Process for preparation of 4-amino-3-quinolinecarbonitriles

Abstract

This invention discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising combining an amine compound with a cyanoacetic acid and an acid catalyst to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline in an alcoholic solvent and a trialkylorthoformate to yield a 3-amino-2-cyanoacrylamide; combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 4-amino-3-quinolinecarbonitrile and also discloses a process for the preparation of a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile comprising combining a disubstituted 3-amino thiophene with a cyanoacetamide and trialkylorthoformate in an alcoholic solvent to obtain a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride and acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile and also discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile by combining an amine compound with a cyanoacetic acid and a peptide coupling reagent to obtain a suspension; filtering the suspension to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline, an alcoholic solvent, and triethylorthoformate to yield a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride to yield a 4-amino-3-quinolinecarbonitrile.

1 . A process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising: 
 a. combining an amine compound with cyanoacetic acid and an acid catalyst to yield a cyanoacetamide;    b. condensing the cyanoacetamide of step a with an aniline, an alcoholic solvent, and a trialkylorthoformate to yield 3-amino-2-cyanoacrylamide; and    c. combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 4-amino-3-quinolinecarbonitrile.    
   
   
       2 . The process of  claim 1  wherein the ratio of cyanoacetic acid to amine is 1 to 1.5 equivalents.  
   
   
       3 . The process of  claim 1  wherein the ratio of cyanoacetic acid to amine is 1.03 equivalents.  
   
   
       4 . The process of  claim 1  wherein the aniline is a hydrochloride salt.  
   
   
       5 . The process of  claim 1  wherein the aniline is a free base.  
   
   
       6 . The process of  claim 1  wherein the alcoholic solvent is iso-propanol.  
   
   
       7 . The process of  claim 1  wherein the condensing step occurs at a temperature of 10-200° C.  
   
   
       8 . The process of  claim 1  wherein the condensing step occurs at a temperature of 20-140° C.  
   
   
       9 . The process of  claim 1  wherein the condensing step occurs at a temperature of 80° C.  
   
   
       10 . The process of  claim 1  wherein the catalyst is an alcohol.  
   
   
       11 . The process of  claim 1  wherein the catalyst is an amine base.  
   
   
       12 . The process of  claim 1  wherein the combining of step c occurs at a temperature of 50-200° C.  
   
   
       13 . The process of  claim 1  wherein the combining of step c occurs at a temperature of 80-110° C.  
   
   
       14 . A process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising: 
 a. combining an amine compound with cyanoacetic acid, a peptide coupling reagent to obtain a suspension;    b. filtering the suspension in step a to yield a cyanoacetamide;    c. condensing the cyanoacetamide of step b with an aniline, an alcoholic solvent, and a trialkylorthoformate to yield 3-amino-2-cyanoacrylamide; and    d. combining the 3-amino-2-cyanoacrylamide in step c with phosphorus oxychloride to yield a 4-amino-3-quinolinecarbonitrile.    
   
   
       15 . The process of  claim 14  wherein the ratio of cyanoacetic acid to amine is 1 to 1.5 equivalents.  
   
   
       16 . The process of  claim 14  wherein the ratio of cyanoacetic acid to amine is 1.03 equivalents.  
   
   
       17 . The process of  claim 14  wherein the peptide coupling reagent is water soluble.  
   
   
       18 . The process of  claim 14  wherein the peptide coupling reagent is 1,3-diisopropylcarbodiimide.  
   
   
       19 . The process of  claim 14  wherein said process occurs at a temperature of 50-100° C.  
   
   
       20 . The process of  claim 14  wherein said process occurs at a temperature of 77-80° C.  
   
   
       21 . The process of  claim 14  wherein the amine is pyridine, triethylamine, and diisopropylamine.  
   
   
       22 . A process for the preparation of a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile comprising: 
 a. combining a 3-amino thiophene with cyanoacetamide and a trialkylorthoformate in an alcoholic solvent to obtain a propenamide;    b. combining the propenamide with phosphorus oxychloride and acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile.    
   
   
       23 . A process for the preparation of a cyanoacetamide comprising: 
 a. combining DMF, an aniline and cyanoacetic acid to yield a mixture;    b. cooling the mixture;    c. adding a solution of N,N′ dicyclohexylcarbodiimide in DMF to keep the temperature below 15° C. and yield a suspension;    d. filtering the suspension and washing a resulting solid by-product to yield a filtrate;    e. adding water to the filtrate of step d to obtain a suspension, cooling to 5° C.; and    f. filtering the suspension to yield a cyanoacetamide.    
   
   
       24 . The process of  claim 23  wherein the by-product is urea.