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Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid

A technology of obeticholic acid and a synthesis method, which is applied in the field of organic chemical synthesis and can solve the problems of high equipment requirements, low yield, and unsuitability for large-scale production.

Inactive Publication Date: 2017-07-11
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to use the high-temperature Huangminglong reaction in the process of preparing 7-ketolithocholic acid, which has higher requirements on equipment, low yield (58.94%), and is not suitable for large-scale production. The reaction formula is as follows:

Method used

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  • Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid
  • Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid
  • Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid

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Experimental program
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Effect test

Embodiment 1

[0112]

[0113] 1. Synthesis of the compound of formula (2): Dissolve cholic acid (9g, 22.0mmol) in a mixed solution of 200mL acetone and water (v / v=3:1), avoid light, slowly add NBS (5.7g, 31.9 mmol), react at room temperature 25°C for 2h. After TLC detected that the reaction was complete, add 100mL saturated sodium bisulfite solution to quench the reaction, remove the solvent under reduced pressure until a white solid appeared, and pour it into 1L of water to precipitate a large amount of white solid, leave it to crystallize, filter and dry, The compound of formula (2) was obtained (8.5 g white solid, yield 95%). used directly in the next step.

[0114]

[0115] 2. Synthesis of the compound of formula (3-1): Dissolve the compound of formula (2) (8.5g, 20.9mmol) in 100mL of methanol, add concentrated sulfuric acid (0.11mL, 2.09mmol), and reflux for 2h. After the reaction was complete as detected by TLC, methanol was removed under reduced pressure, 30 mL of water was a...

Embodiment 2

[0129]

[0130] 1. Synthesis of the compound of formula (2): Dissolve 9g of cholic acid in a mixed solution of 200mL of acetone and water (v / v=3:1), keep away from light, and slowly add 5.7g of NBS (31.9mmol) after it is completely dissolved , room temperature reaction 2h. Add 100mL of saturated sodium bisulfite solution to prevent further oxidation, spin the solvent, when a white solid appears, pour it into clear water, a large amount of white solid precipitates, leave it to crystallize, and after suction filtration and drying, the compound of formula (2) ( 8.5g white solid, yield 95%), used directly in the next step.

[0131]

[0132] 2. Synthesis of the compound of formula (3-1): the compound of formula (2) (8.5 g, 20.8 mol) was dissolved in 100 mL of methanol, 1 mL of concentrated sulfuric acid was added, and the reaction was refluxed for 2 h. After the reaction was complete as detected by TLC, the solvent was evaporated under reduced pressure, 30 mL of water was ad...

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Abstract

The invention discloses a chemical synthesis method for an obeticholic acid intermediate 7-ketolithocholic acid (3alpha-hydroxy-7-keto-5beta-cholestane-24-acid), and belongs to the field of organic chemical synthesis. The method adopts cholic acid as a raw material, and through 7alpha-hydroxyl selective oxidation, side chain carboxyl esterification, 3alpha-hydroxyl etherification, 12alpha-hydroxyl methanesulfonic acid esterification, elimination, hydrogenation, hydrolysis and other reactions, the obeticholic acid intermediate 7-ketolithocholic acid is synthesized. The synthesis method for 7-ketolithocholic acid adopts cheap cholic acid as the raw material, and has the advantages of novel synthesis method, low cost, high yield, environmental friendliness and convenience in industrialized production.

Description

technical field [0001] The invention relates to a chemical synthesis method of 7-ketolithocholic acid (3α-hydroxy-7-keto-5β-cholestane-24-acid), an intermediate of obeticholic acid, belonging to the field of organic chemical synthesis. Background technique [0002] Primary biliary cirrhosis (primary biliary cirrhosis, PBC) is a chronic intrahepatic cholestatic disease, manifested as progressive non-suppurative cholangitis, and can eventually develop into cirrhosis, liver cancer, and even liver failure. Obeticholic acid (trade name Ocaliva) is a potent agonist of farnesoid receptor X (Farnesoid Xreceptor, FXR) developed by Intercept Pharmaceutical Company of the United States, and is used for the treatment of primary biliary cirrhosis. 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. The chemical synthesis of obeticholic acid mainly uses 7-ketolithocholic ac...

Claims

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Application Information

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