SE433080B - INTERMEDIATE FOR THE PREPARATION OF IMIDAZO / 1,5-A / / 1,4 / DIAZEPINE DERIVATIVES - Google Patents

Description

7902667-13 The 5,6-dihydro-imidazo [1,5-a] [1,4] diazepines with the above given Formula I are useful intermediates and can be carried in pharmaceutically valuable imidazo [1,5-a] [1,4] diazepif down with the general formula N R2; R2 N R3 Ra II wherein A is \ | C = N / and R 1, R 2, R 3 and w 1 have it in formula I R6 - meaning given above, by dehydration or deacylation.

The compounds of formula I wherein R 7 is hydroxy can be converted to the corresponding unsaturated imine of formula II by treatment of compound I with a mixture of acetic anhydride / pyridine.

No other solvents are required for this reaction and the temperature the temperature is not critical although the reaction is best performed at room temperature.

The compounds of formula I above, wherein R 7 is acetyl, mesyl or tosyl can be converted into the corresponding unsaturated imine with II by treating compound I with a non-aqueous medium. haltig bass, e.g. potassium tert-butoxide, in the presence of an inert solvents, e.g. THF, DMF, etc. Such a reaction and they conditions under which it is performed are previously well known, compare for example, U.S. Patent No. 3,635,957.

The compounds of formula II and their pharmaceutically acceptable properties acid addition salts are useful as muscle relaxants, sedatives and anticonvulsants and many are particularly reversible when used in intravenous and intramuscular procedures 7902667-0 due to the solubility of the acid addition salts in the water ten solution.

As used herein, the term "lower alkyl" includes both straight and branched (C1-C7) hydrocarbon chains, preferably C1-C4 hydrocarbon chains such as methyl, ethyl, propyl, isopropyl, butyl and the like.

By the term "lower alkanoyl" as used herein is meant an acyl residue of a C1-C7-, preferably C1-C4-alkanoic acid, e.g. acetyl, propionyl, butyryl or the like, i.e. remains with the formula R 20 -E-, wherein R 20 is C 1 -C 6 alkyl or hydrogen. The expression "lower alkanoyl" also as used herein means a protected ketone such as an acetal or ketal having 2 to 7 carbon atoms, e.g.

R ï / / ° \ O 0 a group of the formula wherein R 20 is C 1 -C 6 alkyl or hydrogen. Ketal or aldehyde fl the protection group was used to prevent the conversion of the the ketone or aldehyde (R29- fi-) during oxidation, re- duction and condensation reactions.

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

Preferred compounds are those wherein R 1 is methyl; R 3 is hydrogen; (:::]: L is R, wherein R 4 is preferably located in 8-position of the imidazobenzodiazepine molecule and is hydrogen or halogen, preferably chlorine; R 6 is fluorophenyl, preferably 79026 67-0 with the fluoro substituent in the 2-position of the phenyl group, e.g. compounds of the formula wherein R1 'and R2 have the definition given in formula IB' below and R7 have the above definition.

From the above it thus appears that a special drawn embodiment within the scope of the present invention comprises a compound of the formula wherein R 1 'is methyl, R 4 is hydrogen or halogen, most preferably claws; and is in a particularly preferred embodiment in 8 position on the condensed benzo part of imidazo benzo diazepine, R60 is fluorophenyl, preferably with fluorine sub- stituent located in the 2-position of the phenyl group. R2 is selected from the group consisting of hydrogen and lower alkyl and R7 has meaning given above.

Another preferred class of compounds that fall within the scope 7902667-0 for formula I are those in which R 1 ', R 2, R and R 7 have the 4 'Re between IB 'and R is lower alkyl, preferably 3 vis methyl, e.g. compounds of the formula Cl The compounds of formula I above can be prepared according to the following the procedures.

One of these processes starts with nitrosation of a with the formula NHcH3 ' N 123 'III n A H wherein A 'is -C = N- or -C = N-; ', R and R have it I 1 N 3 6 R R O J 6 "6 meaning given in formula I, for the preparation of a with the formula 7902667-0 Ra: v wherein AY, R3 and <::] ;: have the meanings given above.

Such nitrosation can be carried out with "in situ" sal- 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 as an alcohol, a chlorinated hydrocarbon or e.g. dimethylform- amide; and (3) a nitrosyl chloride-gaseous solution in an inert solvent and in the presence of an acid acceptor such as pyridine.

