CN115651049A - Cholic acid intermediate A3 and preparation method thereof - Google Patents
Cholic acid intermediate A3 and preparation method thereof Download PDFInfo
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- CN115651049A CN115651049A CN202211272193.7A CN202211272193A CN115651049A CN 115651049 A CN115651049 A CN 115651049A CN 202211272193 A CN202211272193 A CN 202211272193A CN 115651049 A CN115651049 A CN 115651049A
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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 209
- 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 206
- 239000004380 Cholic acid Substances 0.000 title claims abstract description 206
- 229960002471 cholic acid Drugs 0.000 title claims abstract description 206
- 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 206
- 235000019416 cholic acid Nutrition 0.000 title claims abstract description 206
- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 150000001875 compounds Chemical class 0.000 claims abstract description 374
- 238000006243 chemical reaction Methods 0.000 claims abstract description 155
- 239000002904 solvent Substances 0.000 claims abstract description 89
- 238000003756 stirring Methods 0.000 claims abstract description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 238000010992 reflux Methods 0.000 claims abstract description 11
- 239000000376 reactant Substances 0.000 claims abstract description 10
- MJTBOJTZBTVRNH-UHFFFAOYSA-N ethyl 2-(6-diphenylphosphanylcyclohexa-2,4-dien-1-ylidene)acetate Chemical compound CCOC(=O)C=C1C=CC=CC1P(C=1C=CC=CC=1)C1=CC=CC=C1 MJTBOJTZBTVRNH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims description 38
- 238000006460 hydrolysis reaction Methods 0.000 claims description 38
- 238000007254 oxidation reaction Methods 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 33
- 238000006722 reduction reaction Methods 0.000 claims description 33
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 28
- 238000001556 precipitation Methods 0.000 claims description 19
- 238000005984 hydrogenation reaction Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 14
- 239000011592 zinc chloride Substances 0.000 claims description 14
- 235000005074 zinc chloride Nutrition 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 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 claims description 7
- 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
- 239000008139 complexing agent Substances 0.000 claims description 4
- 229910021645 metal ion Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 230000009385 viral infection Effects 0.000 abstract description 3
- 210000001835 viscera Anatomy 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 36
- 238000001816 cooling Methods 0.000 description 33
- 238000004809 thin layer chromatography Methods 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000012065 filter cake Substances 0.000 description 24
- 239000007800 oxidant agent Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 230000001590 oxidative effect Effects 0.000 description 21
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 20
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 17
- 238000003379 elimination reaction Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 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 description 13
- 230000002194 synthesizing effect Effects 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 12
- 239000003638 chemical reducing agent Substances 0.000 description 12
- 238000002386 leaching Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 230000002378 acidificating effect Effects 0.000 description 11
- 229910000423 chromium oxide Inorganic materials 0.000 description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000001276 controlling effect Effects 0.000 description 10
- 238000004321 preservation Methods 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 238000001514 detection method Methods 0.000 description 8
- 239000005708 Sodium hypochlorite Substances 0.000 description 7
- HTBVGZAVHBZXMS-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-] HTBVGZAVHBZXMS-UHFFFAOYSA-N 0.000 description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- -1 lithium tri-tert-butoxyaluminum hydride Chemical class 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000003810 Jones reagent Substances 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 5
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 239000002253 acid Substances 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 238000007599 discharging Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 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
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 3
- 229960003964 deoxycholic acid Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000007670 refining Methods 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
- 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
- 239000003613 bile acid Substances 0.000 description 2
- 230000005587 bubbling Effects 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
- 230000006837 decompression Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002244 precipitate Substances 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
- 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
- 239000006227 byproduct Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000008845 cholagoga Substances 0.000 description 1
- 229940124571 cholagogue Drugs 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 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
- 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000024891 symptom Diseases 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
-
- 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
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention provides a cholic acid intermediate A3 and a preparation method thereof. The preparation method of the cholic acid intermediate A3 comprises the following steps: the structural formula of the cholic acid intermediate A3 is shown as a formula A3, a wittig reaction is carried out, a compound shown as a formula A2 and wittig reagent ethoxycarbonyl methylene triphenylphosphine are added into a solvent of toluene or tetrahydrofuran under a stirring state to obtain a reactant system, the reactant system is heated to a reflux state and reacts for a preset time until the reaction is complete, a reaction product containing the compound shown as the formula A3 is obtained, and after the reaction product is cooled to room temperature, the cholic acid intermediate A3 is obtained through post-treatment of the reaction product. The invention provides a chemical synthesis method with mild reaction conditions for producing cholic acid intermediate A3 and cholic acid, so as to solve the risk of virus infection caused by extraction of cholic acid from animal viscera.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a cholic acid intermediate A3 and a preparation method thereof.
Background
Cholic acid, chemical name Cholic acid, chemical formula 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, mainly Cholic Acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA) being the bile acids present in human bile.
The cholic acid can be used for biochemical research and is a medical intermediate. CN201710404532.5 discloses a method for synthesizing lithocholic acid by using cholic acid as a raw material, CN2017102663050.0 discloses a method for synthesizing ursodeoxycholic acid by using cholic acid as a raw material, CN2016107273812 discloses a method for preparing glycocholic acid polyclonal antibody by using cholic acid as a raw material, CN2021102688904 discloses a method for synthesizing deoxycholic acid by using cholic acid as a starting raw material, and the ursodeoxycholic acid, lithocholic acid and the like can be used as therapeutic drugs, and the cholic acid is an important medical intermediate.
In addition, sodium cholate is a cholagogue and can be used for treating cholecystitis, bile deficiency, intestinal dyspepsia and other symptoms.
At present, cholic acid in the market is prepared by extracting and refining internal organs of animal cattle or sheep, and the risk of virus infection inevitably exists.
Disclosure of Invention
The invention aims to provide a chemical synthesis method with mild reaction conditions for producing a cholic acid intermediate A3 and cholic acid so as to solve the risk of virus infection caused by extraction of the cholic acid from animal viscera.
In order to achieve the above object, the present invention provides a cholic acid intermediate A3, wherein the structural formula of cholic acid intermediate A3 is represented by 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 the formula A3, wittig reaction is carried out, toluene or tetrahydrofuran is used as a solvent, a compound shown as the formula A2 and Wittig reagent ethoxycarbonyl methylene triphenylphosphine are added under a stirring state to obtain a reactant system, the reactant system is heated to a reflux state for reaction for a preset time until the reaction is completed, a reaction product containing the compound shown as the formula A3 is obtained, and after the reaction product is cooled to room temperature, the cholic acid intermediate A3 is obtained by post-processing the reaction product, wherein the structural formula of the compound shown as the formula A2 is as follows:
in a specific embodiment, the preset time is 10 to 16 hours.
In a specific embodiment, the weight ratio of the compound of formula A2 to the carbethoxymethylenetriphenylphosphine is: 1: (1.8-2.4).
In a specific embodiment, the post-treatment comprises a precipitation reaction, solid-liquid separation, filtrate separation, organic layer decompression concentration to dryness, water precipitation, filtration and drying which are sequentially carried out.
In a specific embodiment, the metal ion complexing agent added in the precipitation reaction is a zinc chloride solution with the mass fraction of 35% -45%, the temperature of the precipitation reaction is 25-30 ℃, and the reaction time is 10-16 h.
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 the formula A3, and the preparation method is characterized in that Wittig-Horner reaction is carried out, tetrahydrofuran is used as a solvent, a compound shown as the formula A2 reacts with alkali and triethyl phosphonoacetate at the temperature of 20-66 ℃ for 1-3 hours to obtain a reaction product containing the compound shown as the formula A3, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, and the structural formula of the compound shown as the formula A2 is as follows:
in a specific embodiment, the molar ratio of the compound of formula A2 to the base is: 1: (1.5-2.0), wherein the mass-volume ratio of the compound shown as the formula A2 to triethyl phosphonoacetate is 1g: (0.9-1.1) ml.
The invention also provides a cholic acid intermediate A3 obtained by the preparation method.
The invention also provides a preparation method of cholic acid, the molecular formula of cholic acid is shown as formula CA, and the preparation method comprises the following steps: sequentially carrying out ketal protection reaction, oxidation reaction, first hydrolysis reaction, hydrogenation reduction reaction, second hydrolysis reaction and selective reduction reaction on a compound shown as a formula A3 to obtain cholic acid, wherein the complete reaction formula of the six-step reaction is as follows:
the beneficial effects of the invention at least comprise:
the cholic acid intermediate A3 is obtained by the compound shown in the formula A2 through a Wittig reaction or a Wittig-Horner reaction, and the cholic acid intermediate A3 can be used for efficiently preparing cholic acid. The invention also provides a chemical synthesis method of cholic acid, which can synthesize and obtain a compound cholic acid shown in a formula CA by performing ketal protection reaction, oxidation reaction, first hydrolysis reaction, hydrogenation reduction reaction, second hydrolysis reaction and selective reduction reaction on the cholic acid intermediate A3, and has the advantage of mild reaction conditions.
