CN115611961B - Cholic acid intermediate A2 and preparation method thereof - Google Patents
Cholic acid intermediate A2 and preparation method thereof Download PDFInfo
- Publication number
- CN115611961B CN115611961B CN202211272286.XA CN202211272286A CN115611961B CN 115611961 B CN115611961 B CN 115611961B CN 202211272286 A CN202211272286 A CN 202211272286A CN 115611961 B CN115611961 B CN 115611961B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound shown
- reaction
- cholic acid
- acid intermediate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 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 title claims abstract description 207
- 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 title claims abstract description 204
- 239000004380 Cholic acid Substances 0.000 title claims abstract description 204
- 229960002471 cholic acid Drugs 0.000 title claims abstract description 204
- 235000019416 cholic acid Nutrition 0.000 title claims abstract description 204
- 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 title claims abstract description 203
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 407
- 238000006243 chemical reaction Methods 0.000 claims abstract description 155
- 239000002904 solvent Substances 0.000 claims abstract description 89
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 72
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 27
- 238000003379 elimination reaction Methods 0.000 claims abstract description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 229960000583 acetic acid Drugs 0.000 claims abstract description 10
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 80
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- 238000006460 hydrolysis reaction Methods 0.000 claims description 41
- 238000001914 filtration Methods 0.000 claims description 37
- 238000006722 reduction reaction Methods 0.000 claims description 37
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 36
- 238000007254 oxidation reaction Methods 0.000 claims description 36
- 239000012065 filter cake Substances 0.000 claims description 35
- 238000001816 cooling Methods 0.000 claims description 33
- 238000001035 drying Methods 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 230000001590 oxidative effect Effects 0.000 claims description 28
- 239000012074 organic phase Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000007800 oxidant agent Substances 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 22
- 238000005984 hydrogenation reaction Methods 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 17
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 15
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 14
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 14
- 230000002378 acidificating effect Effects 0.000 claims description 14
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 13
- 238000007239 Wittig reaction Methods 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 238000001308 synthesis method Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- MJPPNOYSSOKENI-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li+].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] MJPPNOYSSOKENI-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 22
- 241001465754 Metazoa Species 0.000 abstract description 3
- 230000009385 viral infection Effects 0.000 abstract description 3
- 210000001835 viscera Anatomy 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 108
- 238000003756 stirring Methods 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 34
- 238000004809 thin layer chromatography Methods 0.000 description 30
- 239000007858 starting material Substances 0.000 description 23
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 20
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000001514 detection method Methods 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000003513 alkali Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 230000001105 regulatory effect Effects 0.000 description 12
- 229910000423 chromium oxide Inorganic materials 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000011592 zinc chloride Substances 0.000 description 10
- 235000005074 zinc chloride Nutrition 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000005708 Sodium hypochlorite Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000004321 preservation Methods 0.000 description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000002386 leaching Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 6
- 239000003810 Jones reagent Substances 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- JFBRAUFNAQPWKO-UHFFFAOYSA-N ethyl 2-[methylidene(diphenyl)-$l^{5}-phosphanyl]benzoate Chemical compound CCOC(=O)C1=CC=CC=C1P(=C)(C=1C=CC=CC=1)C1=CC=CC=C1 JFBRAUFNAQPWKO-UHFFFAOYSA-N 0.000 description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 5
- 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 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- -1 lithium aluminum tri-tert-butoxide hydride Chemical compound 0.000 description 4
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[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 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[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 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 3
- 229960003964 deoxycholic acid Drugs 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 2
- 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 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 2
- 229960001661 ursodiol Drugs 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000008845 cholagoga Substances 0.000 description 1
- 229940124571 cholagogue Drugs 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 125000003716 cholic acid group Chemical group 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic 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)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].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 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a cholic acid intermediate A2 and a preparation method thereof. The preparation method of the cholic acid intermediate A2 comprises the following steps: the structural formula of the cholic acid intermediate A2 is shown in a formula A2, water is used as a solvent, the compound shown in A1, concentrated sulfuric acid and glacial acetic acid are subjected to elimination reaction at 20-50 ℃ until the reaction is complete, and a reaction product comprising the compound shown in the formula A2 is obtained, and the reaction product is subjected to post-treatment to obtain the cholic acid intermediate A2. The invention provides a cholic acid intermediate A2 produced by a chemical synthesis method with mild reaction conditions, wherein the cholic acid intermediate A2 can be finally used for efficiently preparing cholic acid so as to solve the risk of virus infection caused by extracting cholic acid from animal viscera.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a cholic acid intermediate A2 and a preparation method thereof.
Background
Cholic acid, chemical name is Cholic acid, chemical formula is C 24 H 40 O 5 The structural formula is as follows:
bile acids are a generic term for a class of cholanic acids present in bile, which are mainly Cholic Acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and lithocholic acid (LCA) in human bile.
Cholic acid can be used in biochemical research, and is a medical intermediate. CN201710404532.5 discloses a method for synthesizing lithocholic acid from cholic acid, CN2017102663050.0 discloses a method for synthesizing ursodeoxycholic acid from cholic acid, CN2016107273812 discloses a method for preparing glycocholic acid polyclonal antibody from cholic acid, CN2021102688904 discloses a method for synthesizing deoxycholic acid from cholic acid as starting material, ursodeoxycholic acid, lithocholic acid and the like can be used as therapeutic drugs, and from the above, it can be seen that cholic acid is an important pharmaceutical intermediate.
In addition, sodium cholate is a cholagogue, and can be used for treating cholecystitis, bile deficiency, intestinal dyspepsia and other diseases.
At present, cholic acid in the market is prepared by extracting and refining viscera of animals, namely cattle or sheep, and the risk of virus infection is unavoidable.
Disclosure of Invention
The invention aims to provide a chemical synthesis method for producing cholic acid intermediate A2 and cholic acid under mild reaction conditions so as to solve the risk of virus infection caused by extracting cholic acid from animal viscera.
In order to achieve the above object, the present invention provides a cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown in formula A2:
The invention provides a preparation method of a cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown in a formula A2, water is used as a solvent, a compound shown in A1, concentrated sulfuric acid and glacial acetic acid are subjected to elimination reaction at 20-50 ℃ until the reaction is complete, a reaction product comprising the compound shown in the formula A2 is obtained, and the reaction product is subjected to post-treatment to obtain the compound shown in the formula A2 (the cholic acid intermediate A2), wherein the structural formula of the compound shown in the formula A1 is as follows:
the structural formula of the compound shown in the formula A2 is as follows: />
In a specific embodiment, the time for the elimination reaction is 2.5 to 4 hours.
In a specific embodiment, the elimination reaction temperature is 35 to 40 ℃.
In a specific embodiment, the mass ratio of the compound represented by the formula A1 to concentrated sulfuric acid is 1: (3.5-3.8), wherein the mass volume ratio of the compound shown in the formula A1 to glacial acetic acid is 1g: (1-1.2) ml.
In a specific embodiment, the post-treatment comprises cooling in an ice bath for more than 30 minutes, filtering, washing a filter cake to be neutral, dissolving the filter cake with dichloromethane, separating liquid, collecting an organic phase, concentrating under reduced pressure, replacing methanol, concentrating to be in a viscous state, filtering, and drying the filter cake.
The invention also provides a preparation method of the cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown in the formula A2, elimination reaction is carried out, dichloromethane or chloroform is used as a solvent, and the compound shown in the formula A1, acetic anhydride and concentrated sulfuric acid react for 3-5 hours at 30-40 ℃ until the reaction is complete, so that the compound shown in the formula A2 (cholic acid intermediate A2) is obtained, wherein the structural formula of the compound shown in the formula A1 is as follows:
the structural formula of the compound shown in the formula A2 is as follows: />
In a specific embodiment, the mass to volume ratio of the compound represented by formula A1 to acetic anhydride is 1g: (1-1.2) ml, wherein the volume ratio of the acetic anhydride to the concentrated sulfuric acid is 1: (0.38-0.4).
The invention provides a cholic acid intermediate A2, which is obtained by adopting the preparation method.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, and the synthesis route is as follows:
the synthesis method comprises the following steps:
(1) Performing Wittig or Wittig-Horner reaction on the cholic acid intermediate A2 to obtain a compound shown in a formula A3;
(2) Carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4;
(3) Carrying out oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5;
(4) Carrying out a first hydrolysis reaction on the compound shown in the formula A5 under an acidic condition to obtain a compound shown in the formula A6;
(5) Carrying out hydrogenation reduction reaction on the compound shown in the formula A6 to obtain a compound shown in the formula A7;
(6) Carrying out a second hydrolysis reaction on the compound shown in the formula A7 under alkaline conditions to obtain a compound shown in the formula A8;
(7) And (3) carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid.
The beneficial effects of the invention at least comprise:
according to the invention, the compound shown in the formula A1 is subjected to elimination reaction to obtain the cholic acid intermediate A2, and the cholic acid intermediate A2 can be finally used for efficiently preparing cholic acid. The invention further provides a chemical synthesis method of cholic acid, and has the advantages of mild reaction conditions, and raw materials for preparing the cholic acid, namely the cholic acid intermediate A2, are finally obtained from a common plant source compound.
Detailed Description
The invention provides a cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown in the formula A2:
the invention provides a preparation method of a cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown in a formula A2, water is used as a solvent, a compound shown in A1, concentrated sulfuric acid and glacial acetic acid are subjected to elimination reaction at 20-50 ℃ until the reaction is complete, a reaction product comprising the compound shown in the formula A2 is obtained, and the reaction product is subjected to post-treatment to obtain the cholic acid intermediate A2, wherein the structural formula of the compound shown in the formula A1 is as follows:
the structural formula of the compound shown in the formula A2 is as follows: />
Preferably, the temperature of the elimination reaction is 35 to 40 ℃.
Preferably, the time of the elimination reaction is 2.5 to 4 hours.
Wherein the mass ratio of the compound shown in the formula A1 to the concentrated sulfuric acid is 1: (3.5-3.8), wherein the mass volume ratio of the compound shown in the formula A1 to glacial acetic acid is 1g: (1-1.2) ml.
Preferably, the post-treatment comprises cooling in an ice bath for more than 30 minutes, filtering, washing a filter cake to be neutral, dissolving the filter cake with dichloromethane, separating liquid, collecting an organic phase, concentrating under reduced pressure, replacing methanol, concentrating to be in a viscous state, filtering, and drying the filter cake.
