SU730308A3 - Method of preparing derivatives of imidazo-/1,5-a/-(1,4)-diazepine or their salts - Google Patents

Description

lower alkoxy or chlorine, with an amine of the general formula

,

where R and R5 have the meanings indicated by Bbttue, and if Y is lower alkoxy, then RS is hydrogen or a group- (CHj) -RjjR, where n is O,

with the subsequent isolation of the target products in free form or in the form of salt.

The expression lower alkyl refers to both branched and unbranched hydrocarbon radicals with 1-7 carbon atoms, preferably hydrocarbon radicals with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and the like, as well as cyclic hydrocarbon radicals, such as cyclopropyl. The expression lower alkanoyl denotes a protected ketone (acetal or ketal with 2-7 carbon atoms, for example, ethylenedioxy). The ketal protecting group or aldehyde is used to avoid the oxidation, reduction or condensation of the contained ketr or aldehyde.

The expression halogen includes all four representatives, i.e. chlorine, bromine fluorine and iodine.

To obtain salts, inorganic or organic pharmaceutical acids of hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, lemon formic, acetic, amber, tartaric, methanesulfonic, p-toluenesulphonic maleic and others are used.

Example 1. 0.74 g (2 mmol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo 1, 4 benzodiazepine-3-carboxylate in 30 ml of methanolic ammonia solution is heated for 18 h in a sealed reactor. The solvent is evaporated, the residue is recrystallized from ethylene chloride / methanol to give 0.49 g (57%) of 8-chloro-1-methyl-6-phenyl-4H-imidazo 1.5-a 1.4 b.nzodiazepin-Z.- carboxamide in the form of colorless crystals, so pl. 335-340 0.

The starting material is prepared as follows. Potassium tert-butylate, (26 g, 0.232 mol) was added to a mixture of 300 ml of dimethylformamide and 50 yl (0.44 mol) of dimethyl malonate. nociie. stirring under nitrogen for 10 minutes a solution of 66 g (0.209 mol) of 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml of dimethylformamide is added over 10 min. After that, the mixture is heated slowly on the steam bath and kept at for 10 minutes. After cooling to room temperature, 40 ml of glacial acetic acid are added.

acid and then 1 liter of water for 30 minutes with occasional mashing. The precipitated crystals are collected, washed with water and dissolved in methylene chloride. The solution is dried with sodium sulfate and concentrated to a small volume. The product is crystallized by the addition of hexane and 66.4 g (81%) of 7-HLOR-1, 3-dihydro-2- (dimetho-xymalonylidene) are obtained.-5-phenyl-2H, 4-benzodiazepin-4-oxide, m. square 188-190 ° C. The analytical sample is recrystallized from methylene chloride / hexane, m.p. 194-195 ° C.

.A, Mixture of 40.8 g (0.1 mol) 7-chloro-1, 3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepin-4-oxide, 250 ml methanol, 250 mp of tetrahydrofuran and 1 tablespoon of Rene nickel are hydrogenated under atmospheric pressure for 5 hours. The catalyst is removed by filtration and the filtrate is evaporated. By crystallization of the residue from methylene chloride / 2-propanol, 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1, 4-benzodiazepine is obtained as colorless crystals, m.p. 1 GOIS. For analysis, it is recrystallized from 2-propanol, mp; 165-166 ° C.

In some cases, a second modification of the crystals is obtained, mp 138-140 ° C.

B. Phosphorus trichloride (4 ml) is added to a solution of 4 g (0.01 mol) of 7-ChLOR-1, H-dihydro-2- (2-dimethoxy-minimalonidene) -5-phenyl-2H-1,4-benzodiazepine. 4-oxide - in 100 ml of methylene chloride. After being kept at room temperature overnight, the solution was washed with a 10% aqueous solution of sodium carbonate. The methylene chloride layer is dried and evaporated. By crystallization of the residue from 2-propanol and recrystallization from methylene chloride / 2-propanol, 7-ChLOR-1, H-dihydro-2- (dimethoxy-minimalonylidene) -5-phenyl-2H-1, 4-benzodiazepine, t. square 165-16b S.

