SE440504B - INTERMEDIATE FOR THE PREPARATION OF IMIDAZO (1,5-A) (1,4) DIAZEPINES - Google Patents

Description

7902666-2 wherein X is hydrogen or chlorine. The 3a, 4-dihydro-imidazo [1,5-a] 1,4] diazepines with the above Formula I are useful intermediates and can be hydrogenation is transferred to the pharmaceutically valuable imidazo / 1,5-a // 1,4 / diazepines of the general formula V ” N R3 II wherein A, R1 «RQ» R3 and <::; I: have it in formula I above given the meaning.

Preferred reactants for the dehydrogenation include manganese. dioxide and palladium-on-carbon, although potassium permanganate as well Can be used. Solvents that can be used include chlorinated hydrocarbons, aromatic hydrocarbons, dimethylformamide, etc. the generation is carried out at room temperature or above, i.e. in range from about 25 ° C to 200 ° C.

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

As used herein, the term "lower alkyl1" includes both straight chain and branched (C1-C7) hydrocarbon groups, preferably C1-C4 hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, butyl and the like. 7902666- By the term "lower alkanoyl" as used herein is meant a acyl residue of a C1-C7-, preferably a C1-C4-alkanoic acid, e.g. acetyl, propionyl, butyryl and the like, i.e. remains with the formula R20- fi-, where R20 O as used herein, the term "lower alkanoyl" also includes a is C 1 -C 6 alkyl or hydrogen. Like that ketone such as an acetal or ketal having 2 to 7 carbon atoms, for example a group of the formula R o give, ,, / \\\ O 0 wherein R 20 is C 1 -C 4 alkyl or hydrogen. Ketal or aldehyde 1 6 the protection group was used to prevent the conversion of the walking ketone or aldehyde (R20- fi-) at oxidation, the reduction and condensation reactions.

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

Preferred compounds are those wherein R 1 is methyl; R 3 is hydrogen; is RL "Éš:; U: wherein R4 is preferably in the 8-position in the imidazobenzodiazepine molecule and is hydrogen or halogenated gene, preferably chlorine; R 6 is fluorophenyl, preferably with the fluorine substituent in the 2-position of the phenyl group, for example compounds of the formula 7902666-2 IB wherein R1 'and R2 have the content given in formula IB' below the burden.

From the above it thus appears that a particularly preferred compound class within the scope of the present invention takes a compound of the formula Rb \ í§N _ R2 N R, ma '. : r-'N Rao wherein R 1 'is methyl, R 4 is hydrogen or halogen, preferably chlorine, and sits in a particularly preferred embodiment in 8-position on the condensed benzo moiety of the imidazobenzodiazepine, R60 is fluorophenyl with the fluorine substituent preferably in the 2-position of the phenyl group. R is selected from the group consisting of hydrogen 2 and lower alkyl.

Another preferred class of compounds that fall within the scope for formula I are the compounds wherein R1, R2, R4 and A has the meaning given in formula IB 'above and R3 is lower alkyl, preferably methyl, for example compounds of the formula 7902666 IC In one of the above-mentioned new procedural aspects of the compounds of formula I above can be prepared by nitrosation of a compound of the formula NHCH3 N R3 III e A H wherein A 'is -C = N- or -C = N-; , R and R have it I | x 3 6 R R O J 6 6 the meaning given above in formula I, for the preparation of a compound of the formula cH3 R3 IV- 7902666-2 wherein A1, R3 and <::] :: have the meaning given above.

Such nitrosation can be performed with "in situ" salt. petersyrlighet. Reagents that can be used include (1) 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, for example 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 gaseous solution in an inert solution and in the presence of an acid acceptor such as pyridine. One such nitrosation reaction should be performed at about or below room temperature, i.e. in the range -20 ° C to 25 ° C. ï fl ß 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. -OCH3; alkylthio, e.g. -SCH3; halogen, e.g. claws; cyano, i.e. -CN, and phosphate, e.g. sei-o, Reactions to give alkoxide and alkylthio substituents in 2- position are previously well known; see e.g. G. A. Archer and L. H.

Sternbach, Journal of Organic Chemistry, 29, 231 (1964) and U.S. Patent 3,681,341.

Compounds of formula IV can then be condensed with a nitro- alkane to a new intermediate of the formula 7902666-2 ZI Ra A H wherein A ', R 2, R 3 and <::] :: have the meanings given above.

The condensation reaction is carried out with a nitroalkane (R 2 -CH 2 -NO 2), i.e. nitromethane, nitroethane, etc., in the presence of a base strong enough to produce one nitroalkananion. Suitable bases include alkali metal or alkaline earth metal alkoxides, e.g. potassium tert-butoxide; amider, for example lithium amide, or hydrides, e.g. sodium hydride. Reactive 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, i.e. i om- -50 ° C to 150 ° C, preferably at about room temperature. lucky.

Compounds of formula V can then be catalytically hydrogenated, for example with Raney nickel, in the presence of hydrogen or with others reducing agents such as lithium aluminum hydride (with the limitation that A 'is not N-oxide) to produce a compound with the formula NH2 Rz Ra WE ZI OH 7902666-2 wherein A, R 2, R 3, R 2 and R 6 have the meaning given above.

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

The reaction temperature may be above or below room temperature. tur, i.e. from -50 ° C 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, for example THF, dioxane, diethyl ether and mixtures of ethers and hydrocarbon solvents, e.g. THF and benzene. The reaction can be carried from below room temperature to reflux temperature, i.e. preferably in the range -50 ° C to 6000.

The compounds of formula VI can then be acylated with an acyl- ringing agent such as an acid halide or acid anhydride, i.e. a group of formula (R 1 CO) 2 O, wherein R 1 has that of formula I specified meaning, e.g. acetic anhydride or acetyl chloride rid, to prepare a compound of the formula hrs Pam / N Rz Y rä Ra VII hrs A wherein A, R 1, R 2, R 3 and have the meaning given above and Y is hydrogen or -COR1.

Upon acylation of the compounds of formula VI to compounds with formula VII there may be a mixture of the dominant 7902666-2 the monoacylated product, i.e. where the NH2 group in VI (2-position) was transferred to NHCORI, and the diacylated pro- product, where both NH2 in VI (2-position) and nitrogen in the 1-position acylated. The yield of the diacylated product can be increased by subjecting the compounds of formula V to more stringent things, i.e. excess acylating agent and increased reactivity time.

The acylation is preferably carried out in the presence of an aqueous solution. 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. United the compounds of formula VII can then be cyclized to the new the compounds of formula I 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, for example kono. sulfuric acid. No solvent is needed, however a solvent such as an aromatic hydrocarbon solvent, for example toluene or xylene, can be used. The reaction is carried out at a temperature in the range of about 100 ° C to 200 ° C.

The compounds of formula VI may also be reacted with an acyl- agents such as an orthoester, e.g. triethyl orthoacetate, en orthoamide, e.g. the dimethylacetal of N, N-dimethylformamide, or a compound of the formula Oh) CC -O m 3 O-Z-Û-Z ~ O E11 T Û EI U) 7902666-2 10 possibly in the presence of an acid catalyst, e.g. an organic or inorganic acid, e.g. p-toluenesulfonic acid, phosphoric acid, etc., and at room temperature or above, i.e. 25 ° C to 150 ° C, in which case the cyclization to compound I takes place spontaneously aunt. Other useful acylating agents include esters, e.g. methyl acetate; amidines, e.g. acetamidine; nitriles, e.g. aceto- nitrile and esterimidates, e.g. a compound of the formula Ycz fi s CH -C = NH The above new procedure can be continued, if desired, from intermediates V or VI to compounds of without the need to isolate any of those formed intermediaries before proceeding to the next procedure step.

