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DE1212082B - Process for the preparation of 3, 11-Dioxo-20-tert-amino-20-alkyl-4-pregnenverbindungen and salts thereof - Google Patents

Process for the preparation of 3, 11-Dioxo-20-tert-amino-20-alkyl-4-pregnenverbindungen and salts thereof

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Publication number
DE1212082B
DE1212082B DER35992A DER0035992A DE1212082B DE 1212082 B DE1212082 B DE 1212082B DE R35992 A DER35992 A DE R35992A DE R0035992 A DER0035992 A DE R0035992A DE 1212082 B DE1212082 B DE 1212082B
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DE
Germany
Prior art keywords
methyl
dioxo
ecm
dimethylamino
salt
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
Application number
DER35992A
Other languages
German (de)
Inventor
Dr-Ing Daniel Bertin
Dr Lucien Nedelec
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
Original Assignee
Roussel Uclaf SA
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Filing date
Publication date
Application filed by Roussel Uclaf SA filed Critical Roussel Uclaf SA
Publication of DE1212082B publication Critical patent/DE1212082B/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

BUNDESREPUBLIK DEUTSCHLANDFEDERAL REPUBLIC OF GERMANY

DEUTSCHESGERMAN

PATENTAMTPATENT OFFICE

AUSLEGESCHRIFTEDITORIAL

Int. Cl.:Int. Cl .:

C07cC07c

Deutschem.: 12 ο-25/05German: 12 ο-25/05

Nummer: 1212 082Number: 1212 082

Aktenzeichen: R 35992IV b/12 οFile number: R 35992IV b / 12 ο

Anmeldetag: 27. August 1963 Filing date: August 27, 1963

Auslegetag: 10. März 1966Opening day: March 10, 1966

Die Erfindung betrifft ein Verfahren zur Herstellung von neuen SJl-Dioxo^O-tert.-amino-^O-alkyl-4-pregnenverbindungen der allgemeinen Formel IThe invention relates to a process for the preparation of new SJl-Dioxo ^ O-tert-amino- ^ O-alkyl-4-pregnenverbindungen of the general formula I.

CH3 CH 3

C —Ν:C --Ν:

RiRi

in Form der freien Basen oder entsprechender Salze.in the form of the free bases or corresponding salts.

In dieser Formel bedeuten R und R1 niedere Alkylreste, Aryl- oder Aralkylreste, und R2 bedeutet einen Alkylrest mit 1 bis 4 Kohlenstoffatomen.In this formula, R and R 1 denote lower alkyl radicals, aryl or aralkyl radicals, and R 2 denotes an alkyl radical having 1 to 4 carbon atoms.

Die nach dem erfindungsgemäßen Verfahren erhaltenen neuen Produkte besitzen interessante physiologische Eigenschaften, vor allem eine spasmolytische, vasodilatatorische und insbesondere eine coronardilatorische Wirkung.The new products obtained by the process according to the invention have interesting physiological properties Properties, especially spasmolytic, vasodilatory and especially coronary dilatory Effect.

Unter diesen Verbindungen ist 3,ll-Dioxo-20-methyl-20-dimethylamino-J4-pregnen von besonderem Interesse.Among these compounds, 3,1-dioxo-20-methyl-20-dimethylamino-J 4 -pregnene is of particular interest.

Die angewandte Dosierung dieser Verbindungen bewegt sich zwischen 5 und 20 mg je Dosis und 10 bis 100 mg je Tag beim Erwachsenen, je nach der Art der Verabreichung.The applied dosage of these compounds ranges between 5 and 20 mg per dose and 10 to 100 mg per day for adults, depending on the route of administration.

