CN117447545A - Synthetic method of deoxycholic acid (DCA) - Google Patents
Synthetic method of deoxycholic acid (DCA) Download PDFInfo
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- CN117447545A CN117447545A CN202311406457.8A CN202311406457A CN117447545A CN 117447545 A CN117447545 A CN 117447545A CN 202311406457 A CN202311406457 A CN 202311406457A CN 117447545 A CN117447545 A CN 117447545A
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- Prior art keywords
- compound
- reaction
- solvent
- deoxycholic acid
- dca
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- 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 title claims abstract description 49
- 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 47
- 229960003964 deoxycholic acid Drugs 0.000 title claims abstract description 46
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000003379 elimination reaction Methods 0.000 claims abstract description 4
- 238000001308 synthesis method Methods 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 239000003880 polar aprotic solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 229940125773 compound 10 Drugs 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910010082 LiAlH Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000423 chromium oxide Inorganic materials 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 3
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].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 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 claims description 3
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 229940009976 deoxycholate Drugs 0.000 claims description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 2
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 2
- 229960002218 sodium chlorite Drugs 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 244000037640 animal pathogen Species 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000002939 deleterious effect Effects 0.000 abstract description 2
- 235000002378 plant sterols Nutrition 0.000 abstract description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 150000003138 primary alcohols Chemical class 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000001799 protein solubilization Methods 0.000 description 2
- 230000007925 protein solubilization Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 239000012459 cleaning agent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- MJPPNOYSSOKENI-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li+].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] MJPPNOYSSOKENI-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 210000004746 tooth root Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention provides a synthetic method of deoxycholic acid (DCA). The method takes plant sterol as an initial raw material, and deoxycholic acid (DCA) is synthesized through the steps of primary alcohol oxidation reaction, witting reaction, hydrogenation reaction, selective reduction reaction, hydroxyl protection reaction, elimination reaction, allyl oxidation reaction, hydrolysis reaction and the like. The synthesis method has the advantages of high reaction yield, high product purity, solid intermediates in each step, easy purification, simple post-treatment method, low cost, suitability for quality control, convenience for industrial production and better application prospect. Furthermore, deoxycholic acid (DCA) synthesized by this method also avoids the risk of containing animal pathogens and other deleterious factors.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for synthesizing deoxycholic acid (DCA).
Background
Deoxycholic Acid (DCA) has a chemical name of 3α,12α -dihydroxy-5β -cholanic Acid, and CAS number of 84-44-3. The pure nature is white to off-white solid powder. The bile acid is free bile acid which is obtained by the derivative of cholic acid losing one oxygen atom and is mainly in the form of taurine and glycine combination in bile and widely exists in animals. Since its impact on proteins was found, people have begun to use in various fields, such as for biochemical and bacteriological, enzymatic studies; as anion removers for disrupting protein-protein interactions; the microbial strain is used as a bacterial culture medium additive for intestinal bacteria culture and separation; as a protein solubilization cleaning agent for the boundary of lipid and cell membrane, as a denaturant, and for protein solubilization and analysis; can be used as potent cell membrane dissolving agent, etc. Wherein, the composition acts on human body, most of the composition is used for emulsifying fat and is beneficial to intestinal absorption of human body; or has surface activity, and can be used as emulsifier in cosmetics and medicaments, and has antifungal and antiinflammatory effects, and can be used for treating dental root diseases; furthermore, the subcutaneous fat can be injected, which is helpful for destroying fat cells, and phagocytes can clean disintegrated cells, thereby achieving the function of local dissolution. Deoxycholic acid obtained from animal sources may however contain pathogens, such as Raney viruses and other harmful substances, and direct action on the human body may lead to oversensitive reactions, shock and even death.
