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Preparation method of thienopyridine compound

A technology of phenopyridine and thiophene, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of complicated operation, poor reaction reproducibility, long reaction time and the like, and achieves the effects of simple operation process, mild reaction conditions and easy-to-obtain production raw materials

Inactive Publication Date: 2014-06-18
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above method still has disadvantages such as cumbersome operation, unstable yield, and poor reaction reproducibility, especially the hydrolysis step of 2-methoxythienopyridine requires the use of hydrogen chloride gas, long reaction time, and poor product purity.

Method used

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  • Preparation method of thienopyridine compound
  • Preparation method of thienopyridine compound
  • Preparation method of thienopyridine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Preparation of 2,5-diacetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0032]

[0033] Add 18.2g (0.1mol) of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 13.4g (0.1mol) of anhydrous aluminum trichloride into a 250mL reaction flask and 80mL of dichloromethane, cooled to -15°C, 7.8g (0.1mol) of acetyl chloride was added dropwise under stirring, after the drop was complete, the reaction was stirred and reacted at the same temperature for 2 hours, and then raised to room temperature and continued to stir and react for 2 hours (TLC monitored the reaction end point, Developing agent: petroleum ether / ethyl acetate=1 / 1). The reaction solution was poured into 100 g of crushed ice, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was filtered off, concentrated under reduced pressure to recover two Chloromethane, the residue was...

Embodiment 2

[0034] Example 2: Preparation of 2,5-diacetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0035]

[0036] Add 18.2g (0.1mol) of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 9.42g (0.12mol) of acetyl chloride and 80mL of dichloro Methane, mixed evenly, cooled to -5°C, stirred for 30min, added dropwise the mixed solution composed of 31.3g (0.1mol) anhydrous tin tetrachloride and 70mL dichloromethane, after dropping, stirred and reacted at the same temperature for 4 hours ( The end point of the reaction was monitored by TLC, developing solvent: petroleum ether / ethyl acetate=1 / 1). The reaction solution was poured into 100 g of crushed ice containing 1 mL of concentrated hydrochloric acid, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was filtered off. Dichloromethane was recovered by concentration under reduced pressure, and the residue...

Embodiment 3

[0037] Example 3: Preparation of 2-acetylamino-5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0038]

[0039] Add 11.2g (0.05mol) 2,5-diacetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 11.1g (0.11mol) triethylamine into a 250mL reaction flask , 60mL absolute ethanol. 7.3g (0.11mol) of hydroxylamine hydrochloride was dissolved in 10mL of water, and the aqueous solution of hydroxylamine hydrochloride was added dropwise to the reaction system under an ice bath. After the dropping was complete, the mixture was refluxed for 4 hours, and a white solid was precipitated during the reaction. Filtrate with suction, wash the filter cake with water, and dry to obtain a white solid, which is the hydroxime intermediate, which is hydrolyzed without purification.

[0040] Mix 6.3g (0.025mol) of the prepared hydroxime intermediate with 80mL tetrahydrofuran evenly, quickly add 6.2g (0.03mol) phosphorus pentachloride under ice bath cooling, stir and react at the same temperature for 3 hou...

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Abstract

The invention relates to a preparation method of a medicine intermediate 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride and the compound can serve as a synthesis intermediate of an anti-platelet-aggregation medicine Prasugrel. The preparation method comprises the following steps: performing Friedel-Crafts acylation on (i)N( / i)-protected thienopyridine as a starting material, thereby preparing 2-acyl thienopyridine; performing Backmenn rearrangement so as to obtain 2-amino thienopyridine; performing amino diazotization and hydrolysis, thereby preparing the target compound. The defects in the existing method are overcome; easily-available production raw materials, moderate reaction conditions and a simple operation process are adopted; the preparation method is suitable to the industrial production of Prasugrel (the formula is shown in the specification).

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to a thienopyridine compound 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine Hydrochloride (or 2-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride) [0002] (1) The preparation method, the prepared compound can be used as a synthetic intermediate of the anti-platelet aggregation drug prasugrel. [0003] Background technique [0004] Prasugre1, chemical name 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c ] Pyridine, an oral anti-platelet aggregation drug jointly developed by Eli Lilly and Japan's Daiichi Pharmaceutical Sankyo Co., Ltd., was approved by the FDA in September 2009 for the treatment of atherosclerosis and acute coronary syndrome. [0005] The classic synthetic method of prasugrel is: 2-halo-2-(2-fluorophenyl)-1-cyclopropyl or 2-sulfonyl-2-(2-fluorophenyl)-1-cyclopropyl The intermediate ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 郭春吕正敏于士龙梁振田野李硕
Owner SHENYANG PHARMA UNIVERSITY
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