Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid

A technology of cholanic acid and dihydroxy, which is applied in the field of drug preparation, can solve the problems of cholic acid without high-purity raw materials and inconvenient operation, and achieve the effect of being suitable for industrial production, high product yield, and high yield

Active Publication Date: 2015-04-29
康美(北京)药物研究院有限公司 +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] CN101203526 reported that 5β-3α-hydroxyl-7-carbonyl-cholanic acid was methylated, trimethylchlorosilane protected 3α-hydroxyl, and carbonyl enolization was protected, and acetaldehyde was generated under the action of boron trifluoride ether 6-ethylene compound, obtain 6-ECDCA through hydrolysis, reduction double bond and carbonyl again, as reaction formula (two), this method yield is higher, but this method has following deficiency: 5β-3α-hydroxyl-7- There is no high-purity raw material for carbonyl-cholanic acid, and it is not convenient to use two-step silyl ether protection

Method used

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  • Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid
  • Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid
  • Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid

Examples

Experimental program
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Embodiment 1

[0041] A preparation method of 6-ECDCA:

[0042] Step 1: Dissolve methyl 5β-3α-ethoxycarbonyloxy-7-carbonylcholanate in tetrahydrofuran with lithium diisopropylamide, cool down to -30°C, add tert-butyldimethyl chloride Silane, stirred, gradually raised to room temperature, added saturated sodium bicarbonate solution and dichloromethane, separated the dichloromethane layer, washed twice with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered off anhydrous sodium sulfate , dichloromethane was recovered under reduced pressure to dryness to obtain a residue. Add dichloromethane to the residue, lower the temperature to below -30°C, add acetal, add anhydrous tin tetrachloride dropwise, stir, gradually rise to room temperature and stir, add water to stir, separate the dichloromethane layer, and water After washing twice, dichloromethane was recovered under reduced pressure to obtain methyl 5β-3α-ethoxycarbonyloxy-6-ethylene-7-carbonylcholanate, whic...

Embodiment 2

[0047] A preparation method of 6-ECDCA:

[0048] Step 1: Dissolve 20 grams of methyl 5β-3α-ethoxycarbonyloxy-7-carbonylcholanate in 200 mL of tetrahydrofuran, cool to -20°C, add 65 mmoles of lithium diisopropylamide (LDA), Stir for 10 minutes, add 6.5 grams of bromotrimethylsilane, stir for 1 hour, gradually rise to room temperature, add 200 mL of saturated sodium bicarbonate solution and 400 mL of dichloromethane, separate the dichloromethane layer, and wash with 150 mL of saturated sodium bicarbonate solution Twice, dry with anhydrous sodium sulfate, filter off anhydrous sodium sulfate, recover dichloromethane under reduced pressure to dryness, and obtain a residue. Add 250 mL of dichloromethane to the residue, lower the temperature to below -20°C, add 7.5 g of acetal, dropwise add 50 g of magnesium bromide ether, stir for 4 hours, gradually rise to room temperature and stir for 2 hours, add 200 mL of water and stir for 10 Minutes, the dichloromethane layer was taken separa...

Embodiment 3

[0057] A preparation method of 6-ECDCA:

[0058] Step 1: Dissolve 10 grams of methyl 5β-3α-ethoxycarbonyloxy-7-carbonylcholanate in 100 mL of tetrahydrofuran, cool down to -60°C, add 35 mmoles of lithium diisopropylamide (LDA), Stir for 10 minutes, add bromotrimethylsilane 4mL, stir for 1 hour, gradually rise to room temperature, add 200mL saturated sodium bicarbonate solution, 300mL dichloromethane, separate the dichloromethane layer, wash with 150mL sodium bicarbonate saturated solution for 2 Once, dry with anhydrous sodium sulfate, filter off anhydrous sodium sulfate, recover dichloromethane under reduced pressure to dryness, and obtain a residue. Add 150 mL of dichloromethane to the residue, lower the temperature to below -60°C, add 2 g of acetaldehyde, 30 mL of boron trifluoride ether, stir for 1 hour, gradually increase to room temperature and stir for 2 hours, add 100 mL of water and stir for 5 minutes, divide Take the dichloromethane layer, wash it twice with 100mL wa...

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Abstract

The invention provides a preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid. The method comprises the following steps: carrying out silanization on 5 beta-3 alpha-ethoxy carbonyloxy-7-carbonyl-methyl cholanate by silicon haloganide in an aprotic solvent in the presence of strong alkali, producing a mukaiyama aldol reaction, reducing 5 beta-3 alpha-ethoxy carbonyloxy-6-ethylidene-7-carbonyl-methyl cholanate by palladium carbon and hydrogen, and hydrolyzing to obtain 5 beta-3 alpha-hydroxy-6 alpha-ethyl-7-carbonyl-cholanic acid; finally, reducing 5 beta-3 alpha-hydroxy-6 alpha-ethyl-7-carbonyl-cholanic acid by sodium borohydride to obtain 6-ECDCA (6 alpha-ethyl-chenodeoxycholic acid). The raw materials adopted in the method are wide in source; only one-step siloxane protection is required, so that a process is simple; the product yield is high.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of 5β-3α, 7α-dihydroxy-6α-ethyl-cholanic acid. Background technique [0002] Farnesoid X receptor (FXR) was discovered in 1995 as an orphan nuclear receptor, which is a core factor regulating bile acid metabolism. Under the regulation of corresponding ligands, synergistic activators and hormones, FXR can precisely regulate various enzymes and bile salt carriers of bile acid metabolism. In recent years, it has been found that various primary and secondary bile acids at physiological concentrations can activate FXR, for example, chenodeoxycholic acid (CDCA) is a commonly used natural agonist. [0003] Since then, Italian scholars have reported that a derivative of CDCA—5β-3α,7α-dihydroxy-6α-ethyl-cholanic acid (6-ECDCA) is a potential high-efficiency FXR agonist, which is two orders of magnitude higher than CDCA. The structural difference between 6-ECDCA a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 乐智勇董婧婧许冬瑾马兴田
Owner 康美(北京)药物研究院有限公司
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