KR830000085B1 - Method for preparing 4-aza-17-substituted-5α-androstan-3-ones useful as 5α-reductase inhibitors - Google Patents
Method for preparing 4-aza-17-substituted-5α-androstan-3-ones useful as 5α-reductase inhibitors Download PDFInfo
- Publication number
- KR830000085B1 KR830000085B1 KR1019790001163A KR790001163A KR830000085B1 KR 830000085 B1 KR830000085 B1 KR 830000085B1 KR 1019790001163 A KR1019790001163 A KR 1019790001163A KR 790001163 A KR790001163 A KR 790001163A KR 830000085 B1 KR830000085 B1 KR 830000085B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- hydrogen
- aza
- product
- androstan
- Prior art date
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- -1 4-aza-17-substituted-5α-androstan-3-ones Chemical class 0.000 title claims description 16
- 238000000034 method Methods 0.000 title description 28
- 239000002677 5-alpha reductase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 39
- 229910052757 nitrogen Chemical group 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 229910052783 alkali metal Chemical group 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 235000013305 food Nutrition 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000006713 (C5-C10) cycloalkyl group Chemical group 0.000 claims 1
- 244000025254 Cannabis sativa Species 0.000 claims 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 claims 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
- 235000009120 camo Nutrition 0.000 claims 1
- 235000005607 chanvre indien Nutrition 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 239000011487 hemp Substances 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 125000003831 tetrazolyl group Chemical group 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 239000000047 product Substances 0.000 description 83
- 239000000243 solution Substances 0.000 description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- GNWBLLYJQXKPIP-ZOGIJGBBSA-N (1s,3as,3bs,5ar,9ar,9bs,11as)-n,n-diethyl-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1h-indeno[5,4-f]quinoline-1-carboxamide Chemical compound CN([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)N(CC)CC)[C@@]2(C)CC1 GNWBLLYJQXKPIP-ZOGIJGBBSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000002844 melting Methods 0.000 description 20
- 230000008018 melting Effects 0.000 description 20
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- 239000012467 final product Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 10
- 239000003098 androgen Substances 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 6
- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical class I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000002280 anti-androgenic effect Effects 0.000 description 5
- 239000000051 antiandrogen Substances 0.000 description 5
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 229960003604 testosterone Drugs 0.000 description 5
- MSEZLHAVPJYYIQ-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 MSEZLHAVPJYYIQ-VMXHOPILSA-N 0.000 description 4
- YQACAXHKQZCEOI-UDCWSGSHSA-N (8s,9s,10r,13s,14s,17s)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(O)=O)[C@@H]4[C@@H]3CCC2=C1 YQACAXHKQZCEOI-UDCWSGSHSA-N 0.000 description 4
- 108010029908 3-oxo-5-alpha-steroid 4-dehydrogenase Proteins 0.000 description 4
- 102000001779 3-oxo-5-alpha-steroid 4-dehydrogenase Human genes 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- XWFWMYFLNHTEBF-RVPRXVRWSA-N methyl (8s,9s,10r,13s,14s)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene-17-carboxylate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC(C(=O)OC)[C@@]1(C)CC2 XWFWMYFLNHTEBF-RVPRXVRWSA-N 0.000 description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 229910003446 platinum oxide Inorganic materials 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QKXFBVMFKBSRTD-WGBDHRSASA-N (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound C(=O)(O)C=1[C@]2(C)[C@@H](CC=1)[C@@H]1CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]1CC2 QKXFBVMFKBSRTD-WGBDHRSASA-N 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 3
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- LBWDOBGKBXFRNJ-XEAGOBSMSA-N C(C)N(C(=O)N1[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(CCC[C@H]43)C)[C@]2(CCC1=O)C)CC Chemical compound C(C)N(C(=O)N1[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(CCC[C@H]43)C)[C@]2(CCC1=O)C)CC LBWDOBGKBXFRNJ-XEAGOBSMSA-N 0.000 description 3
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 3
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 229940030486 androgens Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- XWFWMYFLNHTEBF-YFWFAHHUSA-N methyl (8s,9s,10r,13s,14s,17s)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene-17-carboxylate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)OC)[C@@]1(C)CC2 XWFWMYFLNHTEBF-YFWFAHHUSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 229960000249 pregnenolone Drugs 0.000 description 3
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- SAQFVLWREIPFPG-IJPPCXMXSA-N (3as,3bs,5ar,9ar,9bs,11as)-6,9a,11a-trimethyl-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1h-indeno[5,4-f]quinolin-7-one Chemical compound C([C@]1(C)CCC[C@H]1[C@@H]1CC2)C[C@@H]1[C@]1(C)[C@@H]2N(C)C(=O)CC1 SAQFVLWREIPFPG-IJPPCXMXSA-N 0.000 description 2
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
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- 0 C*C(CC1)C(C)(CC2)C1C1C2C(C)(CCC(C2)O)C2=CC1 Chemical compound C*C(CC1)C(C)(CC2)C1C1C2C(C)(CCC(C2)O)C2=CC1 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- FIMAYKDZLLQUDW-UHFFFAOYSA-N fluoro(dioxido)borane;trimethyloxidanium Chemical compound C[O+](C)C.C[O+](C)C.[O-]B([O-])F FIMAYKDZLLQUDW-UHFFFAOYSA-N 0.000 description 2
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- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
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- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
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- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cosmetics (AREA)
Abstract
내용 없음.No content.
Description
본 발명은 테스토스테론 5α-환원효소 억제제로서 유용한 신규 4-아자-17-치환-5α-안드로스탄-3-온류 및 그들의 A-및 D- 상동성 동족체(相同性 同族體)를 제조하는 방법에 관한 것이다. 바람직하지 못한 생리학적 발현(發現), 예컨대 보통 여드름, 소보르헤아(Soborrhea) 여성 추모증(추毛症), 남성대머리 및 양성의 전립선 비대등은 테스토스테론의 과잉 축적에 의해서 야기되는 과도 안드로겐 자극 또는 신진대사계내의 유사 안드로겐호르몬의 결과라는 것은 공지된 것이다.The present invention relates to a novel 4-aza-17-substituted-5α-androstan-3-ones useful as testosterone 5α-reductase inhibitors and to methods for preparing their A- and D-homologous homologs. will be. Undesirable physiological manifestations, such as acne, Soborrhea female mourning, male baldness and benign prostatic hypertrophy, are usually caused by excessive androgen stimulation caused by excessive accumulation of testosterone or It is known that this is the result of pseudo-androgen hormones in the metabolic system.
일찌기 과도 안드로겐의 바람직하지 못한 결과에 대한 화학요법제를 제공하기를 시도한 결과 그 자체의 바람직하지 못한 호르몬활성을 갖고 있는 몇개의 스테로이드의 항 안드로겐이 발견되었었다. 에스트로겐은 예컨대 안드로겐의 효과를 방해할 뿐만 아니라 또한 여성화하는 효과를 갖는다. 비-스테로이드의 항 안드로겐은 또한 예컨대 4'-니트로-3'-트리플루오로메틸이소부티르 아닐리드로 밝혀졌다. 〔Neri et.al., Endo., 91권 제2호(1972)〕참조. 그러나, 이 생성물들은 호르몬 효과를 피함에도 불구하고 수용기 부위에 대해 천연 안드로겐으로 대항하는 말초적인 작용 및 남성 숙주 또는 여성 숙주의 남성태아를 여성화하는 경향을 촉진시킨다.Early attempts to provide chemotherapeutic agents for the undesirable consequences of excessive androgens have resulted in the discovery of anti-androgens of several steroids that have their own undesirable hormonal activity. Estrogens, for example, not only interfere with the effects of androgens, but also have a feminizing effect. Anti-androgens of non-steroids have also been found, for example, 4'-nitro-3'-trifluoromethylisobutyr anilide. See Neri et. Al., Endo., Vol. 91, No. 2 (1972). However, these products promote the peripheral action of natural androgens against receptor sites despite the hormonal effect and the tendency to feminize the male fetus of a male or female host.
몇몇의 대상기관에서 안드로겐 활성의 주요한 조정제가 5α-디하이드로 테스토스테론이고 대상기관에서 테스토스테론-5α-환원 효소의 작용으로 국부적으로 형성된다는 것은 극히 최근에 알려졌다. 따라서 테스토스테론-5α-환원효소의 억제제는 과도 안드로겐 자극의 증후를 방지하거나 또는 줄일 수 있으리라고 가정하고 이를 설명하였다. 〔Nayfeh et.al., 스테로이드, 14, 269(1969)〕에는 시험관내에서 메틸 4-안드로스텐-3-온-17β-카르복실산염이 테스토스테론-5α-환원효소억제제임이 설명되어 있다. 그후에 〔Voigt 및 Hsia의 내분비학 92, 1216(1973)〕〔캐나다 특허 제970,692호〕에서는 상기 에스테르 및 친(親)유리산, 4-안드로스텐-3-온-17β-카르복실산이 시험관내에 테스토스테론-5α-환원효소의 두가지 활성억제제임이 설명되어 있다. 그들은 또한 암컷쥐의 협복관(脇腹官)의 증대를 야기시키는 테스토스테론 또는 5α-디하이드로 테스트스테론의 국부적인 적용 및 안드로겐 존속물 지방의 구조 등을 설명하였다. 비록 4-안드로스텐-3-온-17β-카르복실산 또는 그의 메틸에스테르가 테스토스테론에 의해 유도된 감응을 억제할지라도 5α-디하이드로 테스토스테론에 의해 유도된 감응을 억제하는 것은 아니다. 이러한 결과는 화합물이 테스토 스테론-5α-환원효소를 억제하는 그들의 능력에 의해서 항 안드로겐임을 나타내는 것이라고 해석된다.It is extremely recently known that the major modulator of androgen activity in some organs is 5α-dihydro testosterone and is locally formed by the action of testosterone-5α-reducing enzymes in the subject organs. Therefore, it is assumed that an inhibitor of testosterone-5α-reductase may prevent or reduce the symptoms of excessive androgen stimulation. Nayfeh et. Al., Steroids, 14, 269 (1969) describe that methyl 4-androsten-3-one-17β-carboxylate is a testosterone-5α-reductase inhibitor in vitro. Subsequently, in Endocrinology of Voitgt and Hsia 92, 1216 (1973) [Canadian Patent No. 970,692], the ester and the protic free acid, 4-androsten-3-one-17β-carboxylic acid, were tested in vitro. It has been described as two inhibitors of -5α-reductase. They also explained the local application of testosterone or 5α-dihydrotestosterone and the structure of androgen-dependent fats, leading to an increase in the canal ducts of female rats. Although 4-androsten-3-one-17β-carboxylic acid or its methylester inhibits the testosterone induced sensitization, it does not inhibit the 5α-dihydro testosterone induced sensitization. These results are interpreted to indicate that the compounds are anti-androgens by their ability to inhibit testosterone-5α-reductase.
따라서 본 발명의 방법에 의해서 제조되는 신규화합물은 그들의 능력에 의해 특히 테스토스테론-5α-환원효소를 억제하는 효력있는 항 안드로겐이다.The novel compounds produced by the methods of the invention are therefore potent anti-androgens which, in particular, inhibit their testosterone-5α-reductase by their ability.
지금까지 과도 안드로겐 상태를 치료하는데 4-아자-17-치환-5α-안드로스탄-3-온을 사용하는 것이 비록 공지된 것이 아닐지라도 셀레(selye)는 벨기에 특허 제775,919호에서 상술한 화합물 및 다소의 다른 화합물, 다른 상태중에서 전립선 비대의 치료에 유용한 독성억제제(Catatoxic agent)로서 부가적으로 하나 또는 그 이상의 카본니트릴 치환체등을 상술하였다.Until now, although it is not known to use 4-aza-17-substituted-5α-androstan-3-one to treat transient androgen conditions, selye is the compound described above in Belgian Patent No. 775,919 and more or less. Other compounds of the above, additionally one or more carbonnitrile substituents, etc. have been described as catatoxic agents useful in the treatment of prostate hypertrophy among other conditions.
다소의 4-아자 스테로이드 화합물은 공지된 것이다. 예컨대 미국특허 제2,227,876호; 제3,239,417호; 제3,264,301호; 제3,285,918호; 프랑스 특허 제1,465,544호; 〔Doorenbos 및 Solomons의 J. Phar. Sci. 62, 4, 페이지 638-640(1973) 및 〔Doorenbos 및 Brown의 J. Phar. Sci., 60, 8, 페이지 1234-1235(1971) 등을 참조. 그러나, 본 발명의 4-아자 화합물 즉 과도 안드로겐 상태를 치료하는데 유용한 화합물은 전혀 공지된 것이 아니다.Some 4-aza steroid compounds are known. See, for example, US Pat. No. 2,227,876; 3,239,417; 3,239,417; 3,264,301; 3,285,918; 3,285,918; French Patent No. 1,465,544; [Doorenbos and Solomons J. Phar. Sci. 62, 4, pages 638-640 (1973) and in J. Phar. Of Doorenbos and Brown. Sci., 60, 8, pages 1234-1235 (1971) and the like. However, the 4-aza compounds of the present invention, ie compounds useful for treating excessive androgen conditions, are not known at all.
