JPS6118559B2 - - Google Patents
Info
- Publication number
- JPS6118559B2 JPS6118559B2 JP5967178A JP5967178A JPS6118559B2 JP S6118559 B2 JPS6118559 B2 JP S6118559B2 JP 5967178 A JP5967178 A JP 5967178A JP 5967178 A JP5967178 A JP 5967178A JP S6118559 B2 JPS6118559 B2 JP S6118559B2
- Authority
- JP
- Japan
- Prior art keywords
- yield
- reaction
- dimethylformamide
- distilled
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000004519 manufacturing process Methods 0.000 claims description 31
- -1 amide acetal Chemical class 0.000 claims description 29
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 42
- 239000000047 product Substances 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 28
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- 238000000034 method Methods 0.000 description 25
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 10
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 10
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 10
- 229960004544 cortisone Drugs 0.000 description 10
- 229960000890 hydrocortisone Drugs 0.000 description 9
- BFZHCUBIASXHPK-ATWVFEABSA-N 11beta-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)C[C@@H]2O BFZHCUBIASXHPK-ATWVFEABSA-N 0.000 description 8
- 150000001241 acetals Chemical class 0.000 description 8
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 7
- 229960005205 prednisolone Drugs 0.000 description 7
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 235000006408 oxalic acid Nutrition 0.000 description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 229960002537 betamethasone Drugs 0.000 description 4
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- IMNDHOCGZLYMRO-UHFFFAOYSA-N n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC=C1 IMNDHOCGZLYMRO-UHFFFAOYSA-N 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 150000003431 steroids Chemical group 0.000 description 4
- DLYZPQGVPVAEME-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethyl-1-phenylmethanamine Chemical compound COC(OC)(N(C)C)C1=CC=CC=C1 DLYZPQGVPVAEME-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GSFFXKGTGPMVLM-UHFFFAOYSA-N 1,1-dibutoxy-n,n-dimethylmethanamine Chemical compound CCCCOC(N(C)C)OCCCC GSFFXKGTGPMVLM-UHFFFAOYSA-N 0.000 description 2
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 2
- FBZVZUSVGKOWHG-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethylethanamine Chemical compound COC(C)(OC)N(C)C FBZVZUSVGKOWHG-UHFFFAOYSA-N 0.000 description 2
- KDISMIMTGUMORD-UHFFFAOYSA-N 1-acetylpiperidine Chemical compound CC(=O)N1CCCCC1 KDISMIMTGUMORD-UHFFFAOYSA-N 0.000 description 2
- WKAVAGKRWFGIEA-DADBAOPHSA-N 11-Ketoprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2=O WKAVAGKRWFGIEA-DADBAOPHSA-N 0.000 description 2
- WKAVAGKRWFGIEA-UHFFFAOYSA-N 11-Ketoprogesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2=O WKAVAGKRWFGIEA-UHFFFAOYSA-N 0.000 description 2
- LGTRJLNCBPEIDL-UHFFFAOYSA-N CC(NN1CCCCC1)(OC)OC Chemical compound CC(NN1CCCCC1)(OC)OC LGTRJLNCBPEIDL-UHFFFAOYSA-N 0.000 description 2
- KGKYFQOVFYIYDV-UHFFFAOYSA-N COC(C1=C(C(=CC=C1)C)C)(N)OC Chemical compound COC(C1=C(C(=CC=C1)C)C)(N)OC KGKYFQOVFYIYDV-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- HDEDWNHZBWFQCB-JZYPGELDSA-N [(8s,9s,10r,11s,13s,14s,17r)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)C)[C@@]1(C)C[C@@H]2O HDEDWNHZBWFQCB-JZYPGELDSA-N 0.000 description 2
- LPEYMYDYPGRLBU-YGZHYJPASA-N [(8s,9s,10r,11s,13s,14s,17r)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl] benzoate Chemical compound O([C@@]1(CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)C(=O)CO)C(=O)C1=CC=CC=C1 LPEYMYDYPGRLBU-YGZHYJPASA-N 0.000 description 2
- YCEQGEMYOUCHON-JZYPGELDSA-N [(8s,9s,10r,11s,13s,14s,17r)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)C)[C@@]1(C)C[C@@H]2O YCEQGEMYOUCHON-JZYPGELDSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- SOQJPQZCPBDOMF-YCUXZELOSA-N betamethasone benzoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@@H]1C)C(=O)CO)C(=O)C1=CC=CC=C1 SOQJPQZCPBDOMF-YCUXZELOSA-N 0.000 description 2
- 229960000870 betamethasone benzoate Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 2
- 150000002905 orthoesters Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- LBKIRBXELMWQRC-UHFFFAOYSA-N 1-methoxypropane-1,1-diol Chemical compound CCC(O)(O)OC LBKIRBXELMWQRC-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FPVRUILUEYSIMD-QZIXMDIESA-N [(8s,9r,10s,11s,13s,14s,16s,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-QZIXMDIESA-N 0.000 description 1
- ITYMTTQVNYAJAA-XGQKBEPLSA-N [(8s,9r,10s,11s,13s,14s,16s,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CC)[C@@]1(C)C[C@@H]2O ITYMTTQVNYAJAA-XGQKBEPLSA-N 0.000 description 1
- JZUOTTDVXIVTTR-RPPPWEFESA-N [(8s,9s,10r,11s,13s,14s,17r)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl] propanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CC)[C@@]1(C)C[C@@H]2O JZUOTTDVXIVTTR-RPPPWEFESA-N 0.000 description 1
- PCDMOOFTYPHGTF-UHFFFAOYSA-N [17-(2-hydroxyacetyl)-10,13-dimethyl-3,11-dioxo-6,7,8,9,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=CC2(C)C2C1C1CCC(C(=O)CO)(OC(=O)C)C1(C)CC2=O PCDMOOFTYPHGTF-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- NSLGQFIDCADTAS-UHFFFAOYSA-N n,n-dimethyl-1,1-dipropoxymethanamine Chemical compound CCCOC(N(C)C)OCCC NSLGQFIDCADTAS-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- IECKAVQTURBPON-UHFFFAOYSA-N trimethoxymethylbenzene Chemical compound COC(OC)(OC)C1=CC=CC=C1 IECKAVQTURBPON-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、プレグナン系ステロイド 17α−エ
ステル化合物の製法に関し、更に詳しくはプレグ
ナン系ステロイド 17α,21−ジヒドロキシ化合
物を環状の17α,21−ジアルキルアミノアルキリ
