CH531484A - 6beta 19-oxidosteroids - Google Patents
6beta 19-oxidosteroidsInfo
- Publication number
- CH531484A CH531484A CH555571A CH555571A CH531484A CH 531484 A CH531484 A CH 531484A CH 555571 A CH555571 A CH 555571A CH 555571 A CH555571 A CH 555571A CH 531484 A CH531484 A CH 531484A
- Authority
- CH
- Switzerland
- Prior art keywords
- oxo
- steroids
- dependent
- hydroxy
- 6beta
- Prior art date
Links
- 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 claims abstract description 4
- 150000003128 pregnanes Chemical class 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052804 chromium Inorganic materials 0.000 claims description 3
- 239000011651 chromium Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 9
- 238000006894 reductive elimination reaction Methods 0.000 claims 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 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 abstract description 4
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 2
- 238000002844 melting Methods 0.000 abstract description 2
- 230000008018 melting Effects 0.000 abstract description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 7
- -1 steroid compounds Chemical class 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960001566 methyltestosterone Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 1
- GCLQUARDBTZPLS-TZUDWKCISA-N (8R,9S,10R,13S,14S,17S)-17-ethenyl-10-(hydroxymethyl)-13-methyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-ol Chemical compound C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@]2(C=C)O)CCC4[C@@]3(CCCC4)CO GCLQUARDBTZPLS-TZUDWKCISA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- 150000000319 19-nortestosterones Chemical class 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
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 description 1
- NONTVBXXCLSVMP-YQKVBRGFSA-N C[C@](CC1)([C@@H](CC2)[C@H]3[C@H]1[C@@](CO)(CCCC1)C1CC3)[C@H]2C=CO Chemical compound C[C@](CC1)([C@@H](CC2)[C@H]3[C@H]1[C@@](CO)(CCCC1)C1CC3)[C@H]2C=CO NONTVBXXCLSVMP-YQKVBRGFSA-N 0.000 description 1
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- SOBYEUHIOKMSEB-NQCUKVFCSA-N [(8S,9S,10R,13R,14S,17R)-17-ethenyl-13-methyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-10-yl]methanol 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
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WDNIVTZNAPEMHF-UHFFFAOYSA-N acetic acid;chromium Chemical compound [Cr].CC(O)=O.CC(O)=O WDNIVTZNAPEMHF-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001737 cardanolides Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- QSHQKIURKJITMZ-BRPMRXRMSA-N cholane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC)[C@@]1(C)CC2 QSHQKIURKJITMZ-BRPMRXRMSA-N 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
- 150000001845 chromium compounds Chemical class 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical class OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical class CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 description 1
- 125000005534 decanoate group Chemical class 0.000 description 1
- NKRNGKIEDAVMHL-UHFFFAOYSA-L dihydroxy(dioxo)chromium;pyridine Chemical compound O[Cr](O)(=O)=O.C1=CC=NC=C1 NKRNGKIEDAVMHL-UHFFFAOYSA-L 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000005911 methyl carbonate group Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 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
- 229960004719 nandrolone Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical class CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane 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
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
6beta:19-Oxido steroids are prepared by reacting 6beta-hydroxy steroids unsubstd. in pos-19, with heavy metal acylates having an oxidising effect. Thus 5alpha-halo-6beta-hydroxy steroids, more specifically 3beta-acyloxy-5alpha-halo-6beta-hydroxy cpds. of the spirostane, androstane and pregnane series may be treated with lead tetraacylates. In an example, residue is recrystallised from methanol ether to give 218 mg. 3beta-acetoxy-5alpha-chloro-6beta:19-oxidocholestane melting at 134-139 deg.C.
Description
Verfahren zur Herstellung von l9-Nor-Steroiden
Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung von 43 -Oxo- 1 9-Norsteroiden aus #4-3-Oxo-6ss,19-oxido-steroiden. Die Verfahrensprodukte besitzen wertvolle pharmakologische Eigenschaften. Sie sind aber auch wertvolle Zwischenprodukte für die Herstellung von anderen nützlichen Stoffen, insbesondere von pharmakologisch wirksamen Verbindungen.
