NO179369B - Reaction mixture for the preparation of antiviral tetrahydroimidazo [1,4Abenzodiazepin-2-one - Google Patents

Description

The present invention relates to a reaction mixture for the production of antiviral tetrahydroimidazo[1,4]benzodiazepine-2-ones.

The present invention is separated from NO-P 891,176 (NO 167,737-B).

NO 167.737-B applies to compounds with the general formula:

where R 1 is hydrogen or alkyl,

as well as pharmaceutically acceptable acid addition salts or stereochemically isomeric forms thereof.

The present invention relates to a reaction mixture comprising compounds of formula (II-a)

where R^ is hydrogen or C^_^alkyl for the preparation of antiviral tetrahydroimidazo[l,4]-benzodiazepine-2-ones, and this reaction mixture is characterized in that it is prepared by the compound of the general formula (XI)

is reduced with a reducing agent.

The compounds of formula (I) can generally be prepared by condensing the corresponding 9-amino-2.3.4.5-tetrahydro-1H-1,4-benzodiazepine of formula (II-a) with a carbonyl-forming agent of formula (III) is L is a suitable leaving group:

In formula (II-a) R<2> is hydrogen or C^_^-alkyl. Suitable carbonyl-forming agents of formula (III) are, for example, urea, di-C 1 -(,-alkyl carbonate, carbonic acid dichloride, trichloromethyl chloroformate, 1,1'-carbonylbis[1H-imidazole] and the like. The condensation reaction can conveniently be carried out by stirring and optionally heating the reactants in a reaction-inert solvent, preferably with a relatively high boiling point, for example an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like; a halogenated hydrocarbon such as trichloromethane, tetrachloromethane, chlorobenzene and the like; an ether such as tetrahydrofuran, 1,4 -dioxane, 1,1'-oxybisbutane, 1,1'-oxybis-(2-methoxyethane), 1,2-bis(2-methoxyethoxy)ethane and the like; a dipolar aprotic solvent such as N,N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, pyridine, methylpyridine, dimethylpyridine, tetrahydrothiophene-1,1-dioxide and the like; or a mixture of such solvents. In some cases, however, it may be preferable to the poor reactants without solvent. Likewise, it may be appropriate to add a base to the reaction mixture, for example a tertiary amine such as N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-methylmorpholine and similar amines.

The intermediates of formula (II-a)

can be prepared from a benzodiazepinedione of the formula

by following known procedures for the reduction of oxo groups, for example by reacting the intermediates of formula (XI) with a complex metal hydride such as lithium tetrahydro-aluminate; a hydride such as diborane or aluminum hydride and the like, in a reaction-inert solvent such as 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; optionally in the presence of a co-solvent, for example an aromatic hydrocarbon such as benzene, methylbenzene and the like and optionally at an elevated temperature.

The intermediates (XI) can be obtained by cyclization of an intermediate with formula:

a) by heating (XII) without solvent under an inert atmosphere, optionally under reduced pressure; b) by heating (XII) with a bifunctional catalyst such as 2-hydroxypyridine, pyrazole, 1,2,4-triazole and the like, in a reaction-initiated solvent such as an aromatic hydrocarbon such as methylbenzene, dimethylbenzene and the like, optionally with elevated temperature; or c) cyclization of the ester (XII) and subsequent treatment of the corresponding carboxylic acid (R = H) with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid and similar acids, or with a halogenating agent such as thionyl chloride or the like. The intermediates (XII) can in turn be prepared from the nitrobenzene

where Q can mean either amino or nitro, by a catalytic reduction of the nitro groups to amino groups. Such catalytic reductions can conveniently be carried out by stirring the starting material in a reaction-inert solvent such as an alkanol such as methanol, ethanol, propanol and the like, an ester such as methyl or butyl acetate and the like in the presence of hydrogen and a suitable metal catalyst sator such as palladium-on-charcoal, Raney-nickel or the like, possibly at elevated temperature and/or pressure. The intermediates (XIII) can be prepared from a suitable protected amino acid (XIV) and a benzoic acid (XV) where Q is either amino or nitro, by following known N-acylation procedures.

The following examples shall illustrate the invention. Unless otherwise stated, all parts are given as parts by weight.

Example 1

a) To a stirred and cooled to -12°C mixture of 9.10 parts of 2-amino-3-nitrobenzoic acid, 6.95 parts of methyl (L)-2-amino-propanoate hydrochloride, 13.50 parts of 1- hydroxy-1H-benzotriazole hydrate and 180 parts of tetrahydrofuran, 5.05 parts of 4-methylmorpholine were added under argon. After stirring for 5 minutes, 10.30 parts of N,N-methanetetraylbis-[cyclohexaneamine] were added to the mixture. After 51 hours, the mixture was allowed to reach room temperature and then stirred for 16 hours. The mixture was cooled for 30 minutes at 0°C and then filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between 225 parts of ethyl acetate and 250 parts of a saturated hydrogen carbonate solution. The separated organic layer was washed with 100 parts of saturated sodium bicarbonate solution, dried, filtered and concentrated under vacuum and 13.08 parts corresponding to 97.9% (-)-methyl-(S)-2-[(2-amino-3 -nitrobenzoyl)-amino]propanoate; melting point 132.9°C (intermediate 5). b) A mixture of 12.58 parts of intermediate 5 and 160 parts of ethanol was hydrogenated in a Parr apparatus at 3*IO<5>Pa and

at room temperature with 3.50 parts 10 #-ig palladium-on-charcoal for 4 hours. The catalyst was filtered off over diatomaceous earth and the filtrate was concentrated under reduced pressure. The oily residue was placed in an oil bath at 150°C and 3.3*10<3>Pa. The temperature was maintained at 200<*>0 for 40 minutes with stirring. After cooling, the precipitated product was filtered off and triturated with 12 parts of ethanol.

The product was filtered off, washed with a small amount of cold ethanol and 1,1'-oxybisethane and dried to give 5.58 parts corresponding to 57.7% (+)-(S)-9-amino-2,3-dihydro -3-methyl-1H-1,4-benzodiazepine-2,5-(4H)-dione (intermediate 6).

Example 2

At 25°C and under argon, 5.0 parts of intermediate 6 were added to a suspension of 5.55 parts of lithium aluminum hydride in 154.5 parts of 1,4-dioxane. The reaction mixture was refluxed for 5 hours. After cooling to 10°C, 5.55 parts of water, 9.16 parts of a 15 µg sodium hydroxide solution and 16.65 parts of water were added successively. The whole thing was stirred for 2 hours and then filtered. The precipitate was washed successively with 178 parts of hot tetrahydrofuran and 133 parts of dichloromethane. The combined filtrates were dried, filtered and evaporated.

The residue was poured into a solution of 7.36 parts of 4-methylmorpholine in 133 parts of dichloromethane. The whole was added to a solution of 4.82 parts of trichloromethylchloroformate in 160 parts of dichloromethane during 15 minutes at 0°C and under argon. After stirring for 10 minutes at 0°C, the reaction mixture was warmed to room temperature and concentrated by evaporation. 70 parts of an aqueous 15 µg 1,4-dioxane solution was added to the residue and the whole was heated on a steam bath under nitrogen for 45 minutes, cooled and extracted with 2 x 66.5 parts of trichloromethane.

The aqueous layer was filtered and basified with concentrated ammonium hydroxide. The precipitate was filtered off, washed with a small amount of cold water, dried and triturated twice with 6.24 parts of 2-propanol to give 1.59 parts corresponding to 32.1% (+)-(S)-4,5 ,6,7-tetrahydro-5-methylimid-azo[4,5,1-jk][1,4]benzodiazepine-2(1H)-one; melting point 206.5°C (compound 12).

Claims (1)

Reaction mixture comprising compounds of formula (II-a) where R<2> is hydrogen or C^_^alkyl for the preparation of antiviral tetrahydroimidazo[1,4]-benzodiazepine-2-ones, characterized in that it is prepared by the compound of the general formula (XI) is reduced with a reducing agent.