When acylating the compounds of formula VI to compounds of formula VII consider that, when R 4 is amino, amino- the group can also be acylated to acylamino. The acylamino group can be converted back to amino by exposing the the compounds of formula I for mild hydrolysis.

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

Another procedure for the preparation of the new intermediate The compounds of formula VI consist of reduction of compounds with the formula 7902666-2 ll ^ CN A H wherein A, R 3, R 2 and R 6 have the meaning given above.

The reduction involves reaction between the compounds of the formula X and a known reducing agent such as Raney nickel in the presence of hydrogen or with other reducing agents such as lithium aluminum hydride. Suitable solvents for hydrogenation with Raney nickel includes alcohols, e.g. ethanol; ethers, e.g. THF; hydrocarbon solvents, e.g. toluene; and dimethylformamide. Reactive temperature may be above or below room temperature (i.e. from -SOOC to 150 ° C) and the reaction can be carried out with or without pressure, i.e. pressure of an atmosphere or higher.

Solvents suitable for hydrogenation in use of a reducing agent such as lithium aluminum hydride ethers such as dioxane, diethyl ether and THF. The reaction can be carried from below room temperature to reflux temperature, preferably in the range -so ° c to eo ° c.

A variant of the method described above comprises mild acid hydrolysis of the compounds of formula X to compounds of the formula CONH2 ZI Ra XI hrs 17902666-2 _ 12 wherein A, R3 and <::: ï: have the meaning given above.

The mild acid hydrolysis is conveniently carried out with a diluent mineral acid, e.g. aqueous HZSO4 in aqueous alcohol.

The reaction temperature may vary from room temperature, i.e. about 25 ° C, to above room temperature, i.e. about 60 ° C.

The compounds of formula XI can then be reduced to the new ones intermediates of formula VI.

Another method can be used in the preparation of the new ones intermediates of formulas V and VI.

The compounds of formula V above can be prepared by successive reaction between the compounds of the formula hrs ID . N-'k Ra / <XII OH wherein A, <::;] ;: and R 3 have the meaning given above, except that R 4 is not amino, lower alkylamino or lower alkanoylamino and dimorpholinophosphinic acid chloride to compounds O II f-x -P N 0 _Jf \ _ / R 2 N 3 g with the formula XIII 7902666-2 13 wherein A, Qsçjšïr and R3 have the meaning given above, after which the iminophosphate groups are replaced with the anion of a nitroalkane so that you get the new intermediates V.

The substitution reaction is carried out with a nitroalkane, i.e. nitromethane, nitroethane, etc., in the presence of a base which is strong enough to produce the nitroalkanion. Suitable bases include alkali metal or alkaline earth metal alkoxides, hydrides, amides or hydroxides. The reaction is carried out before preferably in an inert solvent such as dimethylformamide, dimethyl sulfoxide or an ether, at temperatures below or above room temperature, i.e. in the range from -50 ° C to 150 ° C.

Another process for the preparation of intermediates with Formula V, wherein R 2 is hydrogen and A 'is an N-oxide, comprises ring extension in compounds of the formulas / N R3 n R3 cH cl or e c C12 lll | \\ A A VIII IX wherein A "'is - $ = N;; R 6, and R 3 has the above R6 O meaning except that R4 is not amino.

The ring expansion comprises reaction between the compounds with formula VIII or IX and nitromethane in the presence of a base which is strong enough to produce the nitromethane anion. Suitable bases include alkali metal and alkaline earth metal alkoxides, 37902666-2 14 for example potassium tert-butoxide; amides, e.g. lithium amide; or hydrides, e.g. sodium hydride. The reaction may preferably is carried out in an inert solvent such as an anhydrous ether, for example THF, dimethylformamide, dimethylsulfoxide, etc .; temperature in the range from -20 ° C to 25 ° C.

In this context, the applicant has cited various articles and U.S. patents to complete the application.

The following examples are illustrative but not limiting 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-fluoro- phenyl) -2H-1,4-benzodiazepin-2-one in 2 liters of tetrahydrofuran and 250 ml of benzene were saturated with methylamine while cooling on an ice bath. bad. A solution of 190 g (1 mol) of titanium tetrachloride in 250 ml benzene was added through a dropping funnel over 15 minutes. ter. After the addition, the mixture was stirred and refluxed. for 3 hours. Water (600 ml) was slowly added to it cooled reaction mixture. The inorganic material was separated by filtration and washed well with tetrahydrofuran. Water- the 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 collected, melting point 204 - 2060. The analytical sample was crystallized from methylene chloride / ethanol, m.p. 204 DEG-206 DEG.

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 g) mol) 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 150 ml of glacial acetic acid. After stirring for 1 hour at room temperature the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate. night solution, dried over sodium sulfate and evaporated, at closed azeotrope with toluene to give 29 g of crude 7-chloro- 7902666-1 15 -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 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 in 15 minutes.

After stirring for 1 hour at room temperature, the mixture was acidified. by adding glacial acetic acid, diluted with water and was 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- -5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine, m.p. paragraphs 170 - 1720. The analytical sample was recrystallized from methylene chloride / ethanol, m.p. 174-17 °.

A solution of 16.5 g (0.05 mol) of 7-chloro-1,3-dihydro-5- (2-fluoro- phenyl) -2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetrahydro furan and 250 ml of methanol were hydrogenated with 5 teaspoons of Raney nickel for 2 l / 2 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.

Propionic anhydride (20 ml) was added to a solution of 12 g of the above material in 300 ml of methylene chloride. Solution layered with 300 ml of 10% aqueous sodium carbonate and the biphasic mixture was stirred at room temperature for 30 minutes. The the organic layer was separated, washed with sodium carbonate solution and dried over sodium sulfate. Evaporation gave crude 7- chloro-2,3-dihydro-5- (2-fluorophenyl) -2-propionylaminomethyl-1H-1,4- benzodiazepines.

This material was heated in 50 g of polyphosphoric acid at 150 - 1700 for 10 minutes. The reaction mixture was cooled, dissolved in water and was made alkaline with conc. ammonia and ice. The base was extracted 7902666-2 16 with methylene chloride and the extracts were dried over sodium sulfate and evaporated. The residue was chromatographed over 300 g of silica gel using 20% methanol in methylene chloride. The pure freight the ions were combined, evaporated and the residue crystallized. was prepared from ether to give 8-chloro-3a, 4-dihydro-1-ethyl-6- (2- fluorophenyl) -3H-imidazo [1,5-a] 1,4-benzodiazepine, m.p. 131 - 133 °.

The final product can be further processed in the following way: A mixture of 3.4 g of 8-chloro-3a, 4-dihydro-1-ethyl-6- (2-fluoro- phenyl) -4H-imidazo [1,5-a] 1,4-benzodiazepine, 400 ml of toluene and 30 g of activated manganese dioxide was refluxed with separation of water in a Dean Stark trap for 2 hours. The manganese dioxide separated by filtration over CELITE, and the filtrate was fumes. Crystallization of the residue from ether gave 8-chloro-1- ethyl 6- (2-fluorophenyl) -4H-imidazo [1,5-a] 1,4-benzodiazepine, melting point l40 - 1430. For analysis it was recrystallized from ether, m.p. 143 DEG-145 DEG.

Example 2 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-benzo- diazepine in 200 ml of methylene chloride. The solution was layered with 200 ml saturated aqueous sodium bicarbonate and the mixture is stirred des 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 mate- ' The material was heated with 40 g of polyphosphoric acid at 1500 for 10 minutes.

The cooled reaction mixture was dissolved in water, made alkaline. ammonia and ice and extracted with methylene chloride.

