DE1250815B - Process for the production of 19-nor-steroids - Google Patents
Process for the production of 19-nor-steroidsInfo
- Publication number
- DE1250815B DE1250815B DENDAT1250815D DE1250815DA DE1250815B DE 1250815 B DE1250815 B DE 1250815B DE NDAT1250815 D DENDAT1250815 D DE NDAT1250815D DE 1250815D A DE1250815D A DE 1250815DA DE 1250815 B DE1250815 B DE 1250815B
- Authority
- DE
- Germany
- Prior art keywords
- hydroxy
- oxo
- known per
- androstene
- optionally
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 12
- 238000004519 manufacturing process Methods 0.000 title description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 239000007858 starting material Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910001385 heavy metal Inorganic materials 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000005644 Wolff-Kishner reduction reaction Methods 0.000 claims description 3
- 230000002378 acidificating Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000005755 formation reaction Methods 0.000 claims description 3
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 claims description 3
- 230000001590 oxidative Effects 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (N-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 3
- CPBZARXQRZTYGI-UHFFFAOYSA-N 3-cyclopentylpropylcyclohexane Chemical compound C1CCCCC1CCCC1CCCC1 CPBZARXQRZTYGI-UHFFFAOYSA-N 0.000 claims 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 claims 1
- 229960001566 methyltestosterone Drugs 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000009835 boiling Methods 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 10
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- -1 lead (IV) acetate Chemical compound 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000005712 crystallization Effects 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- AYJRCSIUFZENHW-UHFFFAOYSA-L Barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229960000583 Acetic Acid Drugs 0.000 description 5
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 5
- 230000001264 neutralization Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WGLPBDUCMAPZCE-UHFFFAOYSA-N trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000002211 ultraviolet spectrum Methods 0.000 description 4
- OVTZIJOGPKGLQV-BYZMTCBYSA-N (8S,9S,10R,13R,14S,17S)-17-ethyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene Chemical compound C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 OVTZIJOGPKGLQV-BYZMTCBYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N Decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N Diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N Manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N Potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 239000004133 Sodium thiosulphate Substances 0.000 description 2
- LEDMRZGFZIAGGB-UHFFFAOYSA-L Strontium carbonate Chemical compound [Sr+2].[O-]C([O-])=O LEDMRZGFZIAGGB-UHFFFAOYSA-L 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N Tert-Amyl alcohol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- 230000035969 Vmax Effects 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 229910000018 strontium carbonate Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- JWMFYGXQPXQEEM-WZBAXQLOSA-N (8S,9S,10S,13R,14S,17S)-17-ethyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 1
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- LCJRHAPPMIUHLH-UHFFFAOYSA-N 1-$l^{1}-azanylhexan-1-one Chemical compound [CH]CCCCC([N])=O LCJRHAPPMIUHLH-UHFFFAOYSA-N 0.000 description 1
- NVUUMOOKVFONOM-GPBSYSOESA-N 19-Norprogesterone Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 NVUUMOOKVFONOM-GPBSYSOESA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-Furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- 229940070021 ANABOLIC STEROIDS Drugs 0.000 description 1
- 229940030486 ANDROGENS Drugs 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N Benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XIIAYQZJNBULGD-LDHZKLTISA-N Cholestane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XIIAYQZJNBULGD-LDHZKLTISA-N 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N Cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N Cypionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- GUWSLQUAAYEZAF-UHFFFAOYSA-L Lead(II) acetate Chemical compound O1C(C)=O[Pb]21O=C(C)O2 GUWSLQUAAYEZAF-UHFFFAOYSA-L 0.000 description 1
- NPAGDVCDWIYMMC-IZPLOLCNSA-N Nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 1
- SOBYEUHIOKMSEB-NQCUKVFCSA-N OC[C@]12CCCCC1CC[C@H]1[C@@H]3CC[C@H](C=C)[C@]3(CC[C@H]21)C Chemical compound OC[C@]12CCCCC1CC[C@H]1[C@@H]3CC[C@H](C=C)[C@]3(CC[C@H]21)C SOBYEUHIOKMSEB-NQCUKVFCSA-N 0.000 description 1
- 238000006036 Oppenauer oxidation reaction Methods 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229940069002 Potassium Dichromate Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M Sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 240000006745 Valeriana officinalis Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- XHODMTAOVMFHQJ-UHFFFAOYSA-N aluminum;propan-2-ol Chemical compound [Al].CC(C)O XHODMTAOVMFHQJ-UHFFFAOYSA-N 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 150000001737 cardanolides Chemical class 0.000 description 1
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- AAUNBWYUJICUKP-UHFFFAOYSA-N hypoiodite Chemical compound I[O-] AAUNBWYUJICUKP-UHFFFAOYSA-N 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- 101700043839 lin-5 Proteins 0.000 description 1
- 150000002697 manganese compounds Chemical class 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 229960004719 nandrolone Drugs 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CKOOABJZYWLHMN-UHFFFAOYSA-N phenyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1=CC=CC=C1.C=1C=CC=CC=1C(=O)OC1=CC=CC=C1 CKOOABJZYWLHMN-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- INLFWQCRAJUDCR-LYLBMTSKSA-N spirostane Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 INLFWQCRAJUDCR-LYLBMTSKSA-N 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Description
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
Int. Cl.:Int. Cl .:
co,oco, o
lC07jlC07j
Deutsche Kl.: 12 ο - 25/0/4*- German class: 12 ο - 25/0/4 * -
Nummer: 1 250 815Number: 1 250 815
Aktenzeichen: C30444IVb/12oFile number: C30444IVb / 12o
Anmeldetag: 16. Juli 1963Filing date: July 16, 1963
Auslegetag: 28. September 1967Opening day: September 28, 1967
Gegenstand der vorliegenden Erfindung ist ein neues Verfahren zur Herstellung von 6-oxygenierten J5(10'-19-Nor-steroiden und deren 5,10-Epoxyden sowie von J5- bzw, J4-19-Nor-steroiden.The present invention relates to a new process for the production of 6-oxygenated J 5 (10 '-19-nor-steroids and their 5,10-epoxides, as well as J 5 - or J 4 -19-nor-steroids.
