Composition, preparation method and application of oxygen-containing pidogrel optical isomer or salt thereof

A composition and compound technology, applied in the field of medicine, can solve the problems of preparation method research, lack of preparation technology, etc.

Active Publication Date: 2021-08-10
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In addition, although (7aR,2'S)-2-oxo-clopidogrel has been recorded in many domestic and foreign literatures for a long time, its preparation method has not been studied, so there is a lack of preparation technology for industrial production

Method used

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  • Composition, preparation method and application of oxygen-containing pidogrel optical isomer or salt thereof
  • Composition, preparation method and application of oxygen-containing pidogrel optical isomer or salt thereof
  • Composition, preparation method and application of oxygen-containing pidogrel optical isomer or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation of embodiment 1 (7aR, 2S)-2-oxopidogrel and bisulfate

[0045] The first step: the synthesis of methyl o-chloromandelate p-benzenesulfonate

[0046]

[0047] Add 28g of p-nitrobenzenesulfonyl chloride, 0.3g of dimethylaminopyridine, 30g of methyl 2-chloromandelate and 300ml of dichloromethane into a 500ml three-necked flask at room temperature, add 20g of triethylamine, protect with nitrogen, and stir at room temperature for about 2 hours , TLC monitoring of the reaction until all the raw materials were converted, 400ml of dilute hydrochloric acid was added, the organic layer was separated, and concentrated under reduced pressure to obtain 30g of solid.

[0048] The second step: the preparation of the synthesis of (7aR,2S)-2-oxopidogrel

[0049]

[0050] Add 0.5g of thienopyridine hydrochloride, 2g of sodium bicarbonate, 1g of sulfonate intermediate and 10ml of acetonitrile into a 100ml reaction flask, heat to 50°C for about 20 hours, monitor the ...

Embodiment 2

[0058] The preparation of embodiment 2 (7aR, 2S)-2-oxopidogrel hydrobromide

[0059]

[0060] The preparation method of (7aR, 2S)-2-oxopidogrel is the same as in Example 1 above, dissolve 1 g of (7aR, 2S)-2-oxopidogrel in ethyl acetate, add hydrobromic acid dropwise to form a salt, and filter to obtain (7aR , 0.7g of crude product of 2S)-2-oxopidogrel hydrobromide.

[0061] Adding: add optically active (7aR, 2S)-2-oxopidogrel hydrobromide crude product into the reaction flask, heat to reflux with methanol, then add acetone, control the ratio of methanol to acetone to be 1:5;

[0062] Precipitation of crystals: Slowly lower the temperature to room temperature and stir for crystallization for 24 hours to obtain a white solid of (7aR,2S)-2-oxopidogrel hydrobromide.

[0063] MS m / z(ES):338.06[M+1]

[0064] 1H NMR (300MHz, DMSO), δ1.65~1.75(m, 1H), 2.45-2.52(m, 1H), 2.88~2.94(m, 1H), 3.02~3.05(m, 1H), 3.75(s, 3H), 3.90~3.97(m, 1H), 4.22~4.25(m, 1H), 4.61-4.65(m, 1H), 5.26(s, ...

Embodiment 3

[0065] The preparation of embodiment 3 (7aR, 2S)-2-oxopidogrel hydrochloride

[0066]

[0067] The preparation method of (7aR, 2S)-2-oxopidogrel is the same as in Example 1 above, dissolve 1 g of (7aR, 2S)-2-oxopidogrel in 10 ml of ethyl acetate, add dropwise concentrated hydrochloric acid to form a salt, and filter to obtain (7aR , 2S)-2-oxopidogrel hydrochloride crude product 0.7g.

[0068] Adding: add optically active (7aR, 2S)-2-oxopidogrel hydrochloride crude product into the reaction flask, heat to reflux with methanol, then add acetone, control the ratio of methanol to acetone to be 1:10;

[0069] Precipitation of crystals: Slowly lower the temperature to room temperature and stir for crystallization for 36 hours to obtain a white solid.

[0070] MS m / z(ES):338.06[M+1]

[0071] 1 H NMR (300MHz, DMSO), δ1.72~1.79(m, 1H), 2.42-2.53(m, 1H), 2.79~2.85(m, 1H), 3.04~3.08(m, 1H), 3.69(s, 3H), 3.93~3.95(m, 1H), 4.25~4.28(m, 1H), 4.61-4.65(m, 1H), 5.29(s, 1H), 6.44(s, 1H)...

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Abstract

The invention discloses a composition, a preparation method and an application of an oxygen-containing pidogrel optical isomer or a salt thereof. The optical isomer of oxypidogrel has the structural formula of formula I. The invention provides a method for preparing high-purity (7aR, 2'S)-2-oxo-clopidogrel; the method can obtain (7aR, 2'S)-2-oxo-clopidogrel with a content of more than 85%, especially more than 98%. - Clopidogrel compositions. The composition can be used for quality testing of medicines containing or possibly containing the compound of formula I. At the same time, the composition has remarkable expectorant and antithrombotic functions.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a composition, a preparation method and an application of an oxygen-containing pidogrel optical isomer or a salt thereof. Background technique [0002] Clopidogrel (Clopidogrel) is a thienopyridine derivative, which itself is an inactive prodrug. The absorption of the original drug in the small intestine is regulated by the proton pump P-glycoprotein encoded by the ABCB1 gene, of which 85% pass through the carboxylated Esterase (CES1) is converted into inactive carboxylic acid derivatives and excreted through the intestines, 15% enters the blood circulation and is metabolized into oxypidogrel under the action of liver cytochrome P450 enzyme system, and is further oxidized into active clopidogrel The thiol derivative of Gray (R-130964. That is, its metabolism is divided into two stages, the first stage: Clopidogrel is composed of CYP1A2 (about 36%), CYP2B6 (about 19%)...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4365A61P11/10A61P7/02G01N5/00
CPCA61K31/4365A61P7/02A61P11/10G01N5/00
Inventor 岑国栋杨茂廷谭少军杨宁远
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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