• 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:
    New mercaptoacyl derivatives of substituted prolines which have the general formula <IMAGE> or salts thereof may be used as hypotensive agents. In the formula X-R1 group is located at the 3- or 4- position of the proline ring; X is oxygen or sulfur; R is hydrogen or lower alkyl; R1 is lower alkyl, lower alkenyl, lower alkynyl, phenyl, substituted phenyl, phenyl-lower alkylene, or substituted phenyl-lower alkylene; R2 and R3 are independently selected from hydrogen, lower alkyl and trifluoromethyl; R4 is hydrogen, <IMAGE> or <IMAGE> R5 is lower alkyl, phenyl, or phenyl-lower alkylene; and n is 0, 1 or 2.
    公开号:SU1066460A3
    申请号:SU792800304
    申请日:1979-08-10
    公开日:1984-01-07
    发明作者:А.Ондетти Мигуел；Крапко Джон
    申请人:Е.Р.Сквибб Энд Санз,Инк. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of proline derivatives, which can be used to reduce elevated pressure. It is known to acylate amines with acid anhydrides in aqueous alkaline solution according to the Schotten-Raumann method. The purpose of the invention is to develop a method based on the well-known method of obtaining new compounds possessing new properties. This goal is achieved by the method of obtaining the derivatives of the pline of the general formula about the OT "2 li. t-Co-: --i-coo l4 $ - {; n) -ngde. X is oxygen or sulfur; p - O or 1; R is hydrogen or alkyl; R is alkyl, phenyl or nyl, substituted by halogen by alkyl or alkoxy; R is boron, alkyl or trifluoromethyl; , On, - hydrogen; H is hydrogen, Q C alkanoyl benzoyl or the group "5 R2 NgC -3- (Cn)" - cn- (COOR in that the proline of the resulting formula 3f, HITi-COOE / where X, R and R have the indicated meaning is reacted with haloes with an acid anhydride of the general formula EZ R2 E; - $ - (CH) P-CH-COOH. Where R is hydrogen or R5 is CO; Rg is lower alkyl, phenyl or phenyl is lower alkylene, and the target the product is isolated in free form or as a salt, or, if necessary, a compound of the formula where R is converted into a compound of formula I, where R is hydrogen by the action of an aqueous solution of ammonia or a compound of formula I, where R / is hydrogen, oki iodine is used to prepare a compound of formula I, where R4 group BS Bj is a - (n) -co-: with isolation of the desired product in free form or in the form of a basic salt. The compounds obtained are in the form of stereoisomers or as racemic mixtures thereof. In this case, they can be used either as a racemate or as one of the mirror isomers. When using the racemic starting material, the steroisomers obtained in the final product can be separated using conventional chromatography or fractional crystallization methods. Group X -, R; | is also a source of cis-trans isomerism. Preferably, the center of the asymmetry. In the proline ring has the L-KOH configuration, but if there is a -sim lent center in the mercaptoacyl side chain, then that ring has the D-configuration. A compound of formula I is basic salts with various. inorganic or organic bases. The ion formed by inorganic or organic bases. The salt-forming ion derived from such bases may be a metal ion, such as an alcmini ion, alkali metals such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or ions of amine salts, many of which may be used for this purpose, e.g., aralkylamino such as dibenzylamine, K (N-dibenziletilendio1min, lower alkylamines such as methylamine, t-butylamine, procaine, lower alkylpiperidines such as ethylpiperidine, cycloalkylamines such as cyclohexylamine or Dietz clohexylamine, 1-adamantanamine, benzathine, or salts derived from amino acids, such as arginine, lysine, etc. Physiologically acceptable salts, such as sodium and potassium salts, can be used for medical purposes, as described below, and are preferred These and other not necessarily physiologically acceptable salts are used in the isolation and purification of a product suitable for the purposes described below, as shown by the examples with the dicyclohexylamine and cyclohexylamine salts. Salts are obtained by reacting an acidic compound with an equivalent amount of alkali, giving the desired alkaline ion, in a medium, in which the salt precipitates or in an aqueous medium, followed by lyophilization. Salt can be converted into the free acid by the usual neutralization method, for example, potassium bisulfate, hydrochloric acid, etc. The proposed compounds inhibit the conversion of decapentine angiotensin I to angiotensin: II and, therefore, can be used to reduce the increased pressure. These compounds affect the sequence of transformations of renin-angiotensinogen T angiotensin 1 4. angiotensin II, retaining the enzyme that converts angiotensin, and thus reducing or stopping the formation of pressure-elevating angiotensin II. Thus, with the introduction of an effective amount of a composition containing one or more compounds of the formula I or their physiologically acceptable salts, the increased blood pressure in mammals is reduced. One dose, preferably divided into 2-4 doses per day, at a rate of from 0.1 to 100 mg per kilogram of body weight per day, preferably from 1 to 50 mg per kg per day, is sufficient to reduce blood pressure, as shown by animals. It is advisable to take the medication by mouth, but subcutaneous, intramuscular injections are also possible in the peritoneum. The proposed compounds can be used to lower blood pressure in formulations prepared in the form of tablets, capsules or elixir for oral administration or in the form of sterile solutions or suspensions for injection. About 10 to 500 mg of a compound or a mixture of compounds of the formula I or a physiologically acceptable salt are combined with a physiologically acceptable carrier, inert filler, binder, preserved agent, stabilizer, flavoring agent, etc. per dose in accordance with pharmaceutical requirements. The amount of active substance in these compositions or formulations should be such as to provide a suitable dose within the specified limits. Example. 1- (3-acetylthio-1oxopropyl) -trans-4-methoxy-b-proline (cx) H-acetyl-trans-3-hydroxy-b-proline. In a suspension consisting of 26f2 g (0.2 mol) of trans-4-hydroxy-L-proline in 400 ml of acetic acid, 26 ml of acetic anhydride are added with continuous stirring. The solids gradually dissolve after 2 hours of stirring at room temperature. The solution is poured into a two-liter flask and the solvent is evaporated in a rotary evaporator at a bath temperature of 45 ° C. Syrup residue (57.5 g) - diluted with 100 ml of ether to obtain a crystalline solid. After cooling overnight, the solids are filtered, washed with cold ether and dried in a desiccator. The resulting material (35.7 g) is finely ground, diluted in 100 ml of ether, cooled and filtered to obtain 33.8 g of 98% N-acetyl-trans-4-hydroxy-L-proline, 128-131 ° C. Recrystallization 0, 5 g of this material in 5 ml of acetonitrile gives 0.45 g of a colorless solid with a mp. 130-132 ° C; beats. weight. Ct (1% concentration in EtOH). 5) K-acetyl-trans-4-methoxy-b-pro LIN, methyl ester. A mixture of 30.0 g (0.17 mol) N-acvtiltrans-4-hydroxy-L-proline and 130 g of silver oxide is finely ground in a mortar and this mixture is stirred in a liter flask with 300 ml of acetone. The suspension is stirred, 130 ml of methyl iodide is added in portions and cooled below 40 ° C with cold water. After stirring for 7 hours, the mixture is left overnight. The solids are filtered, washed thoroughly with acetone, and the filtrate is evaporated on a rotary evaporator to give 38.3 g of a syrupy residue. The residue is again dissolved in 350 ml of acetone and 130 g of silver oxide and 130 ml of methyl iodide are added, after which 41 g of residue are obtained. After distillation, 32.2 g of distillate with a boiling point of 130-140 ° C (0.3 mm) are obtained. After digestion in 30 ml of cyclohexane and cooling, the nearly colorless methyl ester is obtained. K-acetyl-trans-4 methoxy-L-proline as a solid, weighing 31.4 g, m.p. 7175 ° C. Recrystallization in 31 ml of ethyl acetate yields 25.1 g (66%) of a colorless solid with mp. 76-77 C; beats weight L-L (1% concentration in E OH) b) trans-4-methoxy-b-proline. 11.0 g (0.05 mol) of N-acetyltrans-4-methoxy-methyl ester was added to a solution containing 27.0 g (0.085 ml) of barium hydroxide 8HoO in 525 ml of water (approximately 3.3N). B-proline. The resulting solution is stirred for 18–20 ° C for 3 hours, cooled, and treated with dilute sulfuric acid (8.8 g of concentrated sulfuric acid in 20 ml of water). The acidic suspension is left overnight. The mixture is filtered through a thick layer of celite and a milky-colored filtrate is obtained, which is evaporated on a rotary evaporator using a high-vacuum pump and 121 g of milk residue are obtained. This material is treated with dilute sulfuric acid (19.0 g of conc. Sulfuric acid c. S ml of water) and the mixture is stirred and cooled for 3 hours. After cooling to 30 ° C, 48 g of barium hydroxide are added in portions to the mixture and once the sulfuric acid is added, the pH is maintained at a level of 6.0 to 4.0. The mixture was left overnight, after which it was filtered through a thick layer of celite. The milky filtrate was evaporated as before, to obtain 50 g of a colorless dry residue, which was digested in 200 ml of hot chloroform and filtered through a layer of celite to remove barium sulfate. The slightly cloudy filtrate is evaporated on a rotary evaporator to give a gel-like material (17.7 g), diluted with 100 ml of ether and after filtration, 7.5 g (94%) of an almost colorless solid with mp. (decomposition). This material is diluted in 30 ml of warm acetonitrile, cooled, and after filtration, 4.0 (50%) of a colorless solid trans-4-methoxy-b-proline are obtained with a melting point of 20 ml. 209-211С (dilution); tct-li -75 ° C (1% concentration in EtOH). 2) 1- (3-acetylthio-1-oxopropyl) trans-4-methoxy-b-proline. A solution containing 3.5 g (0.024 mol) of trans-4-methoxy-b-proline in 50 ml of water, is stirred, cooled to 5 ° C and 3 g of sodium carbonate is added. This mixture is treated with a solution of 4, JO g (0.024 mol) of 3-acetylthiopropionyl chloride in 5 ml of ether for 10 minutes, at the same time adding 3 g of sodium carbonate to maintain the pH at about 8.0. The mixture was stirred for 1 hour in a cold 6arie and 25 ml of water was added. Dilute hydrochloric acid (5 ml of conc. Hydrochloric acid in 25 liters of water is then added, CO is released), Strongly, acidic solution is added; sodium chloride is extracted and extracted with 50 ml of ethyl acetate (4 times). the mixture is dried (MdOts.), filtered off, the solvent is evaporated and 6.0 g (90%) of colorless 1- (3-acetylthio-1-oxopropyl) -trans-4-methoxy-b-proline syrup are obtained. This acid is dissolved in 25 ml of ethyl acetate and 4.7 g of dicyclohexylamine are added to form a rapidly solidifying solution. Another 15 ml of ethyl acetate is added and the mixture is boiled in a steam bath, then cooled, filtered and 8.7 g of the di-cyclohexylamine salt are obtained with a volume of 172 seconds. After crystallization in 60 ml of acetonitrile, 8.3 g (75%) of a colorless solid with m.p. 171-173 ° C, -CeLl -35 ° C (end of titration 1% in EtOH) The dicyclohexylamine salt is converted into 1- (3-acetylthio-1-oxopropyl) -trans-4-methoxy-1g-proline, reconstituted 8.0 g of the salt in 60 ml of ice-cooled ethyl acetate, and added to this mixture in small portions 60 ml 10% potassium biosulfate. A clear separation of the mixture occurs, and a layer of water is extracted with 60 ml of ethyl acetate (2X). The organic phases are combined and dried (MdZotz), filtered off, the solvent is evaporated and 4.6 g (80%) of colorless syrup are obtained. PRI mme R 2. 