CN1694896A - 制备c-7取代的5-雄甾烯的方法 - Google Patents
制备c-7取代的5-雄甾烯的方法 Download PDFInfo
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- CN1694896A CN1694896A CNA038248697A CN03824869A CN1694896A CN 1694896 A CN1694896 A CN 1694896A CN A038248697 A CNA038248697 A CN A038248697A CN 03824869 A CN03824869 A CN 03824869A CN 1694896 A CN1694896 A CN 1694896A
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- 238000000034 method Methods 0.000 title claims abstract description 34
- SBNLPRGISFUZQE-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical class C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 SBNLPRGISFUZQE-VMXHOPILSA-N 0.000 title description 2
- -1 steroid compounds Chemical class 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000004593 Epoxy Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- LUIAERHOFZZBPZ-XFNFOBRPSA-N O=C=C[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C Chemical compound O=C=C[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C LUIAERHOFZZBPZ-XFNFOBRPSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 239000012434 nucleophilic reagent Substances 0.000 claims description 10
- 150000003431 steroids Chemical class 0.000 claims description 10
- 150000002240 furans Chemical class 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 239000010948 rhodium Substances 0.000 claims description 7
- 239000011968 lewis acid catalyst Substances 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 229910052703 rhodium Inorganic materials 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000007037 hydroformylation reaction Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 3
- 150000002596 lactones Chemical class 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 239000012964 benzotriazole Substances 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims 3
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 claims 2
- 150000003855 acyl compounds Chemical class 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims 1
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 238000006317 isomerization reaction Methods 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000011081 inoculation Methods 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 230000036983 biotransformation Effects 0.000 description 21
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000001954 sterilising effect Effects 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 238000004659 sterilization and disinfection Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 235000014347 soups Nutrition 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229920000742 Cotton Polymers 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000005937 allylation reaction Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000008121 dextrose Substances 0.000 description 6
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000002255 vaccination Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000002518 antifoaming agent Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 5
- 229920001296 polysiloxane Polymers 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 description 4
- 241000228212 Aspergillus Species 0.000 description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000013405 beer Nutrition 0.000 description 4
- 230000005587 bubbling Effects 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 4
- VZAWCLCJGSBATP-UHFFFAOYSA-N 1-cycloundecyl-1,2-diazacycloundecane Chemical compound C1CCCCCCCCCC1N1NCCCCCCCCC1 VZAWCLCJGSBATP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 241000122824 Aspergillus ochraceus Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000190144 Lasiodiplodia theobromae Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 3
