CN101519401A - Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof - Google Patents
Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof Download PDFInfo
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- CN101519401A CN101519401A CN 200810033932 CN200810033932A CN101519401A CN 101519401 A CN101519401 A CN 101519401A CN 200810033932 CN200810033932 CN 200810033932 CN 200810033932 A CN200810033932 A CN 200810033932A CN 101519401 A CN101519401 A CN 101519401A
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Abstract
The invention relates to an intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and the preparation of salts thereof. The invention improves the existing technology of preparing the intermediate and the salts thereof, and adopts (S)-(+)-chlorophenylglycine methyl ester L-tartrate as raw materials which directly react with p-substituted thiofuran benzenesulphonate-2-ethyl esters compounds for preparing the intermediate. Compared with the prior art, the improved method has the advantages that the raw materials and reagents are cheap and easily available, the production yield is high, the optical purity of the product is high, the technological operation is simple, and the like, thus being a method for commercially producing the intermediate of clopidogrel and salts thereof.
Description
Technical field
The present invention relates to the preparation of clopidogrel intermediate (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof.
Background technology
Clopidogrel (Clopidogrel), chemistry (S)-α by name-(2-chloro-phenyl-)-6,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-methyl acetate, be anticoagulant of new generation, be mainly used in treatment arteriosclerosis disease, acute coronary syndrome, prevention intracoronary stent and plant people's postoperative in-stent restenosis and thrombotic complications etc.
Up to now, the relevant method for preparing clopidogrel has a lot, and intermediate (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof are its important intermediates, and the method for synthetic this intermediate of report mainly contains following several: patent (EP.Pat.No.466569 US.Pat.No.5204469) adopts following route:
With o-chlorobenzaldehyde and sodium cyanide and azanol reaction generation alpha-amino group (2-chlorine) toluylic acid, with tosic acid thiophene-2-ethyl ester reaction, split then after the esterification, make this intermediate.Use this route, it is very difficult to obtain single enantiomer, because the easy racemization of this intermediate; And, long reaction time (40h), yield also low (50%).
Patent (US.Pat.No.6080875) report:
Split alpha-amino group (2-chlorine) methyl phenylacetate earlier, under the catalysis of acetate, react this intermediate of generation with thiophene-2-glycidic acid sodium and cyaniding sodium borohydride then.Though it is higher that this route respectively goes on foot yield, agents useful for same cyaniding sodium borohydride is not easy to obtain, and raw material thiophene-2-glycidic acid sodium is difficult to preparation, cost height.
Patent (US.Pat.No.4529596 US.Pat.No.4847265) report:
With (S)-(+)-O-chlorobenzene glycine methyl ester, prepare this intermediate with tosic acid thiophene-2-ethyl ester, because (S)-(+)-O-chlorobenzene glycine methyl ester racemization in reaction easily, so the optical purity of product is difficult to be protected, specific rotation is low, is difficult to prepare qualified clopidogrel.
In sum, now general synthetic this intermediate all is to react with (S)-(+)-O-chlorobenzene glycine methyl ester, but its easy racemization, influences the optical purity of product, and this patent provides a kind of new method to prepare this intermediate and salt thereof.
Summary of the invention
The objective of the invention is to, the synthetic method of a kind of improved clopidogrel intermediate (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof is provided.
The present invention has done improvement to the preparation of (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof.
With (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound prepared in reaction (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof, its key step is: with (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate is starting raw material, without the monomer that dissociates (S)-(+)-O-chlorobenzene glycine methyl ester, but directly and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound under alkaline condition, carry out condensation reaction; Products therefrom is through the acidifying salify, and reaction equation is as follows:
(S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof synthetic
Said condensation reaction is performed such:
(S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound are placed there-necked flask, do not add or add a spot of solvent, in 20-150 ℃ (preferred 75-110 ℃), reaction 1-24hr (preferred 5-20hr) obtains this intermediate;
Wherein said solvent is water, methyl alcohol, ethanol, acetonitrile, DMF; Used alkali is that the oxyhydroxide of basic metal or alkaline-earth metal and ammonium class is (as KOH, NaOH, Ba (OH)
2Or Ca (OH)
2), or the carbonate of basic metal or alkaline-earth metal and ammonium class is (as Na
2CO
3, K
2CO
3, NaHCO
3, KHCO
3, (NH
4)
2CO
3, (NH
4) HCO
3); Or alkali is that the phosphoric acid salt of basic metal or alkaline-earth metal and ammonium class is (as Na
3PO
4, Na
2HPO
4, NaH
2PO
4, K
3PO
4, K
2HPO
4, KH
2PO
4, (NH
4)
2HPO
4, (NH
4) H
2PO
4), or alkali is the phosphite such as the Na of basic metal or alkaline-earth metal and ammonium class
3PO
3, Na
2HPO
3, NaH
2PO
3, K
3PO
3, K
2HPO
3, KH
2PO
3, (NH
4)
2HPO
3, (NH
4) H
2PO
3), (S)-(+)-mol ratio (1) of O-chlorobenzene glycine methyl ester L-tartrate, para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound, alkali: (1.1-1.8): (1.2-6.0), (preferred molar ratio (1): (1.3-1.6): (1.6-5.6)).
