from a mixture of methylene chloride (a certain amount of methanol) - ethyl acetate, pure tripeptide I is obtained in the form of white crystals; t. pl. 134-136 ° C; = -30.0 ° (c = 2, in ethanol).
    Tripeptide II. Similarly, when tripeptide II is used as a starting product, a white foam is obtained in a similar manner, which, after crystallization twice from a mixture of ethyl acetate and diisopropyl ether (1: 1), gives pure tripeptide II (white crystals; mp 115-118 ° С, = - 38 ° (s-1 ', 5, in ethanol).
    G. p-Nitrophenyl esters of N- (N-carbobenzoxy-D- and L-tX-methylseryl) -L-phenylalanyl-L-proline (p-nitrophenyl esters of tripeptides I and II, compounds of formula III).
    p-Nitrophenyl ester of tripeptide I. 49.7 g of tripeptide acid I and 34.8 g of p-nitrophenol are suspended in 200 ml of methylene chloride. After about 10 minutes stirring, a solution is obtained. Then, a solution of 24.7 g of Ν, Ν-dicyclohexylcarbodiimide in 200 mp abs. methylene chloride and 50 ml of abs. ether. The yellow suspension was stirred for 2 hours at 20 ° C. After this, 5 ml of 40% acetic acid is added, after 10 minutes, it is filtered and the residue is further washed with methylene chloride. The yellow filtrate is shaken three times with a 20% potassium bicarbonate solution. The aqueous phases are extracted twice more with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated. .
    There remains a yellow resin, which is chromatographed on a 10-fold amount of silica gel 0.2-0.5. For this, the substance is dissolved in a mixture of methylene chloride and diethyl ether (1: 1) and this solution is loaded into the column.
    First, it was eluted with a mixture of diethyl ether and 2% acetonitrile, and the first fractions thus obtained were discarded. Then, 60-90% purity p-nitrophenyl ester I and a mixture of diethyl ether and 8-10% acetonitrile are eluted with a mixture of diethyl ether and 6% acetonitrile. The product is 95-98% pure.
    Tripeptide II p-nitrophenyl ester. By esterification of tripeptide II, a yellow gum is likewise obtained, which is chromatographed on 15 times silica gel (0.063). The substance is dissolved in a mixture consisting of methylene chloride and diethyl ether (1: 1). This solution is placed in a column. First, the first fractions are eluted with diethyl ether, a mixture of diethyl ether with 3% acetonitrile, and then, using a mixture of diethyl ether and 3-8% acetonitrile, tripeptide II p-nitrophenyl ether is obtained in approximately 95-11% purity yellowish foam. Recrystallization from acetone-hexane gives the tri-peptide II p-nitrophenyl ether as colorless needles; so pl. 100-101.5 ° C;
    = -70.5 ° (c = 1, in methylene chloride).
    N- (N-carbobenzoxy-O-L- <2 (-oxyalanyl) -L-phenylalanyl-L-proline p-nitrophenyl ester (compound of formula II).
    3. From p-nitrophenyl ether of tripeptide I.
    In a dry appliance there is 75 ml abs. benzene and 7.5 g molecular sieves. 4 A. After 1 h, 0.3 2 g of lead tetraacetate dried in a high vacuum is added and the solution is stirred for 1/2 hour. A solution of 6.18 g of p-nitrophenyl ether of tripeptide I in 50 ml is added to it. abs. benzene, immediately heat the reaction solution to the boiling point and then mix for 10 minutes with reflux. The white suspension is cooled with an ice bath to 15 ° C, filtered. The filtrate is further washed with benzene, transferred with methylene chloride to a separatory funnel and washed twice with ice water. It is extracted twice more with methylene chloride, the organic solution is dried, it is filtered through activated carbon and the solvent is evaporated at a bath temperature of about 35 ° C, whereby the title compound is obtained as a colorless foam.
    From p-nitrophenyl ether of tripeptide II.
    The title compound is similarly prepared starting from the p-nitrophenyl ester of tripeptide II.
