DEF0016767MA - - Google Patents
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- Publication number
- DEF0016767MA DEF0016767MA DEF0016767MA DE F0016767M A DEF0016767M A DE F0016767MA DE F0016767M A DEF0016767M A DE F0016767MA
- Authority
- DE
- Germany
- Prior art keywords
- oxidation
- acid
- pregnen
- ecm
- organic peracids
- 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.)
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- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 150000004967 organic peroxy acids Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 230000003301 hydrolyzing Effects 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 229960000583 Acetic Acid Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- OVTZIJOGPKGLQV-BYZMTCBYSA-N (8S,9S,10R,13R,14S,17S)-17-ethyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene Chemical compound C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 OVTZIJOGPKGLQV-BYZMTCBYSA-N 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (N-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229940093915 Gynecological Organic acids Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- ZJRXSAYFZMGQFP-UHFFFAOYSA-N Barium peroxide Chemical compound [Ba+2].[O-][O-] ZJRXSAYFZMGQFP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N Sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- FVTRDWMTAVVDCU-UHFFFAOYSA-N acetic acid;hydrogen peroxide Chemical compound OO.CC(O)=O FVTRDWMTAVVDCU-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- SCKXCAADGDQQCS-UHFFFAOYSA-N performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- -1 saturated aliphatic peracids Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
BUNDESREPUBLIK DEUTSCHLANDFEDERAL REPUBLIC OF GERMANY
Tag der Anmeldung: 7. Februar 1955 Bekanntgemacht am 25. Oktober 1956Registration date: February 7, 1955. Advertised on October 25, 1956
DEUTSCHES PATENTAMTGERMAN PATENT OFFICE
PATENTANMELD UNGPATENT APPLICATION UNG
KLASSE 12o GRUPPE 25o5 INTERNAT. KLASSE C 07c CLASS 12o GROUP 25o5 INTERNAT. CLASS C 07c
F 16767 IVb/12 οF 16767 IVb / 12 ο
Dr. Heinrich Ruschig, Bad Soden (Taunus),Dr. Heinrich Ruschig, Bad Soden (Taunus),
Dr. Josef Schmidt-Thome, Dr. Werner Fritsch, Frankfurt/M.-Höchst,Dr. Josef Schmidt-Thome, Dr. Werner Fritsch, Frankfurt / M.-Höchst,
und Dr. Werner Haede, Hofheim (Taunus)and Dr. Werner Haede, Hofheim (Taunus)
sind als Erfinder genannt wordenhave been named as inventors
Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Brüning, Frankfurt/M.Farbwerke Hoechst Aktiengesellschaft formerly Master Lucius & Brüning, Frankfurt / M.
Verfahren zur Herstellung von ungesättigten 17-OxypregnanenProcess for the preparation of unsaturated 17-oxypregnanes
Zusatz zum Patent 948 057Addition to patent 948 057
Gegenstand des Hauptpatents 948 057 ist ein Verfahren zur Herstellung von ungesättigten 17-Oxypregnanen, welches dadurch gekennzeichnet ist, daß man 5-Pregnen-3/3-ol-20-ketimin mit acylierenden Mitteln umsetzt, die Reaktionsprodukte nach partieller Verseifung und gegebenenfalls nach Oxydation der Oxygruppe in 3-Stellung mit organischen Persäuren oxydiert und die Oxydationsprodukte mit hydrolysierenden Mitteln behandelt.The subject of the main patent 948 057 is a process for the production of unsaturated 17-oxypregnanes, which is characterized in that 5-pregnen-3/3-ol-20-ketimine with acylating Reacts agents, the reaction products after partial saponification and optionally after oxidation of the Oxy group in 3-position is oxidized with organic peracids and the oxidation products with hydrolyzing ones Means treated.
Es wurde nun gefunden, daß man bei der Her- ic Stellung von 17-Oxyverbindungen der Steroidreihe die Stufe der partiellen Verseifung vermeiden kann,It has now been found that in the preparation of 17-oxy compounds of the steroid series can avoid the partial saponification stage,
609 659/486609 659/486
F 16767 IVb/12 οF 16767 IVb / 12 ο
wenn man 5, i7(2o)-Pregnadien-3/3-ol-20-acylaminacylate mit organischen Persäuren oxydiert und die Oxydationsprodukte mit. hydrolysierenden Mitteln umsetzt.if you have 5, i7 (2o) -Pregnadien-3/3-ol-20-acylamine acylate oxidized with organic peracids and the oxidation products with. hydrolyzing agents implements.