The current chemical synthesis method of deoxycholic acid mainly comprises the following steps:
patent CN106083969 reports that deoxycholic acid and its salt are prepared by 11 steps of reaction such as hydrogenation reduction reaction, elimination reaction, reduction reaction, witting reaction, etc. using 9-alpha-hydroxyandrosta-4-ene-3, 17-dione as starting material, and the specific route is as follows:
patent CN106146593 reports another method for preparing deoxycholic acid and its salts from 9 alpha-hydroxyandrosta-4-ene-3, 17-dione as starting material, the specific route is as follows:
patent CN114716497 reports another method for preparing deoxycholic acid and its salts from 9 alpha-hydroxyandrosta-4-ene-3, 17-dione as starting material, the specific route is as follows:
in view of the three synthetic methods, the synthetic route is long, the total yield is not high, the hydrogenation reduction reaction is required for three times, the reaction conditions in the middle process are harsh, the risk is high, and the intermediate is required to be purified by column chromatography for multiple times, so that the method is not suitable for industrial production.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide a method for synthesizing deoxycholic acid (DCA) by taking phytosterol as a starting material, which has the advantages of high yield, high purity, solid intermediates in each step, easy purification, simple post-treatment method, low cost, suitability for quality control and convenience for industrial production, and can also avoid the danger of containing animal pathogens and other harmful factors.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention provides a synthetic method of deoxycholic acid (DCA), which comprises the following steps:
step 1:
carrying out oxidation reaction on a compound 1, namely 9 alpha-hydroxy-3-ketodienol-4-en-22-ol (9 alpha-OH BA), sodium hypochlorite and an oxidation catalyst in a solvent to obtain a compound 2;
step 2:
carrying out a Witting reaction on the compound 2 and a Witting-Horner reagent under an alkaline condition to obtain a compound 3;
step 3:
pressurizing and heating the compound 3 in a polar aprotic solvent under the catalysis of palladium carbon to carry out hydrogenation reaction to obtain a compound 4;
step 4:
carrying out reduction reaction on the compound 4 and a reducing agent to obtain a compound 5;
step 5:
performing an acetylation reaction on the compound 5 and acetic anhydride under an alkaline condition, so as to protect 3-hydroxyl and obtain a compound 6;
step 6:
carrying out elimination reaction on the compound 6 under an acidic condition to obtain a compound 7;
step 7:
carrying out oxidation reaction on the compound 7 and an oxidant in a solvent to obtain a compound 8;
step 8:
pressurizing and heating the compound 8 in a polar aprotic solvent under the catalysis of palladium carbon to carry out hydrogenation reaction to obtain a compound 9;
step 9:
carrying out reduction reaction on the compound 9 and a reducing agent in a solvent to obtain a compound 10;
step 10:
and (3) carrying out hydrolysis reaction on the compound 10 under alkaline conditions to obtain deoxycholate, and then adjusting the pH value of the solution to be acidic to obtain deoxycholic acid (DCA).
Preferably, in step 1:
the oxidation catalyst is selected from TEMPO.
The solvent is selected from methylene chloride.
Preferably, in step 2:
the wining-Honer reagent is selected from trimethyl phosphonoacetate or triethyl phosphonoacetate.
The alkaline condition is formed by at least one substance selected from potassium tert-butoxide, sodium hydride and potassium carbonate, preferably potassium tert-butoxide.
Preferably, in step 3:
the palladium carbon is used in an amount of 5% -10%, preferably 10%.
The palladium content in the palladium carbon is 5% -10%, preferably 10%.
The reaction temperature is 20℃to 90℃and preferably 50 ℃.
The reaction time is 16-24h.
The polar aprotic solvent is selected from at least one of N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol and ethanol, and preferably N, N-dimethylformamide.
Preferably, in step 4:
the reducing agent is selected from NaBH 4 、LiAlH 4 、LiAIH(OtBu) 3 At least one of them is preferably NaBH 4 。
The solvent is at least one selected from methanol and ethanol, preferably ethanol.
Preferably, in step 5:
the basic condition is formed by at least one substance selected from triethylamine and pyridine, preferably triethylamine.
The solvent is selected from methylene chloride.
Preferably, in step 6:
the acidic conditions are formed by concentrated sulfuric acid/methylene chloride or thionyl chloride/pyridine.
Preferably, in step 7:
the oxidant is at least one selected from chromium oxide, tert-butyl hydroperoxide/sodium hypochlorite, tert-butyl hydroperoxide/sodium chlorite, tert-butyl hydroperoxide/cuprous iodide, tert-butyl hydroperoxide/hydrated ruthenium trichloride, pyridinium chlorochromate, selenium dioxide and pyridinium dichromate.
The solvent is at least one selected from acetic acid, acetonitrile and ethyl acetate.
The reaction temperature is 0-80 ℃.
Preferably, in step 8:
the palladium carbon is used in an amount of 5% -10%, preferably 5%.
The palladium content in the palladium carbon is 5% -10%, preferably 10%.
The reaction temperature is 50℃to 90℃and preferably 50 ℃.
The reaction time is 8-24h.