    From a mixture of p-nitrophenyl esters of tripeptide I and II.
    '725565' If desired, it is possible to carry out stages D, E and G, without separating the 'esters of tripeptides I and II in stage D, the tripeptides I and II in stage E and the p-nitrofojyl esters of tripeptides I and II' in stage G, whereby in the title compound, in step 3> ''. '’'
    The N-carbobenzoxy-DL-d-methylserine (compound of formula VII) used as the starting material in step p can be obtained as follows.
    Suspended 23.9 g of DL - ^ - methyl series in 160 ml of abs. pyridine. To this white suspension within 20 min at a temperature of 20-25 e C. was added dropwise 68 g of carbobenzoxy. The mixture is stirred for about 6 hours at room temperature, 34 g of carbobenzoxychloride are added dropwise again and additionally. .-stirred at room temperature overnight. Zateyp ^ oYTsyOnnuyu mixture approximation poured carefully! Especially in 400 ml of 2 N. soda solution, extracted twice with ether. The organic phase is further washed with 0.5 n. sodium carbonate solution. After that, the combined aqueous phases using a mixture consisting of; concentrated hydrochloric acid and ice (1: 1), adjusted to. ry 1.0 and the solution is extracted three times with ethyl acetate. Additionally, the combined organic phases are washed once with saturated sodium chloride solution. After drying and concentration, M-carbo-beeoxy-M.-L-methylserine remains in the form of a colorless resin, which crystallizes from a mixture of ethyl acetate and dyeopropyl ether (1: 4) (prisms, mp 115-116 ° С)
    Similarly to example 1 and when using the corresponding starting compounds in steps G and 3, it is possible to obtain the title compound by using the appropriate compounds. the expressions of formulas Na and 11b, in which R ^ means: phenylthio, pentachlorophenoxy, p-chlorophenylthio, o-nitrophenoxy, o, p-dinitrophenoxy or o-methyl-o, p-di ~ 'nitrofenrxi. 1
    PRI me R 2. The natural form of (2R, 5S, 10aS, 10bS) -2-carbobeneoxyamino-2-methyl-5-benzyl-10b-hydroxy-3, b-dioxooctahydro-8H-oxazolo {3,2-a } pyrrolo [2,1-c] pyrazine from the corresponding aci form.
    2.2 g of aci-2-carbobenzoxyamino-2-methyl-5-ben zyl-10-hydroxy-3,6-dioxoctahydro-8H-oxazolo [3,2-a] pyrrolo (2,1-c] pyrazine (see example 1) is suspended in 13 ml of glacial acetic acid, 90 ml of dioxane and 100 ml of water, the suspension is heated to the boiling point until a clear, colorless solution is formed, and then it is kept at reflux for another 9 hours. to room temperature, diluted with a small amount of water and extracted three times with methylene chloride. The combined organic phases are dried and concentrated. Tahl pure starting material (aci-form). The mother liquor was chromatographed on yellowish foam 30kratnom quantity aluminum oxides.
    to
    First, the first fractions elute with methylene chloride. Then, with a mixture of methylene chloride and 0.4% methanol, the title compound is approximately 95% pure and ._ after the still indicated title compound is approximately 50% pure.
    After that, the title compound of 95% purity was crystallized from methylene chloride-ethyl mixture. acetic acid ester, and the mother liquor 20 is crystallized once from a mixture of ethyl acetate, di-o-propyl ether (1: 2).