1- (3-mercapto-1oxopropyl) -trans-4-methoxy-b-proline. To 1- (3-mercapto-1-oxopropyl) trans-4-methoxy-b-proline obtained in Example 1 (4.6 g or 0.017 mol), is added a cold solution of 9 ml of concentrated ammonia in 22 ml of water. The dissolution is complete after 30 minutes and the resulting solution (in argon) is left for 2 hours at room temperature. This solution is cooled. The extract is extracted with. 25 ethyl acetate (2X) and ethyl acetate extract are removed. To the solution again, add 25 ml of ethyl acetate and 17 ml of 1: 1 hydrochloric acid. The mixture is shaken, separated and the aqueous phase is extracted with 25 ml of ethyl acetate (OX). The organic phases are combined, dried (MgSOi), filtered, the solvent is removed on a rotary evaporator, and 2.3 g (59%) of colorless syrup 1- (3mercapto-1-oxopropyl) -trans-4-methoxy-b-proline is obtained, CoC-jj) (concentration and 1% in EtOH); Rf 0.49 (MeOH on silica gel, manifested with nitroprusside). Calculated (%): C 45.45 N 6.57; N 5.87, S 13.48. CdH NOitS "1 / 4HgO Found (%) C 45.42; Nb, 78; N 5.96, S 13.27. By saturating the aqueous phase with sodium chloride and extraction with 25 ml of ethyl acetate (2X), an additional 1.1 g of p can be obtained: roluct (only 3.4 JP - 87%). The sodium salt is formed under pressure in the sodium bicarbonate aqueous solution and freezing. . PRI me R 3 (Trans) (acetylthio) -2-methyl-1-oxopropyl-4methoxy-b-proline. A solution of 4.3 g (0.029 mol) of trans4-meGrxy-β-proline in 50 ml of water is stirred, cooled before and 3 g of sodium carbonate is added. To this solution, 4 5.2 g (0.029 mol) of D-3- (acetylthio) -2-methylpropionyl chloride in 5 ml of ether are added over 10 minutes, at the same time adding 3 g of sodium carbonate to maintain a pH of about 8, 0 This mixture was stirred, cooled in an ice bath for 1.5 hours, then 25 ml of water was added, and a solution of 6 ml of concentrated hydrochloric acid in 25 ml of water (separation of CO) was added. The resulting strongly acidic solution is extracted with 50 ml of ethyl acetate (4 times). The organic phases are combined, dried (MgSOi), the filter is ejected, the solvent is evaporated and 6.1 g (73%) are obtained. (trans) -l-tD (acetylthio) -2-methyl-1-oxopropyl 3-methoxy-b-proline in, in the form of a yellow syrup. This acid is diluted in 50 ml of ethyl acetate and a solution of 4, O g of dicyclohexylamine in 20 ml of ethyl acetate is added. The product begins to crystallize in solution after about 1 minute. After cooling overnight, the almost colorless solid is filtered off, dried, and 6.7 g of m.p. 175-177 ° C; M (end of traction 1% in BtOH). After crystallization in 60 ml of acetonitrile, 5.6 g of an almost clear dicyclohexylamine salt are obtained in the solid state (41%), m.p. 179-181 seconds; VD-62C (1% concentration in EtOH. The dicyclohexylamine salt is converted to acid by diluting 5.5 g of salt in 50 ml of ethyl acetate, cooled with ice and adding 50 ml of 10% potassium bisulfate. The mixture is exfoliated, and the aqueous fraction is extracted with 50 ml of ethyl acetate ( 2X). The organic phases are combined, dried (MgSOi (), filtered, the solvent is decanted, and 3.4 g (41%) of almost colorless (trans) -1-j 3- (acetylthio) -2-methyl-1-oxopropyl 4-methoxy-b-proline as a syrup. EXAMPLE 4 (Trans) -4-methoxy 1-CO-3-mercapto-2-metsh1-1-oxopr saw-B-proline. K (trans ) -1-CD-3- (ace ylthio) -2methyl-1-oxopropyl-1-4-methoxy-1, -proline (3.4 g), add a cold solution of 8 ml of concentrated ammonia in 20 ml of water. The dissolution ends after 10 minutes and the resulting solution (in argon) is kept at room temperature for 2 hours, then it is cooled, extracted with 20 ml of ethyl acetate (2X), 20 ml of ethyl acetate and 15 ml of hydrochloric acid are added at a concentration of 1: 1. The mixture is saturated with sodium chloride, the layers are separated and the aqueous phase is extracted with 20 ml of ethyl acetate (SX). The organic phases are combined, dried (MgSO4), filtered, the solvent is evaporated, and 2.9 g (100% of almost colorless (trans) -4-methoxy-1-CC-3-mercapto-2-methyl-1-oxo- propyl-L-proline LoLl -80 ° C, (concentration 1%); Rf 0.53 / MeOH in silica gel, shown with nitroprusside Calculated (%): 47.69; H 6.83; N 5 , 56,. S 12.73. H4; j. -L / 4H2 0 Found (%): C 47.90; H 6.84; N 5.85, S 12.76. EXAMPLE 5 (Trans) -1-CD-3 (acetylthio) -2-methyl-1-oxopropyl-1-4ethoxy-L-proline. (Trans) -1-CD-3- (acetylthio) -2-methyl-1-oxopropyl) -4-ethoxy-b-proline is prepared according to the method described in Example 3, using instead of (trans) 4-methox -L-proline equivalent amount of trans-4-ethoxy-L-proline. The product is purified as dicyclohexylamine salt, so pl. 170-172s (crystallizes out in isopropyl alcohol); Cctl-64C (1% concentration in EtOH). This salt (7.75 g) was converted to the free acid with potassium bisulfate in solution, as described in Example 4, and 4.85 g of an almost colorless (trans) -1-UD-3- (acetylthio) -2-methyl1-oxopropyl were obtained. -4-ethoxy-b-proline in the form of syrup. PRI me R 6. (Trans) -4-ethoxy1- (P-3-mercapto-2-methyl-1-oxopropyl) 1 | -proline. To the material from Example 5 (4.85 g) is added a cold solution of 9 ml of concentrated ammonia in 22 ml of water (under argon atmosphere). The mixture is treated in the same manner as in Example 4 and 4.2 g (100%) of the almost colorless (trans) -4-ETOXI-1-CD-3-mercapto-2-methyl-1-oxoT1-propyl-b-proline in form of syrup. Oh. -80 ° C (1% concentration in EtOH); Ri 0.64 (MeOH on silica gel is determined using nitroprusside). Calculated (%) i С 50.55; H 7.33 ;, N, 5.36, S, 12.27. S4D. H Found (%): C 50.34; H 7.34; N 5.39, S 12.11. PRI me R 7. (Cis) (acetylthio) -2-methyl-1-oxopropyl 1-4 methoxy-b-proline. . cx) L-carbobenzylbxy-cis-4 hydroxy-b-proline. L-carbobenzyloxy-4-keto-L-proline (10 g or 0.038 mol) was dissolved in 300 ml of methanol and 5.8 g (0.15 mol) of sodium borohydride was added in 20 ml of water. 8.7 g of frothy product are obtained. This material is dissolved in 30 ml of ethanol, treated with 3.5 g of cyclohexylamine in a small amount of ethanol, and diluted to 500 ml with ether. After seeding and wiping, it quickly crystallizes and separates the cyclohexylamine salt in an amount of 10.8 g; m.p. 163-165 0. Then this cyclohexylamine salt
    The mixture is treated with 30 ml of hydrochloric acid (2N solution) and extracted with ethyl acetate (4 times 50 ml each time) to obtain 8 g of glassy N-carbobenzyloxy-cc4-hydrox1-b-proline.
    S) N-carbobenzyloxy-cis-4-methoxy-L-lane, methyl ester.
    K-carbobenzyloxy-cis-4-hydroxy-L-proline (13.9 g or 0.052 mol) processes 40 g of silver oxide and 40 ml of methyl iodide (2 times) in acetone (first time 100 ml, second 120 ml), as described in example iS, and get 17.5 g (100%) of methyl ester N-carbobenzyloxy-CIS-4-methoxy-L-Proline in the form of a yellow oil
    ft) L-carbobenzyloxy-cis-4-methoxy-b-proline.
    N-carbobenzyloxycis-4-methoxy-T-1-proline methyl ester (17.5 g, example, but 0.052 mol) is dissolved in 135 M methanol, 32 ml (0.064 mol) of sodium hydroxide 2 is added dropwise; at a temperature of -1 to, then for 1 h, maintained at and overnight at room temperature. After removing about half of the solvent in a rotary evaporator, the solution is diluted with 300 ml of water, washed with ether (the washing solution is removed), acidified with cooling with -12.5 ml of 1: 1 hydrochloric acid, maintaining the pH at 2, and extracted with ethyl acetate (4-150 m. The extracts are combined, dried (MgSO4), filtered, evaporated to give 15 g of orange-yellow syrup. The syrup is diluted in 60 ml of ethanol, treated with 6 g of cyclohexylamine in 10 ml of ethanol and diluted with 900 ml of ether. - After seeding and rubbing, the crystalline crystal is separated. ska cyclohexylamine salt of K-carbobenzyloxy-cis-4-methoxy-b-proline, which, after cooling overnight, weighs 10.2 g; t, mp 148-150 ° C (hard at); CdJ -35 ° C (concentration 1 % in ethanol. After recrystallization in 40 ml of acetonitrile, 8.8 g of an almost colorless solid was obtained; mp 150-152 ° C (subl. at 145 °); Di-lj). -34 ° С (concentration of 1% in ethanol).
    The cyclohexylamine salt is treated with hydrochloric acid and 6.9 g (48%) of N-carbobenzyloxy-cis are obtained. 4-methoxy-b-proline in the form of a vet yellow gel viscous syrup; Cctl -32 C (1% concentration in ethanol). 2.) Cis-4-methoxy-b-proline. A mixture consisting of 6.8 g of N-carbobenzyloxy-cis-4-methoxy-b-proline 210 ml of methanol and water in a 2: 1 ratio and 2.3 g of 5% Pd-C is placed in a hydrogenator and kept there for 4 h under water pressure
    at 3 atm. The mixture is then filtered to remove: the catalyst, the filtrate is evaporated and a J, ib g of a grayish solid is obtained; mp. (decomposition). After crystallization in a solution of methanol ether, colorless cis-4-methoxy-L proline is obtained; m.p. 224-22bs (decomposition); C (concentration 1% in methanol).
    Calculated (%): C 49.64; H 7.64; N 9.65.
    Synl n05
    Found (%): C 49.63; H 7.71; N 9.54.
    e.) (CysU-1-1: p-3- (acetylthio) -2-methy1-oxopropyl-1-4-methoxy-b-proline.
    Cis-4-meth-6-proline (3 g or 0.021 mol) and 4.2 g (0.023 mol) of D-3-acetylthio-2-methylpropionyl chloride in 5 ml of ether react in 60 ml of water in the presence of sodium bicarbonate, as described in the example; 3 To bring the pH to 8.5 and to maintain it n &amp; level 8.4-7.5, during the acylation, approximately 20 ml of 25% sodium carbonate is required. The resulting crude viscous product (6.4 g) is dissolved in 50 ml of ethyl acetate and treated with a solution of 3.9 g of cyclohexylamine-20 ml of ethyl acetate. In solution, the product is crystallized, which is filtered off, dried and 6.6 g of dicyclohexylamine salt are obtained; m.p. 172-174 ° С (sublim. At 170 ° С) Гс | (concentration of 1% in ethanol). 6.5 g of this material is subjected to recrystallization in 35 ml of acetonitrile and 6 g of a colorless solid dicyclohexylamine salt are obtained; m.p. 173-175 0 (sublim. At 170 ° C); Cot: -ObC (concentration of 1% in ethanol).
