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Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof

A technology of thienylethylamine and o-chlorophenylglycine methyl ester, applied in organic chemistry, chemical instruments and methods, organic chemical methods, etc., can solve the problems of easy racemization and affecting the optical purity of products, and achieve good optical rotation , The effect of shortening the preparation cycle and improving efficiency

Active Publication Date: 2012-12-05
SHANGHAI ECUST BIOMEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] To sum up, the intermediate is generally synthesized now by using (S)-(+)-o-chlorophenylglycine methyl ester for reaction, but it is easy to racemize and affects the optical purity of the product. This patent provides a new The method for preparing this intermediate and its salt

Method used

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  • Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof
  • Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof
  • Intermediate (S)-2-(2-thiophene ethylamine)(2-chlorphenyl)methyl acetate of clopidogrel and method for preparing salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 (S)-(+)-o-chlorophenylglycine methyl ester·L-tartrate (5.00g, 0.0143mol) and thiophene-2-ethyl p-toluenesulfonate (5.00g, 0.0177mol) is placed in the three-necked flask, adding K 2 HPO 4 ·3H 2 O (18.50g), react at 97-99°C for 12hrs, after the reaction, add water (50ml) and ethyl acetate (40ml), stir, separate liquids, extract the organic layer, adjust the pH with concentrated hydrochloric acid: between 1.2-1.5, store on ice Water bath cooled and filtered to obtain 4.08g product, mp: 181.6-181.8°C, [α] D 25 =+109.4° (c=1.0, CH 3 OH);

[0033] Yield: 82.5%. 1 HNMR (D2 O, 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, 4H) (literature value: mp: 180-182℃, [α] D 25 =+108.5-110°).

[0034] Add 4.00g of the product obtained above, 8ml of methanol, and 26ml of formaldehyde (37%) into a three-necked flask equipped with a stirring and reflux device, and follow the process steps of the patent (U...

Embodiment 2

[0035] Example 2 (S)-(+)-methyl o-chlorophenylglycine L-tartrate (5.00g, 0.0143mol) and thiophene-2-ethyl p-toluenesulfonate (5.00g, 0.0177mol) in a three-necked flask, add Na 2 CO 3 (3.70g), water (1ml), and react at 96-99°C for 11hr. After the reaction, add water (50ml) and ethyl acetate (40ml), stir and separate, extract the organic layer, adjust the pH with concentrated hydrochloric acid: 1.2- Between 1.5, cooling and filtering in an ice-water bath, 4.03g of product was obtained, mp: 180.0-180.2°C, [α] D 25 =+108.7° (c=1.0, CH 3 OH), yield: 81.5%.

Embodiment 3

[0036] Example 3 (S)-(+)-o-chlorophenylglycine methyl ester L-tartrate (5.00g, 0.0143mol) and thiophene-2-ethyl benzenesulfonate (5.00g, 0.0177 mol) was placed in a three-necked flask, and Na was added 2 HPO 4 12H 2 O (13g), Na 2 CO 3 (2.60g), react at 94-99°C for 13hr, after the reaction, add water (50ml) and ethyl acetate (40ml), stir, separate liquids, extract the organic layer, adjust the pH between 1.2-1.5 with concentrated hydrochloric acid, store on ice Water bath cooled and filtered to obtain 4.00g product, mp: 179.8-180.1°C, [α] D 25 =+107.5° (c=1.0, CH 3 OH), yield: 80.9%.

[0037] Adopt the synthetic route similar to Example 1 to prepare (S)-2-(2-thienylethylamino)(2-chlorophenyl)methyl acetate and its salts under different process conditions, the results are shown in Table 1:

[0038] Table 1

[0039]

[0040]

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PUM

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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 technologyThe 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 benzenesulphonatof 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 pe-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 clopidogrelroduction 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 clopidogreland salts thereof.and salts thereof.

Description

technical field [0001] The invention relates to the preparation of clopidogrel intermediate (S)-2-(2-thienylethylamino)(2-chlorophenyl)acetic acid methyl ester and salts thereof. Background technique [0002] Clopidogrel (Clopidogrel), the chemical name is (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester, It is a new generation of platelet aggregation inhibitors, mainly used in the treatment of atherosclerosis, acute coronary syndrome, prevention of in-stent restenosis and thrombotic complications after coronary stent implantation. [0003] So far, there are many methods for preparing clopidogrel, and the intermediate (S)-2-(2-thienylethylamino)(2-chlorophenyl)acetic acid methyl ester and its salts are important intermediates, Report the method for synthesizing this intermediate mainly to contain following several kinds: [0004] Patent (EP.Pat.No.466569 US.Pat.No.5204469) adopts the following route: [0005] Use o-chlorobenzaldehyde ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/20C07B53/00
Inventor 吴范宏赵敏杨雪艳陈建中
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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