SU472505A3 - The method of obtaining derivatives of diazepine - Google Patents

Description

indicated for compounds of formula I, or 5N oxide of compound I, and reacted with an amine of general formula III

R-V, where R2 and RS are as indicated, or with an alkali metal derivative of the compound of formula III and, if appropriate, the resulting reaction product is not converted into a salt with an inorganic or organic acid. As reactive and derivatives of oxo compounds of general formula II, for example, sulfonic acid esters (for example, methanesulfonic acid esters), o- or -toluenesulfonic acid esters, o- or p-nitrobenzenesulfonic acid, or o- or chlorobenzenesulfonic esters, are used. Esters of hydrohalogenic acid (in particular, chlorides or bromides), as well as in situ iodides, are also used as reactive derivatives of the general formula II. An excess of the amine of formula III can be used as a solvent and an acid binding agent. At the same time or in place of an excess of amine, an inert organic solvent can be used, for example, a lower alkanal (methanol, ethanol, crocanol, isopropanol or butanol), ketone (acetone or methyl ethyl ketone), dioxane, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide. Instead of an excess of the compound of the formula III, or in addition, it is possible to use another acid-binding agent, for example, a tertiary organic base (ethyldiisopropylamine or collidine) or an inorganic basic substance (eg, potassium carbonate). If the alkali metal produced compound of formula III is used as the reaction reagent, then mainly hydrocarbons (benzene, toluene, xylene), ethers (monoglyme, tetrahydrofuran, dioxane), amides of acids (dimethylformamide, hexametapol) are used as the solvent. sulfoxides The alkali metal derivative of compounds of formula III, with the exception of ammonia, is obtained in situ by reacting the corresponding amine III with an alkali metal hydride, an alkali metal amide, or an organometallic compound of an alkali metal. The required starting compounds of the formula I are obtained, for example, from compounds of the general formula II. For this compound of the formula, diazotized salts are formed diazotized, combined with the esters of (2-chloroalkanamido) -malonic acid, the alkanamido group contains from 2 to 5 carbon atoms, and the corresponding (2-chloroalkanamido) - (2-benzoylphenylazo) - malonic acid esters are obtained, which, by subsequent treatment with hydroxide and acid, are converted to compounds of the formula: Where RI has the above meaning. Next, Compound IIB is cyclized, the resulting carboxylic acid, Eve, where RI is the above-mentioned, is esterified, and the ester is reduced to give Compound II. Oximethyl derivatives II are converted into reactive esters by a known method, by reaction with sulfonic acid chloride in the presence of a base, etc. Example 1. A. 8.05 g (0.02 mol) of 6-phenyl-8-chloro-4H-S methanesulfonate triazolo 1,5-a 1,4 of benodiazine-2-hydroxymethyl in 80 ml of dimethyl sulfoxide was added at 5-10 ° C to 10 g (0.09 mol) of a 40.5% solution of dimethylamine in 20 ml of dimethyl sulfoxide.

Allow the reaction mixture to warm to room temperature, stir for an additional hour at 20-25 ° C, pour into 0.5 L of ice water and extract with benzene (2X250). The combined extracts were washed with water (5 x 100 ml), dried with sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform and the chromatography is carried out on a column with 120 g of basic alumina.

Elute with chloroform, get 2- (dimethylamino) -methyl-6-phenyl-8 - chlorine - 4H-Triazolo 1, 5 - and 1,4 benzodiazepine; m.p. 133-135 ° C (from tsclohexane).

