# US 5,349,086 A · Method for the preparation of 4-phenyl-1,3-benzodiazepins and precursors thereof

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- Number: US 5,349,086 A
- Document ID: US5349086A
- Status: Granted
- Kind: A
- Application number: 07/980,449
- Filed: 1992-11-23
- Granted: 1994-09-20
- Earliest claimed: 1981-05-28
- Assignees: Hoechst-Roussel Pharmaceuticals Inc.
- Inventors: Thomas B. K. Lee; George E. Lee
- Web page: https://patentgrep.com/patent/US5349086A

## CPC

- C07D 243/04: having the nitrogen atoms in positions 1 and 3
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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 form 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.

## Claims

### Claim 1

A process for preparing N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide, wherein the process comprises reacting an N-acylated-o-toluidine of the formula ##STR11## with n-alkyllithium to provide a dilithio intermediate of the formula ##STR12## and quenching the dilithio intermediate with N-benzylidenemethylamine.

### Claim 2 (depends on 1)

Process according to claim 1 comprising reacting the N-acylated-o-toluidine with n-butyllithium in solution in inert ethereal and hydrocarbon solvents and in a substantially anhydrous atmosphere.

### Claim 3 (depends on 2)

Process according to claim 2 wherein the ethereal solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and dimethoxyethane, and the hydrocarbon solvent is hexane.

### Claim 4 (depends on 1)

Process according to claim 1 comprising reacting the N-acylated-o-toluidine with n-alkyllithium at about -70.degree. C. to about 30.degree. C. for about 0.5 to about 5 hours.

### Claim 5 (depends on 2)

Process according to claim 2 wherein said reaction is conducted at about -10.degree. C. to about 30.degree. C. for about 1 to about 2 hours.

### Claim 6 (depends on 2)

Process according to claim 2 wherein a solution of the n-butyllithium is added to the N-acylated-o-toluidine.

### Claim 7 (depends on 1)

Process according to claim 1 in which the quenching is conducted at about -78.degree. C. to about 35.degree. C. for about 5 minutes to about 1 hour in a substantially anhydrous atmosphere.

### Claim 8 (depends on 7)

Process according to claim 7 in which the quenching is conducted at about 0.degree. C. to about 25.degree. C. with about 1 to about 2 molar equivalents of the N-benzylidenemethylamine based on the dilithio intermediate.

### Claim 9

A process for preparing N-[2-(2-methylamine-2-phenylethyl)phenyl]-2,2-dimethylpropanamide, wherein the method comprises 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## and 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.

### Claim 10 (depends on 9)

Process according to claim 9 wherein a solution of the n-butyllithium is added to the N-[(2-methyl)phenyl]-2,2-dimethylpropanamide.