A process for the manufacture of imidazodiazepine derivatives

Abstract: A process for the manufacture of compounds of formula I wherein A together with the two carbon atoms denoted as α and β represents one of the groups R 1 represents cyano or a group of the formula -COOR 4 , R 2 represents hydrogen, R 3 represents lower alkyl, or R 2 and R 3 together signify a di- or trimethylene group, R 4 represents lower alkyl or benzyl; and R 5 , R 6 each signify hydrogen, halogen, trifluoromethyl, lower alkoxy or nitro and the carbon atom denoted by γ has the S-configuration when R 2 is different from hydrogen which process comprises reacting a compound of the formula wherein A, R 2 and R 3 have the significance given above and X represent a halogen atom, in the presence of a base with a compound of the formula wherein R 7 is lower alkyl or cycloalkyl and R 1 has the significance given above.

Description: The present invention relates to a process for the manufacture of imidazodiazepine derivatives. More particularly, the invention is concerned with a process for the manufacture of compounds of the general formula wherein A together with the two carbon atoms denoted as α and β represents one of the groups R 1 represents cyano or a group of the formula -COOR 4 , R 2 represents hydrogen, R 3 represents lower alkyl, or R 2 and R 3 together signify a di- or trimethylene group, R 4 represents lower alkyl or benzyl; and R 5 , R 6 each signify hydrogen, halogen, trifluoromethyl, lower alkoxy or nitro and the carbon atom denoted by γ has the S-configuration when R 2 is different from hydrogen and of pharmaceutically acceptable acid addition salts thereof, which process comprises reacting a compound of the formula wherein A, R 2 and R 3 have the significance given above and X represents a halogen atom, in the presence of a base with a compound of the formula wherein R 7 is lower alkyl or cycloalkyl and R 1 has the significance given above, the process being carried out at temperatures between -30° and -40° C. As used herein, the term "lower alkyl" denotes a straight or branched chain saturated hydrocarbon group containing at most 7, preferably 1-4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl and the like. The term "halogen" means fluorine, chlorine, bromine and iodine. R 1 preferably represents cyano or a group of the formula -COOR 4 in which R 4 preferably represents ethyl. When R 2 represents hydrogen, then R 3 preferably represents methyl. When R 2 and R 3 together represent trimethylene, then the carbon atom denoted by y in formula I preferably has the S-configuration. The symbol A preferably represents the group (a). In this group (a) R 5 preferably represents hydrogen or fluorine and R 6 preferably represents hydrogen, fluorine, chlorine or methyl with at least one of R 5 and R 6 preferably representing hydrogen. Compounds of formula I which are prepared by the above mentioned process are especially preferred, wherein A denotes a group (a), R 5 denotes fluoro, R 6 denotes hydrogen and R 1 represents a cyano group or the group -COOC 2 H 5 . Compounds of formula I which are especially preferred are: Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]-benzodiazepine-3-carboxylate and 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carbonitrile. The compounds of formula I are known compounds (EP 27214). They can be used as pharmaceutically active substances. It has been shown that they have a pronounced affinity to the central benzodiazepine receptors and are capable of antagonising the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquilizing activity. In the above mentioned reference are also described processes for manufacturing these compounds, e.g. reacting a compound of the formula II with an isocyanoacetic ester. DE-A2813549 discloses the conversion reaction of a 1,4-benzodiazepine derivative using an isocyanoacetic acid ester as a reagent and in the presence of a base which is strong enough to allow formation of the corresponding isocyanoacetate. In accordance with this process compounds of formula I, in which R 1 represents a lower alkyl ester, can be manufactured from compounds of formula II, in which X represents a leaving group, and an alkyl isocyanoacetate. The reaction is carried out in an inert solvent and in the presence of a base at a temperature between about -40°C and about room temperature. According to the present invention compounds of formula I are manufactured by reaction of a compound of the formula II with (dialkylamino-methyleneamino)-acetic acid alkyl ester or (dialkylaminomethyleneamino)-nitrile. To use these compounds in place of isocyanoacetic ester as described in the above mentioned reference renders this process economical and more convenient on ecological and toxicological grounds. The process as described below is shown in Scheme 1. wherein A, R 1 , R 2 , R 3 , R 4 and R 7 are described as above and X is a halogen atom. X denotes in formula II, for example chlorine. The reaction of a compound of formula II with a compound of formula III is carried out in tetrahydrofuran, toluene or any other suitable inert organic solvent and at a temperature between about -40°C and -30°C. Suitable bases are n-butyllithium, alkali metal alkoxides, alkali metal hydrides, alkali metal amides such as lithium amides or lithium diisopropylamide or tertiary amines such as triethylamine. The reaction is conveniently carried out with lithiumhexamethyldisilazide which can be prepared in situ from n-butyllithium and 1,1,1,3,3,3-hexamethyl-disilazane. In the following paragraphs, the reaction is described in more detail. A solution containing 1,1,1,3,3,3-hexamethyl-disilazane, n-butyllithium and a compound of formula III, e.g. (dimethylamino-methyleneamino)acetic acid ethyl ester or (dimethylamino-methyleneamino)-nitrile, is treated with a solution containing a compound of the formula II and N,N-dimethyl-p-toluidine at about -30 to -40°C. There are obtained intermediates with an open ring structure of formula V-A and V-B. Cyclisation of these compounds produces compounds of formulae I-A or I-B. The cyclisation can be carried out in the presence of an acid, e.g. acetic acid. Compounds of formula I can be obtained by reaction of compounds of formula IV with phosphorous oxychloride to obtain a compound of formula II. This compound can be used in situ or be isolated to form a compound of formula I as described above. The manufacture of compounds of formula I is described in Examples 1-4 in more detail. Compound of formula IV is a known compound and can be manufactured by well known methods. The following Examples are given by way of illustration. Example 1 2-Chloro-7-fluoro-4-methyl-3,4-dihydro-benzo [e][1,4]diazepine -5-one a) A mixture of 20.8 g (100 mmol) 7-fluoro-4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione, 38 ml (263 mmol) N,N-dimethyl-p-toluidine and 200 ml toluene were stirred and heated to 100° C and then were treated dropwise with 10.2 ml (110 mmol) phosphorous oxychloride within 20 minutes. The solution was stirred for 2 hours at 100° C, then cooled to 5 - 10° C and poured into a stirring solution of 48 g K 2 CO 3 in 150 ml water and 50 g ice. The mixture was filtered and the filtrate was separated. The organic phase was washed with water, filtered and the filtrate was evaporated to give a residue of oily crystals. The residue was then evaporated in high vacuo to dryness. Yield: 58.71 g of crude product (oil). b) Isolation of the free title compound: To the yielded 2-chloro-7-fluoro-4-methyl-3,4-dihydro-benzo[e][1,4]-diazepine-5-one containing N,N-dimethyl-p-toluidine was added 50 ml isopropylether. The solution was stirred under an atmosphere of argon for 30 minutes at room temperature, whereafter 20 ml hexane was added dropwise over 15 minutes. The reaction mixture was stirred for 30 minutes at room temperature and then for 1 hour at 0 - 5° C. The crystals were separated and washed with 50 ml of a cold mixture of solvents and then dried in high vacuum to give the title compound as orange crystals. Yield: 19.32 g (85,5%) Purity: 97% Example 2 Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (via isolated iminochloride) A solution of 24 ml (115 mmol) 1,1,1,3,3,3-hexamethyl-disilazane in 300 ml tetrahydrofuran was stirred and cooled to -35° C. At this temperature there was added dropwise 69 ml (110 mmol) n-butyllithium over 45 minutes. The mixture was stirred 30 minutes at -35° C and then a solution of 15.82 g (100 mmol) (dimethylamino-methylenamino)-acetic acid ethyl ester in 50 ml THF was added dropwise over 1 hour. The solution was stirred at -35°C for 30 minutes. Separately, 12.02 g (50 mmol) of 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepine -5-one were dissolved in 100 ml tetrahydrofuran and 2.9 ml (20 mmol) N,N-dimethyl-p-toluidine and stirred under an atmosphere of argon. This solution was immediately added dropwise at -35 to -40° C over 70 minutes to the mixture obtained according to the preceding paragraph. The resulting mixture was stirred at -35°C for 2 hours. A solution of 15 ml (260 mmol) acetic acid in 10 ml tetrahydrofuran was added dropwise at -35 to -40° C over 20 minutes to the mixture obtained above. The reaction mixture was stirred over night at room temperature. Thereafter was added dropwise 5 ml acetic acid and the reaction mixture was refluxed for 6 hours. The resulting reaction mixture was allowed to cool to room temperature, whereafter it was concentrated on the rotary evaporator at 35° C. 100 ml heptane was added and the mixture again concentrated. An additional 100 ml heptane was added and the mixture stirred at 35°C for 30 minutes. The reaction mixture was then left to cool at 0°C overnight. The crystals were filtered and washed with 100 ml cold heptane and then stirred in a solution of 150 ml methylene chloride and 100 ml 5% NaHCO 3 for 5 minutes and then the layers were separated. The organic phase was extracted two times with water (100 ml) and the resulting water phases were washed two times with methylene chloride. The combined organic extracts were concentrated and then dried at reduced pressure at 35° C. Yield of the crude product: 16.68 g Purity: 86%. The crude product was then dissolved and refluxed in 170 ml ethanol, stirred over night at room temperature and then left for 4 hours at 0° and 2 hours at -20°C. The crystals were filtered and washed with 50 ml of cooled (-20°) ethanol. Yield: 14.73 g of white crystals (98%), Mp: 201 - 202°C. Purity: 99%. Example 3 Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (via non-isolated iminochloride) a) 48 ml (230 mmol) of 1,1,1,3,3,3-hexamethyl-disilazane were dissolved in 300 ml tetrahydrofuran. The solution was cooled to 0° C and then was added dropwise 138 ml (220 mmol) n-butyllithium within 20 minutes. The reaction mixture then was stirred at 0° C for 30 minutes and cooled to -35° C, whereafter a solution of 31.6 g (200 mmol) (dimethylamino-methyleneamino)-acetic acid ethyl ester in 100 ml tetrahydrofuran was added dropwise within 60 minutes. After stirring at -35° C for 30 minutes, 58.71 g (≤100 mmol) 2-Chloro-7-fluoro-4-methyl-3,4-dihydro-benzo[e][1,4]diazepine -5-one, obtained in the process 1a) above, was dissolved in a solution of 200 ml tetrahydrofuran containing 0.2 ml N,N-dimethyl-p-toluidine and added dropwise to the obtained reaction mixture within 1 hour. This mixture was then stirred for 2.5 hours at -35° to -40°C, then treated dropwise with 40 ml acetic acid dissolved in 40 ml tetrahydrofuran. The mixture (pH 6) was warmed to room temperature then refluxed for 2 hours. After cooling to room temperature overnight, it was concentrated on a rotary evaporator at 40° C to remove most of the THF (not to dryness). 150 ml heptane was added to the residue and it was concentratred again. After a further addition of 150 ml heptane the mixture was rotated at 0 - 5°C for 60 minutes without vacuum. The crystals were filtered, washed with 100 ml of cold heptane and then partitioned between a solution of 250 ml methylene chloride and 200 ml 5% NaHCO 3 . After stirring for 5 minutes the layers were separated. The organic phase was extracted twice with 100 ml water and the resulting water phases were back extracted 2 times with 70 ml methylene chloride. The combined organic extracts were concentrated on a rotary evaporator at 35°C and the residue obtained was dried at 40° C/20 mbar. Yield of the crude product: 26.78 g, Purity: 83.5% The crude product was refluxed in 260 ml ethanol, stirred over night at room temperature and 4 hours at 0°C and then the crystals were filtered off and washed with 70 ml cold ethanol and dried at 40°/20 mbar. Yield of the white crystals: 20.6 g (68%) Purity: 96%, Mp: 196 - 197°C. Example 4 8-Fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile a) A solution of 4.8 ml (23 mmol) 1,1,1,3,3,3-hexamethyl-disilazane in 40 ml toluene was cooled to 0°C and was treated dropwise with 13.8 ml (22 mmol) n-butyllithium over 10 minutes. The solution was stirred and cooled to -35°C and treated with 1.7 g (12 mmol) (dimethylamino-methyleneamino)-acetonitrile in 5 ml toluene over 20 minutes. Separately, 2.3 g (10 mmol) of 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one were dissolved in a mixture of 25 ml toluene, 5 ml THF and 0.7 ml (5 mmol) N,N-dimethyl-p-toluidine and stirred under an atmosphere of argon. This solution was immediately added dropwise at -35°C within 35 minutes to the above mixture. The resulting mixture was stirred at -35°C for 2.5 hours. A solution of 5 ml acetic acid in 5 ml toluene was added dropwise at -35°C. The reaction mixture (pH 5) was stirred at room temperature over night and then refluxed for 30 minutes whereafter it was concentrated on a rotary evaporator at 35°C. Then 25 ml n-heptane was added to the reaction mixture and the solution was rotated at room temperature for 30 minutes. The brown mixture was filtered and washed with 10 ml n-heptane and the resultant gum was partitioned between (50 ml) methylene chloride and (30 ml) water. The organic phase was filtered and then extracted with two further portions of (30 ml) water, dried over sodium sulphate, treated with (2.0 g) silica, filtered, evaporated and dried at room temperature under high vacuum. Yield of the crude product: 1.85 g Purity: 72%. The crude compound obtained above was recrystallized from 40 ml ethanol. The reaction mixture was cooled to 0°C and stirred for 2 hours. The obtained crystals were filtered, washed with cold ethanol and dried over night at 40°C/20 mbar. Yield: 1.10 g (42%) Purity: 98%.

Claims: A process for the manufacture of compounds of formula I wherein A together with the two carbon atoms denoted as α and β represents one of the groups R 1 represents cyano or a group of the formula -COOR 4 , R 2 represents hydrogen, R 3 represents C 1 -C 7 alkyl, or R 2 and R 3 together signify a di- or trimethylene group, R 4 represents C 1 -C 7 alkyl or benzyl; and R 5 , R 6 each signify hydrogen, halogen, trifluoromethyl, C 1 -C 7 alkoxy or nitro and the carbon atom denoted by γ has the S-configuration when R 2 is different from hydrogen which process comprises reacting a compound of the formula wherein A, R 2 and R 3 have the significance given above and X represents a halogen atom, in the presence of a base with a compound of the formula wherein R 7 is C 1 -C 7 alkyl or cycloalkyl and R 1 have the significance given above, the process being carried out at temperatures between -30° and -40°C. A process in accordance with claim 1, wherein the base is lithium hexamethyldisilazide. A process in accordance with claim 1, wherein A denotes a group (a), R 5 denotes fluoro, R 6 denotes hydrogen, R 1 represents a cyano group or a group -COOC 2 H 5 and X denotes chloro. A process in accordance with claims 1-3, wherein ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a[]1,4]benzodiazepine-3-carboxylate is prepared. A process in accordance with claims 1-3, wherein 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile is prepared.

Inventors: ROGERS-EVANS MARK, SPURR PAUL, ROGERS-EVANS, MARK, SPURR, PAUL
Applicants: HOFFMANN LA ROCHE, F. HOFFMANN-LA ROCHE AG
Application year: 1997
Main classification: C07D487
IPC codes: C07D487, C07D495