- 229960001208 eplerenone Drugs 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 125000000457 gamma-lactone group Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
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- 235000010755 mineral Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 229910000080 stannane Inorganic materials 0.000 description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance 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
- 241000293029 Absidia caerulea Species 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229910020366 ClO 4 Inorganic materials 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- MMVYPOCJESWGTC-UHFFFAOYSA-N Molybdenum(2+) Chemical compound [Mo+2] MMVYPOCJESWGTC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910019093 NaOCl Inorganic materials 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012499 inoculation medium Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- DSQFYUWSAZEJBL-UHFFFAOYSA-N methyl 2h-benzotriazole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1N=NN2 DSQFYUWSAZEJBL-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- OIPPWFOQEKKFEE-UHFFFAOYSA-N orcinol Chemical compound CC1=CC(O)=CC(O)=C1 OIPPWFOQEKKFEE-UHFFFAOYSA-N 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- HVAMZGADVCBITI-UHFFFAOYSA-N pent-4-enoic acid Chemical compound OC(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- HRADVHZVMOMEPU-UHFFFAOYSA-N 3-iodopyrrolidine-2,5-dione Chemical compound IC1CC(=O)NC1=O HRADVHZVMOMEPU-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- KLZUFWVZNOTSEM-UHFFFAOYSA-K Aluminium flouride Chemical class F[Al](F)F KLZUFWVZNOTSEM-UHFFFAOYSA-K 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 101100008044 Caenorhabditis elegans cut-1 gene Proteins 0.000 description 1
- 101100008046 Caenorhabditis elegans cut-2 gene Proteins 0.000 description 1
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
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- 229920001353 Dextrin Polymers 0.000 description 1
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
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- DJOWTWWHMWQATC-KYHIUUMWSA-N Karpoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1(O)C(C)(C)CC(O)CC1(C)O)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C DJOWTWWHMWQATC-KYHIUUMWSA-N 0.000 description 1
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- 241000013355 Mycteroperca interstitialis Species 0.000 description 1
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
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- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
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- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
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- 238000004440 column chromatography Methods 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
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- GCSJLQSCSDMKTP-UHFFFAOYSA-N ethenyl(trimethyl)silane Chemical compound C[Si](C)(C)C=C GCSJLQSCSDMKTP-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 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
- 239000011521 glass Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
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- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