58.0 g (0.25 mol) of 2-amino-5-chlorobenzophenone in a mixture of 310 ml of glacial acetic acid and concentrated hydrochloric acid (4: 1) are diazotized with an aqueous solution of Patriotol at room temperature (the amount of sodium nitrite 50 ml, 0.25 mol). To the resulting solution of the diazonium salt was added 150 g of ice, a solution of 52.4 g (0.208 mol) of diethyl ester of (2-chloroacetamido) -malonic acid in 600 ml of acetone, then at 5-10 ° C for 20 minutes, solution 276, 0 g (2 mol) of potassium carbonate in 500 ml of water, then stirred for another 1 hour, added benzene and a saturated solution of sodium chloride. The benzene solution is separated, washed with a saturated solution of chromic acid, dried over sodium sulfate and evaporated. 121 g of crude (2-benzoyl-4-chlorophenylazo) - (2 - chloroacetamido) -malonic acid ester is obtained, which is dissolved in 1.5 liters of dioxane. To the resulting solution, 36 g (0.9 mol) of sodium hydroxide in 2 liters of water are added, stirred for 30 minutes and the dioxane is evaporated in vacuo. The residue is diluted with 500 ml of water, 20 g of activated charcoal is added, stirred thoroughly and filtered through diatomaceous earth. 2 N was added to the filtrate during desalting. The hydrochloric acid before the acidic reaction into the Congo, the carboxylic acid which is obtained, is filtered off, washed with water and recrystallized from methanol. 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid is obtained, containing an equimolar amount of methanol; m.p. 169-171 ° C (with decomposition).

B. To 33.2 g (0.200 mol) of potassium iodide in 85 ml of water and 850 ml of dioxane at 25 ° C add 71.5 g (0.175 mol) of the compound obtained according to 16, and the solution is heated for 1 hour to 45-50 ° s Then 0.5 l of a concentrated aqueous solution of ammonia is added, the mixture is heated for 2 hours to 45-50 ° C and evaporated in vacuo. The residue was dissolved in 2 L of water, 2N was added. hydrochloric acid until acidic in the congo, the precipitated carboxylic acid is sucked off, washed with water until neutral, then finally washed with methanol and dried in vacuo at 120-130 ° C. The resulting 6-phenyl-8-chloro-4H - $ -triazolo 1,5a 1,4 beisodiazepia - 2-karyonic acid is decomposed iri.

B. 0.408 g (0.001 mol) of the chloromethyl compound obtained according to paragraph B, containing an equimolar amount of methanol and 0.320 g (0.003 mol) of hexamethylentetramp are dissolved in 20 ml of ethanol, the solution is refluxed for 12 hours under reflux, evaporated at 40 ° C in vacuo, the residue is dissolved in 20 ml of 0.05 n. caustic soda, and add 2 n. hydrochloric acid to acidic congo. The precipitated product is treated similarly to paragraph B. 6-phenyl-8-chloro 4P-5 is obtained - trnazolo 1,5-a 1,4 benzodiazepnp-2 carboxylic acid; m.p. 170 ° C.

G. 6.77 g (0.020 mol) of 6-feiil-8-chloro-4H5-triazolo 1, 5-a 1,4 benzodiazepine - 2-carboxylic acid (obtained by method B

or B) in 250 ml of absolute ethanol, saturate with relocated and heated with hydrogen chloride. It is then boiled for another 10 hours with a reverse fridge; the solution is evaporated at 40 ° C under vacuum, the residue

dissolved in 100 ml of cold 5% sodium bicarbonate in 100 ml of methylene chloride, the organic phase is separated, washed with water, dried with sodium sulphate and evaporated in vacuo at 40 ° C. The residue is boiled over.

1 hour with 100 ml of ether, and crystallization begins. The solution is cooled to 0 ° C, the crystals are sucked off and washed with ether. B-phenyl-8-chloro-4 15-triazolo 1, 5-a 1,4-benzodiazepine -2 carboxylic acid ethyl ester is obtained; m.p. 137-138 ° C.

D. To 11.0 g (0.030 mol) of effra 6-phenyl-8 chloro-4H-S-trpazolo 1,5-a 1,4 benzodiazepine-2-carbopic acid in 100 ml of tetrahydrofuran and 100 ml of methanol are added at room temperature 11.3 g (0.030 mol) of sodium borohydride. Cooling with ice water maintain the temperature at 30 ° C. After the end of the exothermic reaction, the mixture is stirred at room temperature for another 1 hour. Then, 200 ml of ice-cold water is added, methanol and tetrahydrofuran are distilled off in vacuo, the aqueous residue is extracted with methylene chloride (2 x 100 ml). The extract is washed with water, dried.

sodium sulfate and evaporated in vacuo to dryness. The residue after recrystallization from isopropanol gives 6-phenyl-8-chloro-4H-5-tetrazolo 1,5-a 1,4 benzodiazepine-2-oxpmethyl st. square 185-186 ° C.