A mixture of 115 g (0.3 mol) of 7-chloro-1, 3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine, 1.5 liters of methanol and 14.4 g (0, 36 mol of sodium hydroxide is heated under reflux for 5 hours under a nitrogen atmosphere. The cold reaction mixture was gradually diluted with 2.5 L of water while cooling with ice. The precipitated crystals are collected, washed with water and dried under vacuum at 60 ° C to obtain 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1, 4-benzodiazepine as an off-white product m.p. 167-170 ° C. An analytical sample is recrystallized from ether, m.p. 171-173 ° C. Sodium nitrite (2.8 g, 0.04 mol) is added to a solution of 8 g (0.025 mo of 7-ChLOR-1, Z-dihydro-2- (methoxycarbOnylmethylene) -5-phenyl-2H-1,4-benzodisepine in 100 ml of glacial acetic acid. The mixture is stirred in a nitrogen atmosphere for 10 minutes, the products begin to crystallize after a few minutes. After dilution with J.OO ml of water, the precipitated product is collected, washed with water, dried and recrystallized from tetrahydrofuran / methanol and get methyl ester 7-chloro - (, - hydroxyimino-5-phenyl-3N-1, 4-benzodiazepine-2-acetic acid. in the form of yellow crystals, t. 235-237 0 (with decomposition). Methyl ester 7-chloro-l-oxyimino-5-phenyl-3N-1, 4-benzodiaz pin-2-acetic acid (3.6 g, 0.01 mol is dissolved in a mixture of 200 m of tetrahydrofuran and 100 ml of methanol by heating, René nickel (1 teaspoon) is added and the mixture is hydrogenated under atmospheric pressure to decrease the hydrogen uptake (1 hour and 10 minutes). The catalyst is removed by filtration and the filtrate is evaporated finally, azeotropic with toluene. The residue is dissolved in 20 ml of methanol. After adding 3 ml of triethyl-o-acetate and 0.3 ml of ethanolic hydrogen chloride (5%), the solution is heated under reflux for 5 minutes. The residue formed on evaporation is dissolved in methylene chloride and a saturated aqueous solution of bicarbon. that rub. The organic phase is separated., Dried and evaporated. Crystallization of the residue from ether gives 2 g (54%) of methyl 8-chloro-1-methyl-b-phenyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylate, after recrystallization from methyl chloride / ether a / hex san and so pl. 254-256 ° C. Example 2. A mixture of 0.74 g (2 mmol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo U, 5-aJ 11.4 benzodiazepine-3-carboxylate and 20 ml of ethanol containing 25% methylamine, heated for 18 h in a sealed reactor. The solvent was evaporated, the residue was crystallized from methylene chloride / zanol, to give 0.6 g (B1%) 8-chloro-1-methyl-6-phenyl-4H-imidazo 1 g 5-a 1, 4 J benzodiazepin-3-N- MethylCarboccamide, m.p. 260-263 ° C. The analytically pure sample is recrystallized from tetrahydrofuran / ethanol. Example 3. A mixture of 7.7 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylate, 100 ml of isobutanol and 20 ml of hydrazine is heated under reflux for 1 h . The crude product obtained after evaporation is chromatographed on 250 g of silica gel using 5% ethanol in methylene chloride. Pure fractions are combined and evaporated. By crystallization of the residue from methylene chloride / ether, 4.6 g of hydrazide (60%) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 4 benzodiazepine-3-carboxylic acid are obtained as colorless. crystals, so pl. 235-237C. Example 4. 4 ml of pyrrolidine are added to a solution of an acid chloride prepared from 1.85 g of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 5-a 1,4 benzodiazepine-3-carboxylic acids and 1.25 g of phosphorus chloride in 250 ml of methylene chloride. Then 100 ml of a 10% aqueous solution of sodium carbonate are added, the biphasic mixture is stirred at room temperature for 1 hour. The organic phase is separated, dried and evaporated. Crystallization of the residue from 2-propanol / ether yielded 1.6 g (76%) of 1-18-chloro-6- (2gfluorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepine 3-oyl pyrrolidine as a colorless product m.p. 220-221 ° C after recrystallization from ethyl acetate / hexane, Example-5. 10 ml of 2,2-, cimethylgy, crazine is added to a solution of acid chloride prepared from 1.85 g of 8-chloro-6 -. (2-fluorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepin-3-carboxylic acids and 1.25 g of phosphorus chloride in 250 ml of methylene chloride. After adding 100 ml of a 10% aqueous solution of sodium carbonate, the mixture is stirred for half an hour at room temperature. The organic layer is removed, dried and evaporated. Crystallization of the residue from ether / ethanol yields 1.3 g (63%) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 2,2-dimethylhydrazide, 4 benzodiazepine-3-carboxylic acid in as a colorless product. An analytical sample is purified by chromatography on a 30-fold amount of silica gel using 100% ethanol in methylene chloride (by volume). The material is crystallized from methylene chloride / ethyl acetate / hexane, t, pl. 238-240 ° C. Example 6. 1.25 g (O, 06 mol) p-chloride of phosphorus are added to the suspension 1.85 g (0.005 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H imidazo 1, 5- and 1,4 benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride. After stirring for 30 mn in an ice bath, 15 ml of diethylamine are added, then 1.00 ml of a 10% aqueous solution of sodium carbonate. The two-phase system is stirred at room temperature for 30 minutes. The organic layer was separated, dried with sodium sulfate and evaporated. Crystallization of the residue from methylene chloride / ether gives 1.6 g (75%) of 8-chloro-K, H-diethyl-6-, (2-fluorophenyl) -1-methyl-4H-imidazo 1, I j 4 beneodiaepine- 3-carboxamide so pl. 182-188 0. The analytical sample is recrystallized from ethyl acetate / hexane, t, w1.183-185 C.

