Process for the purification of the Axl tyrosine receptor kinase inhibitor “R428”

1. A process for purifying 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base, the process comprising

a) dissolving a quantity of crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine in a mixed solvent of C 1-5 alcohol and water, together with an acid,

b1) increasing the pH of the solution resulting from (a) until 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base is precipitated from the alcohol-water mixed solvent, and

b2) isolating the precipitated 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base from the alcohol-water mixed solvent.

2. The process according to claim 1 , wherein the alcohol in the alcohol-water mixed solvent is ethanol.

3. The process according to claim 1 , wherein the alcohol-water mixed solvent, prior to carrying out step (b1), is adjusted if necessary such that it contains 60-80% alcohol by volume.

4. The process according to claim 3 , wherein the alcohol-water mixed solvent, prior to carrying out step (b1), is adjusted if necessary such that it contains 73-77% alcohol by volume.

5. The process according to claim 1 , wherein, in step (b1), the pH of the resulting solution from (a) is increased to 7.5 to 9.5.

6. The process according to claim 5 , wherein, in step (b1), the pH is increased to 7.8 to 8.8.

7. The process according to claim 1 , wherein, in step (b1), the pH of the resulting solution from (a) is increased using a solution of a base.

8. The process according to claim 7 , wherein the solution of a base used to increase the pH in step (b1) employs an alcohol-water mixed solvent having substantially the same solvent composition as the alcohol-water mixed solvent in which the crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine is presented for this step.

9. The process according to claim 1 , wherein, in step (b1), the pH of the resulting solution from (a) is increased using a base comprising potassium hydroxide.

10. The process according to claim 1 , wherein, in step (a), the dissolution of the crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, and the acid, in the mixed solvent of C 1-5 alcohol and water is performed at elevated temperature.

11. The process according to claim 10 , wherein, in step (b1), the temperature of the resulting solution from (a) is maintained at 70 degrees C. or more while the pH is increased.

12. The process according to claim 1 , wherein, in step (b1), the temperature of the resulting solution from (a) is maintained at 73 degrees C. or more until precipitation of 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base commences.

13. The process according to claim 1 , comprising the further steps of:

c) redissolving the precipitated 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base obtained in step (b2) in a mixed solvent of C 1-5 alcohol and water, together with an acid,

d1) increasing the pH of the resulting solution from (c) until 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base is precipitated from the alcohol-water mixed solvent, and

d2) isolating the precipitated 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base from the alcohol-water mixed solvent.

14. The process according to claim 13 , wherein, during precipitation of the 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base in step (d1), the pH is increased further, as necessary, to maintain a pH at or above the level at which precipitation of 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base commences in step (d1).

15. The process according to claim 1 , wherein the acid used in step (a) is selected from fumaric, citric and hydrochloric acid.

16. The process according to claim 1 , wherein 146,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base and is purified from a quantity of crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

17. The process according to claim 1 , wherein the crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine is the product of a reaction between phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine.

18. The process according to claim 17 , wherein a starting solution of the crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine is brought into contact with the alcohol-water mixed solvent in step (a).

19. The process according to claim 18 , wherein the starting solution of the crude 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine comprises a product solution resulting from the reaction between phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine.

20. The process according to claim 18 , wherein the starting solution employs a solvent other than the alcohol-water mixed solvent used in step (a).

21. The process according to claim 20 , wherein the solvent of the starting solution is immiscible with the alcohol-water mixed solvent used in step (a).

22. The process according to claim 20 , wherein the solvent of the starting solution is removed prior to step (b1).

23. A compound chosen from 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base, or 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3 -(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base, obtained or obtainable by the process of claim 1 .

24. The process according to claim 4 , wherein the alcohol-water mixed solvent, prior to carrying out step (b1), is adjusted if necessary such that it contains approximately 75% alcohol by volume.

25. The process according to claim 6 , wherein, in step (b1), the pH is increased to approximately 8.5.