CN115611962B - Method for synthesizing cholic acid - Google Patents
Method for synthesizing cholic acid Download PDFInfo
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- CN115611962B CN115611962B CN202211276850.5A CN202211276850A CN115611962B CN 115611962 B CN115611962 B CN 115611962B CN 202211276850 A CN202211276850 A CN 202211276850A CN 115611962 B CN115611962 B CN 115611962B
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- Prior art keywords
- formula
- compound shown
- reaction
- cholic acid
- solvent
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- 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 165
- 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 162
- 239000004380 Cholic acid Substances 0.000 title claims abstract description 162
- 229960002471 cholic acid Drugs 0.000 title claims abstract description 162
- 235000019416 cholic acid Nutrition 0.000 title claims abstract description 162
- 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 160
- 238000000034 method Methods 0.000 title claims abstract description 30
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 402
- 238000006243 chemical reaction Methods 0.000 claims abstract description 158
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 48
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 48
- 238000006722 reduction reaction Methods 0.000 claims abstract description 41
- 238000003379 elimination reaction Methods 0.000 claims abstract description 24
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 22
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 105
- 239000002904 solvent Substances 0.000 claims description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 61
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 29
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 239000007800 oxidant agent Substances 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 22
- 230000001590 oxidative effect Effects 0.000 claims description 22
- 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 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 20
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 14
- 230000002378 acidificating effect Effects 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 229910000423 chromium oxide Inorganic materials 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 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 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003810 Jones reagent Substances 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 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 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 5
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- WHFKIZXBVFEJGA-UHFFFAOYSA-L dihydroxy(dioxo)chromium;pyridine Chemical compound O[Cr](O)(=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 WHFKIZXBVFEJGA-UHFFFAOYSA-L 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 abstract description 4
- 230000009385 viral infection Effects 0.000 abstract description 4
- 210000001835 viscera Anatomy 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 description 77
- 238000003756 stirring Methods 0.000 description 50
- 238000001816 cooling Methods 0.000 description 30
- 238000004809 thin layer chromatography Methods 0.000 description 30
- 238000001914 filtration Methods 0.000 description 29
- 238000001035 drying Methods 0.000 description 26
- 239000007858 starting material Substances 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 25
- 239000012065 filter cake Substances 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- 238000001514 detection method Methods 0.000 description 20
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 20
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000007795 chemical reaction product Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000001105 regulatory effect Effects 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
- 239000000047 product Substances 0.000 description 9
- 230000035484 reaction time Effects 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
- 238000002386 leaching Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000004321 preservation Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000001308 synthesis method Methods 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
- 238000006555 catalytic reaction Methods 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000010791 quenching Methods 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
- -1 cholic acid compound Chemical class 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
- 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
- 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
- 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 3
- 238000005406 washing Methods 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
- 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
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000000706 filtrate Substances 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
- 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent 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
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002994 raw material 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
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- 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 method for synthesizing cholic acid. The method comprises the following steps: carrying out a first oxidation reaction on a compound shown in a formula SM to obtain a compound shown in a formula A1; carrying out elimination reaction on the compound shown in the formula A1 to obtain a compound shown in the formula A2; carrying out wittig reaction on the compound shown in the formula A2 to obtain a compound shown in the formula A3; carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4; carrying out a second oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5; carrying out a first hydrolysis reaction on the compound shown in the formula A5 to obtain a compound shown in the formula A6; carrying out hydrogenation reduction reaction on the compound shown in the formula A6 to obtain a compound shown in the formula A7; carrying out a second hydrolysis reaction on the compound shown in the formula A7 to obtain a compound shown in the formula A8; and (3) carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid. The invention provides a method for synthesizing cholic acid to solve the risk of virus infection caused by extracting cholic acid from animal viscera, and has the advantage of mild reaction conditions.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a method for synthesizing cholic acid.
