CN106083971A - A kind of preparation method of (E) 3 α hydroxyl 6 ethylidene 7 ketone 5 β cholane 24 acid - Google Patents
A kind of preparation method of (E) 3 α hydroxyl 6 ethylidene 7 ketone 5 β cholane 24 acid Download PDFInfo
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Abstract
The invention discloses the preparation method of one (E) 3 α hydroxyl 6 ethylidene 7 ketone 5 β cholane 24 acid.Specifically, this preparation method comprises the following steps: 1) 3 alcoholic extract hydroxyl groups and the synchronous protection of 7 enolic hydroxyls；2) introducing of 6 carbon-carbon double bonds and the removing of protection group；3) hydrolysis of ester intermediate and the recrystallization of end-product.Compared with the method being used for preparing (E) 3 α hydroxyl 6 ethylidene 7 ketone 5 β cholane 24 acid in prior art, the preparation method of the present invention has the advantages such as stable reaction, yield is high, side reaction is few, quality is good, possesses wide development and application prospect.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to one (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-
The preparation method of 24-acid.
Background technology
The relevant information of target product is as described below:
Chinese: (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid；
English name: (E)-3 α-hydroxy-6-ethylidene-7-keto-5 β-cholan-24-oic acid；
CAS accession number: 1516887-33-4；
Structural formula:；
Molecular formula: C26H40O4；
Molecular weight: 416.59；
Character: off-white color crystalline powder, odorless, water insoluble, it is soluble in alcohol.
Shellfish cholic acid difficult to understand (being called for short OCA, its structure is as follows) is developed by Intercept drugmaker, is a kind of semi-synthetic
Chenodeoxycholic acid (primary bile acid) analog, it is possible to optionally activate bile acid nuclear receptor FXR.Grind with clinic before clinical
Studying carefully prompting, OCA has preferable anti-cholestasis, anti-inflammatory and the effect of fibrosis, can be obviously improved main tissue
Learn the scoring of terminal i.e. non-alcohol fatty liver disease activity and steatosis, lobular inflammation, hepatocyte balloon and fibre
Dimensionization, is expected to become the novel drugs for the treatment of primary biliary cirrhosis, and (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-gallbladder
Alkane-24-acid is then the important source material preparing shellfish cholic acid difficult to understand.
About the preparation of (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid, report following two at present
Method:
(1) Chinese invention patent application CN 101203526 A is former with 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester
Material, uses trim,ethylchlorosilane 3 hydroxyls of protection, then under the effect of lithium diisopropylamine and trim,ethylchlorosilane,
Make 7 carbonyls form silylenolethers, then under Eorontrifluoride etherate is catalyzed, react generation 3 Alpha-hydroxy-6-Asia second with acetaldehyde
Base-7-ketone-5 β-cholane-24-acid methyl ester, then through hydrolysis, crystallization, obtain 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-
Acid, yield 51.8%(calculates with 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester), process route is as follows:
；
(2) Chinese invention patent application CN 104781272 A is former with 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester
Material, under the effect of lithium diisopropylamine and trim,ethylchlorosilane, a step completes 3 hydroxyl protections and 7 carbonyl shapes
Become silylenolethers, then Eorontrifluoride etherate be catalyzed under, with acetaldehyde react generate 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-
Cholane-24-acid methyl ester, obtains 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid of thick E/Z isomer through hydrolysis
Mixture, is isolated to (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid, yield 41.5%(with 3 Alpha-hydroxies-
7-ketone-5 β-cholane-24-acid methyl ester calculates), process route is as follows.
From the foregoing, it will be observed that target product yield low be one of common problem present in above-mentioned preparation method, due to 3 α-hydroxyl
There are E type and two kinds of cis-trans-isomers of Z-type in base-6-ethylidene-7-ketone-5 β-cholane-24-acid, ratio therebetween cannot obtain
To effectively controlling, the problem that yield is low can be caused undoubtedly.It addition, use trim,ethylchlorosilane as 3 hydroxyl protections and shape
The reaction reagent becoming 7 carbonyls to form silylenolethers is maximum drawback present in above-mentioned preparation method, and its reason is front three
Base silicon ether nature is unstable, easily causes part silicon ether group to come off in building-up process, so that impurity increases in product
Many.In consideration of it, need badly one stablize easy, that yield is higher, the less preparation method of impurity meets (E)-3 Alpha-hydroxy-6-is sub-
The industrialized production of ethyl-7-ketone-5 β-cholane-24-acid.
