A new synthesis of adinazolam has been described: The condensation of phthaloyl-glycyl chloride (I) with 2-amino-5-chlorobenzophenone (II) in refluxing toluene gives 4-chloro-2-(phthaloylglycylamido)benzophenone (III), which is cyclized by means of hydrazine in refluxing ethanol yielding 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (IV). The reaction of (IV) with P2S5 in hot pyridine affords the corresponding thione (V), which is finally cyclized with N,N-dimethylglycine hydrazide by means of triethylamine in refluxing butanol. The starting products (I) and (II) are obtained as follows: The reaction of N-(ethoxycarbonyl)phthalimide (VI) with glycine by means of Na2CO3 in water gives the N-phthaloylglycine (VII), which is then treated with refluxing SOCl2 to give (I). The protection of 2-amino-4-chlorobenzoic acid (VIII) with tosyl chloride gives the corresponding N-tosyl derivative (IX), which by reaction with refluxing SOCl2 is converted into the acyl chloride (X). Finally, this compound is submitted to a Friedel-Craft's condensation with benzene and AlCl3 to afford (II).

The reaction of 2-amino-5-chlorobenzophenone (I) with formic acid gives 2-formylamino-5-chlorobenzophenone (II), which by cyclization with hydrazine in ethanol is converted into 3-amino-6-chloro-4-hydroxy-4-phenyl-3,4-dihydroquinazoline (III). The reaction of (III) with formic acid in acetic anhydride - acetic acid yields 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone (IV), which by reaction with formaldehyde in refluxing xylene affords 5-chloro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone (V). The reaction of (V) with phthalimide (VI), triethylphosphine and diethyl azodicarboxylate in THF gives 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (VII), which is cyclized with hydrazine in hot ethanol to 8-chloro-1-(aminomethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (VIII). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in acetonitrile - acetic acid.

By reaction of 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (IX) with N,N-dimethylmethyleneammonium chloride (X) in hot DMF.

The reaction of (III) with (XI) by means of pyridine in THF gives 1,3-dioxo-2-isoindolineacetic acid [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide (XVI), which by cyclization by means of trifluoroacetic acid in refluxing toluene yields 5-chloro-2-[3-(phtalimidomethyl)-4H-1,2,4-triazol-4-yl-benzophenone (XVII). The reaction of (XVII) with N,N,N',N'-tetramethyldiaminomethane (A) by means of acetyl chloride in DMF affords 5-chloro-2-[3-[(dimethylamino)methyl-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (XVIII), which is finally cyclized by means of hydrazine in hot ethanol.

A new synthesis of adinazolam has been described: The condensation of phthaloyl-glycyl chloride (I) with 2-amino-5-chlorobenzophenone (II) in refluxing toluene gives 4-chloro-2-(phthaloylglycylamido)benzophenone (III), which is cyclized by means of hydrazine in refluxing ethanol yielding 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (IV). The reaction of (IV) with P2S5 in hot pyridine affords the corresponding thione (V), which is finally cyclized with N,N-dimethylglycine hydrazide by means of triethylamine in refluxing butanol. The starting products (I) and (II) are obtained as follows: The reaction of N-(ethoxycarbonyl)phthalimide (VI) with glycine by means of Na2CO3 in water gives the N-phthaloylglycine (VII), which is then treated with refluxing SOCl2 to give (I). The protection of 2-amino-4-chlorobenzoic acid (VIII) with tosyl chloride gives the corresponding N-tosyl derivative (IX), which by reaction with refluxing SOCl2 is converted into the acyl chloride (X). Finally, this compound is submitted to a Friedel-Craft's condensation with benzene and AlCl3 to afford (II).

The reaction of 2-amino-5-chlorobenzophenone (I) with formic acid gives 2-formylamino-5-chlorobenzophenone (II), which by cyclization with hydrazine in ethanol is converted into 3-amino-6-chloro-4-hydroxy-4-phenyl-3,4-dihydroquinazoline (III). The reaction of (III) with formic acid in acetic anhydride - acetic acid yields 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone (IV), which by reaction with formaldehyde in refluxing xylene affords 5-chloro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone (V). The reaction of (V) with phthalimide (VI), triethylphosphine and diethyl azodicarboxylate in THF gives 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (VII), which is cyclized with hydrazine in hot ethanol to 8-chloro-1-(aminomethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (VIII). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in acetonitrile - acetic acid.

By reaction of 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (IX) with N,N-dimethylmethyleneammonium chloride (X) in hot DMF.

The reaction of (III) with (XI) by means of pyridine in THF gives 1,3-dioxo-2-isoindolineacetic acid [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide (XVI), which by cyclization by means of trifluoroacetic acid in refluxing toluene yields 5-chloro-2-[3-(phtalimidomethyl)-4H-1,2,4-triazol-4-yl-benzophenone (XVII). The reaction of (XVII) with N,N,N',N'-tetramethyldiaminomethane (A) by means of acetyl chloride in DMF affords 5-chloro-2-[3-[(dimethylamino)methyl-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (XVIII), which is finally cyclized by means of hydrazine in hot ethanol.

A new synthesis of adinazolam has been described: The condensation of phthaloyl-glycyl chloride (I) with 2-amino-5-chlorobenzophenone (II) in refluxing toluene gives 4-chloro-2-(phthaloylglycylamido)benzophenone (III), which is cyclized by means of hydrazine in refluxing ethanol yielding 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (IV). The reaction of (IV) with P2S5 in hot pyridine affords the corresponding thione (V), which is finally cyclized with N,N-dimethylglycine hydrazide by means of triethylamine in refluxing butanol. The starting products (I) and (II) are obtained as follows: The reaction of N-(ethoxycarbonyl)phthalimide (VI) with glycine by means of Na2CO3 in water gives the N-phthaloylglycine (VII), which is then treated with refluxing SOCl2 to give (I). The protection of 2-amino-4-chlorobenzoic acid (VIII) with tosyl chloride gives the corresponding N-tosyl derivative (IX), which by reaction with refluxing SOCl2 is converted into the acyl chloride (X). Finally, this compound is submitted to a Friedel-Craft's condensation with benzene and AlCl3 to afford (II).