IE43767B1 - Intermediates for the preparation of diazepine derivatives - Google Patents

Description

This invention relates to a process for the·preparation - I - - I of diazepine derivatives, in particular pharmacologically , active imidazo [1,5-a][1,4] diazepine compounds.

In Patent Specification No. '43762· there are described and claimed imidazo[l,5-a][l,4]diazepine compounds wherein A represents -O(Rg)^N-: represents hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl,halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl, pyridyl, aralkyl or the group -COR^q ^ilie:eein S10 represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); Rg represents chloro, bromo, iodo, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, aeylamino, lower alkoxycarbohylamino, aralkyloxycarbonylamino, substituted amino lower alkyl, the group -COOR^Q (wherein ίί^θ represents hydrogen or lower alkyl), the group -COR.J.Q (wherein E10 represents hydrogen or lower Alkyl) or a derivative thereof, i.e., a) the group -Ο(β^θ)= N-R-q wherein R^ represents hydrogen, lower·alkyl, hydroxy, alkoxy, amino, mono or di-alkylamino or arylamino and R10‘ represents hydrogen or lower alkyl; b) the group -CONR12R13 wherein R^2and R^3 represent individually hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or the group - 2 43707 -(^2^^14^15 (wherein R^^ and R^ represent individually hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl, or R.^ and R^^ together form a part of a heterocyclic ring, and n is 1 to 4) or R^ and R^ together form a part of a heterocyclic ring; or c) the group -CONiR^gJl'KR^yR^g), wherein one of R^g, R^ and Rlg represents hydrogen or lower alkyl or the group -(CH2^n^^R14R15^ (^61^11 n is 1 to 4 and R^ and R^ represent individually hydrogen, lower alkyl, hydroxy lover alkyl or lower alkenyl or R.^ and R^ together form a part of a heterocyclic ring) and the remaining R^, R^ and R^g represent hydrogen or lower alkyl; and Rg represents additionally hydrogen or lower alkyl inihe case where renresents hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, the group -COR1Q (wherein R1Q represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl); Rj represents hydrogen or lower alkyl; Rg represents phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; and the group represents T R, a) X c) wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl, R^ represents hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl and Rs represents 7G7 hydrogen and additionally alkanoyloxy or hydroxy in tie case where ZjJ represents the group a), h) or o) above, analogs thereof corresponding to formula I but, wherein A represents the group 6.

CH· I Rr e) fj g) [ZH represents the group ‘a), b) or c) above, R^ is hydrogen, Rp R2, R^ and Rg are as in formula I above, and V represents hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts of these compounds which in the case of compounds of formula I wherein (z j| is R^-phenyl, A is C(Rg)= N- and R5 is hydrogen, have a structure in which the diazepine ring is opened by cleavage of the C/E-double bond in the 5,6-position.

According to the present invention-there is provided a process for the preparation of imidazoLl,5-a][l ,4]diazepine compounds of the general formula I above but wherein R^ is other than hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, the group -COR^q wherein R-^θ represents hydrogen or lower alkyl, or the group -COOR wherein R represents lower alkyl, Rg represents hydrogen without any proviso, Rg represents hydrogen and A represents -C(Rg)=If- (referred to below as compounds of formula I*) - 4 43707 and the pharmaceutically acceptable acid addition salts thereof, which process comprises decarboxylating a compound of formula XVIII wherein Rp ^3, A. and. above, and, if desired, resolving a racemic compound thus-produced into its optical enantiomers, or, if desired, converting a compound thus-produced into a pharmaceutically acceptable acid addition salt by reaction with a suitable acid. Many of the products are claimed PgT se in United Kingdom Specification Ho. 1627131.

As used in this disclosure, the term lower alkyl comprehends both straight and branched chain (Ci - 0γ) hydrocarbon radicals, preferably C^ - C^ carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term lower alkyl comprehends also cyclic hydrocarbon radicals, such as cyclopropyl.

By the term lower alkanoyl or acyl 2'> as utilised herein, an acyl moiety of a C^ Cy preferably a - C^ alkanoic - 5 4 3 7 6 7 acid is intended, e.g:, acetyl, propionyl, butyryl and the like, i.e., moieties of the formula -CORjq, wherein R2q is O^-Og-alkyl or hydrogen. Also a3 utilized herein, the term lower alkanoyl comprehends a protected ketone such as an acetal or ketal having 2 to 7 carbon atoms, e.g. an ethylenedioxy group. .The ketal'or aldehyde protecting group is utilized to prevent conversion of the contained ketone· or aldehyde in oxidation, reduction and condensation reactions.

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

The Rg phenyl moiety may be mono- or di-substituted provided that such di-substitution occurs in che 2,3; 2,5} or, most preferably, in the 2,6 position of the phenyl moiety. Suitable mono-substituents include halogen and nitro and preferably are substituted in the 2-position of the - phenyl moiety, Suitable di-substituents are 2,6 or 2,5 di-halogen and 2,6 or 2,5 halogen-nitro. In tho case of mono-substituted pyridyl, suitable substituents include halogen and nitro.

In the case of differently substituted R^ and R^ substituents, optical isomerism will occur and such optical antipodes and racemates are within the ambit of this invention.

By the term aryl is meant a substituted or unsubstituted monocyclic aromatic moiety such as.phenyl, chlorophenyl, tolyl, and the like. When various moieties are set herein to form a part of a heterocyclic ring, it is intended that the moieties, toqether with the nitrogen atom - 6 437C7 to which they are attached form, preferably, a 5 or 6 membered ring which contains at the most one additional hetero atom, preferably nitrogen or oxygen as the hetero atom. Thus, by the heterocyclic ring, there is intended such moieties as morpholino, piperazino, piperidino and pyrrolidino.

By the term alkoxy is meant straight or branched chain saturated hydrocarhonoxy group containing from 1 to 7 carbon atoms, preferably from 1 to 4- carbon atoms, such as methoxy, ethoxy, propoxy and the like.

By the term substituted amino herein is meant an -NHg group which may he mono or disubstituted by lower alkyl, e.g. methylamino or dimethylamino groups, and an acyl amino group e.g., acetamino which may then be substituted on the nitrogen atom by a lower alkyl e.g., methyl, group.

By the term aralkyl is meant a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl H atom is substituted by a monocyclic aryl group, e.g., phenyl, tolyl and the like.

Preferred compounds encompassed by the present invention are those of the general formula ~ wherein R^' is hydrogen or lower alkyl, preferably methyl, 25 is hydrogen, nitro or halogen, most preferably chlorine, - 7 4 S 7 G 7 and in a most preferred embodiment when positioned on the fused benzo portion of the imidazobenzodiazepine in the 8-position thereof, Rg' is phenyl or halo, nitro or lower alkyl-substituted phenyl, preferably halo, with fluorine being the preferred halogen and preferably positioned in the 2-position of the phenyl moiety and Rg is hydrogen.

Another preferred class of compounds falling within the scope of formula 1' are those of the general formula and R,' is lower alkyl, preferably methyl. 9 Z Compounds of formula IC and their pharmaceutically acceptable salts exhibit optical isomerism. Such a I compound (IC wherein R^' = CH„) has been resolved into its optical enantiomers by a procedure similar to the one generally outlined in Advanced Organic Chemistry, 1. Fieser and M. Fieser, 1961, pp. 85-88, Reinholt Publishing Co.

Both the optical isomers and the racemic form of compound I IC exhibit pharmacological activity. For example, in ehe / case of the tartrate, salt of compounds of formula IC the (+) isomer is Considerably, more active than the (-) isomer. The less active (-) isomer may, if desired, be converted to the active racemic form thereof such as bytreatment with a non-aqueous base, e.g., sodium tertiary butoxide in the presence of an organic solvent in which 43707 the isomer is soluble.

A further preferred, group of compounds are those of formula 1' wherein is an 8-chlorophenyl or an 8-chlorothieno[5,2rf] group, is hydrogen or methyl, Rg is 2'-fluoro- or 2'-chlorophenyl and R^ is hydrogen.

The pharmaceutically acceptable acid addition salts may be formed 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, methanesulfonic acid, para toluenesulfonic acid and the like. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form,in view.

Also within the ambit of the instant invention are compounds which aro obtained by ring opening of formula 1' compounds, wherein (ZJ is R^-phenyl. Such compound: are of the formulaRi\z>HyzR2 ,R3 ID NH® s H 1 x® ”6 wherein X is the anion of an organic or inorganic acid, and Rp Rg, Rp R^ and Rg are as in formula 1'.

It has been found that certain compounds of formula 1' in solution open to corresponding compounds of formula ID. Such open compounds exist in a pH-dependent equilibrium in - 9 solution with compounds of formula I', i.e., their corresponding ring closed compounds. The compounds of formula ID can he isolated as acid addition salts by treatment of their corresponding closed ring compounds with an aqueous mineral acid followed by evaporation of solvent. When isolated, these salts exhibit pharmacological activity comparable to their corresponding closed ring parents.

Formula 1’ compounds are formed by decarboxylation of a compound of formula XVIII with or without catalyst and with or without solvent,· This decarboxylation is conveniently effected by application of heat, e.g. at a temperature between about 100°C and 35O°C, preferably about 150°C and 230°C. Solvents that can be used in this reaction step are hydrocarbons, e.g. mineral oil; chlorinated hydrocarbons, ethers, alcohols e.g. ethylene, glycol, dimethylformamide, dimethylsulfoxide, hexamethyl phosphoric triamide. Useful catalysts are for instance metals such as copper powder or metal salts such as Cu* or Ag+ salts.

The following, general reaction scheme A is illustrative of several of the reactions useful to produce the starting compounds of the formula XVIII. In this reaction scheme unless otherwise indicated R is lower alkyl and A, R^, R^, R^ and Rg are as in formula I1. It is obvious to one skilled in the art that certain of the substituents may be attacked during the reactions below hut such vulnerable groups may he modified before or after such reaction is carried out. The reactions shown in scheme A may also be performed with the corresponding 437G7 N-oxides thereof [A = -C(Sg)=N(g 0)-] but any H-oxide moiety present in compounds of formula VI will be removed during the conversion VI —> VII. Λ /’Λ'·' ·* ’* »1.. 437G7 Step II - III Compounds of foraiula III are produced by the nitrosation of compounds of formula II. Such a nitrosation may be effected by in situo formed nitrous acid, Reagents which may be employed include (l) alkali metal nitrites, i.e., sodium nitrites, in the presence of organic or inorganic acids, i.e., glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites, i.e., methyl nitrites, in the presence of an inert solvent such as an alcohol, chlorinated hydrocarbon or, for example, dimethyl·· formamide; 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 effected at around or below room temperature, i.e., ia the range of -2O°C to 25°C. An amino group or an alkylamino group present in the molecule may be protected during the nitrosation reaction, e.g., by means of acylation. Such protecting group can be removed at a convenient later stage of the reaction sequence.

Step VIII - IX Compounds of formula IX may be produced by the reaction of the compounds of formula VIII with· dimorpholinophosphinic chloride. The reaction of formula VIII compounds with the phosphorylating agent to yield compounds of formula IX is accomplished by treatment of formula VIII compounds with a strong base sufficient to ionize the formula VIII compounds to form the corresponding anion. Suitable bases include alkali metal alkoxides, such as pomassiuntert.- 13 - such as sodium hydride, and alkyl lithium compounds, such as n-butyl lithium. The reaction temperature ranges from 0°C to 100°C and the reaction is carried out preferably in an aprotio polar inert solvent, i.e., one that would solubilize the ambient salts of the formula VIII compounds totally or at least partially. Preferred solvents are ethers, e.g,, tetrahydrofuran or dioxane or tertiary amides, e.g., dimethylformamide.

It is evident that any amino or substituted amino group should be present in protected form in this reaction step the protective moiety can be removed afterwards at any convenient stage, e.g. subsequent to the formation of compound of formula XII.

Step III or IX —> IV Compounds of formula III or formula IX may be condensed with the anion generated from malonic ester of the formula ^ηΛο.

CH 'COOR wherein R is lower alkyl, to produce compounds of formula IV. The anion is generated by deprotonating malonic ester with a suitable strong base such as alkali metal· or alkaline earth metal alkoxides, hydrides or amides, The reaction of the formula III or IX compounds with the malonic ester anion is preferably effected in a solvent such as hydrocarbons, e.g., benzene, toluene, hexane, e+hers e.g., dioxane, THP, diethyl ether, DMF, DMSO etc,, at a temperature range of below room - H 437G7 temperature to 150°C, preferably 0°C to 100°C, most preferably room temperature.

Compounds of the formula V are produced by the decarboxylation of compounds of the formula IV by reacting the formula IV compounds with an alkali metal hydroxide such as ITaOH or KOH in a suitable solvent such as alcohols, ethers or DMSO at a temperature range of room temperature to reflux temperature, preferably 60°C to 100°C.

Sten V —A VI Compounds of formula VI are produced by the nitrosation of compounds of formula V by reactingsame with nitrous acid generated from, for example, an alkali metal nitrite, alkyl nitrite or nitrosyl chloride, by reaction with organic or inorganic acid. Suitable solvents for the nitrosation reaction include, ethers, alcohols, water acids, e.g,, acetic acid, DI-IF, DMSO and chlorinated hydrocarbons. The reaction may be carried out at about room temperature although such temperature is not critical. Sten VI —4 VII Compounds of the formula VII are produced by the reduction of compounds of formula VI e.g., with Raney nickel and hydrogen or with zinc and acetic acid. This reduction results in the predominant production cf compounds of formula VII with concurrent side production of small amounts of several possible isomers, i.e., compounds of the formulae COOR VII Δ COOR -15 vnn W Θ NH COOR Vil Ω . η « Q 7 ***It should be noted that the above reductive step would reduce vulnerable groups; if present, as R^, such as a 7-position N02 or a 7-position CN. These groups may be replaced by methods known in the art and set forth in Patent Specification No. 43762 .

Step VII —» XII Compounds of the formula XII are then formed by the reaction of formula VII compounds with an alkanoic acid ortho ester of the formula r1«c(or)3 wherein R is lower alkyl and R^ is hydrogen, lower alkyl, alkoxy lower alkyl or halo lower alkyl, optienally in the presence of an acid catalyst, e.g., an organic or Inorganic acid; e.g., p-toluene sulfonic acid, phosphoric acid, etc., and at room temperature or above, i,e., ?5°C to 150°C,:in which instance the cyclization to compound XII occurs spontaneously. Technical equivalents of the above ortho ester include ortho amides, e.g., the dimethyl acetal of ΓΓ,Ν-dimethyl formamide; Ν,Ν,Ν',Ν',Ν,!!11hexamethvlmothanetriamine; nitriles, e.g., acetonitrile; ester imidates, e.g., It is evident that any amino or alkylamino group present has to be protected during this reaction.

Step VII —> XI Compounds of formula XI nay be formed by the acylation of formula VII compounds with a compound of the formula R^COX or (r!,1C0)20 wherein X is halo and R^' is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl. Solvents for the above process step include methylene - 16 ♦ ** chloride, ethers, chlorinated hydrocarbons, etc., preferably in combination with an acid acct’ptor such as an organic or inorganic base such as triethylamine, pyridine or an alkali metal carbonate. The reaction may be effected at above or below room temperature but preferably is >’7G7 carried out at room temperature XI are isomeric in nature, that of the following stereochemical Compounds of the formula is, m?.y .exhibit either structures COOR XI B Step IX - XII Compounds of the formula XII may also be formed by dehydration of formula XI compounds or isomers thereof with concurrent cyclization by heating. This reaction step may be carried out with or without solvent, e.g., DMF, ethylene glycol, hexamethyl phosphoric trianide, at a temperature range of 100°C to 300°C, preferably at 150°C to 25O°C, e.g., 200°C, with or without the presence of catalysts and water binding agents.

Sten IX — X Compounds of the formula X may be formed by the condensation reaction of a compound of the formula IX with the anion generated from acylamino malonic ester of the formula COOR © q-NHCOR, COOR wherein R is lower alkyl and R·,1 is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl, to produce a compound of formula X. 3ho anion in generated - 17 f m by deprotonating acylamino malonic ester with a suitable strong base such as alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of the formula IX compounds with, the acyl amino malonic ester anion is preferably effected in a solvent such as hydrocarbons e.g., benzene, toluene, hexane, ethers e.g.,’dioxane, THF, diethyl ether, DMF, DMSO etc., at a temperature range of below room .temperature to 150°0, preferably 0°C to 100°C, most preferably room temperature.

Step X -¾ XI Compounds of formula XI and isomers thereof are formed by the decarboxylation of formula X compounds with an alkali metal alkoxides in a solvent such as ethers, alcohols, DMSO, DMF, etc., at above or below room temperature, preferably at room temperature. Compounds of formula' X and XI need not be isolated but can be converted in situ into compounds of formula XII.

Stew VII —) XIII Compounds of the formula XIII are formed by the reaction of formula VII compounds with an aldehyde of the formula R^CHO, wherein R1 is as in formula I, but any amino or substituted amino group and preferably any RCOgrouji should be present in protected form. The protecting moiety can.be removed afterwards, e.g. subsequent to the formation of compound of formula XII. Solvents suitable for this reaction step are hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, DMF, DMSO, etc., with or without the presence or water-binding agents, e.g., molecular- sieves at above or below room temperature, -Ί8 43767 preferably from room temperature to reflux temperature of the solvent.

Step XIII —A XII Compounds of the formula XIII may be converted to formula XII compounds by oxidation in situ by oxidizing agents such.as manganese dioxide, air, oxygen, etc.

A final compound cf formula XII wherein R^ is amino can be converted into a corresponding compound wherein •R^ 33 nitro or cyano via a Sandmeyer reaction as set forth in Patent Specification No. 43762 .

Another method for the preparation of compounds of formula XII wherein R^ is nitro or cyano consists in preparing a corresponding compound of formula VII. The latter compound can be prepared by reacting a corresponding compound of formula IX with a protected emino malonic ester of the formula COOR wherein R is lower alkyl and Z is benzyloxycarbonyl, converting the compound of formula X, wherein R^ is benzyloxy and is nitro or cyano, thus obtained to a corresponding compound of formula XI as described above for step X — ·> XI and subjecting the compound thus obtained to a treatment with hydrogen bromide in glacial acetic acid yielding a compound of formula VII wherein R^ i3 nitro or cyano. The intermediates of formula X and XI need not be isolated.

The compuund of formula VII thus obtained is further converted to the compound of formula XII via reacting ·. 19 steps VII —} XIII and XIII -¾ XII described above.

Step XII —» XVIII 'Formula XVIII compounds are formed by hydrolyzing formula XII compounds to the corresponding acids, preferably with alkali metal hydroxides, e.g., NaOH or EOH. This hydrolysis is conveniently effected in an inert solvent. Suitable solvents are alcohols, e.g., methanol, ethanol; ethers, e.g., dioxane, tetrahydrofurnn; dimethylformamide, in combination with water, It is preferable to conduct.this reaction 3tep at a temperature between room temperature and the boiling point of the reaction mixture.

It is evident that during this reaction step an acyloxyalkyl group present will be hydrolyzed to the corresponding hydroxyalkyl group which in turn can be converted back to the acyloxyalkyl group at a convenient later stage. An R^-group in the meaning of -COOR^q will alio be hydrolyzed and decarboxylated to a corresponding compound wherein R^ is hydrogen. The -OOOR^q moiety can be reintroduced from a formyl or hydroxyl methyl group in known manner, A haldalkyl group present may be affected in this reaction step yielding a corresponding hydroxyalliyl compound which may also be cohverted back to the haloalkyl compound at a later stage in usual manner. Any compound of formula XII wherein R^ is hydroxyalkyl should be protected during this halogenation reaction step, e.g. in form of the tetrahydropyranylether derivative thereof.

In compounds of formula I1 wherein a ketal group - 20 437G7 e.g., an ethylendioxy group is present in an imidazobenzodiazepine, such ketal group may be converted to the corresponding ketone by subjecting the ketal group to a mild acid hydrolysis. The ketone can then be converted to a secondary or tertiary alcohol which is racemic in nature. The reaction conditions therefore, for the above two steps, are found in U.S. Patent No, 2 846 410.

. I Compounds of the formulae 1' and ID and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants,, sedatives and unticolvulsants and many are particularly useful when utilized in intravenous aid intramuscular preparations because of the acid addition salts' solubility in aqueous solution.

The compounds of formula 1' and their acid addition salts prepared by the process of the invention can be embodied in pharmaceutical dosage formulations containing from about 0.1 to about 40 mgs most preferably 1-40mg with dosage adjusted to species and individual requirements.

The compounds and their pharmaceutically acceptable salts can be administered internally, for example, parenterally or enterally, in conventional pharmaceutical dosage forms. For example, they can be incorporated in conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like to provide tablets, elixirs, capsules, solutions, emulsions and the like according to acceptc,ble pharmaceutical practices.

The process of the invention is illustrated in the following examples.

— C. 1 — Example 1 A suspension of 1.5 g of 8-chloro-6-(2-fluorophenyl)4H-imidazo[l,5-a][l,4]benzodiazepine 3-carboxylic acid in 10 ml of mineral oil was heated up to 230° for 5 minutes. The reaction mixture was partitioned between UT hydrochloric acid and ether. The aqueous phase was made alkaline with ammonia and was extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed over 6o g of silica gel U3ing 25% (v/v) methylene chloride in ethyl acetate.

The les3 polar 8-chloro-6-(2-fluorophenyl)-6H~imidazo [l5,-]-[l,4]benzodiazepine was crystallized from ethyl acetate to yield colorless crystals, m.p. 195-196°.

The more polar component was crystallized from ether to yield 8-chloro-6-(2-fluorophenyl)-4H-imidazo[l,5-a][J,4]benzodiazspine, m.p. 150-151°.

The starting material can be prepared as follows: A solution of 200 g (0.695 m) of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-2H-l,4“benzodiazepin-2-ohe in 2 1 of tetrahydrofuran and 250 ml of benzene was saturated with methylamine with colling in an ice bath. A solution of 190 g (l m) of titaniumtetraehloride in 250 ml of benzene tbs added through a dropping funnel within 15 minutes. After addition the mixture was stirred end refluxed for 3 hours. Water (600 ml) Was added slowly to the cooled reaction mixture. The inorganic material was separated by filtration and was washed well with tetrahydrefuran. The water layer was separated end the organic phase was dried over sodium-sulfate and evaporated. The - 22 43767 crystalline residue of 7-chloro-5-(2-fluorophenyl)-2methylamino-3H-l,4-benzodiazepine was collected, m.p. · 204-206°. The analytical sample was recrystallized frcm methylene chloride/ethanol, m.p. 204-206°.

A) Sodium nitrite, 8.63 g (0.125 m), was added in three portions over a 15 minute period to a solution of 30.15 g (0.1 m) of 7-chloro-5-(2-fluorophenyl;-2-methylamino-3H-l,4benzodiazepine 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, were dried over sodium sulfate and evaporated, at the end azeotropically with toluene to yield 29 g of crude 7-chloro-5-(2-fluorophenyl)2-(N-nitroscmethylamino)-3H-l,4-benzodiazepine as a yellow oil.

B) Sodium nitrite (27.6 g, 0.4 m) was added in portions over a period of 30 minutes to a solution of 90.45 g (0.3 m) of 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H1,4-benzodiazepine in 400 ml of glacial acetic acid. Following completed addition, the mixture was stirred at room temperature for 1 hour and was diluted with 1 1 of water and extracted with methylene chloride. The extracts were washed twice with water and then with 10% aqueous sodium carbonate solution. The solution was dried and evaporated to yield'crude 7-chloro-5-(2-fluorophenyl)-2(Ii-nitrosomethylamino)-3H-lj4-benzodiazepine as a yellow oil.

This material was dissolved in 300 ml of dimethy1- 23 437 017 formamide and was added to a mixtureof 150 ml of dimethyl malonate, 40.4- g of potassium t-butoxide aid 500 ml of dimethylformamide which had been stirred at room temperature for 10 minutes. The reaction mixture was stirred under nitrogen overnight at room temperature, was acidified by addition of 50 ml of glacial' acetic acid, diluted with water and aqueous sodium carbonate solution, were dried over sodium sulfate and evaporated. Crystallization of the residue from ethanol yielded 7-chloro-13,-dihydro-2(dimethoxymalonylidene)-5-(2-fluorophenyl)-2H-l,4-benzodiazepine as colorless crystals, m.p, 170-172°. For analysis the product was recrystallized from methylene chloride/ ethanol, melting point unchanged.

A mixture of 20 g (0.05 m) of 7-chloro-l,3-dihydro-2(dimethoxymalonylidene)-5-(2-fluorophenyl)-2H-l,4-benzodiazepine, 400 ml of methanol and 3.3 g (0.059 m) of potassium hydroxide was heated to reflux under nitrogen for 5 hours. After evaporation of the bulk of the solvent, the residue was gradually diluted with water and the precipitated crystals were collected, washed with water and dried to leave 7-chloro-13,~dihydro-5-(2-fluorophenyl)-2-(dimethoxy carbonylmethylene)-2H-l,4-benzodiazepine, m.p, 158-160°.

' For analysis it was recrystallized from methylene chloride/hexane, m.p. 161-162°.

Sodium nitrite (3.8 g, 1,125 m), was added to a solution of 28 g (0.08 m) of 7-chloro-l,3-di.hydro-5-(2fluorophenyl)-2-(cethoxycarbonylmethylene)-2H -1,4-benzodiazepnne in 2$0 ml glacial acetic acid. The mixture was stirred at room temperature for 10 minutes and then diluted 437c? with 250 ml of water. The crystalline product was filtered off, washed with water, methanol and ether and dried to leave 7-chloro-5-(2-fluorophenyl)-alpha-hydroxyimin.o-3H1.4- benziazepine-2-acetic acid methyl ester as yellow crystals, m.p. 238-241° (dec.). 7-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H1.4- benzodiazepine-2-acetio acid methyl ester (11.25 g, 0.03 m) was dissolved in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol by warming. Raney nickel (20 g)ras added and the mixture was hydrogenated at an atmospheric pressure for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated at the end azeotropically with toluene. The residue was dissolved in 100 ml of methanol. After addition of 10 ml of triethyl ortboformate and 5 ml of ethanolic hydrogen chloride (57$), the mixture was heated to reflux for 10 minutes. It was then evaporated and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer was separated, dried and evaporated and the residue was crystallized from ether to yield methyl 8-chloro-6(2-fluorophenyl)-4H-imidazo[1,5-a][l,4]-benz odiasepine 3-carboxylate which was recrystallized from methylene chloride/ether/hexane, m.p. 179-181°.

A mixture of 1.48 g (0.004 m) of methyl 8-chloro6-(2-fluorophenyl)-4H-imidazo[l,5-a][l,4]benzodiasepine 3-carboxylate, 0.5 g (0.009 m) of potassium hydroxide, ml of methanol and 2 ml of water was heated to reflux for 3 hours under an atmosphere of nitrogen. The methanol - 25 was partially evaporated.and the residue was acidified with glacial acetic acid and diluted with water while the solution was still hot/ The crystals were collected after cooling In ice/water and were dried in vacuum to yield 8-chloro-6-(2-fluorophenyl-4H-irflidazo[l,5-a][l,4[benzodiazepine 3-carboxylio acid, m.p. 245-24.7° (dec.).

Example 2 A solution of 0.5 g (0.00129 m) of ethyl 8-cyano-6(2-fluorophenyl)-1 -methyl-4H~imidazo[l,5-a][l,4]benzodiaze pine-3-carboxylate in 100 ml of ethanol and 10 ml of water was treated with 0.14 g.(0.0026 m) of potassium hydroxide. After refluxing for 30 minutes the reaction was evaporated and 10 ml of water was added.· This was scidified with acetic acid, filtered stnd extracted with 20 ml of dichloro methane, which was separated, dried and evaporated.

About 0.2 g of the hydrolyzed product was obtained from the filtration, and the same amount was obtained from the extraction. This material was added to 3 ml of dry hexamethylphosphoramide and kept at 200-205° for 30 minutes under argon. It was cooled and 50 ml of ice water and 1 ml of ammonium hydroxide were added. The solution was filtered and the filtrates were extracted with 25 ml of dichloromethane arid evaporated to dryness. Water was added and the solution was filtered and the combined precipitates were dissolved in dichloromethane and developed on 2 silica gel thick layer plates in a solution of. ethyl acetate containing 15% methanol. The silica gel containing the product was scraped off (Rf 4-5), stirred with methanol and filtered. This was crystallised from a - 26 43767 mixture of isopropanol and ether to give 8-cyano-6-(2fluorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]bensodiazepine as off white prisms, m.p. 198-203°.

The starting material can be prepared as follows: A solution of 10 g (0.0353 m) of 7-cyano-l,3-dihydro5-(2-fluorophenyl)-lH-l,4-benzodiaaepin-2-one in 150 ml ·> · ·}of dry tetrahydrofuran under argon was treated with 2.4 g (0.0537 m) of 54/ sodium hydride and the reaction was stirred and refluxed for 1 hour. This was cooled to 0° and 1J.7 g (0.0537 m) of phQsphorodimiorpholidic chloride was added. After 18 hours the reaction mixture was filtered, ooncentrated to a small volume and ether was added. The precipitate was filtered and reerystallized from a mixture of dichloromethane end ether to give 7-cyano-5-(2-flUorophenyl)-2-bis-(morpholino)phosrhinyloxy-3H-l,4-benzodiaze~ pine as white rods, m.p, 194-197°.

To 100 ml of dry Ν,Ν-dimethylformamide under nitrogen was added 1.6 g (0.036 m) of 54/ sodium hydride, and 3,3 g (0.038 m) of acetamidodiethyl malonate was added with stirring. After 30 minutes 10 g (0.02 m) of 7-cyano-5-(2-fluorophenyl)-2-bis(morpholino Jphosphinyloxy3H-l,4-benzodiazepine was added and after 64 hours the reaction was poured into ice water containing 4 ml of acetic adid. . This was filtered and the solid was dissolved in 100 ml of dichloromethane, which was washed with 50 ml of water, dried over anhydrous sodium sulfate and concentrated to a small volume. This solution was chromatographed over a column of Florisil (Trade Mark) and eluted with 2 1 of dichloromethane which was discarded. It was then - 27 4370? eluted with 1 1 of a mixture of dichloromethane and ether (lO/l) and then with 2 1 of ether. The ether fraction was recrystallized twice from a mixture of dichloromethane and ether to give (acetylamino) [7-cyano-5-(2-fluorophenyl)3H-l,4-bensodiazepine-2-yl]malonic acid diethyl ester as white prisms, m.p. 138-140°.

The column was eluted with 1.5’ l’’of a mixture of ethyl acetate and methanol (lO/l). The eluent was concentrated and the residue was crystallized from ether. Recrystallization from a mixture of dichloromethane and ether gave ethyl S-cyano-6-(2-fluorophenyl)-l-methyl-4Himidazo[l,5-a][l,4]henzodiazepine-3-carboxylate as off white prisms, m.p. 272-274°.

Example 3 A suspension of 1.5 g (5-48 m) of 8-chloro-6-(2fluorophenyl)-l-phenyl-4H-imidazo[l,5-a][l,4]benzodiazepine3-carboxylic acid in 20 ml of mineral oil was stirred vigorously at 190° for l/2 hr. The dark suspension was then slurried with hexane and extracted twice with IN hydrochloric acid. The acidic aqueous layer was then washed once with hexane and neutralized with 5% aqueous sodium carbonate. The precipitated product was collected and air dried: concentration of the filtrate gave an additional yield of 8-chloro-c-(2-fluorophenyl)-1-phenvl-4H-imidazo[l,5-a][l,4]benzodiazepine as an off-white solid. A.n analytical'sample was obtained by column chromatography on silica gel eluting with ethyl acetate, m. p. 241-245°.

The starting materiel can be prepared as fo.1 lows: A solution of 3.75 g (0.01 m) of 7-chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-l,4-benzodiazepine-2-acetic 437G7 acid methyl ester ir. 300 ml of tetrahydrofuran and 200 ml of methanol was hydrogenated at atmospheric pressure for 1 1/2 hour in presence of one teaspoonful of Raney nickel.

The catalyst was separated by filtration over Celite (Trade Mark) and the filtrate was evaporated under reduced pressure, at the end azotropically with toluene. The residue was dissolved in 20 ml of pyridine and treated with 4 ml of benzoylchloride. After sitting at room temperature fox* 15 minutes, the reaction mixture was partitioned between methylene chloride and IN sodium hydroxide solution.

The organic layer was dried and evaporated, at the end azeotropically with toluene. Crystallization of the residue from ether yielded 2-[benzoylamino)methoxyearbonylmethylene]-7~chloro-5-(2-fluorophenyl)-l,3-dihydro-2H-l;4“ benzodiazepine, m.p. 210-213°. The analytical sample was recrystallized from ethyl acetate/hexane, m.p. 217-219° with softening-at 150-160°, A solution of 1.15 g (2.5 mmol) of 2[(benzoylamino)methoxycarbonylmethylene].-7-chloro-5-(2-fluorophenyl)-l,3dihydro-2H-l,4-benzodiazepine in 10 ml of hexa-methyl phosphoric trianide was heated to reflux for 10 minutes.

The dark mixture was partitioned between water and ether/ methylene chloride. The organic layer was washed with water, dried and evaporated. The residue was dissolved in methylene chloride and filtered over activated aluminum oxide with ethyl acetate. The filtrate was evaporated and chromatographed over 20 g of silica gel using 10% (v/v) ethyl acetate in methylene chloride. Crystallization of the combined clean fractions from- ether/hexane gave - 29 43767 methyl 8-chloro-6-(2-fiuorophenyl)-l-phenyl-4E-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylate, m.p. 208-209°.

To a solution of 2.66 g (5.77 mmol) of methyl 8chloro-6-(2-fluorophenyl)-l-phenyl-4H-imidazo[l,5-a][l,4} benzodiazepine-3-cafboxylate in 50 ml of refluxing methanol was added a solution of 755ng (11.5 mmol) of potassium hydroxide in 10 ml of water and the resulting mixture was heated for 2.5 hr. The solvent was removed in vacuo, the residue was dissolved in 50 ml of hot acetic acid end the solution was then poured, into 100 ml of cold water.

The product T.;as collected, washed with water and air dried to give 8-chloro-6-(2-fluorophenyl)-l-phenyl-4H-imidazo [l,5-a][l,4]benzodiazepine-3-carboxylic acid as an offwhite solid. As analytical sample was recrystallized from benzene, m.p. 267-269°. · Example 4 A solution of 1.3 g of 8-bromo-l-methyl-6-(2-pyridyl)~ 4H-imidazo-[l,5-a]Ll,4]benzodiazepine-3-carboxylic acid in 20 ml of ethylene glycol was heated tc reflux for 1 hour. The reaction mixture was partitioned between water and methylene chloride/toluene. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from ether/2-propanol gave 8-bromo-l-methyl-6--(2-pyridyl)-4Himidazo[l,5-a][l,4]benzodiazepine as tan crystals. The analytical sample was recrystallized from ethyl acetate/ hexane, m.p. 189-190°.

The starting material can be prepared as follows: Fifty-foUr percent sodium hydride in mineral oil - 30 dispersion (ll g, 0.25 m) was added in portions to a stirred solution of 63.2 g (0.2 n) of 7-brono-l,3-dihydro5_(2-pyridyl)-2H-l,4-bcnzodiazepin-2-one in 1 1 of tetrahydrofuran under argon. After refluxing on a steam bath for 1 hour, the solution was cooled to room temperature and treated with 76.2 g (0.3 m) of dimorpholinophosphinic chloride portionwise. Stirring at room temperature was continued for 5 hours. The dark mixture was filtered through Celite. Concentration of the filtrate invacuo, and boiling the dark residue, with ether gave tan crystals of 7-bromo-2-[bis(morpholino)phosphinyloxy]-5-(2-pyridyl)3H-1,4-benzodiazepine. A sample was reerystallized by dissoling it in 2 ol of methylene chloride, filtering, diluting with 10 ml of ethyl acetate and cooling in an ice bath to give light tan plates, m.p. 180-182°.

Diethyl acetamidomalonate (43 g, 0.2 m) was added to a suspension of 10 g (0.2 m) of a dispersion (5'0%) of sodium hydride in mineral oil in 500 ml of dry dimethyl- . formamide. This mixture was stirred under argon for 1 hour at room temperature and for 20 minutes with heating on the steam bath. 7-Bromo-2[bis(morpholino)phosphinyloxy]5-(2-pyridyl)-3H-l,4-benzodiazepine (53·4 g, 0.1 m) was then added to the reaction mixture brought back to room temperature. After stirring for lbour at room temperature, it was again heated on the steam bath for 2 hours. The cooled solution was partitioned between water and methylene chloride/ether. The organic phase was separated, washed with water, dried and evaporated. The residue was crystallized with seeding from ethyl acetate/ether to give - 31 e thyl-8-bromo-l-methyl-6-(2-pyridyl)-4H-imidazo[l,5-a][l,4]benzodiazepine 3-carboxylate as off-white crystals, m.p. 240-243°. Seeds were obtained by chromatographic purification over 30 fold amount of silica gel using 57» (v/v) methanol in ethyl acetate. The analytical sample was recrystallized from ethyl acetate, m.p. 243-244°. *:· 'Ά./* A mixture of 2.15 g (5 mmol) of ethyl 8-bromo-lme thyl-6-(2-pyridyl)-4H-imidazo[l,5-a][1,4]benzodiazepine3-carboxylate, 50 ml of methanol, 0.84 g (15 mmol) of potassium hydroxide and 2.5 ml o.' water was heated to reflux for 5 hours. The bulk of the methanol was evaporated and the residue was partitioned between water and ether. The aqueous phase was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated. Crystallization of the residue from methylene chloride/ethyl acetate gave S-bromo-l-methyl6-(2-pyridyl)-4H-imidaz o[l,5-a][1,4 Jbenzodiazepine-3carboxylic acid as colorless crystals which were recrystallized from methanol for analysis, m.p. 245-250° (dec.) with previous sintering.

Example 5 A mixture of 1.5 g of 6-(2-chlorophenyl)-l-methyl8-nitro-4H-imidazo[l,5-a][l,4]benzodiazepine-5-carboxylic acid and 10 mi of ethylene glycol was heated to reflux for 1 hour. The reaction mixture was then partitioned between methylene chloride/toluene and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, dried and evaporated. The residue was dissolved in 10 ml of 2-propanol and treated with 0.6 g - 32 ^37βγ of maleic acid. The salt crystallized upon addition of ether to the warn solution. It was collected, washed with 2-propanol and ether to yield 6-(2-chlorophenyl)1- methyl-8-nitro-4H-imidazo[l,5-a][l,4]benzodiazepine 5 maleate as tan crystals which were recrystallized from 2- propanol for analysis, m.p. 150-152°. The free base liberated from this salt was crystallized from ethyl acetate/hexane, m.p. 170-173°· The starting material can be prepared as follows: Ϊ0 Diethyl acetamidomalonate (^3 g, 0.2 m) was added to a suspension of 10 g (0.2 m) of sodium hydride (50% in mineral oil) in 500 ml of dry dimethylformamide. The mixture was heated to 50° for 30 minutes under argon. After addition of 53 g (0.1 m) of 5-(2-chlorophenyl)-2-[bis(morpholino)15 phosphinyloxyj-7-nitro-3H-l,4-benzodiazepine, the reaction mixture was heated on the steambath for 1 hour. The cooled brown mixture was partitioned between water and methylene chloride/ether. The organic phase was washed with water, dried and evaporated. The residue was chromato20 graphed over 1 kg of silica gel using ethyl acetate. The clean fractions were combined and evaporated. Crystallization of the residue from methylene chloride/ether yielded ethyl 6-(2-chlorophenyl)-l-methyl-8-nitro-4K-imidazo[l,5-a][1,4]benzodiazepine-3-carboxylate as light yellow crystals, m.p. 233-234°. .The analytical sample was recrystallized from ethyl acetate, m.p. 234-235°· A mixture of 4.25 g (0.01 m) of ethyl 6-(2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo ji,5-aJ [1,4] benzodiazepine-3-carboxylate, 100 ml of methanol,. 1.12 g (0,02 m) of potassium hydroxide and 4 ml of water was heated to reflux under nitrogen for 3 hours. The hulk of the methanol was evaporated and the residue was partitioned between water and ether. The aqueous phase was washed with ether, acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated.

Crystallization of the residue from methylene chloride/ ether acetate yielded 6-(2-chlorophenyl)-l-methyl-8nitro-4H-imidazoLl,5-a][l,4]benzodiazepine 3-carboxylic acid, m.p. 272-274° (dec.). The analytical sample was reerystallized from methanol/ethyl acetate, m.p. 274-276° (dec.).

Example 6 A suspension of 1.2 g of l-methyl-8-nitro-6-phenyl4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylic acid in 15 ml of hexamethyl phosphoric acid triamide was heated to reflux for 3 minutes. The cooled solution was partitioned between methylene chloride/ether and aqueous sodium bicarbonate solution. The organic phase was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed over 30 g of silica gel using 3/ (v/v) of ethanol in methylene chloride. Crystallization of the clean fractions from ether/methylene chloride/ethyl acetate yielded l-methyl-8-nitro-6-phenyl-4K-imidazo[l,5-a][l,4]benzodiazepine with m.p. 168-170°. It was converted to the maleate salt which crystallized from ethyl acetate with 0,5 m of the solvent, m.p. 125-128°.

The starting'material can be prepared as-follows: g (0.125 m) of sodium hydride dispersion (50% in mineral oil), was added to a solution of 28.1 g (0.1 m) of l,5-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2one in 300 ml of dry tetrahydrofuran. After stirring for 1 hour at room temperature 30.2 g (0.12 m) of dimorpholinophosphinic chloride was added and stirringvas continued for 4 hours. The product was crystallized by addition of water and ether. The precipitate was collected and dissolved in methylene chloride. The solution was dried and evaporated, and the rpsidue was crystallized from ethyl acetate to yield crude 7-nitro-2-[bis(morpholino) phosphinuloxy]-5-phenyl-3H-l,4-benzodiazepine, m.p. 208-209°.

Part of this material was added to a mixture of 8.6 g (0,04 m) of diethyl acetaminomalonate, 2 g (0.04 ffi) of sodium hydride suspension (5Ο?ί In mineral oil) and 75 ml of dimethylformamide which had been heated at 40° for 30 minutes. After addition the reaction mixture was heated for 30 minutes on the steambath and was then partitioned between water and ether. The organic phase was washed with water, dried and evaporated. The residue was chromatographed over 250 g of silica gel using ethyl acetate. The combined clean fractions were evaporated and the residue was crystallized from methylene chloride/ether to yield e thyl 1-me thyl-8-nitro-6-phenyl-4H-imidaz o[1,5-a][1,4]benzodiazepine-3-carboxylate as off-white crystals with m.p. 240-241°. The analytical sample was recrystallized from ethyl acetate.

A mixture of 1.95 σ (5 mmol) of ethyl l-methyl-8-nitro6-nhenyl-4H-imidazo £l,5-aj ^.,4^ benzodiazepine-3-carboxylate. - 55 50 ml of methanol, 0.56 g (0.01 m) of potassium hydroxide and 2 ml of water was heated to reflux under nitrogen for 3 hours. After partial evaporation of the solvent the residue was acidified with 2 ml of glacial acetic acid and was partitioned between methylene chloride containing 10% (v/v) of ethanol and water. The organic phase was dried and evaporated. Crystallization of tlie residue from ethyl acetate/methanol yielded l-methyl-8-nitro-6-phenyl4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylic acid as straw colored crystals which were recrystallized from the same solvents for analysis, m.p. 240-243° (dee.).

Example 7 8-chloro-6-(2-f luoro nhen.yl) -l-methyl-AH-imidazo Γ1,5-a][l.4] benzodip-zenine, and 8-chloro-6-(2-fluorophenyl)-l-methylSH-lmidazofl,5-a1[l.4lbenzodiazepine A solution of 185 mg of 8-chloro-6-(2-fluorophenyl)l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylic acid in 5 ml of ethylene glycol was heated to reflux for 1 hr under an. atmosphere of nitrogen. The cooled reaction mixture was partitioned between ether/toluene and saturated sodium bicarbonate solution. The organic ' . phase was separated, dried and evaporated. The residue was chromatographed over 7 g of silica gel using 3% (v/v) of ethanol in methylene chloride to yield both the less polar 8-chloro-6-(2-fluorophenyl)-l-methyl-6H-imidazo [l,5-a][l,4]benzoiazepine with mp 177-179° and 8-chloro6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepir.® with m.p. '151-153°.

The starting material can be prepared as follows: - 36 43767 7-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3Hl, 4-benzodiazepine-2~acetic acid methyl ester (11.25 g, 0.03 m) was hydrogenated at atmospheric pressure with Raney nickel in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol. The nickel was filtered off and the filtrate was evaporated. The residue was dissolved in 100 ml of methanol and 11 mL of triethyl orthoacetate and 5 ml of ethanolic hydrogen chloride (5%) was added.

The mixture was heated to reflux for 10 minutes, was evaporated and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The methylene chloride solution was dried and evaporated and the residue was chromatographed over 300 g of silica gel using methylene chloride/ethyl acetate 1:3 (v/v). The clean fractions were combined and evaporated and crystallized from ether to yield methyi-8-chloro-6-(2-fluorophenyl)-lmethyi-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylate, m. p. 162-164°. The analytical sample was recrystailised from ethyl acetate/hexane.

A mixture of 7.7 g (0.02 m) ofrothyl 8-chloro-6(2-fluorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxyla!;e, 2.24 g (0.04 m) of potassium hydroxide, 200 ml of methanol and 6 ml of water was heated to reflux for 3 l/2 hours. The solvent was partially evaporated and the residue was acidified with glacial acetic acid and diluted with water while hot. The precipitated crystals were collected after cooling in ice-water and were dried- to yield 8-chloro-6-(2-fluorophenyl) -l-methyl-4H-imidazo [1,5-,] [,4] benzodiazepine 3- 37 437 67 carboxylic acid. For analysis it was recrystallized from methylene chloride/’methanol/ethyl acetate, m.p. 271-274° (dec.). - 38 43767

Claims (11)

1. What we claim ia:

1. A process for the preparation of imidazo[l,5-a][l,4] diazepine compounds of the general formula 1' wherein A represents -C(Rg)=N«: R^ represents hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl; R 2 represents hydrogen; Rj represents hydrogen or lower alkyl; Rg represents phenyl, monosubstituted phenyl, di-substituted phenyl, pyridyl or mono-substituted nyridyl; ζζ]Γ represents the group j .. a) b) - cl - d) wherein X is hydrogen, chlorine, bromine or iodine, Ϊ is hydrogen or lowei’ alkyl, R^ represents hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy, lower alkyl or lower alkanoyl; and Rj represents hydrogen, and pharmaceutically acceptable acid addition salts of these compounds which in the case of compounds of formula I’ wherein { Z ]f is R^-phenyl have a structure in which the diazepine ring is opened by cleavage of the C/N-doubls bond in the 5,6-position, which process comprises decarboxylating a compound of formula and, ifdasired, resolving a racemic compound thus-produced into its optical enantiomers, or, if desired, converting a compound thus-produced into a pharmaceutically acceptable acid .addition salt by reaction with a suitable acid.

2. A process as claimed in. claim 1 wherein there are prepared compounds of formula 1' wherein X in the groups b)'and c) is chlorine, bromine or iodine.

3. A process as claimed in claim 1 ' wherein there Is prepared a compound of formula 1' wherein R^ is hydrogen or lower alkyl, hydrogen, nitro or halogen, Rg is phenyl or halo, nitro or lower alkyl substituted phenyl and R-j is hydrogen.

4. A process as claimed in any one of claims 1 to 3, wherein R^ is 8-halo and Rg is 2-halophenyl.

5. A process as claimed in claim 4,wherein R^ is 8-chloro and Rg is 2-chloro- or 2-fluorophenyl.’

6. A process as claimed in any one of claims 1 to 5, wherein is methyl,.

7. A process as claimed in any one of claims 1, 2, 4, 5 or 6, wherein R-j is methyl.

8. A process as claimed in claim 1, wherein 8-chloro6-(2-fluorophenyl)-1-me thyi-4E- -imidas o[l,5-a][l,4]benzodia^epine is prepared.

9. A process as claimed in claim 1, wherein S-chloro40 6-(2~fluorophenyl)-l,4-dimethyl-4H-imidazo[l,5-a][l,4]- 3 7 6 7 benzodiazepine is prepared.

10. A process as claimed in claim 1 substantially as hereinbefore described with reference to any one of the 5 specific Examples.

11. A compound of the general formula 1' when prepared by a process as claimed in any one of the preceding claims.