본 발명은 신규 항 안드로겐의 4-아자-17-치환된 -5α-안드로스탄-3-온류, 그들의 A- 및 D-상동성동족체(homo analogs) 및 이소스테르(isosteres) 및 그의 유도체를 제조하는 방법에 관한 것이다.The present invention provides 4-aza-17-substituted -5α-androstan-3-ones of novel anti-androgens, their A- and D-homologs and isosteres and derivatives thereof. It is about how to.
본 발명은 특히 다음 일반식(1)의 신규 화합물을 제조하는 방법에 관한 것이다.The present invention relates in particular to a process for the preparation of novel compounds of the general formula (1).
일반식(1)은 부분적으로 일반식(2) 및 또는 (3)의 구조를 또한 가질 수 있다.Formula (1) may also partially have the structure of Formula (2) and / or (3).
식중,Food,
A는 (1) -CH2-CH2-;A is (1) -CH 2 -CH 2- ;
(2) -CH=CH-;(2) -CH = CH-;
(3)
R'는 수소 또는 메틸;R 'is hydrogen or methyl;
R''는 수소 또는 β-메틸;R '' is hydrogen or β-methyl;
R' ''는 β-메틸 또는 하이드록시;R '' 'is β-methyl or hydroxy;
Z는 (1) 옥소;Z is (1) oxo;
(2) β-수소 및α-하이드록시; 또는 α-수소 또는 α-하이드록실(2) β-hydrogen and α-hydroxy; Or α-hydrogen or α-hydroxyl
(3) (Y)nQ(3) (Y) n Q
식중, n=0 또는 1Where n = 0 or 1
Y는 1-12개 탄소원자를 갖는 직쇄 또는 분지쇄 탄화수소 고리Y is a straight or branched chain hydrocarbon ring having 1-12 carbon atoms
Q는 (a)
식중, R8은 (1) 수소, (2) 하이드록실, (3) C1-4알킬, (4) NR9R10식중 R9및 R10은 수소, C1-4직쇄 또는 분지쇄 알킬, C3-6싸이클로알킬, 페닐로부터 각각 선태되고; 또는 R9및 R10은 산소 및 질소로부터 선태된 다른 이종원자로 구성되어 있는 5-6개 구성원자로 포화된 환에 질소와 함께 부착된 것으로 표현된다.Wherein R 8 is (1) hydrogen, (2) hydroxyl, (3) C 1-4 alkyl, (4) NR 9 R 10 wherein R 9 and R 10 are hydrogen, C 1-4 straight or branched alkyl , C 3-6 cycloalkyl, phenyl, respectively; Or R 9 and R 10 are represented as being attached with nitrogen to a ring saturated with 5-6 members consisting of other heteroatoms selected from oxygen and nitrogen.
(5) OR''(5) OR ''
식중, R''은 M, 이중 M은 수소 또는 알카리금속 또는 C1-18직쇄 또는 분지쇄 알킬; 벤질; 또는Wherein R '' is M, of which M is hydrogen or an alkali metal or C 1-18 straight or branched chain alkyl; benzyl; or
(b) OR12, 17α-OH로 제공되고 n은 1이어야 한다.(b) provided as OR 12 , 17α-OH and n should be 1.
식중, R12는 (1) C1-20알킬카보닐, (2) 페닐 C-16알킬카보닐, (3) C5-10싸이클로알킬카보닐, (4) 벤조일 또는, (5) C1-8알콕시카보닐Wherein R 12 is (1) C 1-20 alkylcarbonyl, (2) phenyl C- 16 alkylcarbonyl, (3) C 5-10 cycloalkylcarbonyl, (4) benzoyl or (5) C 1 -8 alkoxycarbonyl
(4)
(5)
(6) 시아노; 또는(6) cyano; or
(7) 테트라 아졸릴;(7) tetraazolyl;
또한 상기 화합물의 약학적으로 허용될 수 있는 염이 포함된다.Also included are pharmaceutically acceptable salts of these compounds.
다른 지시가 없는한 여러가지 치환기로서 α 및 β 두입체 배치가 시도되었다.Unless otherwise indicated, arrangement of α and β stereosteres was attempted with various substituents.
본 발명의 방법에 의해서 제조된 각각의 화합물들은 다음과 같다.Each compound prepared by the method of the present invention is as follows.
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
17β-N,N-디에틸카바모일-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-aza-5α-androstan-3-one
17β-N,N-디에틸카바모일-4-아미노-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-amino-4-aza-5α-androstan-3-one
17β-아세톡시-4-아자-5α-안드로스탄-3-원17β-acetoxy-4-aza-5α-androstan-3-one
4-아자-20-스피록스-5α-언-3-원4-aza-20-spirox-5α-un-3-one
4-메틸-4-아자-5α-20-스피록산-3-원4-Methyl-4-aza-5α-20-spiroxane-3-one
17β-N-에틸카바모일-4-메틸-4-아자-5α-안드로스트-3-원17β-N-ethylcarbamoyl-4-methyl-4-aza-5α-androst-3-one
4-에틸-4-아자-5α-20-스피록산-3-원4-ethyl-4-aza-5α-20-spiroxane-3-one
17β-카보메톡시-4-메틸-4-아자-5α-안드로스탄-3-원17β-carbomethoxy-4-methyl-4-aza-5α-androstan-3-one
신규일반식(1)의 화합물 및 본 발명의 일반식(3)의 부분적인 구조를 가지고 있는 일반식(1)의 화합물을 다음 단계로 구성된 방법에 의해 제조될 수 있다.The compound of the general formula (1) and the compound of the general formula (1) having the partial structure of the general formula (3) of the present invention can be prepared by a method consisting of the following steps.
다음 일반식 (가)의 화합물을 (1) 환원온도에서 산화제로 처리하여 상응하는 5-옥소-3,5-세코-안드로스탄-3-온 산화합물을 형성하고;The compound of formula (A) is then (1) treated with an oxidizing agent at a reducing temperature to form the corresponding 5-oxo-3,5-seco-androstan-3-one acid compound;
(2) 단계(1)의 생성물과 일반식 R'NH2의 아민과 처리하여 상응하는 R'으로 4-위치에서 치환된 4-아자-5-안드로스텐-3-원 화합물을 형성하고;(2) treating the product of step (1) with an amine of the general formula R′NH 2 to form a 4-aza-5-androsten-3-one compound substituted at the 4-position with the corresponding R ′;
(3) 단계 (2)의 생성물과 촉매조건하에서 수소화 처리하여 B가
식중 A는 -CH=CH-외에는 상술된 의미를 갖는다. 따라서 본 방법의 마지막 단계는 5α 수소를 도입하는 수소화 단계이다. 상기 반응은 다음 실시예 1-8에서 더욱 상세히 설명하였고; 다음 반응도식에 대략 도시하였다.Wherein A has the meaning described above in addition to -CH = CH-. The final step of the process is therefore the hydrogenation step of introducing 5α hydrogen. The reaction is described in more detail in the following Examples 1-8; It is shown roughly in the following scheme.
B가
(1) 락팀 카보닐을 트리알킬옥소늄 테트라플루오로 보레이트로 알킬화 하여 상당하는 알킬 아미늄 에테르, 예컨대 B가 상기와 같고, R4=OR5인 일반식 (1)의 화합물을 형성한다. 이러한 형태의 전형적인 공정은 다음 실시예 11의 첫번째 공정에 기술되어 있다.(1) Lactim carbonyl is alkylated with trialkyloxonium tetrafluoro borate to form a compound of formula (1) wherein the corresponding alkyl aluminum ether, such as B, is as above and R 4 = OR 5 . A typical process of this type is described in the first process of Example 11 below.
(2) (1)단계의 생성물을 일반식 HNR6R7의 아민과 처리한 후 무기산 처리하여 B가 상술한 바와 같고 R4=NR6R7인 일반식(1)의 화합물을 형성한다. 이러한 형태의 전형적인 공정은 다음 실시예 18에 기술되어 있다.(2) The product of step (1) is treated with an amine of the general formula HNR 6 R 7 followed by inorganic acid treatment to form a compound of formula (1) wherein B is as described above and R 4 = NR 6 R 7 . A typical process of this type is described in Example 18 below.
A가 -CH=CH-, 인 일반식 (1)의 화합물을 제조하는 것이 바람직한데, 상기 페이지 10에 기술된 공정에 의해 조조된 생성물에서 다음 단계로 부가적으로 수행할 수 있다.It is preferred to prepare a compound of formula (1) wherein A is -CH = CH-, which may additionally be carried out in the product prepared by the process described on page 10 above.
(1) 1,2 포화된 화합물을 리튬 디이소프로필 아미드와 처리하여 상당하는 에놀레이트를 형성하고,(1) 1,2 saturated compound is treated with lithium diisopropyl amide to form the corresponding enolate,
(2) 단계 (1)의 에놀레이트를 원위치에서 디페닐 디 설파이드와 처리하여 상당하는 α-페닐-티오 화합물을 형성하고,(2) treating the enolate of step (1) with diphenyl disulfide in situ to form the corresponding α-phenyl-thio compound,
(3) 단계 (2)의 생성물을 산화시켜서 상당하는 설폭사이드 화합물을 형성하고; 및(3) oxidizing the product of step (2) to form the corresponding sulfoxide compound; And
(4) (3)단계의 생성물을 가열하여 A가 -CH=CH-인 일반식 (1)의 화합물을 형성한다.(4) The product of step (3) is heated to form a compound of formula (1) wherein A is -CH = CH-.
이러한 형태의 전형적인 공정은 다음 실시예 10에 기술되어 있다.A typical process of this type is described in Example 10 below.
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 제조하는 바람직한 공정(특히 본 발명의 바람직한 화합물)은 다음 단계로 구성되어 있다.The preferred process for preparing 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (particularly preferred compounds of the present invention) consists of the following steps.
(a) 출발물질로 유용한 프레그네로론(8)을 요오드 및 피리딘과 함께 할로형태의 최상의 반응으로 처리하여 프레그네노론의 20-피리디늄 아이오다이드 유도체(9)를 형성하고;(a) treating pregnerolone (8) useful as a starting material with iodine and pyridine in the best reaction in halo form to form a 20-pyridinium iodide derivative (9) of pregnenolone;
(b) 피리디늄 아이오다이드 유도체(9)를 소디움 메톡사이드 및 메탄올로 메탄올화하여 17-카복시안드로스테놀의 메틸 에스테르를 형성하는데, 에스테르형태는 다음 오펜하우어(oppen hauer) 반응을 수행하는 것이 바람직하다.(b) Pyridinium iodide derivative (9) is methanolized with sodium methoxide and methanol to form a methyl ester of 17-carboxycyandrostenol, the ester form of which is to carry out the following opene hauer reaction. desirable.
(c) 17-카복시 안드로스테놀의 메틸 에스테르(10)를 톨루엔과 같은 적당한 용매하에서 알루미늄 이소프로폭사이드 및 싸이클로헥사논과 처리하여 메틸-4-안드로스텐-3-원-17-카복실레이트(11)을 얻는다.(c) methyl ester of 17-carboxy androstenol (10) is treated with aluminum isopropoxide and cyclohexanone in a suitable solvent such as toluene to give methyl-4-androsten-3-one-17-carboxylate (11 Get)
(d) 그렇게하여 형성된 메틸-4-안드로스텐-3-원-17-카복실레이트(11)을 메탄올중의(물용매와 대강 4 : 1 비율) 산조건하에서 17-산(12)으로 가수분해 하였다.(d) The methyl-4-androsten-3-one-17-carboxylate (11) thus formed is hydrolyzed to 17-acid (12) in acidic conditions (approximately 4: 1 ratio with water solvent) in methanol. It was.
(e) 17산(12)를 옥살릴 클로라이드 : 톨루엔 또는 다른 적당한 용매, 예컨데 크실렌 중의 대강 1 : 1 비율의 피리딘 착물과 처리하여 17-산 크로라이드(13)을 형성하였다.(e) 17-acid (12) was treated with oxalyl chloride: toluene or other suitable solvent such as a roughly 1: 1 ratio of pyridine complex to form 17-acid chromide (13).
(f) 17-산 클로라이드(13)을 과량의 디에틸아민과 원위치에서 처리하여 17β-N,N-디에틸 카바모일-4-안드로스텐-3-원(14)를 형성하였다.(f) 17-acid chloride (13) was in situ treated with excess diethylamine to form 17β-N, N-diethyl carbamoyl-4-androsten-3-one (14).
(g) 그렇게 형성된 4-안드로스텐-3-원(14)를 용매계로서 제3부탄올 및 물을 사용하여 과요오드산나트륨 및 과망간산칼륨으로 산화시켜서 상응하는 5-옥소-3,5-세코안드로스탄-3-온산(15)를 형성하였다.(g) oxidizing the thus formed 4-androsten-3-one (14) with sodium butyrate and potassium permanganate using tert-butanol and water as solvent systems to give the corresponding 5-oxo-3,5-secoandro Stan-3-ionic acid (15) was formed.
(h) 세코안드로스탄산(15)를 0.5-5분간 반응혼합물 온도를 140°-180℃로 상승 유지시켜서 에틸렌 글리콜중의 메틸 아민과 약 1시간 이상 처리하여 상응하는 4-아자화합물(16)으로 전환시켰다.(h) Secoandrostanic acid (15) was treated with methyl amine in ethylene glycol for at least about 1 hour by maintaining the reaction mixture temperature at 140 ° -180 ° C for 0.5-5 minutes to the corresponding 4-aza compound (16). Switched.
