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Method for preparing obeticholic acid from new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid

A technology of obeticholic acid and cholanic acid, which is applied in the field of medicine, can solve the problems of large 7-position chiral inversion impurities, difficult purification and separation of oily substances, etc., and achieves easy purification, significant creativity and practical application value, The effect of increasing the yield

Inactive Publication Date: 2017-11-24
HANGZHOU HEZE PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the intermediates involved in this preparation process are oily substances that are not easy to be refined and purified. The yield of this route is always 26.6%, and the 7-position chiral inversion impurity is relatively large and difficult to separate

Method used

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  • Method for preparing obeticholic acid from new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid
  • Method for preparing obeticholic acid from new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid
  • Method for preparing obeticholic acid from new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] a) Preparation of 3α-hydroxyl-7-oxo-5β-cholanic acid methyl ester

[0021] 3α-Hydroxy-7-oxo-5β-cholanic acid (39.0 g, 100 mmol) and p-toluenesulfonic acid (1.72 g, 10 mmol) were dissolved in 120 ml of methanol, heated to reflux, and kept for 1 hour. Cool down to room temperature, and slowly add 240ml of water to dilute with stirring, and a solid precipitates out. After the dropwise addition, cool to 5°C, stir for 1 hour, and filter. The solid was rinsed and dried with a methanol:water (1:10) solution to obtain methyl 3α-hydroxy-7-oxo-5β-cholanate (37.6 g, yield 93.1%).

[0022] b) Preparation of 3α-triphenylmethoxy-7-oxo-5β-cholanoic acid methyl ester

[0023] 3α-Hydroxy-7-oxo-5β-cholanoic acid methyl ester (40.4g, 100mol), triphenylchloromethane (29.2g, 105mmol), DMAP (4-dimethylaminopyridine) (1g) were dissolved in In 120ml of DMF (N,N-dimethylformamide), the temperature was raised to 50°C with stirring, and the reaction was kept for 24 hours. Cool down to 20°C, a...

Embodiment 2

[0034] a) Preparation of ethyl 3α-hydroxy-7-oxo-5β-cholanate

[0035] 3α-Hydroxy-7-oxo-5β-cholanic acid (39.0 g, 100 mmol) and p-toluenesulfonic acid (1.72 g, 10 mmol) were dissolved in 120 ml of ethanol, heated to reflux, and kept for 1 hour. Cool down to room temperature, and slowly add 240ml of water to dilute with stirring, and a solid precipitates out. After the dropwise addition, cool to 5°C, stir for 1 hour, and filter. The solid was rinsed and dried with ethanol alcohol:water (1:10) solution to obtain ethyl 3α-hydroxy-7-oxo-5β-cholanate (39.8 g, yield 93.1%).

[0036] b) Preparation of 3α-p-benzyloxymethoxy-7-oxo-5β-cholanoic acid ethyl ester

[0037] 3α-Hydroxy-7-oxo-5β-cholanoic acid ethyl ester (41.8g, 100mmol), p-benzyloxychloromethyl ether (17.2g, 110mmol), tetrabutylammonium iodide (1g) were dissolved in 150ml In dichloromethane, diisopropylethylamine (110 mmol) was slowly added dropwise with stirring. After the dropwise addition, the reaction was carried out...

Embodiment 3

[0050] a) Preparation of tert-butyl 3α-hydroxy-7-oxo-5β-cholanate

[0051] Dissolve 3α-hydroxy-7-oxo-5β-cholanic acid (39.0g, 100mmol) and tert-butanol (8.9g, 120mmol) in 180ml of dichloromethane, cool to 5°C in an ice-water bath, add sulfuric acid: sulfuric acid Magnesium (1:4) 5g, stirred for 1 hour, naturally warmed to room temperature, and reacted for 6 hours. Add 100ml of water to wash, separate the organic phase, wash with saturated brine 50ml*2, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain tert-butyl 3α-hydroxy-7-oxo-5β-cholanate (42.9 g, yield 86.1%).

[0052] b) Preparation of tert-butyl 3α-benzyloxy-7-oxo-5β-cholanate

[0053] 3α-Hydroxy-7-oxo-5β-cholanoic acid tert-butyl ester (44.6g, 100mmol), triethylamine (12.5g, 120mmol) were dissolved in 200ml tetrahydrofuran, and benzyl bromide (18.0 g, 105mmol), the dropwise addition was completed and incubated for 4 hours. Add 100 ml of saturated brine for washing, separate ...

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Abstract

The invention discloses a method for preparing obeticholic acid from a new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid. The synthesis method comprises the following steps: firstly, carrying out hydroxyl and carboxyl protection on the 3alpha-hydroxy-7-oxo-5beta-cholanic acid to prepare the corresponding new derivative; secondly, obtaining the obeticholic acid respectively according to two synthesis routes. According to the method disclosed by the invention, a safer protecting group reagent is utilized, and the problem that ultraviolet absorption of an intermediate is not strong is solved; the intermediate is easier to purify, the yield is improved, and the cost is reduced, so that the method is more suitable for industrialized amplification, and has remarkable creativity and actual application value.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of obeticholic acid. More specifically, it relates to a method for preparing obeticholic acid from a new derivative of 3α-hydroxy-7-oxo-5β-cholanic acid. Background technique [0002] Formula (I) 3α-hydroxy-7-oxo-5β-cholanic acid is an important intermediate for preparing formula (V) obeticholic acid. Obeticholic acid was successfully developed by American intercept pharmaceutical company, and it is a drug for the treatment of cholestatic liver disease. By activating the farnesoid X receptor, it indirectly inhibits the gene expression of cytochrome 7A1 (CYP7A1), thereby inhibiting bile acid synthesis. [0003] [0004] CN104926909 discloses that 3α-hydroxyl-7-oxo-5β-cholanic acid is protected by carboxymethyl ester, and the hydroxyl group is protected by 2-tetrahydropyranyl; under the action of a strong base, it is contacted with bromoethane to carry ...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005Y02P20/55
Inventor 倪晟杨政和陈洁蔡烈峰周英雷周亮陈鸿翔
Owner HANGZHOU HEZE PHARMA TECH
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