Such a nitrosation reaction should be performed at about or below room temperature, i.e. in the range -20 ° C to 25 ° C. _ CH3 The nitrosoalkylamine group in the 2-position, e.g. -N-NO, constitutes an “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.

Q 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- 7902667-Ü alkane to a new intermediate of the formula wherein Al, 32, R3 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; amides, for example lithium amide, or ~ hydrides, e.g. sodium hydride. Reak ~. 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- Council -SOOC to 150 ° C, preferably at about room temperature. lucky.

Compounds of formula V may then be catalytically hydrogenated, e.g. with Raney nickel in the presence of hydrogen or with other reducing agents agents such as lithium aluminum hydride (with the restriction that A ' is not N-oxide) to prepare a compound of the formula WE 7902667-0 wherein A, R 2, R 3, R 2 and R 6 are as defined above.

Suitable solvents for the hydrogenation with Raney nickel take alcohols, e.g. ethanol, ethers, eg 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 agents such as lithium aluminum hydride include ethers, e.g.

THF, dioxane, diethyl ether and mixtures of ethers and hydrocarbons solvents, e.g. THF and benzene. The reaction can be carried out from below room temperature to reflux temperature, i.e. preferably in the range -so ° c to eo ° c.

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 (R1CO) 2O wherein R1 has the formula I given meaning, e.g. acetic anhydride or acetyl chloride, to prepare a compound of the formula * å R1oc / Rz Y R N V 3 VII hrs Oh wherein A, R 1, R 2, R 3 and R 2 have the meanings given above. see and Y is hydrogen or -CORI.

Upon acylation of the compounds of formula VI to compounds with formula VII there may be a mixture of the dominant the monoacylated product, i.e. where the NH2 group in VI (2-position) was transferred to NHCOR1, and the diacylated pro- 7902667-0 aukten, where both NH2 1 vi <2 position) een nitrogen: i 1-stä11- acylated. The yield of the diacylated product can be increased by subjecting the compounds of formula V to more stringent conditions, i.e. excess acylating agent and increased reaction 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 new compounds with the formula VIII wherein A, R 1, R 2, R 3 and (a) have the meanings given above.

The cyclization reaction is carried out with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, i.e. organic or inorganic acids, e.g. conc. sulfuric acid. No solvent is needed, but one solvent such as an aromatic hydrocarbon solvent, e.g. toluene or xylene, can be used. The reaction is carried out at a temperature in the range from about 10000 to 20006.

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 7902667 ~ Ü 10 ?HRS N-CH CH | 3 | 3 ç fl n - N - CH n-cs i CH3 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 VIII takes place spontaneous. Other useful acylating agents include esters, for example methyl acetate, amidines, e.g. acetamidine, nitrite, for example acetonitrile and esterimidates, e.g. an association with the formula ? ° 2Hs CH3-c = NH The compounds of formula VIII can then be dehydrogenated to corresponding unsaturated compounds.

Preferred reactants for the dehydration include manganese dioxide and palladium-on-carbon, although potassium permanganate may also be used. turned. Solvents that can be used include chlorinated carbon hydrogen, aromatic hydrocarbons, dimethylformamide, etc. gene is performed at room temperature or above, i.e. in the area from about 2 ° C to 20 ° C.

The above procedure can be continued, if desired, from 7902667- (1 ll intermediates V or VI to said unsaturated compounds without any of the intermediates formed having to be isolated before the next procedure is performed.

Upon acylation of the compounds of formula VI to the compounds with formula VII it should be noted when R4 is amino to amino group ~ pen can also be acylated to acylamino. The acylamino group can then returned to amino by the compounds with flour VIII or formula I is subjected to mild hydrolysis.

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

Reaction of a compound of formula VI with acetic acid and zinc or any other suitable reducing agent, e.g. hydrogen in be of a catalyst, e.g. platinum in dilute acetic acid solution, gives a compound of the formula NH2 Rz HRS .

N R3 VI ' 1 I A H _ I wherein A "is -? H-NH- and R 2, R 3 (Ein: and R 6 have it RE the meaning given in formula VI.

Depending on which of the reduction methods listed above the compounds of formula VI 'when R 2 is hydrogen, iso- clay as a racemic mixture of either of the two possible the diastereomers.

A compound of formula VI 'can be converted to its dihydrogen imidazone derivatives of the formula 79026674; 12 VIII ' wherein Z is 7, A ", R1, fR2 and R3 have the formula VI ' given meaning while maintaining stereochemistry through use of the above direct reaction, i.e. the reaction between compounds of formula VI and an acylating agent such as an orthoester, e.g. triethyl orthoacetate and maintenance of the reaction parameters indicated above for such a reaction. tion.