The elimination reaction specifically comprises the following steps: adding water into a reactor, cooling to 0-10 ℃ in an ice water bath, controlling the temperature T to be less than or equal to 40 ℃ under stirring, dropwise adding concentrated sulfuric acid, then adding glacial acetic acid and a compound shown in a formula A1, controlling the temperature of the system to 20-50 ℃ for reaction for 2.5-4 h, and detecting the reaction by TLC until the reaction is complete. Adding the system into an ice-water bath, stirring for more than 30 minutes after the system is added, filtering, leaching with water to be neutral, dissolving a filter cake with dichloromethane, separating liquid, collecting an organic phase, concentrating under reduced pressure, replacing with methanol, concentrating to be in a viscous state finally, filtering, and drying the filter cake to be qualified to obtain the compound shown in the formula A2.
Preferably, the preparation method of the cholic acid intermediate A2 further comprises: oxidizing the compound shown in the formula SM to obtain a compound shown in the formula A1, wherein the synthetic route is as follows:
in an alternative mode, the oxidation reaction takes TEMPO and 8% sodium hypochlorite as oxidizing agents and takes methylene dichloride as a solvent, and the reaction is carried out for 2.5-4 hours at room temperature to obtain a product comprising the compound shown in a formula A1.
Wherein the mass ratio of the compound shown in the formula SM to the oxidant TEMPO to the oxidant 8% sodium hypochlorite is 1: (0.1-0.13): (2-2.2).
In this example, 8% sodium hypochlorite refers to sodium hypochlorite with 8% available chlorine.
Wherein the mass volume ratio of the compound shown in the formula SM to the solvent dichloromethane is 1g: (7.5-8.5) ml.
The oxidation reaction specifically comprises the following steps: adding 9 alpha-hydroxy BA (shown in a formula SM) and an oxidant TEMPO (shown in a formula SM) into dichloromethane serving as a solvent under stirring, then dropwise adding 8% sodium hypochlorite serving as an oxidant, reacting for 2.5-4h at room temperature after the dropwise adding is completed, detecting the reaction to completion by TLC, adding 5% sodium sulfite solution, and detecting no oxidizing property by using starch potassium iodide test paper. Stirring the system for about 20 minutes, standing for about 30 minutes, separating liquid, collecting an organic phase, adding water into the organic phase, stirring for about 20 minutes, standing for about 30 minutes, separating liquid, and collecting the organic phase; concentrating under reduced pressure at 40deg.C in hot water bath to evaporate dichloromethane, displacing methanol, concentrating to viscous state, cooling, filtering, and drying to obtain compound shown in formula A1.
In another alternative, the oxidation reaction takes acetone as a solvent and Jones reagent as an oxidant, and the reaction is carried out for 4 to 8 hours at a temperature of between 0 and 10 ℃ to obtain a product comprising the compound shown in the formula A1.
Wherein the mass-to-volume ratio of the compound shown in the formula SM to the oxidant Jones reagent is 1g: (1-1.2) ml, preferably 1:1.
Wherein the mass volume ratio of the compound shown in the formula SM to the solvent acetone is 1g: (9-11) ml, preferably 1:10.
the oxidation reaction specifically comprises the following steps: and (3) taking acetone as a solvent, adding 9 alpha-hydroxy BA (shown in a formula SM) under stirring, cooling the system to 0-10 ℃, controlling Wen Dijia Jones reagent, keeping the temperature, stirring for 4-8 hours, and detecting the reaction by TLC until the reaction is complete. Adding isopropanol to quench the reaction, slowly adding the system into ice water for water separation, cooling to 0-10 ℃, filtering, and drying to obtain the compound shown in the formula A1.
The invention also provides a preparation method of the cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown as a formula A2, elimination reaction is carried out, dichloromethane or chloroform is used as a solvent, and the compound shown as a formula A1, acetic anhydride and concentrated sulfuric acid react for 3-5 hours at 30-40 ℃ until the reaction is complete, so that the compound shown as the formula A2 is obtained, wherein the structural formula of the compound shown as the formula A1 is as follows:
the structural formula of the compound shown in the formula A2 is as follows: />
In a specific embodiment, the mass to volume ratio of the compound represented by formula A1 to acetic anhydride is 1g: (1-1.2) ml, wherein the volume ratio of the acetic anhydride to the concentrated sulfuric acid is 1: (0.38-0.4).
In the elimination reaction system, the mass volume ratio of the compound shown in the formula A1 to the solvent dichloromethane or chloroform is 1g: (5.8-6.2) ml.
The elimination reaction specifically comprises the following steps: and (3) adding the compound shown in the formula A1 into a solvent of dichloromethane or chloroform under a stirring state, cooling to 0-10 ℃, dropwise adding acetic anhydride, stirring for 10-20 minutes after the addition, dropwise adding concentrated sulfuric acid, heating to 30-40 ℃ after the dropwise addition, keeping the temperature, stirring for 3-5 hours, and detecting the reaction by TLC (thin layer chromatography) until the reaction is completed. Adding water into the system for quenching, separating liquid, collecting an organic phase, concentrating under reduced pressure, replacing with methanol, concentrating to a viscous state, filtering, and drying a filter cake until the filter cake is qualified to obtain the compound shown in the formula A2.
Preferably, the preparation method of the cholic acid intermediate A2 further comprises the step of carrying out an oxidation reaction on the compound shown in the formula SM to obtain the compound shown in the formula A1.
The invention also provides the cholic acid intermediate A2 prepared by the preparation method.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, and the synthesis route is as follows:
the synthesis method comprises the following steps:
(1) Performing Wittig or Wittig-Horner reaction on the cholic acid intermediate A2 to obtain a compound shown in a formula A3;
(2) Carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4;
(3) Carrying out oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5;
(4) Carrying out a first hydrolysis reaction on the compound shown in the formula A5 under an acidic condition to obtain a compound shown in the formula A6;
(5) Carrying out hydrogenation reduction reaction on the compound shown in the formula A6 to obtain a compound shown in the formula A7;
(6) Carrying out a second hydrolysis reaction on the compound shown in the formula A7 under alkaline conditions to obtain a compound shown in the formula A8;
(7) And (3) carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid.
In the step (1), a Wittig reaction is carried out, toluene or tetrahydrofuran is taken as a solvent, a compound shown in a formula A2 and Wittig reagent ethoxyformyl methylene triphenylphosphine are added under stirring to obtain a reactant system, the reactant system is heated to a reflux state for reaction for a preset time until the reaction is complete, a reaction product comprising the compound shown in a formula A3 is obtained, and after the reaction product is cooled to room temperature, the cholic acid intermediate A3 is obtained through post-treatment.
Preferably, the preset time is 10-16 h, specifically may be 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h, and the like, and preferably, the first preset time is 10-12 h, and tcl is tracked until the raw material is completely reacted.
Preferably, the weight ratio of the compound shown in the formula A2 to the Wittig reagent ethoxyformyl methylene triphenylphosphine is as follows: 1: (1.8-2.4), preferably, the weight ratio of the compound shown in the formula A2 to the Wittig reagent ethoxyformyl methylene triphenylphosphine is 1:2.
Preferably, the mass volume ratio of the compound shown in the formula A2 to the solvent toluene is 1g: (10-15) ml; the mass volume ratio of the compound shown in the formula A2 to the solvent tetrahydrofuran is 1g: (12-15) ml.
Preferably, the post-treatment comprises sequentially performing precipitation reaction, solid-liquid separation, filtrate liquid separation, and reduced pressure concentration of an organic layer to dryness, water separation, filtration and drying.
Preferably, the metal ion complexing agent added in the precipitation reaction is a zinc chloride solution, the mass fraction of the zinc chloride solution is 35% -45%, and preferably, the mass fraction of the zinc chloride solution is 36% -40%.
And (3) removing by-product triphenylphosphine oxide by precipitation reaction with zinc chloride solution as a metal ion complexing agent to obtain a purer target product.
Preferably, the temperature of the precipitation reaction is 25 to 30 ℃, specifically 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, and the reaction time is 10 to 16 hours, specifically 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours, and the like.
The wittig reaction specifically comprises the following steps: under the stirring state, adding the compound shown in the formula A2 and the ethoxyformylmethylene triphenylphosphine into toluene or tetrahydrofuran as solvents, heating the system to a reflux state for reaction for 10-16 h, detecting the reaction to be complete by TLC, and cooling to room temperature. Adding a zinc chloride solution (the mass fraction is 35% -45%) into the system, preserving the temperature for 12h at 25-30 ℃ for precipitation reaction, carrying out suction filtration, filtering the precipitate, separating filtrate, repeating the operation once again with the zinc chloride solution (the mass fraction is 35% -45%), separating the filtrate after filtration, collecting an organic phase, concentrating under reduced pressure, filtering and drying to obtain the compound shown in the formula A3.
In the step (1), a Wittig-Horner reaction is carried out, tetrahydrofuran is used as a solvent, and the compound shown in the formula A2 is reacted with alkali and triethyl phosphonoacetate at 20-66 ℃ until the reaction is completed, so that a reaction product comprising the compound shown in the formula A3 is obtained, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
Preferably, the reaction time of the Wittig-Horner reaction is 1-3 h, and specifically can be 1h, 1.5h, 2h, 2.5h, 3h and the like.
Preferably, the molar ratio of the compound represented by formula A2 to the base is: 1: (0.35-0.5), wherein the mass volume ratio of the compound shown in the formula A2 to the triethyl phosphonoacetate is 1g: (0.9-1.1) ml.
Preferably, the mass volume ratio of the compound shown in the formula A2 to tetrahydrofuran in the mixed solution is 1g: (9-12) ml.
The Wittig-Horner reaction specifically comprises the following steps: adding sodium hydride/potassium tert-butoxide/sodium methoxide/potassium methoxide/sodium ethoxide/potassium ethoxide into tetrahydrofuran solvent under stirring, dropwise adding triethyl phosphonoacetate at room temperature under the protection of nitrogen after bubbles emerge, stirring for 20-30 min, dropwise adding a mixed solution of a compound shown in formula A2 and tetrahydrofuran, controlling the temperature to be 20-66 ℃ after dropwise adding, reacting for 1-3 h, tracking by TCL until the reaction is complete, obtaining a reaction product, and obtaining the compound shown in formula A3 through pH value adjustment, reduced pressure concentration of tetrahydrofuran, water separation, cooling, filtering and drying.
