Process for the preparation of Pazopanib or a pharmaceutically acceptable salt thereof
The present invention is relates to an improved process for the preparation of pazopanib or a pharmaceutically acceptable salts thereof. The present invention also relates to novel polymorphic Forms of pazopanib hydrochloride, and its intermediates thereof.
1. Crystalline Form-K1 of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with FIG. 22 .
2. A process for preparation of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine Form-K1 characterized by a powder X-Ray diffraction (PXRD) pattern according to FIG. 22 , comprising:
a) reacting a compound of Formula II with methyl iodide in presence of potassium tert butoxide in dimethylformamide to obtain a compound of Formula III Form-K1,
and
b) isolating the Formula III Form-K1.
3. The process of claim 2 , wherein the step a) is carried out at a temperature of about 25° C. to about reflux temperature.
4. Crystalline Form-K2 of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with FIG. 23 .
5. A process for preparation of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine Form-K2 characterized by a powder X-Ray diffraction (PXRD) pattern according to FIG. 23 , comprising:
a) reacting a compound of Formula II with methyl iodide in presence of potassium tert butoxide in tetrahydrofuran to obtain a compound of Formula III,
b) concentrating the reaction mass to obtain a residue;
c) adding water to the residue of step b); and
d) isolating the Formula III Form-K2.
6. The process of claim 5 , wherein the step a) is carried out at a temperature of about 25° C. to about reflux temperature.
7. The process of claim 5 , wherein the step b) is carried out by removing the solvent under vacuum at 40° C. to about 45° C.
8. Crystalline Form-K3 of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with FIG. 24 .
9. A process for preparation of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine Form-K3 characterized by a powder X-Ray diffraction (PXRD) pattern according to FIG. 24 , comprising:
a) reacting a compound of Formula II with methyl iodide in presence of potassium tert butoxide in acetonitrile to obtain a compound of Formula III,
and
b) isolating the Formula III Form-K3.
10. The process of claim 9 , wherein the step a) is carried out at a temperature of about 25° C. to about reflux temperature.
11. Crystalline Form-K4 of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with FIG. 25 .
12. A process for preparation of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine Form-K4 characterized by a powder X-Ray diffraction (PXRD) pattern according to FIG. 25 , comprising:
a) reacting compound of Formula II with methyl iodide in presence of potassium tert butoxide in dimethylsulfoxide to obtain a compound of Formula III,
b) concentrating the reaction mass to obtain a residue;
c) adding water to the residue of step b); and
d) isolating the Formula III Form-K4.
13. The process of claim 12 , wherein the step a) is carried out at a temperature of about 25° C. to about reflux temperature.
14. The process of claim 7 , wherein the step b) is carried out by removing the solvent under vacuum at 40° C. to about 45° C.