CN108794557A - A kind of preparation method of chenodeoxycholic acid and intermediate - Google Patents
A kind of preparation method of chenodeoxycholic acid and intermediate Download PDFInfo
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- CN108794557A CN108794557A CN201810194143.9A CN201810194143A CN108794557A CN 108794557 A CN108794557 A CN 108794557A CN 201810194143 A CN201810194143 A CN 201810194143A CN 108794557 A CN108794557 A CN 108794557A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
The invention discloses the preparation methods of a kind of chenodeoxycholic acid and its intermediate, using commercially available hyodesoxycholic acid as raw material, β-bromine, which is introduced, through side chain carboxyl group esterification, recrystallization, 6 Alpha-hydroxy of selective oxidation, 7 obtains intermediate III, total recovery is 16%, intermediate III produces chenodeoxycholic acid through restoring, hydrolyzing, the method reaction route is short, it avoids having used trim,ethylchlorosilane and the reagents such as the unifor that is more toxic, environmental pollution is smaller, and the intermediate III of synthesis plays an important role in Cholic acids pharmaceutical synthesis.
Description
Technical field
The present invention relates to organic chemical synthesis technical field, more particularly to the preparation side of a kind of chenodeoxycholic acid and intermediate
Method.
Background technology
Chenodeoxycholic acid（CDCA）Main function is the saturation degree for reducing bile inner cholesterol, and most patients take
After CDCA, when CDCA accounts for 70% of cholate in bile, lipid restores protomere state, and cholesterol is at undersaturated condition,
To make the cholesterol in calculus dissolve, fall off.The CDCA of large dosage can inhibit the synthesis of cholesterol, and increase cholelithiasis trouble
The secretion of person's bile, but cholate therein and phosphatide secretory volume remain unchanged.In addition, chenodeoxycholic acid is synthesis ursodeoxycholic again
The raw materials of acid and other steroidal compounds, as the epimer of ursodesoxycholic acid, it artificial synthesized also by increasingly
More concerns.Currently, synthesizing the technique of chenodeoxycholic acid by hyodesoxycholic acid, that there are synthesis steps is more, environmental pollution is larger etc.
Problem.
Invention content
To make up the deficiencies in the prior art, that the present invention provides a kind of method is simple, synthetic route is short chenodeoxycholic acid and
The preparation method of intermediate.
The present invention is achieved through the following technical solutions：
The preparation method of a kind of chenodeoxycholic acid and its intermediate, is characterized in that：
Include the following steps：
（a）, under acid catalysis, commercially available hyodesoxycholic acid reacted with methanol generate methyl hyodeoxycholanate crude product；
（b）, methyl hyodeoxycholanate crude product recrystallize in a solvent, isolated methyl hyodeoxycholanate fine work I；
（c）, Jones reagents effect under, I selective oxidation of methyl hyodeoxycholanate fine work generate intermediate II；
（d）, bromide reagent effect under, 7 of intermediate II are replaced by bromine, obtain intermediate III；
（e）, zinc and concentrated hydrochloric acid effect under, carbonyl is reduced to methylene in intermediate III, obtains intermediate IV；
（f）, alkali effect under, intermediate IV occur hydrolysis, generate chenodeoxycholic acid；
The chenodeoxycholic acid of the present invention and its preparation method of intermediate, synthetic route are as follows：
。
A kind of chenodeoxycholic acid of the present invention and its preparation method of intermediate, in III structure of intermediate, R is C1-C8 alkane
Base ester base or H.
A kind of chenodeoxycholic acid of the present invention and its preparation method of intermediate, step（a）In, acid catalyst is dense sulphur
The dropping temperature of acid, the concentrated sulfuric acid is 3-5 DEG C.
Preferably, step（a）In, reaction temperature is 20-30 DEG C, reaction time 12-18h.
A kind of chenodeoxycholic acid of the present invention and its preparation method of intermediate, step（b）In, recrystallization solvent be benzene,
One or more of toluene, dimethylbenzene；Methyl hyodeoxycholanate crude product is 1 with recrystallization solvent mass ratio:2.3-9.3.