デンジオキシ体とし、これを開裂して容易にしか
も選択的にプレグナン系ステロイド 17α−エス
テル化合物を製造する方法に関するものである。
プレグナン系ステロイド 17α−エステルは、
抗炎症作用等を有する医薬品として重要な副腎皮
質ホルモン剤であり、従来よりプレグナン系ステ
ロイド 17α−ヒドロキシ体を直接アシル化する
方法、およびプレグナン系ステロイド 17α,21
−環状オルトエステルを経由する方法等が知られ
ている。
直接アシル化する方法は無水三弗化酢酸やパラ
トルエンスルホン酸の如き強酸を触媒とし、脂肪
族カルボン酸無水物あるいは脂肪族カルボン酸ハ
ライドをアシル化剤としてプレグナン系ステロイ
ド 17α−ヒドロキシ体をエステル化するもので
あるが、不必要な副出成物を与えたり、ステロイ
ド環自体の破壊がしばしば認められる。これを防
止するために室温程度の低温で反応させると極め
て長時間を要し、このため強酸の作用量を多くす
れば、やはり副生成物を生じたり分解を起こしや
すくなる。
この直接の17α−位アシル化法として、炭酸カ
ルシウムの如きアルカリ性触媒を用い、脂肪族カ
ルボン酸無水物をアシル化剤として相当する17α
−エステル化合物を得る方法もわずかに知られて
いるが、反応時間が極めて長く、ケト基を有する
場合にはそれがエノール化し、反応を早めるため
に触媒を多用すると、やはり副生成物を生成し、
また立体的に大きな官能基例えばフエニル基を有
するアシル化剤などは反応に抵抗しエステルの生
成が難しくなるという欠点がある。更にこうした
直接的17α−位アシル化法は、予め21−位および
11−位の水酸基を保護しておき、17α−位をアシ
ル化した後に保護基を除去する工程が必要となる
から工程数が多くなり、目的物の実質的収率が低
下し、従つて工業的には至つて不利な方法であ
る。
このような各種の欠点をもつ直接17α−位アシ
ル化法に代わる方法として知られているのが、プ
レグナン系ステロイド 17α,21−ジヒドロキシ
化合物をジメチルホルムアミド中、酸触媒存在
下、オルトエステル(例えばメチルオルトアセテ
ート、メチルオルトプロピオネート、メチルオル
トベンゾエートなど)と反応させ相当する17α,
21−環状オルトエステル体を得、この中間体を酸
処理して目的のプレグナン系ステロイド17α−エ
ステル体を製造する方法である。しかし、この場
合強酸の触媒を用いなければ17α,21−環状オル
トエステル体は生成せず、また17α,21−環状オ
ルトエステル体の開裂の際に相当する21−エステ
ル体が副生する。このためPHの調整が必要である
がが、それでも全く21−エステル体の副生を防ぐ
ことはできず、純粋な17−エステル体を得るには
手間のかかる方法である。特にプレグナン系ステ
ロイド 17α−ベンゾエートのようなものの合成
に際しては、大きな官能基が立体的に中間体であ
るオルトエステルの生成に抵抗を示し、結果的に
低収率になる。
本発明者らは、プレグナン系ステロイド 17α
−エステルの製造法に関し、以上の従来法の欠点
を除き、工業的に有利な方法を検討した結果、今
でも最も有利とされていた17α,21−環状オルト
エステル体を経由する方法よりも便に反応条件、
目的物の収率などの点において有利な、そしてよ
り工業的に有利な方法を発明した。
以下本発明を説明する。
本発明は部分構造式()
を有する17α,21−ジヒドロキシ−プレグナン系
ステロイドを一般式()
(式中、Rは水素原子、低級アルキル基または
フエニル基を示し、R1は低級アルキル基または
互いに結合して隣接する窒素原子と共に複素環を
形成する基を示し、R2は低級アルキル基を示
す。)で表わされるアミドアセタールと反応さ
せ、部分構造式()
(式中、RおよびR1は前記と同意義である。)
を有する17α,21−環状ジアルキルアミノアルキ
リデンジオキシ−プレグナン系ステロイド〔以下
化合物()と略称する〕を得、これを酸の存在
下に開裂せしめ、部分構造式()
(式中、Rは前記と同意義である。)を有する
プレグナン系ステロイド 17α−エステルを選択
的に製造する方法である。
本発明における試薬であるアミドアセタールと
は、N,N−ジアルキルホルムアミド ジアルキ
ルアセタール、N,N−ジアルキルアルキルアミ
ド ジアルキルアセタールまたはN,N−ジアル
キルベンズアミド ジアルキルアセタールであ
り、N,N−ジアルキルホルムアミド ジアルキ
ルアセタールとは、例えばN,N−ジメチルホル
ムアミド ジメチルアセタール、N,N−ジメチ
ルホルムアミド ジエチルアセタール、N,N−
ジメチルホルムアミド ジプロピルアセタール、
N,Nジメチルホルムアミド ジ−n−ブチルア
セタール、N,N−ジメチルホルムアミド ジ−
tert−ブチルアセタールなどであり、N,N−ジ
アルキルアルキルアミド ジアルキルアセタール
とは、例えばN,Nメチルアセトアミド ジメチ
ルアセタール、N,N−ジエチルアセトアミド
ジメチルアセタール(新規化合物)、ピペリジン
アセトアミド ジメチルアセタール(新規化合
物)などであり、N,N−ジアルキルベンズアミ
ド ジアルキルアセタールとは、例えばN,N−
ジメチルベンズアミド ジメチルアセタールであ
る。
これらの試薬は、例えばN,N−ジメチルホル
ムアミド、ジアルキルアセタールは市販されてい
るが、その他は合成したものを用いた。その際に
既知の合成法を改良したものであり、例えばN,
N−ジメチルアセトアミド ジメチルアセタール
およびジメチルベンズアミド ジメチルアセター
ルは、それぞれ相当するN,N−ジメチルアセト
アミド,N,N−ジメチルベンズアミドをジメチ
ル硫酸と加熱した後、メタノール中にてナトリウ
ムメトキサイドと反応させることによつてすでに
合成されているが、実際に反応を行うといずれも
低収率であつた。そこで、この反応をエーテル中
にてナトリウムメトキサイドを懸濁させて行うと
高収率で目的のアセタールが得られた。この改良
実施例は前記の新規化合物の合成法に加えて後述
する。
本発明で用いられる17α,21−ジヒドロキシ−
プレグナン系ステロイドは9−位,11−位,16−
位などに随意の置換基(例えば水酸基、ケトン
基、ハロゲン基、メチル基等)を有するステロイ
ドであればよく、例えばハイドロコーチゾン、コ
ルチゾン、プレドニゾロン、プレドニゾン、ベー
ターメサゾンなどのそれぞれの17α,21−ジヒド
ロキシ体は好例である。
本発明の反応はステロイド1モルに対して、通
常アミドアセタール1〜1.5モルが用いられ、こ
の際ジメチルホルムアミド、ジオキサン、1,
1,1−トリクロルエタン、クロロホルムなどの
有機溶媒中で行われるのが好ましい。
本発明方法の反応条件は緩和な条件でよく、上
記溶媒中ステロイドとアミドアセタールとを80〜
100℃で10〜30分間加熱するか、室温にて24〜48
時間放置すれば反応は完結し、反応混合物を中性
または塩基性アルミナカラムクロマトグラフイー
にて精製して化合物()を得る。
本反応にて得られる化合物()は全て新規化
合物であり、その構造は元素分析および各種のス
ペクトル分析により確認された。
本反応においては触媒を用いる必要がなく、こ
の点においても前述した17α,21−環状オルトエ
ステル体を合成する方法よりも優れている。
次に化合物()の酸開裂によるプレグナン系
ステロイド 17α−エステルの製造法について説
明する。すなわち化合物()をメタノールのよ
うな低級アルコール類、ジオキサン、アセトン、
ジメチルホルムアミド、ジメチルスルホキシドな
どの極性溶媒に溶解し、これに蓚酸などを少量加
え弱酸性にするか、または化合物()を酢酸に
溶解し、室温にて1〜3時間放置することによ
り、反応は完結する。次いで、溶媒を留去し得ら
れる残渣を再結晶あるいはカラムクロマトグラフ
イーに付すことによりプレグナン系ステロイド
17α−エステルを得る。蓚酸の代わりに酢酸、リ
ン酸、クエン酸またはそれぞれの緩衝液なども利
用できる。
本発明で得られるプレグナン系ステロイド 17
α−エステルは例えばハイドロコーチン 17−ホ
ルメート、ハイドロコーチゾン 17−アセテー
ト、ハイドロコーチゾン 17−プロピオネート、
ハイドロコーチゾン 17−ベンゾエート、コルチ
ゾン 17−ホルメート、コルチゾン 17アセテー
ト、コルチゾン 17−プロピオネート、コルチゾ
ン 17−ベンゾエート、プレドニゾロン 17−ホ
ルメート、プレドニゾロン 17−アセテート、プ
レドニゾロン 17−プロピオネート、プレドニゾ
ロン 17−ベンゾエート、プレドニゾン 17−ホ
ルメート、プレドニゾン 17−アセテート、プレ
ドニゾン 17−プロピオネート、プレドニゾン
17−ベンゾエート、ベーターメサゾン 17−ホル
メート、ベーターメサゾン 17−アセテート、ベ
ーターメサゾン 17−プロピオネート、ベーター
メサゾン 17−ベンゾエートなどであり、臨床上
重要な副腎皮質ホルモン剤またはその原料中間体
である。
次に本発明の利点を明確にするため、ハイドロ
コーチゾンを原料としたハイドロコーチゾン 17
−ベンゾエートの合成において、本発明方法(A
法とする)と、従来最良とされている17α,21−
環状オルトエステルを経由する方法(B法とす
る)とを比較した。本反応は次の反応式によつて
示される。
また、A法とB法の工程1および工程2におけ
る反応条件および収率を比較した表を下記に示
す。
The present invention relates to a method for producing a pregnane steroid 17α-ester compound, and more specifically, it converts a pregnane steroid 17α,21-dihydroxy compound into a cyclic 17α,21-dialkylaminoalkylidene dioxy compound, which can be easily cleaved and The present invention relates to a method for selectively producing a pregnane steroid 17α-ester compound. Pregnane steroid 17α-ester is
It is an adrenal corticosteroid agent that is important as a pharmaceutical with anti-inflammatory effects, etc., and conventional methods have been used to directly acylate pregnane steroid 17α-hydroxy form, and pregnane steroid 17α, 21
- Methods using cyclic orthoesters are known. The direct acylation method uses a strong acid such as trifluoroacetic anhydride or para-toluenesulfonic acid as a catalyst, and uses an aliphatic carboxylic acid anhydride or aliphatic carboxylic acid halide as an acylating agent to esterify the 17α-hydroxy form of a pregnane steroid. However, unnecessary by-products or destruction of the steroid ring itself is often observed. In order to prevent this, if the reaction is carried out at a low temperature of about room temperature, it will take a very long time, and therefore, if the amount of strong acid is increased, by-products will be produced and decomposition will easily occur. In this direct 17α-acylation method, an alkaline catalyst such as calcium carbonate is used, and an aliphatic carboxylic acid anhydride is used as the acylating agent at the corresponding 17α-position.
