CH520131A - Bis-oxido steroids - Google Patents
Bis-oxido steroidsInfo
- Publication number
- CH520131A CH520131A CH1349070A CH1349070A CH520131A CH 520131 A CH520131 A CH 520131A CH 1349070 A CH1349070 A CH 1349070A CH 1349070 A CH1349070 A CH 1349070A CH 520131 A CH520131 A CH 520131A
- Authority
- CH
- Switzerland
- Prior art keywords
- bisoxido
- added
- thf
- oxido
- steroids
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 12
- 239000007858 starting material Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 150000003128 pregnanes Chemical class 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims 2
- PSOWAAFJZPXBAO-YREBWIFWSA-N C[C@](CCCC1)(C1CC1)[C@@H](CC2)[C@@H]1[C@H](CC1)[C@@]2(CO)[C@H]1C(O)=C Chemical compound C[C@](CCCC1)(C1CC1)[C@@H](CC2)[C@@H]1[C@H](CC1)[C@@]2(CO)[C@H]1C(O)=C PSOWAAFJZPXBAO-YREBWIFWSA-N 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 150000004967 organic peroxy acids Chemical class 0.000 claims 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 abstract description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 abstract description 3
- 235000011152 sodium sulphate Nutrition 0.000 abstract description 3
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 abstract description 2
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 abstract description 2
- 229960002478 aldosterone Drugs 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract 6
- 239000007832 Na2SO4 Substances 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 abstract 1
- 229910052593 corundum Inorganic materials 0.000 abstract 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 150000003431 steroids Chemical class 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 229910001845 yogo sapphire Inorganic materials 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 3
- -1 18-oxido-18-hydroxy-20-oxo-pregnane Chemical compound 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 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
- 239000011541 reaction mixture Substances 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- ALSXNTIVNJBNQE-ZWONNITHSA-N (8r,9r,10s,13r,14s,17s)-17-ethyl-13-methyl-1,2,3,4,5,6,7,8,9,10,11,12,14,15,16,17-hexadecahydrocyclopenta[a]phenanthrene Chemical class C1CC2CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 ALSXNTIVNJBNQE-ZWONNITHSA-N 0.000 description 1
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- OMQSWSHLCYIWOB-DJLFKOBASA-N C[C@](CCCC1)(C1CC1)[C@@H](CC2)[C@@H]1[C@H]1[C@@]2(CO)C(C(O)=C)=CC1 Chemical compound C[C@](CCCC1)(C1CC1)[C@@H](CC2)[C@@H]1[C@H]1[C@@]2(CO)C(C(O)=C)=CC1 OMQSWSHLCYIWOB-DJLFKOBASA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- WIRUZQNBHNAMAB-UHFFFAOYSA-N benzene;cyclohexane Chemical compound C1CCCCC1.C1=CC=CC=C1 WIRUZQNBHNAMAB-UHFFFAOYSA-N 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
Steroids I Intermediates for aldosterone and analogues. (a) To DELTA5-3:3:20:20-bisethylenedioxy-11beta:18-oxido-18-hydroxy-preg- nene (433 mg) in PhMei(40 ml) at 0-3 deg.C under N2, was added (5 min.) M-Bu2AlH in PhMe (2.5 ml). Stirred 22 h. at room temp., cooled to 0-3 deg.C., dild. with THF (5 ml), added 1 ml H2O, and stirred 15 min. Added kiesel-guhr (1 g), warmed to 20-5 deg.C., dried (2.5 g Na2SO4), and filtered, washing with 1:3 THF -PhMe (60 ml). Evapd. in vac., residue dissolved in PhH (16 ml), and hexane (144 ml), and chromatographed on Al2O3 activity IV (20 g), eluting with 9:1 and 8.5:1.5 hexane/PhH, to give I (153 mg) m.p. 212-6 deg.C (from Et2O-THF).
Description
Verfahren zur Herstellung von 11,Ç,18;18,20;20,21-Trisoxido-steroide der Pregnanreihe
Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung von 11IP,18;18,20;20,21 -Trisoxido- -steroide der Pregnan- und -19-nor-pregnan-Reihe, welche u.a. als Ausgangsverbindungen zur Herstellung der wegen ihrer interessanten pharmakologischen Wirkungen wichtigen 11!,S,18-Oxido-18,21-dihydroxy-20-oxo- -pregnanverbindungen, insbesondere von Aldosteron und seinen Derivaten, dienen können.
Das Verfahren der vorliegenden Anmeldung zur Herstellung der genannten 11B, 18;18,20;20,21-Trisoxido- -pregnan- und 19 -nor-pregnan-Verbindungen ist dadurch gekennzeichnet, dass man in einer a20-llip,18;18,20-Bis- oxido-pregnen- oder l9-nor-pregnen-Verbindung die 20, 21-Doppelbindung epoxidiert.
Verfahrensgemäss werden die Ausgangsstoffe in an sich bekannter Weise mit Mitteln umgesetzt, die eine Epoxydierung einer aliphatischen Doppelbindung herbeiführen, z.B. Persäuren, wie m-Chlorbenzopersäure, Peressig, Perbenzoe- oder Monoperphthalsäure.