Preferably, step（b）In, recrystallization condition is that temperature is controlled at -5 ~ 10 DEG C, stands 5h-24h.
A kind of chenodeoxycholic acid of the present invention and its preparation method of intermediate, step（c）In, reaction temperature be -25 ~ -
15 DEG C, reaction time 30-60min.
A kind of chenodeoxycholic acid of the present invention and its preparation method of intermediate, step（d）In, bromide reagent used is
One or more of bromine, N- bromo-succinimides, pyridinium tribromide；Step（d）In, bromo-reaction solvent for use is
One or more of chloroform, carbon tetrachloride, glacial acetic acid, ether.
Preferably, step（d）In, intermediate II is 1 with bromide reagent mass ratio：0.1-2.5；Intermediate II with
Solvent quality ratio is 1:10-45.
Further, preferably, step（d）In, bromo-reaction condition is that temperature is controlled at -5 DEG C ~ 45 DEG C,
Stir 4h-12h.
The beneficial effects of the invention are as follows：The present invention by side chain carboxyl group esterification, ties again using common hyodesoxycholic acid as raw material
Crystalline substance, the esterification of 6 Alpha-hydroxy of selective oxidation, 3 Alpha-hydroxies, it is innovative introduced at 7 β-bromine, reduction, hydrolysis and etc. synthesis goose
Deoxycholic aicd.Although the chenodeoxycholic acid purity obtained at present is relatively low.But the invention synthetic route is shorter, for hyodesoxycholic acid
Provide new approaches for Material synthesis chenodeoxycholic acid, wherein the intermediate III synthesized in Cholic acids pharmaceutical synthesis have it is important
Effect.
Specific implementation mode
The present invention will be further described in detail with reference to the specific embodiments, to help those skilled in the art
There is more complete, accurate and deep understanding to the inventive concept of the present invention, technical solution, protection scope of the present invention includes but not
It is limited to following embodiment, any details to technical scheme of the present invention under the premise of without departing from spirit and scope
It is each fallen in protection scope of the present invention with the modification that form is made.
Embodiment 1
A kind of chenodeoxycholic acid of the present embodiment and its preparation method of intermediate, include the following steps：
1, the preparation of methyl hyodeoxycholanate fine work I
Take 7.5g commonly commercially available hyodesoxycholic acids（Hyodesoxycholic acid content is 80%, and pig gall acid content is 20%）, 50mL first is added
Alcohol is down to 5 DEG C, and the 0.25mL concentrated sulfuric acids are added dropwise, are dripped off in 10 minutes, rises to 25 DEG C, temperature control stirring about 15 hours, TLC tracking is opened up
It is dichloromethane to open agent：Acetone：Acetic acid=2:1:0.1.Reaction finishes, and 10mL is added and is saturated NaHCO3Solution, quenching reaction.Subtract
Pressure concentration removes methanol, is extracted twice respectively with 50mL ethyl esters, merges organic phase.35mL is added to be saturated NaHCO3Organic phase is washed,
Layering, adds 50mL saturated brines washed once, and is layered.5g anhydrous sodium sulfates are added to dry, filtering is concentrated to dryness.To obtained solid
In plus 40mL toluene, stirring and dissolving, 0 DEG C stands overnight, filtering, add 10mL methanol to take toluene out of, solid adds 20mL petroleum ethers（Boiling
60-90 DEG C of point）Mashing, filtering, drying obtain methyl hyodeoxycholanate fine work I.Yield is 95.1%, purity 96.0%, content
99.9%。
2, the preparation of intermediate II：
1g methyl hyodeoxycholanates fine work I is taken, 10mL acetone is added, stirring and dissolving is cooled to -20 DEG C, and 0.66mL is added dropwise
Jones reagents, 15min are added dropwise, and TLC tracking, reaction 40min terminates.3mL isopropanols are added and terminate reaction, concentration removes
Acetone.20mL water is added, 25mL ethyl acetate stirs 30min, and static layering, organic phase washed once with 20mL brine, static
Layering adds 5g anhydrous sodium sulfates to dry, and filtering is concentrated to dryness.Column chromatography for separation obtains intermediate II.Yield：67.7%, purity
92.9%。
3, the preparation of III a of intermediate
It takes 1.02g intermediate IIs, is added 18mL chloroforms, stirring and dissolving, for use.0.15mL bromines are taken, add 5.5mL chloroforms successively,
1.5mL acetic acid, 0.2mL hydrogen bromides, stirs evenly, and at 25 DEG C, is added drop-wise in above-mentioned for use liquid, and 20min is dripped off, and rises to 40 DEG C,
React 4h.Reaction terminates to be down to 25 DEG C, and 15mL water and 15mL chloroforms are sequentially added under stirring, stirs 10min, and stratification has
Machine is mutually saturated NaHCO with 20mL3It washes twice, then washed once with 20mL brine, static layering, add 5g anhydrous sodium sulfates dry
Dry, filtering is concentrated to dryness.Column chromatography for separation obtains III a of intermediate.Yield：24.5%, purity 90.6%.
