CN107674107B - Method for refining obeticholic acid - Google Patents
Method for refining obeticholic acid Download PDFInfo
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- CN107674107B CN107674107B CN201710915472.3A CN201710915472A CN107674107B CN 107674107 B CN107674107 B CN 107674107B CN 201710915472 A CN201710915472 A CN 201710915472A CN 107674107 B CN107674107 B CN 107674107B
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- obeticholic acid
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- obeticholic
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- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 title claims abstract description 76
- 229960001601 obeticholic acid Drugs 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title claims abstract description 48
- 238000007670 refining Methods 0.000 title claims abstract description 19
- ZXERDUOLZKYMJM-XHCXGMTMSA-N C([C@@]12C)C[C@@H](O)C[C@H]1[C@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-XHCXGMTMSA-N 0.000 claims abstract description 50
- 239000002904 solvent Substances 0.000 claims abstract description 27
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 25
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical group CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012046 mixed solvent Substances 0.000 claims abstract description 13
- 150000008282 halocarbons Chemical class 0.000 claims abstract description 11
- 239000012535 impurity Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 20
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 20
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims description 15
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 13
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 5
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 description 50
- 239000007787 solid Substances 0.000 description 29
- 238000001914 filtration Methods 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000001291 vacuum drying Methods 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- AOGQPLXWSUTHQB-UHFFFAOYSA-N hexyl acetate Chemical compound CCCCCCOC(C)=O AOGQPLXWSUTHQB-UHFFFAOYSA-N 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 2
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- 102100038637 Cytochrome P450 7A1 Human genes 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 101000957672 Homo sapiens Cytochrome P450 7A1 Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012445 acidic reagent Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102100038495 Bile acid receptor Human genes 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 1
- 241000783099 Obetia Species 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a refining method of obeticholic acid. The invention provides a refining method of obeticholic acid I, which comprises the following steps: crystallizing a solution formed by the crude product of obeticholic acid and a solvent to obtain purified obeticholic acid; the solvent is an ester solvent or a mixed solvent of the ester solvent and a halogenated hydrocarbon solvent; the HPLC purity of the crude product of obeticholic acid reaches more than 85%. The refining method provided by the invention is simple and convenient to operate, high in yield, high in purity of the prepared product, low in impurity content, capable of reaching the standard of raw material medicines, low in production cost and suitable for industrialization.
Description
Technical Field
The invention relates to a refining method of obeticholic acid.
Background
Obeticholic acid (CAS number: 459789-99-2; chemical name: 6-ethyl chenodeoxycholic acid, structure shown in formula I):
a potent agonist of farnesoid derivative X receptor (FXR) developed by Obetia indirectly inhibits the gene expression of cytochrome 7A1(CYP7A1) by activating farnesoid X receptor. Since CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, obeticholic acid can inhibit cholic acid synthesis, and can be used for treating primary biliary cirrhosis and non-alcoholic fatty liver disease.
Intercept pharmaceuticals are developing various indications for obeticholic acid, including primary biliary cirrhosis (phase III clinic), nonalcoholic steatohepatitis NASH (phase II clinic), and primary sclerosing cholangitis (phase II clinic). 5 months 2014, the FDA granted obeticholic acid rapid channel eligibility; in 2015, 1 month, FDA awarded a breakthrough therapy approval for obeticholic acid; in 2016, 6 months, FDA approval to market.
As the diet of developed and developing countries is increasing in fat and sugar content, analysts estimate that non-alcoholic steatohepatitis may be the leading cause of liver transplantation instead of hepatitis C (hepatis C). Obeticholic acid has the opportunity to become a comparable drug to Sovaldii (Sofosbuvir), a hepatitis C therapeutic drug from Giliddes scientific, Calif.
