DE1166189B - Process for the preparation of 3ª ‰ -fluoro-í¸-steroids - Google Patents
Process for the preparation of 3ª ‰ -fluoro-í¸-steroidsInfo
- Publication number
- DE1166189B DE1166189B DEM50194A DEM0050194A DE1166189B DE 1166189 B DE1166189 B DE 1166189B DE M50194 A DEM50194 A DE M50194A DE M0050194 A DEM0050194 A DE M0050194A DE 1166189 B DE1166189 B DE 1166189B
- Authority
- DE
- Germany
- Prior art keywords
- steroids
- fluoro
- hydroxy
- manganese dioxide
- steroid
- 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
- 238000002360 preparation method Methods 0.000 title claims description 3
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 24
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 18
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 8
- 150000003431 steroids Chemical class 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 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 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 150000001441 androstanes Chemical class 0.000 claims 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000003682 fluorination reaction Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- -1 cyano, mercapto Chemical class 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012025 fluorinating agent Substances 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- QADHLRWLCPCEKT-UHFFFAOYSA-N Androstenediol Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)O)C4C3CC=C21 QADHLRWLCPCEKT-UHFFFAOYSA-N 0.000 description 2
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- QADHLRWLCPCEKT-LOVVWNRFSA-N androst-5-ene-3beta,17beta-diol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC=C21 QADHLRWLCPCEKT-LOVVWNRFSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229960002847 prasterone Drugs 0.000 description 2
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000004149 thio group Chemical group *S* 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229910021571 Manganese(III) fluoride Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- ASGJEMPQQVNTGO-UHFFFAOYSA-N benzene chloroform Chemical compound C(Cl)(Cl)Cl.C1=CC=CC=C1.C1=CC=CC=C1 ASGJEMPQQVNTGO-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- SRVINXWCFNHIQZ-UHFFFAOYSA-K manganese(iii) fluoride Chemical compound [F-].[F-].[F-].[Mn+3] SRVINXWCFNHIQZ-UHFFFAOYSA-K 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- NWMIYTWHUDFRPL-UHFFFAOYSA-N sapogenin Natural products COC(=O)C1(CO)C(O)CCC2(C)C1CCC3(C)C2CC=C4C5C(C)(O)C(C)CCC5(CCC34C)C(=O)O NWMIYTWHUDFRPL-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940096017 silver fluoride Drugs 0.000 description 1
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
- C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
-
- 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
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung von 3fl-Fluor-45-steroiden 3ß-Fluor-4 5-steroide besitzen physiologisch interessante Eigenschaften und können als Therapeutika in der Humanmedizin eingesetzt werden.Process for the preparation of 3fl-fluoro-45-steroids 3ß-fluoro-4 5-steroids have physiologically interesting properties and can be used as therapeutics in used in human medicine.
Bisher ließen sich diese Verbindungen aus 3ß-Hydroxy-45-steroiden nur in dreistufigen Verfahren herstellen. T. N. J a c o b s e n und E. V. Jensen (Chemistry and Industry, Bd. 1957, S. 172) überführten 3ß-Hydroxy-d 5-steroide in die 3-Tosylate und diese in die 3-Jodide, die dann mit Silberfluorid in die 3-Fluoride umgewandelt wurden. C. W. S h o p p e e und G. H. R. S u m m e r s (J. chem. Soc. [London], Bd. 1957, S. 4813) überführten ebenfalls 3ß-Hydroxy-4 5-steroide in die 3-Tosylate und diese in die 3,5-Cyclo-6-hydroxy-steroide, die mit Fluorwasserstoff zu den 3-Fluor-4 5-steroiden umgesetzt wurden.So far, these compounds could be made from 3ß-hydroxy-45-steroids only produce in a three-step process. T. N. J a c o b s e n and E. V. Jensen (Chemistry and Industry, Vol. 1957, p. 172) converted 3ß-hydroxy-d 5-steroids into the 3-tosylates and these into the 3-iodides, which then with silver fluoride into the 3-fluorides were converted. C. W. S h o p p e e and G. H. R. S u m e r s (J. chem. Soc. [London], Vol. 1957, p. 4813) also converted 3β-hydroxy-4 5-steroids into the 3-tosylates and these in the 3,5-cyclo-6-hydroxy-steroids, those with hydrogen fluoride to the 3-fluoro-4 5-steroids were converted.