The polar aprotic solvent is at least one selected from ethyl acetate, N-dimethylformamide, acetonitrile and tetrahydrofuran, preferably ethyl acetate.
Preferably, in step 9:
the reducing agent is selected from NaBH 4 、LiAlH 4 、LiAIH(OtBu) 3 At least one of (A) is preferably LiAIH (OtBu) 3 。
The solvent is selected from tetrahydrofuran.
Preferably, in step 10:
the alkaline condition is that sodium hydroxide is used for forming, deoxycholic acid sodium salt is obtained through hydrolysis reaction, and then the pH value of the solution is adjusted to be acidic, so that a deoxycholic acid (DCA) crude product can be obtained.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a method for synthesizing deoxycholic acid (DCA) by taking plant sterol as a starting material, which has the advantages of high reaction yield, high product purity, solid intermediates in each step, easy purification, simple post-treatment method, low cost, suitability for quality control, convenient industrial production and good application prospect. Furthermore, deoxycholic acid (DCA) synthesized by this method also avoids the risk of containing animal pathogens and other deleterious factors.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention. In the drawings:
FIG. 1 is a reaction scheme for synthesizing deoxycholic acid (DCA) from 9α -hydroxy-3-ketodienol-4-en-22-ol (9α -OH BA) as a raw material in accordance with the present invention.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the compound 8 prepared in example 1 of the present invention.
FIG. 3 shows the nuclear magnetic hydrogen spectrum of deoxycholic acid (DCA) prepared in example 1 of the present invention.
Detailed Description
The following detailed description of the embodiments of the present invention is provided for better illustration of the present invention, but is not to be construed as limiting the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
Example 1: a method of synthesizing deoxycholic acid (DCA), comprising:
step 1:
200g of compound 1, namely 9 alpha-hydroxy-3-ketodienol-4-en-22-ol (9 alpha-OH BA), 2.5L of dichloromethane, 8.64g of sodium bromide, 10.24g of sodium bicarbonate, 0.8g of TEMPO and 100mL of water are put into a 5L three-neck flask and stirred uniformly; cooling to 0 ℃, dropwise adding 360mL of sodium hypochlorite aqueous solution, and stirring at constant temperature until the raw materials completely react after the dropwise addition; after separation, the organic layer was washed once with 500mL of an aqueous sodium thiosulfate solution, 500mL of water, and 500mL of saturated brine, dried and suction-filtered, concentrated and dried to give compound 2 (194.02 g, yield 97.58%) as a white powder.
Step 2:
169.35g of triethyl phosphonoacetate and 1.5L of tetrahydrofuran are put into a 5L three-neck flask and stirred uniformly; cooling to 0 ℃, adding the potassium tert-butoxide in batches with equal amount, adding 130.27g, and stirring for 15min; cooling to 0 ℃, adding 200g of compound 2 in batches with equal amount, and stirring for 12 hours at constant temperature; after the reaction was completed, the mixture was poured into 5L of ice water, stirred for crystallization, and suction filtration and drying were carried out to obtain compound 3 (224.32 g, yield: 93.20%) as a white powder.
Step 3:
70g of compound 3, 5g of Pd/C (10%) and 840mLN, N-dimethylformamide are put into a hydrogenation reaction kettle and stirred uniformly; setting the heating temperature at 80 ℃, the internal pressure at 0.75MPa, and reacting for 24 hours; after palladium carbon is recovered by suction filtration, 1L of ice water is added for stirring crystallization, suction filtration and drying are carried out, and then the white powder compound 4 (56.7 g, yield 80.22%) is obtained by column chromatography purification.
Step 4:
200g of compound 4 and 2000mL of ethanol are put into a 3L three-neck flask and stirred uniformly; adding sodium borohydride 44.3g in equal amount at room temperature, stirring at constant temperature for 3h; after the reaction was completed, the mixture was poured into a 0.3 mol/L7L ice water solution of hydrochloric acid, stirred and crystallized, and then suction filtration and drying were carried out to obtain compound 5 (182.27 g, yield 90.70%) as white powder.
Step 5:
150g of compound 5, 750mL of methylene chloride, 72.3g of triethylamine and 1.5g of DMAP are put into a 2L three-necked flask and stirred uniformly; cooling to 0 ℃, dropwise adding 54.6g of acetic anhydride, and stirring for 8 hours; after completion of the reaction, ice water was added to separate the organic layer, and 500mL of water and 500mL of saturated brine were washed once each, dried and suction-filtered, followed by concentration to obtain Compound 6 (132 g, yield 80.00%) as a white powder.
Step 6:
140g of compound 6, 700mL of dichloromethane and 71g of pyridine are put into a 2L three-neck flask and stirred uniformly; cooling to 0 ℃, dropwise adding 54g of sulfoxide chloride, and stirring for 2h; after completion of the reaction, an aqueous ice solution was added, and the organic layer was washed once with 500mL of water and 500mL of saturated brine, dried, suction-filtered, and concentrated to give Compound 7 (124.2 g, yield 92.31%) as a white powder.
Step 7:
100g of compound 7, 800mL of acetic acid and 100g of chromium oxide are put into a 2L three-neck flask and stirred uniformly; heating to 60 ℃ and reacting for 2 hours; after completion of the reaction, the mixture was quenched by dropwise addition of isopropanol, concentrated, 500mL of methyl t-butyl ether and 500mL of aqueous solution were added, and the organic layer was washed once with 300mL of water and 300mL of saturated brine, dried and filtered, concentrated, and purified by column chromatography to give Compound 8 (46.41 g, yield 45.00%) as a white powder.
1H NMR(400MHz,Chloroform-d)δ5.72(d,J＝2.3Hz,1H),4.74(dtt,J＝438.5,11.3,4.5Hz,1H),4.13(ddq,J＝255.2,37.1,7.1Hz,2H),2.46–2.20(m,3H),2.16–1.93(m,3H),2.01(s,3H),1.97–1.60(m,5H),1.63–1.38(m,3H),1.42–1.26(m,3H),1.30–1.23(m,3H),1.21(s,3H),1.03(d,J＝6.5Hz,3H),0.92(s,3H)。
Step 8:
adding 40g of compound 8, 200mL of ethyl acetate and 4g of Pd/C (10%) into a hydrogenation reaction kettle, and uniformly stirring; setting the temperature at 50 ℃, setting the internal pressure at 0.5Mpa, and reacting for 24 hours; after palladium on carbon was collected by suction filtration, the mixture was concentrated to give compound 9 (34 g, yield 84.63%) as a white solid.
Step 9:
60g of compound 9 and 600mL of tetrahydrofuran are put into a 2L three-neck flask and stirred uniformly; 90g of lithium aluminum tri-tert-butoxide is added in equal amount in batches after cooling to 0 ℃, stirred for 2h, poured into 1 mol/L1.8L hydrochloric acid aqueous solution for quenching, 500mL ethyl acetate is added for separating, the organic layer is washed once with 500mL water and 500mL saturated brine respectively, dried and filtered, and concentrated to obtain a transparent oily compound 10 (60 g, yield 99.56%).
Step 10:
80g of compound 10, 300mL of tetrahydrofuran and 300mL of methanol are put into a 2L three-neck flask, stirred evenly, cooled to 5 ℃, added with 4 mol/L200 mL of sodium hydroxide aqueous solution dropwise, and stirred for 3 hours; adding 400mL of water and 500mL of dichloromethane for separating liquid, and concentrating a water layer to obtain deoxycholate sodium salt; the pH of the water layer was adjusted to be acidic with 2mol/L hydrochloric acid aqueous solution, crude deoxycholic acid was precipitated, and a white solid was obtained by suction filtration and drying, and purified by column chromatography to obtain pure white powder of deoxycholic acid (DCA) (59.5 g, yield 87.65%). Purity > 99% by HPLC.