In an alternative mode, in the step (2), toluene is used as a solvent, ethylene glycol is used as a ketal reaction reagent, p-toluenesulfonic acid is used as a catalyst, and after the compound shown in the formula A3 is mixed with toluene, ethylene glycol and p-toluenesulfonic acid, the system is heated to a reflux state for reaction until the reaction is complete, so that a product comprising the compound shown in the formula A4 is obtained.
Preferably, the ketal protection reaction is carried out for a period of 20 to 28 hours.
Preferably, the weight ratio of the compound shown in the formula A3 to the catalyst p-toluenesulfonic acid in the ketal protection reaction is 1: (0.098-0.018), more preferably 0.015.
Preferably, the mass volume of the compound shown in the formula A3 and the solvent toluene in the ketal protection reaction is 1g: (9-11) ml, preferably 1:10g/ml; the mass volume of the compound shown in the formula A3 and the reactant glycol in the ketal protection reaction is 1g: (3-4) ml, preferably 1:2g/ml.
Preferably, the product containing the compound shown in the formula A4 is cooled to room temperature, triethylamine is used for regulating the pH value to 7-8, water separation is carried out, the temperature is continuously reduced to 0-10 ℃, a filter cake is obtained through filtration, the filter cake is recrystallized by methanol, then cooled to room temperature, and the compound shown in the formula A4 is obtained through filtration and drying.
The ketal protection reaction is specifically: toluene, ethylene glycol, toluene sulfonic acid (PTS) and a compound shown in a formula A3 are mixed, the system is heated to a reflux state for reaction for 20-28 h, and TLC detection reaction is completed. Cooling to room temperature, adding a small amount of triethylamine to adjust the pH to be 7-8, washing with water, collecting an organic phase, concentrating a toluene layer under reduced pressure to be in a viscous state, adding petroleum ether for replacement, cooling to 0-10 ℃, filtering, and drying to obtain a compound shown in a formula A4.
In another alternative mode, in the step (2), the ketal protection reaction uses ethylene glycol as a ketal reaction reagent, triethyl orthoformate as a ketal dehydrating agent and p-toluenesulfonic acid as a catalyst, and the ketal protection reaction temperature is 35-80 ℃ and the reaction time is 5-8 h.
Preferably, the temperature of the ketal protection reaction is 40-45 ℃.
Preferably, the mass ratio of the compound shown in the formula A3 to the catalyst p-toluenesulfonic acid in the ketal protection reaction is 1: (0.098-0.018), more preferably 0.015.
Preferably, the mass-volume ratio of the compound shown in the formula A3 to the ethylene glycol and the triethyl orthoformate in the ketal protection reaction is 1g: (6-8) ml: (1-2) ml.
The ketal protection reaction is specifically: and (3) mixing ketal reaction reagent glycol, ketal dehydrating agent triethyl orthoformate and catalyst p-toluenesulfonic acid, adding a compound shown in a formula A3 under stirring, heating the system to 35-80 ℃, reacting for 5-8 h, detecting the complete reaction of TCL, cooling to room temperature, adding triethylamine to adjust the pH value to 7-8, then carrying out water separation, continuously cooling to 0-10 ℃, filtering to obtain a filter cake, recrystallizing the filter cake with methanol, cooling to room temperature, filtering and drying to obtain the compound shown in a formula A4.
In step (3), the oxidation reaction includes: acetone or acetonitrile is used as a solvent, chromic oxide or pyridinium chlorochromate is used as a first oxidant, N-hydroxyphthalimide is used as a second oxidant, and the compound shown in the formula A4 obtained by ketal protection reaction is subjected to oxidation reaction with the first oxidant and the second oxidant at 20-35 ℃ to obtain a product comprising the compound shown in the formula A5.
Preferably, the oxidation reaction time is 20 to 25 hours.
Preferably, the temperature of the oxidation reaction is 20 to 25 ℃.
When the temperature is higher than the temperature of the oxidation reaction, hydrolysis at the 3-position is caused, and the compound represented by the formula A5 as the target product cannot be obtained.
Wherein the first oxidant is chromium oxide, and the weight ratio of the compound shown in the formula A4 to the chromium oxide to the N-hydroxyphthalimide is 1: (1.9-2.2): (0.7 to 0.76), wherein the mass ratio of the first chromium oxide to the second chromium oxide is 1:1, a step of; preferably, the compound shown in the formula A4, chromium oxide and N-hydroxyphthalimide (NHPI) are added in a weight ratio of 1:2:0.72.
wherein the first oxidant is pyridinium chlorochromate, and the weight ratio of the compound shown in the formula A4 to the chromium oxide to the N-hydroxyphthalimide is 1: (2.3-2.6): (0.7-0.76), the mass ratio of the first added pyridinium chlorochromate to the second added pyridinium chlorochromate is 1:1, a step of; preferably, the compound shown in the formula A4 and the pyridinium chlorochromate and the N-hydroxyphthalimide are added in a weight ratio of 1:2:0.72.
Wherein when the solvent for the oxidation reaction is acetone, preferably, the mass-volume ratio of the compound represented by the formula A4 to the acetone is 1g: (13-16) ml.
Wherein when the solvent for the oxidation reaction is acetonitrile, preferably, the mass-to-volume ratio of the compound represented by formula A4 to the acetonitrile is 1g: (18-21) ml.
The oxidation reaction specifically comprises the following steps: adding acetone/acetonitrile and water into a reactor, adding a compound shown in a formula A4 and one half of a first oxidant and a second oxidant N-hydroxyphthalimide (NHPI) under stirring, controlling the temperature to be 20-35 ℃, keeping the temperature and stirring for 3 hours, adding the other half of the first oxidant, keeping the temperature and stirring for 20-25 hours, detecting the reaction to be complete by TCL, adding isopropanol and quenching the reaction, concentrating the acetone, adding dioxymethane to extract chromic acid, separating liquid, washing an organic phase once by water, collecting the organic phase, concentrating the organic phase under reduced pressure, replacing by methanol, cooling and filtering to obtain the compound shown in the formula A5.
In step (4), the first hydrolysis reaction comprises: and (3) taking methanol as a solvent, and enabling the compound shown in the formula A5 prepared by the oxidation reaction to generate a first hydrolysis reaction under an acidic condition to generate a compound shown in the formula A6, wherein the acid adopted by the first hydrolysis reaction is hydrochloric acid or sulfuric acid, the temperature of the first hydrolysis reaction is 20-65 ℃, and the reaction time is 3-5 h.
Preferably, the first hydrolysis reaction temperature is 50 to 55 ℃.
Wherein the mass volume ratio of the compound shown in the formula A5 to the hydrochloric acid is 1g: (0.45-0.6) ml.
The first hydrolysis reaction specifically comprises the following steps: adding methanol, water and acid into a reactor, adding a compound shown in a formula A5 under stirring, heating a system to 20-65 ℃, reacting for 3-5 h, detecting complete reaction by TCL, cooling the system to below 30 ℃, regulating pH to 6-7 by using saturated sodium bicarbonate solution, filtering, and drying to obtain the compound shown in a formula A6.
In step (5), the hydrogenation reduction reaction includes: the method comprises the steps of taking a mixture of absolute ethyl alcohol and pyridine as a solvent, taking palladium carbon with the mass content of 8-12% as a catalyst, and enabling a compound shown in a formula A6 prepared by a first hydrolysis reaction to undergo a hydrogenation reduction reaction with hydrogen to generate a compound shown in a formula A7, wherein the hydrogenation reduction reaction pressure is 0.4-0.45 MPa, the reaction temperature is 30-35 ℃, and the reaction time is 8-13 h.
Wherein, the volume ratio of the absolute ethyl alcohol to the pyridine is 1: (0.9-1.1).
Preferably, the solvent of the hydrogenation reduction reaction further comprises methylimidazole, and the volume ratio of the absolute ethanol to the mixture of pyridine and methylimidazole is 1: (0.9-1.1), or the hydrogenation reduction reaction solvent further comprises DMAP, wherein the volume ratio of the absolute ethanol to the pyridine is 1: (0.9-1.1), the mass ratio of the DMAP to the absolute ethanol is 1g: (48-53) ml, wherein the mass volume ratio of the compound shown in the formula A6 to the solvent is 1g: (9.5-10.5) ml.
Wherein the weight ratio of the compound shown in the formula A6 to the palladium-carbon catalyst is 1: (0.09-0.12).
The hydrogenation reduction reaction specifically comprises the following steps: mixing the hydrogenation reduction reaction solvent, adding the compound shown in the formula A6 and catalyst palladium-carbon under stirring, pressurizing to 0.4-0.45 MPa with hydrogen at 30-35 ℃ for reaction for 8-13 h, and detecting the reaction by TLC; and then filtering to remove palladium carbon, concentrating the solvent under reduced pressure, replacing with water, carrying out water separation, filtering, leaching with a small amount of water, and drying the filter cake until the filter cake is qualified to obtain the compound shown in the formula A7.
In step (6), the second hydrolysis reaction comprises: in a specific solvent, the side chain of the compound shown in the formula A7 prepared by the hydrogenation reduction reaction is subjected to a second hydrolysis reaction under an alkaline condition to generate the compound shown in the formula A8, wherein the alkali adopted by the second hydrolysis reaction is sodium hydroxide or potassium hydroxide, the temperature of the second hydrolysis reaction is 40-60 ℃, and the reaction time is 3-5 h.
Wherein the specific solvent is one of methanol, ethanol, acetone and tetrahydrofuran, or a mixture of dichloromethane and methanol, or a mixture of dichloromethane and ethanol.
Preferably, the second hydrolysis reaction temperature is 50 to 55 ℃.
Preferably, the weight ratio of the compound shown in the formula A7 to sodium hydroxide is 1: (0.19 to 0.22), wherein the weight ratio of the compound represented by the formula A7 to potassium hydroxide is 1: (0.26-0.30).
Preferably, the mass to volume ratio of the compound represented by formula A7 to the specific solvent is 1g: (5-10) ml.
The second hydrolysis reaction specifically comprises the following steps: mixing a specific solvent, water and alkali, adding a compound shown in a formula A7 in a stirring state, heating a reaction system to 50-55 ℃ for reaction for 3-5 h, detecting complete TCL (thermal chemical reaction) reaction, and cooling to 30 DEG C
The pH value is regulated to 2-3 by 6mol/L hydrochloric acid, the methanol is concentrated under reduced pressure, water is separated out, the mixture is filtered, water is leached, and the mixture is dried to obtain the compound shown in the formula A8.
In step (7), the selective reduction reaction includes: and (3) using tetrahydrofuran as a solvent to enable the compound shown in the formula A8 and the lithium aluminum tri-tert-butoxide serving as a reducing agent to undergo selective reduction reaction to generate cholic acid, wherein the reaction temperature of the selective reduction reaction is 20-25 ℃ and the reaction time is 8-13 h.
Preferably, the weight ratio of the compound shown in the formula A8 to the reducing agent lithium aluminum tri-tert-butoxide hydride is 1: (2.8-3.1), preferably the mass ratio of the cholic acid intermediate A8 to the reducing agent lithium aluminum tri-tert-butoxide hydride is 1:3.
Preferably, the mass volume ratio of the cholic acid intermediate A8 to the solvent tetrahydrofuran is 1g: (14-17) ml.
The selective reduction reaction specifically comprises the following steps: mixing the mixture shown in the formula A8 with tetrahydrofuran solvent, cooling to 0-5 ℃ under the protection of nitrogen, slowly adding lithium aluminum hydride tri-tert-butoxy serving as a reducing agent in batches, heating to 20-25 ℃ after the addition, reacting for 8-13 h, detecting the complete reaction by TCL, slowly dropwise adding 1mol/L hydrochloric acid, regulating the pH value to 2-3, concentrating the solvent tetrahydrofuran under reduced pressure, water out, filtering, eluting with a small amount of water, separating the filter cake after dissolving the filter cake with ethyl acetate, and recrystallizing for refining to obtain cholic acid.
The compound 9 alpha-hydroxy BA shown in the formula SM for synthesizing cholic acid is a product in the prior art, and can be self-made or commercially purchased. Specifically, the commercial purchasing supplier is Shenzhen Shengzhen biotechnology Co., ltd, and the homemade synthetic route is:
the invention also provides a cholic acid intermediate A8, wherein the structural formula of the cholic acid intermediate A8 is shown in the formula A8.
The invention also provides a preparation method of the cholic acid intermediate A8, wherein the structural formula of the cholic acid intermediate A8 is shown as a formula A8, and the preparation method comprises the following steps: in a specific solvent, carrying out side chain hydrolysis reaction on a compound shown in a formula A7 under alkaline conditions, cooling to room temperature after the reaction is completed, and carrying out aftertreatment to obtain a cholic acid intermediate A8, wherein the specific solvent is one of methanol, ethanol, acetone and tetrahydrofuran or a mixture of dichloromethane and methanol or a mixture of dichloromethane and ethanol.
In this method for producing cholic acid intermediate A8, it is preferable to subject the compound represented by formula A6 to hydrolysis under acidic conditions to obtain the compound represented by formula A7, it is more preferable to subject the compound represented by formula A5 to hydrolysis under acidic conditions to obtain the compound represented by formula A6, it is still more preferable to subject the compound represented by formula A4 to oxidation to obtain the compound represented by formula A5, it is still more preferable to subject the compound represented by formula A3 to ketal protection to obtain the compound represented by formula A4, it is still more preferable to subject the compound represented by formula A2 to Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, it is still more preferable to subject the compound represented by formula A1 to elimination reaction to obtain the compound represented by formula A2, and it is still more preferable to subject the compound represented by formula SM to oxidation to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A8, which is prepared by adopting the preparation method of the cholic acid intermediate A8.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as a formula CA, and the synthetic route comprises the steps of preparing the cholic acid by adopting the cholic acid intermediate A8; preferably, the cholic acid intermediate A8 is subjected to selective reduction reaction with lithium aluminum tri-tert-butoxide as a reducing agent in the presence of a solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A7, wherein the structural formula of the cholic acid intermediate A7 is shown in the formula A7.
The invention also provides a preparation method of the cholic acid intermediate A7, wherein the structural formula of the cholic acid intermediate A7 is shown as a formula A7, and the preparation method comprises the following steps: absolute ethyl alcohol and pyridine are used as solvents, a compound shown in a formula A6 and palladium carbon serving as a catalyst are added under stirring, hydrogen is used for pressurizing to 0.4-0.45 Mpa at the temperature of 30-35 ℃ for reaction, a reaction product is obtained after the reaction is completed, and a cholic acid intermediate A7 is obtained after the reaction product is subjected to post-treatment.
In the method for producing cholic acid intermediate A7, it is preferable that the compound represented by formula A5 is subjected to hydrolysis under acidic conditions to obtain the compound represented by formula A6, more preferable that the compound represented by formula A4 is subjected to oxidation to obtain the compound represented by formula A5, still more preferable that the compound represented by formula A3 is subjected to ketal protection to obtain the compound represented by formula A4, still more preferable that the compound represented by formula A2 is subjected to Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, still more preferable that the compound represented by formula A1 is subjected to elimination to obtain the compound represented by formula A2, still more preferable that the compound represented by formula SM is subjected to oxidation to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A7, which is prepared by adopting the preparation method of the cholic acid intermediate A7.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of preparing a compound shown as a formula A8 by adopting a cholic acid intermediate A7 as described above, and preparing the cholic acid by using the compound shown as the formula A8; preferably, the compound shown in the formula A7 is subjected to hydrolysis reaction in the presence of alkali in a solvent to obtain a compound shown in the formula A8, and then the compound shown in the formula A8 and a reducing agent lithium aluminum tri-tert-butoxide hydride are subjected to selective reduction reaction in the presence of the solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A6, wherein the structural formula of the cholic acid intermediate A6 is shown as a formula A6.
The invention also provides a preparation method of the cholic acid intermediate A6, wherein the structural formula of the cholic acid intermediate A6 is shown as a formula A6, and the preparation method comprises the following steps: and (3) taking methanol as a solvent, carrying out hydrolysis reaction on the compound shown in the formula A5 under an acidic condition at 20-65 ℃ to obtain a reaction product after the reaction is finished, and obtaining a cholic acid intermediate A6 after post-treatment of the reaction product.
In the method for producing cholic acid intermediate A6, the method preferably comprises subjecting the compound represented by formula A4 to an oxidation reaction to obtain the compound represented by formula A5, more preferably further comprises subjecting the compound represented by formula A3 to a ketal protection reaction to obtain the compound represented by formula A4, still more preferably further comprises subjecting the compound represented by formula A2 to a Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, still more preferably further comprises subjecting the compound represented by formula A1 to an elimination reaction to obtain the compound represented by formula A2, still more preferably further comprises subjecting the compound represented by formula SM to an oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A6, which is prepared by adopting the preparation method of the cholic acid intermediate A6.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of adopting a cholic acid intermediate A6 as described above to prepare a compound shown as a formula A7, then using the compound shown as the formula A7 to prepare a compound shown as a formula A8, and then using the compound shown as the formula A8 to prepare the cholic acid; preferably, the compound shown in the formula A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon serving as a catalyst in a solvent to obtain a compound shown in the formula A7, then the compound shown in the formula A7 is subjected to hydrolysis reaction in the presence of alkali in the solvent to obtain a compound shown in the formula A8, and then the compound shown in the formula A8 and a reducing agent lithium aluminum tri-tert-butoxide are subjected to selective reduction reaction in the presence of the solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A5, wherein the structural formula of the cholic acid intermediate A5 is shown in the formula A5.
The invention also provides a preparation method of the cholic acid intermediate A5, wherein the structural formula of the cholic acid intermediate A5 is shown as a formula A5, and the preparation method comprises the following steps: adding a compound shown in a formula A4, a first oxidant and a second oxidant into acetone or acetonitrile serving as a solvent under stirring, controlling the temperature to be 20-25 ℃, carrying out heat preservation and stirring for a first preset time, adding the first oxidant, carrying out heat preservation and stirring for a second preset time until the reaction is complete, adding isopropanol, quenching the reaction to obtain a reaction solution, and carrying out post-treatment on the reaction solution to obtain a cholic acid intermediate A5, wherein the first oxidant is chromium oxide or pyridinium chlorochromate, and the second oxidant is N-hydroxyphthalimide.
In the method for producing cholic acid intermediate A5, it is preferable to carry out ketal protection of the compound represented by formula A3 to obtain the compound represented by formula A4, more preferable to carry out Wittig or Wittig-Horner reaction of the compound represented by formula A2 to obtain the compound represented by formula A3, even more preferable to carry out elimination of the compound represented by formula A1 to obtain the compound represented by formula A2, and even more preferable to carry out oxidation of the compound represented by formula SM to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A5, which is prepared by adopting the preparation method of the cholic acid intermediate A5.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of adopting a cholic acid intermediate A5 to prepare a compound shown as a formula A6, then using the compound shown as the formula A6 to prepare a compound shown as a formula A7, then using the compound shown as the formula A7 to prepare a compound shown as a formula A8, and then using the compound shown as the formula A8 to prepare the cholic acid; preferably, the compound shown in the formula A5 is subjected to hydrolysis reaction under an acidic condition in a solvent to obtain a compound shown in the formula A6, then the compound shown in the formula A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon serving as a catalyst in the solvent to obtain a compound shown in the formula A7, then the compound shown in the formula A7 is subjected to hydrolysis reaction in the presence of alkali in the solvent to obtain a compound shown in the formula A8, and then the compound shown in the formula A8 and lithium aluminum tri-tert-butoxide serving as a reducing agent are subjected to selective reduction reaction in the presence of the solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A4, wherein the structural formula of the cholic acid intermediate A4 is shown as a formula A4.
The invention also provides a preparation method of the cholic acid intermediate A4, wherein the structural formula of the cholic acid intermediate A4 is shown as a formula A4, and the preparation method comprises the following steps: toluene is used as a solvent, ethylene glycol is used as a ketal reaction reagent, p-toluenesulfonic acid is used as a catalyst, a compound shown in a formula A3 is mixed with toluene, ethylene glycol and p-toluenesulfonic acid, a system is heated to a reflux state for reaction, a reaction product is obtained after the reaction is completed, and a cholic acid intermediate A4 is obtained after post-treatment of the reaction product; or, using ethylene glycol as a ketal reaction reagent, using triethyl orthoformate as a ketal dehydrating agent, using p-toluenesulfonic acid as a catalyst, reacting the compound shown in A3 at 35-80 ℃ to obtain a reaction product after the reaction is finished, and obtaining a cholic acid intermediate A4 after post-treatment of the reaction product.