E. K 16.25 g (0.05 mol) prepared according to

method oxymethyl derivative, 1 7 g

(0.075 mol) of triethylamine in 200 ml of absolute methylene chloride, while cooling with ice and stirring, drop by drop 8.6 g

(0.075 mol) of methanesulfonyl chloride in 50 ml of absolute methylene chloride. The reaction mixture is then heated to 20 ° C, stirred for 30 minutes, cooled to 5 ° C, and 100 ml of ice water is added. Organic

the phase is separated, washed (3 x 100 ml) with ice water, dried with sodium sulfate and evaporated at 30 ° C in vacuo. The methanesulfonic acid ester of 6-phenyl-8-chloro-4H-5-triazolo 1,5-a 1.41 benzodiazepin-2-hydroxymethyl, which is obtained as a dark yellow oil, is further reacted without purification. Example 2. A solution of methanesulonic acid ester obtained from 4.9 g (0.015 mol) of 6-phenyl-8-chloro-4H-S - triazolo 1, 5-a 1,4 benzodiazepine - 2-hydroxymethyl and 2.58 g ( 0.023 mol) of methanesulfonic acid chloride according to Example 1E in 50 ml of methanol is added dropwise to 100 ml of boiling methanol, which is constantly saturated with a stream of ammonia. The mixture is then boiled for 4 hours with a reflux condenser in a stream of ammonia, evaporated to dryness in vacuo, and 0.1 n is added to the residue. caustic soda solution and extracted with bepzol. The benzene extract is washed with water and extracted with 0.1 n. acetic acid. The extracts were combined, brought to alkaline with concentrated ammonia and extracted with benzene. The combined benzene extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue (1.7 g) was diluted in ether-ethanol-triethylamine (3: 5: 2) and chromatographed on a column of 170 g of silica gel. A solvent is used as eluent. An amorphous 2- (aminomethyl) -6-phenyl-8chloro-4H-S-triazolo 1,5-a 1,4 benzodiazepine is obtained, which liquefies at 69-75 ° C. Example 3. To a solution of 2.55 g (0.03 mol) of piperidine in 30 ml of dimethyl sulfoxide, 6.05 g (0.015 mol) of 6-phenyl-8-chloro-methanesulfonic acidic ester is added dropwise at 15-17 ° C 4H - 5-triazolo 1,5-a 1,4 benzodiazepin-2-hydroxymethyl (prepared according to Example IE) in 50 ml of dimethyl sulfoxide, and stirred for 3 hours at room temperature. The reaction mixture is poured into ice water, extracted three times with ether, the organic phase is washed with water and once with a saturated solution of sodium chloride, dried with sodium sulfate and evaporated in vacuo to dryness. The residue was dissolved in benzene-methylene chloride (1: 1) and chromatographed on a column with 100 g of basic alumina (eluted with the same mixture of solvent). An amorphous 2- (piperidknomethyl) 6-phenyl-8-chloro-4H-S-triazolo 1,5-a 1,4 benzodiazepine is obtained, which liquefies at 55-64 ° C. Similarly, from 6.05 g (0.015 mol) of the same methanesulfonic ester and 5.4 g (0.077 mol) of pyrrolidine, amorphous 2- (1-pyrrolidinyl) -methyl-6-phenyl-8chlor-411-S-1riazolo 1 is obtained, 5-a 1,4} benzodialePI11, i (pH = 35 to 63 ° C. Similarly, from 6.05 g of the same methanesulfonic ester and 2.61 g (0.030 mol) of orfolin, 2- (morpholinomethyl) -benyl -8-chloro-4H-5-triazolo 1,5-a 1,4 benodiazepine, mp 111-113 ° C (from ether). Similarly, from the same ether and 3.05 g (0.030 mol) 1- methyl piperazine gives 2 (4-methyl-1-piperazinyl) -methyl-6-phenyl-8-chloro-4H-5 - triazolo 1.5 - and 1.4 benzodiazepia; m.p. 162-163 ° С (from ether). From the same ether and 2.4 g (0.080 mol) of meylamine, amorphous 2- (methylamino) methyl-6-phenyl-8-chloro-4H-S-triazoo 1 is obtained, 