(i) 얻어진 17β-N,N-디에틸-카바모일-4-메틸-4-아자-5-안드로스텐-3-원( 16)을 촉매로서 산화백금을 사용하여 상온에서 60℃까지 또는 더 높은 온도에서 수소로 수소화하여 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원(1 7) 최종생성물이 형성된 후에 분리하고 정제하였다.(i) The obtained 17β-N, N-diethyl-carbamoyl-4-methyl-4-aza-5-androsten-3-one (16) using platinum oxide as a catalyst was used at room temperature to 60 ° C or more. Hydrogenation with hydrogen at high temperature afforded 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (1 7) after the final product had formed and isolated and purified.
상기 반응을 다음 실시예 20에서 더욱 상세히 설명하고 다음 반응도식에 대략적으로 도시하였다.The reaction is described in more detail in the following Example 20 and is shown roughly in the following scheme.
본 발명의 일반식(1)의 신규화합물은 최종단계 치환기 A-환의 질소원자를 메틸기와 함께 다음 단계로 구성된 방법으로 또한 제조할 수 있다. (1) 5-옥소-3,5-세코안드로스탄-3-온 산 화합물을 암모니아로 처리하여 상응하는 4-아자-5-안드로스텐-3-원 화합물을 형성하고;The novel compounds of the general formula (1) of the present invention may also be prepared by a method in which the nitrogen atom of the final substituent A-ring is composed of the methyl group with the next step. (1) treating the 5-oxo-3,5-secoandrostan-3-one acid compound with ammonia to form the corresponding 4-aza-5-androsten-3-one compound;
(2) 단계(1)의 생성물을 촉매조건하에서 수소와 처리하여 4-아자-5α-안드로스탄-3-원 화합물을 형성하고;(2) treating the product of step (1) with hydrogen under catalytic conditions to form a 4-aza-5α-androstan-3-one compound;
(3) 단계(2)의 생성물을 메틸화제, 예컨대 소디움 하이드라이드 및 메틸 아이오다이드로 처리하여 4-메틸-4-아자-5α-안드로스탄-3-원 최종생성물을 형성한다.(3) The product of step (2) is treated with methylating agents such as sodium hydride and methyl iodide to form the 4-methyl-4-aza-5α-androstan-3-one final product.
상술된 방법은 특히 본 발명의 바람직한 화합물인 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 제조하는데 적당하고 출발물질로는 17β-N,N-디에틸카바모일-5-옥소-3,5-세코안드로스탄-3-온산이 적당하다.The above-described method is particularly suitable for preparing 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, which is a preferred compound of the present invention, and starting material 17β-N , N-diethylcarbamoyl-5-oxo-3,5-secoandrostan-3-ionic acid is suitable.
상기반응을 다음 실시예 12에서 더욱 상세히 설명하였고 다음 반응도식에 대략 도시하였다.The reaction is described in more detail in the following Example 12 and is shown roughly in the following scheme.
본 발명의 일반식(1)의 신규화합물은 또한 마지막 단계가 환을 폐쇄하여 질소함유 A환을 형성하는 다음 단계로 구성된 방법에 의해 제조될 수 있다.The novel compounds of general formula (1) of the present invention can also be prepared by a process in which the last step consists of closing the ring to form a nitrogen-containing A ring.
(1) 5-옥소-3,5-세코안드로스탄-3은 산화합물을 메틸아민으로 처리하여 상응하는 5-메틸아민-3,5-세코안드로스탄-3-온산을 형성하고;(1) 5-oxo-3,5-secoandrostan-3 treats the acid compound with methylamine to form the corresponding 5-methylamine-3,5-secoandrostan-3-ionic acid;
(2) 단계(1)의 생성물을 촉매조건하에서 환원시켜서 상응하는 5α-수소화합물을 형성하고;(2) reducing the product of step (1) under catalytic conditions to form the corresponding 5α-hydrogen compound;
(3) 단계(2)의 생성물을 원 위치에서 가열하여 환을 폐쇄시키고 그렇게하여 4-메틸-4-아자-5α-안드로스탄-3-원 최종 생성물을 형성한다.(3) The product of step (2) is heated in situ to close the ring and thus form 4-methyl-4-aza-5α-androstan-3-one final product.
상기 방법은 본 발명의 특히 바람직한 화합물인 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 제조하는데 적당하고, 출발물질은 17β-N,N-디에틸 카바모일-5-옥소-3,5-세코안드로스탄-3-온 산이 적당하다.The method is suitable for preparing 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, which is a particularly preferred compound of the present invention, and the starting material is 17β-N, N-diethyl carbamoyl-5-oxo-3,5-secoandrostan-3-one acid is suitable.
상기 반응을 다음 실시예 13에 더욱 상세히 설명하였고 다음 반응 도식에 대략적으로 도시하였다.The reaction is described in more detail in the following Example 13 and is shown roughly in the following reaction scheme.
특히 바람직한 화합물인 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원 디에틸 아미드 측쇄의 17β-위치에 부가되는 최종단계에서 다음단계로 구성된 방법에 의해 제조될 수 있다.Method consisting of the following steps in the final step added to the 17β-position of the particularly preferred compound 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one diethyl amide side chain It can be prepared by.
(1)17β-카복시-4-안드로스텐-3-원을 산화제, 예컨대 소디움 메타과 요오드산염으로 처리하여 5-옥소-3,5-세코안드로스탄-3, 17β-디온산을 형성하고;(1) treating 17β-carboxy-4-androsten-3-one with an oxidizing agent such as sodium meta and iodide to form 5-oxo-3,5-secoandrostan-3,17β-dioic acid;
(2) 단계(1)의 생성물을 메틸아민으로 처리하여 17β-카복시-4-메틸-4-아자-5-안드로스텐-3-원을 형성하고;(2) treating the product of step (1) with methylamine to form 17β-carboxy-4-methyl-4-aza-5-androsten-3-one;
(3) 단계(2)의 생성물을 촉매조건하에서 수소화하여 17β-카복시-4-메틸-4-아자-5α-안드로스텐-3-원을 형성하고;(3) hydrogenating the product of step (2) under catalytic conditions to form a 17β-carboxy-4-methyl-4-aza-5α-androsten-3-one;
(4) 단계(3)의 생성물의 나트륨염을 형성하고 옥살릴 클로라이드로 처리하여 17β-카보닐-클로로-4-메틸-4-아자-5α-안드로스탄-3-원을 형성하고;(4) forming the sodium salt of the product of step (3) and treating with oxalyl chloride to form the 17β-carbonyl-chloro-4-methyl-4-aza-5α-androstan-3-one;
(5) 단계(4)의 생성물을 디에틸아민으로 처리하여 17β-N, N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 형성한다.(5) The product of step (4) is treated with diethylamine to form 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one.
상기 반응을 다음 실시예(14)에 더욱 상세히 설명하고 다음 반응도식에 대략적으로 도시하였다.The reaction is described in more detail in the following example (14) and outlined in the following scheme.
특히 바람직한 화합물인 17β-N, N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 상응하는 17β-카바모일 화합물을 디에틸화하는 최종단계의 방법 또는 상응하는 17β-N-에틸 카바모일 화합물을 모노에틸화 하는 최종단계의 방법에 의해 또한 제조될 수 있다.Particularly preferred compounds or the final step of deethylation of the corresponding 17β-carbamoyl compound with 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one It can also be prepared by the method of the last step to monoethylate the 17β-N-ethyl carbamoyl compound.
이들 두 방법은 다음 단계로 구성되어 있다.These two methods consist of the following steps.
(1) 17β-카복시-4-메틸-4-아자-5α-안드로스탄-3-원을 옥살릴 클로라이드로 처리하여 17β-카보닐클로로-4-메틸-4-아자-5α-안드로스탄-3-원을 형성하고;(1) 17β-carbonylchloro-4-methyl-4-aza-5α-androstan-3 by treating 17β-carboxy-4-methyl-4-aza-5α-androstan-3-one with oxalyl chloride -Form a circle;
(2) 단계(1)의 생성물을 암모니아로 처리하여 17β-카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 형성하고;(2) treating the product of step (1) with ammonia to form 17β-carbamoyl-4-methyl-4-aza-5α-androstan-3-one;
(3) 단계(2)의 생성물을 동량의 소디움 하이드라이드 또는 소디움 메틸레이트의 존재하에 에틸화제 예컨대 에틸 브로마이드 또는 디에틸설페이트로 처리하여 각각 소망하는 최종생성물을 형성하거나;(3) the product of step (2) is treated with an ethylating agent such as ethyl bromide or diethylsulfate in the presence of the same amount of sodium hydride or sodium methylate to form the desired final product, respectively;
대안으로서, (2a)단계(1)의 생성물을 모노에틸아민으로 처리하여 상응하는 17β-N-에틸 카바모일 화합물을 형성하고; (3a)단계(2a)의 생성물을 모노에틸화제 예컨대 에틸브로마이드 및 소디움 하이드라이드와 처리하여 소망하는 최종생성물을 형성한다.As an alternative, (2a) treating the product of step (1) with monoethylamine to form the corresponding 17β-N-ethyl carbamoyl compound; (3a) The product of step (2a) is treated with a monoethylating agent such as ethyl bromide and sodium hydride to form the desired final product.
상기 반응을 다음 실시예 16 및 17에 더욱 상세히 설명하고 다음 반응도식에 개략적으로 도시하였다.The reaction is described in more detail in the following Examples 16 and 17 and schematically illustrated in the following scheme.
본 발명의 부분적인 일반식(2)의 구조를 혼합한 일반식(1)의 신규 화합물 즉 A-동일 상사체는 다음 단계로 구성된 방법에 의해 제조될 수 있다.A novel compound of formula (1), i.e., an A-identical analog, mixed with the structure of partial formula (2) of the present invention can be prepared by a method consisting of the following steps.
(1) 테스토스테론을 보론 트리플루오라이드의 존재하에 에탄디티올과 반응하여 테스토스테론의 3-디티오케탈 유도체를 형성하고;(1) reacting testosterone with ethanedithiol in the presence of boron trifluoride to form a 3-dithioketal derivative of testosterone;
(2) 단계(1)의 생성물을 소디움 및 암모니아용액으로 반응시켜서 3-디티오케탈 치환기를 제거하고;(2) reacting the product of step (1) with sodium and ammonia solution to remove the 3-dithioketal substituent;
(3) 단계(2)의 생성물을 p-톨루엔-설포닐 클로라이드의 존재하에 디하이드로피란과 반응시켜 17-테트라하이드로피라닐 옥시 유도체를 형성하고;(3) reacting the product of step (2) with dihydropyran in the presence of p-toluene-sulfonyl chloride to form a 17-tetrahydropyranyl oxy derivative;
(4) 단계(3)의 생성물을 보란과 반응시킨 후에 수산화나트륨 및 과산화수소로 반응시켜서 4-하이드록시-5α-수소 화합물을 형성하고;(4) reacting the product of step (3) with borane and then with sodium hydroxide and hydrogen peroxide to form a 4-hydroxy-5α-hydrogen compound;
(5) 단계(4)의 생성물을 클로뮴 트리옥사이드와 반응시켜 4-케토 화합물을 형성하고;(5) reacting the product of step (4) with clomium trioxide to form a 4-keto compound;
(6) 단계(5)의 생성물을 산으로 처리하여 17-테트라 하이드로 피라닐 보호기를 제거하고 17-하이드록시 화합물을 형성하고;(6) treating the product of step (5) with an acid to remove the 17-tetra hydropyranyl protecting group and form a 17-hydroxy compound;
(7) 단계(6)의 생성물을 아세트산 무수물과 반응시켜 17-아세톡시 화합물을 형성하고;(7) reacting the product of step (6) with acetic anhydride to form a 17-acetoxy compound;
(8) 단계(7)의 생성물을 하이드록실아민 하이드로 클로라이드와 반응시켜서 4-옥심화합물을 형성하고;(8) reacting the product of step (7) with hydroxylamine hydrochloride to form a 4-oxime compound;
(9) 단계(8)의 생성물을 티오닐클로라이드와 반응시킨 후에 수산화칼륨으로 반응시켜서 부분적인 일반식(2)의 구조와 혼합된 일반식(1)의 화합물, A-동일(homo)-4α-아자 화합물을 형성한다.(9) A compound of formula (1), A-homo-4α mixed with the structure of partial formula (2) by reacting the product of step (8) with thionyl chloride followed by potassium hydroxide To form an aza compound.
상기 반응을 다음 실시예 9에 더욱 상세히 설명하였고 다음 반응도식에 대략 도시하였다.The reaction is described in more detail in the following Example 9 and is shown roughly in the following scheme.
본 발명의 부분적인 일반식(3)의 구조와 혼합된 일반식(1)의 신규 화합물, 즉 D-동일 상사체는 〔Aliget al 및 Kerb et al의 J. Steroid Biochem, 5권 제4호, 298페이지(6월호 1974) 및 Goldberg 및 Mannier의 Helv. Chim. Acta 23권 376-384페이지 및 840-345페이지〕에 기술된 것을 포함하는 이 분야에 공지된 여러가지 다른 방법에 의해 제조될 수 있다.The novel compounds of formula (1), ie, D-identical analogs, mixed with the structure of partial formula (3) of the present invention are described in J. Steroid Biochem, vol. Page 298 (June 1974) and Helv. By Goldberg and Mannier. Chim. It may be prepared by a variety of other methods known in the art, including those described in Act 23, pages 376-384 and 840-345.
