CN103755721A - Purification method of (S)-clopidogrel - Google Patents
Purification method of (S)-clopidogrel Download PDFInfo
- Publication number
- CN103755721A CN103755721A CN201410004196.1A CN201410004196A CN103755721A CN 103755721 A CN103755721 A CN 103755721A CN 201410004196 A CN201410004196 A CN 201410004196A CN 103755721 A CN103755721 A CN 103755721A
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- Prior art keywords
- clopidogrel
- filter cake
- ethyl acetate
- water
- added
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention belongs to the field of medicinal chemistry and discloses a purification method of (S)-clopidogrel. The method comprises the following steps: dissolving a crude (S)-clopidogrel product in an aprotic solvent; dropwise adding an organic acid with a certain molar ratio; stirring and separating out crystals; filtering; performing vacuum drying on a filter cake; adding the aprotic solvent; pulping at a certain temperature; performing suction filtration; adding the filter cake into a ethyl acetate/water or methylene dichloride/ water two-phase solvent; regulating pH value to 7 to 8 under a stirring condition; separating an organic phase; and drying and concentrating, thereby obtaining the (S)-clopidogrel with a high purity (higher than or equal to 99.5%). The method is simple to operate, moderate in condition and high in (S)-clopidogrel purity.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of purification process of (S)-clopidogrel.
Background technology
(S)-clopidogrel chemistry is by name: (+)-(S)-α-(2-chloro-phenyl-)-6, and 7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-methyl acetate also, pharmaceutically with hydrosulfate form, uses, and its structure is as follows:
At present, the synthetic existing patent report (WO03004502/US5132435) of clopidogrel, produces but technique products obtained therefrom after reappearing all can not be directly used in preparation because purity is not enough.
Summary of the invention
In order to solve the problem of document technique gained (S)-clopidogrel purity deficiency, the invention provides a kind of new (S)-clopidogrel purification process, the method is simple to operate, mild condition, product purity high (>=99.5%), can reach preparation and use standard.
The inventive method comprises the following steps:
(S)-clopidogrel crude product is dissolved in non-protonic solvent, drip the organic acid of mol ratio 1:1.05 ~ 1.2, stirring and crystallizing 3-5h, filters, after filter cake vacuum-drying, be added to non-protonic solvent, 10-30 ℃ of making beating 3-4h, suction filtration, filter cake is added in the two-phase solvent of ethyl acetate/water or methylene dichloride/water, stir, regulate pH to 7-8, separated organic phase, treatedly obtain highly purified (S)-clopidogrel.
Wherein said non-protonic solvent is selected from: acetone, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, preferred acetone, ethyl acetate.
Wherein said organic acid is selected from acetic acid, phenylformic acid or toxilic acid, preferably acetic acid.
Embodiment
Embodiment 1:160g(S)-clopidogrel crude product and 1600mL acetone are added in 3L there-necked flask, and stirring and dissolving drips 32.5g acetic acid, and stirring and crystallizing 4h filters filter cake washing with acetone, 45 ℃ of vacuum-dryings, dried filter cake and 1800mL methylene dichloride are added in 3L there-necked flask, at 10-30 ℃, stir 4h, filter, filter cake eluent methylene chloride, filter cake and 1200mL methylene dichloride, 1200mL water is added in 5L there-necked flask, with 10% sodium bicarbonate, regulate pH to 7-8, separatory, twice of dichloromethane extraction of water, each 400mL, merge organic phase, wash with water twice, each 1200mL, organic phase stirs dry 5h by 200g anhydrous sodium sulphate, concentrating under reduced pressure is removed methylene dichloride, obtain light yellow oily liquid (S)-clopidogrel 132.4g, yield 82.7%, purity 99.6%.