5 - a 1,4 benzodiazepine (liquefies at 56-67 ° C). Example 4. A. Analogously to example 3 of 2.4 g (0.080 mol) of methylamine and 6.32 g (0.015 mol) of 6- (2) methanesulfonic acid ester. o-fluorophenyl) -8-chloro-4H-S-triazolo 1,5-a 1,4 benzodiazepin-2-hydroxymethyl get 2- (methylamino) methyl -6- (o-fluorophenyl-8-chloro 4H-S-triazolo 1.5 and 1.4 benzodiazepine. An ethereal solution of hydrogen chloride in 330 ml of ethyl acetate was added to it until a sample to which water was added showed a pH of 2. After a prolonged cooling, the crystals were filtered and recrystallized twice from ethanol. The hydrochloride obtained after drying contains a double molar amount of water of crystallization; melts at 247-249 ° C. Similarly, from 2.4 g (0.080 mol) of methylamine and 6.57 g (0.015 mol) of methanesulfonic acid ester of 6- (o-chlorophenyl) -8 - chloro-4H5-triazolo 1,5-a 1,4 benzodiazepine - 2- hydroxymethyl get 2- (methylamino) -methyl - 6 (chlorophenyl) -8-chloro-4H-S-triazolo 1,5-a 1,4 benzodiazepine. It is dissolved in 130 ml of ethanol and a saturated ethanolic solution of fumaric acid is added to pH 6. After cooling, the crystals are filtered and recrystallized from methanol. After drying, 2- (methylamino) methyl -6- (o-chlorophenyl) -8 - chlorine - 4H - S - triazolo 1.5 - and 1.4 benzodiazepine fumarate (2: 1) melts at 199-201 ° C. Analogously to example 3 3.:- oleist: .1: cm 2.4 g (0.080 mol) of metitamin with the corresponding methsulfuric acid effluxes, the following 2- (methylamine) methyl derivatives are obtained: from 6.05 g of 6- ester (o-melt .; yl - 4H-Striazolo 1, 5 - and 1,4 benzod1.1zepi 1 - 2-hydroxymethyl 2- (methylamino) -tangle i - 6- (o-chlorophenyl) -4H-S-triazolo 1,5-a 1,4 benziazepine; from 7.07 g of 6- (a, a, a-trifluoro-o-tolyl) ester 8-chloro-4H-8 is triazolo, 5-a 1,4 benzodiazepine-2-hydroxymethyl 2- ( Methylamino) -methyl 6- (a, c, a-trifluoro-o-golyl) -8-chloro-4H - S-triazolo 1,5-a 1,4 benzodiazepn; out of 5.80 g of ether 6-fennl-8 -f70r-4H - S - triazolo 1, 5- "1,4 benzod azazepia - 3-oximetry 9 z- (methylamine) -methyl - 6-phenyl-8-fluoro-4H5-triazolo 1, 5-a and 1,4 benzodiazepine, from 6.71 g of 6-phenyl-8-bromo-4H ether -5-triazolo 1, 5 - a 1,4 benzodiazepine - 2-oximet 1 la 2- (methylamino) -methyl - 6-phenyl-8-bromo 4H-5-triazolo 1,5-a and 1,4 benzoliazepia; of 6, 55 g of 6-phenyl-8- (trifluoromethyl) 4H-5-triazolo 1, 5 - and 1.4 benzodiazepine - 2 oxymethyl-2- (methylamino) -methyl-6-phenyl8- (trifluoromethyl) -4H-5 - triazolo , 5 and 1.4 beisodiazepine; from 6.20 g of 6-phenyl-8-nitro-4H-5-triazolo ester 1, 5-a 1,4 benzodiazepine - 2-hydroxymethyl 2- (methylamino) -methyl-6-phenyl - 8-pitro4H-5- triazolo 1,5-a 1,4 benzodiazepine. The methanesulfonic acid esters necessary as starting materials are prepared as follows. B. Analogy Example 1B is obtained: from 62.5 g (0.25 mol) of 2-amino-5-chloro-2-fluorobisophenone 2-; oforbenzoyl) -4-chlorfei-azo-de (2-chloroacetamido) -malonic acid diethyl ester; from 66.5 g (0.25 mol) of 2-amino-2,5-dichlorbeisophenop, 2- (o-chlorobenzoyl) -4-chlorphenylazo-2-chloroacetamido-malonic acid diethyl ether; from 58.0 g (0.25 mol) of 2-amino-2-chlorobenzopheno and diethyl ester of o- (o-chlorobenzoyl) feiylazo- (2-chloroacetamido)-malonic acid; from 75.0 g (0.25 mol) 2-amino-5-chloro-2 (trifluoromethyl) -benzophenone 2- (a, a, a-trifluoro-o-toluoyl) diethyl ester (-(2 -chloroacetamido) -malonic acid; from 53.8 g (0.25 mol) of 2-amino-5-fluorobisophenone, diethyl ether (2-benzoyl-4-fluorophenylazo) - (2-chloroacetamido) -malonic acid; from 69.9 g (0.25 mol) of 2-amino-5-bromobenzophenone diethyl ether (2-beisoyl-4-bromophenylazo) - (2-chloroacetamido) -malonic acid; from 66.2 g (0.25 mol) of 2-amino- 5- (trifluoromethyl) -benzophenone diethyl ether (2-benzoyl-a, a, a-trifluoro-l-tolilazo) - (2-chloroacetamido) -malonic acid; out of 60.8 g (0.25 mol) 2-amino-5-nitrobenzophenone diethyl ether (2-benzoyl-4-nitrophenylazo) - (2 - chloroacetamido) - malonic acid. B. To 51.2 g (0.10 mol) diethyl ether 2 - (o- fluorobenzoyl) - 4 - chlorphenylazo - (2 chloroacetamido) -malonic acid in 600 ml of dioxane is added dropwise over 2 hours 8.0 g (0.20 mol) of sodium hydroxide in 400 ml of water. The temperature of the reaction mixture rises from 20 to 30 ° C and the pH is 8.5-9.0. The mixture is stirred for 45 minutes at room temperature, neutralized with glacial acetic acid and evaporated in vacuo. Ice and 5% sodium bicarbonate solution are added to the residue, the mixture is shaken twice with ether and the aqueous phase is separated. The organic phase is washed with cold 5% sodium bicarbonate solution, water, dried with sulphate and evaporated in vacuo. The residue is recrystallized with isopropanol. The (o-fluorobenzoyl) -4-chlorophenyl-5- (chloromethyl) -1H-1,2,4-thiazole-3-carboxylic acid ethyl ester is obtained; m.p. 97-. The aqueous solutions of sodium bicarbonate (initial and washings) are combined, 10% hydrochloric acid is added to the acidic reaction over Congo and extracted three times with methylene chloride. The extract is washed with water, with a saturated solution of sodium chloride, dissolved in sodium sulfate and evaporated at vacuum. In this way, (o-fluorobenzoyl) -4-chlorophenyl-5- (chlorophenyl) -1H1, 2,4-triazole-3-carboxylic acid is obtained as a by-product. This acid can be directly used for cyclization as in Example 1B or 1V. Analogously, from 52.9 g (0.10 mol) of 2- (o-chlorobenzoyl) -4-chlorophenylazo-2-chloroacetamido-malonic acid diethyl ester is obtained. 1- 2- (o-chlorobenzoyl) -4-chlorophenyl-5 (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid ethyl ester and the corresponding acid with mp. 170-175 C; from 49.4 g (0.10 mol) of o (o-chlorobenzoyl) -phenylazo- (2-chloroacetamido) -malonic acid diethyl ester (o-chlorobenzoyl) -phenyl-5- (chloromethyl) 1H-1, 2 ethyl ester , 4-triazole-3-carbonoBOY acid and the corresponding acid; from 56.2 g (0.10 mol) of 2- (a, a, a-trifluoro-o-tolyl) -4-chlorophenylazo (2-chloroacetamido) -malonic acid diethyl ether (ethyl ester, a, a, a-trifluoro -o-tolyl) -4-chlorophenyl-5- (chloromethyl) -1H-1.2,4 - triazole-3carboxylic acid and the corresponding acid; from 47.8 g (0.10 mol) of diethyl ether (2benzoyl-4 - fluorophenylazo) - (2 - chloroacetamido) -malonic acid ethyl ester 1- (2benzoyl-4 - fluorophenyl) - 5- (chloromethyl) - 1H1, 2 , 4-triazole-3-carboxylic acid and the corresponding acid; from 53.8 g (0.10 mol) of diethyl ether (2benzoyl-4-bromo-phenylazo) - (2-chloroacetamido) -malonic acid ethyl ester of 1- (2benzoyl-4-bromophenyl) -5- (chloromethyl) - 1H1 , 2,4-triazole-3-carbopic acid and the corresponding acid; from 52.8 g (0.10 mol) of diethyl ether (2benzoyl-a, a, a-trifluoro-p-tolilazo) - (2-chloroacetamido) -alonic acid ethyl ester 1- (2-benzoyl-a, a, a-trifluoro-p-tolyl) -5 (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid and the corresponding acid; from 50.4 g (0.10 mol) of diethyl ether (2benzoyl-4-pit, 1ofs1pmazo) - (2-chloroacetamido) -m lono, OH | acid ethyl firm - (9-11