4, the preparation of IV a of intermediate
It takes III a of 0.25g intermediates, is added 30mL methanol, stirring and dissolving at 25 DEG C is added 5mol/L hydrochloric acid 4mL, work is added portionwise
Change zinc powder 0.72g, added in 1 hour, 25 DEG C are reacted 3 hours.30mL is added and is saturated NaHCO3Terminate reaction.Filtering, concentration.
20mL ethyl acetate is sequentially added, 25mL is saturated NaHCO3Solution stirs 30min, layering.Organic phase 20ml saturated salt solutions
It washed once, 5g anhydrous sodium sulfates is added to dry, filtering is concentrated to dryness.Obtain IV a of intermediate, purity 30.6%.
5, the preparation of chenodeoxycholic acid
IV a of 0.09g intermediates is taken, 15mL methanol is added to dissolve, 15mL water is added, adds 0.6g KOH at 25 DEG C.25 DEG C of reaction 4h.With
Dilute hydrochloric acid is adjusted to neutrality, and concentration removes methanol, and respectively plus 20mL ethyl acetate is extracted twice, and is layered, and organic phase, organic phase are merged
Washed with 20mL saturated brines each primary, static layering adds 2g anhydrous sodium sulfates to dry, and filtering is concentrated to dryness.Chenodeoxycholic acid
Purity be 11.3%.
Claims (10)
1. the preparation method of a kind of chenodeoxycholic acid and its intermediate, it is characterised in that：Include the following steps：
（a）, under acid catalysis, commercially available hyodesoxycholic acid reacted with methanol generate methyl hyodeoxycholanate crude product；
（b）, methyl hyodeoxycholanate crude product recrystallize in a solvent, isolated methyl hyodeoxycholanate fine work I；
（c）, Jones reagents effect under, I selective oxidation of methyl hyodeoxycholanate fine work generate intermediate II；
（d）, bromide reagent effect under, 7 of intermediate II are replaced by bromine, obtain intermediate III；
（e）, zinc and concentrated hydrochloric acid effect under, carbonyl is reduced to methylene in intermediate III, obtains intermediate IV；
（f）, alkali effect under, intermediate IV occur hydrolysis, generate chenodeoxycholic acid；
Synthetic route is as follows：
。
2. the preparation method of a kind of chenodeoxycholic acid according to claim 1 and its intermediate, it is characterised in that：Intermediate
In III structure, R is C1-C8 alkyl ester group or H.
3. the preparation method of a kind of chenodeoxycholic acid according to claim 1 or 2 and its intermediate, it is characterised in that：Step
Suddenly（a）In, acid catalyst is the concentrated sulfuric acid, and the dropping temperature of the concentrated sulfuric acid is 3-5 DEG C.
4. the preparation method of a kind of chenodeoxycholic acid according to claim 3 and its intermediate, it is characterised in that：Step
（a）In, reaction temperature is 20-30 DEG C, reaction time 12-18h.
