NO147109B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE DIAZEPINE DERIVATIVES - Google Patents

Description

The present invention relates to an analogous method for the preparation of pharmacologically active imidazo[1,5-a]-[1,4]diazepine compounds with the following formula

r , R, and R^ are selected from the group consisting of hydrogen and lower alkyl, R^ is selected from the group consisting of hydrogen, halogen, lower-alkyl, lower-alkylamino, lower-alkanoylamino, amino, hydroxy-lower-alkyl and lower-alkanoyl or the group c^'0 I in which R^q .denotes hydrogen or Cj-Cg-alkyl, 0 ~^^0 I

R 6 is selected from the group consisting of phenyl and halophenyl, and

and the pharmaceutically acceptable salts thereof.

In the present description, the term "lower alkyl" means hydrocarbon residues with both straight and branched chains (C1-C7), preferably C-1-C2 hydrocarbon residues such as methyl, ethyl, propyl, isopropyl, butyl and the like.

The term "lower-alkanoyl" here means an acyl part of a C 1 -C 7 , preferably a C 1 -C 3 , alkanoic acid, e.g. acetyl, pro-

pionyl, butyryl and the like.

The term "halogen" is used to include all four forms thereof, i.e. chlorine, bromine, fluorine and iodine.

In the event that R- is lower alkyl, optical isomerism will occur and the preparation of such optical antipodes and racemates is within the scope of the present invention.

Preferred compounds are those where R, is methyl, R^ is hy-

the drug;

is where R^ is preferably in the 8-position in the imidazobenzodiazepine molecule and is hydrogen or halogen, preferably chlorine; where Rg is fluorophenyl, preferably with the fluorine in the 2-position on the phenyl residue, e.g. compounds of the formula where R 1 and R 2 are as defined in formula IB' below. It is thus clear from the above that a particularly preferred type covered by the preamble of the present invention contains a compound of the formula where R-^<1> is methyl, R^ is hydrogen or halogen, preferably chlorine, and in a most preferred form placed in the fused benzo moiety of the imidazobenzodiazepine in the 8-position therein, R 2 is fluorophenyl, preferably with fluorine in the 2-position of the phenyl residue, R 2 is selected from the group consisting of hydrogen and lower alkyl. Another preferred class of compounds falling within the scope of formula I are those where R 1 , R 2 , R 2 , R 3 and A are as in formula IB' above and R 3 is lower alkyl, preferably methyl, e.g. compounds of the formula

Compounds of formula IC and their pharmaceutically acceptable salts exhibit optical isomerism. Such a compound has been resolved into its optical enantiomers by a method similar to that generally disclosed in "Advanced Organic Chemistry", L. Fieser and M. Fieser, 1961, pp. 85-88, Reinholt Publishing Co. Both the optical isomers and the racemic form of the compound IC exhibit pharmacological action. E.g. in the case of the tartaric salt of compounds of formula IC, the (+) isomer is significantly more active than the (-) isomer. The less active (-) isomer can, if desired, be converted to the active racemic form thereof such as by treatment with a non-aqueous base, e.g. sodium tertiary butoxide in the presence of an organic solvent in which the isomer is soluble.

The term "pharmaceutically acceptable salts" is used to include salts with both inorganic and organic pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane sulfonic acid, paratoluenesulfonic acid and the like. Such salts can readily be prepared by those skilled in the art in view of the state of the art and the nature of compounds to be transferred into salt form.

The most preferred pharmaceutically acceptable acid addition salts of the compounds of the formulas IC and ID respectively are: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]-[1,4]-benzodiazepine maleate ;

8-chloro-1-, 4-dimethyl-6-(2-fluorophenyl)-4H-imidazo [1,5-a] [1,4 (benzodiazepine maleate.

The imidazo[1,5-a][1,4]diazepine compounds of formula I and the pharmaceutically acceptable acid addition salts of these compounds can be prepared by the various embodiments indicated in claim 1 below.

Conversion of compounds of formula I, where R 1 is amino, to compounds where R 1 is chlorine or bromine can conveniently be carried out by e.g. The Sandmeyer reaction, where the amino group is replaced by a chlorine or bromine group. The treatment of a compound of formula I, where C 1 is aminophenyl, with excess sodium nitrite in the presence of a copper sulphate/sodium sulphite mixture and using dilute sulfuric acid as solvent, can result in an intermediate of the formula

where R'^ is chlorine or bromine,

R is C-C alkyl and R is O-halophenyl

which can then be converted to an analogous compound of formula I. This process can be carried out in a two-step sequence without isolation of the intermediate product formed by treating the aforementioned compound of formula XXIII<1> with phosphorus tribromide in an inert organic solvent, e.g. . dichloromethane at approx. -10° to 25°C (although the temperature is not critical, and then subsequent treatment in situ with ammonia, preferably liquid ammonia which is allowed to warm • to room temperature.

It is of course for a person skilled in the art that certain other substituents can also be attacked during the aforementioned reactions, but such vulnerable groups can be blocked by a suitable protecting group or modified before the aforementioned reaction sequence is carried out. Such methods for modifying or protecting groups exposed to attack are well known in the field.

In compounds where the ketal group e.g.

is present as a substituent in the 8-position of an imidazobenzodiazepine, such a ketal group can be converted into a ke-

ton in the 8-position by subjecting the ketal group to mild acid hydrolysis. The 8-ketone can then be converted to a secondary or tertiary alcohol in the 8-position which is racemic in nature. The reaction conditions for the aforementioned two steps are found in US Patent No. 3,846,410.

In one of the method aspects that appear in the claims, the compounds of formula I above can be prepared by nitrosation of a compound of the formula

(^zlT' , R-. and R, are as defined in formula I to give a compound of the formula

where A, R-. and ( Z |l Sr S°m ^escribed above.

Such a nitrosation can be carried out with "in situ formed" salp teracidification. The reaction components 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, e.g. methyl nitrite, in the presence of an inert solvent, such as an alcohol, chlorinated hydrocarbon or e.g. dimethylformamide, and (3) a gaseous solution of nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation must take place at approximately or below room temperature, e.g. within the range of -20°C to 25°C.

CH,

■f 3 The nitrosoalkylamine in the 2-position, e.g. -N-—NO, represents a departing group. Equivalent outgoing groups that

can be used as 2-position substituents include groups such as alkoxide, e.g. -OCH3,alkylthio, e.g. -SCH^, habgen, e.g. chlorine; cyano, i.e. -CN and phosphate, e.g.

Reactions that form alkoxide- and - ; The alkylthio substituents in the 2-position are well known in the art, see e.g. GO. Ar here and L.H. Sternbach, "Journal of Organic Chemistry", 29_ 231 (1964) and US Patent No. 3,681,341. Compounds of formula III can then be condensed with a nitroalkane to form a new intermediate of the formula where A, 1*2» R, °g; is as described above. ;The condensation reaction is carried out with a nitroalkane, (R2-CH2-NO2), i.e. nitromethane, nitroethane, etc., in the presence of a base strong enough to generate the nitroalkane anion. Suitable bases include the alkali metal and alkaline earth metal alkoxides, e.g. potassium tertiary 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, i.e. within the range -50°C to 150°C, preferably at approx. room temperature. Compounds of formula IV can then be hydrogenated catalytically, e.g. with Raney nickel in the presence of hydrogen or of other reducing agents such as lithium aluminum hydride (with the restriction that A is not N-oxide) to give a compound of the formula wherein R2, R3, Rg, ; and Rg are as defined; Solvents suitable for 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 -50°C to 150°C) and the reaction can be carried out with or without pressure, ie one atmosphere pressure or higher. ;Solvents suitable for hydrogenation using a reducing agent such as lithium aluminum hydride include ethers, e.g. 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 the reflux temperature, i.e. preferably within the range -50° to 60°C. The compounds of formula V can then be acylated with an acylating agent, such as an acid halide or acid anhydride, i.e. a group of the formula (R^CO^O, where R-^ is as defined in formula I, e.g. acetic anhydride and acetyl chloride to give a compound of the formula wherein A, R^, R2, R^ and ;for, and ;;are as described above- ;Y is hydrogen or -COR^. ;By acylating the compounds of formula V to compounds of formula VI, a mixture can be present consisting of the predominant monoacylated product, i.e. where the NH2 group in formula V (2-position) is converted to NHCOR-^, and the diacylated product, where both NH2 in formula V (2-position) and nitrogen in the 1-position is acylated. The yield of diacylated pro-o.^. can be increased by exposing the compounds of formula V to more i__irous conditions, i.e. an excess of acylating agent and øac<u> reaction time. ;The acylation is preferably carried out in the presence of an aqueous or non-aqueous solvent, e.g. water, methyl chloride, benzene, chloroform, etc. present with an acid acceptor such as an organic exi*-.. inorganic base such as triethylamine, pyridine or an alkali rietal carbonate.

