JP6116550B2 - エステトロール中間体を製造するための方法 - Google Patents
エステトロール中間体を製造するための方法 Download PDFInfo
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- JP6116550B2 JP6116550B2 JP2014513213A JP2014513213A JP6116550B2 JP 6116550 B2 JP6116550 B2 JP 6116550B2 JP 2014513213 A JP2014513213 A JP 2014513213A JP 2014513213 A JP2014513213 A JP 2014513213A JP 6116550 B2 JP6116550 B2 JP 6116550B2
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- 238000000034 method Methods 0.000 title claims description 52
- AJIPIJNNOJSSQC-NYLIRDPKSA-N estetrol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)[C@@H]4O)O)[C@@H]4[C@@H]3CCC2=C1 AJIPIJNNOJSSQC-NYLIRDPKSA-N 0.000 title claims description 15
- 229950009589 estetrol Drugs 0.000 title claims description 15
- 230000008569 process Effects 0.000 title claims description 10
- 239000000543 intermediate Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- -1 metal hydride compounds Chemical class 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 20
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 238000005695 dehalogenation reaction Methods 0.000 claims description 4
- 230000026030 halogenation Effects 0.000 claims description 4
- 238000005658 halogenation reaction Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 3
- 230000031709 bromination Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- NBWIIOQJUKRLKW-UHFFFAOYSA-N chloro(phenyl)silane Chemical compound Cl[SiH2]C1=CC=CC=C1 NBWIIOQJUKRLKW-UHFFFAOYSA-N 0.000 claims description 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- PSNSVDSRLUYDKF-UHFFFAOYSA-N methyl benzenesulfinate Chemical compound COS(=O)C1=CC=CC=C1 PSNSVDSRLUYDKF-UHFFFAOYSA-N 0.000 claims description 3
- CECDAUNJGIUIIW-UHFFFAOYSA-N methyl pyridine-2-sulfinate Chemical group COS(=O)C1=CC=CC=N1 CECDAUNJGIUIIW-UHFFFAOYSA-N 0.000 claims description 3
- PZABZCASVQXUET-UHFFFAOYSA-N phenylsilyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O[SiH2]C1=CC=CC=C1 PZABZCASVQXUET-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910010082 LiAlH Inorganic materials 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- OMGWPAUMPKUGQL-UHFFFAOYSA-N methyl 4-chlorobenzenesulfinate Chemical compound COS(=O)C1=CC=C(Cl)C=C1 OMGWPAUMPKUGQL-UHFFFAOYSA-N 0.000 claims description 2
- MGPLBSPZSIFUQX-LLVKDONJSA-N methyl 4-methylbenzenesulfinate Chemical compound CO[S@@](=O)C1=CC=C(C)C=C1 MGPLBSPZSIFUQX-LLVKDONJSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 9