- There are a few methods known to obtain ester compounds, but the reaction time is extremely long, and if it has a keto group, it will be enolized, and if a large amount of catalyst is used to speed up the reaction, by-products will also be produced. ,
Furthermore, acylating agents having sterically large functional groups, such as phenyl groups, have the disadvantage of resisting the reaction and making it difficult to form esters. Furthermore, such direct acylation at the 17α-position requires that the acylation at the 21-position and
Since it is necessary to protect the 11-position hydroxyl group and remove the protecting group after acylating the 17α-position, the number of steps increases, the actual yield of the target product decreases, and the industrial This is a very disadvantageous method. As an alternative to the direct 17α-acylation method, which has various drawbacks, a pregnane steroid 17α,21-dihydroxy compound is prepared in dimethylformamide in the presence of an acid catalyst to form an orthoester (e.g. methyl orthoacetate, methylorthopropionate, methylorthobenzoate, etc.)
In this method, a 21-cyclic orthoester is obtained, and this intermediate is treated with an acid to produce the desired pregnane steroid 17α-ester. However, in this case, unless a strong acid catalyst is used, the 17α,21-cyclic orthoester is not produced, and the corresponding 21-ester is produced as a by-product when the 17α,21-cyclic orthoester is cleaved. For this reason, it is necessary to adjust the pH, but even this cannot completely prevent the by-product of the 21-ester, and it is a time-consuming method to obtain a pure 17-ester. Particularly in the synthesis of pregnane steroids such as 17α-benzoate, large functional groups sterically resist the formation of the intermediate orthoester, resulting in low yields. The present inventors discovered that pregnane steroid 17α
- As a result of examining industrially advantageous methods for producing esters by eliminating the drawbacks of the conventional methods described above, we found that they are more convenient than the method via the 17α,21-cyclic orthoester, which is still considered the most advantageous method. reaction conditions,
We have invented a method that is advantageous in terms of the yield of the target product and is more industrially advantageous. The present invention will be explained below. The present invention is based on the partial structural formula () A 17α,21-dihydroxy-pregnane steroid with the general formula () (In the formula, R represents a hydrogen atom, a lower alkyl group, or a phenyl group, R 1 represents a lower alkyl group or a group that combines with each other to form a heterocycle with adjacent nitrogen atoms, and R 2 represents a lower alkyl group. ) is reacted with an amide acetal represented by the partial structural formula (). (In the formula, R and R 1 have the same meanings as above.) A 17α,21-cyclic dialkylaminoalkylidene dioxy-pregnane steroid [hereinafter abbreviated as compound ()] was obtained and Cleaved downward, partial structural formula () This is a method for selectively producing a pregnane steroid 17α-ester having the formula (wherein R has the same meaning as above). The amide acetal which is a reagent in the present invention is N,N-dialkylformamide dialkyl acetal, N,N-dialkylalkylamide dialkyl acetal or N,N-dialkylbenzamide dialkyl acetal, and N,N-dialkylformamide dialkyl acetal. For example, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-
dimethylformamide dipropylacetal,
N,N-dimethylformamide di-n-butyl acetal, N,N-dimethylformamide di-
tert-butyl acetal, etc., and N,N-dialkylalkylamide dialkyl acetal is, for example, N,N-methylacetamide, dimethylacetal, N,N-diethylacetamide.
Dimethyl acetal (new compound), piperidine acetamide dimethyl acetal (new compound), etc. N,N-dialkylbenzamide dialkyl acetal is, for example, N,N-
Dimethylbenzamide is dimethyl acetal. These reagents, for example, N,N-dimethylformamide and dialkyl acetal, are commercially available, but the others were synthesized. At that time, the known synthesis method was improved, for example, N,
N-Dimethylacetamide Dimethylacetal and Dimethylbenzamide Dimethylacetal can be prepared by heating the corresponding N,N-dimethylacetamide and N,N-dimethylbenzamide with dimethyl sulfuric acid and then reacting them with sodium methoxide in methanol. However, when the reactions were actually carried out, the yields were low. Therefore, when this reaction was carried out by suspending sodium methoxide in ether, the desired acetal was obtained in high yield. Examples of this improvement will be described below in addition to the method for synthesizing the novel compound described above. 17α,21-dihydroxy used in the present invention
Pregnane steroids are 9-, 11-, and 16-
Any steroid having an optional substituent (e.g., hydroxyl group, ketone group, halogen group, methyl group, etc.) at the 17α, 21- The dihydroxy form is a good example. In the reaction of the present invention, 1 to 1.5 moles of amide acetal are usually used per mole of steroid, and in this case, dimethylformamide, dioxane, 1,
Preferably, the reaction is carried out in an organic solvent such as 1,1-trichloroethane or chloroform. The reaction conditions for the method of the present invention may be mild, and the steroid and amide acetal may be mixed in the above solvent at a temperature of 80 to
Heat at 100℃ for 10-30 minutes or at room temperature for 24-48 minutes.
The reaction is completed by standing for a period of time, and the reaction mixture is purified by neutral or basic alumina column chromatography to obtain the compound (). All of the compounds () obtained in this reaction are new compounds, and their structures were confirmed by elemental analysis and various spectral analyses. This reaction does not require the use of a catalyst, and in this respect is also superior to the method for synthesizing the 17α,21-cyclic orthoester described above. Next, a method for producing pregnane steroid 17α-ester by acid cleavage of compound () will be explained. In other words, the compound () is a lower alcohol such as methanol, dioxane, acetone,
The reaction can be initiated by dissolving the compound in a polar solvent such as dimethylformamide or dimethyl sulfoxide and adding a small amount of oxalic acid to make it weakly acidic, or by dissolving the compound () in acetic acid and leaving it at room temperature for 1 to 3 hours. Complete. Next, the solvent is distilled off and the resulting residue is subjected to recrystallization or column chromatography to obtain pregnane steroids.
17α-ester is obtained. Instead of oxalic acid, acetic acid, phosphoric acid, citric acid, or their respective buffers can also be used. Pregnane steroid obtained by the present invention 17
Examples of α-esters include hydrocortisone 17-formate, hydrocortisone 17-acetate, hydrocortisone 17-propionate,
Hydrocortisone 17-benzoate, cortisone 17-formate, cortisone 17-acetate, cortisone 17-propionate, cortisone 17-benzoate, prednisolone 17-formate, prednisolone 17-acetate, prednisolone 17-propionate, prednisolone 17-benzoate, prednisone 17-formate, Prednisone 17-acetate, Prednisone 17-propionate, Prednisone
17-benzoate, beta-methasone 17-formate, beta-methasone 17-acetate, beta-methasone 17-propionate, beta-methasone 17-benzoate, etc., and are clinically important corticosteroids or their raw material intermediates. . Next, in order to clarify the advantages of the present invention, hydrocortisone made from hydrocortisone 17
- In the synthesis of benzoates, the method of the present invention (A
) and 17α, 21−, which is conventionally considered the best
A comparison was made with a method via a cyclic orthoester (referred to as method B). This reaction is shown by the following reaction formula. In addition, a table comparing the reaction conditions and yields in Step 1 and Step 2 of Method A and Method B is shown below.
【表】【table】
【表】
以上の如く、本発明の製造方法は17α,21−環
状オルトエステルを経由する方法と比較して、工
程数は同じであるが、反応条件は有利であり、し
かも収率がよいことがわかる。すなわち、本発明
方法は工業的に有利な方法といえる。
次に実施例を挙げて本発明を更に詳細に説明す
る。
実施例 1
N,N−ジメチルアセトアミド ジメチルアセ
タールの製造
N,N−ジメチルアセトアミド23.75g(0.27
モル)とジメチル硫酸33.65g(0.26モル)とを
90℃にて2時間加熱した後、除々に温度を室温ま
で下げた。この反応液を金属ナトリウム6.2g
(0.27モル)とメタノールより製したナトリウム
メチラート(白色粉末)のエーテル懸濁液100ml
に0℃にて滴下した。滴下終了後、温度を除々に
室温まで上げつつ1時間撹拌し、析出した結晶を
去し、液を常圧蒸留して目的物を得た。
収量 9.20g 収率 28% bp108〜109℃
実施例 2
N,N−ジメチルベンズアミド ジメチルアセ
タールの製造
N,N−ジメチルベンズアミド10g(0.07モ
ル)とジメチル硫酸8.5g(0.06モル)とを90℃
で4時間加熱した後、除々に温度を室温まで下げ
た。この反応液を金属ナトリウム1.6g(0.7モ
ル)とメタノールより調整したナトリウムメチラ
ート(白色粉末)のエーテル懸濁液50mlに0℃に
て滴下した。滴下後温度を除々に室温まで上げつ
つ1時間撹拌し、析出した結晶を去し、液を
減圧蒸留して目的物を得た。
収量 3.4g 収率 25% bp 120〜125℃(20mm
Hg)
実施例 3
N,N−ジメチルプロピルアミド ジメチルア
セタールの製造
N,N−ジメチルプロピルアミド47.0g(0.47
モル)とジメチル硫酸60g(0.47モル)とを100
℃にて3時間加熱した後、除々に温度を室温まで
下げた。この反応液を金属ナトリウム11.0g
(0.47モル)とメタノールより調整したナトリウ
ムメチラートのエーテル懸濁液150mlに0℃にて
滴下した。滴下後温度を室温まで除々に上げつつ
1時間撹拌し、析出した結晶を去し、液を減
圧蒸留して目的物を得た。
収量 3.0g 収率 4.7% bp 40〜50℃(90mm
Hg)
実施例 4
N,N−ジエチルアセトアミド ジメチルアセ
タールの製造
N,N−ジエチルアセトアミド25.0g(0.22モ
ル)とジメチル硫酸28g(0.22モル)とを90〜
100℃にて4時間加熱した後、除々に温度を室温
まで下げた。この反応液を金属ナトリウム6.0g
(0.26モル)とメタノールより調整したナトリウ
ムメチラートのエーテル懸濁液に0℃にて滴下し
た。滴下後温度を室温まで除々に上げつつ1時間
撹拌し、析出した結晶を去し、液を常圧蒸留
して目的物を得た。
収量 2.8g 収率 7.9% bp 135〜140℃
実施例 5
ピペリジルアセトアミド ジメチルアセタール
の製造
1−アセチルピペリジン25g(0.179モル)と
ジメチル硫酸25g(0.195モル)とを110℃にて3
時間加熱した後、除々に温度を室温まで下げた。
この反応液を金属ナトリウム4.5g(0.196モル)
とメタノールより調整したナトリウムメチラート
のエーテル懸濁液100mlに0℃にて滴下した。滴
下後温度を室温まで除々に上げつつ1時間撹拌
し、析出した結晶を去し、液を減圧蒸留して
目的物を得た。
収量 9.8g 収率 28.8% bp 97℃(33mm
Hg)
実施例 6
17α,21−ジメチルアミノメチレンジオキシ−
4−プレグネン−11β−オール−3,20−ジオ
ンの製造
(1) ハイドロコルチゾン1.0g(2.8ミリモル)を
よく乾燥したクロロホルム100mlに懸濁し、
N,N−ジメチルホルムアミド ジメチルアセ
タール1mlを加え、撹拌しながら室温にて3時
間反応した。反応液が淡黄色透明になつたとこ
ろで減圧下にて溶媒を留去して、中性アルミナ
カラムクロマトグラフイーに付し、クロロホル
ム溶出部より淡黄色油状物を単離した。
収量 250mg 収率 20.4%
これを一部n−ヘキサン−アセトン混液で再
結晶し、無色針状晶を得た。
mp 249〜251℃
IRνCHCl 3naxcm-1:1650,1620
NMR(C5D5N)δ:1.35(3H,s),1.57
(3H,s),2.90(6H,s),4.45(1H,m),
4.80(2H.s),5.80(1H,s)
(2) ハイドロコーチゾン1.0g(2.8ミリモル)を
よく乾燥したジオキサン20mlに溶かし、N,N
−ジメチルホルムアミド ジメチルアセタール
(bp 103℃)0.35g(2.9ミリモル)を加えて、
撹拌しながら温度を80℃にし、生成するメタノ
ールを留去して2時間反応した。反応終了後減
圧下にて溶媒を留去し、アルミナカラムクロマ
トグラフイーに付し、クロロホルム流出物をn
−ヘキサン−アセトン混液より再結晶して目的
物を得た。収量 0.2g収率 13%
(3) 上述(1)において、N,N−ジメチルホルムア
ミド ジメチルアセタールの代わりにN,N−
ジメチルホルムアミド ジエチルアセタール
(bp 135℃)を用いて、室温にて3時間反応
し、同様に処理して、目的物を得た。
収量 0.16g 収率 12%
(4) 上述(1)において、N,N−ジメチルホルムア
ミド ジメチルアセタールの代わりにN,N−
ジメチルホルムアミド ジ−n−ブチルアセタ
ール(bp 88〜90℃/10mmHg)を用いて、室温
にて1時間反応し、同様に処理して目的物を得
た。収量 0.04g 収率 2.6%
(5) 上述(1)において、N,N−ジメチルホルムア
ミド ジメチルアセタールの代わりにN,N−
ジメチルホルムアミド ジ−tert−ブチルアセ
タール(bp 75〜77℃/25mmHg)を用いて、室
温にて1時間反応し、同様に処理して目的物を
得た。収量 0.03g 収率 2.0%
実施例 7
ハイドロコーチゾン 17−ホルメートの製造
17α,21−ジメチルアミノメチレンジオキシ−
4−プレグネン−11β−オール−3,20−ジオン
100mg(0.237ミリモル)をメタノール100mlに溶
解し、飽和蓚酸水溶液2〜3滴を滴下し(PH5〜
6)、反応液を1時間室温にて撹拌した後、溶媒
を留去し、分取薄層シリカゲルクロマトグラフイ
−にて目的物を単離した。アセトン−n−ヘキサ
ン混液より再結晶して無色微細針状晶を得た。
収量 40mg 収率43.3% mp177〜183℃
実施例 8
17α,21−ジメチルアミノメチレンジオキシ−
4−プレグネン−3,11,20−トリオンの製造
コルチゾン0.3g(0.83ミリモル)をよく乾燥
したジメチルホルムアミド3mlに溶解し、N,N
−ジメチルホルムアミド ジメチルアセタール
0.3mlを加え、室温にて3時間撹拌した。反応液
が淡黄色透明になつたところで減圧下にて溶媒を
留去し、アルミナカラムクロマトグラフイーに付
し、クロロホルム溶出部より淡黄色油状物を得
た。
収量 34mg 収率 9.7%
NMR(CDCl3)δ:0.63(3H,s),1.37
(3H,s),2.10(6H,s),3.70(2H,s),
5.60(1H,s)
実施例 9
コルチゾン 17−ホルメートの製造
17α,21−ジメチルアミノメチレンジオキシ−
4−プレグネン−3,11,20−トリオン100mgを
メタノール20mlに溶解し、酢酸緩衝液(PH5〜
6)を5ml加え、室温にて3時間放置する。反応
終了後、メタノールを留去し、100mlの水を加
え、クロロホルムにて抽出する。抽出液を水で洗
浄し、芒硝にて乾燥した後、溶媒を留去し、分取
薄層シリカゲルクロマトグラフイーにて単離精製
し、n−ヘキサン−アセトン混液より再結晶し
て、無色針状晶を得た。
収量 40mg 収率 45% mp 217〜224℃
実施例 10
17α,21−ジメチルアミノメチレンジオキシ−
1,4−プレグナジエン−11β−オール−3,
20−ジオンの製造
プレドニゾロン0.3g(0.83ミリモル)をよく
乾燥したジメチルホルムアミド2mlに溶解し、
N,N−ジメチルホルムアミド ジメチルアセタ
ール0.3mlを加え、100℃にて加熱撹拌して30分間
反応した。反応終了後、減圧下溶媒を留去し、残
渣を中性アルミナカラムクロマトグラフイーに付
し、クロロホルム溶出部より淡黄色油状の目的物
を得た。収量 40mg 収率 11.6%
NMR(CDCl3)δ:1.32(3H,s),1.52
(3H,s),2.04(6H,s)
実施例 11
プレドニゾロン 17−ホルムメートの製造
17α,21−ジメチルアミノメチレンジオキシ−
1,4−プレグナジエン−11β−オール−3,20
−ジオン40mg(0.095ミリモル)をメタノール20
ml中に溶解し、飽和蓚酸水溶液2〜3滴を滴下し
(PH5〜6)、反応液を1時間室温にて撹拌した後
溶媒を留去し、分取薄層シリカゲルクロマトグラ
フイーにて生成物を単離した。n−ヘキサン−ア
セトン混液より再結晶して、無色針状の結晶とし
て目的物を得た。
収量 15mg 収率 41% mp 244〜245℃
実施例 12
17α,21−ジメチルアミノメチレンジオキシ−
9α−フルオロ−16β−メチレン−1,4−プ
レグナジエン−11β−オール−3,20−ジオン
の製造
ベータメサゾン0.2g(0.51ミリモル)をよく
乾燥したジメチルホルムアミド2mlに溶解し、
N,N−ジメチルホルムアミド ジメチルアセタ
ール0.2mlを加え、100℃にて加熱撹拌して30分間
反応した。反応終了後、減圧下溶媒を留去し、残
渣を中性アルミナカラムクロマトグラフイーに付
し、クロロホルム流出部より淡黄色油状の目的物
を得た。収量 36mg 収率 15.6%
NMR(CDCl3)δ:1.20(3H,d,J=8
Hz),1.24(3H,s),1.55(3H,s),2.04
(6H,s)
実施例 13
ベータメサゾン 17−ホルメートの製造
17α,21−ジメチルアミノメチレンジオキシ−
9α−フルオロ−16β−メチル−1,4−プレグ
ナジエン−11β−オール−3,20−ジオン100mg
をメタノール20mlに溶解し、酢酸緩衝液(PH5〜
6)を5ml加え、室温にて3時間放置し、メタノ
