CN1869043A - Synthesis method of chenodeoxycholic acid - Google Patents

Abstract

A process for synthesizing chenodeoxycholic acid includes such steps as preparing the ester used for cholic acid, preparing diacetyl-12a-hydroxy-methyl cholate, preparing 3a, 7a-diacetyloxy-12-oxy-methyl cholanic acid, preparing 12-oxy- chenodeoxycholic acid, preparing chenodeoxycholic acid, and purifying.

Description

A kind of synthetic method of Chenodiol

Technical field

The present invention relates to the synthetic method of a kind of Chenodiol (3 α, 7 alpha-dihydroxy-s-5 β-ursodeoxycholic acid), particularly relate to a kind of method that adopts chemical process to synthesize Chenodiol.

Background technology

Chenodiol (3 α, 7 alpha-dihydroxy-s-5 β-ursodeoxycholic acid) ChenodeoxycholioAcid (being called for short CDCA) is a kind of medicine for the treatment of gallbladdergallstonecholetithiasis.Found that in goose bile nineteen twenty-four is named and is Chenodiol in 1848 first.

Chenodiol have relieving asthma, reduce phlegm, antibechic and antiphlogistic effect, its choleretic effect is particularly remarkable, it is by reducing cholesterol absorption, synthesize, make the bile inner cholesterol to descend, thereby prevents cholesterol calculus to form and short its dissolving, and effective reducing cholesterol saturation ratio.

Chenodiol also can be used as produces ursodesoxycholic acid (3 α, the 7 beta-dihydroxyies-5 β-ursodeoxycholic acid) intermediate of (being called for short UDCA).Ursodesoxycholic acid is the contained main effective constituent of rare Chinese medicine bear gall, is used for the treatment of various courage diseases and digestive tract diseases clinically.At present, traditional famous and precious medicinal animal bile is very in short supply, and seeking has the medicinal animal bile of DEVELOPMENT PROSPECT and synthetic product to become popular research project.Therefore, the preparation Chenodiol also has great importance for further preparation ursodesoxycholic acid.

Chenodiol is mainly by extracting in poultry or the animal bile, traditional extracting and preparing technique process complexity, and yield is low, and uses a large amount of dangerous organic solvents (medicine industry, 1987,18 (9), 416; Utilisation technology, 1998,4:9-10; US Patent, 4,331,607; USPatent, 4,163,017) can not adapt to the requirement of modern industry.

Summary of the invention

The object of the present invention is to provide a kind of fairly large method for preparing high-purity chenodeoxy cholic acid that can be used for, the manufacture craft of this method is simple, safety, and low toxicity, the Chenodiol purity that makes is higher.

The objective of the invention is to be achieved through the following technical solutions:

This preparation method may further comprise the steps:

(1) the cholic acid preparation of ester;

(2) preparation of diacetyl-12 Alpha-hydroxies-Methyl cholate;

(3) 3 α, the preparation of 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid;

(4) preparation of 12-oxo-Chenodiol;

(5) preparation of Chenodiol;

(6) purifying of Chenodiol.

Wherein:

(1) cholic acid being prepared as: get cholic acid, be dissolved in the anhydrous methanol, add concentrated hydrochloric acid, reflux, put into refrigerator-freezer with ester;

(2) being prepared as of diacetyl-12 Alpha-hydroxies-Methyl cholate: get Methyl cholate, be dissolved in the refining pyridine, it is dissolved fully, under agitation add diacetyl oxide, pour in the water, filtration can get diacetyl-12 Alpha-hydroxies-Methyl cholate;

(3) 3 α, being prepared as of 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid: get the above-mentioned crude product that makes, be dissolved in the acetone, filter, stir, slowly add Jones reagent, room temperature reaction refilters, and adds after the entry adularescent precipitation and separates out, filtration can get 3 α, 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid;

(4) being prepared as of 12-oxo-Chenodiol: with ethanol-sodium hydroxide solution saponification, this solution of acidifying in the impouring water, gets 12-oxo-Chenodiol, recrystallization in dehydrated alcohol;

(5) being prepared as of Chenodiol: get 12-oxo-Chenodiol, add ethylene glycol and solid sodium hydroxide, hydrazine hydrate, 100 ℃ of backflows, heat up gradually and steam the hydrazine hydrate of generation, continue temperature rising reflux, cooling is in the impouring heat water, transferring PH with hydrochloric acid is 3, the adularescent precipitation is separated out, and filters filter cake and washes with water, gets Chenodiol;

(6) purifying of Chenodiol is: get Chenodiol, use a small amount of anhydrous alcohol solution, through being soaked with the silicagel column of sherwood oil, use sherwood oil: acetone=2: 1, the beginning wash-out when waiting to occur the single Chenodiol spot of outward appearance, begins to collect elutriant until no Chenodiol spot, behind the vacuum distillation drying, can get pure Chenodiol.

Advantage of the present invention and effect are:

Present method manufacture craft is simple, safety, and low toxicity, the Chenodiol purity that makes is higher.

Description of drawings

Fig. 1 is reaction equation figure of the present invention.