The compounds of formula VI can then be cyclized to new compounds

bonds of the formula

where A. R^, R2, R^ and

above.

is as described

The cyclization reaction takes place with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, i.e. organic or inorganic acids^ e.g. concentrated H-jSO^j. A solvent is not required, but a solvent such as an aromatic hydrocarbon solvent, e.g. toluene, xylene, can be used. The reaction is carried out at a temperature range of from approx. 100°C to 200°C.

The compounds of formula V can also be reacted with an acylating agent such as an orthoester, e.g. triethyl orthoacetate, an orthoamide, e.g. the dimethyl acetal of N,N-dimethylformamide, or a compound of the formula

optionally in the presence of an acidic catalyst, e.g. an organic or inorganic acid, e.g. p-toluenesulfonic acid, phosphophosphoric acid, etc, and at or above room temperature, ie 25°C to 150°C, in which case the cyclization to compound VII occurs spontaneously. Other useful acylating agents include esters, e.g. methyl acetate, amines, e.g. acetamidine, nitriles, e.g. acetonitrile and ester imidates, e.g. a compound of the formula

The compounds of formula VII can then be dehydrogenated to give compounds of formula I above.

Preferred reaction components for the dehydrogenation include manganese dioxide and palladium on carbon although potassium<p>ermanganate can also be used. Solvents that can be used include chlorinated hydrocarbon solvents, aromatic hydrocarbons, dimethylformamide, etc. The dehydrogenation is carried out at or above room temperature, i.e. within the range of approx. 25°C to 200°C.

The aforementioned process can take place, if desired, from the intermediate compounds IV or V to compounds of formula I without the need to isolate any intermediate compounds formed before proceeding to the next process step.

It should be noted that when acylating the compounds of formula V to the compounds of formula VI, when R 1 is amino, the amino can also be acylated to acylamino. The acylamino can be reconverted to amino by subjecting the compounds of formula VII or formula I to mild hydrolysis.

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

The reaction of a compound of the formula V with acetic acid and zinc or hydrogen in the presence of a catalyst, such as platinum in dilute acetic acid solution, gives a

as described above.

Depending on the aforementioned reduction method chosen, formula V<1>, when R2 is hydrogen, can be isolated as a racemic mixture of one of the two possible diastereomers.

A compound of the formula V can be converted into its dihydroimidazo derivative of the formula

where I above

A, R₂, R₂ and R₂ are as indicated with maintenance of stereochemistry, using the direct reaction indicated above, ie the reaction of compounds of formula V with an acylating agent, such as an orthoester, e.g. triethyl orthoacetate and maintaining the reaction parameters indicated above for such a reaction.

Compounds of formula VII' can also be prepared by reduction of a compound of formula VII using reducing agents as mentioned above, e.g. acetic acid and zinc or H2/platinum catalyst in dilute acetic acid, with the specially prepared stereoisomer depending on the reducing agent chosen.

Compounds of formula VII' can, if desired, be oxidized directly to compounds of formula I using an oxidizing agent such as manganese dioxide in toluene or benzene solution. Reaction conditions used and various alternative oxidizing agents that can be used can be found in US Patent No. 3,322,753.

Another method for preparing the new•intermediates of formula V consists of the reduction of compounds of the formula

where A, R^,

and Rg is as described before.

The reduction comprises the reaction of the compounds of formula X with a known reducing agent, such as Raney nickel, in the presence of hydrogen or other reducing agents such as lithium aluminum hydride. Solvents suitable for hydrogenation with Raney nickel include alcohols, e.g. ethanol, ethers, e.g. THF, hydrocarbon solvents, e.g. toluene, and dimethylformamide. The reaction temperature can be above or below room temperature (i.e. -50°C to 150°C) and the reaction can be carried out with or without pressure, i.e. pressure at

one atmosphere or higher.

Solvents suitable for hydrogenation using a reducing agent such as lithium aluminum hydride include ethers such as dioxane, diethyl ether and THF. The reaction can be carried out from below room temperature to reflux temperature, preferably within the range -50°C to 60°C.

A variation of the above method involves a mild acid hydrolysis of the compounds of formula X to give compounds of the formula

where A, R^ and

is as described before.

The mild acid hydrolysis is conveniently carried out by a dilute mineral acid, e.g. aqueous H2SO4 in aqueous alcohol. The reaction temperature can be within the range from room temperature, i.e. approx. 2 5°C to above room temperature, i.e. approx. 60°C. The compounds of formula XI can then be reduced to the new intermediates of formula V.

Another method is applicable for the production of new intermediates of the formulas IV and V.

Compounds of formula IV above can be prepared by the successive reaction of the compounds of the formula

where A,

and R3 is as above, except

that R 1 is not amino, lower alkylamino or lower alkanoylamino,

with dimorpholinophosphinic acid chloride to prepare compound

parts of the formula

where A, (^jl and R3 are as described above, which iminophosphates are then replaced by the anion of a nitroalkane to give the new intermediates IV.

The replacement reaction is carried out with a nitroalkane, ie nitromethane, nitroethane, etc, in the presence of a base strong enough to generate the nitroalkane anion. Suitable bases include the alkali metal or alkaline earth metal alkoxides, hydrides, amides or hydroxides. The reaction is preferably carried out in an inert solvent, such as dimethylformamide, dimethylsulfoxide, or an ether, at temperatures below or above room temperature, i.e. within the range -50°C to 150°C.

Another method for preparing intermediates of formula IV, where R 2 is hydrogen, and A is an N-oxide, consists of ring expansion of compounds of the formulas

described above, except that R 1 is not amino .

The ring expansion involves the reaction of the compounds of formulas VIII or IX with nitromethane in the presence of a base sufficiently strong to generate the nitromethane anion. Suitable bases include alkali metal and alkaline earth metal alkoxides, e.g. potassium tertiary butoxide, amides, e.g. lithium amide or hydrides, e.g. sodium hydride. The reaction can preferably be carried out in an inert solvent, such as anhydrous ether, e.g. THF, dimethylformamide, dimethylsulfoxide, etc. and at a temperature within the range of approx.

-20°C to 25°C.

Compounds of formulas I and IC and their pharmaceutically acceptable. acid addition ion 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. According to the present invention, the new compounds of formula I and their acid addition salts can be incorporated into pharmaceutical dosage formulations containing from approx. 0.1 to approx. 40 mg, most preferably 1-40 mg, and the dosage is regulated according to type and individual needs. The novel compounds of formulas I and IC and their pharmaceutically acceptable salts can be administered internally, e.g. parenterally or enterally, in common pharmaceutical dosage forms. E.g. they can be incorporated into ordinary liquid or solid carriers, such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like to give tablets, elixirs, capsules, solutions, emulsions and the like according to acceptable pharmaceutical practice.

In the description given above, the applicant has cited the content of various articles and US patents. Such citations are intended to incorporate the content of these references for completeness.

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

EXAMPLE 1

A solution of 200 g (0.695 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 2 L of tetrahydrofuran and 250 ml of benzene was saturated with methylamine while dressing in an ice bath. A solution of 190 g (1 m) of titanium tetrachloride in 250 ml of benzene was added through a dropping funnel over 15 minutes. After 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 was washed thoroughly with tetrahydrofuran. The water 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°C. The analytical sample was recrystallized from methylene chloride/ethanol, m.p. 204-206°C.

Sodium nitrite, 8.63 g (0.125 m) was added in three portions

over a 15 minute period to a resolution of 30.15

g (0.1 m) of 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 solution, dried over sodium sulfate and evaporated, finally azeotropically 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 m) of t-butoxide which had been stirred under nitrogen for 15 minutes.

After stirring for 1 hour at room temperature, the reaction 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-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine, m.p. 170-172°C. The analytical sample was recrystallized from methylene chloride/ethanol, m.p. 174-176°C.

A solution of 16.5 g (0.05 m) of 7-chloro-1,3-dihydro-5-(2r-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetra-. hydrofuran and 250 ml of methanol were hydrogenated with 5 teaspoons of Raney nickel for 2 1/2 hours at atmospheric pressure. Removal of 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. The solution was covered with 300 ml of 10% aqueous sodium carbonate and the 2-phase mixture was stirred at room temperature for 30 minutes. 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-benzodiazepine.

