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Method for preparing vicagrel and derivatives thereof

A compound, phenyl technology, applied in the field of preparation of vicagrel and its derivatives, can solve the problems of carcinogenicity, poor product optical purity and high production cost

Active Publication Date: 2013-08-21
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] When we try to adopt the method of US587458 to prepare formula (IV) compound, promptly formula (II) compound and (R)-2-chloro-2-(2-chlorophenyl) methyl acetate or (R)-2- Bromo-2-(2-chlorophenyl) methyl acetate reacts under the presence of alkali, has run into following difficult problem: (1) the chemical yield of generating formula (IV) compound is very low, and the optical purity of product is very poor, not Suitable for industrial production; (2) (R)-2-chloro-2-(2-chlorophenyl) methyl acetate or (R)-2-bromo-2-(2-chlorophenyl) methyl acetate stimulation (3) highly optically pure (R)-2-chloro-2-(2-chlorophenyl) methyl acetate or (R) -2-bromo-2-(2-chlorophenyl) methyl acetate is not easy to prepare, it is easy to racemize in the preparation process, the production cost is high, and it is also unfavorable for industrialized production

Method used

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  • Method for preparing vicagrel and derivatives thereof
  • Method for preparing vicagrel and derivatives thereof
  • Method for preparing vicagrel and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 2-tert-butyldimethylsiloxotetrahydrothieno[3,2-c]pyridine

[0029]Dissolve 3g (0.0157mol) of 5,6,7,7a-tetrahydrothieno[3.2-c]pyridin-2(4H)-one hydrochloride in 60mL of acetonitrile, add 2mL of triethylamine, stir at 20oC until solution clarify. Then add 2.2g (0.0146mol) tert-butyldimethylsilyl chloride, keep the temperature constant, and stir for 6h. The disappearance of raw materials was detected by TLC, the insoluble matter was filtered, and the filtrate was evaporated to dryness to obtain a brown sticky substance, namely 2-tert-butyldimethylsiloxotetrahydrothieno[3,2-c]pyridine: 3.8g, yield 90 %.

[0030] 1H-NMR (300MHz, CDCl3) δ0.22(s, 6H), 0.96(s, 9H), 2.65(m, 2H), 3.17(m, 2H), 3.77(s, 2H), 5.29(s, 1H ), 5.76(s, 1H); ESI-MS m / z 270.1[M+H]+.

Embodiment 2

[0032] (S)-2-(2-((tert-butyldimethylsilyl)oxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2 -(2-Chlorophenyl)-methyl acetate

[0033] 500mg (1.3mmol) (R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid methyl ester, 395mg (1.5mmol) 2-tert-butyldimethyl Siloxotetrahydrothieno[3,2-c]pyridine and 328 mg (2.5 mmol) of potassium bicarbonate were added to 10 mL of acetonitrile, the reaction system was protected with nitrogen, and stirred overnight at 25°C. After the reaction solution was allowed to stand, the insoluble matter was filtered to obtain a yellow mother liquor. The solvent was evaporated to dryness under reduced pressure, and a colorless oil was obtained by flash column chromatography (petroleum ether: ethyl acetate = 50:1), namely (S)-2-(2-((tert-butyldimethylsilyl) Oxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetic acid methyl ester: 500 mg, yield 85%. 1 H-NMR (300MHz, CDCl 3 )δ0.24(s, 6H), 0.95(s, 9H), 2.69-2.85(m, 4H), 3.43-3.56(m...

Embodiment 3

[0035] (S)-2-(2-((tert-butyldimethylsilyl)oxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2 -(2-Chlorophenyl)-methyl acetate

[0036] 250mg (0.65mmol) (R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid methyl ester, 175mg (0.65mmol) 2-tert-butyldimethyl Siloxotetrahydrothieno[3,2-c]pyridine and 0.09 mL (0.65 mmol) of triethylamine were added to 5 mL of acetonitrile, the reaction system was protected with nitrogen, and stirred overnight at 25°C. After the reaction solution was allowed to stand, the insoluble matter was filtered to obtain a yellow mother liquor. The solvent was evaporated to dryness under reduced pressure, and a colorless oil was obtained by flash column chromatography (petroleum ether: ethyl acetate = 50:1), namely (S)-2-(2-((tert-butyldimethylsilyl) Oxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetic acid methyl ester: 220 mg, yield 76%.

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Abstract

The invention relates to the pharmaceutical field, and concretely relates to a method for preparing vicagrel and derivatives thereof. The method comprises a step 1 of adopting optically-active alkyl sulfonate to carry out selective N-alkylation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-ol silyl ether, and a step 2 of directly esterifying a product generated in step 1 to obtain vicagrel. The method has the advantages of less side reactions, high yield, high chemical purity and optical purity, low cost, simple operation, and suitableness for the industrialized production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of vicagrel and its derivatives. Vicagrel and its derivatives can be used as anti-platelet aggregation drugs. Background technique [0002] (S)-2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2- Chlorophenyl)-methyl acetate (vicagrelor: R 1 =methyl) and its derivatives have been disclosed in Chinese patent application (application number: 201010624329.7) and PCT patent application (application number: PCT / CN2011 / 000138), and these compounds can be used to prepare novel antiplatelet drugs to overcome The clinical application defects of existing antiplatelet drugs, such as "clopidogrel resistance" and high bleeding risk of prasugrel, etc. Vicagrel has now entered the preclinical research stage and is expected to be developed into a safer and more effective new anti-platelet drug. [0003] [0004] Among them, the R of formula (I) 1 1 to 10 carbon unsub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCY02P20/55
Inventor 孙宏斌陈冬寅袁方龚彦春
Owner JIANGSU VCARE PHARMATECH
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