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- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- UYDLBVPAAFVANX-UHFFFAOYSA-N octylphenoxy polyethoxyethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCO)C=C1 UYDLBVPAAFVANX-UHFFFAOYSA-N 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
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- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 1
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 description 1
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- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
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- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及制备新的式1的取代的甾族化合物的方法,其中R1是H或-COR2;R2是C1-C6烷基或C1-C6烷氧基;Z1是CH2或,其中OR3是α构型;R3是H或-COR2;Z2是-CH-;或Z1和Z2可连接在一起形成碳-碳双键;Q是或Y是-CN、-CH2-CH=CH2,C1-6-烷基,C1-6-烷基CHR4C(O)XAr或CHR4C(O)XC1-6烷基;CHR4 (O)XAr,或CHR4HC(O)XC1-6烷基;其中R4是OC1-6烷基或芳基,X是O或S。
Description
发明背景
某些C-7取代的甾族化合物,例如环氧孕烯酮(eplerenone),具有醛固酮拮抗剂活性是众所周知的,因而用于治疗和预防循环系统疾病。环氧孕烯酮是若干专利和申请的主题,例如US4,559,332和5,981,744以及国际公开W098/25948和W097/21720。对环氧孕烯酮新的和扩展的临床应用的出现产生了对制备这些和其它相关甾族化合物的改进方法的需求。有效合成环氧孕烯酮和相关甾族化合物的主要障碍是在C-7引入羧基或可转变为羧基的官能团。
已经描述了在称为“烯丙基化”的方法中,已知在路易斯酸影响下烯丙基衍生物,尤其是烯丙基乙酸酯、苯甲酸酯、新戊酸酯等与亲核试剂反应。烯丙基化反应已应用于许多物质。例如在烯丙基化过程中烯糖可产生烯丙基糖苷、糖基氰化物和糖基叠氮化物(Yadav,J.S.等,Tetrahedron Lett.,2001,42,4057。烯丙基乙酸酯和碳酸酯得到相应的氰化物(Yasushi,T.等,J.Org.Chem.,1993,58,16)。富电子芳香和杂芳香化合物得到相应的烯丙基化产物(Malkov,A.V.,等,J.Org.Chem.,1999,64,2751)。然而,烯丙基反应至今未应用于甾族化合物以得到7-取代的甾族化合物,用于转化为7-羧基取代的甾族化合物,例如环氧孕烯酮。3,17-二乙酰氧基-7-羟基雄甾-5-烯,或相应的7-甲磺酸酯与苯酚和苯甲醚使用粗糙催化剂氯化铝反应(Negi,A.S.,等,Steroids,1995,60,470)。生成的7-芳基衍生物以低收率作为C-7差向异构体的混合物得到。此外,7-芳基衍生物非常难以用于制备7-羧基取代的甾族化合物。
发明概述
本发明涉及制备新的式I的7-羧基取代的甾族化合物的方法:
式I
其中R1是-COR2;
R2是C1-C6烷基或C1-C6烷氧基;
Z1是CH2或
其中OR3是α构型;
R3是H或-COR2;
Z2是-CH-;或
Z1和Z2可以一起形成碳-碳双键;
Q是
或
Y是-CN,-CH2-CH=CH2,
CHR4C(O)Ar、CHR4C(O)C1-6烷基、CHR4C(O)XAr或CHR4C(O)XC1-6烷基;
其中R4是OC1-6烷基或芳基
X是O或S。
这些新的中间体用于制备7-羧基取代的甾族化合物,本发明尤其涉及新的和有利的制备9,11-α-环氧-1-α-羟基-3-氧代孕甾-4-烯-α-21-二羧酸,γ-内酯、甲酯(环氧孕烯酮(eplerenone);epoxymexrenone)。
在本发明的方法中,关键步骤是使新的式II甾族中间体:
式II
其中R1和R3独立地选自H、C(O)OR2或COR2,和R1或R2中至少一个是C(O)OR2或COR2;
Z1、Z2、R2和Q如式I定义;
与亲核试剂在路易斯酸催化剂存在下反应,所述亲核试剂选自三C1-4-烷基甲硅烷基氰化物、三C1-4-烷基甲硅烷基烯醇醚、三C1-4-烷基甲硅烷基氧基烯酮硫缩醛(即RCH=C(OSiRC1-6烷基)SRC1-6烷基)、烯丙基三-C1-4-烷基硅烷、烯丙基三-C1-4-烷基锡烷、2-C1-4-烷基呋喃和2-C1-4-烷基吡咯。
其中式II化合物具备烯丙基醇衍生物在C-5、-C-6、-C7-OR3的结构单元。利用“烯丙基化”反应的新合成方案在实施方案描述中详细描述。
实施方案说明
定义
在详细描述中,使用如下定义。
术语“烷基”其本身或作为另一取代基的部分是指,除非另有说明,直链或支链,或环状烃基或它们的组合。饱和烃基的实例包括,但不限于,基团,例如甲基、己基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)乙基、环丙基甲基,其同系物和异构体,例如正戊基、正己基、正庚基、正辛基。
单独使用或与其它术语结合使用(例如芳氧基、芳硫基、芳烷基)的术语“芳基”(Ar)是指,除非另有说明,芳香取代基,它可以是单环或多环(至多三环),它们是稠合或共价连接的。
术语亲核试剂是指富电子试剂,如Morrison,R.T.等,Organic Chemistry,第6版,Prentice Hall pub.,1992,第172页所述,它趋向于攻击碳核。
术语路易斯酸是指电子对受体,如McQuarrie,D.A.等,General Chemistry,第3版,WH.Freeman and Company pub.,1991,第665页所述。
实施方案描述
出乎意料的,本发明人发现式II的C-7-羟基-C-5Δ6-烯甾族化合物的羧基衍生物用各种亲核试剂进行烯丙基化反应生成相应的如表1中所示的式I的C-7取代的甾族衍生物。在路易斯酸催化剂存在下,合适的亲核试剂包括,但不限于,三C1-4-烷基甲硅烷基氰化物、三C1-4-烷基甲硅烷基烯醇醚、三烷基甲硅烷基氧基烯酮硫缩醛(即RCH=C(OSiR3)SR烯丙基三-C1-4-烷基硅烷、烯丙基三-C1-4-烷基锡烷、2-C1-4-烷基呋喃和2-C1-4-烷基吡咯。合适的路易斯酸包括,但不限于过渡元素三氟甲磺酸盐(OTf=OSO2CF3),例如Sc(OTf)3、Ce(OTf)3、Fe(ClO4)2、Cu(ClO4)2和Yb(OTf)3,和钼(II)配合物,例如Mo(CO)5(OTf)2和[Mo(CO)4Br2]2。
TMSCN=三甲基甲硅烷基氰化物。
表1
然而,在类似条件下,吲哚和苔黑酚得到<10%的收率和复杂的混合物。乙烯基三甲基硅烷和三甲基甲硅烷基乙炔不能反应。
方案概述
如上所述,式I化合物可在环氧孕烯酮合成中用作原料,方案I和II提供了使用通过本发明方法制备的式I化合物制备环氧孕烯酮的实例的方案流程图。
方案I
方案II
原料1的制备(方案I),以两种方法之一得到用于方案I-II的(3β,7β,11α-三羟基-5-雄甾烯-17-酮)。一种方法是首先使5-雄甾烯-3β-醇-17-酮与棉色二孢(Diplodia gossypina)ATCC 20517(synonym Botryodiplodia theobromae IFO6469)的深层培养物接触以产生5-雄甾烯-3β,7β-二醇-17-酮(参见实施例10),随后使5-雄甾烯-3β,7β-二醇-17-酮与赭色曲霉(Aspergillus ochraceus)ATCC18500的深层培养物接触以产生5-雄甾烯-3β,7β,11α-三醇-17-酮1(方案I)。用另一种方法,可以使5-雄甾烯-3β-醇-17-酮与蓝色犁头霉(Absidiacoerulea)ATCC 6647的深层培养物接触以产生5-雄甾烯-3β,7β,11α-三醇-17-酮1(方案I)。
