CS203912B2 - Process for preparing derivatives of estradiene - Google Patents
Process for preparing derivatives of estradiene Download PDFInfo
- Publication number
- CS203912B2 CS203912B2 CS766516A CS651676A CS203912B2 CS 203912 B2 CS203912 B2 CS 203912B2 CS 766516 A CS766516 A CS 766516A CS 651676 A CS651676 A CS 651676A CS 203912 B2 CS203912 B2 CS 203912B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- methyl
- estradien
- ethynyl
- hydroxy
- propylenedioxy
- Prior art date
Links
- 150000002158 estradienes Chemical class 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 9
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- HWCYISVQOIISSU-HULBTWJISA-N (8R,9R,10S,13R)-13-methyl-1,2,3,4,5,6,7,8,9,10,11,12-dodecahydrocyclopenta[a]phenanthrene Chemical class C([C@@H]12)CCCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)C1=CC=C2 HWCYISVQOIISSU-HULBTWJISA-N 0.000 claims description 3
- HVFBTBBENYOYMU-YFRXESGTSA-N (8r,9r,10s,13s,14s)-13-methyl-2,3,4,5,6,7,8,9,10,11,12,14-dodecahydro-1h-cyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@@H]2[C@H]3CC[C@](C)(C(C=C4)=O)[C@@H]4[C@@H]3CCC21 HVFBTBBENYOYMU-YFRXESGTSA-N 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 32
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 abstract description 12
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract description 10
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- -1 chloroethynyl Chemical group 0.000 abstract description 4
- 150000003431 steroids Chemical class 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 230000016087 ovulation Effects 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 230000003111 delayed effect Effects 0.000 abstract 1
- 238000002513 implantation Methods 0.000 abstract 1
- KIWSYRHAAPLJFJ-DNZSEPECSA-N n-[(e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enyl]pyridine-3-carboxamide Chemical group [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/CNC(=O)C1=CC=CN=C1 KIWSYRHAAPLJFJ-DNZSEPECSA-N 0.000 abstract 1
- 125000002524 organometallic group Chemical group 0.000 abstract 1
- 230000001072 progestational effect Effects 0.000 abstract 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 abstract 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 abstract 1
- 125000004665 trialkylsilyl group Chemical group 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 239000005457 ice water Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 150000002902 organometallic compounds Chemical class 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 3
- NANJFPZFEUIDND-MYBOQGECSA-N (8r,9s,10r,13s,14s,15s)-13-ethyl-15-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)(C(C[C@@H]4O)=O)[C@@H]4[C@@H]3CCC2=C1 NANJFPZFEUIDND-MYBOQGECSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- ILLZPWXPRIFACW-MYBOQGECSA-N [(8r,9s,10r,13s,14s,15s)-13-ethyl-3,17-dioxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-15-yl] nitrate Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)(C(C[C@@H]4O[N+]([O-])=O)=O)[C@@H]4[C@@H]3CCC2=C1 ILLZPWXPRIFACW-MYBOQGECSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 238000006567 deketalization reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- ARNWQMJQALNBBV-UHFFFAOYSA-N lithium carbide Chemical compound [Li+].[Li+].[C-]#[C-] ARNWQMJQALNBBV-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- SBLHOJQRZNGHLQ-ATIFRJIPSA-N (8r,9s,10r,13s,14s)-13-ethyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SBLHOJQRZNGHLQ-ATIFRJIPSA-N 0.000 description 1
- JFEPJTGMGDGPHJ-PNKHAZJDSA-N (8r,9s,10r,13s,14s)-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 JFEPJTGMGDGPHJ-PNKHAZJDSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- CIHXIRAAMAUYLZ-UHFFFAOYSA-N [K+].[K+].[C-]#[C-] Chemical compound [K+].[K+].[C-]#[C-] CIHXIRAAMAUYLZ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000003152 gestagenic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- LLCOIQRNSJBFSN-UHFFFAOYSA-N methane;sulfurochloridic acid Chemical compound C.OS(Cl)(=O)=O LLCOIQRNSJBFSN-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- RAFYDKXYXRZODZ-UHFFFAOYSA-N octanoyl octanoate Chemical compound CCCCCCCC(=O)OC(=O)CCCCCCC RAFYDKXYXRZODZ-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
- C07J41/0016—Oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Vynález se týká způsobu výroby derivátů estradienu obecného vzorce IThe present invention relates to a process for the preparation of estradien derivatives of the general formula I
kdewhere
R znamená atom vodíku nebo acylovou skupinu s 1 až 16 atomy uhlíku.R represents a hydrogen atom or an acyl group having 1 to 16 carbon atoms.
Sloučeniny podle vynálezu mají cenné vlastnosti steroidních hormonů a jsou použitelné ve farmacii. Tak jsou sloučeniny obecného vzorce I význačné silnou gestagenní účinností a účinkem potlačujícím ovulaci a nidaci. Například se osvědčuje 17a-ethinyl-17i/3-hydroxy-18-methyl-4,15-estradien-3-on (A) a v běžném Claubergově testu předčí 17a-ethinyl-17,/3-hydroxy-18-methyl-4-estren-3-on (B).The compounds of the invention have valuable steroid hormone properties and are useful in pharmacy. Thus, the compounds of formula (I) are distinguished by strong gestagenic activity and an ovulation and nidation suppressing activity. For example, 17α-ethynyl-17β / 3-hydroxy-18-methyl-4,15-estradien-3-one (A) has proven to work well and exceeds 17α-ethynyl-17β / 3-hydroxy-18-methyl- in the conventional Clauberg test. 4-estren-3-one (B).
V následující tabulce jsou uvedeny hodnoty McPhailova testu po orální aplikaci na infantilních samicích králíka:The following table shows the McPhail test values after oral administration to infantile female rabbits:
sloučenina množství (mg) McPhailcompound amount (mg) McPhail
Z McPhailových hodnot vyplývá, že prahová hodnota , (McPhail — 1,5) pro sloučeninu A podle předmětného vynálezu je při 0,01 mg a pro sloučeninu B, která má podobnou strukturu, je při 0,03 až 0,1 mg.The McPhail values indicate that the threshold, (McPhail-1.5) for Compound A of the present invention is at 0.01 mg and for Compound B, which has a similar structure, at 0.03 to 0.1 mg.
Vyšší estery sloučenin podle vynálezu se vyznačují protrahovaným účinkem.The higher esters of the compounds of the invention exhibit a protracted action.
Sloučeniny podle vynálezu mohou být použity například v antikoncepčních preparátech, přičemž se přidávají jako gestagenová komponenta v kombinaci s estrogenně účinnou složkou, jako· je například ethinylestradiol, netra jako jediná účinná látka. Nové sloučeniny se však mohou používat též při gynekologických poruchách.The compounds of the invention can be used, for example, in contraceptives, being added as a gestagen component in combination with an estrogenic active ingredient, such as, for example, ethinylestradiol, or as the only active ingredient. However, the novel compounds can also be used in gynecological disorders.
Pro· aplikaci se sloučeniny obecného vzorce I zpracovávají s přísadami běžnými v galenické farmacii, nosnými látkami a s látkami ovlivňujícími chuť známými metodami na běžné lékové formy. Pro orální aplikaci přicházejí v úvahu zejména kapsle, tablety, dražé, · pilulky, suspenze nebo roztoky. Pro· parenterální aplikaci přicházejí v úvahu zejména olejové roztoky, například v sesamovém nebo ricinovém· oleji, které mohou popřípadě obsahovat ještě zřeďovadlo, například benzylbenzoan nebo benzylalkohol. Koncentrace účinné látky je závislá na formě aplikace. Tablety pro orální aplikaci obsahují například 0,01 až 0,5 mg účinné látky a roztoky pro parenterální aplikaci obsahují výhodně 1 až · 100 mg účinné látky na 1 ml roztoku.For application, the compounds of formula (I) are formulated with conventional pharmaceutical ingredients, carriers and flavorants by known methods into conventional dosage forms. For oral administration, in particular, capsules, tablets, dragees, pills, suspensions or solutions are suitable. For parenteral administration, particularly suitable are oily solutions, for example in sesame or castor oil, which may optionally contain a diluent, for example benzylbenzoate or benzyl alcohol. The concentration of the active ingredient is dependent on the form of application. Tablets for oral administration contain, for example, 0.01 to 0.5 mg of active ingredient and solutions for parenteral administration preferably contain 1 to 100 mg of active ingredient per ml of solution.
Dávkování léčiv · se může měnit podle formy a účelu aplikace. Například denní kontraceptivní dávka při orální aplikaci činí 0,01 až 0,5 mg.The dosage of drugs may vary depending on the form and purpose of the administration. For example, the daily contraceptive dose for oral administration is 0.01 to 0.5 mg.
Deriváty estradienu obecného· vzorce I se podle vynálezu vyrábějí tím · způsobem, že se 17-oxoestren obecného vzorce IIAccording to the invention, the estradiene derivatives of the formula I are prepared by the process of 17-oxoestren of the formula II
kdewhere
Y znamená · oxoskupinu chráněnou výhodně- · ve formě ketalu a jedna z vazeb ................v · poloze 4,5-, · 5,6- nebo· 5,10- znamená dvojnou vazbu uhlík—uhlík a ostatní jednoduché vazby uhlík—uhlík a A—B znamená dvojnou vazbu uhlík—uhlík nebo skupinuY represents an oxo group preferably protected in the form of a ketal and one of the bonds in the position 4,5-, 5,6- or 5,10- means a carbon-carbon double bond and other single carbon-carbon double bonds and A-B means a carbon-carbon double bond or a group
C15—C16,C15-C16
IAND
OR' přičemžOR 'wherein
R’ představuje atom vodíku, trimethylsilylovou skupinu, acylovou skupinu s 1 až 16 atomy uhlíku, sulfonylovou skupinu nebo nitroskupinu, ethinyluje a popřípadě odštěpí ketoskupina v poloze 3- a podle požadovaného významu· pro· R ve výsledném produktu obecného vzorce I se popřípadě 17-hydroxyskupina před nebo po· odštěpení ketalové skupiny esterifikuje.R 'represents a hydrogen atom, a trimethylsilyl group, an acyl group having 1 to 16 carbon atoms, a sulfonyl group or a nitro group, ethynyls and optionally cleaves the keto group at the 3-position and, depending on the desired meaning, the hydroxy group esterifies before or after cleavage of the ketal group.
