CN107936078A - A kind of new method for preparing shellfish cholic acid difficult to understand - Google Patents
A kind of new method for preparing shellfish cholic acid difficult to understand Download PDFInfo
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- CN107936078A CN107936078A CN201610893271.3A CN201610893271A CN107936078A CN 107936078 A CN107936078 A CN 107936078A CN 201610893271 A CN201610893271 A CN 201610893271A CN 107936078 A CN107936078 A CN 107936078A
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- IMYITISAWLKCOM-AURVGCTBSA-N CC[C@H](C(C[C@@H](CC1)[O](C)=C)[C@@]1(C)C(CC1)[C@@H]2C(CC3)[C@@]1(C)[C@H]3[C@H](C)CCC(OC)=O)[C@H]2[O](C)=C Chemical compound CC[C@H](C(C[C@@H](CC1)[O](C)=C)[C@@]1(C)C(CC1)[C@@H]2C(CC3)[C@@]1(C)[C@H]3[C@H](C)CCC(OC)=O)[C@H]2[O](C)=C IMYITISAWLKCOM-AURVGCTBSA-N 0.000 description 1
Classifications
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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
Abstract
The present invention relates to a kind of preparation method of shellfish cholic acid (as compound of formula 7) difficult to understand, this method purification step is few, easy to operate, and high income, environmental pollution is small, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of new method for preparing shellfish cholic acid difficult to understand.
Technical background
Shellfish cholic acid (Obeticholic Acid) difficult to understand is a kind of new of chenodeoxycholic acid (CDCA) in people's primary bile acid
Derivative, is the native ligand of method Buddhist nun's ester derivant X acceptors (FXR), can suppress cholic acid synthesis, for treating primary biliary
Property hepatic sclerosis and non-alcohol fatty liver.
Shellfish cholic acid difficult to understand is researched and developed successfully by Intercept drugmakers of the U.S., is that first research and development are used to treat courage over 20 years
The medicine of juice cholestatic hepatic diseases.Research, which is used for those, not to be had abundant response to old plant medicine urso or is not resistant to
The patient received.In the phase iii clinical trial of placebo, shellfish cholic acid (OCA) difficult to understand improves relevant with the reduction of liver transfer operation risk
The level of two biomarkers.The composite end points of clinical research are that alkaline phosphatase at least declines 15%, Serum Basic phosphoric acid
The activity of enzyme is less than 1.67 times of normal upper limit, and bilirubin is in normal range (NR), and alkaline phosphatase is used to indicate that liver disease
A kind of biomarker of the sick order of severity.
Obeticholic acid are also used for treating a kind of more common fatty liver in test --- non-alcoholic fatty
Hepatitis.The 2 phases clinical research that this medicine one is used to treat such a indication is stopped prematurely because of its definite curative effect.
EvaluatePharma predicts that the sales volume of the year two thousand twenty Austria shellfish cholic acid is expected to reach 29.92 hundred million dollars.
Documents below reports the synthetic route of Obeticholic Acid：
1st, the synthetic route that WO 2002072598 and US 8338628 is reported is as follows：
The synthetic route of this two patents report is substantially similar, and subsequent patent is the base in first compound patent route
The yield of second step is lowly optimized on plinth, n-BuLi is replaced with into lithium diisopropylamine (LDA), is had on yield
Certain lifting.
2nd, the synthetic route that WO 2006122977 is reported is as follows：
The route develops standby patent route to be former, has larger lifting on yield, but process purification operation is very
More, the last each step of four steps has solvent purification operation, very cumbersome.
The content of the invention
The present invention relates to a kind of new method for preparing shellfish cholic acid difficult to understand.
In step 1 of the present invention, the hydroxyl of compound 1 is protected with trimethyl silane, in trim,ethylchlorosilane and
In the presence of lithium diisopropylamine, the tertiary ether of optimization aromatic solvent, more preferably first, ether, acetonitrile are further preferably molten
Agent is acetonitrile.According to preferable experimental program, step 1 obtain compound 2 be not isolated before step 2 is carried out with it is pure
Change.
In step 2 of the present invention, compound 2 connects vinyl by lewis acidic catalysis.Solvent for use is excellent
Elect non-protonic solvent as, more preferably ether, tetrahydrofuran, the tertiary ether of first and toluene, be further optimized for tetrahydrofuran.
According to preferable experimental program, lewis acid used in step 2 is preferably boron trifluoride acetonitrile, boron trifluoride tetrahydrochysene
Furans and titanium tetrachloride, more preferably boron trifluoride tetrahydrofuran.According to preferable experimental program, step 2 reaction temperature
It is preferably -60~-50 degree for -70~-50 degree.According to preferable experimental program, the compound 3 that step 2 obtains is being walked
It is not isolated and purifies before rapid three.