    Calculated (%): C, 61.24; H 9.00; N 5.95, S 6.81.
    С Н #, NOj S С, Hj, N,
    Found (%): C 61.16; H 8.81; N- 5.95, S 6.67.
    According to the method described in Example 3, the dicyclohexylamine salt is converted into acid, diluted with 5.9 g of salt and 60 m of ethyl acetate, followed by cooling in an ice bath and treatment with 60 ml of 10% b1 potassium sulfate. The layers were separated and the aqueous phase was extracted with 50 ml of e (gilacetate (4 times). The organic phases were combined, dried (MgSOv), filtered, the solvent was extracted with 3.5 g (60%) of colorless (bis) -1-ID -3- (acetylthio) -2-methyl-1-oxo-propyl-4-meter-b-prelina; mp-9.0-92 ° C Coi-139C (1% concentration in ethanol); R 0, 62 (metynol in silica gel).
    Calculated (%): C, 49.81; H 6.62; N 4.84.
    A solution of 2.5 g of the material from Example 4 in 25 ml of water is treated with 0.84 sodium bicarbonate. The solution was freeze dried and the sodium salt of (trans) -4-methoxy-1-; p-3-mercapto-2-methyl-1-oxopropyl-1-b-proline was obtained.
    Similarly, using the cis material from Example 8, the sodium salt (cis-4-methoxy-1-CO-3-mercapto-2-methyl-1-oxopropyl-L-proline) is obtained.
    Example 26, 1- (4-Mercapto-1oxobutyl) -cis-4-methoxy-b-proline.
    O.) (Cys) -1- (4-acetylthio-1-oxobutyl) -4-methoxy-b-proline.
    By reacting an equivalent amount of (cis) -4-methoxy-b-proline with 4-acetyl, thiobutyl chloride according to the procedure described in example 1, (cis) -1- (4-acetylthio-1-oxobutyl) -4methoxy is obtained -1 | -prolin.
    S-) 1- {4-Mercaptr-1-oxobutyl) cis-4-methoxy-b-proline.
    Hydrolysis of (cis) -1- (4-acetylthio-1oxobutyl) -4-methoxy-b-proline c. aqueous ammonia solution according to the procedure of Example 2 gives 1- (4-mercapto-1-oxobutyl) -cis-4methoxy-L-proline.
    PRI me R 27. 1- (L-3-mercapto-2-ethyl-1-oxopropyl) -trans-4-methoxy-O-proline.
    D.) (Trans) -1-LL- (3-acetylthio) -2ethyl-1-oxopropyl T-4-methoxy-B-proline. .
    According to the method described in Example 1, but using (trans) -4-hydroxy-D-proline instead of (trans) -4-hydroxy-L-proline in example (X, you get (trans) -4-methoxy-B-proline.) with L- (3-acetylthio) -2-ethylpropionyl chloride, as described in Example 3, (trans) -l-tL- (3-acetylthio) 2-ethyl-1-oxopropyl-4-methoxy-D-proline is obtained.
    S) 1- (b-mercapto-2-ethyl-1-oxo-propyl) -trans-4-methoxy-n-proline.
    Hydrolysis of (trans) -1-tL- (3-acetylthio) -2-ethyl-1-oxo-propyl 1-4-methoxy-D-proline in an aqueous solution of ammonia in accordance with the procedure of example 4 gives 1- (1.-3-mercapto -2-ethyl-1oxopropyl) -trans-4-methoxy-0-proline
    PRI me R 28. 1- (2-Mercapto-1oxoethyl) -trans-4-methoxy-b-proline.
    cx) (Trans) -1- (2-acetylthio-1-oxoethyl) -4-methoxy-b-PrOlin.
    According to the method described in Example 1, but using 2-acetylthioacetyl chloride instead of 3-acetylthiopropionyl chloride, (trans) (2-acetylthio-1-oxoethyl) -4-methoxy-L-proline is obtained.
    f) 1- (2-Mercapto-1-oxo-ethyl) trans-4-methoxy-b-proline.
    Hydrolysis of trans-1- (2-acetylthio-1oxoethyl) -4-methoxy-b-proline in an aqueous solution of ammonia, according to the procedure of Example 2, gives 1- (2 mercapto-1-oxo ethyl) -trans-4-methoxy-b- proline.
    Example 29. 1- (2-Mercapto-1oxoethyl) -Cis-4-methoxy-b-proline. ,
    OL) (Cys) -1- (2-acetylthio-1-oxo-ethyl) -4-methoxy-b-proline.
    According to the method of Example 28, cis-4methoxy-L-proline is treated with a solution of 2-acetylthioethyl ethyl chloride in the presence of sodium carbonate, and (cis) -1- (2-acetylthio-1-oxoethyl) methoxy-b-proline is obtained.
    S) 1- (2-Mercalto-1-oxo-ethyl) -cis4-methoxy-b-proline.
    Hydrolysis of (cis) -1- (2-acetylthio-1oxoethyl) -4-methoxy-b-proline in an aqueous solution of ammonia gives 1- (2-mercapto-1-oxoethyl) -cis-4-methoxy-b-proline.
    Example 30. 1- (2-Mercapt6-1oxoethyl) -cis-4-methylthio-b-proline. (X) (Cis) -1- (2-acetylthio) -1-oxo-ethyl) -4-methylthio-b-proline.
    As a result, the interaction of equivalent amounts of (cis) -4-methylthi-L-proline and 2-acetylthioacetylchloride in the corresponding way and (cis) -1- (2-acetylthio1-oxoethyl) -4-methylthio-b-proline .
    S) 1- (2-Mercapto-1-oxo-ethyl) -cis4-methylthio-b-proline.
    Hydrolysis of (cis) -1- (2-acetylthio-1oxoethyl) -4-methylthio-L-proline in an aqueous solution of ammonia according to the procedure of Example 2 gives 1 (2-mercapto-1-oxoethyl) -cis-4-methylthio- B-proline.
    Example 31. 1- (D-3-mercapto-3-methyl-1-oxopropyl) -cis-4-C4-pentynylthio) -L-proline.
    O.) (Cys) -l-tD-3- (acetylthio) -3-methyl-2-oxopropyl 1-4- (4-pentylthio) L-proline.
    As a result of the interaction (cisY-acetyl-4-mercapto-b-proline with 5 chloro-1-pentine in acetone in the presence of silver oxide, according to the procedure of example iS, 4-pentinyl ether (cis) -N-acetyl4- (4-pentylthio ) -L-proline. Then it is hydrolyzed as described in Example 1c and (cis) -Y-acetyl-4- (4pentylthio) -L-proline is obtained. Interaction of this compound with an equivalent amount of D-3- (acetylthio) - 3-methylpropionyl chloride in accordance with the procedure of Example 3. results in the formation of (cis) -1-CD-3- (acetylthio-3-methyl-1-oxopropyl-1-4- (4-pentynylthio) -L-proline.
    0 1-p-3-mercapto-2-methyl-1-ca-sopropyl) -cis-4- (4-pentynylthio) -L-proline. Hydrolysis of (cis) -1-tD-3- (acetylthio Z-methyl-1-oxopropyl-4- (4-pentenyl thio) -L-proline in an aqueous ammonia solution, as described in Example 4, gives 1- (0 -3-mercapto-3-methyl 1-oxopropyl) -cis-4- {4-enthenylthio) L-npo EXAMPLE 32. (Cys) -4-6enzylthio-1-CD, L-3 mercapto 3-ethyl-1-oxo propyl) -L-proline. X) {Cys) -1-p, L-; 3- (acetylthio) -3ethyl-1-oxopropyl-1-4-benzylthio-b-proline. . as a result of the interaction (cis L-acetyl-4-mercapto-L-proline with benzyl chloride in acetone in the presence of silver oxide, as described in example ID, benzyl ester (cis) K-acetyl-4-benzylthio-b-proline is formed . The ester is hydrolyzed as described in Example 16 and (cis) L-acetyl-4-benzyl-thio-L-proline is obtained. The interaction of this compound with an equivalent amount of D, (acetyl thio) -valeryl chloride, as described in Example 3, is obtained. , leads to the formation of (cis) -1-d. L-3- (acetylthio) -3-ethyl 1-oxpropyl-4- (benzylthio) -L-proline, &amp;) (Cys) -4-benzylthio-X-CP, L-3-mercapto-3-ethyl ™ 1 -oxopropyl1. -L-proline Hydrolysis of (cis) -1-0, L-3 (acetylthio) 3-ethyl-1-oxopropyl-4- (benzylthio) -L-proline in an aqueous ammonia solution according to example 4 gives {cis) 4-benzylthio-1 0 L 3-mercapto-3-ethyl-1-oxopropyl) -L-proline Example 13: 1, 1-Dithiodi-EID-3-1-1capto-2-methyl- 1-ca. copropyl bis- (trans) -4-methylthio-L-pollin. The product from example 21 is treated with a solution of iodine. In this-nol, as described in example 24., and 1,1-dithiodide- (1-B- 3-mercapto 2methyl-1-oxopropyl) -bis - (trans) -4methylthio-b-proline. PRI me R 34. (Cis) 1-O-3- (ben zoylthio) -2 methyl-1-oxopropyl-4-methyl-thio-L-prolol, the Interaction of equivalent amounts of (cis) -4-mel iltio -L-proline and D-3- (benzoylthio) -2-methylpropionyl chloride J. as described in npi-iMepe gives (cis) -D-3 (benzoylthio) -2-methyl-1-ocopropyl-4-methylthio-L-Tr i .. PRI me R 35. (Trans) -l- (D-3 (phenylacetyl) -2-methyl-1-oxopropyl 4 methylthio-L-proline, the Interaction of equivalent amounts of (trans) 4-methylthio-L- propoline and D-3- (phenylacetylthio) 2 methyl propionyl chloride, as described in Example 3, leads to the formation of (trans) l-ilD-3- (phenylacetyl) -2-methyl-l-oxopropyl-4-methylthio- L- pb1Sna- “Tsrim e R, 36, (Cys) -4- (4-fluorophenoxy) -1- (B-3-mercapto-2-methyl-1oxopropyl) -L-proline. a.) (Cys) -4- (4-, fluorophenoxy) -L-proline. In a solution consisting of 8.4 g (0.024 mol) of benzyl ester, N-carobenzoxycritan-4-hydroxy-L-proline -4.0 g (0.036 mol) of 4-fluorophenol and 9.27 g (0.036 mol) of triphenylphosphine in 75 ml of dry tetrahydrofuran, 6.2 g (0.036 mol) of diethyl azobicarboxylate in 25 ml of tetrahydrofuran are added dropwise over 1 hour. The solution is stirred overnight at room temperature. The mixture is evaporated to dryness and 100 ml of ether are added. Ocagdened triphenylphosphine and diethyl azodicarboxyl. T Filtered. In the chromatographic column (silica gel), 8.1 g of the mixture was isolated, containing a about 70% benzyl ether; L-carbobenzoxy-cis-4- (4-fluorophenoxy) -b-proline. A solution of 7.5 g of the resulting mixture, containing benzyl ether, is hydrogenated under pressure, at room temperature 0.8. g 10% Pcl / C. A white precipitate formed during the reaction. After the addition of hydrogen is completed, the mixture is filtered and the solid residue from filtration is leached 3 times with 125 ml of hot methanol. The methanol solution is evaporated to a dry residue and 3.2 g of cis-4- (4 fluorophenoxy) L-IToline are obtained with a mp. 2.35-23b ° C. Calculated (%) S With 57,14; H 5.48; N 6.06, F 8.22. GV, H. 1/3. Found (%). C 56.94; H 5.19; N 5.94, F 7.97 o 6) -1-B-3- (acetylthio) -2 methyl-1oxopropyl-cis-4- (4-fluorophenoxy) L-proline. In a suspension consisting of 2.25 g (0.01 mol) (4-fluorophenoxy) .L-proline in 125 ml of dry pyridine, 1.0 g (0.01 mol) of triethylaman and 2 g are added at room temperature. (0.011 mol) D-3- (acetylthio) -2 methyl propionyl chloride. After stirring overnight at room temperature, the mixture is added to dryness. The residue in water, coatings with ether, is acidified with 10% hydrochloric acid. The water layer is extracted several times with ether, the ether layers are combined, washed with water, dried (NaSOii-), evaporated to a dry residue, and 3.9 g are added. When the residue is chromatographed over 250 ml of silica gel with ether, a fraction containing the desired product is obtained. . The column was washed with methanol, the wash solution was rechromatographed in cds2. H ,, 5 NOgS Found (%): C 49.85; H 6.66; N 4.97. Example (Cys) -4-methoxy1-C.O-3-mercapto-2-methyl-1-oxopropyl) -L-proline. (Cys) -1-to-3- (acetylthio) -2-methyl-1-oxopropyl1 | -4-methoxy-1.