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229960003399 estrone Drugs 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000002657 hormone replacement therapy Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- DRKMXSPELWRTIG-UHFFFAOYSA-M cesium chloride heptahydrate Chemical compound O.O.O.O.O.O.O.[Cl-].[Cs+] DRKMXSPELWRTIG-UHFFFAOYSA-M 0.000 description 3
- 229910021419 crystalline silicon Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 3
- 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 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 206010047791 Vulvovaginal dryness Diseases 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- LSJFMTWFOIHWKQ-UHFFFAOYSA-N prop-1-en-2-yl 2-methylpropanoate Chemical compound CC(C)C(=O)OC(C)=C LSJFMTWFOIHWKQ-UHFFFAOYSA-N 0.000 description 2
- PDBWEHKCAUAROT-UHFFFAOYSA-N prop-1-en-2-yl butanoate Chemical compound CCCC(=O)OC(C)=C PDBWEHKCAUAROT-UHFFFAOYSA-N 0.000 description 2
- NLDFTWSUPLJCQD-UHFFFAOYSA-N prop-1-en-2-yl propanoate Chemical compound CCC(=O)OC(C)=C NLDFTWSUPLJCQD-UHFFFAOYSA-N 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- JQLMBSVQSNYJKF-UHFFFAOYSA-N [dimethyl(phenyl)silyl] trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O[Si](C)(C)C1=CC=CC=C1 JQLMBSVQSNYJKF-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- FHCIILYMWWRNIZ-UHFFFAOYSA-N benzhydryl(chloro)silane Chemical compound C=1C=CC=CC=1C([SiH2]Cl)C1=CC=CC=C1 FHCIILYMWWRNIZ-UHFFFAOYSA-N 0.000 description 1
- ZPVOVHKDYRROOB-UHFFFAOYSA-N benzhydrylsilyl trifluoromethanesulfonate Chemical compound C=1C=CC=CC=1C([SiH2]OS(=O)(=O)C(F)(F)F)C1=CC=CC=C1 ZPVOVHKDYRROOB-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- KWYZNESIGBQHJK-UHFFFAOYSA-N chloro-dimethyl-phenylsilane Chemical compound C[Si](C)(Cl)C1=CC=CC=C1 KWYZNESIGBQHJK-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940106582 estrogenic substances Drugs 0.000 description 1
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 1
- JZRGFKQYQJKGAK-UHFFFAOYSA-N ethenyl cyclohexanecarboxylate Chemical compound C=COC(=O)C1CCCCC1 JZRGFKQYQJKGAK-UHFFFAOYSA-N 0.000 description 1
- 229940124566 female contraceptive agent Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- AIPJCMMALQPRMK-UHFFFAOYSA-N prop-2-enyl cyclohexanecarboxylate Chemical compound C=CCOC(=O)C1CCCCC1 AIPJCMMALQPRMK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
-
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- C07—ORGANIC CHEMISTRY
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
