DE1046042B - Process for the production of multiple unsaturated steroid ketones - Google Patents
Process for the production of multiple unsaturated steroid ketonesInfo
- Publication number
- DE1046042B DE1046042B DEM35823A DEM0035823A DE1046042B DE 1046042 B DE1046042 B DE 1046042B DE M35823 A DEM35823 A DE M35823A DE M0035823 A DEM0035823 A DE M0035823A DE 1046042 B DE1046042 B DE 1046042B
- Authority
- DE
- Germany
- Prior art keywords
- dione
- pregnatetraen
- pregnatriene
- diol
- acylate
- 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 7
- -1 steroid ketones Chemical class 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 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 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 150000003944 halohydrins Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 150000005672 tetraenes Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 230000003054 hormonal effect Effects 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 125000003306 cortisone group Chemical group 0.000 description 1
- 150000001887 cortisones Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 150000005671 trienes Chemical class 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung mehrfach ungesättigter Steroidketone Im Rahmen von Forschungsarbeiten über Cortisonderivate gelang es erstmalig, Steroidketone herzustellen, die vier Doppelbindungen in den Ringen A und B bzw. A, B und C enthalten und die außerdem in 17-Stellung die Cortisonseitenkette besitzen.Process for the production of polyunsaturated steroid ketones Im As part of research work on cortisone derivatives it was possible for the first time to produce steroid ketones that contain four double bonds in rings A and B or A, B and C. and which also have the cortisone side chain in the 17 position.
Gleichzeitig wurde gefunden, daß diese Verbindungen eine ausgeprägte Nebennierenrindenhormonwirkung besitzen.At the same time it was found that these compounds have a pronounced Have adrenal hormone effects.
Das Verfahren nach der Erfindung besteht darin, daß man zunächst ein 1,4,6-Pregnatrien-3,20-dion-Ilß,17a,21-triol-21-acylat in bekannter Weise durch Behandlung mit wasserabspaltenden Mitteln zum 1,4,6,9(11) -Pregnatetraen-3,20-dion-17a,21-diod--21-acylat dehydratisiert. Diese Verbindung kann gegebenenfalls nach üblichen Methoden zum 1,4,6,9(11)-Pregnatetraen-3,20-dion-17a,21-diol verseift oder in das 9,11-Halogenhydrin übergeführt werden. Man erhält auf diesem Wege ein 1,4,6-Pregnatrien-9a-halogen-3,20-dion-Ilß,17a,21-trial-21=acy:st. Das so hergestellte Halogenhydrin kann gleichzeitig oder nacheinander mit dehydrierend und dehydrohalogenierend wirkenden Mitteln behandelt und so in das 1,4,6,8(9)-Pregnatetraen- 3,11, 20 - trion-17a, 21- diol - 21- acylat übergeführt werden. Führt man zuerst die Dehydrierung durch, so bildet sich ein 1,4,6-Pregnatrien-9a-halogen-3,11,20-trion-17a,21-diol-21-acylat, aus welchem durch Behandlung mit halogenwasserstoffabspaltenden Mitteln das 1,4,6,8(9)-Pregn:atetraen-3,11,20-trion-17a,21-diol-21-acylat gewonnen werden kann.The method according to the invention consists in that one first 1,4,6-Pregnatriene-3,20-dione-ILß, 17a, 21-triol-21-acylate in a known manner Treatment with dehydrating agents to give 1,4,6,9 (11) -Pregnatetraen-3,20-dione-17a, 21-diod-21-acylate dehydrated. This compound can optionally by customary methods for 1,4,6,9 (11) -Pregnatetraen-3,20-dione-17a, 21-diol saponified or into the 9,11-halohydrin be transferred. In this way, a 1,4,6-pregnatriene-9a-halogen-3,20-dione-ILß, 17a, 21-trial-21 = acy: st. The halohydrin produced in this way can be dehydrogenating simultaneously or in succession and dehydrohalogenating agents treated and so in the 1,4,6,8 (9) -Pregnatetraen- 3,11, 20-trione-17a, 21-diol-21-acylate are converted. One leads first the dehydration through, forms a 1,4,6-pregnatriene-9a-halogen-3,11,20-trione-17a, 21-diol-21-acylate, from which the 1,4,6,8 (9) -Pregn: atetraen-3,11,20-trione-17a, 21-diol-21-acylate was obtained by treatment with agents that split off hydrogen halide can be won.