즉 A가
A가 -CH=CH이고 4-질소가 수소와 다른 치환기에 있는 일반식(1)의 본 발명의 신규 화합물은 다음 실시예 10에 기술된 공정에 의해 제조될 수 있다. 4-질소가 단지 수소만으로 치환되었을 경우 본 발명의 신규화합물은 다음 실시예 11에 기술된 공정에 의해 제조될 수 있다.The novel compounds of the present invention of formula (1) wherein A is -CH = CH and 4-nitrogen are hydrogen and other substituents can be prepared by the process described in Example 10 below. When 4-nitrogen is substituted with only hydrogen, the novel compounds of the present invention can be prepared by the process described in Example 11 below.
상기 일반적인 항에 이미 기술된 본 발명의 신규화합물을 제조하는 방법을 다음 실시예에 의거 더욱 상세히 설명하면 다음과 같다.The method for preparing a novel compound of the present invention already described in the above general term will be described in more detail based on the following examples.
[실시예 1]Example 1
17β-N,N-디에틸카바모일 -4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
A. 3-옥소-N,N-디에틸-4-에티엔아미드A. 3-oxo-N, N-diethyl-4-ethynamide
20g의 소디움 3-옥소-4-엔티에네이트를 360ml의 부수벤젠 및 0.13ml의 피리딘에 현탁시키고 14℃까지 냉각시켰다. 현탁액을 20ml의 옥살릴 클로라이드로 처리하고 15℃에서 15-20분 동안 교반하였다. 현탁액을 증발시켜 건조시킨 후 125ml의 무수 테트라 하이드로 푸란에서 현탁으로서 슬러리화 하였다.20 g of sodium 3-oxo-4-entenate were suspended in 360 ml of benzene and 0.13 ml of pyridine and cooled to 14 ° C. The suspension was treated with 20 ml of oxalyl chloride and stirred at 15 ° C. for 15-20 minutes. The suspension was evaporated to dryness and then slurried as suspension in 125 ml anhydrous tetrahydrofuran.
이 현탁액을 125ml의 테트라하이드로 푸란중의 25ml의 디에틸아민의 용액에 가한 후에 실온에서 1시간동안 교반한 후에 반응물을 41ml의 빙수에 주입하였다. 얻어진 반 결정성 침전물을 에틸 아세테이트로 추출하고 물로 세척하고 포화된 염수로 세척한 후에 건조시키고 증발시켜 25.7g의 생성물을 얻었다. 생성물을 에틸 에테르로부터 재결정하였더니 첫번째는 127°~129℃의 융점을 갖는 생성물 10.0g이 얻어졌고 두번째는 114-119℃의 융점을 갖는 생성물이 3.1g이 얻어졌다.This suspension was added to a solution of 25 ml of diethylamine in 125 ml of tetrahydrofuran and then stirred at room temperature for 1 hour before the reaction was poured into 41 ml of ice water. The semicrystalline precipitate obtained was extracted with ethyl acetate, washed with water, washed with saturated brine, dried and evaporated to give 25.7 g of product. The product was recrystallized from ethyl ether to give 10.0 g of a product having a melting point of 127 ° to 129 ° C. and 3.1 g of a product having a melting point of 114-119 ° C. at a second.
B. 17β-N,N-디에틸카바모일-5-옥소-3,5-세코안드로스탄-3-온산B. 17β-N, N-diethylcarbamoyl-5-oxo-3,5-secoandrostan-3-ionic acid
단계 A의 생성물 15g을 150ml의 디클로로 메탄 및 75ml의 메탄올에 용해시키고 -78℃까지 냉각시킨후에 푸른 색조가 생길 때까지 용액을 통하여 오존을 발생시켰다. 반응용액을 실온까지 따뜻하게 한 후에 질소로 정화시키고, 35℃에서 증발시키고 건조시켰다. 잔사를 벤젠에 용해시키고, 2.5N-NaOH로 3번 추출하였다. 이러한 염기세척은 화합되고 농염산으로 산성화되고, 벤젠으로 추출하고 세척하여 건조시키고 증발시켜 11.5g의 흰색 결정성 고체를 얻었다. 생성물을 에틸 아세테이트로부터 재결정시켰더니 205°-208℃의 융점을 가짐이 밝혀졌다.15 g of the product of Step A was dissolved in 150 ml of dichloromethane and 75 ml of methanol, cooled to -78 ° C and ozone was generated through the solution until a blue tint occurred. The reaction solution was warmed up to room temperature and then clarified with nitrogen, evaporated at 35 ° C. and dried. The residue was dissolved in benzene and extracted three times with 2.5N-NaOH. This base wash was combined, acidified with concentrated hydrochloric acid, extracted with benzene, washed, dried and evaporated to afford 11.5 g of a white crystalline solid. The product was recrystallized from ethyl acetate and found to have a melting point of 205 ° -208 ° C.
C. 17β-N,N-디에틸카바모일-4-아자-4-메틸-5-안스로스텐-3-원C. 17β-N, N-diethylcarbamoyl-4-aza-4-methyl-5-anthrosten-3-one
에탄올 190ml에 26.3g의 단계 B의 생성물을 가하여 용액을 형성하였다. 용액을 빙욕상에서 냉각시키고, 메틸아민으로 포화시킨 후에 180℃에서 8시간 가열하였다. 반응혼합물을 실온까지 냉각시키고 증발시켜 22.3g의 황색을 띤 고체를 얻었다. 크로마토그래피 한 후에 에텔에테르로부터 재결정한 최종생성물은 120°-122℃의 융점을 가짐이 밝혔다.26.3 g of the product of Step B was added to 190 ml of ethanol to form a solution. The solution was cooled on an ice bath, saturated with methylamine and then heated at 180 ° C. for 8 hours. The reaction mixture was cooled to room temperature and evaporated to afford 22.3 g of a yellowish solid. It was found that the final product recrystallized from ether ether after chromatography had a melting point of 120 ° -122 ° C.
D. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원D. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
1ℓ의 빙초산에 단계C의 생성물 36.5g을 가하였다. 용액을 3.5g의 산화 백금촉매로 처리한 후에 실온에서 8시간동안 40p.s.i.에서 수소화시켰다. 반응혼합물을 여과한 후에 증발 건조시켰다. 잔사를 클로로포름에 용해시키고 중탄산염 용액, 염수로 세척한 후에 건조시키고 증발시켰다. 생성물을 에틸에테르로부터 재결정시켰더니 168°-170℃의 융점을 갖는 흰색 결정성 최종생성물 30.65g이 얻어졌다.To 1 liter of glacial acetic acid was added 36.5 g of the product of Step C. The solution was treated with 3.5 g of platinum oxide catalyst and then hydrogenated at 40 p.s.i. for 8 hours at room temperature. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in chloroform, washed with bicarbonate solution, brine, dried and evaporated. The product was recrystallized from ethyl ether to give 30.65 g of a white crystalline final product having a melting point of 168 ° -170 ° C.
[실시예 2-8]Example 2-8
상기 실시예 1에 기술된 공정에 따라서 단지 A단계의 3-옥소-4-에티네이트를 당량의 다른 유용하거나 또는 쉽게 제조된 3-옥소-Δ4화합물로 치환하거나 또는 디에틸아민을 당량의 다른 적당한 아민으로 치환하여 다음 표에 열거된 본 발명의 일반식(1)의 화합물을 제조하였다.According to the process described in Example 1 above, only step A of 3-oxo-4-ethynate is substituted with an equivalent of another useful or readily prepared 3-oxo-Δ4 compound or diethylamine is substituted with another suitable amount of Substituted with an amine to prepare a compound of formula (1) of the present invention listed in the following table.
[실시예 9]Example 9
17β-아세톡시-4a-아자-5α-A-호모안드로스탄-4-원17β-acetoxy-4a-aza-5α-A-homoandrostan-4-one
A. 17β-하이드록시-4-안드로스텐-3-티오케탈A. 17β-hydroxy-4-androsten-3-thioketal
용액을 7.5g의 테스토스테론, 37.5ml의 빙초산, 4.5ml의 에탄디티올, 3.0ml의 보란 트리 플루오라이드 에테레이트로 부터 0℃에서 제조하였다. 혼합물을 실온으로 방치시키고 1.5시간동안 유지하였다. 혼합물을 물로 희석시킨 후에 클로로포름으로 추출하고 5% 중탄산 나트륨으로 세척한 후에 물로 여러번 세척하고 포화된 염화나트륨 용액으로 세척하였다. 혼합물을 건조시키고 증발시켜서 흰색 고체 생성물을 얻어서 메탄올로 부터 재결정하였더니 160°-162℃의 융점을 가지고 있는 최종생성물 9.0g을 얻었다(수율 95%).The solution was prepared at 0 ° C. from 7.5 g testosterone, 37.5 ml glacial acetic acid, 4.5 ml ethanedithiol, 3.0 ml borane tri fluoride etherate. The mixture was left at room temperature and kept for 1.5 hours. The mixture was diluted with water and then extracted with chloroform, washed with 5% sodium bicarbonate, several times with water and with saturated sodium chloride solution. The mixture was dried and evaporated to afford a white solid product which was recrystallized from methanol to give 9.0 g of the final product with a melting point of 160 ° -162 ° C. (yield 95%).
B. 17β-하이드록시-4-안드로스텐B. 17β-hydroxy-4-androsten
60ml의 무수 암모니아 용액에 1.2g의 금속 나트륨을 가하였다. 이 용액에 무수 테트라 하이드로 푸란 10ml 중의 티오케탈 1.0g을 가하여 용액을 20분 동안 환류시켰다. 용액을 몇 ml의 에탄올로 빙냉하고 실온에서 증발시켰다. 용액을 물로 희석하고 디클로로 메탄으로 추출하여, 물, HCL로 세척한 후 물로 다시 세척하여 건조시키고 증발시켜서 149°-152℃의 융점을 갖는 흰새 고체를 얻었다(609mg, 수율 81%).1.2 g of metallic sodium was added to 60 ml of anhydrous ammonia solution. To this solution was added 1.0 g of thioketal in 10 ml of anhydrous tetrahydrofuran and the solution was refluxed for 20 minutes. The solution was ice cooled with several ml of ethanol and evaporated at room temperature. The solution was diluted with water, extracted with dichloromethane, washed with water, HCL, washed again with water, dried and evaporated to give a white bird solid with a melting point of 149 ° -152 ° C. (609 mg, yield 81%).
C. 17β-테트라하이드로피라닐옥시-4-안드로스텐C. 17β-tetrahydropyranyloxy-4-androsten
430mg의 p-톨루엔 설포닐 클로라이드를 함유하는 30ml 디하이드로 푸란에 B단계의 생성물 6.0g을 가하여 용액을 실온에서 1시간 동안 교반하였다. 용액을 에틸에테르로 희석한 후에 20%의 피리딘 물 혼합물로 2번 세척하고, 다시 물로 세척하고, 다시 염수로 세척한 후에 건조시키고 증발시켜 92°-96℃의 융점을 갖고 결정화된 미황새오일을 얻었다(8.5g).6.0 g of the product of step B was added to 30 ml dihydrofuran containing 430 mg of p-toluene sulfonyl chloride, and the solution was stirred at room temperature for 1 hour. The solution was diluted with ethyl ether and then washed twice with 20% pyridine water mixture, again with water, again with brine, dried and evaporated to give crystallized rice bran oil with a melting point of 92 ° -96 ° C. Obtained (8.5 g).
D.17β-테트라하이드로 피라닐옥시-4β-하이드록시-5α-안드로스탄D.17β-tetrahydro pyranyloxy-4β-hydroxy-5α-androstan
2.7ml의 무수 테트라 하이드로 푸란중의 테트라 하이드로 푸란의 1M 보란 5ml의 냉각된(0℃) 용액에 2.0ml의 무수 테트라하이드로 푸란중의 단계 C의 생성물의 500mg.(1.4밀리몰)을 가하였다. 맑은 용액을 1시간 동안 실온에서 교반시킨 후에 0℃로 냉각시키고 5ml의 2.5N-수산화 나트륨으로 처리하고 이어서 4ml의 30% 과산화수소로 처리하였다. 용액을 1시간 동안 실온에서 교반하고, 물로 희석하여 에틸 에테르로 추출하고, 물, 염수로 세척하여 건조시키고 증발시켜서 오일상 결정성 물질을 얻었다. 생성물을 냉에탄올로 세척하고 건조시켜서 167°-170℃의 융점을 갖는 최종 생성물 175mg을 얻었다.To a cooled (0 ° C.) solution of 5 ml of 1 M borane of tetrahydrofuran in 2.7 ml of anhydrous tetrahydrofuran was added 500 mg. (1.4 mmol) of the product of Step C in 2.0 ml of anhydrous tetrahydrofuran. The clear solution was stirred at room temperature for 1 hour, then cooled to 0 ° C. and treated with 5 ml of 2.5N sodium hydroxide followed by 4 ml of 30% hydrogen peroxide. The solution was stirred for 1 h at room temperature, diluted with water, extracted with ethyl ether, washed with water, brine, dried and evaporated to give an oily crystalline material. The product was washed with cold ethanol and dried to give 175 mg of the final product with a melting point of 167 ° -170 ° C.