This material was heated in 50 g of polyphosphoric acid at 150-170°C for 10 minutes. The reaction mixture was cooled, dissolved in water and made alkaline with concentrated ammonia and ice. The base was extracted with methylene chloride and the extracts were dried over sodium sulfate and evaporated. The remainder was chromatographed over 300

g silica gel using 20% methanol in methylene chloride.

The purified fractions were combined, evaporated and the residue crystallized from ether to give 8-chloro-3α,4-dihydro-1-ethyl-6-(2-fluorophenyl)-3H-imidazo[1,5-a][l ,4]benzodiazepine s.p. 131-133°C

A mixture of 3.4 g of 8-chloro-3a,4-dihydro-1-ethyl-6-(2-fluorophenyl)-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 separator for 2 hours. The manganese dioxide was separated by filtration over celite and the filtrate was evaporated. Crystallization of the residue from ether gave 8-chloro-1-ethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine, m.p. 140-143°C. For analysis it was recrystallized from ether, m.p. 143-145°C.

OAK SAMPLE 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-benzodiazepine in 200 ml of methylene chloride. The solution was covered 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 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 over 120 g of silica gel using 20% methanol in methylene chloride. The pure fractions were combined and evaporated to give resinous 8-chloro-3α,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 1/2 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-4H-imidazo|_1,5-a][1,4]benzodiazepine, m.p. 15 2-154°. The analytical sample was recrystallized from methylene chloride/hexane.

EXAMPLE 3

Reaction as in first paragraph in example 1 of 15 2.5 g (0.5 m) 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one saturated with methylamine with 133 g (0.7 m) of titanium tetrachloride in 2 L of tetrahydrofuran and 400 ml of benzene gave 7-chloro-5-(2-chlorophenyl)-2-methylamino-3H-1,4-benzodiazepine, m.p. 216-219°. The analytical sample was recrystallized from methylene chloride/ethanol and had a melting point of 217-219°.

Sodium nitrite (10 g, 0.145 m) was added portionwise over 45 minutes to a solution of 22.4 g (0.07 m) of 7-chloro-5-(2-chlorophenyl)-2-methylamine-3H-1, 4-benzodiazepine in 150 ml glacial acetic acid. After addition, stirring was continued for 20 minutes under nitrogen. The product was precipitated by adding ice water, collected and dissolved in toluene. The solution was washed with saturated aqueous sodium bicarbonate, dried and evaporated under reduced pressure. According to the thin-layer chromatogram, the yellow viscous oil consisted mainly of the desired nitrosoamidine. This material was dissolved in 100 ml of dimethylformamide and was added -v to a mixture of 30 ml of nitromethane, 100 ml of dimethylformamide and 10 g of potassium t-butoxide. The reaction mixture was slowly heated to 85° with stirring under a stream of nitrogen. After 5 minutes, the reaction mixture was cooled, acidified by the addition of 10 ml of glacial acetic acid. The product was crystallized by gradual addition of water with crystallizer (crystals were obtained by chromatography over silica gel using 10% ethyl acetate in methylene chloride). The separated crystals 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, m.p. 182-185°.

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 h gave crude 2-aminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine. This material was acetylated in the usual manner to give oily 2-acetaminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine which was heated in 15 g of polyphosphoric acid for 10 minutes at 140-150°. The usual work-up gave a yellow resin which was chromatographed over 250 g of silica gel using 20% methanol in methylene chloride.

The crude fractions left resinous 8-chloro-6-(2-chlorophenyl)-3α,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.

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 was separated and the filtrate was evaporated. Crystallization of the residue from ether gave 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, m.p. 140-144°. For analysis, it was recrystallized from methylene chloride/hexane, m.p. 142-144°.

EXAMPLE 4

A solution of 33 g (0.1 m) of 7-chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml of dimethylformamide was added to a mixture of 50 ml of nitromethane , 12.5 g (0.11 m) of potassium t-butoxide and 100 ml of dimethylformamide. The reaction mixture was stirred under a stream of nitrogen for 1 hour. After addition of 10 ml of glacial acetic acid, the product was crystallized by gradual addition of 250 ml of water. The precipitated yellow material was collected, washed with water, methanol and ether to give 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine 4-oxide, m.p. 253-255° (decomposition). 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 m) of 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine 4- oxide in 500 ml of tetrahydrofuran and 250 ml of methanol. The mixture was hydrogenated for 5 hours at atmospheric pressure. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in 2-propanol and the solution made strongly acidic with ethanolic hydrogen chloride. The dihydrochloride of the product crystallized by evaporation of part of the solvent. The orange crystals were collected to give 2-aminomethyl-7-chloro-2,3 -dihydro-5-phenyl-1H-1,4-benzodiazepine dihydrochloride, mp 230-240°.

Acetic anhydride (10 ml) was added to a solution of 10 g of the above dihydrochloride in 50 ml of water and 50 ml of methanol. A 10%<1>s aqueous solution of sodium carbonate (100 mL) was added with stirring over a period of 5 minutes. After addition, the mixture was stirred for an additional 10 minutes and then extracted with methylene chloride. The extracts were washed with sodium carbonate solution, dried over sodium sulfate and evaporated, finally azeotropically with toluene. 2-acetamino-methyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine was obtained as a yellow resin.

The aforementioned material was heated in 50 g of polyphosphoric acid to 135-140° for 10 minutes. The original orange color of the reaction mixture faded to a faint yellow. The cooled reaction mixture was dissolved in water, made alkaline with concentrated ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated. The yellow resin was dissolved in 2-propanol and treated with ethanolic hydrogen chloride, whereupon the colorless dihydrochloride in the product crystallized. Melting point was 240-245°.

This hydrochloride was partitioned between methylene chloride and aq

ammonia. The organic phase was dried and evaporated. Crystallization of the residue from ether gave 8-chloro-3α,4-dihydro-1-methyl-6-phenyl-3H-imidazo[1,5-a][1,4]benzodiazepine as a colorless product, m.p. 116-118° .

A mixture of 3.1 g (0.01 m) 8-chloro-3a,4-dihydro-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. 187-188°.

EXAMPLE 5

A mixture of 11.2 g (0.1 m) of potassium tert-butoxide, 50 ml of nitroethane and 200 ml of dimethylformamide was stirred at room temperature for 15 minutes. A solution of 29 g (0.088 m) of crude 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine in 100 ml of dimethylformamide was then added and stirring under nitrogen continued for 6 hours. The reaction mixture was neutralized by adding glacial acetic acid and diluted with water. The 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-dihydro-5-(2-fluorophenyl-2-(1-nitroethylene)-2H-1,4-benzodiazepine as yellow crystals, m.p. 136-142°).

Raney nickel (5 full teaspoons) was added to a solution

of 17.3 g (0.05 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-(1-nitroethylene)-2H-1,4-benzodiazepine in 750 ml of tetrahydrofuran. The mixture was hydrogenated at atmospheric pressure for 4 hours. The catalyst was removed by filtration over celite and washed well with methanol. The filtrate was evaporated to leave 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 the addition of 14 ml of acetic anhydride, 300 ml of saturated aqueous sodium bicarbonate solution was added and the two-phase mixture was stirred at room temperature for 1 hour. The methylene chloride layer was separated, washed with bicarbonate, dried over sodium sulfate and evaporated. The residue was heated with 40 g of polyphosphoric acid for 10 minutes at 160-170°. The cooled reaction mixture was diluted with water, made alkaline with ammonia and extracted with methylene chloride. The extracts were washed with water, dried and evaporated to leave a brown residue which was chromatographed on 250 g of silica gel using 20% (v/v) methanol in methylene chloride. The thin-layer fractions which were chromatographically homogeneous were combined to give a resin which was subjected to the subsequent oxidation.

A mixture of the above material, 20 g of activated manganese dioxide and 300 ml of toluene was heated to reflux for 3 hours using a Dean-Stark separator to remove 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 pressure chromatographed over 150 g of silica gel H using 3% ethanol in methylene chloride. The 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. 247-250° (decomposition) .

The more polar component could be crystallized from methylene chloride/ether/hexane to give 8-chloro-1,3-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine with melting point 178-180°.

EXAMPLE 6

A warm solution of 6.5 g (0.02 m) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 30 ml of ethanol was combined with a hot solution of 2.6 g (0.022 m) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether. ,..;• and heated on a steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to give 'v '■: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [ 1,4]benzodiazepine maleate, m.p. 148-151°.