Es wurde nun gefunden, daß man 3ß-Hydroxy-A5-steroide unter Verwendung von Mangandioxyd/ Fluorwasserstoff' als Fluorierungsmittel in einer Reaktionsstufe in 3ß-Fluor-45-steroide umwandeln kann.It has now been found that 3β-hydroxy-A5-steroids can be used of manganese dioxide / hydrogen fluoride as a fluorinating agent in one reaction stage can convert into 3ß-fluoro-45-steroids.
Gegenstand der Erfindung ist demnach ein Verfahren zur Herstellung von 3ß-Fluor-45-steroiden durch Behandlung von 3ß-Hydroxy-A5-steroiden mit Fluorwasserstoff und Mangandioxyd in Gegenwart eines inerten Lösungsmittels, wobei das Ausgangssteroid weitere C = C-Doppelbindungen und/oder Substituenten enthalten kann. Die Verwendung von Braunstein/Fluorwasserstoff als Fluorierungsmittel ist neu.The invention accordingly relates to a method of production of 3ß-fluoro-45-steroids by treatment of 3ß-hydroxy-A5-steroids with hydrogen fluoride and manganese dioxide in the presence of an inert solvent, the starting steroid may contain further C = C double bonds and / or substituents. The usage of manganese dioxide / hydrogen fluoride as a fluorinating agent is new.
Im Steroidmolekül gegebenenfalls vorhandene :nicht aktivierte Hydroxylgruppen werden bei dem Fluorierungsverfahren nach der Erfindung nicht angegriffen. Außerdem wurde gefunden, daß sich unter den angegebenen Reaktionsbedingungen im Steroidmclekül etwa vorhandene Hydroxylgruppen, die in -x-Stellung zu einer Ketogruppe stehen, z. B. in 21-Hydroxy-20-keto-steroiden und in 17a-Hydroxy-20-ketosteroiden, höchstens spurenweise mit dem erfindungsgemäß verwendeten Fluorierungsgemisch reagieren. Somit ist es möglich, auch bei 3 B-Hydroxy-ds-steroiden, die noch weitere Hydroxylgr uppen enthalten, eine Fluorierung selektiv in der 3-Stellung durchzuführen. Eine derartige selektive Fluorierung der Hydroxylgruppe in 3-Stellung mit Hilfe von Braunstein/Fluorwasserstoff ist überraschend und war nicht vorauszusehen, zumal durch das in der Literatur bekannte Fluorierungsmittel Mangan(III)-fluorid hochsiedende Kohlenwasserstoffe nicht selektiv fluoriert, sondern in Perfluorverbindungen übergeführt werden (R. D. Fow1er, H. C. Anden son, J. M. Hami1ton jr., W. B. Burford III, A. Spadetti, S. B. Bitter 1 i c h und J. L i t a n t, Ind. Eng. Chet>>., 39, S. 343 [1947]). Verfahrensgemäß können 3ß-Hydroxy-45-steroide eingesetzt werden, die den verschiedensten Steroidreihen, wie der Steran-, 18- oder 19-Nor-androstan-, Androstan-, Pregnan-, Ergostan-, Cholestan-, Gallensäure- oder Sapogeninreihe, angehören können. Diese Steroide können außer in 5 (6)-Stellung noch weiter ungesättigt sein und/oder Substituenten tragen, wie Alkyl-, Alkyliden-, Hydroxy-, Oxo-, Amino-, Halogen-, Cyano-, Mercapto- oder Thiosubstituenten. Die Substituenten können gegebenenfalls in funktionell abgewandelter Form vorliegen. So können Hydroxy-, Amino- und Mercaptogruppen alkyliert oder acyliert sein. An zwei benachbarten C-Atomen stehende Hydroxylgruppen können als cyclisches Acetal vorliegen. Oxo- und Thiogruppen können ketalisiert sein oder als Enolacylat, Enoläther oder Enamin vorliegen. Säureempfindliche Reste wie die Acetalgruppe werden bei der verfahrensgemäßen Reaktion gespalten, wobei die zugrunde liegende Gruppe in Freiheit gesetzt wird.Any present in the steroid molecule: non-activated hydroxyl groups are not attacked in the fluorination process according to the