Improved preparation method of II-type clopidogrel hydrogen sulfate crystal

A technology of clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in directions such as organic chemistry, can solve problems such as low product yield, and achieve the effect of improving yield

Inactive Publication Date: 2014-01-22
吉林省博大伟业制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The invention provides an improved method for preparing type II clopidogrel bisulfate crystals, which impro...

Method used

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  • Improved preparation method of II-type clopidogrel hydrogen sulfate crystal
  • Improved preparation method of II-type clopidogrel hydrogen sulfate crystal
  • Improved preparation method of II-type clopidogrel hydrogen sulfate crystal

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Embodiment 1

[0049] Add 500ml of acetone to a 1000ml three-necked flask, heat to reflux, keep reflux for 10 minutes, stop heating, cool down to room temperature, and set aside.

[0050]At room temperature, 0.31mol of clopidogrel free base is used to prepare 300ml of acetone and stir to dissolve. Under the protection of nitrogen, add 31.0g (0.31mol) of concentrated sulfuric acid and 0.55g of II seed crystals. After white turbidity appears, continue stirring for 8 hours and filter , and dried under reduced pressure at 45°C for 16 hours to obtain 119.8 g of white crystals. Yield 92.0%; HPLC: normalized purity 99.994%, impurity A: 0.006%; melting point: 175.6°C; [α] D 25 +57.87 (C1.0, CH 3 OH); 1 HNMR (DMSO-d6, 600MH Z ), δ: 10.78 (br, 2H + ), δ: 7.73(d, 1H), δ: 7.67(d, 1H), δ: 7.58(t, 1H), δ: 54(t, 1H), δ: 7.44(d, 1H), δ: 6.90 (s, 1H), δ: 5.70 (s, 1H), δ: 4.27 (br, 2H), δ: 3.76 (s, 3H), δ: 3.52 (br, 2H), δ: 3.11 (s, 2H) . 13 CNMR (DMSO-d6, 600MH Z ), δ: 167.36, 134.40, 132.46, 131.70...

Embodiment 2

[0055] Add 500ml of acetone to a 1000ml three-necked flask, heat to reflux, keep reflux for 30 minutes, stop heating, cool down to room temperature, and set aside.

[0056] At room temperature, 0.31mol of clopidogrel free base is used to prepare 300ml of acetone and stir to dissolve. Under the protection of nitrogen, add 31.0g (0.31mol) of concentrated sulfuric acid and 0.55g of II seed crystals. After white turbidity appears, continue stirring for 8 hours and filter , dried under reduced pressure at 45°C for 16 hours to obtain 119.8g of white crystals, yield 92.7%, HPLC: normalized purity 99.993%, impurity A: 0.007%; melting point: 175.1°C; [α] D 25 +56.38 (C1.0, CH 3 OH), see attached Figure 9 .

Embodiment 3

[0058] Add 500ml of acetone to a 1000ml three-neck flask, heat to reflux, keep reflux for 40 minutes, stop heating, cool down to room temperature, and set aside.

[0059] At room temperature, 0.31mol of clopidogrel free base is used to prepare 300ml of acetone and stir to dissolve. Under the protection of nitrogen, add 31.0g (0.31mol) of concentrated sulfuric acid and 0.55g of II seed crystals. After white turbidity appears, continue stirring for 8 hours and filter , dried under reduced pressure at 45°C for 16 hours to obtain 121.4g of white crystals, yield 93.2%, HPLC: normalized purity 99.993%, impurity A: 0.007%; melting point: 174.8°C; [α] D 25 +56.55 (C1.0, CH 3 OH), see attached Figure 10 .

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Abstract

The invention discloses an improved preparation method of a II-type clopidogrel hydrogen sulfate crystal, which is an improvement of the existing II-type clopidogrel hydrogen sulfate crystal form preparation technique. The method greatly enhances the yield on the premise of ensuring the product appearance (the average yield is up to 92%), and prepares the product with better appearance on the premise of obviously enhancing the product yield.

Description

[0001] technical field [0002] The invention discloses an improved preparation method of type II clopidogrel hydrogen sulfate crystal, which is an improvement on the existing preparation process of type II clopidogrel hydrogen sulfate crystal, and belongs to the technical field of chemical drug preparation. Background technique [0003] The present invention relates to clopidogrel hydrogensulfate (2s)-(2-chlorophenyl)[6.7-dihydrothiophene[3,2-c]pyridin-5(4H)-yl]acetate methyl ester hydrogensulfate, which The structure is as follows: [0004] [0005] Clopidogrel bisulfate is a new type of high-efficiency anti-platelet aggregation drug, which was first jointly developed by Japan's Daiichi Pharmaceutical and French Sanofi (Sanofi), and is clinically used in the treatment of atherosclerosis, acute coronary syndrome, prevention of In-stent restenosis and thrombotic complications after coronary stent implantation. Compared with other antiplatelet drugs, clopidogrel has the ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 李晓东林杉黄晓光周凤秋
Owner 吉林省博大伟业制药有限公司
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