CN103172527A - Method for preparing clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester - Google Patents
Method for preparing clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester Download PDFInfo
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- CN103172527A CN103172527A CN2011104443804A CN201110444380A CN103172527A CN 103172527 A CN103172527 A CN 103172527A CN 2011104443804 A CN2011104443804 A CN 2011104443804A CN 201110444380 A CN201110444380 A CN 201110444380A CN 103172527 A CN103172527 A CN 103172527A
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- methyl ester
- chlorophenylglycine
- phenyl glycine
- clopidogrel
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Abstract
The invention provides a method for preparing a clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester. The method comprises the following steps of: (1) generate ortho-chlorophenylglycine by utilizing o-chlorobenzaldehyde and chloroform under the action of a phase transfer catalyst and ammonia water; and (2) enabling the ortho-chlorophenylglycine to react in thionyl chloride and methanol so as to obtain ortho-chlorophenylglycine methyl ester. Compared with the prior art, the method can be used for synthesizing the ortho-chlorophenylglycine through one step, so that the total yield is increased, and the synthesizing cost of clopidogrel is lowered; and moreover, toxic sodium cyanide is prevented from being used, so that the safety problem and environmental pollution problem of an original production way can also be avoided, and considerable social benefit and economic benefit can be generated.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, relate in particular to a kind of method for preparing clopidogrel synthetic intermediate-O-chlorobenzene glycine methyl ester.
Background technology
The cardiovascular and cerebrovascular thrombotic diseases is the common disease of China.Clopidogrel is the acetogenin of ticlopidine, have the advantages such as curative effect is strong, expense is low, side effect is little, be mainly used in treating restenosis and thrombotic complications etc. in arteriosclerosis disease, acute coronary artery syndrome, prevention coronary stenting after poppet.Clopidogrel and acetylsalicylic acid coupling become the standard of antithrombotic therapy in cardiovascular and cerebrovascular disease just gradually.
Clopidogrel (clopidogrel) is that French Sano-Synth labo drugmaker is in the anticoagulant of a new generation of research and development in 1986, chemical name is (S)-α-(2-chloro-phenyl-)-6,7-dichloro-thiophene also [3,2-c] pyridine-5 (4H)-methyl acetate, clinical its vitriol of using, be Clopidogrel Hydrogensulfate, commodity are called Plavix (Plavix).
Clopidogrel Hydrogensulfate suppresses platelet activation by suppressing the ADP approach, thereby anticoagulant is mainly used to prevent and treat the generation of the acute ischemia events such as preventing brain stroke, myocardial infarction.This product took the lead in entering subsequently the multinational markets such as Europe, North America, Australia, Singapore in U.S. listing in March, 1998, and August calendar year 2001 at Discussion on Chinese Listed.In it entered time more than ten years after clinical, it was the situation of selling well medicine of marketable value rank top ten always.
Clopidogrel Hydrogensulfate is the vitriol of clopidogrel, and chemical name is (S)-α-(2-chloro-phenyl-)-6, and the 7-dichloro-thiophene is [3,2-c] pyridine-5 (4H)-methyl acetate vitriol also, and its structural formula is as follows:
The synthetic route of prior art clopidogrel sulfate is as follows
[1]:
This synthesis path begins to synthesize from racemization Chloro-O-Phenyl glycine methyl ester, so the Chloro-O-Phenyl glycine methyl ester is the important intermediate of clopidogrel.Existing Chloro-O-Phenyl glycine methyl ester synthetic method is amino acid whose classical synthetic method, and is as follows
[2,3]:
Synthetic route one:
Synthetic route two:
Existing Chloro-O-Phenyl glycine methyl ester synthetic method is begun by o-chlorobenzaldehyde, by carrying out nucleophilic addition(Adn) with sodium cyanide, then obtains the Chloro-O-Phenyl glycine through hydrolysis, then obtains target product through esterification.These two synthesis paths all can be used sodium cyanide, because sodium cyanide has severe toxicity, cause activity in production dangerous, and can very large pollution be arranged to environment; Need to just can obtain the Chloro-O-Phenyl glycine by three-step reaction, cause the route of synthesis technique long, energy consumption is large.
Summary of the invention
The invention provides a kind of method for preparing clopidogrel synthetic intermediate-O-chlorobenzene glycine methyl ester, can avoid using the sodium cyanide of severe toxicity, reduced simultaneously single step reaction, simplified synthesis step, improved productive rate.