Summary of the invention
For the problems referred to above, the invention discloses one (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid
Preparation method.The method is with 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester as raw material, at N, N-dimethyl-P, P-hexichol
Under the catalysis of base time phosphamide, two (trimethyl is silica-based) Lithamide .s and tert-butyl diphenyl chlorosilane is used to protect 3 hydroxyls,
And make 7 carbonyls form silylenolethers, and then under the catalysis of trifluoromethanesulfonic acid, occur to mountain aldol reaction with acetaldehyde and take off
Water forms E type carbon-carbon double bond, is subsequently adding tetrabutyl ammonium fluoride deprotection, then through ester hydrolysis and recrystallization, obtains (E)-3 α-hydroxyl
Base-6-ethylidene-7-ketone-5 β-cholane-24-acid.
Specifically, the preparation of (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β disclosed in the present invention-cholane-24-acid
Method comprises the following steps:
(1) 3 alcoholic extract hydroxyl group and the synchronous protection of 7 enolic hydroxyls:
Under agitation, 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester is dissolved in 2-methyltetrahydrofuran, adds
N, N-dimethyl-P, P-diphenyl time phosphamide, it is cooled to-25 ~-20 DEG C, adds two (trimethyl is silica-based) Lithamide., constant temperature stirs
Mixing 1.5 ~ 2.5 hours, add tert-butyl diphenyl chlorosilane, constant temperature stirs 2 ~ 2.5 hours, is warming up to-5 DEG C, constant temperature stirring 1.5
~ 2 hours, added water stirring, stratification, and aqueous phase adds methylene chloride and extracts once, merges organic facies, through acid solution washing, nothing
Aqueous sodium persulfate is dried, filters, filtrate concentrates, and obtains 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-24-acid first
Ester intermediate, wherein: described 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester, N, N-dimethyl-P, P-diphenyl time phosphinylidyne
Mol ratio between amine, two (trimethyl is silica-based) Lithamide., tert-butyl diphenyl chlorosilane is 1:0.01 ~ 0.05:2 ~ 5:2 ~ 5；
；
The introducing of (2) 6 carbon-carbon double bonds and the removing of protection group:
Under agitation, by step (1) obtains described 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-
Being dissolved in dichloromethane in 24-acid methyl ester intermediate, be cooled to-45 ~-40 DEG C, add acetaldehyde, constant temperature stirs 1 ~ 1.5 hour,
Adding trifluoromethanesulfonic acid, constant temperature stirring reaction 2 ~ 2.5 hours, add tetrabutyl ammonium fluoride aqueous solution, constant temperature stirring 1 ~ 1.5 is little
Time, stratification, aqueous phase adds dichloromethane extraction once, merges organic facies, be dried through anhydrous sodium sulfate, filter, filtrate dense
Contracting, obtains (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate, wherein: described 3 α, 7-bis-(uncle
Butyl diphenyl siloxy)-5 β-6-cholene-24-acid methyl ester intermediate, acetaldehyde, trifluoromethanesulfonic acid, between tetrabutyl ammonium fluoride
Mol ratio be 1:1 ~ 3:1 ~ 3:0.5 ~ 1.5；
；
(3) hydrolysis of ester intermediate and the recrystallization of end-product:
(E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate obtained in step (2) adds
The alkali of alcohol, water and excess, stirring reaction 2 ~ 3 hours, reclaim alcohol, pH value is regulated to 3 by addition acid, separates out crystallization, through filtration, water
Wash, be dried, recrystallization, obtain (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid；
。
Preferably, in above-mentioned preparation method, 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester described in step (1),
N, N-dimethyl-P, P-diphenyl time rubbing between phosphamide, two (trimethyl is silica-based) Lithamide., tert-butyl diphenyl chlorosilane
That ratio is 1:0.02 ~ 0.03:2.5 ~ 3:2.3 ~ 2.6.
Preferably, in above-mentioned preparation method, described in step (1), the optional substitute of tert-butyl diphenyl chlorosilane is
Tert-butyl chloro-silicane.
Preferably, in above-mentioned preparation method, described in step (1), acid solution is aqueous citric acid solution, preferred mass
Percentage ratio is the aqueous citric acid solution of 2%.