EXAMPLE 7

A mixture of 17.4 g (0.05 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-(1-nitromethylene)-2H-1,4-benzodiazepine 4-oxide, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 full teaspoons of Raney nickel were hydrogenated at atmospheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate evaporated at the end azeotropically with xylene to leave crude 2-aminomethyl-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 orthoacetate and 2.8 g of p-thionesulfonic acid. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic layer was dried and evaporated to give oily 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidaza[1,5-a]

[1,4]benzodiazepine. This crude product was dissolved in 500 ml of xylene. After addition of 50 g of activated manganese dioxide, the mixture was stirred and heated to reflux for 1 1/2 hours with separation of water in a Dean-Stark separator. The inorganic material was removed by filtration and the filtrate was evaporated to leave 10 g of brown oil.

A hot solution of 4.65 g (0.04 m) of maleic acid in 50 ml of ethanol was added to this residue. After the dissolution was complete, the product was crystallized by the addition of ether. It was collected and washed with ether to leave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate, m.p.

112-115°. Heating under vacuum at 90° to 100° converts this product to the higher melting form with m.p. 148-151°.

EXAMPLE 8

A solution of 0.32 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 5 ml of ethanol was treated with excess ethanolic hydrogen chloride. The salt was crystallized by adding 2-propanol and ether. The colorless crystals were collected, washed with ether and dried

ket to leave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine dihydrochloride, m.p. 290-295°.

EXAMPLE 9

A solution of 0.325 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 3 ml of ethanol was combined with a suspension of 0.4 g (1 mmol) of the dihydrochloride of this compound in 5 ml of ethanol. After filtration, the solution was treated with ether and heated on a steam bath for 5 minutes to crystallize. The crystals were collected, washed with ether and dried to leave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride, m.p. 295-297°.

EXAMPLE ■ 10

A solution of 23.6 g (0.10 mol) of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 1 liter of tetrahydrofuran (containing about 20 mol of monoethylamine) was cooled in a 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. The titanium complex was dissolved with 20 ml of water. The inorganic salts that precipitated were removed by filtration. The solvent was evaporated in vacuo, the residue was partitioned between methylene chloride and water. A colorless amorphous solid, m.p. 227-229°, was removed by filtration. A further sample, s.p. 226-228°, of a colorless solid was obtained from the methylene chloride mother liquors after drying over anhydrous sodium sulfate, evaporation to dryness and crystallization from ethyl acetate.

An analytical sample was prepared by recrystallization from dimethylformamide to give colorless prisms, m.p. 227-229°.

To a warm (10°), stirred solution of 10.0 g (0.04 m) 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 anhydride. The solution was stirred for 3 hours during which time it was allowed to warm to ambient temperature. The solution was poured into 300 ml of ice water, and the aqueous solution was extracted with 5,150 ml<1>s portions of methylene chloride. The combined organic extracts were washed with water and brine, dried (CaSO 4 ), and the solvent removed under reduced pressure to give a dark semi-solid. Chromatography at 500

g of silica gel (chloroform elution) gave the 2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine, m.p. 192-199° (decomposition).

This material was used in the following step.

The corresponding base for nitromethane was prepared by treating 50 ml of nitromethane in 200 ml of dimethylformamide with 5.7 g (0.05 m) of potassium tert-butoxide. The resulting stirred yellow suspension was treated with 10.9 g of crude 2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine in 100 ml of dimethylformamide. The dark mixture thus obtained was stirred for 2 hours at 25° and for 1 hour at 85° and then cooled to 25° and poured into 1 liter of water.

After acidification with acetic acid, the aqueous solution was extracted with four 250 ml 1s portions of methylene chloride, and the combined organic extracts were then washed with water and brine, dried (CaSO 4 ) and concentrated in vacuo to give a dark oil which was purified by chromatography over 1 kg silica gel (CHCl-j elution) to give crude 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine, m.p. 131-142°.

An analytical sample, s.p. 141-142° was prepared by recrystallization from ethanol.

A mixture of 8.4 g (0.03 m) of 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine, 75 ml of tetrahydrofuran, 75 ml of methanol and 2 full teaspoons of Raney nickel was hydrogenated at atmospheric pressure for 6 hours. The catalyst was removed by filtration and the filtrate was evaporated to leave crude 2-aminomethyl-2,3-dihydro-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. The methylene chloride layer was separated, washed with bicarbonate solution, dried and evaporated. The residue was treated with 25 g of polyphosphoric acid at 130-150° for 15 minutes. The cooled reaction mixture was partitioned between water and ether. The aqueous phase was made alkaline with ammonia and was extracted with methylene chloride. The extracts were dried and evaporated. Chromatography of the residue over 70 g of silica gel with 20% (v/v) ethanol in methylene chloride gave 3a,4-dihydro-1-methyl-6-phenyl-3H-imidazo[1,5-a]

[l,4]benzodiazepine as a pale yellow resin.

This material was heated in 50 ml of toluene with 7 g of activated manganese dioxide to reflux for 1 1/2 hours. The inorganic material was filtered off and the filtrate was evaporated. The residue was purified by chromatography over 30 g of silica gel using 10% ethanol in methylene chloride. The pure fractions were combined and evaporated. Crystallization of the residue from ether gave 1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine.

EXAMPLE 11_

To a stirred solution of 6 g (0.02 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2H-1,4-benzodiazepine-2-one in 100 ml dry tetrahydrofuran was added to 1.05 g (0.25 m) of 57% sodium hydride dispersion in mineral oil. The mixture was placed under argon and refluxed for 1 hour. After cooling to room temperature, the mixture was treated with 7.4 g (0.03 m) of dimorpholinophosphinic acid chloride and stirring under argon was continued at room temperature for 2 hours. The mixture was filtered and evaporated under reduced pressure to give a gummy residue. Agitation of the gum with 100 ml of anhydrous ether gave white crystals which were collected by filtration, washed with a little ether and air dried. The 7-chloro-2-di-(morpholino)-phosphinyloxy-5-(2-fluorophenyl)-3-methyl-3H-1,4-benzodiazepine thus obtained had a melting point of 90-95°.

A stirred solution of 2.4 g (0.04 m) of nitromethane in 50 ml of dry dimethylformamide was treated with 1 g (0.024 m) 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 m) 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 hours. The dark mixture was poured over a mixture of

ice and acetic acid with stirring to give a yellow solid. Stirring was continued until the ice had melted. The solid was filtered, washed with water and air dried on the funnel to give 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitro-methylene-2H-1,4- benzodiazepine with melting point 215° (decomposition). Recrystallization of a sample from 1:1 methanol/methylene chloride

gave yellow needles, s.p. 219-221° (decomposition).

A solution of 5.2 g (0.015 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine in 450 ml of 2:1 tetrahydrofuranmethanol was hydrogenated for 3 hours using a Parr apparatus, Raney nickel catalyst (3 full teaspoons) and an initial pressure of 1.26 kg/cm 2 . The mixture was filtered 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 orthoacetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml of ethanol. After heating under reflux for 2 hours, the solution was evaporated under reduced pressure. The residue was cooled to room temperature, treated with a mixture of ice and concentrated ammonium hydroxide and extracted with methylene chloride. Evaporation of the dried extracts in vacuo gave crude 8-chloro-3α,4-dihydro-1,4-dimethyl-6-(2-fluorophenyl)-3H-imidazo[1,5-a]',1,4]benzodiazepine like a rubber.

The crude dihydramidazobenzodiazepine was mixed with 20 g of activated manganese dioxide and 200 ml of toluene and heated under reflux for 2 hours. The mixture was filtered and the manganese dioxide was washed with methylene chloride. Evaporation of the combined filtrate and washings under reduced pressure gave a brown gum. The dihydrochloride of 8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-aJ[1,4]:oenzodiazepine was obtained as a white powder by stirring the gum with ethanolic hydrogen chloride in a few minutes. The salt melted at 247-250°.

EXAMPLE 12_

A mixture of 100 g (0.8 m) of chloroacetaldehyde-dimethyl acetal and 100 ml of 1.5 N hydrochloric acid was heated under reflux for 15 minutes and then cooled and added to a solution of 130

g (0.5 m) of 2-amino-2<1->fluoro-5-nitro-benzophenone and 46 g (0.28 m) of hydroxylamine sulfate 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 obtained by filtration. Recrystallization from a mixture of chloroform and methanol gave pure 2-chloromethyl-4-(2-fluorophenyl)-6-nitro-1,2-dihydroquinazoline 3-oxide as yellow prisms, m.p. 220-224°.