A kind of method for preparing clopidogrel synthetic intermediate-O-chlorobenzene glycine methyl ester comprises the steps:
(1) o-chlorobenzaldehyde and chloroform generate the Chloro-O-Phenyl glycine under the effect of phase-transfer catalyst and ammoniacal liquor;
(2) the Chloro-O-Phenyl glycine reacts in thionyl chloride and methyl alcohol, obtains the Chloro-O-Phenyl glycine methyl ester.
Wherein, phase-transfer catalyst used is quaternary ammonium salt or quaternary alkylphosphonium salt in the process of step (1) generation Chloro-O-Phenyl glycine.
Wherein, the ammoniacal liquor that adds in the process of step (1) generation Chloro-O-Phenyl glycine is as ammoniation agent.
Wherein, also add mineral alkali in step (1) generates the process of Chloro-O-Phenyl glycine, be used for and amino acid in carboxyl, in order to avoid salify.
Wherein, described mineral alkali is NaOH, KOH or NaCO
3
The present invention compared with prior art, the synthesis step of Chloro-O-Phenyl glycine is reduced by a step, improved overall yield, reduce the synthetic cost of clopidogrel, simultaneously due to the sodium cyanide of avoiding using severe toxicity, also can avoid safety problem and the problem of environmental pollution of original production line, can produce suitable Social benefit and economic benefit.
Embodiment
The invention will be further described below by specific embodiment:
Embodiment 1
Synthetic route is as follows:
1, in the 250ml there-necked flask, add 6gNaOH (0.15mol), the 20ml strong aqua, and connect mechanical stirrer and ventpipe, stirring and dissolving NaOH under ice bath, the dichloromethane solution 50ml that adds freezing in advance 1.1g (0.005mol) triethyl benzyl benzene ammonium chloride (TEBA), and add freezing 7g (0.05mol) o-chlorobenzaldehyde and 6ml chloroform (approximately 0.07mol), control temperature under-5 ℃～0 ℃, vigorous stirring, and monitor to raw material point with thin-layer chromatography and disappear.Divide water-yielding stratum, use methylene dichloride 20ml * 3 extractions, then concentrated organic phase regulates pH to iso-electric point with concentrated hydrochloric acid, and slightly product is separated out, water-ethyl alcohol recrystallization, and dry sterling (Chloro-O-Phenyl glycine) 5.4g that gets, productive rate is 58%.Wherein triethyl benzyl benzene ammonium chloride is a kind of of quaternary ammonium salt, use as phase-transfer catalyst (Phase Transfer Catalyst, PTC) in the present embodiment,
2, in the 250ml there-necked flask, add 50ml methyl alcohol, 9.3g Chloro-O-Phenyl glycine (0.05mol) adds SOCl in ice bath
2(thionyl chloride) liquid 0.2mol dropwises the recession deicing and bathes, and then is warming up to 65 degree, stirring reaction 6 hours.Thionyl chloride and methyl alcohol are taken out in decompression, have solid to condense, and are Chloro-O-Phenyl glycine methyl ester crude product.Rear with methyl alcohol-ether recrystallization, the dry sterling 9.4g that gets, productive rate is 85%.
Embodiment 2
Synthetic route is the same.
1, in the 250ml there-necked flask, add 4gNaOH (0.10mol), the 15ml strong aqua, and connect mechanical stirrer and ventpipe, stirring and dissolving NaOH under ice bath, the dichloromethane solution 40ml that adds freezing in advance 1.2g (0.002mol) hexadecyl tri-phenyl-phosphorus bromide, and add freezing 4.2g (0.03mol) o-chlorobenzaldehyde and 3.5ml chloroform (approximately 0.042mol), control temperature under-5 ℃～0 ℃, vigorous stirring, and monitor to raw material point with thin-layer chromatography and disappear.Divide water-yielding stratum, with methylene dichloride 20ml * 3 extractions (minute three extractions), concentrate organic phase, then regulate pH to iso-electric point with concentrated hydrochloric acid, thick product is separated out, water-ethyl alcohol recrystallization, dry sterling (Chloro-O-Phenyl glycine) 2.6g that gets, productive rate is 46%.Wherein the hexadecyl tri-phenyl-phosphorus bromide is a kind of of quaternary alkylphosphonium salt, use as phase-transfer catalyst (Phase Transfer Catalyst, PTC) in the present embodiment,
2, in the 250ml there-necked flask, add 90ml methyl alcohol, 18g Chloro-O-Phenyl glycine (0.1mol) adds SOCl in ice bath
2(thionyl chloride) liquid 0.3mol dropwises the recession deicing and bathes, and then is warming up to 65 degree, stirring reaction 6 hours.Thionyl chloride and methyl alcohol are taken out in decompression, have solid to condense, and are Chloro-O-Phenyl glycine methyl ester crude product.Rear with methyl alcohol-ether recrystallization, the dry Chloro-O-Phenyl glycine methyl ester sterling 18.7g that gets, productive rate is 85%.
