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Method for preparing prasugrel intermediate and application of method in synthesizing prasugrel

An intermediate and oxidation reaction technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve problems such as industrial production hazards, achieve the effect of increasing the total yield and being suitable for large-scale industrial production

Inactive Publication Date: 2011-11-16
辽宁远大诺康医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since n-butyllithium is flammable and explosive, large-scale industrial production is too dangerous; therefore, it is urgent to develop a safe and efficient method for the synthesis of compound 1

Method used

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  • Method for preparing prasugrel intermediate and application of method in synthesizing prasugrel
  • Method for preparing prasugrel intermediate and application of method in synthesizing prasugrel
  • Method for preparing prasugrel intermediate and application of method in synthesizing prasugrel

Examples

Experimental program
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Effect test

Embodiment 1

[0025] The preparation method of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (compound 3) described in this example is as follows: 4,5,6,7-tetrahydro Thieno[3,2-c]pyridine (7.0 g), diisopropylethylamine (7.2 g), and acetonitrile (30 mL) were mixed, acetic anhydride (5.6 g) was added, and stirred at room temperature for 5 hours. The solution was concentrated to dryness, ethyl acetate and water were added, the liquid was separated, the water phase was extracted twice and the organic phase was combined, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 5-acetyl - 8.1 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, yield 89%.

Embodiment 2

[0027] The preparation method of 5-acetyl-5,6,7,7α-tetrahydrothieno[3,2-c]pyridin-2-one (compound 4) described in this example is: compound 3 (9.1g) , iron trichloride (16.2g), acetic acid (30mL), and water (30mL) were mixed in an autoclave, fed with oxygen, the pressure was at 0.6-0.7MPa, and stirred at room temperature for 8 hours. Adjust the pH of the solution to neutral with dilute sodium hydroxide, add ethyl acetate, separate the layers, extract the water phase twice, combine the organic phases, wash with saturated brine until neutral, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness 7.2 g of 5-acetyl-5,6,7,7α-tetrahydrothieno[3,2-c]pyridin-2-one was obtained with a yield of 73%.

Embodiment 3

[0029] The preparation method of 5,6,7,7α-tetrahydrothieno[3,2-c]pyridin-2-one (compound 1) described in this example is: compound 4 (9.9g), freshly prepared sodium methoxide Methanol solution (30 mL, containing about 5.4 g of sodium methoxide) was mixed and refluxed for 6 hours. The solution was concentrated to dryness, ethyl acetate and water were added, the layers were separated, the water phase was extracted twice and the organic phases were combined, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 5, 6, 7,7α-tetrahydrothieno[3,2-c]pyridin-2-one 7.0g, yield 90%; 5,6,7,7α-tetrahydrothieno[3,2-c]pyridine- The 2-ketone was thoroughly ground in ether hydrochloride, crystallized, and filtered to obtain 5,6,7,7α-tetrahydrothieno[3,2-c]pyridin-2-one to obtain 7.1 g of hydrochloride, the yield 83%.

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Abstract

The invention relates to a new method for synthesizing a prasugrel intermediate 2,4,5,6,7,7alpha-hexahydro thieno[3,2-c]pyridine-2-ketone and an application of the method in synthesizing prasugrel. The preparation method of the prasugrel intermediate comprises the following steps: 2,4,5,6,7,7alpha-hexahydro thieno[3,2-c]pyridine-2-ketone is obtained through protecting 4,5,6,7-tetrahydro thieno[3,2-c]pyridine hydrochloride, carrying out catalytic oxidation by a metal salt in high pressure oxygen atmosphere and carrying out protective group removal; and an equation is shown in the specification. The method of the present invention which has the characteristics of safety and high yield is suitable for large-scale industrial production, and the method for preparing prasugrel with the intermediate of the present invention has a higher total yield than present preparation methods.

Description

technical field [0001] The invention relates to the fields of chemical industry and pharmacy, and in particular provides a new synthesis method of a prasugrel intermediate and the application of the intermediate in the synthesis of prasugrel. Background technique [0002] Prasugrel (prasugrel) is an oral antiplatelet drug jointly developed by Eli Lilly of the United States and Sankyo Company of Japan. It was approved for marketing by the European Union on February 23, 2009, and approved by the FDA on July 10, 2009. The trade name is Efient . [0003] In the prior art, the synthetic route of prasugrel is mainly the original synthetic route (CN92111584) of Sankyo Company, with o-fluorobenzyl bromide as the starting material, which is made into Grignard reagent and then condensed with cyclopropyl nitrile to obtain 1-cyclopropane Base-2-(2-fluorophenyl)ethanone, and then bromo its α-position, and then undergo a substitution reaction with 2-thienoxopyridine, and the resulting pr...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCY02P20/55
Inventor 薛百忠张良王宏英薛雁刘宏大刘娜齐琰姜麟洲
Owner 辽宁远大诺康医药有限公司
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