invention. aside from that it was found that under the given reaction conditions in the Steroidmclekül any hydroxyl groups that are present in the -x position to a keto group, z. B. in 21-hydroxy-20-keto steroids and in 17a-hydroxy-20-keto steroids, at most react in traces with the fluorination mixture used according to the invention. Consequently it is possible, even with 3 B-hydroxy-ds-steroids, which also contain other hydroxyl groups contain to carry out a fluorination selectively in the 3-position. Such a one selective fluorination of the hydroxyl group in the 3-position with the aid of manganese dioxide / hydrogen fluoride is surprising and could not be foreseen, especially because of what is known in the literature Fluorinating agent Manganese (III) fluoride high-boiling hydrocarbons not selective fluorinated, but converted into perfluorinated compounds (R. D. Fow1er, H. C. Anden son, J. M. Hami1ton jr., W. B. Burford III, A. Spadetti, S. B. Bitter 1 i c h and J. L i t a n t, Ind. Eng. Chet >>., 39, p. 343 [1947]). In accordance with the procedure 3ß-Hydroxy-45-steroids can be used, which correspond to the most diverse steroid series, like the Steran-, 18- or 19-Nor-androstan-, Androstan-, Pregnan-, Ergostan-, Cholestan-, Bile acid or sapogenin series. These steroids can save in the 5 (6) position still further unsaturated and / or carry substituents, such as Alkyl, alkylidene, hydroxy, oxo, amino, halogen, cyano, mercapto or thio substituents. The substituents can optionally be present in a functionally modified form. Hydroxy, amino and mercapto groups can be alkylated or acylated. At Hydroxyl groups in two adjacent carbon atoms can be used as a cyclic acetal are present. Oxo and thio groups can be ketalized or as enol acylate, enol ethers or enamine are present. Acid-sensitive radicals such as the acetal group are used in the procedural reaction split, leaving the underlying group at liberty is set.
Als Ausgangsverbindungen eignen sich z. B. 5-Pregnen-3ß-ol-20-on, 5-Pregnen-3ß,17a-diol-20-on, Dehydro-epiandrosteron, 5-Androsten-3ß,17ß-diol, 17x-Methyl-5-androsten-3ß,17ß-diol, 17x-Methyl.19-nor-5-androsten-3ß,17ß-diol, 19-nor-5-Androsten-3ß-ol-17-on, Cholesterin.Suitable starting compounds are, for. B. 5-pregnen-3ß-ol-20-one, 5-pregnen-3ß, 17a-diol-20-one, dehydro-epiandrosterone, 5-androstene-3ß, 17ß-diol, 17x-methyl-5-androstene-3ß, 17ß-diol, 17x-methyl. 19-nor-5-androsten-3ß, 17ß-diol, 19-nor-5-androsten-3ß-ol-17-one, cholesterol.
Der für die Reaktion verwendete Braunstein kann in der handelsüblichen Form ,angewandt werden. Besonders günstige Ergebnisse werden erzielt, wenn man »aktiven Braunstein nach Attenburrowe verwendet(J. Attenburr ow, A. F. B. Cameron, 1-1,J. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen und T. W a 1 k e r, J. chem. Soc. [London], Bd. 1952, S. 1094). Für die Fluorierungsreaktion können 1 bis 50 Mol Braunstein pro Mol Steroid eingesetzt werden.The manganese dioxide used for the reaction can be found in the commercially available Shape, to be applied. Particularly favorable results are achieved if you are »active Brownstone used according to Attenburrowe (J. Attenburr ow, A. F. B. Cameron, 1-1, J. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen and T. W a 1 k e r, J. chem. Soc. [London], vol. 1952, p. 1094). For the fluorination reaction can 1 to 50 moles of manganese dioxide are used per mole of steroid.
