SE449098B - PHENYL / 2- (5-HYDROXY-1-IMIDAZOLYL) PHENYL / METHANONE DERIVATIVES USED AS INTERMEDIATES FOR THE PREPARATION OF IMIDAZO / 1,5-A // 1,4 / BENZODIAZEPINE DERIVATIVES - Google Patents

Description

449,098 phosphorus tribromide in an inert organic solvent, e.g. dichloromethane, at about -10 to 25 ° C (although the temperature is not critical) and then subsequent in situ treatment with ammonia, preferably liquid ammonia, which is allowed to warm to room temperature.

Compounds of formula II and their pharmaceutically acceptable acid addition salts are useful muscle relaxants, sedatives and anticonvulsants, and many are particularly useful when used in intravenous and intramuscular formulations due to the solubility of the acid addition salts in aqueous solution.

The term "halogen" refers to the four forms of chlorine, bromine, fluorine and iodine.

Compounds of formula I above can be prepared according to the following new procedures.

The compounds of formula I above can be prepared by nitrosation of a compound of formula: NHcH3 iii wherein A 'is - ¥ = N- or -C = N; and R 4 and R 6 have the meaning given in the formula R 0 6 6 I, for the preparation of a compound of the formula ïH 3 N-NO. ....-_ * -_._......: _.__..._.....__ ... . ... 1%! i) - 449 098 wherein A ', R4 and R have the meaning given above. Such nitrosation can be carried out with "in situ" nitric acid. Reagents that can be used include (l) alkali metal nitrites, e.g. sodium nitrite, in the presence of organic or inorganic acids, e.g. glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites, e.g. methyl nitrite, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon or e.g. dimethylformamide; and (3) a nitrosyl chloride gas-containing solution in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should be carried out at, around or below room temperature, i.e. in the range -20 to 25 ° C.

The nitrosoalkylamine group in the 2-position, e.g. -N-NO, constitutes a "leaving group". Equivalent leaving groups that can be used as substituents in the 2-position include groups such as alkoxy, e.g. AND alkylthio, e.g. -SCH3; halogen, e.g. 3; chlorine, cyano, i.e. -CN, and phosphate, e.g.

Reactions giving alkoxide and alkylthio substituents in the 2-position are well known in the art; see e.g. G.A. Archer and L.H. Sternbach, Journal of Organic Chemistry, 22, 231 (1964) and U.S. Patent 3,681,341.

The compounds of formula IV can then be condensed with a nitroalkane to a new intermediate of the formula: "NO2. H ~ k v 4 _ ^ \, _ A _. 449 098 wherein A 'and R4 have the meaning given above.

The condensation reaction is carried out with a nitroalkane, (CH 3 -NO 2) i.e. nitromethane, etc., in the presence of a base strong enough to produce a nitroalkanion. Suitable bases include alkali metal or alkaline earth metal alkoxides, e.g. potassium tert-butoxide, amides, e.g. lithium amide, or hydrides, e.g. sodium hydride. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethylsulfoxide or an ether, e.g. THF, at temperatures below or above room temperature, ie. in the range -50 to 150 ° C, preferably approximately room temperature.

Compounds of formula V can then be catalytically hydrogenated, for example with Raney nickel, in the presence of hydrogen or with other reducing agents such as lithium aluminum hydride (with the limitation that A 'is not N-oxide) to produce a compound of formula: VI wherein A is - $ = N- and R4 and R6 have the meaning given above.

Re Suitable solvents for the hydrogenation with Raney nickel include alcohols, e.g. ethanol, ethers, e.g. THF, diethyl ether, etc., hydrocarbon solvents, e.g. toluene, and dimethylformamide.

The reaction temperature can be above or below room temperature, ie. from -50 to 150 ° C, and the reaction can be carried out with or without pressure, i.e. pressure of an atmosphere or higher.

Suitable solvents for hydrogenation using reducing agents such as lithium aluminum hydride include ethers, e.g. j !! 449,098 THF, dioxane, diethyl ether and mixtures of ethers and hydrocarbon solvents, e.g. THF and benzene. The reaction can be carried out from below room temperature to reflux temperature, i.e. preferably in the range -50 to 60 ° C.

The compounds of formula VI can then be acylated with an acylating agent such as an acid halide or acid anhydride, i.e. a group of formula (R1CO) 20, wherein R1 has the meaning given in formula I, e.g. acetic anhydride or acetyl chloride, for the preparation of a compound of the formula:. H Rice / N VII wherein A, R1, R4 and R6 have the meaning given above and Y represents hydrogen or -CORI.

When acylating the compounds of formula VI to compounds of formula VII, there may be a mixture of the predominant monoacylated product, i.e. where the NH2 group in VI (2-position) has been transferred to NHCORI and the diacylated product, where both NH2 in VI (2-position) and the nitrogen in the 1-position have been acylated. The yield of the diacylated product can be increased by subjecting the compounds of formula V to stricter conditions, i.e., excess acylating agent and increased reaction time.