步骤IA和IIB
羟基中间体1和11(方案II)用酰基化试剂在叔有机碱存在下通过现有技术中已知的方法酰基化得到2和12。酰基化试剂包括低级链烷酸酐、低级链烷酰氯、低级烷基羰基氯、低级烷基碳酸酐等。合适的叔有机碱包括吡啶、4-二甲基氨基吡啶、三乙胺、二异丙基乙胺等。或者,混合碳酸酯(RO-CO-O-)制备可通过与烷氧基羰基氧基苯并三唑在叔有机碱存在下用改进的公开方法(Harada,T.等,J.Carbohydrate Chem.,(1995),14,165)反应进行。
步骤I-B和II-E
三酰基化化合物2(方案I)和14(方案II)与亲核试剂在路易斯酸存在下通常在惰性溶剂,例如乙腈或二氯甲烷中反应分别得到3(方案I)和15(方案II)。合适的亲核试剂包括,但不限于,三烷基甲硅烷基氰化物、3-甲硅烷基取代的烯烃,烯醇乙酸酯、甲硅烷基烯醇醚、烯丙基锡烷、N-烷基吡咯、N,N-二烷基苯胺、甲硅烷基烯醇硫酯、甲硅烷基烯醇酯和富电子杂芳族化合物,例如2-烷基取代的呋喃。合适的路易斯酸包括,但不限于过渡元素三氟甲磺酸盐(OTf=OSO2CF3),例如Sc(OTf)3、Ce(OTf)3和Yb(OTf)3,和钼(II)配合物,例如Mo(CO)5(OTf)2和[Mo(CO)4Br2]2。
步骤I-C和II-F
3(方案I)和15(方案II)的酰基水解得到4(方案I)或16(方案II)使用碱土金属氢氧化物、碳酸氢盐或碳酸盐,例如氢氧化钠、碳酸钾、碳酸氢钠、氢氧化铯、碳酸氢锂等,使用甲醇作为溶剂,任选用共溶剂进行。
步骤I-D和II-A
17-氧代中间体4(方案I)和1(方案I)与乙炔根据文献中描述的方法反应得到相应的加成化合物5(方案I)和11(方案II)(参见例如:Schwede,W.等,Steroids,(1998),63 166;Corey,E.J等,J.Amer.Chem.Soc.(1999),121,710-714;Schwede,W.等,Steroids(1998),63(3),166-177;Ali,H.等,J.Med.Chem.(1993),36(21),3061;Turuta,A.M.等,Mendeleev Commun.(1992),47-8;Kumar,V.等,Tetrahedron(1991),47(28),5099;Page,P.C.,Tetrahedron(1991),47,2871-8;Curts,S.W.等,Steroids(1991),56,8;Kataoka,H.等Chem.Lett.(1990),1705-8;Christiansen,R.G.等,J.Med.Chem.(1990),33(8),2094-100)。在步骤II-A中的三羟基化合物可任选在加入乙炔前无需分离被三甲基甲硅烷基化。甲硅烷基化过程用六甲基乙硅氮烷和温和的酸性催化剂,例如三甲基甲硅烷基氯或糖精进行。在加成乙炔后,在用温和无机酸、乙酸、磷酸、四烷基氟化铝等反应处理中除去三甲基甲硅烷基。
步骤E
根据文献中描述的方法(Wuts,P.G.M.等,J.Org.Chem.1989,54,5180;Botteghi,C.等,Tetrahedron,2001,57,1631)邻位羟基内醚中间体6(方案I)和13(方案II)的形成通过用一氧化碳和氢气在催化量的铑催化剂和铑配合配位体存在下5和12的加氢甲酰基化实现。反应在14-500psi,优选100-200psi的压力下进行,氢气与一氧化碳的比率是1/5-5/1,通常是1/1。合适的铑催化剂包括乙酸铑、氯化铑和二羰基乙酰基丙酮根合铑II。合适的配位体包括三芳基膦、三烷基亚磷酸二齿膦,例如xantphos,二齿亚磷酸等。
步骤I-Fa和II-D
6(方案I)氧化至6a(方案I)和16(方案II)氧化成7(方案II)可用各种标准氧化剂实现。合适氧化剂的实例包括碘代琥珀酰亚胺/四丁基碘化铵(Kraus,George A.Bioorganic & Medicinal Chemistry Letters(2000),10(9),895-897;Barrett,A.G.M.等,J.Org.Chem.(1989),54(14),3321);Jones试剂(在丙酮中的铬酸)(Panda,J.等,Tetrahedron Letters(1999),40,6693;Tomioka,K.等,J.Org.Chem.(1988),53(17),4094);碳酸银(Chow,T.J.等,J.Chem.Soc.,PerkinTransactions 1,(1999),1847);氯铬酸吡啶鎓(Uchiyama,M.等,TetrahedronLetters(2000),41(51),10013;Vanderiei,J.M.de L.,Synthetic Communications(1998),28(16),3047;Kassou,M.等,Journal of Organic Chemistry(1997),62,3696;Rehnberg,N.等,J.Org.Chem.(1990),55(14),4340-9;RuO4/四烷基铵盐/叔胺N-氧化物,Jeewoo,K.等,Chem.Lett.(1995),(4),299;重铬酸吡啶鎓,Paquette,L.A.等,J.Am.Chem.Soc.(1995),117(4),1455-6);次氯酸钠/叔胺N-氧化物(Waldemar,A.等,Chem.Rev.,(2001),101,3499);链烷醇铝/丙酮(Ooi,T.等,Synthesis(2002),279);Djerassi,C.等,Org.React.(1951),6,207);三乙酰氧基全碘二氢化茚(Martin,J.C.等,J.Amer.Chem.Soc.,(1991),113,7277)。
步骤Fb
在其中步骤Fa的氧化产生非共轭5-6双键的情况下,6a(方案I)中的双键由C5-6位置向C4-5位置的迁移通过使6a(方案I)与有机或无机酸在惰性有机溶剂或溶剂的含水混合物中在0-80℃的温度下接触完成。合适的有机酸包括,但不限于,甲苯磺酸、甲磺酸、苯磺酸、三氟乙酸、草酸、三氯乙酸等。合适的无机酸包括,但不限于,盐酸、氢溴酸、磷酸、高氯酸等。另一方面,催化剂可以是叔有机碱,例如三乙胺、二氮杂双环十一烷(DBU)等或无机碱,例如氢氧化钠、氢氧化钾、氢氧化钙等。双键迁移在(Bakshi等,U.S.5,237,064;Pollack,等,J.Amer.Chem.Soc.,1987,109,5048;Tsubuki等,J.Org.Chem.,1992,57,2930;Zeng等,J.Amer.Chem.Soc.,1991,113,3838)中描述。
步骤I-H和II-I,J
11-羟基中间体7(方案I)和18(方案II)的脱氢如(US4,559,332)所述用五氯化磷完成。另一方面,如WO97/21720和WO98/25948中所述,11-羟基中间体7(方案I)可转化为磺酰基酯,例如甲磺酸酯或对甲苯磺酸酯,随后用碱处理进行脱水。
步骤I-H和II-H
在7(方案I)中呋喃环降解为8的甲酯(方案II)如实施例中所述通过臭氧分解、氧化和酯化完成。
步骤I-J和II-K
已知的中间体9(方案I)向10(方案I)(环氧孕烯酮)的转化过程在US4,559,332和5,981,744中描述。
实施例
原料1的制备,方法1
步骤1:5-雄甾烯-3β-醇-17-酮向5-雄甾烯-3β,7β-二醇-17-酮的生物转化
5-雄甾烯-3β-醇-17-酮向5-雄甾烯-3β,7β-二醇-17-酮的生物转化过程以10L发酵规模用棉色二孢(Diplodia gossypina ATCC)20517(synonymBotryodiplodia theobromae IFO 6469)的深层培养物进行。
(A)初级接种阶段
解冻冷冻的棉色二孢ATCC 20571植物细胞,转移到马铃薯-葡萄糖-琼脂板(PDA),在28℃培养72小时。单一菌丝体-塞(直径6-7mm)用于接种含有100mL初级接种培养基的硅化500-mL点刻的振荡烧瓶。初级接种培养基由以下成分组成:糊精,50g;soyflour,35g;结晶葡萄糖,5g;氯化钴六水合物,2mg;硅氧烷消泡剂(SAG 471),0.5mL;预杀菌,pH 7.0-7.2,用氢氧化钠(2N)调节。使用设定在280r.p.m.(1”轨道冲程)控制环境培养箱-振荡器将棉色二孢ATCC 20571在28℃培养48小时。