Preferably, in above-mentioned preparation method, 3 α, 7-bis-described in step (2) (tert-butyl diphenyl siloxy)-5 β-
Mol ratio between 6-cholene-24-acid methyl ester intermediate, acetaldehyde, trifluoromethanesulfonic acid, tetrabutyl ammonium fluoride be 1:1.5 ~ 2:1.5 ~
2:0.5~0.75。
Preferably, in above-mentioned preparation method, described in step (2), the molar concentration of tetrabutyl ammonium fluoride aqueous solution is
0.5 ~ 1.0 mol/L, preferably 0.5 mol/L.
Preferably, in above-mentioned preparation method, it is any one that alcohol described in step (3) is selected from methanol, ethanol, isopropanol
Kind, preferably methanol.
Preferably, in above-mentioned preparation method, alkali described in step (3) is in sodium hydroxide, potassium hydroxide, ammonia
Any one, preferably sodium hydroxide.
Preferably, in above-mentioned preparation method, any one in hydrochloric acid, sulphuric acid, the phosphoric acid of acid described in step (3)
Kind, preferably hydrochloric acid.
Preferably, in above-mentioned preparation method, recrystallization described in step (3) uses ethyl acetate-acetonitrile mixture
Completing, ethyl acetate is 1:0.5 ~ 1.5, preferably 1:0.7 ~ 0.9 with the volume ratio of acetonitrile.
Preferably, in above-mentioned preparation method, described stirring is completed by mechanical stirring device.
With the method phase being used for preparing (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid in prior art
Ratio, the preparation method of the present invention has the advantages such as stable reaction, yield is high, side reaction is few, quality is good, possess wide exploitation with
Application prospect.
Accompanying drawing explanation
Fig. 1 is (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β in embodiment 1-cholane-24-acid1H-NMR spectrum.
Fig. 2 is the MS spectrogram of (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β in embodiment 1-cholane-24-acid.
Fig. 3 is the HPLC spectrogram of (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β in embodiment 1-cholane-24-acid.
Detailed description of the invention
Below in conjunction with accompanying drawing and specific embodiment, the present invention is made further instructions, but the protection model of the present invention
Enclose and be not limited to drawings and Examples.Except as otherwise noted, the various instruments used by the following example, material, reagent
Obtained by commercial means.
Embodiment one: the preparation of (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid.
Under agitation, 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester (40.5 g, 0.1 mol) is dissolved in 2-
In methyltetrahydrofuran (120 g), add N, N-dimethyl-P, P-diphenyl time phosphamide (0.5 g, 0.002 mol), cooling
To-20 DEG C, adding two (trimethyl is silica-based) Lithamide. (42 g, 0.25 mol), constant temperature stirs 1.5 h, adds tert-butyl group hexichol
Base chlorosilane (63 g, 0.23 mol), constant temperature stirs 2.5 h, is warming up to-5 DEG C, and constant temperature stirs 1.5 h, adds water (60 g),
Stirring 30 min, stratification, aqueous phase adds dichloromethane (50 g) and extracts once, merges organic facies, 2% aqueous citric acid solution
Washing, anhydrous sodium sulfate is dried, and filters, and concentrates, and obtains 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-24-acid
Methyl ester intermediate crude product, the most purified, it is directly used in next step；
；
Under agitation, by above-mentioned 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-24-acid methyl ester intermediate
Dissolving crude product, in dichloromethane (350 g), is cooled to-45 DEG C, adds acetaldehyde (6.6 g, 0.15 mol), and constant temperature stirs 1 h,
Add trifluoromethanesulfonic acid (22.5 g, 0.15 mol), constant temperature stirring reaction 2 h, add tetrabutyl ammonium fluoride aqueous solution (0.5
Mol/L, 100 mL), constant temperature stirs 1 h, stratification, and aqueous phase adds dichloromethane extraction once, merges organic facies, anhydrous sulfur
Acid sodium is dried, filters, concentrates, and obtains (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate crude product,
The most purified, it is directly used in next step；
；
Methanol is added in above-mentioned (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate crude product
(300mL), water (20 mL), sodium hydroxide (24 g, 0.6 mol), stirring reaction 2 h, reclaim methanol, add dilute hydrochloric acid by pH
Value regulation, to 3, separates out crystallization, filters, and washing is dried, through ethyl acetate-acetonitrile mixture (v/v=1:0.7) recrystallization, obtains white
Color or off-white color crystalloid (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-(31.8 g, yield 76.2%, with 3 in cholane-24-acid
Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester meter)；
。
Gained compound is carried out physical and chemical identification, its1H-NMR spectrum is as it is shown in figure 1, MS spectrogram is as in figure 2 it is shown, HPLC composes
Figure is as shown in Figure 3.From figure 1 it appears that the alkene hydrogen atom that the signal peak at δ 6.0 is attributed in ethylidene, its peak shape is relatively
For complexity, reason be this alkene Hydrogen Proton not only by the coupling of side methyl hydrogen atom, and by 5 hydrogen atoms
Long-range coupling effect, this also demonstrates that the double bond configuration of products therefrom is really for E type.[the M+ of products therefrom can be found from Fig. 2
H]+Signal peak (m/z 417.2999), the molecular formula of the neutral molecule corresponding to this signal peak is C26H40O4, complete with target product
Complete consistent.From figure 3, it can be seen that the target product obtained by above-mentioned preparation method has gratifying purity and yield,
On the premise of ensureing high purity 99.24%, remaining able to realize the yield of more than 70%, effect is ideal.