Dieser Ester kann gegebenenfalls zum 1,4,6,8(9)-Pregnatetraen-3,11,20-trion-17a,21-diol in bekannter Weise verseift werden. Zweckmäßigerweise arbeitet man dabei unter Ausschluß von Sauerstoff. Der Reaktionsverlauf entspricht dem folgenden Schema: R bedeutet Acyl, vorzugsweise einen niederen aliphatischen Acylrest, wie Acetyl, und X Halogen, vorzugsweise Brom.This ester can optionally be saponified in a known manner to give 1,4,6,8 (9) -Pregnatetraen-3,11,20-trione-17a, 21-diol. It is expedient to work with the exclusion of oxygen. The course of the reaction corresponds to the following scheme: R denotes acyl, preferably a lower aliphatic acyl radical such as acetyl, and X denotes halogen, preferably bromine.
Die als Ausgangsmaterial dienende Verbindung I kann z. B. hergestellt werden durch Dehydrierung von Hydrocortison-21-acetat mit Ch.loranil (vgl. hierzu Journ. Amer. Chem. Soc., Bd. 79, 1957, S. 1258), wobei sich 6-Dehydro-hydrocortison-21-acetat bildet, ,welches sich durch Behandlung mit Selendioxyd in bekannter Weise zum 1,4,6-Pregnatrien-3,20-dion-11ß,17a,21-triol-21-acetat dehydrieren läßt. Das so hergestellte Trien (I; R = Acetyl) ist als Ausgangsmaterial für die Synthese der Tetraensteroidketone nach der Erfindung besonders geeignet. Für die Herstellung der Ausgangsverbindungen wird im Rahmen der vorliegenden Erfindung Schutz nicht begehrt.The compound I serving as the starting material can, for. B. manufactured are obtained by dehydrating hydrocortisone-21-acetate with chloranil (cf. Journ. Amer. Chem. Soc., Vol. 79, 1957, p. 1258), 6-dehydro-hydrocortisone-21-acetate forms, which is formed by treatment with selenium dioxide in a known manner to 1,4,6-pregnatriene-3,20-dione-11ß, 17a, 21-triol-21-acetate dehydrate. The triene (I; R = acetyl) produced in this way is used as the starting material particularly suitable for the synthesis of the tetraensteroid ketones according to the invention. For the preparation of the starting compounds, in the context of the present invention Protection not desired.
Die Dehydratisierung von I zu II gelingt durch Behandlung mit wasserabspaltenden Mitteln, z. B. Thionylchlorid oder Phosphoroxychlorid. Wie bei solchen Wasserabspaltungsreaktionen üblich, arbeitet man zweckmäßigerweise in Gegenwart einer organischen Base, wie Pyridin, Chinolin, Lutidin, Picolin oder Dimethylanilin. Den Ester II kann man unter Anwendung üblicher Methoden, z. B. durch Behandlung mit Natriumhydrogencarbonat oder NaOH und zweckmäßig in Abwesenheit von Sauerstoff, zum 1,4,6,9(11)-Pregnatetraen-3,20-dion-17a,21-diol (III) verseifen. Als Halogenhydrin (IV) eignet sich für die weitere Umsetzung besonders das 1,4,6-Pregnatrien-9o"-brom-3,20-dion-11ß,17a,21-triol-21-acetat (IV; X= Br, R = Acetyl). Diese Verbindung läßt sieh herstellen, indem man das Tetraen (II) mit N-Bröm-cärbonsäureimiden oder -amiden, vorzugsweise mit N-Bromaeetamid oder N-Bromsuccinimid in Gegenwart von Wasser und einem inerten organischen Lösungsmittel, wie Dioxan oder tert.-Butänol, in bekannter Weise behandelt. Als vorteilhaft bei dieser Reaktion hat sich der Zusatz geringer Mengen einer starken Säure, wie Schwefel-, p-Toluölsulfon- oder Perchlorsäure, erwiesen, wobei besonders - durch Zugabe der letzteren gute Erfolge erzielt werden können.The dehydration of I to II is achieved by treatment with dehydrating agents, e.g. B. thionyl chloride or phosphorus oxychloride. As is customary in such dehydration reactions, it is expedient to work in the presence of an organic base, such as pyridine, quinoline, lutidine, picoline or dimethylaniline. The ester II can be obtained using conventional methods, e.g. B. by treatment with sodium hydrogen carbonate or NaOH and expediently in the absence of oxygen, saponify 1,4,6,9 (11) -Pregnatetraen-3,20-dione-17a, 21-diol (III). 1,4,6-Pregnatriene-9o "-bromo-3,20-dione-11ß, 17a, 21-triol-21-acetate (IV; X = Br, R = acetyl) .This compound can be prepared by treating the tetraene (II) with N-bromocarboximides or amides, preferably with N-bromoeetamide or N-bromosuccinimide, in the presence of water and an inert organic solvent such as dioxane or The addition of small amounts of a strong acid, such as sulfuric, p-toluenesulfonic or perchloric acid, has proven advantageous in this reaction, and particularly good results can be achieved by adding the latter .