Jako acylové zbytky R’ jsou vhodné zbytky organických karboxylových kyselin, zejména acetylová skupina, trifluoracetylová skupina, propionylová skupina, butyrylová skupina, valerylová skupina, heptanoylová skupina a benzoylová skupina.Suitable acyl radicals R 'are organic carboxylic acid radicals, in particular acetyl, trifluoroacetyl, propionyl, butyryl, valeryl, heptanoyl and benzoyl.
Ze sulfonylových zbytků R’ jsou vhodné například mesylový zbytek, ethansulfonylový, propionsulfonylový a p-tosylový zbytek.Among the sulfonyl radicals R ', for example, mesyl, ethanesulfonyl, propionsulfonyl and p-tosyl are suitable.
Zavádění ethinylové skupiny se může provádět známými metodami pomocí organókovových sloučenin ethinylových. Takové organokovové sloučeniny jsou například acetylidy alkalických kovů, například acetylid draselný nebo acetyiid lithný.The introduction of the ethinyl group can be carried out by known methods using organometallic compounds of ethynyl. Such organometallic compounds are, for example, alkali metal acetylides, for example potassium acetylide or lithium acetylide.
Organokovové sloučeniny se mohou též vytvořit in sítu a reagovat se 17-ketonem obecného· vzorce II. Tak se může například nechat působit na 17-keton ve vhodném rozpouštědle acetylén a alkalický kov, zejména draslík, sodík nebo lithium, za přítomnosti alkoholu se 4 až 5 uhlíkovými atomy nebo amoniaku nebo ve formě butyllithia.The organometallic compounds can also be formed in situ and reacted with the 17-ketone of formula II. Thus, for example, acetylene and an alkali metal, in particular potassium, sodium or lithium, may be reacted on the 17-ketone in a suitable solvent in the presence of an alcohol having 4 to 5 carbon atoms or ammonia or in the form of butyllithium.
Jako organokovové sloučeniny jsou též vhodné ethinylmagnesiumhalogenidy nebo· ethinylzinekhalogenidy, zejména ethinylmagnesiumbromid nebo ethinylmagnesiumjodid.Ethinylmagnesium halides or ethinylzinc halides, in particular ethinylmagnesium bromide or ethinylmagnesium iodide, are also suitable as organometallic compounds.
Jako rozpouštědla jsou vhodné diethylether, tetrahydrofuran, dioxan, benzen, toluen a podobně.Suitable solvents are diethyl ether, tetrahydrofuran, dioxane, benzene, toluene and the like.
Pro případně následující esterifikaci přicházejí v úvahu způsoby používané běžně v chemii k esterifikaci steroidů.For the possible subsequent esterification, the methods commonly used in the chemistry for the esterification of steroids are suitable.
Pro· esterifikaci 17-hydroxyskupiny se uvádí například reakce s kyselinou nebo an. hydridem kyseliny za přítomnosti silné kyseliny, například kyseliny trifluoroctové nebo kyseliny p-toluensulfonové, při teplotě místnosti nebo· zvýšené, nebo reakce s anhydridem kyseliny za přítomnosti terciárního aminu při teplotě asi 20 až 200 °C.For the esterification of the 17-hydroxy group, for example, reaction with an acid or an is mentioned. an acid hydride in the presence of a strong acid such as trifluoroacetic acid or p-toluenesulfonic acid at room temperature or elevated, or reaction with an acid anhydride in the presence of a tertiary amine at a temperature of about 20 to 200 ° C.
Použijí-li se společně pyridin a 4-(dimethylamino) pyridin jako· terciární aminy, může se esterifikace provádět při teplotě místnosti.When pyridine and 4- (dimethylamino) pyridine are used together as tertiary amines, the esterification can be carried out at room temperature.
Odštěpení ochranné skupiny v poloze 3-, které může probíhat před nebo po možné esterifikaci, se provádí známými metodami. Pro ketalové štěpení přicházejí v úvahu například minerální kyseliny, jako kyselina chloristá, kyselina sírová nebo kyselina chlorovodíková, nebo organické kyseliny, například kyselina šťavelová, Ketalové· štěpení se provádí výhodně v alkoholickém roztoku nebo v jiném polárním· rozpouštědle, například v acetonu, při teplotě v roz203912 mezí 20 až 100 °C.The cleavage of the protecting group in the 3- position, which may take place before or after possible esterification, is carried out by known methods. Suitable ketal cleavages are, for example, mineral acids such as perchloric acid, sulfuric acid or hydrochloric acid, or organic acids such as oxalic acid. Ketal cleavage is preferably carried out in an alcoholic solution or in another polar solvent, for example acetone, at a temperature of at 203912 between 20 and 100 ° C.
Příprava 17-^(^j^i^í^t(^i?oidů obecného vzorce II, jež se používají jako výchozí produkty, je popsána v následujících příkladech:The preparation of the 17 - (- (-) - (-) (II) starting materials is described in the following examples:
A. 15a-hydroxy-18-methyl-4-estren-3,17-dionA. 15α-Hydroxy-18-methyl-4-estrene-3,17-dione
Erlenmeyerova baňka o objemu 500 ml, obsahující 500 ml živného roztoku složeného· z 3,0 % glukózy, 1,0 % kukuřičného extraktu, 0,2 % dusičnanu sodného, 0,1 % dihydrogenfosforečnanu draselného, 0,2 % hydrogenfosforečnanu draselného, 0,05 % síranu horečnatého, 0,002 % síranu železnatého a 0,05 % chloridu draselného· a sterilizovaného· po· dobu 30 minut v autoklávu při teplotě 120 °C, se zaočkuje kulturou Penicillium· raistrickii (ATCC 10 · 490) a třepe· se na rotační třepačce po dobu 72 hodin při teplotě 30 °C. Dvacetiiitrový ferm-entor naplněný 15 litry média o stejném složení, které bylo· sterilizováno při teplotě 121 °C a tlaku 0,11 MPa, se zaočkuje 250 ml kultury připravené výše uvedeným postupem. Za přídavku silikonového odpěňovadla se kultivuje při teplotě 29 · °C za provzdušňování (10 litrů za minutu), tlaku 70 kPa a míchání (220 otáček za minutu), po dobu 24 hodin; 1,8 litru kultivační · břečky se za sterilních podmínek převede do 26 1 výše uvedeného sterilizovaného živného roztoku a kultivuje se za stejných podmínek. Po 12 hodinách se přidají 2 litry jemné suspenze 120 g 18-methyl-4-estren-3,17-dionu v destilované vodě za přídavku smáčedla a kultivuje se dále.Erlenmeyer flask of 500 ml capacity, containing 500 ml of nutrient solution composed of 3.0% glucose, 1.0% corn extract, 0.2% sodium nitrate, 0.1% potassium dihydrogen phosphate, 0.2% potassium hydrogen phosphate, 0 , 05% magnesium sulphate, 0.002% ferrous sulphate and 0.05% potassium chloride · and sterilized for 30 minutes in an autoclave at 120 ° C, are seeded with a Penicillium · raistrickii culture (ATCC 10 · 490) and shaken. on a rotary shaker for 72 hours at 30 ° C. A twenty liter fermenter filled with 15 liters of the same composition sterilized at 121 ° C and 0.11 MPa was inoculated with 250 ml of the culture prepared as described above. With the addition of a silicone antifoam, cultivate at 29 ° C with aeration (10 liters per minute), 70 kPa pressure and stirring (220 rpm) for 24 hours; 1.8 liters of culture broth are transferred under sterile conditions into 26 l of the above sterilized nutrient solution and cultured under the same conditions. After 12 hours, 2 liters of a fine suspension of 120 g of 18-methyl-4-estrene-3,17-dione in distilled water are added with the addition of a wetting agent and cultured further.
Průběh se sleduje pomocí chromatografie na tenké vrstvě methylisobutylketonového extraktu vzorků z fermentoru. Asi po 70 hodinách doby styku je konverse úplná. Nyní se mycelium· odfiltruje a kultivační břečka se extrahuje dvakrát po 20 litrech methylisobutylketonu. Současně se odfiltrované mycelium několikrát promísí se směsí methylisobutylketonu, acetonu a vody a extrahuje až není · prokazatelná žádná steroidní látka.Progress is monitored by thin layer chromatography of methyl isobutyl ketone extract of fermenter samples. After about 70 hours of contact time, the conversion is complete. Now the mycelium is filtered off and the culture broth is extracted twice with 20 liters of methyl isobutyl ketone. At the same time, the filtered mycelium is mixed several times with a mixture of methyl isobutyl ketone, acetone and water and extracted until no steroid is detectable.
Organické extrakční roztoky se spojí a ve vakuu odpaří k suchu při teplotě lázně 50 °C. Zbylé hnědé krytalky se několikrát promyjí hexanem k odstranění silikonového oleje, vysuší · a nakonec se po zpracování aktivním, uhlím překrystalují · z ethylacetátu, přičemž se získá 97,5 g (76,5 proč, teorie) čistého 15<^^l^^^(^^oxy-18-^m^t:hyl-4-estren-3,17-dionu s teplotou tání 175 až 177 °C.The organic extraction solutions were combined and evaporated to dryness in vacuo at a bath temperature of 50 ° C. The remaining brown caps were washed several times with hexane to remove the silicone oil, dried and finally recrystallized from ethyl acetate after charcoal treatment to give 97.5 g (76.5% of theory) of pure 15%. 175 DEG-177 DEG C. (4-Oxy-18-methyl-4-estrene-3,17-dione).
B. 15a-hydroxy-18-methyl-3,3-(2’,2’-dimethyl-r,3’-pr opylendioxy) -5-estren-17-on a 15a-hydroxy-18-methyl-3,3- (2’,2’-dimethyl-l’,3’-propylendioxy )-5(10) -estren-17-on g 15a-hydroxy-18-methyl-4-estren-3,17-dionu se míchá ve 150 ml methylenchloridu a 40 ml triethylesteru kyseliny mraven- čí se 60 g 2,2-dimethyl-l,3-propandiolu a 200 mg kyseliny p-toluensulfonové po dobu 20 hodin při teplotě místnosti. Roztok se zředí ethylacetátem, neutralizuje roztokem hydrogenuhličitanu sodného a promyje· vodou. Potom se roztok vysuší síranem· sodným a zahustí ve vakuu. Surový produkt se chromatografuje na ai-ikagt-u gradientem aceton—hexan (0 až 20 % acetonu); 20% acetonem· se eluuje 10,0 g 15a-hydroxy-3,3-(2’2’-dimethyllΓ,3’-propy-endioxy)18-methyl-5-estren-17-onu s teplotou tání 206 až 209 °C. Dále· se získá 15 g olejovité· směsi 15a-nydroxy-18-methyl-3,3- (2’,2’-dimethyllΓ,3,-proρy]e;ndioxy)-5-ettren-17-onu a 15a-hydroxy-18-m.ethyl-3,3-(2’,2’-dimethyl—’,3’-propylendioxy )-5(10) -estren-17-onu.B. 15α-hydroxy-18-methyl-3,3- (2 ', 2'-dimethyl-1,3'-propylenedioxy) -5-estren-17-one and 15α-hydroxy-18-methyl-3, 3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5 (10) -estren-17-one 15α-hydroxy-18-methyl-4-estren-3,17-dione is stirred in 150 ml of methylene chloride and 40 ml of triethyl formate with 60 g of 2,2-dimethyl-1,3-propanediol and 200 mg of p-toluenesulfonic acid for 20 hours at room temperature. The solution was diluted with ethyl acetate, neutralized with sodium bicarbonate solution and washed with water. The solution was dried over sodium sulfate and concentrated in vacuo. The crude product is chromatographed on aalko-gradient with an acetone-hexane gradient (0 to 20% acetone); Eluting with 20% acetone · 10.0 g of 15α-hydroxy-3,3- (2'2'-dimethyl-3'-propylenedioxy) 18-methyl-5-estren-17-one, m.p. 206-209 Deň: 32 ° C. · Next, 15 g of an oily mixture · 15a-nydroxy-18-methyl-3,3- (2 ', 2'-dimethyllΓ, 3 -proρy] e; ndioxy) -5-ettren-17-one and 15a hydroxy-18-methyl-3,3- (2 ', 2'-dimethyl-', 3'-propylenedioxy) -5 (10) -estren-17-one.
C. 15a-mesyloxy-18-methy--3,3l (2’ ,2’-dimethyllΓ,3’-propy-endioxy )-5-0^0^17-(^1 a 15a-m·esyloxy-18-methyll3,3-(2’,2’-dimeihyl-Γ,3’-propylendioxy )-5(10) -estren-n-on g 15a-hydroxy-18-methyl-3,3-{2’,2’ldinlethylll’,3’-propy-en.dioxy)-5-esiren-17-onu a 15a-hydroxy-18-methyl-3,3-(2’,2’-dimethyllΓ,3’-propylendioxy )-5(10] -estren-17-onu se za chlazení ledem smísí s 27,1 ml methansulfochloridu a · potom míchá po dobu 3 hodin při teplotě ledové lázně. Potom· se reakční směs vmísí do směsi ledu a vody, sraženina se odsaje a promyje vodou. Poté se vyjme do· methylenchloridu a vysuší. Získá se· směs (40 g), sestávající z 15a-γπ05υ1οχ·ι-18-π16'Πιυ1-3,3- (2’,2’-dimethyl-Γ,3’-pr(lpy-endioxy)-5-ettren-17-onu a 15a-mesyloxy-18-methyl-3,3- (2’,2’-dimethyl-l’,3’-propylendioxy )-5(10) -estren-n-onu ve formě oleje.C. 15α-mesyloxy-18-methyl-3,3l (2 ', 2'-dimethylΓΓ, 3'-propylenedioxy) -5-O-O-17- (β 1 and 15α-mesyloxy-18) -methyl 11,3- (2 ', 2'-dimethyl-Γ, 3'-propylenedioxy) -5 (10) -estren-n-one 15α-hydroxy-18-methyl-3,3- {2', 2 1'-ethylethylll ', 3'-propylenedioxy) -5-esiren-17-one and 15α-hydroxy-18-methyl-3,3- (2', 2'-dimethyllΓ, 3'-propylenedioxy) -5 (10) -estren-17-one is treated with 27.1 ml of methanesulfochloride under ice-cooling and then stirred for 3 hours at an ice bath temperature, then the reaction mixture is stirred into ice-water, the precipitate is filtered off with suction and washed It is then taken up in methylene chloride and dried to give a mixture (40 g) consisting of 15α-γπ05υ1οχ · ι-18-π16'Πιυ1-3,3- (2 ', 2'-dimethyl-Γ, 3 1'-pr (1-endioxy) -5-ettren-17-one and 15α-mesyloxy-18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5 (10 -estren-n-one in the form of an oil.
D. 18-methyll3,3-(2’,2’ldiIπethyllΓ,3’-propylendioxy)-5,15-ettradien-17-on a 18-methyl-3,3- (2’,2’-dime-thylpropylendioxy) -D. 18-Methyl-3,3- (2 ', 2'-diethyllΓ, 3'-propylenedioxy) -5,15-ettradien-17-one and 18-methyl-3,3- (2', 2'-dimethylpropylenedioxy) ) -
-5 (10) ,15-estradien-17-on g 15a-mesyioxy-18-теШу1-3,3-(2’,2’ldimethyllΓ,3’-propylendioxy)-5-estren-17-onu a 15α-mesyloxy-18-methyl-3,3-(2’,2’-dimethyllΓ,3’-propylendioxy )-5(10) -estren-17-onu se míchá ve 350 ml dimethylformamidu se 105 g bezvodého octanu sodného po dobu 20· hodin při teplotě místnosti. Poté se reakční směs vmísí do směsi ledu a vody a vzniklá sraženina se odsaje. Sraženina se promyje vodou a vyjme do methylenchloridu. Po odpaření rozpouštědla se získá 28,9 g surového 18-methyl-3,3- (2’,2’-dimethyllΓ,3’-propylendioxy) -5,15-estradien-17-onu a 18-ιπ6^γ1-3,3-(2’,2ΜίmethyllΓ,3’-propy-endioxy )-5(10) ,15-estradien-17-onu.-5 (10), 15-estradien-17-one g of 15α-mesyioxy-18-trans-1,3- (2 ', 2'-dimethyl-3', 3'-propylenedioxy) -5-estren-17-one and 15α- mesyloxy-18-methyl-3,3- (2 ', 2'-dimethyllΓ, 3'-propylenedioxy) -5 (10) -estren-17-one is stirred in 350 ml of dimethylformamide with 105 g of anhydrous sodium acetate for 20 min. · Hours at room temperature. The reaction mixture was then added to ice-water and the precipitate formed was filtered off with suction. The precipitate was washed with water and taken up in methylene chloride. Evaporation of the solvent yielded 28.9 g of crude 18-methyl-3,3- (2 ', 2'-dimethyl-3'-propylenedioxy) -5,15-estradien-17-one and 18-α-6-methyl-3-carboxylic acid. 3- (2 ', 2'-methyl-3', 3'-propylenedioxy) -5 (10), 15-estradien-17-one.
E. ^-те^-З.З·^’^’^^^^-’^™pylendioxy) -15α-trimethyltiloxy-5-ettren-17-on a 18-methyl-3,3-(2’,2’-dimethyllΓ,3’-pr opylendioxy) -15α-trimethyltiloxy-5 (10) -estren-17-on .E. (3-Methyl-thioxy-5-ettren-17-one) and 18-methyl-3,3- (2 ', 2'-methyl) 2'-Dimethyl-3 ', 3'-propylenedioxy) -15a-trimethylthiloxy-5 (10) -estren-17-one.
10,0 g 15a-hydroxy-18-methyl-3,3-(2’,2’-dimethyl-r,3’-propylendioxy) -5-estren-17-onu a 15a-hydroxy-18-methyl-3,3-(2’,2’-dimethyl-r,3’-propylendioxy )-5 (10) -estren-17-onu se míchá po dobu 4 hodin při teplotě místnosti ve 40 m- pyridinu a 10 ml trimethy-ch-orsi-anu. . Roztok se smísí s ledovou vodou a reakční produkt se extrahuje methy-ench-oridem. Extrakt se promyje vodou, vysuší síranem sodným· a ve vakuu se odpaří rozpouštěd-o· k suchu. Surový · produkt se chromatografuje na silikage-u 2,5 až 3,5 · % acetonu/hexan. Získá se10.0 g of 15α-hydroxy-18-methyl-3,3- (2 ', 2'-dimethyl-1,3'-propylenedioxy) -5-estren-17-one and 15α-hydroxy-18-methyl-3 3- (2 ', 2'-dimethyl-1,3'-propylenedioxy) -5 (10) -estren-17-one was stirred for 4 hours at room temperature in 40m-pyridine and 10mL of trimethylsilyl. -orsi-anu. . The solution was treated with ice water and the reaction product was extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and the solvent was evaporated to dryness in vacuo. The crude product is chromatographed on silica gel with 2.5-3.5% acetone / hexane. It is obtained
3,2 g 18-methyl-3,3-(2’,2’-dimethyllΓ,3'-p^Όpy-endioxy ] -15a-trimethylsiloxy-5-estren-17-onu a 18-rnethyl-3,3-(2^2^11^1^-+,3^ -propylendioxy) -15a-trimethy lsiloxy-5 (10] -estren-7-onu.3.2 g of 18-methyl-3,3- (2 ', 2'-dimethyl-3', 3'-β-β-endioxy] -15a-trimethylsiloxy-5-estren-17-one and 18-methyl-3,3 - (2? 2? 11? 1? - +, 3? -Propylenedioxy) -15? -Trimethylsiloxy-5 (10) -estren-7-one.
F. 15α-l-bnzoylooχ--1-шethyll3,3-- 2’,2’-diInethyll,Γ,3’-propylendioxy)-5-estren-17-on a 15a'-benzoyloxy-18-methyl-3,3-(2’,2’-dimethyl-Γ,3’-propylendioxy )-5(10)-estren-17-onF. 15α-1-Benzoyloxy-1-methyl-3,3- (2 ', 2'-dimethylmethyl , Γ, 3'-propylenedioxy) -5-estren-17-one and 15a'-benzoyloxy-18-methyl-3 3- (2 ', 2'-dimethyl-Γ, 3'-propylenedioxy) -5 (10) -estren-17-one
10,0 g 15a-hydroxy-18-methyl-3,3-(2’,2’-dimethyllΓ,3’-propylendioxy)-5-estren-17-onu a 15ια--ιγύΓθχγ--1--ηβΗηί··3,3-(2’,2’-Ρίmethyl-r,3’-propylendioxy )-5(10) -estren-17-onu v 25 mi pyridinu na ledové lázni smísí s· 10 m- benzoy-ch-oridu. Reakční směs se nechá poté míchat při teplotě místnosti po dobu 4,5 hodiny a pak se vhje do směsi -edu a vody. Reakční produkt se extrahuje · methy-ench-oridem, extrakt se promyje vodou a vysuší síranem sodným. Po chromatografickém · čištění surového produktu na si-ikage-u s 2 až 3,5 % acetonu/hexan se získá 7,3 g 15a-benzoyloxy-18-methyl-3,3- (2/241126+71+,3+^--endioxyj-5-estren-17-onu a 15a-benzoyloxy-18-methyl-3,3-(2’,2’-ΓimethyllΓ,3’-propy-enclioxy^^Cn-estren-^-onu ve formě pěnovitého· produktu.10.0 g of 15α-hydroxy-18-methyl-3,3- (2 ', 2'-dimethyllΓ, 3'-propylenedioxy) -5-estren-17-one and 15α-γγύΓθχγ-1-ηβΗηί · · 3,3- (2 ', 2'-Dimethyl-1,3'-propylenedioxy) -5 (10) -estren-17-one in 25 ml pyridine on an ice bath mixed with 10 m-benzoyl chloride . The reaction mixture was then allowed to stir at room temperature for 4.5 hours and then poured into ice-water. The reaction product was extracted with methylene chloride, the extract was washed with water and dried over sodium sulfate. Chromatographic purification of the crude product on silica using 2-3% acetone / hexane yielded 7.3 g of 15α-benzoyloxy-18-methyl-3,3- (2/241126 + 71 +, 3 + 4'-endioxy-5-estren-17-one and 15a-benzoyloxy-18-methyl-3,3- (2 ', 2'-dimethyllΓ, 3'-propylenedioxo) -. in the form of a foamed product.
G. 18-methyl-15a-nitrooxy-4-estren-3,17-dionG. 18-Methyl-15α-nitrooxy-4-estren-3,17-dione
K 8,0 g 15α-hyΓroxy-18-methyl-4-estren-3,17-dionu v 60 ml acetanhydridu se přikape při tep-otě —20 °C 6 m- koncentrované kysehny dusičné. Reakční roztok se · po jedné hodině vhje do směsi -edu a vody. Vyloučený produkt se odsaje, , někohkrát promyje vodou a · vyjme do methylenchlo·ridu. Extrakt se vysuší síranem sodným. Po chromatografii surového produktu na silikagelu se za použití soustavy aceton/hexan získá· 6,4 g ’18-methyl-15a-nitrooxy-4-estren-3,17-dionu.To 8.0 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 60 ml of acetic anhydride is added dropwise 6 m of concentrated nitric acid at -20 ° C. After one hour, the reaction solution was poured into ice-water. The precipitated product is filtered off with suction, washed several times with water and taken up in methylene chloride. The extract was dried over sodium sulfate. Chromatography of the crude product on silica gel yields 6.4 g of 18-methyl-15α-nitrooxy-4-estrene-3,17-dione using acetone / hexane.
H. 18-methyl-15.a-nitrooxy-3,3-(2’,2’-dimethyl+,3’-pгopylenΓioxy]-5-estren-17-on a 18-meihyM5a-mtrooxy-3,3- (2’,2’-dimethyl+,3’-propylenΓioxy )-5(10) -estren-17ionH. 18-Methyl-15.alpha.-nitrooxy-3,3- (2 ', 2'-dimethyl +, 3'-popylene-thioxy] -5-estren-17-one and 18-methyl-5a-nitrooxy-3,3- ( 2 ', 2'-dimethyl +, 3'-propylenothioxy) -5 (10) -estren-17-one
5,9 g 18-methyl-15a-nitrooxy-4-estren-5.9 g of 18-methyl-15α-nitrooxy-4-estren-
-3,17-dionu se smísí ve 40 ml methylenchloridu a 10 ml triethylesteru kyseliny mravenčí s 18 g 2,2-dim^thyl-l.,3-pro^pandio-u a 50 ml kyseliny p-toluensulfonové a reakční směs se míchá po dobu 3 hodin při tep-otě místnosti. Reakční směs se poté zředí ethylacetátem a zpracuje se dále, jak je uvedeno· v příkladu B. Po chromatografování surového produktu soustavou aceton/hexan se získá 4,7 · g 18-methyl-15ia-nitrooxy-3,3- (2/2411^1^-+,3+^-^0dioxyj-b-estren-^-onu a 18-methyl-15a-nitгooxy-3,3-(2’,2’-Γímethy-+,3+ropylendioxy)-5(1Ó)-^£^^i^^^-^17-onu ve formě olejovitého produktu.-3,17-dione was mixed in 40 ml of methylene chloride and 10 ml of triethyl formate with 18 g of 2,2-dimethyl-1,3,3-propanedioate and 50 ml of p-toluenesulfonic acid and the reaction mixture was Stir for 3 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and worked up as described in Example B. After chromatography of the crude product with acetone / hexane, 4.7 g of 18-methyl-15-nitrooxy-3,3- (2/2411) was obtained. 4 ', 4' - +, 3 + - (4-Dioxy) -b-estren-4-one and 18-methyl-15α-nitro-oxy-3,3- (2 ', 2'-methyl-+, 3 + ropylenedioxy) -5 (10) - (17-one) as an oily product.
í. 15a-acetoxy-18-methyl-3,3- (2’,2’-dimethyl-r,3’-propylendioxy)-5-estren-17-on a 15a-acetoxy-18-methyl-3,3- (2’,2’-dimethyl-Γ,3’-propylenΓioxy )-5(10) -estren-'17-onand. 15α-acetoxy-18-methyl-3,3- (2 ', 2'-dimethyl-1,3'-propylenedioxy) -5-estren-17-one and 15α-acetoxy-18-methyl-3,3- ( 2 ', 2'-dimethyl-Γ, 3'-propylenothioxy) -5 (10) -estren-17-one
12,0 g 15α-hyΓroxy-18-methyl-3,3-(2’,2’-dimethy l-Γ, 3’-propylendioxy)-5-estren-17-onu a 15<a-hydroxy-18-methyl-3,3-(2’,2’-Γimethyl-Γ,3’-propylenΓίoxy )-5(10)-estren-17-onu se smísí ve 30 ml pyridinu s 10 · ml acetanhydridu. Reakční směs se míchá po dobu 3 hodin při tep-otě místnosti a · potom · se vlije do směsi ledu a vody. Vysrážený . produkt se odsaje, promyje vodou a vyjme do methylenchloridu. Extrakt se· vysuší síranem sodným a zahustí ve vakuu. Získá se 9,7 g surového· 15a-acetoxy-18-methyl-3,3- (2’,2’-ΓimethyllΓ,3’-propy-enΓίoxy)-5-estren-17-onu a 15a-acetoxy-18-methyl-3,3-(2’,2’-Γimethy--Γ,3’-propylenΓioxyj-5(1ój-estren-17-onu ve formě · olejovité látky.12.0 g of 15α-hydroxy-18-methyl-3,3- (2 ', 2'-dimethyl-Γ, 3'-propylenedioxy) -5-estren-17-one and 15α-hydroxy-18- methyl 3,3- (2 ', 2'-dimethyl-Γ, 3'-propylenedioxy) -5 (10) -estren-17-one is mixed in 30 ml of pyridine with 10 ml of acetic anhydride. The reaction mixture is stirred for 3 hours at room temperature and then poured into ice-water. Precipitated. the product is filtered off with suction, washed with water and taken up in methylene chloride. The extract was dried over sodium sulfate and concentrated in vacuo. 9.7 g of crude 15α-acetoxy-18-methyl-3,3- (2 ', 2'-dimethyllΓ, 3'-propyleneoxy) -5-estren-17-one and 15α-acetoxy-18 are obtained. methyl-3,3- (2 ', 2'-dimethyl-Γ, 3'-propylenethioxy) -5 (1 H) -estren-17-one as an oily substance.
J. 18-methyl-3,3- ( 2’,2’-dimeth у--l’,3’-propylendioxy )-5,15-estradien-17-on a 18-me+---3,3-(2/24^6^1+,3+^-^^oxy) -5 (10),15-estradien-17-onJ. 18-methyl-3,3- (2 ', 2'-dimetho-1', 3'-propylenedioxy) -5,15-estradien-17-one and 18-me + --- 3,3- (2/24 ^ 6 ^ 1 +, 3 + 1 - ^ ^ oxy) -5 (10), 15-estradien-17-one
Ke 123 g 15x-hydгoxy-18-me+y--3,3-(2’,2’- -Γimethy--Γ,3’-pгopylendioxy)-5-estгen-17-onu a 15й-11уГгоху- 18-me+yl-3,3-(2’,24imethyl-Γ,3’-propylenΓioxy )-5(10) -estren-17-onu, připraveného podle postupu B, se v jednom litru pyridinu přikape · pozvolna za chlazení ledem a míchání 100 ml chloridu kyseliny methansulfonové. Po 3,5 hodinách se přidá 500 ml · , dimethylformamidu a 317 g octanu sodného a reakční směs se míchá dále 24 hodiny při teplotě místnosti. Poté se reakční směs vlije do· ledové vody. Vysrážený produkt se odsaje, vyjme do ethylacetátu, promyje vodou · a vysuší síranem· sodným. Surový produkt (103 g) se chromatografuje na silikagelu za použití 10 až 14 % acetonu/hexanu. Získá seTo 123 g of 15-Hydroxy-18-methyl-3,3- (2 ', 2'-dimethyl-Γ, 3'-p-propylenedioxy) -5-estgen-17-one and 15-γ-11-hydroxy-18 -me + yl-3,3- (2 ', 24-methyl-3, 3'-propylenthioxy) -5 (10) -estren-17-one, prepared according to Procedure B, is slowly added dropwise in one liter of pyridine with ice cooling and stirring with 100 mL methanesulfonic acid chloride. After 3.5 hours, 500 ml of dimethylformamide and 317 g of sodium acetate are added and the reaction mixture is stirred for a further 24 hours at room temperature. The reaction mixture was then poured into ice water. The precipitated product is filtered off with suction, taken up in ethyl acetate, washed with water and dried over sodium sulphate. The crude product (103 g) was chromatographed on silica gel using 10-14% acetone / hexane. It is obtained
48,5 g · 18-me+y-l3,3-(2/24íme+y-+’3’-propylenΓioxy)-5,15-estraΓien-17-onu- a 18-methyl-3,3- (2’,2’-Γimethyl·-Γ,3’-pгopylen- dioxy )-5(10) , ,15-estradien-17-onu.48.5 g · 18-methyl-γ-1,3,3- (2/24-methyl-γ-3'-propylenedioxy) -5,15-estranien-17-one and 18-methyl-3,3- ( 2 ', 2'-Dimethyl-Γ, 3'-β-propylenedioxy) -5 (10), 15-estradien-17-one.
Způsob výroby derivátů estradienu pod-Process for the preparation of estradien derivatives
2039'12 le vynálezu je blíže objasněn v následujících příkladech provedení:The following examples illustrate the invention in more detail:
Příklad 1Example 1
17a-ethinyl-17+-hydroxy-18-methyl-4,15-estradien-17-on17α-ethynyl-17 + -hydroxy-18-methyl-4,15-estradien-17-one
7,5 g hořčíkových hoblin se uvede v reakci ve 140 ml tetrahydrofuranu se 24 ml ethylbromidu na ethylmagnesiumbromid. K tomuto Grígnardovu roztoku se přidá 300 ml tetrahydrofuranu a za chlazení ledem se zavádí přibližně po dobu 40 minut acetylén. Poté se přikape roztok 5 g 18-methyl-3,3- (2’,2’-dímethyll-.’,3’-propandlol) -5,15-estradien-17-onu a 18-methyl-3,3-(2’,2’-dimethyllΓ,3’-propandiol )-5(10) ,15-estradien-17-onu ve 200 ml tetrahydrofuranu a roztok se' míchá při teplotě místnosti. Po dvou hodinách se roztok opatrně smísí s roztokem chloridu amonného a zředí etherem. Organická fáze se několikrát promyje vodou a vysuší síranem sodným. Potom' se odpaří ve vakuu k suchu. Po' chromatografickém čištění surového produktu ' na silikagelu za pomoci 2,5 až 2,9% aceton/hexanu se získá 3,1 g 17a-ethinyl-18-methyl-3,3- (2’,2’-dimethyl-Γ,3’-propylendioxy )-5,15-estraďien-17/3-olu a 17a-ethinyl-18-methyl-3,3-( 2’,2’-dimeihyl-Γ,3’-ptcιpylendio.χy) -5(lOj.l5-cstradienll7S-olu, které se míchají po dobu 40 minut pod zpětným chladičem v 70 ml methylalkoholu a 14 ml vody s 2,3 g kyseliny šťavelové. Reakční roztok se zředí etherem, promyje vodou, vysuší a zpracuje na aktivním uhlí. Po rekrystalizaci ze směsi aceton/hexan se získá 1,4 g 17a-hydroxy-18-methyl-4,15-estra-dien-3-onu. Teplota tání je 197,9 °C.7.5 g of magnesium shavings are reacted in 140 ml of tetrahydrofuran with 24 ml of ethyl bromide to give ethylmagnesium bromide. To this Grigard solution was added 300 mL of tetrahydrofuran and acetylene was introduced over approximately 40 minutes under ice-cooling. A solution of 5 g of 18-methyl-3,3- (2 ', 2'-dimethyl-3', 3'-propanediol) -5,15-estradien-17-one and 18-methyl-3,3- is then added dropwise. (2 ', 2'-dimethyllΓ, 3'-propanediol) -5 (10), 15-estradien-17-one in 200 ml tetrahydrofuran and the solution was stirred at room temperature. After two hours, the solution was carefully mixed with ammonium chloride solution and diluted with ether. The organic phase is washed several times with water and dried over sodium sulfate. It is then evaporated to dryness in vacuo. Chromatographic purification of the crude product on silica gel with 2.5-2.9% acetone / hexane afforded 3.1 g of 17α-ethynyl-18-methyl-3,3- (2 ', 2'-dimethyl-2 H). , 3'-propylenedioxy) -5,15-estradien-17/3-ol and 17α-ethynyl-18-methyl-3,3- (2 ', 2'-dimethyl-Γ, 3'-pentylenedioxy) - 5 (10 < 15 > -15-Cstradien-17S-ol), which are stirred for 40 minutes under reflux in 70 ml of methanol and 14 ml of water with 2.3 g of oxalic acid, diluted with ether, washed with water, dried and worked up Recrystallization from acetone / hexane gave 1.4 g of 17α-hydroxy-18-methyl-4,15-estra-dien-3-one, mp 197.9 ° C.
Příklad 2 ,Example 2,
17a-ethinyl-17/3-hydroxy-18-metbyl-4,15-estradien-3-on17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one
3,0 g hořčíkových hoblin se nechá reagovat v 56 ml tetrahydrofuranu s 9,6 ml ethylbtomidu na ethylmagnesiumbromid. Grígnardův roztok se zředí 100 ml tetrahydrofuranu a ochladí na teplotu 0 °C. Po dobu 30 minut se zavádí acetylen a potom se přikape roztok 2,0 g 18-methyl-3,3-(2’,2’-dimethyl-Γ,3’-ptopylendioxy)-15a-trimethylsiloxy-5-estten-17-onu a 18-methyl-3,3-(2’,2’-dim'ethyl-Γ,3’-propylendioxy-15a-trimethylsiloxy-5(10)estren-17-onu v 80 ml tetrahydrofuranu a reakční směs se míchá po dobu jedné hodiny při teplotě místnosti. Roztok se zpracuje stejným způsobem jak je popsáno' v příkladu 1. Surový produkt se chromatografuje na silikagelu; 3,5 až 4,5% aceton/hexanem se eluuje 700 mg 17a-ethinyl-18-methyl-3,3- (2’,2’-dimethyl-l’,3’-pr opylendioxy)-5(10) ,15-estradien-17^-olu: (t. t. 223 až 225 °C), který se stej ně jak popsáno· v příkladu 1 míchá pod zpětným chladičem s 500 mg kyseliny šťavelové ve' 12 ml methanolu a 1,5 ml vody. Surový produkt se překrystaluje ze směsi aceton/hexan. Výtěžek: 510 mg 17a-ethinyl-17.3-hydroxy-18-methyl-4,15-estradien-3-onu s teplotou tání 190 až 192 °C.3.0 g of magnesium shavings are treated in 56 ml of tetrahydrofuran with 9.6 ml of ethyl bromide to give ethylmagnesium bromide. The Grigard solution was diluted with 100 mL of tetrahydrofuran and cooled to 0 ° C. Acetylene is introduced over 30 minutes and then a solution of 2.0 g of 18-methyl-3,3- (2 ', 2'-dimethyl-Γ, 3'-propylenedioxy) -15α-trimethylsiloxy-5-estten-17 is added dropwise. of 18-methyl-3,3- (2 ', 2'-dimethyl-Γ, 3'-propylenedioxy-15α-trimethylsiloxy-5 (10) estren-17-one in 80 ml of tetrahydrofuran and the reaction mixture was The solution was worked up in the same manner as described in Example 1. The crude product was chromatographed on silica gel, eluting with 3.5-4.5% acetone / hexane with 700 mg of 17α-ethynyl-18- methyl 3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5 (10), 15-estradien-17β-ol: (mp 223-225 ° C), which was as in Example 1, stirred under reflux with 500 mg of oxalic acid in 12 ml of methanol and 1.5 ml of water, and the crude product was recrystallized from acetone / hexane to yield 510 mg of 17α-ethynyl-17.3-hydroxy. -18-methyl-4,15-estradien-3-one, m.p. 190-192 ° C.