Das crfindungsgemäße Verfahren besteht darin, s daß man ein ld-19-Hydroxy-steroid, das gegebenenfalls geschützte Oxogruppen oder freie Oxogruppen trägt, letzterenfalls jedoch unter Vermeidung erhöhter Temperatur, mit einem oxydierenden Schwermctallacylat in An- oder Abwesenheit säurebindender Mittel umsetzt, das Reaktionsprodukt alkaliseh hydrolysiert und, falls erwünscht, in den erhaltenen Jäa0|-6-Hydroxy-19-nor-steroiden (II) die Hydroxygruppe in an sich bekannter Weise verestert oder veräthert oder mit Mitteln, die eine sekundäre Hydroxygruppe in eine Oxogruppe überführen, oxydiert und, wenn erwünscht, erhaltene 6-Hydroxy-, 6-Acyloxy-, 6-Alkoxy- oder 6-Ketoverbindungen (II, III oder TV) nach an sich bekannten Methoden in 5(10)-Stellung epoxydiert. Gegebenenfalls kann in erhaltenen 6-Hydroxy-5,10-epoxyden die 6-Hydroxygruppe in an sich bekannter Weise zur Oxogruppe oxydiert werden. Gegebenenfalls erhaltene J5ll0)-6-Oxo-19-nor-steroide (V) können auch nach Wolff—Kishner in l5l6)-19-Nor-steroidc umgewandelt und, falls erwünscht, nach Ausbildung einer freien 3-Oxogruppe, in _H-3-Oxo-19-nor-steroide übergeführt werden. Gegebenenfalls können in erhaltenen Verbindungen vorhandene Ketalgruppen in an sich ebenfalls bekannter Weise durch Einwirkung saurer Mittel einzeln oder gemeinsam hydrolysiert werden.The crfindungsgemäße method is s reacting a l d -19-hydroxy steroid, the optionally protected oxo groups or free oxo groups carrying, but the latter case is reacted while avoiding elevated temperature, with an oxidizing Schwermctallacylat in the presence or absence of acid-binding agents, the reaction product of alkali hydrolysed and, if desired, in the resulting J äa0 | -6-Hydroxy-19-nor-steroids (II) esterified or etherified the hydroxy group in a manner known per se or oxidized with agents which convert a secondary hydroxy group into an oxo group and, if desired, obtained 6-hydroxy, 6- Acyloxy, 6-alkoxy or 6-keto compounds (II, III or TV) are epoxidized in the 5 (10) position by methods known per se. If appropriate, the 6-hydroxy group in the 6-hydroxy-5,10-epoxides obtained can be oxidized to the oxo group in a manner known per se. Any I 50) -6-oxo-19-nor-steroids (V) obtained can also be converted according to Wolff-Kishner into 1516) -19-nor-steroids and, if desired, after formation of a free 3-oxo group, into _H -3-Oxo-19-nor-steroids are transferred. If appropriate, ketal groups present in the compounds obtained can be hydrolyzed individually or together in a manner likewise known per se by the action of acidic agents.
Die verfahrensgemäßen Umsetzungen sind am Beispiel der den Ring B darstellenden Partialformeln veranschaulicht :The implementations according to the method are based on the example of the partial formulas representing ring B. illustrates:
Verfahren zur Herstellung von 19-Nor-steroidenProcess for the production of 19-nor-steroids
Anmelder:Applicant:
CIBA Aktiengesellschaft, Basel (Schweiz)CIBA Aktiengesellschaft, Basel (Switzerland)
Vertreter:Representative:
Dr.-Ing. Dr. jur. F. Redies,Dr.-Ing. Dr. jur. F. Redies,
Dr. rer. nat. B. Redies und Dr. rer. nat. D. Türk,Dr. rer. nat. B. Redies and Dr. rer. nat. D. Turk,
Patentanwälte,Patent attorneys,
Düsseldorf-Benrath, Erich-Ollenhauer-Str. 7Düsseldorf-Benrath, Erich-Ollenhauer-Str. 7th
Als Erfinder benannt:Named as inventor:
Dr. Oskar Jeger,Dr. Oskar Jeger,
Dr. Kurt Schaffner, Zürich (Schweiz)Dr. Kurt Schaffner, Zurich (Switzerland)
Beanspruchte Priorität:Claimed priority:
Schweiz vom 18. Juli 1962 (8677)Switzerland of July 18, 1962 (8677)
R =R =
OH xORiOH x ORi
oder =0,or = 0,
CH2OHCH2OH
Ri = Acyl- oder Kohlen vvasserstoffrestRi = acyl or carbon hydrogen radical
Als oxydativ wirkende Schwcrmetallacylate finden insbesondere Acylate des vierwertigen Bleis Verwendung, deren Säurekomponente sich von einer niederaliphatischen, cycloaliphatischen, araliphatischen oder aromatischen Säure ableitet, wieBlei(IV)-acetat, ferner -propionat, -trimethylacetat, -hexahydrobenzoat, -phenylacetat oder -benzoat; weiter Silber- oder Quecksüberacylate.Acylates of tetravalent lead are used in particular as oxidative heavy metal acylates, whose acid component differs from a lower aliphatic, cycloaliphatic, araliphatic or aromatic acid, such as lead (IV) acetate, also propionate, trimethylacetate, hexahydrobenzoate, phenyl acetate or benzoate; further silver or mercury acylates.
Die Umsetzung mit den obengenannten Schwermetallacylaten erfolgt vorzugsweise durch Erwärmen der Ausgangsstoffe in einem inerten Lösungsmittel, z. B. in aliphatischen, cycloaliphatischen und/oder aromatischen Kohlenwasserstoffen, wie Hexan, Heptan, Cyclohcxan, Methylcyclohexan oder Benzol gegebenenfalls unter Zugabc von schwachen anorganischen oder organischen Basen, z. B. Erdalkalicarbonaten, wie Calcium-, Barium- oder Strontiumcarbonat, oder tertiären organischen Basen, wieThe reaction with the above heavy metal acylates takes place preferably by heating the starting materials in an inert solvent, z. B. in aliphatic, cycloaliphatic and / or aromatic hydrocarbons, such as hexane, heptane, Cyclohexane, methylcyclohexane or benzene, optionally with the addition of weak inorganic compounds or organic bases, e.g. B. alkaline earth carbonates, such as calcium, barium or strontium carbonate, or tertiary organic bases, such as
709 649/460709 649/460
Pyridin oder Collidin. Es wird mit Vorteil bei Temperaturen über 60° C gearbeitet, vorzugsweise beim Siedepunkt des jeweiligen Lösungsmittels. Die Reaktionsdauer ist im allgemeinen von der Reaktionstemperatur abhängig und beträgt im Durchschnitt 2 bis 20 Stunden.Pyridine or collidine. It will be beneficial at Temperatures above 60 ° C worked, preferably at the boiling point of the respective solvent. the The reaction time is generally dependent on the reaction temperature and is on average 2 to 20 hours.
Die darauffolgende alkalische Hydrolyse des Reaktionsproduktes erfolgt z. B. durch Umsetzung mit wäßrig-alkoholischen Lösungen von Alkalioder Erdalkalihydrogencarbonaten, -carbonaten oder -hydroxyden, wie Natrium- oder Kaliumhydrogencarbonat, Natrium-, Kalium-, Barium- oder Strontiumcarbonat oder -hydroxyd, gegebenenfalls bei erhöhter Temperatur.The subsequent alkaline hydrolysis of the reaction product takes place, for. B. through implementation with aqueous-alcoholic solutions of alkali or alkaline earth hydrogen carbonates, carbonates or hydroxides, such as sodium or potassium hydrogen carbonate, sodium, potassium, barium or strontium carbonate or hydroxide, optionally at elevated temperature.