    The afternoon title thus indicated in the title compound was mp. 171-172.5 ° C; (<A] 20 = + 7.1 ° <
    (c = 1.8, in ethanol).
    mixtures of ethyl acetate
    权利要求:
    Claims (2)
    [1]
    R stands for N-succinimidoxy, Fengesi-, phenylthio-, methylphenoxy-, methylphenyl-pheno- / nitrophenylthio-, foams.  tafluorophenoxy-, pentachlorophenoxy-, p-chlorophenylthio, OR unsubstituted or mono-OR disubstituted nitro-1-hp and / or chlorine or methyl nytrofenoksyradyk, al, is subjected to intramolecular cycling in aqueous organic plant. solvent at pH 7.3-1. 0 and temperature 0-° C,.  : -.   as the aqueous organic solvent, aqueous acetone, dimethyl sulfoxide, dimetho siethan are preferably used; dioxane, tetragi irofuran. , dimethyl formate / amide or dimethyl aschetamide.  .  .  -. .  , -.  : Compound formula II - can be used in any steric way. So, a compound of formula Ila ,, ,,.  . .  . .  ,, „.  RR “S-V.  I IEd. .  ", -H, x" 3 4. . . . ; . :; .  . / v is cycled to a compound of formula la B. , -3JH- 3 4. ё.  The irribed form, where the absolute Hbje configuration of asymmetric carbon atoms is the same as that of dihydroergotamine cyclone.  , Combining the fop 5ylib.  . - :: /. :,.  . . .  yu-1;: ;;;;.   I It-: y: . ; , . . . ,:  .   .  .  ;% four .  ; cyclizes to Formula Ib Bj-m-j -n,:.  : -.  H y4 / t. e.  at . Starfish} is an ac-form.  The acid form and the natural shape of the straight mild acidic conditions can be brought into equilibrium with each other.  The compound of the formula II is expediently used as a diastereoisomer mixture of the Compounds of forralul Na and li.  moreover, both natural and aci-form are formed, which can be separated.  The compounds of the formula II are mainly unstable and can be used as a raw material, which is formed by exchanging the R, Q group for hydroxyl during oxidizing or. the mild hydrolytic conditions of the compound, the SRI of the formula III. -.   -.   : -v--:,:. :. / ,. . . . . .  . . . , .  . .     In which R) -Rg have the above-mentioned yyacheny - and R, Q means a group, detached under oxidizing or li hydrolytic conditions k. .   . . . . .   .  R, Q. means, for example, halogen, chlorine, bromine or iodine, isocyanate, the group -CH {OH) OH or preferably group C. HgON  When the main hydraulic conditions are, co-conditions are ill.  directly. P. translation t in.  Compounds of Formula I, Compounds of Formulas a. .  Ii. get some training oxidation, for example, oxidation.  It is possible to carry out the viability with lead tetraadetate,. In this case, the reactions with. carbon with which.  H is connected - there is a racemization site, Therefore, on the basis of steric. oh mixture: compounds of formula 111 are obtained;  .  dyasteroisomers / KOTopjrto can be used. long  obtaining natural and auH-0opvj compounds of the formula I, K of the compound of Formula 11 can be obtained by etherification of the compounds of the formula IV yi I, I I g.  , x «« 0, H 3 44 i in which Rj-Rg 10 have the above-mentioned values. Esterification can be carried out} with the help of - the compound RgH in the presence of cyclohexylcarboimide, -: / -. J -; -; ; -.  . . .  ; .  v Compounds of formula IV can be cleaved under the acidic conditions of the parent group R ,,; from; connections.  Formula V.  .  .   .    "V-NH-f o o Kv of which and RIP have the above-mentioned meanings, and H" means the residue that can be cleaved under acidic conditions, for example, t-butyl.  Compounds of formula V can be obtained by condensation of a compound of formula VI 1.   W o.  . . -, S in which RJ-RS has the above-mentioned meanings, with a compound of the formula VI) 1, -1 CBh - | - a / ta / -OJ.   , 0 in which R, Pu and Rjo are as defined above.  