The synthesis of obeticholic acid under the conditions of the prior art can be referred to the method reported in patent CN 201380043964.8. This process mentions purification of obeticholic acid on silica gel, which is clearly not feasible for large-scale preparation and industrialization. In addition, the patent US2014/148428 mentions a method of adjusting with acid and alkali, but obviously cannot remove isomers and main impurities of chenodeoxycholic acid, and the patent WO2013/192097 mentions a method of refining with dichloromethane, but the method has poor impurity removal effect, cannot obtain qualified products, has large residual solvent, and cannot be dried and removed.
Therefore, the search for a refining method of obeticholic acid, which is simple and convenient to operate, high in yield, high in purity of the prepared product, low in production cost and suitable for industrial production, is a technical problem which needs to be solved urgently at present.
Disclosure of Invention
The invention aims to solve the technical problems that the purification method of obeticholic acid in the prior art is complex in operation, low in total yield, poor in purity of the prepared product, not capable of reaching the standard of raw material medicines, high in production cost, not suitable for industrial production and the like. The refining method provided by the invention is simple and convenient to operate, high in yield, high in purity of the prepared product, low in impurity content, capable of reaching the standard of raw material medicines, low in production cost and suitable for industrialization.
The invention provides a refining method of obeticholic acid I, which comprises the following steps: crystallizing a solution formed by the crude product of obeticholic acid and a solvent to obtain purified obeticholic acid; the solvent is an ester solvent or a mixed solvent of the ester solvent and a halogenated hydrocarbon solvent; the HPLC purity of the crude product of obeticholic acid reaches more than 85%.
In the method for refining obeticholic acid I, the purity of the crude obeticholic acid is preferably 90-100%, and the purity refers to HPLC purity; for example 97.38%, 94.37%, 92.44% or 90.56%. If the purity of the crude obeticholic acid is less than 85%, the crude obeticholic acid can be refined by the method disclosed by the invention or the method in the prior literature to the purity of more than 85%.
In the method for refining obeticholic acid I, the ester solvent is preferably one or more of ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, n-pentyl acetate and n-hexyl acetate.
In the purification method of obeticholic acid I, the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the purification method of obeticholic acid I, when a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent is used, the volume ratio of the ester solvent to the halogenated hydrocarbon solvent is preferably 1-10, for example, 1, 3, 7 or 10.
In the method for refining obeticholic acid I, when a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent is adopted, the mixed solvent of the ester solvent and the halogenated hydrocarbon solvent is preferably a mixed solvent of ethyl acetate and dichloromethane, a mixed solvent of isopropyl acetate and dichloromethane, a mixed solvent of n-propyl acetate and dichloromethane, a mixed solvent of n-butyl acetate and dichloromethane, a mixed solvent of n-pentyl acetate and dichloromethane or a mixed solvent of n-hexyl acetate and dichloromethane.
In the method for purifying obeticholic acid I, the volume-to-mass ratio of the solvent to the crude obeticholic acid is preferably 3mL/g to 15mL/g, for example, 3mL/g, 5mL/g, 6mL/g, 8mL/g, 10mL/g or 15 mL/g.
In the method for purifying obeticholic acid I, the temperature of the solution formed by the crude obeticholic acid and the solvent is preferably 30-70 ℃, more preferably 40-70 ℃, for example 40 ℃, 60 ℃ or 70 ℃.
In the method for refining obeticholic acid I, the 'solution formed by the crude obeticholic acid and the solvent' is preferably prepared by mixing the crude obeticholic acid and the solvent and heating until the crude obeticholic acid and the solvent are dissolved. The mixing is preferably stirred. The stirring speed is preferably 60rpm to 180rpm, for example 60rpm, 120rpm or 180 rpm. The stirring time is preferably 1 hour to 5 hours, for example 1 hour, 2 hours, 3 hours or 4 hours. The heating temperature is preferably 30 to 70 ℃, more preferably 40 to 70 ℃, for example 40 ℃, 60 ℃ or 70 ℃. The dissolving time is preferably 1 to 4 hours; for example 1 hour, 2 hours, 3 hours or 4 hours.