In den erhaltenen zl5<10>-6-Hydroxy-19-nor-steroiden kann die Hydroxylgruppe in an sich bekannter Weise verestert oder veräthert werden. Als veresternde Mittel eignen sich z. B. Anhydride oder Halogenide von aliphatischen, cycloaliphatischen, araliphatischen oder aromatischen Carbon- oder Sulfonsäuren, wie Essig-, Propion-, Trifluoressig-, Hexahydrobenzoe-, Phenylessig-, Benzoe-, Methansulfon- oder p-Toluolsulfonsäure. Als Verätherungsmittel kommen z. B. reaktionsfähig veresterte aliphatische oder araliphatische Alkohole in Frage, insbesondere Halogenwasserstoffsäureester oder Sulfonsäureester, oder Tetrahydropyran. Die Veresterung oder Verätherung kann gegebenenfalls in Gegenwart von Basen, wie Pyridin oder Natriumacetat, durchgeführt werden.In the zl 5 10 -6-hydroxy-19-nor-steroids obtained, the hydroxyl group can be esterified or etherified in a manner known per se. As esterifying agents are such. B. anhydrides or halides of aliphatic, cycloaliphatic, araliphatic or aromatic carboxylic or sulphonic acids, such as acetic, propionic, trifluoroacetic, hexahydrobenzoic, phenylacetic, benzoic, methanesulphonic or p-toluenesulphonic acid. As an ethereal agent z. B. reactive esterified aliphatic or araliphatic alcohols in question, in particular hydrohalic acid esters or sulfonic acid esters, or tetrahydropyran. The esterification or etherification can, if appropriate, be carried out in the presence of bases such as pyridine or sodium acetate.
Die Umwandlung der verfahrensgemäß erhältlichen ^5<10>-6-Hydroxy-steroide in die entsprechenden obengenannten 6-Oxoverbindungen erfolgt in an sich bekannter Weise z. B. durch Einwirkung von Verbindungen des sechswertigen Chroms, wie Chrom(VI)-oxyd, in Pyridin oder in Schwefelsäure oder Kaliumbichromat, ferner von Manganverbindungen, wie Mangandioxyd, oder unter den Bedingungen einer Oppenauer-Oxydation, d. h. durch Umsetzung mit überschüssigen aliphatischen, alicyclischen oder araliphatischen Ketonen, wie Aceton, Cyclohexanon oder Benzophenon, in Gegenwart von Metallalkoholate^ insbesondere von Alkalimetall- oder Aluminiumverbindungen niederaliphatischer Alkohole, wie Isopropanol, tert.-Butanol oder tert.-Amylalkohol. Anschließend oder gleichzeitig kann eine gegebenenfalls vorhandene Sauerstoffunktion in Stellung 3 in eine freie Oxogruppe umgewandelt werden.The conversion of the ^ 5 < 10 > -6-hydroxy steroids obtainable according to the process into the corresponding above-mentioned 6-oxo compounds takes place in a manner known per se, for. B. by the action of compounds of hexavalent chromium, such as chromium (VI) oxide, in pyridine or in sulfuric acid or potassium dichromate, also of manganese compounds such as manganese dioxide, or under the conditions of an Oppenauer oxidation, ie by reaction with excess aliphatic, alicyclic or araliphatic ketones, such as acetone, cyclohexanone or benzophenone, in the presence of metal alcoholates ^ in particular of alkali metal or aluminum compounds of lower aliphatic alcohols such as isopropanol, tert-butanol or tert-amyl alcohol. Subsequently or at the same time, any oxygen function present in position 3 can be converted into a free oxo group.
Aus den Verfahrensprodukten, die in Stellung 6 des Steroidgerüstes eine Oxogruppe aufweisen, können nach Wolff — Kishner durch Behandlung mit Hydrazin und Alkalimetallhydroxyden bei erhöhter Temperatur, unter Eliminierung der 6-Oxogruppe und gleichzeitiger Verschiebung der Doppelbindung J5((M9-Nor-steroide gebildetwerden, die frei von unerwünschten Isomeren sind. Erhaltene Verbindungen, die in Stellung 3 durch eine Saucrstoffunktion, z. B. eine freie oder veresterte Hydroxygruppe oder eine ketalisierte Oxogruppe, substituiert sind, können nach Ausbildung einer freien 3-Oxogruppe in bekannte, pharmakologisch wirksame /J4-3-Oxo-19-nor-steroide übergeführt werden.According to Wolff-Kishner, the products of the process which have an oxo group in position 6 of the steroid structure can be formed by treatment with hydrazine and alkali metal hydroxides at elevated temperature, with elimination of the 6-oxo group and simultaneous displacement of the double bond J 5 (( M9-nor-steroids Compounds obtained which are substituted in position 3 by an oxygen function, e.g. a free or esterified hydroxyl group or a ketalized oxo group, can after formation of a free 3-oxo group in known, pharmacologically active / J 4 -3-oxo-19-nor-steroids are transferred.
In den Verfahrensprodukten, die eine J5<10>-Doppelbindung enthalten, kann diese, ebenfalls in an sich bekannter Weise, z. B. durch Behandlung mit Persäuren, wie Benzopersäure oder Phthalmonopersäure, epoxydiert werden, wodurch man zu einem neuen interessanten Typus von 19-Nor-verbindungen, nämlich den 5,10-Oxido-6-oxo- oder -6-hydroxysteroiden sowie den Estern oder Äthern der letzteren, gelangt.In the products of the process which contain a J 5 < 10 > double bond, this can, likewise in a manner known per se, e.g. B. by treatment with peracids such as benzoperic acid or phthalmonoperic acid, which leads to a new interesting type of 19-nor compounds, namely the 5,10-oxido-6-oxo- or -6-hydroxysteroids and the esters or Ethers of the latter.
Enthalten die Verfahrensprodukte Ketalgruppen,If the process products contain ketal groups,
z. B. in Stellung 3 und/oder in Stellung 17 oder 20, so können diese durch Einwirkung saurer Mittel einzeln oder gemeinsam hydrolysiert werden.z. B. in position 3 and / or in position 17 or 20, so these can be hydrolyzed individually or together by the action of acidic agents.
Als Ausgangsstoffe für das vorliegende VerfahrenAs starting materials for the present process
ίο eignen sich J5-19-Hydroxy-steroide, z. B. Androstan-, Pregnan-, Cholan-, Cholestan-, Spirostan- und Cardanolidreihe. Sie können in einer oder mehreren der Stellungen 2, 3, 4, 7,11, 12,14,15, 16, 17, 20, 21 und in der Seitenkette weitere Substituenten, z. B.ίο are J 5 -19-hydroxy steroids, z. B. Androstan, Pregnan, Cholan, Cholestan, Spirostan and Cardanolide series. You can in one or more of the positions 2, 3, 4, 7, 11, 12, 14, 15, 16, 17, 20, 21 and in the side chain further substituents, for. B.
Alkylgruppen, wie Methylgruppen, Halogenatome, funktionell abgewandelte, d. h. veresterte oder verätherte Hydroxygruppen und/oder freie, insbesondere jedoch geschützte, d. h. zum Beispiel ketalisierte oder in Form ihrer Enolderivate vorliegende Oxogruppen, aufweisen. Die Verbindungen können ebenfalls eine oder mehrere Doppelbindungen, insbesondere im Ring D und in der Seitenkette, und/oder Oxidogruppen enthalten.Alkyl groups such as methyl groups, halogen atoms, functionally modified, d. H. esterified or etherified Hydroxy groups and / or free, but especially protected, d. H. for example ketalized or oxo groups present in the form of their enol derivatives. The connections can also one or more double bonds, especially in ring D and in the side chain, and / or contain oxo groups.
Besonders wichtige Ausgangsstoffe sind J5-19-Hydroxy-androstene und -pregnene, z. B. /I5-17-Oxo-19-hydroxy-androsten, J5-30-Acyloxy-17-oxo-19-hydroxy-androstene und deren 17-Äthylendioxyverbindungen, J5-3/3,17/J-DIaCyIoXy-19-hydroxy-androstene, J5-3,17-Dioxo-19-hydroxy-androsten und dessen 3,17-Bisäthylendioxyverbindung, J5-3/?,17/?-Diacyloxy-17a-alkyl- und -17a-alkeny]-19-hydroxyandrostene, wie 3β,Πβ - Diacyloxy - 17a - methyl-, -Ha-äthyl-, -17a-vinyl- oder -Ua-allyl-^-hydroxyandrostene und die entsprechenden 3-Oxo-17/i-acyloxyverbindungen oder ihre 3-Äthylenketale, ferner zl5-3,20-Dioxo-19-hydroxy-pregnen und dessen 3,20 ■ Bisäthylendioxyverbindung, Δ 5 - 3/3 - Acyloxy-19-hydroxy-20-oxo-pregnene und deren Äthylendioxyverbindungen, Δ5 - 3ß,20ß - Diacyloxy -19 - hydroxy-pregnene, J5-3,20-Bisäthylendioxy-16a-methyl-19-hydroxy-pregnen, J5-30,11 a,20/?-Triacyloxy-Particularly important starting materials are J 5 -19-Hydroxy-androstene and -pregnene, z. B. / I 5 -17-oxo-19-hydroxy-androstene, J 5 -30-acyloxy-17-oxo-19-hydroxy-androstene and their 17-ethylenedioxy compounds, J 5 -3 / 3.17 / J-DIaCyIoXy -19-hydroxy-androstene, J 5 -3,17-dioxo-19-hydroxy-androstene and its 3,17-bisethylenedioxy compound, J5-3 / ?, 17 /? - diacyloxy-17a-alkyl- and -17a-alkeny ] -19-hydroxyandrostenes, such as 3β, Πβ - diacyloxy-17a-methyl-, -Ha-ethyl-, -17a-vinyl- or -Ua-allyl- ^ - hydroxyandrostenes and the corresponding 3-oxo-17 / i-acyloxy compounds or their 3-ethylene ketals, also zl 5 -3,20-dioxo-19-hydroxy-pregnen and its 3.20 ■ bisäthylendioxyverbindungen, Δ 5 - 3/3 - acyloxy-19-hydroxy-20-oxo-pregnene and their ethylenedioxy compounds , Δ 5 - 3ß, 20ß - diacyloxy -19 - hydroxy-pregnene, J 5 -3,20-bisäthylenedioxy-16a-methyl-19-hydroxy-pregnen, J5-30,11 a, 20 /? - triacyloxy-
19-hydroxy-pregnene und zls-3,20-Bisäthylendioxy-Ha- oder -ll/J-acyloxy-^-hydroxy-pregnene.19-hydroxy-pregnene and zl s -3,20-bisäthylendioxy-Ha- or -II / J-acyloxy - ^ - hydroxy-pregnene.
Die obengenannten Ausgangsstoffe können z. B.The above starting materials can, for. B.
durch Realisierung von J4-3-Oxo-19-acyloxy-steroiden und nachfolgende basische Hydrolyse der 19-Acyloxygruppe oder vorteilhaft auch nach den in den belgischen Patentschriften 606 179, 606 180, 606 181 und 606 182 angegebenen Verfahren hergestellt werden. Diese bestehen z. B. darin, daß man 5a-Halogen-, insbesondere 5a-Brom-6/?,19-oxidosteroide oder J4-3-Oxo-6/9,19-oxido-steroide mit reduzierenden Mitteln, z. B. mit Zink in Eisessig, behandelt und die gebildeten J5-19-Hydroxy- bzw. J5-3-Oxo-19-hydroxyverbindungen isoliert.by realizing J 4 -3-oxo-19-acyloxy-steroids and subsequent basic hydrolysis of the 19-acyloxy group or, advantageously, also by the processes given in Belgian patents 606 179, 606 180, 606 181 and 606 182. These consist e.g. B. in that one 5a-halogen, especially 5a-bromo-6 / ?, 19-oxidosteroids or J 4 -3-oxo-6 / 9,19-oxido-steroids with reducing agents, e.g. B. treated with zinc in glacial acetic acid and isolated the J 5 -19-hydroxy or J 5 -3-oxo-19-hydroxy compounds formed.
In den obengenannten Estern bedeuten die Säurereste, insbesondere solche von aliphatischen, cycloaliphatischen, araliphatischen, aromatischen und heterocyclischen Carbonsäuren, vorzugsweise solche mit 1 bis 15 Kohlenstoffatomen, wie Ameisen-, Essig-, Trifluoressig-, Propion-, Butter-, Valerian-, Trimethylessig-, Capron-, önanth-, Decan-, Hexahydrobenzoe-, Cyclopentylpropion-, Phenylpropion-, Benzoe- oder Furancarbonsäure.In the above-mentioned esters, the acid radicals, in particular those of aliphatic, cycloaliphatic, araliphatic, aromatic and heterocyclic carboxylic acids, preferably those with 1 to 15 carbon atoms, such as ants, vinegar, trifluoroacetic, propion, butter, valerian, Trimethyl acetic, capron, oenanth, decane, hexahydrobenzoic, Cyclopentylpropionic, phenylpropionic, benzoic or furancarboxylic acid.
Von den erhaltenen J4-3-Oxo-19-nor-steroiden finden insbesondere Vertreter der Androstan- und Pregnanreihe, wie z. B. 19-Nor-testosteron und seine in Stellung 17 durch gesättigte oder ungesättigteOf the J 4 -3-oxo-19-nor-steroids obtained, representatives of the androstane and pregnane series, such as, for. B. 19-Nor-testosterone and its in position 17 by saturated or unsaturated
Kohlenwasserstoffreste substituierten Derivate, sowie dieser Verbindungen oder 19-Nor-progesteron und seine 17-Acyloxyderivate als Anabolika, Androgene, Progestativa oder ovulationshemmende Mittel Verwendung. Hydrocarbon radicals substituted derivatives, as well as these compounds or 19-nor-progesterone and its 17-acyloxy derivatives as anabolic steroids, androgens, Progestative or anti-ovulation agent use.
