DE1445888B - Process for the preparation of benzodiazepine derivatives - Google Patents

Description

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The invention relates to a process for the preparation of benzodiazepine derivatives of the general formula

in which R ₁ denotes a hydrogen atom or the methyl radical, R ₂ and R ₃ denotes methyl or ethyl radicals and R ₄ denotes a hydrogen or a fluorine atom, which is characterized in that a benzodiazepine derivative of the general formula is used in a manner known per se

in which R _{4 has} the meaning given above, with a compound of the general formula

in which X and Z are halogen atoms and R _{1 has} the meaning given above, and the compound obtained is reacted with a secondary amine of the general formula

in which R ₂ and R 3 have the meaning given above.

In a preferred embodiment, X is a bromine atom and Z is a chlorine atom.

It is advisable to first convert a compound of the general formula II into a 1-sodium derivative, z. B. by treatment with sodium methoxide or sodium hydride before applying the compound brings with a dihalide of the general formula III to implement.

The reaction of a compound of the general formula II with a dihalide of the general Formula III is expediently in an inert organic solvent using a or more of the following solvents: methanol, ethanol, dimethylformamide, benzene, Toluene, nitromethane, N-methylpyrrolidone. The reaction can be at room temperature or elevated Temperature and can be carried out at normal pressure or elevated pressure.

The further reaction with a secondary amine of the formula IV can be carried out in one of the preceding Paragraph mentioned inert organic solvents take place in the manner indicated there. It was also found that in this reaction the presence of an alkali halide, such as sodium iodide, is advantageous in the reaction mixture.

Compounds of the general formula I have anticonvulsant properties. Connections with similar Constitution and the same direction of action are already from the French patent 839 M known. Compared to the 1-methyl-5-phenyl-7-chloro-1,2-dihydro-3 described there H-1,4-benzodiazepin-2-one and the also previously known 7-chloro-2-methylamino-5-phenyl-3 H-1,4-benzodiazepine-4-oxide, the process end products have a significantly more favorable ratio of with comparable toxicity anticonvulsant effect to sedative effect, as determined by testing in the test on the inclined plane and could be detected in the pentamethylenetetrazole test. This fact is special Advantage in the treatment of epileptics.

The following example illustrates the method according to the invention. All temperatures are in Degrees Celsius and the melting points are corrected.

example

A solution of 20.6 g (0.0713 mol) of 5- (2-fluorophenyl) -7-chloro-1,2-dihydro-3 Hl, 4-benzodiazepin-2-one in 150 ml of N, N-dimethylformamide is treated with 18.3 ml (0.0892MoI) of a 4.87 normal sodium methoxide solution. The solution is cooled to 4 °, whereupon 13.3 g (0.0927 mol) of 1-bromo-2-chloroethane are added. The reaction mixture is heated and stirred at 65 ° for 6 hours. The solvent is removed under reduced pressure and the residue is dissolved in 100 ml of dichloromethane. The solution obtained is washed three times with 100 ml of water each time, dried and evaporated to dryness. Unreacted starting material is removed by dissolving the residue in ether and filtering. The filtrate is evaporated and the residue is dissolved in benzene, whereupon it is chromatographed on aluminum oxide. It is eluted with ether and then with ethyl acetate, the eluates are combined and evaporated to dryness. Recrystallization from a mixture of ether and hexane gives 1 - (2-chloroethyl) - 5 - (2 - fluorophenyl) - 7 - chlorine. -, |, 2 - dihydro - 3 H-

1,4-benzodiazepin-2-one in the form of white prisms with a melting point of 111 ° to 114 °.

10 mmol of 1- (2-chloroethyl) -5- (2-fluorophenyl) -7-chloro-1,2-dihydro-3 H-l, 4-benzodiazepin-2-one, 11ml diethylamine, 5 g sodium iodide and about 25 ml ethajioJ

are 8V2 hours under nitrogen overpressure of shaken about 80 atmospheres at 125 °. The crude reaction mixture is diluted with water and washed with λ benzene extracted. The organic layer is extracted with 100 ml of 0.3 normal hydrochloric acid and the Washed extract with benzene. The aqueous layer is neutralized with ammonia and with benzene extracted. ' The extract is dried and evaporated to dryness. The raw rubbery pro-

product (1.9 g) is determined by means of preparative thin layer chromatography (Silica gel; eluent ethyl acetate: hexane / 3: 2) worked up, methanol being used as Extractant used. The reaction product 1 - (2-diethylaminoethyl) -5- (2-fluorophenyl) -7-chloro, 2-dihydro-3 H-1,4-benzodiazepin-2-one gives colorless crystals on recrystallization from petroleum ether from m.p. 79 to 80 °. The product provides an identical infrared spectrum and a mixed melting point of 77 to 80 ° compared to a product made by a different method.

In a manner analogous to that described above, one can prepare:

1- (2-dimethylaminoethyl) -5-phenyl-7-chloro-1,2-dihydro-3 H-1,4-benzodiazepin-2-one; yellow prisms Ether — hexane, mp 96 ° to 98 °.

1- (2-diethylaminoethyl) -5-phenyl-7-chloro-1,2-dihydro-3 H-1,4-benzodiazepin-2-one; colorless prisms from ether-pentane, melting point 79 to 80 °.

1 - (2 - Dimethylamine -1 - methylethyl) - 5 - phenyl-7 - chlorine -1,2 - dihydro - 3 H -1,4 - benzodiazepin - 2 - one; Mp. 134-135 ° (from hexane). Mp. Of the dihydrochloride 165 to 168 °.

Claims (1)

Claim: Process for the preparation of benzodiazepine derivatives of the general formula 35 40 R ₂ and R ₃ denote methyl or ethyl radicals and R ₄ denotes a hydrogen or a fluorine atom, characterized in that a benzodiazepine derivative of the general formula is used in a manner known per se in which R _{4 has} the meaning given above, with a compound of the general formula X - CH - CH ₂ - Z III in which X and Z are halogen atoms and R _{1 has} the meaning given above, and the compound obtained is reacted with a secondary amine of the general formula Η — Ν IV in which R _{1 is} a hydrogen atom or the methyl radical in which R ₂ and R ₃ are as defined above.