In the process for producing cholic acid intermediate A4, it is preferable that the process comprises subjecting the compound represented by formula A2 to a Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, more preferable that the process further comprises subjecting the compound represented by formula A1 to an elimination reaction to obtain the compound represented by formula A2, and still more preferable that the process further comprises subjecting the compound represented by formula SM to an oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A4, which is prepared by adopting the preparation method of the cholic acid intermediate A4.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of adopting a cholic acid intermediate A4 to prepare a compound shown as a formula A5, then using the compound shown as the formula A5 to prepare a compound shown as a formula A6, then using the compound shown as the formula A6 to prepare a compound shown as a formula A7, then using the compound shown as the formula A7 to prepare a compound shown as a formula A8, and then using the compound shown as the formula A8 to prepare the cholic acid; preferably, the compound shown in a formula A4 is subjected to oxidation reaction in a solvent to obtain a compound shown in a formula A5, then the compound shown in a formula A5 is subjected to hydrolysis reaction under an acidic condition in the solvent to obtain a compound shown in a formula A6, then the compound shown in a formula A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon as a catalyst in the solvent to obtain a compound shown in a formula A7, then the compound shown in a formula A7 is subjected to hydrolysis reaction in the presence of alkali in the solvent to obtain a compound shown in a formula A8, and then the compound shown in a formula A8 and a reducing agent lithium aluminum tri-tert-butoxide are subjected to selective reduction reaction in the presence of the solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A3, wherein the structural formula of the cholic acid intermediate A3 is shown in the formula A3.
The invention also provides a preparation method of the cholic acid intermediate A3, wherein the structural formula of the cholic acid intermediate A3 is shown as a formula A3, and the preparation method comprises the following steps: performing Wittig reaction, namely adding a compound shown in a formula A2 and Wittig reagent ethoxyformyl methylene triphenylphosphine into the mixture under stirring by taking toluene or tetrahydrofuran as a solvent to obtain a reactant system, heating the reactant system to a reflux state for reaction for a preset time until the reaction is complete to obtain a reaction product comprising the compound shown in a formula A3, and cooling the reaction product to room temperature, and then performing post-treatment on the reaction product to obtain a cholic acid intermediate A3; or, carrying out Wittig-Horner reaction, and reacting the compound shown in the formula A2 with alkali and triethyl phosphonoacetate at 20-66 ℃ by taking tetrahydrofuran as a solvent until the reaction is complete to obtain a reaction product comprising cholic acid intermediate A3, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
In the method for producing cholic acid intermediate A3, it is preferable that the method further comprises subjecting the compound represented by formula A1 to an elimination reaction to obtain the compound represented by formula A2, and it is more preferable that the method further comprises subjecting the compound represented by formula SM to an oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A3, which is prepared by adopting the preparation method of the cholic acid intermediate A3.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of adopting a cholic acid intermediate A3 as described above to prepare a compound shown as a formula A4, then using the compound shown as the formula A4 to prepare a compound shown as a formula A5, then using the compound shown as the formula A5 to prepare a compound shown as a formula A7, then using the compound shown as the formula A7 to prepare a compound shown as a formula A8, and then using the compound shown as the formula A8 to prepare the cholic acid; preferably, the compound shown in A3 is subjected to ketal protection reaction in a solvent to obtain a compound shown in a formula A4, then the compound shown in A4 is subjected to oxidation reaction in the solvent to obtain a compound shown in a formula A5, then the compound shown in a formula A5 is subjected to hydrolysis reaction under acidic condition in the solvent to obtain a compound shown in a formula A6, then the compound shown in A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon as a catalyst in the solvent to obtain a compound shown in a formula A7, then the compound shown in a formula A7 is subjected to hydrolysis reaction in the presence of alkali in the solvent to obtain a compound shown in a formula A8, and then the compound shown in a formula A8 and the lithium aluminum tri-tert-butoxide as a reducing agent are subjected to selective reduction reaction in the solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown in the formula A2.
The invention also provides a preparation method of the cholic acid intermediate A2, wherein the structural formula of the cholic acid intermediate A2 is shown as a formula A2, and the preparation method comprises the following steps: taking water as a solvent, reacting a compound shown in A1 with concentrated sulfuric acid and glacial acetic acid at 20-50 ℃ until the reaction is complete to obtain a reaction product containing a compound shown in a formula A2, and performing post-treatment on the reaction product to obtain a cholic acid intermediate A2; or, using dichloromethane or chloroform as a solvent to react the compound shown in the formula A1 with acetic anhydride and concentrated sulfuric acid at 30-40 ℃ for 3-5 hours until the reaction is complete, thus obtaining a reaction product comprising the compound shown in the formula A2.
In the method for producing cholic acid intermediate A2, the compound represented by formula SM is preferably subjected to an oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A2, which is prepared by adopting the preparation method of the cholic acid intermediate A2.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of adopting a cholic acid intermediate A2 to prepare a compound shown as a formula A3, then using the compound shown as the formula A3 to prepare a compound shown as a formula A4, then using the compound shown as the formula A4 to prepare a compound shown as a formula A5, then using the compound shown as the formula A5 to prepare a compound shown as a formula A7, then using the compound shown as the formula A6 to prepare a compound shown as a formula A8, and then using the compound shown as the formula A8 to prepare the cholic acid; preferably, the compound shown in A2 is subjected to Wittig or Wittig-Horner reaction in a solvent to obtain a compound shown in a formula A3, then the compound shown in A3 is subjected to ketal protection reaction in the solvent to obtain a compound shown in a formula A4, then the compound shown in A4 is subjected to oxidation reaction in the solvent to obtain a compound shown in a formula A5, then the compound shown in the formula A5 is subjected to hydrolysis reaction under acidic condition in the solvent to obtain a compound shown in a formula A6, then the compound shown in A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon catalyst in the solvent to obtain a compound shown in a formula A7, then the compound shown in the formula A7 is subjected to hydrolysis reaction in the presence of alkali in the solvent to obtain a compound shown in a formula A8, and then the compound shown in the formula A8 and lithium aluminum tri-tert-butoxide as a reducing agent are subjected to selective reduction reaction in the solvent to obtain the cholic acid.
The invention also provides a cholic acid intermediate A1, wherein the structural formula of the cholic acid intermediate A1 is shown in the formula A1.
The invention also provides a preparation method of the cholic acid intermediate A1, wherein the structural formula of the cholic acid intermediate A1 is shown as a formula A1, and the preparation method comprises the following steps: using dichloromethane as a solvent, and using TEMPO and 8% sodium hypochlorite to perform oxidation reaction on the compound shown in the formula SM at room temperature until the reaction is complete, so as to obtain a product containing the compound shown in the formula A1; or acetone is used as a solvent, jones reagent is used as an oxidant, and the compound shown in the formula SM is subjected to oxidation reaction at 0-10 ℃ until the reaction is complete, so that a product comprising the compound shown in the formula A1 is obtained.
The invention also provides a cholic acid intermediate A1, which is prepared by adopting the preparation method of the cholic acid intermediate A1.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of adopting a cholic acid intermediate A1 to prepare a compound shown as a formula A2, then adopting the compound shown as the formula A2 to prepare a compound shown as a formula A3, then adopting the compound shown as the formula A3 to prepare a compound shown as a formula A4, then adopting the compound shown as the formula A4 to prepare a compound shown as a formula A6, then adopting the compound shown as the formula A6 to prepare a compound shown as a formula A7, then adopting the compound shown as the formula A7 to prepare a compound shown as a formula A8, and then adopting the compound shown as the formula A8 to prepare the cholic acid; preferably, the compound shown in A1 is subjected to elimination reaction in a solvent to obtain a compound shown in a formula A2, then the compound shown in A2 is subjected to Wittig or Wittig-Horner reaction in the solvent to obtain a compound shown in a formula A3, then the compound shown in A3 is subjected to ketal protection reaction in the solvent to obtain a compound shown in a formula A4, then the compound shown in A4 is subjected to oxidation reaction in the solvent to obtain a compound shown in a formula A5, then the compound shown in the formula A5 is subjected to hydrolysis reaction under acidic condition in the solvent to obtain a compound shown in a formula A6, then the compound shown in A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon in the solvent to obtain a compound shown in a formula A7, then the compound shown in the formula A7 is subjected to hydrolysis reaction in the presence of alkali to obtain a compound shown in a formula A8, and then the compound shown in the solvent is subjected to selective reduction reaction with lithium aluminum tri-tert-butoxide as a reducing agent to obtain the cholic acid.
The invention also provides a synthesis method of cholic acid, the molecular formula of the cholic acid is shown as a formula CA, the synthesis route comprises the steps of preparing a cholic acid intermediate A1 by adopting a compound shown as a formula SM through oxidation reaction, preparing a compound shown as a formula A2 by adopting the compound shown as the formula A1, preparing a compound shown as a formula A3 by adopting the compound shown as the formula A2, preparing a compound shown as a formula A4 by adopting the compound shown as the formula A3, preparing a compound shown as a formula A5 by adopting the compound shown as the formula A4, preparing a compound shown as a formula A6 by adopting the compound shown as the formula A5, preparing a compound shown as a formula A7 by adopting the compound shown as the formula A6, preparing a compound shown as a formula A8 by adopting the compound shown as the formula A7, and preparing the cholic acid by adopting the compound shown as the formula A8.
EXAMPLES 1-2 Synthesis of Compounds represented by formula A1
The synthetic route is as follows:
example 1
800.0ml of methylene chloride is added into a clean and dry reaction bottle, 100.0g of 9 alpha-hydroxy BA (shown as a formula SM) is added under stirring, 11.0g of TEMPO is added at room temperature, then 200.0g of 8% sodium hypochlorite is added dropwise, the reaction is carried out for 2.5h after the dropwise addition is finished, a TLC detection reaction is carried out until the completion, a 5% sodium sulfite solution is added, and no oxidizing property is detected by using starch potassium iodide test paper. The system was stirred for about 20 minutes, allowed to stand for about 30 minutes, separated, and the organic phase was collected. 200.0ml of water was added to the organic phase, stirred for about 20 minutes, left to stand for about 30 minutes, and the organic phase was collected. Concentrating under reduced pressure at 40deg.C in hot water bath, displacing with methanol, and concentrating to viscous state. Cooling, filtering and drying to obtain 95.5g of the compound shown in the formula A1.