(B)二次接种阶段
10升二次接种发酵物用1.2mL植物初级接种培养物接种(0.012%[v/v]接种率)。二次接种培养基含有(每升RO水):结晶葡萄糖60g;soyflour,25g;大豆油,30mL;硫酸镁七水合物,1g;磷酸二氢钾,0.74g;聚氧乙烯山梨糖醇单油酸酯,2mL;硅氧烷消泡剂(SAG 471),0.5mL;预杀菌pH 3.95-4.00,用浓硫酸调节。含有二次接种培养基的发酵器用夹套和注射蒸汽在121℃杀菌20分钟。杀菌时搅拌速率是200r.p.m.,后杀菌,培养基pH用无菌硫酸(5%)调节至4.0。采用如下初始参数在28℃培养棉色二孢ATCC 20571:搅拌,100r.p.m.;背压=5psig;空气流量=2.5SLM(0.25VVM);低DO设定点,30%;pH控制,无。当DO首次下降至30%时,空气流量增加至5SLM(0.5VVM)。当培养物重新达到低DO时,用搅拌控制保持30%DO。在接种后约60小时,当OUR在约10-15mM/L/h时,收获二次接种培养物。
(C)甾族化合物生物转化
将10升甾族化合物生物转化发酵物用500mL植物二次接种培养物接种(5%[v/v]接种率),甾族化合物生物转化培养基与二次接种培养基相同。杀菌条件和pH调节如二次接种培养基所述。棉色二孢ATCC 20571在28℃下用基本上与用于二次接种培养使用的相同初始参数培养,只是低DO设定点由30%增加到50%。当DO首次下降至50%时,空气流量由2.5SLM(0.25VVM)增加至5SLM(0.5VVM)。当培养基重新达到低DO时,用搅拌控制保持50%DO。在接种后24小时开始,以1小时间隔向发酵物中加入在最少体积的0.2%聚氧乙烯山梨糖醇单油酸酯中成浆的微粉化5-雄甾烯-3β-醇-17-酮,直至加入总共400g。在接种后约3天,向10-L发酵物中加入附加的100g结晶葡萄糖。
每日用TLC分析生物转化培养物的5-雄甾烯-3β,7β-二醇-17-酮。用10mL甲醇萃取1毫升全啤酒。通过离心(3,000xg 10分钟)由含水甲醇混合物分离细胞,几微升用于TLC板。TLC板在环己烷∶乙酸乙酯∶甲醇(90∶60∶15)中展开,通过用50%硫酸喷洒TLC观察到产物,随后在烘箱中炭化。产物与在喷洒50%硫酸时转变为蓝色的真实标准比较。5-雄甾烯-3β-醇-17-酮向5-雄甾烯-3β,7β-二醇-17-酮的生物转化在接种后约4天完成。
(D)分离方法
离心收获的全啤酒,通过离心回收富集固体,富集固体用10升二氯甲烷萃取,离心收集富集萃取物。精制萃取物,通过蒸馏浓缩至约1升,结晶浆状物冷却到-10℃。经过滤回收结晶,用冷的二氯甲烷洗涤以脱色,干燥得到227g纯化的结晶5-雄甾烯-3β,7β-二醇-17-酮。
步骤2:5-雄甾烯-3β,7β-二醇-17-酮向5-雄甾烯-3β,7β,11α-三醇-17-酮的生物转化
5-雄甾烯-3β,7β-二醇-17-酮向5-雄甾烯-3β,7β,11α-三醇-17-酮的生物转化以10L发酵物规模用赭色曲霉(Aspergillus ochraceus)ATCC 18500(synonym NRRL 405)的深层培养物进行。
(A)初级接种阶段
如实施例12中用于棉色二孢ATCC 20571所述制备赭色曲霉ATCC18500初级接种培养物。
(B)二次接种阶段
10升二次接种发酵物用1.2mL植物初级接种培养物接种(0.012%[v/v]接种率)。二次接种培养基含有(每升RO水):结晶葡萄糖40g;soyflour,25g;大豆油,30mL;硫酸镁七水合物,1g;磷酸二氢钾,0.74g;壬基苯氧基聚乙氧基乙醇0.25mL;硅氧烷消泡剂(SAG 471),0.5mL;预杀菌pH 3.95-4.00,用浓硫酸调节。含有二次接种培养基的发酵器用夹套和注射蒸汽在121℃杀菌20分钟。杀菌时搅拌速率是200r.p.m.,后杀菌,培养基pH用无菌硫酸(5%)调节至4.0。采用如下初始参数在28℃培养Aspergillus ochraceus ATCC18500:搅拌,100r.p.m.;背压=5psig;空气流量=2.5SLM(0.25VVM);低DO设定点,50%;pH控制,无。当DO首次下降至50%时,空气流量增加至5SLM (0.5VVM)。当培养物重新达到低DO时,用搅拌控制保持50%DO。在接种后50-54小时,当OUR在约20-26mM/L/h时,收获二次接种培养物。
(C)甾族化合物生物转化
10升甾族化合物生物转化发酵物用500mL植物二次接种培养物接种(5%[v/v]接种率)。甾族化合物生物转化培养基与二次接种培养基基本相同,只是壬基苯氧基聚乙氧基乙醇由0.25mL/L增加至2mL/L,预杀菌pH用浓硫酸调节至2.95-3.00。杀菌条件如二次接种培养基所述。接种后,培养基pH用无菌浓硫酸(5%)调节至3.0。赭色曲霉ATCC18500在28℃下用基本上与用于二次接种培养的相同初始参数培养,只是搅拌最初设定为200r.p.m.。在接种后约18小时,向10-L发酵物中加入在最少体积的0.2%壬基苯氧基聚乙氧基乙醇中成浆的200g微粉化5-雄甾烯-3β,7β-二醇-17-酮。
如实施例10所述,每日用TLC分析生物转化培养物的5-雄甾烯-3β,7β,11α-三醇-17-酮。5-雄甾烯-3β,7β-二醇-17-酮向5-雄甾烯-3β,7β,11α-三醇-17-酮的生物转化在接种后约4天完成。
(D)分离方法
离心回收全啤酒固体,弃掉液体。富集固体用10升的80%丙酮20%水在45-50℃下萃取,通过过滤温萃取物变得澄清。通过蒸馏浓缩富集滤液以除去丙酮得到粗结晶的含水浆状物。过滤回收粗结晶,弃掉母液。水湿结晶在600mL二氯甲烷中研制以除去杂质,溶解在700mL甲醇(加热至55℃)中,随后用5g Darco G-60 carbon脱色。在过滤除去碳后,滤液浓缩以结晶产物。通过加入300mL乙酸正丁基酯和浓缩至粘稠结晶浆状物进一步除去甲醇。过滤结晶,用乙酸正丁基酯洗涤,干燥得到158g纯化的结晶5-雄甾烯-3β,7β,11α-三醇-17-酮。
1的制备,方法2:5-雄甾烯-3β-醇-17-酮向5-雄甾烯-3β,7β,11α-三醇-17-酮的生物转化
5-雄甾烯-3β-醇-17-酮向5-雄甾烯-3β,7β,11α-三醇-17-酮的生物转化以10L发酵物规模用蓝色犁头霉(Absidia coerulea)ATCC 6647的深层培养物进行。
(A)初级接种阶段
如实施例12中用于棉色二孢ATCC 20571所述制备蓝色犁头霉ATCC6647初级接种培养物。
(B)二次接种阶段
10升二次接种发酵物用1.2mL植物初级接种培养物接种(0.012%[v/v]接种率)。二次接种培养基含有(每升RO水):糖精50g;soyflour,35g;结晶葡萄糖,5g;氯化钴六水合物,2mg;硅氧烷消泡剂(SAG 471),0.5mL;预杀菌pH 4.95-5.00,用浓硫酸调节。含有二次接种培养基的发酵器用夹套和注射蒸汽在121℃杀菌20分钟。杀菌时搅拌速率是200r.p.m.,杀菌后,培养基pH用无菌硫酸(5%)调节至5.0。采用如下初始参数在28℃培养蓝色犁头霉ATCC 6647:搅拌,100r.p.m.;背压=5psig;空气流量=2.5SLM(0.25VVM);低DO设定点,50%;pH控制,无。当DO首次下降至30%时,空气流量增加至5SLM(0.5VVM)。当培养物重新达到低DO时,用搅拌控制保持30%DO。在接种后约76小时,当OUR在约4-7mM/L/h时,收获二次接种培养物。
(C)甾族化合物生物转化
10升甾族化合物生物转化发酵物用500mL植物二次接种培养物接种(5%[v/v]接种率),甾族化合物生物转化培养基含有(每升RO水):糖精50g;soyflour,35g;结晶葡萄糖,20g;硅氧烷消泡剂(SAG 471),0.5mL;预杀菌pH 2.95-3.00,用浓硫酸调节。杀菌条件如二次接种培养基所述。杀菌后,培养基pH用无菌浓硫酸(5%)调节至3.0。蓝色犁头霉ATCC 6647在28℃下用与用于二次接种培养的相同初始参数培养。在接种后约17小时,向10-L发酵物中加入在最少体积的0.2%辛基苯氧基聚乙氧基乙醇中成浆的200g微粉化5-雄甾烯-3β-醇-17-酮。
如实施例1所述,每日用TLC分析生物转化培养物的5-雄甾烯-3β,7β,11α-三醇-17-酮。5-雄甾烯-3β-醇-17-酮向5-雄甾烯-3β,7β,11α-三醇-17-酮的生物转化在接种后约6-7天完成。