The extracts were dried and evaporated and the residue chromatographed. was prepared over 120 g of silica gel using 20% methanol in methyl lenchloride. The pure fractions were combined and evaporated. to give resinous 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) - 7902666-2 17 -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. The end product can be further worked up as follows: A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide heated to reflux for 1/2 hour. The manganese dioxide is separated by filtration over CELITE. The filtrate was evaporated and the residue was crystallized from ether to give 8-chloro-6- phenyl) -1-methyl-4H-imidazo [1,5-a] 1,4-benzodiazepine, m.p. 152 - 1540. The analytical sample was recrystallized from methyl len chloride / hexane.

Example 3 Reaction as in the first paragraph of Example 1 of 152.5 g (0.5 mol) 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one saturated with methylamine with 133 g (0.7 mol) of titanium tetrachloride in 2 liters of tetrahydrofuran and 400 ml of benzene gave 7-chloro-5- (2- chlorophenyl) -2-methylamino-3H-1,4-benzodiazepine, m.p. 2190. The analytical sample was recrystallized from methylene chlorine / ethanol and had a melting point of 217 - 219 °.

Sodium nitrite (10 g, 0.145 mol) was added portionwise below 45 minutes to a solution of 22.4 g (0.07 mol) of 7-chloro-5- (2- chlorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 150 ml of glacial acetic acid.

After the addition, stirring was continued for 20 minutes nitrogen. The product was precipitated by the addition of ice water, was collected and dissolved in toluene. The solution was washed with saturated aqueous sodium bicarbonate, dried and evaporated reduced pressure. The yellow, viscous olyn1 consisted according to layer chromatography mainly of the desired nitrosoamide nen. This material was dissolved in 100 ml of dimethylformamide and added to a mixture of 30 ml of nitromethane, 100 ml of dimethylformamide and 10 g of potassium t-butoxide. The reaction mixture was heated slowly to 85 ° with stirring under a stream of nitrogen. After 5 minutes, the reaction mixture was cooled, then acidified by adding 10 ml of glacial acetic acid. The product crystallized by gradual addition of water by inoculation (inoculum crystals was obtained by chromatography on silica gel using 7902666-2 18 10% ethyl acetate in methylene chloride). The separated crystals 7 were collected, washed with water and recrystallized from methylene chloride / ethanol to give 7-chloro-5- (2-chlorophenyl) - -1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine, melting point 182 - 1ss °.

Hydrogenation of 7 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2- nitromethylene-2H-1,4-benzodiazepine in 300 ml of tetrahydrofuran and 150 ml of methanol in the presence of Raney nickel (5 teaspoons) for 1 hour gave crude 2-aminomethyl- 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4- benzodiazepines. This material was acetylated in the usual manner to oily 2-acetaminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-di- hydro-1H-1,4-benzodiazepine heated in 15 g of polyphosphorus acid for 10 minutes at 140 - 1500. Usual reprocessing gave one yellow resin which was chromatographed on 250 g of silica gel using conversion of 20% methanol in methylene chloride. The pure fractions gave resinous 8-chloro-6- (2-chlorophenyl) -3a, 4-dihydro-1-methyl- -4H-imidazo / 1,5-a // 1,4 / benzodiazepine. The end product can be further worked up as follows: This material was oxidized with 10 g of manganese dioxide in 200 ml of toluene. After heating to reflux for 1 1/2 hours, the manganese dioxide and filtrate were separated evaporated. Crystallization of the residue from ether gave 8-chloro- -6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] 1,4-benzodiazepine, melting point 140 - 1440. For analysis, it was recrystallized from methylene chloride / hexane, m.p. 142 DEG-144 DEG.

Example 4 A solution of 33 g (0 μl mol) of 7-chloro-2- (N-nitrosomethylamino) -5- phenyl 3H-1,4-benzodiazepine-4-oxide in 100 ml of dimethylformamide to a mixture of 50 ml of nitromethane, 12.5 g (0.1 mol) potassium t-butoxide and 100 ml of dimethylformamide. Reaction mixture The mixture was stirred under a stream of nitrogen for 1 hour. After addition of 10 ml of glacial acetic acid, the product was gradually crystallized by addition of 250 ml of water. The precipitated yellow material is were collected, washed with water, methanol and ether, whereupon received 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzo- 7902666- 19 diazepine-4-oxide, m.p. 253-2550 (dec.). The the analytical sample was recrystallized from methylene chloride and showed the same melting point.

Raney nickel (5 teaspoons) was added to a solution of 16.5 g (0.05 mol) 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4 benzodiazepine-4-oxide in 500 ml of tetrahydrofuran and 250 ml of nol. The mixture was hydrogenated for 5 hours at atmospheric pressure.

The catalyst was removed by filtration and the filtrate was concentrated. fumes. The residue was dissolved in 2-propanol and the solution was strongly acidified with ethanolic hydrogen chloride. The product is dihydro- chloride was crystallized on evaporation of part of the solution. medlet. The orange crystals which consisted of 2-amino- Methyl 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine dihydro- chloride was collected, m.p. 230-2400. Acetic anhydride (10 ml) was added to a solution of 10 g of it the above dihydrochloride in 50 ml of water and 50 ml of ethanol.

A 10% aqueous solution of sodium carbonate (100 ml) was added. was stirred for a period of 5 minutes. After the batch was stirred for a further 10 minutes and was then extracted with methylene chloride. The extracts were washed with sodium carbonate solution, dried over sodium sulfate and evaporated, at the end azeotroped with toluene. 2-Acetate aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine as a yellow resin.

The above material was heated in 50 g of polyphosphoric acid to 135 - 140 ° for 10 minutes. The initially orange color of the reaction mixture faded to light yellow. The cooled reaction The mixture was dissolved in water, made alkaline with conc. ammonia and ice and extracted with methylene chloride. The extracts dried and evaporated. The yellow resin was dissolved in 2-propanol and treated with ethanolic hydrogen chloride, whereupon the product dissolved dihydrochloride was crystallized. Melting point was 240 - 24s °. 7902666-2 20 This hydrochloride was partitioned between methylene chloride and aqueous containing ammonia. The organic phase was dried and evaporated.

Crystallization of the residue from ether gave 8-chloro-3a, 4-dihydro- -1-methyl-6-phenyl-3H-imidazo [1,5-a] 1,4-benzodiazepine as a colorless product with melting point 116 - 11s °.

The final product can be further processed in the following way: A mixture of 3.1 g (0.1 mol) of s-chloro-sa, 4-dinydrin-1-methyl- -6-phenyl-3H-imidazo [1,5-a] [1,4] benzodiazepine, 20 g activated manganese dioxide and 150 ml of toluene were refluxed for 1 hour.

The manganese dioxide was removed by filtration over CELITE and washed well with methylene chloride. The filtrate was evaporated and the residue was crystallized from ether to give 8-chloro-1- methyl-6-phenyl-4H-imidazo [1,5-a] 1,4-benzodiazepine as colorless crystals, m.p. 187-1880.

Example 5 A mixture of 11,2 (0,1 mol) of potassium tert-butoxide, 50 ml nitroethane and 200 ml of dimethylformamide were stirred at room temperature. tour for l5 minutes. A solution of 29 g (0.088 mol) of crude] -chloro-5- - (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine i 100 ml of dimethylformamide were then added and continued stir under nitrogen for 6 hours. The reaction mixture neutralizes was added by adding glacial acetic acid and diluted with water. Product was extracted with ether. The extracts were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. Crystallization from ether gave 7-chloro-1,3-3 dihydro-5- (2-fluorophenyl) -2- (1-nitroethylene) -2H-1,4-bendodiazepine as yellow crystals, m.p. 136 - 1420.