1HNMR(400MHz,DMSO-d6)δ11.93(s,1H),4.46(s,1H),4.20(d,J＝4.0Hz,1H),3.80(d,J＝3.7Hz,1H),2.24(ddd,J＝15.1,9.6,5.2Hz,1H),2.11(ddd,J＝15.6,9.1,6.7Hz,1H),1.88–1.68(m,2H),1.78(s,2H),1.66(d,J＝3.6Hz,1H),1.66–1.52(m,2H),1.48(dd,J＝15.7,5.5Hz,1H),1.37(dd,J＝9.6,3.8Hz,3H),1.32(d,J＝11.6Hz,4H),1.29–1.15(m,3H),1.05(dtd,J＝25.1,12.4,4.4Hz,2H),0.93(s,1H),0.92(s,2H),0.86(s,3H),0.61(s,3H)。
It is apparent that the above examples are only illustrative of the present invention and are not limiting of the embodiments of the present invention. Various modifications and alterations of this invention may be made by those skilled in the art without departing from the spirit and scope of this invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (10)
1. A method of synthesizing deoxycholic acid (DCA), the method comprising:
step 1:
carrying out oxidation reaction on a compound 1, namely 9 alpha-hydroxy-3-ketodienol-4-en-22-ol (9 alpha-OH BA), sodium hypochlorite and an oxidation catalyst in a solvent to obtain a compound 2;
step 2:
carrying out a Witting reaction on the compound 2 and a Witting-Horner reagent under an alkaline condition to obtain a compound 3;
step 3:
pressurizing and heating the compound 3 in a polar aprotic solvent under the catalysis of palladium carbon to carry out hydrogenation reaction to obtain a compound 4;
step 4:
carrying out reduction reaction on the compound 4 and a reducing agent to obtain a compound 5;
step 5:
performing an acetylation reaction on the compound 5 and acetic anhydride under an alkaline condition, so as to protect 3-hydroxyl and obtain a compound 6;
step 6:
carrying out elimination reaction on the compound 6 under an acidic condition to obtain a compound 7;
step 7:
carrying out oxidation reaction on the compound 7 and an oxidant in a solvent to obtain a compound 8;
step 8:
pressurizing and heating the compound 8 in a polar aprotic solvent under the catalysis of palladium carbon to carry out hydrogenation reaction to obtain a compound 9;
step 9:
carrying out reduction reaction on the compound 9 and a reducing agent in a solvent to obtain a compound 10;
step 10:
and (3) carrying out hydrolysis reaction on the compound 10 under alkaline conditions to obtain deoxycholate, and then adjusting the pH value of the solution to be acidic to obtain deoxycholic acid (DCA).
2. The synthetic method according to claim 1, wherein the oxidation catalyst in step 1 is selected from TEMPO and the solvent is selected from dichloromethane.
3. The synthetic method according to claim 1, wherein the wining-horner reagent in step 2 is selected from trimethyl phosphonoacetate or triethyl phosphonoacetate, and the alkaline condition is formed by at least one selected from potassium tert-butoxide, sodium hydride and potassium carbonate.
4. The synthesis method according to claim 1, wherein in the step 3, the palladium-carbon content is 5% -10%, the reaction temperature is 20 ℃ -90 ℃, the reaction time is 16-24h, and the polar aprotic solvent is at least one selected from N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol and ethanol.
5. The synthetic method according to claim 1, wherein the reducing agent in step 4 is selected from NaBH 4 、LiAlH 4 、LiAIH(OtBu) 3 The solvent is at least one selected from methanol and ethanol.
6. The synthetic method according to claim 1, wherein the basic condition in step 5 is formed by at least one selected from the group consisting of triethylamine and pyridine, and the solvent is selected from the group consisting of dichloromethane.
7. The synthetic method according to claim 1, characterized in that the acidic condition in step 6 is formed by concentrated sulfuric acid/dichloromethane or thionyl chloride/pyridine.
8. The synthesis method according to claim 1, wherein the oxidant in the step 7 is at least one selected from chromium oxide, tert-butyl hydroperoxide/sodium hypochlorite, tert-butyl hydroperoxide/sodium chlorite, tert-butyl hydroperoxide/cuprous iodide, tert-butyl hydroperoxide/ruthenium trichloride hydrate, pyridinium chlorochromate, selenium dioxide and pyridinium dichromate, the solvent is at least one selected from acetic acid, acetonitrile and ethyl acetate, and the reaction temperature is 0 ℃ to 80 ℃.
9. The synthesis method according to claim 1, wherein in the step 8, the palladium-carbon content is 5% -10%, the reaction temperature is 50 ℃ -90 ℃, the reaction time is 8-24h, and the polar aprotic solvent is at least one selected from ethyl acetate, N-dimethylformamide, acetonitrile and tetrahydrofuran.
10. The synthetic method according to claim 1, wherein the reducing agent in step 9 is selected from NaBH 4 、LiAlH 4 、LiAIH(OtBu) 3 At least one of the solvents is selected from tetrahydrofuran;
the alkaline condition in the step 10 is that sodium hydroxide is used for forming, deoxycholic acid sodium salt is obtained through hydrolysis reaction, and then the pH value of the solution is adjusted to be acidic, so that a deoxycholic acid (DCA) crude product can be obtained.
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