Detailed Description
The invention provides a cholic acid intermediate A3, which is characterized in that the structural formula of the cholic acid intermediate A3 is shown as a 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 the formula A3, a Wittig reaction is carried out, toluene or tetrahydrofuran is used as a solvent, a compound shown as the formula A2 and a Wittig reagent ethoxycarbonyl methylene triphenylphosphine are added under a stirring state to obtain a reactant system, the reactant system is heated to a reflux state and reacts for a preset time till the reaction is complete, a reaction product containing the compound shown as the formula A3 is obtained, and after the reaction product is cooled to room temperature, the reaction product is subjected to post-treatment to obtain the cholic acid intermediate A3, wherein the structural formula of the compound shown as the formula A2 is as follows:
as a further improvement of the preparation method, the preset time is 10 to 16 hours, specifically 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours and the like, preferably, the first preset time is 10 to 12h, TCL tracking is carried out until the raw materials are completely reacted.
As a further improvement of the preparation method, the weight ratio of the compound shown in the formula A2 to the Wittig reagent, namely, the carbethoxymethylene triphenylphosphine, is as follows: 1: (1.8-2.4), preferably, the weight ratio of the compound shown in the formula A2 to the Wittig reagent carbethoxymethylene triphenylphosphine is 1:2.
as a further improvement of the preparation method, the mass-to-volume ratio of the compound shown in the formula A2 to the solvent toluene is 1g: (10-15) ml; the mass-to-volume ratio of the compound shown as the formula A2 to the solvent tetrahydrofuran is 1g: (12-15) ml.
As a further improvement of the preparation method, the post-treatment comprises the steps of sequentially carrying out precipitation reaction, solid-liquid separation, filtrate liquid separation, organic layer decompression concentration to dryness, elutriation, filtration and drying.
As a further improvement of the preparation method, 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% to 45%, and preferably the mass fraction of the zinc chloride solution is 36% to 40%.
Removing a byproduct triphenylphosphine oxide by using a zinc chloride solution as a metal ion complexing agent through a precipitation reaction to obtain a purer target product.
As a further improvement of the preparation method, the temperature of the precipitation reaction is 25-30 ℃, specifically 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ and 30 ℃, and the reaction time is 10-16 h, specifically 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h and the like.
The post-treatment process specifically comprises the following steps: adding a zinc chloride solution (with the mass fraction of 35% -45%) into the reaction product, carrying out heat preservation for 12 hours at the temperature of 25-30 ℃ for precipitation reaction, filtering, carrying out liquid separation on the filtrate, repeating the operation once again with the zinc chloride solution (with the mass fraction of 35% -45%), filtering, carrying out liquid separation on the filtrate, collecting an organic phase, carrying out reduced pressure concentration on the organic phase until the organic phase is dried, carrying out water precipitation, filtering, and drying to obtain a cholic acid intermediate A3.
The wittig reaction specifically comprises the following steps: under the stirring state, adding the compound shown in the formula A2 and carbethoxymethylene triphenylphosphine into a solvent toluene or tetrahydrofuran, heating the system to a reflux state, reacting for 10-169h, detecting by TLC until the reaction is complete, and cooling to room temperature. Adding zinc chloride solution into the system, keeping the temperature at 25-30 ℃ for 12h for precipitation reaction, carrying out suction filtration, filtering the precipitate, separating the filtrate, and repeating the operation once again by using the zinc chloride solution. And separating liquid after filtration, collecting an organic phase, concentrating and drying under reduced pressure, filtering and drying to obtain the compound shown in the formula A3.
Preferably, the preparation method of cholic acid intermediate A3 further comprises: subjecting a compound represented by formula A1 to an elimination reaction to obtain a compound represented by formula A2, the synthetic route being:
in an optional mode, the elimination reaction is carried out under an acidic condition, 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 ℃.
Wherein the mass ratio of the compound shown in the formula A1 to concentrated sulfuric acid is 1: (3.5-3.8), wherein the mass-to-volume ratio of the compound shown as the formula A1 to glacial acetic acid is 1g: (1-1.2) ml.
The elimination reaction is specifically as follows: 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 the compound shown in the formula A1, controlling the temperature of a system to be 20-50 ℃ to react for 2.5-4h, and detecting by TLC until the reaction is complete. Adding the system into an ice water bath, stirring for more than 30 minutes after the addition is finished, 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, finally concentrating to be in a viscous state, filtering, and drying the filter cake to be qualified to obtain the compound shown in the formula A2.
In another alternative mode, the elimination reaction takes dichloromethane or trichloromethane as a solvent, and the compound shown as the formula A1 reacts with acetic anhydride and concentrated sulfuric acid at the temperature of 30-40 ℃ for 3-5 h.
Preferably, the mass-to-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).
In a system for eliminating reaction, the mass-to-volume ratio of the compound shown as the formula A1 to a solvent of dichloromethane or trichloromethane is 1g: (5.8-6.2) ml.
The elimination reaction is specifically as follows: adding the compound shown in the formula A1 into a solvent dichloromethane or trichloromethane under the stirring state, cooling to 0-10 ℃, dropwise adding acetic anhydride, stirring for 10-20 minutes after the addition is finished, dropwise adding concentrated sulfuric acid, heating to 30-40 ℃, keeping the temperature and stirring for 3-5h after the dropwise addition is finished, and detecting by TLC 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, finally concentrating to a viscous state, filtering, and drying a filter cake to be qualified to obtain the compound shown in the formula A2.
Preferably, the preparation method of cholic acid intermediate A3 further comprises: carrying out an oxidation reaction on a compound shown as a formula SM to obtain a compound shown as a formula A1, wherein the synthesis route is as follows:
in an alternative mode, TEMPO and 8% sodium hypochlorite are used as oxidants in the oxidation reaction, dichloromethane is used as a solvent, and the reaction is carried out at room temperature for 2.5-4h to obtain a product containing the compound shown as the formula A1.
Wherein the mass ratio of the compound shown in the formula SM to an oxidant TEMPO and an oxidant 8% sodium hypochlorite is 1: (0.1-0.13): (2-2.2).
In this example, 8% sodium hypochlorite refers to sodium hypochlorite with an available chlorine of 8%.
Wherein the mass-volume ratio of the compound shown in the formula SM to the solvent dichloromethane is 1g: (7.5-8.5) ml.
The oxidation reaction specifically comprises the following steps: dichloromethane is used as a solvent, 9 alpha-hydroxy BA (shown in formula SM) and an oxidant TEMPO are added under stirring, then the oxidant 8% sodium hypochlorite is added dropwise, the reaction is carried out for 2.5-4h after the dropwise addition is finished, TLC detection reaction is carried out till the completion, 5% sodium sulfite solution is added, and the non-oxidation property is detected 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 40 deg.C in hot water bath to evaporate dichloromethane, replacing with methanol, concentrating until viscous, cooling, filtering, and drying to obtain compound represented by formula A1.
In another alternative mode, the oxidation reaction takes acetone as a solvent and Jones reagent as an oxidant, and the reaction is carried out at the temperature of 0-10 ℃ for 4-8 h to obtain a product containing the compound shown in the formula A1.
Wherein the mass-to-volume ratio of the compound represented by the formula SM to the oxidant Jones reagent is 1g: (1-1.2) ml, preferably 1:1.
wherein the mass-volume ratio of the compound shown in the formula SM to the solvent acetone is 1g: (9-11) ml, preferably 1:10.
the oxidation reaction specifically comprises the following steps: taking acetone as a solvent, adding 9 alpha-hydroxy BA (shown in a formula SM) under stirring, cooling the system to 0-10 ℃, dropwise adding a Jones reagent at a controlled temperature, keeping the temperature and stirring for 4-8h, and detecting and reacting by TLC until the reaction is complete. Adding isopropanol to quench the reaction, slowly adding the system into ice water for water precipitation, cooling to 0-10 ℃, filtering and drying to obtain the compound shown in the formula A1.
The invention also provides a cholic acid intermediate A3 prepared by the preparation method.
A preparation method of a cholic acid intermediate A3 is characterized in that the structural formula of the cholic acid intermediate A3 is shown as a formula A3, a Wittig-Horner reaction is carried out, tetrahydrofuran is used as a solvent, a compound shown as a formula A2, alkali and triethyl phosphonoacetate are reacted at 20-66 ℃ until the reaction is complete, and a reaction product containing the compound shown as the formula A3 is obtained, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, and the structural formula of the compound shown as the formula A2 is as follows:
preferably, the reaction time of the Wittig-Horner reaction is 1-3 h, and specifically, the reaction time can be 1h, 1.5h, 2h, 2.5h, 3h and the like.