Said salt-forming reaction is performed such:
In above-mentioned condensation reaction thing, add entry and ethyl acetate, separatory; In organic layer, drip acid solution, under insulation and agitation condition, the reaction times is 1-8hr (preferred 2-6hr), the after-filtration drying obtains this intermediate salt.
Wherein used acid is hydrochloric acid, sulfuric acid, formic acid, acetate (HCl, H
2SO
4, HCOOH, CH
3COOH).
The used starting raw material para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound of the present invention can be made by corresponding para-orientation benzene sulfonyl chloride compounds and thiophene ethanol.Concrete steps are referring to patent EP466569.
In preferred version of the present invention, in para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound-R is :-H ,-CH
3,-C
12H
25,-CH=CH
2,-NO
2,-Br ,-a kind of among the Cl, the best is-H ,-CH
3
About the report of clopidogrel,, find that the patent content relevant with the present invention is as follows: US.Pat.No.5204469, US.Pat No.20040073057, WO.Pat.No.2006/003671A1 both at home and abroad through self check and the retrieval of service center of patent office searching.
The present invention improves some principal reaction technologies in the prior art, has obtained good effect, and principal character is as follows:
1, in carrying out condensation reaction, existing processing condition (referring to patent EP466569), (S)-(+) after adopt splitting-O-chlorobenzene glycine methyl ester L-tartrate earlier with the alkali neutralization, boil off solvent through separatory, extraction, thin film evaporation and obtain (S)-(+)-O-chlorobenzene glycine methyl ester, condensation obtains this intermediate again, obtains its salt through acidifying.The present invention has adopted without neutralization, separatory, has extracted, revolved steaming, the free step that obtains (S)-(+)-O-chlorobenzene glycine methyl ester, but adopt (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate as raw material, direct and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound reacts, condensation obtains target product again, becomes its salt after the acidifying.
2, the present invention avoids free (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate to generate (S)-(+)-O-chlorobenzene glycine methyl ester, because (S)-(+)-and racemization and instability easily take place in O-chlorobenzene glycine methyl ester.Method of the present invention is simplified step of condensation, shortens the reaction times, thereby the product preparation cycle is shortened dramatically, and raises the efficiency.
Advantages such as in sum, technical scheme provided by the present invention has easy and simple to handle, and yield is higher, and the opticity maintenance is better are a kind of methods that is easy to commercialization preparation (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof.
Embodiment
Embodiment 1 with optically-active be 94 ° (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate (5.00g, 0.0143mol) and tosic acid thiophene-2-ethyl ester (5.00g 0.0177mol) places there-necked flask, adds K
2HPO
43H
2O (18.50g), 97-99 ℃ of reaction 12hr, reaction adds water (50ml), ethyl acetate (40ml) after finishing, stirring, separatory extract organic layer, and concentrated hydrochloric acid is regulated between the PH:1.2-1.5, the ice-water bath cold filtration, obtain the 4.08g product, mp:181.6-181.8 ℃, [α]
D 25=+109.4 ° of (c=1.O, CH
3OH); Yield: 82.5%.
1HNMR (D
2O, 500MHz), δ: 7.65～7.51 (m, 4H), 7.30 (t, J=3.5Hz, 1H), 6.98 (t, J=3.5Hz, 2H), 5.75 (s, 1H), 3.85 (s, 3H), 3.84～3.12 (m, and 4H) (literature value: mp:180-182 ℃, [α]
D 25=+108.5-110 °).
With above-mentioned products therefrom 4.00g, 8ml methyl alcohol, 26ml formaldehyde (37%), join in the there-necked flask that stirring, reflux are housed, react according to patent (US.Pat.No.4529596 US.Pat.No.4847265) processing step, obtain the 3.48g white solid, 181.7 ℃ of fusing points (incipient melting), HPLC:99.2%, yield 71.6%.I type SR-25990C for qualified meets standards of pharmacopoeia.
Embodiment 2 with optically-active be 94 ° (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate (5.00g, 0.0143mol) and tosic acid thiophene-2-ethyl ester (5.00g 0.0177mol) places there-necked flask, adds Na
2CO
3(3.70g), water (1ml), at 96-99 ℃ of reaction 11hr, after reaction finishes, add water (50ml), ethyl acetate (40ml), stirring, separatory extract organic layer, and concentrated hydrochloric acid is regulated between the PH:1.2-1.5, the ice-water bath cold filtration, obtain the 4.03g product, mp:180.0-180.2 ℃, [α]
D 25=+108.7 ° of (c=1.0, CH
3OH), yield: 81.5%.
Embodiment 3 with optically-active be 94 ° (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate (5.00g, 0.0143mol) and Phenylsulfonic acid thiophene-2-ethyl ester (5.00g 0.0177mol) places there-necked flask, adds Na
2HPO
412H
2O (13g), Na
2CO
3(2.60g), at 94-99 ℃ of reaction 13hr, after reaction finishes, add water (50ml), ethyl acetate (40ml), stir, separatory, extract organic layer, concentrated hydrochloric acid is regulated between the PH:1.2-1.5, the ice-water bath cold filtration, obtain the 4.00g product, mp:179.8-180.1 ℃, [α]
D 25=+107.5 ° of (c=1.0, CH
3OH), yield: 80.9%.
Adopt with the similar synthetic route of embodiment 1 to prepare (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof under different technology conditions, it the results are shown in Table 1:
Table 1
Claims (10)
1. the preparation method of a clopidogrel intermediate (S)-2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) methyl acetate and salt thereof: its key step is: with (S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate is starting raw material, without the monomer that dissociates (S)-(+)-O-chlorobenzene glycine methyl ester, but directly and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound under alkaline condition, carry out condensation reaction, products therefrom is salify after acidifying.
Said condensation reaction is performed such:
(S)-(+)-O-chlorobenzene glycine methyl ester L-tartrate and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound are placed there-necked flask, do not add or add a spot of solvent, in 20-150 ℃ (preferred 75-110 ℃), reaction 1-24hr (preferred 5-20hr) obtains this intermediate;
Wherein said solvent is water, methyl alcohol, ethanol, acetonitrile, DMF; Used alkali is that the oxyhydroxide of basic metal or alkaline-earth metal and ammonium class is (as KOH, NaOH, Ba (OH)
2Or Ca (OH)
2), or the carbonate of basic metal or alkaline-earth metal and ammonium class is (as Na
2CO
3, K
2CO
3, NaHCO
3, KHCO
3, (NH
4)
2CO
3, (NH
4) HCO
3); Or alkali is that the phosphoric acid salt of basic metal or alkaline-earth metal and ammonium class is (as Na
3PO
4, Na
2HPO
4, NaH
2PO
4, K
3PO
4, K
2HPO
4, KH
2PO
4, (NH
4)
2HPO
4, (NH
4) H
2PO
4), or alkali is the phosphite such as the Na of basic metal or alkaline-earth metal and ammonium class
3PO
3, Na
2HPO
3, NaH
2PO
3, K
3PO
3, K
2HPO
3, KH
2PO
3, (NH
4)
2HPO
3, (NH
4) H
2PO
3), (S)-(+)-mol ratio (1) of O-chlorobenzene glycine methyl ester L-tartrate, para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound, alkali: (1.1-1.8): (1.2-6.0), (preferred molar ratio (1): (1.3-1.6): (1.6-5.6)).
Said salt-forming reaction is performed such:
In above-mentioned condensation reaction thing, add entry and ethyl acetate, separatory in organic layer, drips acid solution, and under insulation and agitation condition, salt time is 1-8hr (preferred 2-6hr), and filtration drying obtains this intermediate salt.
Wherein used acid is hydrochloric acid, sulfuric acid, formic acid, acetate (HCl, H
2SO
4, HCOOH, CH
3COOH)
2. preparation method as claimed in claim 1, in preferred version of the present invention, the R group is-H ,-CH
3,-C
12H
25,-CH=CH
2,-NO
2,-Br ,-Cl.
3. preparation method as claimed in claim 2 is characterized in that, R be wherein-H ,-CH
3
4. as the described preparation method of claim 1-3, it is characterized in that the oxyhydroxide of its said basic metal or alkaline-earth metal, ammonium is KOH, NaOH, Ba (OH)
2, Ca (OH)
2, NH
4OH.
5. as any said preparation method among the claim 1-3, it is characterized in that the carbonate of wherein said basic metal or alkaline-earth metal, ammonium is Na
2CO
3, K
2CO
3, NaHCO
3, KHCO
3, (NH
4)
2CO
3, NH
4HCO
3
6. as any said preparation method among the claim 1-3, it is characterized in that the phosphoric acid salt of wherein said basic metal or alkaline-earth metal, ammonium is Na
3PO
4, K
3PO
4, Na
2HPO
4, NaH
2PO
4, K
2HPO
4, KH
2PO
4, (NH
4)
2HPO
4, NH
4H
2PO
4
7. as the described preparation method of claim 1-3, it is characterized in that the phosphite of its said basic metal or alkaline-earth metal, ammonium is K
2HPO
3, Na
2HPO
3, BaHPO
3, CaHPO
3, (NH
4)
2HPO
3
8. as any said preparation method among the claim 1-3, it is characterized in that wherein said solvent is water, methyl alcohol, ethanol, acetonitrile, DMF or anhydrous.
9. as any said preparation method among the claim 1-3, it is characterized in that the temperature of reaction of the sweet sour methyl esters L-tartrate of the adjacent chlorobenzene of S-(+) and para-orientation Phenylsulfonic acid thiophene-2-ethyl ester compound is 75～110 ℃.
The mol ratio (1) of (10.S-+) O-chlorobenzene glycine methyl ester L-tartrate, para-orientation Phenylsulfonic acid thiophene ethyl ester compound, alkali: (1.1-1.8): (1.2-6.0), (preferred molar ratio (1): (1.3-1.6): (1.6-5.6)).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172527A (en) * | 2011-12-26 | 2013-06-26 | 湖北德洲科技发展有限公司 | Method for preparing clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester |
| CN103980288A (en) * | 2014-06-03 | 2014-08-13 | 成都医路康医学技术服务有限公司 | Production process of clopidogrel |
| CN110862372A (en) * | 2019-12-03 | 2020-03-06 | 江西川奇药业有限公司 | Synthesis of clopidogrel intermediate (S) -2- (2-thiophene ethylamino) - (2-chlorphenyl) -methyl acetate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100491382C (en) * | 2006-10-18 | 2009-05-27 | 深圳信立泰药业股份有限公司 | Preparation process of clopidogre and its salt |
-
2008
- 2008-02-27 CN CN 200810033932 patent/CN101519401B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172527A (en) * | 2011-12-26 | 2013-06-26 | 湖北德洲科技发展有限公司 | Method for preparing clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester |
| CN103980288A (en) * | 2014-06-03 | 2014-08-13 | 成都医路康医学技术服务有限公司 | Production process of clopidogrel |
| CN110862372A (en) * | 2019-12-03 | 2020-03-06 | 江西川奇药业有限公司 | Synthesis of clopidogrel intermediate (S) -2- (2-thiophene ethylamino) - (2-chlorphenyl) -methyl acetate |
| CN110862372B (en) * | 2019-12-03 | 2024-01-12 | 江西川奇药业有限公司 | Synthesis of clopidogrel intermediate (S) -2- (2-thiophenoethylamine) - (2-chlorophenyl) -methyl acetate |
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Application publication date: 20090902 Assignee: Jiangsu Baju Pharmaceutical Co., Ltd. Assignor: East China University of Science and Technology|Shanghai Huali biopharmaceutical Co Ltd Contract record no.: 2014320000198 Denomination of invention: Preparation of clopidogrel intermediate (S) -2- (2- thiophene) (2- chloro) methyl acetate and its salts Granted publication date: 20121205 License type: Exclusive License Record date: 20140311 |
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Address after: 200231 four floor, block B, 18 lane, 1305 lane, Huajing Road, Shanghai. Co-patentee after: East China University of Science and Technology Patentee after: Shanghai Huali bio medicine Limited by Share Ltd Address before: 200231 four floor, block B, 18 lane, 1305 lane, Huajing Road, Shanghai. Co-patentee before: East China University of Science and Technology Patentee before: Shanghai Huali Biopharmaceutical Co., Ltd. |
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