Compounds of formula VIII 'may also be prepared by reducing preparation of a compound of formula VIII using reducing agents such as those mentioned above, e.g. acetic acid and zinc or H2 / platinum catalyst in dilute acetic acid, wherein it particular stereoisomers obtained depend on the selected reduction the agent.

Compounds of formula VIII 'may, if desired, be oxidized directly to analogous unsaturated compounds of formula I using use of an oxidizing agent such as manganese dioxide in toluene or benzene solution. Use reaction conditions and different alternative useful oxidizing agents are found in perhaps patent specification 3,322,753.

Another procedure for the preparation of the new the products of formula VI consist of reduction of compounds with the formula 7902667-0 l3 - CN s H I N ns XI A H wherein A, R 3, and R 6 are as defined above.

The reduction involves reaction between the compounds with XI and a known reducing agent such as Raney nickel in the hydrogen or with other reducing agents such as lithium aluminum hydride. Suitable solvents for hydration with Raney nickel includes alcohols, e.g. ethanol, ethers, e.g.

THF, hydrocarbon solvents, e.g. toluene and dimethylformamide.

The reaction temperature may be above or below room temperature. turn (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.

Solvents suitable for hydration using a reducing agent such as lithium aluminum hydride comprises 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 60 ° C.

A variant of the process described above comprises mild acid hydrolysis of the compounds of formula XI to compounds of the formula CONHZ XII gïeozeev-0 14 wherein A, R 3 and have the meaning given above.

The mild acid hydrolysis is conveniently carried out with a diluent mineral acid, e.g. aqueous H2SO4 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 XII can then be reduced to the new ones the intermediates of formula VI, Other methods can be used to make the new ones the intermediates of formulas_V and VI.

The compounds of formula V above can be prepared by successive reaction between the compounds of the formula ' OH wherein A, w and R 3 are as defined above except that R 4 is not amino, lower alkylamino or lower alkanoyl amino, i with dimorpholinophosphinic acid chloride to compounds of the formula 7902667-0 15 O || _ / \ 'O-P N Û g \ _ / 2 M R3 XIV hrs wherein A, <::;: i: and R3 have the meaning given above, wherein after the iminophosphate groups are replaced by the anion of a nitro- alkane for the preparation of 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 nitroalkanionjon§ 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 -SOOC 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 of compounds of the formulas N R3 "" 'f4 Z I CPiCl or '_ Å C12 * \\\ Am, \ “ IX X 79Û26'67-ü 16 wherein A "1 is -? = N-; R R6 0 meaning except that R4 is not amino. 6, and R 3 has the above The ring expansion comprises reaction between the compounds with formula IX or X 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. there, e.g. potassium tert-butoxide, amides, e.g. lithium amide, or hydrides, e.g. sodium hydride. The reaction may be performed in an inert solvent such as an anhydrous ether, e.g. THF, dimethylformamide, dimethylsulfoxide, etc. and at a temperature in the range from -20 ° C to 25 ° C.

The compounds of formula I wherein R 7 represents acetyl, mesyl or tosyl is formed by reduction of the corresponding unsaturated compounds obtained in the above manner to compounds with the formula wherein R 1, R 2, R 3, R 4, R 6 and has it in formula I specified meaning, which compound can then be transferred to compounds of the formula 7902667-U 17 wherein R 1, R 2, R 3, R 4 and R 6 have the meaning given in formula XV and R7 'is acetyl, mesyl or tosyl.

The reduction to the compounds of formula XV is carried out with each suitable reducing agent but is preferably carried out with hydrogen in presence of a platinum oxide catalyst or zinc in the presence of acetic acid. These compounds of formula XV can be transferred to compounds I with a substituent R 7 other than hydrogen by reaction with, for example, tosyl chloride, mesyl chloride or acetyl chloride. rid.

This process aspect is conveniently carried out in the presence of an inert organic solvent such as an alkanol, e.g. ethanol or methanol, an ether such as diethyl ether and tetrahydrofuran, di- methylformamide or the like. Suitably, an acid acceptor to the reaction zone to take up that hydrogen halide which is formed using a halide. Suitable acid- ' acceptors are tertiary amines, e.g. triethylamine, pyridine and similar.