Der für die Reaktion benötigte Fluorwasserstoff wird in einer Menge von 1 bis 100 Mol pro Mol Steroid angewendet.The hydrogen fluoride required for the reaction is used in an amount of 1 to 100 moles per mole of steroid.
Als Lösungsmittel für die Reaktion können Kohlenwasserstoffe verwendet werden, wie Benzinfraktionen, Benzol, Toluol, Xylol sowie halogenierte Kohlenwasserstoffe, wie Methylenchlorid, Chloroform, Tetrachlorkohlenstoff, Trichloräthylen, aliphatische oder aromatische Äther, wie Diäthyläther, Dioxan, Tetrahydrofuran, aliphatische oder aromatische Nitroverbindungen, wie Nitromethan, Nitrobenzol, Alkohole, wie Methanol, Äthanol, Isopropanol, Hexanol oder Benzylalkohol, und andere inerte Lösungsmittel, wie Acetonitril. Es können auch Gemische dieser Lösungsmittel eingesetzt werden, gegebenenfalls auch unter Zusatz von Wasser.Hydrocarbons can be used as the solvent for the reaction such as gasoline fractions, benzene, toluene, xylene and halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichlorethylene, aliphatic or aromatic ethers such as diethyl ether, dioxane, tetrahydrofuran, aliphatic or aromatic nitro compounds such as nitromethane, nitrobenzene, alcohols such as Methanol, ethanol, isopropanol, hexanol or benzyl alcohol, and other inert solvents, like acetonitrile. Mixtures of these solvents can also be used, optionally with the addition of water.
Die Fluorierung nach der Erfindung wird vorteilhaft zwischen -80 und + 100°C, vorzugsweise zwischen -30 und -150'C, ausgeführt. Die Reaktionszeiten liegen zwischen 30 Minuten und mehreren Tagen. Es empfiehlt sich, das Reaktionsgemisch zu schütteln oder zu rühren.The fluorination according to the invention is advantageous between -80 and + 100 ° C, preferably between -30 and -150'C. The response times are between 30 minutes and several days. It is recommended that the reaction mixture to shake or stir.
Es ist nicht erforderlich, die Reaktionspartner in einer bestimmten Reihenfolge zusammenzugeben. Jedoch hat es sich besonders bewährt, der Fluorwasserstofflösung zunächst den Braunstein und erst nach einer Zeit das 3ß-Hydroxy-45-steroid hinzuzufügen.It is not necessary to be the reactant in a particular Order together. However, the hydrogen fluoride solution has proven particularly useful first add the manganese dioxide and only after a while the 3ß-hydroxy-45-steroid.
Nach dem Verfahren der Erfindung können z. B. die folgenden Verbindungen hergestellt werden: Die nach dem Verfahren der Erfindung hergestellten 3ß-Fluor-A 5-steroide sollen als Pharmazeutika in der Humanmedizin verwendet werden. Die Verbindungen zeigen zum Teil anabole, sedative, diuretische, blutdrucksenkende und antihormonelle Wirksamkeit.According to the method of the invention, for. B. the following compounds are prepared: The 3ß-fluoro-A prepared by the process of the invention 5-steroids are said to be used as pharmaceuticals in human medicine. The connections partly show anabolic, sedative, diuretic, antihypertensive and antihormonal Effectiveness.