ールを留去し、クロロホルム抽出後、摘出液を水
で洗浄し、芒硝乾燥後溶媒を留去し、分取薄層シ
リカゲルカラムクロマトグラフイーにて目的物を
単離精製し、n−ヘキサン−アセトン混液より再
結晶して無色針状晶を得た。
収量 55mg 収率 60% mp 238〜247℃
実施例 14
17α,21−(1′−ジメチルアミノ)エチリデン
ジオキシ−4−プレグネン−11β−オール−
3,20−ジオンの製造
ヒドロコルチゾン3.0g(8.2ミリモル)をジメ
チルホルムアミド3mlに溶かし、N,N−ジメチ
ルアミド ジメチルアセタール1.0g(8.4ミリモ
ル)を加え、100℃にて10分間加熱撹拌した。反
応終了後、溶媒を留去し、塩基性アルミナカラム
クロマトグラフイーに付し、クロロホルム流出部
より淡黄色油状の目的物を単離した。
収量 3.0g 収率 84%
これを一部n−ヘキサン−アセトン混液より再
結晶して淡黄色微細針状晶を得た。
mp244〜245℃
NMR(CDCl3)δ:1.20(3H,s),1.40
(3H,s),2.10(3H,s),3.07(6H,s)
実施例 15
17α,21−(1′−ピペリジノ)エチリデンジオ
キシ−4−プレグネン−11β−オール−3,20
−ジオンの製造
ヒドロコルチゾン1.0g(2.8ミリモル)をジメ
チルホルムアミド3mlに溶かし、ピペリジルアセ
トアミド ジメチルアセタール0.5g(2.9ミリモ
ル)を加え、100℃にて60分間加熱撹拌した。反
応終了後、減圧下溶媒を留去し、アルミナカラム
クロマトグラフイーに付し、クロロホルム流出部
より淡黄色油状の目的物を得た。
収量 0.2g 収率 15.2%
NMR(CDCl3)δ:1.32(3H,s),1.57
(3H,s),1.62(3H,s),5.62(1H,s)
実施例 16
ヒドロコルチゾン 17−アセテートの製造
17α,21−(1′−ジメチルアミノ)エチリデン
ジオキシ−4−プレグネン−11β−オール−3,
20−ジオン0.3gをメタノール10mlに溶解し、飽
和蓚酸水溶液2〜3滴加えて室温にて2時間放置
した。反応後溶媒を留去し、分取薄層シリカゲル
クロマトグラフイーにて目的物を単離し、n−ヘ
キサン−アセトンより再結晶し無色柱状晶を得
た。
収量 0.11g 収率 40% mp 227〜232℃
実施例 17
17α,21−(1′−ジメチルアミノ)エチリデン
ジオキシ−4−プレグナジエン−11β−オール
−3,20−ジオンの製造
プレゾニゾロン0.3g(0.83ミリモル)とN,
N−ジメチルアセトアミド ジメチルアセタール
(bp 106〜110℃)0.1g(0.84ミリモル)とをジ
メチルホルムアミド2ml中で100℃にて30分間加
熱撹拌した。反応終了後、減圧下溶媒を留去し、
残渣をアルミナカラムクロマトグラフイーに付
し、クロロホルム流出部より淡黄色油状の目的物
を得た。
収量 60mg 収率 17.2%
NMR(CDCl3)δ:1.20(3H,g),1.36
(3H,s),1.60(3H,s),2.15(6H,s)
実施例 18
プレドニゾロン 17−アセテートの製造
17α,21−(1′−ジメチルアミノ)エチリデン
ジオキシ−1,4−プレグナジエン−11β−オー
ル−3,20−ジオン50mgをメタノール10mlに溶解
し、蓚酸飽和溶液を1〜2滴加え、室温にて2時
間放置後溶媒を留去し、分取薄層シリカゲルクロ
マトグラフイーにて目的物を単離し、n−ヘキサ
ン−アセトン混液より再結晶して無色針状晶を得
た。
収量 28mg 収率 67% mp 240〜242℃
実施例 19
17α,21−(1′−ジメチルアミノ)エチリデン
ジオキシ−4−プレグネン−3,11,20−トリ
オンの製造
コルチゾン0.3g(0.83ミリモル)とN,N−
ジメチルアセトアミド ジメチルアセタール0.1
g(0.84ミリモル)とを、ジメチルホルムアミド
2ml中で100℃にて30分間加熱撹拌した。反応終
了後、減圧下溶媒を留去し、残渣をアルミナカラ
ムクロマトグラフイーに付し、クロロホルム流出
部より淡黄色油状の目的物を得た。
収量 0.1g 収率 28.7%
NMR(CDCl3)δ:0.65(3H,s),1.40
(3H,s),1.60(3H,s),2.05(3H,s),
3.35(2H,s)
実施例 20
コルチゾン 17−アセテートの製造
17α,21−(1′−ジメチルアミノ)エチリデン
ジオキシ−4−プレグネン−3,11,20−トリオ
ン0.1gをメタノール10mlに溶解し、飽和蓚酸水
溶液2〜3滴加え、室温にて2時間放置後溶媒を
留去し、分取薄層シリカゲルクロマトグラフイー
にて目的物を単離し、アセトン−n−ヘキサン混
液より再結晶して無色針状晶を得た。
収量 30mg 収率 33% mp 194〜198℃
実施例 21
17α,21−ジメチルアミノベンジリデンジオキ
シ−4−プレグネン−11β−オール−3,20−
ジオンの製造
ヒドロコルチゾン2.0g(5.5ミリモル)とN,
N−ジメチルベンズアミド ジメチルアセタール
(bp 65〜68℃/5mmHg)1.1g(5.6ミリモル)
とをジメチルホルムアミド2ml中で80℃にて10分
間加熱撹拌した。反応終了後、溶媒を減圧下留去
し、残渣をアルミナカラムクロマトグラフイーに
付し、クロロホルム流出部をn−ヘキサン−アセ
トン混液より再結晶して淡黄色針状晶を得た。収
量 1.85g 収率 68% mp 160〜163℃
IRνKBr naxcm-1:1710,1665,1610
NMR(C5D5N)δ:1.25(3H,s),1,50
(3H,s),2.05(6H,s),4.30(1H,m),
4.80(2H,s),5.75(1H,s),7.40(5H,
m)
実施例 22
ヒドロコルチゾン 17−ベンゾエートの製造
17α,21−ジメチルアミノベンジリデンジオキ
シ−4−プレグネン−11β−オール−3,20−ジ
オン0.1g(0.2ミリモル)をメタノール100mlに
溶かし、飽和蓚酸水溶液2〜3滴を加えて室温に
て2時間放置した。減圧下溶媒を留去し、残渣を
分取薄層クロマトグラフイーにて分離し、目的物
をn−ヘキサン−アセトンより再結晶して無色針
状晶として得た。
収量 40mg 収率 42% mp 227〜231℃
実施例 23
17α,21−ジメチルアミノベンジリデンジオキ
シ−1,4−プレグナジエン−11β−オール−
3,20−ジオンの製造
プレドニゾロン1g(2.8ミリモル)とN,N
−ジメチルベンズアミド ジメチルアセタール
0.5g(2.8ミリモル)とをジメチルホルムアミド
2ml中で100℃にて30分間加熱撹拌した。反応終
了後、減圧下溶媒を留去し、残渣をアルミナカラ
ムクロマトグラフイーに付し、クロロホルム流出
部より淡黄色油状の目的物を得た。
収量 0.85g 収率 60%
NMR(CDCl3)δ:0.90(3H,s),1.30
(3H,s),2.04(6H,s),4.15(3H,m),
5.95(1H,s),7.35(5H,m)
実施例 24
プレドニゾロン 17−ベンゾエートの製造
17α,21−ジメチルアミノベンジリデンジオキ
シ−4−プレグナジエン−11β−オール−3,20
−ジオン0.8g(1.63ミリモル)をメタノール100
mlに溶かし、飽和蓚酸水溶液2〜3滴を滴下し、
室温にて2時間放置後、減圧下にて溶媒を留去
し、分取薄層クロマトグラフイーにて目的物を単
離し、n−ヘキサン−アセトンより再結晶して無
色針状晶を得た。
収量 200mg 収率 26.3% mp 270〜273℃
実施例 25
17α,21−ジメチルアミノベンジリデンジオキ
シ−1,4−プレグナジエン−9α−フルオロ
−11β−オール−16β−メチル−3,20−ジオ
ンの製造
ベータメサゾン1.0g(2.6ミリモル)とN,N
−ジメチルベンズアミド ジメチルアセタール
0.6g(3.1ミリモル)とを、ジメチルホルムアミ
ド2ml中で100℃にて30分間加熱撹拌した。反応
終了後、減圧下にて溶媒を留去し、残渣をアルミ
ナカラムクロマトグラフイーに付し、淡黄色油状
の目的物を得た。
収量 0.5g 収率 36.6%
NMR(CDCl3)δ:1.20(3H,d,J=8
Hz),1.22(3H,s),1.55(3H,s),2.05
(6H,s),7.10〜7.70(5H,m)
実施例 26
ベータメサゾン 17−ベンゾエートの製造
17α,21−ジメチルアミノベンジリデンジオキ
シ−1,4−プレグナジエン−9α−フルオロ−
11β−オール−16β−メチル−3,20−ジオン
0.1gをメタノール20mlに溶解し、飽和蓚酸水溶
液2〜3滴を滴下し(PH5〜6)、室温にて2時
間放置後、減圧下にて溶媒を留去し、分取薄層ク
ロマトグラフイーにて目的物を単離し、n−ヘキ
サン−アセトン混液より再結晶して無色鱗片状結
晶を得た。
収量 30mg 収率 35% mp 225〜231℃
実施例 27
17α,21−ジメチルアミノベンジリデンジオキ
シ−4−プレグネン−3,11,20−トリオンの
製造
コルチゾン1.0g(2.8ミリモル)とジメチルベ
ンズアミド ジメチルアセタール0.6g(3.0ミリ
モル)とを、ジメチルホルムアミド2ml中にて
100℃にて30分間加熱撹拌した。反応終了後、減
圧下にて溶媒を留去し、残渣をアルミナカラムク
ロマトグラフイーに付し、黄色油状の目的物を得
た。収量 600mg 収率 54.5%
NMR(CDCl3)δ:0.63(3H,s),1.37
(3H,s),2.05(6H,s),7.10〜7.60(5H,
m)
実施例 28
コルチゾン 17−ベンゾエートの製造
17α,21−ジメチルアミノベンジリデンジオキ
シ−4−プレグネン−3,11,20−トリオン0.2
g(0.4ミリモル)をメタノール30mlに溶解し、
飽和蓚酸水溶液2〜3滴を滴下し(PH5〜6)、
室温にて2時間放置後、減圧下にて溶媒を留去
し、分取薄層クロマトグラフイーにて目的物を単
離し、アセトン−n−ヘキサン混液より再結晶し
て無色針状結晶を得た。
収量 70mg 収率 41.0% mp 227〜230℃。[Table] As described above, the production method of the present invention has the same number of steps as the method using 17α,21-cyclic orthoester, but has more advantageous reaction conditions and a better yield. I understand. That is, the method of the present invention can be said to be an industrially advantageous method. Next, the present invention will be explained in more detail with reference to Examples. Example 1 N,N-dimethylacetamide Production of dimethylacetal 23.75g (0.27g) of N,N-dimethylacetamide
mol) and 33.65 g (0.26 mol) of dimethyl sulfate.
After heating at 90°C for 2 hours, the temperature was gradually lowered to room temperature. Add this reaction solution to 6.2g of metallic sodium
100 ml of an ether suspension of sodium methylate (white powder) prepared from (0.27 mol) and methanol
It was added dropwise at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under normal pressure to obtain the desired product. Yield 9.20g Yield 28% bp108-109℃ Example 2 N,N-dimethylbenzamide Production of dimethyl acetal 10g (0.07 mol) of N,N-dimethylbenzamide and 8.5g (0.06 mol) of dimethyl sulfate were heated at 90℃.
After heating for 4 hours, the temperature was gradually lowered to room temperature. This reaction solution was added dropwise at 0° C. to 50 ml of an ether suspension of sodium methylate (white powder) prepared from 1.6 g (0.7 mol) of sodium metal and methanol. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under reduced pressure to obtain the desired product. Yield 3.4g Yield 25% bp 120-125℃ (20mm
Hg) Example 3 Production of N,N-dimethylpropylamide dimethyl acetal 47.0g (0.47g) of N,N-dimethylpropylamide
mol) and 60 g (0.47 mol) of dimethyl sulfate to 100
After heating at ℃ for 3 hours, the temperature was gradually lowered to room temperature. Add this reaction solution to 11.0g of metallic sodium.
(0.47 mol) and methanol were added dropwise to 150 ml of an ether suspension of sodium methylate at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under reduced pressure to obtain the desired product. Yield 3.0g Yield 4.7% bp 40-50℃ (90mm
Hg) Example 4 N,N-diethylacetamide Production of dimethyl acetal 25.0 g (0.22 mol) of N,N-diethylacetamide and 28 g (0.22 mol) of dimethyl sulfuric acid were mixed at 90 to 90 g (0.22 mol).
After heating at 100°C for 4 hours, the temperature was gradually lowered to room temperature. Add this reaction solution to 6.0g of metallic sodium.
(0.26 mol) was added dropwise to an ether suspension of sodium methylate prepared from methanol at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under normal pressure to obtain the desired product. Yield 2.8g Yield 7.9% bp 135-140°C Example 5 Production of piperidyl acetamide dimethyl acetal 25 g (0.179 mol) of 1-acetylpiperidine and 25 g (0.195 mol) of dimethyl sulfate were mixed at 110°C.
After heating for an hour, the temperature was gradually lowered to room temperature.
Add this reaction solution to 4.5 g (0.196 mol) of metallic sodium.
The mixture was added dropwise to 100 ml of an ether suspension of sodium methylate prepared from methanol at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under reduced pressure to obtain the desired product. Yield 9.8g Yield 28.8% bp 97℃ (33mm
Hg) Example 6 17α,21-dimethylaminomethylenedioxy-
Production of 4-pregnen-11β-ol-3,20-dione (1) 1.0 g (2.8 mmol) of hydrocortisone was suspended in 100 ml of well-dried chloroform.
1 ml of N,N-dimethylformamide dimethyl acetal was added, and the mixture was reacted at room temperature for 3 hours with stirring. When the reaction solution became pale yellow and transparent, the solvent was distilled off under reduced pressure and subjected to neutral alumina column chromatography, and a pale yellow oil was isolated from the chloroform eluate. Yield: 250 mg Yield: 20.4% A portion of this was recrystallized from a mixture of n-hexane and acetone to obtain colorless needle crystals. mp 249-251℃ IRν CHCl 3nax cm -1 : 1650, 1620 NMR (C 5 D 5 N) δ: 1.35 (3H, s), 1.57
(3H, s), 2.90 (6H, s), 4.45 (1H, m),
4.80 (2H.s), 5.80 (1H, s) (2) Dissolve 1.0g (2.8 mmol) of hydrocortisone in 20ml of well-dried dioxane and add N,N
- Dimethylformamide Add 0.35 g (2.9 mmol) of dimethyl acetal (bp 103°C),
The temperature was raised to 80° C. while stirring, the methanol produced was distilled off, and the reaction was continued for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the chloroform effluent was subjected to alumina column chromatography.