Example 2
1000.0ml of acetone was placed in a clean and dry reaction flask, 100.0g of 9. Alpha. -hydroxy BA (represented by formula SM) was added with stirring, the system was cooled to 8℃and Wen Dijia 100.0.0 ml of Jones reagent was controlled, and the reaction was stirred under heat for 6 hours with TLC detection until completion. The reaction was quenched by adding 100.0ml of isopropyl alcohol, slowly adding the system into 5000.0ml of ice water for water separation, cooling to 6 ℃, filtering, and drying to obtain 95.1g of the compound represented by formula A1.
The analytical data were:
1 HNMR(400MHz,CDCl3)：δ9.55(s，1H)，5.71(s,1H)，3.51(s,1H-9-OH)， 2.99-1.12(m，20H)，1.37(s，3H-19-CH 3 )，1.14(d，3H-21-CH 3 )，1.06(s,3H-18- CH 3 )。
EXAMPLES 3-4 Synthesis of Compounds represented by formula A2
The synthetic route is as follows:
example 3
48.0ml of water is added into a clean and dry reaction bottle, the temperature is reduced to 8 ℃ by ice water bath, the temperature T is controlled to be less than or equal to 40 ℃ under stirring, 351.0g of concentrated sulfuric acid is added dropwise, 96.0ml of glacial acetic acid and 95.0g of a compound shown as a formula A1 are added, the system is controlled to be at 37 ℃ for reaction for 2.5 hours, and TLC detection reaction is completed. Adding the system into 1500.0ml ice water bath, stirring for more than 30 minutes after adding, filtering, eluting with water to neutrality, dissolving the filter cake with 400.0ml dichloromethane, separating, collecting organic layer, concentrating under reduced pressure, replacing with methanol, concentrating to viscous state, filtering, and drying the filter cake to obtain 87.0g compound shown in formula A2.
Example 4
570ml of dichloromethane is added into a clean and dry reaction bottle, 95.0g of a compound shown in a formula A1 is added under stirring, the temperature is reduced to 6 ℃, 95.0ml of acetic anhydride is added dropwise, the mixture is stirred for 15 minutes after the addition, 38.0ml of concentrated sulfuric acid is added dropwise, the temperature is raised to 35 ℃ after the addition is completed, the mixture is stirred for 4 hours under heat preservation, and TLC detection reaction is completed. Adding 95.0ml of water into the system, quenching, separating liquid, collecting an organic phase, concentrating under reduced pressure, replacing with methanol, concentrating to a viscous state, filtering, and drying a filter cake until the filter cake is qualified to obtain 86.7g of a compound shown in a formula A2.
The analytical data were:
1 HNMR(400MHz,CDCl3)：δ9.55(s，1H)，5.71(s,1H)，5.23(m,1H)，3.00- 1.13(m，18H)，1.38(s，3H-19-CH 3 )，1.13(d，3H-21-CH 3 )，1.06(s,3H-18- CH 3 )。
EXAMPLES 5 TO 7 Synthesis of Compounds of formula A3
The synthetic route is as follows:
example 5
1050.0ml of toluene and 85.0g of the compound of formula A2 and 173.0g of ethoxyformyl methylene triphenylphosphine were added to a clean and dry reaction flask, the reaction was allowed to proceed to reflux for 12 hours with stirring, TLC detection was complete, and the reaction was allowed to cool to room temperature. A zinc chloride solution (355.0 ml of water+210.0g of zinc chloride) was added to the system, the reaction was allowed to precipitate at 28℃for 12 hours, the precipitate was filtered off with suction, the filtrate was separated, and the operation was repeated once again with a zinc chloride solution (142.0 ml of water+85.0g of zinc chloride). The mixture was separated after filtration, and the organic phase was collected, concentrated to dryness under reduced pressure, filtered and dried to give 94.3g of the compound represented by formula A3.
Example 6
170.0ml of tetrahydrofuran is added into a clean and dry reaction bottle, 18.0g of sodium hydride is added under stirring, bubbles emerge, nitrogen protection is realized, 85.0ml of triethyl phosphonoacetate is dripped at room temperature, stirring is carried out for 25 minutes, 85.0g of a compound shown in formula A2 and 850.0ml of tetrahydrofuran mixed solution are dripped, the temperature is controlled to be 40 ℃ after dripping is finished, the reaction is carried out for 2 hours, TLC detection reaction is completed, 6N hydrochloric acid is used for regulating the PH to be 6.5 at room temperature, the tetrahydrofuran is concentrated under reduced pressure, 200.0ml of water is added for water precipitation, cooling, filtration and drying are carried out, and 95.0g of the compound shown in formula A3 is obtained.
Example 7
170.0ml of tetrahydrofuran is added into a clean and dry reaction bottle, 18.0g of sodium hydride is added under stirring, bubbles emerge, nitrogen protection is realized, 85.0ml of triethyl phosphonoacetate is dripped at room temperature, stirring is carried out for 25 minutes, 85.0g of a compound shown in formula A2 and 850.0ml of tetrahydrofuran mixed solution are dripped, the temperature is controlled to be 40 ℃ after dripping is finished, the reaction is carried out for 2 hours, TLC detection reaction is completed, 6N hydrochloric acid is used for regulating the PH to be 6.5 at room temperature, the tetrahydrofuran is concentrated under reduced pressure, 200.0ml of water is added for water precipitation, cooling, filtration and drying are carried out, and 95.0g of the compound shown in formula A3 is obtained.
The analytical data were:
1 HNMR(400MHz，CDCl3)：δ6.82(dd，J＝15.3，9.0Hz，1H)，5.85(d， 1H)，5.72(d，J＝15.6Hz，1H)，5.25(m，1H-11-CH)，4.26-4.09(m，2H)，3.05-2.86(m，2H)，2.40-2.26(m，1H-20-CH)，2.10-1.12(m，18H)，1.37(s，3H- 19-CH 3 )，1.12(d，3H-21-CH 3 )，1.06(s,3H-18-CH 3 )
EXAMPLES 8-9 Synthesis of Compounds represented by formula A4
The synthetic route is as follows:
example 8
640.0ml of ethylene glycol, 143.0ml of triethyl orthoformate and 1.4g of p-toluenesulfonic acid are added into a clean and dry reaction bottle, 93.0g of cholic acid intermediate A3 is added under stirring, the system is heated to 45 ℃ for 7h of reaction, TLC detection reaction is completed, the temperature is reduced to room temperature, and triethylamine is added to adjust the PH to 7.2. 3500.0ml of water is added into the system for water precipitation, the temperature is reduced, and the filtration is carried out. Recrystallizing the filter cake with methanol, cooling, filtering, and drying to obtain 84.6g of the compound shown in formula A4.
Example 9
In a clean dry reaction flask 930.0ml toluene, 186.0ml ethylene glycol, 0.93g PTS and 93.0g cholic acid intermediate A3, the system was warmed to reflux for 25h and the reaction was complete by TLC. Cooling, adding a small amount of triethylamine at room temperature to adjust pH=7.2, adding 370ml of water for washing for 2 times, collecting an organic phase, concentrating a toluene layer under reduced pressure to a viscous state, adding 370.0ml of petroleum ether, cooling to 6 ℃, filtering, and drying to obtain 81.9g of a compound shown in a formula A4.
The analytical data were:
1 HNMR(400MHz，CDCl 3 )：δ6.82(dd，J＝15.6，8.9Hz，1H)，5.72(d，J＝ 15.6Hz，1H)，5.23(m，1H-11-CH)，5.18(m，1H)，4.18(q，J＝7.1Hz，2H)， 3.97-3.90(m，4H)，2.31-1.12(m，21H)，1.37(s，3H-19-CH 3 )，1.12(d，3H-21- CH 3 )，1.06(s,3H-18-CH 3 )
examples 10 to 13: synthesis of Compound of formula A5
The synthetic route is as follows:
example 10
1200.0ml of acetone and 133.0ml of water are added into a clean reaction flask, 83.0g of the compound shown in formula A4, 83.0g of chromium oxide and 60.0g of NHPI are added under stirring, the temperature is controlled to 22 ℃, the mixture is kept warm and stirred for 3 hours, then 83.0g of chromium oxide is added, the mixture is kept warm and stirred for 23 hours, and TLC detection reaction is completed. The reaction was quenched by the addition of 72.0g of isopropanol, concentrated to dryness with acetone, added with 500.0ml of dichloromethane, separated, the organic phase washed once with water and the organic phase collected. The treated organic layer was concentrated under reduced pressure, displaced with methanol, cooled, filtered and dried to give 64.4g of the compound of formula A5.
Example 11
1200.0ml of acetone and 133.0ml of water are added into a clean reaction flask, 83.0g of a compound shown in formula A4, 100.0g of pyridinium chlorochromate and 60.0g of NHPI are added under stirring, the temperature is controlled to 22 ℃, the mixture is stirred for 5 hours under heat preservation, 100.0g of pyridinium chlorochromate is added again, the mixture is stirred for 23 hours under heat preservation, and the TLC detection reaction is completed. The reaction was quenched by the addition of 80.0g of isopropanol, concentrated to dryness with acetone, added 500.0ml of dichloromethane, separated, the organic phase washed once with water and the organic phase collected. The treated organic layer was concentrated under reduced pressure, displaced with methanol, cooled, filtered and dried to give 63.9g of the compound of formula A5.
Example 12
1600.0ml of acetonitrile and 133.0ml of water are added into a clean reaction bottle, 83.0g of a compound shown in a formula A4, 83.0g of chromium oxide and 60.0g of NHPI are added under stirring, the temperature is controlled to 22 ℃, the mixture is kept warm and stirred for 4 hours, then 83.0g of chromium oxide is added, the mixture is kept warm and stirred for 23 hours, and TLC detection reaction is completed. The reaction was quenched by the addition of 72.0g of isopropanol, concentrated to dryness with acetone, added with 500.0ml of dichloromethane, separated, the organic phase washed once with water and the organic phase collected. The treated organic layer was concentrated under reduced pressure, displaced with methanol, cooled, filtered and dried to give 63.8g of the compound of formula A5.