(D)分离方法
用离心回收全啤酒固体,弃掉液体。富集固体用10升的85%丙酮15%水在45-50℃下萃取,温萃取物通过过滤变得澄清。通过蒸馏浓缩富集滤液以除去丙酮得到粗结晶的含水浆状物。过滤结晶浆状物,弃掉母液。水湿结晶在600mL二氯甲烷中研制以除去杂质,溶解在700mL甲醇(加热至55℃)中,随后用5g Darco G-60炭脱色。在过滤除去炭后,滤液浓缩以结晶产物。通过加入300mL乙酸正丁基酯和浓缩至粘稠结晶浆状物进一步除去甲醇。过滤结晶,用乙酸正丁基酯洗涤,干燥得到75.5g粗结晶5-雄甾烯-3β,7β,11α-三醇-17-酮。
粗结晶在600mL二氯甲烷中研制以除去其它杂质,溶解在700mL甲醇(加热至55℃)中,随后用5g Darco G-60炭脱色。在过滤除去炭后,滤液浓缩以结晶产物。通过加入300mL乙酸正丁基酯和浓缩至粘稠结晶浆状物进一步除去甲醇。过滤结晶,用乙酸正丁基酯洗涤,干燥得到42.1g纯化的结晶5-雄甾烯-3β,7β,11α-三醇-17-酮。
实施例1:三碳酸酯2的制备
向3N 250ml RBF中加入溶解在吡啶(100ml)中的三醇1(方案I)(10.00g,31mmol)。向该溶液中加入三乙胺(31ml,218mmol)、甲氧羰基苯并三唑(24.2g,125mmol)和4-N,N-二甲基氨基吡啶(1.2g,9.4mmol)。得到的浆状物搅拌2小时,此时全部溶解。加入附加的甲氧羰基苯并三唑(12g,62mmol)和三乙胺(10ml,73mmol)。一旦固体溶解,则反应完成。缓慢加入水(300ml),混合物在冰浴中冷却。过滤出沉淀,用10%HCl(2×35ml)和己烷(3×50ml)洗涤,在真空烘箱中干燥24小时得到标题化合物2(方案I)。13C NMR(CDCl3)δ 217.78,155.60,155.23,154.88,144.48,122.35,78.58,76.81,75.39,55.29,54.93,51.09,49.47,47.79,38.48,37.89,36.19,36.08,27.96,23.58,19.07,14.40。
实施例2:呋喃3的制备(方案I)
三碳酸酯2(1.0g,2.02mmol)在7mL乙腈中的溶液在室温下用2-甲基呋喃(0.2mL,2.22mmol)和0.298g Sc(OTf)3处理1小时。TLC(30%EtOAc/Hex)显示反应完成。在硅胶上用25%EtOAc/Hex进行色谱纯化得到0.92g(96%收率)呋喃3。13C NMR(CDCl3)δ 217.88,171.08,155.34,154.93,152.38,151.49,140.72,123.98,110.56,106.45,77.50,75.89,60.51,54.98,54.71,47.45,46.57,38.73,37.66,36.21,35.91,27.96,22.22,19.14,13.98,13.77。
实施例3:二醇4的制备(方案I)
二碳酸酯3(1.0g)在10mL MeOH中的溶液用500mg K2CO3处理,加热到40℃。搅拌混合物考虑到TLC显示反应完成。反应完成后将浆状物倾入水中,用EtOAc分离产物,浓缩有机物得到二醇4粘稠油状物。
1H NMR(CDCl3)δ 5.7(s,H),5.45(d,J=5.7Hz,1H),3.45(m,1H),3.29(t,J=5.1Hz,1H),2.09(s,3H),1.1(s,3H),0.75(s,3H)。
实施例4:炔5的制备(方案I)
2.8g(25.0mmol)t-BuOK在50mL THF中的溶液在-10℃下用乙炔鼓泡30分钟,随后缓慢加入酮11在10mL THF中的溶液,同时持续乙炔鼓泡。混合物在-10℃下搅拌1小时,随后加入在10mL水中的2.0mL乙酸。在混合物倾入水中后,经EtOAc萃取分离产物。用甲苯经共沸除去乙酸。NMR谱显示存在少量乙酸和甲苯;产量2.25g。13C NMR(CDCl3)δ153.77,151.21,142.66,122.83,110.12,106.1,87.3,79.42,74.03,72.29,69.48,50.61,47.49,45.70,43.64,42.87,39.38,39.06,38.29,37.68,31.84,23.7,21.26,19.27,14.19,13.9。
实施例5:邻位羟基内醚6的制备(方案I)
将1.55g炔5(方案I)、27mg Rh2(OAc)2和92mg Ph3P在20mL EtOAc中的溶液用CO和H2加压至100psi,加热至80℃过夜。浓缩混合物,在硅胶上用90%EtOAc/Hex进行色谱纯化得到两个馏分。经NMR显示馏分1是回收的原料,馏分2是所需的邻位羟基内醚。CMR显示邻位羟基内醚混合物的信号在94.8和94.5ppm。
实施例6:5,6-烯酮6a的制备(方案I)
将2.0g邻位羟基内醚、50mg KBr、12mg TEMPO、800mg NaHCO3在20mL CH2Cl2和5mL水中的混合物冷却到5℃,混合物随后缓慢地用8mL 1.1M NaOCl处理,同时保持温度低于6℃。在加完后,混合物再搅拌30分钟,随后用CH2Cl2分离产物得到6a(方案I)。13C NMR(CDCl3)δ 209.82,176.37,153.19,151.78,143.34,128.15,121.41,110.62,106.53,94.35,72.0,55.39,50.44,47.99,44.41,42.26,39.03,38.63,37.1,35.67,31.9,29.19,23.39,18.33,15.69,14.07。
实施例7:使用酸制备4,5-烯酮7(方案I)
将5,6-烯酮6a(方案I)(500mg)和草酸(200mg)在乙醇(10ml)中的混合物在40℃加热3小时,减压除去乙醇,残余物溶解在乙酸乙酯(50ml)中,有机溶液用水(2×50ml)洗涤,用硫酸钠干燥并浓缩。残余物经硅胶柱色谱纯化得到4,5-烯酮7(方案I)。
实施例8:用碱制备4,5-烯酮7
将5,6-烯酮6a(500mg)和DBU(200mg)在四氢呋喃(5ml)中的混合物回流加热3小时,随后冷却,用氯化铵溶液稀释,用乙酸乙酯萃取。萃取液用硫酸钠干燥并浓缩。残余物经硅胶柱色谱纯化得到4,5-烯酮7。
实施例9:二烯酮的制备(方案I)
将1.2g醇7溶解在10mL THF中,所得溶液冷却到-33℃。随后一次加入PCl5(950mg)。溶液在-33℃搅拌3小时,随后加入水猝灭。用EtOAc分离产物得到二烯9(方案I),它用硅胶色谱分离用EtOAc/Hex纯化。
实施例10:由呋喃取代基制备甲酯
方法A
将呋喃衍生物8(方案I)(1.0g,2.280mmol)在100ml二氯甲烷中的溶液冷却到-79℃,将O3/O2通过溶液10分钟,随后将混合物温热到室温,浓缩至固体残余物,将其溶解在50ml 1/1甲醇/二氯甲烷中,用1.0ml吡啶处理,在室温下搅拌18小时。将溶液冷却到-80℃,随后将O3/O2气流通过溶液4分钟。混合物随后用100ml乙酸乙酯稀释,用70ml碳酸氢钠水溶液萃取。水相用含水盐酸酸化至pH 0.5,随后用二氯甲烷萃取,浓缩至泡沫状物(重量:250mg)。将泡沫状物溶解在甲苯/甲醇中,在室温下用三甲基甲硅烷基重氮甲烷(0.5ml 2.0M己烷溶液,1.0mmol)处理,随后浓缩溶液得到酯9油状物。
方法B
步骤1)5α,17β-二羟基孕-9(11)-烯-3-酮,7α,21-二羧酸,双-γ-内酯8a(方案I)
