DE1071081B - Process for the preparation of 6-alkoxy-3-keto steroids - Google Patents
Process for the preparation of 6-alkoxy-3-keto steroidsInfo
- Publication number
- DE1071081B DE1071081B DENDAT1071081D DE1071081DA DE1071081B DE 1071081 B DE1071081 B DE 1071081B DE NDAT1071081 D DENDAT1071081 D DE NDAT1071081D DE 1071081D A DE1071081D A DE 1071081DA DE 1071081 B DE1071081 B DE 1071081B
- Authority
- DE
- Germany
- Prior art keywords
- alkoxy
- preparation
- keto steroids
- steroids
- process according
- 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
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- -1 aliphatic alcohols Chemical class 0.000 claims description 4
- 239000004593 Epoxy Substances 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 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 description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 150000003460 sulfonic acids Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 2
- 150000003128 pregnanes Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Es ist bekannt, daß sich 9/3,1 l~Epoxysteroide in Methanol in Gegenwart von Perchlorsäure zu den entsprechenden 11/3 - Hydroxy - 9α - methoxy - V erbindungen aufspalten lassen.It is known that 9 / 3.1 l ~ epoxy steroids are found in Methanol in the presence of perchloric acid to the corresponding 11/3 - hydroxy - 9α - methoxy compounds let split.
Es wurde nun gefunden, daß 3-Kctale von 5a,6-Epoxy-3-ketosteroiden in alkoholischer Lösung in Gegenwart von sauren Katalysatoren in 6-Alkoxy-J 4-3-ketosteroide übergeführt werden. Es war dabei überraschend, daß in einer Stufe drei Reaktionen erfolgen, und zwarIt has now been found that 3-octals are converted from 5a, 6-epoxy-3-keto steroids in alcoholic solution in the presence of acidic catalysts into 6-alkoxy-J 4 -3-keto steroids. It was surprising that three reactions take place in one stage, namely
1. die Aufspaltung des Epoxydes zur 5-Hydroxy-6-methoxy-Verbindung, 1. the splitting of the epoxy to the 5-hydroxy-6-methoxy compound,
2. die A\ifspaltung des Ketals mm 3-Keton und2. the cleavage of the ketal mm 3-ketone and
3. die Abspaltung der Hydroxylgruppe am Kohlenstoffatom 5 unter Bildung der A '•-Doppclbindung.3. The cleavage of the hydroxyl group on carbon atom 5 with the formation of the A '• double bond.
Als Ketosteroide kommen sowohl Androstan- wie auch Pregnanverbindungen in Frage, sie können im Kern ■/.. B. durch Hydroxyl-, Halogengruppen u. dgl. substituiert sein. Als Ketale sind insbesondere cyclische Ketale, wie z. B. die Äthylenketale, geeignet.As ketosteroids both androstane as well Pregnanverbindungen eligible, they can and in the core ■ / .. example by hydroxyl, halogen groups. Like. Be substituted. As ketals are in particular cyclic ketals, such as. B. the ethylene ketals, suitable.
Als Alkohole werden die niederen aliphatischen Alkohole, insbesondere Methylalkohol und Äthylalkohol, benutzt. Schließlich kommen als saure Katalysatoren mit Vorteil Perchlorsäure, Schwefelsäure sowie organische Sulfosäuren, wie z. ß. p-Toluolsulfosäure, in Betracht.The lower aliphatic alcohols, especially methyl alcohol and ethyl alcohol, are used as alcohols, used. Finally, perchloric acid, sulfuric acid and organic ones are advantageous as acidic catalysts Sulfonic acids, such as. ß. p-toluenesulfonic acid, into consideration.
Die so erhaltenen o-Alkoxy-S-ketosteroide sollen als solche therapeutische Verwendung finden oder als Zwischenprodukte für die Herstellung von Arzneimitteln dienen.The o-alkoxy-S-ketosteroids obtained in this way are said to be find such therapeutic use or as intermediates for the manufacture of pharmaceuticals to serve.
2 g 5,6a-Oxido-androstan-17/?-ol"3-on-äthylcnketal werden in 100 ecm Methanol gelöst, mit 0,75 ecm 70%iger Perchlorsäure versetzt und 48 Stunden bei Raumtemperatur stehengelassen. Danach wird mit Natriumbicarbonat neutralisiert, im Vakuum unter Stickstoff die Lösung auf 1Z3 eingeengt, mit der 5fachen Menge Wasser versetzt iind mit Methylenchlorid ausgeschüttelt. Nun wird diese Lösung mit Wasser neutral gewaschen, mit Natriumsulfat getrocknet und zur Trockne eingeengt. Der verbleibende Rückstand läßt sich aus Essigester Umkristallisieren, und man erhält so 760 mg 6-Methoxytestosteron vom Schmelzpunkt 210,5 bis 212° C. Die Substanz zeigt im V V bei 234ηιμ ein Maximum (ε — 13 500).2 g of 5,6a-oxido-androstan-17 /? - ol "3-one-ethylcnketal are dissolved in 100 ecm of methanol, 0.75 ecm of 70% perchloric acid are added and the mixture is left to stand for 48 hours at room temperature. It is then neutralized with sodium bicarbonate , the solution is concentrated to 1 Z 3 in vacuo under nitrogen, mixed with 5 times the amount of water and extracted with methylene chloride. This solution is then washed neutral with water, dried with sodium sulfate and evaporated to dryness. The remaining residue can be recrystallized from ethyl acetate, and 760 mg of 6-methoxytestosterone with a melting point of 210.5 to 212 ° C. are thus obtained. The substance shows a maximum in VV at 234ηιμ (ε - 13,500).