Eine bevorzugte Ausführungsform der Synthese besteht darin, das Halogenhydrin IV ohne Isolierung des Halogenketons V direkt zum Tetraenketon VI umzusetzen. Die Durchführung gelingt leicht, wenn man das Halogenhydrin IV, vorzugsweise 1,4,6-Pregnatrien - 9a -Brom - 3, 20-dion=11 ß,17a"21-triol-21-acetat (IV; X = Br, R = Acetyl), mit Chromsäureanhydrid (Cr03) in Pyridin oder einer anderen organischen Base, wie z. B. Lutidin oder Chi.nolin, behandelt. Man erreicht durch diese Behandlung nicht nur die Dehydrierung der 11ß-0 H-Gruppe zur 11-Carbonyl-Gruppe, sondern die Gegenwart des Pyridins (bzw. anderer organischer Basen) bewirkt gleichzeitig eine Dehyd.rohalogenierung unter Ausbildung der 8(9)-ständigen Doppelbindung. Das so gewonnene 6,8(9)-bis-Dehydiro p.rednison-21-acylat (VI) läßt seich leicht, z. B. mit Natriumhydrogencaxbonat oder mit Na OH, zweckmäßigerweise unter Ausschluß von Sauerstoff, zum 6,8(9)-bis-Dehydro-prednison (VII) verseifen.A preferred embodiment of the synthesis consists in converting the halohydrin IV directly to the tetraenketone VI without isolating the haloketone V. It is easy to carry out if the halohydrin IV, preferably 1,4,6-pregnatriene-9a-bromine-3, 20-dione = 11 ß, 17a "21-triol-21-acetate (IV; X = Br, R = Acetyl), treated with chromic anhydride (Cr03) in pyridine or another organic base such as lutidine or quinoline.This treatment not only results in the dehydrogenation of the 11β-0 H group to 11-carbonyl -Group, but the presence of the pyridine (or other organic bases) simultaneously causes a dehyd.rohalogenation with the formation of the 8 (9) double bond Acylate (VI) can easily be saponified, for example with sodium hydrogen carbonate or with Na O H, expediently with the exclusion of oxygen, to give 6,8 (9) -bis-dehydroprednisone (VII).
Die nach dem erfindungsgemäßen Verfahren herstellba@ren neuen Verbindungen sollen als Chemotherapeutika mit Nebennierenrindenhormonwirkung Verwendung finden. Beispiele a) Dehydratisierung 10 g 6-Dehydro-prednisolon-21-acetat (I; R = Acety 1) werden in 100 ccm absolutem Pyridin gelöst. 1,5 ccm Thionylchlorid zugefügt und das Reaktionsgemisch 35 Minuten auf dem Dampfbad erhitzt, danach wird abgekühlt, in Wasser eingegossen, mit Chloroform extrahiert und wie üblich aufgearbeitet.The new compounds which can be prepared by the process according to the invention should be used as chemotherapeutic agents with adrenal cortical hormone effects. Examples a) Dehydration 10 g of 6-dehydro-prednisolone-21-acetate (I; R = Acety 1) will be dissolved in 100 cc of absolute pyridine. 1.5 cc of thionyl chloride was added and the reaction mixture Heated for 35 minutes on the steam bath, then cooled, poured into water, extracted with chloroform and worked up as usual.