The reaction can be carried out in a manner known to bind two amino acids, for example in the presence of dicyclohexylcarbodIimide.  The compounds of formula VII can be in activated form, for example, after reaction with N-oxysuccinimide.   If I have a compound of formula VII, with a remic form, I get compounds of formula V in the form of their diastrereoisomeric mixture, which can be separated.  Tai as in the preparation of compounds of formula II from compounds of formula ill bc, e. Equally takes place; racemization, t6 is not advisable at this stage to assess the separation of the compounds of the formula Vl Hydrgenolytic elimination of the residue R ,, 6t of the formula V; 6 PPP - / f DYN-S from 4 in which Rj-R5 and R have higher these values, and R, 2 means o, cleaved under hydrogenic conditions, for example, a carboxybenzoic radical.   Compounds of formula VIII can be obtained by condensation of compounds of the formula IXJR "0-C, RN in which R and have the above-mentioned meanings, with compounds of the formula X.  ECM1-C-CbOH af a, X in which Rj, R4 and R, 2 are as previously defined.  Compounds of formula X may be. naturally occurring amino acids. In this case, the resulting formula VII formula exists as a mixture of steric isomers.  Compounds of formulas IX can be prepared as described in Examples 1a and Ib,.  In the following Examples, temperatures are indicated in degrees Celsius.  A commonly used high vacuum is 0.01 mm Hg. Art.  The individual optical isomers of the compounds of formulas III, IV, and V are characterized using tripeptides or complex esters of trippeptides I and II.  Example 1  Adi-form {2S, 5S, lOaS, lObS) and the natural form (2R, 5S, lOaS, lObS) 2-carbenzoxy-amino-2-methyl-5-benzyl-lOb-oxy-3, b-dioxoocta-2-dioxooctaca-2-dioxoocta-3, b-dioxoctaca-3, b-dioxoctaca-3, b-dioxoctaca-3, b-dioxoctaca-3, b-dioxoctaca-3, b-dioxocta-3 ) b-8Y-oxylate 6l 3, 2-a pyrrolo 2,1-e) pyrazine.  Compounds of formula I where R is -car6o6eH3OKCH, R2-methyl, Rj is hydrogen, is benzyl, Rg is hydrogen.  .  6.1 g of the crude p-nitrophenyl ester of L- (L-carbobenzoxy-OP-l-oxyalanyl) -b-phenylLalanyl-L-proline are grown in 300 MP of acetone, added.  to 300 ml of 10% potassium tartrate solution (pH 7.9).  The reaction mixture is stirred for 18 hours at room temperature, placed in a separatory funnel, adjusted to pH 5.0 with 10% tartaric acid solution, and then extracted three times with methylene chloride.  The partially crystallized crude compound is warm, suspended using ethyl acetate.  Allow to cool and crystallize for approximately 2 hours, then filtered and further washed with ethyl ether. acetic acid.  After yushki in high vacuum, it remains clean. according to thin layer chromatography a cyf6pma compounds (t. square  206-208 С; different ) (-28 ° (ct: 0.5 in methanol).  Uterine. This solution was diluted with 0.5 l of methyl enchloride, shaken well three times, each time with 400 ml of 0.5 n.  soda solution and extracts sody twice more additionally extracted with methylene chloride.  The methylene chloride phases are dried, evaporated and chromatographed on.  silica gel.  Head fractions eluted with a mixture of methylene chloride and 4-6% acetonitrile are discarded.  Then, the target compound in its natural form is eluted with a mixture of methylene chloride with 10-14% acetonitrile.  The natural form is purified by chromatography on alumina (TI-III activity), and it is eluted with methylene chloride-acetone (1: 1).  The first fractions are crystallized from a mixture of wet ethyl acetate and a small amount of diisopropyl ether.  A H: a compound is obtained according to thin layer chromatography (natural form), in the form of prisms (m. square  170-172 ° C; (+9.8 (, 6 in ethanol).  Another acid form of the target compound can be obtained by adjusting the soda extracts with tartaric acid to a pH of 4-9 and extracting twice with methylene chloride.  The extracts are dried, concentrated and chromatographed on a 10-fold amount of silica gel 0.06-0.2. First of all, nitrophenol and unspecified by-products elute with a mixture of methylene chloride with 6% acetonitrile.  Then, a mixture of methylene chloride and 20% acetonitrile elutes the aci-form of the compound, which crystallizes from ethyl acetate.  Then elute in the above chromatography with a mixture of methylene chloride with 14-20% acetonitrile, the fractions are washed with 0.5 n.  soda solution and crystallized from ethyl acetate, and get aciform form.  -.  The starting compounds can be obtained as follows.  BUT. , N-carbobenzoxy-b-proline tertiary butyl ester.  To a solution of 200 ml abs. dimethylformamide in 500 ml abs.  acetonitrile with stirring with the addition of 126.9 g (1 mol) of oxalyl chloride for 15 minutes  The solution is then stirred for another 15 minutes at -20-C and 249 g (1 mol) of N-carbobenzoxy-L-proline are introduced into it.  After a newly completed 15 minute shivin to the resulting clear yellow solution was added dropwise. a mixture of 250 ml abs.  tert-butanol and 200 ml abs.  pyridine in such a way that the temperature of the mixture did not occur at -15 ° C.  After removing the cooling, the gradually becoming red reaction mixture is left to react for 3 hours at room temperature.  For separation, distribute between 1200 ml of 2N.  soda solution and methylene chloride and from the methylene chloride phase, a compound is obtained in the form of an oil, n-g 1.5015, which is immediately converted into s crystals.   B.  Tertiary butyl ester of L-ripo lin (compound of formula. Ix).  2.67 g of phosphorus of the product obtained in stage A is hydrogenated in 1.5 liters of ethanol with the aid of a U catalyst a palladium-activated carbon (5% Pd) at normal pressure and room temperature. The title compound is obtained as a colorless oil; t. kip  43-4bs (0.01 mm Hg. Art. ); 4 1.4435; L -41.7 ° (s-2, in ethanol).  B, Tert-Butylbutyl ester of N-carboxyH oxy-b-phenylalanyl-b-proline (compound of formula VIII).    to a solution consisting of 157 g of L-carbobenzoxy-b-phenylalanine in 500 ml of methylene chloride and 300 ml of abs.  of diethyl ether, 85.5 g of tert-butyl ether of L-strait and 100 ml of diethyl ether are added at 15-18s over 5 minutes and then 114 g of N, N-dicyclohexylcarbodiimide in 150 ml of diethyl ether over 15 minutes in such a way that the temperature of the reaction mixture did not exceed 18s.  i The mixture is stirred 1. h at room temperature, filtered and the residue is washed with ether.  After that, the filtrate is alternately treated with 2 n.  hydrochloric acid, water, potassium bicarbonate and water, the aqueous phases are twice extracted with diethyl ether.  The organic phases are dried with sodium sulfate and concentrated.  The residual oil is dissolved in methylene chloride and filtered until transparent.  The filtrate for drying is concentrated and dried under high vacuum, this being obtained. in the title compound as yellowish oil.  G.  L-phenylalanyl-L-proline t-butyl ester (compound of formula VI).  223 g of N-carbobenzoxy-b-phenylalanyl-b-proline t-butyl ester are hydrogenated in a manner similar to Step B, and 2100 ml of abs is used as a solvent.  tetrahydrofuran, instead of ethanol.  Populate the title compound as a colorless oil.  D.  N- (N-Kapbobenzoxy-D- and (-methylserine) -b-phenylalanyl-L-proline tert-butyl esters (esters of tripeptides I and II; compound of formula V).  7.2 g of H-carbobenzoxy-OH- | L-methylserine is introduced into the reaction with 9.5 g of tert-butyl ester of L-phenylalanyl-b-proline in the presence of 6.8 g of N, N-dicyclohexylcarbodiimide and treated as described in stage B.  