Be1130yl-4-11Itrophenyl) -5- (chlorfeiyl) -1 H1, 2,4-triazole-3-carboxylic acid and the corresponding acid.

G. A solution of 16.88 g (0.04 mol) of ethyl (o-fluorobenzoyl) -4-chlorophenyl 5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid and 11.2 g (0.08 mol) of hexamethytetramine in 250 ml of absolute ethanol is boiled for 6 hours with reverse hololin. The solution is then evaporated at 40 ° C in vacuo, 800 ml of ice-water is added to the residue and it is extracted twice with methylene chloride. The organic phase is washed twice with ice. 1N. hydrochloric acid and three times with water, dried with sodium sulfate and evaporated in vacuo. The residue is recrystallized from nzopropanol. Ethyl efffr of 6- (o-fluorophenl) -8-chloro-4H-5-trnazolo 1, 5-a 1.4 beisodiazepine-2-carboxylic acid is obtained; m.p. 177-179 ° C.

Similarly, receive:

from 17.54 g (0.04 mol) of (o-chlorobenzoyl) -4-chlorophenyl-5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid ethyl ester of 6- (o- chlorophenyl) -8-chlorop4H-S - triazolo 1,5-a 1,4 benzodiazep - 2carboxylic acid;

from 16.16 g (0.04 mol) of ethyl ester of (o-chlorobepzoyl) -phenyl - 5 - (chloromethyl) 1H-1, 2,4-triazole-3-carboxylic acid ethyl ester of 6- (o-chlorophenyl) - 4H-3-triazolo 1,5a 1,4 benzodiazepine - 2-carboxylic acid;

from 18.88 g (0.04 mol) of ethyl eqbipa (a, a, a-trifluoro-o-tolyl) -4 is chlorophenyl-5 (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid 6- (a, a, a-trifluoro-otolyl) ethyl ester) -8-chloro-4H-5 - triazolo 1,5-a 1,4 benzodiazepia-2-carboxylic acid;

