• 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:
    1. METHOD OF OBTAINING 1-GZ- -M RKANTO-
    公开号:SU1139374A3
    申请号:SU803228098
    申请日:1980-12-15
    公开日:1985-02-07
    发明作者:Фишер Янош；Рожа Ласло；Баконьи Анна；Фазекаш Габор；Ваго Пал
    申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    Od
    co 4 The invention relates to a process for the preparation of 1- 3-mercapto- (25) -methyl and-propionyl-3-pyrrolidine- (23) -carboxylic acid of the formula which has hypotensive effect. The closest in technical essence and the achieved result to the proposed method is the preparation of 1- 3-mercapto- (28) -methyl-N-propionyl} -pyrrolidine- (25) -carboxylic acid, which is that a proline acylir from 3-ace1-shthio-2-metsh1-n-propionic acid in the presence of an alkali metal hydroxide, the resulting product is converted into salt by the action of dicyclohexylamine, the salt is recrystallized and recrystallized from isopropanol. In this way, the dicyclohexylamine salt of 1- 3-acetylthio- (2S) -methyl-n-propionyl-pyrrolidine- (28) -carboxylic acid is obtained in a yield of 30% of the calculated, from which the free, carboxylic acid is made in the form of the racemate with the yield 83% of the calculated. The acetyl group protecting the mercapto group is then removed with an aqueous solution of ammonia and the compound (I) is free in B1 or the 2B-isome R. on the column containing the cation-exchange resin in a yield of 42% of the calculated one. The method consists of five stages, the total yield is 10.5% of the calculated (calculated for b proline) tlJ. The disadvantages of this method are its complexity and the low yield of the target product. The purpose of the invention is to simplify the process and increase the yield of the target product. This goal is achieved by the fact that according to the method for producing 1-C3-mercapto- (28) -methyl-H-propionium-pyrrolidine- (28) -carboxylic acid by acylation of L-3-substituted 3-substituted 1-MeOH-propionyl chloride with the subsequent separation of the resulting racemate into isomers as 3-substituted 2-methyl-c-propionyl chloride derivative is used 3-bromo-2-methyl-n-propionyl chloride, precipitated by acidification of 1- 3-bromo- (28) -methyl-n-propionyl -pyrrolidine- (23) -carboxylic acid, which is converted into the target compound by treatment with sodium thiosulfate Or sodium tritiocarbonate. Followed by hydrolysis with a mineral acid. It is preferable to use sulfuric or hydrochloric or phosphoric acid as the mineral acid. Acetylation of L-proline at ShottenBauman should be carried out in an aqueous medium in the presence of an alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate at 0-25 ° C. The base is applied in an amount twice as large as equimolar. 1-3-Bromo- (2S) -methyl-N-propionyl-pyrrolidine- (28) -carboxylic acid is precipitated after acidification of the reaction mixture while cooling, another diastereomer - 1- 3-bromo- (2K) -methyl-n-propionyl The 1-pyrrolidine- (28) -carboxylic acid remains. in aqueous mother liquor. 1- 3-Halogen- (28) -metsch1-n-propionyl-pyrrolidine- (28) -carboxylic acid, obtained with a yield of 40% of the calculated one, is clean, homogeneous and does not require purification, which would otherwise carry out by salt formation with dicyclohexnlamine or another base in a complex way and with large losses. From the other diastereomer that remains in the mother liquor as a by-product, you can select L-proline in the free state with acidic 1 hydrolysis and introduce it back into the acylation reaction. The corresponding 3-bromo- (28) -methyl-n-propionyl chloride isomer can also be used for the acylation of L-proline. In this case, only the desired 1 nd diastereomer is formed. Interaction with sodium thiosulfate or an alkali metal tritiocarbonate is advisable to be carried out in an aqueous medium. The reaction product thus obtained may be hydrolyzed to a compound of formula 311 (I). The hydrolysis is carried out with mineral acid. Thus, a product of formula (I) is obtained in a yield of 70% of that calculated from L-proline. The resulting product does not require further purification. P r and m. 6 p 1. A. 1- 3-EpoM- (2S) -met11G1-n-propionyl-pyrrolidine- (28) -carboxylic acid. 2.88 g (0.072 mol) of sodium hydroxide is dissolved in 35 ml of water, and 8.28 g (0.072 mol) of L-proline is added to jpacTBOpy. 13.34 (0.072 mol) of 3-bromo-2-methyl-n-progionyl chloride and at the same time a solution of 2.88 g (0.072 mol) of sodium hydroxide in 35 ml of water are added dropwise to the solution obtained. Both components were added with constant stirring, adjusting the addition so that one ended one time with the other and without heating the reaction mixture to a temperature above 10 ° C. The reaction mixture was stirred for another 6 hours at room temperature, then held for 12 hours. It is extracted with 15 ml of ether and acidified with 37% hydrochloric acid to RP 2 with cooling with ice water. The product, which is concentrated in the form of a colorless oil, crystallizes within half an hour. The resulting crystals are filtered and washed with a small amount of ice water. The resulting white crystalline product melts at 62-72 ° C. After crossing | Istalizatsii from 44 ml. water receive 8.0 g (40% of the calculated) monohydrate t-f3-6poM- (2S) -methyl-n-propionyl pyrrolidine- (25) -carboxylic acid, so pl. 7t-74 C, tot -89 (c 1; ethanol). After drying over phosphorus pentoxide for 1 h under a vacuum of 20 mm Hg. get anhydrous form with so pl. 1lO-1l4C, 0 -94.9 (c 1, ethanol). The mother liquor (8-5) of the diastereomer is extracted three times with chloroform, the organic solution is dried and evaporated. The residue is crystallized by the addition of carbon tetrachloride and recrystallized from 50-fold amount of ether. Get 1- 3-bromo- (2K) -metsch1 .N-propionsh1 -pirrolidin- (28) -carboxylic acid with so pl. 102-104 C, -33.5 (c 1, ethanol)., 44. at. 1-GZ-Merkdpo- (28) -methyl-n-propionyl-pyrrolidine- (28) -carboxylic acid. 14.1 g (0.050 mol) of 1-GZ-bromo- (28) -methyl-H-propiopyl-3-pyrrole-1 (28) -carboxylic acid are dissolved in a solution of 4.4 g (0.053 mol) of sodium bicarbonate in 100 ml of water . To the resulting solution was added 13.0 g (0.053 mol) of crystalline sodium thiosulfate (NajS Oj-5H20). The reaction mixture was heated for 1 hour to boiling, cooled, acidified with 20 ml of 37% hydrochloric acid, boiled 1 more hour and cooled to 20 ° C. The mixture is extracted three times with ethyl acetate, the combined organic solutions are washed with 40 ml of a saturated aqueous solution of chloride, dried over anhydrous magnesium sulphate, and evaporated. The colorless oily residue is dissolved in 40 ml of ethyl acetate under heating and, after filtration, the product is precipitated with n-hexane. Obtain 7.0 g (70% of the calculated) white crystalline 1- 3-mercaptr- (28) -methyl- H-propion of w-pyrrolidine- (28) -carboxylic acid, so pl. 103 105 ° C, d, 3 ° C (s 1.7, ethanol). Example 2. 1- 3-Mercapto- (28) -methyl-n-propionic 13-pyrrolidesh1- (28) -carboxylic acid. To 5.0 g (0.02 mol) of 1- 3-bromo- (28) -metish-n-propionyl-L-proline, obtained according to Example 1A, add 10 ml of sodium tritiocarbonate solution and 10 ml of water. The reaction mixture is stirred for 3 hours at 40-45 ° C, left to stand for 1 hour and then removed with a small amount of ether. After the addition of 1 g of powder, the reaction mixture is acidified with 37% hydrochloric acid, stirred 8 hours, then held for 12 hours, then filtered, the three extracted with ethyl acetate, dried over anhydrous magnesium sulphate and ground.The colorless oily residue is dissolved in hot ethyl acetate and the product is planted with n-hexane to give 3.1 g (75% from the calculation) 1- 3-mercapto- (2B) -metSh1-N-propi6n s-pyrrolidine- (28) -carboxylic acid, jj (c 1.7, ethanol). Example 3, Proceed as in example 1 with the difference that after reaction with sodium thiosulfate, the reaction mixture was acidified with 11 ml of 98% sulfuric acid and the mixture is heated for 30 minutes. 6.7 g (62%) of 1-CZ-mercap to- (2i5} -methyl - "- propionyl-3-pyrolidine- (25) -carboxylic acid is obtained, mp. 102 -105 C, fofJ2 ".129, (c 1.7; ethanol). Example 4, Proceed as in example 1 with the difference that after reaction with sodium thiosulfate, 30 ml of 85% phosphoric acid and the mixture is heated for e 2h 4.45 g (41%) of 1- 3-mercapto- (28) -methyl-n-propionyl-pyrrolidin- (28) -carboxylic acid are obtained, t, Ø 102-105 С, oCXl -129 ,, (with 1.7, ethanol). Preparation of the starting compound 3-bromo-2-metsh1-N-propionichlornd, A, 3-Bromo-2-methyl-n-propionic acid. 86 ml (1.01 mol) of methacrylic acid are dissolved in 80 ml of chloroform and hydrogen bromide is passed into the solution with stirring. After absorbing the calculated amount of hydrogen bromide, the solution is held at 12 h, then evaporated and the residue is distilled under vacuum (7 mm pTo,). Receive 164.8 g (97.3% of the calculated) 3-bromine 2-metip-And-propionic acid, t, Kip, 10; 1-104 C / 7 mm Hg. St ,, Z, bV53, B, 3-Bromo-2-1U1etnl-N-propionyl chloride, a mixture of 125.0 g (0.75 mol) of 3-bromo-2-methyl-propionic acid and 150 ml of thionyl chloride is heated 6 h at, Excess thionyl chloride is distilled off under a vacuum of 40 mm Hg, st, and the residue is distilled under a vacuum of 8 mm Hg, st. This gives 126.8 g (91.4% of the calculated) 3-bromo-2-methyl-n-propionyl chloride, t, bales. 40-41 C / 8 mmHg, PU 1.4815,
    权利要求:
    Claims (2)
    [1]
    :, 1. METHOD FOR PRODUCING 1- £ 3- '-MERCAPTO- (2S) -METHYL-I-PROPIONYL] -PYRROLIDINE- (2 S) -CARBOXYLIC ACID by acylation of L-proline with a 3-substituted 2-methyl-n-propionyl derivative - chloride, followed by separation of the obtained racemate into isomers, which is related to the fact that, in order to simplify the method and increase the yield of the target product, as a 3-substituted derivative of 2-methyl-n-propionylchloride, they call 3-bromo-2-methyl-th-propionylchlorozz, planted by acidification of 1- [3-bromo- (2 S) -methyl-n-pr opionyl ^ -pyrrolidine ^ 2 S) -carboxylic acid, which odyat the title compound; treatment with sodium thiosulfate or 'sodium trithiocarbonate, followed by hydrolysis with a mineral acid.
    [2]
    2 Method according to π. 1, characterized in that sulfuric or hydrochloric or phosphoric acid is used as a mineral acid.
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