CH544746A - 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 - Google Patents
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 chromiumInfo
- Publication number
- CH544746A CH544746A CH399161A CH399161A CH544746A CH 544746 A CH544746 A CH 544746A CH 399161 A CH399161 A CH 399161A CH 399161 A CH399161 A CH 399161A CH 544746 A CH544746 A CH 544746A
- Authority
- CH
- Switzerland
- Prior art keywords
- oxo
- steroids
- hydroxy
- oxido
- delta4
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims abstract description 11
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 title claims description 4
- 229910052804 chromium Inorganic materials 0.000 title claims description 4
- 239000011651 chromium Substances 0.000 title claims description 4
- 239000007858 starting material Substances 0.000 claims abstract description 9
- 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 5
- 150000003431 steroids Chemical class 0.000 claims abstract description 4
- 150000003128 pregnanes Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 7
- SUPOKHOQAKXOHJ-BYZMTCBYSA-N (8s,9s,10r,13r,14s,17s)-17-ethyl-10,13-dimethyl-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CC2=CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 SUPOKHOQAKXOHJ-BYZMTCBYSA-N 0.000 claims description 6
- 230000001419 dependent effect Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000000155 melt Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 238000009940 knitting Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 8
- 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 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 235000014113 dietary fatty acids Nutrition 0.000 abstract 1
- 229930195729 fatty acid Natural products 0.000 abstract 1
- 239000000194 fatty acid Substances 0.000 abstract 1
- 150000004665 fatty acids Chemical class 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 150000002739 metals Chemical class 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 230000001131 transforming effect Effects 0.000 abstract 1
- 239000011701 zinc Substances 0.000 abstract 1
- 229910052725 zinc Inorganic materials 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- -1 steroid compounds Chemical class 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000006114 decarboxylation reaction Methods 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
- 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 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
- 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
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GKBHKNPLNHLYHT-UHFFFAOYSA-N 5beta-Stigmastan Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 GKBHKNPLNHLYHT-UHFFFAOYSA-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZXSWTMLNIIZPET-ZOFHRBRSSA-N Normethandrolone Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 ZXSWTMLNIIZPET-ZOFHRBRSSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 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
- WLRCZTUKVKICCZ-VPAKFMSCSA-N [(8s,9s,10s,13s,14s)-13-methyl-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-10-yl]methanol Chemical compound C1CC2=CCCC[C@]2(CO)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 WLRCZTUKVKICCZ-VPAKFMSCSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 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
- 239000012965 benzophenone Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001737 cardanolides Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 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
- 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
- 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
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 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
- 239000000284 extract 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
- 150000002373 hemiacetals Chemical class 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 239000000203 mixture Substances 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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 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
- LBZIXWRZFXPLJU-UHFFFAOYSA-N propan-2-one;sulfuric acid Chemical compound CC(C)=O.OS(O)(=O)=O LBZIXWRZFXPLJU-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- GKBHKNPLNHLYHT-LWQAOISPSA-N stigmastane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 GKBHKNPLNHLYHT-LWQAOISPSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- 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
- 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
- C07J75/00—Processes for the preparation of steroids in general
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
19-Oxygenated steroids and 19-nor-steroids are prepared by treating DELTA4-3-oxo-6beta:19-oxido-steroids of the spirostane, androstane and pregnane series, with reducing agents, and transforming, if necessary, the resulting DELTA5-3-oxo-steroids into the DELTA4-3-oxo-steroids, and removing therefrom, if necessary, the 19-C after oxidation of the 19-OH. Suitable starting materials are DELTA4-3-oxo-6beta:19-oxido steroids contng. another OH or oxo gp. in the 19-pos., and 19:6beta-lactones of DELTA4-3-oxo-6beta-hydroxy-19-oic acids. The reduction may be effected with metals, suitably with zinc and fatty acid. Cpds. include DELTA4-3-oxo-17alpha-ethinyl-17beta-hydroxyandrostene-19-oic acid and its esters; DELTA4-3:19-dioxo-17alpha-ethinyl-17beta-hydroxy-androstene;.
