DK145758B - Fremgangsmaade til fremstilling af 15-oestren-3,17-dionderivater - Google Patents
Fremgangsmaade til fremstilling af 15-oestren-3,17-dionderivater Download PDFInfo
- Publication number
- DK145758B DK145758B DK506075AA DK506075A DK145758B DK 145758 B DK145758 B DK 145758B DK 506075A A DK506075A A DK 506075AA DK 506075 A DK506075 A DK 506075A DK 145758 B DK145758 B DK 145758B
- Authority
- DK
- Denmark
- Prior art keywords
- group
- general formula
- methyl
- dimethyl
- carbon atoms
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical class 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 title description 4
- 150000003431 steroids Chemical class 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- -1 o-phenylenedioxy group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- BJALMYZFOSDDSF-LJRKRDDSSA-N (8r,9r,10s,13s,14s)-13-methyl-1,2,4,5,6,7,8,9,10,11,12,14-dodecahydrocyclopenta[a]phenanthrene-3,17-dione Chemical class C1C(=O)CC[C@@H]2[C@H]3CC[C@](C)(C(C=C4)=O)[C@@H]4[C@@H]3CCC21 BJALMYZFOSDDSF-LJRKRDDSSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 150000001805 chlorine compounds Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 4
- 238000005907 ketalization reaction Methods 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000221779 Fusarium sambucinum Species 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
- 241000985516 Penicillium raistrickii Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000004362 fungal culture Methods 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- 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
- BTTWKVFKBPAFDK-UHFFFAOYSA-N (9beta,10alpha)-Androst-4-ene-3,17-dione Natural products OC1CCC2(C)C3CCC(C)(C(CC4)O)C4C3CCC2=C1 BTTWKVFKBPAFDK-UHFFFAOYSA-N 0.000 description 1
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- JRIZOGLBRPZBLQ-QXUSFIETSA-N 19-Norandrostenedione Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JRIZOGLBRPZBLQ-QXUSFIETSA-N 0.000 description 1
- QPYKYDBKQYZEKG-UHFFFAOYSA-N 2,2-dimethylpropane-1,1-diol Chemical compound CC(C)(C)C(O)O QPYKYDBKQYZEKG-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 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
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical group O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000006567 deketalization reaction Methods 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
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 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
- 244000005700 microbiome Species 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- 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
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
- C07J53/008—3 membered carbocyclic rings in position 15/16
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
- Y10S435/929—Fusarium
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
- Y10S435/933—Penicillium
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
- Y10S435/933—Penicillium
- Y10S435/935—Penicillium chrysogenum
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
i 145758
Opfindelsen angår en særlig fremgangsmåde til fremstilling af 15-østren-3,17-dionderivater med den almene formel I
X ^ Δ ^ hvori X betegner en oxogruppe, en alkylendioxygruppe inde-5 holdende 2-6 carbonatomer eller en o-phenylendioxygruppe, Δ et med de nabostillede carbonatomer ved hjælp af en dobbeltbinding og to enkeltbindinger forbundet Ce-carbonatom og
1 3 R en methylgruppe eller en ethylgruppe, som er ejendommelig ved, at man fermenterer et steroid med den almene formel 10 II
r1JL
/-yU-‘ (II)
hvori R^ har ovennævnte betydning, med en svampekultur af slægten Penicillium raistrickii (ATCC 10490), i vilkårlig rækkefølge ketaliserer de dannede 15a-hydroxysteroider med den almene formel III
n0 II I (in) 2 145758
hvori har ovennævnte betydning, med en alkandiol indeholdende 2-6 carbonatomer eller med o-diphenol i nærværelse af sure katalysatorer og acylerer med et alkyl- eller arylsul-fonsyrechlorid i nærværelse af baser, og overfører de opnåe-5 de forbindelser med den almene formel IV
1 o J_[ (IV) rvy °γ l hvori Δ og R1 har ovennævnte betydning, X betegner en alkylen= dioxygruppe indeholdende 2-6 carbonatomer eller en o-phenylen= dioxygruppe, og Y betegner en alkylsulfonylgruppe eller en 1Q arylsulfonylgruppe, til Δ"^-steroiderne med den almene formel I ved behandling med baser og om ønsket hydrolyserer de opnåede ketaler på i og for sig kendt måde.