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 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 method for synthesizing cholic acid, wherein the structural formula of the cholic acid is shown in formula CA, and the method comprises the following steps:
(1) Carrying out a first oxidation reaction on a compound shown in a formula SM to obtain a compound shown in a formula A1;
(2) Carrying out elimination reaction on the compound shown in the formula A1 to obtain a compound shown in the formula A2;
(3) Carrying out Wittig or Wittig-Horner reaction on the compound shown in the formula A2 to obtain a compound shown in a formula A3;
(4) Carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4;
(5) Carrying out a second oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5;
(6) Carrying out a first hydrolysis reaction on the compound shown in the formula A5 to obtain a compound shown in the formula A6;
(7) Carrying out hydrogenation reduction reaction on the compound shown in the formula A6 to obtain a compound shown in the formula A7;
(8) Carrying out a second hydrolysis reaction on the compound shown in the formula A7 to obtain a compound shown in the formula A8;
(9) Carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid;
the complete reaction formula of the nine-step reaction is as follows:
in a specific embodiment, in the step (1), the first oxidation reaction is to react the compound shown in the formula SM with an oxidant TEMPO and 8% sodium hypochlorite in a solvent of dichloromethane at room temperature, or the first oxidation reaction is to react the compound shown in the formula SM with an oxidant jones reagent in a solvent of acetone at 0-10 ℃.
In a specific embodiment, in the step (2), the elimination reaction is to react the compound shown in the A1 with concentrated sulfuric acid and glacial acetic acid in solvent water at 20-50 ℃; or the elimination reaction is to react the compound shown in the formula A1 with acetic anhydride and concentrated sulfuric acid in methylene dichloride or chloroform at 30-40 ℃.
In a specific embodiment, in the step (3), the Wittig reaction is carried out by mixing a compound shown in a formula A2 and a Wittig reagent ethoxyformyl methylene triphenylphosphine in toluene or tetrahydrofuran as a solvent to obtain a reactant system, and heating the reactant system to a reflux state for reaction; or the Wittig-Horner reaction is carried out by reacting a compound shown in a formula A2 with alkali and triethyl phosphonoacetate in tetrahydrofuran solvent at 20-66 ℃, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
In a specific embodiment, in the step (4), the ketal protection reaction is carried out by mixing a compound shown in a formula A3 with a ketal reaction reagent ethylene glycol and a catalyst p-toluenesulfonic acid in toluene, and then heating the system to a reflux state for reaction; or the ketal protection reaction is to react the compound shown in A3 with ketal reactant glycol, ketal dehydrating agent triethyl orthoformate and catalyst p-toluenesulfonic acid at 35-80 ℃.
In a specific embodiment, in the step (5), the second oxidation reaction is an oxidation reaction of the compound represented by the formula A4 with a mixture of an oxidizing agent of chromium oxide and N-hydroxyphthalimide or a mixture of an oxidizing agent of pyridinium chromate and N-hydroxyphthalimide in acetone or acetonitrile at 20 to 35 ℃.
In a specific embodiment, in the step (6), the first hydrolysis reaction is performed in methanol solvent, and the compound shown in the formula A5 is reacted under an acidic condition at 20-65 ℃, wherein the acid adopted in the first hydrolysis reaction is hydrochloric acid or sulfuric acid.
In a specific embodiment, in the step (7), the hydrogenation reduction reaction is performed by reacting a compound shown in a formula A6 with hydrogen under preset conditions in a mixture of absolute ethanol and pyridine, wherein the mixture contains 8-12% of palladium carbon by mass as a catalyst, and the preset conditions include: the hydrogenation reduction reaction pressure is 0.4-0.45 MPa, and the reaction temperature is 30-35 ℃.
In a specific embodiment, in the step (8), the second hydrolysis reaction is performed in a specific solvent, and the side chain of the compound shown in the formula A7 is reacted under alkaline conditions at 40-60 ℃, 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, and the base adopted in the second hydrolysis reaction is sodium hydroxide or potassium hydroxide.
In a specific embodiment, the selective reduction reaction in step (9) is carried out by reacting the compound of formula A8 with lithium aluminum tri-tert-butoxide as a reducing agent at 20 to 25 ℃ in tetrahydrofuran as a solvent.