Embodiment

(1) the cholic acid preparation of ester

Take by weighing 50 gram cholic acid, be dissolved in 150 milliliters of anhydrous methanols, add 5 milliliters of concentrated hydrochloric acids, refluxed 30 minutes, slowly put into refrigerator-freezer after the cooling, can get the Methyl cholate productive rate is 95%.

(2) preparation of diacetyl-12 Alpha-hydroxies-Methyl cholate

Take by weighing Methyl cholate 50 grams; be dissolved in 100 milliliters of refining pyridines; it is dissolved fully, under agitation add 100 milliliters diacetyl oxide, room temperature reaction 3～4 hours; pour in 500 ml waters; the adularescent precipitation is put into refrigerator, filters in second day; can get diacetyl-12 Alpha-hydroxies-Methyl cholate, productive rate 40%.

(3) 3 α, the preparation of 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid

Take by weighing above-mentioned crude product 25 grams that make, be dissolved in 250 milliliters of acetone, filter and remove insolubles, having under the stirring condition, slowly add Jones reagent, room temperature reaction 30 minutes, filter, add entry adularescent precipitation and separate out in filtrate, filtration can get 3 α, 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid.Productive rate is 100%.

(4) preparation of 12-oxo-Chenodiol

With 10% ethanol-sodium hydroxide solution, saponification is 1 hour under the room temperature, and this solution of acidifying in the impouring water, gets 12-oxo-Chenodiol, productive rate 100%.Recrystallization in dehydrated alcohol.

(5) preparation of Chenodiol

Take by weighing 12-oxo-Chenodiol 20 grams, add 300 milliliters ethylene glycol and solid sodium hydroxide 30 grams, 300 milliliters of hydrazine hydrates (85%), 100 ℃ were refluxed 2 hours, rose to 130 ℃ gradually, steamed the hydrazine hydrate of generation, continue to be warming up to 185～190 ℃, continue to reflux 4 hours, to temperature cooling down, in the impouring heat water, transferring PH with hydrochloric acid (20%) is 3, the adularescent precipitation is separated out, and filters filter cake and washes with water, gets Chenodiol.

(6) purifying of Chenodiol

Take by weighing a certain amount of Chenodiol that gets, use a small amount of anhydrous alcohol solution, go up through being soaked with the silicagel column of sherwood oil, flow velocity is pressed the linear speed 1～5cm/ of chromatography column liquid and is divided control, uses sherwood oil: acetone=2: 1, the beginning wash-out, detect with the thin-layer chromatography chromatogram therebetween, when waiting to occur the single Chenodiol spot of outward appearance, begin to collect elutriant until no Chenodiol spot, behind the vacuum distillation drying, can get pure higher Chenodiol.

Claims (2)

1. the synthetic method of a Chenodiol is characterized in that this preparation method may further comprise the steps:

(1) the cholic acid preparation of ester;

(2) preparation of diacetyl-12 Alpha-hydroxies-Methyl cholate;

(3) 3 α, the preparation of 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid;

(4) preparation of 12-oxo-Chenodiol;

(5) preparation of Chenodiol;

(6) purifying of Chenodiol.

2. the synthetic method of a kind of Chenodiol according to claim 1 is characterized in that:

(1) cholic acid being prepared as: get cholic acid, be dissolved in the anhydrous methanol, add concentrated hydrochloric acid, reflux, put into refrigerator-freezer with ester;

(2) being prepared as of diacetyl-12 Alpha-hydroxies-Methyl cholate: get Methyl cholate, be dissolved in the refining pyridine, it is dissolved fully, under agitation add diacetyl oxide, pour in the water, filtration can get diacetyl-12 Alpha-hydroxies-Methyl cholate;

(3) 3 α, being prepared as of 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid: get the above-mentioned crude product that makes, be dissolved in the acetone, filter, stir, slowly add Jones reagent, room temperature reaction refilters, and adds after the entry adularescent precipitation and separates out, filtration can get 3 α, 7 α-diacetoxy-12-oxo-methyl ursodeoxycholic acid;

(4) being prepared as of 12-oxo-Chenodiol: with ethanol-sodium hydroxide solution saponification, this solution of acidifying in the impouring water, gets 12-oxo-Chenodiol, recrystallization in dehydrated alcohol;

(5) being prepared as of Chenodiol: get 12-oxo-Chenodiol, add ethylene glycol and solid sodium hydroxide, hydrazine hydrate, 100 ℃ of backflows, heat up gradually and steam the hydrazine hydrate of generation, continue temperature rising reflux, cooling is in the impouring heat water, transferring PH with hydrochloric acid is 3, the adularescent precipitation is separated out, and filters filter cake and washes with water, gets Chenodiol;

(6) purifying of Chenodiol is: get Chenodiol, use a small amount of anhydrous alcohol solution, through being soaked with the silicagel column of sherwood oil, use sherwood oil: acetone=2: 1, the beginning wash-out when waiting to occur the single Chenodiol spot of outward appearance, begins to collect elutriant until no Chenodiol spot, behind the vacuum distillation drying, can get pure Chenodiol.

Images