Preferably, the molar ratio of the compound represented by the formula A2 to the base is: 1: (0.35-0.5), wherein the mass-volume ratio of the compound shown as the formula A2 to triethyl phosphonoacetate is 1g: (0.9-1.1) ml.
Preferably, the mass-to-volume ratio of the compound represented by the formula A2 to tetrahydrofuran in the mixed solution is 1g: (9-12) ml.
The Wittig-Horner reaction specifically comprises the following steps: adding sodium hydride/potassium tert-butoxide/sodium methoxide/potassium methoxide/sodium ethoxide/potassium ethoxide into a solvent tetrahydrofuran under stirring, dropwise adding triethyl phosphonoacetate at room temperature under the protection of nitrogen after bubbles emerge, stirring for 20-30 minutes, dropwise adding a mixed solution of a compound shown in a formula A2 and tetrahydrofuran, controlling the temperature to be 20-66 ℃ after dropwise adding is finished, reacting for 1-3 hours, tracking by TCL until the reaction is complete to obtain a reaction product, and regulating the pH value, concentrating the tetrahydrofuran under reduced pressure, eluting, cooling, filtering and drying to obtain the compound shown in the formula A3.
Preferably, the preparation method of cholic acid intermediate A3 further comprises subjecting the compound represented by formula A1 to an elimination reaction to obtain a compound represented by formula A2, and more preferably further comprises subjecting the compound represented by formula SM to an oxidation reaction to obtain a compound represented by formula A1.
The invention also provides a cholic acid intermediate A3 prepared by the preparation method.
A preparation method of cholic acid, wherein the molecular formula of the cholic acid is shown as a formula CA, and the preparation method comprises the following steps: sequentially carrying out ketal protection reaction, oxidation reaction, first hydrolysis reaction, hydrogenation reduction reaction, second hydrolysis reaction and selective reduction reaction on a compound shown as a formula A3 to obtain cholic acid, wherein the complete reaction formula of the six-step reaction is as follows:
in an optional manner, after the ketal protection reaction uses toluene as a solvent, ethylene glycol as a ketal reaction reagent, and p-toluenesulfonic acid as a catalyst, the compound represented by formula A3 is mixed with toluene, ethylene glycol, and p-toluenesulfonic acid, the system is heated to a reflux state for reaction until the reaction is complete, so as to obtain a product including the compound represented by formula A4.
Preferably, the time of the ketal protection reaction is 20 to 28 hours.
Preferably, the weight ratio of the compound represented by formula A3 to the p-toluenesulfonic acid catalyst in the ketal protection reaction is 1: (0.098 to 0.018), more preferably 0.015.
Preferably, the mass volume of the compound represented by 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 as the formula A3 and the reaction reagent ethylene glycol in the ketal protection reaction is 1g: (3-4) ml, preferably 1:2g/ml.
Preferably, the product containing the compound shown in the formula A4 is cooled to room temperature, triethylamine is used for adjusting the pH value to 7-8, water is separated out, the temperature is continuously reduced to 0-10 ℃, a filter cake is obtained through filtering, the filter cake is recrystallized by methanol, cooled to room temperature, filtered and dried, and the compound shown in the formula A4 is obtained.
The ketal protection reaction is specifically as follows: toluene, ethylene glycol, toluenesulfonic acid (PTS) and a compound shown in a formula A3 are mixed, the system is heated to a reflux state for reaction for 20-28h, and TLC detection reaction is carried out until the reaction is complete. Cooling to room temperature, adding a small amount of triethylamine to adjust the pH value 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 the compound shown in the formula A4.
In another optional mode, the ketal protection reaction takes ethylene glycol as a ketal reaction reagent, takes triethyl orthoformate as a ketal dehydrating agent, and takes p-toluenesulfonic acid as a catalyst, and 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 to 45 ℃.
Preferably, the mass ratio of the compound represented by formula A3 to the catalyst p-toluenesulfonic acid in the ketal protection reaction is 1: (0.098 to 0.018), and more preferably 0.015.
Preferably, the mass-to-volume ratio of the compound represented by the formula A3 to ethylene glycol and triethyl orthoformate in the ketal protection reaction is 1g: (6-8) ml: (1-2) ml.
The ketal protection reaction is specifically as follows: mixing ketal reaction reagent ethylene glycol, ketal dehydrating agent triethyl orthoformate and catalyst p-toluenesulfonic acid, adding the compound shown in the formula A3 under the stirring state, heating the system to 35-80 ℃, reacting for 5-8h, detecting by TCL until the reaction is complete, cooling to room temperature, adding triethylamine to adjust the pH value to 7-8, then carrying out elutriation, continuously cooling to 0-10 ℃, filtering to obtain a filter cake, recrystallizing the filter cake by methanol, cooling to room temperature, filtering, and drying to obtain the compound shown in the formula A4.
Preferably, the oxidation reaction comprises: and (2) carrying out an oxidation reaction on the compound shown as the formula A4 obtained by the ketal protection reaction, a first oxidant and a second oxidant at the temperature of 20-35 ℃ by using acetone or acetonitrile as a solvent, chromium oxide or pyridinium chlorochromate as the first oxidant and N-hydroxyphthalimide as the second oxidant to obtain a product containing the compound shown as the formula A5.
Preferably, the oxidation reaction time is 20 to 25 hours.
Preferably, the temperature of the oxidation reaction is 20 to 25 ℃.
When the temperature is higher than the temperature of the oxidation reaction, hydrolysis of the 3-position occurs, and the target compound represented by formula A5 cannot be obtained.
Wherein the first oxidant is chromium oxide, and the weight ratio of the compound shown in the formula A4 to the chromium oxide to the N-hydroxyphthalimide is 1: (1.9-2.2): (0.7-0.76), wherein the mass ratio of the first-time added chromium oxide to the second-time added chromium oxide is 1:1; preferably, the compound shown in the formula A4, the chromium oxide and the N-hydroxyphthalimide (NHPI) are added in a weight ratio of 1:2:0.72.
wherein the first oxidant is pyridinium chlorochromate, and the weight ratio of the compound shown in the formula A4 to the chromium oxide to the N-hydroxyphthalimide is 1: (2.3-2.6): (0.7-0.76), wherein the mass ratio of the pyridinium chlorochromate added for the first time to the pyridinium chlorochromate added for the second time is 1:1; preferably, the compound shown in the formula A4, pyridinium chlorochromate and N-hydroxyphthalimide are added in a weight ratio of 1:2:0.72.
wherein, when the solvent of the oxidation reaction is acetone, the mass-to-volume ratio of the compound represented by the formula A4 to the acetone is preferably 1g: (13-16) ml.
Wherein, when the solvent of the oxidation reaction is acetonitrile, the mass volume ratio of the compound represented by the formula A4 to the acetonitrile is preferably 1g: (18-21) ml.
The oxidation reaction specifically comprises the following steps: adding acetone/acetonitrile and water into a reactor, adding a compound shown as a formula A4 and half of N-hydroxyphthalimide (NHPI) serving as a first oxidant and a second oxidant under stirring, controlling the temperature to be 20-35 ℃, stirring for 3 hours under heat preservation, then adding the other half of the first oxidant, stirring for 20-25hours under heat preservation, detecting and reacting to be complete by TCL, then adding isopropanol to carry out quenching reaction, concentrating and drying the acetone, adding methylene dioxide to extract chromic acid, separating liquid, washing an organic phase once by using water, then collecting the organic phase, concentrating the organic phase under reduced pressure, replacing by methanol, cooling, and filtering to obtain a compound shown as a formula A5.
Preferably, the first hydrolysis reaction comprises: and (2) taking methanol as a solvent, and carrying out a first hydrolysis reaction on the compound shown in the formula A5 prepared by the oxidation reaction under an acidic condition to generate a compound shown in the formula A6, wherein the acid adopted by the first hydrolysis reaction is hydrochloric acid or sulfuric acid, the temperature of the first hydrolysis reaction is 20-65 ℃, and the reaction time is 3-5 h.
Preferably, the first hydrolysis reaction temperature is 50 to 55 ℃.
Wherein the mass-to-volume ratio of the compound shown as the formula A5 to hydrochloric acid is 1g: (0.45-0.6) ml.
The first hydrolysis reaction specifically comprises: adding methanol, water and acid into a reactor, adding the compound shown as the formula A5 under stirring, heating the system to 20-65 ℃, reacting for 3-5h, detecting by TCL until the reaction is complete, cooling the system to below 30 ℃, adjusting the pH to 6-7 by using a saturated sodium bicarbonate solution, filtering, and drying to obtain the compound shown as the formula A6.