from 15.50 g (0.04 mol) of ethyl ether 1 (2-benzoyl-4-fluorophenyl) -5- (chloromethyl) -1H1, 2,4-triazole 3-carboxylic acid to 1slot 6-phenyl-8 ethyl ether -fluoro-4H-5-toiazolo 1.5a 1,4 benzodiazepine - 2-carboxylic acid;

from 17.94 g (0.04 mol) of ethyl ester of 1 (2-benzoyl-4-bromophenyl) -5- (chloromethyl) -IH1, 2,4-triazole-3-carboxylic acid 6-phenyl-8- ethyl ester bromine - 4H-5-triazolo-1,5-a 1,4 benzodiappen-2-carboxylic acid;

from 17.50 g (0.04 mol) of ethyl ester I (2-benzoyl trifluoro- "- tolyl) - 5- (chloromethyl) 1H-1, 2,4-triazole-3-carboxylic acid 6-feiyl-8 ethyl ester - (trifluoromethyl) -4H-Striazolo 1, 5-a 1,4 benzodiazepine - 2-carboxylic acid;

from 16.58 g (0.04 mol) of I (2-benzoyl-4-nitrophenyl) -5- (chloromethyl) -1H1, 2,4-triazole-3-carboxylic acid ethyl ester 6-phenyl-8- ethyl ester nitro-4H-5-triazolo 1,5-a 1, 4 benzodiazepine-2-carboxylic acid.

D and E. Similarly, the example of IE and F receive:

from 11.54 g (0.03 mol) of ethyl ester G (o-fluorophenyl) -8-chloro-4H-5-triazolo 1,5-a | .4 Be1 3Dopaspine - 2-carboxylic acid 6 (o-ftbrphenyl) -8-chloro-4H-S-triazolo 1,5-a

12

1,4 bepsodiazepine - 2-hydroxymethyl, t. Pl. 154-175 ° C (from isopropanol) and its ester with methanesulfopic acid (crude product);

from 12.04 g (0.03 mol) of ethyl ester 6 (o-chlorophenyl) -8-chloro-4H-5-triazolo 1,5-a 1,4 benzodiazenin-2-carboxylic acid 6 (o-chlorophenyl) - 8-chloro-4H-5-triazolo 1,5-about 1,4 benzodiazepine-2-oxymethyl, t. Il. 169-171 ° C (from methylene chloride-hexap), and

its ester with methanesulfonic acid;

from 11.0 g (0.03 mol) of ethyl 6- (o. chlorophenyl) -4H-5 - triazolo 1,5-a 1,4 benzodiapp-2-carboxylic acid 6- (o-chlorofeyl) -4H- 5 - triazolo 1,5 - and 1,4 bepzodiazepin-2-hydroxymethyl and its ester with methanesulfonic acid;

from 13.04 g (0.03 mol) of ethyl ether 6 (a, a, a-trifluoro-o-tolyl) -8-chloro-4H-S-triazolo 1, 5-a 1,4 benzodiazepine-2-carbonoboy acids 6- (a, a, a-trifluoro-o-tolyl) -8 chloro-4H-S - triazolo 1.5 - and 1.4 benzodiazepin-2-hydroxymethyl and its ester with methanesulfonic acid; from 10.50 g (0.03 mol) of ethyl 6phenyl-8-fluoro-4H-5 - triazolo 1,5-about 1,4 benzodiazepine-2-carboxylic acid 6-phenyl-8fluoro-4H-5 - triazolo 1, 5 - a 1,4 benzodiazepin-2-hydroxymethyl and its ester with methanesulfonic acid;

pz 12.33 g (0.03 mol) of 6phenyl-8-bromo-4H-5-triazolo 1,5-a ethyl ester 6-phenyl-8-bromo-4H-benzodnazine-2-carboxylic acid ethyl 6-phenyl-8bromo-4H-5 - triazolo , 5 - about 1, 4 benzodiazepin-2-oxymethyl and its ester with methanesulfonic acid;

from 12.0 g (0.03 mol) of 6phenyl-8- (trifluoromethyl) -4H-5-triazolo 1 ethyl ester; 4 benzodiazepine — 2-carboxylic acid 6-feiil-8- (trifluoromethyl) - 4H-5- triazolo 1,