Die Umsetzung verläuft wahrscheinlich entsprechend nachstendem Formelschema: CH3 CH3 The implementation probably proceeds according to the following equation: CH 3 CH 3
C — NH —CO-Ac C-NH- CO-AcC-NH-CO-Ac C-NH-CO-Ac
CH,CH,
AcOAcO
AcOAcO
Das erfindungsgemäße Verfahren hat den Vorteil, daß neben der Einsparung einer Verfahrensstufe erheblich bessere Ausbeuten erzielt werden, da die Acylgruppe in 3-Stellung offenbar einen schützenden Einfluß auf die 5 ständige Doppelbindung ausübt.The method according to the invention has the advantage that, in addition to saving one method step, it is considerable Better yields can be achieved, since the acyl group in the 3-position apparently has a protective Influence on the 5 permanent double bond.
Es ist nach der Methode von Gallagher (Journ. Amer. Chem. Soc, Bd. 73, 1951, S. 184ff.) bisher nicht möglich gewesen, 5, i7(2o)-Pregnadien-3/3-ol-2O-enolacylat-acylate mit Benzopersäure partiell.in 17(20)-Stellung zu oxydieren, da die 5 ständige Doppelbindung ebenfalls angegriffen wird und undefinierbare. Gemische erhalten werden. Es war daher nicht zu erwarten, daß sich im Gegensatz dazu im Falle der Verwendung entsprechender Enacylamine die Oxydation zu den 17, 20-Oxidoverbindungen und deren Hydrolyse mit guten Ausbeuten durchführen läßt.According to the method of Gallagher (Journ. Amer. Chem. Soc, Vol. 73, 1951, pp. 184ff.) It has not yet been used possible, 5, i7 (2o) -Pregnadien-3/3-ol-2O-enolacylate acylate to partially oxidize with benzoperic acid in the 17 (20) position, since the 5 double bond also attacked and indefinable. Mixtures are obtained. It was therefore not closed expect that, in contrast, if the corresponding enacylamines are used, the oxidation will occur to the 17, 20-oxido compounds and their hydrolysis can be carried out with good yields.
Die Anlagerung von Sauerstoff an die 17 (2o)ständige Doppelbindung der Ausgangsstoffe wird mit organischen Persäuren in bekannter Weise vorgenommen. Es ist zweckmäßig, die Oxydation unter schonenden; Bedingungen durchzuführen, d. h. in schwach konzentrierten Lösungen und bei Temperaturen zwischen — 20 und + 20°, vorzugsweise bei etwa o°, zu arbeiten.The addition of oxygen to the 17 (2o) permanent The double bond of the starting materials is made with organic peracids in a known manner. It is advisable to keep the oxidation under gentle; Perform conditions, d. H. in weakly concentrated Solutions and at temperatures between -20 and + 20 °, preferably at about 0 ° work.
Als organische Persäuren kommen beispielsweise in Frage: organische Säuren, wie Perbenzoesäure, Phthalmonopersäure oder gesättigte aliphatische Persäuren, wie Perameisensäure, Peressigsäure oder Perbernsteinsäure. Es ist nicht erforderlich, freie Persäuren einzusetzen . Diese können vielmehr während der Reaktion aus den verwendeten organischen Säuren durch Zugabe von Peroxyden, beispielsweise von Natriumperoxyd oder Bariumperoxyd, gebildet werden. Auch ein Gemisch aus Wasserstoffsuperoxyd und Eisessig kann verwendet werden.Examples of organic peracids that can be used are: organic acids such as perbenzoic acid and phthalic monoperacid or saturated aliphatic peracids such as performic acid, peracetic acid or succinic acid. It is not necessary to use free peracids. Rather, these can occur during the reaction from the organic acids used by adding peroxides, for example sodium peroxide or barium peroxide. A mixture of hydrogen peroxide and glacial acetic acid can also be used be used.