In the method for refining obeticholic acid I, the crystallization temperature is preferably-5-15 ℃; for example-5 deg.C, 0 deg.C, 5 deg.C, 10 deg.C or 15 deg.C.
In the purification method of obeticholic acid I, the time for crystallization is preferably 1 to 4 hours; for example 1 hour, 2 hours, 3 hours or 4 hours.
In the purification method of obeticholic acid I, the crystallization is preferably performed by stirring, and the stirring speed is preferably 60rpm to 180rpm, for example, 60rpm, 120rpm, or 180 rpm.
The purification method of obeticholic acid I preferably further comprises the following steps: and adjusting the pH of the solution formed by the purified obeticholic acid I and alkali to 1-7 to obtain the refined obeticholic acid.
The purification method of obeticholic acid I preferably further comprises the following steps of: adding dihydrogen phosphate into a solution formed by the purified obeticholic acid I and alkali, cooling, adding inorganic protonic acid, and adjusting the pH value to 1-7.
The purification method of obeticholic acid I preferably further comprises a step of adding an alkali, which may be an inorganic alkali or an organic alkali; further preferred is an organic base. The organic base is preferably ammonia. The ammonia water can be the ammonia water which is generally sold on the market in the field, the mass concentration of the ammonia water is preferably 5-40%, for example 25%, and the mass concentration refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution.
The inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The inorganic base is preferably in the form of an aqueous solution of an inorganic base, the mass concentration of the aqueous solution of the inorganic base is preferably 10% to 25%, for example 10%, 15% or 25%, and the mass concentration refers to the mass percentage of the inorganic base to the total mass of the aqueous solution of the inorganic base.
The purification method of obeticholic acid I preferably further comprises the steps of adjusting the pH preferably by using an inorganic protonic acid; the inorganic protonic acid may be an inorganic protonic acid conventional in the art, and is preferably one or more of phosphoric acid, dihydrogen phosphate, sulfuric acid, hydrochloric acid and hydrobromic acid. The dihydric phosphate is a salt formed by phosphoric acid and metal cation or ammonium ion; one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, and ammonium dihydrogen phosphate are preferred. The dihydric phosphate may be used in the form of an aqueous solution thereof, the concentration of the aqueous solution of dihydric phosphate is preferably 0.5% to 1.5%, for example 0.5%, 1.0% or 1.5%, the concentration being the mass percentage of the dihydric phosphate to the total mass of the aqueous solution of dihydric phosphate. The hydrochloric acid can be a hydrochloric acid reagent which is conventional and commercially available in the field, and the mass concentration of the hydrochloric acid reagent can be 1-35%, such as 18%. The mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the hydrochloric acid aqueous solution. The sulfuric acid can be a commercially available sulfuric acid reagent which is conventional in the field, and the mass concentration of the sulfuric acid reagent can be 1-98%, such as 98%. The mass concentration refers to the mass percentage of the sulfuric acid in the total mass of the sulfuric acid aqueous solution. The hydrobromic acid can be a commercially available hydrobromic acid reagent which is conventional in the art, and the mass concentration of the hydrobromic acid reagent can be 1-40%, for example, 40%. The mass concentration refers to the mass percentage of the hydrogen bromide in the total mass of the hydrobromic acid aqueous solution.
The inorganic protonic acid is preferably in the form of an inorganic protonic acid aqueous solution, the mass concentration of the inorganic protonic acid aqueous solution is preferably 18-98%, such as 18%, 40%, 50% or 98%, and the mass concentration refers to the mass percentage of the inorganic protonic acid in the total mass of the inorganic protonic acid aqueous solution.
The purification method of obeticholic acid I preferably further comprises the step of adjusting the pH value to 1-2, 3-4, 5-6 or 6-7.