5. the preparation method of a kind of chenodeoxycholic acid according to claim 1 or 2 and its intermediate, it is characterised in that：Step
Suddenly（b）In, recrystallization solvent is one or more of benzene,toluene,xylene；Methyl hyodeoxycholanate crude product and recrystallization are molten
Agent mass ratio is 1:2.3-9.3.
6. the preparation method of a kind of chenodeoxycholic acid according to claim 5 and its intermediate, it is characterised in that：Step
（b）In, recrystallization condition is that temperature is controlled at -5 ~ 10 DEG C, stands 5h-24h.
7. the preparation method of a kind of chenodeoxycholic acid according to claim 1 or 2 and its intermediate, it is characterised in that：Step
Suddenly（c）In, reaction temperature is -25 ~ -15 DEG C, reaction time 30-60min.
8. the preparation method of a kind of chenodeoxycholic acid according to claim 1 or 2 and its intermediate, it is characterised in that：Step
Suddenly（d）In, bromide reagent used is one or more of bromine, N- bromo-succinimides, pyridinium tribromide；Step
（d）In, bromo-reaction solvent for use is one or more of chloroform, carbon tetrachloride, glacial acetic acid, ether.
9. the preparation method of a kind of chenodeoxycholic acid according to claim 8 and its intermediate, it is characterised in that：Step
（d）In, intermediate II is 1 with bromide reagent mass ratio：0.1-2.5；Intermediate II is 1 with solvent quality ratio:10-45.
10. the preparation method of a kind of chenodeoxycholic acid according to claim 8 and its intermediate, it is characterised in that：Step
（d）In, bromo-reaction condition is that temperature is controlled at -5 DEG C -45 DEG C, stirs 4h-12h.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369765A (en) * | 2018-12-10 | 2019-02-22 | 华南理工大学 | A kind of preparation method of cowardly acid |
| CN109988256A (en) * | 2019-03-26 | 2019-07-09 | 北京晨光同创医药研究院有限公司 | A kind of preparation method of relax more glucose sodium and its intermediate |
| CN111961105A (en) * | 2020-09-23 | 2020-11-20 | 安徽科宝生物工程有限公司 | Method for separating hyodeoxycholic acid from pig bile paste by extraction method |
| CN112209982A (en) * | 2019-07-12 | 2021-01-12 | 华南理工大学 | Preparation method of chenodeoxycholic acid |
| CN113336818A (en) * | 2021-05-31 | 2021-09-03 | 中山百灵生物技术股份有限公司 | Preparation method of alpha-murine cholic acid |
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| CN101434632B (en) * | 2008-12-16 | 2011-05-25 | 同济大学 | Preparation of 3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid |
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| CN101434632B (en) * | 2008-12-16 | 2011-05-25 | 同济大学 | Preparation of 3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid |
| CN106831923A (en) * | 2017-03-15 | 2017-06-13 | 眉山市新功生物科技有限公司 | A kind of preparation method of chenodeoxycholic acid |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369765A (en) * | 2018-12-10 | 2019-02-22 | 华南理工大学 | A kind of preparation method of cowardly acid |
| CN109988256A (en) * | 2019-03-26 | 2019-07-09 | 北京晨光同创医药研究院有限公司 | A kind of preparation method of relax more glucose sodium and its intermediate |
| CN112209982A (en) * | 2019-07-12 | 2021-01-12 | 华南理工大学 | Preparation method of chenodeoxycholic acid |
| CN112209982B (en) * | 2019-07-12 | 2021-07-20 | 华南理工大学 | Preparation method of chenodeoxycholic acid |
| CN111961105A (en) * | 2020-09-23 | 2020-11-20 | 安徽科宝生物工程有限公司 | Method for separating hyodeoxycholic acid from pig bile paste by extraction method |
| CN113336818A (en) * | 2021-05-31 | 2021-09-03 | 中山百灵生物技术股份有限公司 | Preparation method of alpha-murine cholic acid |
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Application publication date: 20181113 |