Example 7. Pichloride phosphorus (1.25 g, 0.006 mol) is added to the suspension 1.85 g (0.005 mol) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 4 benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride. After stirring for 30 minutes, 5 ml of 2- (dimethylamino) ethylamine was added in an ice bath. Then, while adding 100 ml of a 10% aqueous solution of sodium carbonate, the mixture is stirred for half an hour at room temperature. The methylene chloride layer is separated,. dried and evaporated. Crystallization of the residue from 2-propanol / ether gives 1 g (45%) of 8-chloro-2-dimethylaminoethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 4 benzodiazepin-3-carboxamide, t .pl. 209-2I C. The analytical sample is recrystallized from ethyl acetate / hexane, so pl. 210-213 s.

Example 8. P-chloride phosphorus (1.25 g, 0.06 mol) was added to the suspension 1.85 g (0.005 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo 1, , 4 benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride. After stirring for 30 minutes in an ice bath, 25 ml of 25% methanolic ammonia solution are added. After stirring for 10 minutes, 50 ml of 10% is added. aqueous sodium carbonate solution, continuing to stir at room temperature for 1 hour. The methylene chloride layer is separated, dried and evaporated. The residue is dissolved in a mixture of methylene chloride and ethanol. The solution is filtered through a layer of silica gel, the filtrate is evaporated. Crystallization of the residue from ethanol gives 0.7 g (38%) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxamide as colorless crystals. An analytical sample is recrystallized from ethanol / tetrahydzofuran, m.p. 300-305 ° C.

Example 9; Pichloride phosphorus (1.25 g, 0.06 mol) is added to the suspension 1.85 g (0.005 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 4 benzodiazepine -3-carboxylic acid in 250 ml of methylene chloride. After stirring for 30 minutes, 4 ml of dimethylamine was added in an ice bath. After stirring for 1 h at room temperature, the reaction mixture was washed with 10% aqueous sodium carbonate solution, dried and evaporated. The residue is purified by chromatography on 40 g of silica gel ic using 5% by volume of ethanol in methylene chloride. By crystallization of the combined pure fraction from ether / hexane, 1.1 g (55%) of 8-chloro-b- (2-fluorophenyl) -1-M, N-dimethyl-4H-imidazo 1, 4 benzodiazepine-3-carboxamide in as colorless crystals, so pl. 177-179 ° C. A fraction with a lower melting point (158-160 ° C) is also obtained.

Example 10. A solution of 1.0 g (2.31 mol) of 8-chloro-b- (2-fluorophenyl) -1-phenyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylic acid in 5 vin thionyl chloride is heated in reverse by cooling for half an hour, then it is carefully added dropwise to 70 ml of cold 40% aqueous dimethylamine. The brown solid is collected, washed with water, dried and chromatographed on silica gel using ethyl acetate as an eluent to give 0.5 g. Y, H-dimethyl-8-chloro-b- (2-fluorophenyl) -1-phenyl. 4H-imidazo 1 ,, 4 benzodiazepine-3-carboxamide in the form of brown foam. By a 3-fold recrystallization from acetone / water, an analytically pure sample is obtained, mp 221223 ° C.

Example 11. A solution of 1.0 g (2.31 mmol) of 8-chloro-b- (2-fluorophenyl) -1-phenyl-4H-imidazo 1 ,, 4 benzodiazepin-3 carboxylic acid in 5 ml of thionyl chloride is refluxed within half an hour, then it is carefully added to 70 ml of cold ammonium hydroxide. The pink solid was collected, washed with water, dried in air, and chromatographed on silica gel using ethyl acetate as eluent to give 0.48 g of 8-chloro-6t (2-fluorophenyl) -1-phenyl-4H-imidazo 1. 4 benzodiazepin-3-carboxamide in the form of brown foam. By powdering with acetone, an analytically pure sample is obtained in the form of a white powder, m.p. 260262 ° C.

Example 12. Stirring suspension 1,2. G (0,0031 mol) of ethyl 8-chloro-b- (2-chlorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylate in 25 ml of chloride methylene is cooled in an ice bath and treated with 0.7 g (0.004 mol) in phosphorus pentachloride in portions. The mixture is protected using a drying tube and continue to mix in the cold for half an hour; during this time, most of the solid product is dissolved. Continue cooling and stirring, the mixture is treated with ammonia gas for 5 minutes and continue to stir for half an hour in the cold. The mixture is evaporated in vacuo to obtain a light solid product, which is mixed with dilute aqueous ammonia and filtered through a large funnel made of special glass. After washing with water the solid is air-dried on a funnel and 1 g (83%) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo 1, 4 benzodiazepine-3-carboxamide is obtained. By recrystallization of the sample from a solution of methylene chloride / ethanol (2; 1), white tiles are obtained, so pl. 318-3200с (with decomposition).

Example 13. 8-Chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo 1, 4 benzodiazepn-3-carboxamide.

3 g (0.0145 mol) of phosphorus pentachloride were added to a suspension of 4 g. (0,0089 mol) 8-chloro-b- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo 1,5-a 1,4 benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride, cooled ice / water. After stirring for 30 minutes, ice / water is added and ammonia is admitted until the mixture is alkaline. Then 20 ml of aqueous ammonium, 200 ml of methylene chloride are added and stirring is continued for 15 minutes. The organic layer is separated, dried with sodium sulfate and passed over a pad of silica gel using 5% (v / v) ethanol in methylene chloride. The solution is evaporated and the residue is crystallized from ethanol / ethyl acetate to obtain 3.25 g (81%) of off-white crystals, which are recrystallized for analysis from methylene chloride / / ethyl acetate, mp. 25.5-257 ° C. After the second settling and melting, so pl. 275-278 ° C.

Example 14. 8-Chloro-6- (2 chlorophenyl) -1-propyl-4H-imidazo 1, 4 benzodiazepin-3-carbox. Amide.

By the reaction of 1.5 g (3,5) methyl-8-chloro-b- (2-chlorophenyl) -1-propyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylate with 20 ml of methanolic ammonia is prepared according to the conditions described in example 15, 1.1 g (75%) of the desired product, crystallized from methylene chloride / ethanol, so l. 298-ZOOOs.

Example 15. 8-Chloro-b- (2-chlorophenyl) -1-isopropyl-4H-imidazo 1,5-a 1,4 benzodiazepine-3-carboxamide.

A mixture of 1.3 g (3 mmol) methyl-8-chloro-b- (2-chlorophenyl) -1-isopropyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylate and 20 ml of methanol containing 20 wt.% Ammonium , heated in an autoclave at 130 ° C for 20 hours. The solvent is evaporated, the residue is crystallized from methylene chloride / ethanol and 1.1 g (87%) of the desired product are obtained, mp. 328ЗЗ С. The analytical sample is recaptured, Talsed from the same solvents.

Example 16 Phosphorus pentachloride (1.1 g, 5.2 mmol) was added to a suspension of 1.6 g (4 mol) of 6- (20-chlorophenyl) -1-methyl-8-nitro-4H-imidazo 1, , 4 benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride, cooled with ice water. After stirring for 30 minutes, pass a stream of ammonia until the mixture becomes alkaline, and stirring is continued for 1 hour at room temperature. Water is added and the organic layer is separated, dried and evaporated. Crystallization of the residue from methanol / ethyl acetate gives 1.1 g (69%) of 3- carboxamide b- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo 1, 4J benzodiazepine as

5 yellowish crystals, so pl. 300 ° C. The sample for analysis is recrystallized from the same solvent.

Example 17. To a solution of 0.8 g (0.00204 mol) of 8-chloro-b- (2-chlorofo0 nyl) -1-methyl-4H-imidazo 1,5-a thieno 3, 4 diazepine 3-carboxylic acid In a 100 MP dry dichloromethane, 0.46 g (0.0022 mol) of phosphorus chloride was added in an ice bath.

5 After 30 ivMH ammonia is passed through the solution for 5 minutes with stirring. After 2 hours, 75 ml of water was added and the product was filtered off. Dichloromethane is separated, dried and evaporated. The product obtained by crystallization of the residue from ethanol is combined with the first precipitate and recrystallized from a mixture of chloroform and ethanol to obtain 0.65 g (81%) of 3-carboxamide 8-chloro-6- (2-chlorofe-5-nyl) -1-methyl- 4H-imidazo 1,5-a tieno 3 ,, 4 diazepine in the form of white sticks, so pl. 300-305 ° C.

Example 18. 0.46 g (2.2 mmol) of phosphorus pentachloride are added.

0 to a suspension of 0.785 g (2 mmol) of 8-chloro-b- (2-chlorophenyl) -1-methyl-4H-imidazo 1, 5-a thieno 3, 4 diazepin-3-carboxylic acid in 50 ml of methylene chloride. After stirring in an ice bath, dimethylamine is introduced for 30 minutes to achieve an alkaline reaction. Then it is stirred for 30 minutes at room temperature and washed with saturated sodium bicarbonate solution, dried and

0 evaporated. Crystallization of the residue from ethyl acetate / npOCTOio ether gives 8-chloro-b- (2-fluorophenyl) -1, N, N-trimethyl-4H-imidazo, 5-a thieno, 2-f 1,4 diazepine-3-carboxy and i

five

in the form of off-white crystals, which are recrystallized for analysis from ethyl acetate, m.p. 197.

Example 19. 8-Chloro-b- {2-chlorophenyl) -1- (2-dimethylaminoethyl} -4H-imidazo 1, 5-aj 11.4 benzodiazepin-3 carboxamide.

A mixture of 0.46 g of methyl 8-chloro-b- (2-chlorophenyl) -1- (2-dimethylaminoethyl) 4H imidazo U, 5-a 1,4 benzodiazegan 3-carboxylate and 10 ml of methanol containing 20% ammonia, heated in a bomb for 20 h at 130 ° C, the solvent is evaporated and the residue is subjected to chromatography on silica gel (7 g) using 20% ethanol in methylene chloride. By crystallizing the pure fractions from 2-propanol, 80 mg (18%) of the pure product are obtained, mp. 249-251 ° C.

Example 20, 8 - Chloro-b- {2-chlorophenyl) N-methyl-1 methylaglinomethyl-4H-imidazo L1,5-a 1,4 benzodiazepin-3 carboxamide.

A solution of methylamine in tetrahydrofuran (75 ml) containing 20% methylamine was added to a solution of 3 g. (Br9 mmol) methyl 8-chloro 1-chloromethyl b (2-chloroshenyl) -4H imidazo 1,5-a 1,4 benzodiazepine-3-carboxylate in 50 ml of tetrahydrofuran. The mixture is heated to 100 ° C for 18 hours in a sealed vessel. The solvent is evaporated, the residue is crystallized from ethanol and 1.9 g (64%) of the desired product is obtained, which is chromatographed over 50 g of silica gel using 5% (v / v) ethanol in methylene chloride. The combined pure fractions give 1.5 g of product, t „Ш1. 270 273-C after evaporation and crystallization from methylene chloride / ethanol, Example 21. 13 g (66%) of 1-besyl-a-chloro-b- (2-chlorophenyl) -4H-imide30, 1, 5, and 1 4} benzodiazepine-3-carboxylic acid, so pl. 305-310 0 (-C decomposition) is weighed into 30 ml of methylene chloride. Phosphorus chloride (0.8 g) was added and the mixture was stirred in an ice-water bath for 30 minutes. Ammonia is then introduced until the reaction mixture becomes alkaline. After stirring for 15 minutes at a constant temperature, aqueous ammonia is added; As well as the two-phase system, I continue the stirring for 15 minutes. The methylene chloride phase is separated, dried and evaporated. The crystalline residue is recrystallized from ethyl acetate / methanol to give 0.85 (63%) 3-carboxamide 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo 1, 5-a 11.4 benzodiazepine as a colorless product, so pl. 282-284 S.

The sample is chromatographed on silica gel for analysis (4–0 kinks in total), using methylene chloride / ethyl acetate (Itl) for elution, m.p. 286-288 ° C.

Example 22. 8-Chloro-6-phenyl-4H-Iidazo 1, 5-a 1,4 benzodiazepin-3-carboxamide.

A mixture of 5 g of methyl 8-chloro-6-phenyl-4H-imidazo 1, 4 benzodiazepine-3-carboxylate and 100 ml of methanol containing 20% ammonia is heated in an autoclave to 8 hours. The precipitated crystals are collected, recrystallized from tetrahydrofuran / methanol and get 2.2 (46%) of the target product, so pl. 295296С. An analytical sample is recrystallized from dimethylformamide / / simple ether, so pl. 296-297 ° C.

Example 23. 8-Chloro-6- (2-ftprphenyl) -4H-imidazo C, 5-a 1,4 benzodiazepine-3-carboxamide.

2.6 g (0.0125 mol) of phosphorus pentachloride were added to the suspension 3.55 g (0.01 mol) of 8-chloro-b- (2-fluorophenyl) -4H-imidazo C, 5-a 1.4j benzodiazep 1H-3-carbon. acids in 200 ml of methylene chloride cooled with ice / water. After stirring for 30 minutes, ammonia is passed through until the reaction mixture becomes alkaline. After 15 minutes, aqueous 1 miac was added and stirring was continued for 30 minutes. The reaction mixture is then partitioned between water and methylene chloride containing 10% (v / v) ethanol. The solution is evaporated, the solid residue is recrystallized from ethanol and obtain 1.6 g (45%) of the desired product. An analytical sample is recrystallized from tetrahydrofuran / ethanol, m.p. 292-294 ° C.