Embodiment 2:(E) preparation of-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid.
Under agitation, 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester (40.5 g, 0.1 mol) is dissolved in 2-
In methyltetrahydrofuran (200 g), add N, N-dimethyl-P, P-diphenyl time phosphamide (0.8 g, 0.003 mol), cooling
To-25 DEG C, adding two (trimethyl is silica-based) Lithamide. (50 g, 0.3 mol), constant temperature stirs 1.5 h, adds tert-butyl diphenyl
Chlorosilane (71.5 g, 0.26 mol), constant temperature stirs 3 h, is warming up to-5 DEG C, and constant temperature stirs 1.5 h, adds water (80 g), stirs
Mixing 30 min, stratification, aqueous phase adds dichloromethane (70 g) and extracts once, merges organic facies, and 2% aqueous citric acid solution is washed
Washing, anhydrous sodium sulfate is dried, and filters, and concentrates, obtains 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-24-acid first
Ester crude intermediate, the most purified, it is directly used in next step；
Under agitation, by above-mentioned 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-24-acid methyl ester intermediate
Dissolving crude product, in dichloromethane (300 g), is cooled to-40 DEG C, adds acetaldehyde (7 g, 0.16 mol), and constant temperature stirs 1.5 h,
Add trifluoromethanesulfonic acid (30 g, 0.2 mol), constant temperature stirring reaction 2.5 h, add tetrabutyl ammonium fluoride aqueous solution (0.5
Mol/L, 150 mL), constant temperature stirs 1.5 h, stratification, and aqueous phase adds dichloromethane extraction once, merges organic facies, anhydrous
Sodium sulfate is dried, and filters, and concentrates, obtains (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate thick
Product, the most purified, it is directly used in next step；
Methanol (250 is added in above-mentioned (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate crude product
ML), water (20 mL), sodium hydroxide (20 g, 0.5 mol), stirring reaction 3 h, reclaim methanol, add dilute hydrochloric acid by pH value adjust
Joint, to 3, separates out crystallization, filters, and washing is dried, through ethyl acetate-acetonitrile mixture (v/v=1:0.9) recrystallization, obtains white
Or off-white color crystalloid (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-(32.1 g, yield 77%, with 3 α-hydroxyl in cholane-24-acid
Base-7-ketone-5 β-cholane-24-acid methyl ester meter), its every physical and chemical identification data are basically identical with the result of product in embodiment 1.
