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Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine

A branched chain alkyl and ethyl technology, applied in the field of preparation of 7-keto-6α-alkylcholanic acid derivatives, can solve the unfavorable purification of obeticholic acid, 7-keto-6α-ECDCA purification difficulties, steps low conversion rate

Active Publication Date: 2016-06-15
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In this route, the conversion rate of the step of preparing 7-keto-6α-ECDCA by 6-ethyl configuration conversion from 7-keto-6β-ECDCA is low, and the purification of 7-keto-6α-ECDCA is difficult, and the impurities introduced by this step reaction Not conducive to the purification of the final product obeticholic acid

Method used

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  • Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine
  • Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine
  • Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Embodiment 1: Preparation of 7-keto-6β-ECDCA-methyl ester (II-a)

[0141]

[0142] Preparation of compound B-II-a:

[0143] Add anhydrous tetrahydrofuran (THF) and compound B-Ⅲ-a to the reaction flask, stir to dissolve, add 10eq. (LDA) solution, stirred at -70~-60°C for 0.5h, added dropwise 5eq. triethylamine (TEA), and stirred at the same temperature for 2h. Purified water was added dropwise below 5°C to quench the reaction, n-hexane was added, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain compound B-II-a.

[0144] The preparation of compound B-I-a:

[0145] Add dichloromethane, compound B-Ⅱ-a, 5eq. acetaldehyde into the reaction flask, cool to -78°C under nitrogen protection, add dropwise 5eq boron trifluoride ether (BF 3 ), stirred at the same temperature for 2 hours after dropping, rose to 20-30°C, stirred for 6 hours, transferred the reaction solution to a mixed solvent of me...

Embodiment 2

[0149] Example 2: Preparation of 7-keto-6α-ECDCA-methyl ester

[0150]

[0151] ①Add 10g of 7-keto-6β-ECDCA-methyl ester, 1.5g of sodium methoxide, and 100ml of methanol to the reaction flask, heat to reflux until the reaction is complete, adjust the pH to neutral with hydrochloric acid, add ethyl acetate to extract the organic layer, and concentrate under reduced pressure 7-keto-6α-ECDCA-methyl ester was obtained after drying, and the conversion rate was 98.5%.

[0152] ②Add 10g of 7-keto-6β-ECDCA-methyl ester and 100ml of hydrogen chloride / methanol solution to the reaction flask, heat to reflux until the reaction is complete, and concentrate under reduced pressure to dryness to obtain 7-keto-6α-ECDCA-methyl ester with a conversion rate of 98.9% .

[0153] 1 HNMR (400Hz, CDCl 3 )δ3.68(s,C 27 Methyl 3H), 3.55(m, C 3 methine's 1H), 2.70(dd, J=12.8Hz, J=6.4Hz, C 6 methine's 1H), 1.24(s, C 19 Methyl 3H), 0.94(d, J=6.4Hz, C 21 Methyl 3H), 0.83(t, J=6.4Hz, C 26 Methyl 3...

Embodiment 3

[0165] Example 3: Preparation of 7-keto-6α-ECDCA-ethyl ester

[0166] ①Add 10g of 7-keto-6β-ECDCA-ethyl ester, 1.5g of sodium ethoxide, and 100ml of ethanol to the reaction flask, heat and reflux until the reaction is complete, adjust the pH to neutral with hydrochloric acid, add ethyl acetate to extract the organic layer, and concentrate under reduced pressure 7-keto-6α-ECDCA-ethyl ester was obtained after drying, and the conversion rate was 97.6%.

[0167]②Add 10g of 7-keto-6β-ECDCA-ethyl ester and 100ml of acetyl chloride / ethanol solution to the reaction flask, heat to reflux until the reaction is complete, and concentrate under reduced pressure to dryness to obtain 7-keto-6α-ECDCA-ethyl ester with a conversion rate of 99.0 %.

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PUM

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Abstract

The invention provides a preparation method of a 7-keto-6[alpha]-alkyl cholanic acid derivative. According to the preparation method provided by the invention, a 7-keto-6[beta]-alkyl cholanic acid derivative, as shown by a formula II, is used as a raw material, and the 7-keto-6[alpha]-alkyl cholanic acid derivative is prepared by converting a 6[beta] configuration into a 6[alpha] configuration under an acid or alkali condition. The invention also provides a 7-keto-6[beta]-alkyl cholanic acid derivative and an application thereof in preparation of 3[alpha],7[alpha]-dihydroxy-6[alpha]-alkyl-5[beta]-cholanic acid. The preparation method provided by the invention is simple and convenient, and is high in configuration conversion rate, and the product, the 7-keto-6[alpha]-alkyl cholanic acid derivative, is easy to purify, so that the purification difficulty for preparing the 3[alpha],7[alpha]-dihydroxy-6[alpha]-alkyl-5[beta]-cholanic acid is reduced.

Description

technical field [0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, in particular, the present invention relates to novel 7-keto-6β-alkylcholanic acid derivatives and their preparation methods and preparation of 7-keto-6α-alkylcholanic acid derivatives use of things. Background technique [0002] Currently, two bile acid (BA) receptors have been identified: the farnesoid X receptor (FXR) and the G-protein bile acid-coupled receptor (TGR5) receptor. [0003] Farnesoid X receptors (FXR) were originally orphan nuclear receptors (OrphanNuclearReceptors), which were first identified from a mouse liver cDNA library (B.MForman et al., Cell.81:687-693 (1995)), they are ligand Members of the nuclear receptor family of body-activated transcription factors, including receptors for steroids, retinoids, and thyroid hormones (D.J. Mangelsdorf et al., Cell. 83:841-850 (1995)). [0004] WO0037077 discloses that several natural types of bile aci...

Claims

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Application Information

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IPC IPC(8): C07J9/00C07J41/00C07J17/00C07J75/00A61K31/575A61K31/58A61K31/695A61P3/10A61P3/08
Inventor 程兴栋张爱明张喜全杨玉雷朱雪焱袁哲东夏春光
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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