-Proline 2.9 g (0.01 mol) is hydrolyzed in 15 ml of water containing 6, 5 ml of concentrated ammonia, as described in Example 4, yield 2, .3 g (93%) of a very viscous (cis) -4-metoxy-l-CD-3-mercapto-2-methyl-1-o-propropyl 1- L-pollen, which after some time becomes wax-like; Cctl -88 ° C (1% concentration in ethanol). OL) (Cis) -4-methoxy-1-CO-3-mercapto-2-methyl-1-oxopropyl) -L-proline, 1-adamantanamine salt. A solution consisting of 0.55 g (0.0022 mol) of cis-4-methoxy-1-1o3-mercapto-2-methyl-1-oxopropyl-1-proline in 16 ml of ethyl acetate is treated in the argon-atmosphere with a warm solution 0 , 34 g (0.0022 mol) of 1 admantanamine in 10 ml of ethyl acetate salt precipitates. After 3 hours in the cold, the colorless solid is filtered off under argon, washed with cold ethyl acetate and dried under vacuum for 20 hours, after which 0.7 g (79%) are obtained, 1- adomanthanamine salt (cis) -4-methoxy -1-110-3-mercapto-2metsh-1-oxopropyl-1-b strait; m.p. 215-217 0 (sublime at 210 ° C, decomposed at; CoLlf -60 ° C (concentration 1% in methanol). I .. Example 9. (Cys) -4-methoxy1- (3-mercapto-2-methyl- .-oxopropyl L-proline. d) (Cys) -4-methoxy-1-C3- (benzoyl thio) -2-methyl-1-oxopropyl-L-prol as a result of the reaction of 3-benzylthio-2-methylpropanoic acid chloride obtained by the interaction of 3-benzolylthio-2-methylpropane novil acid with thionyl chloride) with a cis-4-methoxy-L-pollen in accordance with the general procedure described in example 3, receive (cis) -4-methoxy-1-3 - (Benzoylthio) -2-methyloxo-PRQ-Pil-L is proline. S) (Cis) -4-methoxy-1- (3-mercapto-2-methyl-1-okspoppil) -L-proline. As a result of hydrolysis. (Cis) -2methoxy-1- "13- (benzoylthio) -2-methyl1-oxopropyl-L-proline with an aqueous solution of ammonia, in accordance with the general procedure of example 4, the resulting cis) -4-methoxy 1- 3-mercapto-2-methyl-1-oxopropyl-L-proline. Example 10. (Trans) -I-LD-3 (acetylthio) -2-methyl-1-oxopropyl 4-propoxy-L-poline. : O.) N-acetyl-trans-4-propoxy-L proline, propyl ether. As a result of the interaction of N-acetyl-trans-4-hydroxy-L-poline from example lex with 110 g of silver oxide and 110 ml of propyl iodide in 300 ml of acetone, as described in example iS, 19.6 g (41%) of light yellow orange-orange propyl ester of Na-acetyl- (trans) -4-propoxy-L-poline; bp 155-165C (0.2 mm). &amp;) N-acetyl-trans-4-propoxy-L proline. A solution of 6 g (0.15 mol) of sodium hydroxide, in 150 ml of water, is mixed with 19.4 g (0.007 mol) of N-acetyl-trans-4-propoxy-L-proline propyl ester and a light orange solution is obtained, which is kept at room temperature. overnight and extracted with 60 ml of ethyl acetate (washing removed). It is then acidified with 1: 1 hydrochloric acid, saturated with sodium chloride and extracted with 50 ml of chloroform (3 times). The organic phases are combined, dried (MgSOi.), Filtered, the solvent is evaporated and 12.6 g of brown oil are obtained. It is dissolved in 80 ml of ethyl acetate and treated with a solution of 10.7 g of dicyclohexylamine in 20 ml of ethyl acetate. The salt crystallizes out at room temperature. The dicyclohexylamine salt is cooled overnight, filtered and washed with cold ethyl acetate, after which 17.3 g of an almost colorless solid dicyclohexylamine salt is obtained; m.p. 148-153 p. Recrystallization of this material in 125 ml of ethyl acetate gives 14.5 g of a colorless dicyclohexylamine salt with a mp. 157-159 0; Coi-l -30 ° C (concentration of 1% in ethanol). Calculated (%): C, 66.63; H 10.17; N 7.07. Shho N0.0 Ngz N Found (%): - About 66.47; H 10.22; N 7.06. The dicyclohexylamine salt (14.4 g) is converted into the free acid by fine grinding, diluted with 100 ml of ethyl acetate and adding 100 ml of 10% potassium bisulfate in small portions. The organic phase is separated and the aqueous phase is extracted with 100 ml of ethyl acetate (2 times). The organic phases are combined, dried (MgSO4), filtered, the solvent is evaporated and 6.7 g (41%) of Nat-methyl-trans-4-propane-L-pollin are obtained in the form of a light brown liquid. ft) (Trans) -l-tlD-3- (acetylthio) -2-methyl-1-oxypropyl-4-pro-L-proline.
    L-acetyl-trans-4-propoxy-L-proline (6., 4 g or 0.03 mol) is treated with a solution of 10 g of concentrated sulfuric acid in 100 ml of water. The resulting mixture is stirred and cooled for 3 hours. The solution is then cooled to, by adding 12 g of sodium carbonate in small portions to obtain a pH of about 8.0, and treated with a solution of 5.4 g (0.03 mol
    N-3-acetylthio-2-methylpropionyl chloride in 5 ml of ether over 10 minutes, at the same time adding 7 g of sodium carbonate to maintain a pH of about 8.0. The mixture was stirred in an ice bath for 30 minutes and at room temperature for 1 hour. Then the product was separated and purified as a dicyclohexylamine salt by the method described in Example 3, and 6.3 g of the dicyclohexylamine salt was obtained. 165-167s (from acetonitrile); Lo (.j -56 ° C (1% concentration in ethanol).
    Calculated (%): C, 62.62; H 9.30,) N 5, -61; S 6.43.
    SATS H23 NOsS H2iN,
    Found (%): C, 62.35; H 9.48; N 5.88, S 6.45.
    Dicyclohexylamine salt (6.1 is converted into the free acid by dilution with 60 ml of ethyl acetate, cooled in ice and not treated with 60 ml of 10% bisulfite, potassium. The layers are separated and the aqueous phase is extracted with 60 ml of ethyl acetate 2 times.) The organic phases are combined, dried (), filtered, the solvent is evaporated and 4.0 g (42%) (trans) 3- (acetylthio) -2-methyl-1-oxopropyl 3-propoxy-b-strait are obtained in the form of an almost colorless syrup.
    , For example 11. 1- (D-3-mercapto-2-methyl-2-oxopropyl) -trans-4-propoxy-b-proline.
    As a result of hydrolysis, 4.0 g of (trans) -l-tD-3- (acetylthio) -2-methyl 1-oxopropyl 1-4-propoxy-L-proline 8 ml of concentrated ammonia in 20 ml of water under argon atmosphere, as described in Example 4, 3.42 (97%) 1-11O-3-mercapto-2-methyl-1-oxopropyl} -trans-4-propoxy-b-proline was obtained in the form of an almost colorless syrup; Ldl -72 ° C (1% concentration in ethanol).
    Calculated (%) S With 51,49; H 7.74; N 5; 05, S 11.46,
    With HiiNO4S 1/4.
    Found (%): C 51-66; H 7.76; N 5.94; S 10,51.
    Example 12, 1- (3-mercapto-1oxopropyl) -cis-4-methoxy-L-1rolin.
    O.) 1- (3-methylthio-1-oxopropyl) cis 4-methoxy-b-proline.
    According to the method described in Example 1, cis-4-methoxy-L-proline is treated with a solution of 3-acetylthiopropyl chloride in the presence of sodium carbonate to give 1- (3-acetylthio-1-oxopropyl) -cis-4-methoxy-L proline,
    S-) 1- (3-mercapto-1-oxopropyl) -cis-4-methoxy-b-proline.
    1- (3-acetylthio-1-oxopropyl) cis-4 methoxy-b-proline is subjected to hydrolysis in an aqueous solution of ammonia as described in example 2, and receive 1- (3-mercapto-1-oxopropyl) -cis-4methoxy- B-proline.
    EXAMPLE 13 (Cys) -4-methoxy1-CD-3-mercapto-2-methyl-1-oxopropyl-1-L-proline.
    (X) Cys-4-ethoxy-b-proline.
    According to the method described in Example 7, including from (d) to (g), not using ethyl iodide instead of methyl iodide in Example 8, (cis) -4-et6xi7-proline is obtained.
    , g-) (Cis) -1-OD-3- (acetylthio) -2met il-1-oxopropyl-4-ethoxy-b-PE ol
    (Cys) -4-ethoxy-b-proline reacts with a solution of D-3-acetylthio2-methylpropionyl chloride and in the presence of sodium carbonate, as described in Example 7cj, and (dis) 1 - {;: B-3- (acetylthio ) -2-methyl-1-oxopropyl-4-ethoxy-1.-n {yulin.
    b) (Cys) -4-ethoxy-1-CO-3-mercapto-2-methyl-1-oxopropyl-1-L-proline.
    Cys-1-CO-3- (acetylthio) -2-methyl-1oxopropyl D-4-etrxy-b-proline is hydrolyzed in aqueous ammonia solution, as described in Example 8, and (cis) -4-ethoxy 1-III- is formed mercapto-2-methyl-1-oxopropyl-l-proline.
    Example 14. (Trans) -4-amyloxy-1-to-3-mercapto-2-methyl-1-oxopropyl-1-L-proline.
    I: .a.) (Trans) -4-allylox L-p15olyn, According to the method described in Example 16 g, but using allyl bromide instead of methyl iodide, get (trans) -K-acetyl-4allyl-L-proline allyl ether, then hydrolyzed, as described in Example 16, and (trans) -4-allyloxy-benzine is obtained.
    B-) (Trans) -l-tD-3- (acetylthio) 2-methyl-1-oxopropyl-4-allyloxy-b-proline.
