New technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials

A kind of arachidic acid and new process technology, applied in the field of organic synthesis, can solve the problems of difficult material circulation, low yield, and large environmental pollution

Active Publication Date: 2019-03-22
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this route step is too long, and cost is high, and yield is lower (according to cholic acid, Aramchol total yield only has 12.7%)
During the reaction process, the materials are difficult to circulate, a large amount of intermediate raw materials are consumed, the utilization rate of atoms is too low, and the environmental pollution is relatively large
This route is only suitable for small batch synthesis in the laboratory, and is limited for industrial mass production

Method used

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  • New technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials
  • New technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials
  • New technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 1, the synthesis of intermediate b (methyl cholate)

[0057]

[0058] Slowly add 10mL of cold acetyl chloride dropwise into the cold methanol solution, and continue to stir evenly under the condition of an ice-salt water bath. After the temperature drops, add 10g of cholic acid, continue to stir for 30min, remove the ice bath, return to room temperature naturally, and continue Reaction 12h. After the reaction, use saturated NaHCO 3 After the solution was washed and suction filtered, a white solid product b could be obtained, the purity of which was detected by liquid chromatography >99%, and the yield was 99%, and its structure was confirmed by NMR.

[0059] 1 H NMR (600MHz, cdcl 3 )δ3.94(s,1H),3.82(s,1H),3.64(s,3H),3.42(t,J=10.8Hz,1H),2.35(ddd,J=14.6,9.8,4.5Hz,1H ),2.26–2.12(m,3H),2.03(d,J=8.5Hz,1H),1.94–1.21(m,18H),1.09(ddd,J=24.0,14.9,8.9Hz,1H),0.96( d,J=6.2Hz,3H),0.88(s,3H),0.66(s,3H).

[0060] 2. Synthesis of intermediate c (3α-O-p-tert-butylbenzenesulfony...

Embodiment 2

[0081] Intermediate b is synthesized with embodiment 1;

[0082] Synthesis of intermediate c: Dissolve 2g of b (methyl cholate) into 25mL of carbon tetrachloride, and ice-bath the resulting solution to subzero with brine, and dissolve 1.9g of m-dimethylphenylsulfonyl chloride into 7.5mL Pyridine solution, and then the resulting solution was slowly added dropwise to the pyridine solution of b, stirring was continued for 1 h, the ice bath was removed, and the reaction was carried out at 40°C for 4 h. After the reaction was finished, the pH was adjusted, and then washed three times with saturated brine, separated, dried, and the solvent was evaporated to obtain a white solid. The crude product was separated by column chromatography with petroleum ether: ethyl acetate = 3:1, and the yield was 75%.

[0083] 1 H NMR (600MHz, cdcl 3 )δ7.82(s,1H),7.55(d,J=8.5Hz,2H),4.37(ddd,J=16.2,11.0,5.2Hz,1H),3.97(s,1H),3.83(t,J =13.2Hz,1H),3.68(s,3H),2.54(dd,J=25.2,13.1Hz,2H),2.39(ddd,J=16.0,14...

Embodiment 3

[0086] Intermediate b is synthesized with embodiment 1;

[0087] Synthesis of intermediate c: Dissolve 2g b (methyl cholate) and 0.5g triethylamine into 20mL of dichloroethane solution, and ice-bath the resulting solution to subzero with brine, take 1.7g p-tert-butylbenzene Sulfonyl chloride was dissolved in 5 mL of dichloroethane solution, and the resulting solution was slowly added dropwise to the dichloromethane solution of b, and reacted at 30°C for 4h. After the reaction was completed, it was washed three times with saturated brine, separated, dried, and dichloroethane was evaporated to obtain a white solid. The crude product was separated by column chromatography with petroleum ether: ethyl acetate = 3:1, and the yield was 50%.

[0088] 1 H NMR (600MHz, cdcl 3 )δ7.81(d, J=8.6Hz, 2H), 7.52(d, J=8.6Hz, 2H), 3.96(s, 1H), 3.83(d, J=2.6Hz, 1H), 3.66(s, 3H), 2.40–2.32(m,2H), 2.28–2.01(m,2H), 1.95–1.38(m,16H), 1.35(s,9H), 1.30–1.23(m,2H), 1.12(ddd, J=24.5,12.1,6.1Hz,2H),0.9...

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Abstract

The invention discloses a new technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials. According to the new technology disclosed by the invention,a 3- hydroxyl group of cholic acid is activated by selecting para-butyl benzene sulfonyl chloride in larger steric hindrance and the like, 3alpha-O-para-butyl benzene sulfonyl methyl cholate, chiral3-C can be attacked by an azide group just through a direction against an alkylbenzene sulfonyloxy group of a leaving group during a nucleophilic substitution reaction process of the 3alpha-O-para-butyl benzene sulfonyl methyl cholate and sodium azide, inversion of 3-C configuration of a product-3-azido methyl cholate is ensured, and a firm foundation is laid for controlling the optical purity ofa final product-Aramchol.

Description

technical field [0001] The invention relates to a method for synthesizing known compounds, in particular to a novel process for efficiently synthesizing Aramchol by using cholic acid and arachidic acid as raw materials, and belongs to the technical field of organic synthesis. Background technique [0002] Non-alcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, which seriously threatens human health. It is also a chronic liver disease that has received more and more attention in my country. So far, there is still a lack of drugs that can effectively treat nonalcoholic steatohepatitis in the market, and weight loss drugs (such as orlistat and sibutramine, etc.), drugs that regulate lipid metabolism (such as insulin hypertrophy, etc.) are widely used clinically. Sensitizers metformin and thiazolidinediones) and liver-protecting anti-inflammatory drugs (such as vitamin E, ursodeoxychol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 冯乙巳浦同俊朱天彩王旭东陈威豪徐文艺李晓萱
Owner HEFEI UNIV OF TECH
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