Beispiel l 3ß-Fluor-5-pregnen-20-on Zu einer Lösung von 42 g wasserfreier Flußsäure in 150 ccm Methylenchlorid gibt man bei -20°C portiorisweise unter Rühren 33 g Mangandioxyd nach A t t e n b u r r o w und läßt 10 Minuten reagieren. Dann werden 15 g 5-Pregnen-3ß-ol-20-on, gelöst in 300 ccm Methylenchlorid, hinzugefügt. Danach wird das Gemisch 4 Stunden bei -20°C gerührt. Anschließend tropft man die Reaktionsmischung unter starkem Rühren in ein Gemisch aus wäßriger Natriumhydrogencarbonatlösung und Chloroform ein und arbeitet mit Chloroform in üblicher Weise auf. Das Rohprodukt wird in Benzol an 350 g Kieselgel chromatographiert. Die im Dünnschichtchromatogramm einheitlichen Berizolfraktionen (nach etwa 300 ccm Vorlauf in etwa 0,71) werden vereinigt und abgezogen. Den Rückstand kristallisiert man zunächst aus Äther, dann aus Aceton um. Schmp. des so erhaltenen 3ß-Fluor-5-pregnen-20-on: 163 bis 164`C, [i] ö = +14° (Chloroform). Ausbeute: 50°/o.Example l 3β-Fluoro-5-pregnen-20-one To a solution of 42 g of anhydrous Hydrofluoric acid in 150 cc of methylene chloride is added in portions at -20 ° C. with stirring 33 g manganese dioxide according to A t t e n b u r o w and let react for 10 minutes. then 15 g of 5-pregnen-3β-ol-20-one, dissolved in 300 cc of methylene chloride, are added. The mixture is then stirred at -20 ° C. for 4 hours. Then you drip the Pour the reaction mixture into a mixture of aqueous sodium hydrogen carbonate solution with vigorous stirring and chloroform and works with chloroform in the usual way. The raw product is chromatographed in benzene on 350 g of silica gel. The one in the thin-layer chromatogram uniform berizol fractions (after about 300 ccm forerun in about 0.71) united and withdrawn. The residue is crystallized first from ether, then from acetone. Melting point of the 3β-fluoro-5-pregnen-20-one thus obtained: 163 to 164 ° C, [i] δ = + 14 ° (chloroform). Yield: 50%.
Beispiel 2 3ß-Fluor-5-androsten-17-orr Zu einer Lösung von 14g wasserfreier Flußsäure in 50 ccm Methylenchlorid gibt man bei -20°C portionsweise unter Rühren 11 g Mangandioxyd nach A t t e n b u r r o w und läßt 10 Minuten reagieren. Dann fügt man 5 g Dehydro-epiandrosteron in 100 ccm Methylenchlorid hinzu und rührt 3 Stunden bei 0°C. Nach Aufarbeitung wie im Beispiel 1 wird das Rohprodukt an Aluminiumoxyd chromatographiert. Das mit Benzol eluierte 3ß-Fluor-5-androsten-17-on wird aus Essigester umkristallisiert. Schmp. 153 bis 154°C, [cx] ä = -19° (Chloroform). Ausbeute: 52°/0.Example 2 3ß-Fluor-5-androsten-17-orr To a solution of 14g of anhydrous Hydrofluoric acid in 50 cc of methylene chloride is added in portions at -20 ° C. with stirring 11 g manganese dioxide according to A t t e n b u r o w and let react for 10 minutes. then 5 g of dehydro-epiandrosterone in 100 cc of methylene chloride are added and the mixture is stirred for 3 Hours at 0 ° C. After working up as in Example 1, the crude product becomes aluminum oxide chromatographed. The 3ß-fluoro-5-androsten-17-one eluted with benzene is converted from ethyl acetate recrystallized. Mp. 153 to 154 ° C, [cx] = -19 ° (chloroform). Yield: 52 ° / 0.
Beispiel 3 3ß-Fluor-5-androsten-17ß-ol Ein Gemisch von 14 g wasserfreier Flußsäure, 11 g Mangandioxyd nach A t t e n b u r r o w und 5 g 5-Androsten-3ß,17ß-diol in I 50 ccm Methylenchloridwird über Nacht bei -5 ° C geschüttelt und dann wie im Beispiell aufgearbeitet. Man chromatographiert an Aluminiumoxyd und eluiert mit Benzol-Chloroform-Gemischen das 3ß-Fluor-5-androsten-17ß-ol, das nach Umkristallisieren aus Aceton bei 160 bis 161'C schmilzt; [.x] ö` _ -60° (Chloroform). Ausbeute: 44"/,.Example 3 3β-Fluoro-5-androsten-17β-ol A mixture of 14 g of anhydrous hydrofluoric acid, 11 g of A ttenburrow's manganese dioxide and 5 g of 5-androstene-3β, 17β-diol in 50 cc of methylene chloride is overnight at -5 ° C shaken and then worked up as in the example. It is chromatographed on aluminum oxide and eluted with benzene-chloroform mixtures the 3ß-fluoro-5-androsten-17ß-ol, which melts after recrystallization from acetone at 160 to 161 ° C; [.x] ö` _ -60 ° (chloroform). Yield: 44 "/ ,.