19-Nor-steroide, insbesondere gewisse Derivate des I9-Nor-testosterons und 19-Nor-progesterons haben in den letzten Jahren grosse Bedeutung erlangt. So haben zum Beispiel das 19-Nor-17;a-methyl-testosteron. das 19 -Nor-17.cu,-äthinyl-testosteron und gewisse Ester des 19 -Nor-testosterons therapeutische Verwendung gefunden.
Alle diese Verbindungen waren bisher nur durch Redukton von Steroidverbindungen mit einem aromatischen Ring A zugänglich, welche ihrerseits aus ungesättigten 3-Keto-Steroiden durch thermische Eliminierung gewonnen werden mussten. Gemäss der vorliegenden Erfindung wird nun die Herstellung von 19-Nor-steroiden auf äussert einfache Weise, ohne dass dabei der Ring A zuerst aromatisiert werden muss, ermöglicht.
Das Verfahren der vorliegenden Erfindung besteht darin, dass man 19-unsubstituierte #4-3-Oxo-6ss,19-oxido- steroide reduktiv spaltet, die erhaltenen A4-3-Oxo-19- -hydroxy-steroide zu den entsprechenden 19-Oxo-steroiden oxydiert und anschliessend die anguläre 10-Formylgruppe abspaltet.
Die Ausgangsstoffe können z.B. der Spirostan-, Androstan-, Pregnan-, Cholan-, Cholestan-, Stiginastan-, Spirostan- und Cardanolidreihe angehören, welche im Ringsystem insbesondere in einer oder mehreren der Stellungen 1,2,4,7,8,9,11,12,14,15,16,17,20 und 21 weitere Substituenten aufweisen können, wie freie oder funktionell abgewandelte Oxogruppen, veresterte oder ver ätherte Hydroxylgruppen, Alkyl- (z.B. Methyl-)-Gruppen und/oder Halogenatome. Unter funktionell abgewandelten Oxogruppen kommen ketalisierte oder in Enolderivate, z.B. Enoläther oder Enolester, übergeführte Oxogruppen in Frage. Ausserdem können die Ausgangsstoffe auch Doppelbindungen oder Oxidogruppen aufweisen, z.B. in 9,11- oder 16,17-Stellung.
Diese Ausgangsstoffe werden gemäss dem Verfahren des Patentes 412 874 durch Einwirkung oxydierend wirkender Schwermetallacylate, insbesondere Bleitetraacylaten, gegebenenfalls in Gegenwart von Jod, auf 19unsubstituierte 6 -Hydroxysteroide und anschliessende Einführung eine A4-3-Oxogruppierung in die gebildeten 6,19-Oxidoteroide gewonnen.
Besonders wichtige Ausgangsstoffe sind A4-3-Oxo- -6p,19-oxido-verbindungen der Androstan-, Pregnan- und Spirostanreihe z.B. das A4-3, l7-Dioxo-6, 1 9-oxido-an- drosten, das #4-3-Oxo-6ss,19-oxido-17ss-hydroxy-andro- sten und seine Ester, #4-3-Oxo-6ss,19-oxido-17ss-hydroxy- -170X-alkyl-, 17*a-alkenyl- und -17α-alkinyl-androstene, insbesondere die 17,ss-Methyl-, 17lo-Athyl-, 17ios-Isobutyl-, 1 7oc-Butyl, 1 7o-Alkyl-, 1 7oc-Vinyl-, 17α-Äthinyl-, 1 7- -(2-Methyl)-äthinylverbindungen und ihre Ester.
Weiter sind zu nennen A4-3,20-Dioxo-6l3, l9-oxido-pregnen, A4- -3,20-Dioxo-6ss,19-oxido-21 -hydroxy-pregnen und seine Ester. #4-3.20-Dioxo-6ss,19-oxido-17α,2.1-dihydroxy-preg- nen und seine Ester, #4-3,20-Dioxo-6ss,19-oxido-17α-hy- droxy-pregnen und seine Ester, das #4-3,20-Dioxo-6ss,19; l6,17-bisoxido-pregnen, das 18,20-Lakton der A4-3- -Oxo-6,19-oxido-203-hydroxy-pregnon-18-säure, das A4- -3-Oxo-6E,19-oxido-spirosten usw.