The acylation is preferably carried out in the presence of an aqueous or non-aqueous solvent, e.g. water, methylene chloride, benzene, chloroform, etc. and preferably with an acid acceptor such as an organic or inorganic base, e.g. triethylamine, pyridine or an alkali metal carbonate. The compounds of formula VII can then be cyclized to new compounds of formula I above,. .. ,, .........-.-..........._. v .. _ V .. .............__ ....... «..__......_... ...___-_ __, _ _,. 449,098 VIII wherein A, R1, R4 and R6 have the meanings given above.

The cyclization reaction is carried out with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, i.e. organic or inorganic acids, e.g. concentrated sulfuric acid. No solvent is required, but a solvent such as an aromatic hydrocarbon solvent, e.g. toluene or xylene, can be used. The reaction is carried out at a temperature in the range of about 100 to 200 ° C.

The compounds of formula VIII can then be dehydrogenated to the corresponding unsaturated compounds.

Preferred reactants for the dehydration include manganese dioxide and palladium on carbon, although potassium permanganate may also be used. Solvents that can be used include chlorinated hydrocarbons, aromatic hydrocarbons, dimethylformamide, etc. The dehydration is carried out at room temperature or above, ie. in the range from about 25 to 200 ° C.

It has also been found that the compounds of formulas V, VI, VII and VIII can exhibit both optical and geometric isomerism.

In solution, the unsaturated compounds obtained in the above manner are opened into compounds of the formula: wherein R is Y the anion of an organic or inorganic acid and R 1, R 4 and R 6 have it in the meaning of formula I.

Such open compounds are present in a pH-dependent equilibrium in solution with their corresponding cyclized compounds. The compounds of formula ID may be isolated as acid addition salts by treating the corresponding closed ring compounds with an aqueous mineral acid followed by evaporation of the solvent.

The compounds of formula I wherein X represents hydroxy may be formed by reacting a compound of formula ID with sodium nitrite in the presence of a compatible solvent such as water or dilute mineral acid. The reaction temperature may be -10 ° C to room temperature. The reaction between the compounds of phosphorus tribromide thus obtained, preferably in an inert organic solvent such as dichloromethane at about room temperature, although this temperature is not critical, leads to compounds of formula I wherein X is bromine.

The following examples are illustrative but not limiting of the invention. All temperatures are given in Celsius degrees.

Example 1 A solution of 200 g (0.695 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -ZH-1,4-benzodiazepin-2-one in 2 liters of tetrahydrofuran and 250 ml of benzene saturated with methylamine while cooling in an ice bath. A solution of 190 g (1 mol) of titanium tetrachloride in 250 ml of benzene was added through a dropping funnel over 15 minutes. After the addition, the mixture was stirred and refluxed for 3 hours. Water (600 ml) was slowly added to the cooled reaction mixture. The inorganic material was separated by filtration and washed well with tetrahydrofuran.

The aqueous layer was separated and the organic phase was dried over sodium sulfate and evaporated. The crystalline residue of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine was collected, m.p. 204-206 °. The analytical sample was recrystallized from methylene chloride / ethanol, m.p. 204-206 °.

Sodium nitrite, 8.63 g (0.125 mol) was added in three portions over a 15 minute period to a solution of 30.15 g (0.1 mol) of 7-chloro-5- (2-fluorophenyl) -2-methylamino -3H-1,4-benzodiazepine in 150 ml of glacial acetic acid. After stirring for one hour at room temperature, the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, finally azeotroped with toluene to give 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1, 4-benzodiazepine as a yellow oil. This material was dissolved in 100 ml of dimethylformamide and added to a mixture of 200 ml of dimethylformamide, 50 ml of nitromethane and 11.1 g (0.1 mol) of potassium t-butoxide, which was stirred under nitrogen for minutes.

After stirring for one hour at room temperature, the mixture was acidified by adding glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated.

Crystallization of the residue from ether gave 7-chloro-1,3-dihydro- - (2-fluorophenyl) -2-nitromethylene-ZH-1,4-benzodiazepine, m.p. 170-172 °. The analytical sample was recrystallized from methylene chloride / ethanol, m.p. 174-176 °.

A solution of 16.5 g (0.05 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol were hydrogenated with 5 teaspoons of Raney-449,098 nickel for 2.5 hours at atmospheric pressure. Separation of the catalyst and evaporation gave crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine. Acetic anhydride (7 ml) was added to a solution of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine in 200 ml of methylene chloride . The solution was layered with 200 ml of saturated aqueous sodium bicarbonate, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to give a resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4 -benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150 ° for 10 minutes. The cooled reaction mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed on 120 g of silica gel using 20% methanol in methylene chloride. The pure fractions were combined and evaporated to give a resinous 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a // 1,4] benzodiazepine .