The method for refining obeticholic acid I preferably further comprises the step of refining obeticholic acid, wherein the purity of the obeticholic acid is more than or equal to 99.00%, the content of impurities chenodeoxycholic acid is less than 0.50%, and the maximum single impurities are less than 0.10%. Because the criteria of the crude drug of obeticholic acid formulated by Intercept pharmaceutical company is that the impurity chenodeoxycholic acid is less than 3.0%, and the criteria of the crude drug of ursodeoxycholic acid formulated by pharmacopoeia is that the impurity chenodeoxycholic acid is less than 1.0%, the obeticholic acid I prepared by the invention meets the requirements of the original research Intercept pharmaceutical company and the pharmacopoeia.
The purification method of obeticholic acid I preferably adopts the following steps: dissolving the purified obeticholic acid I in an inorganic alkali solution, adding a dihydrogen phosphate aqueous solution, and then adjusting the pH value to 1-7 by using an inorganic protonic acid solution to obtain the refined obeticholic acid.
The purification method of obeticholic acid I preferably adopts the following post-treatment steps: and adjusting the pH value to 1-7, stirring, filtering, washing and drying to obtain the refined obeticholic acid I. The stirring, filtering, washing and drying can be carried out by methods conventional in the art for such operations. The stirring speed is preferably 60rpm to 180rpm, for example 120 rpm. The filtration is preferably suction filtration or centrifugation. The washing is preferably pure water. The drying is preferably vacuum drying; the drying pressure is preferably-0.08 to-0.1 MPa, and the drying temperature is preferably 45 to 55 ℃.
The crude obeticholic acid I in the invention can be prepared by a method disclosed in patent document CN 201380043964.8; the other starting materials or reagents are all commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the refining method provided by the invention is simple and safe to operate, does not need special equipment, is high in yield, is high in purity of the prepared product (the purity of related substances is more than 99.0%, the purity of chenodeoxycholic acid is less than 0.5%, and all other impurities are less than 0.1%, and reach the standard of raw material medicines), is low in production cost, is environment-friendly, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: synthesis of obeticholic acid intermediate III (see method reported in patent CN 201380043964.8)
In a 500L hydrogenation reactor, 20.6Kg of obeticholic acid starting material II (commercially available) and 2.1Kg of palladium-carbon catalyst with the mass percent of 10% (the mass percent refers to the mass percent of palladium in the total mass of the palladium-carbon reagent) are added, and 200L of sodium hydroxide aqueous solution with the mass percent of 2.5% (the mass percent refers to the mass percent of sodium hydroxide in the total mass of the sodium hydroxide aqueous solution). Replacing the nitrogen, replacing the hydrogen, and hydrogenating at 45 ℃ for 24 hours under the pressure of 5-7 atm. Filtering the reaction solution, heating the filtrate to 100 ℃, stirring for 16 hours, cooling, adding 50 mass percent phosphoric acid aqueous solution, adjusting the pH value to 2-3 (the mass percent refers to the mass percent of phosphoric acid in the total mass of the phosphoric acid aqueous solution), adding 150L of water, stirring, filtering, washing with water to obtain a white solid, and drying in vacuum (-0.01 to-0.1 MPa, 45-55 ℃) for 16 hours to obtain the white solid. This white solid was recrystallized from acetonitrile (80L) and n-butyl acetate (80L) to give 16.2Kg of obeticholic acid intermediate III in 78.2% yield and 97.18% purity (HPLC).