E. 17β-테트라하이드로피라닐옥시-5α-안드로스탄-4-원E. 17β-tetrahydropyranyloxy-5α-androstan-4-one
0.42ml의 무수 피리딘 및 6.3ml의 무수 디클로로메탄에 0.264g의 클로뮴 트리옥사이드를 서서히 가하고 이 혼합물을 실온에서 15분 동안 교반하였다. 이 혼합물에 디클로로메탄 0.7ml중의 단계 D의 생성물 175mg의 용액을 가하여, 얻어진 혼합물을 실온에서 20분간 교반하였다. 혼합물을 물로 희석하고, 에틸에테르로 추출하여 2.5N 수산화나트륨, 물, 염수로 세척하였다.0.264 g of clomium trioxide was slowly added to 0.42 ml of anhydrous pyridine and 6.3 ml of anhydrous dichloromethane and the mixture was stirred at room temperature for 15 minutes. To this mixture was added a solution of 175 mg of the product of step D in 0.7 ml of dichloromethane and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was diluted with water, extracted with ethyl ether and washed with 2.5N sodium hydroxide, water and brine.
혼합물을 건조시키고 증발시켜서 맑은 오일을 얻었다.The mixture was dried and evaporated to give a clear oil.
F. 17β-하이드록시-5α-안드로스탄-4-원F. 17β-hydroxy-5α-androstan-4-one
75ml의 에탄올에 단계 E의 생성물 2.32g을 가하여 용액을 형성하고, 이를 5ml의 2.5N-염산으로 처리한 후에 증기욕상에서 40분간 따뜻하게 하여 123°-126℃의 융점을 갖고 있는 결정성생성물 2.1g이 얻어졌다.2.32 g of the product of step E was added to 75 ml of ethanol to form a solution, which was then treated with 5 ml of 2.5 N hydrochloric acid and warmed in a steam bath for 40 minutes to give 2.1 g of crystalline product having a melting point of 123 ° -126 ° C. Obtained.
G. 17β-아세톡시-5α-안드로스탄-4-원G. 17β-Acetoxy-5α-androstan-4-one
12ml의 무수 피리딘 및 6ml의 아세트 무수물에 단계 F의 생성물 2.0g을 가하여 용액을 형성하고 이를 30분간 증기욕상에서 가열한 후에 175ml의 빙수에 주입하고 과량의 무수물을 분해시키기 위하여 교반하였다. 반응혼합물을 여과하고 물로 세척하여 50℃의 고진공하에 건조시켜서 160°-163℃의 융점을 갖는최종생성물 1.7g을 얻었다.12 g of anhydrous pyridine and 6 ml of acetic anhydride were added 2.0 g of the product of step F to form a solution, which was heated in a steam bath for 30 minutes, then poured into 175 ml of ice water and stirred to decompose excess anhydride. The reaction mixture was filtered, washed with water and dried under high vacuum at 50 ° C. to obtain 1.7 g of the final product having a melting point of 160 ° -163 ° C.
H. 17β-아세톡시-5α-안드로스탄-4-옥심H. 17β-acetoxy-5α-androstan-4-oxime
125ml의 에탄올 및 30ml의 무수피리딘에 단계 G의 생성물 2.0g을 가하여 용액을 형성하고 이를 420mg의 하이드록실아민 하이드로 클로라이드로 처리하여 실온에서 교반하였다.To 125 ml ethanol and 30 ml anhydropyridine was added 2.0 g of the product of step G to form a solution which was treated with 420 mg of hydroxylamine hydrochloride and stirred at room temperature.
반응혼합물을 20% 에틸아세테이트/벤젠중의 실리카겔상에서 박층 크로마토그래피에 의해 크로마토그래피하고 철야 방치하였다.The reaction mixture was chromatographed by thin layer chromatography on silica gel in 20% ethyl acetate / benzene and left overnight.
생성물을 고진공하의 30°-40℃에서 적은량으로 농축시키고 물로 희석하여 흰새 결정성 물질을 형성하였다. 이를 여과하고 물로 세척하여 에틸에테르에 용해시키고 건조시켜 에틸에테르로부터 재결정하였다.The product was concentrated in small amounts at 30 ° -40 ° C. under high vacuum and diluted with water to form a white crystalline material. It was filtered, washed with water, dissolved in ethyl ether, dried and recrystallized from ethyl ether.
최종생성물의 융점은 222°-224℃였다.The melting point of the final product was 222 ° -224 ° C.
I. 17β-아세톡시-4-아자-5α-A-호모 안드로스탄-4-원I. 17β-acetoxy-4-aza-5α-A-homo androstane-4-one
3.3ml의 증류된 티오닐 클로라이드에 78℃에서 500mg의 단계 H의 생성물을 가하고 얻어진 용액을 1-2분간 교반한 후에 50ml의 4N-수산화칼륨을 20℃에서 서서히 가하였다. 형성된 고체 침전물을 여과하고 물로 잘 세척하여 에틸에테르로 세척하였다. 생성물을 에틸아세테이트로부터 재경하고 에틸아세테이트, 에틸에테르로 세척하고 건조시켜서 232-235℃의 융점을 갖는 최종생성물 210mg을 얻었다.To 3.3 ml of distilled thionyl chloride was added 500 mg of the product of Step H at 78 ° C. and the resulting solution was stirred for 1-2 minutes, followed by the slow addition of 50 ml of 4N-potassium hydroxide at 20 ° C. The solid precipitate formed was filtered, washed well with water and washed with ethyl ether. The product was purified from ethyl acetate, washed with ethyl acetate, ethyl ether and dried to give 210 mg of a final product having a melting point of 232-235 ° C.
[실시예 10]Example 10
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스트-1-엔-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androst-1-ene-3-one
5.0ml 무수 테트라하이드로 푸란중의 0.20g의 무수 디이소프로필아민의 용액을 -78℃의 질소하에서 0.9ml의 2.2M 부틸 리튬으로 처리하였다. -78℃에서 20분후에 3ml의 테트라하이드로 푸란중의 388mg의 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원의 용액을 반응 혼합물에 적가하였다. -78℃에서 30분간 교반시킨 후에 1ml의 테트라하이드로 푸란중의 440mg의 페닐 디설파이드 용액을 반응혼합물에 서서히 적가하였다. 78℃에서 10분간 교반시킨 후에 반응혼합물을 실온까지 따뜻해지도록 방치하였다. 혼합물을 물에 가한 후에 생성물을 에틸아세테이트로 추출하였다. 유기층을 희석수산화나트륨 용액으로 세척하고 물로 세척한 후 다시 묽은 염산으로 세척하고 끝으로 포화된 염화 나트륨 용액으로 세척하였다. 용액을 황산 칼슘상에서 건조시키고 조잡한 고체생성물로 농축시켰다. 헥산중의 에틸아세테이트의 증가하는 량으로 30g의 실리카겔을 통한 용리로 2-페닐티오 유도체가 분명한 2개 이성체의 혼합물로 산출된다. 5ml의 20% 수성 메탄올에 현탁시킨 이 물질을 2ml의 수중에 225mg의 소디움 메타과요오드산염의 용액으로 처리하였다. 16시간 교반시킨후 반응혼합물을 물로 희석시키고 메틸렌 클로라이드로 추출하였다. 유기층을 물로 세척하고 건조시켜서 조잡한 설폭사이드가 되도록 농축시켰다.A solution of 0.20 g of anhydrous diisopropylamine in 5.0 ml anhydrous tetrahydrofuran was treated with 0.9 ml of 2.2 M butyl lithium under nitrogen at -78 ° C. After 20 minutes at −78 ° C., a solution of 388 mg of 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one in 3 ml of tetrahydrofuran is added dropwise to the reaction mixture. It was. After stirring at −78 ° C. for 30 minutes, a solution of 440 mg of phenyl disulfide in 1 ml of tetrahydrofuran was slowly added dropwise to the reaction mixture. After stirring at 78 ° C. for 10 minutes, the reaction mixture was allowed to warm to room temperature. After the mixture was added to water, the product was extracted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution, washed with water, washed with dilute hydrochloric acid and finally with saturated sodium chloride solution. The solution was dried over calcium sulfate and concentrated to a crude solid product. Elution through 30 g of silica gel in increasing amounts of ethyl acetate in hexane yielded a mixture of two isomers in which 2-phenylthio derivatives were evident. This material, suspended in 5 ml of 20% aqueous methanol, was treated with a solution of 225 mg of sodium meta periodate in 2 ml of water. After stirring for 16 hours, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water and dried to give a crude sulfoxide.
톨루엔 5ml 중의 이물질의 용액을 30분간 환류시켰다. 용매를 제거하고 잔사를 에테르중의 증가하는 량의 에틸 아세테이트로 용출시킨 20g의 실리카겔상의 크로마토 그래피하였다.A solution of foreign matter in 5 ml of toluene was refluxed for 30 minutes. The solvent was removed and the residue was chromatographed on 20 g silica gel eluted with increasing amount of ethyl acetate in ether.
최종 생성물을 에테르와 함께 분쇄하여 결정시켰다.The final product was determined by trituration with ether.
[실시예 11]Example 11
17β-N,N-디에틸카바모일-4-아자-5α-안드로스트-1-엔-3-원17β-N, N-diethylcarbamoyl-4-aza-5α-androst-1-ene-3-one
3ml의 메틸렌 클로라이드 중의 291mg의 17β-N,N-디에틸카바모일-4-아자-5α-안드로스탄-3-원의 용액을 0℃에서 메틸렌 클로라이드 중의 117mg의 트리메틸옥소늄 플루오로보레이트의 용액에 가하였다. 혼합물을 0℃에서 6시간 동안 교반 후 125mg의 1,5디아조비싸이클로〔5,4,0〕운데크-5-엔으로 처리하였다. 2시간동안 계속 교반하여 반응혼합물을 무수 에테르로 희석시켰다. 유기용액을 잔사로 부터 분리시키고 감압하에서 조잡한 락팀 에테르가 되도록 농축시켰다. 이 물질을 상응하는 Δ1 화합물로 실시예 15에 상술된 공정에 의해 전환시켰다.A solution of 291 mg of 17β-N, N-diethylcarbamoyl-4-aza-5α-androstan-3-one in 3 ml methylene chloride was added to a solution of 117 mg trimethyloxonium fluoroborate in methylene chloride at 0 ° C. Was added. The mixture was stirred at 0 ° C. for 6 hours and then treated with 125 mg of 1,5 diazobicycle [5,4,0] undec-5-ene. Stirring continued for 2 hours to dilute the reaction mixture with anhydrous ether. The organic solution was separated from the residue and concentrated to crude crude lactim ether under reduced pressure. This material was converted to the corresponding Δ1 compound by the process detailed in Example 15.
[실시예 12]Example 12
12β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원12β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
A. 17β-N,N-디에틸카바모일-4-아자-5-안드로스텐-3-원A. 17β-N, N-diethylcarbamoyl-4-aza-5-androsten-3-one
0℃에서 암모니아로 포화된 600ml의 무수 에탄올중의 90g의 17β-N,N-디에틸 카바모일-5-옥소-3,5-세코안드로스탄-3-온산의 용액을 범브(bomb)에서, 180℃에서 8기간 동안 가열하였다. 냉각시킨후, 다소 갈새을 띤 용액을 방치하여 증발시키고 농축시켜서 건조시켰더니 황색을 띤 거품이 생기게 하여 싸이클로 헥산으로 분쇄하여 17β-N,N-디에틸카바모일-4-아자-5-안드로스텐-3-원을 얻었다.In a bomb, a solution of 90 g of 17β-N, N-diethyl carbamoyl-5-oxo-3,5-secoandrostan-3-ionic acid in 600 ml of anhydrous ethanol saturated with ammonia at 0 ° C., Heated at 180 ° C. for 8 periods. After cooling, the slightly browned solution was left to evaporate, concentrated to dryness and dried to give a yellowish foam which was triturated with hexane and cyclized to 17β-N, N-diethylcarbamoyl-4-aza-5-androsten- 3-membered.
B. 17β-N,N-디에틸카바모일-4-아자-5α-안드로스탄-3-원B. 17β-N, N-diethylcarbamoyl-4-aza-5α-androstan-3-one
140ml의 빙초산중의 상기 A단계에서 제조된 화합물 25g의 용액을 2.5g의 산화백금 및 0.1ml의 과염소산의 존재하에 실온 및 40psi에서 수소화하였다. 요구된 이론적량의 수소를 흡수시키고 약 6시간 후에 잔사를 여과하고 여액을 농축시켜 건조시켰다. 잔사를 100ml의 메틸렌 클로라이드에 용해시키고 50ml의 포화된 염화나트륨 용액으로 2번 세척한 후에 50ml의 5% 중탄산 나트륨 용액으로 세척하였다. 황산 마그네슘상에서 건조시킨 후에 용액을 농축시켜서 건조시키고, 잔사 오일을 에탄올에 용해시켜 활성화 된 목탄으로 여과하여 결정이 시작될 때까지 물을 서서히 가하였다. 5℃에서 냉각시킨 후에 결정성 생성물을 여벌하고 물로 세척하여 건조시켰다.A solution of 25 g of the compound prepared in step A in 140 ml glacial acetic acid was hydrogenated at room temperature and 40 psi in the presence of 2.5 g platinum oxide and 0.1 ml perchloric acid. After absorbing the required theoretical amount of hydrogen and after about 6 hours the residue was filtered and the filtrate was concentrated to dryness. The residue was dissolved in 100 ml of methylene chloride and washed twice with 50 ml of saturated sodium chloride solution followed by 50 ml of 5% sodium bicarbonate solution. After drying over magnesium sulfate, the solution was concentrated to dryness, the residue oil was dissolved in ethanol and filtered over activated charcoal and water was added slowly until crystals started. After cooling at 5 ° C., the crystalline product was spared and washed with water to dry.
C. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원C. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
톨루엔 700ml 중의 상기 B단계의 생성물 36g의 용액을 20ml의 톨루엔중의 5.4g의 50% 소디움 하이드라이드 유탁액의 슬러리로 처리하고, 이어서 16g의 메틸 아이오다이드를 서서히 가하였다. 3시간 동안 실온에서 교반시킨 후 미반응된 소디움 하이드라이드를 25ml 톨루엔중의 5ml의 에탄올로 급냉시키고 이어서 1ℓ의 물로 급냉시켜서 생성물을 매번 500ml의 톨루엔으로 3번 추출하고 결합된 추출액을 물로 3번 세척한후에 황산 마그네슘상에서 건조시켜 여과액을 농축시켜서 건조시켰다. 순수한 17β-N,N-디에틸 카바모일-4-메틸-4-아자-5α-안드로스탄-3-원이 에탄올 및 물로부터 재결정에 의해 얻어졌다.A solution of 36 g of the product of step B in 700 ml of toluene was treated with a slurry of 5.4 g of 50% sodium hydride emulsion in 20 ml of toluene followed by the slow addition of 16 g of methyl iodide. After stirring for 3 hours at room temperature, the unreacted sodium hydride was quenched with 5 ml of ethanol in 25 ml toluene and then quenched with 1 L of water to extract the product three times each time with 500 ml of toluene and the combined extracts washed three times with water. After drying over magnesium sulfate, the filtrate was concentrated to dryness. Pure 17β-N, N-diethyl carbamoyl-4-methyl-4-aza-5α-androstan-3-one was obtained by recrystallization from ethanol and water.
[시시예 13][Example 13]
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
120ml의 에탄올중의 20g의 17β-N,N-디에틸카바모일-5-옥소-3,5-세코안드로스탄-5-온산의 슬러리를 메틸아민 가스로 포화시키고 에탄올 25ml 중의 앞에서 환원된 산화백금의 2g을 포함하는 고압솥(autoclave)에 가하였다.20 g of 17β-N, N-diethylcarbamoyl-5-oxo-3,5-secoandrostan-5-ionic acid in 120 ml of ethanol was saturated with methylamine gas and platinum reduced in 25 ml of ethanol It was added to an autoclave containing 2 g of.
혼합물을 6시간 동안 40psi 및 40℃에서 환원시켰다. 고압솥을 열고 다시 닫아서 180℃에서 8시간 동안 환폐쇄를 실시하기 위하여 가열하였다. 혼합물을 여과하고 여액을 진공하에서 농축시켜 건조시켰다.The mixture was reduced at 40 psi and 40 ° C. for 6 hours. The autoclave was opened and closed again and heated to 180 ° C. for 8 hours. The mixture was filtered and the filtrate was concentrated in vacuo to dryness.
잔사를 에테르로 부터 결정화하였다. 여과하고 건조시켜서 순순한 17β-N,N-디에틸-카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 얻었다.The residue was crystallized from ether. Filtration and drying afforded pure 17β-N, N-diethyl-carbamoyl-4-methyl-4-aza-5α-androstan-3-one.
[실시예 14]Example 14
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
A. 5-옥소-3,5-세코안드로스탄-3,17β-디온산A. 5-oxo-3,5-secoandrostan-3,17β-dioic acid
1100ml의 3급 부탄올중의 31.6g(0.1몰)의 17α-카복시-4-안드로스탄-3-원에 물 150ml 중의 탄산칼륨 27.6g의 용액을 가하였다. 수 925ml 중의 148g의 소디움 메타 과요오드산염의 용액을 준비하고 이 용액의 158ml를 일부분씩 가하고 나머지는 분당 37ml의 비율로 가하였다. 과망간산 칼륨의 A 1.6% 수성용액(18.5ml)을 본래의 과요오드산염 용액과 함께 일부씩 가한 후에 핑크색으로 착색된 반응 혼합물이 유지되도록 필요한만큼 가하였다. 부가하는 동안의 온도를 35℃로 유지시켰다. 2시간 더 교반한 후에 혼합물을 여과하고 충분히 소디움 비설파이트를 가하여 핑크색을 탈색시켰다. 혼합물을 용적이 반이 되도록 농축시키고 산성화하여 에틸아세테이트로 추출하였다.A solution of 27.6 g of potassium carbonate in 150 ml of water was added to 31.6 g (0.1 mol) of 17α-carboxy-4-androstan-3-one in 1100 ml of tert-butanol. A solution of 148 g sodium meta periodate in 925 ml of water was prepared and 158 ml of this solution was added in portions and the remainder at a rate of 37 ml per minute. A 1.6% aqueous solution of potassium permanganate (18.5 ml) was added portionwise with the original periodate solution and then added as necessary to maintain the pink colored reaction mixture. The temperature during the addition was kept at 35 ° C. After stirring for 2 more hours the mixture was filtered and sodium bisulfite was sufficiently added to decolorize pink. The mixture was concentrated to half volume, acidified and extracted with ethyl acetate.
용액을 농축시켜서 다음 단계에 사용될 수 있을만큼 충분히 순수한 생성물 5-옥소-3,5-세코안드로스탄-3,17β-디온산을 얻었다.The solution was concentrated to give the product 5-oxo-3,5-secoandrostan-3,17β-dioic acid sufficiently pure to be used in the next step.
B. 17β-카복시-4-메틸-4-아자-5-안드로스텐-3-원B. 17β-carboxy-4-methyl-4-aza-5-androsten-3-one
상기 A단계의 생성물 20g의 슬러리 및 150ml의 에탄올을 메틸아민 가스로 포화시키고 혼합물을 고압솥으로 옮겨서 8시간 동안 180℃에서 가열하였다. 혼합물을 냉각시킨 후에 농축시켜서 건조시켰다. 잔사를 수중에서 슬러리화 하고 산성화하여 여과해서 17-카복시-4-메틸-4-아자-5-안드로스탄-3-원을 얻었다.The slurry of 20 g of the product of step A and 150 ml of ethanol were saturated with methylamine gas and the mixture was transferred to an autoclave and heated at 180 ° C. for 8 hours. The mixture was cooled and then concentrated to dryness. The residue was slurried in water, acidified and filtered to give 17-carboxy-4-methyl-4-aza-5-androstan-3-one.
C.17-카복시-4-메틸-4-아자-5α-안드로스탄-3-원C.17-carboxy-4-methyl-4-aza-5α-androstan-3-one
40ml의 빙초산 및 0.05ml의 과염소산 중의 상기 B단계의 생성물 10.0g의 용액을 40psi 및 실온에서 촉매로서 1.0g의 산화백금으로 수소화하였다. 수소흡수가 끝난 후에 촉매를 여별하고 여액을 농축하여 거의 건조시켰다. 잔사를 묽은 수성 중탄산 나트륨에 용해시키고 1.0g의 활성화된 목탄으로 처리하여 여과하고 여액을 산성화하였다. 생성물을 여과하고 건조시켰다.A solution of 10.0 g of the product of step B in 40 ml of glacial acetic acid and 0.05 ml of perchloric acid was hydrogenated with 1.0 g of platinum oxide as catalyst at 40 psi and room temperature. After hydrogen absorption, the catalyst was filtered off and the filtrate was concentrated to almost dryness. The residue was dissolved in dilute aqueous sodium bicarbonate, treated with 1.0 g of activated charcoal and filtered and the filtrate was acidified. The product was filtered and dried.
D. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원D. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
상기 C단계의 생성물 5.0g을 동량의 1N-수산화나트륨 용액으로 처리하였다. 혼합물을 밤새 교반한후에 친액화(親液化)하고 진공에서 포스포러스 펜트옥사이드 상에서 건조시켰다. 그렇게 형성된 17-카복시 화합물의 나트륨염을 100ml의 무수 톨루엔에 현탁시켰다. 슬러리를 15℃로 냉각시키고 3ml의 옥살릴 클로라이드를 15℃에서 적가하였다. 혼합물을 20분 동안 더 교반시킨 후에 농축시켜서 건조시켰다.5.0 g of the product of step C were treated with the same amount of 1N-sodium hydroxide solution. The mixture was stirred overnight, then lyophilized and dried over phosphorus pentoxide in vacuo. The sodium salt of the 17-carboxy compound thus formed was suspended in 100 ml of anhydrous toluene. The slurry was cooled to 15 ° C. and 3 ml of oxalyl chloride was added dropwise at 15 ° C. The mixture was further stirred for 20 minutes before it was concentrated to dryness.
30ml의 테트라하이드로푸란을 가하고 이 혼합물을 30ml의 테트라 하이드푸란중의 6ml의 디에틸아민 용액에 냉각시키고 교반시키면서 가하였다. 혼합물을 1시간 동안 교반하고 1ℓ의 물에 주입하였다. 생성물을 클로로 포름에서 추출하고 희석 중탄산 나트륨 용액으로 연달아서 세척하고, 염화나트륨 용액으로 포화시킨 후에 황산 마그네슘상에서 건조시켰다. 클로로포름 추출액을 진공하에서 증류하고 잔사를 에테르로 부터 결정화하여 실제로 순수한 17β-N,N-디에틸 카바모일-4-메틸-4-아자-5α-안드로스탄-3-원을 얻었다.30 ml of tetrahydrofuran was added and the mixture was added to 6 ml of diethylamine solution in 30 ml of tetrahydrofuran while cooling and stirring. The mixture was stirred for 1 hour and poured into 1 L of water. The product was extracted in chloroform and washed successively with dilute sodium bicarbonate solution, saturated with sodium chloride solution and dried over magnesium sulfate. The chloroform extract was distilled under vacuum and the residue was crystallized from ether to give actually 17 [beta] -N, N-diethyl carbamoyl-4-methyl-4-aza-5 [alpha] -androstan-3-one.
[실시예 15]Example 15
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
A. (3β-하이드록시프레근-5-엔-2C-원-21-일) 피리디늄 아이오다이드A. (3β-hydroxypregan-5-en-2C-one-21-yl) pyridinium iodide
2ℓ의 피리딘에 1kg(3.16몰)의 프레그네놀론을 가하고 이 혼합물을 적당히 교반하면서 90-95℃까지 가열하여서, 프레그네놀론을 모두 용해시켰다. 혼합물에 총 866.1g(3.41몰)의 아이오딘을 15-20분간 서서히 가하고 반응혼합물의 온도를 120℃까지 상승시켰다. 혼합물을 100℃ 또는 그 이상의 온도에서 교반시킨 후에 방치하여 1시간 동안 서서히 냉각시키고 냉수욕상에 방치하여 실온이 되도록 하였다. 생성물을 중간 다공성 실리카겔 깔대기상에서 수집하였더니 고무질 및 겔(gel)과 유사함이 밝혀졌다. 피리딘을 가하여 여과를 촉진시키고 여과된 생성물 300ml의 피리딘으로 6번 세척하고 난 후에 300ml의 에테르로 다시 6번 세척한 후에 공기에서 건조시켰다. 228°-230℃의 융점을 갖고있는 생성물을 99% 수율로 얻었다.(1635.8g).1 kg (3.16 moles) of pregnenolone was added to 2 L of pyridine and the mixture was heated to 90-95 ° C. with moderate stirring to dissolve all of the pregnenolone. A total of 866.1 g (3.41 mol) of iodine was slowly added to the mixture for 15-20 minutes and the temperature of the reaction mixture was raised to 120 ° C. The mixture was stirred at a temperature of 100 ° C. or higher, then left to cool slowly for 1 hour and left to cool to room temperature. The product was collected on a medium porous silica gel funnel and found to be similar to rubbery and gel. Pyridine was added to facilitate filtration and washed six times with 300 ml of pyridine filtered product, followed by six more washes with 300 ml of ether, followed by drying in air. A product having a melting point of 228 ° -230 ° C. was obtained in 99% yield (1635.8 g).
B. 메틸 5-안드로스텐-3β-올17β 카복실레이트B. Methyl 5-androsten-3β-ol 17β carboxylate
플라스크에 2.7kg(5,177몰)의 (3β-하이드록시프레근-5-엔-20-원-21-일) 피리디늄 아이오다이드, 13.5ℓ의 메탄올 및 900g의 소디움 모노옥사이드를 장입하였다. 혼합물을 1시간 동안 환류시키고 약 53℃까지 냉각되도록 방치하고, 24ℓ의 얼음 및 2ℓ의 물을 가하여 급냉시켜서 반응 혼합물을 5℃가 되도록 하였다. 혼합물을 2100ml의 1 : 1 비율의 염산 및 물을 가하여 중성화시켜서 pH가 6-7이 되게 하였다. 혼합물을 45분간 방치한 후에 랩(Lapp) 깔대기상에서 수집하고 색이 거의 없어질 때까지 냉수로 잘 세척하였다. 생성물을 깔대기상에서 대강 건조시킨 후에 2개의 유리쟁반이 있는 50℃의 공기 오븐에서 철야 방치하여 건조시켰다. 생성물의 수율은 83.6%였다(1440g).To the flask was charged 2.7 kg (5,177 moles) of (3β-hydroxypregan-5-en-20-one-21-yl) pyridinium iodide, 13.5 L of methanol and 900 g of sodium monooxide. The mixture was refluxed for 1 hour and left to cool to about 53 ° C. and quenched by addition of 24 L ice and 2 L water to bring the reaction mixture to 5 ° C. The mixture was neutralized by addition of 2100 ml of 1: 1 ratio hydrochloric acid and water to a pH of 6-7. The mixture was allowed to stand for 45 minutes before it was collected on a Lapp funnel and washed well with cold water until the color disappeared. The product was roughly dried on a funnel and then left to dry overnight in an air oven at 50 ° C. with two glass trays. The yield of the product was 83.6% (1440 g).
