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Preparation method of chenodeoxycholic acid derivatives

A technology for compound and hydrochloride, applied in the field of preparation and purification of chenodeoxycholate, can solve the problems of difficult removal of impurities in final products, difficult separation of intermediates, and needs for intermediates and products.

Pending Publication Date: 2020-09-29
SUZHOU ZELGEN BIOPHARML
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Patent WO02072598 discloses a method for synthesizing chenodeoxycholic acid derivatives by using 3α-dihydroxy-7-keto-5β-chole-24-acid as the starting material through steps such as alkylation at the 6-position, but the patent There are many deficiencies in the synthetic method in, as all intermediates and products need chromatographic column purification, the total reaction yield is extremely low (only 3.5%), and the reaction steps have used carcinogenic reagents etc.
[0004] In addition, the patent WO2006122977 discloses a method for obtaining obeticholic acid by using 3α-dihydroxy-7-keto-5β-chole-24-acid as a starting material, through steps such as Aldol condensation, but there are The intermediates are difficult to separate, the reaction steps are long, the yield of the configuration conversion step is low, and the impurities of the final product are not easy to remove, etc.

Method used

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  • Preparation method of chenodeoxycholic acid derivatives
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  • Preparation method of chenodeoxycholic acid derivatives

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preparation example Construction

[0109] Compared with the prior art, the preparation method of the present invention has a series of advantages. Its main advantages include:

[0110] (1) The intermediates obtained by the amide condensation of the present invention are all in solid form, easy to purify, pack and store;

[0111] (2) Compared with the disclosed preparation technology, the route of the present invention is shorter;

[0112] (3) Compared with the disclosed preparation technology, the present invention adopts a "one-pot" process, which has stronger production continuity and is more suitable for large-scale production.

[0113] (4) Compared with the disclosed preparation technology, the corresponding bile salt obtained in the present invention has higher purity and better product quality, especially the magnesium salt, calcium salt, sodium salt and potassium salt of obeticholic acid prepared by the method of the present application Less impurities, suitable for pharmaceutical production.

Embodiment 1

[0115] Example 1 Preparation of 3α, 7α-dihydroxy-6α-ethyl-5β-chole-24-acid (compound 1, compound of formula (Ⅴ))

[0116]

[0117] 1. Preparation of 3α-hydroxy-6-ethylene-7-ketone-5β-chol-24-amide (compound 2)

[0118] Add 3α-hydroxyl-6-ethylene-7-keto-5β-chole-24-acid (formula (VII), 60.0g, 0.144mol), PyBOP (90.0g, 0.173mol) and N successively in the flask, N-Dimethylformamide (400ml); stirred under ice bath, the temperature was lowered to 0°C, DIPEA (74.4g, 0.576mol) was added, and the temperature was controlled at 0°C to continue stirring for 30min. Under nitrogen protection, ammonium chloride (12.3 g, 0.230 mol) and N,N-dimethylformamide (100 ml) were added. Warm to room temperature and stir overnight. With stirring, the reaction mixture was slowly poured into 4L of 5% aqueous sodium bicarbonate solution, solids were precipitated, stirred for 2 h, filtered, washed with pure water (500 ml), and dried in vacuo to obtain a crude product. Add ethyl acetate (360ml) to the...

Embodiment 2

[0121] Example 2 Preparation of 3α, 7α-dihydroxy-6α-ethyl-5β-chole-24-acid (compound 1)

[0122]

[0123] 1. Preparation of 3α-hydroxy-6-ethylene-7-ketone-5β-chol-24-(N-methyl-N-methoxy)amide (compound 3)

[0124] Add 3α-hydroxyl-6-ethylene-7-keto-5β-chole-24-acid (formula (VII), 60.0g, 0.144mol), PyBOP (90.0g, 0.173mol) and N successively in the flask, N-Dimethylformamide (400ml); stirred under ice bath, the temperature was lowered to 0°C, DIPEA (74.4g, 0.576mol) was added, and the temperature was controlled at 0°C to continue stirring for 30min. Under nitrogen protection, N,O-dimethylhydroxylamine hydrochloride (128.4g, 0.288mol) and N,N-dimethylformamide (100ml) were added. Warm to room temperature and stir overnight. With stirring, the reaction mixture was slowly poured into water (4L), extracted with ethyl acetate (1L×3), and the organic phase was then mixed with saturated sodium bicarbonate solution (2L×3), water (2L) and saline (2L ), dried over anhydrous sodium s...

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Abstract

The invention relates to a preparation method of chenodeoxycholic acid derivatives. Specifically, the invention discloses a method for preparing high-purity obeticholic acid sodium salt, potassium salt, magnesium salt and calcium salt by performing one-pot reduction on a compound 3[alpha]-hydroxyl-ethylene-7-keto-5[beta]-cholanate-24-alkanolamide shown as a formula (VI) to obtain a compound namely3[alpha],7[alpha--dihydroxyl-6[alpha]-ethyl-5[beta]-cholanic acid shown as a formula (V) and performing salt-forming and crystallization.

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to a novel preparation and purification method of chenodeoxycholate. Background technique [0002] Farnesoid X Receptor (FXR) is a member of the nuclear receptor (Nuclear Receptor) family. It is mainly expressed in the liver, small intestine and other intestinal systems, and participates in bile acid metabolism and cholesterol metabolism. Bile acids have a variety of physiological functions and play an important role in the process of fat absorption, transport, distribution and cholesterol homeostasis. As a receptor for bile acids such as chenodeoxycholic acid, the farnesoid X receptor maintains the balance of bile acids in the body by regulating the expression of genes involved in bile acid metabolism. In addition, farnesoid X receptor also plays an important role in glucose homeostasis and insulin resistance in vivo. Therefore, farnesoid X receptor agonists...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005C07J41/0061C07J51/00
Inventor 吕彬华李成伟郭超
Owner SUZHOU ZELGEN BIOPHARML
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