Example 2: synthesis of crude Obeticholic acid (refer to the method reported in patent CN 201380043964.8)
28.3Kg of obeticholic acid intermediate III, 400L of purified water and 9.5Kg of sodium hydroxide are added into a reaction bottle, stirred and heated to the internal temperature of about 80 ℃, 8.8Kg of sodium borohydride is dissolved in 60L of water to prepare a solution, the solution is dripped into the system, and after the dripping is finished, the temperature is kept at about 80 ℃ for reaction for 3 hours. And (3) completely reacting the TLC spot plate (petroleum ether: ethyl acetate ═ 1:1), cooling to room temperature, adding the TLC spot plate into 1mol/L hydrochloric acid for quenching, adjusting the pH value to 5-6, stirring for 1 hour at 15-20 ℃, centrifugally filtering to obtain an off-white solid, and drying in a forced air drying oven at 50 ℃. Adding 200L of dichloromethane, heating to 40 ℃, stirring for 3 hours, cooling to 0 ℃ after filtering, stirring for 3 hours, centrifuging, filtering, washing with 40L of dichloromethane, and drying in vacuum (-0.01-0.1 MPa, 45-55 ℃) for 12 hours to obtain 21.7Kg of crude obeticholic acid as a white solid, wherein the yield is 76.3%; purity 92.44% (HPLC).
Example 3: purification of Obeticholic acid I
15.04Kg of crude obeticholic acid (prepared from example 2, having an HPLC purity of 92.44%), 82L of n-butyl acetate, and 8.2L of dichloromethane were taken, heated to 40 ℃ and stirred (120rpm) for 2 hours to completely dissolve the obeticholic acid, and then cooled to 5 ℃ within 3 hours and stirred (120rpm) for 2 hours. And (4) performing centrifugal filtration to obtain a white solid, and performing vacuum drying (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain 12.44Kg of purified obeticholic acid. Taking 12.44Kg of purified obeticholic acid, adding 150L of 25% ammonia water solution by mass (the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution), and stirring (120rpm) to dissolve the obeticholic acid. Then adding 50L of 1.0% by mass sodium dihydrogen phosphate aqueous solution (the mass percentage refers to the mass percentage of the sodium dihydrogen phosphate in the total mass of the sodium dihydrogen phosphate aqueous solution), cooling to 0-5 ℃, dropwise adding 50% by mass phosphoric acid aqueous solution until the pH value is 5-6 (the mass percentage refers to the mass percentage of the phosphoric acid in the total mass of the phosphoric acid aqueous solution), precipitating white solid, and stirring (120rpm) for 2 hours. Centrifugally filtering, washing with purified water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 11.75Kg of refined obeticholic acid I with yield of 78.1%. HPLC purity: 99.51% (main peak), 0.22% (chenodeoxycholic acid), 0.062% (other largest single hetero).
Example 4: purification of Obeticholic acid I
Crude obeticholic acid (prepared as described in example 2, with an HPLC purity of 92.44%), 210g crude obeticholic acid (prepared as described above), 1.26L isopropyl acetate, and 0.42L dichloromethane were heated to 40 deg.C and stirred (180rpm) for 3 hours to completely dissolve the crude obeticholic acid, followed by cooling to 0 deg.C and stirring (180rpm) for 1 hour over 3 hours. Filtering to obtain a white solid, drying in vacuum (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain purified obeticholic acid, adding 2L of a 15% sodium hydroxide aqueous solution by mass (the mass percentage refers to the mass percentage of sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), and stirring (180rpm) to dissolve the obeticholic acid. Then adding 1L of sodium dihydrogen phosphate aqueous solution with the mass percent of 0.5% (the mass percent refers to the mass percent of the sodium dihydrogen phosphate in the total mass of the sodium dihydrogen phosphate aqueous solution), cooling to 0-5 ℃, dropwise adding 18% hydrochloric acid aqueous solution until the pH value is 6-7, precipitating white solid, and stirring (180rpm) for 2 hours. Filtering, washing with purified water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 155.7g refined obeticholic acid I with yield of 74.1%. HPLC purity: 99.55% (main peak), 0.22% (chenodeoxycholic acid), 0.07% (other largest single hetero).