Raney nickel (5 teaspoons) was added to a solution of 17.3 g (0.05 mol) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitro- ethylene) -2H-1,4-benzodiaxane in 750 ml of tetrahydrofuran. Among- The mixture was hydrogenated at atmospheric pressure for 4 hours. Catalyst The tower was removed by filtration over CELITE 'and washed 7902666 21 well with methanol. The filtrate was evaporated to give crude 2- (1-aminoethyl) -7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4 benzodiazepine as a reddish oil.

This material was dissolved in 300 ml of methylene chloride. After addition of 14 ml of acetic anhydride was added 300 ml of saturated water sodium bicarbonate solution and the biphasic mixture was stirred at room temperature for 1 hour. The methylene chloride layer was separated, washed with bicarbonate, dried over sodium sulfate and concentrated. fumes. The residue was heated with 40 g of polyphosphoric acid for 10 h minutes at 160 - 1700. The cooled reaction mixture diluted with water, made alkaline with ammonia and extracted with methylene chloride. The extracts were washed with water, dried and evaporated to a brown residue, which was chromatographed on 250 g of silica gel using 20% (v / v) methanol in methylene chloride. The thin layer chromatographically homogeneous fractions the ions were combined into a resin which was subjected to the following oxidation.

The final product can be further processed in the following way: A mixture of the above material, 20g activated dioxide and 300 ml of toluene were heated to reflux for 3 hours. using a Dean Stark trap to eliminate the water. The manganese dioxide was separated by filtration over CELITE and washed well with methylene chloride. The filtrate was evaporated and the residue was chromatographed at a pressure above 150 g of silica gel H using 3% ethanol in methylene chloride. It first eluted major component was 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H- imidazo / 1,5-a // 1,4 / benzodiazepine.

It was converted to a crystalline dihydrochloride by treatment. with ethanolic hydrogen chloride in ether, m.p. 247 - 2500 (decomposition).

The more polar component could be crystallized from methylene chloride / ether / hexane to give 8-chloro-1,3-dimethyl-6- (2- 7202666-2 22 fluorophenyl) -4H-imidazo [1,5-a] 1,4-benzodiazepine, m.p. 178-100 °. ' Example 6 A mixture of 17.4 g (0.05 mol) of 7-chloro-1,3-dihydro-5- (2-fluoro- phenyl) -2- (1-nitromethylene) -2H-1,4-benzodiazepine-4-oxide, 500 ml tetrahydrofuran, 200 ml of methanol and 5 teaspoons of Raney nickel hydrogenated at atmospheric pressure for 0.5 hours. The catalyst was removed by filtration and the filtrate was evaporated, at the end azeotrope with xylene to give crude 2Laminomethyl-7-chloro- -5- (2-fluorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine.

This material was dissolved in 200 ml of ethanol and the solution was heated to reflux for 2 hours after the addition of 14 ml of triethyl ortho- acetate and 2.8 g of p-toluenesulfonic acid. The solvent is evaporated at reduced pressure and the residue was partitioned between len chloride and 10% aqueous sodium carbonate solution. The the organic layer was dried and evaporated to give oily 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazo - / 1,5-a // 1,4 / benzodiazepine.

The final product can be further processed in the following way: This crude product was dissolved in 500 ml of xylene. After adding 50 g activated manganese dioxide, the mixture was stirred and heated to reflux l l l / 2 hour with water separation in a Dean Stark- trap. The inorganic material was removed by filtration and the filtrate was evaporated to give 10 g of brown oil.

A warm solution of 4.65 g (0.04 mol) of maleic acid in 50 ml of ethanol was added to this residue. After complete dissolution the product was crystallized by adding ether. The was collected and washed with ether to give 8-chloro-6- (2- fluorophenyl) -1-methyl-4H-imidazo [1,5-a] 1,4-benzodiazepine maleate with melting point 112 - 115 °. heating under vacuum at 90 ° to 10 °, this product converted to the higher melting point 7902666-2 23 the mold with melting point 148 - 15 °.

Example 7 A solution of 23.6 g (1.0 mol) of 1,3-dihydro-5-phenyl-2H-1,3- benzodiazepin-2-one in 1 liter of tetrahydrofuran (containing about 20 moles of monomethylamine) was cooled on an ice bath. To this mixture was added 14 ml (d = 1.73; 0.125 mol) of titanium tetrachloride in 200 ml of benzene.

This mixture was stirred at room temperature for 2 days. Titanium the complex was destroyed with 20 ml of water. The inorganic salts which precipitated was removed by filtration. The solvent evaporated in vacuo and the residue partitioned between methylene chloride and water. A colorless, amorphous solid with a molten items 227 - 2290 were removed by filtration. One more batch of colorless solid, m.p. 226 DEG-288 DEG from the methylene chloride mother liquor after drying over anhydrous sodium sulphate, evaporation to dryness and crystallization from ethyl acetate.

An analytical sample was prepared by recrystallization from di- methylformamide for colorless prisms, m.p. 227-2290.

To a cooled (10), stirred solution of 10.0 g (0.04 mol) of 2- methylamino-5-phenyl-3H-1,4-benzodiazepine in 100 ml of pyridine was added 100 ml of a saturated solution of nitrosyl chloride in acetic acid hydride. The solution was stirred for 3.5 hours, during which time it was allowed to warm to room temperature. The solution was poured into 300 ml ice water and the aqueous solution was extracted with five 500 ml portions. methylene chloride. The combined organic extracts washed with water and brine, dried (CaSO 4) and dissolved. The solvent was removed under reduced pressure to give a dark semi-solid. Chromatography on 500 g silica gel (chloroform elution) gave 2- (N-nitrosomethylamino) -5-phenyl-3H-1,4 benzodiazepine, m.p. 192 ~ 1990 (decomposition). This materials were used in the following step: 7902666-2 24 The conjugate base to nitromethane was prepared by 50 ml of nitromethane in 200 ml of dimethylformamide with 5.7 g (0.05 mol) of potassium tert-butoxide. The resulting stirred yellow sus- the pension was treated with 10.9 g of crude 2- (N-nitrosomethylamino) -5- phenyl-3H-1,4-benzodiazepine in 100 ml of dimethylformamide. The so- The resulting dark mixture was stirred for 2 hours at 250 ° C and for 1 hour at 850 and then cooled to 250 and poured on 1 liter of water. After acidification with acetic acid was extracted the aqueous solution with four 250 ml portions of methylene chloride and de the combined organic extracts were then washed with water and brine, dried (CaSO 4) and concentrated in vacuo to a dark oil which was purified by chromatography over 1 kg silica gel (CHCl3 nitromethylene-5-phenyl-2H-1,4-benzodiazepine, m.p. 142 °. elution) to give crude 1,3-dihydro-2- An analytical sample, m.p. 141-1420, was prepared by crystallization from ethanol.

A mixture of 8.4 g (0.03 mol) of 1,3-dihydro-2-nitromethylene -5-phenyl-2H-1,4-benzodiazepine, 75 ml tetrahydrofuran, 75 ml methanol and 2 teaspoons of Raney nickel were hydrogenated at pre-press for 6 hours. The catalyst was removed by filtration. and the filtrate was evaporated to crude 2-aminomethyl-2,3-di- hydro-5-phenyl-1H-1,4-benzodiazepine.

This material was dissolved in 50 ml of methylene chloride and treated with 6 ml of acetic anhydride and 200 ml of saturated aqueous sodium bicarbonate solution for 15 minutes with stirring. Methylene- the chloride layer was separated, washed with bicarbonate solution, dried and evaporated. The residue was treated with 25 g of polyphosphate. acidify at 130 - 150 ° for 15 minutes. The cooled reaction mixture The distribution was partitioned between water and ether. The aqueous phase was done alkaline with ammonia and extracted with methylene chloride. Ex- the area was dried and evaporated. Chromatography of the residue over 70 g of silica gel with 20% (v / v) ethanol in methylene chloride gave 3α, 4-dihydro-1-methyl-6-phenyl-3H-imidazo [1,5-a] [1,4] 7902666-2 25 benzodiazepine as a light yellow resin.

The final product can be further processed in the following way: This material was heated in 50 ml of toluene with 7 g of activated manganese dioxide to reflux for 1/2 hour. The inorganic material The material was filtered off and the filtrate was evaporated. The remainder re- was chromatographed on 30 g of silica gel using of 10% ethanol in methylene chloride. The pure fractions were combined man and evaporated. Crystallization of the residue from ether gave 1-methyl-6-phenyl-4H-imidazo [1,5-a] 1,4-benzodiazepine.

Example 8 To a stirred solution of 6 g (0.02 mol) of 7-chloro-1,3-dihydro- -5- (2-fluorophenyl) -3-methyl-2H-1,4-benzodiazepin-2-one in 100 ml dry tetrahydrofuran was added 1.05 g (0.25 mol) of 57% sodium hydride dispersion in mineral oil. Mixture was placed underneath argon and refluxed for 1 hour. After cooling to room temperature, the mixture was treated with 7.4 g (0.03 mol) of di- morpholinophosphinic acid chloride and stirring under argon was set at room temperature for 2 hours. The mixture was filtered and evaporated under reduced pressure to a rubbery return. stood. Stirring the rubber with 100 ml of anhydrous ether gave the whites crystals collected by filtration were washed with a small amount of ether and air dried. Thus obtained 7-chloro-2- di- (morpholino) -phosphinyloxy-5- (2-fluorophenyl) -3-methyl-3H-1,4- benzodiazepines had a melting point of 90-950.

A stirred solution of 2.4 g (0.04 mol) of nitromethane in 50 ml of dry matter dimethylformamide was treated with 1 g (0.024 mol) of 57% sodium hydride dispersion in mineral oil at room temperature under argon.

After stirring for 1 hour at room temperature, the mixture was treated. with 5.2 g (0.01 mol) of 7-chloro-2-di- (morpholino) -phosphinyl oxy-5- (2-fluorophenyl) -3-methyl-3H-1,4-benzodiazepine in one portion and stirring under argon was continued at room temperature for 24 h hours. The dark mixture was poured over a mixture of ice 7902666-2 26 and glacial acetic acid with stirring to give a yellow solid sub- stop. Stirring was continued until the ice had melted. The fast the substance was filtered, washed with water and air dried on the filter funnel to give 7-chloro-1,3-dihydro-5- (2- fluorophenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine with melting point 2150 (decomposition). Recrystallization of a sample from methanol / methylene chloride 1: 1 gave yellow needles with melting point 219 - 2210 (decomposition).

A solution of 5.2 g (0.05 mol) of 7-chloro-1,3-dihydro-5- (2-fluoro- phenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine in 450 ml tetrahydrofuran / methanol 2: 1 was hydrogenated for 3 hours with use of a Parr apparatus, Raney nickel catalyst (3 spoons) and an initial pressure of 1.22 atm. The mixture is filtered was evaporated and evaporated under reduced pressure to give crude 2-Aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -3-methyl-1H- -1,4-benzodiazepine as a yellow oil.

The crude aminomethyl compound was mixed with 5 ml of triethyl ortho- acetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml of ethanol.

After heating under reflux for 2 hours, the solvent was evaporated. at reduced pressure. The residue was cooled to room temperature. luckily, was treated with a mixture of ice and concentrated ammonium hydroxide and extracted with methylene chloride. Evaporative drying of the dried extracts in vacuo gave crude 8-chloro-3a, 4-di- hydro-1,4-dimethyl-6- (2-fluorophenyl) -3H-imidazo [1,5-a] [1,4] benzo- diazepine in the form of a rubber.

The final product can be further processed in the following way: The crude dihydroimidazobenzodiazepine was mixed with 20 g of active manganese dioxide and 200 ml of toluene and heated under reflux for 2 hours. The mixture was filtered and manganese dioxide it was washed with methylene chloride. Evaporation of the combined beaten filtrate and washes at reduced pressure gave one brown rubber. The dihydrochloride of 8-chloro-1,4-dimethyl- -6- (2-fluorophenyl) -4H-imidazo [1,5-a] 1,4-benzodiazepine as a 7902666- 27 white powder by stirring the rubber with ethanolic hydrogen chloride in a few minutes. The salt melted at 247 - 2500.

Example 9 A mixture of 100 g (0.8 mol) of chloroacetalaldehyde dimethylacetal and 100 ml of 1.5 N hydrochloric acid were heated under reflux for 15 minutes minutes, after which it was cooled and added to a solution of 130 g (0.5 mol) of 2-amino-2'-fluoro-5-nitrobenzophenone and 46 g (0.28 mol) of hydroxylamine sulphate and 1 liter of ethanol. The mixture was stirred at room temperature for 2 hours and then heated to reflux for 1.5 hours. The mixture was cooled and the product recovered by filtration. Recrystallization from a mixture of chloroform and methanol gave pure 2-chloromethyl-4- (2-fluorophenyl) -6- nitro-1,2-dihydroquinazoline-3-oxide in the form of yellow prisms with melting point 220 - 224 °.

A solution of 142 g (0.423 mol) of 2-chloromethyl-4- (2-fluorophenyl) - -6-nitro-1,2-dihydroquinazoline-3-oxide in 2.3 liters of dichloromethane treated with 400 g of manganese dioxide and after stirring for 18 hours. The solution was filtered. The manganese dioxide was washed with 600 ml tetrahydrofuran and 800 ml of dichloromethane. The merged filters The concentration was concentrated to 400 ml and 1 liter of ether was added. The the whole was cooled and filtered to give 2-chloromethyl-4- (2- fluorophenyl) -6-nitroquinazoline-3-oxide A sample recrystallized from from a mixture of dichloromethane and methanol to the pure the product in the form of light yellow prisms, melting point 127 - 1300. 15.6 g (0.678 mol) of lithium amide were added to 500 ml of dimethyl sulfate oxide and 75 ml (1.4 mol) of nitromethane with stirring and in nitrogen atmosphere. After 30 minutes, the solution was cooled to 50 and 104 g (0.3l mol) 3-chloromethyl-4- (2-fluorophenyl) -6-nitroquinazoline-3-oxide was added slowly, keeping the temperature below 80. After 68 hours at room temperature, the reaction mixture was poured into a mixture of 2.5 liters of ice and water and 25 ml of acetic acid and the solution was filtered. The rubbery precipitate was dissolved in 1 liters of dichloromethane, which was washed with dilute ammonium hydroxide, 7902666-2 28 H dried over anhydrous sodium sulfate and evaporated. Re- The residue was crystallized from ethyl acetate to give 1,3-dihydro-5- (2- fluorophenyl) -7-nitro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide and the filtrates were evaporated, dissolved in dichloromethane and filtered. was passed through a glass filter funnel containing 200 g of "Florisil".

This was eluted with dichloromethane (600 ml), ether (600 ml) and ethyl acetate (1.2 liters). The ether and ethyl acetate fractions were beaten concentrated and concentrated to give additional product. A sample was recrystallized from a mixture of tetra- hydrofuran and hexane to the pure product in the form of yellow prisms, m.p. 216-2200.