Description
Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung von 19-oxygenierten #4-3-Oxo- steroiden, d.h. 19-Hydroxy- oder 19-Oxo-#4-3-Oxosteroi- den und #4-3-Oxosteroid-19-säuren aus in 19-Stellung unsubstituierten oder durch eine Hydroxyl- oder Oxogruppe substituierten #4-3-Oxo-68,19-oxidosteroiden. Die Verfahrensprodukte sind wichtige Ausgangsstoffe zur Herstellung von 19-steroiden.
l9-Nor-steroide, insbesondere gewisse Derivate des 19-Nor-testosterons und 19-Nor-progesterons haben in den letzten Jahren grosse Bedeutung erlangt. So haben zum Beispiel das 19-Nor-17α-methyl-testosteron. das 19 -Nor-l7-äthinyl-testosteron und gewisse Ester des 19 -Nor-testosterons therapeutische Verwendung gefunden.
Alle diese Verbindungen waren bisher nur durch Reduktion von Steroidverbindungen mit einem aromatischen Ring A -ngbch', wdd > e ihrerseits aus ungesät- tigten 3-Keto-Sleroiden durch thermische Eliminierung der angulären C-19-Methylgruppe und gleichzeitige Aro matisierung gewonnen werden mussten.
Die gemäss der vorliegenden Erfindung nunmehr leicht zugänglichen 19oxigenierten #4-3-Oxo-steroide ermöglichen nun die Herstellung von 19-Nor-steroiden auf äusserst einfache Wei se, ohne dass dabei der Ring A zuerst aromatisiert wer- den muss
Das Verfahren der vorliegenden Erfindung zur Herstellung der genannten 19-oxygenierten #4-3-Oxo-steroi- de besteht darin, dass man in 19-Stellung unsubstituierte oder in dieser Stellung durch eine Hydroxy. oder Oxo- gruppe substituierte #4-3-Oxo-6ss,19-oxido-steroide mit Salzen des zweiwertigen Chroms reduziert und erbaltene
19-oxygenierte #5-3-Oxo-steroide zu den 19-oxygenierten A,4-3-o-steroiden isomerisiert.
Zur verfahrensmässigen Reduktion verwendet man zB. Chromochlorid oder Chromoacetat in mit Wasser mischbaren Lösungsmitteln wie Dioxan/Wasser oder Eisessig.
Je nach der Reaktionstemperatur und dem verwen deten Lösungsmittel erhält man die 19-oxygenierten #5-3- -oxo-steroide oder direkt die 19-oxygenierten #4-3-Oxo- -steroide. Erstere lassen sich in bekannter Weise mit sau ren oder alkalischen Mitteln zu den #4-3-Oxo-Verbindun- gen isomerisieren.
Die Ausgangsstoffe für das vorliegende Verfahren sind in 19-Stellung unsubstituierte #4-3-Oxo-6ss,19-oxido- steroide oder solche, die durch eine Hydroxy- oder Oxogruppe substituiert sind, d.h. Hemiaaetale von 6ss-Hy- droxy-19-oxosteroiden oder 19,6ss-Laktone von droxysteroid-19-Säuren. 4m Übrigen gehören die Ausgangsstoffe der Spirostan-, Androstan-, Pregnan-, Cholan-, Cholestan-, Stigmastan- und Cardanolid-Reihe an, welche im Ringsystem, insbesondere in einer oder mehreren der Stellungen 1,2,3,7,8,9,11,12,14,15,16,17,20 und 21 weitere Substituenten aufweisen können, wie freie oder funktionell abgewandelte Oxogruppen,
veresterte oder verätherte Hydroxylgruppen, M-kyl. z.B. Methyl-) Gruppen und/oder Halogenatome. Unter funktionell abgewandelten Oxogruppen werden ketalisierte oder in Enolderivate, z!B. Enoläther oder Enolester, übergeführte Oxogruppen verstanden. Ausserdem können die Ausgangsstoffe auch {Doppelbindungen oder Oxidogruppen aufwei sen, z.B. in 9,11- oder 16,17-Stellung.