Example 24. 8-Chloro-6- (2-chlorophenyl) -4H-imidazo 1,5-a 1,4 benzodiazepin-3-carboxg.,

A mixture of 5 g (0.013 mol) of methyl 8-chloro-6- (2-chlorophenyl) -4H-imidazo, 4 benzodiazepine-3-carboxylate and 75 ml of methanol containing 20% ammonia is heated in an autoclave for 18 h. The reactant ionic mixture, from which the desired product crystallizes, is heated in methanol / methylene chloride until the dissolution is complete. By filtration and concentration, 3.5 g of the expected product are obtained. Mp. An analytical sample is recrystallized from methylene chloride / ethano

Example 25. 8-Hop-N, N-dimethyl-6-phenyl-4H-imidazo L1,5-a 1,4 benzodiazepine-3-carboxamide.

A mixture of 5 g (0.014 mol) of methyl L-chloro-6-phenyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylate, 2.4 g (0.043 mol) of potassium hydroxide, 10 ml of water and 140 ml of methanol is heated to reflux temperatures for 6 hours. The solvent is evaporated and the residue is dissolved in water. The solution is filtered and acidified with glacial acetic acid. The precipitated crystals are collected and crystallized from methylene chloride / ethanol to obtain 4.0 g (83%) of B-chloro-b-phenyl-4H-imidaeo 1.5-1.4.4 benzodiazepine-3-carboxylic acid, m.p. 2b8-270 ° C. 1 g of this acid is stirred from 1.30 g of phosphorus pentachloride and 100 m of methylene chloride at room temperature for 2 hours. Dimethylamine is bubbled into the mixture while cooling until a clear solution with basic pH is obtained. The solution is then washed with sodium chloride solution and water. The chloromethylene layer is dried and evaporated. By crystallisation of the residue from ether, 0.6 g (57%) of the desired product is obtained, which is recrystallized from methylene chloride / ethyl acetate. 231-233 ° C. Example 26. 8-chloro-b- (2-chloro-phenyl) -Y, L-dimethyl-4H-imidazo 1,5-a 11.4 benzodiazepine-3-carboxamide. A mixture of 2 g of methyl 8-chloro-b- (2-chlorophenyl) -4H-imidazo 1, 4 benzodiazepine-3-carboxylate, 15 ml of methylphosphoric triamide and 1.5 g of lithium chloride is heated to 225s. The cooled reaction mixture is partitioned between water and methylene chloride / ether. The organic phase is washed with an aqueous solution of bicarbonate, dried and evaporated. By crystallization from ether, 1.2 g (58%) of the desired product is obtained which is recrystallized from ethyl acetate / methanol for analysis, mp. 240-242QC. Example 27. 8-Chloro-6-phenyl-1, N, N-trimethyl-4H-imidazo 11,5-a 1, benzodiazepin-3-carboxamide. A mixture of 1.5 g (4.2 mol) of 8-chloro-1-methyl-b-phenyl-4H-imidazo, 1,4 benzodiazepine-3-carboxylic acid, 1.7 (8 mmol) of phosphorus pentachloride and 100 ml of methylene chloride is stirred under an argon atmosphere for 3 hours. Dimethylamine is added at room temperature until a clear solution is obtained with basic pH. The solution is washed with water, dried and evaporated. By crystallization of the residue from ethyl acetate / ether / hexane and recrystallization from ether, 0.6 g (37%) of the desired product is obtained, mp. 173-1 750s. Example 28. 8-Chloro-6- (2-fluoro-phenyl) -1-methyl-E-phenyl-4H-imidazo-1,5-a 1,4 benzodiazepine 3-carbox mid.1, 3 g (6.25 mmol ) phosphorus pentachloride added yut- to a suspension of 1.9 g (5 mmol) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1, 5-a 1,4 1,4 benodeazepine-3-carboxylic acid in 100 ml of methylene chloride. After stirring for 30 minutes, 7 ml of aniline are added with ice / water cooling and stirring is continued for 30 minutes at room temperature. The reaction mixture is partitioned between 10% aqueous sodium carbonate solution and chloride methylene. The organic layer is dried and evaporated. By crystallization of the residue from ether and recrystallization from methylene chloride / ethanol, 1.4 g (63%) of the desired product is obtained, which is recrystallized from tetrahydrofuran / ethanol for analysis, mp. 228-288 ° C. Example 29. 8-Chloro-Y-cyclopropyl-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepin-3-carboxes d. 1.3 g (6.25 mmol) of phosphorus pentachloride 1.9 g (5.1 mmol) of 8-chloro-b- (2-fluorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride are added to the suspension. After stirring for 30 minutes over ice / water, 3 ml of cyclopropylamine are added and stirring is continued for 10 minutes. The reaction mixture is washed with an aqueous solution of sodium carbonate, dried and evaporated. The residue is passed over a pad of silica gel with the name of 10% (v / v) ethanol in methylene chloride. By crystallization of the product from ethyl acetate / hexane, 1.3 g (62%) of the desired product is obtained in the form of crystals, m.p. 19b -197 ° C. Example 30. 8-Chloro-b- (2-chlorophenyl) -1, N, N-trimethyl-4H-imidazo 1, 4 benzodiazepine-3-carboxamide. A stirred suspension of 3.6 g (0.0093 mol) of 8-chloro-b- (2-chlorophenyl) -1-methyl-4H-imidazo 1 ,, 4 benzodiazepine-3-carboxylic acid in 75 ml of dichloromethane is cooled in an ice bath and treated with 2.1 g (0.01 mol) in phosphorus pentachloride in portions. The reaction is carried out in the absence of moisture with a drying tube, stirring in the cold is continued for another 30 minutes. Cool further, dimethylamine is bubbled into the solution for 5 minutes and stirring is continued for another 30 minutes. The mixture is evaporated under reduced pressure to dryness. The rubbery residue is stirred with water and alkalinized with ammonium hydroxide. By extraction with methylene chloride followed by drying and evaporation in vacuo, a reddish brown foam is obtained. The foam is dissolved in 600 ml of boiling ether and filtered to remove the insoluble residue. After