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- 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
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- 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
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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- 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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
前記方法は、
a)式(II)の化合物を、シリル化剤またはアシル化剤と反応させて、式(III)の化合物を製造する工程と、
(式(III)中、P1は、R2−Si−R3R4またはR1CO−から選択される保護基であり、R1は、C1−6アルキルまたはC3−6シクロアルキルから選択される基(各基は、任意選択でフルオロまたはC1−4アルキルから独立して選択される1つ以上の置換基により置換される)であり;R2、R3およびR4は、それぞれ独立して、C1−6アルキルまたはフェニルから選択される基(各基は、任意選択でフルオロまたはC1−4アルキルから独立して選択される1つ以上の置換基により置換される)である。)
b)式(III)の化合物を、ハロゲン化またはスルフィニル化して、式(IV)の化合物を製造する工程と、
c)式(IV)の化合物を、脱ハロゲン化または脱スルフィニル化して、式(V)の化合物を製造する工程と、
d)式(V)の化合物を、還元剤と反応させて、式(I)の化合物を製造する工程とを含む。
(式(I)中、P1は、R2−Si−R3R4またはR1CO−から選択される保護基であり;
R1は、C1−6アルキルまたはC3−6シクロアルキルから選択される基(各基は、任意選択でフルオロまたはC1−4アルキルから独立して選択される、1、2または3つの置換基により置換され)であり;R1は、好ましくは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチル、シクロプロピル、シクロブチル、シクロペンチルまたはシクロヘキシルを含む群から選択され(各基は、任意選択でフルオロまたはC1−4アルキルから独立して選択される、1、2または3つの置換基により置換される);R1は、より好ましくは、メチル、エチル、プロピル、イソプロピル、シクロペンチルまたはシクロヘキシルであり、R1は、さらにより好ましくは、メチルまたはエチルであり;
R2、R3およびR4は、それぞれ独立して、C1−6アルキルまたはフェニルから選択される基であり、前記C1−6アルキルまたはフェニルは、任意選択で、フルオロまたはC1−6アルキルから独立して選択される、1、2または3つの置換基により置換され;R2、R3およびR4は、好ましくは、それぞれ独立して、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチルおよびフェニルを含む群から選択され(各基は、任意選択でフルオロまたはC1−4アルキルからそれぞれ独立して選択される、1、2または3つの置換基により置換される);R2、R3およびR4は、好ましくは、それぞれ独立して、メチル、エチル、プロピル、イソプロピルまたはtert−ブチルおよびフェニルを含む群から選択される(各基は、任意選択でフルオロまたはC1−2アルキルからそれぞれ独立して選択される1、2または3つの置換基により置換される)。)
前記方法は、
a)式(II)のエストロンにおけるヒドロキシルを保護して、式(III)の化合物(式(III)中、P1は、上記定義の通りである)を製造する工程と、
b)式(III)の化合物を、ハロゲン化またはスルフィニル化して、式(IV)の化合物を製造する工程と、
c)式(IV)の化合物を、脱ハロゲン化または脱スルフィニル化して、式(V)の化合物を製造する工程と、
d)式(V)の化合物を、還元剤と反応させて、式(I)の化合物を製造する工程とを含み、
必要であれば、上記反応に使用される任意の保護基が、同時にまたは後に開裂され、
必要に応じて、式(I)の化合物が、官能基の変換に適用可能な常用の方法により、後で別の化合物に変換され、
必要に応じて、このようにして得られた式Iの化合物が、その立体異性体に光学分割される。
工程1:3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オン
3−ヒドロキシ−エストラ−1,3,5(10)−トリエン−17−オン(100g、0.370モル)の500mlジクロロメタン溶液に、tert−ブチルジメチルシリル−クロリド(58.3g、0.388モル)、および、イミダゾール(26.4g、0.388モル)を添加した。混合物を室温で24時間攪拌した。水(300ml)を添加し、有機層を200mlの水で洗浄した。濃縮後、生成物をエタノール/ジイソプロピルエーテルの混合物から結晶化し、ろ過により収集し、乾燥させた。重量は145g(収率95%)であった。
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),0.90(s,3H,CH3 at C−18),1.00(s,9H,(CH3)3−C−Si−),1.20−2.60(m,13H),2.75−2.95(m,2H),5.65−5.75(m,1H),6.58(broad s,1H,H4),6.63(dd,1H,H2),7.12(d,1H,H1)mp:171.6℃