A suspension of 25 g (0.0698 mol) of 1,3-dihydro-5- (2-fluoro- phenyl) -7-nitro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide in 1.3 liters of absolute ethanol were treated with 10 teaspoons of Raney nickel and hydrogenated at atmospheric pressure and room temperature. tour for 9 hours. The mixture was filtered through CELITE and the filtrate was evaporated to dryness. A sample of the oil crystalline was lysed from tetrahydrofuran to the intermediate 7-amino-2- Aminomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine as yellow prisms, which melted with decomposition at l85 - 192 °.

Without further purification, it was heated from the reduction. kept the oil under reflux for 2 hours in a solution of 300 ml absolute ethanol containing 4.5 ml (0.0257 mol) of ethanolic hydrogen chloride and 50 g (0.309 mol) of triethyl orthoacetate. The mixture then evaporated to dryness and the residue was dissolved in 150 ml of dichloromethane, which was washed with 100 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. to dryness to give 8-acetylamino-3a, 4-dihydro-6, (2-fluoro- phenyl) -1-methyl-3H-imidazo [1,5-a] 1,4-benzodiazepine.

The final product can be further processed in the following way: The residual oil, consisting of crude 6-acetylamino-3a, 4- dihydro ¥ 6- (2-fluorophenyl) -1-methyl-3H-imidazo [1,5-a] [1,4] benzo- 7902666-2 29 diazepine, was dissolved in 500 ml of benzene and treated with 100 g activated manganese dioxide. The mixture was refluxed and stirred. was stirred for 9 hours using a Dean Stark trap. Outside- 25 g of activated manganese dioxide was added and after 4 hours March reflux, the manganese dioxide was removed by filtration. and washed with 500 ml of tetrahydrofuran. The filtrate was beaten together and evaporated to 8-acetylamino-6- (2-fluorophenyl) -1- methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine.

Example 10 A solution of 19.3 g (0.06 mol) of 1,3-dihydro-7- (2-methyl-1,3-dihydro- oxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one in 300 ml dry tetrahydrofuran was treated under an argon atmosphere with 3.1 g (0.075 mol) of a 57% suspension of sodium hydride in mineral oil. The mixture was heated under reflux for 1 hour and cooled to room temperature, after which 22.2 g (0.0B7 mol) of di- morpholinophosphinic acid chloride was added. The mixture was stirred at room temperature for 2 hours and then allowed to stand overnight.

Sodium chloride was eliminated by filtration to give crude 7- (2-methyl-1,3-dioxolan-2-yl) -2- [bis (morpholino) phosphinyloxy] -5- phenyl-3H-1,4-benzodiazepine by elimination of the solvent and crystallization of the residue from ether.

A mixture of 100 ml of dry N, N-dimethylformamide and 6.8 g nitromethane was treated under an argon atmosphere with 2.8 g (0.066 mol) of a 57% suspension of sodium hydride in mineral oil. Among- The mixture was stirred for 1 hour at room temperature, after which a solution was added. 18 g (0.033 mol) of crude 7- (2-methyl-1,3-dioxolan-2-yl) -2- - [bis (morpholino) phosphinyloxy] -5-phenyl-3H-1,4-benzodiazepine i 50 ml of dry N, N-dimethylformamide were added. The reaction mixture was allowed to stand at room temperature for 15 hours, after which the dark, the viscous liquid was poured over a mixture of ice and diluted acetic acid. The bright yellow precipitate was removed by filtration and dissolved in dichloromethane, which was washed with dilute ammonium hydroxide and water, dried over anhydrous sodium sulfate and evaporated. The original filtrate was extracted with 79026-66-2 30 dichloromethane, which was washed, dried and evaporated as evaporator given above. The two crude residues were combined and chromatographed. was graphed over "Florisil" using dichloromethane / 10% (volume / volume) ether as eluent and monitoring of fractions thin-layer chromatography collected several fractions. containing the product and evaporated. Crystallization and recrystallization from a mixture of dichloromethane and hexane gave pure 2,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -2-nitromethylene- -5-phenyl-1H-1,4-benzodiazepine as light yellow prisms with molten point lss - 161 °.

Hydrogenation of 5 g (0.0137 mol) of 2,3-dihydro-7- (1-methyl-1,3- dioxolan-2-yl) -2-nitromethylene-5-phenyl-1H-1,4-benzodiazepine in 250 ml of absolute ethanol in the presence of a teaspoon of Raney nickel in 3.5 hours gave crude 2-aminomethyl-2,3-dihydro-7- (1-methyl-1,3- dioxolan-2-yl) -5-phenyl-1H-1,4-benzodiazepine. To a solution of 4 g (0.019 mol) of this compound in 75 ml of absolute ethanol 0.7 g (0.0037 mol) of p-toluenesulfonic acid and 6 g (0.037 mol) triethyl orthoacetate. The mixture was refluxed for 2 hours. evaporated to dryness and the residue was dissolved in 50 ml of dichloro- methane. This was washed with 25 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to give crude 3α, 4-dihydro-1-methyl-8- (1-methyl-2,3-dioxolan-2-yl) - -6-phenyl-3H-imidazo [1,5-a] [1,4] benzodiazepine as an oil.

The final product can be further processed in the following way: A solution containing 3.8 g (0.005 mol) of this crude oil and 18 g of activated manganese dioxide in 100 ml of toluene reflux and stirred for 2 hours using a Dean Stark- trap. It was filtered and washed with a mixture of 250 ml dichloromethane and 250 ml of tetrahydrofuran. The filtrate was evaporated and dissolved in a small amount of isopropanol and treated with 1.4 g (0.012l mol) of maleic acid in ethanol. Ether was added and the precipitate was filtered and recrystallized from a mixture of methanol and ether to give 1-methyl-8- (2-methyl-1,3- dioxolan-2-yl) -6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine- 7902666- 31 maleate-methanol (2 / l) as off-white prisms, m.p. 1s2 °.

Example ll A solution of 56.4 g (0.2O mol) of 1,3-dihydro-7-ethyl-5- (2-fluoro- phenyl) -2H-1,4-benzodiazepin-2-one in 2.0 liters of tetrahydrofuran containing 4 moles of monomethylamine was cooled on an ice bath. To to this was added 33.0 ml (0.30 mol) of titanium tetrachloride in 350 ml of late. The mixture was stirred at room temperature for 3 days.

The titanium tetrachloride was decomposed with 100 ml of water. The transition The organic salts were removed by filtration. The filtrate is evaporated to dryness in vacuo. The residue was divided between methylene chloride and water. The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuum. The residue on crystallization from acetonitrile gave 7- ethyl 5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine as light yellow prisms with melting point 172 - l740.

An analytical sample was prepared by recrystallization from aceto- nitrile to light yellow prisms, m.p. 172 - 1743.

Sodium nitrite (8.6 g, 0.125 mol) was added in three portions for 1/2 hour to a solution of 29.5 g (0.1 mol) of 7-ethyl- -5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 100 ml glacial acetic acid. After stirring for another 1/2 hour at room temperature temperature, the mixture was diluted with ice water and extracted with methylene chloride. The extracts were washed with water and water. bicarbonate, dried over sodium sulphate and evaporated to give crude 7-ethyl-5- (2-fluorophenyl) -2- (N-nitrosophenyl) methylamino) -3H-1,4-benzodiazepine in the form of a yellow oil.