Beispiel 4 3ß-Fluor-5-cholesten Man gibt in ein fiußsäurefestes Druckgefäß eine Lösung von 14g wasserfreier Flußsäure in 150 ccm Methylenchlorid, 11 g Mangandioxyd nach A t t e nb u r r o w und 7 g Cholesterin, verschließt und erwärmt unter Schütteln allmählich auf +50`C. Nachdem diese Temperatur 30 Minuten eingehalten wurde, kühlt man auf -20°C, öffnet den Autoklav und arbeitet wie im Beispiel 1 auf. Das Rohprodukt wird an Aluminiumoxyd, Aktivitätsstufe Il, chromatographiert. Die Petroläthereluate werden aus Aceton umkristallisiert. Schmp. des so erhaltenen 3ß-Fluor-5-cholestens: 94bis95°C, [1] ö =-46° (Chloroform). Ausbeute: 600/,. EXAMPLE 4 3β-Fluoro-5-cholesterol A solution of 14 g of anhydrous hydrofluoric acid in 150 cc of methylene chloride, 11 g of manganese dioxide according to A tte nburrow and 7 g of cholesterol is placed in a pressure vessel which is resistant to hydrofluoric acid, and it is closed and gradually warmed to + 50 ° C. while shaking . After this temperature has been maintained for 30 minutes, the mixture is cooled to -20 ° C., the autoclave is opened and the process is carried out as in Example 1. The crude product is chromatographed on aluminum oxide, activity level II. The petroleum ether eluates are recrystallized from acetone. Melting point of the 3β-fluoro-5-cholest obtained in this way: 94 to 95 ° C, [1] δ = -46 ° (chloroform). Yield: 600 / ,.
Beispiel s Analog Beispiel 1 werden 15 g 5-Pregnen-3ß,17,x-diol-20-on-17-acetat zu 3ß-Fluor-5-pregnen-l7a-ol-20-on-17-acetat umgesetzt. Schmp. 193°C, [a] -80° (Chloroform). Ausbeute: 510/,.Example s Analogously to Example 1, 15 g of 5-pregnen-3β, 17, x-diol-20-one-17-acetate are used converted to 3ß-fluoro-5-pregnen-l7a-ol-20-one-17-acetate. Mp 193 ° C, [a] -80 ° (chloroform). Yield: 510 / ,.
In analoger Weise wird aus 12,5 g 5-Pregnen-3ß,17x-dio1-20-on das 3 f3-Fluor-5-pregnen-17 t-o1-20-on hergestellt. Ausbeute: 47°;o.In an analogous manner, 12.5 g of 5-pregnen-3β, 17x-dio1-20-one become the 3 f3-fluorine-5-pregnen-17 t-o1-20-one produced. Yield: 47 °; o.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012160006A1 (en) * | 2011-05-20 | 2012-11-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antagonists of cb1 receptor. |
| US10259839B2 (en) | 2012-11-28 | 2019-04-16 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | 3-(4′-substituted)-benzyl-ether derivatives of pregnenolone |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012160006A1 (en) * | 2011-05-20 | 2012-11-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antagonists of cb1 receptor. |
| RU2593751C2 (en) * | 2011-05-20 | 2016-08-10 | Энсэрм (Энститю Насьональ Де Ля Санте Э Де Ля Решерш Медикаль) | Cb1 receptor antagonists |
| US10040816B2 (en) | 2011-05-20 | 2018-08-07 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Antagonists of CB1 receptor |
| US10150793B2 (en) | 2011-05-20 | 2018-12-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antagonists of CB1 receptor |
| US10259839B2 (en) | 2012-11-28 | 2019-04-16 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | 3-(4′-substituted)-benzyl-ether derivatives of pregnenolone |
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