カリウムターブチレート(50g、0.45モル)の800mlテトラヒドロフラン溶液を、3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オン(86.5g、0.225モル)で、窒素下において処理し、1時間攪拌し、ついで、メチルベンゼンスルフィネート(70.2g、0.45モル)およびトリエチルアミンを添加した。2時間の攪拌後、溶液を、5℃未満に温度を保ちながら、1000mlの水および70mlの塩酸に注いだ。1000mlのトルエンを添加し、相を分離し、溶液を加熱して、温度が115℃に達するまで、溶媒を蒸留した。還流を5時間維持した。
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),1.00(s,9H,(CH3)3−C−Si−),1.13(s,3H,CH3 at C−18),1.20−2.70(m,11H),2.80−3.00(m,2H),6.10(dd,1H,H15),6.58(broad s,1H,H4),6.62(dd,1H,H2),7.11(d,1H,H1),7.63(dd,1H,H16),mp:165℃
工程2で収集した材料をTHF300mlに溶解し、塩化セシウム七水和物(123g、0.33モル)のメタノール溶液(300ml)を添加した。混合物を、0℃に冷却し、9℃未満に温度を保ちながら、ホウ素化水素ナトリウム(sodium borohybride)(17.8g、0.47モル、1.5当量)を、一部ずつ添加した。添加の最後に、混合物を1時間攪拌し、ついで、2N HCl溶液(100ml)の添加により、反応を停止させ、酢酸エチルで抽出し、水で洗浄した。有機層を部分的に蒸発させ、ついで、ジイソプロピルエーテルを添加した。沈殿物を、ろ過により収集し、乾燥させた。エタノール/ジイソプロピルエーテルの混合物から(form)の結晶化後、表題の化合物を、オフホワイトの固形物として、収率90%で単離した。
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),0.89(s,3H,CH3 at C−18),1.00(s,9H,(CH3)3−C−Si−),1.20−2.40(m,10H),2.75−2.95(m,2H),4.40(broad s,1H,H17),5.65−5.75(m,1H),5.95−6.10(m,1H),6.57(broad s,1H,H4),6.60(dd,1H,H2),7.13(d,1H,H1)mp:107.5℃
工程1:3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オン
3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オンを、実施例1の工程1に記載のように調製した。
3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オン(86.4g、0.225モル)の温めたメタノール溶液(500ml)に、臭化銅(II)(100g、0.45モル)を添加し、混合物を、還流下で2時間加熱した。熱混合物をろ過し、ジクロロメタン(1000ml)と水(800ml)との混合物に注いだ。有機層を水で洗浄した。
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),1.00(s,9H,(CH3)3−C−Si−),1.13(s,3H,CH3 at C−18),1.20−2.70(m,11H),2.80−3.00(m,2H),6.10(dd,1H,H15),6.58(broad s,1H,H4),6.62(dd,1H,H2),7.11(d,1H,H1),7.63(dd,1H,H16),mp:165℃
還元工程を、実施例1の工程3に記載のように行った。実施例2の工程2で収集した材料を、THFに溶解し、塩化セシウム七水和物(約1当量)のメタノール溶液を添加した。混合物を、0℃に冷却し、9℃未満に温度を保ちながら、ホウ素化水素ナトリウム(1.5当量)を一部ずつ添加した。添加の最後に、混合物を1時間攪拌し、ついで、2N HCl溶液の添加により反応を停止させ、酢酸エチルで抽出し、水で洗浄した。有機層を部分的に蒸発させ、ついで、ジイソプロピルエーテルを添加した。沈殿物をろ過により収集し、乾燥させた。エタノール/ジイソプロピルエーテルの混合物から(form)の結晶化後、表題の化合物を、オフホワイトの固形物として単離した。
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),0.89(s,3H,CH3 at C−18),1.00(s,9H,(CH3)3−C−Si−),1.20−2.40(m,10H),2.75−2.95(m,2H),4.40(broad s,1H,H17),5.65−5.75(m,1H),5.95−6.10(m,1H),6.57(broad s,1H,H4),6.60(dd,1H,H2),7.13(d,1H,H1)mp:107.5℃
工程1:3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オン
3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オンを、実施例1の工程1に記載のように調製した。
