CN102452970A - Preparation method of D-3-bromo-2-methylpropionyl-L-proline - Google Patents
Preparation method of D-3-bromo-2-methylpropionyl-L-proline Download PDFInfo
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- CN102452970A CN102452970A CN2010105143018A CN201010514301A CN102452970A CN 102452970 A CN102452970 A CN 102452970A CN 2010105143018 A CN2010105143018 A CN 2010105143018A CN 201010514301 A CN201010514301 A CN 201010514301A CN 102452970 A CN102452970 A CN 102452970A
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- bromo
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- methyl propionyl
- methyl
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- 229960002429 proline Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 12
- 229930182821 L-proline Natural products 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- ZVDKTPOXSAEUQU-UHFFFAOYSA-N 3-bromo-2-methylpropanoyl chloride Chemical compound BrCC(C)C(Cl)=O ZVDKTPOXSAEUQU-UHFFFAOYSA-N 0.000 abstract 1
- 229940024606 amino acid Drugs 0.000 abstract 1
- 150000001413 amino acids Chemical class 0.000 abstract 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 11
- 229960000830 captopril Drugs 0.000 description 9
- 238000000034 method Methods 0.000 description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 4
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- -1 amine salt Chemical class 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- BUPXDXGYFXDDAA-UHFFFAOYSA-N 3-bromo-2-methylpropanoic acid Chemical compound BrCC(C)C(O)=O BUPXDXGYFXDDAA-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of D-3-bromo-2-methylpropionyl-L-proline, which adopts 3-bromo-2-methylpropionyl chloride and L-prolylThe amino acid takes alkaline substances such as sodium hydroxide and the like as a condensing agent, and reacts in organic solvents such as water or ethanol, acetone, tetrahydrofuran and the like to directly prepare the D-3-bromo-2-methylpropionyl-L-proline, and does not need to adopt any reagent to separate optical isomers, and dicyclohexylamine and isopropanol in the prior art are eliminated, so that the production process is greatly simplified, the production period is shortened, and the production cost is greatly reduced.
Description
Technical field
The present invention relates to the preparation method of a kind of D-3-of preparation bromo-2-methyl propionyl-L-proline(Pro).
Background technology
D-3-bromo-2-methyl propionyl-L-proline(Pro), it is the midbody of preparation captopril, its structural formula is following:
Captopril is claimed CP again, and its chemical name is (2S)-1-(3-dredges base-2-methyl isophthalic acid-oxo-propyl group)-L-proline(Pro), and its structural formula is following:
Captopril is mainly used in the various essential hypertensions of treatment, has advantages such as onset is rapid, step-down is steady, late result is outstanding, simultaneously in heart failure and mellitus, ephrosis is also had good therapeutic action.U.S. FDA was in approval listing in 1981, and existing warp extensively clinical verification is obtained obvious curative effects, still in hypertensive clinical treatment, is playing the part of important role so far.
Because captopril has characteristics such as clinical application is extensive, economic benefit is obvious, the research of its compound method has caused various countries scholars' extensive concern, attempts having designed many synthetic routes.Ondetti MA in 1977 at U.S. Patent number 4,046,889 and Jose AJ equal 1981 at Span ES 497; On 020 reported first the synthesis technique of captopril; This reaction scheme is to be raw material with 2-methylacrylic acid (IV), and (III) carries out addition reaction with thioacetic acid, obtains the racemoid that 3-acetyl is dredged base-2-methyl-prop acyl chlorides (V) through the thionyl chloride chlorination again; Make 3-acetyl with the condensation of L-proline(Pro) again and dredge base-2-methyl propionyl-L-proline(Pro) (VI); The latter and dicyclohexyl amine salify get thick amine salt, again through Virahol refining D-amine salt (VII), free with sal enixum subsequently; Obtain D-3-acetyl and dredge base-2-methyl propionyl-L-proline(Pro) (VIII), after hydrolysis, make captopril (II).Its production process route is following:
Owing to possess advantages such as low in raw material cost is easy to get, this route is widely used in industrial production, and domestic pharmaceutical manufacturer mainly adopts this technology to carry out the production of captopril.Meanwhile; The shortcoming that this route exists also can not be ignored; Raw material thioacetic acid (III) needs to use hydrogen sulfide to prepare usually; And hydrogen sulfide is harmful gas, and a kind of horrible, smell of being difficult to remove is arranged, and the raffinate of the thioacetic acid that leaks outside in the production and the hydrogen sulfide of generation all causes serious pollution to environment.For solving the pollution problem of thioacetic acid to environment, the Liu Renyong of Shenyang Pharmaceutical University etc. has tested bromomethyl propionic acid route successfully, and its synthetic route is following:
This reaction scheme is to be raw material with 2-methylacrylic acid (IV), carries out addition reaction with hydrogen bromide, obtains the racemoid of 3-bromo-2-methyl-prop acyl chlorides (IX) again through the thionyl chloride chlorination; Make 3-bromo-2-methyl propionyl-L-proline(Pro) (X) with the condensation of L-proline(Pro) again; The latter and dicyclohexyl amine salify get thick amine salt, again through Virahol refining D-amine salt (XI), free with sal enixum subsequently; Obtain D-3-bromo-2-methyl propionyl-L-proline(Pro) (I), after hydrolysis, make captopril (II).But the aforesaid method reactions step is long; And need to carry out the separation of optical isomer with dicyclohexyl amine, production cost is high, and the yield of D-3-bromo-2-methyl propionyl-L-proline(Pro) (I) is lower and purity is also not high; Therefore, the purity of the captopril of its hydrolysis of usefulness preparation is also influenced.
Summary of the invention
The objective of the invention is: the preparation method that preparation D-3-bromo-2-methyl propionyl-L-proline(Pro) (I) that a kind of purity and yield all be improved is provided.
The technical scheme that realizes the object of the invention is: with 3-bromo-2-methyl-prop acyl chlorides (IX) and L-proline(Pro) in water or ethanol, acetone, THF equal solvent; Adopt Pottasium Hydroxide, sodium hydroxide or pyridine, triethylamine etc. are inorganic or organic bases is made condensing agent; Reaction is 0.5-5 hour under the condition of pH=7.0-9.0, directly makes D-3-bromo-2-methyl propionyl-L-proline(Pro) (I).Its operational path is following:
The present invention prepares the preparation method of D-3-bromo-2-methyl propionyl-L-proline(Pro) (I), and concrete steps are following:
1. be raw material with 3-bromo-2-methyl-prop acyl chlorides (IX) and L-proline(Pro); With alkali is condensing agent; Regulate and control pH=7.0-9.0; In-5 ℃-20 ℃ reactions 0.5-5 hour, promptly make the solution of 3-bromo-2-methyl propionyl-L-proline(Pro) (X), its 3-bromo-2-methyl propionyl-L-proline(Pro) (X) is D type and two kinds of non-corresponding mixture of isomers of L type of 3-bromo-2-methyl propionyl-L-proline(Pro);
2. 3-bromo-2-methyl propionyl-L-proline(Pro) (X) solution that 1. step is made washs 3 times with ETHYLE ACETATE, divides and removes ethyl acetate layer, keeps the gained water layer;
3. with the 2. water layer of gained of step, be acidified to pH=1.0-2.0, separate out and contain the 3-bromo-2-methyl propionyl-D type of L-proline(Pro) and the oil reservoir of two kinds of non-corresponding isomer of L type, separate the oil reservoir of separating out and keep;
4. lower the temperature under stirring in 0 ℃ to-5 ℃ crystallization 3-5 hour, left standstill 10 hours in-10 ℃ again;
5. the cold water washing crystallization is used in filtering separation crystallization, again in 55 ℃ of drying under reduced pressure crystallizations, promptly gets D-3-bromo-2-methyl propionyl of the present invention-L-proline(Pro) (I).
Among the above-mentioned preparation method, the reaction solvent that 1. said step is used is organic solvents such as water or ethanol, acetone, THF; Employed alkali is mineral alkali or organic bases, and mineral alkali wherein is sodium hydroxide or Pottasium Hydroxide, and organic bases wherein is pyridine or triethylamine.
Among the above-mentioned preparation method, 2. said step is 3-bromo-2-methyl propionyl-L-proline(Pro) (X) solution that earlier 1. step is made, with the ETHYLE ACETATE washing and remove the ester layer that contains impurity.Because through the washing of ETHYLE ACETATE, the impurity that partly dissolves in ETHYLE ACETATE in 3-bromo-2-methyl propionyl-L-proline(Pro) (X) solution that 1. step makes is removed, and is more conducive to improve the yield and the purity of product.
Among the above-mentioned preparation method, the acid that 3. said step is used is hydrochloric acid or sulfuric acid, and adjustment pH value is 1.0-2.0, separates out and contains the 3-bromo-2-methyl propionyl-D type of L-proline(Pro) and the oil reservoir of two kinds of non-corresponding isomer of L type, separates the oil reservoir and the reservation of separating out.
Among the above-mentioned preparation method, said step 4. be lower the temperature under stirring in 0 ℃ to-5 ℃ crystallization 3-5 hour, left standstill 10 hours in-10 ℃ again.
Technique effect of the present invention is: it is condensing agent with alkaline matters such as sodium hydroxide that the present invention adopts 3-bromo-2-methyl-prop acyl chlorides and L-proline(Pro); In organic solvents such as water or ethanol, acetone, THF, react, directly make D-3-bromo-2-methyl propionyl-L-proline(Pro), need not adopt any reagent to carry out the separation of optical isomer; And dicyclohexyl amine, the Virahol of existing technology have been got rid of; Simplified production technique greatly, shortened the production cycle, production cost significantly reduces.
Embodiment
Below in conjunction with embodiment the present invention is done further specific descriptions, but be not limited to this.The used raw material of embodiment unless otherwise indicated is the commercially available article of technical grade, and also available certainly more highly purified raw material such as pharmaceutical grade, analytical pure be better effects if then, specifically selects for use grades of raw materials to take all factors into consideration according to cost.
Embodiment one preparation D-3-bromo-2-methyl propionyl-L-proline(Pro) (I)
57.5g (0.5mol) L-proline(Pro) is dissolved in the 200ml water, is cooled to-5 ℃-0 ℃, under agitation condition, drip 20%NaOH solution and regulate pH=8.0-9.0; Drip 3-bromo-2-methyl-prop acyl chlorides (IX) 92.7g (0.5mol) then, in the dropping process, constantly add NaOH solution control pH and remain on 8.0-9.0, after dropwising; Under this temperature, stirred 0.5 hour, reaction solution divides and goes ethyl acetate layer, the aqueous solution to change in the there-necked flask with 200ml ETHYLE ACETATE washing 3 times; Be acidified to pH=2.0 with concentrated hydrochloric acid, react after 0.5 hour, standing demix separates the oil reservoir that obtains lower floor; Lower the temperature in 0 ℃ to-5 ℃ crystallization 3-5 hour, left standstill 10 hours in-10 ℃ again, filter; Use the cold water washing crystallization, 55 ℃ of dryings in the decompression baking oven promptly get D-3-bromo-2-methyl propionyl-L-proline(Pro) (I) 52.8g again; Yield 40%, fusing point: 72-74 ℃, [α]
D 20=-89 ° of (c=1; Absolute ethyl alcohol).