The above; be only the specific embodiment of the present invention, but protection scope of the present invention is not limited to this, anyly belongs to those skilled in the art in the technical scope that the present invention discloses; the variation that can expect easily or replacement are within all should being encompassed in protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain of claim.
Claims (5)
1. a method for preparing clopidogrel synthetic intermediate-O-chlorobenzene glycine methyl ester, is characterized in that comprising the steps:
(1) o-chlorobenzaldehyde and chloroform generate the Chloro-O-Phenyl glycine under the effect of phase-transfer catalyst and ammoniacal liquor;
(2) the Chloro-O-Phenyl glycine reacts in thionyl chloride and methyl alcohol, obtains the Chloro-O-Phenyl glycine methyl ester.
2. the method for claim 1 is characterized in that: generate in step (1) that in the process of Chloro-O-Phenyl glycine, phase-transfer catalyst used is quaternary ammonium salt or quaternary alkylphosphonium salt.
3. the method for claim 1 is characterized in that: generate the ammoniacal liquor that adds in the process of Chloro-O-Phenyl glycine as ammoniation agent in step (1).
4. the method for claim 1, is characterized in that: also add mineral alkali in the process of step (1) generation Chloro-O-Phenyl glycine.
5. method as claimed in claim 4, it is characterized in that: described mineral alkali is NaOH, KOH or NaCO
3
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174841A (en) * | 2020-11-09 | 2021-01-05 | 唐山晋广化工有限公司 | Production method of p-chlorophenylglycine |
| CN115784914A (en) * | 2022-12-20 | 2023-03-14 | 石家庄中硕科技有限公司 | Preparation method of o-chlorophenylglycine |
Citations (5)
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| US5204469A (en) * | 1990-07-10 | 1993-04-20 | Sanofi | Process for the preparation of an n-phenylacetic derivative of tetrahydrothieno(3,2-c)pyridine and its chemical intermediate |
| US6080875A (en) * | 1997-03-05 | 2000-06-27 | Sanofi-Synthelabo | Method for preparing 2-thienylethylamine derivatives |
| US20040176637A1 (en) * | 2003-03-03 | 2004-09-09 | Robert C. C. Wu | Process for preparation of 2-chlorophenylglycine derivatives and enantiomerically separation |
| CN101519401A (en) * | 2008-02-27 | 2009-09-02 | 上海华理生物医药有限公司 | Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof |
| CN101864464A (en) * | 2010-04-29 | 2010-10-20 | 重庆凯乐尔生物催化技术有限公司 | Chemical-enzyme method for preparing (S)-2-chlorophenyl glycine methyl ester clopidogrel chiral intermediate |
-
2011
- 2011-12-26 CN CN2011104443804A patent/CN103172527A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5204469A (en) * | 1990-07-10 | 1993-04-20 | Sanofi | Process for the preparation of an n-phenylacetic derivative of tetrahydrothieno(3,2-c)pyridine and its chemical intermediate |
| US6080875A (en) * | 1997-03-05 | 2000-06-27 | Sanofi-Synthelabo | Method for preparing 2-thienylethylamine derivatives |
| US20040176637A1 (en) * | 2003-03-03 | 2004-09-09 | Robert C. C. Wu | Process for preparation of 2-chlorophenylglycine derivatives and enantiomerically separation |
| CN101519401A (en) * | 2008-02-27 | 2009-09-02 | 上海华理生物医药有限公司 | Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof |
| CN101864464A (en) * | 2010-04-29 | 2010-10-20 | 重庆凯乐尔生物催化技术有限公司 | Chemical-enzyme method for preparing (S)-2-chlorophenyl glycine methyl ester clopidogrel chiral intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 杨光: "不对称相转移催化合成光活性α-氨基酸", 《化学试剂》, vol. 24, no. 2, 31 December 2002 (2002-12-31), pages 136 - 138 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174841A (en) * | 2020-11-09 | 2021-01-05 | 唐山晋广化工有限公司 | Production method of p-chlorophenylglycine |
| CN112174841B (en) * | 2020-11-09 | 2023-02-17 | 唐山晋广化工有限公司 | Production method of p-chlorophenylglycine |
| CN115784914A (en) * | 2022-12-20 | 2023-03-14 | 石家庄中硕科技有限公司 | Preparation method of o-chlorophenylglycine |
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Application publication date: 20130626 |