WO2018147345A1 - 15-オキソステロイド化合物及びその製造方法 - Google Patents
15-オキソステロイド化合物及びその製造方法 Download PDFInfo
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- WO2018147345A1 WO2018147345A1 PCT/JP2018/004295 JP2018004295W WO2018147345A1 WO 2018147345 A1 WO2018147345 A1 WO 2018147345A1 JP 2018004295 W JP2018004295 W JP 2018004295W WO 2018147345 A1 WO2018147345 A1 WO 2018147345A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 87
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 239000007800 oxidant agent Substances 0.000 claims abstract description 37
- 125000005843 halogen group Chemical group 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 125000002252 acyl group Chemical group 0.000 claims abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 8
- 150000002978 peroxides Chemical class 0.000 claims abstract description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 7
- 150000002497 iodine compounds Chemical class 0.000 claims abstract description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 17
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 5
- 150000004965 peroxy acids Chemical class 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 abstract description 13
- 125000002345 steroid group Chemical group 0.000 abstract 1
- -1 pregnane steroids Chemical class 0.000 description 29
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- 150000007513 acids Chemical class 0.000 description 11
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- 230000000144 pharmacologic effect Effects 0.000 description 9
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- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 5
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- 239000013078 crystal Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
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- 125000001424 substituent group Chemical group 0.000 description 4
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
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- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- PGJLOGNVZGRMGX-UHFFFAOYSA-L iron(2+);trifluoromethanesulfonate Chemical compound [Fe+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PGJLOGNVZGRMGX-UHFFFAOYSA-L 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940071125 manganese acetate Drugs 0.000 description 1
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229910001960 metal nitrate Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 description 1
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 description 1
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000005527 organic iodine compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Inorganic materials [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- GYLIOGDFGLKMOL-UHFFFAOYSA-N trichloromethanol Chemical compound OC(Cl)(Cl)Cl GYLIOGDFGLKMOL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WZCZNEGTXVXAAS-UHFFFAOYSA-N trifluoromethanol Chemical compound OC(F)(F)F WZCZNEGTXVXAAS-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- 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
Definitions
- the present invention relates to a 15-oxosteroid compound useful as an intermediate for preparing a compound having an oxo group introduced at the 15-position of a steroid skeleton and having pharmacological activity (for example, antiandrogenic activity), and a method for producing the same.
- Pregnane compounds having various physiological activities or pharmacological activities have been prepared by introducing various functional groups or active groups into the steroid skeleton, and steroids having antiandrogenic activity are prostatic hypertrophy It is used as a therapeutic agent for diseases.
- steroids having antiandrogenic activity are prostatic hypertrophy It is used as a therapeutic agent for diseases.
- introducing an oxygen-containing functional group at position 15 of the steroid skeleton requires a complicated process.
- Patent Document 1 Japanese Patent No. 2591640 (Patent Document 1) and Chem. Pharm. Bull. 41 (5) 870-875 (1993) (Non-Patent Document 1) describe 2-oxapregnane having an acetoxy group introduced at the 15-position of the steroid skeleton. Regarding the compound, 17 ⁇ -acetoxy-6-chloro-2-oxa-4,6-pregnadien-3,15,20-trione (compound 16 in Chart 2 of Non-Patent Document 1) is described.
- Non-patent Document 2 uses diacetoxyiodobenzene (DIB) and t-butyl hydroperoxide (TBHP) to produce cyclohexane.
- DIB diacetoxyiodobenzene
- TBHP t-butyl hydroperoxide
- an object of the present invention is to provide a compound in which an oxo group is specifically introduced at position 15 of the steroid skeleton and a method for efficiently producing such a compound without going through complicated steps. It is in.
- Another object of the present invention is to provide a compound having an oxo group at the 15-position of the steroid skeleton and a method by which this compound can be produced in a high yield by a one-step (or one-pot) reaction.
- Still another object of the present invention is to provide a steroid compound useful for preparing a compound having high pharmacological activity (for example, antiandrogenic activity) and a method for producing the same.
- the present inventors specifically oxidized the 15-position when a substituent (such as a hydroxy group) is located at the 7-position of the steroid skeleton. It was found that a compound having a high pharmacological activity (for example, antiandrogenic activity) can be easily prepared by using a compound having an oxo group introduced at position 15 of the steroid skeleton as an intermediate. Completed the invention.