将17β-羟基-7α-(5’-甲基-2’-呋喃基)-孕-4,9(11)-二烯-3-酮-21-羧酸,γ-内酯(100g,0.23778mol)和乙酸钾(50.0g,0.5094mol,2.14当量)在丙酮(500ml)和水(150ml)中的混合物冷却到-10℃,用dibromantin(34.0g,0.1189mol,0.50摩尔当量)在水(100ml)中的浆状物处理直至出现氧化还原电势升高。此时,LC分析显示完成转化为烯二酮(III-顺)。含有烯二酮(III-顺)的反应混合物随后用异丁基乙烯基醚(1.0ml,0.768g,7.668mmol,0.032当量)猝灭,浓缩到粘稠浆状物,用二氯甲烷(200ml)稀释,用20℃浓盐酸(50.0ml,0.50mol,2.10当量)处理。混合物在20-25℃搅拌2小时,此时,LC分析显示完全转化为烯二酮(III-顺)。分离出含有烯二酮(III-反)的有机相,用二氯甲烷(80ml)和甲醇(300ml)稀释,冷却到-48℃。将O3/O2气流鼓泡通过该混合物直至LC分析显示烯二酮(III-反)完全消失,随后混合物用二甲基硫醚(30.0ml,25.38g,0.4085mol,1.72当量)猝灭,在-10℃搅拌16小时,浓缩至约300ml的体积,用甲醇(350ml)稀释,浓缩至约300ml的体积,用异丙醇(40ml)和甲醇(80ml)稀释,随后用碳酸氢钾(120g,1.1986mol,5.04当量)在水(240ml)中的温(55-60℃)溶液处理。将该浆状物冷却到5-10℃,在3小时内加入过氧化氢(50%,66.0g,含有33.0g(0.9703mol,4.08当量)过氧化氢)。混合物搅拌4小时,用二甲基硫醚(40ml,33.84g,0.5447moles,2.29当量)猝灭。在20-25℃下搅拌23小时后,混合物用二氯甲烷(100ml)和水(80ml)稀释,用浓盐酸酸化至pH=3.0。将两相混合物加热至36℃,进行相分离,水相用二氯甲烷(100ml)萃取,合并有机相,用水(75ml)洗涤,水相用二氯甲烷(25ml)反萃取。合并有机相,浓缩到150ml的体积,随后用苯磺酸(1.0g 90%纯原料,含有0.90g(5.690mmol,0.0239当量)苯磺酸)和丙酮(50ml)处理。混合物常压浓缩至160ml的体积,随后用丙酮(250ml)稀释,浓缩至200ml的体积,冷却到12℃,过滤。滤饼用冷丙酮(2×25ml)洗涤,用氮气气流干燥得到标题化合物,CMR(100MHz,CDCl3)206.08,176.47,175.41,139.63,124.00,94.89,90.97,47.08,43.90,42.36,41.58,41.07,38.93,36.97,35.16,33.01,32.42,32.42,31.35,29.10,23.08,22.98和14.23δ;NMR(400MHz,CDCl3)0.94,1.40,1.4-2.8和5.70;MS(CI,NH3)m/e=385(P+H,100%)。
步骤2)17β-羟基-7α-羰基甲氧基孕-4,9(11)-二烯-3-酮-21-羧酸,γ-内酯9(方案I)
将5α,17β-二羟基孕-9(11)-烯-3-酮,7α,21-二羧酸,双-γ-内酯(50.0g,0.13005mol)和碳酸氢钾(16.92g,0.1690mol,1.30当量)在丙酮(200ml)和水(100ml)中的混合物在45℃下搅拌2小时,此时LC显示5,7-内酯(VII)向羧酸(VI)的转化完成。得到的混合物随后用二甲基硫醚(22.92g,0.1817mol,1.40当量)处理,在45℃下搅拌3小时,随后用碳酸氢钾(1.3g,0.0130mol,0.100当量)在水(10ml)中的溶液和纯三乙胺(1.81ml,1.314g,0.0130mol,0.100当量)处理。混合物在45℃下搅拌1小时,用浓盐酸(1.92ml,2.304g,含有0.852g(0.0234mol,0.180当量)盐酸)猝灭,冷却到0℃,减压浓缩至150ml的体积(釜温13℃),随后过滤,滤饼用水(2×25ml)洗涤,干燥得到标题化合物9(方案I)。
实施例11:制备环氧孕烯酮
如US4,559,332和5,981,744,和WO97/21720和WO98/25948中所述,二烯酮9(方案I)被氧化得到环氧孕烯酮。
实施例12:三甲基甲硅烷基氰与I的烯丙基化作用
将三乙酸酯I(表1)(1.0g,2.24mmol)在10mL CH2Cl2中的溶液冷却到14℃,用0.6ml TMSCN和100mg Sc(OTf)3处理。混合物搅拌5小时,用乙酸乙酯萃取。在浓缩萃取物过程中,由溶液中沉淀出结晶。过滤出结晶,干燥得到腈18,是异构体的混合物。13C NMR(CDCl3,混合物)δ147.31,146.0,131.68,129.39,128.12,119.23,115.47,115.04,62.74,82.50,51.13,49.0,47.72,44.38,43.67,43.05,37.32,37.04,36.32,33.58,32.09,32.0,27.92,27.79,26.75,23.68,23.32,20.45,19.13,18.26,12.30。
实施例13:烯丙基三甲基甲硅烷与V的烯丙基化作用
在室温下用Sc(OTf)3处理三乙酸酯V(表1)和烯丙基三甲基硅烷在乙腈中的溶液。1小时后,缓慢加入水以沉淀产物。过滤和干燥得到烯丙基衍生物19。13C NMR(CDCl3)δ 221.05,170.89,193.87,137.62,127.15,116.36,74.26,47.81,46.29,38.61,37.49,36.23,35.61,35.31,31.57,28.04,22 61,20.56,19.64,13.48。
实施例14:乙炔与17-氧代中间体的加成
步骤1:
将六甲基乙硅氮烷(HMDS)(100ml)加入50.0g三醇1在400ml二氯甲烷中的搅拌浆状物中。加入糖精(0.57g),混合物回流加热3小时,在此期间浆状物逐渐溶解成透明琥珀色溶液。加入水(5ml)以猝灭任何过量的HMDS。在回流5分钟后,混合物通过在350ml粗玻璃料填料漏斗中32.6g酸式硅酸镁的CH2Cl2湿层过滤。滤液应是透明和几乎无色的。滤饼用2×100mlCH2Cl2洗涤,合并的滤液减压浓缩,通过与2×500ml部分的四氢呋喃一起蒸发除去残余二氯甲烷,在每次加入后浓缩至干得到白色固体。
步骤2:
用冰/甲醇浴将叔丁醇钾(42.0g)在500ml THP中的悬浮液冷却到-9℃±5℃,在温和搅拌下乙炔鼓泡入表面下混合物中至少1小时。将在THF(400ml)中的如上得到的甲硅烷基化甾族中间体在30分钟内加入,同时保持0℃±5℃的反应温度。加完后,在5℃±5℃下再搅拌混合物1小时。缓慢加入水(100ml)使反应混合物温热到15℃±5℃,缓慢加入125ml 10% HCl以降低pH至2.5-3。混合物在pH 2.5-3下在20℃±5℃下搅拌1-2小时,根据需要加入少量5%HCl以保持pH 2.5-3。当水解完成时,加入半饱和的NaHCO3溶液以提高pH至5.5-6。混合物用乙酸乙酯(500ml)稀释,分相。水相用乙酸乙酯萃取,合并的乙酸乙酯相用水、盐水洗涤,用硫酸镁干燥,浓缩得到加成产物2。13C NMR(DMSO-d6)δ141.99,127.38,89.37,77.73,75.24,72.13,70.54,67.68,54.13,49.57,47.43,43.94,42.58,40.52,40.22,39.01,38.09,31.95,25.8,18.58,14.09。
实施例15:羟基乙酰基化:
将四醇11(方案II)(50.00g,144mmol)溶解在吡啶(150ml)中的混合物在冰浴中冷却到<10℃。加入二甲基氨基吡啶(DMAP)(1.7g,14mmol),随后以保持溶液温度低于10℃的速率缓慢加入乙酐(41.4ml,439mmol)。加完后,反应混合物温热到室温,混合物用乙酸乙酯(75ml)和水(50ml)稀释,搅拌5分钟,分层。有机层用10% HCl(4×25ml)和水(2×50ml)洗涤,用MgSO4干燥并浓缩。产物由甲苯(100ml)重结晶。13C NMR(CDCl3)δ170.68,170.10,143.48,128.90,128.10,125.17,122.59,86.63,78.21,75.07,74.40,72.79,71.47,50.16,48.07,47.02,38.76,38.06,37.83,37.67,36.92,27.66,24.18,21.74,21.44,18.65,13.06。
实施例16:乙炔加合物的加氢甲酰基化
将三乙酸酯12(方案II)(25.4g,54mmol)、PPh3(2.13g,8.1mmol)和Rh2(OAc)4(716mg,1.62mmol)在乙酸乙酯(200ml)中的溶液在80℃在氢气/一氧化碳的1/1混合物下在170psi压力下加热12小时。混合物减压浓缩,产物13(方案II)用柱色谱(70/30EtOAc/Hex和500g硅胶)纯化。由于开环和闭环异构体该化合物的CMR谱是复杂的,没有完全表征。
实施例17:邻位羟基内醚氧化成内酯