5 - a 1,4 benzodiazepine - 2-hydroxymethyl and its

ester with methanesulfonic acid;

from 11.31 g (0.03 mol) of 6phenyl-8-nitro-4H-S ethyl ester, triazolo 1.5 - and 1.4

benzodiazepine-2-carboxylic acid 6-phenyl8-nitro-4H-S-triazolo 1.5 -and 1.4 benzodiazine-2-hydroxymethyl and its ester with methanesulfonic acid. Example 5. Analogously to example 1 receive;

from 8.41 g of methanesulfonic acid ester of 6- (o-fluorophenyl) -8-chloro-4H-5-triazolo 1,5a 1, -4 benzodiazepia-2-hydroxymethyl 2- (dimethylamino) methyl-6- (o - fluorophenyl) - 8 chloro-4H - 5-triazolo 1.5 - about 1.4 benzodiazepine; m.p. 114-116 ° C (ether - petroleum ether);

from 8.74 g of methanesulfonic acid ester 6- (o-chlorfeiyl) -8-chloro-4H-5-triazolo 1.5a 1.4 benzodiazepia-2-hydroxymethyl 2 - (dimethylamino) methyl -6- (o-chlorophenyl ) -8 chloro-4H-5 - triazolo 1.5 - and 1.4 benzodiazepine.

Example 6

Analogously to Example 3, interaction was obtained with 2.55 g (0.03 mol) of piperidine and

13

6.32 g (0.015 mol) of 6- (o-fluorofeyl) -8-chloro-4H-S-triazolo 1, 5-a 1,4-benzodiazepine-2-hydroxymethyl-2- (ligridinomethyl) -6 methyl ester of ester of methapsulfopic acid - (o-fluorophenyl) -8 chloro-4H-S - triazolo 1.5 - and 1.4 benzodiazepine.

Out of 2.55 g (0.03 mol) of piperidine and 6.57 g (0.015 mol) of 6- (o-chlorophenyl) -8-chloro-4H-S methanesulfonic acid ester, trpazolo 1.5-a 1,4 beg13 diazepine - 2 - hydroxymethyl 2 (piperidi 11methyl) -6- (o-chlorophenyl) -8 - chloro 4 H-5-tr 1 azolo 1,5-a 1,4 beesodiazepia.

P re dm C t invented and

Claims (3)

1. A process for the preparation of diazepine derivatives of general formula I SNG-b where RI means hydrogen or alkyl group with 1-3 carbon atoms; R2 and Kz are hydrogen, alkyl or oxyalkyl groups with 1-6 carbon atoms, aralkyl group with 7-9 carbon atoms, and the lower alkyl groups R2 and Ra can be bonded to each other in the p-position directly or through an oxygen atom, an imino group lower alkylimino or oxyalkylminogrunia, with a maximum of 4 carbon atoms, rings A and B may be substituted with halogen to atomic number 35, alkyl or alkoxy groups with 1-6 carbon atoms, trifluoromethyl- or nitro group 14 iamn or their 5N-OKi; ceii, or their salts, from, 1 and h and 10 y and the fact that the reactive ester of the compound of the general formula II Cha-oh ten AND 15 in which RI has the above meaning, and rings A and B can be substituted as indicated in formula I, or its 5Y-oxide, is reacted with a compound of general formula III Rn And And, wherein Ro and Ra are as defined above, or with alkali metal derivatives of a compound of formula III, followed by isolation of the desired product in the free state or as a salt by known techniques. 2. A method according to claim 1, characterized in that a sulfonic acid ester, a methanesulfonic acid ester, a halide ester of hydrochloric acid is used as the reactive ester of the compound of the general formula II. 3. Method no. 1, on tl and h ay HUI and with leM. that ammonia, methylamine 45 or dimethylamine are used as starting compound of general formula III.