The resulting oil is chromatographed on silica gel using a mixture of methylene chloride and 1% methanol as eluent.  Tripeptide 1 ether is eluted first.  This compound is obtained in amorphous form; f -28,2- (in methylene chloride).  Further elution with methylene chloride with an increasing methanol content (1-4%, volume / volume) leads to the tripeptide ester II, which crystallizes from a mixture of ethyl ether, acetic acid and hexane (1: 3) and has a melting point of 120-121 °; -48.4 (, in methylene chloride).  .  .  E.  The diasteroisomers of N- (N-carbobenzoxy-D- and L- (L-methylseril) -L-phenylalanyl-b-proline (tripeptides I and II, soy &ny; of formula IV).  Tripeptide I.  2.2 g of amorphous ester of trippeptide I stage D is dissolved in 3 ml of trifluoroacetic acid and left to stand for 3/4 h at room temperature.  A portion of the trifluoroacetic acid is sucked off at room temperature under high vacuum, leaving the resin dissolved in methylene chloride, and the solution is made alkaline with potassium bicarbonate solution.  Ec is drained three times with a mixture of methylene chloride and some ethanol. The organic phases are washed twice with a dilute potassium bicarbonate solution, the aqueous phases are acidified with 16% hydrochloric acid, and then extracted three times with methylene chloride.  The organic phases are further washed once with water, dried with sodium sulfate and concentrated.  By crystallization, a white foam and methylene chloride mixture was thus obtained.  (some amount of methanol) - ethyl acetic acid ester gives pure Tripeptide I in the form of white crystals; t.  square  134-136С-З0.0 (, in ethanol).  Tripeptide II.  Similarly, when using trippeptide II as the starting product, a white foam is obtained in a similar way, which, after two-fold crystallization from a mixture of ethyl acetate and diisopropyl ether (1: 1), gives pure tripeptide II (white crystals; t. square  115-118s, -38 ° (s-G, 5, in ethanol).  G.  p-Nitrophenyl esters of N- (N-carbobenzoxy-D- and L-sl-methylsethyl) -b-phenylalanyl-B proline (p-nitrophenyl esters of tripeptides I and II, compounds of formula III)  p-Nitrophenyl ester of tripopept I.  49.7 g of tripeptide acid I and 34.8 g of p-nitrophenol are suspended in 200 ml of methylene chloride.  After about 10 minutes of stirring, a solution is obtained.  Then, a solution of 24.7 g of N, N -dicyclohexylcarbodiimide in 200 ml abs is added to it.  methylene chloride and 50 ml abs.  the ether.  The yellow suspension is stirred for 2 hours at.  After this, 5 ml of 40% acetic acid is added, after 10 minutes filtered and the residue is washed with methylene chloride.  The yellow filtrate was shaken three times with 20% potassium bicarbonate solution.  The aqueous phases are extracted twice more with methylene chloride, and the combined organic is dried. phase over sodium sulfate and concentrate them.  . A yellow resin remains, which is chromatographed on a 10-fold amount of silica gel, 0.2-0.5.  For this, the substance is dissolved in a mixture of methylene chloride and diethyl ether of ether (Ijl) and this solution is loaded into a column.  First eluted with a mixture of diethyl ether and 2% acetonitrile, the first fractions thus obtained are discarded.  Then, a mixture of di, ethyl ether and 6% acetonitrile is eluted with tripotent I p-nitrophenyl ether of 60-90% purity and a mixture of diethyl ether and 8-10% of acetonitrile.  Product 95-98% purity.  Tripeptide p-nitrophenyl ester II.  By esterification of trippeptide TI, a yellow resin is likewise obtained, which is chromatographed on a 15-fold amount of silica gel (0.063).  The substance is dissolved in a mixture consisting of methylene hydrochloride and diethyl ether (1: 1).  