CN105585605A - Synthetic method for obeticholic acid intermediate - Google Patents
Synthetic method for obeticholic acid intermediate Download PDFInfo
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- CN105585605A CN105585605A CN201610148290.3A CN201610148290A CN105585605A CN 105585605 A CN105585605 A CN 105585605A CN 201610148290 A CN201610148290 A CN 201610148290A CN 105585605 A CN105585605 A CN 105585605A
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- acid intermediate
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- cholic acid
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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 a synthetic method for an obeticholic acid intermediate. The method includes the steps that organic solvent is poured into a reactor protected by inert gas, 3 alpha-hydroxyl-7-keto-5beta-cholane-24-oate is dissolved into the organic solvent, and then organic alkali is added; the solution is cooled to 0 DEG C-5 DEG C, then carbonate is slowly added dropwise to protect the 3-position hydroxyl group, after dropwise addition is completed, the reaction solution is heated to 20 DEG C-50 DEG C and is stirred for 2-8 h, and then the organic solvent is removed through decompression concentration; ice water is added for dissolution, ethyl acetate is added to extract the water phase, organic layers are combined and washed, an appropriate amount of anhydrous sodium sulfate is adopted for drying so that the organic layers are concentrated, and the obeticholic acid intermediate is obtained. The 3-position hydroxyl group is protected with carbonate first, the 7-position carbonyl enol is protected in a trimethylsilylation mode, the dosage of LDA is reduced by a half, and the efficiency of the condensation reaction is higher.
Description
Technical field
Embodiments of the present invention relate to medical technical field, and more specifically, embodiments of the present invention relate toA kind of synthetic method of shellfish cholic acid intermediate difficult to understand.
Background technology
Shellfish cholic acid difficult to understand is a kind of new drug for cholestasis type cirrhosis, and its synthetic route all need to be 7 at presentPosition carbonyl and acetaldehyde condensation, before this, need to protect 3 hydroxyls; Patent US2008/0214515A1 has adopted 3 hydroxyls and 7 methods that the protection of carbonyl enol trimethyl silicone hydride is carried out simultaneously, concreteFlow process is as follows:
But said method need to adopt more than at least two equivalents LDA as alkali, and the volume of reaction is bigger than normal,Efficiency is lower; Therefore develop a kind of LDA consumption few, the effective method of condensation reaction is necessary.
Summary of the invention
The present invention has overcome the deficiencies in the prior art, and a kind of synthetic method of shellfish cholic acid intermediate difficult to understand is provided, withIt is large that expectation can solve in shellfish cholic acid building-up process difficult to understand LDA consumption, the problem that reaction efficiency is low.
For solving above-mentioned technical problem, one embodiment of the present invention by the following technical solutions:
A synthetic method for shellfish cholic acid intermediate difficult to understand, adopts 3 hydroxyls of carbonic ester protection, concrete steps asUnder:
A, first organic solvent is packed in the reactor of inert gas shielding, then by 3 Alpha-hydroxies-7-ketone-5 β-courageAlkane-24-acid methyl esters is dissolved in described organic solvent, adds subsequently organic base;
B, the solution that steps A is obtained are cooled to 0～5 DEG C, then slowly drip 3 hydroxyls of carbonic ester protectionBase, after dripping, is warming up to 20～50 DEG C by reactant liquor and stirs 2～8h, and then reduced pressure concentration is removed organicSolvent;
C, the concentrate obtaining to step B add frozen water that it is dissolved, and then add ethyl acetate to extract water,Merge organic layer, washing organic layer, then adopts appropriate anhydrous sodium sulfate drying, makes organic layer concentrated dry,Obtain described shellfish cholic acid intermediate difficult to understand.
In the synthetic method of above-mentioned shellfish cholic acid intermediate difficult to understand, described organic solvent be ethyl acetate, butyl acetate,Carrene or oxolane.
In the synthetic method of above-mentioned shellfish cholic acid intermediate difficult to understand, described organic base is triethylamine or pyridine.
In the synthetic method of above-mentioned shellfish cholic acid intermediate difficult to understand, described carbonic ester is ethyl chloroformate, chloro-carbonic acid thirdEster or butyl chlorocarbonate.
In the synthetic method of above-mentioned shellfish cholic acid intermediate difficult to understand, described 3 Alpha-hydroxies-7-ketone-5 β-cholane-24-acid methyl estersWith the mass ratio of organic base be 8～9:4.5.
In the synthetic method of above-mentioned shellfish cholic acid intermediate difficult to understand, described 3 Alpha-hydroxies-7-ketone-5 β-cholane-24-acid methyl estersWith the mass ratio of carbonic ester be 8～9:4.
In the synthetic method of above-mentioned shellfish cholic acid intermediate difficult to understand, described washing organic layer refers to uses 10%HCl successivelyThe aqueous solution, saturated sodium bicarbonate solution and saturated nacl aqueous solution washing.
Prepared by the present invention is that shellfish cholic acid intermediate difficult to understand i.e. 3 α-carbonic ester-7-ketone-5 β-cholane-24-acid methyl esters (is changedCompound 2), utilize this intermediate can prepare 3 Alpha-hydroxies-6-ethylidene-7-ketone-5 β-cholane-24-acid methyl esters and (changeCompound 4), idiographic flow is as follows:
The concrete grammar of preparing compound 3 from compound 2 is: by vacuum/nitrogen displacement three times for reaction bulb,Under micro-nitrogen air-flow protection, add shellfish cholic acid intermediate 10.0g difficult to understand that anhydrous tetrahydro furan 80g, the present invention synthesize,Trim,ethylchlorosilane 6.84g, replaces three times by vacuum/nitrogen again. Mixed solution is precooled to-30～-25 DEG C.Keep-30～-25 DEG C to drip 26.0gLDA (2.0M/L). After dripping ,-30～-25 DEG C are stirred 2～3h,Monitoring reacts completely. Add 8.5g triethylamine, stir 30～60min. Be warming up to 0～10 DEG C, drip 80gSaturated sodium bicarbonate solution. Reactant liquor adds respectively 100g, the extraction of 50g ethyl acetate. Merging organic layer dividesYong 100g saturated sodium bicarbonate, 100g water, the washing of 100g saturated nacl aqueous solution. Add anhydrous in right amountDried over sodium sulfate. Be evaporated to dryly, obtain crude product 12.6g.
The concrete grammar of preparing compound 4 from compound 3 is: by vacuum/nitrogen displacement three times for reaction bulb,Be dissolved in anhydrous methylene chloride (30g) by preparing the described crude product 12.6g that compound 3 obtains, then use vacuum/Nitrogen replacement three times. Mixed solution is cooled to-78～-70 DEG C. Keep-78～-70 DEG C and add 1.7g acetaldehyde.Keep-78～-70 DEG C to drip 10.7g BFEE. After dripping, keep-78～-70 DEG C stir 2～3h, monitoring raw material reaction is complete. Rising temperature to 25～30 DEG C, stir 1～2h. Adjustment temperature to 10～20 DEG C, drip 10g saturated sodium bicarbonate solution. Add 50g carrene and 30g water, washing point water outletLayer. Organic layer is respectively with 30g saturated sodium bicarbonate solution and the washing of 30g saturated nacl aqueous solution. Organic layerBe concentrated into dry 10.5g, obtain 4.2g compound 4 through recrystallization.
Compared with prior art, one of beneficial effect of the present invention is: the present invention is first by 3 hydroxyl carbonic estersProtect, then to 7 carbonyl enol trimethyl silicone hydride protections, not only LDA consumption reduces half, meanwhile,The efficiency of condensation reaction is higher.
Detailed description of the invention
In order to make object of the present invention, technical scheme and advantage clearer, below in conjunction with embodiment,The present invention is further elaborated. Should be appreciated that specific embodiment described herein only in order toExplain the present invention, be not intended to limit the present invention.
Embodiment 1:
Ethyl acetate (40g) is packed in the reactor of inert gas shielding, by 3 Alpha-hydroxies-7-ketone-5 β-cholane-24-acid methyl esters (8.47g) is dissolved in wherein, adds 4.5g pyridine. This solution is cooled to 0 DEG C, slowlyDrip ethyl chloroformate (4.0g). After ethyl chloroformate drips, reactant liquor is warming up to 22 DEG C, keeps22 DEG C are stirred 2.5h. Reduced pressure concentration is removed ethyl acetate. Add 34g frozen water to dissolve concentrate, then divideDo not add 17g, 17g, 8.5g ethyl acetate to extract water three times, merge three times organic layer. Organic layerUse respectively the 8.5g10%HCl aqueous solution, 8.5g saturated sodium bicarbonate solution, 8.5g saturated sodium-chloride is moltenLiquid washing, then use appropriate anhydrous sodium sulfate drying, make organic layer concentrated dry, obtain crude product 10.1g, straightConnect the preparation for above-claimed cpd 4, three step total recoverys 46%.
Embodiment 2:
Oxolane (40g) is packed in the reactor of inert gas shielding, by 3 Alpha-hydroxies-7-ketone-5 β-cholane-24-acid methyl esters (8.47g) is dissolved in wherein, adds 4.5g pyridine. This solution is cooled to 5 DEG C, slowlyDrip propyl chlorocarbonate (4.0g). After propyl chlorocarbonate drips, reactant liquor is warming up to 25 DEG C, keeps25 DEG C are stirred 2h. Reduced pressure concentration is removed oxolane. Add 34g frozen water to dissolve. Add respectively 17g,17g, 8.5g ethyl acetate extract water three times, merge three times organic layer. Organic layer is used respectively 8.5g10%The HCl aqueous solution, 8.5g saturated sodium bicarbonate solution, the washing of 8.5g saturated nacl aqueous solution, anhydrous in right amountDried over sodium sulfate. Organic layer is concentrated dry, obtains crude product 10.3g and be directly used in the preparation of above-claimed cpd 4,Three step total recoverys 48%.
Embodiment 3:
Butyl acetate (40g) is packed in the reactor of inert gas shielding, by 3 Alpha-hydroxies-7-ketone-5 β-cholane-24-acid methyl esters (8.47g) is dissolved in wherein, adds 4.5g triethylamine. This solution is cooled to 2 DEG C, slowThe slow butyl chlorocarbonate (4.0g) that drips. After butyl chlorocarbonate drips, reactant liquor is warming up to 20 DEG C, protectsHold 20 DEG C and stir 3h. Reduced pressure concentration is removed butyl acetate. Add 34g frozen water to dissolve. Add respectively 17g,17g, 8.5g ethyl acetate extract water three times, merge three times organic layer. Organic layer is used respectively 8.5g10%The HCl aqueous solution, 8.5g saturated sodium bicarbonate solution, the washing of 8.5g saturated nacl aqueous solution, anhydrous in right amountDried over sodium sulfate. Organic layer is concentrated dry, obtains crude product 10.2g and be directly used in the preparation of above-claimed cpd 4,Three step total recoverys 47%.
Embodiment 4:
Carrene (40g) is packed in the reactor of inert gas shielding, by 3 Alpha-hydroxies-7-ketone-5 β-courageAlkane-24-acid methyl esters (8.47g) is dissolved in wherein, adds 4.5g triethylamine. This solution is cooled to 0 DEG C, slowlyDrip ethyl chloroformate (4.0g). After ethyl chloroformate drips, reactant liquor is warming up to 25 DEG C, keeps 25 DEG CStir 3 hours. Reduced pressure concentration is removed carrene. Add 34g frozen water to dissolve. Add respectively 17g, 17g,8.5g ethyl acetate extracts water three times, merges three times organic layer. Organic layer is used respectively 8.5g10%HCl waterSolution, 8.5g saturated sodium bicarbonate solution, the washing of 8.5g saturated nacl aqueous solution, appropriate anhydrous sodium sulfate is dryDry. Organic layer is concentrated dry, obtains crude product 10.0g and be directly used in the preparation of above-claimed cpd 4, three step total recoverys46％。
Although with reference to explanatory embodiment of the present invention, invention has been described here,, should manageSeparate, those skilled in the art can design a lot of other amendment and embodiments, these amendments and enforcementWithin mode will drop on the disclosed principle scope and spirit of the application. More particularly, disclosed in the applicationIn scope, can carry out multiple modification and improvement to the building block of subject combination layout and/or layout. ExceptThe modification that building block and/or layout are carried out and improve outside, to those skilled in the art, otherPurposes will be also obvious.
Claims (7)
1. a synthetic method for shellfish cholic acid intermediate difficult to understand, is characterized in that adopting 3 hydroxyls of carbonic ester protection,Concrete steps are as follows:
A, first organic solvent is packed in the reactor of inert gas shielding, then by 3 Alpha-hydroxies-7-ketone-5 β-courageAlkane-24-acid methyl esters is dissolved in described organic solvent, adds subsequently organic base;
B, the solution that steps A is obtained are cooled to 0～5 DEG C, then slowly drip 3 hydroxyls of carbonic ester protectionBase, after dripping, is warming up to 20～50 DEG C by reactant liquor and stirs 2～8h, and then reduced pressure concentration is removedOrganic solvent;
C, the concentrate obtaining to step B add frozen water that it is dissolved, and then add ethyl acetate to extract waterPhase, merges organic layer, and washing organic layer, then adopts appropriate anhydrous sodium sulfate drying, makes organic layerConcentrated dry, obtain described shellfish cholic acid intermediate difficult to understand.
2. the synthetic method of shellfish cholic acid intermediate difficult to understand according to claim 1, is characterized in that described organicSolvent is ethyl acetate, butyl acetate, carrene or oxolane.
3. the synthetic method of shellfish cholic acid intermediate difficult to understand according to claim 1, is characterized in that described organicAlkali is triethylamine or pyridine.
4. the synthetic method of shellfish cholic acid intermediate difficult to understand according to claim 1, is characterized in that described carbonic acidEster is ethyl chloroformate, propyl chlorocarbonate or butyl chlorocarbonate.
5. the synthetic method of shellfish cholic acid intermediate difficult to understand according to claim 1, it is characterized in that described 3 α-The mass ratio of hydroxyl-7-ketone-5 β-cholane-24-acid methyl esters and organic base is 8～9:4.5.
6. the synthetic method of shellfish cholic acid intermediate difficult to understand according to claim 1, it is characterized in that described 3 α-The mass ratio of hydroxyl-7-ketone-5 β-cholane-24-acid methyl esters and carbonic ester is 8～9:4.
7. the synthetic method of shellfish cholic acid intermediate difficult to understand according to claim 1, is characterized in that described washingOrganic layer refers to uses the 10%HCl aqueous solution, saturated sodium bicarbonate solution and saturated nacl aqueous solution successivelyWashing.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115785183A (en) * | 2020-04-23 | 2023-03-14 | 江西青峰药业有限公司 | Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| CN104558086A (en) * | 2014-12-25 | 2015-04-29 | 康美（北京）药物研究院有限公司 | Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid |
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2016
- 2016-03-15 CN CN201610148290.3A patent/CN105585605A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| CN104558086A (en) * | 2014-12-25 | 2015-04-29 | 康美（北京）药物研究院有限公司 | Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid |
Non-Patent Citations (1)
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| R. PÉREZ GIL ET AL.: "Synthesis of Analogues of Brassinosteroids with 5β-Cholanic Acid Skeleton", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115785183A (en) * | 2020-04-23 | 2023-03-14 | 江西青峰药业有限公司 | Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde |
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