Method for the preparation of 4-phenyl-1,3-benzodiazepins
AssigneeHoeschst-Roussel Pharmaceuticals, Inc.
InventorsThomas B. K. Lee, George E. Lee
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Abstract
A compound of the formula ##STR1## is prepared by reacting an N-acylated-o-toluidine of the formula ##STR2## with n-alkyllithium to form a dilithio intermediate of the formula ##STR3## which can then be quenched with N-benzylidenemethylamine to fore compound II. Hydrolysis of compound(II) yields the free base ##STR4## or its salt, which can be cyclized to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or its physiologically acceptable salts, which are useful as pharmacological agents.
Claims9
A process for preparing 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or a pharmaceutically acceptable salt thereof, said process comprising
- (A) reacting N-[(2-methyl)phenyl]-2,2-dimethylpropan-amide with n-alkyllithium to provide a dilithio intermediate of the formula ##STR11## (B) quenching the dilithio intermediate with N-benzyli-denemethylamine to form N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide.
- (C) hydrolyzing the N-[2-(2-methylamino-2-phenymethyl) phenyl]-2,2-dimethylpropanamide to form N-methyl-2-amino-.alpha.-phenylphenethylamine as a free base or salt thereof, and
- (D) cyclizing said N-methyl-2-amino-a-phenylphenethylamine by reaction with a compound of the formula ##STR12## to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or a pharmaceutically acceptable salt thereof.
A process for preparing 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or a pharmaceutically acceptable salt thereof said process comprising
- (A) reacting N-[(2-methyl)phenyl]-2,2-dimethylpropanamide with n-butyllithium in solution in tetrahydrofuran and hexane and in a substantially anhydrous atmosphere at about -10.degree. C. to about 30.degree. C. for about 1 to about 2 hours to form a dilithio intermediate of the formula ##STR13## (B) quenching the dilithio intermediate with about 1 to about 2 molar equivalents of N-benzylidenemethylamine, based on the dilithio intermediate, at about 0.degree. C. to about 25.degree. C. for about 5 minutes to about 1 hour and in a substantially anhydrous atmosphere to form N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethyl propanamide;
- (C) hydrolyzing the N-[2-(2-methylamino-2-phenylethyl) phenyl]-2,2-dimethylpropanamide by reaction in solution with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid or sulfuric acid at about 70.degree. C. to the reflux temperature of the solvent for a period of about 12 to about 48 hours;
- and
- (D) cyclizing said N-methyl-2-amino-.alpha.-phenylphenethylamine by reaction with about 1 to about 5 equivalents of a compound of the formula ##STR14## for a time of about 1 to about 8 hours to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.