This solution is placed in a column.  The first fractions are first eluted with diethyl ether — a mixture of diethyl ether and 3% acetonitrile, and then using a mixture consisting of diethyl ether and 3-8% acetonitrile, tryptide II p-nitrophenyl ether is obtained in about 95% pure purity. in the form of a yellowish foam.  By recrystallization from an acetone-hexane mixture, the tripeptide II p-nitrophenyl ether is obtained in the form of colorless needles; t. square  100-101, M-70.5, in methylene chloride).  N- (N-carbobenzene (:: i-Pb- 1-hydroxyalanyl) -L-phenylalanyl-b-proline p-nitrophenyl ester (compound of formula II).  3  From p-nitrophenyl ether tripeptide 1.  In the dry device, there is 75 ml abs.  benzene and 7.5 g molecular sieves.  4 A.  After 1 hour, add 0.3 2 g of lead dried in high vacuum to tetraacetate. and the solution is stirred further 1/2 hours  To it is added a solution consisting of 6.18 g of trippeptic p p-nitrophenyl ether in 50 ml.  abs  benzene, immediately heat the reaction solution to a temperature of penny and then move for 10 minutes with reflux.  The white suspension is cooled with an ice bath until filtered.  The filtrate is additionally washed with benzene, transferred to a separatory funnel with methylene chloride, and washed twice with ice water.  Extraction is carried out twice with methylene chloride, the organic solution is dried, filtered through activated carbon and the solvent is evaporated at a bath temperature of approximately, and the title compound is obtained as a colorless foam.  From p-nitrophenyl ether tripeptide II.  In a similar manner, the title compound is obtained, starting from the tripeptide II p-nitrophenyl ester.  From a mixture of p-nitrophenyl ethers of trippeptide I and II.  If desired, you can carry out stages D, E and W, without separating the ether in tript birds I and 11 in stage D, tripeptides I and II in stage E, and p-nitrophenyl ethers in trippeptides I and II in stage g, and get the specified S header squat at stage 3, v.  ,,.  .  .  . . . .  .  . -. . . . . .  . , -. . J. . .  The applied on stage p as the starting compound L-car-n (shedicke formula VII) can be obtained as follows.  Suspended 23/9 g Pb - (- yeats on 160 MP abs.  pyridine.  68 g of sar (5 p 5 5 monoxychloride) are added to this white suspension over 20 ftrtJf at a temperature of 20-25 C.  After transferring Prnbläytelnb 6 h at room temperature FltepaVype / once again dribble 34 g carbs and supplement elNb.  stirred at room temperature overnight.  Then the reaction mixture is carefully poured into approximately 400 ml 2.  in a two-sided solution, waiting to be extracted with ether.  The organic phase is additionally about lva t 0.5 n.  sodium carbonate solution.  After that, oft-bejciHHieWH e of the solid phase with the help of a mixture, with 6 hundred (T11 | her from the Chlorinated single chloride to slots and ice (1: 1) / brought to.  pj 1/0 and pactebp t {I1 are extracted with acetic acid talamine.  Fully washed combined organic phases once with nasi HatpHH solution.  Pouring and concentrating remains Y-carg adxy-b-b-methyl serine in the Ida colorless resin, which is crystallized from a mixture of ethyl ester of acetic acid and dyooprotein Vfyr (1: 4) (prism / t. pl, IIS-IIS C Analogously to example 1 and with the acceptance of the biyi ss otvetstvuiaie initial average scientific research institutes ff in stages g and 3, you can get the connection in the title topic that H.SH.SH.  Formulas lia, in Kotdp &amp; x R, mean: phenylthio, pentachlorophenoxy p-chlorophenylthio / o-nitrophenoxy, o, p-dinitrophenoxy, or o-methyl-o / P-intrufenrxy. .  