合成路线: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).
参考文献标题:Synthesis of adinazolam mesylate-multiply labeled with carbon-13 and deuterium
文献作者:Stelzer,L.S.; Hsi,R.S.P.
参考来源:J Label Compd Radiopharm 1989,26(3),287
合成路线: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.
参考文献标题:
文献作者:Gall,M.; Hester,J.B.
参考来源:US 3947466
合成路线: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.
参考文献标题:
文献作者:Gall,M.
参考来源:US 4001262
合成路线: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.
参考文献标题:
文献作者:Gall,M.; Hester,J.B.
参考来源:US 3957761
合成路线: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).
参考文献标题:Carbon-14 labeled 1,4-benzodiazepines.3
文献作者:Johnson,T.D.; Hsi,R.S.P.
参考来源:J Label Compd Radiopharm 1976,12(4),613-619
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