Example 13
1600.0ml of acetonitrile and 133.0ml of water are added into a clean reaction bottle, 83.0g of a compound shown in a formula A4, 100.0g of pyridinium chlorochromate and 60.0g of NHPI are added under stirring, the temperature is controlled to 22 ℃, the mixture is stirred for 3 hours under heat preservation, then 100.0g of pyridinium chlorochromate is added, the mixture is stirred for 23 hours under heat preservation, and the TLC detection reaction is completed. The reaction was quenched by the addition of 80.0g of isopropanol, concentrated to dryness with acetone, added 500.0ml of dichloromethane, separated, the organic phase washed once with water and the organic phase collected. The treated organic layer was concentrated under reduced pressure, displaced with methanol, cooled, filtered and dried to give 63.3g of the compound of formula A5.
The analytical data were:
1 HNMR(400MHz，CDCl 3 )：δ6.82(dd，J＝15.6，9.0Hz，1H)，5.99(s， 1H)，5.90-5.70(m，2H)，4.16(q，J＝7.1Hz，2H)，3.97-3.90(m，4H)，3.04 (m，1H)，2.31-1.12(m，16H)，1.37(s，3H-19-CH 3 )，1.12(d，3H-21-CH 3 )， 1.06(s,3H-18-CH 3 )。
example 14: synthesis of Compound of formula A6
The synthetic route is as follows:
in a clean reaction flask were added 630.0ml of methanol, 63.0ml of water and 38.0ml of concentrated hydrochloric acid, 63.0g of the compound represented by formula A5 was added with stirring, the system was warmed to 55℃and reacted for 4 hours, and the reaction was detected by TLC until completion. The system was cooled to 25 ℃, PH was adjusted to 6.5 with saturated sodium bicarbonate solution and filtered. Drying gives 55.1g of the compound of formula A6.
The analytical data were:
1 HNMR(400MHz，CDCl3)：δ6.82(dd，J＝15.6，9.0Hz，1H)，5.99(s， 1H)，5.90-5.70(m，2H)，4.16(q，J＝7.1Hz，2H)，3.20-2.80(m，5H)，2.35 (m，1H)，2.21-1.13(m，11H)，1.37(s，3H-19-CH 3 )，1.13(d，3H-21-CH 3 )， 1.04(s,3H-18-CH 3 )。
examples 15 to 17: synthesis of Compound of formula A7
The synthetic route is as follows:
example 15
270.0ml of absolute ethanol and 270.0ml of pyridine were placed in a clean and dry autoclave, 54.0g of the compound represented by formula A6 and 5.4g of 10% palladium on carbon were added with stirring, the reaction was carried out at 35℃under pressure of 0.42MPa with hydrogen for 10 hours, and the completion of the reaction was detected by TLC. The system is filtered to remove palladium carbon, then the system is decompressed and concentrated, water is used for replacement, water is used for separation, a small amount of water is used for leaching, and a filter cake is dried to be qualified, thus 50.6g of a compound shown as a formula A7 is obtained, wherein the purity of A7 is: 5α—h isomer purity = 89.8: 10.2.
Example 16
270.0ml of absolute ethanol, 216.0ml of pyridine and 54.0ml of 1-methylimidazole are placed in a clean and dry autoclave, 54.0g of the compound represented by formula A6 and 5.4g of 10% palladium on carbon are added with stirring, the reaction is carried out under pressure at 35℃to 0.42MPa with hydrogen for 10 hours, and the reaction is detected by TLC until completion. The system is filtered to remove palladium carbon, then the system is decompressed and concentrated, water is used for replacement, water is used for separation, a small amount of water is used for leaching, and a filter cake is dried to be qualified, thus 51.3g of a compound shown in a formula A7 is obtained, wherein the purity of A7 is: 5α—h isomer purity = 92.7:7.3.
Example 17
270.0ml of absolute ethanol, 270.0ml of pyridine and 5.4g of DMAP were placed in a clean and dry autoclave, 54.0g of the compound represented by formula A6 and 5.4g of 10% palladium on carbon were added with stirring, the mixture was pressurized to 0.42MPa with hydrogen at 35℃and reacted for 10 hours, and the reaction was detected by TLC. The palladium carbon is filtered off from the system, then the material is separated out by water, a small amount of water is used for leaching, and the filter cake is dried to be qualified, so that 50.9g of a compound shown in a formula A7 is obtained, wherein the purity of the A7 is: 5α—h isomer purity = 98.3:1.7.
| examples | Feeding quantity (g) | Product dry weight (g) | A7 purity 5. Alpha. Isomer purity | Weight yield (%) |
| Example 15 | 54.0 | 50.6 | 89.8：10.2 | 93.7％ |
| Example 16 | 54.0 | 51.3g | 92.7：7.3 | 95.0％ |
| Example 17 | 54.0 | 50.9g | 98.3：1.7 | 94.3％ |
From the above table, it can be seen that when the solvent is absolute ethanol, pyridine and DMAP in a certain ratio range, the purity of the cholic acid intermediate A7 prepared is higher.
The analytical data were:
1 H NMR(400MHz,CDCl 3 ):δ4.11(m,2H),2.87(m,3H)；2.47-0.80(m,24H)；1.39(s,3H, 19-CH 3 )；1.06(s,3H,18-CH 3 )；0.84(d,3H,J＝6.5Hz,21-CH 3 )。
examples 18 to 22: synthesis of Compound of formula A8
The synthetic route is as follows:
/>
example 18: 500.0ml of methanol, 150.0ml of water and 10.0g of sodium hydroxide are added into a clean reaction flask, 50.0g of a compound shown in formula A7 is added under stirring, the system is heated to 50-55 ℃ for reaction for 3h, and TLC detection reaction is completed. Cooling below 30deg.C, regulating pH to 2.5 with 6N hydrochloric acid, concentrating under reduced pressure to obtain methanol, eluting with small amount of water, and drying the filter cake to obtain 46.1g of compound shown in formula A8.
Example 19: 250.0ml of tetrahydrofuran, 150.0ml of water and 14.0g of potassium hydroxide are added into a clean reaction flask, 50.0g of a compound shown in formula A7 is added under stirring, the system is heated to 40-45 ℃ for reaction for 4 hours, and TLC detection reaction is completed. Cooling below 30deg.C, regulating pH=2.5 with 6N hydrochloric acid, concentrating under reduced pressure to obtain methanol, eluting with small amount of water, and drying the filter cake to obtain 45.9g of compound shown in formula A8.
Example 20: 500.0ml of ethanol, 150.0ml of water and 14.0g of potassium hydroxide are added into a clean reaction flask, 50.0g of the compound shown in formula A7 is added under stirring, the system is heated to 45-50 ℃ for reaction for 3.5h, and TLC detection reaction is completed. Cooling below 30deg.C, regulating pH=2.5 with 6N hydrochloric acid, concentrating under reduced pressure to obtain methanol, eluting with small amount of water, and drying the filter cake to obtain 45.5g of compound shown in formula A8.
Example 21: 300.0ml of acetone, 150.0ml of water and 10.0g of sodium hydroxide are added into a clean reaction bottle, 50.0g of a compound shown as a formula A7 is added under stirring, the system is heated to 55-60 ℃ for reaction for 5h, and TLC detection reaction is carried out until the reaction is complete. Cooling below 30deg.C, regulating pH=2.7 with 6N hydrochloric acid, concentrating under reduced pressure to obtain methanol, eluting with small amount of water, and drying the filter cake to obtain 46.2g of compound shown in formula A8.
Example 22: 100.0ml of methylene chloride, 50.0ml of methanol, 150.0ml of water and 10.0g of sodium hydroxide are added into a clean reaction bottle, 50.0g of a compound shown as a formula A7 is added under stirring, the temperature of the system is raised to 50-55 ℃ for reaction for 5 hours, and TLC detection is carried out to complete the reaction. Cooling below 30deg.C, regulating pH=2.3 with 6N hydrochloric acid, concentrating under reduced pressure to obtain methanol, eluting with small amount of water, and drying the filter cake to obtain 45.8g of compound shown in formula A8.
The analytical data were:
1 H NMR(400MHz,CDCl 3 ):2.87(m,3H)；2.47-0.80(m,21H)；1.39(s,3H,19-CH 3 )； 1.06(s,3H,18-CH 3 )；0.84(d,3H,J＝6.5Hz,21-CH 3 )。
example 23: synthesis of cholic acid
The structural formula of cholic acid is shown as formula CA, and the synthetic route is as follows:
700.0ml of tetrahydrofuran and 45.0g of the compound shown in formula A8 are added into a clean and dry reaction bottle, the temperature is reduced to 3 ℃ under the protection of nitrogen, 130.0g of lithium aluminum tri-tert-butoxide is slowly added in batches, the temperature is raised to 25 ℃ after the addition is finished, the reaction is carried out for 11h through TLC detection, 1N hydrochloric acid is slowly added dropwise, the pH value is regulated to be 2.5, the tetrahydrofuran is concentrated under reduced pressure, water is separated and discharged, a small amount of water is used for leaching, and the filter cake is separated after being dissolved by ethyl acetate, recrystallized and refined to obtain 28.1g of target product cholic acid.
The analytical data were:
1H-NMR((D5)pyridine，500MHz):：4.25(s，H-C(12))；4.09(s，H-C (7))；3.78-3.73(m，H-C(3))；3.11(q,J＝13.0，H-C(8))；2.92(dt， J＝12.0，4.2，H-C(9))；2.79-2.73(m，H-C(14))；2.67-2.61(m，H-C (23a))；2.56-2.50(m，H-C(23b))；2.39-2.34(m，H-C(17))；2.15-
2.13(m，CH2(22))；2.13-2.11(m，H-C(4a))；2.07-2.00(m，H-C (15a))；1.94-1.91(m，H-C(1a,2a))；1.88-1.86(m，H-C(11a))；1.68- 1.67(m，CH2(6))；1.67-1.62(m，H-C(20,4b,2b,11b))；1.51-1.49(m，H-C (5))；1.44-1.37(m，CH 2 (16))；1.23(d，J＝5.5，Me(21))；1.21-1.19 (m，H-C(15b)；1.09-1.03(m，H-C(1b))；1.00(s，Me(19))；0.81(s，Me (18))。
the foregoing is a further detailed description of the invention in connection with specific preferred embodiments, and is not intended to limit the practice of the invention to such description. It will be apparent to those skilled in the art that several simple deductions and substitutions can be made without departing from the spirit of the invention, and these are considered to be within the scope of the invention.
