Process for preparation of 4-amino-3-quinolinecarbonitriles
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.