- a substituent such as a hydroxy group
- the 15-oxosteroid compound of the present invention can be represented by the following formula (1).
- the position number is attached
- R 1 to R 3 are the same or different and each represents a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group, and R 4 represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group
- An acyl group, or an alkoxycarbonyl group R 5 represents a hydrogen atom, an alkyl group, or an acyl group
- R 6 represents a hydrogen atom, an alkyl group, an acyl group, or a sulfonyl group
- X represents an oxygen atom ( O) or a methylene group (CH 2 )
- R 1 may be a halogen atom
- R 2 to R 3 may be the same or different and may be an alkyl group or a haloalkyl group
- R 4 and R 5 may be the same or different acyl groups.
- R 6 may be a hydrogen atom, an acyl group or a sulfonyl group
- X may be an oxygen atom (O).
- the 15-oxosteroid compound represented by the formula (1) may be a racemate, for example, an optically active substance (or an optical isomer) represented by the following formula (1a).
- the present invention also includes a method for producing the 15-oxosteroid compound.
- a compound represented by the formula (1) can be prepared by oxidizing a compound represented by the following formula (2) and introducing an oxo group at the 15-position of the steroid skeleton.
- the 15-oxosteroid compound represented by the formula (1) can be produced by oxidizing the compound represented by the formula (2) with an oxidizing agent and a co-oxidizing agent.
- the optical isomer represented by the formula (1a) is maintained while maintaining the steric configuration by using the optically active compound represented by the formula (2a) as the compound represented by the formula (2).
- the body can be manufactured.
- the oxidizing agent may contain, for example, a hypervalent iodine compound, and the co-oxidizing agent may contain a peroxide and / or a peracid.
- the reaction may be performed in the presence of coexisting substances such as an acid, a base, and a salt.
- the coexisting material only needs to coexist with the oxidant and the co-oxidant in the reaction, and may be added to the reaction system in advance before adding the oxidant and the co-oxidant, and the oxidant and the co-oxidant are added. It may be added later.
- the compound represented by the formula (2) after reacting the compound represented by the formula (2) with a hypervalent iodine compound and a peroxide in a solvent (for example, a solvent inert to the reaction) in the presence of a strong acid.
- a solvent for example, a solvent inert to the reaction
- an alkali metal carbonate may be added and reacted to produce the compound represented by the formula (1).
- the present invention allows a compound in which an oxo group is specifically introduced at the 15-position of a steroid skeleton to be easily and efficiently passed through a specific intermediate (compound (2)) without complicated steps. Can be manufactured.
- a compound having an oxo group at the 15-position of the steroid skeleton can be produced in a high yield in one step (or one pot reaction).
- a compound having an oxo group introduced at the 15-position of the steroid skeleton as an intermediate a compound having high pharmacological activity (for example, antiandrogenic activity) can be easily produced with few steps.
- the compound represented by the formula (1) is a novel compound and is useful for producing a compound having high pharmacological activity (for example, antiandrogenic activity).
- the halogen atom represented by R 1 to R 4 includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the halogen atom is often a fluorine atom, a chlorine atom, a bromine atom, particularly a fluorine atom or a chlorine atom.
- Examples of the alkyl group represented by R 1 to R 6 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, Examples thereof include linear or branched C 1-12 alkyl groups such as hexyl group and octyl group.
- the alkyl group is usually a linear or branched C 1-6 alkyl group, preferably a linear or branched C 1-4 alkyl group, more preferably a linear or branched C 1-3 alkyl group. It is an alkyl group.
- Examples of the alkoxy group represented by R 1 to R 4 include an alkoxy group corresponding to the alkyl group, for example, a linear group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and a t-butoxy group.
- a branched C 1-12 alkoxy group can be exemplified.
- the alkoxy group is usually a linear or branched C 1-6 alkoxy group, preferably a linear or branched C 1-4 alkoxy group, more preferably a linear or branched C 1-3 An alkoxy group;
- halogen atom of the haloalkyl group and haloalkoxy group represented by R 1 to R 3 include the same halogen atoms as described above, and are usually a fluorine atom, a chlorine atom, a bromine atom, particularly a fluorine atom or a chlorine atom. There are many cases.
- haloalkyl group examples include chloromethyl group, trichloromethyl group, fluoromethyl group, trifluoromethyl group, 2,2,2-trichloroethyl group, perchloroethyl group, 2,2,2-trifluoroethyl group, Examples thereof include linear or branched halo C 1-12 alkyl groups such as a perfluoroethyl group and a perfluoroisopropyl group.