Østren-3,17-dionderivaterne med den almene formel I er som bekendt farmakologisk virksomme stoffer og/eller værdifulde 15 mellemprodukter til fremstilling af farmakologisk virksomme steroider, som ved de hidtil kendte fremgangsmåder kun kunne fremstilles ved hjælp af meget omstændelige flertrinssynteser (tyske offentliggørelsesskrifter nr. 15 93 500, 15 93 501 og 16 43 050 samt J. Fried og J.A. Edwards: Organic Reaction 20 in steroid Chemistrys van Nostrand, Reinhold Comp., New York et al., 1972, bd. 1, side 301 ff).
forhold hertil har fremgangsmåden ifølge opfindelsen det fortrin, at østren-3,17-dionderivaterne med den almene formel I kan fremstilles på enkel måde og i højere udbytter, 25 end dette er muligt ved hjælp af de kendte fremgangsmåder.
I det første trin i fremgangsmåden ifølge opfindelsen fermenteres et steroid med den almene formel II med en svampe- 3 145758 kultur af slægten Penicillium raistrickil (ATCC 10490).
Fra USA patentskrift nr. 3.243.355 kendes en fremgangsmåde til 15a-hydroxylering af 19-norandrost-4-en-3,17-dion med Fusarium roseum, og ifølge patentskriftets eksempler er 5 det ved hydroxyleringen muligt at opnå 15a-hydroxy-19-nor= androst-4-en-3,17-dion i et udbytte fra 29-49% under samtidig dannelse af en ikke ubetydelig mængde 6β-hydroxyforbindelse. Fusarium roseum kan tilsvarende anvendes til 15a-hydroxylering af de ovenfor nævnte forbindelser med den al-10 mene formel II, men det har ifølge opfindelsen vist sig, at mikroorganismen Penicillium raistrickii (ATCC 10490) muliggør opnåelse af udbytter, der er betydeligt højere end de udbytter, der kan opnås med Fusarium roseum (ATCC 14717).
Under de nævnte betingelser kan steroiderne med den almene 15 formel II give overraskende høje udbytter yed hydroxylering til 15a-hydroxysteroiderne med den almene formel III. Dette gunstige resultat kunne ikke forudses, da penicilliner og fusarier som bekendt ikke kun har evnen til at hydroxylere steroiderne i 15a-stillingen, men derudover også er i stand 20 til eksempelvis at hydroxylere steroider i 6β- eller 11a- stillingen samt i stand til at reducere ketosteroiderne til de tilsvarende hydroxysteroider.
I det andet og tredje trin i fremgangsmåden ifølge opfindelsen ketaliseres 15α-hydroxysteroiderne med den almene for-25 mel III i vilkårlig rækkefølge med en alkandiol eller o-di= phenol og acyleres med et sulfonsyrechlorid.
Den selektive ketalisering gennemføres under de betingelser, som man sædvanligvis anvender til ketalisering af 3-keto-A4-steroider. Således kan man eksempelvis omsætte steroiderne 30 med alkandiolen (f.eks. glycol, 1,3-propandiol, 2,3-butan-diol eller 2,2-dimethylpropandiol) eller med o-diphenolen i et indifferent opløsningsmiddel (f.eks. benzen, chloro- 4 145758 form, methylenchlorid, tetrachlorethan, diethylether eller tetrahydrofuran) med en sur katalysator (f.eks. hydrogen= chlorid, svovlsyre, perchlorsyre, trifluoreddikesyre eller p-toluensulfonsyre). Til opnåelse af høje udbytter af keta-5 liseringsproduktet sætter man til reaktionsblandingen hen- sigtmæssigt yderligere et vandbindende middel (f.eks. calcium= sulfat, magnesiumsulfat, molekularsigter eller myresyre-trialkylestere).
Ved denne ketalisering er det principielt muligt, at også 10 17^-ketogruppen medketaliseres under kraftige reaktionsbetin gelser og ved lang reaktionsvarighed. For at undgå dette er det hensigtsmæssigt at fastslå den optimale reaktionstid på sædvanlig måde ved et forudgående forsøg.
Ved ketaliseringsreaktionen forskydes den i steroidet til-15 stedeværende Δ^-dobbeltbinding til eller til ^5(10)^ stillingen. Denne dobbeltbindingsforskydning er imidlertid uden betydning for gennemførligheden af fremgangsmåden ifølge opfindelsen, da man ved en efterfølgende ketalspaltning (som altid er nødvendig til fremstilling af farmakologisk 20 virksomme steroider) atter opnår steroider med en 3-keto- 4 Δ -struktur.
Acyleringen af 15a-hydroxygruppen med alkylsulfonsyrechlorider eller arylsulfonsyrechlorider sker ved hjælp af de hertil kendte arbejdsmetoder. Således kan man omsætte 15a-hydroxy= 25 steroiderne med eksempelvis sulfonsyrechlorider (f.eks. benzensulfonsyrechlorid, p-toluensulfonsyrechlorid eller især methansulfonsyrechlorid) i nærværelse af tertiære aminer (såsom pyridin, lutidin, collidin eller 4-dimethylamino= pyridin).
30 De således opnåede forbindelser med den almene formel IV kan 15 ved behandling med baser omdannes til Δ ^steroiderne med den almene formel I.
145758 5
Elimineringen af sulfonsyregruppen gennemføres i nærværelse af baser.
Egnede baser er eksempelvis alkalimetalhydroxider/ jordalka-limetalhydroxider, alkalimetalcarbonater, alkalimetalsalte 5 af lavere carboxylsyrer eller tertiære aminer.
Som egnede baser kan eksempelvis nævnes; natriumhydroxid, kaliumhydroxid, calciumhydroxid, natriumcarbonat, kalium= carbonat, natriumacetat, kaliumacetat, pyridin, lutidin eller collidin. Anvender man til denne omsætning tertiære 10 aminer, kan disse samtidig fungere som opløsningsmidler.
Ved anvendelse af uorganiske baser gennemføres omsætningen fortrinsvis i nærværelse af dipolære, aprotiske opløsningsmidler, såsom dimethylformamid, N-methylacetamid, N-methylpyrrolidon, acetonitril, dimethylsulfoxid eller 15 hexamethylphosphorsyretriamid.
Ved denne eliminering er der fare for, at den primært danne- 15 14 de Δ -dobbeltbinding isoraeriseres til Δ -dobbeltbindingen, hvilket er kendt fra analoge elimineringer (J. Araer. Chem.
Soc., 78, 1956, 6347). For at undgå dette er det nødvendigt 20 at være opmærksom på den nøjagtige overholdelse af den optimale reaktionstemperatur og reaktionstid (som kan fastslås ved hjælp af forudgående forsøg)..
Faren for isomerisering er ikke til stede, når man gennemfører elimineringen under anvendelse af alkalimetalsalte af 25 lavere carboxylsyrer (fortrinsvis natriumacetat eller kali= umacetat) i dipolære, aprotiske opløsningsmidler ved en reaktionstemperatur fra -20°C til +40°C. Under disse betingelser bliver sulfonsyreresten overraskende ikke udskiftet med basens carboxylsyrerest, men elimineret under dannelse 30 af en Δ"^-dobbeltbinding.
145758 6
Om ønsket kan de opnåede ketaler på i og for sig kendt måde hydrolyseres ved behandling med vandige syrer. På den anden side er det imidlertid også muligt at anvende selve ketalerne som mellemprodukter til fremstilling af farmako-5 logisk virksomme steroider.
Det efterfølgende eksempel tjener til belysning af opfindelsen.
Eksempel a) En 2 liter Erlenmeyerkolhe, der indeholder 5Q0 ml af en 10 i 30 minutter ved 120°C i autoklav steriliseret næringsopløsning bestående af 3,0% glucose, 1,0% majsstøbevæske, 0,2%
NaN03, 0,1% KH2P04, 0,2% K2HP04, 0,05% MgSC>4, 0,002% FeSC>4 og o,05% KC1, podes med en lyofil kultur af Penicillium rai-strickii (ATCC 10490) og rystes i 72 timer ved 30°C på en 15 rotationsryster. Med 250 ml af denne forkultur podes derpå en 20 liter glasfermenteringsbeholder, som er fyldt med 15 ml af et ved 121°C og 1,1 ato steriliseret medium af samme sammensætning. Under tilsætning af "silicon SH" som anti-skummemiddel bliver der ved 29°C under luftning (10 liter 20 pr. minut), et tryk på 0,7 ato og omrøring (220 omdrejninger /minut) udviklet kim i 24 timer.
1,8 liter af kulturvæsken overføres under sterile betingelser til 26 liter af et som ovenfor anført steriliseret næringsmedium af samme sammensætning som dyrkningsmediet og 25 dyrkes under samme betingelser som forfermenteringskulturen. Efter 12 timer tilsættes 2 liter af en steriliseretr i nærværelse af vandig "Tween 80" finmalet suspension af 120 g nat.-18-methyl-4-østren-3,17-dion i destilleret vand, og kimdannelsen fortsættesi 145758 7
Forløbet af omdannelsen følges ved hjælp af tyndtlagskroma-tografisk analyse af methylisobutylketonekstrakter af fermenteringsprøver. Efter ca. 70 timers kontakttid er omdannelsen fuldstændig. Derefter frafiltreres svampemycelet, 5 og kulturvæsken ekstraheres to gange, hver gang med 20 liter methylisobutylketon. Parallelt dermed omrøres og ekstraheres det frafiltrerede mycelium flere gange med en blanding af methylisobutylketon, acetone og vand, indtil intet steroidmateriale længere kan påvises.
10 De organiske ekstraktopløsninger forenes og inddampes i vakuum til tørhed ved en badtemperatur på 50°C. Den brunkrystallinske rest vaskes flere gange med hexan til fjernelse af siliconeolien, tørres og omkrystalliseres til slut fra eddikeester efter behandling med aktivt carbon, hvorved 15 der opnås 97,3 g (76,5% af teoretisk! rent nat.-15a-hydroxy-18-methyl-4-østren-3,17-dion med smeltepunkt 175-177°C.
b) 32 g nat.-15a-hydroxy-18-methyl-4-østren-3,17-dion tilsættes i 240 ml methylenchlorid og 64 ml o-myresyreethyl= ester 96 g 2,2-dimethyl-l,3-propandiol og 320 mg p-toluen= 20 sulfonsyre, og der omrøres i 30 minutter under en nitrogen- strøm ved 50°C. Derpå fortyndes med ether, vaskes med natrium= hydrogencarbonatopløsning og vand, tørres og inddampes. Resten kromatograferes på silicagel, og der opnås 37 g nat.-15a-hydroxy-3,3—(2',2'-dimethyl-1',3'-propylendioxy)-18-25 . methyl-5- eller -5 (10)-østren-17-on soro olie.
c) 37 g nat.-15a-hydroxy-3,3-(2!,2!-dimethyl-1!,3'-propylen= dioxy)-18-methyl-5- eller -5(10}-østren-17-on tilsættes i 370 ml pyridin under iskøling 27,1 ml methansulfochlorid, og der efterrøres i 3 timer ved isbadtemperatur. Der indrøres 30 derpå i isvand, bundfaldet frasuges, vaskes med yand og optages derpå i methylenchlorid og tørres. Der opnås 40 g nat.-15a-mesyloxy-3,3—(2',2'-dimethyl-1',3'-propylendioxy)-18-methyl-5- eller -5(10)-østren-17-on som olie.
Claims (2)
145758 d) 35 g nat. -15ct-mesyloxy~3,3- (2 ',2 ! -dimethyl-1',3' -propylen= dioxy)-18-methyl-5- eller -5 (10l-østren-17-on omrøres i 350 ml i dimethylformamid med 105 g vandfrit natriumacetat i 20 timer ved stuetemperatur. Derpå indrøres det i isvand, 5 det udfældede bundfald frasuges, vaskes og optages i methylen= chlorid. Efter inddampning opnås 28,9 g råt nat.-3,3-(2',2 dimethyl-1',3'-propylendioxy)-18-methyl-5- eller -5(101,15-østradien-17-on. Paten tkray
10 Fremgangsmåde til fremstilling af 15-østren-3,17-dionderivater med den almene formel I 11 fj—l i hvori X betegner en oxogruppe, en alkylendioxygruppe med 2-6 carbonatomer eller en o-phenylendioxygruppe, Δ et med de 15 nabostillede carbonatomer ved hjælp af en dobbeltbinding og to enkeltbindinger forbundet C^-carbonatom og R1 en methylgruppe eller en ethylgruppe, kendetegnet ved, at man fermenterer et steroid med den almene formel IX 3*1 -’ (II)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK492177A DK145759C (da) | 1974-11-23 | 1977-11-04 | Fremgangsmaade til fremstilling af 15beta,16beta-methylen-oestren-3,17-dionderivater |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2456068 | 1974-11-23 | ||
| DE19742456068 DE2456068A1 (de) | 1974-11-23 | 1974-11-23 | Verfahren zur herstellung von oestren3,17-dion-derivaten |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK506075A DK506075A (da) | 1976-05-24 |
| DK145758B true DK145758B (da) | 1983-02-21 |
| DK145758C DK145758C (da) | 1983-08-15 |
Family
ID=5931850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK506075A DK145758C (da) | 1974-11-23 | 1975-11-11 | Fremgangsmaade til fremstilling af 15-oestren-3,17-dionderivater |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4036695A (da) |
| JP (1) | JPS6030517B2 (da) |
| BE (1) | BE835831A (da) |
| CH (1) | CH620225A5 (da) |
| DE (1) | DE2456068A1 (da) |
| DK (1) | DK145758C (da) |
| FR (1) | FR2291984A1 (da) |
| GB (1) | GB1536875A (da) |
| HU (1) | HU173395B (da) |
| NL (1) | NL7513614A (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1008820B (zh) * | 1985-05-10 | 1990-07-18 | 施林工业产权保护股份公司 | 17α-乙炔基-17β-羟基-18-甲基-4，15-雌甾二烯-3-酮的制备方法 |
| DE3710728A1 (de) * | 1987-03-31 | 1988-10-13 | Schering Ag | Verfahren zur herstellung von 17(alpha)-ethinyl-17ss-hydroxy-18-methyl-4,15-estradien-3-on und die neuen zwischenprodukte fuer dieses verfahren |
| JPS63195705U (da) * | 1987-06-04 | 1988-12-16 | ||
| HU227238B1 (en) | 2006-09-15 | 2010-12-28 | Richter Gedeon Nyrt | Process for obtaining selectively monohydroxylated 3,17-diketo steroid compounds, purification and separation thereof |
| DE102007027637A1 (de) | 2007-06-12 | 2008-12-18 | Bayer Schering Pharma Aktiengesellschaft | 17ß-Cyano-19-nor-androst-4-en-Derivat, dessen Verwendung und das Derivat enthaltende Arzneimittel |
| EP2354150A1 (en) * | 2010-02-09 | 2011-08-10 | Laboratoire Theramex | Process for the preparation of gestodene |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3214448A (en) * | 1962-07-27 | 1965-10-26 | American Cyanamid Co | 14alpha-hydroxyestrone and ester thereof |
| US3243355A (en) * | 1965-07-30 | 1966-03-29 | American Cyanamid Co | Method of hydroxylating 19-nor-androstenedione |
| US3517036A (en) * | 1966-11-15 | 1970-06-23 | Squibb & Sons Inc | Hydroxy,acyloxy and 11-keto-1,3,5(10),7-estratetraenes |
| DE2109555C3 (de) * | 1971-02-24 | 1980-10-30 | Schering Ag | Neue 15 a , 16 a -Methylensteroide, diese enthaltende Arzneimittel sowie Verfahren zu ihrei Herstellung |
| DE2334559A1 (de) * | 1973-07-04 | 1975-01-23 | Schering Ag | 15 alpha-sulfonyloxy-12 beta-hydroxypregnane und verfahren zu ihrer herstellung |
-
1974
- 1974-11-23 DE DE19742456068 patent/DE2456068A1/de not_active Ceased
-
1975
- 1975-11-11 DK DK506075A patent/DK145758C/da not_active IP Right Cessation
- 1975-11-18 CH CH1496075A patent/CH620225A5/de not_active IP Right Cessation
- 1975-11-19 US US05/633,415 patent/US4036695A/en not_active Expired - Lifetime
- 1975-11-21 HU HU75SCHE547A patent/HU173395B/hu not_active IP Right Cessation
- 1975-11-21 NL NL7513614A patent/NL7513614A/xx not_active Application Discontinuation
- 1975-11-21 BE BE162088A patent/BE835831A/xx not_active IP Right Cessation
- 1975-11-24 GB GB48189/75A patent/GB1536875A/en not_active Expired
- 1975-11-24 FR FR7535775A patent/FR2291984A1/fr active Granted
- 1975-11-25 JP JP50141056A patent/JPS6030517B2/ja not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5188693A (en) | 1976-08-03 |
| FR2291984B1 (da) | 1979-03-30 |
| BE835831A (fr) | 1976-05-21 |
| DK145758C (da) | 1983-08-15 |
| GB1536875A (en) | 1978-12-20 |
| DE2456068A1 (de) | 1976-08-12 |
| DK506075A (da) | 1976-05-24 |
| FR2291984A1 (fr) | 1976-06-18 |
| NL7513614A (nl) | 1976-05-25 |
| US4036695A (en) | 1977-07-19 |
| JPS6030517B2 (ja) | 1985-07-17 |
| HU173395B (hu) | 1979-04-28 |
| CH620225A5 (da) | 1980-11-14 |
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| PBP | Patent lapsed |