Příklad 3Example 3
17α-ethinyl1leι('j-hyddOxy-Ί8-methyl-4,15-estradien-3-on17α-ethinyl1le ι ( 'j hyddOxy Ί8-methyl-4,15-diene-3-one
5,0 g hořčíkových hoblin se ' nechá zreagovat ve 100 ml tetrahydrofuranu s 18 ml ethylbromidu na ethylmagnesiumbromid. Roztok se zředí 100 ' ml tetrahydrofuranu a ochladí na teplotu 0 °C. Po dobu 30 minut se do roztoku zavádí acetylen a poté přidá roztok 4,5 g 15a-acetoxy-18-methyl-3,3-(2’,2’-díInethyllΓ,3’-ptopylendioxy)-5-estren-17-onu a 15a-acetoxy-18-methyl-3,3-5.0 g of magnesium shavings were reacted in 100 ml of tetrahydrofuran with 18 ml of ethyl bromide to give ethylmagnesium bromide. The solution was diluted with 100 mL of tetrahydrofuran and cooled to 0 ° C. Acetylene is introduced into the solution for 30 minutes and then a solution of 4.5 g of 15α-acetoxy-18-methyl-3,3- (2 ', 2'-diethyllΓ, 3'-propylenedioxy) -5-estrene-17- is added. 15a-acetoxy-18-methyl-3,3-
- (2’,2’-dimethyl-Γ,3’-pгopylendioxy) -5(.10) estren-n-onu v 80 ml tetrahydrofuranu.- (2 ´, 2´-dimethyl-Γ, 3´-popylenedioxy) -5 (.10) estren-n-one in 80 ml of tetrahydrofuran.
Reakční směs se nechá po' dobu jedné hodiny míchat při teplotě místnosti a poté se zpracuje stejně jak je uvedeno v příkladuThe reaction mixture was allowed to stir at room temperature for one hour and then worked up as in the example
1. lískaný 17a-ethinyl-18-methyl-3,3-(2’,2’-dim.eth.yl-Γ,3’-propylendioxy)-5,15'esttadien-17/3-ol a 17a-ethinyl-18-methyl-3,3-1. bisected 17α-ethynyl-18-methyl-3,3- (2 ', 2'-dimethylethyl-Γ, 3'-propylenedioxy) -5,15'-estadiene-17/3-ol and 17a- ethinyl-18-methyl-3,3-
- (2’,2’-dimethylll’,3’-propylendioxy)-5(10),15-estradien-173-ol (3,7 g) se míchá po' dobu 45 minut pod zpětným chladičem v 70 ml methylalkoholu a 14 ml vody s- (2 ', 2'-dimethyl-11', 3'-propylenedioxy) -5 (10), 15-estradien-173-ol (3.7 g) was stirred under reflux in 70 ml of methanol for 45 minutes and 14 ml of water p
2,5 g ' kyseliny šťavelové. Reakční roztok se zředí etherem, promyje vodou a vysuší 'síranem' sodným. Surový produkt se chromatografuje na silikagelu směsí aceton/hexan. Získá se 2,1 g 17a-ethinyl-17Д-hydtoxy-18-methyl-4,15-estradien-3-onu. Teplota tání 189 až 192 °C.2.5 g of oxalic acid. The reaction solution was diluted with ether, washed with water and dried over sodium sulfate. The crude product is chromatographed on silica gel with acetone / hexane. 2.1 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one are obtained. Mp 189-192 ° C.
PřikládáHe attaches
17íl·aceiooχll1«-eihmyl-18-metbyl-4,15-estradien-3-οη17 · · aceiooχ111--ehihyl-18-methyl-4,15-estradien-3-οη
Roztok 2 g 17a-ethinyl-l7.3-hydroxy-18-methyl-4,15-esttadien-3-onu ve 40 ml kolidinu a 13 ml acetanhydridu se po' dobu . 5 hodin zahřívá ' k varu pod dusíkovou · atmosférou. Po' ochlazení se roztok vlije do směsi vody a ledu. Reakční produkt se extrahuje ' methylenchloridem a poté se postupně promyje 2 N ' kyselinou chlorovodíkovou, roztokem hydrogenuhličitanu . sodného a vodou. Naknnec se extrakt vysuší síranem sodným. Surový produkt se · chromatografuje na silikagelu; 25 až 30%o ethylace^t^á^t/hK^í^^i^i^m! se eluuje 950 mg 17$-acetoxy-17l«-ethínyl-18-methyl-á,15-estta- . dien-3-onu, který má po rekrystalizaci za směsi aceton/methanol teplotu tání 163 až 164 °C.A solution of 2 g of 17α-ethynyl-17,3-hydroxy-18-methyl-4,15-esttadien-3-one in 40 ml of collidine and 13 ml of acetic anhydride is added over a period of time. Heat at reflux for 5 hours. After cooling, the solution was poured into a mixture of water and ice. The reaction product was extracted with methylene chloride and then washed sequentially with 2N hydrochloric acid, bicarbonate solution. sodium and water. Finally, the extract is dried over sodium sulfate. The crude product is chromatographed on silica gel; 25 to 30% of ethylation. eluted with 950 mg of 17-acetoxy-$ 17 l «ethynyl-18-methyl-15-estta-. dien-3-one having a melting point of 163-164 ° C after recrystallization with acetone / methanol.
Příklad 5 ]^7a-ethinyl-1^7^-butyryloxy-l8-methyl-4,15-estradien-3-onExample 5] 4α-Ethinyl-1β-β-butyryloxy-18-methyl-4,15-estradien-3-one
500 mg 17a-ethinyl-17/3-hydroxy-18-methyl-4,15-estradlen-3-onu se zahřívá se 2 ml anhydridu kyseliny máselné a 2 ml kolidinu po dobu 10 . hodin pod dusíkovou atmosférou a pod zpětným: chladičem. Reakční směs se zpracuje stejným způsobem jak je popsáno: v příkladu 4. Po chromatografování suroyého produktu na silikagelu směsí aceton/hexan se získá 310 mg 17a-ethinyl-l7lJíi-t^Lltt^7y^7l5?^y^-l^8-Inc^tt^h^7l^-4,:^!^-(^‘^1^^^,ad:ien-3-onu, který má po rekrystalizaci ze směsi aceton/methylalkohol teplotu tání 160 až 162 stupňů Celsia.500 mg of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradlen-3-one is heated with 2 ml of butyric anhydride and 2 ml of collidine for 10 minutes. h under nitrogen and under reflux: condenser. The reaction mixture was treated in the same manner as described In Example 4. After chromatography suroyého product on silica gel with acetone / hexane gave 310 mg of 17.alpha.-ethynyl-L7 ii-Lj ^ t ^ 7y Lltt 7l5 ^? ^ Y ^ -l ^ 8-Incotetyl-4-ol, adenen-3-one having a melting point of 160 to 162 degrees after recrystallization from acetone / methanol. Celsius.
P ř í k 1 a d 6 ^a-ethinyl-^^-heptanoyloxy-^-methyl-4,15-estradien-3-onEXAMPLE 6 6a-Ethinyl-4-Heptanoyloxy-4-methyl-4,15-estradien-3-one
300 mg' 17α-ethiny--17/3-hydrox7-18-methyl-4,15-estradien-3-onu se míchá se 2 ml anhydridu kyseliny enantové a 2 ml kolidinu po. 'dobu 17 hodin pod zpětným, chladičem a pod dusíkovou atmosférou při teplotě 170 °C. Reakční produkt se zpracuje stejným způsobem jak je popsáno, v příkladu 4. , Přebytečná kyselina enantová se odstraní destilací vodní párou. Po extrakci etherem se získá surový produkt, který se chromatografuje na silikagelu směsí aceton/hexan. Získá se 175 mg 17a-ethiny 1-17^-heptanoyloxy-4,15-estradien-3-onu ve formě olejovité ' látky. UV (methanol): ε239 = 17 800.300 mg of 17α-ethines - 17β-hydrox7-18-methyl-4,15-estradien-3-one are stirred with 2 ml of enantic anhydride and 2 ml of collidine po. 17 hours under reflux and under nitrogen atmosphere at 170 ° C. The reaction product was treated in the same manner as described in Example 4. Excess enantic acid was removed by steam distillation. Extraction with ether gave the crude product which was chromatographed on silica gel with acetone / hexane. 175 mg of 17.alpha.-ethynyl-17.beta.-heptanoyloxy-4,15-estradien-3-one is obtained as an oil. UV (methanol): ε239 = 17,800.
Příklad 7Example 7
17a-ethinyl-17/3-oktanoyloxy-18-methyl-4,15-estradien-3-on17α-Ethinyl-17β-octanoyloxy-18-methyl-4,15-estradien-3-one
Z roztoku 3,5 ml anhydridu kyseliny kaprylové ve 250 ml benzenu se oddestiluje' 50 ml. Po ochlazení na teplotu místnosti se smísí s 3,5 ml anhydridu kyseliny trifluoroctové. Po 30 minutách se přidají 4 g 17 a-ethin71-17n-hydroxy-18-methyl-4,15-estradien-3-onu a reakční směs se míchá další 2 hodiny. Dále' se reakční směs smísí za chlazení ledem s 50 ml , směsi aceton—voda (1 : 1), míchá po dobu 30 minut a poté se ve vakuu zahustí. Zbytek , se vyjme do methyíenchloridu, promyje roztokem hydrogenuhličitanu sodného, vodou a vysuší síranem sodným. , Surový' produkt se chromatografuje ' na silikagelu. Eluuje' se 14 až 18% ethylacetát/hexanem 2,3 g 17a-'ethinyl-17^-oktano7lox7-18-methyl-4,15-estradien-3-onu ve formě olejovité látky.50 ml is distilled from a solution of 3.5 ml of caprylic anhydride in 250 ml of benzene. After cooling to room temperature, 3.5 ml of trifluoroacetic anhydride are added. After 30 minutes, 4 g of 17α-ethin-17-17-n-hydroxy-18-methyl-4,15-estradien-3-one was added and the reaction stirred for a further 2 hours. Next, the reaction mixture was treated with 50 ml of acetone-water (1: 1) under ice-cooling, stirred for 30 minutes and then concentrated in vacuo. The residue was taken up in methylene chloride, washed with sodium bicarbonate solution, water and dried over sodium sulfate. The crude product is chromatographed on silica gel. Eluting with 14-18% ethyl acetate / hexane 2.3 g of 17α-ethynyl-17'-octanoanilo-7-18-methyl-4,15-estradien-3-one as an oil.
UV (methanol): £239 ' = 17 600.UV (methanol): 239 239 '= 17,600.
Příklad 8 ^«-ethinyl-W-methyl-^-undekanoyloxy-4,15-estradien-3-onuExample 8 N, N-Ethinyl-N-methyl-N-undecanoyloxy-4,15-estradien-3-one
Z roztoku 4,0 g kyseliny undecylové ve 300 ml benzenu se oddestiluje 50 ml. Po' ochlazení na (teplotu místnosti se smísí se50 ml is distilled from a solution of 4.0 g undecylic acid in 300 ml benzene. After cooling to room temperature, mix
4,5 ml anhydridu kyseiiny trlfloroctoivé. Po 30 minutách se přidají 4,0 g 17a'-ethinyl-17β-3-уУгоху-11-ппШуУ-4,1 1-estra dien-3-onu. Reakční směs se míchá po dobu' 2,5 hodin a roztok se zpracuje stejným způsobem jak uvedeno v příladu 7. Surový produkt se chromatografuje na silikagelu 18 . až 25% ethylacetát/hexanem. Získá se 2,6 g 17a-etУmy--18-nethyl-17;3-шldekanoyloXy-4,15-estradien-3-onu ve formě olejovité látky.4.5 ml of trifluoroacetic anhydride. After 30 minutes, 4.0 g of 17α'-ethynyl-17β-3-уггоху-11-piperidin-4,1-estra dien-3-one is added. The reaction mixture was stirred for 2.5 hours and the solution was treated in the same manner as in Example 7. The crude product was chromatographed on silica gel 18. up to 25% ethyl acetate / hexane. 2.6 g of 17α-ethyl-18-methyl-17,3-decanoyloxy-4,15-estradien-3-one are obtained in the form of an oily substance.
UV (methanol): £239 = 16 900.UV (methanol): 239 239 = 16,900.
Příklad 9Example 9
17^-(1111^1-17/3-1^301^31107^7-18-11^tУ7--4,15-estradien-3-on17 ^ - (1111 ^ 1-17 / 3-1 ^ 301 ^ 31107 ^ 7-18-11 ^ tУ7--4, 15-estradien-3-one
Z roztoku 4,1 g kyseliny palmitové ve 200 nul benzenu se oddestiluje 40 ml. ' Po ochlazení na teplotu místnosti se smísí s 2,3 ml anhydridu kyseliny trlfluoroctové. ' Po' 30 minutách se přidá 4,2 g 17a-ethinyl-17^-hydroxy-18-metУ7--4,15-estradien-3-onu a míchá další dvě hodiny. Reakční produkt se za chlazení ledem smísí s 30 ' ml směsi acetonu a vody (1 1), míchá se po dobu 30 ' minut a potom se ve vaku odpaří k suchu. Zbytek se vyjme do neth7lenchloriΓu . a extrakt se promyje 10 ml 10% roztoku hydroxidu sodného. Vzniklá sraženina palmitanu sodného se odsaje, roztok se promyje do neutrální reakce, vysuší a ve vakuu zahustí. Surový produkt se chromatografuje na silikage-u. ' Elucí 12 až 16% ethylacetát/hexanem se získá 2,8 g 17a-ethinyl-17^eУexadekano7-oxy-18-nethyl-4,15-estradien-3-onu ve formě olejovité látky. UV (methanol): £239 = '17 100.From a solution of 4.1 g of palmitic acid in 200 µl of benzene, 40 ml was distilled off. After cooling to room temperature, 2.3 ml of trifluoroacetic anhydride are added. After 30 minutes, 4.2 g of 17? -Ethynyl-17? -Hydroxy-18-methyl-4,15-estradien-3-one is added and stirred for a further two hours. The reaction product was treated with 30 ml of acetone / water (1 L) under ice-cooling, stirred for 30 minutes and then evaporated to dryness in a bag. The residue was taken up in n-ethylene chloride. and the extract was washed with 10 ml of 10% sodium hydroxide solution. The resulting sodium palmitate precipitate is filtered off with suction, the solution is washed neutral, dried and concentrated in vacuo. The crude product is chromatographed on silica gel. Elution with 12-16% ethyl acetate / hexane gave 2.8 g of 17α-ethynyl-17-hexadecano-7-oxy-18-methyl-4,15-estradien-3-one as an oil. UV (methanol): 239 239 = 1717.
Příklad 10Example 10
17a-ethiny--171β-hyΓroxye18-nethyl-4,15-estrarien-3-on17a-ethines - 17 1 β-hydroxy18-methyl-4,15-estrarien-3-one
Do roztoku 100 ml n-butyllithia (asi 15% v hexanu) v 350 ml tetrahydrofuranu, chlazeného ledovou vodou, se zavádí acetylen poi dobu 45 minut. Potom se za míchání přikape 10,0 g 18-metyyl-3,3-(2’,2’-dmiethyl-l’,3’-propylenrioxy) -5,15-estradien-17-onu a 18-methyl-3,3-(2’,2’-rimetyylir,3’-propylendioxy )-5(10) ,15-estrarien-17-onu ve 10 ml tetrahydrofuranu. Po 30 minutách se roztok smísí s nasyceným roztokem chloridu amonného, zředí ethylacetátem a promyje vodou do neutrální ' reakce. Poté ' se vysuší síranem sodným. Roztok se dále . ve ' vakuu zahustí k suchu, přičemž se získáAcetylene was introduced into a solution of 100 ml of n-butyllithium (about 15% in hexane) in 350 ml of ice-cold tetrahydrofuran for 45 minutes. Then 10.0 g of 18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenrioxy) -5,15-estradien-17-one and 18-methyl-3 are added dropwise with stirring. 3- (2 ', 2'-rimethyylir, 3'-propylenedioxy) -5 (10), 15-estrarien-17-one in 10 ml of tetrahydrofuran. After 30 minutes, the solution was treated with saturated ammonium chloride solution, diluted with ethyl acetate, and washed with water until neutral. It was then dried over sodium sulfate. The solution is further added. it is concentrated to dryness under vacuum to obtain
11,4 g surového 17a-ethinyl-18-methyl-3,3- (2’,2’-dlmethyl-l’,3’-propylendioxy) -5,15-estradien-17i|3-olu a 17a-ethinyl-18-methyl-3,3- (2’,2’-dimethyl-l’,3’-propylendioxy) -5(10),15-estradien-17jí?-olu, který se suspenduje v acetonu (70 ml). К této suspensi se přidá 0,1 ml koncentrované kyseliny chlorovodíkové a reakční směs se míchá po dobu 2 hodin při teplotě místnosti. Poté se roztok vlije do ledové vody. Vysrážený produkt se odsaje, rozpustí v ethylacetátu a vysuší síranem sodným. Po cbromatografickém čištění surového produktu na silikagelu 20% aceton/hexanem se získá 4,8 g 17a-ethinyl-17^-hydroxy-18-methyl-4,15-estradien-3-onu o teplotě tání 199 až 200 stupňů Celsia.11.4 g of crude 17α-ethynyl-18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5,15-estradien-17β-ol and 17α-ethynyl -18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5 (10), 15-estradien-17β-ol, which is suspended in acetone (70 mL) . Concentrated hydrochloric acid (0.1 ml) was added to the suspension, and the reaction mixture was stirred at room temperature for 2 hours. The solution was then poured into ice water. The precipitated product is filtered off with suction, dissolved in ethyl acetate and dried over sodium sulfate. Chromatographic purification of the crude product on silica gel with 20% acetone / hexane yielded 4.8 g of 17α-ethynyl-17H-hydroxy-18-methyl-4,15-estradien-3-one, m.p. 199-200 ° C.
Příklad 11Example 11
17i/3-acetoxy-17a-ethinyl-18-methyl-4,15-estradien-3-on17i / 3-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one
К 2,0 g 17a-ethinyl-17iá-hydroxy-18-methyl-4,15-estradien-3-onu ve 20 ml methylenchloridu se přidá 40 ml acetanhydridu a 10 mg kyseliny p-toluensulfonové. Roztok se míchá po dobu 6 hodin při teplotě místnosti pod ochrannou atmosférou dusíku. Potom se zředí ethylacetátem, promyje roztokem hydrogenuhličitanu sodného do neutrální reakce a vysuší síranem sodným. Po chromatografování na silikagelu se elucí 7 až 9% aceton/hexanem získá 560 mg 17(|S-acetoxy-17a-ethinyl-18-methyl-4,15-estradien-3-onu. Teplota tání činí po rekrystalizaci ze směsi aceton—hexan 163 až 164 °C.К 2.0 g 17a-ethynyl-17 i-hydroxy-18-methyl-4,15-diene-3-one in 20 ml of methylene chloride was added 40 ml of acetic anhydride and 10 mg of p-toluenesulfonic acid. The solution was stirred for 6 hours at room temperature under a nitrogen atmosphere. It is then diluted with ethyl acetate, washed neutral with sodium bicarbonate solution and dried over sodium sulfate. Chromatography on silica gel, eluting with 7-9% acetone / hexane, affords 560 mg of 17 (β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one), m.p. hexane 163-164 ° C.
Příklad 12Example 12
17a-ethinyl-17/3-trimethylsiloxy-18-methyl-4,15-estradien-3-on17α-Ethinyl-17β-trimethylsiloxy-18-methyl-4,15-estradien-3-one
1,5 g 17a-ethinyl-17/?-hydroxy-18-methyl-4,15-estradien-3-onu ve 30 ml pyridinu se smísí za chlazení ledem s 8 ml trimethylchlorsilanu. Po třech hodinách se reakční směs vlije do ledové vody. Vysrážený produkt se odsaje, rozpustí v metfaylenchloridu, roztok se promyje vodou a vysuší síranem sodným. Po zpracování surového produktu v acetonu aktivním uhlím a rekrystalizaci ze směsi aceton—hexan se získá 1,18 g lya-ethinyl-iy^-trimethylsiloxy-18-methyl-4,15-estradien-3-onu o teplotě tání 158 až 159 °C.1.5 g of 17.alpha.-ethynyl-17.beta.-hydroxy-18-methyl-4,15-estradien-3-one in 30 ml of pyridine was mixed with 8 ml of trimethylchlorosilane under ice-cooling. After three hours, the reaction mixture was poured into ice water. The precipitated product is filtered off with suction, dissolved in metafaylene chloride, the solution is washed with water and dried over sodium sulfate. Treatment of the crude product in acetone with charcoal and recrystallization from acetone-hexane gave 1.18 g of lya-ethynyl-4-trimethylsiloxy-18-methyl-4,15-estradien-3-one, m.p. 158-159 °. C.
Příklad 13Example 13
17cr-ethinyl-17(3-hydroxy-18-methyl-4,15-estradien-3-on17 C-ethynyl-17 (3-hydroxy-18-methyl-4,15-estradien-3-one)
Do tříhrdlé baňky se naplní 240 ml tetrahydrofuranu a 60 ml hexanu a ochladí se na —70 °C. Poté se přidá za zavádění acetylenu směs ze 180 ml 15% roztoku butyllithia (v hexanu) a 180 ml tetrahydrofuranu; 30 g 18-methyl-4,15-estradien-3,17-dionu se rozpustí ve 210 ml tetrahydrofuranu, tetrahydrofuranový roztok se přikape do roztoku lithiumacetylidu a spláchne 30 ml tetrahydrofuranu. Za pokračujícího zavádění acetylenu se míchá 60 minut při —70 °C. Po vypuzení přebytečného acetylenu se provede rozklad 150 ml methanolu a 45 ml koncentrované kyseliny chlorovodíkové. Přidá se 375 ml vody a směs rozpouštědel se oddestiluje. Vypadlá látka se odsaje, promyje vodou do neutrální reakce a vysuší. Surový produkt (34,6 g) se překrystaluje z etheru a ethylacetátu.A three-necked flask was charged with 240 mL tetrahydrofuran and 60 mL hexane and cooled to -70 ° C. A mixture of 180 ml of a 15% butyllithium solution (in hexane) and 180 ml of tetrahydrofuran is then added under the introduction of acetylene; 30 g of 18-methyl-4,15-estradien-3,17-dione are dissolved in 210 ml of tetrahydrofuran, the tetrahydrofuran solution is added dropwise to the lithium acetylide solution and washed with 30 ml of tetrahydrofuran. Stirring is continued at -70 ° C for 60 minutes while the acetylene is introduced. After expulsion of the excess acetylene, 150 ml of methanol and 45 ml of concentrated hydrochloric acid are decomposed. 375 ml of water was added and the solvent mixture was distilled off. The precipitated substance is filtered off with suction, washed with water until neutral and dried. The crude product (34.6 g) was recrystallized from ether and ethyl acetate.
Získá se 24,0 g lZa-ethinyl-lZp-hydroxy-18-methyl-4,15-estradien-3-onu o teplotě tání 198 °C.24.0 g of 1α-ethynyl-1β-hydroxy-18-methyl-4,15-estradien-3-one, m.p. 198 ° C, are obtained.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS795403A CS203913B2 (en) | 1976-08-12 | 1979-08-06 | Process for preparing derivatives of estradiene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752546062 DE2546062A1 (en) | 1975-10-10 | 1975-10-10 | (17)-Alkynyl-(17)-hydroxy-(4,15)-oestradienones and derivs. - progestational agents inhibiting ovulation and implantation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS203912B2 true CS203912B2 (en) | 1981-03-31 |
Family
ID=5959135
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS766516A CS203912B2 (en) | 1975-10-10 | 1976-10-08 | Process for preparing derivatives of estradiene |
Country Status (3)
| Country | Link |
|---|---|
| CS (1) | CS203912B2 (en) |
| DE (1) | DE2546062A1 (en) |
| ZA (1) | ZA766034B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2636404C2 (en) * | 1976-08-12 | 1983-12-08 | Schering AG, 1000 Berlin und 4709 Bergkamen | ?? 1?? 5? -17? -Ethynyl steroids of the estran series, processes for their preparation and pharmaceutical preparations containing them |
| DE2749104C2 (en) * | 1977-10-31 | 1982-03-25 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Process for the preparation of?? 15? -Steroids |
| CN1008820B (en) * | 1985-05-10 | 1990-07-18 | 施林工业产权保护股份公司 | Process for the production of 17 alpha-ethynyl-17beta-hydroxy-18-methyl-4, 15-estradien-3-one |
| DE3710728A1 (en) * | 1987-03-31 | 1988-10-13 | Schering Ag | METHOD FOR PRODUCING 17 (ALPHA) -ETHINYL-17SS-HYDROXY-18-METHYL-4.15-ESTRADIEN-3-ON AND THE NEW INTERMEDIATE PRODUCTS FOR THIS METHOD |
| DE4329242A1 (en) * | 1993-08-26 | 1995-03-02 | Schering Ag | Agent for transdermal application containing gestodenester |
| DE4344462C2 (en) | 1993-12-22 | 1996-02-01 | Schering Ag | Composition for contraception |
| ITMI20040443A1 (en) * | 2004-03-08 | 2004-06-08 | Poli Ind Chimica Spa | PROCESS FOR THE PREPARATION OF .. 15-16-17-KETO-STEROIDS AND THEIR USE IN THE SYNTHESIS OF PHARMACOLOGICALLY ACTIVE COMPOUNDS |
| EP2354150A1 (en) | 2010-02-09 | 2011-08-10 | Laboratoire Theramex | Process for the preparation of gestodene |
-
1975
- 1975-10-10 DE DE19752546062 patent/DE2546062A1/en active Granted
-
1976
- 1976-10-08 ZA ZA766034A patent/ZA766034B/en unknown
- 1976-10-08 CS CS766516A patent/CS203912B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA766034B (en) | 1977-09-28 |
| DE2546062C3 (en) | 1980-12-18 |
| DE2546062B2 (en) | 1980-04-30 |
| DE2546062A1 (en) | 1977-04-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI56389C (en) | FRAMEWORK FOR THERAPEUTIC ADJUSTMENT OF THERAPEUTIC ANALYSIS 18-METHYL-4,15-ESTRADIENDERIVAT | |
| HU191131B (en) | Process for preparing 13-alpha-alkyl-gonanes and pharmaceutical compositions containing such compounds | |
| CZ287740B6 (en) | 11-(Substituted phenyl)-estra-4,9-diene derivative, process of its preparation and pharmaceutical preparation in which it is comprised | |
| DK168444B1 (en) | 7beta-methyl or 7beta-ethyl-11-aminophenyl steroid compounds, processes for their preparation and pharmaceutical preparations containing them | |
| CS203912B2 (en) | Process for preparing derivatives of estradiene | |
| EP0318490B1 (en) | 14,17-g(b)-ethano-14-g(b)-estratrienes, process for their manufacture and pharmaceutical preparations containing these | |
| EP0051762B1 (en) | 11-methylene-delta-15 steroids, process for their preparation and pharmaceutical compositions containing them | |
| US3380886A (en) | 7alpha-methyl-3beta-hydroxy-5-androstenes | |
| US3275666A (en) | 16-methylene steroids of the esterne series | |
| CS205009B2 (en) | Process for preparing 7-hydroxyestradioles | |
| WO1991001994A1 (en) | 11β-SUBSTITUTED 16α,17α-METHYLENE-ESTRA-4,9-DIENE-3-ONES | |
| EP0430386B1 (en) | 14Alpha, 17alpha bridged 16-hydroxyestratrienes | |
| US3461118A (en) | 3beta-tetrahydrofuranyloxy - and 3beta-tetrahydropyranyloxyestra - 4,9(10) - dienes and -4,9(10),11-trienes,their preparation and intermediates thereof | |
| US3709878A (en) | 8 alpha-methyl-substituted-steroids | |
| CS203913B2 (en) | Process for preparing derivatives of estradiene | |
| US4390530A (en) | 3-Deoxy-Δ15 -steroids | |
| US3159643A (en) | 6-methylene-3-oxo-delta4 steroids and process for preparation of same | |
| EP0092174B1 (en) | 11-beta-chloro-delta-15-steroids, process for their preparation and pharmaceutical compositions containing them | |
| US3840568A (en) | Estratriene derivatives | |
| US3389135A (en) | Process for prrparation of estra-4, 9-diene-3, 17-dione and intermediates in said process | |
| EP0017094A1 (en) | 11-Methylene steroids, process for their preparation and pharmaceutical compositions containing them | |
| EP0513947B1 (en) | 14 Alpha, 16alpha-ethano- and 14alpha, 16alpha ethenoestratrienes | |
| HU186687B (en) | Process for preparing 11beta-chloro-steroids and pharmaceutical compositions containing such compounds | |
| MXPA96003476A (en) | Derivatives of 11- (substituted phenyl) -estra-4,9-di |