Temperature and pressure are not critical aspects in the first place step of the procedure. However, the reaction preferably takes place. at approximately room temperature and atmospheric pressure for position of the compounds of formula XV and room temperature or more for the transfer of compounds XV to IA. .79Û2667-U tis The compounds of formula I wherein R 7 represents hydroxy are formed by transferring the corresponding unsaturated compounds into the N- the oxides thereof. This transfer takes place by oxidation with a organic peracid. A suitable organic peracid, such as acetic acid, perpropionic acid, m-chloroperbenzoic acid, etc. can be used reversed in carrying out this reaction. The oxidation can take place at room temperature or above or below room temperature.

Reduction of the compounds thus obtained with hydrogen in the presence of platinum catalyst and acetic acid lead to the compounds Wherein R 7 is hydroxy.

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

Example 1 A solution of 200 g (0.695 mgl) of 7-chloro-1,3-dihydro-5- (2- fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 liters of tetrahydro- furan and 250 ml of benzene were saturated with methylamine under cooling on an ice bath. A solution of 190 g (1 mol) of titanium tetrachloride in 250 ml of benzene were added through a dropping funnel over the course of 15 minutes. After the addition, the mixture was stirred and was boiled for 3 hours. Water (600 ml) was added slowly to the cooled reaction mixture. The inorganic material separated by filtration and washed well with tetrahydrofuran furan. The aqueous layer was separated and the organic phase was dried. was added to sodium sulfate and evaporated. The crystalline the state of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzo- diazepine was collected, m.p. 204 - 2060. The analytical the sample was recrystallized from methylene chloride / ethanol, m.p. 204 - 2o6 °. ' 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-A 7902667-0 19 In turn, 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, at the end azeotrope with toluene to give 29 g of crude 7- chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzo- diazepine 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 1.1 g (0.1 mol) of potassium t-butoxide, which was stirred under nitrogen in l5 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 - 176 °.

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 tetra- hydrofuran and 250 ml of methanol were hydrogenated with 5 teaspoons of Raney nickel for 2 1/2 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. 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 of saturated aqueous sodium bicarbonate and the mixture stirred for 20 minutes. The organic layer was separated, washed was treated with sodium bicarbonate, dried over sodium sulfate and concentrated. evaporated to give a resinous 2-acetaminomethyl-7-chloro- 2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine. This material 7902667-Ü 20 The material was heated with 40 g of polyphosphoric acid at 1500 10 min. ter. 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 chromatographed. was prepared over 120 g of silica gel using 20% methanol in methylene chloride. The pure fractions were combined and evaporated. to give resinous 8-chloro-3a, 4-dihydro-6- (2- fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. One mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1 1/2 hours. Mangandioxi- it was separated by filtration through CELITÉÉZ The filtrate was 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, mp 152 - 1540. The analytical sample was recrystallized from methylene chloride / hexane. 3 g of zinc dust was added to a solution of 2.8 g of 8-chloro-6- (2- fluorophenyl) -1-methyl-4H-imidazofl, 5-a] [1,4] benzodiazepine i 75 ml of methylene chloride and 75 ml of glacial acetic acid. After stirring at room temperature for 2 hours, the inorganic material was filtered off. and washed with methylene chloride and water.

The filtrate was diluted with 100 ml of methylene chloride and 200 ml of water and was made alkaline with ammonia. The methylene chloride layer is separated, dried and evaporated. Crystallization of recyclable the ether / hexane column gave 8-chloro-5,6-dihydro-6- (2-fluorophenyl) - 1-methyl-4H-imidazo [1,5-a] [1,4] melting point benzodiazepine zoo - 2o3 °. 'a To a solution of 1.6 g (5 mmol) of s-chloro-s, s-aihyar¿-e- (2- fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine i To 10 ml of pyridine was added 1.2 g (6 mmol) of p-toluenesulfonyl chloride.

After storage at room temperature for 19 hours, the reaction was diluted. the mixture with water and extracted with methylene chloride.

The organic extract was dried and concentrated to dryness. in a vacuum. The residue was crystallized from a mixture of methylene chloride and ether to give 8-chloro-6- (2-fluorophenyl) -5,6- 7902667-0 21 dihydro-1-methyl-5- (4-methylphenylsulfonyl) -4H-imidazol, 5-a] [1,4] - benzodiazepine melting at 252 DEG-2530 DEG. from tetrahydrofuran, the pure product formed yellow mother with the same melting point.

The final product can be further processed as follows: To a stirred solution of 2.4 g (5 mmol) of 8-chloro-6- (2-fluoro- phenyl) -5,6-dihydro-1-methyl-5- (4-methylphenylsulfonyl) -4H- imidazo [1,5-a] [1,4] benzodiazepine in 120 ml of dry tetrahydrofuran was added 1.1 g of potassium tert-butoxide. After stirring at room temperature temperature for 2 hours, the reaction mixture was poured into ice water and extracted with a 50% mixture of ether and petroleum ether. The organic extract was dried and concentrated dryness in vacuum. The residue was crystallized from a mixture of ether and petroleum ether to give 8-chloro-6- (2-fluorophenyl) -1- methyl 4H-imidazol [1,5,5-a] [1,4] benzodiazepine melting at 152 - 1530. The mixed melting point with an authentic sample gave no reduction.

Example 2 A mixture of 9.75 g (0.03 mol) of 8-chloro-6- (2-fluorophenyl) -1- methyl 4H-imidazo [1,5-a] [1,4] benzodiazepine, 200 ml of methylene chloride and 12 g (0.07 mol) of m-chloroperbenzoic acid were stirred for 1/2 hour. The solution was then extracted three times with 150 ml 1N hydrochloric acid. The extracts were washed with ether, made alkaline with ammonia and extracted with methylene chloride. Methylene- the chloride extracts were dried and evaporated and the residue crystallized from ethyl acetate to give a product which was further purified by chromatography over 100 g silica gel using 5% (v / v) ethanol in methylene chloride. The pure fractions were combined and evaporated.

Crystallization of the residue from ethyl acetate / ether gave 8-chloro- 6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine- 5-oxide as colorless crystals, m.p. 245-2460 (Sun. division). 7902667-Ü 22 will a stirred solution of 1.2 g (3.5 mmol) of s-chloro-el (2-fluoro- phenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-5-oxide i 120 g (31 mmol) of sodium borohydride were slowly added to 120 ml of ethanol.

After stirring for 4 l / 2 h at room temperature, the reaction was diluted. mixture with approximately 175 ml of water and product as melt at 246 - 24s ° was separated by filtration. After em- crystallization from a mixture of methylene chloride / ether formed the pure 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-5-hydroxy-1-methyl- 4H-imidazo [1,5-a] [1,4] benzodiazepine colorless needles that melt at 251 - 2s2 °.

The final product can be further processed as follows: A solution of 0.3 g of 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-5- hydroxy-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in a mixture of 10 ml of pyridine and 2 ml of acetic anhydride was left at room temperature for 19 hours. The reaction mixture is concentrated was allowed to dry in vacuo. The residue was dissolved in 20 ml of nol and 0.2 g of sodium methoxide were added. After being allowed to stand 45 minutes at room temperature, the reaction mixture was concentrated. to dryness in vacuo. The remainder was divided between methylene chloride and water. The organic layer was separated, was dried and concentrated to dryness in vacuo. The remainder was crystallized from a methylene chloride / ether mixture to give starting material melting at 255 - 2560. Concentration of filtrate and crystallization of the residue from ether gave 8-chloro- 6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine which melted at l58 - 1600. The mixed melting point with a authentic sample gave no reduction.

Example 3 A solution of 1.5 g of 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -1- methyl 4H-imidazo [1,5-a] [1,4] benzodiazepine in a mixture of 10 ml of pyridine and 5 ml of acetic anhydride were left at room temperature. temperature for 18 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in methylene chloride and 7902667-o 23 was washed with dilute potassium hydroxide. The organic layer was separated, dried and concentrated to dryness in vacuo. The residue was crystallized from a mixture of methylene chloride, ether, petroleum ether to give 5-acetyl-8-chloro-6- (2-fluorophenyl) - 5,6-dihydro-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as melted at 185 - 1s6 °. After recrystallization from methylene chloride formed the pure product colorless prisms which melted at 186 - 1a7 °.

Claims (1)

Intermediate for use in the preparation of therapeutically valuable 4H-imidazole, 5-α, β-benzodiazepines, characterized by the general formula MYM Rz 'N Ra I cH-N H \ I R., Ra wherein R 1, R 2 and R 3 represent hydrogen or lower alkyl; R6 bed represents phenyl or halophenyl; R 7 represents hydroxy, acetyl, mesyl or tosyl; and <:::]; & represents one of the groups sixmmsa) b) I. c) wherein X is hydrogen or chlorine and R 4 represents hydrogen, halogen, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl or lower alkanoyl.