- the haloalkyl group is usually a linear or branched halo C 1-6 alkyl group such as a trichloromethyl group or a trifluoromethyl group, preferably a halo C 1-4 alkyl group, more preferably a halo C 1-3 alkyl group. It is a group.
- haloalkoxy group represented by R 1 to R 3 examples include a haloalkoxy group corresponding to the haloalkyl group, such as a trichloromethoxy group, a trifluoromethoxy group, a perchloroethoxy group, a perfluoroethoxy group, and a perfluoropropoxy group.
- a haloalkoxy group corresponding to the haloalkyl group such as a trichloromethoxy group, a trifluoromethoxy group, a perchloroethoxy group, a perfluoroethoxy group, and a perfluoropropoxy group.
- a linear or branched halo C 1-12 alkoxy group examples include a linear or branched halo C 1-12 alkoxy group.
- the haloalkoxy group is usually a linear or branched halo C 1-6 alkoxy group such as a trichloromethoxy group or a trifluoromethoxy group, preferably a halo C 1-4 alkoxy group, more preferably a halo C 1-3 An alkoxy group;
- Examples of the acyl group represented by R 4 , R 5 and R 6 include formyl group; acetyl group, propionyl group, butyryl group, isobutyryl group, t-butyryl group, pentanoyl group (valeryl group), hexanoyl group, etc.
- Substituents such as C 3-10 cycloalkyl-carbonyl groups such as linear or branched C 1-12 alkyl-carbonyl groups and cyclohexylcarbonyl groups, benzoyl groups, toluoyl groups, naphthoyl groups (C 1-4 alkyl groups)
- a heterocyclic acyl group furoyl having at least one heteroatom selected from a C 6-12 aryl-carbonyl group, an oxygen atom, a sulfur atom and a nitrogen atom, optionally having a halogen atom, a nitro group, etc.
- Group, nicotinoyl group, isonicotinoyl group and the like
- the acyl group is usually an alkylcarbonyl group, for example, a linear or branched C 1-6 alkyl-carbonyl group, preferably a C 2-4 alkyl-carbonyl group, more preferably a C 2-3 alkyl-carbonyl group. It is.
- Examples of the alkoxycarbonyl group represented by R 4 include linear chains such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a t-butoxycarbonyl group, and a hexyloxycarbonyl group. Or, a branched C 1-12 alkoxy-carbonyl group can be exemplified.
- the alkoxycarbonyl group is usually a linear or branched C 1-6 alkoxy-carbonyl group, preferably a C 1-4 alkoxy-carbonyl group, more preferably a C 1-3 alkoxy-carbonyl group.
- Examples of the sulfonyl group represented by R 6 include substituents such as a C 1-6 alkanesulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group, and a t-butanesulfonyl group, a benzenesulfonyl group, and a toluenesulfonyl group (C 1 -4 alkyl group, halogen atom, nitro group and the like, which may have a C 6-12 arenesulfonyl group.
- substituents such as a C 1-6 alkanesulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group, and a t-butanesulfonyl group, a benzenesulfonyl group, and a toluenesulfonyl group (C 1 -4 alkyl group,
- X may be either an oxygen atom (O) or a methylene group (CH 2 ).
- R 1 is a halogen atom (for example, a fluorine atom or a chlorine atom)
- R 2 and R 3 are the same or different, and an alkyl group (for example, a straight chain) Or a branched C 1-4 alkyl group) or a haloalkyl group (for example, a linear or branched C 1-4 alkoxy group) in many cases.
- R 4 and R 5 are the same or different acyl groups, for example, an alkylcarbonyl group (for example, a linear or branched C 1-4 alkyl-carbonyl group), and R 6 is a hydrogen atom or an acyl group (for example, In most cases, X is an oxygen atom (O), and an alkylcarbonyl group such as a linear or branched C 1-4 alkyl-carbonyl group).
- the 15-oxosteroid compound represented by the formula (1) may be a racemate or an optical isomer.
- a preferred 15-oxosteroid compound is an optically active substance (optical isomer) represented by the following formula (1a).
- the 15-oxosteroid compound represented by the formula (1) or (1a) may have physiological activity or pharmacological activity.
- a compound having physiological activity or pharmacological activity can be obtained simply and in high yield.