Diese Ausgangsstoffe können z.B. gemäss den Verfahren des Patents 412 874, gegebenenfalls unter nachträglicher Einführung der A4.3-Oxogruppierung und, wenn erwünscht, unter Bildung der oben genannten Hemiacetal- oder lactongruppe, hergestellt werden.
Besonders wichtige Ausgangsstoffe sind #4-3-Oxo-6ss,- 19-oxido-verbindungen der Androstan-, Pregnan- und Spirostanreihe z.B. das A4-3,17;Dioxo-6,B,I9-oxido-andro- sten, das #4-3-Oxo-6ss,19-oxido-17ss-hydroxy-androsten u.
seine Ester, #4-3-Oxo-6ss,19-oxido-17ss-hydroxy-17a-al- kyl-, -17a-alkenyl- und -17a-alkinyl-androstene, insbesondere die 17a-Methyl-, 17α-Äthyl-, 17α-Isobutyl-, 17α-Bu- tyl-, 17α-Allyl-, 17α-Vinyl-, 17α-Äthinyl- 17α-(2-Methyl)- -ithinylVerbindungen und ihre Ester.
Weiter sind zu nennen das #4-3,20-Dioxo-6ss,19-oxido-pregnen, #4-3,20- -Dioxo-6ss,19-oxido-21-hydroxy-pregnen und seine Ester, #4-3,20-Dioxo-6ss,19-oxido-17α,21-dihydroxy-pregnen und seine Ester,#4-3,20-Dioxo-6ss,19-oxido-17α-hydroxy-preg- nen und seine Ester, das #4-3,20-Dioxo-6ss,19;16,17α-bis- oxido-pregnen, das 18,20-Lakton der #4-3-Oxo-6ss,19- -oxido-20ss-hydroxy-pregnen-18-säure, das #4-3-Oxo-6ss,19- 19-oxido-spirosten usw.
In den oben genannten Estern bedeuten die Säurereste insbesondere solche von aliphatischen, cycloaliphatischen, araliphatischen und aromatischen Carbonsäuren mit 1-15 Kohlenstoffatomen, z.B. Formiate, Acetate, Propionate, Butyrate, Trimethylacetate, Önanthate, Capronate, Decanoate, Cyclopentylpropionate, Valerianate, Benzoate, Furoate. Hexahydrobenzoate, Phenylpropionate, Trifluoracetate, Äthyl- und Methylcarbonate usw.
Für die Überführung der verfahrensgemäss erhaltenen #4-3-Oxo-19-hydroxy-steroide in 19-Nor-steroide behandelt man diese z.B. in bekannter Weise mit starken Alkalien wie Alkalimetailhydroxyden oder Alkoholaten. Es ist jedoch vorteilhaft, vor der Abspaltung des angulären 19 Kohlenstoffatoms die 19-Hydroxygruppe zur 19-Oxooder 19-Säuregruppe zu oxydieren z.ss. mit Chromsäure Pyridin-Komplex bzw. Chromtrioxyd in Eisessig oder in Aceton-Schwefelsäure. Die #4-3,19-Dioxo-verbindungen spalten schon bei milder Alkalibehandlung Ameisensäure ab und die Decarboxylierung von #4-3-Oxo-19-säure gelingt noch leichter.
Wie bekannt, entstehen bei der Decarboxylierung durch Erwärmen in Pyridin vorwiegend #5(10)-3-Oxo-19-Norverbindungen, die dann in bekannter Weise z.3. durch Säurebehandlung in A4-3-Oxo-19-nor -steroide umgewandelt werden.
Die Abspaltung des 19-Kohlenstoffatoms gelingt auch wenn man die #4-3-Oxo-19-hydroxy-verbindungen mit einem Keton und einem Aluminium- oder Magnesiumalkoholat z.B. mit Cyclohexanon, Chinonen, Benzophenon und Aluminiumisopropylat, -tert.-butylat oder -phenolat in einem geeigneten Lösungsmittel wie Benzol oder Toluol erhitzt.
Die Erfindung wird im nachfolgenden Beispiel näher beschrieben. Die Temperaturen sind in Celsiusgraden angegeben.
Beispiel I
Eine Lösung von 1,0 g 3,17-Dioxo-6ss,19-oxido-#4- -andresten in 20 ml 96%iger Essigsäure (unter Kohlendioxid) wird mit einer Mischung von 17,0 ml 0,335 N Chrom- I)-chloridaLösung und 10 ml 96% Essigsäure versetzt und 21/2 Minuten im verschlossenen Kolben geschüttelt. Dann verdünnt man mit 350 ml Wasser, extrahiert dreimal mit Chloroform, wäscht die organischen Auszüge zweimal mit Wasser, trocknet und dampft im Wasserstrahlvakuum ein. Der Eindampfrückstand wird in 10 ml 96%iger Essigsäure gelöst und 15 Minuten unter Rückfluss gekocht.
Durch Eindampfen im Vakuum und dreimaligem Abdampfen des Rückstandes mit Benzol erhält man das rohe 3,17-Dioxo-19-hydroxy-#4-andro- sten, aus dem durch Knstallisafion das reine bei 170-171 schmelzende Produkt gewonnen wird.
In analoger Weise erhält man aus 3,20-Dioxo-6ss,19- -oxido-17α-acetoxy-#4-pregnen das bei 240-241 schmelzende 3,20-Dioxo-17α-acetoxy-19-hydroxy-#4-pregnen.
PATENTANSPRUCH I
Verfahren zur Herstellung von 19-Hydroxy- oder 19 -Oxo-#4-3-Oxosteroiden oder #4-3-Oxosteroid-19-säuren, dadurch gekennzeichnet, dass man in 19-Stellung unsubstituierte oder in dieser Stellung durch eine Hydroxyoder Oxogruppe substituierte #4-3-Oxo-6ss,19-oxido-ste- roide mit Salzen des zweiwertigen Chroms reduziert und erhaltene 19-oxygenierte A5-3-Oxo-steroide zu den entsprechenden #4-3-Oxosteroiden isomerisiert.
UNTERANSiPIRÜCHE
1. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man erhaltene #5-3-Oxo-steroide mittels eines sauren Mittels zu den A4-3-Oxo-steroiden isomerisiert.
2. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man die Reduktion in einem mit Wasser mischbaren Lösungsmittel ausführt.
3. Verfahren nach Patentanspruch I oder Unteranspruch 2, dadurch gekennzeichnet, dass man Eisessig als Lösungsmittel verwendet.
4. Verfahren nach Patentanspruch I oder Unteranspruch 2, dadurch gekennzeichnet, dass man Dioxan/ Wasser als Lösungsmittel verwendet.
5. Verfahren nach Patentanspruch I oder einem der Unteransprüche 1-4, dadurch gekennzeichnet, dass man Ausgangsstoffe der Androstan- oder Pregnanreihe verwendet.
PATENTANSPRUCH II
Verwendung von nach dem Verfahren gemäss Patentanspruch I erhaltenen Steroiden zur Herstellung von A4-3-Oxo-19-Norsteroiden, dadurch gekennzeichnet, dass man in erhaltenen l9Aldehyden oder 19-Carbonsäuren die anguläre 1 9-Gruppe abspaltet.
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
The present invention relates to a process for the preparation of 19-oxygenated # 4-3 oxosteroids, i. E. 19-hydroxy- or 19-oxo- # 4-3-oxosteroids and # 4-3-oxosteroid-19-acids from # 4-3-oxo-68 which are unsubstituted in the 19-position or substituted by a hydroxyl or oxo group , 19-oxide steroids. The process products are important starting materials for the production of 19-steroids.
19-nor-steroids, in particular certain derivatives of 19-nor-testosterone and 19-nor-progesterone, have gained great importance in recent years. For example, they have 19-nor-17α-methyl testosterone. 19 -Nor-l7-äthinyl-testosterone and certain esters of 19 -Nor-testosterone have found therapeutic use.
All these compounds were previously only obtained by reducing steroid compounds with an aromatic ring A -ngbch ', which in turn had to be obtained from unsaturated 3-keto-sleroids by thermal elimination of the angular C-19 methyl group and simultaneous aromatization.
