Process for preparing 2-methyl-thieno-benzodiazepine

Abstract

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure:

1. A method of preparing 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]-benzodiazepine comprising the following steps:
 A) preparing 2-amino-5-methylthiophene-3-carbonitrile by mixing sulfur, propional-dehyde  propionaldehyde in dimethylformamide, then adding triethyl amine, then adding malononitrile;  
 B) preparing 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile from the reaction product of step (A) by reaction with a slurry of sodium hydride dispersed in oil in tetrahydrofuran and 2-fluoro-nitrobenze   2 - fluoronitrobenzene;    
 C) preparing 4-amino-2-methyl-10H-thiono thieno[2,3-b][1,5]benzodiazepine hydrochloride from the reaction product of step (B) by reacting with a slurry of 2-(2-nitroanilino)-5-methyl-thiophene-3-carbonitrile in ethanol and a solution of anhydrous stannous chloride in hydrochloric acid;  
 D) preparing 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine by refluxing the reaction product of step (C) with a mixture of N-methylpiperazine, dimethylsulphoxide and toluene.  
 
     
     
       2. A method of preparing  2 - methyl -   4   -(   4   - methyl -   1   - piperazinyl )-   10 H - thieno[ 2 , 3   - b][ 1 , 5 ] - benzodiazepine comprising the following steps:      A )  preparing  2   - amino -   5   - methylthiophene -   3   - carbonitrile by mixing sulfur, propionaldehyde in dimethylformamide, then adding triethyl amine, then adding malononitrile;        B )  preparing  2   -(   2   - nitroanilino )-   5   - methylthiophene -   3   - carbonitrile from the reaction product of step  ( A )  by reaction with potassium carbonate or lithium hydroxide in dimethylsulphoxide and  2   - fluoronitrobenzene;        C )  preparing  4   - amino -   2   - methyl -   10 H - thieno[ 2 , 3   - b][ 1 , 5 ]benzodiazepine hydrochloride from the reaction product of step  ( B )  by reacting with a slurry of  2   -(   2   - nitroanilino )-   5   - methyl - thiophene -   3   - carbonitrile in ethanol and a solution of anhydrous stannous chloride in hydrochloric acid;        D )  preparing  2   - methyl -   4   -(   4   - methyl -   1   - piperazinyl )-   10 H - thieno[ 2 , 3   - b][ 1 , 5 ]benzodiazepine by refluxing the reaction product of step  ( C )  with a mixture of N - methylpiperazine, dimethylsulphoxide and toluene.     
     
     
       3. A method of preparing  2 - methyl -   4   -(   4   - methyl -   1   - piperazinyl )-   10 H - thieno[ 2 , 3   - b][ 1 , 5 ] - benzodiazepine comprising the following steps:      A )  preparing  2   - amino -   5   - methylthiophene -   3   - carbonitrile by mixing sulfur, propionaldehyde in dimethylformamide, then adding triethyl amine, then adding malononitrile;        B )  preparing  2   -(   2   - nitroanilino )-   5   - methylthiophene -   3   - carbonitrile from the reaction product of step  ( A )  by reaction with aqueous sodium hydroxide in dimethylsulphoxide and  2   - fluoronitrobenzene;        C )  preparing  4   - amino -   2   - methyl -   10 H - thieno[ 2 , 3   - b][ 1 , 5 ]benzodiazepine hydrochloride from the reaction product of step  ( B )  by reacting with a slurry of  2   -(   2   - nitroanilino )-   5   - methyl - thiophene -   3   - carbonitrile in ethanol and a solution of anhydrous stannous chloride in hydrochloric acid;        D )  preparing  2   - methyl -   4   -(   4   - methyl -   1   - piperazinyl )-   10 H - thieno[ 2 , 3   - b][ 1 , 5 ]benzodiazepine by refluxing the reaction product of step  ( C )  with a mixture of N - methylpiperazine, dimethylsulphoxide and toluene.