- the group —OR 6 at the 7-position of the steroid skeleton is eliminated by a conventional method, which is represented by the following formula (3) or (3a). 1 can be prepared (such as Compound 16).
- a compound in which the group —OR 6 is a hydroxyl group is subjected to a dehydration reaction in the presence of a leaving agent (thionyl chloride, phosphorus oxychloride, martinsulfuran, etc.).
- a leaving agent thionyl chloride, phosphorus oxychloride, martinsulfuran, etc.
- a compound in which the group —OR 6 is an alkoxy group can be converted into a hydroxyl group by reacting with an acid (eg, sulfuric acid, hydroiodic acid, hydrobromic acid, etc.), and the dehydration reaction similar to the above
- an acid eg, sulfuric acid, hydroiodic acid, hydrobromic acid, etc.
- the compound represented by formula (3) or (3a) may be prepared by:
- a compound in which the group —OR 6 is an acyloxy group (such as an acetyloxy group) or a sulfonyloxy group includes, for example, a basic solvent or a base (an alkali metal such as an alkali metal hydroxide, an antkari metal carbonate, sodium acetate, or potassium acetate).
- the group —OR 6 can be eliminated by subjecting to elimination reaction in the presence of acetate or the like.
- the 15-oxosteroid compound represented by the formula (1) can be prepared by oxidizing a compound represented by the following formula (2), and even if the compound represented by the following formula (2a) is oxidized,
- the optically active substance represented by the formula (1a) can be prepared while maintaining the configuration.
- the compound represented by the formula (2) or (2a) is a known substance.
- a compound in which R 6 is a hydroxyl group and a compound in which R 6 is an acetyl group are described in Chem. Pharm. Bull. 40 (4), 935-941 (1992), described as Chart 11 and Compound 13 in Chart 2. Therefore, the compound represented by the formula (2) or (2a) can be prepared according to the method described in this document, and may be obtained from the market if possible.
- the oxidation reaction can be performed using an oxidant and a co-oxidant.
- Oxidizing agents include hypervalent iodine compounds (organic periodides or catalysts) such as iodosobenzene diacetate (or iodobenzene diacetate), [bis (trifluoroacetoxy) iodo] benzene, (di tert -Butylcarbonyloxyiodo) benzene, (hydroxytosyloxyiodo) benzene (Koser reagent), (difluoroiodo) toluene, 2-iodoxybenzoic acid, 2-iodoxybenzenesulfonic acid, iodosylbenzene, iodoxybenzene, etc. it can.
- iodosobenzene diacetate or iodobenzene diacetate
- [bis (trifluoroacetoxy) iodo] benzene di tert -Butylcarbony
- the oxidizing agent may be an active species generated from an organic iodine compound in the reaction system or the catalyst. These oxidizing agents can be used alone or in combination of two or more. Preferred oxidizing agents are iodobenzene diacetate, [bis (trifluoroacetoxy) iodo] benzene, and the like.
- the amount of the oxidizing agent used is, for example, 0.1 to 50 mol, preferably 0.5 to 25 mol (eg 1 to 20 mol), more preferably 1 mol of the compound represented by the formula (2). May be about 2 to 10 mol (eg, 3 to 8 mol).
- Co-oxidants include peroxides such as hydrogen peroxide, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, tert-amyl hydroperoxide, di-tert-amyl peroxide, cumene.
- peroxides such as hydrogen peroxide, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, tert-amyl hydroperoxide, di-tert-amyl peroxide, cumene.
- Hydroperoxide dicumyl peroxide, tert-butylcumyl peroxide, tert-butylperoxypivalate, benzoyl peroxide, lauroyl peroxide, ethylbenzene hydroperoxide, etc .; peracids such as peracetic acid, trichloroperacetic acid, trifluoroperacetic acid And benzone, such as potassium salt of persulfuric acid (potassium peroxymonosulfate).
- cooxidants may be used alone or in combination of two or more.
- a peroxide or a peracid for example, a peroxide such as tert-butyl hydroperoxide (TBHP) is often used.
- the amount of the co-oxidant used is, for example, 0.1 to 100 mol (eg 1 to 50 mol), preferably 1.5 to 30 mol, based on 1 mol of the compound represented by the formula (2). Preferably, it may be about 5 to 25 mol (for example, 5 to 15 mol).
- the oxidation reaction may be performed in the presence of coexisting substances (for example, acid, base, salt, etc.).