Example 2  The natural form (2R / 5S / 1OaS / 1ObS) -2-k Arbobens: here, 2-methyl-5-benzyl-10b-oxy-3/6-dioxooctahydro-8H-oxazodO: DZ, 2-a} pyrrolo 2/1-c of pyrazine from so6 acetyl form.  2.2 g of aci-2-car6-benzoxyamino-2-methyl-5-benzyl-10-rxy-3, b-dioxooctahydro-8H-oxas, 2-a pyrrolo C2 / l-c pyrazine (see  Example 1) suspensions {13 ml of glacial acetic acid, 90 ml of dioxane and 100 ml of water.  The suspension is heated to boiling point, until a transparent colorless solution is formed, and then kept for 9 hours at reflux temperature.  The solution is cooled to room temperature / diluted with a small amount of vrdy tridhal extractable with methylene chloride.  The combined organic phases are dried and concentrated.  Crystals of pure izsodnogo material (aci-form) fall out.  The mother liquor / yellow foam is chromatographed on a 30-fold amount of alumina.  First, the first fractions are eluted with methylene chloride.  Then, methylene chloride - a mixture of methyl chloride and 0.4% methanol is used to elute the title compound of about 95% purity and, after that, the compound of the title manufacturer has a 50% purity.  After StdrcJWaga Hpe in the title compound 9S% purity crystallized.  from a mixture of mbTileicillrid - ethyl.  ester of acetic acid, and the uterine solution, once crystallized from ethyl ether ethyl acetate (1: 2) from a mixture of acetic acid.  A compound that is specified in this way is not in the header of the connection. square  171-172.5; Г s + 7.1 °: (, 8, in ethanol). .  .  Claims. The method of obtaining oxalhydrooxazolo derivatives 3, 2-a pyrrolo 2,1-e pyrazine of the formula, where R is a carbobenzoxy group; alkyl with 1-4 carbon atoms Rn yes. ; . ;.  hydrogen or alkyl with 1-4 atr-.  MaMy carbon; hydrogen, alkyl with 1-4 atomM carbon, phenyl, benzyl or benzyl, monosubstituted alkoxy with 1-4 carbon atoms; ,  hydrogen or alkyl with 1-4 atoms of carbon, characterized in that, in order to simplify the process, the compound of the formula nO fi 1 about X where R, -R.  have the above meanings jj means M-succini # 1loxyphenoxy-, phenylthio-, methylphenoxy-, methylphenylthio, nitrophenylthio-, pentafluorophenoxy-, pentachlorophenoxyr p-chlorophenyltisz- or unsubstituted or mono- or di- or “disulfide”, i'm not using i'ah, I am in a set i'I'l or i'm i'I'l, or i'm i'I'l or i'm i'I'l, or i'm i'I'l or i'm i'I'l; ,   subjected to intramolecular cyclization in an aqueous organic solvent prNH, 7.3-10 at temperatures g 0-30 ° C.  
    [2]
    2. The method according to p. 1, about tl and h and sch and with the fact that as the aqueous organic solvent is used aqueous acetone or dimethylsulfox, or dimethoxyethane, or dioxane or tetragon drofuran, or dimethylfo amide. Shch dimethyl schistamide. Sources of information taken into account in the examination. i, Patent number 563393, cl. C O f) 498/14, published. 1975 (prototype).
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    同族专利:
    公开号 | 公开日
    DK150490B|1987-03-09|
    AT364817B|1981-11-25|
    YU6277A|1982-10-31|
    SE434401B|1984-07-23|
    DE2700234A1|1977-07-14|
    FI62094C|1982-11-10|
    FI62094B|1982-07-30|
    ES454917A1|1978-04-01|
    CA1108128A|1981-09-01|
    DK577A|1977-07-13|
    FR2337727A1|1977-08-05|
    IE44560L|1977-07-12|
    CH619468A5|1980-09-30|
    CS200205B2|1980-08-29|
    DK150490C|1987-10-19|
    AU2122877A|1978-07-20|
    US4145549A|1979-03-20|
    GB1571835A|1980-07-23|
    IE44560B1|1982-01-13|
    ATA8777A|1981-04-15|
    FR2337727B1|1980-04-30|
    AU512003B2|1980-09-18|
    FI770008A|1977-07-13|
    HU176871B|1981-05-28|
    NL7700124A|1977-07-14|
    BE850304A|1977-07-12|
    JPS5287197A|1977-07-20|
    YU39377B|1984-12-31|
    NZ183045A|1979-03-16|
    ZA77151B|1978-08-30|
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    CH26976A|CH619468A5|1976-01-12|1976-01-12|
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