A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1.5 hours. The manganese dioxide was separated by filtration over CELITE. The filtrate was evaporated and the residue was crystallized from ether to give 8-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 152-145 °. The analytical sample was recrystallized from methylene chloride / hexane.

A solution of 3 g (0.00920 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] 1,4] -benzodiazepine in 50 ml of water and .5 ml (0.4092 mol) of concentrated sulfuric acid were treated with 1.5 g (0.0217 mol) of sodium nitrite. After 18 hours, an additional 0.5 ml of sulfuric acid and 1.5 g of sodium nitrite were added, and after 10 minutes, the reaction mixture was basified with 10 N sodium hydroxide. The reaction mixture was extracted with 75 ml of dichloromethane, which was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the redox from a mixture of ethyl acetate and ether gave (2-fluorophenyl) - [2- (5-449,098 hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl / methanone as white prisms, m.p. 165-168 ° .

Example 2 A solution of 25 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine in 50 ml of water and 50 ml of concentrated hydrochloric acid was allowed to stand at room temperature for 3 hours. After adding 250 ml of 2-propanol, the mixture was partially evaporated under reduced pressure without heating. An additional 200 ml of 2-propanol was added and the mixture was partially evaporated again. The precipitated crystals were collected and washed well with 2-propanol and ether to give 5-aminomethyl-1- [4-chloro-2- (2-fluorobenzoyl) phenyl] -2-methylimidazole dihydrochloride, m.p. 302-307 ° C (decomposition). The analytical sample was recrystallized from methanol / 2-propanol without heating.

A solution of 1g (0.00240 mol) of 5-aminomethyl-1- [4-chloro-2- (2-fluorobenzoyl) -phenyl] -2-methylimidazole dihydrochloride was dissolved in 20 ml of water and 1g (0.0l45 mol) sodium nitrite was added slowly while stirring on an ice bath. After 3 hours, the reaction mixture was basified with 10 N sodium hydroxide and extracted with 50 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.

Crystallization from ethyl acetate gave (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl / methanone as white prisms, m.p. and bsmp. with a sample prepared as above 163-166 °.

Example 3 "m1 a compound of 0.1 g (0,20213 ml) s-amino-e- (z-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a // 1,4] benzodiazepine-isopropanol and 5 ml of water were added to 1 ml of concentrated hydrochloric acid, the reaction mixture was cooled in an ice bath and 0.15 g (0.0002 mol) of sodium nitrite was added slowly with stirring. 2 g (0.00202 mol) of copper (I) chloride in 50 ml of water heated to 70 DEG C. After 18 hours, the reaction mixture was basified with sodium hydroxide, extracted with dichloromethane (2 x 50 ml), dried over anhydrous sodium sulfate and 449,098 ml. The residue was developed on a silica gel thick layer plate in a mixture of ethyl acetate and methanol (10 / l) The product having an Rf value of 0.7 was scraped off the plate, stirred with methanol and filtered. tallization of the crude product from a mixture of ethyl acetate and ether gave (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-k lorfenyl / methanone as white prisms, m.p. and bsmp. with an authentic sample 159-166 °. The final product can be further processed as follows: A solution of 0.5 g (0.00145 mol) of (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl-5-chlorophenyl / methanone) in 25 ml of dichloromethanone was treated with 0.15 ml (0.00155 mol) of phosphorus tribromide in an ice bath and poured after one hour at room temperature into 50 ml of liquid ammonia. After the ammonia evaporated, the reaction mixture was partitioned between 50 ml of dichloromethane and water.The organic phase was separated and dried over anhydrous sodium sulfate.The solution was concentrated and the residue was applied to two silica gel thick layer plates developed in a mixture of ethyl acetate / 10% methanol.

The compound having an Rf value of 0.6 was scraped off, stirred with methanol and filtered. The solution was treated with 0.1 g (0.000962 mol) of maleic acid and evaporated. The residual salt was crystallized from a mixture of isopropanol and ether to give the maleate of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo / 1,5-a / 1 , 4 / benzodiazepine as white prisms, m.p. and bsmp. with an authentic sample ll2-115 ° (melting point of the solvated product). The base was obtained by partitioning the salt between dichloromethane and water, adjusting the pH, separating the layers and evaporating the organic phase. Crystallization of the product from ether gave white prisms, m.p. and bsmp. with an authentic sample 154-167 °.

Claims (1)

Patent 44 Phenyl / 2- (5-hydroxy-1-imidazolyl) phenyl / methanone derivative of the general formula: R 1 Y 1 N 1 c 2 zof: R 5 wherein R 1 represents C 1-4 alkyl; R 4 represents halogen; halophenyl, for use as intermediates in the preparation of therapeutically valuable imidazo [1,5-a] - [1,4] benzodiazepine derivatives.