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Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde

A dihydroxy and ethyl technology, applied in the field of medicinal chemistry, can solve the problems of low content found, unfavorable for purification, etc., and achieve the effects of high yield and content, and simple and convenient preparation method

Active Publication Date: 2020-08-11
JIANGZI QINGFENG PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] US2016145295A1 discloses the preparation method of the obeticholic acid impurity formula (I), which is likely to produce multiple by-products such as dimers and alcohols in practice. No UV absorption, unfavorable for purification, when using CAD detector to detect the product prepared by this method, it is found that the content is low

Method used

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  • Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde
  • Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde
  • Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde

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Embodiment 1

[0038] Embodiment 1: the preparation of formula II compound

[0039] Add 100.0g of the compound of formula III, 29.3g of dimethylhydroxylamine hydrochloride into the reaction flask, add 2000ml of dichloromethane, then add 60.7g of triethylamine, 42.2g of 1-hydroxybenzotriazole and 59.8g of 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, after adding the reaction at room temperature, after HPLC confirms that the remaining raw materials are less than 2.0%, then water, sodium bicarbonate solution, saturated sodium chloride solution After washing and concentration under reduced pressure, 108.2 g of a light yellow solid compound of formula II was obtained.

Embodiment 2

[0040] Embodiment 2: the preparation of formula II compound

[0041] Add 100.0g of the compound of formula III, 29.3g of dimethylhydroxylamine hydrochloride into the reaction flask, add 2000ml of methyl tetrahydrofuran, then add 77.6g of diisopropylethylamine, 42.5g of 1-hydroxy-7-azabenzene Triazole and 59.8g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and reacted at room temperature. After HPLC confirmed that the remaining raw materials were less than 2.0%, water, carbonic acid Wash with sodium hydrogen solution and saturated sodium chloride solution, and concentrate under reduced pressure to obtain 107.6 g of the compound of formula II as a white solid compound.

Embodiment 3

[0042] Embodiment 3: the preparation of formula II compound

[0043]Add 100.0g of the compound of formula III, 29.3g of dimethylhydroxylamine hydrochloride into the reaction flask, add 2000ml of ethyl acetate, then add 86.87g of diisopropylethylamine, 40.8g of 1-hydroxybenzotriazole and 37.8 g diisopropylcarbodiimide, after adding the reaction at room temperature, after HPLC confirms that the remaining raw material is less than 2.0%, wash with water, sodium bicarbonate solution, saturated sodium chloride solution successively, and concentrate under reduced pressure to obtain the compound of formula II as a white solid Compound 104.4g.

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Abstract

The invention relates to a preparation method of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde. The method is simple, convenient and high in yield and content. The3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde can be conveniently used as a reference substance of related substances for quality control of obeticholic acid or derivatives of obeticholic acid,or used for impurity identification of obeticholic acid or diffracted substances of obeticholic acid, and is beneficial to detection control in the production process of obeticholic acid or derivatives of obeticholic acid and quality control of drugs containing obeticholic acid or derivatives of obeticholic acid.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of 3α, 7α-dihydroxy-6α-ethyl-5β-cholane-24-aldehyde and an application thereof. Background technique [0002] Obeticholic acid (OCA, chemically named 6-ethylchenodeoxycholic acid) is a new generation of primary biliary cirrhosis (PBC) drug developed by Intercept Pharmaceuticals of the United States. The marketing application for the indication of non-spinal steatohepatitis (NASH) with grade liver fibrosis is under review. [0003] [0004] During the research of obeticholic acid, our company found that there will be a reducing impurity 3α,7α-dihydroxy-6α-ethyl-5β-cholane-24-aldehyde (such as formula I structure), because obeticholic acid and its related impurities have no ultraviolet absorption, conventional ultraviolet liquid detection methods cannot detect and quantify it. [0005] [0006] The preparation method of the obeticholic acid impurity for...

Claims

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Application Information

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IPC IPC(8): C07J9/00G01N30/02G01N30/06G01N30/34G01N30/64
CPCC07J9/00G01N30/02G01N30/06G01N30/34G01N30/64Y02P20/55
Inventor 欧阳婷郭正友付敏古亮刘晓斌刘健
Owner JIANGZI QINGFENG PHARMACEUTICALS INC
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