    By reacting (trans) -4-allyloxy-b-proline from example Q. with an equivalent amount of D-3- (acetylthio) -2-methypropion chloride, as described in example 3, (trans) -l-tD-3- is formed (acetylthio) -2-methyl-1-oxopropyl-4-allyloxy-b-proline. fe) (Trans) -4-allyloxy-1- (3-mercapto-2-methyl-1-oxopropyl) -L-proline. (Trans) -l-tD-3- (acetylthio) -2-methyl-1-oxopropyl-4-allyloxy-11-prolin is hydrolyzed in an aqueous solution of ammonia, as described in Example 4, and (trans) -4- is formed allyloxy-1-1 0 3-mercapto-2-methyl-1-oxopropyl-1-proline. Example 15. 1-CO 3-mercapto-2-methyl-1-oxopropyl-trans-4-propargyloxy-b-proline. &amp;) (trans) -4-propargyloxy-proline. In the manner described in Example 1 &amp; , but using methyl bromide propargyl and methyl iodide, get propargyl ester (ttrans) -N acetyl-4-propargyl-b-proline. It is then hydrolyzed, as described in Example 1 g; i, and (trans) -4-propargyloxy-b-proline is obtained. S) (Trans) -1-CD-3- (acetylthio) -2methyl-1-oxopropyl-1-4-propargyloxy L-proline. As a result of the interaction of (trans) -4-propargyloxy-b-proline from the example with an equivalent amount of D-3- (acetylthio) -2-methylpropionyl chloride, as described in winner 3, tyluchut (trans) -1-CD-3- (acetylthio ) -2-methyl-1-oxopropyl-4-pro pargyloxy-b-proline. b) 1- (O-3-mercapto-2-methyl-1-oxopropyl) -trans-4-propargyloxy-L proline. (Trans) -1-CD-3- (acetylthio) -2-methyl-1-oxopropyl-4-propargyl-b-prolin is hydrolyzed in an aqueous solution of eliac as described in Example 4, and 1-CO-3 is obtained. -mercapto-2-me yl-1oxopropyl1-trans-4-propargyloxyL-proline. PRI me R 16. (Trans) -4-bsnoyloxy-1- (O-3-mercapto-2-met1 l-1-o.C propyl) -b-proline. a,) (Trans) -4-benzyloxy-b-proline According to the method described in Example IS / but using benzyl chloride instead of methyl iodide, (trans) -N-acetyl-4-benzyloxy-b-proline benzyl ester is obtained. Then it is hydrolyzed as described in Example 1 6, and (trans) -4-benzyloxy-b-proline is obtained. $) (Trans) -1-r3-3- (acetylthio) -2methyl-1-oxopropyl-4-benzyloxy-benzyl. By reacting (trans) -4-benzyloxy-b-proline from Example OL with an equivalent amount of D-3- (acetylthio) -2-methylpropionyl chloride, as described in Example 3, trans-1-10-3- (acetyl- thio) -2-methyl-1-oxopropyl-4-benzyloxy-b-proline. 6) (Trans) -4-benzyloxy-1-tD-3-mercapto-2-methyl-1-oxopropyl-L-proline. (Trans) -1-D-3- (acetylthio) -2-methyl-1-oxopropyl 1-4-benzyloxy-G, proline is hydrolyzed in an aqueous solution of ammonia, as described in Example 4, and (trans) -4-benzyloxy is obtained -1-CP3-mercapto-2-methyl-1-oxopropyl 1-L proline. Note 17. l-LD-3-mercapto-2-methyl-1-oxopropyl-trans-4-phenyl-Iloxy-b-proline. OL) (Trans) -4-phenethyloxy-b-proline. According to the method described in iS, but using phenethyl bromide instead of methylene iodide, phenethyl ether, (trans) -N-acetyl4-phenethyloxy-b-proline is obtained. It is then hydrolyzed, as described in Example 1c, and (trans) -4-phenethyloxy-b-proline is obtained. B) (Trans) -1-CD-3- (acetylthio) -2methyl-1-oxopropyl-4-phenethyloxy-L proline. By reacting (trans) -4-phenethyloxy-b-proline from example ix with an equivalent amount and D-3- (acetylthio) -2-methylpropionyl chloride, as described in example 3, we obtain (trans) -1-CD-3- (acetylthio) 2-methyl-1-oxopropyl-1-4-phenethyloxy-L-proline. b) 1- (P-3-mercapto-2-methyl-1-oxopropyl) -trans-4-phenethyloxy-b-proline. Trans-1-CD- (acetylthio) -2-methyl-oxypropyl-4-phenethyl-L-proline is hydrolyzed with an aqueous solution of ammonia, as described in Example 4, to give 1- (0-3-mercapto-2-methyl-1 1-xopropyl-1-trans-4-phenethyloxy-b-proline Example 18. 1-tD-3-mercapto-2-methyl-1-oxopropyl-1-cis-3-methoxy-L-pro-lin CO 1-CP-3 {acetylthio) -2-methyl-1-oxopropyl 1-cis-3-methoxy-b-proline, according to the method described in example 7, not using an equivalent amount of (cis) -3-methoxy-b-proline instead of (cis) -4-methoxy-b-proline, get 1 -CD-3- (a. Acetylthio) -2-methyl1-oxopropyl1-cis-3-methoxy-b-proline. S) 1-SP-3-mercapto-2-methyl-1-oxOPropylT-cis-3-methoxy-b-proline. l-tD-3- (acetylthio) -2-methyl-1-oxopropyl-cis-3-methoxy-b-proline is hydrolyzed in an aqueous solution of ammonia, as described in example 4, and receive 1-Sh-3-mercapto-2 -methyl-1-oxopropyl-cis-3-methoxy-b-proline .. Note EP 19. 1-tpL-3-mercapto-2-me yl-1-oxopropyl 1-trans-3-methoxy-b-proline. (X) 1-CDL-3- (acetylthio) -2-methyl-o-scop-6-p-l-trans-3-methoxy-L-polyline. As a result of the interaction of equivalent amounts of (trans) -3-methoxy-b-proline and DL-3- (acetylthio) methylpropionyl chloride, as described in example 3, 1-LDL-3- (acetyl-thio) -2-methyl-1-oxopropyl 1 is obtained -trans-3methoxy-b-proline. 5 ((DL 3-mercapto-2-methyl-lox scopotyl) -trans-3-methoxy-L-propol l tDL-3- (acetylthio) -2-methyl-1oxopropyl-trans-3-methoxy-b-proline hydrolyze with an aqueous solution of ammonia, as described in example 4-, and receive 1- (Bb-3-mercapto-2-methyl 1-oxo 1propyl) -trans-3-methox-i-Lprolin, Pp. and m and p 20 , 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4-methylthio-b-proline. CO (acgtilthio) -2-methyl-1oxopropyl-cis-4 - methylthio-b-proline B as a result of the interaction of ecBivalent amounts of cis-4-methylthio-b-proline and D-3- (acetylthio) -2-methylpropionyl chloride in accordance with the procedure described in example 3, 1-C.0-3- (acetylthio) -2 methyl-1-oxopropyl-cis-4-methylthio-L-proline, S) 1-CO-3-mercapto-2-methyl-1-oxopropyl) -cis-4 is obtained -methylthio-b-proline. 1-CD-3- (acetylthio) -2-methyl-1-oxopropyl1-cis 4-methylthio-b-proline is hydrolyzed with an aqueous solution of ammonia in accordance with the procedure described in example 4, and receive 1-1GP-3-mercapto -2-methyl-1-oxopropyl), - cis-4-methylthio-b - proline, Example 21. ue-3-mercapto2-methyl-1 oxopropyl 3 trans-4-methylthio-b-proline, aJ 1-CD -3- (acetylthio) -2-methyl-1oxopropyl-trans-4-methylthio-b-prol. As a result of the interaction of equivalent amounts of trans-4-methylthio-b-proline and tP-3- (acetylthio) 2-methylpropionylchlorides, according to the procedure of example 3, 1 CD-3- (acetylthio) 2-methyl-1-ok copropyl1- is obtained. trans-4 methylthio-b-proline S) 1 PO-3- (mercapto-2-methyl-1-ok copropyl) -trans-4-methylthio-b-proline 1-W-3- (acetylthio) 2-methyl- 1-oxopropyl-trans-4-meth. Thio-b-proline is hydrolyzed in an aqueous solution of ammonia, as described in Example 4, and 1-CO-3 mercapto-2-methyl-1 g sopropyl 11-trans-4-methylthio-b is obtained -proline Example 22, 17CO-3-merk-apto-3-methyl-1-oxopropyl-cis-4-H4-pent enylthio) -L-proline O.) (cis) -4- (4-pentenylthi6) -b-proV by reacting (cis M-acetyl 4-mercapto-b-proline with 5 bromo-1-pentene in acetone in the presence of silver oxide as described in Example 13, 4-pentenyl ether, (cis) -Y-acetyl-4- (4-pentenylthio) -L-proline is obtained. It is then hydrolyzed, as described in Example iS, and cis-4- ( 4-pentenylthio) -Lproline .Si l-tD-3- (acetylthio) -3-methyl-1oxopropyl-cis-4- (4-pentenylthio) L-proline. As a result of the interaction of cis4- (4-: pentenylthio) -L-proline with an equivalent amount of D-3- (acetylthio) -3-methylpropionyl chloride in accordance with example 3, 1-Nr-Cr- (acetylthio) -GZ-methyl- 1-oxopr6pyl1-cis-4- (4-pentenylthio) -Lproline. S) 1-Lo-3-mercapto-3-methyl-1-oxopropyl 1-TIO-CIS-4- (4-pentenylthio) - L-proline with 1-: P-3- (acetylthio) -3-methyl- 1-oxopropyl-CIS-4- (4-pentenylthi) -L-proline is hydrolyzed in an aqueous solution of ammonia, as described in example 4, and receive 1- (0-3-mercapto-3-methyl-1oxopropyl) -cis-4 - (4-Pentenylthio) L-proline. PRI me R 23. (Trans) -1-ClD-3 (acetylthio) -2-methyl-1-oxopropyl 14-methoxy-L-propanol, methyl ester. A solution of the material from Example 3 in ether is treated with diazomethane with a slight excess. After aging at room temperature, the solvent is evaporated, and methyl ester (trans) -1-CO-3- (acetylthio) 2-methyl-1-ca. 1-4-me copolypropyl: Socxy-L proline is obtained. Similarly, using cis material from Example 7, (cis) -1-Sh-3- (acetylthio) -2-methyl-1-o-scopropyl or l-4-methoxy-L-proline methyl ester is obtained, p 24, 1,1-Dithiodi-p. (D-3-mercapto-2-methyl-1-oxopropyl) bis-Ztrans) -4-methoxy-L-proline 1. The solution of the material from Example 4 is dissolved in ethanol, stirred and treated with a solution of 1 equivalent of iodine in ethanol. The pH of the solution is maintained at 6-7 by adding sodium hydroxide solution. The solvent is evaporated and the residue is extracted with ethyl acetate. After drying (MdZoz), the solution is filtered, the solvent is removed, and 1,1-tio- tl- (B-3-mercapto-2-methyl-1-oxocropyl) bis is obtained (tranc) -4-methoxy-Lproline. using the cis material from Example 8, 1.1, dithiodi-1- (O-3-mercapto-2-methyl-1-oxopropyl) 1-bis. | (cis) -4-methoxy-L-proline are obtained. PRI me R. 25. The sodium salt of (trans) -4-methoxy-1-Shee-3-mercapto-2-methyl 1-oxopropyl-J-L-proline.
    column and get an additional product. This procedure is repeated once more, after which the total product yield is 1.2 g of pure (acetylthio) -2-methyl-1-oxopropyl7 cis-4- (4-fluorophenoxy) -L-proline.
    b) (Cys) -4- (4 fluorophenoxy) -1- (D3-mercapto-2-methyl-1-oxopropyl) L-proline.