C. 메틸-4-안드로스텐-3-원-17β-카복실레이트C. Methyl-4-androsten-3-one-17β-carboxylate
플라스크에 160.0g의 메틸-5-안드로스텐-3β-올-17β-카복실레이트, 2.4ℓ의 체질하여(sieve) 건조된 톨루엔 및 680ml의 싸이클로헥사논을 장입하였다. 혼합물을 가열하여 환류시키고 존재하는 물을 15분동안 공비(共沸)하여 제거하였다.(즉 증류액이 맑아질 때까지). 320ml의 부수 톨루엔 중의 88g의 알루미늄이소프로폭사이드를 슬러리로 한번에 모두 가하였다. 반응 혼합물을 약 800ml의 톨루엔이 제거되는 동안 1시간 이상 환류시켰다. 혼합물을 25℃까지 냉각시키고 40g의 규조토를 가하고 이어서 80ml의 물을 가하였다. 혼합물을 10분 동안 교반하고, 규조토를 통하여 여과시킨 후에 300ml의 톨루엔으로 3번 세척하였다. 여액을 농축하여 거의 건조시키고 빙욕상에서 냉각시켰다. 생성물을 결정화하여 0°-5℃로 방치하고, 수집하여 냉헥산으로 세척한 후 진공에서 건조시켰다. 수율이 83.6%(133g)이고 융점이 130°-132℃인 생성물을 얻었다.The flask was charged with 160.0 g of methyl-5-androsten-3β-ol-17β-carboxylate, 2.4 L of sieved dried toluene and 680 ml of cyclohexanone. The mixture was heated to reflux and the water present was azeotropically removed for 15 minutes (ie until the distillate became clear). 88 g of aluminum isopropoxide in 320 ml of incident toluene were added all at once as a slurry. The reaction mixture was refluxed for at least 1 hour while about 800 ml of toluene was removed. The mixture was cooled to 25 ° C. and 40 g of diatomaceous earth were added followed by 80 ml of water. The mixture was stirred for 10 minutes, filtered through diatomaceous earth and washed three times with 300 ml of toluene. The filtrate was concentrated to near dryness and cooled on an ice bath. The product was crystallized and left at 0 ° -5 ° C., collected, washed with cold hexane and dried in vacuo. The yield was 83.6% (133 g) and the product had a melting point of 130 ° -132 ° C.
D. 4-안드로스텐-3-원-17β-카복실산D. 4-androsten-3-one-17β-carboxylic acid
24.6ℓ의 메탄올 중의 2.462kg의 메틸 4-안드로스텐-3-원-17β-카복실레이트에 4.9ℓ 수중의 1.23kg의 수산화칼륨을 가하였다. 반응혼합물을 질소하에서 6시간동안 환류시킨 후에 실온으로 냉각되도록 철야 방치하였다. 혼합물을 3200ml의 6N-염산으로 산성화하였다. 대부분의 생성물이 미세한 결정으로 결정화 되었다. 14ℓ의 물을 수증기중에 30분이상 가하고, 모든 생성물을 침전시켰다. 혼합물을 4시간 동안 30℃에서 교반하여 방치하였다. 혼합물을 캡(Cap) 깔대기 상에서 여과하고 세척수가 중성이 될때까지 물로 세척하였다. 생성물을 50℃의 오븐에서 철야 건조시켰다. 245°-248℃의 융점을 갖고 있는 생성물이 98%수율로 얻어졌다(2.313g).To 2.462 kg of methyl 4-androsten-3-one-17β-carboxylate in 24.6 L of methanol was added 1.23 kg of potassium hydroxide in 4.9 L of water. The reaction mixture was refluxed under nitrogen for 6 hours and then left to cool to room temperature overnight. The mixture was acidified with 3200 ml of 6N-hydrochloric acid. Most of the product was crystallized into fine crystals. 14 liters of water was added in the steam over 30 minutes and all the product precipitated out. The mixture was left to stir at 30 ° C. for 4 h. The mixture was filtered on a Cap funnel and washed with water until the wash water was neutral. The product was dried overnight in an oven at 50 ° C. A product having a melting point of 245 ° -248 ° C. was obtained in 98% yield (2.313 g).
E. 17β-N,N-디에틸카바모일-4-안드로스텐-3-원E. 17β-N, N-diethylcarbamoyl-4-androsten-3-one
플라스크에 700g의 4-안드로스텐-3-원-17-카복실산 및 공비(azeotroping)에 의해 건조된 11.6ℓ의 톨루엔을 장입하였다. 혼합물에 226ml의 체에 걸러 건조된 피리딘을 가하고 250ml의 건조된 톨루엔중의 250ml의 옥살틸 클로라이드를 20분 이상 서서히 가하였다. 반응혼합물을 1시간 동안 실온에서 방치하고 10℃까지 냉각시켰다. 동일한 용적의 무수 톨루엔중의 체에 걸러 건조된 디에틸아민을 충분한 량으로 가하여 영구적인 알카리성 pH를 얻었다. 이는 약2.4ℓ의 용액이 필요하였다. 반응혼합물을 30분간 방치하고 16ℓ의 빙수를 가하여 식혔다. 얻어진 층을 분리하여 수성층을 4ℓ의 에틸아세테이트로 3번 추출하였다. 결합된 유기층을 8ℓ의 물로 세척하고 염산으로 세척하여 산성으로 만들었다(pH 3). 8ℓ로 세척한 후에 최종적으로 8ℓ의 포화된 염화나트륨 용액으로 세척하였다. 이를 황산 나트륨상에서 건조시키고 거대한 순환 건조기에서 3-4의 소량이 되도록 농축시켰다. 4ℓ 헥산을 가하고 1시간동안 0°-5℃까지 냉각시켰다. 생성물을 수집하고 소량의 냉헥산으로 3번 세척한 후에 40°-50℃의 공기오븐에서 철야 건조시켰다. 119°-121℃의 융점을 갖는 생성물을 수율 75%로 얻었다(616.5g).To the flask was charged 700 g of 4-androsten-3-one-17-carboxylic acid and 11.6 L of toluene dried by azeotroping. To the mixture was added filtered pyridine, filtered through 226 ml of sieve, and 250 ml of oxaltyl chloride in 250 ml of dried toluene was added slowly over 20 minutes. The reaction mixture was left at room temperature for 1 hour and cooled to 10 ° C. A sufficient amount of dried diethylamine was added to a sieve in the same volume of anhydrous toluene to obtain a permanent alkaline pH. This required about 2.4 liters of solution. The reaction mixture was left for 30 minutes and cooled by adding 16 L of ice water. The obtained layer was separated and the aqueous layer was extracted three times with 4 L of ethyl acetate. The combined organic layers were washed with 8 L of water and made acidic by washing with hydrochloric acid (pH 3). After washing with 8 L, it was finally washed with 8 L of saturated sodium chloride solution. It was dried over sodium sulfate and concentrated to a small amount of 3-4 in a large circulation dryer. 4 L hexane was added and cooled to 0 ° -5 ° C. for 1 hour. The product was collected and washed three times with a small amount of cold hexane and then dried overnight in an air oven at 40 ° -50 ° C. A product having a melting point of 119 ° -121 ° C. was obtained in yield 75% (616.5 g).
F. 17β-N,N-디에틸카바모일-5-옥소-3,5-세코안드로스탄-3-온산F. 17β-N, N-diethylcarbamoyl-5-oxo-3,5-secoandrostan-3-ionic acid
플라스크에 600g의 17β-N,N-디에틸카바모일-4-안드로스텐-3-원 및 18ℓ의 3급-부탄올을 장입하여 용해시켰다. 1200ml 수중의 253g의 탄산나트륨 용액을 가하였다. 18ℓ 수중의 2.4kg의 소디움 퍼 아이오데이트의 용액을 1.5시간 이상 가하면서 같은 시간 이상 1340ml의 2% 과망간산 칼륨을 가하여 반응 혼합물의 핑크색을 유지하였다. 부가하는 동안의 온도를 25°및 40℃ 사이로 유지하였다. 혼합물을 2시간동안 방치하고 여과하여 고형체를 물로 세척하였다. 3급 부탄올을 단지 수성용액이 남을 때까지 농축제거하고 이를 10℃까지 냉각시킨 후에 110ml의 50% 황산으로 산성화하였다(pH 3). 수성용액을 6ℓ의 에틸아세테이트로 3번 추출하였다. 결합된 에틸 아세테이트 세척을 4ℓ의 5% 소디움 비설페이트 용액으로 세척한 후에 4ℓ의 포화된 염화나트륨 용액으로 세척하였다. 결합된 추출액을 황산 나트륨상에서 건조시키고 1.5ℓ가 되도록 농축시킨 후에 비점까지 상승시켜서 2시간 동안 5°-10℃에서 방치하였다. 이를 여과하여 여과 고형체를 에틸 아세테이트로 세척하였다. 205°-208℃의 융점을 가하고 있는 생성물을 77%의 수율로 얻었다.(488g).600 g of 17β-N, N-diethylcarbamoyl-4-androsten-3-one and 18 L tert-butanol were charged and dissolved in the flask. 253 g sodium carbonate solution in 1200 ml water was added. A solution of 2.4 kg of sodium periodate in 18 L water was added for at least 1.5 hours while 1340 ml of 2% potassium permanganate was added for the same time to maintain the pink color of the reaction mixture. The temperature during the addition was kept between 25 ° and 40 ° C. The mixture was left for 2 hours and filtered to wash the solid with water. The tert-butanol was concentrated off until only the aqueous solution remained, cooled to 10 ° C. and acidified with 110 ml of 50% sulfuric acid (pH 3). The aqueous solution was extracted three times with 6 L of ethyl acetate. The combined ethyl acetate washes were washed with 4 L of 5% sodium bisulfate solution followed by 4 L of saturated sodium chloride solution. The combined extracts were dried over sodium sulfate, concentrated to 1.5 L, then raised to boiling point and left at 5 ° -10 ° C. for 2 hours. It was filtered to wash the filter solid with ethyl acetate. A product having a melting point of 205 ° -208 ° C. was obtained in a yield of 77% (488 g).
G. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5-안드로스텐-3-원G. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one
눈금있는(graduated) 실린더에 응축된 200ml의 메틸렌 아민을 가하여 무수 빙욕상에서 유지시킨 후에 1250ml의 에틸렌 글리콜을 실온에서 교반하면서 가하였다. 용적이 16% 증가됨이 밝혀졌다. 메틸아민/에틸렌 글리콜 용액을 3ℓ 플라스크 중의 250g의 17β-N,N-디에틸 카바모일-5-옥소-3,5-세코인드로스텐-3-온산에서 가하였다. 수분 후에 용액을 얻었다. 반응혼합물을 40분 이상 110℃까지 가열하고 온도가 180℃에 도달될 때까지 분당 2°의 비율로 가열을 지속한 후에 가열을 중지하였다. 총 경과된 가열시간은 70분이었다. 반응 혼합물을 10ℓ의 물에서 식히고, 얻어진 우유빛의 용액을 2ℓ의 디클로로메탄으로 5번 추출하였다. 결합된 유기추출액을 4ℓ의 물로 세척하고 농염산으로 산성화하고, 4ℓ의 중탄산나트륨 용액으로 세척하고 4ℓ의 물로 3번 세척하였다. 결합된 유기 추출액을 황산 나트륨상에서 건조시킨 후에 50g의 실리콘 디옥사이드로 처리하여 농축시켜서 건조시켰다. 잔사를 750ml n-헥산중의 750mg의 싸이클로헥사논의 용액에 용해시킨 후에 실온에서 교반하면서 철야 방치하였다. 생성물을 여과하고 n-헥산으로 세척하여 진공에서 건조시켰다. 115°-118℃의 융점을 갖는 생성물을 91%의 수율로 얻었다(226g).200 ml of methylene amine condensed in graduated cylinders were added and maintained on anhydrous ice bath followed by 1250 ml of ethylene glycol with stirring at room temperature. It was found that the volume increased by 16%. Methylamine / ethylene glycol solution was added in 250 g of 17β-N, N-diethyl carbamoyl-5-oxo-3,5-cecoindrosten-3-ionic acid in a 3 L flask. After a few minutes a solution was obtained. The reaction mixture was heated to 110 ° C. for at least 40 minutes and heating was stopped after continuing heating at a rate of 2 ° per minute until the temperature reached 180 ° C. Total elapsed heating time was 70 minutes. The reaction mixture was cooled in 10 L of water and the milky solution obtained was extracted 5 times with 2 L of dichloromethane. The combined organic extracts were washed with 4 L of water, acidified with concentrated hydrochloric acid, washed with 4 L of sodium bicarbonate solution and three times with 4 L of water. The combined organic extracts were dried over sodium sulfate and then concentrated to dryness by treatment with 50 g of silicon dioxide. The residue was dissolved in a solution of 750 mg of cyclohexanone in 750 ml n-hexane, then left overnight with stirring at room temperature. The product was filtered off, washed with n-hexane and dried in vacuo. A product having a melting point of 115 ° -118 ° C. was obtained in a yield of 91% (226 g).
H. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원H. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
플라스크에 150g의 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원 및 750ml의 빙초산을 장입하였다. 혼합물을 60℃까지 45psi의 질소하에서 4시간 동안 가열하였다. 생성물을 여과하여 여과 고형체를 디클로로메탄으로 세척하여 여액을 농축시켜서 건조하였다. 잔사를 750ml의 디클로로메탄에 용해시키고 500ml의 1N-황산으로 2번 세척하고, 500ml의 물로 1번 세척하고, 500ml의 포화된 경탄산 나트륨 용액으로 한번 세척한 후에 포화된 염화나트륨 용액으로 한번 세척하였다. 용액을 황산 마그네슘상에서 건조시키고 15g의 활성화된 목탄으로 처리하고 75g의 실리콘 디옥사이드의 패드(pad)를 통하여 여과하였다. 여과 고형체를 1ℓ의 디클로로 메탄으로 세척하고 농축시켜서 건조시켰다. 잔사를 450ml의 에틸아세테이트에 용해시킨 후에 1시간 동안 실온에서 방치하고 1시간 동안 빙욕상에서 방치하였다. 생성물을 여과하고 50ml의 에틸아세테이트로 세척하고 난후에 100ml의 n-헥산으로 세척하고 건조시켰다. 여액을 농축시켜서 건조시키고 100ml의 에틸아세테이트에 용해시키고 2시간 동안 실온에서 방치하여 여과하고 15ml의 에틸아세테이트로 세척하고 100ml의 n-헥산으로 세척하였다. 172°-174℃의 융점을 갖는 생성물을 76.6%의 수율로 얻었다(115g).To the flask was charged 150 g of 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one and 750 ml of glacial acetic acid. The mixture was heated to 60 ° C. under 45 psi of nitrogen for 4 hours. The product was filtered, the filtered solid was washed with dichloromethane and the filtrate was concentrated to dryness. The residue was dissolved in 750 ml of dichloromethane and washed twice with 500 ml of 1N-sulfuric acid, once with 500 ml of water, once with 500 ml of saturated sodium light carbonate solution and then with saturated sodium chloride solution. The solution was dried over magnesium sulfate, treated with 15 g of activated charcoal and filtered through a pad of 75 g of silicon dioxide. The filtered solid was washed with 1 L dichloro methane and concentrated to dryness. The residue was dissolved in 450 ml of ethyl acetate and then left at room temperature for 1 hour and on an ice bath for 1 hour. The product was filtered, washed with 50 ml of ethyl acetate and then washed with 100 ml of n-hexane and dried. The filtrate was concentrated to dryness, dissolved in 100 ml of ethyl acetate, left at room temperature for 2 hours, filtered, washed with 15 ml of ethyl acetate and washed with 100 ml of n-hexane. A product having a melting point of 172 ° -174 ° C. was obtained in a yield of 76.6% (115 g).
[실시예 16]Example 16
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
A. 17β-카바모일-4-메틸-4-아자-5α-안드로스탄-3-원A. 17β-carbamoyl-4-methyl-4-aza-5α-androstan-3-one
17β-카보닐클로로-4-메틸-4-아자-5α-안드로스탄-3-원의 톨루엔 용액에 테트라하이드로 푸란중의 암모니아 용액을 가하고, 반응 혼합물은 2시간 동안 실온에서 교반하였다. 물을 가하고 에틸 아세테이트로 추출하여 중간물질 아미드를 얻었다.To a toluene solution of 17β-carbonylchloro-4-methyl-4-aza-5α-androstan-3-one was added an ammonia solution in tetrahydrofuran and the reaction mixture was stirred at room temperature for 2 hours. Water was added and extraction with ethyl acetate gave intermediate amides.
B. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원B. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
단계 A의 생성물을 톨루엔 용액중의 동량의 소디움 하이드라이드의 존재하에 에틸 브로마이드를 에틸화하였다. 단계A의 생성물 몰당 2몰의 에틸 브로마이드를 사용하여 최종 생성물을 얻었다.The product of step A was ethylated with ethyl bromide in the presence of the same amount of sodium hydride in toluene solution. 2 moles of ethyl bromide per mole of product of Step A were used to obtain the final product.
[실시예 17]Example 17
17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
A. 17β-N-에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원A. 17β-N-ethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
17β-카보닐클로로-4-메틸-4-아자-5α-안드로스탄-3-원의 톨루엔 용액에 테트라하이드로 푸란중의 모노에틸아민 용액을 가하고, 반응 혼합물을 2시간 동안 실온에서 교반하였다. 물을 가하고 에틸 아세테이트로 추출하였더니 17β-N-에틸카바모일 생성물이 얻어졌다.To a toluene solution of 17β-carbonylchloro-4-methyl-4-aza-5α-androstan-3-one was added a solution of monoethylamine in tetrahydrofuran and the reaction mixture was stirred at room temperature for 2 hours. Water was added and extraction was performed with ethyl acetate to afford 17β-N-ethylcarbamoyl product.
B. 17β-N,N-디에틸카바모일-4-메틸-4-아자-5α-안드로스탄-3-원B. 17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
단계 A의 생성물을 단계 A의 생성물 몰당 에틸브로마이드 1몰을 사용하는 것외에는, 실시예 16의 단계 B에 상술된 바와 동일한 방법으로 에틸 브로마이드 및 소디움 하이드라이드를 사용하여 에틸화하였다.The product of step A was ethylated using ethyl bromide and sodium hydride in the same manner as described above in step B of Example 16, except that 1 mole of ethyl bromide per mole of product of step A was used.
[실시예 18]Example 18
N-메틸-N-〔17β-(N', N'-디에틸 카바모일)-4-아자-4-메틸-5α-안드로스트-3-엔-3-일〕아민 하이드로클로라이드N-methyl-N- [17β- (N ', N'-diethyl carbamoyl) -4-aza-4-methyl-5α-androst-3-en-3-yl] amine hydrochloride
3ml의 메틸렌 클로라이드중의 160ml의 트리메틸옥소늄 플루오로 보레이트의 혼합물에 0℃에서 3ml의 메틸렌 클로라이드 중의 375mg의 17β-N,N-디에틸 카바모일-4-메틸-4-아자-5α-안드로스탄-3-원의 용액을 가하였다.To a mixture of 160 ml trimethyloxonium fluoro borate in 3 ml methylene chloride, 375 mg of 17β-N, N-diethyl carbamoyl-4-methyl-4-aza-5α-androstane in 3 ml methylene chloride at 0 ° C. A 3-membered solution was added.
0°-5℃에서 6시간 동안 교반시킨 후 혼합물을 실온에서 철야 방치하였다. 디아조 비싸이클로〔5,4,0〕운데크-5-엔(160mg)을 가하고 유기층을 무수에테르로 희석시켰다. 고체잔사를 원심분리에 의해 제거하고 유기층을 증발시켜 건조시키고 Δ2-락티미노 메틸 에테르를 잔존시켰다. 이 물질과 5ml 톨루엔 중의 1.0g의 메틸아민의 혼합물을 100℃에서 24시간 동안 폐쇄된 관에서 가열하였다. 냉각시킨 후에 관을 열고 용액을 질소 스트림하에서 농축시켜서 증발시켰다. 잔사를 8ml의 에틸 아세테이트에 용해시키고 무수 염화수소의 느린 스트림을 0℃에서 도입하였다. 원심분리에 의해 침전된 생성물을 에테르로 2번 세척하고 진공에서 건조시켰더니 N-메틸-N-〔17β-(N', N'-디에틸 카바모일)-4-아자-4-메틸-5α-안드로스트-3-엔-3-일〕아민 하이드로클로라이드가 얻어졌다.After stirring at 0 ° -5 ° C. for 6 hours the mixture was left overnight at room temperature. Diazo bicycle [5,4,0] undec-5-ene (160 mg) was added and the organic layer was diluted with anhydrous ether. The solid residue was removed by centrifugation, the organic layer was evaporated to dryness and Δ 2 -lactimino methyl ether remained. A mixture of this material and 1.0 g of methylamine in 5 ml toluene was heated in a closed tube at 100 ° C. for 24 hours. After cooling down the tube was opened and the solution was concentrated by evaporation under a stream of nitrogen. The residue was dissolved in 8 ml of ethyl acetate and a slow stream of anhydrous hydrogen chloride was introduced at 0 ° C. The product precipitated by centrifugation was washed twice with ether and dried in vacuo. N-methyl-N- [17β- (N ', N'-diethyl carbamoyl) -4-aza-4-methyl-5α- Androst-3-en-3-yl] amine hydrochloride was obtained.
Claims (1)
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU45697/79A AU527030B2 (en) | 1978-04-13 | 1979-04-04 | 4-aza-17-substituted-5a-androstan-3-ones |
| NZ190119A NZ190119A (en) | 1978-04-13 | 1979-04-06 | 4-aza-17-substituted-5alpha-androstan-3-ones |
| EP79101131A EP0004949B1 (en) | 1978-04-13 | 1979-04-12 | 4-aza-17-substituted-5-alpha-androstan-3-one, their a and d homo analogs, process for their preparation and pharmaceutical compositions containing them |
| ZA791752A ZA791752B (en) | 1978-04-13 | 1979-04-12 | 4-aza-17 beta -substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors |
| CA000325640A CA1142914A (en) | 1978-04-13 | 1979-04-12 | 4-AZA-17-SUBSTITUTED-5.alpha.-ANDROSTAN-3-ONES USEFUL AS 5.alpha.-REDUCTASE INHIBITORS |
| KR1019790001163A KR830000085B1 (en) | 1978-04-13 | 1979-04-12 | Method for preparing 4-aza-17-substituted-5α-androstan-3-ones useful as 5α-reductase inhibitors |
| JP4445879A JPS54145669A (en) | 1978-04-13 | 1979-04-13 | 44azaa177substitutedd5 alphaaandrostanee33one which is testosteronee5 alphaareductase repressor |
| IE765/79A IE48127B1 (en) | 1978-04-13 | 1979-08-08 | 4-aza-17-substituted-5 -androstan-3-one,their a- and d- homo analogues,process for their preparation and pharmaceutical compositions containing them |
| US06/189,981 US4377584A (en) | 1978-04-13 | 1980-09-23 | 4-Aza-17β-substituted-5α-androstan-3-one-reductase inhibitors |
| JP62231223A JPS63152320A (en) | 1978-04-13 | 1987-09-17 | Teststerone-5 alpha-reductase inhibitor composition containing 4-aza-17-substituted 5 alpha-androstane-3-one |
| HK801/87A HK80187A (en) | 1978-04-13 | 1987-10-29 | 4-aza-17-substituted-5-alpha-androstan-3-one,their a and d homo analogs,process for their preparation and pharmaceutical compositions containing them |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89611878A | 1978-04-13 | 1978-04-13 | |
| KR1019790001163A KR830000085B1 (en) | 1978-04-13 | 1979-04-12 | Method for preparing 4-aza-17-substituted-5α-androstan-3-ones useful as 5α-reductase inhibitors |
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| KR830000085B1 true KR830000085B1 (en) | 1983-02-08 |
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| KR1019790001163A KR830000085B1 (en) | 1978-04-13 | 1979-04-12 | Method for preparing 4-aza-17-substituted-5α-androstan-3-ones useful as 5α-reductase inhibitors |
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| JP (2) | JPS54145669A (en) |
| KR (1) | KR830000085B1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS5669952A (en) * | 1979-11-09 | 1981-06-11 | Nec Corp | Result report control system in message communication |
| NZ211145A (en) * | 1984-02-27 | 1988-10-28 | Merck & Co Inc | 4-aza-5-alpha-androst-1-en-3-ones and pharmaceutical compositions |
| ZA851426B (en) * | 1984-02-27 | 1986-10-29 | Merck & Co Inc | 17 beta-n-monosubstituted carbamoyl-4-aza-5 alpha-androst-1-en-3-ones as 5 alpha reductase inhibitors |
| US4888336A (en) * | 1987-01-28 | 1989-12-19 | Smithkline Beckman Corporation | Steroid 5-alpha-reductase inhibitors |
| CA2084799C (en) * | 1991-12-17 | 2003-01-28 | Glenn J. Gormley | Method of prevention of prostatic carcinoma with 17 beta-n-monosubstituted-carbamoyl-4-aza-5 alpha-androst-1 -en-3-ones |
| EP0547687A1 (en) * | 1991-12-18 | 1993-06-23 | Merck & Co. Inc. | 17B-N-Substituted adamantyl/norbonanyl carbamoyl-4-aza-5a-and-rost-1-en-3-ones and androstan-3 ones |
-
1979
- 1979-04-12 KR KR1019790001163A patent/KR830000085B1/en active
- 1979-04-12 ZA ZA791752A patent/ZA791752B/en unknown
- 1979-04-13 JP JP4445879A patent/JPS54145669A/en active Granted
-
1987
- 1987-09-17 JP JP62231223A patent/JPS63152320A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54145669A (en) | 1979-11-14 |
| JPS6361315B2 (en) | 1988-11-28 |
| JPS63152320A (en) | 1988-06-24 |
| JPH0246566B2 (en) | 1990-10-16 |
| ZA791752B (en) | 1980-11-26 |
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