Example 5: purification of Obeticholic acid I
100g of crude obeticholic acid (prepared in example 2, 92.44% HPLC purity), 700mL of n-propyl acetate, and 100mL of dichloromethane were taken, heated to 40 ℃ and stirred (180rpm) for 4 hours to completely dissolve, and then cooled to 0 ℃ over 3 hours and stirred (180rpm) for 1 hour. Filtering to obtain a white solid, drying in vacuum (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain purified obeticholic acid, adding 1L of 10 mass percent potassium hydroxide aqueous solution (the mass percent refers to the mass percent of potassium hydroxide in the total mass of the potassium hydroxide aqueous solution), and stirring (180rpm) to dissolve the white solid. Then adding 1L of sodium dihydrogen phosphate aqueous solution with the mass percentage of 1.5% (the mass percentage refers to the mass percentage of the sodium dihydrogen phosphate in the total mass of the sodium dihydrogen phosphate aqueous solution), cooling to 5 ℃, dropwise adding sulfuric acid aqueous solution with the mass percentage of 98% (the mass percentage refers to the mass percentage of the sulfuric acid in the total mass of the sulfuric acid aqueous solution) until the pH value is 1-2, precipitating white solid, and stirring (180rpm) for 2 hours. Filtering, washing with pure water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 76.4g refined obeticholic acid I with a yield of 76.4%. HPLC purity: 99.64% (main peak), 0.142% (chenodeoxycholic acid), 0.059% (other largest single hetero).
Example 6: purification of Obeticholic acid I
120g of crude obeticholic acid (prepared in example 2, 92.44% HPLC purity), 180mL of ethyl acetate, and 180mL of dichloromethane were taken, heated to 40 ℃ and stirred (60rpm) for 1 hour to completely dissolve the obeticholic acid, and then cooled to-5 ℃ within 3 hours and stirred (60rpm) for 4 hours. Filtering to obtain a white solid, drying in vacuum (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain purified obeticholic acid, adding 1.2L of lithium hydroxide aqueous solution with the mass percent of 10% (the mass percent refers to the mass percent of the lithium hydroxide in the total mass of the lithium hydroxide aqueous solution), and stirring (60rpm) to dissolve the white solid. Then adding 1L of ammonium dihydrogen phosphate aqueous solution with the mass percentage of 1.5% (the mass percentage refers to the mass percentage of the ammonium dihydrogen phosphate to the total mass of the ammonium dihydrogen phosphate aqueous solution), cooling to 5 ℃, dropwise adding 40% of hydrobromic acid aqueous solution to the solution until the pH value is 3-4 (the mass percentage refers to the mass percentage of the hydrogen bromide to the total mass of the hydrobromic acid aqueous solution), separating out white solids, and stirring (60rpm) for 2 hours. Filtering, washing with purified water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 85.1g refined obeticholic acid I with yield of 70.9%. HPLC purity: 99.30% (main peak), 0.29% (chenodeoxycholic acid), 0.074% (other largest single hetero).
Example 7: purification of Obeticholic acid I
60g of crude obeticholic acid (HPLC purity 90.56%) and 600mL of n-amyl acetate are taken, heated to 70 ℃ and stirred (120rpm) for 2 hours to be completely dissolved, and then cooled to 15 ℃ within 3 hours and stirred (120rpm) for 2 hours. And (3) centrifugally filtering to obtain a white solid, drying in vacuum at (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain purified obeticholic acid, adding 400mL of an ammonia water solution with the mass percentage of 25% (the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution), and stirring (120rpm) to dissolve the obeticholic acid. Then adding 150mL of 1.0 mass percent sodium dihydrogen phosphate aqueous solution (the mass percent refers to the mass percent of the sodium dihydrogen phosphate in the total mass of the sodium dihydrogen phosphate aqueous solution), cooling to 0-5 ℃, dropwise adding 50 mass percent phosphoric acid aqueous solution until the pH value is 5-6 (the mass percent refers to the mass percent of the phosphoric acid in the total mass of the phosphoric acid aqueous solution), precipitating white solid, and stirring (120rpm) for 2 hours. Centrifugally filtering, washing with purified water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 42.1g refined obeticholic acid I with a yield of 70.2%. HPLC purity: 99.48% (main peak), 0.090% (chenodeoxycholic acid), 0.079% (other largest single hetero).