Verfahrensprodukte, die eine 15'l0>-3,6-Dioxogruppierung aufweisen und der 17/?-Hydroxy-androstanreihe angehören, sind ebenfalls nach der britischen Patentschrift 893 450 biologisch wirksam.Process products which have a 1 5 'l0> -3,6-Dioxogruppierung and 17 /? - hydroxy-androstane belong, are biologically active also by British Patent Specification 893,450.
Die nachfolgenden Beispiele erläutern das erfindungsgemäße Verfahren. Die Temperaturen sind in Celsiusgraden angegeben.The following examples explain the process according to the invention. The temperatures are in Degrees Celsius.
3,25 g BIei(VI)-acetat werden 21Iz Stunden im Hochvakuum bei Zimmertemperatur getrocknet und dann mit 3,25 g Calciumcarbonat in 175 ml absolutem Benzol kurz auf Siedetemperatur erhitzt. Nach dem Abkühlen gibt man 3,25 g J5-3,I7-Bisäthylendioxy-19-hydroxy-androsten in festem Zustand zu und kocht das Gemisch 6 Stunden unter Rühren. Das Reaktionsgemisch wird über Nacht bei Zimmertemperatur stehengelassen und dann wie üblich aufgearbeitet. Das resultierende öl (3,5 g) ist nach Dünnschichtchromatogramm [Fließmittel Benzol— Methanol (9:1); Kieselgel G »Merck«] einheitlich. IR-Spektrum (CHCb): vmax = 1725, 1245 cm-1.3.25 g biei (VI) acetate are heated for 2 hours 1 Iz in a high vacuum dried at room temperature and then treated with 3.25 g calcium carbonate in 175 ml of absolute benzene briefly to boiling temperature. After cooling, 3.25 g of I 5 -3,17-bisäthylenedioxy-19-hydroxy-androstene in the solid state are added and the mixture is boiled for 6 hours while stirring. The reaction mixture is left to stand overnight at room temperature and then worked up as usual. The resulting oil (3.5 g) is according to thin-layer chromatogram [eluent benzene - methanol (9: 1); Silica gel G "Merck"] uniform. IR spectrum (CHCb): vmax = 1725, 1245 cm- 1 .
Die Hydrolyse des obigen Rohproduktes in 250 ml 5%iger methanolischer Kaliumhydroxydlösung bei Siedetemperatur während 1 Stunde gibt 3,35 g Kristalle, die man in Ätherlösung durch basisches Aluminiumoxyd (Aktivität III) filtriert. Man erhält so nach einmaliger Kristallisation aus Aceton— Petroläther 2,71 g J5<10>-3,17-Diäthylendioxy-6f-hydroxy-19-nor-androsten vom F. 150 bis 152°. Ein dreimal umkristallisiertes Analysenpräparat schmilzt konstant bei 157 bis 158°. [a]c = +73° (c = 0,92). IR-Spektrum (CHCb): vmax = 3610 cm1.The hydrolysis of the above crude product in 250 ml of 5% strength methanolic potassium hydroxide solution at boiling temperature for 1 hour gives 3.35 g of crystals, which are filtered through basic aluminum oxide (activity III) in ethereal solution. After a single crystallization from acetone petroleum ether, 2.71 g of I 5 10 -3,17-diethylenedioxy-6f-hydroxy-19-nor-androstene with a melting point of 150 to 152 ° are obtained. An analytical preparation recrystallized three times melts constantly at 157 to 158 °. [a] c = + 73 ° (c = 0.92). IR spectrum (CHCb): v max = 3610 cm 1 .
Das als Ausgangsstoff verwendete Jä-3,17-Bisäthylendioxy-19-hydroxy-androsten kann wie folgt hergestellt werden: The J ä -3,17-Bisäthylendioxy-19-hydroxy-androsten used as starting material can be prepared as follows:
8,6 g J4 - 3,17 - Dioxo -19 - hydroxy - androsten werden in 100 ml Acetanhydrid-Pyridin-(1 : I)-Gemisch über Nacht bei Zimmertemperatur acetyliert. Die Reaktionslösung wird darauf im Vakuum eingedampft und in Benzollösung durch neutrales Aluminiur.ioxyd (Aktivität II) filtriert.8.6 g of I 4 - 3.17 - dioxo-19 - hydroxy - androstene are acetylated in 100 ml of acetic anhydride / pyridine (1: I) mixture overnight at room temperature. The reaction solution is then evaporated in vacuo and filtered through neutral aluminum oxide (activity II) in benzene solution.
Das resultierende ölige O-Acetylderivat wird in 500 ml Benzol und 50 ml Äthylenglykol in Gegenwart von 500 mg p-Toluolsulfonsäure im Wasserabscheider unter Rühren in der Siedehitze ketalisiert. Nach 22stündiger Reaktionsdauer wird das abgekühlte Gemisch auf Eis gegossen, mit Äther extrahiert und die organische Phase mit Natriumhydrogencarbonatlösung und viel Wasser gewaschen.The resulting oily O-acetyl derivative is in 500 ml of benzene and 50 ml of ethylene glycol in the presence of 500 mg of p-toluenesulfonic acid in a water separator ketalized with stirring at the boiling point. After a reaction time of 22 hours, the cooled Poured mixture onto ice, extracted with ether and the organic phase with sodium hydrogen carbonate solution and washed plenty of water.
Man erhält ein öliges Rohprodukt, das direkt in 400 ml 5%igcr methanolischer Kaliumhydroxydlösung bei Siedetemperatur hydrolysiert wird. Nach 1 Stunde tropft man der heißen Lösung bis zum Kristallisationsbeginn Wasser zu. Die anfallenden Kristalle werden in Essigesterlösung durch basisches Aluminiumoxyd (Aktivität II) filtriert. Nach einmaliger Kristallisation des Filterrückstandes aus Aceton—Petroläther erhält man 6,8 g ..I5-3,17-Bisäthylendioxy-19-hydroxy-androsten vom F. 199 bis 200°. [α]β = -59° (c = 1,20). IR-Spektrum(CHCb):An oily crude product is obtained which is hydrolyzed directly in 400 ml of 5% strength methanolic potassium hydroxide solution at the boiling point. After 1 hour, water is added dropwise to the hot solution until crystallization begins. The crystals obtained are filtered through basic aluminum oxide (activity II) in ethyl acetate solution. After a single crystallization of the filter residue from acetone-petroleum ether, 6.8 g of .I 5 -3,17-bisäthylenedioxy-19-hydroxy-androstene with a melting point of 199 to 200 ° are obtained. [α] β = -59 ° (c = 1.20). IR spectrum (CHCb):
αχ — etwa 3600 cm-1. αχ - about 3600 cm- 1 .