- coexisting substances for example, acid, base, salt, etc.
- the yield of the target compound may be improved.
- the acid may be any of an inorganic acid, an organic acid and a Lewis acid.
- the inorganic acid include hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, sulfuric acid, sulfurous acid, fuming sulfuric acid, nitric acid, fuming
- mineral acids such as nitric acid, nitrous acid, phosphoric acid, boric acid, borohydrofluoric acid, carbonic acid, and silicic acid.
- Organic acids include organic carboxylic acids and sulfonic acids.
- organic carboxylic acids include halogens such as formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, and lauric acid.
- Alkanecarboxylic acids which may have atoms; hydroxycarboxylic acids such as glycolic acid, lactic acid, malic acid, tartaric acid and citric acid; cycloalkanecarboxylic acids such as cyclohexanecarboxylic acid; oxalic acid, malonic acid, succinic acid and glutamic acid And dicarboxylic acids or polycarboxylic acids such as adipic acid, fumaric acid, maleic acid and aconitic acid; arene carboxylic acids or polycarboxylic acids such as benzoic acid, phthalic acid, melittic acid and cinnamic acid.
- sulfonic acids examples include alkanesulfonic acids that may have a halogen atom such as methanesulfonic acid and trifluoromethanesulfonic acid; arenesulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; camphorsulfonic acids and the like Examples thereof include cycloalkanesulfonic acid which may be bridged ring type.
- Lewis acid examples include scandium trifluoromethanesulfonate and iron trifluoromethanesulfonate.
- acids can be used alone or in combination of two or more.
- Preferable acids are strong acids, for example, inorganic acids such as sulfuric acid, haloalkanecarboxylic acids such as trifluoroacetic acid, sulfonic acids and the like, and sulfuric acid is often used.
- the amount of the acid (or acid catalyst) to be used is not particularly limited, and is, for example, 0.0001 to 0.1 equivalent, preferably 0.0005 to 0.000, per 1 mol of the compound represented by formula (2). It may be about 05 equivalents, more preferably about 0.001 to 0.01 equivalents.
- the base examples include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, alkali hydrogen carbonate such as potassium hydrogen carbonate, hydrogen carbonate, alkali metal alkoxide such as t-butoxy potassium, water Alkali metal hydroxides such as sodium oxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; polyvalent metal hydroxides such as aluminum hydroxide; alkyls such as n-butyllithium Examples include alkali metal halides; organic bases such as tertiary amines such as pyridine and triethylamine. These bases or salts can also be used alone or in combination of two or more. As the base, an alkali metal carbonate such as potassium carbonate is often used.
- Salts include inorganic salts, for example, metal halides such as alkali metal halides such as sodium chloride, potassium chloride and potassium bromide, and alkaline earth metals such as calcium chloride; sodium sulfate Alkali metal sulfates such as potassium sulfate, alkaline earth metal sulfates such as magnesium sulfate, calcium sulfate and barium sulfate, polyvalent metal sulfates such as aluminum sulfate, copper sulfate, iron sulfate, nickel sulfate and cobalt sulfate; nitric acid Inorganic acid salts such as alkali metal nitrates such as sodium and potassium nitrate, alkaline earth metal nitrates such as magnesium nitrate and barium nitrate, and polyvalent metal nitrates such as nickel nitrate; carboxylates such as magnesium acetate and manganese
- the amount of the base or salt used is, for example, 0.1 to 15 mol, preferably 0.5 to 10 mol, more preferably 1 to 7 mol (eg, 1 mol) relative to 1 mol of the compound represented by the formula (2). 2 to 6 moles).
- the coexisting material only needs to coexist with the oxidizing agent and the cooxidant in the reaction, and the timing of adding the coexisting material to the reaction system is not particularly limited, and is added to the reaction system before adding the oxidizing agent and the cooxidant. Or may be added after the addition of the oxidizing agent and the co-oxidizing agent.
- the reaction can be performed in a solvent.
- the solvent include various solvents (especially a solvent inert to the reaction), for example, ether solvents (dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, chain ethers such as dimethoxyethane, cyclopentyl methyl ether, Cyclic ethers such as tetrahydrofuran and dioxane), hydrocarbon solvents [aromatic hydrocarbon solvents (benzene, toluene, xylene, chlorobenzene, etc.), aliphatic hydrocarbon solvents (pentane, hexane, heptane, octane, etc.), etc.
- ether solvents dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, chain ethers such as dimethoxyethane, cyclopentyl
- Amide solvents N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.
- alcohol solvents methanol, trichloromethanol, trifluoromethanol, ethanol, trifluoroethane
- Alkanols such as cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, etc .
- alkanols such as cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol
- Diols such as ethylene glycol, 1,3-propanediol, 1,4-butanediol and 1,5-pentanediol
- polyhydric alcohols such as glycerin
- ester solvents methyl acetate, ethyl acetate, isopropyl acetate, etc.
- Nitrile solvents
- the reaction can be performed at a temperature of about ⁇ 50 ° C. to 50 ° C. (eg, ⁇ 30 ° C. to 0 ° C.).
- the atmosphere can be, for example, an oxygen-containing atmosphere (eg, in the air) or an inert atmosphere. Good.
- the reaction can usually be carried out while continuously or intermittently adding a strong oxidizing agent to the reaction system.
- the reaction in the presence of the base or salt can also be performed at a temperature of about ⁇ 50 ° C. to 50 ° C. (for example, ⁇ 30 ° C. to 0 ° C.) as described above.
- the target compound is obtained in high yield by separating and purifying the reaction mixture by a conventional separation and purification means such as solvent extraction, neutralization, concentration, washing, crystallization, recrystallization and the like. be able to.
- Non-Patent Document 2 The reaction of oxidizing a substrate such as acetyloxycyclopentane with an oxidizing agent and a co-oxidant in the presence of the acid is described in Non-Patent Document 2.
- the target compound is obtained only in a low yield.
- the optically active compound maintains an optical activity while maintaining an oxo group at the 15-position of the steroid skeleton. Can be selectively or specifically introduced, and the target compound can be produced with high conversion and selectivity.
- the reaction mixture was poured into a solution of sodium pyrosulfite (90.0 g) and sodium chloride (540.0 g) cooled to 2 ° C. in water (1.53 L), washed with ethyl acetate (720 mL), and stirred at room temperature. The mixture was separated and the lower layer was re-extracted with ethyl acetate (360 mL). The upper layers were combined and washed with a solution of sodium dihydrogen phosphate (180.0 g) and sodium chloride (270.0 g) adjusted to pH 7.5 with 30% strength by weight sodium hydroxide in water (1.8 L).
- the organic layer was washed with a solution of sodium chloride (225.0 g) in water (720 ml) and concentrated under reduced pressure at a temperature of 50 ° C. or lower until the remaining amount was about 2.52 L.
- the concentrate was stirred vigorously, heptane (5.4 L) was added and stirred at 18 ° C. overnight.
- the precipitated crystals were collected by filtration and washed with heptane (315 mL).
- the obtained crude crystals were dissolved in a mixture of acetone (378 mL) and water (38 mL), and water (1.44 L) was added with vigorous stirring.
- the obtained suspension was concentrated under reduced pressure at a temperature of 50 ° C. or lower until the remaining amount was about 1.44 L.
- the 15-oxosteroid compound of the present invention represented by the formula (1) can generate a compound having an oxo group at the 15-position of the steroid skeleton by eliminating the group —OR 6 . Therefore, the compound of the present invention is useful for producing a compound having high pharmacological activity (for example, antiandrogenic activity) by utilizing it as an intermediate.