Example 8: purification of Obeticholic acid I
40g of crude obeticholic acid (94.37% in HPLC purity) and 600mL of n-hexyl acetate are taken, heated to 60 ℃ and stirred (120rpm) for 2 hours to be completely dissolved, and then cooled to 10 ℃ within 3 hours and stirred (120rpm) for 2 hours. And (3) centrifugally filtering to obtain a white solid, drying in vacuum at (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain purified obeticholic acid, adding 270mL of an ammonia water solution with the mass percentage of 25% (the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution), and stirring (120rpm) to dissolve the obeticholic acid. Then 100mL of 1.0 mass percent sodium dihydrogen phosphate aqueous solution is added (the mass percent refers to the mass percent of the sodium dihydrogen phosphate in the total mass of the sodium dihydrogen phosphate aqueous solution), the mixture is cooled to 0-5 ℃, 50 mass percent phosphoric acid aqueous solution is dropwise added until the pH value is 5-6 (the mass percent refers to the mass percent of the phosphoric acid in the total mass of the phosphoric acid aqueous solution), white solid is precipitated, and the mixture is stirred (120rpm) for 2 hours. Centrifugally filtering, washing with purified water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 30.7g refined obeticholic acid I with yield of 76.8%. HPLC purity: 99.51% (main peak), 0.12% (chenodeoxycholic acid), 0.054% (other largest single hetero).
Example 9: purification of Obeticholic acid I
30g of crude obeticholic acid (HPLC purity 97.38%) and 150mL of n-butyl acetate are taken, heated to 60 ℃ and stirred (180rpm) for 2 hours to be completely dissolved, and then cooled to 5 ℃ within 3 hours and stirred (180rpm) for 2 hours. And (3) performing centrifugal filtration to obtain a white solid, performing vacuum drying (-0.01 to-0.1 MPa, 45 to 55 ℃) for 16 hours to obtain purified obeticholic acid, adding 200mL of an ammonia water solution with the mass percentage of 25% (the mass percentage refers to the mass percentage of ammonia gas in the total mass of the ammonia water solution), and stirring (180rpm) to dissolve the obeticholic acid. And then adding 70mL of 1.0 mass percent sodium dihydrogen phosphate aqueous solution (the mass percent refers to the mass percent of the sodium dihydrogen phosphate in the total mass of the sodium dihydrogen phosphate aqueous solution), cooling to 5 ℃, dropwise adding 50 mass percent phosphoric acid aqueous solution until the pH value is 5-6 (the mass percent refers to the mass percent of the phosphoric acid in the total mass of the phosphoric acid aqueous solution), precipitating white solid, and stirring (180rpm) for 2 hours. Centrifugally filtering, washing with purified water to obtain white solid, and vacuum drying (-0.01-0.1 MPa, 45-55 deg.C) for 16 hr to obtain 23.7g refined obeticholic acid I with yield of 79.0%. HPLC purity: 99.71% (main peak), 0.24% (chenodeoxycholic acid), 0.030% (other largest single hetero).
Comparative example 1: purification of Obeticholic acid I (see the method reported in patent CN 201380043964.8)
10g of crude obeticholic acid (92.44% pure by HPLC) was chromatographed on silica gel column eluting with n-heptane/ethyl acetate to give 6.4g of obeticholic acid in 64% yield.
HPLC purity: 98.18% (main peak), 0.80% (chenodeoxycholic acid), 0.37% (other largest single hetero).