In step 3 of the present invention, compound 3 is dissolved with solvent, and catalytic hydrogenation obtains compound 4.The solvent
Preferably alcohols solvent, more preferably methanol, ethanol and isopropanol, more preferably methanol.According to preferable experimental program,
Step 4 preferred catalyst is palladium carbon and Raney's nickel, more preferably palladium carbon.
According to preferable experimental program, the reaction temperature of step 3 is preferably 20~60 degree, is further optimized for 30~40
Degree.According to preferable experimental program, the reaction pressure of step 3 is preferably 1 atmospheric pressure~3 atmospheric pressure, more preferably
3 atmospheric pressure.According to preferable experimental program, step 3 obtain compound 4 be not isolated before step 4 is carried out with it is pure
Change.
In step 4 of the present invention, compound 4 carries out configuration with the non-aromatic solvent solvent of acid gas-containing
Upset obtains compound 5.The non-aromatic solvent of the acid gas-containing is hydrochloric acid dioxane, hydrochloric acid tetrahydrofuran, hydrochloric acid
Methanol, acidic alcohol, are preferably that hydrochloric acid dioxane closes hydrochloric acid tetrahydrofuran, more preferably hydrochloric acid tetrahydrofuran.
According to preferable experimental program, step 4 reaction temperature is preferably 30~60 degree, is preferably 30~40 degree.According to excellent
The experimental program of choosing, the compound 5 that step 4 obtains are not isolated and purify before step 5 is carried out.
In step 5 of the present invention, compound 5 is dissolved with alcohols solvent, then passes through reducing agent reduction
Compound 6.The alcohols solvent is methanol, ethanol and isopropanol, more preferably ethanol.
According to preferable experimental program, reducing agent described in step 6 is preferably sodium borohydride.According to preferable experimental program,
Step 5 reaction temperature is 0 degree~50 degree, preferably 40~50 degree.The compound 6 obtained according to preferable experimental program, step 5
It is not isolated and purifies before step 6 is carried out.
In step 6 of the present invention, compound 6 is dissolved with alcohols solvent, then makes its water by alkaline aqueous solution
Solution obtains compound 7.The alcohols solvent is methanol, ethanol and isopropanol, is preferably ethanol.According to preferable experimental program,
The alkali of step 6 is preferably sodium hydroxide and potassium hydroxide, is preferably sodium hydroxide.It is anti-according to preferable experimental program, step 6
It is preferably 20~60 degree to answer temperature, more preferably 50~60 degree.
According to preferable experimental program, step 6 after reaction, isolates and purifies to obtain preferably using following mode of operation
Compound 7 (shellfish cholic acid i.e. difficult to understand).
1) dichloromethane is added into the reaction solution, hydrochloric acid adjusts reaction medium pH as 1~3；
2) two phase stratification removes water phase, and organic phase is concentrated to give grease；
3) grease is recrystallized to give compound 7 by butyl acetate.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
Apply among a scope.
Embodiment 1：The synthesis of compound 2
Compound 1 (72g, 1.0eq) is loaded into the reaction bulb under inert conditions, and is dissolved in acetonitrile in (350mL), nitrogen
Under protection, system is cooled to -30 DEG C, by TMSCl (48.5g, 2.5eq) addition system, and continues to stir 15min；Then
LDA (2M in THF, 2.5eq) is slowly dropped into reaction system, after dripping off, when insulation reaction 24 is small；System is warming up to 0~5
DEG C, add water (350mL) and stir 10~15min, stratification, aqueous phase discarded afterwards；Obtain liquid separation obtained by organic phase, organic phase into
One step is washed with water (350mL), stratification, aqueous phase discarded；By being evaporated under reduced pressure the solvent in organic phase at 40 DEG C maximum
It is evaporated off；Gained oily liquids obtains the oily liquids of compound 2, directly further using toluene after the de- band of 50 DEG C of vacuum distillations 3 times
Connect for reacting in next step, yield 100%.
Embodiment 2：The synthesis of compound 3
Compound 2 (30g) is dissolved in tetrahydrofuran in (90mL), acetaldehyde (6g, 3eq) is added and nitrogen is protected；By body
System is cooled to -65~-60 DEG C；By boron trifluoride tetrahydrofuran solution (15.3g, 2eq) toward being slowly added dropwise in system, after dripping off,
Continue insulated and stirred 20h；System temperature is risen to 20~30 DEG C, is added in 300mL saturated sodium bicarbonate solutions and is quenched；
Stratification, obtains organic phase；Organic phase is further washed using water (150mL), aqueous phase discarded；By organic phase in 40 DEG C of water-baths
In be concentrated under reduced pressure and remove organic solvent, obtain 3 common 21.2g of compound, yield 90%, grease is directly used in reaction in next step.