Aus Methanol kristallisiert 1,4,6,9(11)-Pregnatetraen-3,20-dion-17a,21-diol-21-acetat (II; R = Acetyl) mit Fp. 222 bis 226° C. Ausbeute 80 0/0, UR-Spektrum Nr. I.1,4,6,9 (11) -Pregnatetraen-3,20-dione-17a, 21-diol-21-acetate crystallizes from methanol (II; R = acetyl) with melting point 222 to 226 ° C. Yield 80%, UR spectrum No. I.
b) H O Br-Anlagerung 2 g 1,4,6,9(11)-Pregnatetraen-3,20-dion-17a,21-diol-21-acetat (II ; R = Acetyl) werden in 80-ccm Dioxan und; 30ccm Wasser gelöst und danach 990 mg N-Bromacetamid und 0,428 ccm Perchlorsäure (70o/oig) zugefügt. Die Lösung wird 3 Stunden bei Zimmertemperatur stehengelassen, anschließend in 1 1 Wasser eingerührt und das kristallin anfaulende Rohprodukt abgesaugt. Ausbeute 1,9 g 1,4,6-Pregnatrien-9a-brom-3,20-dion-11ß,17a,21-triol-21-acetat (IV; R = Acetyl, X = Br) vom Fp. 131 bis 132,5° C, nach Umkristallisation aus Methanol: Fp. 167 bis 170° C, UR-Spektrum Nr. II.b) H O Br addition 2 g 1,4,6,9 (11) -Pregnatetraen-3,20-dione-17a, 21-diol-21-acetate (II; R = acetyl) are dissolved in 80 ccm of dioxane and; 30ccm of water dissolved and then 990 mg of N-bromoacetamide and 0.428 cc of perchloric acid (70%) were added. The solution will be Left to stand for 3 hours at room temperature, then stirred into 1 liter of water and sucked off the crystalline decomposing crude product. Yield 1.9 g of 1,4,6-pregnatriene-9a-bromo-3,20-dione-11β, 17a, 21-triol-21-acetate (IV; R = acetyl, X = Br) from melting point 131 to 132.5 ° C, after recrystallization from methanol: Mp. 167 to 170 ° C, UR spectrum no. II.
Man kann auch 3,4g 1,4,6,9(11)-Pregnatetraen-3,20-dion-17a,21-diol-21-acetat (1I; R = Acetyl) in 136 ccm Dioxan und 51 ccm Wasser lösen, dann 2,37g N-Bromsuccinimid und 0,727 ccm Perchlorsäure (70 °/a) zufügen und dieses Reaktionsgemisch 1,5 Stunden bei Raumtemperatur stehenlassen Nach dem Einrühren in 21 Wasser kristallisiert das 1,4,6-Pregnatrien-9a-brom-3,20-dion-11ß,17a,21-triol-21-acetat (IV; R = Acetyl, X = Br) aus, Fp. 130°C. Nach Umkristallisation aus Methanol liegt der Schmelzpunkt bei 167 bis 170° C.3.4g 1,4,6,9 (11) -Pregnatetraen-3,20-dione-17a, 21-diol-21-acetate can also be used Dissolve (1I; R = acetyl) in 136 cc of dioxane and 51 cc of water, then 2.37 g of N-bromosuccinimide and 0.727 ccm of perchloric acid (70 ° / a) and this reaction mixture for 1.5 hours Leave to stand at room temperature. After stirring into 21 water, the crystallizes 1,4,6-Pregnatriene-9a-bromo-3,20-dione-11ß, 17a, 21-triol-21-acetate (IV; R = acetyl, X = Br) off, m.p. 130 ° C. After recrystallization from methanol, the melting point is at 167 to 170 ° C.
