• 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 substituted acyl derivatives of amino acids which have the general formula <IMAGE> are useful as angiotensin converting enzyme inhibitors.
    公开号:SU731891A3
    申请号:SU772549899
    申请日:1977-12-02
    公开日:1980-04-30
    发明作者:Анджел Ондетти Мигуел；Ли Вейсенборн Фрэнк
    申请人:Е.Р. Сквибб Энд Санз, Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new substituted acyl
    amino acid derivatives of the general formula I 5 $ H- (CH g ) p —CH — CO — K—— Ueo, 4> 1where Rj is hydroxyl or lower C 4 -C- 10 alkoxy; w - 0 or 1;η is 0 or 1;or their salts with biologicactivity. LS Acetal hydrolysis reaction is known 10
    tiltothio derivatives with concentrated ammonia to give compounds with a free mercapto group [1].
    The application of this method allows to obtain new substituted acyl derivatives of amino acids of General Formula I.
    The method according to the invention consists in the fact that the compound of general formula II
    where R 2 = C ^ —C 4 alkanoyl is hydrolyzed with concentrated aqueous ammonia, preferably in argon atmosphere, after acidification of the reaction mixture, the desired products are isolated in free form or in the form of a salt.
    Example 1.2- (Acetylthiomethyl) -3- (acetylthio) propionic acid.
    A solution of 3.36 g (40 mol) of thiolacetic acid in 40 ml of 1 N. a solution of potassium hydroxide is added dropwise to a solution of 2-bromomethyl-3-bromopropionic acid in 20 ml of 1 N. potassium hydroxide solution. The mixture was stirred at room temperature for 12 hours, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo. The residue is converted to dicyclohexylammonium salt; mp. 116118 C, after which the salt is again converted into 2- (acetylthiomethyl) -3- (acetylthio) propionic acid.
    Example 2. 1- [2- (Acetylthiomethyl) -3- (acetylthio) -propanol] -L-proline-tert-butyl ether.
    2.35 g of 2- (acetylthiomethyl) -3- (acetylthio) propionic acid are added to a solution of 1.71 g of L-proline tert-butyl ether, 1.35 g of hydroxybenzotriazole and 2.06 g of dicyclohexylcarbodiimide in 15 ml of dichloromethane, chilled in an ice bath. The reaction mixture was stirred for 12 hours at 20 ° C., dicyclohexylurea was filtered off and the filtrate was washed until neutral. The organic layer is dried and concentrated to dryness in vacuo to form 3.7 g of 1- [2- (adetyl.thiomethyl) -3- (acetylthio) propanoyl] : -L-proline tert-butyl ether in a vice heavy oil-like product ; Rn0.7 (silica gel benzene-acetic acid 7: 1).
    Example 3. 1- [2- (Acetylthiomethyl) - 3- (acetylthio) propanoyl] —L— proline.
    A. 2.7 g of 1- [2- (acetylthiomethyl) -3- (acetylthio) propanoyl] -L-proline-tert-butyl ether are dissolved in a mixture of trifluoroacetic acid with anisole and the prepared mixture is kept at room temperature for 1 h The solvent is removed in vacuo and the residue is dissolved in a saturated solution of sodium bicarbonate. The aqueous solution was extracted with ethyl acetate, acidified with concentrated hydrochloric acid and re-extracted with ethyl acetate. Then this second organic layer is dried and concentrated to dryness in vacuo. The residue was subjected to silica gel column chromatography using a mixture of benzene and acetic acid in a ratio of 7: 1. Fractions that contain the desired material are combined and concentrated to dryness to give 1.3 g of 1- [2- (acetylthiomethyl) -3- (acetylthio) propanoyl] -L-proline as an oil-like product; R ^ 0.3 (silica gel benzeneacetic acid 75:25).
    B. To a solution of 1.44 g of L-based and 2.7 g of sodium carbonate in 25 ml of water in an ice bath add 3.9 g of 2- (acetylthiomethyl) -3- (acetylthio) -propanoic acid as its acid chloride obtained from 2- (acetylthiomethyl) -3- (acetylthio) propionic acid and thionyl chloride. The mixture was stirred vigorously at room temperature for 2 hours. After extraction with ethyl acetate, the aqueous layer was acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness. The remainder of 1- (2- (acetylthiomethyl) -3- (acetylthio) propanoyl] -L-proline is chromatographed as described in paragraph A.
    Example 4. 1- (2-Mercaptomethyl-3-mercaptopropanoyl) -L-proline.
    1- (2- (Acetylthiomethyl) -3- (acetylthio) -propanoyl] -L-proline in an amount of 1.2 g is dissolved in a mixture of 12 ml of water with 12 ml of a concentrated solution of ammonia in argon atmosphere. After 20 minutes, the mixture is acidified with concentrated hydrochloric acid. The crystalline precipitate of 1- (2-mercaptomethyl-3-mercaptopropanoyl) -L-proline is filtered off and dried to obtain 0.63 g of product; mp 138-140 ° C.
    Example 5. 2,3- (Diacetylthio) -propionic acid.
    Using 2,3-dibromopropionic acid instead of 2-bromomethyl-3-bromocropionic acid, analogously to Example 1, 2,3- (diacetylthio) -propionic acid is obtained as an oil-like product; Rj 0.4 (silica gel benzene-acetic acid 7: 1).
    Example 6. 1- [2,3- (Diacetylthio) propanoyl] —L — proline tert-butyl ether.
    Using 2,3- (diacetylthio) propionic acid instead of 2- (acetylthiomethyl) -3- (acetylthio) propionic acid, analogously to Example 2, 1- [2,3- (diacetylthio) propanoyl] -L- is obtained as an oil-like product proline; Rr 0.5 (silica gel chloroform - methane * 98: 2).
    Example 7. 1- [2,3- (Diacetylthio) propanoyl] -L-proline.
    Using 1- [2,3 - (diacetylthio) -propanoyl] -L-proline-tert-butyl ether instead of 1- [2- (acetylthiomethyl) -3-acetylthiopropanoyl] -L-proline-tert-butyl ether, as in Example 3A 1- (2,3- (diacetylthio) propanoyl] -L-proline; Rj. 0.4 5 (silica gel benzene-acetic acid 75:25).
    Example 8. 1- (2, 3-Dimercaptopropanoyl) -L-proline.
    Using 1- [2,3- (diacetylthio) propanoyl] -L-proline instead of 1- (2- (acetylthiomethyl) -3- (acetylthio) propanoyl] -L-proline, analogously to example 4, 1- ( 2,3-dimercaptopropanoyl) -L-proline: This product is isolated as an oil-like substance by extraction with ethyl acetate after acidification of the reaction mixture, Rj 0.43 (silica gel: no indicator, benzene - acetic acid 75: 25).
    权利要求:
    Claims (1)
    [1]
    2.35 g of 2- (acetylthiomethyl) -3- (acetylthio) -propionic acid are added to a solution of 1.71 g of L-prolino-tert-butylbio ether, 1.35 g of oxybenzotriazole and 2.06 g of dicyclohexyl carbodiimide in 15 ml dichloromethane, cooled in a bath with ice. The reaction mixture is stirred for 12 hours at 20.degree. C., the dicyclohexyl urea is filtered off and the filtrate is washed until neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3.7 g (adethyl, thiomethyl) -3- (acetylthio) propanoyl-L-prolino-tert-butyl ether as a heavy oil; RpO, 7 (silica gel benzene-acetic acid 7: 1). Example 3, (Acetylthiomethyl) -3- (acetylthio) propanoyl -L-proline. , A. 2.7 g of (acetylthiomethyl) -3- (acetylthio) -propanoyl-L-prolino-tert-butyl ether is dissolved in a mixture of trifluoroacetic acid with an anEIOL and the prepared mixture is kept at room temperature for 1 h. The solvent is removed The residue is dissolved in vacuo and the residue is dissolved in an overnight sodium bicarbonate solution. The aqueous solution is extracted with ethyl acetate, acidified with concentrated hydrochloric acid and re-extracted with ethyl acetate. Then this second organic layer is dried and concentrated to dryness in vacuo. The residue is subjected to chromatographic treatment in a column of silica gel using a mixture of benzene with acetic acid in a ratio of 7: 1. The fractions that contain the target material are combined and concentrated to a dry state to obtain 1.3 g of 1- (2- (acetylthiomethyl) -3- (acetylthio) -propanoyl-L-proline a as an oil-like product; Kr 0 , 3 (silica gel, benzene acetic acid 75:25). B, To a solution of 1.44 g of L-proline and 2.7 g of sodium carbonate in a 25 ml water bath with ice, add 3.9 g of 2- (acetylthiomethyl) -3- (acetylthio) propanoic acid in the form of its acid chloride, obtained from 2- (acetylthiomethyl) -3- (acetylthio) -propionic acid and thionyl chloride. The mixture is intensively mixed at room temperature during e 2 hr. After extraction with ethyl acetate, the aqueous layer is acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness. The residue (acetylthiomethyl) -3- (acetylthio) propanoyl-L-proline is subjected to chromatographic treatment as described in paragraph A. Example 4 1- (2-Mercaptomethyl-3-mercaptopropanoyl) -L-proline. 1- (2- (Acetylthiomethyl) -3- (acetylthio) -propanoyl-L-proline in an amount of 1.2 g is dissolved in a mixture of 12 ml of water With 12 ml of concentrated ammonia solution under argon atmosphere. After 20 minutes, the mixture is acidified with concentrated salt. acidic acid. The crystalline precipitate of 1- (2-mercaptomethyl-3-mercaptopropanoyl) -L-proline is filtered off and dried to give 0.63 g of product; m.p. 138-140 ° C. Example 5. 2,3- (Diacetylthio) -propionic acid. Using 2,3-dibromopropionic acid instead of 2-bromomethyl-3-bromo | ropionic acid as in Example 1, 2,3-(diacetylthio) propionic acid is obtained in the form of an oil-like product; Rj 0.4 (silica gel benzene-acetic acid 7: 1). Example 6., 3- (Diacetylthio) -propanoyl-L-proline-t-butyl ether. Using 2,3- (diacetylthio) -propionic acid instead of 2- (acetylthiomethyl) -3- (acetylthio) -propionic acid as in Example 2, it is obtained as an oil-like product, 3- (diacetylthio) propanoyl-L-pololine; Kg 0,5 (silica gel chloroform - methane 98: 2). Example 7, 3- (Diacetylthio) -propanoyl-L-proline. With the use of 3- (diacetylthio) -propanoyl-L-proline-t-butyl ether instead of (acetylthiomethyl) -3-acetylthiopropanoyl -L-proline-t-butyl ether, analogously to example 3a, 3- (diacetylthio) -propanoyl-L - proline; Kg 0.45 (silica gel benzene - acetic acid 75:25). Example 8. 1- (2,3-Dimercaptopropanoyl) -L-proline. Using 3- (diacetylthio) -propanoyl-L-proline instead of 1- {2- (acetylthiomethyl) -3- (acetylthio) -propanoyl-L-proline, analogously to example 4, 1- (2,3-dimercaptopropanoyl) is obtained -L-proline. This product was isolated as an oil-like substance by extracting with ethyl acetate after acidifying the reaction mixture, Kj 0.43 (silica gel: no indicator, benzene - acetic acid 75: 25). Claims of Invention A method for producing substituted acyl derivatives of amino acids of the general formula (sig) t c - (Sig) p-CH-CO-h LcDRj, where K is hydroxyl or C-C-alkoxy; m is O or 1; - ("p - O or 1; 5 or their salts, and it is also distinguished by the fact that compounds are general formulas G R, -5- (CK, n-CH-CO-HLCOR. IT I 1 13 (g) t where C-alkanoyl units, 7318916 are subjected to hydrolysis with concentrated ammonia, and the target products are produced in free form or as salt. Sources of information 5 taken into account in examination 1, oswaed A.A., NaegeEe M. Free-radica cteanage of (5-hydroxy thioetfur to ketonus and mercaptans. J. Org. Chem. 31, 3366, 1966.;
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/747,280|US4116962A|1976-12-03|1976-12-03|Pyrrolidine and piperidine-2-carboxylic acid derivatives|
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