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Obeticholic acid dimer impurities and preparation method thereof

A technology of obeticholic acid dimer and obeticholic acid, which is applied in the field of medicinal chemistry, can solve the problems of undisclosed preparation methods of obeticholic acid dimers and undisclosed preparation methods of dimer impurities, and achieve good The effects of control, high product purity, and improved safety

Inactive Publication Date: 2016-10-26
FUJIAN COSUNTER PHARMA
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Problems solved by technology

[0006] The Chinese patent document whose authorization notification number is CN101203526B discloses the method for preparing 3A(B)-7A(B)-dihydroxy-6A(B)-alkyl-5B-cholanic acid (obeticholic acid), but does not disclose The preparation method of obeticholic acid dimer; the Chinese patent document with application publication number CN104781272A discloses the preparation, use and solid form of obeticholic acid and the control of the limit of dimer impurities, but does not disclose the dimer impurities preparation method

Method used

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  • Obeticholic acid dimer impurities and preparation method thereof
  • Obeticholic acid dimer impurities and preparation method thereof
  • Obeticholic acid dimer impurities and preparation method thereof

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specific Embodiment approach

[0043] A preparation method of obeticholic acid dimer, comprising the steps of following successively:

[0044] S1: Preparation of a crude compound of obeticholic acid dimer impurity; it comprises the following sub-steps performed in sequence:

[0045] S1-1: adding obeticholic acid to 20-40 volume times of n-hexane or toluene or petroleum ether,

[0046] S1-2: Stir and heat reflux with water, keep the reaction at 65~120℃ for 4~8h, when the amount of water collected by weighing is about 80% of the theoretical water amount, cool down to 30~35℃, the theoretical water amount=input The weight of obeticholic acid ÷ 420.63 ÷ 2 × 18;

[0047] S1-3: add 5% sodium bicarbonate solution, stir and wash for 10 minutes, stand for stratification;

[0048] S1-4: the organic layer is evaporated to dryness under reduced pressure to obtain the crude compound of obeticholic acid dimer impurity;

[0049] S2: column chromatography separation and purification of obeticholic acid dimer impurity cru...

Embodiment 1

[0056] Embodiment 1 (best embodiment):

[0057] In a three-necked flask equipped with a stirrer, a water separator, and a thermometer, add 12 g of obeticholic acid, 360 ml of n-hexane, and 1 drop of concentrated sulfuric acid, reflux and dehydrate at 70 ± 2 °C for 6 h, cool to room temperature, and add 100 ml of water to wash , the aqueous layer was discarded, washed with 50 ml of 5% sodium bicarbonate solution, the aqueous sodium bicarbonate layer was discarded, and the organic layer was decompressed to dryness at 50 ° C to obtain the crude compound of obeticholic acid dimer impurity; Add 55 ml of petroleum ether to dissolve 11 g of the crude compound of cholic acid dimer impurity, add 20 g of 200-300 mesh silica gel, and rotate to steam until the solid in the bottle is quicksand. At the same time, 250g of 200-300 mesh silica gel was added to 500ml of petroleum ether as the stationary phase, and then added to the glass chromatography column after stirring evenly, and the glas...

Embodiment 2

[0058] Embodiment 2 (preferred embodiment):

[0059] In a three-necked flask equipped with a stirrer, a water separator, and a thermometer, add 12 g of obeticholic acid, 360 ml of toluene, and 1 drop of phosphoric acid, reflux and dehydrate at 112 ± 2 °C for 6 h, cool to room temperature, add 100 ml of water to wash, discard The aqueous layer was removed, washed with 50 ml of 5% sodium bicarbonate solution, the aqueous sodium bicarbonate layer was discarded, and the organic layer was decompressed to dryness at 55°C to obtain the crude compound of obeticholic acid dimer impurity; Add 55 ml of petroleum ether to dissolve 12 g of the dimer impurity crude compound, add 20 g of 200-300 mesh silica gel, and rotate to steam until the solid in the bottle is quicksand. At the same time, 250g of 200-300 mesh silica gel was added to 500ml of petroleum ether as the stationary phase, and then added to the glass chromatography column after stirring evenly, and the glass chromatography colum...

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Abstract

The invention relates to obeticholic acid dimer impurities and a preparation method thereof. The preparation method sequentially includes the steps of S1, preparing a beticholic acid dimer impurity coarse compound; S2, performing column chromatography separation and purification on the beticholic acid dimer impurity coarse compound. The preparation method has the advantages that the method is used for preparing the dimer impurities generated during the synthesizing and degrading process of obeticholic acid, the quality of the obeticholic acid can be well controlled, and medicine safety can be increased.

Description

technical field [0001] The invention relates to an obeticholic acid dimer impurity and a preparation method thereof, belonging to the field of medicinal chemistry. Background technique [0002] Obeticholic acid (OCA) is a semi-synthetic chenodeoxycholic acid and a farnesoid derivative X receptor (FXR) agonist. Animal experiments have shown that it can improve insulin resistance and reduce liver fat content. [0003] The structural formula of obeticholic acid is as follows: [0004] [0005] Intercept is intended for use in primary biliary cirrhosis (PBC) and nonalcoholic steatohepatitis (NASH). The primary biliary cirrhosis (PBC) indication is in the NDA review stage, and the nonalcoholic steatohepatitis (NASH) indication is in the phase III clinical stage. [0006] The Chinese patent document with the authorization announcement number CN101203526B discloses a method for preparing 3A(B)-7A(B)-dihydroxy-6A(B)-alkyl-5B-cholanoic acid (obeticholic acid), but does not discl...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 廖龙辉陈国华刘燕清姚文松傅世武朱小兰彭珍香姚建堤伍虹蓉冯彬陈仕魁
Owner FUJIAN COSUNTER PHARMA
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