The beneficial effects of the invention at least comprise:
the invention sequentially passes through a first oxidation reaction, an elimination reaction, a wittig reaction, a ketal protection reaction, a second oxidation reaction, a first hydrolysis reaction, a hydrogenation reduction reaction, a second hydrolysis reaction and a selective reduction reaction to obtain the cholic acid compound shown in the formula CA, provides a chemical synthesis method for synthesizing the cholic acid by taking the compound shown in the formula SM as a plant source fermentation product as a raw material, has the advantage of mild reaction conditions, and can overcome the risk of virus infection caused by extracting the cholic acid through animal viscera in the prior art.
Detailed Description
A method for synthesizing cholic acid, wherein the structural formula of the cholic acid is shown as a formula CA, and the method comprises the following steps:
(1) Carrying out a first oxidation reaction on a compound shown in a formula SM to obtain a compound shown in a formula A1;
(2) Carrying out elimination reaction on the compound shown in the formula A1 to obtain a compound shown in the formula A2;
(3) Carrying out Wittig reaction or Wittig-Horner reaction on the compound shown in the formula A2 to obtain a compound shown in a formula A3;
(4) Carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4;
(5) Carrying out a second oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5;
(6) Carrying out a first hydrolysis reaction on the compound shown in the formula A5 to obtain a compound shown in the formula A6;
(7) Carrying out hydrogenation reduction reaction on the compound shown in the formula A6 to obtain a compound shown in the formula A7;
(8) Carrying out a second hydrolysis reaction on the compound shown in the formula A7 to obtain a compound shown in the formula A8;
(9) Carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid;
the complete reaction formula of the nine-step reaction is as follows:
in this example, the compound of formula SM is a plant-derived fermentation product, which may be prepared by itself or purchased commercially. The self-preparation synthetic route is as follows:
in an alternative manner, the first oxidation reaction in step (1) uses TEMPO and 8% sodium hypochlorite as the oxidizing agent, and the mass ratio of the compound represented by formula SM to TEMPO and 8% sodium hypochlorite as the oxidizing agent is 1: (0.1-0.13): (2-2.2).
In this example, 8% sodium hypochlorite refers to sodium hypochlorite with 8% available chlorine.
Preferably, the solvent used in the step (1) is dichloromethane, and the mass volume ratio of the compound shown in the formula SM to the solvent dichloromethane is 1g: (7.5-8.5) ml.
Preferably, the temperature of the first oxidation reaction in the step (1) is room temperature, and the time of the first oxidation reaction is 2.5-4 h.
The first 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 after dropwise adding, detecting the reaction by TLC until the reaction is complete, 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 solvent used in the first oxidation reaction in the step (1) is acetone, the oxidant is jones reagent, the first oxidation reaction temperature is 0-10 ℃, and the first oxidation reaction time is 4-8 h.
Preferably, the mass to volume ratio of the compound represented by formula SM to the oxidant jones reagent is 1g: (1-1.2) ml, preferably 1:1.
Preferably, 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 first 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.
In an alternative mode, the elimination reaction in the step (2) is carried out under an acidic condition, wherein the acid adopted in the elimination reaction is concentrated sulfuric acid and glacial acetic acid, the temperature of the elimination reaction is 20-50 ℃, and the time of the elimination reaction is 2.5-4h.
Preferably, the temperature of the elimination reaction is 35 to 40 ℃.
Preferably, in the step (2), the mass ratio of the compound represented by 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.
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 2.5-4h, 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.
In another alternative, the elimination reaction uses methylene dichloride or chloroform as a solvent, and the compound shown in the formula A1 is reacted with acetic anhydride and concentrated sulfuric acid for 3-5 hours at 30-40 ℃.
Preferably, the mass volume ratio of the compound shown in the 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).
Preferably, 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.
In an alternative mode, the compound shown in the formula A2 is subjected to a wittig reaction to obtain the compound shown in the formula A3, the wittig reaction is performed, toluene or tetrahydrofuran is used as a solvent, the ethoxyformylmethylene triphenylphosphine is used as a wittig reagent, the compound shown in the formula A2 and the wittig reagent ethoxyformylmethylene triphenylphosphine are heated to a reflux state to perform the reaction, and the duration of the wittig reaction is 10-16 h.
Preferably, the mass ratio of the compound shown in the formula A2 to the wittig reagent ethoxyformyl methylene triphenylphosphine is 1: (1.8-2.4), preferably, the mass ratio of the compound shown in the formula A2 to the wittig reagent ethoxyformyl methylene triphenylphosphine is 1:2.
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 zinc chloride solution into the system, preserving heat for 12h at 25-30 ℃ for precipitation reaction, filtering the precipitate, separating filtrate, and repeating the operation once again with the zinc chloride solution. Separating the solution after filtration, collecting the organic phase, concentrating and drying under reduced pressure, filtering and drying to obtain the compound shown in the formula A3.
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%.
Preferably, the temperature of the precipitation reaction is 25-30 ℃ and the reaction time is 10-16 h.
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.
In another alternative mode, the compound shown in the formula A2 is subjected to a Wittig-Horner reaction to obtain a compound shown in the formula A3, wherein the Wittig-Horner reaction in the step (3) uses tetrahydrofuran as a solvent, uses a mixture of alkali and triethyl phosphonoacetate as a Wittig-Horner reagent, and reacts for 1-3 hours at 20-66 ℃ until the reaction is complete; wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
Preferably, the molar ratio of the compound represented by formula A2 to the base is: 1: (1.5-2.0), wherein the mass volume ratio of the compound shown in the formula A2 to the triethyl phosphonoacetate is 1g: (0.9-1.1) ml.
The Wittig-Horner reaction specifically comprises the following steps: adding one of 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 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, concentrating tetrahydrofuran under reduced pressure, water out, cooling, filtering and drying.
Preferably, the mass volume ratio of the compound shown in the formula A2 to tetrahydrofuran in the mixed solution is 1g: (9-12) ml.
In an alternative way, in the step (4), 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, wherein the ketal protection reaction time is 20-28 h.
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 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 in the ketal protection reaction and the reactant glycol is 1g: (3-4) ml, preferably 1:2g/ml.
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, the ketal protection reaction in the step (4) uses ethylene glycol as a ketal reaction reagent, triethyl orthoformate as a ketal dehydrating agent, and p-toluenesulfonic acid as a catalyst, wherein the temperature of the ketal protection reaction 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.
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.
Preferably, in the step (5), the second oxidation reaction uses acetone or acetonitrile as a solvent, uses a mixture of chromic oxide and N-hydroxyphthalimide or uses pyridinium chlorochromate and N-hydroxyphthalimide as an oxidant, and enables the compound shown in the formula A4 to react with the oxidant for 20-25 hours at 20-35 ℃.
Preferably, the temperature of the second 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.
Preferably, the oxidant is a mixture of chromium oxide and N-hydroxyphthalimide, 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): (0.7-0.76); more preferably, the compound of formula A4, chromium oxide and N-hydroxyphthalimide (NHPI) are added in a weight ratio of 1:2:0.72.
preferably, the oxidant is a mixture of pyridinium chlorochromate and N-hydroxyphthalimide, 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); more preferably, the compound of formula A4, pyridinium chlorochromate and N-hydroxyphthalimide are added in a weight ratio of 1:2:0.72.
preferably, when the solvent of the second oxidation reaction is acetone, the mass-volume ratio of the compound shown in the formula A4 to the acetone is 1g: (13-16) ml.
Preferably, when the solvent of the second oxidation reaction is acetonitrile, the mass-volume ratio of the compound shown in the formula A4 to the acetonitrile is 1g: (18-21) ml.
The second oxidation reaction specifically comprises the following steps: adding acetone/acetonitrile and water into a reactor, adding a compound shown in a formula A4, half of chromium oxide or pyridinium chlorochromate and 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 chromium oxide or pyridinium chlorochromate, keeping the temperature and stirring for 20-25 hours, detecting the reaction till the reaction is complete, adding isopropanol and quenching the reaction, concentrating the acetone, adding dioxymethane to extract chromic acid, separating liquid, washing an organic phase once with water, collecting the organic phase, concentrating the organic phase under reduced pressure, replacing methanol, cooling and filtering to obtain the compound shown in a formula A5.
Preferably, the first hydrolysis reaction comprises: and (3) taking methanol as a solvent, and 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 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.
Preferably, the first hydrolysis reaction temperature is 50 to 55 ℃.
Preferably, 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.
Preferably, the hydrogenation reduction reaction comprises: 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 and hydrogen to undergo hydrogenation reduction reaction 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.
Preferably, the volume ratio of the absolute ethyl alcohol to the pyridine is 1: (0.9-1.1).
Preferably, the solvent for the hydrogenation reduction reaction further comprises methylimidazole, and the ratio of the volume 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.
Preferably, 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 solvent of hydrogenation reduction reaction, 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.
Preferably, the second hydrolysis reaction comprises: in a specific solvent, the side chain of the compound shown in the formula A7 is subjected to a second hydrolysis reaction under alkaline conditions to generate the compound shown in the formula A8, wherein the alkali adopted in 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.
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 50-55 ℃ and the reaction time is 3h.
Preferably, the mass volume ratio of the compound shown in the formula A7 to the solvent is 1g: (5-10) ml.
Preferably, the mass ratio of the compound shown in the formula A7 to sodium hydroxide is 1: (0.19 to 0.22), or the mass ratio of the compound represented by the formula A7 to potassium hydroxide is 1: (0.26-0.30).
The alkali used in the side chain hydrolysis reaction can be a mixture of sodium hydroxide and potassium hydroxide; if solid alkali is added, water-soluble alkali is also added, and of course, sodium hydroxide solution and potassium hydride solution may be directly added.
The second hydrolysis reaction specifically comprises the following steps: mixing a specific solvent, water and alkali sodium hydroxide or potassium hydroxide, adding a compound shown in a formula A7 under stirring, heating a reaction system to 50-55 ℃ for reaction for 3-5 h, cooling to below 30 ℃ after TCL detection reaction is completed, regulating the pH value to 2-3 by using 6mol/L hydrochloric acid, concentrating methanol under reduced pressure, carrying out water precipitation, filtering, leaching with a small amount of water, and drying to obtain the compound shown in a formula A8.
Preferably, the selective reduction reaction comprises: 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 mass ratio of the compound shown in the formula A8 to the reducing agent lithium aluminum tri-tert-butoxide hydride is 1: (2.8 to 3.1), preferably 1:3.
preferably, the mass volume ratio of the compound shown in the formula A8 to the solvent tetrahydrofuran is 1g: (14-17) ml.
The selective reduction reaction specifically comprises the following steps: mixing a compound shown in a formula A8 with tetrahydrofuran as a solvent, cooling to 0-5 ℃ under nitrogen protection, slowly adding lithium aluminum hydride as a reducing agent in batches, heating to 20-25 ℃ after the addition, reacting for 8-13 h, detecting complete reaction by TCL, slowly dropwise adding 1mol/L hydrochloric acid, regulating the pH value to 2-3, concentrating the tetrahydrofuran as the solvent under reduced pressure, carrying out water separation, filtering, eluting with a small amount of water, separating a 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 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 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 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.
EXAMPLES 1-2 Synthesis of Compounds represented by formula A1
The synthetic route is shown in the following formula:
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 9α -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 allowed to stand with stirring for 6h, and TLC detection was complete. 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 shown in the following formula:
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 shown in the following formula:
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 shown in the following formula:
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 shown in the following formula:
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 shown in the following formula:
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 shown in the following formula:
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 of 0.42MPa at 35℃for 10 hours, and the reaction is 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 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 are placed in a clean and dry autoclave, 54.0g of the compound of formula A6 and 5.4g of 10% palladium on carbon are added with stirring, the reaction is carried out at 35℃under pressure of 0.42MPa with hydrogen for 10 hours, and the completion of the reaction is 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 shown in the following formula:
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 shown as the following formula:
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，CH2(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 (5)
1. A method for synthesizing cholic acid, wherein the structural formula of the cholic acid is shown as formula CA, and the method comprises the following steps:
(1) Carrying out a first oxidation reaction on a compound shown in a formula SM to obtain a compound shown in a formula A1, wherein the first oxidation reaction is carried out in a solvent dichloromethane, so that the compound shown in the formula SM reacts with an oxidant TEMPO and 8% sodium hypochlorite at room temperature, or the first oxidation reaction is carried out in a solvent acetone, so that the compound shown in the formula SM reacts with an oxidant Jones reagent at 0-10 ℃;
(2) Carrying out elimination reaction on the compound shown in the formula A1 to obtain a compound shown in the formula A2;
(3) Carrying out Wittig or Wittig-Horner reaction on the compound shown in the formula A2 to obtain a compound shown in a formula A3;
(4) Carrying out ketal protection reaction on the compound shown in the formula A3 to obtain a compound shown in the formula A4;
(5) Carrying out a second oxidation reaction on the compound shown in the formula A4 to obtain a compound shown in the formula A5, wherein the second oxidation reaction is carried out in acetone or acetonitrile as a solvent, so that the compound shown in the formula A4 and a mixture of an oxidant chromium oxide and N-hydroxyphthalimide or a mixture of an oxidant pyridinium chromate and N-hydroxyphthalimide are subjected to oxidation reaction at 20-35 ℃;
(6) Carrying out a first hydrolysis reaction on the compound shown in the formula A5 to obtain a compound shown in the formula A6, wherein the first hydrolysis reaction is carried out in a solvent methanol, and the compound shown in the formula A5 is reacted under an acidic condition at 20-65 ℃, wherein the acid adopted in the first hydrolysis reaction is hydrochloric acid or sulfuric acid;
(7) 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 is carried out in a mixture of absolute ethyl alcohol serving as a solvent and pyridine, and the compound shown in the formula A6 and hydrogen are reacted under preset conditions by taking palladium carbon with the mass content of 8-12% as a catalyst, wherein the preset conditions comprise: the hydrogenation reduction reaction pressure is 0.4-0.45 MPa, and the reaction temperature is 30-35 ℃;
(8) Carrying out a second hydrolysis reaction on the compound shown in the formula A7 to obtain a compound shown in the formula A8;
(9) Carrying out selective reduction reaction on the compound shown in the formula A8 to obtain cholic acid, wherein the selective reduction reaction is carried out in tetrahydrofuran solvent, and the compound shown in the formula A8 and lithium aluminum tri-tert-butoxide serving as a reducing agent are reacted at 20-25 ℃;
the complete reaction formula of the nine-step reaction is as follows:
。
2. The method for synthesizing cholic acid according to claim 1, wherein in the step (2), the elimination reaction is carried out by reacting the compound represented by A1 with concentrated sulfuric acid and glacial acetic acid in solvent water at 20 to 50 ℃; or the elimination reaction is to react the compound shown in the formula A1 with acetic anhydride and concentrated sulfuric acid in methylene dichloride or chloroform at the temperature of 30-40 ℃.
3. The method for synthesizing cholic acid according to claim 1, wherein in the step (3), the Wittig reaction is performed by mixing a compound represented by formula A2 with a Wittig reagent ethoxyformyl methylene triphenylphosphine in toluene or tetrahydrofuran as a solvent to obtain a reactant system, and heating the reactant system to a reflux state; or the Wittig-Horner reaction is carried out in solvent tetrahydrofuran by reacting a compound shown in a formula A2 with alkali and triethyl phosphonoacetate at 20-66 ℃, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
4. The method for synthesizing cholic acid according to claim 1, wherein in the step (4), the ketal protecting reaction is performed by mixing the compound represented by formula A3 with ketal reagent ethylene glycol and catalyst p-toluenesulfonic acid in toluene, and then heating the system to reflux state; or the ketal protection reaction is to react the compound shown in A3 with ketal reaction reagent glycol, ketal dehydrating agent triethyl orthoformate and catalyst p-toluenesulfonic acid at 35-80 ℃.
5. The method for synthesizing cholic acid according to claim 1, wherein in the step (8), the side chain of the compound represented by formula A7 is reacted at 40 to 60 ℃ in a specific solvent, wherein the specific solvent is one of methanol, ethanol, acetone, tetrahydrofuran, a mixture of dichloromethane and methanol, or a mixture of dichloromethane and ethanol, and the base used in the second hydrolysis is sodium hydroxide or potassium hydroxide.
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