Embodiment 2:160g(S)-clopidogrel crude product and 1600mL ethyl acetate are added in 3L there-necked flask, and stirring and dissolving drips 67.4g phenylformic acid, and stirring and crystallizing 4h filters, and filter cake washs by ethyl acetate, 45 ℃ of vacuum-dryings, dried filter cake and 1800mL tetrahydrofuran (THF) are added in 3L there-necked flask, at 10-30 ℃, stir 4h, filter, filter cake tetrahydrofuran (THF) drip washing, filter cake and 1200mL ethyl acetate, 1200mL water is added in 5L there-necked flask, with 10% sodium bicarbonate, regulate pH to 7-8, separatory, water is extracted with ethyl acetate twice, each 400mL, merge organic phase, wash with water twice, each 1200mL, organic phase stirs dry 5h by 200g anhydrous sodium sulphate, concentrating under reduced pressure is removed ethyl acetate, obtain light yellow oily liquid (S)-clopidogrel 128.4g, yield 80.2%, purity 99.5%.
Embodiment 3:160g(S)-clopidogrel crude product and 1600mL methylene dichloride are added in 3L there-necked flask, and stirring and dissolving drips 63.1g toxilic acid, and stirring and crystallizing 4h filters filter cake washed with dichloromethane, 45 ℃ of vacuum-dryings; Dried filter cake and 1800mL acetone are added in 3L there-necked flask, at 10-30 ℃, stir 4h, filter, filter cake acetone drip washing, filter cake and 1200mL methylene dichloride, 1200mL water are added in 5L there-necked flask, with 10% sodium bicarbonate, regulate pH to 7-8, separatory, water is got twice with methylene dichloride, each 400mL, merges organic phase, washes with water twice, each 1200mL, organic phase stirs dry 5h by 200g anhydrous sodium sulphate, and concentrating under reduced pressure is removed methylene dichloride, obtains light yellow oily liquid (S)-clopidogrel 125.8g, yield 78.6%, purity 99.6%.
Embodiment 4:160g(S)-clopidogrel crude product and 1600mL ethyl acetate are added in 3L there-necked flask, and stirring and dissolving drips 32.5g acetic acid, and stirring and crystallizing 4h filters, and filter cake washs by ethyl acetate, 45 ℃ of vacuum-dryings; Dried filter cake and 1800mL acetone are added in 3L there-necked flask, at 10-30 ℃, stir 4h, filter, filter cake acetone drip washing, filter cake and 1200mL ethyl acetate, 1200mL water are added in 5L there-necked flask, with 10% sodium bicarbonate, regulate pH to 7-8, separatory, water is got twice by ethyl acetate, each 400mL, merges organic phase, washes with water twice, each 1200mL, organic phase stirs dry 5h by 200g anhydrous sodium sulphate, and concentrating under reduced pressure is removed ethyl acetate, obtains light yellow oily liquid (S)-clopidogrel 137.4g, yield 85.9%, purity 99.8%.
?
Embodiment 5:160g(S)-clopidogrel crude product and 1600mL methylene dichloride are added in 3L there-necked flask, and stirring and dissolving drips 32.5g acetic acid, and stirring and crystallizing 4h filters filter cake washed with dichloromethane, 45 ℃ of vacuum-dryings, dried filter cake and 1800mL methylene dichloride are added in 3L there-necked flask, at 10-30 ℃, stir 4h, filter, filter cake eluent methylene chloride, filter cake and 1200mL ethyl acetate, 1200mL water is added in 5L there-necked flask, with 10% sodium bicarbonate, regulate pH to 7-8, separatory, water is got twice by ethyl acetate, each 400mL, merge organic phase, wash with water twice, each 1200mL, organic phase stirs dry 5h by 200g anhydrous sodium sulphate, concentrating under reduced pressure is removed ethyl acetate, obtain light yellow oily liquid (S)-clopidogrel 135.4g, yield 84.6%, purity 99.5%.
Embodiment 6:160g(S)-clopidogrel crude product and 1600mL acetone are added in 3L there-necked flask, and stirring and dissolving drips 67.4g phenylformic acid, and stirring and crystallizing 4h filters filter cake washing with acetone, 45 ℃ of vacuum-dryings, dried filter cake and 1800mL tetrahydrofuran (THF) are added in 3L there-necked flask, at 10-30 ℃, stir 4h, filter, filter cake tetrahydrofuran (THF) drip washing, filter cake and 1200mL ethyl acetate, 1200mL water is added in 5L there-necked flask, with 10% sodium bicarbonate, regulate pH to 7-8, separatory, water is got twice by ethyl acetate, each 400mL, merge organic phase, wash with water twice, each 1200mL, organic phase stirs dry 5h by 200g anhydrous sodium sulphate, concentrating under reduced pressure is removed ethyl acetate, obtain light yellow oily liquid (S)-clopidogrel 130.8g, yield 81.7%, purity 99.6%.
