Composition of oxyclopidogrel optical isomer or salt thereof and application of composition

A kind of technology of optical isomer and composition, applied in the field of medicine

Pending Publication Date: 2020-05-15
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, CN104245707A discloses a substantially pure optical isomer (7aS, 2'S)-2-oxo-clopidogrel, only the isomer is controlled, but no other impurities are controlled

Method used

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  • Composition of oxyclopidogrel optical isomer or salt thereof and application of composition
  • Composition of oxyclopidogrel optical isomer or salt thereof and application of composition
  • Composition of oxyclopidogrel optical isomer or salt thereof and application of composition

Examples

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preparation example 1

[0038] This preparation example discloses the preparation method of the compound of formula ⅡA, specifically:

[0039] (S)-2-(2-Chlorophenyl)-2-((S)-7a-hydroxy-2-oxo-2,6,7,7a-tetrahydrothieno[3,2-c]pyridine Synthesis of -5(4H)methyl Acetate

[0040] Step 1. Synthesis of IM1:

[0041]

[0042] At room temperature, slowly drop 35 mL of anhydrous THF suspension with 7.1 g of sodium hydride into 586 mL of anhydrous THF dissolved with 58.6 g of SM1, stir for 30 min, then slowly drop into 70 mL of anhydrous THF with 69.2 g of SM2 dissolved therein and Stir at room temperature for 12 h, and monitor the reaction by TLC iodine display. After the reaction was completed, 650 mL of saturated brine was added and extracted with 1500 mL of DCM. Organic layer with Na 2 SO 4 After drying, the solvent was removed by evaporation under reduced pressure. The residue was purified on a silica gel column to obtain 52.3 g (62.3% yield) of IM1 as a colorless oily liquid (PE / EA=20 / 1 to 5 / 1). L...

preparation example 2

[0059] This preparation example discloses the preparation method of formula IIB, specifically:

[0060] N-Oxo-(S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydrothiopheno[3,2-c]pyridine Synthesis of -5(4H)yl)methyl acetate.

[0061] Step 1. Resolution of the racemic product

[0062]

[0063] Referring to the patent CN104245707A, after we synthesized the structure of the SMX compound, the obtained racemic product 4.6gSMX was resolved by preparing a chiral column to obtain two relatively pure enantiomers SMX-1 and SMX-2. SMX-1 is 1.24g and SMX-2 is 1.51g. (Yield 59.8%) LC-MS (ESI) [M+H + ] + =338.8(M+H + ) is consistent with the structure.

[0064] Step 2. Synthesis of formula IIB:

[0065]

[0066] Put 1.24g of SMX-1 and 10mL of glacial acetic acid into a 50mL three-neck flask at room temperature, add 1ml of hydrogen peroxide dropwise in an ice bath, raise the temperature to 80°C for 2 hours after the addition, and monitor the reaction by TLC (developer: ethyl ...

Embodiment 1

[0068] This example discloses a composition comprising 4% of the compound of formula IIA.

[0069] The optical isomer (7aS,2'S)-2-oxo-clopidogrel synthesized according to CN104245707A has a purity of 98.0% (nitrogen protection, no impurity compound of formula IIA or formula IIB). To 0.96g (7aS,2'S)-2-oxo-clopidogrel, add 0.04g of the compound of formula IIA with a purity of 98.0%, and mix evenly to obtain a composition with a content of compound of formula IIA of 4%.

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Abstract

The invention discloses a composition of an oxyclopidogrel optical isomer or a salt thereof and application of the composition, and belongs to the technical field of medicines. The composition comprises an optical isomer of clopidogrel represented by a formula I or a salt thereof, and one or two compounds represented by formula IIA and formula IIB and salts thereof.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the composition and application of oxygen-containing pidogrel optical isomers or salts 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%), CYP2C19 (about 45%) Is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4365C07D495/04A61P9/10A61P9/00A61P7/02
CPCA61K31/4365C07D495/04A61P9/10A61P9/00A61P7/02C07B2200/07A61K2300/00
Inventor 牟霞杨茂廷谭少军江杰陆瑶
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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