c) Dehydrierung und Halogenwasserstoffabspaltung 10g 1,4,6-Pregnatrien-9a-brom-3,20-dion-11ß,17a, 21-triol-21-acetat (IV; R = Acetyl, X = Brom) werden in 100 ccm absolutem Pyridin gelöst und unter Kühlung zu einer Lösung von 10g Cr 03 in 100 ccm absolutem Pyridin hinzugefügt. Nach 24stündigem Stehen wird das Reaktionsgemisch in 1,5 1 angesäuertes Wasser eingegossen, die braune Fällung abgesaugt, in Aceton ausgekocht und über wenig Kieselgel abfiltriert. Anschließend wird die acetonische Lösung eingeengt. Dabei scheidet sich das 1,4,6,8(9)-Pregnatetraen-3,11,20-trion-17a,21-diol-21-acetat (VI; R = Acetyl) in gelben prismatischen Nadeln ab, die nach Umkristallisation aus Aceton-Methanol bei 157 bis 160° C schmelzen; [a] ö° = -I- 1024° C (Dioxan), [a] 'D' = -f- 981,5° C (Aceton). UV-Spektrum: Amax 220 m[., E = 19 800; 272 mR,, a = 16100; 380 mg" a = 8510, UR-Spektrum Nr. III.c) dehydrogenation and elimination of hydrogen halide 10g 1,4,6-pregnatriene-9a-bromo-3,20-dione-11ß, 17a, 21-triol-21-acetate (IV; R = acetyl, X = bromine) are dissolved in 100 cc of absolute pyridine dissolved and with cooling to a solution of 10 g of Cr 03 in 100 cc of absolute pyridine added. After standing for 24 hours, the reaction mixture is acidified in 1.5 liters Poured in water, suctioned off the brown precipitate, boiled it in acetone and poured it over a little silica gel filtered off. The acetone solution is then concentrated. The 1,4,6,8 (9) -Pregnatetraen-3,11,20-trione-17a, 21-diol-21-acetate separates (VI; R = acetyl) in yellow prismatic needles, which after recrystallization from Melt acetone-methanol at 157 to 160 ° C; [a] ö ° = -I- 1024 ° C (dioxane), [a] 'D' = -f- 981.5 ° C (acetone). UV spectrum: Amax 220 m [., E = 19,800; 272 mR ,, a = 16100; 380 mg "a = 8510, UR spectrum No. III.
d) Verseifung 2,9g 1,4,6,8(9)-Pregnatetraen-3,11,20-trion-17a,21-diol-21-acetat (VI; R = Acetyl) werden in 125 ccm Methanol unter Stickstoff zum Sieden erhitzt, 0,77g Natriumhydrogencarbonat in 12 ccm Wasser hinzufügt und das Reaktionsgemisch 7 Minuten unter Rückfluß gekocht. Danach wird es in Wasser eingegossen, mit Chloroform ausgeschüttelt und wie üblich aufgearbeitet. 1,4,6,8 (9) -Pregnatetraen-3,11,20-trion-17a, 21-diol (VII) kristallisiert aus Aceton und läßt sich aus Aceton-Äther reinigen. Schmelzpunkt: 232 bis 234° C; [a] öo = -I- 1049',3°C (Dioxan), UV-Spektrum: .lm", 218 mR, E = 18 900; 275 m@l,, = 12 900; 385 mR., s = 6600. UR-Spektrum Nr. IV.d) Saponification 2.9 g 1,4,6,8 (9) -Pregnatetraen-3,11,20-trione-17a, 21-diol-21-acetate (VI; R = acetyl) are dissolved in 125 cc of methanol under nitrogen heated to boiling, 0.77 g of sodium hydrogen carbonate in 12 ccm of water is added and the reaction mixture is refluxed for 7 minutes. Then it is poured into water, extracted with chloroform and worked up as usual. 1,4,6,8 (9) -Pregnatetraen-3,11,20-trione-17a, 21-diol (VII) crystallizes from acetone and can be purified from acetone-ether. Melting point: 232 to 234 ° C; [a] öo = -I- 1049 ', 3 ° C (dioxane), UV spectrum: .lm ", 218 mR, E = 18,900; 275 m @ l ,, = 12,900; 385 mR., s = 6600. UR spectrum No. IV.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEM35823A DE1046042B (en) | 1957-11-06 | 1957-11-06 | Process for the production of multiple unsaturated steroid ketones |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEM35823A DE1046042B (en) | 1957-11-06 | 1957-11-06 | Process for the production of multiple unsaturated steroid ketones |
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| Publication Number | Publication Date |
|---|---|
| DE1046042B true DE1046042B (en) | 1958-12-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEM35823A Pending DE1046042B (en) | 1957-11-06 | 1957-11-06 | Process for the production of multiple unsaturated steroid ketones |
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| DE (1) | DE1046042B (en) |
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1957
- 1957-11-06 DE DEM35823A patent/DE1046042B/en active Pending
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