Preferably, the hydrogenation reduction reaction comprises: and taking a mixture of absolute ethyl alcohol and pyridine as a solvent, taking palladium-carbon with the palladium mass content of 8-12% as a catalyst, and carrying out hydrogenation reduction reaction on the compound shown as the formula A6 and hydrogen, which are prepared by the first hydrolysis reaction, to generate a compound shown as a formula A7, wherein the hydrogenation reduction reaction pressure is 0.4-0.45 MPa, the reaction temperature is 30-35 ℃, and the reaction time is 8-13 h.
Wherein the volume ratio of the absolute ethyl alcohol to the pyridine is 1: (0.9-1.1).
Preferably, the solvent for the hydrogenation reduction reaction further comprises methylimidazole, and the volume ratio of the anhydrous ethanol to the mixture of pyridine and methylimidazole is 1: (0.9-1.1), or the solvent of the hydrogenation reduction reaction also comprises DMAP, and the volume ratio of the absolute ethyl alcohol to the pyridine is 1: (0.9-1.1), wherein the mass ratio product ratio of the DMAP to the absolute ethyl alcohol is 1g: (48-53) ml, wherein the mass-to-volume ratio of the compound shown as the formula A6 to the solvent is 1g: (9.5-10.5) ml.
Wherein the weight ratio of the compound shown as the formula A6 to the palladium carbon serving as the catalyst is 1: (0.09-0.12).
The hydrogenation reduction reaction specifically comprises the following steps: mixing solvents for hydrogenation reduction reaction, adding a compound shown as a formula A6 and a catalyst palladium carbon under stirring, pressurizing to 0.4-0.45 MPa at 30-35 ℃ by using hydrogen, reacting for 8-13h, and detecting by TLC until the reaction is complete; then filtering to remove palladium carbon, then decompressing and concentrating the solvent, replacing with water, elutriating, filtering, leaching with a small amount of water, and drying a filter cake to be qualified to obtain the compound shown in the formula A7.
Preferably, the second hydrolysis reaction comprises: and in a specific solvent, carrying out a second hydrolysis reaction on the side chain of the compound shown in the formula A7 prepared by the hydrogenation reduction reaction under an alkaline condition to generate a 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.
Wherein the specific solvent is one of methanol, ethanol, acetone and tetrahydrofuran or a mixture of dichloromethane and methanol or a mixture of dichloromethane and ethanol.
Preferably, the second hydrolysis reaction temperature is 50 to 55 ℃.
Preferably, the weight ratio of the compound represented by the formula A7 to sodium hydroxide is 1: (0.19 to 0.22), wherein the weight ratio of the compound shown as the formula A7 to the potassium hydroxide is 1: (0.26-0.30).
Preferably, the mass-to-volume ratio of the compound represented by the formula A7 to the specific solvent is 1g: (5-10) ml.
The second hydrolysis reaction is specifically as follows: mixing a specific solvent, water and alkali, adding the compound shown as the formula A7 under a stirring state, heating a reaction system to 50-55 ℃ for reaction for 3-5h, detecting by TCL (thermal conductive liquid chromatography), cooling to below 30 ℃, adjusting the pH value to 2-3 by using 6mol/L hydrochloric acid, decompressing, concentrating, drying methanol, performing water precipitation, filtering, rinsing with water, and drying to obtain the compound shown as the formula A8.
Preferably, the selective reduction reaction comprises: tetrahydrofuran is used as a solvent, and a compound shown as a formula A8 and a reducing agent lithium aluminum tri-tert-butoxy hydride are subjected to selective reduction reaction to generate cholic acid, wherein the reaction temperature of the selective reduction reaction is 20-25 ℃, and the reaction time is 8-13 h.
Preferably, the weight ratio of the compound represented by the formula A8 to the reducing agent lithium tri-tert-butoxyaluminum hydride is 1: (2.8-3.1), preferably the mass ratio of the cholic acid intermediate A8 to the reducing agent lithium aluminum tri-tert-butoxyhydride is 1:3.
preferably, the mass-to-volume ratio of the cholic acid intermediate A8 to the solvent tetrahydrofuran is 1g: (14-17) ml.
The selective reduction reaction specifically comprises the following steps: mixing the mixture shown in the formula A8 with a solvent tetrahydrofuran, cooling to 0-5 ℃ under the protection of nitrogen, slowly adding a reducing agent lithium aluminum tri-tert-butoxy hydride in batches, heating to 20-25 ℃ after adding, reacting for 8-13h, detecting by TCL until the reaction is complete, slowly dropwise adding 1mol/L hydrochloric acid, adjusting the pH value to 2-3, decompressing and concentrating the dry solvent tetrahydrofuran, elutriating, filtering, leaching with a small amount of water, dissolving a filter cake with ethyl acetate, separating the liquid, recrystallizing and refining to obtain cholic acid.
The compound 9 α -hydroxy BA represented by formula SM, which is a raw material for synthesizing cholic acid, is a product of the prior art, and can be obtained by self-manufacture or commercial purchase. Specifically, the supplier for commercial procurement is Shenzhen Zhenzhen Shenqiang Biotechnology Limited, and the self-made synthetic route is as follows:
the invention also provides a cholic acid intermediate A8, wherein the structural formula of the cholic acid intermediate A8 is shown as 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 the formula A8, and the preparation method comprises the following steps: in a specific solvent, a compound shown as a formula A7 is subjected to side chain hydrolysis reaction under an alkaline condition, the temperature is reduced to room temperature after the reaction is finished, and a cholic acid intermediate A8 is obtained after post-treatment, 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 the method for preparing cholic acid intermediate A8, preferably, the compound represented by formula A6 is subjected to a hydrolysis reaction under acidic conditions to obtain the compound represented by formula A7, more preferably, the compound represented by formula A5 is subjected to a hydrolysis reaction under acidic conditions to obtain the compound represented by formula A6, more preferably, the compound represented by formula A4 is subjected to an oxidation reaction to obtain the compound represented by formula A5, more preferably, the compound represented by formula A3 is subjected to a ketal protection reaction to obtain the compound represented by formula A4, more preferably, the compound represented by formula A2 is subjected to a Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, more preferably, the compound represented by formula A1 is subjected to an elimination reaction to obtain the compound represented by formula A2, and more preferably, the compound represented by formula SM is subjected to an oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A8, which is prepared by 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 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 a selective reduction reaction with a reducing agent lithium tri-tert-butoxyaluminum hydride 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 a 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 the formula A7, and the preparation method comprises the following steps: absolute ethyl alcohol and pyridine are used as solvents, a compound shown as a formula A6 and palladium carbon serving as a catalyst are added under the stirring state, hydrogen is used for pressurizing to 0.4-0.45 Mpa at the temperature of 30-35 ℃ to carry out reaction, a reaction product is obtained after the reaction is finished, and a cholic acid intermediate A7 is obtained after the reaction product is subjected to aftertreatment.
In the method for preparing cholic acid intermediate A7, preferably, the compound represented by formula A5 is subjected to a hydrolysis reaction under acidic conditions to obtain the compound represented by formula A6, more preferably, the compound represented by formula A4 is subjected to an oxidation reaction to obtain the compound represented by formula A5, more preferably, the compound represented by formula A3 is subjected to a ketal protection reaction to obtain the compound represented by formula A4, more preferably, the compound represented by formula A2 is subjected to a Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, more preferably, the compound represented by formula A1 is subjected to an elimination reaction to obtain the compound represented by formula A2, and more preferably, the compound represented by formula SM is subjected to an oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A7, which is prepared by the preparation method of the cholic acid intermediate A7.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a compound shown as formula A8 by adopting the cholic acid intermediate A7, and then preparing the cholic acid by using the compound shown as formula A8; preferably, the compound represented by formula A7 is hydrolyzed in the presence of a base in a solvent to obtain a compound represented by formula A8, and the compound represented by formula A8 is selectively reduced with a reducing agent lithium aluminum tri-tert-butoxyhydride in the presence of a 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 the 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 the formula A6, and the preparation method comprises the following steps: and (2) taking methanol as a solvent, carrying out hydrolysis reaction on the compound shown as the formula A5 under an acidic condition at 20-65 ℃, obtaining a reaction product after the reaction is finished, and carrying out post-treatment on the reaction product to obtain a cholic acid intermediate A6.
In the method for preparing cholic acid intermediate A6, preferably, the method comprises subjecting the compound represented by formula A4 to oxidation reaction to obtain the compound represented by formula A5, more preferably, the method further comprises subjecting the compound represented by formula A3 to ketal protection reaction to obtain the compound represented by formula A4, more preferably, the method further comprises subjecting the compound represented by formula A2 to Wittig or Wittig-Horner reaction to obtain the compound represented by formula A3, more preferably, the method further comprises subjecting the compound represented by formula A1 to elimination reaction to obtain the compound represented by formula A2, and more preferably, the method further comprises subjecting the compound represented by formula SM to oxidation reaction to obtain the compound represented by formula A1.