In den oben genannten Estern bedeuten die Säurereste insbesondere solche von aliphatischen, cycloaliphatischen, araliphatischen und aromatischen, cycloaliphatischen, araliphatischen und aromatischen Carbonsäuren mit 1-15 Kohlenstoffatomen, z.B. Formiate, Acetate, Propionate, Butyrate, Trimethylacetate, Oenanthate, Capronate, Decanoate, Cyclopentylpropionate, Valerianate, Benzoate, Furoate, Hexahydrobenzoate, Phenylpropionate, Trifluoracetate, Athyl- und Methylcarbonate usw.
Als Reduktionsmittel für die verfahrensgemässe Reduktion der genannten Ausgangs stoffe verwendet man insbesondere Zink oder Salze des zweiwertigen Chroms.
Bei der Reduktion mit Zink entstehen unter Öffnung des Oxidrings Zinkenolate, die bei der Aufarbeitung mit Säuren oder Basen oder mit Wasser die A4-3-Oxo-l9- -hydroxy-steroide liefern. Als Lösungsmittel verwendet man vorteilhaft eine niedrige aliphatische Carbonsäure, wie Essigsäure, Propionsäure und dgl., gegebenenfalls unter Zusatz eines Verdünnungsmittels, wie Benzol, Dioxan, usw., oder einen niederaliphatischen Alkohol wie Isopropanol. Man erhält so nach Hydrolyse der Enolate je nach den Reaktionstemperaturen A5-3-Oxo- - 1 9-hydroxy- oder direkt A4-3-Oxo-19-hydroxy-steroide.
Die A5-3-Oxoverbindungen lassen sich in bekannter Weise mit sauren oder alkalischen Mitteln zu den A4-3-Oxoverbindungen isomerisieren. Führt man die Reduktion mit Zink in einem Carbonsäureanhydrid durch, z.B. in Essigsäureanhydrid, so bilden sich zuerst die A35-Enol- acetate der 19-Acetoxy-steroide, welche bei der milden sauren Hydrolyse, z.B. in einem Alkohol mit Hilfe einer Mineralsäure, wie Schwefelsäure, Salzsäure, Perchlorsäure usw. in A4-3-Oxo-19-acetoxy-steroide übergehen.
Zur Reduktion mit Salzen des zweiwertigen Chroms verwendet man z.B. Chrom(II)-chlorid oder Chrom(II) -acetat in mit Wasser mischbaren Lösungsmitteln wie Dioxan-Wasser oder Eisessig.
Die verfahrensemässe Überführung der erhaltenen Ä'4-3 -oxo- 1 9-hydroxy-steroide in die entsprechenden 19 -Oxo-verbindungen kann nach bekannten Methoden ausgeführt werden. Eine vorteilhafte Ausführungsform der Oxydation ist die Umsetzung mit Chromsäure-Pyridin Komplex in Pyridin.
Die verfahrensgemässe Abspaltung der 1 0-Formyl- gruppe in den erhaltenen A4-3,19-Dioxo-steroiden kann ebenfalls nach an sich bekannten Methoden durchgeführt werden. Die Abspaltung der angulären 10-Formylgruppe in Form von Ameisensäure erfolgt vorzugsweise durch Erwärmen des Steroid-19-aldehyds, mit milden Alkalien. Zwischenprodukte der verfahrensgemässen Abspaltung der 10-Formylgruppe aus h4-3,19-Dioxo-steroiden sind die A5't '-31-Oxo-19-norsteroidee die jedoch meistens unter den Reaktionsbedingungen direkt zu den A4-3-Oxo-19-norsteroiden isomerisieren.
Die Überführung von isolierten a5'10' -3-Oxo-19-norsteroiden in die isomeren \4-Verbindungen kann in an sich bekannter Weise mit Alkali oder Säuren ausgeführt werden.
