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Method for synthesizing, separating and determining obeticholic acid (OCA) isomer

A technology of ethanol and compound, which is applied in the field of synthesis of obeticholic acid isomers, and can solve the problems such as a method for chromatographic separation of obeticholic acid without a synthetic method.

Inactive Publication Date: 2016-02-03
YANGTZE RIVER PHARM GRP NANJING HAILING PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Document WO2013192097 reports the control limits of the above two isomers in OCA, but does not give the synthesis method of the above isomers and the chromatographic separation method with obeticholic acid

Method used

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  • Method for synthesizing, separating and determining obeticholic acid (OCA) isomer
  • Method for synthesizing, separating and determining obeticholic acid (OCA) isomer
  • Method for synthesizing, separating and determining obeticholic acid (OCA) isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the preparation of intermediate B

[0058] Dissolve 50g of compound A (mw: 416.3) in 500mL of 2.5% sodium hydroxide, add 5.0g of 10% Pd / C, control the temperature at 25°C, and pass in hydrogen to complete the reaction. After the reaction is completed, filter the reaction solution and concentrate the organic phase Afterwards, about 45 g of compound B was obtained, and the purity of the obtained compound B was 97%.

Embodiment 2

[0059] Example 2: Preparation of obeticholic acid αβα crude product

[0060] Compound B 20g (mw: 418.3) was dissolved in 250mL of 2% sodium hydroxide aqueous solution, 12.5g of sodium tetrahydroborate was added, and the temperature was raised to 35°C to complete the reaction. After the reaction, 1M hydrochloric acid solution was slowly added dropwise to the reaction solution to adjust the pH to about 3-4, during which time 500ml of water was added, and filtered to obtain 16g of white solid with an HPLC purity of about 89%.

Embodiment 3

[0061] Example 3: Separation and purification of obeticholic acid αβα

[0062] Soak HP20SS400mL resin in 1L acetone overnight, fill it into a glass chromatography column, and then rinse it with 10L water. Dissolve 10g of obeticholic acid ααβ crude product in 50mL of 5% sodium hydroxide solution, slowly flow the resulting solution through the chromatography column, and then carry out gradient elution with methanol / water mixed system, the ratio of methanol / water is 3:10 , using HPLC chromatograph to monitor the separation effect, and according to the monitoring results, collect fractions with more than 98% of the target components. After receiving, the methanol was concentrated under reduced pressure to remove methanol, and then the pH was adjusted to 3-5 with phosphoric acid to precipitate a solid, which was filtered and dried to obtain obeticholic acid ααβ, with an HPLC purity of about 97.7%. The obtained obeticholic acid ααβ was confirmed by HNMR and MS, see attached Figur...

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Abstract

The invention relates to an obeticholic acid (OCA) isomer namely an OCA-alpha alpha beta body, a synthetic method of the OCA-alpha beta alpha body, and a method adopting the reversed phase liquid chromatography condition to separate the OCA isomer. With adoption of the technical scheme disclosed by the invention, the OCA-alpha alpha beta body and the OCA-alpha beta alpha body with the HPLC purity greater than 98% can be obtained to meet quality control of the isomer in OCA.

Description

technical field [0001] The invention relates to the synthesis of obeticholic acid (OCA) isomers and the separation method of obeticholic acid and its isomers. Specifically, it relates to the synthesis of OCA-ααβ body and OCA-αβα body, and the method for separating and measuring OCA and OCA-ααβ body and OCA-αβα body. Background technique [0002] Obeticholic acid (Obeticholic Acid, OCA), also known as 6-ethyl chenodeoxy egg powder, is a kind of bile acid secretion that inhibits cytochrome 7A1 by activating the nisolin X receptor, thereby treating primary biliary sclerosis and non-alcoholic Novel drugs for fatty liver disease. The main drug activity is higher than that of ursodeoxycholic acid, with low side effects, and can effectively reduce alkaline phosphatase and serum phosphatase (alkaline phosphatase is a biomarker indicating the degree of liver disease). [0003] Obeticholic acid (I) has significant clinical advantages over ursodeoxycholic acid. It is in the clinical ...

Claims

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Application Information

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IPC IPC(8): C07J9/00G01N30/02
Inventor 王先登邓飞黄丁菲张明明
Owner YANGTZE RIVER PHARM GRP NANJING HAILING PHARM CO LTD
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