200 mg S.ö/y
werden in 10 ecm Methanol gelöst, mit 0,08 ecm OZ0g
p-Toluolsulfosäure versetzt und 48 Stunden bei Raumtemperatur stehengelassen. Aufarbeitung wie Beispiel 1
ergibt 6-Methoxytestosteron mit Schmelzpunkt von 209 bis 211° C.200 mg S.ö / y
are dissolved in 10 ecm methanol, with 0.08 ecm OZ 0 g
added p-toluenesulfonic acid and left to stand for 48 hours at room temperature. Working up as in Example 1 gives 6-methoxytestosterone with a melting point of 209 to 211 ° C.
Verfahren zur Herstellung
von 6-Alkoxy-3-ketosteroidenMethod of manufacture
of 6-alkoxy-3-keto steroids
Anmelder:Applicant:
Schering Aktiengesellschaft,
Berlin N 65, Müllerstr. 170-172Schering Aktiengesellschaft,
Berlin N 65, Müllerstr. 170-172
Dr. Emanuel Kaspar, Berlin-WilmeTSdorf,Dr. Emanuel Kaspar, Berlin-WilmeTSdorf,
Dr. Rudolf Wiechert, Berlin-Lichterfelde,
und Dr. Martin Schenck, Berlm-Frohn.au,
sind als Erfinder genannt wordenDr. Rudolf Wiechert, Berlin-Lichterfelde,
and Dr. Martin Schenck, Berlm-Frohn.au,
have been named as inventors
600 mg 5,6a-Oxido-arKlrostan-17/ji-ol-3-on-äthylenketal werden in 30 ecm Äthanol gelöst, mit 0,228 ecm 700/0ige.r Perchlorsäure versetzt und 72 Stunden bei Zimmertemperatur stehengelassen. Aufarbeitung wie Beispiel 1 ergibt ein Öl, woraus man durch Chromatographie über 42 g Kieselsäuregel (das 10°/0 Wasser enthält) mit Chloroform 6-Äthoxy-testosteron, F. = 157 bis 160r C, erhält. Die Substanz zeigt im UV bei 235 ιημ ein Maximum (R = 11800).600 mg of 5,6a-oxido-arKlrostan-17 / ji-ol-3-one-äthylenketal are dissolved in 30 cc of ethanol, with 0.228 cc of 70 0/0 ige.r perchloric acid and allowed to stand for 72 hours at room temperature. Work-up as Example 1 yields an oil from which one (containing 10 ° / 0 water) by chromatography over 42 g silica gel ethoxy-testosterone-6 with chloroform, mp = 157 to 160 of r C, obtained. The substance shows a maximum in the UV at 235 μm (R = 11800).
200 mg S.oa-Oxido-androstan-^ß-ol-S-on-äthylenketal werden in 10 ecm Methanol gelöst, mit 0,08 ecm 70%iger Schwefelsäure versetzt und 48 Stunden bei Zimmertemperatur stehengelassen. Abarbeitung wie Beispiel 1 ergibt 6-Methoxytestostcron mit Schmelzpunkt von 209 bis 211° C200 mg S.oa-Oxido-androstan- ^ ß-ol-S-one-ethyl ketal are dissolved in 10 ecm methanol, with 0.08 ecm 70% Added sulfuric acid and left to stand for 48 hours at room temperature. Processing as in example 1 gives 6-methoxytestostcron with a melting point of 209 to 211 ° C
160 mg S.oa-Oxido-allopregnan-S^Cl-dion-diäthylenkctal werden in einem Gemisch von 4 ecm Dioxan und 8 ecm Methanol gelöst, mit 0,06 ecm 70°/0iger Perchlorsäure versetzt und über Nacht bei Zimmertemperatur stehengelassen. Aufarbeitung wie Beispiel 1 ergibt ein Rohprodukt, aus dem man durch Umkristallisation 6-Methoxyprogestcron, F. = 167 bis 168,5° C, erhält. Die Substanz zeigt im UV bei 234 rau ein Maximum (ε = 13000).160 mg S.oa-oxido-allopregnan-S ^ are dissolved in a mixture of 4 cc of dioxane and 8 cc of methanol Cl-dione diäthylenkctal, with 0.06 cc of 70 ° / 0 perchloric acid and allowed to stand overnight at room temperature. Working up as in Example 1 gives a crude product from which 6-methoxyprogestcrone, mp = 167 to 168.5 ° C., is obtained by recrystallization. The substance shows a maximum in the UV at 234 rough (ε = 13000).
909 689/575909 689/575
Claims (5)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1071081B true DE1071081B (en) | 1959-12-17 |
Family
ID=595845
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DENDAT1071081D Pending DE1071081B (en) | Process for the preparation of 6-alkoxy-3-keto steroids |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1071081B (en) |
-
0
- DE DENDAT1071081D patent/DE1071081B/en active Pending
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