2-Methyl-4- benzodiazepine, preparation

An important feature of the synthesis of substituted benzodiazepines is the stereochemistry of the substituents in the reduced heterocyclic ring. In this context, further studies on the preparation of enantiomeric 3-amino- and 3-methyl-benzodiazepines have been published <95JOC730>, <95T(A)849>, <95ii(4(>)7i7> The asymmetric reduction of the 3,4-double bond in 4-methyl-2,3-benzodiazepines is also reported <95JCS(PI)1423>. 

The residue was dissolved in 75 ml of tetrahydrofuran, treated with charcoal, and sodium sulfate and filtered. This solution was added to a solution in 250 ml of tetrahydrofuran of phenyl magnesium bromide prepared from 17.7 ml (0.17 mol) of bromobenzene. This mixture was stirred and heated under reflux for 1 hour. It was then cooled and diluted with 400 ml of ether and sufficient 3N hydrochloric acid to make it acidic. The aqueous phase was separated, adjusted to pH 8 with 3N sodium hydroxide and extracted 3 times with 200 ml of ether. The ether extracts were combined, washed with water and dried over sodium sulfate. The residue left on removal of the ether in vacuo was crystallized from petroleum ether to give 3.3 g of 7-chloro-2,3-dihvdro-1-methyl-5-phenvl-1 H-1,4-benzodiazepine, according to U.S. Patent 3,624,703. 

For testing sedative hypnotic drugs of the triazolam type the preparation was undertaken of 8-chloro-6-(o-chlorophenyl)-4ff-.y-triazolo[4,3-a][l,4]benzodiazepin-1 -valeric acid methyl ester as an intermediate, with subsequent cyclization and amida-... 

The 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-577-2,3-benzodiazepine 63, a known anxiolytic agent, is prepared by the reaction of a monoketal derivative of a 1,5-dicarbonyl compound 62 with hydrazine or its hydrate or its salt <2003W02003050092A2> (Equation 7). 

Gas chromatography [9, 10] Fast gas chromatography/negative-ion chemical ionization mass spectrometric (GC/NICI-MS) assay combined with rapid and nonlaborious sample preparation is presented for the simultaneous determination of benzodiazepines and a-hydroxy metabolites, zaleplon, and zopiclone in whole blood. The compounds were extracted from 100 pi of whole blood by liquid-liquid extraction (LLE) and derivatized by N-methyl-N-(ferf-butyldimethylsilyl)trifluoroaceta-mide (MTBSTFA). 

The methyl selenienyl salt (62, Y = CH3) (Fig. 6), readily obtained from diben-zoselenophene, is a powerful methylation agent even in water as a solvent. Its trif-luoromethyl analogue (62, Y = CF3) can be used as a trifluoromethylating electrophile, although the sulfur analog is more reactive [98, 99], 2-Benzoselenopyrylium salts (83) were used in preparation of benzodiazepines (84) (Scheme 21) by treatment with hydrazine [116]. 

Prepare a solution of sodium methylate by dissolving 3.9 g of sodium metal in 500 ml of methanol. Add 39.0 g of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepine-2-one. Evaporate the reaction mixture to a residue and dissolve the residue in 170 ml of dimethylformamide. Add 30 g of 2,2,2-trifluoroethyl iodide and stir at room temperature for Vi hour, then heat to 60°C to 70°C for an additional 7 hours. Add 19 g of 2,2,2-trifluoroethyl iodide and resume the heating and stirring at 60°C to 70°C for an additional 16 hours. Filter off the solids and evaporate the filtrate to a residue in vacuo. Triturate the residue with water and extract with ethyl ether. Wash the ethereal extract with water, dry over anhydrous sodium sulfate and evaporate... 

A) Preparation of 4-Acetyl-7-Chloro-l,2,3,4-Tetrahydro-l-Methyl-5H-l,4-Benzodiazepin-5-one A mixture of 68.5 g (0.37 mol) of 5-chloro-N-methylanthranilic acid, 51 g (0.51 mol) of calcium carbonate, 76 g (0.37 mol) of bromoethylamine hydrobromide and 2.5 liters of water was stirred and heated under reflux for 3 hours. A solution of 23.4 g (0.26 mol) of anhydrous oxalic acid in 250 ml of water was slowly added to the refluxing mixture. The precipitated calcium oxalate was filtered off, and the filtrate adjusted to pH 7... 

B) Preparation of 7-Chloro-l,2,3,4-Tetrahydro-l-Methyl-5H-l,4-Benzodiazepin-5-one A mixture of 25.25 g (0.1 mol) of 4-acetyl-7-chloro-l,2,3,4-tetrahydro-l-methyl-5H-l,4-benzodiazepin-5-one, 33.3 ml (0.1 mol) of 3 N sodium hydroxide and 350 ml of ethanol was heated under reflux for 15 minutes and then concentrated to dryness in vacuo. The residue was treated with 500 ml of water, collected and washed with ethanol to give 20.2 g of 7-chloro-l,2,3,4-tetrahydro-l-methyl-5H-l,4-benzodiazepin-5-one. 

It is therefore not surprising that an alternative approach to the synthesis of benzodiazepines involves the reaction of /3-chlorovinylcarbonyl compounds with o-phenylenediamine. In the first example methyl 3-chlorovinyl ketone was used to obtain 5-methylbenzodiazepinium chloride (62 JPR163). An extensive investigation has been made of the use of /3-chlorovinylaldehydes for the preparation of 2,3-substituted benzodiazepines (64ZC458 67CB584). The preferred conditions for reaction were in... 

Methane diluted with nitrogen was passed over the catalyst (Cul, CuBr2, etc.) adsorbed on pumice at 600 °C, nCH3Br and nCH3I have been isolated in 15-20%. nCH3Br prepared by this method has been used for methylation of nor RO 151788 (benzodiazepine ligand)236. 

Derivatives of 1-methyl-3//-l,4-benzodiazepine-2,5(l/I,4/I)dione (193) were synthesized by ring closure of substituted 2-(A-chloro-acetyl-A-methylaminoJbenzamides with sodium methoxide in methanol.209 Treatment of 193 with lithium aluminum hydride led to reduction of both carbonyl groups.209 The parent tetrahydro system (194) has been prepared by reaction of the tosylate (195) with 1,2-dibromoethane followed by hydrolysis.210 The preparation of 194 by another route had previously been noted.204 Reaction of 194 with formaldehyde or benzaldehyde gave a compound formulated as 196 (R = H or C6H5).210 Hydrolysis of 196 (R = C6H5) with 0.1 N hydrochloric acid gave 194 while 196 (R = H) was not hydrolyzed at this acidity. 

Dihydro-3-methyl-2-(l-methylethyl)-4-(2-thienyl)-3H-1,3-benzodiazepine hydrochloride, (I), has been prepared (2) by the reaction of 2-amino-N-methyl-a-(2-thienyl)benzeneethaneamine with trimethyl orthoisobutyrate as illustrated in Eq. 1 ... 

Benzodiazepines and naphthodiazepines (16) have also been prepared by addition and condensation of o-phcnylenediamine, JV-methyl-and A7-phenyl-o-phenylcnediamines, and 2,3-diaminonaphthalene with a-alkynyl ketones.34 ... 

C) Preparation of 7-Chloro-2 -Dihydro-1-Methyl-5-Phenyl-1H-1,4-Benzodiazepine A mixture of 4.7 g (22.6 mol) of 7-chloro-1,2,3,4-tetrahvdro-1-methyl-5H-1,4-benzodiazepin-5-one and 100 ml of phosphorus oxychloride was heated in an oil bath at 100°C for 15 minutes. The solution was concentrated to dryness in vacuo. The residue was partitioned... 

An efficient conversion of 5-chloro-)V-methylisatoic anhydride and glycine into 7-chloro-l-methyl-3,4-dihydro-lJT-l,4-benzodiazepine-2,5-dione has been described. Further reaction of its (V-acetyl derivative with phenylmagnesium chloride followed by treatment with hydroxylamine and then sodium bisulphite provides another new synthesis of Diazepam in ca. 50% overall yield. The 1,4,5-benzotriazocinium salts (103), prepared by the cyclization of (2-chloro-acetamido)benzophenone ATV-dimethylhydrazones (102), reacted with sodium methoxide in a Stevens-type reaction to give 3-amino-l,4-benzodiazepin-2-ones (104) in good yield. The same products were also obtained by direct treatment of (102) with base. 

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