Comparative example 2: purification of Obeticholic acid I (refer to the methods reported in patents US2014/148428 or WO 2013/192097)
Taking 20g of crude obeticholic acid (with the HPLC purity of 92.44%), recrystallizing twice with dichloromethane to obtain a white solid, and drying in vacuum (-0.01-0.1 MPa, 45-55 ℃) for 16 hours to obtain 13.6g of obeticholic acid I with the yield of 68%. HPLC purity (high performance liquid chromatography analysis): 98.13% (main peak), 0.51% (chenodeoxycholic acid), 0.70% (other largest single hetero).
Claims (5)
1. The refining method of obeticholic acid I is characterized by comprising the following steps: crystallizing a solution formed by the crude product of obeticholic acid and a solvent to obtain purified obeticholic acid; the HPLC purity of the crude obeticholic acid reaches more than 85%; the solvent is a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent, and the volume ratio of the ester solvent to the halogenated hydrocarbon solvent in the mixed solvent of the ester solvent and the halogenated hydrocarbon solvent is 7-10; the ester solvent is n-butyl acetate or n-propyl acetate; the halogenated hydrocarbon solvent is dichloromethane; the 'solution formed by the crude product of obeticholic acid and the solvent' is formed by mixing the crude product of obeticholic acid and the solvent, heating to dissolve the mixture at the temperature of 40 ℃, forming the solution at the temperature of 40 ℃, crystallizing at the temperature of-5-15 ℃, and crystallizing for 1-4 hours;
adding dihydrogen phosphate into a solution formed by the purified obeticholic acid I and alkali, cooling, adding inorganic protonic acid, and adjusting the pH value to 1-7 to obtain refined obeticholic acid; the alkali is ammonia water, or the alkali is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the dihydric phosphate is one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate and ammonium dihydrogen phosphate; the inorganic protonic acid is one or more of phosphoric acid, hydrochloric acid, sulfuric acid and hydrobromic acid; the purity of the refined obeticholic acid is more than or equal to 99.00%, the content of impurities chenodeoxycholic acid is less than 0.50%, and the maximum single impurities are less than 0.10%.
2. The method for purifying obeticholic acid I according to claim 1, characterized in that:
the volume-mass ratio of the solvent to the crude obeticholic acid product is 3-15 mL/g;
and/or the presence of a gas in the gas,
the crystallization is stirring crystallization.
3. The method for purifying obeticholic acid I according to claim 2, characterized in that: the stirring speed is 60 rpm-180 rpm.
4. The method for purifying obeticholic acid I according to claim 1, characterized in that:
the mixing is stirring and mixing; and/or the dissolving time is 1-4 hours.
5. The method for purifying obeticholic acid I according to claim 4, wherein:
the stirring speed is 60 rpm-180 rpm.
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| CN112824400A (en) * | 2019-11-20 | 2021-05-21 | 华创合成制药股份有限公司 | Preparation method of posaconazole |
| CN114113395B (en) * | 2021-11-26 | 2023-10-31 | 中山百灵生物技术股份有限公司 | Method for detecting ethyl p-toluenesulfonate in obeticholic acid |
| CN114295750B (en) * | 2021-12-30 | 2023-08-15 | 江苏正济药业股份有限公司 | Method for detecting related substances in ursodeoxycholic acid synthesis |
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| CN105859814A (en) * | 2015-01-23 | 2016-08-17 | 江苏奥赛康药业股份有限公司 | Obeticholic acid compound and pharmaceutical composition thereof |
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| TR01 | Transfer of patent right |
Effective date of registration: 20230608 Address after: 201306 floor 3 and 4, Building 29, No. 356, ZHENGBO Road, Lingang xinpian District, China (Shanghai) pilot Free Trade Zone, Fengxian District, Shanghai Patentee after: Shanghai xinlitai Pharmaceutical Co.,Ltd. Address before: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang hi tech park, Zhangjiang hi tech park, Pudong New Area, Shanghai Patentee before: Shanghai Yunshengyan neoplasm Technology Co.,Ltd. Patentee before: Shanghai xinlitai Pharmaceutical Co.,Ltd. |