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Preparation method of chenodeoxycholic acid derivative

A compound and oxidation reaction technology, applied in the field of preparation of chenodeoxycholic acid derivatives, can solve the problems of low product yield, long process route, 6ECDCA needs to be improved, etc.

Active Publication Date: 2016-09-07
HUBEI BIO PHARMA IND TECHCAL INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process route is long and the resulting product yield is low
[0006] Therefore, the current method for preparing 6ECDCA still needs to be improved

Method used

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  • Preparation method of chenodeoxycholic acid derivative
  • Preparation method of chenodeoxycholic acid derivative
  • Preparation method of chenodeoxycholic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Compound 1 (5 g, 12.7 mmol) was added to the reaction flask, and 50 mL of dichloromethane, DMSO (1.12 g, 14.3 mmol), and triethylamine (4.2 g, 41.5 mmol) were added. The reaction temperature was lowered to -30°C, trifluoroacetic anhydride (3.2 g, 15.2 mmol) was added dropwise thereto, and after 1.5 h of heat preservation reaction, 10 mL of water was added, stirred to rise to room temperature, left to separate liquids, and the water phase was dichloromethane Methane was extracted twice, 20ml each time, the organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness to obtain compound 2. The yield was 4.89g, and the yield was 98.6%. .

[0039] The analysis data is:

[0040] 1 H NMR (CD3OD) δ3.50(m, 1H), 2.94(m, 1H), 2.52(t, 1H), 2.30(m, 2H), 2.19(m, 6H), 1.70(m, 2H), 1.43 (m, 4H), 1.31(m, 6H), 1.19(s, 3H), 1.12(m, 4H), 0.92(d, 3H), 0.67(s, 3H).

Embodiment 2

[0042] Compound 1 (5 g, 12.7 mmol) was added to the reaction flask, and 50 mL of dichloromethane, DMSO (1.0 g, 12.8 mmol), and triethylamine (3.5 g, 34.6 mmol) were added. The reaction temperature was lowered to -50°C, trifluoroacetic anhydride (2.7g, 12.8mmol) was added dropwise thereto, and after the heat preservation reaction for 0.5h, the post-treatment was the same as in Example 1 to obtain compound 2 with a yield of 4.80g and a yield of 96.8 %.

Embodiment 3

[0044] Compound 1 (5 g, 12.7 mmol) was added into the reaction flask, and 50 mL of dichloromethane, DMSO (3 g, 38.1 mmol), and triethylamine (4.2 g, 41.5 mmol) were added. The reaction temperature was lowered to -70°C, and trifluoroacetic anhydride (8 g, 38.1 mmol) was added dropwise thereto. After 3 hours of heat preservation, the post-treatment was the same as in Example 1 to obtain compound 2 with a yield of 4.76 g and a yield of 96.0%.

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Abstract

The invention relates to a preparing method of a chenodeoxycholic acid derivative, and particularly relates to a preparing method of a compound shown as a formula I. The method includes (1) subjecting a compound shown as a formula 1 to Swern oxidation to obtain a compound shown as a formula 2; (2) subjecting the compound shown as the formula 2 to hydroxy protection to obtain a compound shown as a formula 3; (3) bringing the compound shown as the formula 3 into contact with iodoethane to obtain a compound shown as a formula 4; (4) subjecting the compound shown as the formula 4 to a reduction reaction to obtain a compound shown as a formula 5; and (5) bringing the compound shown as the formula 5 into contact with hydrogen under the existence of palladium / carbon that is a catalyst to obtain the compound shown as the formula I. The method is short in steps, simple in operation, and suitable for industrial production, and raw materials are easily available.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a preparation method of a compound, more specifically, to a preparation method of a chenodeoxycholic acid derivative (6ECDCA). Background technique [0002] 6ECDCA (alias 6α-ethyl chenodeoxycholic acid, INT-747, obeticholic acid, compound shown in formula I) is a derivative of chenodeoxycholic acid (CDCA). Chenodeoxycholic acid is a common gallstone drug in clinic, and 6ECDCA has been proved to be a highly active farnesoid X receptor agonist. On January 9, 2014, Intercept Pharmaceuticals announced that the Phase III clinical trial of 6ECDCA in the treatment of nonalcoholic steatohepatitis (NASH) reached the primary clinical endpoint. In addition, Intercept's research on the treatment of primary biliary cirrhosis with 6ECDCA is currently in phase III clinical trials in the United States. [0003] [0004] Donna Yu et al. (Steroids, 2012, 77(13): 1335-1338) disclosed that chenodeoxycho...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 王学海许勇乐洋冯权武黄璐
Owner HUBEI BIO PHARMA IND TECHCAL INST
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