Ausgangsstoffe für das neue Verfahren sind A20-ll,ss, 18;18,20-Bisoxido-steroide der Pregnan- oder 19-nor -pregnan-Reihe, wie sie z.B. durch Einwirkung einer Lewissäure auf eine in 21-Stellung unsubstituierte 1 lp 1 8-Oxido- 1 8-hydroxy-20-oxo-pregnan- oder 19-nor-preg- nan-Verbindung mit einer freien oder funktionell abgewandelten, reaktionsfähigen 20-Oxogruppe in einem inerten wasserfreien Medium erhalten werden können. Die Ausgangsstoffe können in den Ringen A und B gesättigt sein, der 51CG- oder 5,-Reihe angehören und/oder Doppelbindungen enthalten, insbesondere in 1(2)- und/ oder 4(5)- oder 5(6)-Stellung.
Sie können einen oder mehrere Substituenten im Ringsystem aufweisen, wie beispielsweise freie, veresterte oder verätherte Hydroxylgruppen, freie, ketalisierte oder in Enolderivate umgewandelte Oxogruppen, niedere Alkyl- oder Alkenylgruppen, wie Methyl-, Äthyl- oder Methylengruppen, oder Halogen-, wie Fluor- oder Chloratome.
Zur Darstellung der 1 lia,18-0xido-18,21-dihydroxy- -20-oxo-pregnan oder 19- nor-pregnan -Verbindungen werden die Verfahrensprodukte z.B. acylolysiert, z.B.
durch Behandlung mit wasserfreien organischen Carbonsäuren. Man verwendet vorzugsweise Säuren mit höchstens 12 Kohlenstoffatomen wie Ameisensäure, Essig-, Trifluoressig-, Trimethylessig-, Propion-, Bernstein-, Capron-, Hexahydrobenzoe-, Cyclopentylpropion-, Benzoeoder Furancarbonsäure.
Das folgende Beispiel erläutert die Erfindung. Die Temperaturen sind in Celsiusgraden angegeben.
Beispiel
9,3 mg A5'20-3,3-Äthylendioxy - 18;18,20-bisoxi- do-pregnadien löst man unter Feuchtigkeitsausschluss in 2,5 ml Methylenchlorid, welches 4 Volumenprozent Tetrahydrofuran enthält, setzt der Lösung 50 mg m-Chlorbenzopersäure mit einem Persäuregehalt von ca. 85 Prozent zu und rührt all/2 Stunden bei Raumtemperatur. Das Reaktionsgemisch wird alsdann auf 0-30 abgekühlt, mit 17,5 ml eiskaltem Methylenchlorid-Äther(l :3)Gemisch verdünnt und zur Entsäuerung bei 0-3 mit 0,1-n. Natriumcarbonat und Wasser ausgeschüttelt.
Die mit Natriumsulfat getrocknete Methylenchlorid-Äther-Lösung hinterlässt beim Eindampfen das A5-3,3-Äthylendioxy - 1 1:f3 18; 1 8,20;20,21 -trioxidopregnen als nahezu farblosen, beim Stehen langsam festwerdenden Rückstand.
Das erhaltene, rohe 20,21-Epoxyd wird unter Feuchtigkeitsausschluss in 1,2 ml Eisessig und 0,05 ml Acetanhydrid gelöst, der Lösung 50 mg wasserfreies Kaliumacetat zugesetzt und das Ganze in Stickstoffatmosphäre 15 Minuten auf dem kochenden Wasserbad erwärmt.
Man kühlt das Reaktionsgemisch sodann auf Raumtemperatur ab und dampft an der Ölrotationspumpe schonend ein. Der Rückstand wird in Methylenchlorid-Äther (1:2)Gemisch und Wasser aufgenommen, die obere Phase mit 0,2-n. Ammoniumhydrogencarbonat und Wasser gewaschen, mit Natriumsulfat getrocknet und im Vakuum eingedampft. Das Rohprodukt wird zur Vervollständigung der Hydrolyse in 1,25 ml 67-prozentiger wässeriger Essigsäure in Stickstoffatmosphäre noch 2 Stunden auf 62-65 erwärmt, die Lösung nach dem Erkalten an der Ölrotationspumpe eingedampft und zurückgehaltene Essigsäure durch wiederholtes Zusetzen von Toluol und Abdampfen bei Raumtemperatur entfernt.
Aus dem er haltenen Rückstand gewinnt man durch präparative papierchromatographische Reinigung im Lösungsmittelsystem Formamid/Cyclohexan-Benzol(1:2) reines A4-3,20- -Dioxo- 1131 8-oxido- 1 8-hydroxy-21 -acetoxy-pregnen vom F. 183-1860.
