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Method for preparing obeticholic acid and intermediate thereof

A technology for obeticholic acid and intermediates, which is applied in the field of preparation of obeticholic acid and its intermediates, can solve the problems of low separation yield, achieve the effects of reducing side reactions, mild reaction conditions, and suitable for large-scale production

Inactive Publication Date: 2017-01-04
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this process can realize large-scale production, however, during the preparation of compound IX by palladium-carbon hydrogenation reduction of compound VII under strong basic conditions and high-temperature treatment under strong basic conditions, side reactions such as dehydration of hydroxyl groups occur, resulting in a low separation yield of this process.

Method used

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  • Method for preparing obeticholic acid and intermediate thereof
  • Method for preparing obeticholic acid and intermediate thereof
  • Method for preparing obeticholic acid and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of compound III

[0042] Add 10.0g of compound IV and 100ml of methanol to the reaction flask, add 1.3g of sodium borohydride, keep warm at 20-40°C for 5 hours, concentrate to dryness under reduced pressure, add 100ml of water and 100ml of ethyl acetate, separate liquid, anhydrous sodium sulfate The organic phase was dried, filtered and concentrated to obtain 9.8 g of compound III with a yield of 97.6%.

[0043] MS (ESI, m / z): 433.6 ([M+H] + )

[0044] H-NMR: 5.556(d,1H), 4.483(d,1H), 4.138(d,1H), 3.736(s,1H), 3.573(s,3H), 3.403(s,1H), 2.290~2.401( m,2H), 2.177~2.237(m,1H), 0.839~1.945(m,27H), 0.699(s,3H), 0.585(s,3H).

Embodiment 2

[0045] Embodiment 2: the preparation of intermediate II

[0046] Dissolve 5.0g of compound III in 40ml of methanol, add 0.5g of palladium carbon (10wt%), react for 5h under hydrogen pressure of 1-2MPa and 20-40°C, and obtain 4.8g of intermediate II after filtration and concentration, with a yield of 95.6%.

[0047] MS (ESI, m / z): 435.6 ([M+H] + )

[0048] H-NMR: 4.028(m,2H), 3.573(s,3H), 3.493(s,1H), 3.126(t,1H), 2.299~2.342(m,1H), 2.191~2.232(m,1H), 1.902(d,1H), 1.670~1.815(m,7H), 0.875~1.527(m,17H), 0.845(d,3H), 0.821(d,6H), 0.602(s,3H).

Embodiment 3

[0049] Example 3: Preparation of Obeticholic Acid (Compound I)

[0050] Dissolve 4.0 intermediate II in 16ml of methanol, add 8ml of 10% sodium hydroxide aqueous solution, react at 20-40°C for 1h, concentrate under reduced pressure, evaporate the organic solvent, add 40ml of purified water and 40ml of dichloromethane, and stir for 10-20min , separated, and the aqueous phase was washed twice with 40 ml of dichloromethane. Use 3mol / L hydrochloric acid to adjust the pH value of the aqueous phase to 7~8, add 40ml ethyl acetate, continue to use 3mol / L hydrochloric acid to adjust the pH value to 2~3, separate the liquids, and use 40ml water and 40ml saturated chlorine for the organic phase respectively. washed with sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. Physic agent ammonium iyi was suction-filtered, the filtrate was concentrated under reduced pressure to near-dryness, and 2.2 g of obeticholic acid was refined by adding 80 ml of dichlorometh...

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Abstract

The invention belongs to the technical field of medical chemistry, particularly relates to a new method for preparing obeticholic acid and an intermediate thereof. The method comprises the steps that a compound III is subjected to catalytic hydrogenation to produce an intermediate II, and then the obeticholic acid is prepared. The method has the advantages of being simple in operation, mild in reaction conditions, and reduces the reaction temperature, reduces side reactions such as the dehydration of hydroxyls, improves yields and is suitable for a large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new method for preparing obeticholic acid and its intermediates. The method is easy to operate, has mild reaction conditions, reduces the occurrence of side reactions, improves the yield, and is suitable for large-scale production. Background technique [0002] Obeticholic acid, chemical name 3α-hydroxy-6α-ethyl-7α-hydroxy-5β-cholanic acid, has the chemical structure shown in formula I, is a farnesoid derivative X receptor ( FXR) specific agonist, is the first drug developed for the treatment of cholestatic liver disease in two decades. Obeticholic acid was developed by Intercept Pharmaceuticals of the United States, and was approved by the FDA in May 2016 for the combined treatment of primary biliary cirrhosis (PBC) with ursodeoxycholic acid (UDCA). [0003] [0004] Patent WO02072598 reports that 3-α-hydroxy-7-keto-5β-cholanic acid is used as raw ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 张红卫庄红伟李国锋林栋
Owner QILU PHARMA
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