Das erfindungsgemäße Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I ist dadurch gekennzeichnet, daß man in an sich bekannter Weise ein primäres Amin der Formel NH2R, worin R die vorstehend angegebene Bedeutung hat, mit einem in 3- und 11-Stellung oxygenierten 20-Oxo-5/9-pregnan, dessen etwa vorhandene andere Ketofunktionen man vorher durch Bildung eines cyclischen Ketals geschützt hat, umsetzt, das erhaltene 20-Iminoderivat durch Behandlung mit einem niederen Alkylhalogenid oder einem Aryl- oder Aralkylhalogenid der Formel Hai—R1, worin Hai ein Halogenatom darstellt und R1 die vorstehend angegebene Bedeutung hat, in das ternäre Iminiumsalz überführt, das erhaltene Salz mit einem Alkylmagnesiumhalogenid der Formel Hai—MgR2, worin Hai ein Halogenatom bedeutet und R2 die vorstehend angegebene Bedeutung hat, umsetzt, das erhaltene 20-Alkyl-20-tert.-aminosteroid nach vorübergehender Salzbildung isoliert und vorhandene geschützte Ketofunktionen gegebenenfalls durch Hydrolyse freisetzt, in der erhaltenen Ver-Verfahren zur Herstellung von 3,11-Dioxo-20-tert.-amino-20-alkyl-4-pregnenverbindungen
und Salzen derselbenThe process according to the invention for the preparation of the compounds of general formula I is characterized in that, in a manner known per se, a primary amine of the formula NH 2 R, in which R has the meaning given above, with a 20 oxygenated in the 3- and 11-positions -Oxo-5/9-pregnane, the other keto functions which may be present, have previously been protected by the formation of a cyclic ketal, and the 20-imino derivative obtained is reacted by treatment with a lower alkyl halide or an aryl or aralkyl halide of the formula Hai-R 1 , wherein Hai represents a halogen atom and R 1 has the meaning given above, converted into the ternary iminium salt, the salt obtained with an alkylmagnesium halide of the formula Hai — MgR 2 , wherein Hai is a halogen atom and R 2 has the meaning given above, which 20-alkyl-20-tert-aminosteroid obtained isolated after temporary salt formation and protected keto functions, if appropriate, dur ch hydrolysis is released, in the resulting process for the preparation of 3,11-dioxo-20-tert-amino-20-alkyl-4-pregnenverbindungen
and salts thereof

Anmelder:Applicant:

Roussel-Uclaf, ParisRoussel-Uclaf, Paris

Vertreter:Representative:

Dr. F. Zumstein,Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. AssmannDipl.-Chem. Dr. rer. nat. E. Assmann

und Dipl.-Chem. Dr. R. Koenigsberger,and Dipl.-Chem. Dr. R. Koenigsberger,

Patentanwälte, München 2, Bräuhausstr. 4Patent Attorneys, Munich 2, Bräuhausstr. 4th

Als Erfinder benannt:
Dr.-Ing. Daniel Bertin, Montrouge, Seme;
Dr. Lucien Nedelec, Clichy-sur-Bois,
Seine-et-Oise (Frankreich)Named as inventor:
Dr.-Ing. Daniel Bertin, Montrouge, Seme;
Dr. Lucien Nedelec, Clichy-sur-Bois,
Seine-et-Oise (France)

Beanspruchte Priorität:
Frankreich vom 27. August 1962 (907 856),
vom 3. Mai 1963 (933 624)Claimed priority:
France of August 27, 1962 (907 856),
of May 3, 1963 (933 624)

bindung vorhandene freie Hydroxylfunktionen in 3- und 11-Stellung oxydiert und durch 4-Bromierung und anschließende Dehydrobromierung eine Doppelbindung in 4(5)-Stellung einführt und gegebenenfalls die erhaltene Verbindung in ein Salz einer Mineralsäure oder einer organischen Säure überführt.bond existing free hydroxyl functions in the 3- and 11-positions and oxidized by 4-bromination and subsequent dehydrobromination introduces a double bond in the 4 (5) position and optionally the compound obtained is converted into a salt of a mineral acid or an organic acid.

Zur Herstellung der oben angegebenen Verbindung 3,ll-Dioxo-20-methyl-20-dimethylamino-zl4-pregnen arbeitet man wie folgt:To prepare the compound 3, ll-dioxo-20-methyl-20-dimethylamino-zl 4 -pregnen given above, the procedure is as follows:

Man stellt zuerst 3«,ll/?-Dihydroxy-20-methyl-20-dimethylamino-5j3-pregnan her, indem man 3«-Acetoxy-Ilß-hydroxy-20-oxo-5j3-pregnan mit Methylamin in Gegenwart von Natriummethylat umsetzt, das erhaltene 3«,ll/3-Dihydroxy-20-methylimino-5/3-pregnan durchBehandlungmit Methyljodid in das entsprechende Jodmethylat überführt, letztere Verbindung mit Methylmagnesiumbromid reagieren läßt und so das 3«,ll/?-Dihydroxy-20-methyl-20-dimethylamino-5^-pregnan erhält. Dann stellt man daraus das 3,ll-Dioxo-20-methyl-20-dimethylamino-5/?-pregnan her, indem man das erhaltene 3&,llß-Dihydroxy-20-methyl-20-dimethylamino-5/3-pregnan der Einwirkung eines energischen Oxydationsmittels, wie Chromschwefelsäure, unterwirft. First one prepares 3 ", ll /? - dihydroxy-20-methyl-20-dimethylamino-5j3-pregnan by adding 3'-acetoxy-ILß-hydroxy-20-oxo-5j3-pregnane reacted with methylamine in the presence of sodium methylate, the resulting 3 ", ll / 3-dihydroxy-20-methylimino-5/3-pregnane converted into the corresponding iodine methylate by treatment with methyl iodide, the latter compound with methyl magnesium bromide lets react and so the 3 ", ll /? - dihydroxy-20-methyl-20-dimethylamino-5 ^ -pregnane receives. Then the 3, ll-dioxo-20-methyl-20-dimethylamino-5 /? - pregnane is made from it by processing the obtained 3 &, llß-dihydroxy-20-methyl-20-dimethylamino-5/3-pregnane subjected to the action of an energetic oxidizing agent, such as chromosulfuric acid.

609 537/440609 537/440

3 43 4

Zur Überführung des S^l-Dioxo-^O-methyl^O-di- Das Produkt wurde in der Literatur bisher nochTo transfer the S ^ l-Dioxo- ^ O-methyl ^ O-di- The product has been in the literature so far

methylamino-5/i-pregnans in das gewünschte 3,11-Di- nicht beschrieben.
oxo-20-methyl-20-dimethylamino-44-pregnen wird diemethylamino-5 / i-pregnans into the desired 3,11-di- not described.
oxo-20-methyl-20-dimethylamino-4 4 -pregnen is the

Doppelbindung in 4(5)-Stellung durch Bromieren in Stufe C:Double bond in 4 (5) position by bromination in stage C:

Essigsäure und Bromwasserstoffabspaltung mit dem 5 3a5l¥.Dihydroxy.20-methyl-20-dimethylamino- Acetic acid and elimination of hydrogen bromide with the 5 3 a5l ¥. Dihydroxy . 2 0-methyl-20-dimethylamino

Salzpaar Lithiumbromid—Lithiumcarbonat in Di- co Salt pair lithium-lithium in di- co

methylformamid eingeführt. ^-pregnanmethylformamide introduced. ^ -pregnan

Das folgende Beispiel erläutert das Verfahren der Man gibt 330 ecm einer 3,42 molaren ätherischenThe following example illustrates the procedure of giving 330 ecm of a 3.42 molar essential

Erfindung. Lösung von Methylmagnesiumbromid in 470 ecmInvention. Solution of methyl magnesium bromide in 470 ecm

Beispiell 10 Tetrahydrofuran, fügt langsam 31,25 g des in Stufe BFor example 10 tetrahydrofuran, slowly add 31.25 g of the in step B

erhaltenen Jodmethylats von 3a,llß-Dihydroxy-obtained iodine methylate of 3a, llß-dihydroxy

Herstellung von 3,ll-Dioxo-20-methyl-20-dimethyl- 20-methylimino-5/?-pregnan zu, bringt 16 StundenProduction of 3,1-dioxo-20-methyl-20-dimethyl-20-methylimino-5 /? - pregnane takes 16 hours

amino-zl4-pregnen unter Stickstoffatmosphäre zum Rückfluß und gießtamino-zl 4 -pregnen under a nitrogen atmosphere to reflux and pour

dann in ein Gemisch von 3000 ecm Wasser, 300 gthen in a mixture of 3000 ecm of water, 300 g

Stufe Ä: 1S Ammoniumchlorid und 450 ecm konzentriertem Am-Level Ä: 1 S ammonium chloride and 450 ecm concentrated am-

3«,ll/3-Dihydroxy-20-methylimino-5yS-pregnan moniak. „..„.,.3 ", ll / 3-dihydroxy-20-methylimino-5yS-pregnan moniak. "..".,.

r 3 J * ' F ö Man rührt 30 bis 40 Minuten und extrahiert mit r 3 J * ' F ö The mixture is stirred for 30 to 40 minutes and extracted with

Man kühlt eine Lösung von 250 ecm Monomethyl- einer Mischung von Benzol und Äther (1:1). Man amin in 300 ecm Methanol auf 00C ab und fügt 43 g wäscht mit Wasser, trocknet über Magnesiumsulfat 3a-Acetoxy-llß-hydroxy-20-oxo-5|8-pregnan und 20 g 20 und verdampft im Vakuum zur Trockne. Man löst Natriummethylat zu. Man rührt das Reaktions- das erhaltene Produkt in 500 ecm Äther und leitet gemisch eine Nacht bei 1200C, kühlt auf 00C ab, durch die Lösung einen Strom von Chlorwasserstoffsaugt ab und wäscht den Niederschlag mit eisgekühltem gas bis zur sauren Reaktion. Man rührt 30 Minuten, Methanol, dann mit Wasser und trocknet im Vakuum. saugt ab und versetzt mit 250 ecm wäßrigem Äthanol Man erhält so 12,51 g 3«,ll^-Dihydroxy-20-methyl- 25 und dann mit 500 ecm Wasser und läßt die Mischung imino-5/J-pregnan. Die eingeengten methanolischen über Nacht bei Zimmertemperatur unter Stickstoff-Mutterlaugen liefern noch 11,97 g, was eine Gesamt- atmosphäre stehen.A solution of 250 ecm monomethyl- a mixture of benzene and ether (1: 1) is cooled. It amine in 300 cc methanol at 0 0 C and adds 43 g washed with water, dried over magnesium sulfate, 3a-acetoxy-LLSs-hydroxy-20-oxo-5 | 8-pregnane and 20 g of 20 and evaporated in vacuo to dryness. Sodium methylate is dissolved. Stir the reaction, the obtained product in 500 cc of ether and forwards mixture overnight at 120 0 C, cooled to 0 0 C., through the solution for a stream of hydrogen chloride filtered off and the precipitate is washed with ice-cooled gas until acidic. The mixture is stirred for 30 minutes, methanol, then with water and dried in vacuo. Sucked off and mixed with 250 ecm of aqueous ethanol. This gives 12.51 g of 3 ", ll ^ -dihydroxy-20-methyl-25 and then with 500 ecm of water, and the mixture is left imino-5 / I-pregnan. The concentrated methanolic solution overnight at room temperature under nitrogen mother liquors still yield 11.97 g, which is a total atmosphere.

ausbeute von 24,48 g ergibt (F. =234°C). [«]o° Man wäscht mit Äther und mit Petroläther undyield of 24.48 g results (m.p. = 234 ° C). [«] O ° One washes with ether and with petroleum ether and

= +79,l±l° (C-I0I0, Chloroform). Ausbeute versetzt mit 40ecm Natronlauge. Man saugt den= + 79.1 ± 1 ° (CI 0 I 0 , chloroform). 40 cm of sodium hydroxide solution are added to the yield. One sucks the

= 62 °/0. 3o gebildeten Niederschlag ab und extrahiert die wäßrige= 62 ° / 0 . 3o formed precipitate and extracted the aqueous

Die Mutterlaugen der zweiten Ausbeute ergibt nach Lösung mit einer Mischung von Benzol und Äther (1:1).The mother liquors of the second crop are obtained after dissolution with a mixture of benzene and ether (1: 1).

Verdünnen mit Wasser 13 g 3a,ll/3-Dihydroxy-20-oxo- Man erhält 19,18 g rohes SaAlß-Dihydroxy^O-me-Dilute with water 13 g of 3a, ll / 3-dihydroxy-20-oxo-19.18 g of crude SaAlß-dihydroxy ^ O-me-

5j5-pregnan (F. = 209 bis 21O0C). thyl^O-dimethylamino-S^-pregnan.5J5-pregnane (F. = 209 to 21O 0 C). thyl ^ O-dimethylamino-S ^ -pregnane.

Das 3a,ll^-Dihydroxy-20-methylimino-5jS-pregnan Das durch Umkristallisieren aus IsopropylätherThe 3a, ll ^ -dihydroxy-20-methylimino-5jS-pregnane Das by recrystallization from isopropyl ether

ergibt sich in Form von farblosen Kristallen, die in 35 gereinigte Produkt zeigt die folgenden Konstanten:results in the form of colorless crystals, the purified product in 35 shows the following constants:

Alkohol und Äther wenig löslich, in Chloroform F. = etwa 15O0C, [«]!? =+39,5 ± 1° (c = l%,Alcohol and ether, slightly soluble in chloroform F. = about 15O 0 C, [ «] !? = + 39.5 ± 1 ° (c = l%,

löslich und in Wasser unlöslich sind. Äthanol).are soluble and insoluble in water. Ethanol).

r< τι r-> -KT ιλι e.n ^as Produkt ergibt sich in Form von farblosen r < τι r-> -KT ιλι en ^ as product results in the form of colorless

Analyse: C22H37U2N = 34/,53. Kristallen, die in Alkohol, Äther, Aceton, Benzol undAnalysis: C 22 H 37 U 2 N = 34 /, 53. Crystals found in alcohol, ether, acetone, and benzene

Berechnet ... N 4,03 %; 40 Chloroform löslich sind.Calculated ... N 4.03%; 40 chloroform are soluble.

gefunden ... N 4,4«/.found ... N 4.4 «/.

Das Produkt wurde in der Literatur bisher noch Berechnet ... C76,34%, H 11,47%, N3,71%;The product has so far been calculated in the literature ... C76.34%, H 11.47%, N3.71%;

nicht beschrieben. gefunden ... C76,5%, H 11,3%, N3,9%.not described. found ... C76.5%, H 11.3%, N3.9%.

Stufe B- ^as Pr0CUIkt wurde in der Literatur bisher nochLevel B- ^ as P r0CUI kt has hitherto been in the literature

nicht beschrieben.not described.

Jodmethylat von Sajllß-Dihydroxy^O-methyh'mino- Man erhält das Hydrochlorid, indem man eineIodomethylate of Sajllß-Dihydroxy ^ O-methyh'mino- The hydrochloride is obtained by adding a

5/J-pregnan Lösung des Produkts in Äthylacetat mit 1,45 normalem5 / J-pregnan solution of the product in ethyl acetate with 1.45 normal

50 salzsaurem Äther behandelt (F. = etwa 3000C).
Man gibt 23,39 g 3a,ll|ö-Dihydroxy-20-methyl-50 hydrochloric acid ether treated (F. = about 300 0 C).
23.39 g of 3a, ll | ö-dihydroxy-20-methyl-

imino-5/?-pregnan in 300 ecm Chloroform, destilliert Stufe D:imino-5 /? - pregnan in 300 ecm chloroform, distilled stage D:

30 ecm Lösungsmittel ab, setzt 70 ecm Methyljodid Herstellung von30 ecm solvent off, 70 ecm methyl iodide continues production of

zu und bringt unter Stickstoffatmosphäre 2V2 Stunden s^l-Dioxo^O-methyl^O-dimethylamino^-pregnanand brings 2V 2 hours s ^ l-Dioxo ^ O-methyl ^ O-dimethylamino ^ -pregnane under a nitrogen atmosphere

zum Ruckfluß. 55 r to the reflux. 55 r

Man kühlt, saugt den Niederschlag ab, wäscht Man löst 14,6 g des in der Stufe C erhaltenen rohenIt is cooled, the precipitate is filtered off with suction and washed. 14.6 g of the crude obtained in stage C are dissolved

mit Chloroform und mit Äther und trocknet im 3a,ll/3 - Dihydroxy - 20 - methyl - 20 - dimethylamino-with chloroform and with ether and dries in 3a, ll / 3 - dihydroxy - 20 - methyl - 20 - dimethylamino-

Trockenschrank bei 8O0C. Man erhält 31,25 g Jod- 5/3-pregnans in 220 ecm Essigsäure und versetzt unterOven at 8O 0 C. This gives 31.25 g of iodine 5/3-pregnane in 220 cc of acetic acid and added with

methylat von 3oi,lljö-Dihydroxy-20-methylimino- Rühren, während man die Temperatur auf 20°Cmethylate of 3oi, lljö-dihydroxy-20-methylimino- Stir while the temperature is raised to 20.degree

5/?-pregnan (F. > 300° C), was einer Ausbeute von 60 hält, mit 26,5 ecm einer Lösung von 135 g Chrom-5 /? - pregnane (m.p.> 300 ° C), which holds a yield of 60, with 26.5 ecm of a solution of 135 g of chromium

95 % entspricht. Säureanhydrid und 115 ecm konzentrierter Schwefel-95% corresponds. Acid anhydride and 115 ecm concentrated sulfur

Das Produkt ist in Wasser und Alkohol wenig säure, die man mit Wasser auf 500 ecm aufgefülltThe product is not very acidic in water and alcohol, which is made up to 500 ecm with water

löslich und in Äther, Aceton, Benzol und Chloroform hat.soluble in ether, acetone, benzene and chloroform.

unlöslich. Man rührt 30 Minuten, versetzt mit 15 ecm Methanolinsoluble. The mixture is stirred for 30 minutes, and 15 ecm of methanol are added

65 und 250 ecm Wasser, kühlt ab und neutralisiert mit65 and 250 ecm of water, cools down and neutralizes with it

Analyse: C23H40O2NJ = 489,47. 880 ecm konzentriertem Ammoniak. Man kühltAnalysis: C 23 H 40 O 2 NJ = 489.47. 880 ecm of concentrated ammonia. One cools

Berechnet ... J25,93%, N2,86%; 1 Stunde, saugt ab, wäscht mit Wasser und trocknetCalculated ... J25.93%, N2.86%; 1 hour, vacuum, wash with water and dry

gefunden ... J25,2%, N2,6%. im Vakuum.found ... J25.2%, N2.6%. in a vacuum.

Man löst das erhaltene Produkt in heißem Äthylacetat, engt ein, kühlt 1 Stunde, saugt ab und wäscht mit Äthylacetat.The product obtained is dissolved in hot ethyl acetate, concentrated, cooled for 1 hour, filtered off with suction and washed with ethyl acetate.

Man erhält 8,33 g S^l-Dioxo^O-methyl^O-dimethylamino-5/9-pregnan (F. = 216°C). [x]! D° = +54,5° ±2° (c = 0,45%, Äthanol), was einer Ausbeute von 57,7% entspricht.8.33 g of S ^ l-dioxo ^ O-methyl ^ O-dimethylamino-5/9-pregnane (mp = 216 ° C.) are obtained. [x] ! D ° = + 54.5 ° ± 2 ° (c = 0.45%, ethanol), which corresponds to a yield of 57.7%.

Das Produkt ergibt sich in Form von farblosen Kristallen, die in Alkohol, Aceton und Chloroform löslich und in Wasser unlöslich sind.The product results in the form of colorless crystals that exist in alcohol, acetone and chloroform are soluble and insoluble in water.

15minutiges Anteigen in 50 ecm siedendem Äthylacetat ergibt 1,07 g des reinen Hydrochlorids, das bei 280 bis 2900C schmilzt.15minutiges pasting in 50 cc of boiling ethyl acetate yields 1.07 g of pure hydrochloride of which melts at 280-290 0 C.

Claims (2)

Patentansprüche:Patent claims: 1. Verfahren zur Herstellung von 3,11-Dioxo-20-tert.-amino-20-alkyl-4-pregnenverbindungen der allgemeinen Formel1. Process for the preparation of 3,11-Dioxo-20-tert-amino-20-alkyl-4-pregnenverbindungen the general formula 1010 2020th Analyse: C24H39O2N = 373,56.Analysis: C 24 H 39 O 2 N = 373.56. Berechnet ... C 77,17%, H 10,52%, N 3,75%;
gefunden ... C77,2%, H 10,3%, N4,0%.Calculated ... C 77.17%, H 10.52%, N 3.75%;
found ... C77.2%, H 10.3%, N 4.0%. Das Produkt wurde in der Literatur bisher noch nicht beschrieben.The product has not yet been described in the literature. Stufe E:Level E: Sjll-Dioxo^O-methyl^O-dimethylamino-J4-pregnen Sjll-Dioxo ^ O-methyl ^ O-dimethylamino-J 4 -pregnen Man erhitzt ein Gemisch von 4,85 g des in der vorherigen Stufe erhaltenen 3,ll-Dioxo-20-methyl-20-dimethylamino-5/?-pregnans, 30 ecm Essigsäure und 4,3 ecm 3,1 normaler wäßriger Bromwasserstofflösung auf 45°C. Man versetzt langsam mit 18 ecm einer Lösung von 6,18 g Brom in 50 ecm Essigsäure, kühlt ab und verdünnt mit 200 ecm Äthylacetat. Man kühltA mixture of 4.85 g of the 3,1-dioxo-20-methyl-20-dimethylamino-5 /? - pregnans obtained in the previous stage is heated, 30 ecm acetic acid and 4.3 ecm 3.1 normal aqueous hydrogen bromide solution to 45 ° C. 18 ecm of a solution of 6.18 g of bromine in 50 ecm of acetic acid are added slowly, and the mixture is cooled off and diluted with 200 ecm ethyl acetate. One cools 1 Stunde, saugt ab, wäscht mit Äthylacetat und trocknet im Vakuum. Man erhält 5,56 g des Produktes, das man in eine auf HO0C erhitzte Mischung von 55 ecm Dimethylformamid, 5,5 g Lithiumcarbonat und 2,75 g Lithiumbromid gibt.1 hour, filtered off with suction, washed with ethyl acetate and dried in vacuo. 5.56 g of the product are obtained, which is added to a mixture, heated to HO 0 C, of 55 ecm of dimethylformamide, 5.5 g of lithium carbonate and 2.75 g of lithium bromide. Man hält die Reaktionsmischung 4V2 Stunden unter Rühren in Stickstoffatmosphäre, kühlt ab, gießt in ein Gemisch von Eis und Wasser, rührt 1 bisThe reaction mixture is kept for 4 hours with stirring in a nitrogen atmosphere, cooled, poured into a mixture of ice and water, stirred for 1 to 2 Stunden, saugt ab, wäscht mit Wasser und trocknet im Vakuum. Man kristallisiert das Produkt aus Äthylacetat und erhält 1,522 g 3,ll-Dioxo-20-methyl-20-dimethylamino-Zl 4-pregnen vom F. = 232 bis 234° C. [<%]?? = +158 ± 5° (c = 0,2%, Äthanol). Die Ausbeute bei der Dehydrobromierung beträgt 40 %.2 hours, sucks off, washed with water and dried in vacuo. The product is crystallized from ethyl acetate and 1.522 g of 3, ll-dioxo-20-methyl-20-dimethylamino-Zl 4 -pregnen with a mp = 232 to 234 ° C. [<%] ?? = +158 ± 5 ° (c = 0.2%, ethanol). The yield in the dehydrobromination is 40%. Das Produkt ergibt sich in Form von weißen Kristallen, die in Äther und Äthanol wenig löslich und in Säuren und Chloroform löslich sind.The product results in the form of white crystals, which are sparingly soluble in ether and ethanol and are soluble in acids and chloroform. Analyse: C24H37O2N = 371,54.Analysis: C 24 H 37 O 2 N = 371.54. Berechnet ... C77,59%, H 10,04%, N3,76%;
gefunden ... C 77,6%, H 9,7%, N 3,9%.Calculated ... C77.59%, H 10.04%, N 3.76%;
found ... C 77.6%, H 9.7%, N 3.9%. Das Produkt wurde in der Literatur bisher noch nicht beschrieben.The product has not yet been described in the literature. Beispiel2Example2 Herstellung des Hydrochloride des 3,11-Dioxo-20-methyl-20-dimethylamino-/d4-pregnens Preparation of the hydrochloride of 3,11-dioxo-20-methyl-20-dimethylamino- / d 4 -pregnens Man löst unter leichtem Erwärmen in 18 ecm Äthylacetat 1,5 g des nach Beispiel 1 erhaltenen 3,ll-Dioxo-20-methyl-20-dimethylamino-^l4-pregnens, läßt dann abkühlen und versetzt unter Rühren mit1.5 g of the 3, ll-dioxo-20-methyl-20-dimethylamino- ^ l 4 -pregnens obtained according to Example 1 are dissolved in 18 ecm of ethyl acetate with slight warming, then allowed to cool and mixed with stirring 3 ecm einer Lösung von Salzsäure in Äther (l,5n). Man rührt 15 Minuten, um den Niederschlag in Suspension zu halten, trennt den Niederschlag durch Filtration ab, saugt ab und wäscht anschließend mit Äther. Auf diese Weise erhält man 1,41 g des Hydrochloride, das bei etwa 240 bis 26O0C schmilzt.3 ecm of a solution of hydrochloric acid in ether (1.5n). The mixture is stirred for 15 minutes in order to keep the precipitate in suspension, the precipitate is separated off by filtration, filtered off with suction and then washed with ether. In this manner there is obtained 1.41 g of the hydrochloride, melting at about 240 to 26O 0 C. worin R und R1 niedere Alkylreste, Aryl- oder Aralkylreste und R2 einen Alkylrest mit 1 bis 4 Kohlenstoffatomen bedeuten, sowie von Salzen dieser Verbindungen, dadurch gekennzeichnet, daß man in an sich bekannter Weise ein primäres Amin der Formel NH2R, worin R die vorstehend angegebene Bedeutung hat, mit einem in 3- und 11-Stellung oxygenierten 20-Oxo-5/3-pregnan, dessen etwa vorhandene andere Ketofunktionen vorher durch Bildung eines cyclischen Ketals geschützt worden sind, umsetzt, das gebildete 20-Iminoderivat durch Behandlung mit einem niederen Alkylhalogenid oder einem Aryl- oder Aralkylhalogenid der Formel Hai—R1, worin Hai ein Halogenatom bedeutet und R1 die vorstehend angegebene Bedeutung hat, in das ternäre Iminiumsalz überführt, letzteres mit einem Alkylmagnesiumhalogenid der Formel Hai—MgR2, worin Hai ein Halogenatom bedeutet und R2 die vorstehend angegebene Bedeutung hat, reagieren läßt, das erhaltene 20-Alkyl-20-tert.-aminosteroid nach vorübergehender Salzbildung isoliert und vorhandene geschützte Ketofunktionen gegebenenfalls durch Hydrolyse freisetzt, in der erhaltenen Verbindung vorhandene freie Hydroxyfunktionen in 3- und 11-Stellung oxydiert und durch 4-Bromierung und anschließende Dehydrobromierung eine Doppelbindung in 4(5)-Stellung einführt und gegebenenfalls die erhaltene Verbindung in ein Salz einer Mineralsäure oder einer organischen Säure überführt.wherein R and R 1 are lower alkyl radicals, aryl or aralkyl radicals and R 2 is an alkyl radical having 1 to 4 carbon atoms, and salts of these compounds, characterized in that a primary amine of the formula NH 2 R, in which R. Treatment with a lower alkyl halide or an aryl or aralkyl halide of the formula Hai — R 1 , in which Hal is a halogen atom and R 1 has the meaning given above, is converted into the ternary iminium salt, the latter with an alkyl magnesium halide of the formula Hai — MgR 2 , in which Hal denotes a halogen atom and R 2 has the meaning given above, allows the 20-alkyl-20-tert-aminosteroid obtained to react after temporary salt formation g is isolated and any protected keto functions present are released by hydrolysis, free hydroxyl functions present in the compound obtained are oxidized in the 3- and 11-positions and, by 4-bromination and subsequent dehydrobromination, a double bond is introduced in the 4 (5) position and, if appropriate, the compound obtained in transferred to a salt of a mineral acid or an organic acid. 2. Verfahren zur Herstellung von 3,11-Dioxo-20-methyl-20-dimethylamino-Zl4-pregnen bzw. eines Salzes desselben nach Anspruch 1, dadurch gekennzeichnet, daß man als Ausgangsverbindung 3«-Acetoxy-ll(5-hydroxy-20-oxo-5/?-pregnan verwendet, dieses mit Methylamin in Gegenwart von Natriummethylat reagieren läßt, das erhaltene 3«,ll/?-Dihydroxy-20-methylimino-5/9-pregnan mit Methyljodid in das entsprechende Jodmethylat überführt, das erhaltene Iminiumsalz mit Methylmagnesiumbromid umsetzt, das gebildete 3#,ll/?-Dihydroxy-20-methyl-20-dimethylamino-5/?-pregnan der Einwirkung eines Oxydationsmittels, insbesondere Chromschwefelsäure, unterwirft, in das erhaltene S^l-Dioxo^O-methyl^O-dimethylamino-5/?-pregnan durch Bromieren in Essigsäure und2. Process for the preparation of 3,11-dioxo-20-methyl-20-dimethylamino-Zl 4 -pregnen or a salt thereof according to claim 1, characterized in that the starting compound 3 "-acetoxy-II (5-hydroxy -20-oxo-5 /? - pregnane is used, this is allowed to react with methylamine in the presence of sodium methylate, the 3 «, ll /? - dihydroxy-20-methylimino-5/9-pregnane obtained is converted into the corresponding iodine methylate with methyl iodide, the iminium salt obtained is reacted with methylmagnesium bromide, the 3 #, ll /? - dihydroxy-20-methyl-20-dimethylamino-5 /? - pregnane formed is subjected to the action of an oxidizing agent, in particular chromosulfuric acid, into the resulting S ^ l-dioxo ^ O-methyl ^ O-dimethylamino-5 /? - pregnane by bromination in acetic acid and 7 87 8 Bromwasserstoffabspaltung mit dem Salzpaar Salz einer Mineralsäure oder einer organischenElimination of hydrogen bromide with the salt pair salt of a mineral acid or an organic one Lithiumcarbonat-Lithiumbromid in Dimethylform- Säure überführt,Lithium carbonate lithium bromide converted into dimethylform acid, amid eine Doppelbindung in 4(5)-Stellung einführtamide introduces a double bond in the 4 (5) position ldld pp ()pp () und das erhaltene S^l-Dioxo-ZO-methyl^O-di- In Betracht gezogene Druckschriften:and the obtained S ^ l-Dioxo-ZO-methyl ^ O-di- Considered publications: jmethylamino-id4-pregnen gegebenenfalls in ein 5 USA.-Patentschrift Nr. 3 013 008.methylamino-id 4 -pregnen optionally in US Pat. No. 3,013,008. 609 537/440 3.66 © Bundesdruckerei Berlin609 537/440 3.66 © Bundesdruckerei Berlin
DER35992A 1962-08-27 1963-08-27 Process for the preparation of 3, 11-Dioxo-20-tert-amino-20-alkyl-4-pregnenverbindungen and salts thereof Pending DE1212082B (en)

