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Preparation method of alpha-murine cholic acid

A technology for murine cholic acid and cholanoic acid, applied in the field of organic chemical synthesis, can solve the problems of high process cost of murine acid, unsuitable for mass production, difficult process and the like, and achieves a wide range of raw material sources, few impurities and simple reaction. Effect

Active Publication Date: 2021-09-03
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The artificial synthesis is mainly obtained through a series of chemical reactions of chenodeoxycholic acid and hyodeoxycholic acid. The muricholic acid obtained by these two methods needs to introduce a hydroxyl group at the 6-position or 7-position carbon atom respectively, and the process is relatively difficult. There are many reactions and low conversion rate, which is not suitable for mass production, resulting in high process cost and high price of murichic acid

Method used

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  • Preparation method of alpha-murine cholic acid
  • Preparation method of alpha-murine cholic acid
  • Preparation method of alpha-murine cholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation method of murichic acid of the present embodiment, refer to figure 2 Shown synthetic route map, comprises the following steps:

[0052] a. Preparation of 3α, 6α, 7α trihydroxy-5β-cholanoic acid methyl ester

[0053] In a 500ml three-neck flask, add 50g of 3α, 6α, 7α trihydroxy-5β-cholic acid (hyocholic acid), 200ml of methanol and stir to dissolve, add 0.25ml of concentrated sulfuric acid, heat and reflux for 2 hours, and take a sample to measure the residual hyocholic acid. 0.732%. Add 50ml of sodium bicarbonate solution with a concentration of 1%, stir evenly, distill in vacuum, remove methanol, obtain a large amount of white crystals, filter, wash the filter cake with 200ml of water, dry in a hot air circulation oven at 75°C for 8 hours, and obtain 3α, 6α, 7α Hydroxy-5β-cholanic acid methyl ester 49.8g, HPLC detection purity 98.365%.

[0054] b. Preparation of 3α, 7α-diacetoxy-6α-hydroxy-5β-cholanoic acid methyl ester

[0055]Add 49.8g of 3α, 6α,...

Embodiment 2

[0065] a. Preparation of 3α, 6α, 7α trihydroxy-5β-cholanoic acid methyl ester

[0066] In a 500ml three-necked flask, add 50g of 3α, 6α, 7α trihydroxy-5β-cholic acid (hyocholic acid), 300ml of methanol and stir to dissolve, add 1.0ml of concentrated hydrochloric acid, heat and reflux for 3 hours, and take a sample to measure the residual hyocholic acid. 0.617%. Add 25ml of sodium bicarbonate solution with a concentration of 1%, stir evenly, and vacuum distill to remove methanol to obtain a large amount of white crystals, filter, wash the filter cake with 300ml of water, and dry in a hot air circulation oven at 80°C for 6h to obtain 3α, 6α, 7α Hydroxy-5β-cholanic acid methyl ester 49.6g, HPLC detection purity 99.547%.

[0067] b. Preparation of 3α, 7α-diacetoxy-6α-hydroxy-5β-cholanoic acid methyl ester

[0068] Add 49.6g of 3α, 6α, 7α trihydroxy-5β-cholanoic acid methyl ester and 400ml of dichloromethane into a dry 1000ml three-necked flask, add 0.75g of 4-dimethylaminopyridi...

Embodiment 3

[0078] a. Preparation of 3α, 6α, 7α trihydroxy-5β-cholanoic acid ethyl ester

[0079] In a 500ml three-necked flask, add 50g of 3α, 6α, 7α trihydroxy-5β-cholic acid (hyocholic acid), 350ml of ethanol and stir to dissolve, add 0.5ml of concentrated sulfuric acid, heat up and reflux for 2.5h, and take a sample to measure the residual hyocholic acid is 0.805%. Add 80ml of sodium bicarbonate solution with a concentration of 1%, stir evenly, distill in vacuum, remove ethanol, obtain a large amount of white crystals, filter, wash the filter cake with 200ml of water, dry in a hot air circulation oven at 80°C for 7 hours, and obtain 3α, 6α, 7α Hydroxy-5β-cholanoic acid ethyl ester 49.5g, HPLC detection purity 99.679%.

[0080] b. Preparation of ethyl 3α, 7α-diacetoxy-6α-hydroxy-5β-cholanate

[0081] In a dry 1000ml three-necked flask, add 49.5g of 3α, 6α, 7α trihydroxy-5β-cholanoic acid ethyl ester from the previous step, 300ml of dichloromethane, add 0.25g of 4-dimethylaminopyridin...

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Abstract

The invention discloses a preparation method of alpha-murine cholic acid. The method takes 3alpha, 6alpha, 7alpha-trihydroxy-5beta-cholanic acid (hyocholic acid) as an initial raw material, and comprises the following steps: carboxyl esterification, acetylation of 3-site and 7-site hydroxyl, oxidation of 6-site hydroxyl, reduction of 6-site carbonyl, hydrolysis and recrystallization to obtain high-purity 3alpha, 6beta, 7alpha-trihydroxy-5beta-cholanic acid, namely alpha-murine cholic acid. The alpha-murine cholic acid synthesized and prepared by the route is wide in raw material source; and the method has the advantages of high yield, high purity and few side reactions, and is suitable for large-scale preparation.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and specifically refers to a method for synthesizing alpha-muricholic acid from hyocholic acid as a starting material. Background technique [0002] Bile acids are important endogenous molecules associated with myriad biological functions, including cholesterol absorption and excretion, and play an important role in fat metabolism. Cellular damage induced by accumulation of hydrophobic bile acids in the liver can lead to various diseases such as hepatitis and jaundice. Hydroxylation of hydrophobic bile acids by cytochrome P450 (CYP) enzymes is considered a defense mechanism against bile acid toxicity. [0003] Muricholic acid (MCA) is an important bile acid, and there are mainly three different configurations, namely α-muricholic acid (α-MCA), β-muricholic acid (β-MCA) and ω-muricholic acid (ω-MCA), its structure is as figure 1 shown. [0004] Through continuous research, it has been...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 秦和平张和平祝国祥林志锋凌芬娜
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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