Claims (5)
1. the purification process of a (S)-clopidogrel, detailed process is: (S)-clopidogrel crude product is dissolved in non-protonic solvent, drip the organic acid of mol ratio 1:1.05 ~ 1.2, stirring and crystallizing 3-5h, filter, after filter cake vacuum-drying, be added to non-protonic solvent, 10-30 ℃ of making beating 3-4h, suction filtration, filter cake is added in the two-phase solvent of ethyl acetate/water or methylene dichloride/water, stirs, regulate pH to 7-8, separated organic phase, drying, obtains the (S)-clopidogrel of high purity (>=99.5%) after concentrated.
2. purification process as claimed in claim 1, described non-protonic solvent is selected from: acetone, tetrahydrofuran (THF), ethyl acetate, methylene dichloride.
3. purification process as claimed in claim 1, described non-protonic solvent is acetone, ethyl acetate.
4. purification process as claimed in claim 1, described organic acid is selected from acetic acid, phenylformic acid or toxilic acid.
5. purification process as claimed in claim 1, the preferred acetic acid of described organic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410004196.1A CN103755721A (en) | 2014-01-06 | 2014-01-06 | Purification method of (S)-clopidogrel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410004196.1A CN103755721A (en) | 2014-01-06 | 2014-01-06 | Purification method of (S)-clopidogrel |
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| CN103755721A true CN103755721A (en) | 2014-04-30 |
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| CN201410004196.1A Pending CN103755721A (en) | 2014-01-06 | 2014-01-06 | Purification method of (S)-clopidogrel |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059696A1 (en) * | 2003-05-08 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the recovery of S -(+)-methyl- (2-chlorophenyl)- (6,7-dihydro- 4H-thieno [3,2-c] pyrid-5-yl) acetate hydrogen sulfate (clopidogrel bisulfate) from its (R) and mixture of (R) and (S)- isomers |
| WO2008062421A1 (en) * | 2006-11-24 | 2008-05-29 | Cadila Healthcare Limited | A process for preparing (s)-(+)-clopidogrel base and its salts |
| EP1980563A1 (en) * | 2007-04-09 | 2008-10-15 | BATTULA, Srinivasa Reddy | Procedure for the preparation of methyl (+)-(S)-Alpha-(O-chlorophenyl)-6,7-dihydrothieno-[3,2-C]pyridine-5(4H) acetate |
| CN101845050A (en) * | 2010-06-01 | 2010-09-29 | 上虞京新药业有限公司 | Method for preparing clopidogrel |
| CN103044444A (en) * | 2013-01-21 | 2013-04-17 | 上海现代哈森（商丘）药业有限公司 | Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate |
-
2014
- 2014-01-06 CN CN201410004196.1A patent/CN103755721A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059696A1 (en) * | 2003-05-08 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the recovery of S -(+)-methyl- (2-chlorophenyl)- (6,7-dihydro- 4H-thieno [3,2-c] pyrid-5-yl) acetate hydrogen sulfate (clopidogrel bisulfate) from its (R) and mixture of (R) and (S)- isomers |
| WO2008062421A1 (en) * | 2006-11-24 | 2008-05-29 | Cadila Healthcare Limited | A process for preparing (s)-(+)-clopidogrel base and its salts |
| EP1980563A1 (en) * | 2007-04-09 | 2008-10-15 | BATTULA, Srinivasa Reddy | Procedure for the preparation of methyl (+)-(S)-Alpha-(O-chlorophenyl)-6,7-dihydrothieno-[3,2-C]pyridine-5(4H) acetate |
| CN101845050A (en) * | 2010-06-01 | 2010-09-29 | 上虞京新药业有限公司 | Method for preparing clopidogrel |
| CN103044444A (en) * | 2013-01-21 | 2013-04-17 | 上海现代哈森（商丘）药业有限公司 | Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate |
Non-Patent Citations (1)
| Title |
|---|
| 安德森: "《实用有机合成工艺研发手册》", 31 January 2011 * |
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Application publication date: 20140430 |