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Obeticholic acid derivative and obeticholic acid preparation method

An obeticholic acid and compound technology, which is applied in the field of drug synthesis, can solve the problems of low reaction yield, complicated post-processing, and limited trial range, and achieves the effects of high yield, simple post-processing and simple purification method.

Inactive Publication Date: 2018-08-28
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, ordinary carboxylic acid esters are prone to hydrolysis during the process of double bond reduction and configuration reversal, and cannot protect the carboxyl group. Therefore, it is inevitable to avoid hydrolysis during the reaction process. For some esters, methanol is generally used as a solvent to hydrolyze part of the carboxyl groups to generate methyl esters under such conditions when alkali is used for configuration reversal. This scheme greatly increases the difficulty of industrial operation, and the trial range is not wide; Straight-chain alkylamide scheme, which can avoid hydrolysis in the configuration inversion step, and keep the original amide structure for purification, but the examples disclosed in the text and our corresponding alkylamide experiments found that the reaction yield is relatively low. Low and more complex post-processing

Method used

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  • Obeticholic acid derivative and obeticholic acid preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: When R 4 and R 5 Form N-methylpiperazinyl for linked rings

[0053] Compound A-2 Preparation Method 1

[0054] Add 50 grams of compound A-1 (1.0eq), 500 milliliters of dichloromethane, nitrogen methyl piperidine (1.2eq), DCC (1.5eq), DMAP (0.2eq), nitrogen protection, room temperature stirring reaction in reaction flask To complete, add water, separate the layers, wash the organic phase with water, dry with anhydrous ammonium sulfate, and concentrate to obtain compound A-2 with a molar yield of 88%. m / z=473.4[M+H] + .

[0055] 1 H NMR (400MHz, Chloroform-d) δ3.55 (ddt, J=15.5, 10.7, 4.6Hz, 1H, C 3 H), 3.36(t, J=7.4Hz, 4H, piperazine hydrogen), 2.20(t, J=7.4Hz, 4H, piperazine hydrogen), 1.30(s, 3H, C 19 on H), 0.66(s,3H, C 18 H above).

[0056] Compound A2 Preparation Method 2

[0057] Add 50 grams of compound A1 (1.0eq), dichloromethane, 0-10°C to the reaction flask, drop in oxalyl chloride, react for 3h, concentrate to dryness, and then add 4-azani...

Embodiment 2

[0064] Embodiment 2 is prepared according to the method of embodiment 1 when R 3 for hydrogen, R 4 Preparation of IV-2 for 4-aminopyridyl

[0065] Add 40 grams of compound A3-2 (1.0eq) to the reaction flask, methylene chloride, nitrogen protection, cool to -60°C to -50°C, add acetaldehyde (2eq), then drop boron trifluoride ether (3eq ), kept at -60°C for 2 hours, raised to room temperature and reacted for 1 hour, added 2N hydrochloric acid, stirred for 30 minutes, filtered, and washed with water to obtain Compound IV-2 with a purity of 93%, Compound A-2 Preparation Method 1, and a molar yield of 90%. m / z=493.3[M+H] + .

Embodiment 3

[0066] Example 3 was prepared according to the method of Example 1. When R3 was hydrogen and R4 was 4-N,N dimethylphenyl, IV-1 was prepared.

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Abstract

The present invention provides an obeticholic acid derivative and an obeticholic acid preparation method, wherein configuration transformation of a compound represented by a formula III, carbonyl reduction and amide hydrolysis are performed to obtain obeticholic acid. According to the present invention, the route has characteristics of simple operation, convenient post-treatment, and high yields and high purities of intermediates in each step.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a preparation method of obeticholic acid derivatives and farnesoid X receptor (FXR) obeticholic acid. Background technique [0002] Obeticholic acid was developed by Intercept Pharmaceuticals for the treatment of portal hypertension and liver disease. The company's Asian licensor, Sumitomo Pharmaceuticals of Japan, is studying the drug for the treatment of PBC, as well as NASH. In 2016, the PBC indication of obeticholic acid was launched in the United States, and the phase II / III clinical trial of NASH began in 2011. The drug has obtained orphan drug approval for PBC indications in the United States and Europe. The chemical name is 6α-ethyl-3α,7α-dihydroxy-5β-cholanic acid, and its structure is as follows: [0003] [0004] Intercept Pharmaceuticals discloses a method for preparing obeticholic acid from bromoethane in patent WO02072598, but the molar yield is only 3.5%, an...

Claims

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Application Information

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IPC IPC(8): C07J9/00C07J43/00
CPCC07B2200/07C07J9/00C07J9/005C07J43/003Y02P20/55
Inventor 郭四根徐苗焕
Owner ZHEJIANG JINGXIN PHARMA
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