Zu einer kurz aufgekochten Suspension von 3,0 g vorgetrocknetem Blci(IV)-acetat und 2,0 g Bariumcarbonat in 150 ml Cyclohexan werden 2,0 g Δ5 - Ιβ,Πβ - Diacetoxy -19 - hydroxy · androsten vom F. 148 bis 149° zugegeben und das Reaktionsgemisch unter Rühren während 8 Stunden am Rückfluß gekocht. Nach Abkühlen wird von anorganischen Anteilen abfiltriert, die Lösung im Vakuum eingedampft, der erhaltene Rückstand ohne Reinigung in 100 ml Methanol-Wasser-(3 : 1)-Gemisch gelöst und nach Zugabe von 2,0 g Kaliumcarbonat 2 Stunden am Rückfluß gekocht. Das durch Ausfällen mit Wasser erhaltene rohe 15<*°>-3/?,6,l7/J-Trihydroxy-19-nor-androsten (1,40 g) wird in 50 ml Aceton gelöst und während 1 Stunde bei 0° mit 2 ml 8 n-Chrom(VI)-oxydlösung in Schwefelsäure oxydiert. Nach der Aufarbeitung und anschließender Kristallisation aus Aceton—Petroläther werden 980 mg /J5<l0'-3,6,17-Trioxo-19-nor-androsten vom F. 163°, [α}%* = +219° (c = 0,63), erhalten.To a briefly boiled suspension of 3.0 g of predried Blci (IV) acetate and 2.0 g of barium carbonate in 150 ml of cyclohexane, 2.0 g of Δ 5 - Ιβ, Πβ - diacetoxy -19 - hydroxydrosten from F. 148 to 149 ° were added and the reaction mixture was refluxed for 8 hours while stirring. After cooling, inorganic components are filtered off, the solution is evaporated in vacuo, the residue obtained is dissolved in 100 ml of methanol-water (3: 1) mixture without purification and, after the addition of 2.0 g of potassium carbonate, refluxed for 2 hours. The crude 1 5 <* °> -3 / ?, 6, l7 / J-trihydroxy-19-nor-androstene (1.40 g) obtained by precipitation with water is dissolved in 50 ml of acetone and kept at 0 ° for 1 hour oxidized with 2 ml of 8 n-chromium (VI) oxide solution in sulfuric acid. After working up and subsequent crystallization from acetone-petroleum ether, 980 mg / J 5 < 10 '-3,6,17-trioxo-19-nor-androstene with a temperature of 163 °, [α}% * = + 219 ° (c = 0.63).
Die analoge Behandlung von J5-3/?,20/?-Diacetoxy-19-hydroxy-pregnen liefert in etwa 50%iger Ausbeute das /!5<'°>-3,6,20-Trioxo-19-nor-pregnen. UV-Spektrum: kmax 249 πΐμ (e = 10 000).The analogous treatment of J 5 -3 / ?, 20 /? - Diacetoxy-19-hydroxy-pregnen gives the /! 5 <'°> -3,6,20-trioxo-19-nor-pregnen. UV spectrum: kmax 249 πΐμ (e = 10 000).
2,715 g /j5<i°)-3,17-Bisäthylendioxy-6-hydroxy-19-nor-androsten werden in 46 ml einer Chloroformlösung eingetragen, die 2,37 g Benzopersäure enthält, und über Nacht bei 4° gehalten. Dann wird das Reaktionsgemisch mit Äther verdünnt, auf Eis gegossen und die organische Phase nacheinander mit Kaliumiodid- und Natriumthiosulfatlösung, Wasser, Natriumhydrogencarbonatlösung und wieder Wasser gewaschen. Man erhält ein Rohprodukt, das an neutralem Aluminiumoxyd (Aktivität III) chromatographiert wird, wobei man mit Benzol und Benzol-Äther-(1 : 1)-Gemisch 1,763 g 3,17-Bisäthylendioxy-5,10-oxido-6-hydroxy-19-nor-androstan eluiert, das nach Umlösen aus Aceton—Petroläther konstant bei 133° schmilzt (1,336 g). [a]o = +12° (c = 1,33). IR-Spektrum (CHCb): vmax = 3580cm"1.2.715 g / j5 <1 °) -3,17-bisäthylenedioxy-6-hydroxy-19-nor-androstene are introduced into 46 ml of a chloroform solution containing 2.37 g of benzoperic acid and kept at 4 ° overnight. The reaction mixture is then diluted with ether, poured onto ice and the organic phase is washed successively with potassium iodide and sodium thiosulphate solution, water, sodium hydrogen carbonate solution and water again. A crude product is obtained which is chromatographed on neutral aluminum oxide (activity III), 1.763 g of 3,17-bisäthylenedioxy-5,10-oxido-6-hydroxy- 19-nor-androstane elutes which, after being redissolved from acetone-petroleum ether, melts constantly at 133 ° (1.336 g). [a] o = + 12 ° (c = 1.33). IR spectrum (CHCb): v max = 3580cm " 1 .
245mg 3,17-Bisäthylendioxy-5,10-oxido-6-hydroxy-19-nor-androstan werden in wenig Pyridin gelöst und zu einer Aufschlämmung von 250 mg Chrom(VI)-oxyd in 1 ml Pyridin getropft. Nach Stehenlassen über Nacht bei Zimmertemperatur wird wie üblich aufgearbeitet und 227 mg 3,17-Bisäthylendioxy - 5,10 - oxido - 6 - oxo -19 - nor - androstan erhalten, das nach zweimaliger Kristallisation aus Aceton—Petroläther bei 137 bis 138° schmilzt; [a]o = -94° (c = 1,14). IR-Spektrum (CHCb): vmax = 1700 cm-».245 mg of 3,17-bisäthylenedioxy-5,10-oxido-6-hydroxy-19-nor-androstane are dissolved in a little pyridine and added dropwise to a suspension of 250 mg of chromium (VI) oxide in 1 ml of pyridine. After standing overnight at room temperature, the mixture is worked up as usual and 227 mg of 3,17-bisäthylenedioxy-5,10-oxido-6-oxo-19-nor-androstane are obtained which, after crystallizing twice from acetone-petroleum ether, melts at 137 ° to 138 ° ; [a] o = -94 ° (c = 1.14). IR spectrum (CHCb): vmax = 1700 cm- ».
200mg . 15<10>-3,17-BisäthyIendioxy-6-hydroxy-19-nor-androsten werden in 40 ml absolutem Benzol und 4 ml absolutem Aceton gelöst und mit 500 mg Aluminiumisopropylat 16 Stunden unter Rühren am Rückfluß gekocht. Nach der üblichen Aufarbeitungerhält man 197 mg kristallines Rohprodukt, das in Benzol-Äther-(9 : 1)-Lösung durch basisches200mg. 1 5 10 -3,17-BisäthyIendioxy-6-hydroxy-19-nor-androsten are dissolved in 40 ml of absolute benzene and 4 ml of absolute acetone and refluxed with 500 mg of aluminum isopropoxide for 16 hours while stirring. After the usual work-up, 197 mg of crystalline crude product are obtained, which in benzene-ether (9: 1) solution by basic
Aluminiumoxyd (Aktivität H) filtriert wird. Man isoliert so 160mg JS(l0>-3,17-Bisäthylendioxy-6-oxo-19-nor-androsten, das nach zweimaliger Kristallisation aus Aceton—Petroläther konstant bei 178 bis .180° schmilzt. [«]„ = +43° (c = 0,94). IR-Spektrum (CHCl3): vmax = 1657, 1619 cm-'. UV-Spektrum: lm«x — 249 tu μ (e = U. 900).Aluminum oxide (activity H) is filtered. 160 mg of J S (10 > -3,17-bisäthylenedioxy-6-oxo-19-nor-androstene are isolated in this way, which, after crystallizing twice from acetone-petroleum ether, melts constantly at 178 to 180 °. [«]„ = +43 ° (c = 0.94). IR spectrum (CHCl 3 ): v max = 1657, 1619 cm- '. UV spectrum: 1 m «x - 249 tu µ (e = U. 900).
