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Method for preparing maropitant impurity

A compound and reaction technology, applied in the field of medicinal chemistry, can solve the problems of unpublished preparation of maropitant mirror image impurities and inability to pass, and achieve the effects of shortening reaction time, simple operation and mild reaction conditions

Inactive Publication Date: 2018-07-31
科贝源(北京)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the existing literature, the method of preparing the mirror image impurities (2R, 3R) of maropitan has never been disclosed
And the inventor finds that there are isomers (mirror image impurities) after analyzing the crude product of Maropitan, but through a large number of experimental verifications, it is impossible to determine suitable separation conditions by HPLC

Method used

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  • Method for preparing maropitant impurity
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  • Method for preparing maropitant impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0072] Preparation of (R, R)-2-benzhydryl-3-benzylaminoquinuclidine camphorsulfonate (compound VIa')

[0073] 50g compound VIb' (50g, 0.13mol) was suspended in 500 milliliters of acetonitrile, D-camphorsulfonic acid (30g, 0.13mol) was added to the suspension at one time, after adding D-camphorsulfonic acid, the reaction solution became clear, Stirring was continued for 30 minutes, a large amount of solids were precipitated, kept stirring at room temperature for 3 hours and then filtered, the filter cake was rinsed with 30 mL of acetonitrile, the filter cake was collected, and dried in a blast drying oven at 50 degrees to obtain 58 g of compound VIa', with a yield of 73%. , white solid.

[0074] Purification of (R,R)-2-Benzhydryl-3-benzylaminoquinucidine camphorsulfonate (VIa')

[0075] Suspend compound VIa' (58g, 0.095mol) in 580mL of methyl isobutyl ketone, add 29mL of water, heat to 100 degrees to dissolve it completely, then cool down to room temperature while stirring, fi...

Embodiment 2

[0082] Embodiment 2. Detection and separation of mirror image impurities

[0083] The maropitan sample containing the mirror image impurity of maropitan is detected by HPLC chromatography, and the HPLC chromatographic conditions adopted are as follows:

[0084] Chromatographic column: Dalu IC (4.6×250mm, 5μm);

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Abstract

The present invention relates to a method for preparing a maropenitan mirror image impurity (2R, 3R), and the method is as follows: 1) compound VIb is reacted with D-camphorsulfonic acid to obtain compound VIa'; 2) optionally, the compound VIa' is subjected to debenzylation to obtain compound VII'; 3) the compound VIa' of the step 1) or the compound VII' of the step 2) is reacted with 5-(tert-butyl)-2-methoxybenzaldehyde to obtain compound IXa'; and 4) the compound IXa' is reduced to obtain compound I'. The method has mild conditions, a crude product can be directly used for a next step of reaction, the post-treatment is simple, the cost is greatly saved, the reaction time of the whole process is shortened, and the final yield of the reaction is within an acceptable range. The invention also proposes for the first time a method for detecting and separating the compound I' impurity in a maropenitan drug, and solves the problem that the compound I' impurity in the maropenitan drug is difficult to detect and separate, and a basis is provided for preparing high purity maropenitan satisfying medicine requirements.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for preparing maropitan mirror-image impurities (2R, 3R). Background technique [0002] The chemical structure of Maropitan is: [0003] [0004] Maropitan is a type 1 neurokinin (NK1) receptor antagonist that acts on the central nervous system by inhibiting substance P, the key neurotransmitter that causes emesis. Maropitan inhibits both peripheral and central emesis. [0005] The quality control of drugs is mainly to control the content of active ingredients and related substances, especially the content of related substances needs to meet the requirements for medicinal use. Related substances can also be called impurities, which mainly come from the preparation process of the active ingredient and the degradation of the drug. "Technical Guidelines for Research on Impurities in Chemical Drugs" ([H] GPH3-1, pages 6-7) points out that HPLC i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02G01N30/02
CPCC07D453/02G01N30/02
Inventor 宋启义黄振宇张媛媛满艳哲
Owner 科贝源(北京)生物医药科技有限公司