Claims (10)
1. a preparation method for (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid, it comprises the following steps:
1) 3 alcoholic extract hydroxyl groups and the synchronous protection of 7 enolic hydroxyls:
Under agitation, 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester is dissolved in 2-methyltetrahydrofuran, adds
N, N-dimethyl-P, P-diphenyl time phosphamide, it is cooled to-25 ~-20 DEG C, adds two (trimethyl is silica-based) Lithamide., constant temperature stirs
Mixing 1.5 ~ 2.5 hours, add tert-butyl diphenyl chlorosilane, constant temperature stirs 2 ~ 2.5 hours, is warming up to-5 DEG C, constant temperature stirring 1.5
~ 2 hours, added water stirring, stratification, and aqueous phase adds methylene chloride and extracts once, merges organic facies, through acid solution washing, nothing
Aqueous sodium persulfate is dried, filters, filtrate concentrates, and obtains 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-24-acid first
Ester intermediate, wherein: described 3 Alpha-hydroxy-7-ketone-5 β-cholane-24-acid methyl ester, N, N-dimethyl-P, P-diphenyl time phosphinylidyne
Mol ratio between amine, two (trimethyl is silica-based) Lithamide., tert-butyl diphenyl chlorosilane is 1:0.01 ~ 0.05:2 ~ 5:2 ~ 5；
；
2) introducing of 6 carbon-carbon double bonds and the removing of protection group:
Under agitation, by step 1) obtains described 3 α, 7-bis-(tert-butyl diphenyl siloxy)-5 β-6-cholene-
Being dissolved in dichloromethane in 24-acid methyl ester intermediate, be cooled to-45 ~-40 DEG C, add acetaldehyde, constant temperature stirs 1 ~ 1.5 hour,
Adding trifluoromethanesulfonic acid, constant temperature stirring reaction 2 ~ 2.5 hours, add tetrabutyl ammonium fluoride aqueous solution, constant temperature stirring 1 ~ 1.5 is little
Time, stratification, aqueous phase adds dichloromethane extraction once, merges organic facies, be dried through anhydrous sodium sulfate, filter, filtrate dense
Contracting, obtains (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate, wherein: described 3 α, 7-bis-(uncle
Butyl diphenyl siloxy)-5 β-6-cholene-24-acid methyl ester intermediate, acetaldehyde, trifluoromethanesulfonic acid, between tetrabutyl ammonium fluoride
Mol ratio be 1:1 ~ 3:1 ~ 3:0.5 ~ 1.5；
；
3) hydrolysis of ester intermediate and the recrystallization of end-product:
To step 2) in obtain (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl ester intermediate in add
The alkali of alcohol, water and excess, stirring reaction 2 ~ 3 hours, reclaim alcohol, pH value is regulated to 3 by addition acid, separates out crystallization, through filtration, water
Wash, be dried, recrystallization, obtain (E)-3 Alpha-hydroxy-6-ethylidene-7-ketone-5 β-cholane-24-acid；
。
Preparation method the most according to claim 1, it is characterised in that 3 Alpha-hydroxy-7-ketone-5 β-gallbladder described in step 1)
Alkane-24-acid methyl ester, N, N-dimethyl-P, P-diphenyl time phosphamide, two (trimethyl is silica-based) Lithamide., tert-butyl diphenyl
Mol ratio between chlorosilane is 1:0.02 ~ 0.03:2.5 ~ 3:2.3 ~ 2.6.
Preparation method the most according to claim 1, it is characterised in that tert-butyl diphenyl chlorosilane described in step 1)
Optional substitute is tert-butyl chloro-silicane.
Preparation method the most according to claim 1, it is characterised in that acid solution described in step 1) is that citric acid is water-soluble
Liquid.
Preparation method the most according to claim 1, it is characterised in that step 2) described in 3 α, 7-bis-(tert-butyl diphenyl
Siloxy)-5 β-6-cholene-24-acid methyl ester intermediate, acetaldehyde, trifluoromethanesulfonic acid, mol ratio between tetrabutyl ammonium fluoride be
1:1.5~2:1.5~2:0.5~0.75。
Preparation method the most according to claim 1, it is characterised in that step 2) described in tetrabutyl ammonium fluoride aqueous solution
Molar concentration is 0.5 ~ 1.0 mol/L.
Preparation method the most according to claim 1, it is characterised in that alcohol described in step 3) is selected from methanol, ethanol, isopropyl
Any one in alcohol.
Preparation method the most according to claim 1, it is characterised in that alkali described in step 3) is selected from sodium hydroxide, hydrogen-oxygen
Change in potassium, ammonia any one.
Preparation method the most according to claim 1, it is characterised in that described in step 3), acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid
In any one.
Preparation method the most according to claim 1, it is characterised in that the employing ethyl acetate of recrystallization described in step 3)-
Acetonitrile mixture completes, and ethyl acetate is 1:0.5 ~ 1.5 with the volume ratio of acetonitrile.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986910A (en) * | 2017-04-19 | 2017-07-28 | 成都百特万合医药科技有限公司 | The preparation method of shellfish cholic acid intermediate difficult to understand |
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
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| CN108680696B (en) * | 2018-05-15 | 2020-06-30 | 南京正大天晴制药有限公司 | Detection method of obeticholic acid starting material |
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