Claims (1)

Claim 1. The method of obtaining derivatives of imidazo [1,5 — al [1,4] diazepine of the general formula · ί η is 0-4 or R4 and Ry together form pyrrolidinoradiol; R ₃ is phenyl or o-halo phenyl; group where Rq <group, OR 1 nd with the formula denotes a halogen or nitro salts, characterized in that the compound is common R ₄ t ^A. and have the meanings indicated above; where are the Y denotes lower alkoxyl or chlorine, is reacted with an amino general formula hnr ₄ r ₅ , R ₅ have the meanings indicated, if Y is lower then R ₅ is hydrogen or a group R _fi R ^, where η is 0, where A is —C (R ₃ ) = N—; R4 is hydrogen, lower alkyl, phenyl, mono (lower) alkylamino (lower) alkyl, di (lower) alkylamino (lower) alkyl, (lower) alkanoylamino (lower) alkyl, N— (lower) -alkyl, N- (lower) ) alkanoylamino. (lower) alkyl, pyridyl, phenyl (lower) alkyl, or tolyl (lower) alkyl; R ₂ is a —CONR ₄ R ₅ group, where R ^ is hydrogen or lower alkyl, R ₅ is hydrogen, lower alkyl, phenyl, chlorophenyl, tolyl or the group is (CHg) _n R ₆ R _? where Rg and Ry are hydrogen or lower alkyl, and