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Method for preparing obeticholic acid, ursodeoxycholic acid and 7-ketolithocholicacid

A technology of ursodeoxycholic acid and obeticholic acid, which is applied in the production of steroids, organic chemistry, and bulk chemicals, can solve the problems of unsuitability for large-scale production, high equipment requirements, and low total yield, and achieve Facilitate industrial production, environmental friendliness and low cost

Inactive Publication Date: 2018-10-19
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] (2) The synthetic route (g) uses chenodeoxycholic acid as a raw material to synthesize ursodeoxycholic acid. Although the yield (85.7%) is relatively high, the cost is high with chenodeoxycholic acid as a raw material
This method needs to use high-temperature Huangminglong reaction in the process of preparing 7-ketolithocholic acid, has higher requirements on equipment, and the total yield is low (59%), so it is not suitable for large-scale production

Method used

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  • Method for preparing obeticholic acid, ursodeoxycholic acid and 7-ketolithocholicacid
  • Method for preparing obeticholic acid, ursodeoxycholic acid and 7-ketolithocholicacid
  • Method for preparing obeticholic acid, ursodeoxycholic acid and 7-ketolithocholicacid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] 1, the synthesis of formula (2-1) compound

[0154]

[0155] Cholic acid (10.00 g, 24.5 mmol) was dissolved in pyridine (50 mL), succinic anhydride (3.43 g, 34.3 mmol) was added, and the temperature was raised to 25° C. for 7 hours. After the reaction of the raw materials was detected by TLC, the reaction solution was cooled to room temperature, poured into 2M hydrochloric acid, stirred for 15 minutes, and suction filtered. The filter cake was washed with ether and dried to obtain the compound of formula (2-1) (12.5 g, white solid, 99 %). 1 HNMR (400MHz, DMSO-d 6 )δ12.07(s,2H),4.44(s,1H),4.03(d,J=7.2Hz,1H),3.79(s,1H),0.94(t,J=11.8Hz,5H),0.84( s,3H),0.59(s,3H).

[0156] 2, the synthesis of formula (3-1) compound

[0157]

[0158] The crude compound of formula (2-1) (12.50g, 24.5mmol) was dissolved in a mixed solvent of acetone (60mL) and water (60mL), added with NBS (5.7g, 31.9mmol), and reacted at 25°C for 2 hours. After the reaction of the raw materials was de...

Embodiment 2

[0193] 1, the synthesis of formula (2-2) compound

[0194]

[0195] Formula (1) cholic acid (4.08g, 10mmol) was dissolved in pyridine (50mL), glutaric anhydride (1.5g, 13mmol) was added, the temperature was raised to 80°C for 7 hours, and 300mg of glutaric anhydride was added for 7 hours. After the reaction of the raw materials was detected by TLC, the reaction liquid was cooled to room temperature, poured into 2M hydrochloric acid, and stirred for 15 min. After suction filtration, the filter cake was dried to obtain the compound of formula (2-2) (4.18 g, white solid, 82%). 1 H NMR (400MHz, CDCl 3 )δ4.59(s,1H),4.01(s,1H),3.87(s,1H),3.67(s,1H),1.00(d,J=5.6Hz,3H),0.90(s,3H), 0.70(s,3H).

[0196] 2, the synthesis of formula (3-2) compound

[0197]

[0198] The crude compound of formula (2-2) (4.18g, 8.2mmol) was dissolved in a mixed solvent of acetone (60mL) and water (20mL), NBS (2.3g, 13.3mmol) was added, and reacted in the dark for 2 hours. After the reaction of the...

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Abstract

The invention discloses a method for preparing obeticholic acid, 7-ketolithocholicacid and ursodeoxycholic acid. Cholic acid is used as a raw material for preparing obeticholic acid through selectiveprotection by a 3-alpha-hydroxyl group, selective oxidation of a 7-alpha-hydroxyl group, esterification of a 24th carboxyl group, methanesulfonation of a 12-alpha-hydroxyl group, elimination, hydrolysis, silylation, condensation, hydrolysis, catalytic hydrogenation, carbonyl reduction and other reactions; an intermediate is subjected to catalytic hydrogenation to prepare the 7-ketolithocholicacidand then is reduced to prepare the ursodeoxycholic acid. The method provided by the invention uses cheap cholic acid as the raw material, and has advantages of novel synthesis method, low cost, high yield, mild reaction condition, high simplicity in operation, environmental friendliness and high convenience in industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of obeticholic acid, ursodeoxycholic acid and 7-ketolithocholic acid. Background technique [0002] Obeticholic acid, chemical name 3α,7α-dihydroxy-6α-ethyl-5β-cholestane-24-acid, trade name Ocaliva, also known as INT-747 or 6α-ethylchenodeoxy Cholic acid, developed by American Intercept Pharmaceuticals. Its mechanism is mainly through activating farnesoid X receptors, regulating related genes, and affecting the synthesis, secretion, transport and absorption of bile acids. Obeticholic acid has the function of treating primary biliary cirrhosis (PBC), and was approved by the FDA in 2016. In addition, obeticholic acid also has a good therapeutic effect on non-alcoholic steatohepatitis (NASH), and this indication is currently in phase III clinical stage. Statistics show that worldwide, the incidence of NASH is 2-3%. In recent years, NAS...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/00C07J9/005Y02P20/55
Inventor 仇文卫
Owner EAST CHINA NORMAL UNIV
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