MS(ESI)m/z 431.31([M+H]+)。
Embodiment 3：The synthesis of compound 4
In compound 3 (20g) the input hydrogenation bottle that upper step is obtained, dissolved with 400mL methanol；Add 7%Pd/C
(0.2g), it is 3 atmospheric pressure to control Hydrogen Vapor Pressure, and 35 degree are stirred 20~24h.After the completion of reaction, filter to get filtrate, filtrate is in 45
It is concentrated to dryness to obtain compound 4, common 20g, yield 99% at DEG C.MS(ESI)m/z 433.31([M+H]+)。
Embodiment 4：The synthesis of compound 5
Previous step is obtained compound 4 (15g) to be added in the hydrochloric acid tetrahydrofuran solution of 8% concentration of 150mL, 35 degree
React 12h.After the reaction was complete, concentration removes reaction solution and can obtain compound 5 (15g, yield 100%).MS(ESI)m/z
433.31([M+H]+)。
Embodiment 5：The synthesis of compound 6
The compound 5 (15g, 1eq) that previous step obtains ethanol (150mL) is dissolved, 45 degree is warming up to, boron is added portionwise
Sodium hydride (1.6g, 1.2eq), insulation reaction 12h.After the reaction was complete, room temperature is down to, is quenched instead with 100mL saturated sodium bicarbonates
Answer system.100mL dichloromethane extractive reaction liquid is added, organic phase, which directly concentrates, to be done, and obtains compound 6 (14g, yield
93%).MS(ESI)m/z 457.34([M+Na]+)。
Embodiment 6：The synthesis of compound 7
Compound 6 (12g) ethanol (120mL) is dissolved, the water (100mL) that sodium hydroxide (1.3g, 1.2eq) is added dropwise is molten
Liquid, then heat to 50 degree of insulation reactions 4 it is small when.After reaction, concentration removes ethanol, and the salt acid for adjusting pH with 10% is 1.
200mL dichloromethane extractive reaction systems are added, gained organic phase washed once with saturated salt solution, and concentration organic phase obtains oil
Shape thing.Gained grease 100mL butyl acetates are dissolved, then slow cooling there are the precipitations of a large amount of solids to 10 degree, filters
It is the shellfish cholic acid (10.5g, yield 90%) difficult to understand of compound 7 to solid.MS(ESI)m/z 443.32([M+Na]+)。
Claims (27)
1. the method that one kind prepares shellfish cholic acid (as compound of formula 7) difficult to understand, the described method comprises the following steps
A) trim,ethylchlorosilane and LDA are used in non-aromatic solvent by compound 1
It is transformed into compound 2；
C) optionally, in non-protonic solvent, under lewis acid existence condition, compound 2 and acetaldehyde are reacted, synthesize compound
3；
D) in non-aromatic solvent, compound 3 is hydrogenated as compound 4 by palladium carbon, hydrogen；
E) optionally, compound 4 is handled in the non-aromatic solvent of acid gas-containing, obtains respective compound 5；
F) alcohols solvent dissolved compound 5, compound 6 is reduced to by sodium borohydride；
G) in alcohols solvent, alkaline aqueous solution Hydrolysis of compound 6 obtains shellfish cholic acid 7 difficult to understand.
2. method according to claim 1, it is characterised in that non-aromatic solvent used in step 1 is the tertiary ether of first, ether, second
Nitrile.
3. method according to claims 1 to 2, it is characterised in that step 2 is first molten by compound 2 and acetaldehyde aprotic
Agent is dissolved, and then reacts to obtain compound 3 by Louis acid catalysis.
4. method according to claim 3, the non-protonic solvent is ether, tetrahydrofuran, the tertiary ether of first and toluene.
5. method according to claim 4, it is characterised in that the lewis acid is boron trifluoride acetonitrile, boron trifluoride four
Hydrogen furans and titanium tetrachloride.
6. method according to claim 5, it is characterised in that the reaction temperature is -70~-50 degree.
7. method according to claim 6, it is characterised in that step 2 obtain compound 3 before step 3 is carried out not
Separated and purified.
8. method according to claims 1 to 7, it is characterised in that compound 3 is dissolved in alcohols solvent by step 3, is urged
Change hydrogenation and obtain compound 4.
9. method according to claim 8, it is characterised in that the alcohols solvent is methanol, ethanol, isopropanol.
10. method according to claim 9, it is characterised in that the catalyst is Raney's nickel, palladium carbon.
11. method according to claim 10, it is characterised in that catalytic hydrogenation temperature is 20~60 degree.