The invention also provides a cholic acid intermediate A6, which is prepared by the preparation method of the cholic acid intermediate A6.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a compound shown as formula A7 by adopting the cholic acid intermediate A6, preparing a compound shown as formula A8 by using the compound shown as formula A7, and preparing the cholic acid by using the compound shown as formula A8; preferably, the compound represented by formula A6 is subjected to a hydrogenation reduction reaction in a solvent under the catalysis of palladium on carbon as a catalyst to obtain a compound represented by formula A7, the compound represented by formula A7 is subjected to a hydrolysis reaction in a solvent in the presence of a base to obtain a compound represented by formula A8, and the compound represented by formula A8 is subjected to a selective reduction reaction with lithium tri-tert-butoxyaluminum hydride as a reducing agent in the presence of a 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 as 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 the formula A5, and the preparation method comprises the following steps: adding a compound shown as a formula A4, a first oxidant and a second oxidant into acetone or acetonitrile serving as a solvent under a stirring state, controlling the temperature to be 20-25 ℃, keeping the temperature and stirring for a first preset time, then adding the first oxidant, keeping the temperature and stirring for a second preset time until the reaction is complete, then adding isopropanol to quench the reaction to obtain a reaction solution, and carrying out aftertreatment on the reaction solution to obtain a cholic acid intermediate A5, wherein the first oxidant is chromic oxide or pyridinium chlorochromate, and the second oxidant is N-hydroxyphthalimide.
In the preparation method of cholic acid intermediate A5, the ketal protection reaction of the compound represented by formula A3 to obtain the compound represented by formula A4 is preferably performed, the Wittig or Wittig-Horner reaction of the compound represented by formula A2 to obtain the compound represented by formula A3 is more preferably performed, the elimination reaction of the compound represented by formula A1 to obtain the compound represented by formula A2 is more preferably performed, and the oxidation reaction of the compound represented by formula SM to obtain the compound represented by formula A1 is more preferably performed.
The invention also provides a cholic acid intermediate A5, which is prepared by the preparation method of the cholic acid intermediate A5.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a compound shown as formula A6 from the cholic acid intermediate A5, preparing a compound shown as formula A7 from the compound shown as formula A6, preparing a compound shown as formula A8 from the compound shown as formula A7, and preparing the cholic acid from the compound shown as formula A8; preferably, the compound represented by the formula A5 is subjected to a hydrolysis reaction under an acidic condition in a solvent to obtain a compound represented by the formula A6, the compound represented by the formula A6 is subjected to a hydrogenation reduction reaction under a catalyst of palladium on carbon in a solvent to obtain a compound represented by the formula A7, the compound represented by the formula A7 is subjected to a hydrolysis reaction in a solvent in the presence of a base to obtain a compound represented by the formula A8, and the compound represented by the formula A8 is subjected to a selective reduction reaction with a reducing agent lithium aluminum tri-tert-butoxyhydride in the presence of a 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 the 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 the formula A4, and the preparation method comprises the following steps: mixing a compound shown as a formula A3 with toluene, ethylene glycol and p-toluenesulfonic acid by taking toluene as a solvent, ethylene glycol as a ketal reaction reagent and p-toluenesulfonic acid as a catalyst, heating the system to a reflux state for reaction to obtain a reaction product after the reaction is finished, and carrying out post-treatment on the reaction product to obtain a cholic acid intermediate A4; or using ethylene glycol as a ketal reaction reagent, using triethyl orthoformate as a ketal dehydrating agent, and using p-toluenesulfonic acid as a catalyst, so that the compound shown in A3 reacts at 35-80 ℃, obtaining a reaction product after the reaction is finished, and obtaining a cholic acid intermediate A4 after the reaction product is subjected to post-treatment.
In the preparation method of the cholic acid intermediate A4, the preparation method preferably comprises subjecting the compound represented by the formula A2 to Wittig or Wittig-Horner reaction to obtain the compound represented by the formula A3, more preferably further comprises subjecting the compound represented by the formula A1 to elimination reaction to obtain the compound represented by the formula A2, and more preferably further comprises subjecting the compound represented by the formula SM to oxidation reaction to obtain the compound represented by the formula A1.
The invention also provides a cholic acid intermediate A4, which is prepared by the preparation method of the cholic acid intermediate A4.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing the compound shown as formula A5 from the cholic acid intermediate A4, preparing the compound shown as formula A6 from the compound shown as formula A5, preparing the compound shown as formula A7 from the compound shown as formula A6, preparing the compound shown as formula A8 from the compound shown as formula A7, and preparing the cholic acid from the compound shown as formula A8; preferably, the cholic acid is obtained by subjecting a compound represented by the formula A4 to an oxidation reaction in a solvent to obtain a compound represented by the formula A5, subjecting a compound represented by the formula A5 to a hydrolysis reaction under acidic conditions in a solvent to obtain a compound represented by the formula A6, subjecting a compound represented by the formula A6 to a hydrogenation reduction reaction under the catalysis of palladium on carbon as a catalyst in a solvent to obtain a compound represented by the formula A7, subjecting a compound represented by the formula A7 to a hydrolysis reaction in the presence of a base in a solvent to obtain a compound represented by the formula A8, and subjecting a compound represented by the formula A8 to a selective reduction reaction with a reducing agent lithium tri-tert-butoxyaluminum hydride in the presence of a solvent.
The invention also provides a cholic acid intermediate A3, wherein the structural formula of the cholic acid intermediate A3 is shown as 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 the formula A3, and the preparation method comprises the following steps: carrying out Wittig reaction, taking methylbenzene or tetrahydrofuran as a solvent, adding a compound shown as a formula A2 and a Wittig reagent carbethoxymethylene triphenylphosphine under a stirring state to obtain a reactant system, heating the reactant system to a reflux state, reacting for a preset time until the reaction is complete to obtain a reaction product containing the compound shown as the formula A3, cooling to room temperature, and carrying out post-treatment on the reaction product to obtain a cholic acid intermediate A3; or carrying out Wittig-Horner reaction, taking tetrahydrofuran as a solvent, and reacting the compound shown in the formula A2 with alkali and triethyl phosphonoacetate at the temperature of 20-66 ℃ until the reaction is complete to obtain a reaction product containing the 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 to further include subjecting the compound represented by formula A1 to an elimination reaction to obtain a compound represented by formula A2, and it is more preferable to further include subjecting the compound represented by formula SM to an oxidation reaction to obtain a compound represented by formula A1.
The invention also provides a cholic acid intermediate A3, which is prepared by the preparation method of the cholic acid intermediate A3.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a compound shown as formula A4 by adopting the cholic acid intermediate A3, preparing a compound shown as formula A5 by using the compound shown as formula A4, preparing a compound shown as formula A6 by using the compound shown as formula A5, preparing a compound shown as formula A7 by using the compound shown as formula A6, preparing a compound shown as formula A8 by using the compound shown as formula A7, and preparing the cholic acid by using the compound shown as formula A8; preferably, in a solvent, a compound represented by A3 is subjected to a ketal protection reaction to obtain a compound represented by a formula A4, in the solvent, a compound represented by A4 is subjected to an oxidation reaction to obtain a compound represented by a formula A5, in the solvent, a compound represented by a formula A5 is subjected to a hydrolysis reaction under an acidic condition to obtain a compound represented by a formula A6, in the solvent, the compound represented by a formula A6 is subjected to a hydrogenation reduction reaction under the catalysis of palladium carbon as a catalyst to obtain a compound represented by a formula A7, in the solvent, the compound represented by a formula A7 is subjected to a hydrolysis reaction in the presence of a base to obtain a compound represented by a formula A8, and in the presence of the solvent, the compound represented by a formula A8 is subjected to a selective reduction reaction with lithium tri-tert-butoxyaluminum hydride as a reducing agent 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 as 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 the formula A2, and the preparation method comprises the following steps: using water as a solvent, enabling a compound shown as A1 to react with concentrated sulfuric acid and glacial acetic acid at the temperature of 20-50 ℃ until the reaction is complete to obtain a reaction product including a compound shown as a formula A2, and carrying out aftertreatment on the reaction product to obtain a cholic acid intermediate A2; or using dichloromethane or trichloromethane as a solvent, and reacting the compound shown in the formula A1 with acetic anhydride and concentrated sulfuric acid at 30-40 ℃ for 3-5h until the reaction is complete to obtain a reaction product containing the compound shown in the formula A2.
In the method for producing cholic acid intermediate A2, it is preferable to subject 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 A2, which is prepared by the preparation method of the cholic acid intermediate A2.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a compound shown as formula A3 from the cholic acid intermediate A2, preparing a compound shown as formula A4 from the compound shown as formula A3, preparing a compound shown as formula A5 from the compound shown as formula A4, preparing a compound shown as formula A6 from the compound shown as formula A5, preparing a compound shown as formula A7 from the compound shown as formula A6, preparing a compound shown as formula A8 from the compound shown as formula A7, and preparing the cholic acid from the compound shown as formula A8; preferably, in a solvent, a compound represented by A2 is subjected to Wittig or Wittig-Horner reaction to obtain a compound represented by a formula A3, then in the solvent, a compound represented by A3 is subjected to ketal protection reaction to obtain a compound represented by a formula A4, then in the solvent, a compound represented by A4 is subjected to oxidation reaction to obtain a compound represented by A5, then in the solvent, a compound represented by A5 is subjected to hydrolysis reaction under acidic condition to obtain a compound represented by A6, then in the solvent, the compound represented by A6 is subjected to hydrogenation reduction reaction under the catalysis of palladium carbon as a catalyst to obtain a compound represented by A7, then in the solvent, the compound represented by the formula A7 is subjected to hydrolysis reaction under the condition of alkali to obtain a compound represented by A8, and then in the presence of the solvent, the compound represented by the formula A8 is subjected to selective reduction reaction with lithium aluminum tri-tert-butoxyhydride as a reducing agent 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 as 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 the formula A1, and the preparation method comprises the following steps: performing an oxidation reaction on the compound shown in the formula SM at room temperature by taking dichloromethane as a solvent and TEMPO and 8% sodium hypochlorite until the reaction is complete to obtain a product containing the compound shown in the formula A1; or, using acetone as a solvent and Jones reagent as an oxidant, and carrying out an oxidation reaction on the compound shown in the formula SM at 0-10 ℃ until the reaction is complete to obtain a product containing the compound shown in the formula A1.
The invention also provides a cholic acid intermediate A1, which is prepared by the preparation method of the cholic acid intermediate A1.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a compound shown as formula A2 by using the cholic acid intermediate A1, preparing a compound shown as formula A3 by using the compound shown as formula A2, preparing a compound shown as formula A4 by using the compound shown as formula A3, preparing a compound shown as formula A5 by using the compound shown as formula A4, preparing a compound shown as formula A6 by using the compound shown as formula A5, preparing a compound shown as formula A7 by using the compound shown as formula A6, preparing a compound shown as formula A8 by using the compound shown as formula A7, and preparing the cholic acid by using the compound shown as formula A8; preferably, the cholic acid is obtained by subjecting a compound represented by formula A1 to elimination reaction in a solvent to obtain a compound represented by formula A2, subjecting a compound represented by formula A2 to Wittig or Wittig-Horner reaction in a solvent to obtain a compound represented by formula A3, subjecting a compound represented by formula A3 to ketal protection reaction in a solvent to obtain a compound represented by formula A4, subjecting a compound represented by formula A4 to oxidation reaction in a solvent to obtain a compound represented by formula A5, subjecting a compound represented by formula A5 to hydrolysis reaction under acidic conditions in a solvent to obtain a compound represented by formula A6, subjecting a compound represented by formula A6 to hydrogenation reduction reaction under the catalysis of palladium carbon as a catalyst in a solvent to obtain a compound represented by formula A7, subjecting a compound represented by formula A7 to hydrolysis reaction under the presence of a base in a solvent to obtain a compound represented by formula A8, and subjecting a compound represented by formula A8 to selective reduction reaction with a reducing agent lithium tri-tert-butoxyaluminum hydride in the presence of a solvent.
The invention also provides a method for synthesizing cholic acid, wherein the molecular formula of the cholic acid is shown as formula CA, the synthetic route comprises the steps of preparing a cholic acid intermediate A1 by using the compound shown as formula SM through an oxidation reaction, preparing the compound shown as formula A2 by using the compound shown as formula A1, preparing the compound shown as formula A3 by using the compound shown as formula A2, preparing the compound shown as formula A4 by using the compound shown as formula A3, preparing the compound shown as formula A5 by using the compound shown as formula A4, preparing the compound shown as formula A6 by using the compound shown as formula A5, preparing the compound shown as formula A7 by using the compound shown as formula A6, preparing the compound shown as formula A8 by using the compound shown as formula A7, and preparing the cholic acid by using the compound shown as formula A8.
EXAMPLES 1 to 2 Synthesis of Compound represented by formula A1
The synthetic route is shown as the following chart:
example 1
800.0ml of methylene chloride was added to a clean and dry reaction flask, 100.0g of 9 α -hydroxy BA (formula SM) was added with stirring, 11.0g of TEMPO was added at room temperature, then 200.0g of 8% sodium hypochlorite was added dropwise, after completion of the dropwise addition, the reaction was carried out for 2.5 hours, TLC detection was carried out until completion, 5% sodium sulfite solution was added, and no oxidation was detected with a potassium iodide starch test paper. The system was stirred for about 20 minutes, left to stand for about 30 minutes, separated, and the organic phase was collected. Adding 200.0ml of 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 40 deg.C in hot water bath, replacing with methanol, and concentrating until it is viscous. The temperature was reduced, filtered and dried to obtain 95.5g of the compound represented by the formula A1.
Example 2
Adding 1000.0ml of acetone into a clean and dry reaction bottle, adding 100.0g of 9 alpha-hydroxy BA (shown in formula SM) while stirring, cooling the system to 8 ℃, dropwise adding 100.0ml of Jones reagent while controlling the temperature, keeping the temperature and stirring for 6h, and detecting the reaction by TLC until the reaction is complete. Adding 100.0ml of isopropanol to quench the reaction, slowly adding the system into 5000.0ml of ice water for water precipitation, cooling to 6 ℃, filtering and drying to obtain 95.1g of the compound shown in the 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 to 4 Synthesis of Compound represented by the formula A2
The synthetic route is shown as the following chart:
example 3
Adding 48.0ml of water into a clean and dry reaction bottle, cooling to 8 ℃ in an ice water bath, controlling the temperature T to be less than or equal to 40 ℃ under stirring, dropwise adding 351.0g of concentrated sulfuric acid, adding 96.0ml of glacial acetic acid and 95.0g of a compound shown as a formula A1, controlling the temperature of the system to be 37 ℃ for reacting for 2.5h, and detecting by TLC until the reaction is complete. Adding the system into 1500.0ml of ice-water bath, stirring for more than 30 minutes after the addition is finished, filtering, leaching with water to be neutral, dissolving a filter cake with 400.0ml of dichloromethane, separating liquid, collecting an organic layer, concentrating under reduced pressure, replacing with methanol, finally concentrating to be in a viscous state, filtering, and drying the filter cake to be qualified to obtain 87.0g of the compound shown as the formula A2.
Example 4
Adding 570ml of dichloromethane into a clean and dry reaction bottle, adding 95.0g of a compound shown as a formula A1 while stirring, cooling to 6 ℃, dropwise adding 95.0ml of acetic anhydride, stirring for 15 minutes after the addition is finished, dropwise adding 38.0ml of concentrated sulfuric acid, heating to 35 ℃ after the dropwise addition is finished, keeping the temperature and stirring for 4 hours, and detecting by TLC until the reaction is completed. And adding 95.0ml of water into the system for quenching, separating, collecting an organic phase, concentrating under reduced pressure, performing methanol replacement, finally concentrating to be in a viscous state, filtering, and drying a filter cake to be qualified to obtain 86.7g of the compound shown as the 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 Compound represented by formula A3
The synthetic route is shown as the following chart:
example 5
1050.0ml of toluene is added into a clean and dry reaction bottle, 85.0g of the compound shown as the formula A2 and 173.0g of carbethoxymethylenetriphenylphosphine are added under stirring, the system is heated to a reflux state for reaction for 12h, TLC detection is carried out until the reaction is complete, and the temperature is reduced to room temperature. Adding zinc chloride solution (355.0 ml water +210.0g zinc chloride), keeping the temperature at 28 ℃ for 12h for precipitation reaction, filtering the precipitate, separating the filtrate, and repeating the operation once again with the zinc chloride solution (142.0 ml water +85.0g zinc chloride). After filtration, the mixture was separated, and the organic phase was collected, concentrated to dryness under reduced pressure, filtered, and dried to obtain 94.3g of the compound represented by formula A3.
Example 6
Adding 170.0ml of tetrahydrofuran into a clean and dry reaction bottle, adding 18.0g of sodium hydride while stirring, bubbling out, adding 85.0ml of triethyl phosphonoacetate dropwise at room temperature under the protection of nitrogen, stirring for 25 minutes, adding 85.0g of a compound shown in the formula A2 and 850.0ml of tetrahydrofuran mixed solution dropwise, controlling the temperature to react for 2 hours after the dropwise adding is finished, detecting the reaction by TLC (thin layer chromatography), adjusting the pH to be =6.5 by using 6N hydrochloric acid at room temperature, decompressing and concentrating the tetrahydrofuran, adding 200.0ml of water for elutriation, cooling, filtering and drying to obtain 95.0g of the compound shown in the formula A3.