Die Hydrolyse der 17,20-Oxidoverbindung wird zweckmäßig mit verdünnten Alkalilaugen, wie Natronlauge oder Kalilauge, vorgenommen.The hydrolysis of the 17,20-oxido compound will expediently made with dilute alkali solutions, such as sodium hydroxide solution or potassium hydroxide solution.
Beispiel
5-Pregnen~3/?, I7a-diol-2o-onexample
5-pregnen ~ 3 / ?, 17a-diol-2o-one
Zu einer Lösung aus 1 g 5, i7(2o)-Pregnadien-3/3-ol-20-acetylamin-acetat in einem Gemisch von 80 ecm Benzol und 9 ecm Toluol läßt man unter KühlungTo a solution of 1 g of 5,17 (2o) -Pregnadien-3/3-ol-20-acetylamine acetate in a mixture of 80 ecm benzene and 9 ecm toluene is left with cooling
HO —HO -
auf o° und Rühren langsam innerhalb 1 Stunde eine 75 Lösung aus 313 mg Benzopersäure in einem Gemisch aus 60 ecm Benzol und 6 ecm Toluol einfließen und rührt das Reaktionsgemisch noch 20 Minuten nach (bis zum Verbrauch der Benzopersäure). Anschließend « wird das Reaktionsgemisch mit 100 ecm Äther versetzt, mit 0,3 η-Natronlauge zur Entfernung der gebildeten Benzoesäure geschüttelt und mit Wasser neutral gewaschen. Nach dem Trocknen über, Natriumsulfat destilliert man das Lösungsmittel bei einer Badtemperatur von höchstens 25 ° im Vakuum ab.to 0 ° and stirring slowly within 1 hour a 75 solution from 313 mg benzoperic acid in a mixture of 60 ecm benzene and 6 ecm toluene and pour in the reaction mixture is stirred for a further 20 minutes (until the benzoperic acid is consumed). Subsequently " 100 ecm of ether is added to the reaction mixture, shaken with 0.3 η sodium hydroxide solution to remove the benzoic acid formed and with water washed neutral. After drying over sodium sulfate, the solvent is distilled off a bath temperature of at most 25 ° in a vacuum.
Der Rückstand, das rohe 17, 2O-Oxido-5~pregnen-3/?-ol-2o-acetylamin-acetat, wird in 126 ecm kaltem Methanol gelöst. Man fügt 62 ecm 0,3 n-Natronlauge hinzu und erhitzt das Gemisch 1 Stunde in einer Stickstoffatmosphäre unter Rückfluß zum Sieden. Nach dem Abkühlen neutralisiert man mit 2 n-Essigsäure und läßt über Nacht bei Raumtemperatur stehen. Hierbei kristallisiert allmählich das 5-Pregnen-3/?, i7a-diol-2O-on aus. Man erhält nach dem Abfiltrieren und Waschen des Filterrückstandes mit wenig Aceton und Äther 537 mg Rohprodukt vorn Schmelzpunkt 262 bis 263° (Kofler-Schmelzbank). Durch Umkristallisieren aus heißem Eisessig kann das Produkt weiter gereinigt werden und schmilzt dann bei 272 bis 2740 (Kofler-Schmelzbank). Es ist mit nach bekannten Verfahren hergestelltem 5-Pregnen~3/?, T1Jadiol-20-on identisch, wie durch Mischschmelzpunkt und Infrarotspektrum bewiesen werden konnte.The residue, the crude 17, 2O-Oxido-5 ~ pregnen-3 /? - ol-2o-acetylamine acetate, is dissolved in 126 ecm cold methanol. 62 ecm of 0.3 N sodium hydroxide solution is added and the mixture is heated to boiling under reflux in a nitrogen atmosphere for 1 hour. After cooling, it is neutralized with 2N acetic acid and left to stand overnight at room temperature. During this, the 5-pregnen-3 / ?, i7a-diol-2O-one gradually crystallizes out. After filtering off and washing the filter residue with a little acetone and ether, 537 mg of crude product with a melting point of 262 to 263 ° (Kofler melting bench) are obtained. The product can be purified further by recrystallization from hot glacial acetic acid and then melts at 272 to 274 0 (Kofler melting bank). It is identical to 5-pregnen ~ 3 / ?, T 1 Ja diol-20-one produced by known processes, as could be proven by the mixed melting point and infrared spectrum.
Claims (1)
Family
ID=
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