Claims (6)
1.D-3-the preparation method of bromo-2-methyl propionyl-L-proline(Pro) is characterized in that: in water or ethanol, acetone, tetrahydrofuran solvent, adopt mineral alkali or organic bases to make condensing agent 3-bromo-2-methyl-prop acyl chlorides and L-proline(Pro); In-5 ℃-20 ℃, reaction is 0.5-5 hour under the condition of pH=7.0-9.0, after reaction solution washs with ETHYLE ACETATE; Acidified aqueous solution is to pH=1.0-2.0, stir lower the temperature in 0 ℃ to-5 ℃ crystallization 3-5 hour, left standstill 10 hours in-10 ℃ again; Filter; Washing, the dry D-3-bromo-2-methyl propionyl-L-proline(Pro) that gets, its structural formula is following:
2. the preparation method of D-3-bromo-2-methyl propionyl according to claim 1-L-proline(Pro) is characterized in that concrete operation steps is following:
1. be raw material with 3-bromo-2-methyl-prop acyl chlorides (IX) and L-proline(Pro); With alkali is condensing agent; Regulate and control pH=7.0-9.0; In-5 ℃-20 ℃ reactions 0.5-5 hour, promptly make the solution of 3-bromo-2-methyl propionyl-L-proline(Pro) (X), its 3-bromo-2-methyl propionyl-L-proline(Pro) (X) is D type and two kinds of non-corresponding mixture of isomers of L type of 3-bromo-2-methyl propionyl-L-proline(Pro);
2. 3-bromo-2-methyl propionyl-L-proline(Pro) (X) solution that 1. step is made washs 3 times with ETHYLE ACETATE, divides and removes ethyl acetate layer, keeps the gained water layer;
3. with the 2. water layer of gained of step, be acidified to pH=1.0-2.0, separate out and contain the 3-bromo-2-methyl propionyl-D type of L-proline(Pro) and the oil reservoir of two kinds of non-corresponding isomer of L type, separate the oil reservoir of separating out and keep;
4. lower the temperature under stirring in 0 ℃ to-5 ℃ crystallization 3-5 hour, left standstill 10 hours in-10 ℃ again;
5. the cold water washing crystallization is used in filtering separation crystallization, again in 55 ℃ of drying under reduced pressure crystallizations, promptly gets D-3-bromo-2-methyl propionyl of the present invention-L-proline(Pro).
3. the preparation method of D-3-bromo-2-methyl propionyl according to claim 2-L-proline(Pro) is characterized in that: the reaction solvent that 1. said step is used is organic solvents such as water or ethanol, acetone, THF; Employed alkali is mineral alkali or organic bases, and mineral alkali wherein is sodium hydroxide or Pottasium Hydroxide, and organic bases wherein is pyridine or triethylamine.
4. the preparation method of D-3-bromo-2-methyl propionyl according to claim 2-L-proline(Pro); It is characterized in that; 2. said step is 3-bromo-2-methyl propionyl-L-proline(Pro) (X) solution that earlier 1. step is made, with the ETHYLE ACETATE washing and remove the ester layer that contains impurity, because through the washing of ETHYLE ACETATE; The impurity that partly dissolves in ETHYLE ACETATE in 3-bromo-2-methyl propionyl-L-proline(Pro) (X) solution that 1. step makes is removed, and is more conducive to improve the yield and the purity of product.
5. the preparation method of D-3-bromo-2-methyl propionyl according to claim 2-L-proline(Pro); It is characterized in that: the acid that 3. said step is used is hydrochloric acid or sulfuric acid; Adjustment pH value is 1.0-2.0; Separate out and contain the 3-bromo-2-methyl propionyl-D type of L-proline(Pro) and the oil reservoir of two kinds of non-corresponding isomer of L type, separate the oil reservoir and the reservation of separating out.
6. the preparation method of D-3-bromo-2-methyl propionyl according to claim 2-L-proline(Pro) is characterized in that: said step 4. be lower the temperature under stirring in 0 ℃ to-5 ℃ crystallization 3-5 hour, left standstill 10 hours in-10 ℃ again.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4332725A (en) * | 1979-12-29 | 1982-06-01 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of 1-[3-mercapto-(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid |
| CN1051909A (en) * | 1989-11-24 | 1991-06-05 | 国家医药管理局上海医药工业研究院 | The process modification of captopril |
| CN101289417A (en) * | 2008-06-05 | 2008-10-22 | 常州制药厂有限公司 | Process for preparing D-3-thioacetyl-2-methylpropionyl-L-proline |
-
2010
- 2010-10-16 CN CN2010105143018A patent/CN102452970A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4332725A (en) * | 1979-12-29 | 1982-06-01 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of 1-[3-mercapto-(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid |
| CN1051909A (en) * | 1989-11-24 | 1991-06-05 | 国家医药管理局上海医药工业研究院 | The process modification of captopril |
| CN101289417A (en) * | 2008-06-05 | 2008-10-22 | 常州制药厂有限公司 | Process for preparing D-3-thioacetyl-2-methylpropionyl-L-proline |
Non-Patent Citations (2)
| Title |
|---|
| NAM DH ET AL: "An improved synthesis of captopril", 《J. PHARM. SCI.》 * |
| 刘仁涌等: "卡托普利合成方法的改进", 《沈阳药科大学学报》 * |
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Application publication date: 20120516 |