A solution of 142 g (0.423 g) of 2-chloromethyl-4-(2-fluorophenyl)-6-nitro-1,2-dihydroquinazoline 3-oxide in 2.3 liters of dichloromethane was 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 of tetrahydrofuran and 800 ml of dichloromethane. The combined filtrates were concentrated to 400 ml and 1 liter of ether was added. This was cooled and filtered to give 2-chloromethyl-4-(2-fluorophenyl)-6-nitroquinazoline 3-oxide. A sample was recrystallized from a mixture of dichloromethane and methanol to give the pure product as pale yellow prisms, m.p. 127-130°.

To 500 ml of dimethyl sulfoxide and 75 ml (1.4 m) of nitromethane was added with stirring under nitrogen 15.6 g (0.678 m) of lithium amide. After 30 minutes, the solution was cooled to 5° and 104

g (0.31 m) of 3-chloromethyl-4-(2-fluorophenyl)-6-nitroquinazoline 3-oxide was added slowly keeping the temperature below 8°. After 68 hours at room temperature, the reaction mixture became complete

in a mixture of 2.5 liters of ice and water and 25 ml of acetic acid, and the solution was filtered. The gummy precipitate was dissolved in 1 liter of dichloromethane, which was washed with dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. 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 through a sintered glass funnel containing 200

g "Florisil". The "Florisil" was eluted with dichloromethane (600 mL), ether (600 mL) and ethyl acetate (1.2 L). The ether and ethyl acetate fractions were combined and concentrated to give additional final product. A sample was recrystallized from a mixture of tetrahydrofuran and hexane to give the pure product as yellow prisms, m.p. 216-220°.

A suspension of 25 g (0.0698 m) of 1,3-dihydro-5-(2-fluorophenyl)-7-nitro-2-nitromethylene-2H-1,4-benzodiazepine 4-oxide in 1.3 liters of absolute ethanol was treated with 10 teaspoons of Raney nickel and hydrogenated at atmospheric pressure and room temperature for 9 hours. The mixture was filtered through celite and the filtrate was evaporated to dryness. A sample of the oil was crystallized from tetrahydrofuran to give the intermediate 7-amino-2-amino-methyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine as yellow prisms which melted on cleavage at 185-192°.

Without further purification, the oil obtained from the reduction was heated under reflux for 2 hours in a solution of 300 ml of absolute ethanol, containing 4.5 ml (0.0257 m) of ethanolic hydrogen chloride and 50 g (0.309 m) of triethyl orthoacetate. The mixture was 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.

The remaining oil, which was crude 8-acetamido-3α,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine, was dissolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The mixture was refluxed and stirred for 9 hours using a Dean Stark separator. A further 25 g of activated manganese dioxide was added and after 4 hours of reflux treatment, the manganese dioxide was removed by filtration and was washed with 500 ml of tetrahydrofuran. The filtrates were combined and evaporated to dryness. The remaining oil, which was 8-acetamido-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepine, was dissolved in 75 ml of methanol and an excess of ethanolic hydrogen chloride was added. After 10 minutes, 100 ml of water was added, and after another 20 minutes, during which time the 8-acetyl group was hydrolyzed, a mixture of ice and dilute ammonium hydroxide was added until the solution was basic. The reaction mixture was filtered and the precipitate and filtrates were extracted separately with dichloromethane. The extracts were dried and evaporated. The extract from the filtrates was crystallized from isopropanol to give 8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepine isopropanol, and the extract from the precipitate was chromatographed through "Florisil", first with dichloromethane and then with ether, and ethyl acetate containing 10% (v/v) methanol gave, after evaporation and crystallization from isopropanol, additional product. Recrystallization of the combined products from isopropanol gave the product as white rod-shaped crystals, m.p. 135-145°.

EXAMPLE 13

A mixture of 17 g (0.05 m) of racemic 8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazoLi,5-a][1,4]benzodiazepine which had been freed from its dihydrochloride by partitioning between methylene chloride and aqueous ammonia, 18.8 g (0.05 m) of 0,0'-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol were boiled until dissolution was complete. For crystallization, the solution was allowed to stand overnight. The precipitated crystals were collected, washed with ethanol and ether to give 0,0'-dibenzoyl-d-tartaric acid of m.p. 140-142°. Recrystallization from ethanol/ether gave a product with m.p. 141-142° and [et]p5 - 43.39 (c = 1% in methanol).

A solution of 1.6 g (0.0106 m) of 1-tartaric acid in 11 ml of ethanol was added to a solution of 3.5 g of the levorotatory base released from the aforementioned 0,0'-dibenzoyl-d-tartrate in 11 ml ethanol. The crystals obtained were collected and washed with ethanol and ether to give (+)-8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo [1,5-a] (.1 , 4]benzodiazepine 1-tartrate, m.p. 178-180° Recrystallization from ethanol gave product with melting point 183-185°

°g [cc]^<5> +25.69° (c = 1.012% in methanol). The amorphous base released from this salt showed a rotation of [ct]D 25 -36.74<o >(c = 0.939% in methylene chloride).

EXAMPLE 14

The mother liquor remaining after separation of the crystalline salt with 0,0'-dibenzoyl-d-tartaric acid described in the previous example was evaporated and reconverted to the base by partitioning between aqueous ammonia and methylene chloride. The methylene chloride solution was dried over sodium sulfate and evaporated to give partially dissolved base.

A solution of 9.7 g (0.029 m) of this material in 15 ml of ethanol was treated with a solution of 4.4 g of d-tartaric acid in 14 ml of ethanol. The crystals that separated after several hours were collected to give (-)-8-chloro-1,4-dimethyl-6-(1-fluorophenyl)-4H-imidazo[1,5-a][1,4 ]benzodiazepine d-tartrate, s.p. 176-178°. Recrystallization from ethanol gave product with m.p. 182-184° and [α]^ -24.96° (0.9616% in methanol). The amorphous base released from this salt showed a rotation of [et ]^ +37.6° (c = 1.0% in methylene chloride).

EXAMPLE 15

A solution of 19.3 g (0.06 m) of 1,3-dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-5-phenyl-2H-1,4-benzodiazepine-2 -one in 300 ml of dry tetrahydrofuran was treated under an argon atmosphere with 3.1 g

(0.075 m) of a 57% suspension of sodium hydride in mineral oil. The mixture was heated under reflux for 1 hour, cooled to room temperature when 22.2 g (0.087 m) of dimorpholinophosphinic acid chloride was added. The mixture was allowed to stir at room temperature for 2 hours and then allowed to stand overnight. Sodium chloride was removed by filtration and the crude 7-(2-methyl-1,3-dioxolan-2-yl)-2-[-bis(morpholino)phosphinyloxy]-5-phenyl-3H-1, 4-benzodiazepine was obtained by removal of the solvent and crystallization of the residue from ether.

A mixture of 100 ml of dry N,N-dimethylformamide and 6.8 g of nitromethane was treated under an argon atmosphere with 2.8 g (0.066 m) of a 57% suspension of sodium hydride in mineral oil. The mixture was stirred for 1 hour at room temperature when a solution of 18 g (0.033 m) of crude 7-(2-methyl-1,3-dioxolan-2-yl)-2[bis(morpholino)

-phosphinyloxy]-5-phenyl-3H-1,4-benzodiazepine in 50 ml of dry N.TSI-dimethylformamide was added. The reaction mixture was allowed to stand at room temperature for 15 hours when the dark viscous liquid was poured over a mixture of ice and dilute acetic acid. The pale yellow precipitate was removed by filtration, 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 dichloromethane which was washed, dried and evaporated as before. The two crude residues were combined and chromatographed over "Florisil". Using dichloromethane, 10%

(vol/vol) ether as the eluent and monitor the fractions by thin-layer chromatography, many fractions containing the product were collected and evaporated. Crystallization and recrystallization from a mixture of dichloromethane and hexane gave the crude 2,3-dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-1H-1,4 -benzodiazepine as pale yellow prisms, s.p. 158-161°.

Hydrogenation of 5 g (0.0137 m) of 2,3-dihydro-7-(1-methyl-1,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-1H-1,4-benzodiazepine in 250 ml absolute ethanol in the presence of 1 teaspoon Raney nickel for 3', 5 hours gave crude 2-aminomethyl-2,3-dihydro-7-(1-methyl-1,3-d.oxolan-2-yl)- 5-phenyl-1H-1,4-benzodiazepine. To a solution of 4 g (0.0119 m) of this compound in 75 ml of absolute ethanol was added 0.7 g (0.0037 m) of p-toluenesulfonic acid and 6 g (0.037 m) of triethyl orthoacetate. The mixture was refluxed for 2 hours, evaporated to dryness and the residue was dissolved in 50 ml of dichloromethane. This was washed with 25 ml of dilute ammonium hydroxide, triturated 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[l,5-a][l,4]benzodiazepine as an oil.

