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Method for preparing obeticholic acid type 1

A technology for the preparation of obeticholic acid, which is applied in the field of preparation of obeticholic acid type 1, can solve the problems of unfavorable commercial production, prolongation of production cycle, and increase of operation steps, and achieve shortening of synthesis steps, short production cycle and low cost cheap effect

Active Publication Date: 2016-06-08
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to prepare high-purity crystalline obeticholic acid type C in advance, and there are disadvantages such as high reagent cost, high boiling point of solvent, difficult recovery, increased operation steps, complicated post-treatment, and prolonged production cycle, which is not conducive to commercial production.

Method used

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  • Method for preparing obeticholic acid type 1
  • Method for preparing obeticholic acid type 1
  • Method for preparing obeticholic acid type 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Preparation of (E)-3α,7α-dihydroxy-6-ethylene-5β-cholan-24-oic acid

[0047] Add (E)-3α-hydroxyl-6-ethylene-7-keto-5β-cholan-24-acid (400.0g, 0.96mol), sodium hydroxide (192.0g, 4.8mol) and Water (4.0 L) was heated to 95° C. under stirring, and sodium borohydride (36.3 g, 0.96 mol) was added, and reacted for 3 hours. TLC traced that the reaction of the raw materials was complete. After the reaction, cool to 40°C, add ethyl acetate (6.0L) and water (4.0L), adjust the pH to 3 with 37% hydrochloric acid, separate the layers, dry the organic phase with anhydrous sodium sulfate for 2 hours, filter, and filter the filtrate at 40 °C and evaporated to dryness under reduced pressure to obtain a white solid, namely (E)-3α,7α-dihydroxy-6-ethylene-5β-cholan-24-acid (394.6g, purity: 99.6%, yield: 98.2%) .

Embodiment 2

[0049] Preparation of (E)-3α,7α-dihydroxy-6-ethylidene-5β-cholane-24-oic acid methyl ester

[0050] Add (E)-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (50.0 g, 0.12 mol), anhydrous methanol (100 mL) and methanesulfonic acid ( 0.5 g), the temperature was raised to 60° C. under stirring, and the reaction was carried out for 2 hours. TLC traced that the reaction of the raw materials was complete. After the reaction, water (75mL) was added to the reaction mixture, cooled to 5-10°C and stirred for 3 hours, filtered, the filter cake was washed with a small amount of water and methanol, and the filter cake was vacuum-dried at 50°C to obtain a white solid, namely (E)- 3α,7α-Dihydroxy-6-ethylene-5β-cholane-24-oic acid methyl ester (45.8 g, purity: 99.5%, yield: 88.2%).

Embodiment 3

[0052] Preparation of obeticholic acid type 1

[0053] Add (E)-3α-dihydroxy-6-ethylene-7-keto-5β-cholan-24-acid (50.0g, 0.12mol), sodium hydroxide (9.6g, 0.24mol) in the reaction flask , water (400mL) and 5% palladium carbon (5.0g), the reaction mixture was heated up to 80°C under a pressure of 1 to 3 atmospheres, and hydrogenation was indicated after 3 hours of hydrogenation no longer absorbed. The reaction solution was cooled to 50°C, filtered, and water (750 mL) was added to the filtrate, and the temperature was raised to 50°C. Add 1.0 mol / L hydrochloric acid solution dropwise to adjust the pH to 3.0, continue to heat and stir for 30 minutes, cool to 10°C and stir for crystallization for 2 hours, filter, and vacuum-dry the filter cake at 50°C for 3 hours to obtain a white solid, namely obeticholic acid 1 Form (42.5g, purity: 99.3%, yield: 84.2%).

[0054] Present embodiment sample X-ray powder diffraction pattern (XRPD) sees attached figure 1 , the X-ray powder diffracti...

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Abstract

The invention discloses a method for preparing obeticholic acid type 1. The method comprises the steps that firstly, (E)-3 alpha,7 alpha-dyhydroxyl-6-ethylidene-5 beta-cholane-24-acid or (E)-3 alpha,7 alpha-dyhydroxyl-6-ethylidene-5 beta-cholane-24-acid ester (a compound II), alkali, a solvent and 5% palladium on carbon are loaded into a reactor, the mixture reacts under the pressure of 1-3 atmospheres, a hydrogenation reaction is carried out at the preserved temperature until it is indicated that hydrogen does not conduct absorption any more; reaction liquid is cooled to 40-50 DEG C and filtered, filter liquid is added with water and heated to 40-50 DEG C, and a solution is obtained; secondly, the obtained solution is dipped with a thin acid solution to regulate the pH value to be 1-6, the solution is cooled, stirred for crystallization and filtered, and obeticholic acid type 1 is obtained through vacuum drying. By means of the preparing method, crystallized obeticholic acid type C does not need to be obtained, and obeticholic acid type 1 is obtained in one step, so that production steps are reduced, operation is simplified, aftertreatment is easy, and cost is reduced.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a method for preparing obeticholic acid type 1. Background technique [0002] Obeticholic acid (compound Ⅰ) is a farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals of the United States for the treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease. liver disease. The structural formula is as follows: [0003] [0004] Molecular formula: C 26 h 44 o 4 Molecular weight: 420.63 [0005] Polymorphism exists widely in pharmaceuticals. Different crystal forms of the same drug have significant differences in solubility, melting point, density, and stability, which affect the stability, uniformity, bioavailability, efficacy, and safety of the drug to varying degrees. Therefore, comprehensive and systematic polymorph screening in drug development and selection of the most suitable crystal form for development is one of the importa...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 赵磊林辉汤新坡谢少斐李纬
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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