CN106279328A - A kind of method preparing 6 alpha-alkyl chenodeoxycholic acid - Google Patents
A kind of method preparing 6 alpha-alkyl chenodeoxycholic acid Download PDFInfo
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- CN106279328A CN106279328A CN201510258575.8A CN201510258575A CN106279328A CN 106279328 A CN106279328 A CN 106279328A CN 201510258575 A CN201510258575 A CN 201510258575A CN 106279328 A CN106279328 A CN 106279328A
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Abstract
The invention discloses one and prepare 3 α, the new method of 7 alpha-dihydroxy-6 alpha-alkyl-5 β-cholanic acid I.The method is without compressive reaction, and intermediate, without isolated and purified, can obtain required product by one kettle way, and reaction condition is gentle, and yield is high, is suitable for industrialized production.
Description
Technical field
The present invention relates to medicine organic synthesis field, particularly relate to the preparation method of 6 alpha-alkyl chenodeoxycholic acid.
Background technology
Bile acid is the general name of a class cholanic acid present in bile, account for the 50% ~ 70% of bile total solid, because it has the strongest surface-active action, modern medicine thinks that lipid and liposoluble substance are digested and assimilated by bile acid and cholesterol regulating metabolism plays an important role.But, bile acid activates the discovery of nuclear receptor signal pathway and has broken relatively simple traditional understanding this to bile acid.
Farnesoid X receptor (farnesoid X receptor; FXR) be a kind of bile acid activate nuclear receptor; substantial amounts of research confirms that FXR is the metabolism regulators of a kind of key; participate in the regulation of the multiple physiological activity of body, the process such as including bile acid biosynthesis, lipid metabolism, carbohydrate metabolism and liver protecting.FXR is the main induction apparatus of bile acid, in conjunction with uncombined cholate can physiological concentration activate FXR.Chenodeoxycholic acid in primary bile acid is that the FXR endogenous agonist of a kind of strength, secondary bile acid lithocholic acid and deoxycholic acid can also activate FXR, but its activation effect is weaker than chenodeoxycholic acid.6-ethyl chenodeoxycholic acid (shellfish cholic acid difficult to understand) is a kind of synthetic FXR part, its several times stronger than native ligand with FXR adhesion.
Reporting the synthetic method of the FXR agonist with formula (A) in WO02072598, synthetic route is as follows:
Wherein R ' is ethyl, propyl group or pi-allyl.
The intermediate product of the method needs column chromatography purification, gross production rate extremely low (< 3.5%) and need to use the HMPA with carcinogenesis, is unfavorable for industrialized production.
Chinese patent CN101203526A discloses one and prepares 3 α, the method for 7 alpha-dihydroxy-6 alpha-alkyl-5 β-cholanic acid:
Wherein R is C1~C5Straight or branched alkyl.
The method is without column chromatography purification, and productivity (24.6%) that can be higher obtains required product, but it needs to use pressure hydration, there is certain danger in industrialized production.
The method is optimized by patent WO2013192097, but needs also exist for pressure hydration reaction.
Summary of the invention
It is an object of the invention to provide a kind of new preparation 3 α, the method for 7 alpha-dihydroxy-6 alpha-alkyl-5 β-cholanic acid I.The method is without compressive reaction, and response speed is fast and can realize one kettle way operation, is more suitable for industrialized production and can obtain high-quality product and satisfied yield.
Wherein R is hydrogen or C1~C5Straight or branched alkyl.
The present invention adopts the following technical scheme that
3 Alpha-hydroxy-6-thiazolinyl-7-ketone group-5 β-cholanic acid II in alcoholic solvent under the effect of palladium catalyst with ammonium formate generation transfer hydrogenation, obtain 3 Alpha-hydroxy-6 β-alkyl-7-ketone group-5 β-cholanic acid ammonium III;The aqueous solution heating being subsequently adding alkali turns structure and obtains 3 Alpha-hydroxy-6 alpha-alkyl-7-ketone group-5 β-cholane hydrochlorate IV;Being directly added into sodium borohydride reduction ketone group again, adding water and adding acid for adjusting pH value i.e. can get compound shown in Formulas I to acidity.In the present invention, each intermediate all can purify without isolation, and direct one kettle way obtains end product.Synthetic route is as follows:
Wherein R is hydrogen or C1~C5Straight or branched alkyl.
Wherein, described alcoholic solvent is selected from C1~C3Straight chain and branched-chain alcoho, preferably methanol；Described palladium catalyst is selected from palladium carbon, palladium black, palladium dydroxide and palladium, preferably palladium carbon；The mol ratio of compound II and ammonium formate is 1:2 ~ 10, preferably 1:5 ~ 10；Transfer hydrogenation temperature is 20 DEG C ~ 80 DEG C, preferably 50 DEG C ~ 60 DEG C；The aqueous solution of described alkali is the sodium hydrate aqueous solution of 10% ~ 40%, the sodium hydrate aqueous solution of preferably 30% ~ 40%；Temperature when heating turns structure is 60 DEG C ~ 100 DEG C, preferably 70 DEG C ~ 80 DEG C, and reaction temperature when adding sodium borohydride reduction ketone group is 60 DEG C ~ 100 DEG C, and preferably 80 DEG C ~ 90 DEG C, the mol ratio of compound II and sodium borohydride is 1:2 ~ 6, preferably 1:3 ~ 5.
Available HPLC or TLC monitors reaction process, determines each elementary reaction terminal by material content change.After having reacted, add water in reaction system after Filtration of catalyst and regulate alkali and the sodium borohydride that pH remains to acid cancellation, 0 DEG C ~ 30 DEG C cooling crystallizations, filtering, refined, obtain 3 α, 7 alpha-dihydroxy-6 alpha-alkyl-5 β-cholanic acid I after drying.
Wherein, 3 Alpha-hydroxy-6-thiazolinyl-7-ketone group-5 β-cholanic acid II can refer to the method in Chinese patent CN101203526A or WO2013192097 or other known methods prepare.
Use method of the present invention to prepare 3 α, 7 alpha-dihydroxy-6 alpha-alkyl-5 β-cholanic acid, it is not necessary to pressure hydration equipment, required product can be obtained by one kettle way.Present invention process is simple to operate, course of reaction can gradient increased temperature, save equipment investment and the energy；Product yield is high, and solvent load is few, decreases quantity of three wastes and processing cost thereof, greatly reduces production cost, is more suitable for industrialized production.
Detailed description of the invention
In order to be better understood from the present invention, illustrate by the following examples.Described embodiment, only for helping to understand present invention, is understood not to the restriction to present subject matter and protection domain.
Embodiment 1
Being dissolved in 500mL methanol by 120g 3 Alpha-hydroxy-6-vinyl-7-ketone group-5 β-cholanic acid (0.279mol) under room temperature, add 12g 10% palladium carbon and 175.6g ammonium formate (2.79mol), be heated to 50 DEG C ~ 60 DEG C and react 1 hour, HPLC monitors reaction.Adding 40% sodium hydroxide solution 100ml after generating 3 Alpha-hydroxy-6 β-ethyl-7-ketone group-5 β-cholanic acid ammonium completely, be heated to 70 DEG C ~ 80 DEG C and react 1 hour, HPLC monitors reaction.Adding the sodium borohydride aqueous solution 500ml of 10% after generating 3 Alpha-hydroxy-6 α-ethyl-7-ketone group-5 β-cholane hydrochlorate completely, be warming up to 80 DEG C ~ 90 DEG C and react 3 hours, HPLC monitors reaction.React rear Filtration of catalyst, filtrate has added 1L water be 4 ~ 5 with 1M salt acid for adjusting pH value, has a large amount of white precipitate to produce, crystallize 1 hour at 0 DEG C ~ 5 DEG C, filters, and filter cake 200ml water washs, it is dried to obtain 3 α, 7 alpha-dihydroxy-6 α-ethyl-5 β-cholanic acid crude product 110.5g.Gained crude product is with being dried to obtain white powdery solids 3 α, 7 alpha-dihydroxy-6 α-ethyl-5 β-cholanic acid 98.1g after 400ml butyl acetate recrystallization, HPLC purity is 99.3%, and productivity is 83.7%.
Embodiment 2
Being dissolved in 500mL ethanol by 100g 3 Alpha-hydroxy-6-acrylic-7-ketone group-5 β-cholanic acid (0.225mol) under room temperature, add 10g 10% palladium carbon and 70.9g ammonium formate (1.12mol), react 5 hours at 20 ~ 30 DEG C, HPLC monitors reaction.Adding 10% sodium hydroxide solution 300ml after generating 3 Alpha-hydroxy-6 β-propyl group-7-ketone group-5 β-cholanic acid ammonium completely, be heated to 60 DEG C ~ 70 DEG C and react 1 hour, HPLC monitors reaction.Adding the sodium borohydride aqueous solution 250ml of 10% after generating 3 Alpha-hydroxy-6 α-propyl group-7-ketone group-5 β-cholane hydrochlorate completely, be incubated 60 DEG C ~ 70 DEG C and react 4 hours, HPLC monitors reaction.React rear Filtration of catalyst, filtrate has added 500ml water be 4 ~ 5 with 1M salt acid for adjusting pH value, has a large amount of white precipitate to produce, crystallize 1 hour at 20 DEG C ~ 30 DEG C, filters, and filter cake 200ml water washs, it is dried to obtain 3 α, 7 alpha-dihydroxy-6 α-propyl group-5 β-cholanic acid crude product 85.9g.Gained crude product is with being dried to obtain white powdery solids 3 α, 7 alpha-dihydroxy-6 α-propyl group-5 β-cholanic acid 76.6g after 400ml butyl acetate recrystallization, HPLC purity is 98.7%, and productivity is 78.3%.
Embodiment 3
Being dissolved in 200mL isopropanol by 50g 3 Alpha-hydroxy-6-isobutenyl-7-ketone group-5 β-cholanic acid (0.109mol) under room temperature, add 5g 10% palladium carbon and 13.8g ammonium formate (0.218mol), react 5 hours at 70 DEG C ~ 80 DEG C, HPLC monitors reaction.Adding 30% sodium hydroxide solution 100ml after generating 3 Alpha-hydroxy-6 β-isobutyl group-7-ketone group-5 β-cholanic acid ammonium completely, be heated to 90 DEG C ~ 100 DEG C and react 1 hour, HPLC monitors reaction.Adding the sodium borohydride aqueous solution 80ml of 10% after generating 3 Alpha-hydroxy-6 α-isobutyl group-7-ketone group-5 β-cholane hydrochlorate completely, be incubated 90 DEG C ~ 100 DEG C and react 1 hour, HPLC monitors reaction.React rear Filtration of catalyst, filtrate adds 300ml water be 4 ~ 5 with 1M salt acid for adjusting pH value, a large amount of white precipitate is had to produce, crystallize 1 hour at 10 DEG C ~ 20 DEG C, filter, filter cake 100ml water washs, and is dried to obtain 3 α, 7 alpha-dihydroxy-6 α-isobutyl group-5 β-cholanic acid crude product 42.6g.Gained crude product is with being dried to obtain white powdery solids 3 α, 7 alpha-dihydroxy-6 α-isobutyl group-5 β-cholanic acid 36.4g after 200ml butyl acetate recrystallization, HPLC purity is 98.5%, and productivity is 74.4%.
Embodiment 4
Being dissolved in 200mL methanol by 50g 3 Alpha-hydroxy-6-cyclobutenyl-7-ketone group-5 β-cholanic acid (0.109mol) under room temperature, add 5g 10% palladium carbon and 54.9g ammonium formate (0.872mol), react 1 hour at 40 DEG C ~ 50 DEG C, HPLC monitors reaction.Adding 30% sodium hydroxide solution 100ml after generating 3 Alpha-hydroxy-6 β-butyl-7-ketone group-5 β-cholanic acid ammonium completely, be heated to 90 DEG C ~ 100 DEG C and react 1 hour, HPLC monitors reaction.Adding the sodium borohydride aqueous solution 250ml of 10% after generating 3 Alpha-hydroxy-6 α-butyl-7-ketone group-5 β-cholane hydrochlorate completely, be incubated 90 DEG C ~ 100 DEG C and react 1 hour, HPLC monitors reaction.React rear Filtration of catalyst, filtrate has added 300ml water be 4 ~ 5 with 1M salt acid for adjusting pH value, has a large amount of white precipitate to produce, crystallize 1 hour at 10 DEG C ~ 20 DEG C, filters, and filter cake 100ml water washs, it is dried to obtain 3 α, 7 alpha-dihydroxy-6 α-butyl-5 β-cholanic acid crude product 40.3g.Gained crude product is with being dried to obtain white powdery solids 3 α, 7 alpha-dihydroxy-6 α-butyl-5 β-cholanic acid 35.4g after 200ml butyl acetate recrystallization, HPLC purity is 98.0%, and productivity is 72.4%.
Claims (10)
1. prepare 3 α with formula I for one kind, the method of 7 alpha-dihydroxy-6 alpha-alkyl-5 β-cholanic acid, described method includes: 3 Alpha-hydroxy-6-thiazolinyl-7-ketone group-5 β-cholanic acid II carries out transfer hydrogenation with ammonium formate under the effect of palladium catalyst in alcoholic solvent, obtains 3 Alpha-hydroxy-6 β-alkyl-7-ketone group-5 β-cholanic acid ammonium III；It is subsequently adding aqueous slkali heating to turn structure and obtain 3 Alpha-hydroxy-6 alpha-alkyl-7-ketone group-5 β-cholane hydrochlorate IV；Regulate pH value after being directly added into sodium borohydride reduction ketone group again and i.e. can get compound shown in Formulas I to acidity；Synthetic route is as follows:
Wherein R is hydrogen or C1~C5Straight or branched alkyl.
2. preparation method as claimed in claim 1, it is characterised in that the intermediate of each step reaction does not separates, and direct one kettle way obtains compound shown in Formulas I.
3. preparation method as claimed in claim 1 or 2, it is characterised in that 3 Alpha-hydroxy-6-thiazolinyl-7-ketone group-5 β-cholanic acid II is 1:2 ~ 10 with the mol ratio of ammonium formate, and compound II is 1:2 ~ 6 with the mol ratio of sodium borohydride.
4. preparation method as claimed in claim 3, it is characterised in that 3 Alpha-hydroxy-6-thiazolinyl-7-ketone group-5 β-cholanic acid II is 1:5 ~ 10 with the mol ratio of ammonium formate, and compound II is 1:3 ~ 5 with the mol ratio of sodium borohydride.
5. preparation method as claimed in claim 1 or 2, it is characterised in that described alcoholic solvent is selected from C1~C3Straight or branched alcohol, described palladium catalyst is selected from palladium carbon, palladium black, palladium dydroxide or palladium, and the reaction temperature of transfer hydrogenation is 20 DEG C ~ 80 DEG C.
6. preparation method as claimed in claim 5, it is characterised in that described alcoholic solvent is methanol, and described palladium catalyst is palladium carbon, and the reaction temperature of transfer hydrogenation is 50 DEG C ~ 60 DEG C.
7. preparation method as claimed in claim 1 or 2, it is characterised in that the aqueous solution of described alkali is the sodium hydrate aqueous solution of 10% ~ 40%, and temperature when heating turns structure is 60 DEG C ~ 100 DEG C.
8. preparation method as claimed in claim 7, it is characterised in that the aqueous solution of described alkali is the sodium hydrate aqueous solution of 30% ~ 40%, and temperature when heating turns structure is 70 DEG C ~ 80 DEG C.
9. preparation method as claimed in claim 1 or 2, it is characterised in that reaction temperature when adding sodium borohydride reduction ketone group is 60 DEG C ~ 100 DEG C.
10. preparation method as claimed in claim 9, it is characterised in that reaction temperature when adding sodium borohydride reduction ketone group is 80 DEG C ~ 90 DEG C.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854229A (en) * | 2015-12-08 | 2017-06-16 | 陈剑 | One class soap, it is prepared and its in application pharmaceutically |
| US10131688B2 (en) | 2014-11-19 | 2018-11-20 | NZP UK Limited | 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators |
| CN109485686A (en) * | 2018-12-27 | 2019-03-19 | 重庆华邦胜凯制药有限公司 | A method of improving 6 β content of key intermediate in the synthesis of Methylprednisolone succinate impurity |
| US10301350B2 (en) | 2014-11-19 | 2019-05-28 | NZP UK Limited | 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal FXR modulators |
| US10538550B2 (en) | 2014-11-19 | 2020-01-21 | NZP UK Limited | 6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal FXR modulators |
| US10597423B2 (en) | 2014-11-19 | 2020-03-24 | NZP UK Limited | 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal FXR modulators |
| US10968250B2 (en) | 2016-05-18 | 2021-04-06 | NZP UK Limited | Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid |
| EP3943502A4 (en) * | 2019-03-19 | 2022-11-23 | Suzhou Zelgen Biopharmaceutical Co., Ltd. | Method for preparing chenodeoxycholic acid derivative |
-
2015
- 2015-05-20 CN CN201510258575.8A patent/CN106279328A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10131688B2 (en) | 2014-11-19 | 2018-11-20 | NZP UK Limited | 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators |
| US10301350B2 (en) | 2014-11-19 | 2019-05-28 | NZP UK Limited | 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal FXR modulators |
| US10538550B2 (en) | 2014-11-19 | 2020-01-21 | NZP UK Limited | 6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal FXR modulators |
| US10597423B2 (en) | 2014-11-19 | 2020-03-24 | NZP UK Limited | 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal FXR modulators |
| CN106854229A (en) * | 2015-12-08 | 2017-06-16 | 陈剑 | One class soap, it is prepared and its in application pharmaceutically |
| US10968250B2 (en) | 2016-05-18 | 2021-04-06 | NZP UK Limited | Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid |
| US11479577B2 (en) | 2016-05-18 | 2022-10-25 | NZP UK Limited | Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid |
| CN109485686A (en) * | 2018-12-27 | 2019-03-19 | 重庆华邦胜凯制药有限公司 | A method of improving 6 β content of key intermediate in the synthesis of Methylprednisolone succinate impurity |
| CN109485686B (en) * | 2018-12-27 | 2021-08-27 | 重庆华邦胜凯制药有限公司 | Method for improving content of key intermediate 6 beta in methylprednisolone succinate impurity synthesis |
| EP3943502A4 (en) * | 2019-03-19 | 2022-11-23 | Suzhou Zelgen Biopharmaceutical Co., Ltd. | Method for preparing chenodeoxycholic acid derivative |
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