SU309516A1 - - Google Patents

Description

METHOD OF OBTAINING PROFILE 1 The invention may find wide application in the pharmaceutical industry. A known method for producing benzodiazepine derivatives is of the general formula </ BR> where RI is hydrogen, halogen, nitro, etc .; R2 is hydrogen, lower alkyl, etc. The method is that 2-phthalylglycylaminobenzophenone is obtained from 2-aminobenzophenone and phthalylglycidine chloride. The latter is heated in the presence of hydrazine hydrate. The resulting intermediate products immediately after that are subjected to alkaline hydrolysis. Target products are recovered by known techniques. In order to simplify the process, a method is proposed for obtaining benzodiazepine derivatives of the general formula of the following benzodiazepine 2 where X is a halogen atom; RI is a hydrogen atom, lower alkyl, having 1-3 carbon atoms, or cycloalkylmethyl, having 4-7 carbon atoms; R2 is a hydrogen or halogen atom. The method consists in the fact that 2-aminomethylindole derivatives of the general formula where X, RI and R2 are as defined above, are treated with an oxidizing agent, for example, chromic acid, ozone, hydrogen peroxide. The reaction is carried out at room temperature.

temperature in the presence of a solvent followed by isolation of the target product by known techniques.

Example 1. To a solution of 3 g of chromic anhydride in 3 ml of water, a solution of 2.9 g of 2-aminomethyl-5-chloro-3- (o-chlorophenyl) indole in 20 ml of acetic acid is gradually added. The mixture is stirred at room temperature for 26 hours. 10 ml of water are added to the reaction mixture, then 50 ml of 28% ammonium hydroxide solution with stirring and cooling. The mixture is extracted with chloroform, the organic layer is separated, dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel. 7-chloro-5 (o-chlorophenyl) -1,3-dihydro -2H-1,4-benzodiazepainPIN-2-OH is obtained with m.p. 199-201 ° C.

Example 2. To a solution of 40 g of chromic anhydride in 30 ml of water is gradually added a suspension of 40 g of 2-aminomethyl-5-chloro-3- (oforophenyl) -indole hydrochloride in 400 ml of acetic acid at a temperature of 15-20 ° C. The mixture is stirred at room temperature overnight, and then 850 ml of 28% ammonium hydroxide solution, 850 ml of water and 700 ml of methylene chloride are added with stirring and cooling.

The aqueous layer was separated and extracted with methylene chloride. The organic layer is combined and concentrated in vacuo. The residue is triturated with benzene, then filtered, washed with benzene and dried. As a result, 18 g of a crude product is obtained, which is recrystallized, and 4.5 g of 7-chloro-5-o-fluorophenyl-1,3-dihydro-2H-1, 4-benzodiazepin-2-one hydrochloride with m.p. 205 ° C (decomposition).

Example 3. A solution of 3 g of chromic anhydride in 3 g of water is gradually added to a suspension of 3.6 g of 1-cyclopropylmethyl-2-amino-3- (o-fluorophenyl) -5 - chloroindole hydrochloride at a temperature below 25 ° C. After stirring at room temperature overnight, the reaction mixture was poured into ice-cold water, basified with an aqueous solution of ammonium hydroxide, and extracted with methylene chloride. The organic layer is dried with sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography. 1-cyclopropylmethyl-5- (oforophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one is obtained. Ultraviolet absorption spectrum Yamax. 229.314 t.1. Infrared absorption spectrum v 3080, 1670 cm-.

Found,%: C 61.42; H 4.58; N 8.04.

CisHisNaOClF.

Calculated,%: C, 61.57; H 4.70; N 8.17.

to a suspension of 60 g of 2-aminomethyl-1-methyl-5-chloro- (o-fluorophenyl) -indole hydrochloride in 600 ml of acetic acid. The mixture is stirred at room temperature overnight. 1.1 l of ether and 1 l of water are added to the reaction mixture, and then 800 ml of 28% ammonium hydroxide solution are added in small portions. The ether layer is separated, washed with water, dried and concentrated under reduced pressure. The residue (51.8 g) was dissolved in 100 ml of ethanol, and a 20% solution of ethyl alcohol saturated with hydrogen chloride was added to the solution. The mixture is cooled. The precipitate is collected by filtration. 46.5 g of 1-methyl-7-chloro-5 - (o-fluorophenyl) -1,3-dihydro2P-1, 4-benzodiazepin-2-one hydrochloride are obtained, with a mp. 218 ° C (decomposition). After recrystallization from ethanol, m.p. 218.5-219 ° C (decomposition).

Found,%: C 56.72; N8.13.

CieHisNaOClF-HCI.

Calculated,%: C 56.65; N 8.26.

Similarly, the following compounds were prepared:

5- (o-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one;

5- (o-fluorophenyl) -1,3-dihydro -2H-1,4-benzodiazepin-2-one;

5- (o-chlorophenyl) -7-chloropl, 3-dihydro-2H-l, 4 benzodiazepin-2-o;

5- (o-fluorophenyl) -7-chloro-1,3 - dihydro-2P-1,4benzodiazepin-2-one;

5- (o-bromophenyl) -7-chloro - 1,3-dihydro-2H-1,4benzodiazepin-2-one;

5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4benzodiazepin-2-one;

5 - ((5-chlorophenyl) -7-bromo-1,3 - dihydro-2H-1,4benzodiazepin-2-one;

1-methyl-5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-1, 4-benzodiazepin-2-one;

1-methyl - 5 - (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-1, 4-benzodiazepin-2-one;

1-methyl-5 - (o-fluorophenyl) -7-bromo-1,3-dihydro-2H-1, 4-benzodiazepin-2-one;

1-ethyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydrp2H-1; 4-benzodiazepin-2-one;

1-propyl-5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-1; 4-benzodiazepin-2-one;

1-cyclopropylmethyl-5- (o-fluorophenyl) -1,3-dihydro-2H-1; 4-benzodiazepin-2-one;

1-cyclopropylmethyl-5- (o-chlorophenyl) -1,3 dihydro-2H-1, 4-benzodiazin-2-one;

1-cyclopropylmethyl-5- (o-fluorophenyl) -7 chloro-1, 3-dihydro-2P-1,4-benzodiazepin-2-one;

1-cyclopentylmethyl - 5 - (o - fluorophenyl) - 7 chloro-1, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1-cyclopropylmethyl-5- (o-chlorophenyl) -7 chloropen, 3-dihydro-2H-1, 4-benzo-diazepin-2-one;

1 - cyclopropylmethyl - 5- (o - fluorophenyl) - 9 chloro-1, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1-cyclopropylmethyl-5- (o-fluorophenyl) -7brom-1, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1-cyclopentylmethyl- 5- (o-fluorophenyl) -7brom-1, 3-dihydro-2H-1,4-benzodiazepin-2-one;

1-cyclohexylmethyl-5- (o-fluorophenyl) -7 chloro-1, 3-dihydro-2H-1,4-benzodiazepin-2-one.

Subject invention

The method of obtaining benzodiazepine derivatives of the general formula

where X is halogen;

RI is hydrogen, a lower alkyl radical containing 1-3 carbon atoms or a cycloalkylmethyl radical containing 4-7 carbon atoms;

R2 is hydrogen or halo, characterized in that, in order to simplify the process, derivatives of 2-aminomethylindole of the general formula

SNGKNg

where X, RI and H have the above values, are treated with an oxidizing agent, for example chromic acid, ozone, hydrogen peroxide, followed by isolation of the target product by known techniques.