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Preparation method of hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative

A 4-c, derivative technology, applied in the direction of organic chemistry, etc., can solve the problems of difficult purification, low yield, and difficulty in amplification, and achieve the effect of easy amplification, high yield and mild conditions

Inactive Publication Date: 2011-05-25
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a method for the preparation of hexahydro-pyrrole[3,4-c]pyrrol-1-one derivatives with stable and mild reaction conditions, high yield and easy purification, mainly to solve the problem that the current synthesis process is easy to eliminate , Difficult to purify, low yield, difficult to scale up and other technical problems

Method used

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  • Preparation method of hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative
  • Preparation method of hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative
  • Preparation method of hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative

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Effect test

example 1

[0026]

[0027] Dissolve 72g (0.5mol) of monoethyl maleate in a mixture of 1L of dichloromethane and 57g (0.25mol) of trifluoroacetic acid, then cool to 0°C with ice water, and slowly add dropwise under nitrogen protection 142.2 g (0.6 mol) of the silicon reagent was added dropwise, and the reaction was naturally raised to room temperature, and stirred overnight. Quench with 10% sodium hydroxide solution, stand still, separate layers, and wash the organic layer with water and saturated brine respectively, anhydrous NaSO 4 Dry and concentrate to obtain 105g, yield: 75%.

example 2

[0029]

[0030] Dissolve 72g (0.5mol) of monoethyl maleate in a mixture of 1L of dichloromethane and 57g (0.25mol) of trifluoroacetic acid, then cool to 0°C with ice water, and slowly drop 190 g (0.8 mol) of the silicon reagent was added dropwise, and the reaction was naturally raised to room temperature, and stirred overnight. Quench with 10% sodium hydroxide solution, stand still, separate layers, and wash the organic layer with water and saturated brine respectively, anhydrous NaSO 4 Dry and concentrate to obtain 108g, yield: 78%.

example 3

[0032]

[0033] Dissolve 72g (0.5mol) of monoethyl maleate in a mixture of 1L of dichloromethane and 57g (0.25mol) of trifluoroacetic acid, then cool to 0°C with ice water, and slowly add dropwise under nitrogen protection Silicon reagent 237g (1 mol), after the dropwise addition, the reaction naturally rose to room temperature and stirred overnight. Quench with 10% sodium hydroxide solution, stand still, separate layers, and wash the organic layer with water and saturated brine respectively, anhydrous NaSO 4 Dry and concentrate to obtain 106g, yield: 76.5%.

[0034] The second step: the preparation of intermediate (03) N-tert-butyl-tetrahydropyrrole-3,4-dicarboxy 3-ethyl acetate:

[0035] Example 1:

[0036]

[0037] 105g (0.38mol) intermediate 02 and 82.8g (0.38mol) (Boc) 2 Dissolve O acid anhydride and a certain amount of catalyst Pd / C in 1.5L ethanol, stir overnight at 45-50°C in a hydrogen environment with a certain pressure of 30psi, filter to remove the catalys...

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Abstract

The invention relates to a preparation method of a hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative, which mainly solves the technical problems of long route, low yield, difficult purification and difficult repetition and amplification of reaction of the conventional synthesis method. The preparation method comprises the following steps of: firstly, performing a 1,3-dipolar cycloaddition on monoethyl maleate and N-methoxy-methyl-N-(trimethylsilyl methyl) benzyl amine which serve as raw materials to obtain a benzyl-protected pyrrole ring so as to finish a basic skeleton of an intermediate; secondly, reducing carboxylic acid into hydroxyl groups by using borane, converting the hydroxyl groups into activated ester by using methane sulfonyl chloride, and alkylating 'N'; and finally, reducing azido ester groups under a hydrogenation condition, and closing the ring to obtain the hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative. The hexahydro-pyrrolo [3,4-c] pyrrole-1-ketone derivative prepared by the method is a useful intermediate or product of the synthesis of a number of medicaments.

Description

Technical field: [0001] The present invention relates to a novel synthesis method of hexahydro-pyrrole [3,4-c] pyrrol-1-one derivatives. Background technique: [0002] Hexahydro-pyrrole[3,4-c]pyrrol-1-one derivatives are used as intermediates or products of pharmaceutical synthesis, and the intermediates and related derivatives are widely used in medicinal chemistry and organic synthesis. [0003] According to literature reports, the pharmaceutical intermediate mainly uses maleic anhydride as a raw material at present, and is completed through 7 steps according to the following reaction formula. [0004] [0005] This route has the following defects: on the one hand, the steps are relatively long, and on the other hand, some steps yield is not high, as reported in the literature [Bulletin de la Societe Chimique de France 1997, 283 and US2007 / 93480], the removal of hydroxyl groups The one-step yield is only more than 30%, resulting in a low yield of the whole process, dif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 董鹏超杨亚讯崔素花马建义郭爱新姜鲁勇马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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