Claims (9)
1. The cholic acid intermediate A2 is characterized in that the structural formula of the cholic acid intermediate A2 is shown as a formula A2:
。
2. the preparation method of the cholic acid intermediate A2 is characterized in that water is used as a solvent, and a compound shown in A1, concentrated sulfuric acid and glacial acetic acid are subjected to elimination reaction at 20-50 ℃ until the reaction is complete, so that a reaction product containing the compound shown in the formula A2 is obtained, and the reaction product is subjected to post-treatment to obtain the compound shown in the formula A2, wherein the compound shown in the formula A1 has the following structural formula:
the structural formula of the compound shown in the formula A2 is as follows: />。
3. The method for preparing cholic acid intermediate A2 according to claim 2, wherein the elimination reaction time is 2.5-4 hours.
4. The method for preparing cholic acid intermediate A2 according to claim 2, wherein the elimination reaction temperature is 35-40 ℃.
5. The method for preparing cholic acid intermediate A2 according to claim 2, wherein the mass ratio of the compound represented by formula A1 to concentrated sulfuric acid is 1: (3.5-3.8), wherein the mass volume ratio of the compound shown in the formula A1 to glacial acetic acid is 1 g: (1-1.2) ml.
6. The process for preparing cholic acid intermediate A2 according to claim 2, wherein the post-treatment comprises cooling in an ice bath for more than 30 minutes, filtering, washing the filter cake with water to neutrality, dissolving the filter cake with dichloromethane, separating the liquid, collecting the organic phase, concentrating under reduced pressure, displacing methanol, concentrating to a viscous state, filtering, and drying the filter cake.
7. The preparation method of the cholic acid intermediate A2 is characterized in that elimination reaction is carried out, dichloromethane or chloroform is used as a solvent, and a compound shown in the formula A1, acetic anhydride and concentrated sulfuric acid react for 3-5 hours at 30-40 ℃ until the reaction is complete, so that a compound shown in the formula A2 is obtained, wherein the structural formula of the compound shown in the formula A1 is as follows:
the structural formula of the compound shown in the formula A2 is as follows: />。
8. The method for preparing cholic acid intermediate A2 according to claim 7, wherein the mass-to-volume ratio of the compound represented by formula A1 to acetic anhydride is 1 g: (1-1.2 ml), wherein the volume ratio of acetic anhydride to concentrated sulfuric acid is 1: (0.38 to 0.4).
9. A method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as a formula CA, and the synthetic route is shown as follows:
the synthesis method comprises the following steps:
(1) Performing Wittig or Wittig-Horner reaction on the cholic acid intermediate A2 to obtain a compound shown in a formula A3;
(2) Carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4;
(3) Carrying out an oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5, wherein the oxidation reaction comprises the following steps: using acetone or acetonitrile as a solvent, using chromic oxide or pyridinium chlorochromate as a first oxidant and using N-hydroxyphthalimide as a second oxidant, and carrying out oxidation reaction on a compound shown in a formula A4, the first oxidant and the second oxidant at 20-35 ℃;
(4) Carrying out a first hydrolysis reaction on the compound shown in the formula A5 under an acidic condition to obtain a compound shown in the formula A6, wherein the first hydrolysis reaction comprises: taking methanol as a solvent, and enabling a compound shown in a formula A5 to undergo a first hydrolysis reaction under an acidic condition, wherein the acid adopted in the first hydrolysis reaction is hydrochloric acid or sulfuric acid, the temperature of the first hydrolysis reaction is 20-65 ℃, and the reaction time is 3-5 h;
(5) Carrying out hydrogenation reduction reaction on the compound shown in the formula A6 to obtain a compound shown in the formula A7, wherein the hydrogenation reduction reaction comprises the following steps: taking a mixture of absolute ethyl alcohol and pyridine as a solvent, and taking palladium carbon with the mass content of 8-12% as a catalyst, so that the compound shown in the formula A6 and hydrogen undergo hydrogenation reduction reaction, wherein the hydrogenation reduction reaction pressure is 0.4-0.45 MPa, the reaction temperature is 30-35 ℃, and the reaction time is 8-13 h;
(6) Carrying out a second hydrolysis reaction on the compound shown in the formula A7 under alkaline conditions to obtain a compound shown in the formula A8;
(7) And (3) carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid, wherein the selective reduction reaction comprises the following steps: and (3) using tetrahydrofuran as a solvent to carry out selective reduction reaction on the compound shown in the formula A8 and a reducing agent lithium aluminum tri-tert-butoxide at 20-25 ℃ for 8-13 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211272286.XA CN115611961B (en) | 2022-10-18 | 2022-10-18 | Cholic acid intermediate A2 and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211272286.XA CN115611961B (en) | 2022-10-18 | 2022-10-18 | Cholic acid intermediate A2 and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115611961A CN115611961A (en) | 2023-01-17 |
| CN115611961B true CN115611961B (en) | 2024-02-13 |
Family
ID=84862622
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211272286.XA Active CN115611961B (en) | 2022-10-18 | 2022-10-18 | Cholic acid intermediate A2 and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115611961B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0912493D0 (en) * | 2008-04-25 | 2009-08-26 | Kythera Biopharmaceuticals Inc | Preparation of bile acids and intermediates thereof |
| WO2018054300A1 (en) * | 2016-09-20 | 2018-03-29 | 江苏豪森药业集团有限公司 | Cholic acid derivative free alkali, crystalline form, preparation methods therefor and applications thereof |
| CN108676049A (en) * | 2017-11-02 | 2018-10-19 | 华东师范大学 | A kind of preparation method of Austria's shellfish cholic acid, ursodesoxycholic acid and 7- Ketocholic acid |
| WO2019085963A1 (en) * | 2017-11-02 | 2019-05-09 | 正大天晴药业集团股份有限公司 | Method for preparing cholic acid compound |
| WO2020177240A1 (en) * | 2019-03-06 | 2020-09-10 | 华南理工大学 | Chenodeoxycholic acid and preparation method therefor |
| CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
| WO2022100722A1 (en) * | 2020-11-14 | 2022-05-19 | 湖南科瑞生物制药股份有限公司 | 5,6-epoxy sterol compound, preparation method therefor and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6653492B2 (en) * | 2001-05-02 | 2003-11-25 | Novo Nordick A/S | Preparation of bile acids |
-
2022
- 2022-10-18 CN CN202211272286.XA patent/CN115611961B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0912493D0 (en) * | 2008-04-25 | 2009-08-26 | Kythera Biopharmaceuticals Inc | Preparation of bile acids and intermediates thereof |
| WO2018054300A1 (en) * | 2016-09-20 | 2018-03-29 | 江苏豪森药业集团有限公司 | Cholic acid derivative free alkali, crystalline form, preparation methods therefor and applications thereof |
| CN108676049A (en) * | 2017-11-02 | 2018-10-19 | 华东师范大学 | A kind of preparation method of Austria's shellfish cholic acid, ursodesoxycholic acid and 7- Ketocholic acid |
| WO2019085963A1 (en) * | 2017-11-02 | 2019-05-09 | 正大天晴药业集团股份有限公司 | Method for preparing cholic acid compound |
| WO2020177240A1 (en) * | 2019-03-06 | 2020-09-10 | 华南理工大学 | Chenodeoxycholic acid and preparation method therefor |
| CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
| WO2022100722A1 (en) * | 2020-11-14 | 2022-05-19 | 湖南科瑞生物制药股份有限公司 | 5,6-epoxy sterol compound, preparation method therefor and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115611961A (en) | 2023-01-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10981946B2 (en) | Methods for the purification of deoxycholic acid | |
| CN110003301B (en) | Cholane derivatives for the treatment and/or prevention of FXR and TGR5/GPBAR1 mediated diseases | |
| US4183852A (en) | Process for preparing 25-hydroxycholesterol | |
| WO2020177240A1 (en) | Chenodeoxycholic acid and preparation method therefor | |
| CN115611962B (en) | Method for synthesizing cholic acid | |
| JP5107257B2 (en) | Method for purifying chenodeoxycholic acid | |
| DE2429040C2 (en) | Steroid haptens, processes for their production and their use | |
| CN115466300A (en) | Cholic acid intermediate A7 and synthesis method thereof | |
| CN115611961B (en) | Cholic acid intermediate A2 and preparation method thereof | |
| AU775831B2 (en) | Process for preparing 17alpha-acetoxy-11beta-(4-N,N-(dimethylamino)phenyl)-21- methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates | |
| CN115651049B (en) | Cholic acid intermediate A3 and preparation method thereof | |
| CN116023424B (en) | Cholic acid intermediate A4 and preparation method thereof | |
| CN115626944B (en) | Cholic acid intermediate A5 and preparation method thereof | |
| JP5107262B2 (en) | Method for purifying chenodeoxycholic acid | |
| CN114276406B (en) | Preparation method of intermediate of deoxomilpine | |
| CN115536720A (en) | Cholic acid intermediate A8 and preparation method thereof | |
| EP0614908B1 (en) | Method of preparation of 3-beta-aminocholanic acid derivatives | |
| WO2007076655A1 (en) | METHOD FOR SYNTHESIS OF CHOLEST-3β,5α,6β,19-TETRAHYDROXY-24-ONE AND ITS DERIVATIVES | |
| CN111944004A (en) | Preparation method of halometasone | |
| US4145357A (en) | Steroid derivatives and process for preparing the same | |
| WO2019020067A1 (en) | Method for preparing steroid derivative fxr agonist | |
| CA1041479A (en) | Chenodeoxycholic acid | |
| WO2024083775A1 (en) | Process for the preparation of nor-ursodeoxycholic acid | |
| US6653491B1 (en) | Method for producing 4,4-dimethyl-3β-hydroxypregna-8, 14-diene-21-carboxylic acid esters and intermediate products obtained by said method | |
| CN115057906A (en) | Method for synthesizing cholesterol by using dehydroepiandrosterone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |