CN1051909A - The process modification of captopril - Google Patents
The process modification of captopril Download PDFInfo
- Publication number
- CN1051909A CN1051909A CN 89108856 CN89108856A CN1051909A CN 1051909 A CN1051909 A CN 1051909A CN 89108856 CN89108856 CN 89108856 CN 89108856 A CN89108856 A CN 89108856A CN 1051909 A CN1051909 A CN 1051909A
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- CN
- China
- Prior art keywords
- acetylthio
- proline
- pro
- methyl
- methyl propionyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Captopril is an angiotensin converting enzyme inhibitor, is the novel hypertension and the medicine of congestive heart failure.It is condensing agent with alkaline matters such as sodium hydroxide that the present invention adopts 3-acetylthio-2-methyl-prop acyl chlorides and L-proline(Pro), in organic solvents such as water or ethanol, acetone, tetrahydrofuran (THF), react, directly make D-3-acetylthio-2-methyl propionyl-L-proline(Pro), raw materials for production cost and man-hour reduce by 40% than existing operational path.
Description
Captopril is an angiotensin converting enzyme inhibitor, be the novel hypertension and the medicine of congestive heart failure, U.S. FDA was in approval listing in 1981, now obtain obvious curative effects through extensive clinical verification, become one of world's situation of selling well medicine since in 1987, ranked the 4th.The existing manufacturing technique route is as follows:
This reaction scheme is that 3-acetylthio-2-methyl-prop acyl chlorides (I) and the condensation of L proline(Pro) are made-3-acetylthio-2-methyl propionyl-L-proline(Pro) (II), the latter and bicyclohexylamine salify get thick amine salt, again through Virahol refining D-amine salt (III), free with sal enixum subsequently, obtain D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV), after hydrolysis, make captopril (V).Aforesaid method once by Ondetti MA in 1977 at U.S. Patent number 4,046,889 and Jose AJ equal on Span ES 497,020, to do respectively in 1981 report.But the aforesaid method reactions steps is long, and needs to carry out the separation of optical isomer with two cyclic group amine, the production cost height.For overcoming these shortcomings, we have carried out the research of process modification, and operational path of the present invention is as follows:
Technology of the present invention be with 3-acetylthio-2-methyl-prop acyl chlorides (I) and L-proline(Pro) in water or ethanol, acetone, tetrahydrofuran (THF) equal solvent, adopt potassium hydroxide, sodium hydroxide or pyridine, triethylamine etc. are inorganic or organic bases is made condensing agent, consumption with 1: 1～3 ratios, in-5～20 ℃, reacted under the condition of PH5～10 0.5～3 hour, and directly made D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV).The present invention need not adopt any reagent to carry out the separation of optical isomer, and has got rid of dicyclohexyl amine, Virahol, has greatly simplified production technique, makes raw materials cost reduce 40% man-hour with producing.
Embodiment one
Preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV)
With 23.7g(0.21M) the L-proline(Pro) is dissolved in the 100ml water, is cooled to-5～0 ℃, under agitation condition, drip 2N NaOH, making solution PH is 8～9, under uniform temp, drips NaOH and 3-acetylthio-2-methyl-prop acyl chlorides (I) 37.9g(0.21M simultaneously then), in the dropping process, control PH8～9, after dropwising, under the PH7 condition, reactant was stirred 0.5 hour, reaction solution washs 3 times with ethyl acetate, divide and to remove ethyl acetate layer, the aqueous solution is acidified to PH2 in stirring at room 5 hours, 10 ℃ of standing over night with 6N HCl, filter, collecting precipitation washes with water, gets 20g product, yield 36% after the drying, 70～80 ℃ of fusing points, [α]
20 D-155～170 ° (C, 1,95%EtOH).
Ultimate analysis: C
11H
17O
4NSH
2O
Calculated value %:C 47.64, H 6.95, and N 5.41, and S 11.2
Experimental value %:C 48.10, H 7.31, and N 5.45, and S 11.61
Embodiment two
Preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV)
With 23.7g(0.21M) the L-proline(Pro) is dissolved in the 100ml50% ethanol, be cooled to-5～0 ℃, under agitation condition, in solution, drip triethylamine, making its PH is 8～9, under uniform temp, drip triethylamine and 3-acetylthio-2-methyl-prop acyl chlorides (I) 37.9g(0.21M simultaneously then), in the dropping process, control PH8～9, after dropwising, under the PH7 condition, reactant was stirred 0.5 hour, remove ethanol under reduced pressure after, reaction solution washs 3 times with ethyl acetate, divide and to remove ethyl acetate layer, the aqueous solution was acidified to PH2 with 6N HCl, in stirring at room 6 hours, 10 ℃ of standing over night, filter, collecting precipitation washes with water, get the 20g product after the drying, yield 36%, fusing point: 80～82 ℃, [α]
20 D-155～170 ° (C, 1,95%EtOH).
Ultimate analysis: C
11H
17O
4NS
Calculated value %:C 50.94, H 6.61, and N 5.40, and S 12.36
Experimental value %:C 50.47 H 6.87, N 5.54, and S 11.98
Claims (3)
1, a kind of method for preparing D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV), it is characterized in that with 3-acetylthio-2-methyl-prop acyl chlorides (I) and-the L-proline(Pro) is in water or organic solvent, adopt mineral alkali or organic bases to make condensing agent, consumption with 1: 1～3 ratios, in-5～20 ℃, reacted under the condition of PH5～10 0.5～3 hour, and made D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV).
2, by the described method for preparing D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV) of claim 1, organic solvent wherein is ethanol, acetone or tetrahydrofuran (THF) etc.
3, by the described method for preparing D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (IV) of claim 1, mineral alkali wherein is potassium hydroxide or sodium hydroxide etc., and the machine alkali that wherein has is pyridine or triethylamine etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 89108856 CN1021044C (en) | 1989-11-24 | 1989-11-24 | Preparation method for acidophobic-methyl propyl proline intermediate d-3-acetylsulfuric-2-methyl-propiony-l-proline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 89108856 CN1021044C (en) | 1989-11-24 | 1989-11-24 | Preparation method for acidophobic-methyl propyl proline intermediate d-3-acetylsulfuric-2-methyl-propiony-l-proline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1051909A true CN1051909A (en) | 1991-06-05 |
| CN1021044C CN1021044C (en) | 1993-06-02 |
Family
ID=4857773
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 89108856 Expired - Lifetime CN1021044C (en) | 1989-11-24 | 1989-11-24 | Preparation method for acidophobic-methyl propyl proline intermediate d-3-acetylsulfuric-2-methyl-propiony-l-proline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1021044C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102452970A (en) * | 2010-10-16 | 2012-05-16 | 华中药业股份有限公司 | Preparation method of D-3-bromine-2-methyl propionyl-L-proline |
| CN104513292A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Preparation method of ramipril |
-
1989
- 1989-11-24 CN CN 89108856 patent/CN1021044C/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102452970A (en) * | 2010-10-16 | 2012-05-16 | 华中药业股份有限公司 | Preparation method of D-3-bromine-2-methyl propionyl-L-proline |
| CN104513292A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Preparation method of ramipril |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1021044C (en) | 1993-06-02 |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |
Granted publication date: 19930602 |