Synthetic method for obeticholic acid intermediate

A technology of obeticholic acid and synthesis method, which is applied in the field of medicine, can solve the problems of low reaction efficiency and large amount of LDA, and achieve the effect of high efficiency and reduced amount of LDA

Inactive Publication Date: 2016-05-18
四川新功生物科技集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present invention overcomes the deficiencies in the prior art, and provides a synthetic method of an obeticholic acid intermediate, hoping to solve the problems of large amount of LDA and low reaction efficiency in the synthesis of obeticholic acid

Method used

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  • Synthetic method for obeticholic acid intermediate

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Embodiment 1

[0024] Ethyl acetate (40 g) was charged into a reactor protected by inert gas, 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester (8.47 g) was dissolved therein, and 4.5 g of pyridine was added. The solution was cooled to 0°C, and ethyl chloroformate (4.0 g) was slowly added dropwise. After the ethyl chloroformate was added dropwise, the temperature of the reaction solution was raised to 22°C, and kept stirring at 22°C for 2.5h. Concentrate under reduced pressure to remove ethyl acetate. Add 34 g of ice water to dissolve the concentrate, then add 17 g, 17 g, and 8.5 g of ethyl acetate to extract the aqueous phase three times, and combine the three organic layers. The organic layer was washed with 8.5g of 10% HCl aqueous solution, 8.5g of saturated sodium bicarbonate solution, and 8.5g of saturated sodium chloride solution, and then dried with an appropriate amount of anhydrous sodium sulfate, and the organic layer was concentrated to dryness to obtain 10.1g of crude product...

Embodiment 2

[0026] Tetrahydrofuran (40 g) was charged into a reactor protected by inert gas, 3α-hydroxy-7-keto-5β-cholane-24-oic acid methyl ester (8.47 g) was dissolved therein, and 4.5 g of pyridine was added. The solution was cooled to 5°C, and propyl chloroformate (4.0 g) was slowly added dropwise. After the propyl chloroformate was added dropwise, the temperature of the reaction solution was raised to 25°C and kept at 25°C with stirring for 2h. Concentrate under reduced pressure to remove tetrahydrofuran. Add 34g of ice water to dissolve. 17g, 17g and 8.5g of ethyl acetate were added to extract the aqueous phase three times, and the three organic layers were combined. The organic layer was washed with 8.5 g of 10% HCl aqueous solution, 8.5 g of saturated sodium bicarbonate solution, and 8.5 g of saturated sodium chloride solution, and dried with an appropriate amount of anhydrous sodium sulfate. The organic layer was concentrated to dryness to obtain 10.3 g of the crude product, w...

Embodiment 3

[0028] Butyl acetate (40g) was packed into a reactor protected by an inert gas, 3α-hydroxyl-7-ketone-5β-cholan-24-acid methyl ester (8.47g) was dissolved therein, and 4.5g triethylamine was added . The solution was cooled to 2°C, and butyl chloroformate (4.0 g) was slowly added dropwise. After the butyl chloroformate was added dropwise, the temperature of the reaction solution was raised to 20°C, and kept stirring at 20°C for 3h. Concentrate under reduced pressure to remove butyl acetate. Add 34g of ice water to dissolve. 17g, 17g and 8.5g of ethyl acetate were added to extract the aqueous phase three times, and the three organic layers were combined. The organic layer was washed with 8.5 g of 10% HCl aqueous solution, 8.5 g of saturated sodium bicarbonate solution, and 8.5 g of saturated sodium chloride solution, and dried with an appropriate amount of anhydrous sodium sulfate. The organic layer was concentrated to dryness to obtain 10.2 g of the crude product, which was ...

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Abstract

The invention discloses a synthetic method for an obeticholic acid intermediate. The method includes the steps that organic solvent is poured into a reactor protected by inert gas, 3 alpha-hydroxyl-7-keto-5beta-cholane-24-oate is dissolved into the organic solvent, and then organic alkali is added; the solution is cooled to 0 DEG C-5 DEG C, then carbonate is slowly added dropwise to protect the 3-position hydroxyl group, after dropwise addition is completed, the reaction solution is heated to 20 DEG C-50 DEG C and is stirred for 2-8 h, and then the organic solvent is removed through decompression concentration; ice water is added for dissolution, ethyl acetate is added to extract the water phase, organic layers are combined and washed, an appropriate amount of anhydrous sodium sulfate is adopted for drying so that the organic layers are concentrated, and the obeticholic acid intermediate is obtained. The 3-position hydroxyl group is protected with carbonate first, the 7-position carbonyl enol is protected in a trimethylsilylation mode, the dosage of LDA is reduced by a half, and the efficiency of the condensation reaction is higher.

Description

technical field [0001] Embodiments of the present invention relate to the field of medical technology, and more specifically, embodiments of the present invention relate to a method for synthesizing an obeticholic acid intermediate. Background technique [0002] Obeticholic acid is a new drug for cholestatic liver cirrhosis. At present, its synthetic route needs to condense the 7-position carbonyl with acetaldehyde. Before that, the 3-position hydroxyl needs to be protected; the patent US2008 / 0214515A1 uses The method that the trimethyl silylation protection of the hydroxyl group and the 7-position carbonyl enol is carried out simultaneously, and the specific process is as follows: [0003] [0004] However, the above method needs to adopt at least two equivalents of LDA as the base, and the volume of the reaction is too large and the efficiency is low; therefore, it is necessary to develop a method with a small amount of LDA and a good condensation reaction effect. Con...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 李虹霖占伟谢建赖永新
Owner 四川新功生物科技集团有限公司
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