Novel method for synthesizing related substance B of clopidogrel bisulfate

A technology of clopidogrel hydrogen sulfate and related substances, applied in the new synthesis field of clopidogrel hydrogen sulfate related substance B, can solve the problems of high price and high cost of raw materials, and achieves the advantages of industrialized production, improvement of total yield, and cost reduction. Effect

Active Publication Date: 2009-12-02
北京华禧联合科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The tetrahydrothienopyridine synthesis process in the starting material of this route still needs to use 3-thiophenethanol, and the price of another starting material α-halophenylacetic acid methyl ester is also relatively high, although compared with the previous route, the route is shorter and the income The rate has increased, but the cost of raw materials is still high

Method used

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  • Novel method for synthesizing related substance B of clopidogrel bisulfate
  • Novel method for synthesizing related substance B of clopidogrel bisulfate
  • Novel method for synthesizing related substance B of clopidogrel bisulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Synthesis of methyl 2-(2-chlorophenyl)-2-(4-tetrahydropyridon-1-yl)acetate (III).

[0021] Add 8.21g (0.1mol) of I and 20g (0.1mol) of II into 200ml of DMF (such as other solvents mentioned above) and stir to dissolve, keeping a certain temperature. Afterwards, the reaction solution was slowly poured into ice water, and the oily matter was stirred to solidify, filtered, and recrystallized from ethanol to obtain a white solid powder. It was filtered and dried to obtain 22.6g III with a yield of 80% and a melting point of 152-154°C. 1H NMR spectrum data (chemical shift δ): 2.64(t, 4H, N-CH 2 ), 2.55(t, 4H, CH 2 -CO), 3.68(s, 3H, CH 3 ), 4.74(s, 1H, N-CH), 7.37, 7.43, 7.44, 7.51(m, 4H, Ph-H).

Embodiment 2

[0022] Example 2: 2-(2-amino-4,5 dihydrothiophene[2,3-c]pyridin-6(7H)-yl)-2-(2-chlorophenyl)methyl acetate (IV) synthesis.

[0023] Dissolve 22.5g (0.08mol) III, 2.56g (0.08mol) of sulfur powder, 9.05g (0.08mol) of ethyl cyanoacetate in 200ml of ethanol, add dropwise 15.75ml (0.18mol) of morpholine, and keep the reaction solution at a certain temperature The mixture was reacted at room temperature, filtered to obtain a solid, and recrystallized from ethanol to obtain 17.5 g of light yellow crystals, with a yield of 65% and a melting point of 195-197°C. 1H NMR spectrum data (chemical shift δ) is: 2.69~2.75(tt, 4H, CH 2 -CH 2 ), 3.62 (s, 2H, CH 2 ), 3.68 (s, 3H, CH 3 ), 4.74(s, 1H, CH), 5.55(s, 1H, CH), 6.99(s, 2H, NH 2 ), 7.51, 7.59, 7.65, 7.68 (m, 4H, Ph-H).

Embodiment 3

[0024] Example 3: Synthesis of methyl 2-(2-chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)acetate (V).

[0025] Add 17.5g (0.052mol) III, hydrochloric acid into ice water, add sodium nitrite dropwise, keep at -5°C ~ 0°C, stir for reaction, then add hypophosphorous acid, stir at room temperature, add dichloromethane, add concentrated ammonia water dropwise, adjust pH to 8, liquid separation, concentration of the organic layer to obtain an oily substance, after adding acetone, concentrated sulfuric acid was added dropwise under ice bath conditions, stirred until a large amount of solid appeared, filtered, and dried to obtain 15.9 g of white solid as the target product V, the yield was 73 %. 1H NMR spectrum data (chemical shift δ): 2.69~2.75(tt, 4H, CH 2 -CH 2 ), 3.62 (s, 2H, CH 2 ), 3.68 (s, 3H, CH 3 ), 4.74 (s, 1H, CH), 5.55 (s, 1H, CH), 5.86, 7.38 (d, 2H, C 4 h 2 S), 7.52, 7.60, 7.67, 7.69 (m, 4H, Ph-H).

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Abstract

The invention relates to a method for preparing a related substance B in a platelet aggregation inhibition medicament-clopidogrel bisulfate. The method comprises the steps of: adopting dienone and L-2-chlorophenylglycine methyl ester to obtain tetrahydropyridone through a closed-loop reaction; then obtaining a 2-aminothienopyridine derivative through a Gewald reaction; and finally obtaining a target product through diazotization and acid hydrolysis. The process takes the synthesis of a pyridine ring first and then the synthesis of a thiophene ring as a route, obtains the target product with higher yield through a classical reaction, and provides novel thought for the synthesis of the related substance B of the clopidogrel bisulfate.

Description

technical field [0001] The invention relates to a new synthesis method of a related substance B of clopidogrel hydrogen sulfate. Its specific structure is as follows: [0002] Background technique [0003] The existing synthetic methods usually use 3-thiophenethanol as a raw material, and react with o-chlorophenylglycine methyl ester through sulfonation, substitution, ring closure, and acidification (US 225320) to obtain the target product. The reaction scheme is as follows: [0004] [0005] The starting material of this route is 3-thiophenethanol, and finally the related substances are separated by column chromatography. Due to the high price of raw materials, the market price is about 500 to 700 yuan per 5g, and this route is longer, the total yield is about 10% lower, and the required cost is higher. [0006] Another route is [0007] [0008] The tetrahydrothienopyridine synthesis process in the starting material of this route still needs to use 3-thiophene...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61P7/02
Inventor 唐功秉张凯王玉莉毕华
Owner 北京华禧联合科技发展有限公司
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