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A method for preparing obeticholic acid and related compound

A technology of obeticholic acid and hydrochloric acid, which is applied in the field of medicine, can solve the problems of complex operation, difficulty in removing isomers, and high cost, and achieve the effects of improving refining efficiency, facilitating industrial production, and facilitating operation

Active Publication Date: 2017-04-26
SUZHOU LANXITE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The intermediate compound VIII generated during the hydrogenation reduction of compound VII in this route generates compound IX after heat treatment in an aqueous alkaline environment. During this process, the content of compound VIII is balanced at about 3%, so it will be introduced in subsequent reactions Isomers of obeticholic acid, and the isomers are difficult to remove, requiring repeated crystallization operations
Therefore, this route is complicated to operate and high in cost, and is not suitable for industrial production of obeticholic acid.

Method used

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  • A method for preparing obeticholic acid and related compound
  • A method for preparing obeticholic acid and related compound
  • A method for preparing obeticholic acid and related compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of E / Z-3α-tetrahydropyranyl hydroxy-6-ethylene-7-keto-5β-cholan-24-acid methyl ester (OB-3)

[0029] Weigh 200 g of E / Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholane-24-acid methyl ester (OB-4) and dissolve it in 10 times the volume of dichloromethane, and cool to 0-5°C, add 78g of dihydropyran and 0.8g of p-toluenesulfonic acid in sequence, react for 8-10 hours, and the reaction of raw materials is complete. Add the reaction solution into 500mL of 5% sodium bicarbonate solution, stir for 15-30 minutes, and separate the organic phase; back-extract the water phase with 500mL of dichloromethane, combine the organic phases, wash with 500mL of water, and use 200g of anhydrous sodium sulfate for the organic phase dry. Filtration, the filtrate was concentrated to obtain the target product E / Z-3α-tetrahydropyranyl hydroxyl-6-ethylene-7-keto-5β-cholane-24-acid methyl ester (OB-3) 213g, yield 89.1% with a purity of 98.63%.

[0030] 1 H-NMR (CDCl 3 ): 6.11...

Embodiment 2

[0031] Example 2: Preparation of 3α-tetrahydropyranyl hydroxy-6β-ethyl-7-keto-5β-cholan-24-acid (OB-2)

[0032] Weigh 210 g of E / Z-3α-tetrahydropyranyl hydroxy-6-ethylene-7-keto-5β-cholan-24-acid methyl ester (OB-3) prepared in Example 1 and dissolve in Add 5 times the volume of MeOH to 10 times the volume of 2% NaOH solution, add 10 g of palladium carbon, hydrogenate at room temperature for 18-24 hours, heat the reaction solution to 90-95 ° C, and react for 2-4 hours. Most of the methanol was distilled off under reduced pressure, adjusted to PH=4-6 with 2N hydrochloric acid, extracted with 1L×2 ethyl acetate, combined organic phases, washed with 1L water, and dried with 250 g of anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue was washed with ethyl acetate / n-heptane=1 / 1, filtered, and air-dried at 40-50°C to obtain the target product 3α-tetrahydropyranylhydroxy-6α-ethyl-7-keto-5β- Cholan-24-acid (OB-2) 197g, yield 93.4%, purity 98.95%, OB2-A 0.32%....

Embodiment 3

[0033] Example 3: Preparation of 3α-tetrahydropyranyl hydroxy-6α-ethyl-7α-hydroxyl-5β-cholan-24-acid (OB-1)

[0034] Weigh 195 g of 3α-tetrahydropyranyl hydroxy-6α-ethyl-7-keto-5β-cholan-24-acid (OB-2) prepared in Example 2 and dissolve in 10 times the volume of 2% NaOH In the solution, heat to 85-95°C, add 21g of sodium borohydride, react at 85-95°C for 5-8 hours, and the reaction of raw materials is complete. Cool to 40-50°C, adjust the pH to 4-6 with 2N hydrochloric acid, extract with 1L×2 ethyl acetate, combine the organic phases, wash with 1L water, and dry the organic phase with 250g of anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue was washed with ethyl acetate / n-heptane=1 / 1, filtered, and air-dried at 40-50°C to obtain the target product 3α-tetrahydropyranylhydroxy-6α-ethyl-7α-hydroxy-5β-cholate Alkane-24-acid (OB-1) 177g, yield 90.7%, purity 99.16%, OB-1A content 0.06%.

[0035] 1 H-NMR (CDCl 3 ): 4.75(1H, br), 3.90-3.95(1H, m), 3.71(1...

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Abstract

This invention provides a new method for preparing obeticholic acid which belongs to the technical field of medicine. Its raw material is E / 2 -3alpha-hydroxy-b-ethylidene-keto-5beta-cholane-24-acid methyl ester(OB-4)which can be gained easily. First, OB-3 can be produced through hydroxy-protection with tetra hydropyrane protecting group. Then, OB-2 can be produced through hydrogenation-reduction in alkaline aqueous solution. Then, OB-1 can be produced through reducing again. At last, the target product--obeticholic acid can be got through catalyzing and removing tetrahydropyrane. The method is simple in production process, the content of isomer impurity is low, and the method is a new synthetic method of obeticholic acid suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of obeticholic acid and related compounds. Background technique [0002] Obeticholic acid is a structural modification of chenodeoxycholic acid, 6-ethylchenodeoxycholic acid, a farnesoid X receptor agonist developed by Intercept Pharmaceuticals, which activates the farnesoid X receptor , indirectly inhibit the gene expression of the rate-limiting enzyme cytochrome 7A1 (CYP7A1) of bile acid biosynthesis, and then inhibit bile acid synthesis, which can be used for the treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease. [0003] A completed phase III POISE clinical trial for PBC showed that obeticholic acid can significantly reduce the serum alkaline phosphatase level, which is a biomarker precursor to the progression of PBC, and alkaline phosphatase in the placebo group Phosphatase decreased by an average of 5% from baseline, while the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00C07J17/00
CPCY02P20/55
Inventor 张健俞蒋辉马仕珉徐西宁肖鹏
Owner SUZHOU LANXITE BIOTECH
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