Process for the preparation of 11, Ç, 18; 18.20; 20,21-trisoxido-steroids of the pregnane series
The present invention relates to a new process for the preparation of 11IP, 18; 18.20; 20.21 -trisoxido- steroids of the pregnan and -19-nor-pregnan series, which i.a. can serve as starting compounds for the preparation of 11!, S, 18-oxido-18,21-dihydroxy-20-oxo-prepregnane compounds, in particular of aldosterone and its derivatives, which are important because of their interesting pharmacological effects.
The process of the present application for the preparation of the mentioned 11B, 18; 18,20; 20,21-trisoxido- -pregnan- and 19 -nor-pregnane-compounds is characterized in that one in an a20-llip, 18; 18, 20-bis-oxido-pregnen- or 19-nor-pregnen compound epoxidizes the 20, 21 double bond.
According to the method, the starting materials are reacted in a manner known per se with agents which cause an epoxidation of an aliphatic double bond, e.g. Peracids, such as m-chlorobenzoperic acid, peracetic, perbenzoic or monoperphthalic acid.
The starting materials for the new process are A20-II, ss, 18; 18,20-bisoxido-steroids of the pregnan or 19-nor -pregnan series, as e.g. by the action of a Lewis acid on a 1 lp 18-oxido-18-hydroxy-20-oxo-pregnane or 19-nor-preg-nan compound with a free or functionally modified, reactive 20-oxo group which is unsubstituted in the 21-position can be obtained in an inert anhydrous medium. The starting materials can be saturated in rings A and B, belong to the 51CG or 5 series and / or contain double bonds, in particular in the 1 (2) and / or 4 (5) or 5 (6) position.
They can have one or more substituents in the ring system, such as free, esterified or etherified hydroxyl groups, free, ketalized or converted into enol derivatives oxo groups, lower alkyl or alkenyl groups, such as methyl, ethyl or methylene groups, or halogen, such as fluorine or chlorine atoms.
To represent the 1 lia, 18-0xido-18,21-dihydroxy--20-oxo-pregnane or 19-nor-pregnane compounds, the process products are e.g. acylolyzed, e.g.
by treatment with anhydrous organic carboxylic acids. Acids with a maximum of 12 carbon atoms such as formic acid, acetic, trifluoroacetic, trimethyl acetic, propionic, succinic, caproic, hexahydrobenzoic, cyclopentylpropionic, benzoic or furancarboxylic acid are preferably used.
The following example illustrates the invention. The temperatures are given in degrees Celsius.
example
9.3 mg of A5'20-3,3-ethylenedioxy-18; 18,20-bisoxido-pregnadiene are dissolved in 2.5 ml of methylene chloride, which contains 4 percent by volume of tetrahydrofuran, with exclusion of moisture, and 50 mg of m-chlorobenzoperic acid is added to the solution with a peracid content of about 85 percent and stir every / 2 hours at room temperature. The reaction mixture is then cooled to 0-30, diluted with 17.5 ml of ice-cold methylene chloride-ether (1: 3) mixture and for deacidification at 0-3 with 0.1-n. Sodium carbonate and water extracted.
The methylene chloride-ether solution, dried with sodium sulfate, leaves behind the A5-3,3-ethylenedioxy - 11: f3 18; 18.20; 20.21 -trioxidopregnen as an almost colorless residue that slowly solidifies on standing.
The crude 20,21-epoxide obtained is dissolved in 1.2 ml of glacial acetic acid and 0.05 ml of acetic anhydride with exclusion of moisture, 50 mg of anhydrous potassium acetate are added to the solution and the whole is heated in a nitrogen atmosphere for 15 minutes on the boiling water bath.
The reaction mixture is then cooled to room temperature and gently evaporated on the rotary oil pump. The residue is taken up in methylene chloride-ether (1: 2) mixture and water, the upper phase with 0.2-n. Washed ammonium hydrogen carbonate and water, dried with sodium sulfate and evaporated in vacuo. To complete the hydrolysis, the crude product is heated to 62-65 for a further 2 hours in 1.25 ml of 67 percent aqueous acetic acid in a nitrogen atmosphere, the solution is evaporated on an oil rotary pump after cooling and retained acetic acid is removed by repeated addition of toluene and evaporation at room temperature .
From the residue he obtained is obtained by preparative paper chromatographic purification in the solvent system formamide / cyclohexane-benzene (1: 2) pure A4-3,20- -Dioxo- 1131 8-oxido- 1 8-hydroxy-21-acetoxy-pregnen from F. 183-1860.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1349070A CH520131A (en) | 1963-10-03 | 1963-10-03 | Bis-oxido steroids |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1446167A CH512456A (en) | 1963-10-03 | 1963-10-03 | Bis-oxido steroids |
| CH1217363A CH438293A (en) | 1963-10-03 | 1963-10-03 | Process for the preparation of bisoxide steroids of the pregnane series |
| CH1349070A CH520131A (en) | 1963-10-03 | 1963-10-03 | Bis-oxido steroids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH520131A true CH520131A (en) | 1972-03-15 |
Family
ID=25709742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1349070A CH520131A (en) | 1963-10-03 | 1963-10-03 | Bis-oxido steroids |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH520131A (en) |
-
1963
- 1963-10-03 CH CH1349070A patent/CH520131A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |