DE1190946B - Process for the preparation of 2-oxo-1, 2-dihydro-3 H-1, 4-benzodiazepine-4-oxides - Google Patents

Process for the preparation of 2-oxo-1, 2-dihydro-3 H-1, 4-benzodiazepine-4-oxides

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Publication number
DE1190946B
DE1190946B DEH41135A DEH0041135A DE1190946B DE 1190946 B DE1190946 B DE 1190946B DE H41135 A DEH41135 A DE H41135A DE H0041135 A DEH0041135 A DE H0041135A DE 1190946 B DE1190946 B DE 1190946B
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Germany
Prior art keywords
benzodiazepine
dihydro
oxo
alkyl
hydrogen
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DEH41135A
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German (de)
Inventor
Earl Reeder
Leo Henryk Sternbach
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Publication of DE1190946B publication Critical patent/DE1190946B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Verfahren zur Herstellung von 2-Oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyden Die Erfindung betrifft ein Verfahren zur Herstellung von 2-Oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyden der allgemeinen Formel worin R ein Wasserstoffatom oder eine Alkyl-, Alkenyl- oder Aralkylgruppe, R1 ein Wasserstoffatom oder eine Alkylgruppe, R2 ein Wasserstoff-oder Halogenatom, eine Alkyl-, Alkoxy- oder Triluormethylgruppe, R3 ein Wasserstoff oder ein Halogenatom, eine Trifluormethyl-, Alkyl-, Alkoxy-, Alkylmercapto-, Alkylsulfinyl-, Alkylsulfonyl- oder Nitrogruppe und R1 ein Wasserstoff oder Halogenatom, eine Alkyl-, Alkoxy-, Alkylmercapto-, Alkylsulfinyl-, Alkylsulfonyl- oder Nitrogruppe bedeutet.Process for the preparation of 2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxides The invention relates to a process for the preparation of 2-oxo-1,2-dihydro-3 H-1,4 -benzodiazepine-4-oxides of the general formula where R is a hydrogen atom or an alkyl, alkenyl or aralkyl group, R1 is a hydrogen atom or an alkyl group, R2 is a hydrogen or halogen atom, an alkyl, alkoxy or triluomethyl group, R3 is a hydrogen or a halogen atom, a trifluoromethyl, alkyl , Alkoxy, alkylmercapto, alkylsulphinyl, alkylsulphonyl or nitro group and R1 is a hydrogen or halogen atom, an alkyl, alkoxy, alkylmercapto, alkylsulphinyl, alkylsulphonyl or nitro group.

Die Alkyl- und Alkenylgruppen im Molekül sind vorzugsweise niedere Alkyl- bzw. niedere Alkenylreste, die geradkettig oder verzweigt sein können, wie die Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, tert.-Butyl-, Amyl-, Hexyl-, Allyl- und Butenylgruppe. Als Halogenatom in beiden Benzolringen sind Chlor- und Bromatome bevorzugt. Der Aralkylrest ist vorzugsweise eine Benzylgruppe.The alkyl and alkenyl groups in the molecule are preferably lower Alkyl or lower alkenyl radicals, which can be straight-chain or branched, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, Hexyl, allyl and butenyl groups. The halogen atoms in both benzene rings are chlorine and bromine atoms are preferred. The aralkyl group is preferably a benzyl group.

Das erfindungsgemäße Verfahren besteht darin, daß man ein 2-Acylamino-benzophenon-i3-oxim der allgemeinen Formel in der R, Ri, R2, R3 und R4 die oben angegebene Bedeutung haben und X ein Halogenatom bedeutet, mit etwa 1 Mol einer Base behandelt und gegebenenfalls anschließend erhaltene Verbindungen in an sich bekannter Weise nitriert.The process according to the invention consists in that a 2-acylamino-benzophenone-i3-oxime of the general formula in which R, Ri, R2, R3 and R4 have the meaning given above and X is a halogen atom, treated with about 1 mol of a base and, if appropriate, compounds obtained subsequently nitrated in a manner known per se.

Das erfindungsgemäße Verfahren wird vorzugsweise mit verdünnter Natronlauge durchgeführt. Die Nitrierung kann mittels Salpetersäure erfolgen, wobei eine oder zwei - Nitrogruppen eingeführt werden können.The method according to the invention is preferably carried out with dilute sodium hydroxide solution carried out. The nitration can be carried out by means of nitric acid, with one or two - nitro groups can be introduced.

Die Verbindungen der vorstehenden allgemeinen Formel (I) weisen sedative, muskelrelaxierende oder antikonvulsive Eigenschaften auf. Sie können entsprechend den therapeutischen Anforderungen (angepaßt an die Verabreichungsart und die individuellen Erfordernisse) entweder oral oder parenteral verabreicht werden.The compounds of the above general formula (I) have sedative, muscle relaxant or anticonvulsant properties. You can accordingly the therapeutic requirements (adapted to the mode of administration and the individual Requirements) can be administered either orally or parenterally.

Das folgende Beispiel veranschaulicht das erfindungsgemäße Verfahren. Alle Temperaturen sind in Celsiusgraden angegeben, und die Schmelzpunkte sind korrigiert.The following example illustrates the method according to the invention. All temperatures are given in degrees Celsius and the melting points are corrected.

Beispiel 20 ml 1 n-Natronlauge werden zu einer Lösung von 6,4g 2-Chloracetamido-5-chlor-benzophenonß-oxim in 60 ml Dioxan zugesetzt. Nach 15 Stunden wird die Reaktionsmischung mit eiskalter 1 n-Natronlauge (20 mMol) verdünnt und mit Äther extrahiert. Der Ätherextrakt wird verworfen. Die alkalische Lösung wird mit Salzsäure angesäuert und mit Methylenchlorid extrahiert. Die Methylenchloridlösung wird auf ein geringes Volumen eingeengt und hierauf mit Petroläther verdünnt, wobei das 5-Phenyl-7-chlor-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyd ausfällt; F.235 bis 236° (Zersetzung) ; Ausbeute: 54%.Example 20 ml of 1N sodium hydroxide solution are converted into a solution of 6.4 g of 2-chloroacetamido-5-chloro-benzophenone-3 oxime added in 60 ml of dioxane. After 15 hours, the reaction mixture becomes ice-cold with 1 N sodium hydroxide solution (20 mmol) diluted and extracted with ether. The ether extract is discarded. The alkaline solution is acidified with hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is low Concentrated in volume and then diluted with petroleum ether, the 5-phenyl-7-chloro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide precipitates; F. 235 to 236 ° (decomposition); Yield: 54%.

Das als Ausgangsmaterial verwendete 2-Chloracetamido - 5 -chlor - benzophenon - ß - oxim wird auf folgende Weise hergestellt: In eine auf 10 bis 15° gekühlte Lösung von 26,2 g 2-Amino-5-chlor -benzophenon-ß-oxim in 150 ml Dioxan werden unter Rühren in kleinen Anteilen 12,4 g Chloracetylchlorid und eine äquivalente Menge von 3 n-Natronlauge eingetragen. Das Chloracetylchlorid und die Natronlauge werden abwechselnd derart zugesetzt, daß die Temperatur unterhalb 15° bleibt und die Reaktionsmischung neutral oder leicht alkalisch ist. Nach 30 Minuten ist die Reaktion abgeschlossen. Man säuert die Reaktionsmischung hierauf mit Salzsäure leicht an, verdünnt mit Wasser und extrahiert mit Äther. Der Ätherextrakt wird getrocknet und im Vakuum eingedampft. Der ölige Rückstand wird mit Äther versetzt, worauf 2-Chloracetamido - 5 - chlor - benzophenon - ß - oxim in farblosen Prismen vom Schmelzpunkt 161 bis 162°C kristallisiert.The 2-chloroacetamido - 5 -chlor - used as starting material Benzophenone - ß - oxime is made in the following way: In one at 10 to 15 ° cooled solution of 26.2 g of 2-amino-5-chloro-benzophenone-ß-oxime in 150 ml of dioxane are stirred in small portions 12.4 g of chloroacetyl chloride and an equivalent Amount of 3 N sodium hydroxide solution entered. The chloroacetyl chloride and the caustic soda are alternately added so that the temperature remains below 15 ° and the reaction mixture is neutral or slightly alkaline. After 30 minutes it is Reaction completed. The reaction mixture is then acidified slightly with hydrochloric acid on, diluted with water and extracted with ether. The ether extract is dried and evaporated in vacuo. Ether is added to the oily residue, whereupon 2-chloroacetamido - 5 - chloro - benzophenone - ß - oxime in colorless prisms from melting point 161 to 162 ° C crystallized.

In analoger Weise wurden die folgenden Verbindungen hergestellt: 1-Methyl-5-phenyl-7-chlor-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyd; farblose Prismen; F. 188 bis 189°; 5-Phenyl-7-methyl-2-oxo-1,2-dihydro-3 H-1,4 - benzodiazepin - 4 - Oxyd; farblose rhombische Platten; F. 226 bis 227°; 5 - Phenyl - 7 - brom - 2 - oxo -1,2 - dihydro - 3 H-1,4-benzodiazepin-4-oxyd; F. 230 bis 231°; 5-Phenyl-7,8-dimethyl-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyd; farblose Platten; F. 234 bis 235°; 5-(p-Tolyl)-7-brom-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyd; farblose Platten; F. 237 bis 238'; 5-(4'-Chlor-phenyl)-7-chlor-2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd; farblose Platten; F. 250 bis 252'; 1-Allyl-5-phenyl-7-chlor-2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd; farblose Platten; F. 150 bis l51 °; 5 - Phenyl- 7- trifluormethyl-2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd ; F. 211 bis 212°; 1 - Methyl - 5 - phenyl - 7 - trifluormethyl - 2 - oxo-1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyd; kleine Prismen; F. 170 bis 180°; 5-Phenyl-7-methylmercapto-2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd; Nadeln; F. 191 bis 193'; 1-Benzyl-5-phenyl-7-chlor-2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd; farblose Prismen; F. 151 bis 152°; 5-(2'-Chlor-phenyl)-7-chlor-2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd ; F. 248 bis 249`; 5-Phenyl-7-nitro-2-oxo- 1,2-dihydro-3 H-1,4-benzodiazepin-4-oxyd; F. 218 bis 220°C; 1-Äthyl -5-phenyl-7-chlor -2-oxo-1,2-dihydro-3 H - 1,4 - benzodiazepin - 4 - Oxyd; farblose Platten; F. 207 bis 208°.The following compounds were prepared in an analogous manner: 1-methyl-5-phenyl-7-chloro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless prisms; 188-189 °; 5-phenyl-7-methyl-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless rhombic plates; M.p. 226 to 227 °; 5-phenyl-7-bromo-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; M.p. 230 to 231 °; 5-phenyl-7,8-dimethyl-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless plates; M.p. 234 to 235 °; 5- (p-Tolyl) -7-bromo-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless plates; F. 237 to 238 '; 5- (4'-chloro-phenyl) -7-chloro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless plates; F. 250 to 252 '; 1-allyl-5-phenyl-7-chloro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless plates; Mp 150-151 °; 5-phenyl-7-trifluoromethyl-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; Mp 211-212 °; 1 - methyl - 5 - phenyl - 7 - trifluoromethyl - 2 - oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; small prisms; Mp 170-180 °; 5-phenyl-7-methylmercapto-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; Needles; F. 191 to 193 '; 1-benzyl-5-phenyl-7-chloro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless prisms; 151-152 °; 5- (2'-chloro-phenyl) -7-chloro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; F. 248 to 249 '; 5-phenyl-7-nitro-2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; Mp 218-220 ° C; 1-ethyl -5-phenyl-7-chloro -2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxide; colorless plates; 207 to 208 °.

Claims (1)

Patentanspruch: Verfahren zur Herstellung von 2-Oxo-1,2-dihydro - 3 H - 1,4 - benzodiazepin - 4 - Oxyden der allgemeinen Formel worin R ein Wasserstoffatom oder eine Alkyl-, Alkenyl- oder Aralkylgruppe, Ri ein Wasserstoffatom oder eine Alkylgruppe, R2 ein Wasserstoff-oder Halogenatom, eine Alkyl-, Alkoxy- oder Trifluormethylgruppe, R3 ein Wasserstoff oder ein Halogenatom, eine Trifluormethyl-, Alkyl-, Alkoxy-, Alkylmercapto-, Alkylsulfinyl-, Alkylsulfonyl- oder Nitrogruppe und R,4 ein Wasserstoff= oder Halogenatom, eine Alkyl-, Alkoxy-, Alkylmercapto-, Alkylsulfinyl-, Alkylsulfonyl-oder Nitrogruppe bedeutet, d a d u r c h g e k e n n -z e i c h n e t, daß man ein 2-Acylamino-benzophenon-ß-oxim der allgemeinen Formel in der R, Ri, R2, R3 und R4 die oben angegebene Bedeutung haben und X ein Halogenatom bedeutet, mit etwa 1 Mol einer Base behandelt und gegebenenfalls anschließend erhaltene Verbindungen in an sich bekannter Weise nitriert. In Betracht gezogene Druckschriften USA.-Patentschrift Nr. 2 893 992.Claim: Process for the preparation of 2-oxo-1,2-dihydro-3 H-1,4-benzodiazepine-4-oxides of the general formula where R is a hydrogen atom or an alkyl, alkenyl or aralkyl group, Ri is a hydrogen atom or an alkyl group, R2 is a hydrogen or halogen atom, an alkyl, alkoxy or trifluoromethyl group, R3 is a hydrogen or a halogen atom, a trifluoromethyl, alkyl , Alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl or nitro group and R, 4 denotes a hydrogen = or halogen atom, an alkyl, alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl or nitro group, dadu rchgekenn that one a 2-acylamino-benzophenone-ß-oxime of the general formula in which R, Ri, R2, R3 and R4 have the meaning given above and X is a halogen atom, treated with about 1 mol of a base and, if appropriate, compounds obtained subsequently nitrated in a manner known per se. Referred to U.S. Patent No. 2,893,992.
DEH41135A 1959-12-10 1960-12-07 Process for the preparation of 2-oxo-1, 2-dihydro-3 H-1, 4-benzodiazepine-4-oxides Pending DE1190946B (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
US2893992A (en) * 1959-07-07 I ii i i

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2893992A (en) * 1959-07-07 I ii i i

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