The 19-oxygenated # 4-3-oxo-steroids, which are now easily accessible according to the present invention, now enable the production of 19-nor-steroids in an extremely simple manner without first having to aromatize ring A
The process of the present invention for the preparation of the mentioned 19-oxygenated # 4-3-oxo-steroids consists in unsubstituted in the 19-position or in this position by a hydroxy. or # 4-3-Oxo-6ss, 19-oxido-steroids substituted with oxo groups, reduced and inherited with salts of divalent chromium
19-oxygenated # 5-3-oxo-steroids isomerized to the 19-oxygenated A, 4-3-o-steroids.
For procedural reduction one uses, for example. Chromochloride or chromoacetate in water-miscible solvents such as dioxane / water or glacial acetic acid.
Depending on the reaction temperature and the solvent used, the 19-oxygenated # 5-3-oxo-steroids or the 19-oxygenated # 4-3-oxo-steroids are obtained directly. The former can be isomerized in a known manner with acidic or alkaline agents to give the # 4-3-oxo compounds.
The starting materials for the present process are # 4-3-oxo-6ss unsubstituted in the 19-position, 19-oxido steroids or those which are substituted by a hydroxyl or oxo group, i.e. Hemia acetals of 6ss-hydroxy-19-oxosteroids or 19,6ss-lactones of droxysteroid-19-acids. In addition, the starting materials belong to the spirostan, androstan, pregnan, cholan, cholestan, stigmastan and cardanolide series, which in the ring system, especially in one or more of the positions 1,2,3,7,8 9, 11, 12, 14, 15, 16, 17, 20 and 21 can have further substituents, such as free or functionally modified oxo groups,
esterified or etherified hydroxyl groups, M-kyl. e.g. Methyl) groups and / or halogen atoms. Functionally modified oxo groups are ketalized or converted into enol derivatives, e.g. Enol ethers or enol esters, converted oxo groups understood. 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 can e.g. according to the process of patent 412 874, optionally with subsequent introduction of the A4.3-oxo group and, if desired, with formation of the hemiacetal or lactone group mentioned above.
Particularly important starting materials are # 4-3-oxo-6ss, - 19-oxido compounds of the androstane, pregnan and spirostane series e.g. A4-3,17; dioxo-6, B, 19-oxido-androstene, # 4-3-oxo-6ss, 19-oxido-17ss-hydroxy-androstene and the like.
its esters, # 4-3-oxo-6ss, 19-oxido-17ss-hydroxy-17a-alkyl-, -17a-alkenyl- and -17a-alkynyl-androstenes, especially the 17a-methyl-, 17α- Ethyl, 17α-isobutyl, 17α-butyl, 17α-allyl, 17α-vinyl, 17α-ethynyl, 17α- (2-methyl) -ithynyl compounds and their esters.
Also to be mentioned are # 4-3,20-Dioxo-6ss, 19-oxido-pregnen, # 4-3,20- -Dioxo-6ss, 19-oxido-21-hydroxy-pregnen and its esters, # 4- 3,20-Dioxo-6ss, 19-oxido-17α, 21-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; 16,17 α-bis-oxido-pregnen, the 18,20-lactone the # 4-3-oxo-6ss, 19- -oxido-20ss-hydroxy -pregnen-18-acid, the # 4-3-oxo-6ss, 19- 19-oxido-spirosten etc.
In the above esters, the acid radicals mean in particular those of aliphatic, cycloaliphatic, araliphatic and aromatic carboxylic acids having 1-15 carbon atoms, e.g. Formates, acetates, propionates, butyrates, trimethylacetates, enanthates, capronates, decanoates, cyclopentylpropionates, valerians, benzoates, furoates. Hexahydrobenzoates, phenylpropionates, trifluoroacetates, ethyl and methyl carbonates, etc.
To convert the # 4-3-oxo-19-hydroxy-steroids obtained according to the process into 19-nor-steroids, these are treated e.g. in a known manner with strong alkalis such as alkali metal hydroxides or alcoholates. However, it is advantageous to oxidize the 19-hydroxyl group to the 19-oxo or 19-acid group before the angular 19 carbon atom is split off. with chromic acid pyridine complex or chromium trioxide in glacial acetic acid or in acetone-sulfuric acid. The # 4-3,19-dioxo compounds split off formic acid even with mild alkali treatment and the decarboxylation of # 4-3-oxo-19-acid is even easier.