将邻位羟基内醚4(方案I)(25g,50mmol)、二氯甲烷(250ml)、水(38ml)、2,2,6,6-四甲基哌啶-1-基氧基(TEMPO)(156mg,1mmol)、KBr(595mg,5mmol)和NaHCO3(5.5g,65mmol)的混合物在冰浴中冷却到<10℃。缓慢加入次氯酸钠(NaOCl)的1.1M溶液(50ml,55mmol)。使混合物温热至室温,用水(50ml)稀释。分层,有机层用盐水(2×50ml)洗涤,有机层用MgSO4干燥,过滤和浓缩得到5,灰白色泡沫状物。13C NMR(CDCl3)δ177.94,172.60,172.15,171.58,145.49,124.36,96.18,(79.22,78.90,78.59 CDCl3),76.59,74.57,72.63,52.14,49.55,47.75,40.00,39.75,39.61,38.65,37.47,32.74,30.85,29.56,26.01,23.61,23.37,23.17,23.11,20.52,16.19。
实施例18:呋喃化
将三乙酸酯14(方案I)(1.30g,2.58mmol)、2-甲基呋喃(0.8mL)在25mL乙腈中的溶液在20℃用250mg Sc(OTf)3处理,随后搅拌1小时。通过EtOAc萃取分离产物,用40% EtOAc/Hex经硅胶柱色谱纯化得到1.0g(74%收率)呋喃15。13CNMR(CDCl3)δ176.27,170.45,169.85,152.53,150.96,140.60,123.45,110.05,106.01,94.95,73.39,71.37,46.50,45.40,44.60,38.55,38.37,38.06,37.78,37.74,36.89,35.41,31.81,30.72,28.96,28.93,27.69,23.07,22.63,21.74,20.98,18.80,14.83,14.13,14.06,13.62。
实施例19:乙酸酯水解
将810mg二乙酸酯15(方案II)、112mg K2CO3在20mL甲醇中的混合物在室温下搅拌过夜。TLC显示反应未完全,因而加入附加的100mg K2CO3,持续搅拌直至TLC显示完全反应。混合物用1MHCl酸化,产物用EtOAc萃取。用100% EtOAc经硅胶色谱分离得到610mg(89.5%收率)二醇16(方案II)。13C NMR(CDCl3)δ176.68,153.20,150.79,142.05,122.32,109.80,105.94,95.3,71.83,68.64,50.13,45.81,44.88,42.73,42.62,39.01,38.56,37.73,36.81,35.44,31.57,30.84,29.06,23.13,18.81,15.27,13.64。
实施例20:16氧化制备17
将二醇16(方案II)溶解在2mL甲苯和0.1mL丙酮中,用50mg异丙醇铝处理,加热至100℃。几小时后,显示未转化,因而加入0.1mL环己酮,混合物加热过夜。使用乙酸乙酯作洗脱剂经硅胶色谱分离得到产物17(方案II)。13C NMR(CDCl3)δ199.96,177.05,170.32,153.34,150.74,126.7,109.14,106.33,95.54,69.08,52.50,46.26,46.0,43.58,40.13,39.05,38.8,37.93,36.92,35.66,34.59,31.33,29.47,23.06,18.83,16.01,13.90。
Claims (8)
3、权利要求1的方法,其进一步包括下列步骤:
a)使式1的酮甾族化合物与氯甲酸C1-C6烷基酯或氯甲酸苄基酯或烷氧基羰基苯并三唑在叔有机碱存在下反应得到其中R是C1-C6烷基或苄基的式2的三碳酸酯;
式2
b)使式2的三酰基化合物与2-C1-C6烷基呋喃在路易斯酸催化剂存在下反应得到式3的二酰基酯化合物;
式3
c)在碱存在下水解式3的二酰基酯化合物得到式4的二羟基酯;
式4
d)使式4的化合物与乙炔在强碱存在下反应得到式5的乙炔化合物;
式5
e)使式XVII的乙炔化合物与一氧化碳在铑催化剂配位体存在下反应得到式6的邻位羟基内醚;
式6
f)氧化式6的邻位羟基内醚得到式6a的内酯;
式6a
g)异构化6a的4,5-双键得到式7的内酯;
式7
h)溴化、臭氧化、氧化和酯化式7化合物得到式8的酯;
式8
i)式8的化合物脱水得到式9的中间体;
式9
j)氧化式9的二烯酮从而得到环氧孕烯酮(式10)。
式10
7、通过如下方法制备的产物,所述方法包括下列步骤:
a)使5-雄甾烯-3β,7β,11α-三醇-17-酮与与乙炔反应得到式11的化合物;
b)酰基化式11化合物得到式12的化合物;
c)加氢甲酰基化式12化合物得到式13化合物;
d)氧化式13化合物得到式14化合物;
e)使式14化合物与2-烷基呋喃在路易斯酸存在下接触得到式15化合物;
f)水解式15化合物得到式16化合物;
g)氧化式16化合物得到式17化合物;
h)转化式17化合物的呋喃环为式18的甲氧基羰基化合物;
i)转化式18化合物为式19的磺酸酯;
j)除去式19的磺酸酯基得到式9的化合物;
k)氧化式9的化合物得到式10的化合物,环氧孕烯酮。
8、权利要求6的制备环氧孕烯酮的方法,其还包括在与乙炔反应前甲硅烷基化式1的化合物以得到甲硅烷基化中间体和在分离式11化合物过程中除去所述甲硅烷基。
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CN105753930A (zh) * | 2016-03-30 | 2016-07-13 | 北京万全德众医药生物技术有限公司 | 依普利酮的一种合成方法 |
CN103087139B (zh) * | 2011-11-08 | 2016-08-03 | 中国科学院上海药物研究所 | 一种坎利酮衍生物类甾体化合物、其制备方法及其在制备依普利酮中的用途 |
CN110698529A (zh) * | 2019-11-19 | 2020-01-17 | 湖南新合新生物医药有限公司 | 一种依普利酮中间体△9,11烯酯的制备方法 |
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US7235655B2 (en) * | 2002-03-22 | 2007-06-26 | Pharmacia & Upjohn Company | Processes to prepare eplerenone |
CN1321128C (zh) * | 2005-07-15 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | 孕甾-4-烯-7,21-二甲酸,9,11-环氧-17-羟基-3-氧代,γ-内酯,甲酯,(7α,11α,17α)-的制备方法 |
CN101472579B (zh) * | 2006-04-22 | 2013-07-03 | 霍利斯-伊登医药公司 | 药物和用途 |
KR20080112413A (ko) * | 2006-04-22 | 2008-12-24 | 홀리스-에덴 파마슈티칼즈, 인코포레이티드 | 약물 및 그 용도 |
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US8486926B2 (en) * | 2006-11-17 | 2013-07-16 | Harbor Therapeutics, Inc. | Steroid tetrol solid state forms |
US20080221074A1 (en) * | 2006-11-17 | 2008-09-11 | Jaime Flores-Riveros | Drug Screen and Treatment Method |
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CN105753930A (zh) * | 2016-03-30 | 2016-07-13 | 北京万全德众医药生物技术有限公司 | 依普利酮的一种合成方法 |
CN110698529A (zh) * | 2019-11-19 | 2020-01-17 | 湖南新合新生物医药有限公司 | 一种依普利酮中间体△9,11烯酯的制备方法 |
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