Example 7
Adding 170.0ml of tetrahydrofuran into a clean and dry reaction bottle, adding 18.0g of sodium hydride while stirring, bubbling out, adding 85.0ml of triethyl phosphonoacetate dropwise at room temperature under the protection of nitrogen, stirring for 25 minutes, adding 85.0g of a compound shown in the formula A2 and 850.0ml of tetrahydrofuran mixed solution dropwise, controlling the temperature to react for 2 hours after the dropwise adding is finished, detecting the reaction by TLC (thin layer chromatography), adjusting the pH to be =6.5 by using 6N hydrochloric acid at room temperature, decompressing and concentrating the tetrahydrofuran, adding 200.0ml of water for elutriation, cooling, filtering and drying to obtain 95.0g of the compound shown in the formula A3.
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 to 9 Synthesis of Compound represented by the formula A4
The synthetic route is shown as the following chart:
example 8
Adding 640.0ml of ethylene glycol, 143.0ml of triethyl orthoformate and 1.4g of p-toluenesulfonic acid into a clean and dry reaction bottle, adding 93.0g of cholic acid intermediate A3 while stirring, heating the system to 45 ℃, reacting for 7h, detecting by TLC until the reaction is complete, cooling to room temperature, adding triethylamine, and adjusting the pH to 7.2. Adding 3500.0ml of water into the system, carrying out water precipitation, cooling and filtering. The filter cake was recrystallized from methanol, cooled, filtered and dried to yield 84.6g of the compound represented by formula A4.
Example 9
In a clean and dry reaction bottle, 930.0ml of toluene, 186.0ml of ethylene glycol, 0.93g of PTS and 93.0g of cholic acid intermediate A3 are put, the system is heated to a reflux state for reaction for 25h, and the reaction is detected by TLC until the reaction is completed. Cooling, adding a small amount of triethylamine at room temperature to adjust the pH to be =7.2, adding 370ml of water for washing for 2 times, collecting an organic phase, concentrating a toluene layer under reduced pressure to be in a viscous state, adding 370.0ml of petroleum ether, cooling to 6 ℃, filtering, and drying to obtain 81.9g of the compound shown as the 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 a Compound of formula A5
The synthetic route is shown as the following chart:
example 10
1200.0ml of acetone and 133.0ml of water are added into a clean reaction bottle, 83.0g of the compound shown in the formula A4, 83.0g of chromium oxide and 60.0g of NHPI are added under stirring, the temperature is controlled to be 22 ℃, the mixture is kept and stirred for 3 hours, then 83.0g of chromium oxide is added, the mixture is kept and stirred for 23hours, and TLC detection reaction is carried out until the reaction is completed. The reaction was quenched by the addition of 72.0g of isopropanol, acetone was concentrated to dryness, 500.0ml of dichloromethane was added, the layers were separated, the organic phase was washed once with water and the organic phase was collected. The treated organic layer was concentrated under reduced pressure, replaced with methanol, cooled, filtered, and dried to obtain 64.4g of a compound represented by the formula A5.
Example 11
1200.0ml of acetone and 133.0ml of water are added into a clean reaction bottle, 83.0g of the compound shown in the formula A4, 100.0g of pyridinium chlorochromate and 60.0g of NHPI are added under stirring, the temperature is controlled at 22 ℃, after 5 hours of heat preservation and stirring, 100.0g of pyridinium chlorochromate is added, 23hours of heat preservation and stirring are carried out, and the TLC detection reaction is carried out until the reaction is completed. The reaction was quenched by the addition of 80.0g of isopropanol, acetone was concentrated to dryness, 500.0ml of dichloromethane was added, the layers were separated, the organic phase was washed once with water and the organic phase was collected. The treated organic layer was concentrated under reduced pressure, displaced with methanol, cooled, filtered and dried to obtain 63.9g of a compound represented by the formula A5.
Example 12
1600.0ml of acetonitrile and 133.0ml of water are added into a clean reaction bottle, 83.0g of the compound shown in the formula A4, 83.0g of chromium oxide and 60.0g of NHPI are added under stirring, the temperature is controlled at 22 ℃, after stirring for 4 hours under heat preservation, 83.0g of chromium oxide is added, stirring for 23hours under heat preservation, TLC detection reaction is carried out till completion. The reaction was quenched by the addition of 72.0g of isopropanol, acetone was concentrated to dryness, 500.0ml of dichloromethane was added, the layers were separated, the organic phase was washed once with water and the organic phase was collected. The treated organic layer was concentrated under reduced pressure, replaced with methanol, cooled, filtered, and dried to obtain 63.8g of a compound represented by formula A5.
Example 13
1600.0ml of acetonitrile and 133.0ml of water are added into a clean reaction bottle, 83.0g of the compound shown in the formula A4, 100.0g of pyridinium chlorochromate and 60.0g of NHPI are added under stirring, the temperature is controlled at 22 ℃, after stirring for 3 hours under heat preservation, 100.0g of pyridinium chlorochromate is added, stirring for 23h under heat preservation is carried out, and TLC detection reaction is carried out until the reaction is completed. The reaction was quenched by addition of 80.0g of isopropanol, acetone was concentrated to dryness, 500.0ml of dichloromethane was added, the layers were separated, the organic phase was washed once with water and the organic phase was collected. The treated organic layer was concentrated under reduced pressure, displaced with methanol, cooled, filtered and dried to obtain 63.3g of a compound represented by the 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 a Compound of formula A6
The synthetic route is shown as the following chart:
630.0ml of methanol, 63.0ml of water and 38.0ml of concentrated hydrochloric acid were added to a clean reaction flask, 63.0g of the compound represented by the formula A5 was added with stirring, the system was heated to 55 ℃ for 4 hours, and the reaction was checked by TLC until completion. The system was cooled to 25 ℃, adjusted to PH 6.5 with saturated sodium bicarbonate solution and filtered. Drying gives 55.1g of the compound of the 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 represented by the formula A7
The synthetic route is shown as the following figure:
example 15
A clean dry autoclave was charged with 270.0ml of absolute ethanol and 270.0ml of pyridine, and 54.0g of the compound represented by formula A6 and 5.4g of 10% palladium on carbon were added with stirring, and the mixture was pressurized to 0.42MPa with hydrogen at 35 ℃ for 10 hours and checked by TLC until completion. Filtering the system to remove palladium carbon, then carrying out reduced pressure concentration, replacing with water, carrying out elutriation to discharge materials, leaching with a small amount of water, and drying a filter cake to be qualified to obtain 50.6g of a compound shown as a formula A7, wherein the purity of A7 is as follows: 5 α -H isomer purity =89.8:10.2.
example 16
Into a clean and dry autoclave were charged 270.0ml of absolute ethanol, 216.0ml of pyridine and 54.0ml of 1-methylimidazole, and 54.0g of the compound represented by formula A6 and 5.4g of 10% palladium on carbon were added with stirring, and the reaction was carried out for 10 hours under a pressure of 0.42MPa with hydrogen gas at 35 ℃ and was checked by TLC until completion. Filtering the system to remove palladium carbon, then concentrating under reduced pressure, replacing with water, precipitating with water, discharging, leaching with a small amount of water, and drying a filter cake to be qualified to obtain 51.3g of a compound shown as a formula A7, wherein the purity of A7 is as follows: 5 α -H isomer purity =92.7:7.3.
example 17
Into a clean and dry autoclave were charged 270.0ml of absolute ethanol, 270.0ml of pyridine and 5.4g of DMAP, and 54.0g of the compound represented by the formula A6 and 5.4g of 10% palladium on carbon were added with stirring, and the reaction was carried out for 10 hours under a pressure of hydrogen gas at 35 ℃ to 0.42MPa and checked for completion by TLC. Filtering the system to remove palladium carbon, then performing elutriation to discharge a material, leaching with a small amount of water, and drying a filter cake to be qualified to obtain 50.9g of a compound shown as a formula A7, wherein the purity of A7 is as follows: 5 α -H isomer purity =98.3:1.7.
| examples | Batch (g) | Dry weight of product (g) | Purity of A7-purity of 5 alpha isomer | 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％ |
As can be seen from the above table, when the solvent is absolute ethanol, pyridine and DMAP in a certain ratio range, the purity of the prepared cholic acid intermediate A7 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 represented by the formula A8
The synthetic route is shown as the following chart:
example 18: adding 500.0ml of methanol, 150.0ml of water and 10.0g of sodium hydroxide into a clean reaction bottle, adding 50.0g of the compound shown as the formula A7 while stirring, heating the system to 50-55 ℃, reacting for 3h, and detecting by TLC until the reaction is complete. And (3) cooling to below 30 ℃, adjusting the pH value to be =2.5 by using 6N hydrochloric acid, decompressing, concentrating dry methanol, performing elutriation, discharging, leaching by using a small amount of water, and drying a filter cake to be qualified to obtain 46.1g of the compound shown in the formula A8.