Die Temperaturen sind im nachfolgenden Beispiel in Celsiusgraden angegeben.
Beispiel
Eine Lösung von 1 g A4-3,20-Dioxo-0,S,19-oxido-17cc- -acetoxy-pregnen in 20 ml Eisessig wird nach Zugabe von 25 g Zinkstaub (durch Waschen mit verdünnter Essigsäure, Wasser und Eisessig aktiviert) 20 Minuten bei 900 gerührt. Dann nutscht man vom unverbrauchten Zink ab, wäscht den Filterrückstand mit Eisessig nach und engt das Filtrat im Wasserstrahlvakuum ein. Der Rückstand wird in Chloroform aufgenommen und die Lösung wird mit Wasser und Natriumbicarbonat-Lösung gewaschen, getrocknet und im Wasserstrahlvakuum eingedampft. Man erhält so das A4-3,20-Dioxo-17X-acetoxy- - 1 9-hydroxy-pregnen.
Eine Lösung von A4-3,20-Dioxo- l7acetoxy- 1 9-hy- droxy-pregnen in 10 ml Pyridin wird unter Kühlung zu 1 g Chromtrioxid in 50 ml Pyridin gegeben und während 1 Stunde bei 20-25 gerührt. Man verdünnt das Reaktionsgemisch mit 250 ml Benzol und rührt während 10 Minuten mit 25 g trockenem Natriumhydrogencarbonat.
Die abfiltrierte Benzollösung wird mit Hilfe einer kurzen Säule von Aluminiumoxid von Chromverbindungen befreit, mit 2-n. Salzsäure gewaschen, mit Natriumsulfat getrocknet, dann im Vakuum eingedampft. Man erhält durch Umlösen aus Äther A4-3,19,20-Trioxo-17-acetoxy- -pregnen.
Man löst 5g A4-3.19.20-Trioxo-17sc-acetoxy-pregnen in 20 ml Methylenchlorid, versetzt mit 30 ml Aceton und erhitzt zum Sieden. Hierauf lässt man innert 15 Minuten 5,5 ml 10%ige Natronlauge zutropfen, kühlt nach weiteren 15 Minuten auf Raumtemperatur ab und stellt mit Essigsäure auf pH 4-5 ein. Man destilliert sodann das Lösungsmittel im Vakuum ab und ersetzt es fortlaufend durch 45 ml Wasser. Dabei fällt das rohe A4-170c- -Acetoxy-3,20-dioxo-19-nor-pregnen in kristalliner Form aus. Das an Aluminiumoxid gereinigte Produkt weist einen Schmelzpunkt von 238-242 und ein [zlo20 = 560 in Chloroform auf.
Process for the preparation of 19-nor-steroids
The present invention relates to a process for the preparation of 43-oxo-19-norsteroids from # 4-3-oxo-6ss, 19-oxido-steroids. The products of the process have valuable pharmacological properties. But they are also valuable intermediate products for the production of other useful substances, especially pharmacologically active compounds.
19-nor-steroids, in particular certain derivatives of 19-nor-testosterone and 19-nor-progesterone, have gained great importance in recent years. For example, have the 19-nor-17; a-methyl-testosterone. 19 -Nor-17.cu, -äthinyl-testosteron and certain esters of 19 -Nor-testosterone have found therapeutic use.
All of these compounds were previously only accessible by reducing steroid compounds with an aromatic ring A, which in turn had to be obtained from unsaturated 3-keto steroids by thermal elimination. According to the present invention, the production of 19-nor-steroids is now made possible in an extremely simple manner, without the ring A having to be aromatized first.
The process of the present invention consists in that 19-unsubstituted # 4-3-oxo-6ss, 19-oxido steroids are reductively cleaved and the A4-3-oxo-19- hydroxy steroids obtained are cleaved to give the corresponding 19-oxo -steroid oxidized and then splitting off the angular 10-formyl group.
The starting materials can e.g. belong to the spirostan, androstan, pregnan, cholan, cholestan, stiginastan, spirostan and cardanolide series, which in the ring system in particular in one or more of the positions 1,2,4,7,8,9,11,12 , 14,15,16,17,20 and 21 may have further substituents, such as free or functionally modified oxo groups, esterified or etherified hydroxyl groups, alkyl (eg methyl) groups and / or halogen atoms. Functionally modified oxo groups include ketalized or enol derivatives, e.g. Enol ethers or enol esters, converted oxo groups in question. In addition, the starting materials can also have double bonds or oxo groups, e.g. in the 9.11 or 16.17 position.
These starting materials are obtained according to the method of patent 412 874 by the action of oxidizing heavy metal acylates, in particular lead tetraacylates, optionally in the presence of iodine, on 19-unsubstituted 6-hydroxysteroids and subsequent introduction of an A4-3-oxo group into the 6,19-oxidoteroids formed.
Particularly important starting materials are A4-3-oxo- -6p, 19-oxido compounds of the androstane, pregnane and spirostane series e.g. the A4-3, l7-dioxo-6,19-oxido-androsten, the # 4-3-oxo-6ss, 19-oxido-17ss-hydroxy-androsten and its esters, # 4-3- Oxo-6ss, 19-oxido-17ss-hydroxy- -170X-alkyl-, 17 * a-alkenyl- and -17α-alkynyl-androstenes, especially the 17, ss-methyl-, 17lo-ethyl-, 17ios-isobutyl -, 17oc-butyl, 17o-alkyl, 17oc-vinyl, 17α-ethynyl, 17- (2-methyl) -ethinyl compounds and their esters.
Also to be mentioned are A4-3,20-dioxo-613, 19-oxido-pregnen, A4-3,20-dioxo-6ss, 19-oxido-21-hydroxy-pregnen and its esters. # 4-3.20-Dioxo-6ss, 19-oxido-17α, 2.1-dihydroxy-pregnen and its esters, # 4-3,20-dioxo-6ss, 19-oxido-17α-hydroxy-pregnen and its esters, the # 4-3,20-dioxo-6ss, 19; l6,17-bisoxido-pregnen, the 18,20-lactone of A4-3- -oxo-6,19-oxido-203-hydroxy-pregnon-18-acid, the A4- -3-oxo-6E, 19- oxido spirosts, etc.
In the above-mentioned esters, the acid radicals mean in particular those of aliphatic, cycloaliphatic, araliphatic and aromatic, cycloaliphatic, araliphatic and aromatic carboxylic acids having 1-15 carbon atoms, e.g. Formates, acetates, propionates, butyrates, trimethylacetates, oenanthates, capronates, decanoates, cyclopentylpropionates, valerianates, benzoates, furoates, hexahydrobenzoates, phenylpropionates, trifluoroacetates, ethyl and methyl carbonates, etc.
The reducing agent used for the process according to the reduction of the starting materials mentioned is in particular zinc or salts of divalent chromium.
During the reduction with zinc, zinc enolates are formed with the opening of the oxide ring, which, when worked up with acids or bases or with water, yield the A4-3-oxo-19- -hydroxy-steroids. The solvent used is advantageously a lower aliphatic carboxylic acid such as acetic acid, propionic acid and the like, optionally with the addition of a diluent such as benzene, dioxane, etc., or a lower aliphatic alcohol such as isopropanol. After hydrolysis of the enolates, A5-3-oxo-19-hydroxy-steroids or directly A4-3-oxo-19-hydroxy-steroids are obtained, depending on the reaction temperatures.
The A5-3-oxo compounds can be isomerized to the A4-3-oxo compounds in a known manner using acidic or alkaline agents. If the reduction is carried out with zinc in a carboxylic acid anhydride, e.g. in acetic anhydride, the A35-enol-acetates of 19-acetoxy-steroids are formed first, which in mild acid hydrolysis, e.g. in an alcohol with the help of a mineral acid such as sulfuric acid, hydrochloric acid, perchloric acid, etc. convert into A4-3-oxo-19-acetoxy-steroids.
