Method for preparing obeticholic acid intermediate

A technology for obeticholic acid and intermediates, which is applied in the field of preparing obeticholic acid intermediates, can solve problems such as unfavorable industrialized production, long process route, complicated operation and the like

Active Publication Date: 2016-05-18
CHONGQING PHARMA RES INST
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0008] The process route of this method is longer and the yield is higher (the total yield is 24.6%, the yield of the intermediate in the fifth step is 44.12%), but the process contains two ultra-low temperature reactions, and the operation is cumbersome and inconvenient
Among them, the preparation process of the important intermediate 3-α-hydroxy-6-ethylene-7-keto-5-β-cholanic acid or ester and ether in this reaction circuit also uses toxic, volatile, corrosive Strong trimethylchlorosilane and strong irritating and corrosive boron trifluoride ethyl ether are not friendly to the environment and are not conducive to industrial production. In addition, the use of double silane protection has a high cost

Method used

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  • Method for preparing obeticholic acid intermediate
  • Method for preparing obeticholic acid intermediate
  • Method for preparing obeticholic acid intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] 1) Preparation of 3-α-hydroxy-6-(1-hydroxy)-ethyl-7-keto-5-β-cholanic acid

[0058] Dissolve 2g of 7-oxo-lithocholic acid (II) in 100ml of tetrahydrofuran, add 14.2ml of lithium diisopropylamide (1.8M) at -78°C, control the reaction at -78°C for 3h, and then add 3ml of ethyl alcohol Aldehyde, react at -78°C for 5 hours, add saturated ammonium chloride solution to quench the reaction, evaporate the reaction solvent tetrahydrofuran, then extract with ethyl acetate, evaporate to dryness to obtain oil, oil: methanol: water = 1:3:1 The product was refined to obtain 1.1g of the product with a yield of 49.42%. The product was detected by MS [M-1]=433.

[0059] 2) Preparation of 3-α-hydroxy-6-ethylidene-7-keto-5-β-cholanic acid

[0060] Dissolve 0.6g of 3-α-6-(1-hydroxy)-ethyl-7-keto-5-β-cholanic acid in 10ml of toluene, add 0.26g of p-toluenesulfonic acid monohydrate, and control the temperature React at about 60°C for 2 hours, then wash with saturated sodium bicarbonate unt...

Embodiment 2

[0062] 1) Preparation of 3-α-tetrahydropyranyl ether-7-keto-5β-cholanic acid

[0063] Dissolve 1Kg of 7-oxo-lithocholic acid (II) in a reaction kettle with 20L of dichloromethane, add 122g of p-toluenesulfonic acid monohydrate and 538g of dihydropyran in sequence, react at room temperature for 1 hour, add saturated carbonic acid Sodium hydrogen solution until the pH of the system is about 7, separate the liquids, extract the water layer with dichloromethane three times, combine the organic layers, dry to obtain a semi-solid, and refine with ethyl acetate:n-hexane=1:5 to obtain 1Kg of the product. Yield 82.3%

[0064] 2) Preparation of 3-α-tetrahydropyranyl ether-6-(1-hydroxy)-ethyl-7-keto-5-β-cholanic acid

[0065] Dissolve 1Kg of 3-α-tetrahydropyranyl ether-7-keto-5β-cholanic acid in 30L tetrahydrofuran, add 3.5L lithium diisopropylamide (1.8M) at -78°C, and keep it at low temperature Reacted for 3.5h, then added 465g of acetaldehyde. React at -78°C for 6 hours, add satura...

Embodiment 3

[0069] 1) Preparation of 3-α-acetoxy-7-keto-5-β-cholanic acid

[0070] Dissolve 2g of 7-oxo-lithocholic acid (II) in 10ml of acetonitrile, add 0.008g of dimethylaminopyridine and 1.05g of acetic anhydride, react under reflux for 4h, add water to obtain a solid, refine with acetonitrile to obtain 2.0g of the product, and collect The rate is 90.3%.

[0071] 2) Preparation of 3-α-acetoxy-6-(1-hydroxy)-ethyl-7-keto-5-β-cholanic acid

[0072] Dissolve 2g of 3-α-acetoxy-7-keto-5-β-cholanic acid in 150ml of tetrahydrofuran, add 13ml of lithium diisopropylamide (1.8M) at -78°C, and keep the reaction at low temperature for 4.5h , then add acetaldehyde 1.3ml, continue the reaction for 5h, quench the reaction with 10% hydrochloric acid, evaporate part of tetrahydrofuran, extract and separate liquid with ethyl acetate, evaporate to dryness to obtain 2.5g of oil. Oily matter: ethyl acetate: n-hexane = 1:10:5 and refined to obtain 1.3 g of the product, with a yield of 59.0%. The product w...

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Abstract

The invention discloses a method for preparing an obeticholic acid intermediate 3-alpha-hydroxyl-6-ethylidene-7-keto-5-beta-cholanic acid (I) by taking 7-oxo-lithocholic acid (II) as a raw material as well as its derivative (IA). According to the invention, 7-oxo-lithocholic acid (II) is protected or directly unprotected through 3-hydroxy or 3-hydroxy and 24-hydroxy, the is further subjected to an aldol condensation reaction with acetaldehyde to obtain the 3-alpha-hydroxyl-6-ethylidene-7-keto-5-beta-cholanic acid (I) and the derivative, and the method is used for preparing the obeticholic acid. The method has the advantages of simple process and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the preparation of 3-alpha-hydroxy-6-ethylidene-7-keto-5-beta-cholic acid, an important intermediate of obeticholic acid, from 7-oxo-lithocholic acid and method of its derivatives. Background technique [0002] Obeticholic acid has a similar structure to chenodeoxycholic acid (CDCA), a natural bile acid in the body, and its bioavailability, pharmacology and toxicology properties are easier to adapt to the requirements of organisms. The results of phase II clinical trials of this drug are very successful. In the trial, the adverse reaction was relatively mild, and the patient's compliance was good. Currently, the phase III clinical trial of the drug alone in the treatment of PBC is being carried out. The drug may be used as a targeted treatment for a new class of non-alcoholic fatty liver disease / non-alcoholic steatosishepatitis (NAFLD / NASH) and primary cholestasis cirrhosis (PBC) medication. [0003] WO02072598 discloses a m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCY02P20/55
Inventor 上官彦刘启万董小峰吴禄春万咏清郑德平叶文润雷皇书
Owner CHONGQING PHARMA RES INST
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