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Abstract
Description
前記式(1)で表される化合物は新規化合物であり、高い薬理活性(例えば、抗アンドロゲン活性など)を有する化合物を製造するのに有用である。
前記式(1)で表される15-オキソステロイド化合物は、下記式(2)で表される化合物を酸化することにより調製でき、下記式(2a)で表される化合物を酸化しても、立体配置を維持しつつ、式(1a)で表される光学活性体を調製できる。
MASS:m/z 438(M+)
実施例2
非特許文献1に記載のチャート2及び各反応工程の条件に従って、化合物8を出発原料として、化合物9、化合物10を経て、化合物12を調製したところ、収率は7.8%であった。さらに、化合物12から、化合物13、化合物14、化合物15aを経て化合物16を調製したところ、収率は7.7%であった。
Claims (7)
- R1がハロゲン原子であり、R2及びR3が、同一又は異なって、アルキル基又はハロアルキル基であり、R4及びR5が同一又は異なるアシル基であり、R6が水素原子、アシル基またはスルホニル基であり、Xが酸素原子である請求項1又は2記載の15-オキソステロイド化合物。
- 酸化剤及び共酸化剤で酸化する際、共存物質を添加して反応させる請求項4記載の方法。
- 酸化剤が超原子価ヨウ素化合物を含み、共酸化剤が過酸化物及び/又は過酸を含む請求項4又は5記載の方法。
- 溶媒中、強酸の存在下、超原子価ヨウ素化合物及び過酸化物と反応させた後、アルカリ金属炭酸塩を添加して反応させる請求項4~6のいずれかに記載の方法。
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CN201880011073.7A CN110267967B (zh) | 2017-02-10 | 2018-02-08 | 15-酮固醇化合物及其制备方法 |
EP18752066.3A EP3581577B1 (en) | 2017-02-10 | 2018-02-08 | 15-oxosteroid compound and method for producing same |
KR1020197024864A KR102467727B1 (ko) | 2017-02-10 | 2018-02-08 | 15-옥소스테로이드 화합물 및 그 제조 방법 |
BR112019016361A BR112019016361A2 (pt) | 2017-02-10 | 2018-02-08 | composto 15-oxoesteróide, e processo para a produção de um composto 15-oxo-esteróide |
CA3049753A CA3049753A1 (en) | 2017-02-10 | 2018-02-08 | 15-oxosteroid compound and process for producing the same |
ES18752066T ES2968278T3 (es) | 2017-02-10 | 2018-02-08 | Compuesto 15-oxosteroide y procedimiento para producir el mismo |
MX2019009560A MX2019009560A (es) | 2017-02-10 | 2018-02-08 | Compuesto de 15-oxoesteroide y proceso para producir el mismo. |
IL268584A IL268584B2 (en) | 2017-02-10 | 2018-02-08 | A 15-oxosteroid compound and its production method |
US16/481,970 US10815268B2 (en) | 2017-02-10 | 2018-02-08 | 15-oxosteroid compound and process for producing the same |
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Citations (2)
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JPH01199993A (ja) * | 1988-02-04 | 1989-08-11 | Teikoku Hormone Mfg Co Ltd | 新規な2−オキサプレグナン化合物 |
JP2001503732A (ja) * | 1996-07-11 | 2001-03-21 | インフラジム ファーマシューティカルズ リミテッド | 6,7―酸素化ステロイドおよびそれに関連した用途 |
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US2823170A (en) * | 1955-05-11 | 1958-02-11 | Searle & Co | Process for the oxygenation of steroids with nigrospora |
US3010877A (en) * | 1959-09-03 | 1961-11-28 | American Cyanamid Co | Method of preparing 15-hydroxy pregnenes |
JP2591640Y2 (ja) | 1993-05-13 | 1999-03-10 | 株式会社吉野工業所 | 液体収納袋 |
CN100368425C (zh) * | 1996-07-11 | 2008-02-13 | 茵弗莱采姆药物有限公司 | 6,7-氧化的甾族化合物及其用途 |
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JPH01199993A (ja) * | 1988-02-04 | 1989-08-11 | Teikoku Hormone Mfg Co Ltd | 新規な2−オキサプレグナン化合物 |
JP2591640B2 (ja) | 1988-02-04 | 1997-03-19 | 帝国臓器製薬株式会社 | 新規な2−オキサプレグナン化合物 |
JP2001503732A (ja) * | 1996-07-11 | 2001-03-21 | インフラジム ファーマシューティカルズ リミテッド | 6,7―酸素化ステロイドおよびそれに関連した用途 |
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JP2018127434A (ja) | 2018-08-16 |
EP3581577B1 (en) | 2023-10-11 |
BR112019016361A2 (pt) | 2020-04-07 |
EP3581577A1 (en) | 2019-12-18 |
CN110267967A (zh) | 2019-09-20 |
IL268584A (en) | 2019-09-26 |
KR20190116986A (ko) | 2019-10-15 |
EP3581577A4 (en) | 2020-12-30 |
IL268584B2 (en) | 2023-12-01 |
JP6892278B2 (ja) | 2021-06-23 |
ES2968278T3 (es) | 2024-05-08 |
MX2019009560A (es) | 2019-10-15 |
US20190389900A1 (en) | 2019-12-26 |
IL268584B1 (en) | 2023-08-01 |
CA3049753A1 (en) | 2018-08-16 |
KR102467727B1 (ko) | 2022-11-15 |
US10815268B2 (en) | 2020-10-27 |
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