This material was dissolved in 100 ml of dimethylformamide and the solution was added to a mixture of 100 ml of dimethylformamide, 35 ml nitromethane and 9.9 g of potassium t-butoxide, which was stirred for 1/2 hour at room temperature. After the addition was complete, the reaction mixture was stirred. 7902666-2 32 the mixture for 1 hour at room temperature and for 30 minutes on steam bath. The cooled solution was acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts washed with water, dried and evaporated. The remainder was dissolved in 50 ml of ethanol and allowed to crystallize in a refrigerator the night after inoculation. The yellow crystals were collected and crystallized from ethanol to give 1,3-dihydro-7- ethyl 5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine with melting point l38 - l40 °. Seedling crystals were obtained by chromatography. tograph of the crude product over 40-fold the amount of silica gel using 5% (v / v) ethyl acetate in methylene chloride. The analytical sample was recrystallized from ether / hexane. melting point 138 - 141 °. 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitromethylene-2H-1,3- benzodiazepine (2.6 g) was hydrogenated for 4 hours with Raney nickel (1 teaspoon) in 30 ml of ethanol. The catalyst was separated by filtration and the filtrate was evaporated. The residue was dissolved in ether and the amine was extracted with 10% aqueous acetic acid. acid. The extracts were washed with ether and made alkaline ammonia. The precipitated amine was extracted with methylene chloride.

The extracts were dried and evaporated to give 1.5 g of crude 2-Aminomethyl-2,3-dihydro-7-ethyl-5- (2-fluorophenyl) -1H-1,4 benzodiazepines. This material was dissolved in 50 ml of xylene. Solution was then heated to reflux for 2 hours after addition of 3 ml of triethyl orthoacetate. The after evaporation at reduced pressure obtained the residue was chromatographed on 50 g of silica gel using 20% methanol in methylene chloride. The homogeneous the fractions were combined and evaporated to give 3a, 4-Dihydro-8-ethyl-6- (2-fluorophenyl) -1-methyl-3H-imidazo [1,5-a] - / 1,4 / benzodiazepine.

The final product can be further processed in the following way: This material was dissolved in 50 ml of toluene and the solution was heated. was refluxed for 1 hour after the addition of 5 g of activated manganese dioxide. The inorganic material was separated by filtration. 7902666- 33 and the filtrate was evaporated. The residue was dissolved in ether and treated with ethanolic hydrogen chloride and acetone. The crystalline the dihydrochloride (m.p. 248-2550) was collected and was returned to the base by partitioning between methylene chloride and aqueous ammonia. The methylene chloride layer was dried and evaporated. Crystallization of the residue from ether / hexane gave 8-ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzo- diazepine, m.p. 152-1540.

Example 12 A solution of 2.9 g (0.00927 mol) of 2,3-dihydro-5- (2-fluoro- phenyl) -2-nitromethylene-1H-1,4-benzodiazepine-4-oxide in a mixture 1 teaspoon of Raney nickel, 90 ml of tetrahydrofuran and 45 ml methanol was hydrogenated at atmospheric pressure and at room temperature. tour for 2.3 hours. The mixture was filtered and the nickel was washed. des with dichloromethane. The combined filtrates were evaporated and the resulting oil was dissolved in 50 ml of dichloromethane which was washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. A solution of 2.2 g (0.019 mol) of maleic acid in 15 ml of ethanol were added to the oil and after ether was added, 2-aminomethyl-2,3- dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine dimaleate hemi- hydrate. Recrystallization from a mixture of methanol and ether gave a product in the form of yellow rods with a melting point of 147 ~ 150 °.

A solution of 4.0 g (0.0499 mol) of the base of 2-aminomethyl-2,3- dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine dimaleate hemi- hydrate in 125 ml of absolute ethanol was treated with 4 g (0.0247 mol) triethyl orthoacetate and 0.5 g (0.00263 mol) of p-toluenesulfonic acid.

After refluxing the mixture for 2 hours, it was evaporated the reaction mixture to dryness. The resulting oil was dissolved in 50 ml of dichloromethane, which was washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and concentrated evaporated to dryness to give crude 3a, 4-dihydro-6- (2- fluorophenyl) -1-methyl-3H-imidazo [1,5-a // 1,4] benzodiazepine as a oil. f ' ¿ 75902666-2 34 The final product can be further processed in the following way: A) The crude product from the previous section was dissolved in 100 ml toluene, was treated with 18 g of activated manganese dioxide and mixed The mixture was stirred and refluxed for 3 1/2 hours using a Dean Stark trap. The reaction mixture was filtered through CELITE and the precipitate was washed with 100 ml of tetrahydro furan and then with 100 ml of dichloromethane. The merged filters The residue was evaporated and the residue was dissolved in 25 ml of dichloromethane.

This solution was chromatographed on a "Florisil" column with dichloromethane and then eluted with ether. Elution with ethyl acetate and then with a 10% (v / v) solution of methanol in ethyl acetate gave the crude product which crystallized out ether and then recrystallized from ethyl acetate to give received 6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzo- diazepine as white prisms, m.p. 164-1680.

B) A solution of 1.2 g (0.004l mol) of 3α, 4-dihydro-6- (2-fluoro- phenyl) -1-methyl-3H-imidazo [1,5-a] 1,4-benzodiazepine in 50 ml mesitylene and 0.5 g of 10% palladium-on-carbon were stirred and refluxed for 28 hours, then filtered and filtered. evaporated to dryness. Crystallization from ethyl acetate gave 6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] 1,4-benzodiazepine as white prisms with melting point l62 - 1670 and a mixed melting point with authentic product was 162 - 1680.

Example 13 A mixture of 10 g (0.036 mol) of 1,3-dihydro-5-phenyl-2H- thieno- / 3,2-e // 1,4 / diazepin-2-one in 50 ml of benzene and 300 ml tetrahydrofuran was stirred on an ice bath and saturated with methylamine. gas. To this mixture was added dropwise a solution of titanium tetrachloride (9.48 g, 0.05 mol) in 50 ml of benzene. After completed addition, the mixture was stirred on an ice bath for 15 minutes. The ice bath was then replaced with a heating mantle and the mixture was refluxed. boiled for 1/2 hour. The mixture was cooled and 100 g of ice were added. was set carefully. The mixture was filtered and the residue 7902666 * 35 was washed with tetrahydrofuran. The filtrates were combined, dried and evaporated. The product was crystallized from methylene chloride, to give 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine, m.p. 223 - 2270. From the concentrated parent the liquors gave an additional product with melting point 222 - 2250.

The analytical sample was recrystallized from methylene chloride. melting point 222 - 2290.

