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Intermediate for preparing obeticholic acid, preparation method of intermediate and preparation of obeticholic acid

A technology of obeticholic acid and compound, applied in the field of medicine, can solve problems such as unfavorable product quality and cost control, increase of deethylated products, enhanced reaction conditions, etc., to achieve yield improvement, reduction of deethylated by-products, high yield effect

Inactive Publication Date: 2018-04-24
CHANGZHOU PHARMA FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This route can successfully produce intermediate 8, but in the process of catalytic hydrogenation, the use of harsher conditions (20 kg, 80 ° C) failed to reduce the double bond, further enhancing the reaction conditions, the deethylated product increased significantly, resulting in a yield of Very low, not conducive to product quality and cost control

Method used

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  • Intermediate for preparing obeticholic acid, preparation method of intermediate and preparation of obeticholic acid
  • Intermediate for preparing obeticholic acid, preparation method of intermediate and preparation of obeticholic acid
  • Intermediate for preparing obeticholic acid, preparation method of intermediate and preparation of obeticholic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: the compound of formula I obtains the compound of formula II through esterification

[0053]

[0054] Add 36g of the compound of formula I into a 500mL reaction flask, add 360mL of acetonitrile, add 45.05g of cesium carbonate while stirring, add 18.91g of benzyl bromide, stir at room temperature overnight, TLC detection, the raw materials are completely reacted. Evaporate acetonitrile under reduced pressure, add 300mL saturated aqueous sodium bicarbonate solution and 200mL ethyl acetate to the concentrated solution, stir to dissolve and separate layers, extract the water layer with 50mL ethyl acetate again, combine the organic layers, wash with 100mL water, and dry over anhydrous sodium sulfate , and concentrated to dryness to obtain 47.4 g of light yellow oil.

[0055] The hydrogen spectrum and mass spectrum data of formula II compound are as follows:

[0056] 1 H NMR (500MHz, DMSO) δ7.72-7.25(m, 15H), 5.08(q, J=12.5Hz, 6H), 4.03(q, J=7.1Hz, 2H), 3.6...

Embodiment 2

[0058] Embodiment 2: the compound of formula II reacts with trimethylchlorosilane to obtain the compound of formula III

[0059]

[0060]Add 48.4mL of diisopropylamine and 260mL of tetrahydrofuran to a 1000mL four-necked bottle, replace with nitrogen three times, cool down to -50°C, add 132mL of 2.5M n-butyllithium dropwise, and drop it in about 30 minutes. Control the temperature not to exceed -30°C. After dropping, keep warm at -30°C for 3 hours. Cool down to -65°C, add 34.3mL of trimethylchlorosilane dropwise, and drop it over 10 minutes, control the temperature not to exceed -50°C, keep it warm for 30 minutes after dropping, add 13.2g of the compound of formula (II) in 100mL of tetrahydrofuran solution dropwise, drop for about 20 minutes After completion of dripping, keep at -50°C for 1h. TLC detection, the raw material reacted completely. Naturally raise the temperature to -40°C, add 68.6mL triethylamine, raise the temperature to -20°C, add 200mL saturated sodium bic...

Embodiment 3

[0063] Embodiment 3: compound of formula III and acetaldehyde obtain formula IV compound through aldol condensation

[0064]

[0065] Add 23.6g of the compound of formula (III) in 300mL of dichloromethane solution into a 500mL four-neck flask, replace with nitrogen three times, cool down to -65°C, add 8.6mL of acetaldehyde, dropwise add 48.5mL of boron trifluoride diethyl ether, and drop it in 10 minutes. Control the temperature not to exceed -60°C, keep stirring for 4 hours, then naturally warm up to room temperature, stir overnight, and TLC detection shows that the raw materials have completely reacted. Slowly add 500mL of saturated sodium bicarbonate, a large number of bubbles emerge, separate layers, extract the aqueous layer with 200mL of dichloromethane, combine the organic layer, wash with 200mL of saturated sodium chloride, dry over anhydrous sodium sulfate, decolorize with activated carbon, and concentrate under reduced pressure. 20.6 g of a reddish-brown oil were ...

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Abstract

The invention relates to the technical field of medicine, and particularly relates to a intermediate for preparing obeticholic acid, a preparation method of the intermediate and a preparation of obeticholic acid. A route is provided to take acetaldehyde as electrophilic reagent, compared with a method of introducing ethenyl and ethyl iodide through an aldol condensation reaction, the yield is sharply improved; cyclohexylamine salt is refined to form a compound (V), the product quality can be sharply improved; double bonds are hydrogenated and then carbonyl is reduced so that ethenyl can be reduced, and by controlling appropriate temperature, by-products of deethylation can be sharply reduced. The method is mild, green and environmentally friendly, besides, the yield is higher than an existing preparation method, the route reaction condition is economical and effective, and suitable for industrial production on a large scale.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an intermediate for preparing obeticholic acid, a preparation method thereof and the preparation of obeticholic acid. Background technique [0002] Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease caused by accumulation of fat in the liver, which can lead to cirrhosis, liver failure and hepatocellular carcinoma. There are about 2% to 5% of NASH patients in the United States, and some epidemiological estimates suggest that the prevalence of NASH in the United States can reach as high as 17%. NASH is currently the second leading cause of liver transplantation in the United States and is expected to become the number one cause of liver transplantation in the United States by 2020. As of now, the FDA has not approved any effective drugs for the treatment of NASH. However, according to the forecast of EvaluatePharme, the global market size of NASH drugs ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J17/00C07J9/00
Inventor 孙光祥俞风山张云然王兵孙海江王敏峰周文顾斌陶维洁
Owner CHANGZHOU PHARMA FACTORY
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