Eine Lösung von 470 mg /l5(10)-3,17-Bisäthylendioxy-6-oxo-l 9-nor-androsten in 15 ml Essigsäure, 15 ml Methanol und 7 Tropfen Wasser wird 1 Stunde auf 60° erwärmt. Es resultieren 490mg eines amorphen Rohproduktes, das durch Filtration an neutralem Aluminiumoxyd (Aktivität III) in Benzol-Äther-(1:1)-Lösung gereinigt wird (406 mg Kristalle). Das so erhaltene z.1r'<l0)-3-Äthylendioxy-6,l7-dioxo-l9-norandrosten schmilzt nach dreimaliger Kristallisation aus Aceton—Petroläther bei 189 bis 190°. [a]0 = +167° (c = 0,63). 1R-Spektrum (CHCl3): = 1736, 1660, 1620cm-1. UV-Spektrum: = 249ΐημ(ί = Π300).A solution of 470 mg / l 5 (10) -3,17-bisäthylenedioxy-6-oxo-l 9-nor-androstene in 15 ml acetic acid, 15 ml methanol and 7 drops of water is heated to 60 ° for 1 hour. 490 mg of an amorphous crude product result, which is purified by filtration on neutral aluminum oxide (activity III) in benzene-ether (1: 1) solution (406 mg crystals). The resulting z.1 r '<l0) -3-ethylenedioxy-6, l7-dioxo-l9-Nora Drosten melts after three crystallization from acetone-petroleum ether at 189 to 190 °. [a] 0 = + 167 ° (c = 0.63). 1R spectrum (CHCl 3 ): = 1736, 1660, 1620cm- 1 . UV spectrum: = 249ΐημ (ί = Π300).
250 mg J5<10>-3-Äthylendioxy-6,I7-dioxo-19-norandrosten werden in 10 ml Eisessig 1 Stunde auf Siedetemperatur erhitzt und darauf im Vakuum eingedampft. Chromatographie an neutralem Aluminiumoxyd (Aktivität III) ergibt mit Benzol und Benzol - Äther - (9 : I)-Gemisch 136 mg J^ut>-3,6, .^-Trioxo-W-nor-androsten, das nach dreimaligem Umlösen aus Aceton—Petroläther konstant bei .163° schmilzt und mit dem im Beispiel 2 beschriebenen Präparat identisch ist. IR-Spektrum (CHCl3): vmax = 1735, 1673, 1628 cm-1. UV-Spektrum: kmax = 249 τημ (e == 9650).250 mg of I 5 10 -3-ethylenedioxy-6,17-dioxo-19-norandrosten are heated to boiling temperature in 10 ml of glacial acetic acid for 1 hour and then evaporated in vacuo. Chromatography on neutral aluminum oxide (activity III) with benzene and benzene - ether - (9: I) mixture gives 136 mg of I ^ ut > -3.6 ,. ^ - Trioxo-W-nor-androsten, which after redissolving three times Acetone petroleum ether melts constantly at .163 ° and is identical to the preparation described in Example 2. IR spectrum (CHCl 3 ): v ma x = 1735, 1673, 1628 cm- 1 . UV spectrum: k max = 249 τημ (e == 9650).
Eine Lösung von 1 g J5<10>-3,17-Bisätbylendioxy-6-oxo-l 9-nor-androsten in 10 ml Äthanol, 31ml Diäthylenglykol und 10 ml Hydrazinhydrat wird · I1Za Stunden zum Sieden erhitzt, dann abgekühlt und 5 g zerriebenes Kaliumhydroxyd zugefügt. Nach weiterem Erhitzen während 30 Minuten auf Rückfluß temperatur (100°) werden nochmals 60 ml Diätbylenglykol zugesetzt und so lange Äthanol wegdestilliert, bis die Siedetemperatur der Reaktionslösung 190° erreicht. Nach 3'/4Stündigem Kochen wird abgekühlt und wie üblich aufgearbeitet. Das resultierende Rohprodukt wird an basischem Aluminiumoxyd (Aktivität II) chromatographiert. Man isoliert mit Petroläther-Benzol-(1 : 1)-Gemisch und Benzol 483 mg ,J5-3,l7-Bisälhylcndioxy-19-nor-androsten vom F. 135 bis 137°, nach zweimaliger Kristallisation aus Aceton—Petroläther. [a]0 = -196° (c = 1,49). IR-Spektrum (CHCl3): keine Banden oberhalb von 3100 cm-' und zwischen 1500 und 2800cm-'.A solution of 1 g of I 5 < 10 > -3,17-bisätbylenedioxy-6-oxo-l 9-nor-androstene in 10 ml of ethanol, 31 ml of diethylene glycol and 10 ml of hydrazine hydrate is heated to boiling for 1 Za hours, then cooled and 5 g of grated potassium hydroxide added. After further heating for 30 minutes at reflux temperature (100 °), another 60 ml of dietbylene glycol are added and ethanol is distilled off until the boiling temperature of the reaction solution reaches 190 °. After boiling for 3/4 hours, the mixture is cooled and worked up as usual. The resulting crude product is chromatographed on basic aluminum oxide (activity II). With petroleum ether-benzene (1: 1) mixture and benzene, 483 mg, I 5 -3,17-bisälhylcndioxy-19-nor-androstene with a melting point of 135 ° to 137 ° are isolated after two crystallizations from acetone-petroleum ether. [a] 0 = -196 ° (c = 1.49). IR spectrum (CHCl 3 ): no bands above 3100 cm- 'and between 1500 and 2800 cm-'.
40 mg , I5-3,17-Bisäthylendioxy- 19-nor-androstcn werden in 6 ml Eisessig und 10 Tropfen Wasser 1 Stunde auf Siedetemperatur erhitzt und darauf die Lösung im Vakuum eingedampft. Filtration des Rückstandes in Ätherlösung durch neutrales Aluminiumoxyd (Aktivität II) liefert 20 mg Kristalle, die nach zweimaliger Kristallisation aus Aceton— Petroläther bei 163 bis 164': schmelzen. Das Präparat ist nach Mischprobe, IR-Spektrum und Dünnschichtchromatogramm [Kieselgel G »Merck«; Fließmittel: Benzol—Methanol (19:1)] mit J4-3,17 - Dioxo-19-nor-androsten identisch.40 mg of I 5 -3,17-bisäthylendioxy-19-nor-androstcn are heated to boiling temperature in 6 ml of glacial acetic acid and 10 drops of water for 1 hour and the solution is then evaporated in vacuo. Filtration of the residue in ether solution through neutral alumina (activity II) gives 20 mg of crystals which after two crystallization from acetone-petroleum ether at 163-164 ': melt. The preparation is according to mixed sample, IR spectrum and thin-layer chromatogram [silica gel G »Merck«; Mobile phase: benzene — methanol (19: 1)] identical to I 4 -3.17 - dioxo-19-nor-androstene.
500 mg 3ß-Acetoxy-19-hydroxy-20-oxo-J5-pregnen werden in 50 ml absolutem Benzol gelöst und unter Zugabe von 1,0 g Blei(lV)-acetat und 0,25 ml Pyridin 30 Minuten bei Raumtemperatur gerührt. Anschließend wird das Reaktionsgemisch von unlöslichen Anteilen abfiltriert, das Filtrat mit Äther verdünnt und nacheinander mit 10%iger Kaliumjodid- und Natriumthiosulfatlösung, Wasser, verdünnter Salzsäure, gesättigter Natriumhydrogcncarbonatlösung und erneut mit Wasser gewaschen, getrocknet und im Wasserstrahlvakuum eingedampft. Das erhaltene Rohprodukt (510 mg) enthält nach Dünnschichtcbromatogramm (System Toluol-Essigester-4 : 1-Geroisch) neben 3/i,6-Diacetoxy-20-oxozl5<lü)-19-nor-pregnen noch etwa 10% Ausgangsmaterial und 5 bis 10% 3/J - Acetoxy - 20 - oxo-J1(lin 5-19-nor-pregnadien. Durch Chromatographie an Silicagel ( + 15% Wasser) wird das 3,6-Diacetat von Nebenprodukten abgetrennt. Die Verbindung ist amorph und kristallisiert auch nach mehrwöchigem Stehen nicht. Im IR-Spektrum treten unter anderem Banden bei 5,79, 5,86, 8,15, 8,30, 9,30, 9,80 und 10,50 μ auf.500 mg of 3β-acetoxy-19-hydroxy-20-oxo-J 5 -pregnene are dissolved in 50 ml of absolute benzene and stirred for 30 minutes at room temperature with the addition of 1.0 g of lead acetate and 0.25 ml of pyridine . The reaction mixture is then filtered off from insoluble components, the filtrate is diluted with ether and washed successively with 10% potassium iodide and sodium thiosulphate solution, water, dilute hydrochloric acid, saturated sodium hydrogen carbonate solution and again with water, dried and evaporated in a water jet vacuum. The crude product obtained (510 mg) contains, according to the thin-layer chromatogram (toluene-ethyl acetate-4: 1-Geroic system), in addition to 3 / i, 6-diacetoxy-20-oxozl 5 < lü) -19-nor-pregnen, about 10% starting material and 5 to 10% 3 / J - acetoxy - 20 - oxo-J 1 (lin 5 -19-nor-pregnadiene. The 3,6-diacetate is separated from by-products by chromatography on silica gel (+ 15% water). The compound is amorphous and does not crystallize even after standing for several weeks.
500 mg rohes ^,ö-Diacetoxy^O-oxo- I5"0>-19-norpregnen werden in 10 ml Methanol gelöst und nach Zugabe einer Lösung von 150 mg Kaliumhydroxyd in 2 ml Wasser über Nacht bei 30° gerührt. Das Reaktionsgemisch wird anschließend mit 50 ml Wasser verdünnt und mit Methylenchlorid erschöpfend extrahiert. Die mit Wasser gewaschenen organischen Auszüge werden getrocknet und im Wasscrstrahlvakuum eingedampft. Das so erhaltene rohe, amorphe 3/3,6-Dihydroxy-20-oxo- J5(10>-19-norpregnen enthält kleine Mengen der am C-17 epimeren Verbindung. Es weist im IR-Spektrum unter anderem Banden bei 2,80, 2,95, 5,85 und 9,05 (* auf.500 mg of crude ^, δ-diacetoxy ^ O-oxo-I 5 " 0 > -19-norpregnen are dissolved in 10 ml of methanol and, after the addition of a solution of 150 mg of potassium hydroxide in 2 ml of water, stirred overnight at 30 °. The reaction mixture is then diluted with 50 ml of water and exhaustively extracted with methylene chloride. The organic extracts washed with water are dried and evaporated in a water jet vacuum. The crude, amorphous 3 / 3,6-dihydroxy-20-oxo- 5 (10 > - 19-norpregnen contains small amounts of the compound epimeric at C-17 and has bands at 2.80, 2.95, 5.85 and 9.05 ( * in the IR spectrum).
Das als Ausgangsstoff verwendete 3/3-Acetoxy-19-hydroxy-20-oxo-..l5-pregnen wird vorteilhaft aus dem durch Blei(lV)-acetat- oder Hypojoditreaktion aus Sß-Acetoxy-Sa-brom-ö/J-hydroxy^O-oxo-pregnen leicht zugänglichen S/J-Acetoxy-Sa-brom-ö^l^-oxido-20-oxo-pregnen wie folgt hergestellt: 2,00 g der letztgenannten Verbindung werden in einem Gemisch von 40 ml Eisessig und 2 ml Wasser gelöst und unter Rühren bei 30 bis 40° portionenweise mit 12 g Zinkpulver versetzt. Das Reaktionsgemisch wird weitere 30 Minuten bei 40° gerührt; dann abgekühlt, von anorganischen Anteilen abfiltriert (den Nutschenrückstand wäscht man mit Methanol nach), das Filtrat mit Wasser auf 1,51 verdünnt, das ausgefallene 3ß-Acetoxy-19-hydroxy-20-oxo-/l5-pregnen abgenutscht, mit Wasser gewaschen und getrocknet. Das Rohprodukt (1,5 g) liefert nach Umlösen aus Methylcnchlorid—Äther 1,2 g der reinen, bei 170° schmelzenden Verbindung.The 3/3-acetoxy-19-hydroxy-20-oxo - .. l 5 -pregnen used as the starting material is advantageously obtained from the Sß-acetoxy-sa-bromo-ö / J by lead (IV) acetate or hypoiodite reaction -hydroxy ^ O-oxo-pregnen easily accessible S / J-acetoxy-Sa-bromo-ö ^ l ^ -oxido-20-oxo-pregnen prepared as follows: 2.00 g of the last-mentioned compound are in a mixture of 40 ml Glacial acetic acid and 2 ml of water are dissolved and 12 g of zinc powder are added in portions while stirring at 30 to 40 °. The reaction mixture is stirred for a further 30 minutes at 40 °; then cooled, the inorganic components filtered off (the residue on the suction filter was washed with methanol), the filtrate was diluted to 1.51 with water, the precipitated 3β- acetoxy-19-hydroxy-20-oxo / l 5 -pregnene filtered off with suction, with water washed and dried. The crude product (1.5 g), after redissolving from methylene chloride-ether, gives 1.2 g of the pure compound which melts at 170 °.
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