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DER35991A Pending DE1212081B (en) 1962-08-27 1963-08-27 Process for the preparation of 11-oxo-20-tert-amino-20-alkyl-5beta-pregnane compounds and salts thereof
DER35990A Pending DE1212080B (en) 1962-08-27 1963-08-27 Process for the preparation of 20-tert-amino-20-alkyl steroids and salts thereof
DER35993A Pending DE1212083B (en) 1962-08-27 1963-08-27 Process for the preparation of 20-tert-amino-20-alkyl-5alpha-pregnane compounds and salts thereof
DER35992A Pending DE1212082B (en) 1962-08-27 1963-08-27 Process for the preparation of 3, 11-Dioxo-20-tert-amino-20-alkyl-4-pregnenverbindungen and salts thereof

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DER35990A Pending DE1212080B (en) 1962-08-27 1963-08-27 Process for the preparation of 20-tert-amino-20-alkyl steroids and salts thereof
DER35993A Pending DE1212083B (en) 1962-08-27 1963-08-27 Process for the preparation of 20-tert-amino-20-alkyl-5alpha-pregnane compounds and salts thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3013008A (en) * 1961-01-09 1961-12-12 Searle & Co N-substituted 20-aminopregnan-3-ols, esters thereof, and deta-derivatives corresponding

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3013008A (en) * 1961-01-09 1961-12-12 Searle & Co N-substituted 20-aminopregnan-3-ols, esters thereof, and deta-derivatives corresponding

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GB1025907A (en) 1966-04-14
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