    1.2 g of 1-CD-3- (acetylthio) -2-methyl-1-oxopropyl-cis-4- (fluorophenoxy) -L-proline is dissolved in 25 ml of methanol and treated in 5 ml of concentrated ammonia in atmospheric argon in for 40 minutes The volatiles are separated and the residue is covered with ethyl acetate. The water layer is acidified with 10% hydrochloric acid. The layers are separated and the acidic layer is washed with ethyl acetate. The organic phases are combined and purified with water (2 times), a saturated solution of sodium chloride (2 times) and dried (.). The solvent is evaporated and 1.1 g of a foamy residue of cis-4- {4-fluorophenoxy) -1- (O-3-mercapto-2-methyl-1-oxopropyl) -L-proline are obtained.
    Calculated (%): C, 54.05; H 5.70; N 4.20, F 5.70, S 9.60.
    C15 Ndarkkots 1/3 P
    Found (%): C 54.04; H 5.71; N 4.05, .F 5.40, S 9.61.
    Chromatography on a thin layer showed the product in ultraviolet light: reagent H (yellow spot) and vaiylin (yellow spot) CH (.1e-80 ° C (concentration 1% in chloroform).
    Example 37. 2- (3-Mercapto-1oxopropyl) -cis-4-phenoxy-L-proline, L) (Cys) -4-phenoxy-L-pollin.
    In accordance with the procedure described in Example 36 sk, but using an equivalent amount of phenol instead of 4-fluorophenol, (cis) -4-f-noxy-b-proline is obtained.
    &) 1- (3- (acetylthio) -1-oxopropyl) -cis-4-phenoxy-L-poline.
    (Cis) -4-phenoxy-L-proline reacts with a solution of 3-acetylthiopropionyl chloride in the presence of sodium carbonate, as described in Example 1, to form (acetylthio) l-oxopropyl3-Cis-4-phenoxy-L-floor
    S) 1- (3-Mercapto-1-oxopropyl) cis-4-phenoxy-L-proline.
    Hydrolysis of l-t3- (acetylthio) -1-oxopropyl 3-cis-4-phenoxy-L-poline in an aqueous solution of ammonia as described. but in example 2, gives 1- (3-mercapto-1-oxopropyl) -cis-4-phenoxy-L-pol
    PRI me R 38. 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4- (4-methibenzyloxy) -L-proline.
    In accordance with the procedure described in example 36, but using an equivalent amount of 4-methylbenzyl alcohol instead of 4-fluorophenol in example a, 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4- ( 4-;. Methylbenzyloxy) -L-proline.
    PR ime R 39; 1- (0-3-mercapto-2-methyl-1-oxopropyl) -cis-4-phenethyc-L-proline.
    In accordance with the procedure of Example 36, but using an equivalent amount of phenethyl alcohol instead of 4-fluorophenol in Example 1, 1- (0-mercapto-2-methyl-1 oxo-propyl) -cis-4-phenethyloxy-L-pollin is obtained.
    PRI me R 40. 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4- (3-methylthiophenoxy) -L-proline.
    In accordance with the procedure of Example 36, but using an equivalent amount of 3-methylthiophenol instead of 4-fluorophenol in Example QL, (O-3-mercapto-2-methyl; -1-oxopropyl) cis-4- (3-methylthiophenoxy) -L is obtained - proline.
    PRI me R 41. (Cis) -4- (4-chlorophenoxy) -1- (D-3-mercapto-2-methyl-1oxopropyl) -L-proline.
    In accordance with the procedure of Example 36, but using an equivalent amount of 4-chlorophenol instead of 4-fluorophenol in Example Q., (cis) -4- (4-chlorophenoxy) -1- (D-3-mercapto-2-methyl-1 -oxopropyl) -L-Proli
    Example 42 1- (2-mercapto-1oxoethyl) -cis-4- (4-methoxyphenoxy) L-proline.
    CL) (Cis) -4- (4-methoxyphenoxy) -Lproline.
    In accordance with the procedure of Example 36l, but using an equivalent amount of 4-methoxyphenol instead of 4-fluorophenol, (cis) 4- (4-methoxyphenoxy) -L-proline is obtained.
    S) 1- C2- (acetylthio) -1-oxoethyl cis-4- (4-methoxyphenoxy) -L-prrlin.
    (Cys) -4- (4-methoxyphenoxy) -Lproline reacts with a solution of 2-acetylthioacetyl chloride, as described in Example 1d, and forms 1 2- (acetylthio) -1-OXO-ethyl1-cis 4 (4-methoxyphenoxy) -L -npo hh.
    c) 1- (2-Mercapto-1-oxoethyl) -cis .4- (4-methoxyphenoxy) -L-proline
    Hydrolysis of 1- D- (acetylthio) -1-oxoethyl-cis-4- (4-methoxyphenoxy) -Lproline in an aqueous solution of ammonia, as described in Example 2, gives 1- (2-mercapto-1-oxoethyl) -cis- 4- (4-metoksfeNoksi) -L-proline.
    Example 43. (Cys) -4- (4-fluorophenylthio) -1- (O-3-mercapto-2-methyl-1oxopropyl) -L-proline.
    In accordance with the procedure of Example 3, but using an equivalent amount of 4-fluorophenyl mercaptan instead of 4-fluorophenol in Example a, (cis) -4- (4-fluorophenylthio) -1 (O-3-mercapto-2-methyl-1-oxopropyl) is obtained A) L-proline.
    Example 44. 1 (O-Z-mercapto-2-methyl-1 oxopropyl) -cis-4-phenyl-L-proline,
    a) L-car-benzylenexy-cis-4-phenylthio-b-proline, methyl ester.
    0.85 g of sodium metal (0.037 mol) is dissolved in 40 ml of pure ethanol, 3f7 g (0.036 mol) of thiophenol is added with stirring, then 7.5 g (0.017 mol) of methyl ester, N-carboboyloxyloxy-4-tosyloxy- B-proline. The ester gradually dissolves in the solution, but soon after that the solid product separates. After stirring for 4 hours and incubating overnight at room temperature, the bulk of the ethanol is removed in a rotary evaporator. Most of the solid residue is mixed with 120 ml of chloromethane and 60 ml of water. The layers are separated (a small amount of methanol is added to facilitate the dilution process) and the aqueous phase is extracted with additional dichloromethane (2 x 60 ml). The organic phases are combined and washed with 100 ml of saturated sodium chloride solution, dried (MgSOi,), the solvent is evaporated and 6.5 g (100%) of W-carbobenzyloxy-cis-4-phenylthio B-proline methyl ester are obtained in the form of light yellow. viscous oil „
    Y) K-carbobenzyloxy-cis-4-phenylthio-b-proline.
    Methyl ether prepared in GL, 6.5 g (0.017 mol) is dissolved in 55 ml of methanol, treated with a solution of 2 M sodium hydroxide, adding it in an amount of 13 ml (o, 026 mol) in small portions at a temperature of -1 to 4 ° C, stir at 0 ° C for 1 h and incubate at room temperature for about 16 h. After removing about half of the solvent in a rotary evaporator, the cooled solution is diluted with 100 ml of water, washed with 60 ml of ether (washing 70 ml of ethyl acetate are added, stirred, cooled and acidified with 4.8 ml of hydrochloric acid, the concentration iey 1: 1. After separation of the layers, the aqueous phase is extracted with additional ethyl acetate (3x40 ml), the organic phases are combined and dried (MgSO4), then evaporated to obtain 5.9 g of a light yellow viscous oil, Et-O is diluted in 30 ml of ethanol, treated with a solution 1f 9 g of cyclohexylamine in 3 ml of ethanol and diluted to 330 ml with ether. After seeding, the cyclohexylamine salt crystallizes, and after cooling for about 16 hours, the salt weighs 5.3 g t, pl.V-14L .s. (Sublim. At).
    This material is combined with 1.5 g of the same product from the pretreatments: (of the test, it is mixed with 200 ml of boiling acetonitrile, cooled, and 6.3 g of colorless cyclohexyl1.1 and new salt are obtained with mp. 152- 155 ° C (sublim, at 137 ° C} Cci-l -24 (concentration in ethanol),
    The cyclohexylamine salt obtained is diluted in 25 ml of hydrochloric acid solution. After peeling off the layers, the layers are separated, and the aqueous phase is extracted with additional ethyl acetate (3 x 25 ml). The phases are combined organically and dried (MdZO), the solvent is evaporated and a 5.0 (65%) H-carbobenzyloxy-cis-4 fenitolite b-proline is obtained in the form of an almost colorless, very viscous syrup.
    } (Cys) 4-f, enilthio-L-proline, g of hydrobromide H-carbobenzyloxy-cis 4 --- g. phenylthio-b - proline 4.9 g, (0.014 mol) is treated with a solution of 25 ml of hydrogen bromide in acetic acid (32%), the flask is closed with a stopper and stirred using a magnet. After 1 h, the orange-yellow solution is diluted to 250 ml with ether, after which the product precipitates as a heavy oil, which gradually crystallizes after washing, wiping and cooling. After stirring on ice, for 1 h, the material is filtered off under nitrogen, washed with ether, diluted with fresh ether, cooled for about 16 h, filtered off again and 3.2 g (77%) of anhydrous solid are obtained. hydrobromide (cide) -4-phenylthio-L-proline with m of pl 106-109 ° C (subl / at 99 °; Coal-3 {concentration of 1% in methanol)
    Z) 1-Go-3- (acetylthio) -2-methyl-1 ™ oxo propyl.} -Cis-4-phenylthio-b proline,
    As a result of the interaction of AP) g (0; 0094 mol) of hydrobromide (cis) -4phenylthio B proline and 2.0 g (mol) of D-3-acetylthio-2-methylpropionyl chloride in 25 ml of water, as described in example la, using approximately .15 A 20% sodium carbonate solution to maintain the pK at 8.08, 4 gives 3.8 g of a light yellow viscous oil. Dicyclohexylamine salt (prepared from 1.8 g dicyclic. Oxyxylamine in 30 ml of ethyl acetate) weighs 2.9 g (separately, two rborah); m.p. 184-188 ° C (subl. At 18.0 °), after trituration in 15 ml of acetonitrile, 2.4 g of a colorless solid g cyclohexyl-mine salt are obtained, 184-186 ° C (sublic, at 180) Cd-75 (concentration 1% of ethanol),
    To this dicyclohexylamine salt, 30 ml of 10% potassium bisulfate is added and ethyl acetate is extracted.
    as described in Example 1, after which 2.0 g (59%) of vitreous 1-CD-3- (acetylthio) -2-methyl-1-oxopropyl-1-cis-4-phenylthio-b-proline are obtained.
    o) 1- (0-3-mercapto-2-methyl-1-oxopropyl) -cis-4-phenylthio-L-proline.
    1-CD-3- (acetylthio) -2-methyl-1-oxopropyl-cis-4-phenylthio-L-proline 2.0 g (Oh,) is treated with a solution of concentrated ammonia (3.5 ml) in 8.5 ml water, as described in Example 2 (solid ammonium salt is substituted in the reaction mixture) and 1.35 g (100%) of a viscous syrup formed 1- (0-3-mercapto-2-methyl-1-oxopropyl) -cis- 4-phenylthioG-proline; tJot -43 ° C (concentration of 1% in ethanol).
    PRI me R 45. 1- (O-3-mercapto-2-methyl-1-pcropropyl) -cis-4- (4-chlorophenylthio) -L-proline,
    In the manner described in Example 44, but using an equivalent amount of 4-chlorophenyl mercaptan instead of thiophenol in Example 4, 1- (D3-mercaptr-2-methyl-1-oxopropyl) -cis4- (4-chlorophenylthio) -L-proline is obtained.
    Example 46. 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4- (3-triftrrmethylphenylthio) -L-proline.
    In the manner described in example 44, but using instead of thiophenol in example o. an equivalent amount of 3-trifluoromethyl-phenylmercaptan / get 1- (B-3-mercapto-2-methyl-1-oxopropyl) -cis- (3-trifluoromethylphenylthio) -I, proline.
    Example 47., (Cys) -4-4-hydroxyphenylthio) -1- (3-mercapto-1-oxopropyl) -L-proline.
    CL) (Cis) -4- (4-acetyloxyphenylthio) L-proline, hydrobromide.
    By the method described in examples 44, but using an equivalent amount of 4-acetyloxyphenylmercaptan instead of thiophenol in example O., hydrobromide (cis) -4- (4-acetyloxy-phenylthio) -L-proline is obtained.
    B) (Cys) -4.- (4-acetyloxyphenylthio) 1-C-3-acetylthio) -1-oxopropyl-1-L proline.
    As a result of the interaction of (cis) -4- (4-acetylbxyphenylthio) -L-proline hydrobromide and 3-acetylthiopropionyl chloride, as described in example 1 g, (cis -) - 4- (4-acetyl. Oxyphenylthio) -1-GZ - (acetylthio) -1tOxopropyl-L-proline.
    ft) (Cys) -4- (4-hydroxyphenylthio) -1 (3-mercapto-1-oxopropyl-L-pollin.
    Hydrol3 (cis) -4- (4-acetyloxyphenylthio) -1-C3- (acetylthio) -1-oxopropyl-L-proline in aqueous ammonia, as described in Example 2, gives (cis) -4- (4-hydroxyphenylthio ) -1- (3mercapto-1-oxopropyl) -L-proline.
    Example 48. (Cis) -4-benzyloxy-1- (D-3-mercapto-2-methylg1-oxOpropyl) -L-proline.
    By the method described in Example 44, but using an equivalent amount of benzyl alcohol instead of the thiophenol in Example L, (cis) -4benzyloxy-1- (0-3-mercapto-2-ethyl1-oxopropyl) -L-proline is obtained.
    Example 49. (Trans) -1- (30 mercapto-1-oxopropyl) -3-methylthio D, L-proline.
    cx) Tert-butyl Ely ester of 1,2-dehydroproline.
    In a stirred solution of 34.2 g
    5 (0.20 mol) t-butyl ether prelin in 600 ml of ether at a temperature of from -5 to OC add 21.7 g (23.9 ml 0.20 mol) just obtained t-butyl hypochlorite.
    0 During the addition, the temperature is maintained within t-5) -OC. After completing the addition, the solution is stirred at the same temperature for another 5 minutes.
    five
    A solution of 7.8 g (0.20 mol) of potassium in freshly distilled dry (CaH) t-butanol is quickly added (within 3-5 minutes) to the vigorously stirred solution. After addition temperature
    0 reaction mixture about. The container with the reaction mixture is removed from the cooling bath and stirred for 30 minutes. The mixture is filtered over celite (diatomaceous earth) and
    5, the filtrate is evaporated in vacuo. The residue is taken up in ether and washed several times with water. The ether solution was dried and evaporated in vacuo to give 31.6 yellow liquids. Traces of hydroquinone are added, the crude product is distilled and 22.4 g (66%) of 1,2-dehydroproline tert-butyl ester are obtained with a bp. 60-62 C (0.1 mm) with
    S) 1-Benzyloxycarbonyl-4, 5-dihydro-1H-pyrrole-2-carboxylic acid t-butyl sulphate.
    A solution of 16.9 g (0.1 mol) of 1,2-dehydroproline tert-butyl ether in 70 ml of dichloromethane is cooled in the atmosphere of argon to -10 ° C. A solution of freshly obtained benzyl chloromate 14.2 ml (0.1 mol) so kip. 62-64 ° C (0.4 mm) in 70 ml of dichloromethane is added dropwise over 30 minutes. Then it is stirred in the cold for another 30 minutes and over the next 20 minutes a solution of 15.22 g (0.1 mol) of 1,5-diazobicyclo-5,4,0-undec-5-lene in 70 ml of dichloromethane is added. The mixture is then removed from the cooling bath and stirred at room temperature for 1 hour. After that, it is washed twice with cold dilute hydrochloric acid and once with saturated sodium carbonate solution. The solution is dried in vacuo and 8.2 g (60%) of 1-benzyloxycarbonyl-4,5-dihydro-1I-pyrrole-2-carboxylic acid tert-butyl ester are obtained in the form of a light yellow oil. &amp; ) Tert-butyl ether (trans) 1-benoyloxycarbonyl-3-methylthio-0 L proline. A solution of t-butyl ether 18, 2 (0.06 mol) of 1-benzyloxy-carbonyl4, 5-ligidro-1H-pyrrole-2-carboxylic acid in 180 ml of dry methanol is mixed with 3.24 g (0.06 mol) of methylate sodium and cool in an ice bath. Methantiol is passed through the solution slowly over 30 minutes. The mixture is stirred overnight at room temperature under argon atmosphere. The solution is slightly acidified with dilute water with acetic acid. Argon is passed through the solution for 1 h, then dried under vacuum until almost dry. Ethyl acetate is added and the solution is washed 2 times with a saturated solution of sodium carbonate, dried and the solvent is removed in vacuo to give 17 g of a yellow oil. After chromatography on 300 g of sylkagel with petroleum ether: ether (4: 1), 11.1 g of (trans) benzyloxycarbonyl-3-methylthio-D, L-proline are obtained in the form of a bicoloured mnsl. (A) (trans) -3-methylthio-D L-proline. To 8.4 g (0.024 mol) (trans) -benzyloxycarbonyl-3-methylthio-D, Lproline, add 45 ml of 4 N-hydrobromic acid in acetic acid. After stirring for 1 hour at room temperature, the solution is dried in vacuo, a small amount of water is added and washed twice with ether. The aqueous solution is introduced into a column containing .300 ml of ion exchange resin and washed with water until the extract from the adsorbent retains strong acidity. Then the product is extracted with a buffer solution with a pH of 6.5 (aqueous solution of pyridine acetate). Fractions with a positive reaction to the ninhydride are combined, and after lyophilization, 3.4 g (88%) of a white fluffy substance is obtained. This material crystallizes in methanol and forms (trans) methylthio-D, L-proline with m.p. 196-200 (decomposition) (sublim. At 192). Calculated (%): C, 44.70; H 6.88; N 8.69, S 19.89. CgH dd OjNS Found (%): C 44.53; H 7.10; N 8.61; S 19.95 d) (Trans) -1-C3- (acetylthio) -1-ox-propyl 3-3-methylthio-D, L-proline. 3.05 g (0.019 mol) of (trans) -3-methylthio-D L-proline is dissolved in 19 ml of 1m sodium carbonate and diluted with 10 ml of water. The solution is cooled in an ice bath and a solution of 3-acetylthiopropionyl chloride in 20 ml of ether is added with rapid stirring. The pH is maintained at 8 by adding IN sodium carbonate solution. After 30 minutes, the pH stabilizes, during which time a total of 45 ml of sodium carbonate solution was added. The layers are separated and the aqueous layer is washed once with ether. The aqueous layer is then acidified with a 10% potassium bisulfate solution and the product is extracted with ethyl acetate, dried and freed from solvent in vacuo to give 5.2 g of oil. After chromatography on 150 g of silica gel using ethyl acetate for washing, 3.85 g of not completely pure (trans) -1-C3- (acetylthio) -1-oxoprocil -3-methylthio-D, L-proline is obtained. A small sample of the resulting material is diluted in ether and converted to the dicyclohexylamine salt, which, after recrystallization in ethyl acetate, forms the (trans) -1-13-acetylthio) -1-oxopropyl-D-3-methylthio-D, L-proline dicyclohexylamine salt, m.p. 153-157 ° C. Calculated (%): C, 58.44; H 8.53; N 5.83; S 13.57 С ,,, Н ,, 0ч NS. СеН Found (%): С 58.77; H 8.57; N 5.68; S 13.74. e) (Trans) -1- (3-mercapto-1-oxopropyl) -3-methylthio-D, L-proline. 2.05 g (0.007 mole) of (trans) -1-L3 (acetylthio) -1-oxopropyl-3-methylthio-D, L-proline is cooled in an ice bath under argon atmosphere and treated with cold argon-saturated mixture of 7 ml of water and 7 ml of concentrated ammonia. After stirring for 30 minutes, the solution was acidified with hydrochloric acid. The product is extracted with ethyl acetate, dried and freed from solvent in vacuo, and 1.85 g of material is obtained, which after some time is partially crystallized. After trituration with ether, 1.0 g (57%) of a white crystalline product is obtained. After recrystallization in ethyl acetate (5 ml), 0.85 g of (trans) -1- (3-mercapto-1-oxopropyl) 3-methylthio-D, L-proline, Art. square 8993s. Calculated (%): C, 43.35; H 6.06; N 5.62, S 25., 72. Cq Oz NS2 Found (%): C 43.35; H 6.27; N 5.54, S 25.91. PRI me R 50, (TRANS) -1- (D-3 mercapto-2-methyl-1-oxopropyl) -3 ethylthio-1 -proline.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING VALVES OF DERIVATIVES OR THEIR BASIC SALTS. A method of producing derivatives of proline of the general formula 5 in 2 and <a < and 1
    R4 - $ - (CH) n -CH-C0-TC - * - Juice where
    X * is oxygen or sulfur; U is 0 or 1;
    R is hydrogen or Cd — Cs alkyl;
    Cd — C l — Cц-alkyl, phenyl or phenyl substituted with halogen, Cд — Cц-alkyl or alkoxy;
    Rj is hydrogen, Cί-C / d-alkyl or trifluoromethyl;
    Rj is hydrogen; R a is hydrogen, benzoyl,
    C, -C _ (- alkanoyl or or group
    V 2 N g C <K | X R1
    - $ - (CH) p -CH-Co-to - * - C00R or their basic salts, characterized in that the proline of the general formula
    NgS-'X * R1
    NK - t-co OR where X, R and R <have the indicated meanings, are reacted with an acid halide of the general formula
    R 3 R 2
    R; -S- (CH) n -CH-COOH where R / d is hydrogen or R $ is CO;
    Rg is lower alkyl, phenyl or phenyl-lower alkylene, and the target product is isolated in its free form or as a salt, or, if necessary, a compound of formula I, where Ri | = R ^ —CO, is converted to a compound of formula I, where R., is hydrogen, by the action of an aqueous solution of ammonia, or a compound of formula t, g 1 -, hydrogen, is oxidized with iodine to obtain a compound of formula I, where R /, - Group
    B 5 H 2 C-O <A ~ K1
    -8- (sn} l- sn-so-n — L f00R
    SU „o 1066460 with the allocation of the target product in free form or in the form of a basic salt.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1066460A3|1984-01-07|Process for preparing proline derivatives or their basic salts
    US4316906A|1982-02-23|Mercaptoacyl derivatives of substituted prolines
    SU747422A3|1980-07-23|Method of producing proline derivatives
    US4154935A|1979-05-15|Halogen substituted mercaptoacylamino acids
    US4129566A|1978-12-12|Derivatives of dehydrocyclicimino acids
    US4046889A|1977-09-06|Azetidine-2-carboxylic acid derivatives
    SU1139374A3|1985-02-07|Method of obtaining 1-/3-mercapto-|-methyl-h-propionyl/-pyrrolidine-|-carboxylic acid
    US4226775A|1980-10-07|Substituted thio-substituted benzyl-propionyl-L-prolines
    US4296033A|1981-10-20|4-Azido-1-mercaptoacyl proline
    US4241076A|1980-12-23|Halogenated substituted mercaptoacylamino acids
    EP0010347A1|1980-04-30|Novel substituted omega-aroyl|-L-prolines, pharmaceutical compositions containing them and processes for their preparation
    CH639370A5|1983-11-15|HALOGENATED MERCAPTOACYLAMINE ACIDS AND PROCESS FOR THEIR PREPARATION.
    CA1124726A|1982-06-01|Derivatives of pyrrolidinecarboxaldehydeand piperidinecarboxaldehyde andintermediates therefor
    US4181663A|1980-01-01|Selenium containing derivatives of proline and pipecolic acid
    Southwick et al.1955|The addition of N-bromomorpholine to benzalacetophenone
    ES2253761T3|2006-06-01|PROCEDURE TO PREPARE ACIDS | -CHIRAL, NON-RACEMICAL.
    JP3250806B2|2002-01-28|N- | amino acids, processes for their preparation, their use in therapy and pharmaceutical compositions containing them
    US3803202A|1974-04-09|Process for the production of 2-cyano-3,4,5,6-tetrahalogenbenzoic acid alkyl esters
    US4217458A|1980-08-12|Acylmercaptoacyl derivatives of 4,5-dihydro-1H-pyrrole-2-carboxylic acids and 1,4,5,6-tetrahydropyridine-2-carboxylic acids
    FR2510560A1|1983-02-04|PROCESS FOR THE PREPARATION OF 4-AMINO BUTYRAMIDE
    FR2482099A1|1981-11-13|MERCAPTOACYLDIHYDROPYRAZOLE CARBOXYLIC ACID DERIVATIVES WITH ANTI-HYPERTENSIVE ACTION
    FR2636624A1|1990-03-23|METHOD FOR STEREOCHIMIC INVERSION OF HYDROXY FUNCTION OF AN ESTER BY MODIFIED MITSUNOBU REACTIONAL PROCESS
    SU1281565A1|1987-01-07|Method of producing m-chlorbenzoic acid
    CH633782A5|1982-12-31|Derivatives of thiazolidine- and thiazanecarboxylic acids
    KR840000193B1|1984-02-28|Process for preparing substituted waroye|-l-prolines
    同族专利:
    公开号 | 公开日
    KR830002450B1|1983-10-26|
    NL990024I1|1999-11-01|
    DE2932021C2|1994-05-19|
    JPS5527199A|1980-02-27|
    AU4919079A|1980-02-14|
    GR72420B|1983-11-03|
    PT70049A|1979-09-01|
    GB2028327B|1982-11-24|
    IT1117782B|1986-02-24|
    AR229081A1|1983-06-15|
    SE7906722L|1980-02-12|
    RO78870A|1982-07-06|
    FR2435469B1|1983-02-11|
    NL7906120A|1980-02-13|
    JPH0134987B2|1989-07-21|
    IE791544L|1980-02-11|
    LU90403I2|2000-07-07|
    NL193374B|1999-04-01|
    BE878191A|1980-02-11|
    CS228118B2|1984-05-14|
    PH15030A|1982-05-13|
    NZ191036A|1984-05-31|
    FI69834B|1985-12-31|
    AU530690B2|1983-07-28|
    AT379589B|1986-01-27|
    IN152712B|1984-03-17|
    IE48802B1|1985-05-15|
    DE2932021A1|1980-02-21|
    JPH01287069A|1989-11-17|
    ATA541679A|1985-06-15|
    YU41876B|1988-02-29|
    ZA793633B|1980-07-30|
    YU192379A|1983-02-28|
    CA1144930A|1983-04-19|
    LU81593A1|1979-12-07|
    DK154553B|1988-11-28|
    ES483311A1|1980-04-16|
    DK335879A|1980-02-12|
    GB2028327A|1980-03-05|
    FI792498A|1980-02-12|
    DD145749A5|1981-01-07|
    IT7949954D0|1979-08-03|
    FI69834C|1986-05-26|
    NL990024I2|1999-11-01|
    FR2435469A1|1980-04-04|
    DK154553C|1989-04-17|
    SE447477B|1986-11-17|
    KR830001269A|1983-04-29|
    RO78870B|1985-01-30|
    NL193374C|1999-08-03|
    CH642064A5|1984-03-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2340092B2|1976-02-09|1982-01-08|Roussel Uclaf|
    AU509899B2|1976-02-13|1980-05-29|E.R. Squibb & Sons, Inc.|Proline derivatives and related compounds|
    US4116962A|1976-12-03|1978-09-26|E. R. Squibb & Sons, Inc.|Pyrrolidine and piperidine-2-carboxylic acid derivatives|
    US4113715A|1977-01-17|1978-09-12|E. R. Squibb & Sons, Inc.|Amino acid derivatives|
    US4108886A|1977-03-11|1978-08-22|E. R. Squibb & Sons, Inc.|Thiopropanoylamino acid derivatives|
    PH15381A|1978-02-21|1982-12-17|Squibb & Sons Inc|Halogen substituted mercaptoacylamino acids|
    US4154934A|1978-08-11|1979-05-15|E. R. Squibb & Sons, Inc.|Mercaptoacylamino derivatives of heterocyclic carboxylic acids|US4483861A|1978-10-31|1984-11-20|Santen Pharmaceutical Co., Ltd.|Antihypertensive sulfur-containing compounds|
    CA1132985A|1978-12-22|1982-10-05|John Krapcho|Ketal and thioketal derivatives ofmercaptoacyl prolines|
    US4347371A|1978-12-30|1982-08-31|Santen Pharmaceutical Co., Ltd.|Disulfide compounds|
    US4234489A|1979-06-25|1980-11-18|E. R. Squibb & Sons, Inc.|Pyroglutamic acid derivatives and analogs|
    US4288368A|1979-07-30|1981-09-08|E. R. Squibb & Sons, Inc.|Dithioacylproline derivatives|
    US4291040A|1979-10-22|1981-09-22|E. R. Squibb & Sons, Inc.|Mercaptoacyl derivatives of 4-disubstituted prolines and 4-substituted dehydroprolines|
    US4692458A|1980-03-05|1987-09-08|University Of Miami|Anti-hypertensive agents|
    AU542211B2|1980-03-07|1985-02-14|Gruppo Lepetit S.P.A.|Mercaptocycloalkyl carbonyl prolines|
    SE431331B|1980-03-21|1984-01-30|Squibb & Sons Inc|NEW THERAPEUTICALLY ACTIVE SULFUR CONTAINING N-ACYLATED DERIVATIVES OF 4-OXO-L-PROLINE|
    US4284624A|1980-05-02|1981-08-18|E. R. Squibb & Sons, Inc.|Mixed disulfides|
    US4497953A|1981-06-01|1985-02-05|E. R. Squibb & Sons, Inc.|Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids|
    US4390695A|1980-06-23|1983-06-28|E. R. Squibb & Sons, Inc.|Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids|
    US4578474A|1980-06-23|1986-03-25|E. R. Squibb & Sons, Inc.|Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids|
    US4316905A|1980-07-01|1982-02-23|E. R. Squibb & Sons, Inc.|Mercaptoacyl derivatives of various 4-substituted prolines|
    US4332726A|1980-08-25|1982-06-01|E. R. Squibb & Sons, Inc.|Purification of mercaptoacyl amino acids|
    US4307110A|1980-09-12|1981-12-22|E. R. Squibb & Sons, Inc.|Mercaptoacyl derivatives of 3-substituted proline derivatives|
    US4311705A|1980-10-06|1982-01-19|E. R. Squibb & Sons, Inc.|Carboxyalkanoyl and hydroxycarbamoylalkanoyl derivatives of substituted prolines|
    US4312809A|1980-10-31|1982-01-26|E. R. Squibb & Sons, Inc.|Lactam derivatives of mercaptoacylamino acids|
    US4462943A|1980-11-24|1984-07-31|E. R. Squibb & Sons, Inc.|Carboxyalkyl amino acid derivatives of various substituted prolines|
    US4384123A|1980-12-04|1983-05-17|E. R. Squibb & Sons, Inc.|Phosphinylalkanoyl substituted prolines|
    US4337201A|1980-12-04|1982-06-29|E. R. Squibb & Sons, Inc.|Phosphinylalkanoyl substituted prolines|
    US4416831A|1981-04-27|1983-11-22|E. R. Squibb & Sons, Inc.|Amino and substituted amino phosphinylalkanoyl compounds|
    US4374131A|1981-04-27|1983-02-15|E. R. Squibb & Sons, Inc.|Amino and substituted amino phosphinyl-alkanoyl compounds|
    US4381297A|1981-05-04|1983-04-26|E. R. Squibb & Sons, Inc.|Substituted carbonyl phosphinyl-alkanoyl compounds|
    US4416833A|1981-05-04|1983-11-22|E. R. Squibb & Sons, Inc.|Substituted carbonyl phosphinyl-alkanoyl compounds|
    US4377701A|1981-09-21|1983-03-22|E. R. Squibb & Sons, Inc.|4-Methylene-1-[[mercapto]acyl]proline and pipecolic acid|
    US4555506A|1981-12-24|1985-11-26|E. R. Squibb & Sons, Inc.|Phosphorus containing compounds and use as hypotensives|
    US4452791A|1982-03-15|1984-06-05|E. R. Squibb & Sons, Inc.|Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors|
    US4560680A|1982-03-15|1985-12-24|E. R. Squibb & Sons, Inc.|Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors|
    US4452790A|1982-06-23|1984-06-05|E. R. Squibb & Sons, Inc.|Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives|
    US4616005A|1982-06-23|1986-10-07|E. R. Squibb & Sons, Inc.|Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives|
    US4703043A|1982-06-23|1987-10-27|E. R. Squibb & Sons, Inc.|Phosphonyl hydroxyacyl amino acid derivatives as antihypertensive|
    US4567166A|1982-07-14|1986-01-28|E. R. Squibb & Sons, Inc.|Amino and substituted amino phosphinylalkanoyl compounds useful for treating hypertension|
    EP0187037A3|1984-12-21|1988-03-23|Takeda Chemical Industries, Ltd.|Piperidine derivatives, their production and use|
    CA2021409A1|1989-08-21|1991-02-22|Donald S. Karanewsky|Phosphonate substituted amino or imino acids useful as antihypertensives|
    JPH05344844A|1992-06-12|1993-12-27|Suzumo Kiko Kk|Method for producing roasted rice ball cracker|
    EP0640594A1|1993-08-23|1995-03-01|Fujirebio Inc.|Hydantoin derivative as metalloprotease inhibitor|
    US5435286A|1994-05-02|1995-07-25|Cummins Engine Company, Inc.|Ball link assembly for vehicle engine drive trains|
    US7659305B2|2002-10-31|2010-02-09|Pfizer Inc.|Therapeutic proline derivatives|
    GB0225379D0|2002-10-31|2002-12-11|Pfizer Ltd|Therapeutic proline derivatives|
    WO2006038119A1|2004-10-08|2006-04-13|Warner-Lambert Company Llc|Stereoselective synthesis of n-protected alkoxy prolines|
    GB0715626D0|2007-08-10|2007-09-19|Generics Uk Ltd|Crystalline form of zofenopril calcium|
    US8853421B2|2008-02-27|2014-10-07|Generics [Uk] Limited|Crystalline forms of zofenopril calcium|
    CA2715726C|2008-02-27|2014-12-02|Vinayak Gore|Novel crystalline forms|
    SI23949A|2011-12-19|2013-06-28|Silverstone Pharma|The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US93288378A| true| 1978-08-11|1978-08-11|
    KR1019790002731A|KR830002450B1|1978-08-11|1979-08-10|Method for preparing mercaptoacyl derivative of substituted proline|
    [返回顶部]