3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−トリエン−17−オン(8.64g、0.0225モル)を、水素化カリウムの100mlのテトラヒドロフラン懸濁液(3当量、油中に35%分散)に添加した。メチル2−ピリジンスルフィネート(5.3g、0.034モル、1.5当量)を添加した。室温で30分後、反応物を硫酸塩緩衝液中に注いだ。水相を、炭酸ナトリウムの水溶液により中和し、ついで、トルエンで抽出した。溶液を1時間、110℃に加熱した。室温に冷却後、溶液を、水酸化ナトリウムの希釈溶液で洗浄し、ついで、水で洗浄した。有機層を部分的に濃縮し、続けてヘプタンを添加した。3−tert−ブチルジメチルシリルオキシ−エストラ−1,3,5(10)−15−テトラエン−17−オンを、ろ過により収集した。
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),1.00(s,9H,(CH3)3−C−Si−),1.13(s,3H,CH3 at C−18),1.20−2.70(m,11H),2.80−3.00(m,2H),6.10(dd,1H,H15),6.58(broad s,1H,H4),6.62(dd,1H,H2),7.11(d,1H,H1),7.63(dd,1H,H16),mp:165℃
還元工程を、実施例1の工程3に記載のように行った。実施例3の工程2で収集した材料を、THFに溶解し、塩化セシウム七水和物のメタノール溶液を添加した。混合物を、0℃に冷却し、9℃未満に温度を保ちながら、ホウ素化水素ナトリウム(1.5当量)を一部ずつ添加した。添加の最後に、混合物を1時間攪拌し、ついで、2N HCl溶液の添加により反応を停止させ、酢酸エチルで抽出し、水で洗浄した。有機層を部分的に蒸発させ、ついで、ジイソプロピルエーテルを添加した。沈殿物をろ過により収集し、乾燥させた。エタノール/ジイソプロピルエーテルの混合物から(form)の結晶化後、表題の化合物を、オフホワイトの固形物として単離した
1HNMR(CDCI3)δ0.20(s,6H,(CH3)2−Si−),0.89(s,3H,CH3 at C−18),1.00(s,9H,(CH3)3−C−Si−),1.20−2.40(m,10H),2.75−2.95(m,2H),4.40(broad s,1H,H17),5.65−5.75(m,1H),5.95−6.10(m,1H),6.57(broad s,1H,H4),6.60(dd,1H,H2),7.13(d,1H,H1)mp:107.5℃
Claims (14)
- 式(I)の化合物の調製方法であって、
b)式(III)の化合物を、ハロゲン化またはスルフィニル化して、式(IV)の化合物を製造する工程と、
c)式(IV)の化合物を、脱ハロゲン化または脱スルフィニル化して、式(V)の化合物を製造する工程と、
- 工程(b)が、スルフィニル化であり、該スルフィニル化が、式(III)の化合物を、塩基およびスルフィニル化試薬と反応させることにより行われる、請求項1に記載の方法。
- 工程(b)が、スルフィニル化であり、スルフィニル化試薬が、メチル2−ピリジンスルフィネート、メチルベンゼンスルフィネート、メチル4−メチル−ベンゼンスルフィネート、メチル4−クロロ−ベンゼンスルフィネートである、請求項1または2に記載の方法。
- スルフィニル化工程に使用される塩基が、水素化カリウム、カリウムターブチレート、水素化ナトリウム、ナトリウムターブチレートおよびこれらの混合物を含む群から選択される、請求項2または3に記載の方法。
- 工程(b)が、ハロゲン化であり、該ハロゲン化が、式(III)の化合物を、ハロゲン化試薬と反応させることにより行われる、請求項1に記載の方法。
- 工程(b)が、臭素化であり、臭素化試薬が、臭化銅(II)、臭素および過臭化臭化ピリジニウムを含む群から選択される、請求項1または5記載の方法。
- 脱スルフィニル化工程が、加熱により行われ、場合により硫酸銅の存在下で行われる、請求項1〜4のいずれかに記載の方法。
- 脱ハロゲン化工程が、塩基の存在下で行われる、請求項1、5および6のいずれかに記載の方法。
- 塩基が、イミダゾール、コリジン、2,6−ルチジン、トリエチルアミンまたは1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エンを含む群から選択される、請求項8に記載の方法。
- 工程(d)が、金属ヒドリド化合物の群から選択される還元剤を使用して行われる、請求項1〜9のいずれかに記載の方法。
- 工程(d)が、NaBH4/CeCl3、LiAlH4、NaBH4、NaBH(OAc)3およびZnBH4を含む群から選択される還元剤を使用して行われる、請求項1〜10のいずれかに記載の方法。
- シリル化剤は、C1−6アルキルシリルクロリド、C1−6アルキルシリルトリフラート、フェニルシリルクロリド、フェニルシリルトリフラート、C1−6アルキルフェニルシリルクロリド、C1−6アルキルフェニルシリルトリフラートを含み、各基が、任意選択でフルオロまたはC1−4アルキルから独立して選択される1つ以上の置換基により置換されている、群から選択される、請求項1〜11のいずれかに記載の方法。
- アシル化剤が、C2−6アルケニルC1−6アルカノエート、C2−6アルケニルC3−6シクロアルカノエート、アシルクロリドおよび無水物を含む群から選択される、請求項1〜11のいずれかに記載の方法。
- エステトロールの調製方法であって、
請求項1〜13のいずれかに記載の方法により、式(I)の化合物を調製する工程と、さらに、式(I)の化合物を反応させてエステトロールを製造する工程とを含む、方法。
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