Nitrosyl chloride was introduced into a solution of 7.8 g (0.03 mol) of 2- methylamino-5-phenyl-3H-thieno / 3,2-e // 1,4 / diazepine in 100 ml methylene chloride and 40 ml of pyridine cooled in ice water. The reactions was followed by thin layer chromatography and when the starting material disappeared, the addition of nitrosyl chloride was stopped and the reaction the mixture was partitioned between methylene chloride and water. Methy- the len chloride solution was dried and evaporated. Crystallization of the residue from methylene chloride / hexane gave 2- (N-nitrosomethyl- amino) -5-phenyl-3H-thieno [3,2-e ],4,4-diazepine as yellow crystalline smiles with melting point 156 - l59 °. The analytical sample is recrystallized. was lysed from ether / hexane, m.p. 158-1600. 2- (N-Nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e ],4,4-diazepine (5.7 g, 0.02 mol) was added to a mixture of 15 ml of nitro methane, 4.5 g of potassium t-butoxide and 60 ml of dimethylformamide as stirred for 10 minutes at room temperature. After the addition, the reaction mixture was stirred under nitrogen and heated steam bath for l0 minutes. After acidification with 4 ml of glacial acetic acid, the mixture was partitioned between methylene chloride / toluene and saturated sodium bicarbonate solution. The organic layer was washed with water, dried and evaporated. Crystallization of recyclable The methanol grafted solution gave 1,2-dihydro-2-nitromethylene -5-phenyl-3H-thieno [3,2-e] [1,4] diazepine as yellow crystals with mp 160-163 °. Seed crystals were obtained by chromatography. graphic purification over 30-fold the amount of silica gel using of 10% (v / v) ethyl acetate in methylene chloride. The analy- The sample was recrystallized from methanol, m.p. 1e4 °. 7902666-2 36 A solution of 1.42 g (5 mmol) of 1,2-dihyaro-2-nitromethylene-s-I phenyl-3H-thieno [3,2-e] 1,4-diazepine in 200 ml of ethanol hydrogen over Raney nickel (2 teaspoons) for 1 hour at atmospheric print. The catalyst was removed by filtration and the filtrate evaporated. The residue was treated with 1.2 g of maleic acid in 10 ml of 2-propanol. The salt was crystallized by the addition of ether to give 2-aminomethyl-2,3-dihydro-5-phenyl-1H- thieno / 3,2-e // 1,4 / diazepine dimaleate with yellow crystals melting point 170 - 1730. The analytical sample recrystallized was obtained from methanol / 2-propanol, m.p. 187-189 °. 2-Aminomethyl-2,3-dihydro-5-phenyl-1H-thieno [3,2-e] [1,4] diazepine- dimaleate (1 g, 2 mmol) was partitioned between methylene chloride and aqueous ammonia. The methylene chloride layer was dried and fumes. The residue was heated to reflux for 1 hour 1 ml of triethyl orthoacetate in 20 ml of xylene. The solvent was evaporated at reduced pressure and the residue was crystallized from 2- propanol / ether to give 1-methyl-3a, 4-dihydro-6-phenyl-3H- imidazo [1,5-a] thieno [2,3-f] diazepine, m.p. 150-1520.

The final product can be further processed in the following way: This material was heated to reflux in 30 ml of toluene with 2 g activated manganese dioxide for 2 hours. The manganese dioxide was filtered and washed well with methylene chloride. The filtrate evaporated and the residue was chromatographed on 7 g of silica gel using 3% (v / v) ethanol in methylene chloride. The fractions containing pure product were combined and evaporated. des. Crystallization from methylene chloride / ether and recrystallization from thion from ethyl acetate / hexane gave 1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [2,3-f] diazepine, m.p. 223 DEG-225 DEG.

Example 14 A mixture of 7.7 g (0.278 mol) of 7-chloro-1,3-dihydro-5-phenyl- -2H-thieno / 2,3-e // 1,4 / diazepin-2-one, 50 ml of benzene and 250 ml tetrahydrofuran was stirred on an ice bath and saturated with methylamine. . 7902666- 37 gas. To this mixture was added a solution of titanium tetra chloride (7.38 g, 0.0389 mol) in 50 ml of benzene from a dropping funnel.

After the addition was complete, the mixture was stirred on an ice bath for 15 hours minutes. The ice bath was then replaced with a heating mantle and reacted. the ion mixture was refluxed for 20 minutes. The mixture cooled and 100 g of ice were carefully added. was then washed and the residue was washed with tetrahydrofuran.

The filtrates were combined, dried and evaporated. The remainder crystallized from methylene chloride / ether to give 7- chloro-5-phenyl-2-methylamino-3H-thieno [2,3-e] 1,4-diazepine with melting point 246 - 249 °. The analytical sample recrystallizes was obtained from methylene chloride, m.p. 247-2500.

Nitrosyl chloride was introduced into a solution of 5.8 g (0.02 mol) of 7- chloro-5-phenyl-2-methylamino-3H-thieno [2,3-e ],4,4-diazepine i 100 ml of methylene chloride and 50 ml of pyridine, until the reaction was complete according to thin layer chromatogram. The mixture was placed between water and toluene. The organic phase was dried and evaporated. Crystallization of the residue from ether / hexane gave 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] - - / 1,4 / diazepine as yellow crystals, m.p. 108 - 1100.

For analysis, it was recrystallized from ether / hexane, m.p. 111 - 113 °. 7-Chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] [1,4] diazepine (3.2 g, 0.01 mol) was added to a 10 ml mixture nitromethane, 35 ml of dimethylformamide and 2.26 g (0.02 mol) potassium t-butoxide stirred under nitrogen for 10 minutes at room temperature. After heating for 10 minutes in a steam bath the reaction mixture was made by adding 2 ml of glacial acetic acid and partitioned between water and toluene. The toluene layer washes taken with water, dried and evaporated. The crystalline residue was reacted from ethyl acetate / hexane to give crude 7-chloro-2,3- dihydro-2-nitromethylene-5-phenyl-1H-thieno [2,3-e ],4,4-diazepine.

It was purified by chromatography on 40 g of silica gel using conversion of 10% (v / v) ethyl acetate in methylene chloride. MAN received the pure product in the form of yellow crystals with molten 7902666-2 38 point 154 - 1ss °.

A) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro-2-nitro- methylene-5-phenyl-1H-thieno [2,3-e] 1,4] diazepine in 20 ml of ethanol hydrogenated over Raney nickel for 5 hours at atmospheric print. The catalyst was removed by filtration and filtration. evaporated. The residue was chromatographed over 7 g of silica gel using methylene chloride, methanol and triethylamine in a ratio of 13: 6: 1. The fractions that contained pure product was combined and evaporated and the residue was treated with maleic acid in 2-propanol. Crystallization of dimaleate the salt from 2-propanol / ether and recrystallization from ethyl acetate / ethanol gave 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno- - / 2,3-e // 1,4 / diazepine dimaleate as yellow crystals with molten point 176 - 177 °.

B) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro-2-nitro- methylene-5-phenyl-1H-thieno [2,3-e ],4,4-diazepine in 3 ml of tetra- hydrofuran was added to a suspension of 0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After heating to return to flow for 5 minutes, the reaction mixture was cooled and hydrolyzed. was obtained by adding 5 ml of water. The inorganic material was separated by filtration and the filtrate was evaporated. Re- the residue was chromatographed as described above and the pure the product was transferred to the material to give 2-amino- methyl 7-chloro-2,3-dihydro-5-phenyl-1H-thieno [2,3-e] [1,4] diazepine- aimaleat with melting point 176 - 17th °. 2-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno [2,3-e] [1,4] diazepine dimaleate (0.52 g, 1 mmol) was partitioned between methylene chloride and aqueous ammonia. The methylene chloride solution is dried. was evaporated and evaporated. The residue was heated to reflux in 1 hour with 0.5 ml of triethyl orthoacetate in 10 ml of xylene. The raw product obtained after evaporation under reduced pressure in 25 ml of toluene and the solution was heated to reflux in 1 l / 2 hour after addition of 2.5 g of activated manganese dioxide.

The manganese dioxide was then filtered off and the filtrate was evaporated. 7902666 39 des. the residue was chromatographed on 6 g of silica gel using 4% (v / v) ethanol in methylene chloride. Fractions containing the pure compound was combined and evaporated.

Crystallization of the residue from ether / hexane gave B-chloro-1- methyl-6-phenyl-1H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine with melting point 168 - 17 °.

Claims (2)

7902666-2 I mi CLAIMS 1. A compound of the formula wherein A is the group -? = N-; R 1, R 2 and R 3 represent hydrogen or R 5 is lower alkyl; R 4 represents hydrogen, halogen, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl; R 6 represents phenyl or halophenyl; and represents one of the groups a) b) or c) wherein X is hydrogen or chlorine; for use as an intermediate for the preparation of therapeutically valuable imidazole, 5-a7-E1, Q7 diazepines. A compound according to claim 1 having the formula RP 10 R 2 on H 7902666-1 41 wherein A is the group -f = N-; R 1, R 2 and R 3 represent hydrogen or R 5 is lower alkyl; R 4 represents hydrogen, halogen, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl; and R 6 represents phenyl or halophenyl.