As is known, mainly # 5 (10) -3-oxo-19-nor compounds are formed during decarboxylation by heating in pyridine, which are then z.3. can be converted into A4-3-oxo-19-nor -steroids by acid treatment.
The 19-carbon atom can also be split off if the # 4-3-oxo-19-hydroxy compounds are mixed with a ketone and an aluminum or magnesium alcoholate, e.g. heated with cyclohexanone, quinones, benzophenone and aluminum isopropoxide, tert-butoxide or phenolate in a suitable solvent such as benzene or toluene.
The invention is described in more detail in the following example. The temperatures are given in degrees Celsius.
Example I.
A solution of 1.0 g of 3,17-dioxo-6ss, 19-oxido- # 4- and residues in 20 ml of 96% acetic acid (under carbon dioxide) is mixed with a mixture of 17.0 ml of 0.335 N chromium-I) -chlorida solution and 10 ml of 96% acetic acid and shaken for 21/2 minutes in the sealed flask. Then it is diluted with 350 ml of water, extracted three times with chloroform, the organic extracts are washed twice with water, dried and evaporated in a water-jet vacuum. The evaporation residue is dissolved in 10 ml of 96% acetic acid and refluxed for 15 minutes.
Evaporation in vacuo and evaporation of the residue three times with benzene gives the crude 3,17-dioxo-19-hydroxy- # 4-andro- sten, from which the pure product, which melts at 170-171, is obtained by artificialization.
In an analogous manner, 3,20-dioxo-17α-acetoxy-19-hydroxy- # 4-pregnen is obtained from 3,20-dioxo-6ss, 19-oxido-17α-acetoxy- # 4-pregnen, which melts at 240-241. 4-pregnen.
PATENT CLAIM I
Process for the preparation of 19-hydroxy- or 19-oxo- # 4-3-oxosteroids or # 4-3-oxosteroid-19-acids, characterized in that they are unsubstituted in the 19-position or substituted in this position by a hydroxy or oxo group # 4-3-Oxo-6ss, 19-oxido-steroids reduced with salts of divalent chromium and the 19-oxygenated A5-3-oxo-steroids obtained isomerized to the corresponding # 4-3-oxosteroids.
SUB-ANSIPIRUMS
1. The method according to claim I, characterized in that # 5-3-oxo-steroids obtained are isomerized to the A4-3-oxo-steroids by means of an acidic agent.
2. The method according to claim I, characterized in that the reduction is carried out in a water-miscible solvent.
3. The method according to claim I or dependent claim 2, characterized in that glacial acetic acid is used as the solvent.
4. The method according to claim I or dependent claim 2, characterized in that dioxane / water is used as the solvent.
5. The method according to claim I or one of the dependent claims 1-4, characterized in that starting materials of the androstane or pregnane series are used.
PATENT CLAIM II
Use of steroids obtained by the process according to claim I for the preparation of A4-3-oxo-19-norsteroids, characterized in that the 19-aldehydes or 19-carboxylic acids obtained are cleaved from the 19-angular group.
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| CH555571A CH531484A (en) | 1961-04-05 | 1961-04-05 | 6beta 19-oxidosteroids |
| SE728961A SE303487B (en) | 1960-07-15 | 1961-07-13 | |
| DK291261A DK107226C (en) | 1960-07-15 | 1961-07-14 | Process for the preparation of 19-oxygenated steroids. |
| GB2589761A GB994749A (en) | 1960-07-15 | 1961-07-17 | 19-oxygenated and 19-nor-steroids and process for their manufacture |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1439360A CH451925A (en) | 1960-12-23 | 1960-12-23 | Process for the preparation of 19-hydroxy steroids |
| 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 |
|---|---|
| CH544746A true CH544746A (en) | 1974-01-15 |
Family
ID=25694350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH399161A CH544746A (en) | 1960-07-15 | 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 |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH544746A (en) |
-
1961
- 1961-04-05 CH CH399161A patent/CH544746A/en unknown
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