Example 19: adding 250.0ml of tetrahydrofuran, 150.0ml of water and 14.0g of potassium hydroxide into a clean reaction flask, adding 50.0g of the compound shown in the formula A7 while stirring, heating the system to 40-45 ℃, reacting for 4h, and detecting by TLC until the reaction is complete. Cooling to below 30 ℃, adjusting the pH value to be =2.5 by using 6N hydrochloric acid, decompressing, concentrating dry methanol, elutriating and discharging, leaching by using a small amount of water, and drying a filter cake to be qualified to obtain 45.9g of the compound shown in the formula A8.
Example 20: adding 500.0ml of ethanol, 150.0ml of water and 14.0g of potassium hydroxide into a clean reaction bottle, adding 50.0g of the compound shown in the formula A7 while stirring, heating the system to 45-50 ℃, reacting for 3.5h, and detecting by TLC until the reaction is complete. Cooling to below 30 ℃, adjusting the pH value to be =2.5 by using 6N hydrochloric acid, decompressing and concentrating dry methanol, performing elutriation to discharge a material, leaching with a small amount of water, and drying a filter cake until the filter cake is qualified to obtain 45.5g of the compound shown as the formula A8.
Example 21: adding 300.0ml of acetone, 150.0ml of water and 10.0g of sodium hydroxide into a clean reaction bottle, adding 50.0g of the compound shown in the formula A7 while stirring, heating the system to 55-60 ℃, reacting for 5h, and detecting by TLC until the reaction is complete. Cooling to below 30 ℃, adjusting the pH value to be =2.7 by using 6N hydrochloric acid, decompressing, concentrating dry methanol, performing elutriation, discharging, leaching by using a small amount of water, and drying a filter cake to be qualified to obtain 46.2g of the compound shown in the formula A8.
Example 22: adding 100.0ml of dichloromethane, 50.0ml of methanol, 150.0ml of water and 10.0g of sodium hydroxide into a clean reaction bottle, adding 50.0g of the compound shown in the formula A7 while stirring, heating the system to 50-55 ℃, reacting for 5h, and detecting by TLC until the reaction is complete. Cooling to below 30 ℃, adjusting the pH value to be =2.3 by using 6N hydrochloric acid, decompressing and concentrating dry methanol, performing elutriation to discharge a material, leaching with a small amount of water, and drying a filter cake until the filter cake is qualified to obtain 45.8g of the compound shown as the 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 figure:
adding 700.0ml of tetrahydrofuran and 45.0g of a compound shown as a formula A8 into a clean and dry reaction bottle, cooling to 3 ℃ under the protection of nitrogen, slowly adding 130.0g of lithium aluminum tri-tert-butoxyhydride in batches, heating to 25 ℃ after the addition, reacting for 11h, detecting by TLC until the reaction is complete, slowly adding 1N hydrochloric acid dropwise, adjusting the pH to be 2.5, concentrating the tetrahydrofuran under reduced pressure, separating out materials by water, rinsing with a small amount of water, dissolving a filter cake by ethyl acetate, separating liquid, recrystallizing and refining to obtain 28.1g of target product cholic acid.
The analytical data were:
1H-NMR((D5)pyridine，500MHz):：4.25(s，H-C(12))；4.09(s，H-C(7))；3.78–3.73(m，H-C(3))；3.11(q,J＝13.0，H-C(8))；2.92(dt，J＝12.0，4.2，H-C(9))；2.79–2.73(m，H-C(14))；2.67–2.61(m，H-C(23a))；2.56–2.50(m，H-C(23b))；2.39–2.34(m，H-C(17))；2.15–2.13(m，CH2(22))；2.13–2.11(m，H-C(4a))；2.07–2.00(m，H-C(15a))；1.94–1.91(m，H-C(1a,2a))；1.88–1.86(m，H-C(11a))；1.68–1.67(m，CH2(6))；1.67–1.62(m，H-C(20,4b,2b,11b))；1.51–1.49(m，H-C(5))；1.44–1.37(m，CH 2 (16))；1.23(d，J＝5.5，Me(21))；1.21–1.19(m，H-C(15b)；1.09–1.03(m，H-C(1b))；1.00(s，Me(19))；0.81(s，Me(18))。
the foregoing is a further detailed description of the present invention in connection with specific preferred embodiments thereof, and it is not intended to limit the invention to the specific embodiments thereof. For those skilled in the art to which the invention pertains, several simple deductions and substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (10)
1. A cholic acid intermediate A3, wherein the structural formula of cholic acid intermediate A3 is represented by formula A3:
2. a preparation method of a cholic acid intermediate A3 is characterized in that a Wittig reaction is carried out, toluene or tetrahydrofuran is used as a solvent, a compound shown in a formula A2 and a Wittig reagent ethoxycarbonyl methylene triphenylphosphine are added under a stirring state to obtain a reactant system, the reactant system is heated to a reflux state for reaction for a preset time until the reaction is complete, a reaction product containing the compound shown in the formula A3 is obtained, and after the reaction product is cooled to room temperature, the cholic acid intermediate A3 is obtained through post-treatment, wherein the structural formula of the compound shown in the formula A2 is as follows:
3. the method for preparing a cholic acid intermediate A3 according to claim 2, wherein the predetermined time is 10 to 16 hours.
4. The method for preparing cholic acid intermediate A3 according to claim 2, wherein the weight ratio of the compound represented by formula A2 to carbethoxymethylenetriphenylphosphine is: 1: (1.8-2.4).
5. The method for preparing a cholic acid intermediate A3 according to claim 2, wherein the post-treatment comprises a precipitation reaction, solid-liquid separation, liquid separation of the filtrate, reduced pressure concentration of the organic layer to dryness, elutriation, filtration and drying which are sequentially performed.
6. The preparation method of cholic acid intermediate A3 according to claim 5, wherein the metal ion complexing agent added in the precipitation reaction is 35-45% by mass of zinc chloride solution, the temperature of the precipitation reaction is 25-30 ℃, and the reaction time is 10-16 h.
7. A preparation method of a cholic acid intermediate A3 is disclosed, wherein the structural formula of the cholic acid intermediate A3 is shown as formula A3, and is characterized in that Wittig-Horner reaction is carried out, tetrahydrofuran is used as a solvent, a compound shown as formula A2 reacts with alkali and triethyl phosphonoacetate at the temperature of 20-66 ℃ for 1-3 hours, so as to obtain a reaction product containing the cholic acid intermediate A3, wherein the alkali is one of sodium hydride, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, and the structural formula of the compound shown as formula A2 is as follows:
8. the method for preparing cholic acid intermediate A3 according to claim 6, wherein the molar ratio of the compound represented by formula A2 to the base is: 1: (1.5-2.0), wherein the mass-to-volume ratio of the compound shown as the formula A2 to triethyl phosphonoacetate is 1g: (0.9-1.1) ml.
9. A cholic acid intermediate A3 obtainable by the process of any one of claims 2 to 8.
10. A preparation method of cholic acid is disclosed, wherein the molecular formula of the cholic acid is shown as formula CA, and the preparation method comprises the following steps: sequentially carrying out ketal protection reaction, oxidation reaction, first hydrolysis reaction, hydrogenation reduction reaction, second hydrolysis reaction and selective reduction reaction on a compound shown as a formula A3 to obtain cholic acid, wherein the complete reaction formula of the six-step reaction is as follows:
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| US2752369A (en) * | 1954-02-25 | 1956-06-26 | Upjohn Co | Oxidation of steroid-enamines |
| CN112341516A (en) * | 2020-11-14 | 2021-02-09 | 湖南科瑞生物制药股份有限公司 | 5, 6-epoxy steroid compound and preparation method and application thereof |
| CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
| CN113968890A (en) * | 2021-11-15 | 2022-01-25 | 湖南科瑞生物制药股份有限公司 | Preparation method of plant source 7-ketolithocholic acid isomer impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2752369A (en) * | 1954-02-25 | 1956-06-26 | Upjohn Co | Oxidation of steroid-enamines |
| CN112341516A (en) * | 2020-11-14 | 2021-02-09 | 湖南科瑞生物制药股份有限公司 | 5, 6-epoxy steroid compound and preparation method and application thereof |
| CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
| CN113968890A (en) * | 2021-11-15 | 2022-01-25 | 湖南科瑞生物制药股份有限公司 | Preparation method of plant source 7-ketolithocholic acid isomer impurity |
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