12. according to claim 11 the method, it is characterised in that the hydrogenation pressure 1 atmospheric pressure and 3 atmospheric pressure it
Between.
13. according to claim 12 the method, it is characterised in that the compound 4 that step 3 obtains is before step 4 is carried out
It is not isolated and purifies.
14. according to claim 1~13 the method, it is characterised in that step 4 is non-aromatic by the use acid gas-containing of compound 4
Fragrant race's solvent carries out configuration reversal and obtains compound 5.
15. according to claim 14 the method, it is characterised in that the non-aromatic solvent of the acid gas-containing is hydrochloric acid two
Six ring of oxygen, hydrochloric acid tetrahydrofuran, hydrochloric acid methanol, acidic alcohol.
16. according to claim 15 the method, it is characterised in that the reaction temperature is 30~60 degree of
17. according to claim 16 the method, it is characterised in that the compound 5 that step 4 obtains is before step 5 is carried out
It is not isolated and purifies.
18. according to claim 1~17 the method, it is characterised in that step 5 dissolves compound 5 with alcohols solvent, so
Reduce to obtain compound 6 by reducing agent afterwards.
19. according to claim 18 the method, it is characterised in that the alcohols solvent is methanol, ethanol, isopropanol.
20. according to claim 19 the method, it is characterised in that the reducing agent is sodium borohydride.
21. according to claim 20 the method, it is characterised in that the reaction temperature is 0 degree~50 degree.
22. according to claim 21 the method, it is characterised in that the compound 6 that step 5 obtains is before step 6 is carried out
It is not isolated and purifies.
23. according to claim 1~22 the method, it is characterised in that step 6 dissolves compound 6 with alcohols solvent, so
Its hydrolysis is set to obtain compound 7 by alkaline aqueous solution afterwards.
24. according to claim 23 the method, it is characterised in that the alcohols solvent is methanol, ethanol and isopropanol.
25. according to claim 24 the method, it is characterised in that the alkali is sodium hydroxide, potassium hydroxide.
26. according to claim 25 the method, it is characterised in that the reaction temperature is 20~60 degree.
27. according to claim 23~26 the method, it is characterised in that obtain product according to following mode of operation
1) dichloromethane is added into the reaction solution, hydrochloric acid adjusts reaction medium pH as 1~3；
2) two phase stratification removes water phase, and organic phase is concentrated to give grease；
3) grease is recrystallized to give compound 7 by butyl acetate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108070014A (en) * | 2016-11-08 | 2018-05-25 | 北京藏卫信康医药研发有限公司 | A kind of preparation method of compound and its application in shellfish cholic acid difficult to understand is prepared |
| CN111087436A (en) * | 2019-12-26 | 2020-05-01 | 中山百灵生物技术有限公司 | Preparation method of obeticholic acid |
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| WO2006122977A2 (en) * | 2005-05-19 | 2006-11-23 | Erregierre S.P.A. | PROCESS FOR PREPARING 3α(β)-7α(β)-DIHYDROXY-6α(β)-ALKYL-5β-CHOLANIC ACID |
| CN104926909A (en) * | 2015-06-30 | 2015-09-23 | 浙江天顺生物科技有限公司 | Preparation method for obeticholic acid |
| CN105481925A (en) * | 2015-12-17 | 2016-04-13 | 南京济群医药科技有限公司 | Preparation method for obeticholic acid and intermediate thereof |
| CN105669811A (en) * | 2014-11-17 | 2016-06-15 | 正大天晴药业集团股份有限公司 | Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine |
-
2016
- 2016-10-13 CN CN201610893271.3A patent/CN107936078A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006122977A2 (en) * | 2005-05-19 | 2006-11-23 | Erregierre S.P.A. | PROCESS FOR PREPARING 3α(β)-7α(β)-DIHYDROXY-6α(β)-ALKYL-5β-CHOLANIC ACID |
| CN105669811A (en) * | 2014-11-17 | 2016-06-15 | 正大天晴药业集团股份有限公司 | Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine |
| CN104926909A (en) * | 2015-06-30 | 2015-09-23 | 浙江天顺生物科技有限公司 | Preparation method for obeticholic acid |
| CN105481925A (en) * | 2015-12-17 | 2016-04-13 | 南京济群医药科技有限公司 | Preparation method for obeticholic acid and intermediate thereof |
Non-Patent Citations (1)
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| CLAUDIO D’AMORE等: "Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", 《J. MED. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108070014A (en) * | 2016-11-08 | 2018-05-25 | 北京藏卫信康医药研发有限公司 | A kind of preparation method of compound and its application in shellfish cholic acid difficult to understand is prepared |
| CN111087436A (en) * | 2019-12-26 | 2020-05-01 | 中山百灵生物技术有限公司 | Preparation method of obeticholic acid |
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