The desired product was obtained by recrystallization from a hexane-acetone mixture. Yield: 0.2g Yield: 13% (3) In (1) above, N,N-dimethylformamide and N,N-dimethylacetal were used instead of dimethylacetal.
Using dimethylformamide diethyl acetal (bp 135°C), the mixture was reacted at room temperature for 3 hours and treated in the same manner to obtain the desired product. Yield: 0.16g Yield: 12% (4) In (1) above, N,N-dimethylformamide and N,N-dimethylacetal were used instead of dimethylacetal.
Using dimethylformamide di-n-butyl acetal (bp 88-90°C/10mmHg), reaction was carried out at room temperature for 1 hour, and the desired product was obtained by the same treatment. Yield: 0.04g Yield: 2.6% (5) In (1) above, N,N-dimethylformamide instead of dimethylacetal
Using dimethylformamide di-tert-butyl acetal (bp 75-77°C/25mmHg), reaction was carried out at room temperature for 1 hour, and the desired product was obtained by the same treatment. Yield 0.03g Yield 2.0% Example 7 Production of hydrocortisone 17-formate 17α,21-dimethylaminomethylenedioxy-
4-Pregnen-11β-ol-3,20-dione
Dissolve 100 mg (0.237 mmol) in 100 ml of methanol and drop 2 to 3 drops of saturated oxalic acid aqueous solution (pH 5 to
6) After stirring the reaction solution for 1 hour at room temperature, the solvent was distilled off, and the target product was isolated by preparative thin layer silica gel chromatography. Recrystallization from an acetone-n-hexane mixture gave colorless fine needle-like crystals. Yield 40mg Yield 43.3% mp177-183℃ Example 8 17α,21-dimethylaminomethylenedioxy-
Production of 4-pregnene-3,11,20-trione Dissolve 0.3 g (0.83 mmol) of cortisone in 3 ml of well-dried dimethylformamide and add N,N
-dimethylformamide dimethyl acetal
0.3 ml was added and stirred at room temperature for 3 hours. When the reaction solution became pale yellow and transparent, the solvent was distilled off under reduced pressure and subjected to alumina column chromatography to obtain a pale yellow oil from the chloroform eluate. Yield 34mg Yield 9.7% NMR (CDCl 3 ) δ: 0.63 (3H, s), 1.37
(3H, s), 2.10 (6H, s), 3.70 (2H, s),
5.60 (1H, s) Example 9 Production of cortisone 17-formate 17α,21-dimethylaminomethylenedioxy-
Dissolve 100 mg of 4-pregnene-3,11,20-trione in 20 ml of methanol, add acetate buffer (PH5~
Add 5 ml of 6) and leave at room temperature for 3 hours. After the reaction is complete, methanol is distilled off, 100 ml of water is added, and the mixture is extracted with chloroform. The extract was washed with water, dried over Glauber's salt, the solvent was distilled off, isolated and purified by preparative thin-layer silica gel chromatography, and recrystallized from a mixture of n-hexane and acetone to obtain colorless needles. Obtained crystals. Yield 40mg Yield 45% mp 217-224℃ Example 10 17α,21-dimethylaminomethylenedioxy-
1,4-pregnadiene-11β-ol-3,
20-Production of dione Dissolve 0.3 g (0.83 mmol) of prednisolone in 2 ml of well-dried dimethylformamide.
0.3 ml of N,N-dimethylformamide dimethyl acetal was added, and the mixture was heated and stirred at 100°C to react for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to neutral alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform eluate. Yield 40mg Yield 11.6% NMR (CDCl 3 ) δ: 1.32 (3H, s), 1.52
(3H, s), 2.04 (6H, s) Example 11 Production of prednisolone 17-formmate 17α,21-dimethylaminomethylenedioxy-
1,4-pregnadiene-11β-ol-3,20
−40 mg (0.095 mmol) of dione in 20 methanol
ml, dropwise added 2 to 3 drops of a saturated oxalic acid aqueous solution (PH 5 to 6), stirred the reaction solution at room temperature for 1 hour, distilled off the solvent, and produced the product using preparative thin-layer silica gel chromatography. The substance was isolated. Recrystallization from a mixture of n-hexane and acetone gave the desired product as colorless needle-like crystals. Yield 15mg Yield 41% mp 244-245℃ Example 12 17α,21-dimethylaminomethylenedioxy-
Preparation of 9α-fluoro-16β-methylene-1,4-pregnadiene-11β-ol-3,20-dione 0.2 g (0.51 mmol) of betamethasone was dissolved in 2 ml of well-dried dimethylformamide.
0.2 ml of N,N-dimethylformamide dimethylacetal was added, and the mixture was heated and stirred at 100°C to react for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to neutral alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 36 mg Yield 15.6% NMR (CDCl 3 ) δ: 1.20 (3H, d, J = 8
Hz), 1.24 (3H, s), 1.55 (3H, s), 2.04
(6H,s) Example 13 Production of betamethasone 17-formate 17α,21-dimethylaminomethylenedioxy-
9α-fluoro-16β-methyl-1,4-pregnadiene-11β-ol-3,20-dione 100mg
Dissolve in 20 ml of methanol and add acetate buffer (PH5~
Add 5 ml of 6), leave at room temperature for 3 hours, distill off the methanol, extract with chloroform, wash the extracted solution with water, dry the sodium sulfate, remove the solvent, and perform preparative thin-layer silica gel column chromatography. The target product was isolated and purified, and recrystallized from a mixture of n-hexane and acetone to obtain colorless needle crystals. Yield 55mg Yield 60% mp 238-247℃ Example 14 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnen-11β-ol-
Production of 3,20-dione 3.0 g (8.2 mmol) of hydrocortisone was dissolved in 3 ml of dimethylformamide, 1.0 g (8.4 mmol) of N,N-dimethylamide dimethyl acetal was added, and the mixture was heated and stirred at 100°C for 10 minutes. After the reaction was completed, the solvent was distilled off, and the product was subjected to basic alumina column chromatography to isolate the desired product as a pale yellow oil from the chloroform outflow. Yield: 3.0g Yield: 84% A portion of this was recrystallized from a mixture of n-hexane and acetone to obtain pale yellow fine needle-shaped crystals. mp244-245℃ NMR ( CDCl3 ) δ: 1.20 (3H, s), 1.40
(3H, s), 2.10 (3H, s), 3.07 (6H, s) Example 15 17α,21-(1′-piperidino)ethylidenedioxy-4-pregnen-11β-ol-3,20
-Production of dione 1.0 g (2.8 mmol) of hydrocortisone was dissolved in 3 ml of dimethylformamide, 0.5 g (2.9 mmol) of piperidyl acetamide dimethyl acetal was added, and the mixture was heated and stirred at 100° C. for 60 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 0.2g Yield 15.2% NMR (CDCl 3 ) δ: 1.32 (3H, s), 1.57
(3H, s), 1.62 (3H, s), 5.62 (1H, s) Example 16 Production of hydrocortisone 17-acetate 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnen-11β-ol -3,
0.3 g of 20-dione was dissolved in 10 ml of methanol, 2 to 3 drops of a saturated aqueous oxalic acid solution was added, and the mixture was left at room temperature for 2 hours. After the reaction, the solvent was distilled off, the desired product was isolated by preparative thin layer silica gel chromatography, and recrystallized from n-hexane-acetone to obtain colorless columnar crystals. Yield 0.11g Yield 40% mp 227-232℃ Example 17 Production of 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnadiene-11β-ol-3,20-dione Prezonisolone 0.3g (0.83 mmol) and N,
N-dimethylacetamide 0.1 g (0.84 mmol) of dimethyl acetal (bp 106-110°C) was heated and stirred in 2 ml of dimethylformamide at 100°C for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure.
The residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 60mg Yield 17.2% NMR (CDCl 3 ) δ: 1.20 (3H, g), 1.36
(3H, s), 1.60 (3H, s), 2.15 (6H, s) Example 18 Production of prednisolone 17-acetate 17α,21-(1′-dimethylamino)ethylidenedioxy-1,4-pregnadiene-11β -Dissolve 50 mg of ol-3,20-dione in 10 ml of methanol, add 1 to 2 drops of oxalic acid saturated solution, leave to stand at room temperature for 2 hours, distill off the solvent, and perform preparative thin-layer silica gel chromatography. The product was isolated and recrystallized from a mixture of n-hexane and acetone to obtain colorless needles. Yield 28mg Yield 67% mp 240-242℃ Example 19 Production of 17α,21-(1'-dimethylamino)ethylidenedioxy-4-pregnene-3,11,20-trione Cortisone 0.3g (0.83 mmol) and N, N-
Dimethylacetamide Dimethylacetal 0.1
g (0.84 mmol) was heated and stirred at 100° C. for 30 minutes in 2 ml of dimethylformamide. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 0.1g Yield 28.7% NMR (CDCl 3 ) δ: 0.65 (3H, s), 1.40
(3H, s), 1.60 (3H, s), 2.05 (3H, s),
3.35 (2H, s) Example 20 Production of cortisone 17-acetate Dissolve 0.1 g of 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnene-3,11,20-trione in 10 ml of methanol, Add 2 to 3 drops of a saturated aqueous oxalic acid solution, leave to stand at room temperature for 2 hours, then evaporate the solvent, isolate the target product by preparative thin layer silica gel chromatography, and recrystallize from an acetone-n-hexane mixture to obtain a colorless product. Needle crystals were obtained. Yield 30mg Yield 33% mp 194-198℃ Example 21 17α,21-dimethylaminobenzylidenedioxy-4-pregnen-11β-ol-3,20-
Production of dione Hydrocortisone 2.0g (5.5 mmol) and N,
N-dimethylbenzamide dimethyl acetal (bp 65-68℃/5mmHg) 1.1g (5.6 mmol)
The mixture was heated and stirred in 2 ml of dimethylformamide at 80°C for 10 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was subjected to alumina column chromatography, and the chloroform effluent was recrystallized from a mixture of n-hexane and acetone to obtain pale yellow needle crystals. Yield 1.85g Yield 68% mp 160-163℃ IRν KBr nax cm -1 : 1710, 1665, 1610 NMR (C 5 D 5 N) δ: 1.25 (3H, s), 1,50
(3H, s), 2.05 (6H, s), 4.30 (1H, m),
4.80 (2H, s), 5.75 (1H, s), 7.40 (5H,
m) Example 22 Production of hydrocortisone 17-benzoate Dissolve 0.1 g (0.2 mmol) of 17α,21-dimethylaminobenzylidenedioxy-4-pregnen-11β-ol-3,20-dione in 100 ml of methanol, and dissolve saturated oxalic acid aqueous solution 2 ~3 drops were added and left at room temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue was separated by preparative thin layer chromatography, and the desired product was recrystallized from n-hexane-acetone to obtain colorless needles. Yield 40mg Yield 42% mp 227-231℃ Example 23 17α,21-dimethylaminobenzylidenedioxy-1,4-pregnadiene-11β-ol-
Production of 3,20-dione Prednisolone 1g (2.8 mmol) and N,N
-dimethylbenzamide dimethyl acetal
0.5 g (2.8 mmol) was heated and stirred in 2 ml of dimethylformamide at 100° C. for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 0.85g Yield 60% NMR (CDCl 3 ) δ: 0.90 (3H, s), 1.30
(3H, s), 2.04 (6H, s), 4.15 (3H, m),
5.95 (1H, s), 7.35 (5H, m) Example 24 Production of prednisolone 17-benzoate 17α,21-dimethylaminobenzylidenedioxy-4-pregnadiene-11β-ol-3,20
- 0.8 g (1.63 mmol) of dione in 100 g of methanol
ml, drop 2 to 3 drops of saturated oxalic acid aqueous solution,
After standing at room temperature for 2 hours, the solvent was distilled off under reduced pressure, the target product was isolated by preparative thin layer chromatography, and recrystallized from n-hexane-acetone to obtain colorless needles. . Yield 200mg Yield 26.3% mp 270-273℃ Example 25 Production of 17α,21-dimethylaminobenzylidenedioxy-1,4-pregnadiene-9α-fluoro-11β-ol-16β-methyl-3,20-dione betamethazone 1.0g (2.6 mmol) and N,N
-dimethylbenzamide dimethyl acetal
0.6 g (3.1 mmol) was heated and stirred in 2 ml of dimethylformamide at 100° C. for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil. Yield 0.5g Yield 36.6% NMR (CDCl 3 ) δ: 1.20 (3H, d, J = 8
Hz), 1.22 (3H, s), 1.55 (3H, s), 2.05
(6H, s), 7.10-7.70 (5H, m) Example 26 Production of betamethasone 17-benzoate 17α,21-dimethylaminobenzylidenedioxy-1,4-pregnadiene-9α-fluoro-
11β-ol-16β-methyl-3,20-dione
Dissolve 0.1 g in 20 ml of methanol, add 2 to 3 drops of a saturated aqueous oxalic acid solution (PH 5 to 6), and leave it at room temperature for 2 hours. The solvent is distilled off under reduced pressure and subjected to preparative thin layer chromatography. The desired product was isolated and recrystallized from a mixture of n-hexane and acetone to obtain colorless flaky crystals. Yield 30mg Yield 35% mp 225-231℃ Example 27 Production of 17α,21-dimethylaminobenzylidenedioxy-4-pregnene-3,11,20-trione Cortisone 1.0g (2.8 mmol) and dimethylbenzamide Dimethyl acetal 0.6 g (3.0 mmol) in 2 ml of dimethylformamide.
The mixture was heated and stirred at 100°C for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a yellow oil. Yield 600mg Yield 54.5% NMR (CDCl 3 ) δ: 0.63 (3H, s), 1.37
(3H, s), 2.05 (6H, s), 7.10~7.60 (5H,
m) Example 28 Production of cortisone 17-benzoate 17α,21-dimethylaminobenzylidenedioxy-4-pregnene-3,11,20-trione 0.2
Dissolve g (0.4 mmol) in 30 ml of methanol,
Drop 2-3 drops of saturated oxalic acid aqueous solution (PH5-6),
After standing at room temperature for 2 hours, the solvent was distilled off under reduced pressure, the target product was isolated by preparative thin layer chromatography, and recrystallized from an acetone-n-hexane mixture to obtain colorless needle crystals. Ta. Yield 70mg Yield 41.0% mp 227-230℃.
Claims (1)
ステロレドを一般式 (式中、Rは水素原子、低級アルキル基または
フエニル基を示し、R1は低級アルキル基または
互いに結合して隣接する窒素原子と共に複素環を
形成する基を示し、R2は低級アルキル基を示
す。)で表わされるアミドアセタールと反応さ
せ、部分構造式 (式中、R,R1は前記と同意義である。)を有
する17α,21−環状ジアルキルアミノアルキリデ
ンジオキシ−プレグナン系ステロイドを得、これ
を酸の存在下に開裂させることを特徴とする部分
構造式 (式中、Rは前記と同意義である。)を有する
プレグナン系ステロイド 17α−エステルを製造
する方法。[Claims] 1. Partial structural formula A 17α,21-dihydroxy-pregnane steroredo with the general formula (In the formula, R represents a hydrogen atom, a lower alkyl group, or a phenyl group, R 1 represents a lower alkyl group or a group that combines with each other to form a heterocycle with adjacent nitrogen atoms, and R 2 represents a lower alkyl group. ) is reacted with an amide acetal represented by the partial structural formula (In the formula, R and R 1 have the same meanings as above.) A 17α,21-cyclic dialkylaminoalkylidene dioxy-pregnane steroid is obtained, and this is cleaved in the presence of an acid. substructure formula A method for producing a pregnane steroid 17α-ester having the formula (wherein R has the same meaning as above).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5967178A JPS54151958A (en) | 1978-05-19 | 1978-05-19 | Preparation of pregnane steroid 17alpha-ester |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5967178A JPS54151958A (en) | 1978-05-19 | 1978-05-19 | Preparation of pregnane steroid 17alpha-ester |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS54151958A JPS54151958A (en) | 1979-11-29 |
JPS6118559B2 true JPS6118559B2 (en) | 1986-05-13 |
Family
ID=13119875
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5967178A Granted JPS54151958A (en) | 1978-05-19 | 1978-05-19 | Preparation of pregnane steroid 17alpha-ester |
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Country | Link |
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JP (1) | JPS54151958A (en) |
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AU2014361790B2 (en) * | 2013-12-13 | 2019-05-23 | Allergan, Inc. | Polymorphic and amorphous forms of cortisol 17-alpha-benzoate and methods for the preparation and use thereof |
-
1978
- 1978-05-19 JP JP5967178A patent/JPS54151958A/en active Granted
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