A solution containing 3.8 g (0.0105 m) of this crude oil and 18 g of activated manganese dioxide in 100 ml of toluene was refluxed and stirred for 2 hours using a Dean Stark separator. It was filtered and washed with a mixture of 250 ml of dichloromethane and 250 ml of tetrahydrofuran. The filtrates were evaporated and dissolved in a small amount of isopropanol and treated with 1.4 g (0.0121 m) 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[l ,5-a][l,4]benzodiazepine maleate methanol (2/1) as off-white prisms, m.p. 179-182°.

A solution of 0.3 g (0.1000607 m) of 1-methyl-8-(2-methyl-1,3-" ioxolan-2-yl)-6-phenyl-4H-imidazo[1,5-a] [1,4]benzodiazepine maleate methanol (2/1) in 10 ml (0.01 m) IN hydrochloric acid was allowed to stand

for 18 hours. A small amount of charcoal was added and the reaction mixture was filtered. The solution was basified with ammonium hydroxide, extracted with 25 ml of dichloromethane, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in isopropanol and 0.35 g (0.10015 m) of picric acid in 5 ml of ethanol was added. The solution was evaporated and the residue was crystallized from methanol. Recrystallization from a mixture of tetrahydrofuran and isopropanol gave 8-acetyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine dipicrate as yellow prisms, m.p. 225-230°.

EXAMPLE . 16

A solution of 1 g (0.00317 m) of 8-acetyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine dipicrate in 75 ml of absolute ethanol was treated with 0.78 g (0.0205 m) of sodium borohydride and after 18 hours the solution was evaporated to dryness. The residue was acidified with dilute acetic acid, basified with ammonium hydroxide and the mixture was extracted with 75 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to dryness. The oil thus obtained was dissolved in isopropanol and 1.6 g (0.007 m) of picric acid in 20 ml of ethanol was added. The precipitated salt was filtered and recrystallized twice from methanol to give 8-(1-hydroxyethyl)-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine dipicrate as yellow rod crystals, s.p. 223-225°.

EXAMPLE 17

A solution of 56.4 g (0.20 mol) of 1,3-dihydro-7-ethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 2.0 liters of tetrahydrofuran containing 4 mol of monomelylamine was cooled in an ice bath. To this was added 33.0 ml (0.30 mol) of titanium tetrachloride in 350 ml of benzene. The mixture was stirred at room temperature for three days.

The titanium tetrachloride was decomposed with 100 ml of water. The inorganic salts were removed by filtration. The filtrate was evaporated to dryness in vacuo. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried over anhydrous sodium sulfate, evaporated to dryness in vacuo. The residue, after crystallization from acetonitrile, gave 7-ethyl-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine as pale yellow prisms, m.p. 172-174°.

An analytical sample was prepared by recrystallization from acetonitrile to give pale yellow prisms, m.p. 172-174°.

Sodium nitrite (8.6 g, 0.125 m) was added in three portions

in the course of 1/2 hour to a solution of 29.5 g (0.1 m) of 7-ethyl-

5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine in 100 ml of glacial acetic acid. After stirring for an additional 1/2 hour at room temperature, the mixture was diluted with ice water and extracted with methylene chloride. The extracts were washed with water and aqueous bicarbonate, dried over sodium sulfate and evaporated to give crude 7-ethyl-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine as 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 of nitromethane and 9.9 g of potassium t-butoxide which had been stirred for 1/2 hour at room temperature. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature and for 30 minutes on a steam bath. The cooled solution was acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated. The residue was dissolved in 50 ml of ethanol and allowed to crystallize in a refrigerator overnight after inoculation. The yellow crystals were collected and recrystallized from ethanol to give 1,3-dihydro-7-ethyl-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine, m.p. 138-140°. Seed crystals were obtained by chromatography of the crude product over a 40-fold amount of silica gel using 25% (v/v) ethyl acetate in methylene chloride. The analytical sample was recrystallized from ether/hexane, m.p. 138-141°.

1,3-dihydro-7-ethyl-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (2.6 g) was hydrogenated for 4 hours with Raney nickel (one 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. The extracts were washed with ether and made alkaline with ammonia. The precipitated amine was extracted with methylene chloride. The extracts were dried and evaporated to leave 1.5 g of crude 2-amino-methyl-2,3-dihydro-7-ethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. This material was dissolved in 50 ml of xylene. The solution was then heated to reflux for 2 hours after the addition of 3 ml of triethyl orthoacetate. The residue, obtained after evaporation under reduced pressure, was chromatographed over 50 g of silica gel using 20% methanol in methylene chloride. The homogeneous

The homogeneous fractions were combined and evaporated to give 3α,4-dihydro-8-ethyl-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine. This material was dissolved in 50 ml of toluene and the solution was heated to reflux for 1 hour after the addition of 5 g of activated manganese dioxide. The inorganic material was separated by filtration and the filtrate was evaporated

in. The residue was dissolved in ether and treated with ethanolic hydrogen chloride and acetone. The crystalline dihydrochloride (m.p. 248-255°) was collected and reconverted 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]benzodiazepine, m.p. 152-154°.

EXAMPLE 18

To 5 ml of acetic anhydride was added 0.3 g (0.00082 m) of 8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo [l, 5-a].[l, 4 ]benzo-diazepine isopropanol and the reaction mixture was heated on a steam bath for 1 hour and then evaporated to dryness. The residue was dissolved in 25 ml of dichloromethane which was washed with 15 ml of 5% potassium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The product was recrystallized twice from a mixture of methanol and ethyl acetate to give 8-acetamido-6-(2-fluorophenyl)-1-methyl-4H-imidazo(1,5-a][1,4]benzodiazepine as white rod crystals , mp 3 26-331°.

A solution of 0.8 g (0.0024 m) of 8-acetamido-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 10 ml of tort N ,N-dimethylformamide under nitrogen was treated with 0.13 g (0.003 m) of 55% sodium hydride in mineral oil and after 30 minutes the reaction mixture was cooled in an ice bath. To the stirred reaction mixture 0.43 g (0.003 m) of methyl iodide was added and after 18 hours at room temperature the reaction mixture was poured into water. Filtration gave the crude product which was recrystallized from a mixture of ethyl acetate and ether to give 6-(2-fluorophenyl)-1-methyl-8-(N-methylacetamido)-4H-imidazo[l,5-a][l ,4]benzodiazepine as off-white prisms, s.p. 217-223°.

A solution of 0.3 g (0.000828 m) of 6-(2-fluorophenyl)-1-methyl-8-(N-methylacetamido)-4H-imidazo [l,5-a][l?4]benzodiazepine in 10 ml of methanol was treated with 3 ml of concentrated hydrochloric acid and refluxed for 1 hour. The solution was made basic with ammonium hydroxide and then partitioned between 50 ml of dichloromethane and 50 ml of water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The remaining oil was dissolved in 10 ml of dichloromethane and filtered through "Florisil". It was eluted with ether ethyl acetate and finally ethyl acetate containing 5% methanol.This last mixture was evaporated and crystallized from a mixture of ethyl acetate and ether to give 6-(2-fluorophenyl)-1-methyl-8-methylamino-4H- imidazo[l,5-a][l,4]benzo diazepine as off-white prisms, m.p. 255-259°.

EXAMPLE 19

To a stirred solution of 27.8 g (92 mmol) DL-2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in a mixture of 450 ml methylene chloride and 300 ml of acetic acid were slowly added to 27.8 g of zinc dust. After stirring at room temperature for 4 hours, the reaction mixture was filtered over celite. The filtrate was diluted with ice water, made alkaline with 50% potassium hydroxide solution and extracted with methylene chloride. The organic extract was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from ether to give 2-aminomethyl-7-chloro-2,3,4,5-tetrahydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine melting at 119-120°. After recrystallization from ether, the pure product formed pale yellow prisms melting at 127-128°.

The hydrochloride was prepared by treating a solution of the base in isopropanol with an excess of concentrated hydrochloric acid. After recrystallization of the salt from a mixture of water and isopropanol, the pure product formed pale yellow prisms melting at 268-271°.

A) A solution of 3 g (10 mmol) of racemic 2-aminomethyl-7-chloro-2,3,4,54Etrahydro-5-(2-fluorophenyl)-1H-1,4-benzo-

diazepine in a mixture of 30 ml xylene and 10 ml triethyl orthoacetate (97%) was refluxed for 4 hours. The reaction mixture was diluted with ether and extracted with dilute glacial hydrochloric acid. The acid extract was made alkaline with dilute potassium hydroxide and extracted with methylene chloride. The organic layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from ether to give 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H -imidazo[l,5-a]

[1,4]benzodiazepine (isomer A) melting at 187-189°. After recrystallization from a mixture of methylene chloride and ether, the pure product formed pale yellow prisms melting at 189-190°.

B) To a stirred solution of 2.5 g of 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine in a mixture of 100 ml of methylene chloride and 25 ml of acetic acid was slowly added. 2.5 g of zinc dust. After stirring at room temperature for 4 hours, the reaction mixture was filtered over Celite. The filtrate was diluted with ice water, made alkaline with 50% potassium hydroxide and extracted with methylene chloride. The organic extract was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from ether to give 8-chloro-6-(2-fluorophenyl)-3α,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine ( isomer A) which was identical to the product prepared above, m.p. and b.s.p. 189-190°. C) A solution of 3.2 g (10 mmol) of 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo [1,5-a] [1, 4]benzodiazepine in 50 ml of acetic acid and 10 ml of water was hydrogenated at room temperature and atmospheric pressure in the presence of 0.4 g of prehydrogenated platinum oxide. After 15 minutes, 10 mmol of hydrogen had been absorbed. The catalyst was separated by filtration and the filtrate concentrated in vacuo to dryness. The residue was dissolved in methylene chloride and washed with an excess of ice-cold dilute sodium carbonate. The organic layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from an ether/petroleum ether mixture to give 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a][l ,4]benzodiazepine (isomer B) which melts at 108-110°. After recrystallization from ether, the pure product formed colorless crystals melting at 110-112°.

A mixture of 2.9 g of 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4] benzodiazepine, 90 ml of toluene and 15 g of activated manganese dioxide were stirred and refluxed for 2 hours. The reaction mixture was filtered over "Hyflo" and the filtrate concentrated in vacuo to dryness. The residue was crystallized from ether to give 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine which gave no melting point depression. ning with an authentic sample.

LK EXAMPLE 20

A solution of 2.9 g (0.00927 m) of 2,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-1H-1,4-benzodiazepine-4-oxide in a mixture of 1 teaspoon Raney- nickel, 90 ml of tetrahydrofuran and 45 ml of methanol were hydrogenated at atmospheric pressure and at room temperature for 2.3 hours. The mixture was filtered and the nickel was washed 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 m) of maleic acid in 15 ml of ethanol was added to the oil and after ether was added, 2-aminomethyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4 crystallized -benzodiazepine dimethyl maleate hydrate. Recrystallization from a mixture of methanol and ether gave a product as yellow rod crystals, m.p. 147-150°.

A solution of 4.0 g (0.0419 m) of Dåden, of 2-aminomethyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleathemihydrate in 125 ml of absolute ethanol was treated with 4 g (0.0247 "•0 triethyl orthoacetate and 0.5 g (0.00 263 m) p-toluenesulfonic acid. One, t-il-baking of the mixture for 2 hours was reaction bias. ""none evaporated to dryness The resulting oil was dissolved in 50 ml of dichloromethane, which was washed with 50

ml of dilute amn._ ^roxide, dried over anhydrous .--^trium sulfate and evaporated inr . :. s~ s'.\ e' z crude 3a, 4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[l,5-aj[l,4]benzodiazepine as an oil. A) The crude product from the previous section was dissolved in 100 mL of tchiene, treated with 18 g of activated manganese dioxide, and the mixture was stirred and refluxed for 3.5 hours using a Dean Stark separator. The reaction mixture was filtered through Celite and the precipitate was washed with 100 ml tetrahydrofuran and then 100 ml dichloromethane. The combined filtrates were evaporated and the residue was dissolved in 25 ml of dichloromethane. This solution was chromatographed through a "Florisil" column with dichloromethane, and then eluted with ether. Elution with ethyl acetate and then a 10% (v/v) solution of methanol in ethyl acetate gave the crude product, which was crystallized from ether and then recrystallized from ethyl acetate to give 6-(2-fluorophenyl)-1-methyl- 4H-imidazo[l,5-aJ[l,4Jbenzo-diazepine as white prisms, m.p. 164-168°. B) A solution of 1.2 g (0.004 l m) of 3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[l,5-a][l,4Jbenzodiazepine in 50 ml mesitylene and 0.5 g of 10% palladium on charcoal were stirred and refluxed for 28 hours, then filtered and evaporated to dryness. Crystallization from ethyl acetate gave 6-(2-f.fluorophenyl)-1-methyl-4H-imidazo[1,5-aj[1,4J benzodiazepine as white prisms, m.p. 162-167°, and a mixed melting point with

-authentic product melted at 162-168°.

EXAMPLE 21

4-1.3 g of 8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a]-[1,4]benzodiazepine dihydrochloride was partitioned between methylene chloride and aqueous ammonia. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated to dryness to leave the free base. This material was dissolved in 50

ml of 2-propanol and the solution was treated with a solution of 12 g of maleic acid in 40 ml of 2-propanol. The solution was gradually diluted with 300 ml of ether. The precipitated crystals were collected and dried to leave 8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine maleate, m.p. 130-132° after recrystallization from ethanol/ether.

EXAMPLE 22

A mixture of 10 g (0.036 m) of 1,3-dihydro-5-phenyl-2H-thien-[3,2-e][1,4]benzodiazepine-2-one in 50 ml of benzene and 300 ml of 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 m) in 50 ml of benzene. After the addition was complete, the mixture was stirred in the ice bath for 15 minutes. The ice bath was then replaced with a heating mantle and the mixture refluxed for 1/2 hour. The mixture was cooled and 100 g of ice was carefully added. The mixture was filtered and the residue washed with tetrahydrofuran. The filtrates were combined, dried and evaporated. The product was crystallized from methylene chloride to give 2-methylamino-5-phenyl-3H-thien-[3,2-e][1,4]diazepine, m.p. 223-227°. From the concentrated mother liquors additional product was obtained, m.p. 222-225°.

The analytical sample was recrystallized from methylene chloride, m.p. 222-229°.

Nitrosyl chloride was added to a solution of 7.8 g (0.03 m) of 2-methylamino-5-phenyl-3H-thien[3,2-e][1,4]diazepine in 100 ml of methylene chloride and 40 ml of pyridine cooled in ice water. The reaction mixture was checked by thin layer chromatography and when the starting material had disappeared the nitrosyl chloride addition was terminated and the reaction mixture was partitioned between methylene chloride and water. The methylene chloride solution was dried and evaporated. Crystallization of the residue from methylene chloride/hexane gave 2-(N-nitrosomethylamino)-5-phenyl-3H-thien[3,2-e][1,4]diazepine as yellow crystals, m.p. 156-159°. The analytical sample was recrystallized from ether/hexane, m.p. 158-160

2-(N-nitrosomethylamino)-5-phenyl-3H-thien[3,2-e][1,4]diazepine (5.7 g, 0.02 m) was added to a mixture of 15 mL of nitromethane, 4 .5 g of potassium t-butoxide and 60 ml of dimethylformamide which had been stirred for 10 minutes at room temperature. After addition, the reaction mixture was stirred under nitrogen and heated on a steam bath for 10 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 the residue from methanol with grafting gave 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thien[3,2-e][1,4]diazepine as yellow crystals, m.p. 160-163°. Seed crystals were obtained by chromatographic purification over a 30-fold amount of silica gel using 10% (v/v) ethyl acetate in methylene chloride. The analytical sample was recrystallized from methanol, m.p. 163-164°.

A solution of 1.42 g (5 mmol) of 1,2-dihydro-2-nitromethylene--5-phenyl-3H-thien[3,2-e][1,4]diazepine in 200 ml of ethanol was hydrogenated over Raney -nickel (2 full teaspoons) for 1 hour at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated. The residue was treated with 1.2 g of maleic acid in 10 ml of 2-propanol. The salt was crystallized by addition of ether to give 2-aminomethyl-2,3-dihydro-5-phenyl-1H-thien[3,2-e][1,4]diazepinedimaleate as yellow crystals,

s.p. 170-173°. The analytical sample was recrystallized from methanol/2-propanol, m.p. 187-189°.

2-Aminomethyl-2,3-dihydro-5-phenyl-1H-thien[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 evaporated. The residue was heated to reflux for 1 hour with 1 ml

triethyl orthoaoetate in 20 ml of xylene. The solvent was evaporated under 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]thien-[2,3 -f]diazepine, s.p. 150-152°. This material was heated to reflux in 30 ml of toluene with 2 g of activated manganese dioxide for 2 hours. The manganese dioxide was filtered off and washed well with methylene chloride. The filtrate was evaporated and the residue was chromatographed over 7 g of silica gel using 3% (v/v) ethanol. in methylene chloride. The fractions containing pure product were combined and evaporated. Crystallization from methylene chloride/ether and recrystallization from ethyl acetate/hexane gave 1-methyl-6-phenyl-4H-imidazo[1,5-a]-thien[2,3-f]diazepine, m.p. 223-225°..,

EXAMPLE 2 3

A mixture of 7.7 g (0.278 m) of 7-chloro-1,3-dihydro-5-phenyl-2H-thien[2,3-e]Li,4]diazepin-2-one, 50 ml of benzene and 250 ml of tetrahydrofuran was stirred in an ice bath and saturated with methylamine gas. To this mixture was added a solution of titanium tetrachloride (7.38 g, 0.0389 m) in 50 ml of benzene from a dropping funnel. After the addition was complete, the mixture was stirred in an ice bath for 15 minutes. The ice bath was then replaced with a heating mantle and the reaction mixture was refluxed for 20 minutes. The mixture was cooled and 100 tg of ice was carefully added. The mixture was then filtered, and the residue washed with tetrahydrofuran. The filtrate was combined, dried and evaporated. The residue was crystallized from methylene chloride/ether to give 7-chloro-5-phenyl-2-methylamino-3H-thien-[2,3-e]

[1,4]diazepine, m.p. 246-249°. The analytical sample was recrystallized from methylene chloride, m.p. 247-250°.

Nitrosyl chloride was added to a solution of 5.8 g (0.0 2 m) of 7-chloro-5-phenyl-2-methylamino-3H-thien[2,3-e][1,4]diazepine in 100 ml of methylene chloride and 50 ml of pyridine until the reaction was complete according to thin layer chromatography. The mixture was partitioned 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-thien[2,3-e][1,4]diazepine

as yellow crystals, m.p. 108-110°. For analysis, it was recrystallized from ether/hexane, m.p. 111-113°.

To a mixture of 10 ml of nitromethane, 35 ml of dimethylformamide and 2.26 g (0.02 m) of potassium t-butoxide which had been stirred under nitrogen for 10 minutes at room temperature. After heating in a steam bath for 10 minutes, the reaction mixture was acidified by adding 2 ml of glacial acetic acid and was partitioned between water and toluene. The toluene layer was washed with water, dried and evaporated. The residue crystallized from ethyl acetate/hexane to give crude 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno[2,3-e][1,4]diazepine. It was purified by chromatography over 40 g of silica gel using 10% (v/v) ethyl acetate in methylene chloride. The pure product was obtained as yellow crystals with m.p. 154-156°.

A) A solution of 3 20 mg (1 mmol) 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thien[2,3-e][1,4]diazepine in 20 ml of ethanol was hydrogenated over Raney nickel for 5 hours at atmospheric pressure.-The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed over 7 g of silica gel using methylene chloride, methanol and triethylamine in the ratio 13:6:1. The fractions containing pure product were combined, evaporated and the residue treated with maleic acid in 2-propanol. Crystallization of the dimaleate salt from 2-propanol/ether and recrystallization from ethyl acetate/ethanol gave 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thien[2,3-e][1,4]- diazepine dimaleate as yellow crystals, m.p. 176-177? B) A solution of 3 20 g (1..mmol) 7-chloro-2, 3-dihydro-2-nitromethylene-5-phenyl-1H-thien|_2, 3-e] [1, 4]diazepine in 3 ml of tetrahydrofuran was added to a suspension of 0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After heating to reflux for 5 minutes, the reaction mixture was cooled and hydrolyzed by the addition of 5 ml of water. The inorganic material was separated by filtration and the filtrate was evaporated. The residue was chromatographed as described above, and the pure product was converted to the maleate to give 2-amino-methyl-7-chloro-2,3-dihydro-5-phenyl-1H-thien[2,3-e][l ,4]diazepine dimaleate, s.p. 176-178°.

2-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thien[2,3-e][1,4]-diazepine dimaleate (0.52 g, 1 mmol) was partitioned between methylene chloride and aqueous ammonia. The methylene chloride solution was dried and evaporated. The residue was heated to reflux for 1 hour with 0.5 ml of triethyl orthoacetate in 10 ml of xylene. The crude product obtained after evaporation under reduced pressure was dissolved in 25 ml of toluene and the solution was heated to reflux for 1 1/2 hours after the addition of 2.5 g of activated manganese dioxide. The manganese dioxide was then filtered off and the filtrate was evaporated. The residue was chromatographed over 6 g of silica gel using 4% (v/v) ethanol in methylene chloride. Fractions containing the pure compound were combined and evaporated. Crystallization of the residue from ether/hexane gave 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a]thien|_3,2-f]-[1,4]diazepine, m.p. 168-170°.

EXAMPLE 24

To a mixture of 0.1 g (0.000273 m) of 8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-isopropanol and 5 ml of water was added with 1 ml of concentrated hydrochloric acid. The reaction mixture was cooled in an ice bath and 0.15 g (0.00217 m) of sodium nitrite was slowly added with stirring. After 1 hour, the reaction mixture was poured into a solution of 0.2 g (0.00 202 m) of cupric chloride in 50 ml of water which had been heated to 70°. After 18 hours, the reaction mixture was made alkaline with sodium hydroxide, extracted with dichloromethane (2 x 50 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was developed on a thick layer plate of silica gel in a mixture of

ethyl acetate and methanol (10/1). The product that had an Rf on it

0.7 was scraped off the plate, stirred with methanol and filtered. Evaporation and crystallization of the crude product from a mixture of ethyl acetate and ether gave (2-fluorophenyl)-[2-(5-hydroxymethyl-2-methyl-1-imidazolyl)-5-chlorophenyljmethanone as white prisms,

s.- mmp with an authentic sample 159-166°.

A solution of 0.5 g (0.00145 m) of (2-fluorophenyl)[2-(5-hydroxy-methyl-2-methyl-1-imidazolyl)-5-chlorophenyl]-methanone in 25 ml of dichloromethanone was treated with 0.15 ml (0.00155 m) of phosphorus tribromide 1 in an ice bath and after 1 hour at room temperature it was poured into 50 ml of liquid ammonia. After the ammonia had 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 2 thick layer plates of silica gel which were developed in a mixture of ethyl acetate/10%<1>s methanol.

The compound which had an Rf of 0.6 was scraped off, stirred

with methanol and filtered. The solution was treated with 0.1 g (0.000 96 2 m) of maleic acid and evaporated. The remaining 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, s.p. and mmp with an authentic sample 112-115° (melting point for dissolved 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 mmp with an authentic sample 154-157°.

Claims (3)

] . Analogous process for the preparation of therapeutically active imidazo [1,5-a][1,4]-diazepine compounds of the general formula where A is the group R1, R2, R3 is the group P611 consisting of hydrogen and lower alkyl, Rj is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkylamino, lower alkanoylamino, amino. hydroxy-lower-alkyl and lower-alkanoyl or the group in which R?f. means hydrogen or C -C -alkyl, r6 is selected from the group consisting of phenyl and halophenyl, r.g sr selected from the group consisting of where X is hydrogen or chlorine, and pharmaceutically acceptable acid addition salts of these compounds, characterized by a) the dehydrogenator compound with formula where A, Rx, R2, R3,<R>4,<R>g and are as in formula I, to a corresponding compound of formula I, or<b>) transfers a 2,3-lower alkylenedioxy substituent in the benzo group to R^ equal to a lower alkanoyl substituent, orc) transfers a lower alkanoyl substituent present as R. substituent in an imidazobenzodiazepine to a hydroxy lower alkyl substituent, or d) cyclizes a compound of formula where R, is C-C, alkyl, R„ is chlorine or bromine and R' is Xio 4 "6 O-halophenyl^ or e) mildly hydrolyzes a compound of formula I, where R 4 is alkanoyllamdno so that one obtains a corresponding compound of formula I, where R^ is amino, or f) converts R^ equal to a lower- alkanoylamino substituent of R^ equal to lower-alkylamino, or g) oxidizes a compound of formula where A" is>g Rx, R2, R3, R4, Rg and is as in formula VII, to a corresponding compound of formula I, or h) dissolves a racemic compound into its optical enantio-. more, or i) transfers a compound of formula I in a pharmaceutically acceptable acid addition salt. 2. Process according to claim 1 for the production of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine or its maleate, characterized in that one uses correspondingly substituted starting materials. 3. Process according to claim 1 for the production of 8-chloro-6-(2-fluorophenyl)-1,4-dimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine or its maleate, characterized in that correspondingly substituted starting materials are used.