For reduction with salts of divalent chromium, e.g. Chromium (II) chloride or chromium (II) acetate in water-miscible solvents such as dioxane-water or glacial acetic acid.
The process-related conversion of the erhaltenen'4-3 -oxo- 19-hydroxy-steroids obtained into the corresponding 19 -oxo compounds can be carried out by known methods. An advantageous embodiment of the oxidation is the reaction with a chromic acid-pyridine complex in pyridine.
The elimination of the 10-formyl group in the A4-3,19-dioxo-steroids obtained in accordance with the process can likewise be carried out by methods known per se. The angular 10-formyl group is split off in the form of formic acid preferably by heating the steroid 19-aldehyde with mild alkalis. Intermediate products of the process according to the splitting off of the 10-formyl group from h4-3,19-dioxo-steroids are the A5't '-31-oxo-19-norsteroids which, however, mostly under the reaction conditions directly to the A4-3-oxo-19-norsteroids isomerize.
The conversion of isolated a5'10 '-3-oxo-19-norsteroids into the isomeric 4-compounds can be carried out in a manner known per se with alkali or acids.
The temperatures are given in degrees Celsius in the example below.
example
A solution of 1 g of A4-3,20-Dioxo-0, S, 19-oxido-17cc- -acetoxy-pregnen in 20 ml of glacial acetic acid is activated after adding 25 g of zinc dust (by washing with dilute acetic acid, water and glacial acetic acid) Stirred at 900 for 20 minutes. The unused zinc is then sucked off, the filter residue is washed with glacial acetic acid and the filtrate is concentrated in a water-jet vacuum. The residue is taken up in chloroform and the solution is washed with water and sodium bicarbonate solution, dried and evaporated in a water jet vacuum. The A4-3,20-dioxo-17X-acetoxy- - 19-hydroxy-pregnene is obtained in this way.
A solution of A4-3,20-dioxol7acetoxy-19-hydroxy-pregnene in 10 ml of pyridine is added with cooling to 1 g of chromium trioxide in 50 ml of pyridine and stirred for 1 hour at 20-25. The reaction mixture is diluted with 250 ml of benzene and stirred for 10 minutes with 25 g of dry sodium hydrogen carbonate.
The filtered benzene solution is freed from chromium compounds with the help of a short column of aluminum oxide, with 2-n. Washed hydrochloric acid, dried with sodium sulfate, then evaporated in vacuo. A4-3,19,20-trioxo-17-acetoxy-pregnene is obtained by redissolving from ether.
5 g of A4-3.19.20-trioxo-17sc-acetoxy-pregnen are dissolved in 20 ml of methylene chloride, 30 ml of acetone are added and the mixture is heated to the boil. 5.5 ml of 10% sodium hydroxide solution are then added dropwise over a period of 15 minutes, after which the mixture is cooled to room temperature after a further 15 minutes and adjusted to pH 4-5 with acetic acid. The solvent is then distilled off in vacuo and it is continuously replaced by 45 ml of water. The crude A4-170c- acetoxy-3,20-dioxo-19-nor-pregnen thereby precipitates in crystalline form. The product, purified on alumina, has a melting point of 238-242 and a [zlo20 = 560 in chloroform.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH555571A CH531484A (en) | 1961-04-05 | 1961-04-05 | 6beta 19-oxidosteroids |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH555571A CH531484A (en) | 1961-04-05 | 1961-04-05 | 6beta 19-oxidosteroids |
| CH399161A CH544746A (en) | 1960-12-23 | 1961-04-05 | Delta-4-3-oxosteroid-19-ols, 19-als or 19-acids prepn - by redn of delta-4-3-oxo-6-beta, 19-oxidosteroids with divalent chromium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH531484A true CH531484A (en) | 1972-12-15 |
Family
ID=4267755
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH555571A CH531484A (en) | 1961-04-05 | 1961-04-05 | 6beta 19-oxidosteroids |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH531484A (en) |
-
1961
- 1961-04-05 CH CH555571A patent/CH531484A/en not_active IP Right Cessation
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