Process for preparing quinolin-2-yl-phenylamine derivatives and their salts

1. A process for preparing a compound of formula (I)

wherein:

R independently means a hydrogen atom, a halogen atom or a group selected from a (C 1 -C 3 ) alkyl group, a —NR 1 R 2 group, a (C 1 -C 3 )fluoroalkoxy group, a phenoxy group or a (C 1 -C 4 )alkoxy group, with R 1 and R 2 are independently a (C 1 -C 3 )alkyl group;

R′ is a hydrogen atom, a halogen atom except fluorine, or a group selected from a (C 1 -C 3 )alkyl group;

R″ is a hydrogen atom or a (C 1 -C 4 )alkyl group;

R″′ is a hydrogen atom, a halogen atom, or a group selected from a (C 1 -C 3 )alkyl group or a (C 1 -C 4 )alkoxy group;

n is 1, 2 or 3; and

n′ is 1 or 2;

which comprises the step of reacting a compound of formula (II)

wherein:

R′, R″′ and n′ are defined as in formula (I); and

L means a leaving group, preferably selected from a halogen atom; in particular selected from a fluorine atom, a chlorine atom or a bromine atom;

with a compound of formula (III)

wherein R″, R, and n are defined as in formula (I); and

wherein the compound of formula (III) is present in excess and no metal catalyst is present.

2. The process according to claim 1 , wherein

R is a (C 1 -C 3 )fluoroalkoxy group;

R′ is a chlorine atom or a bromine atom;

R″ is a hydrogen atom;

R″′ is a hydrogen atom, a chlorine atom or a bromine atom; and

n and n′ are 1.

3. The process according to claim 1 , wherein the reaction is carried out in the presence of an (C 1 -C 4 ) alcohol.

4. The process according to claim 1 , wherein the reaction is carried out with 1 mole of compound (II) and 2-5 mole of compound (III).

5. The process according to claim 1 , further comprising the step of precipitating the compound of formula (I) by adding water.

6. The process according to claim 5 , further comprising the step of recrystallizing, and optionally drying, the compound of formula (I).

7. The process according to claim 6 , further comprising the step of preparing a pharmaceutically acceptable salt of the compound of formula (I).

8. The process according to claim 1 , further comprising the step of formulating the compound of formula (I), and optionally its pharmaceutically acceptable salt, with a pharmaceutically acceptable carrier.

9. A polymorphic form of the free base of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine, characterized by a single endotherm with an onset temperature of 120° C. (±2° C.) and a peak temperature of 121° (±2° C.) in the DSC thermogram and/or characterized by characteristic signals in the x-ray powder diffractogram at angles 7.3, 14.6 and 24.8.

10. The polymorphic form of the free base of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine according to claim 9 , characterized by characteristic signals in the x-ray powder diffractogram at angles 7.3, 14.6, 18.3, 23.0 and 24.8.

11. The process according to claim 1 wherein:

R is a chlorine atom or a bromine atom;

R″ is a hydrogen atom;

R″′ is a hydrogen atom, a chlorine atom or a bromine atom;

n is 1 or 2;

n′ is 1; and

L is a fluorine atom or a chlorine atom.

12. The process according to claim 1 wherein:

R′ is a chlorine atom

R is a trifluoromethoxy group;

R″ and R″′ are independently a hydrogen atom; and

n and n′ are 1.

13. The process according to claim 1 wherein compound (I) is (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

14. The process according to claim 3 , wherein the (C 1 -C 4 ) alcohol is butanol or propanol.

15. The process according to claim 3 , wherein the reaction is carried out at a temperature between 25° C. and 130° C.

16. The process according to claim 15 , wherein the reaction is carried out at a temperature between 80° C. and 100° C.

17. The process according to claim 3 , wherein the reaction is carried out for 0.5 h to 15 h.

18. The process according to claim 17 , wherein the reaction is carried out for 3 h to 4 h.

19. The process according to claim 1 , wherein the reaction is carried out with 1 mole of compound (II), 2-5 mole of an (C 1 -C 4 ) alcohol, and 2-5 mole of compound (III).

20. The process according to claim 1 , wherein the reaction is carried out with 1 mole of compound (II), 5 mole of an (C 1 -C 4 ) alcohol, and 2-3 mole of compound (III).

21. The process according to claim 1 , wherein the reaction is carried out with 1 mole of compound (II), 5 mole of an (C 1 -C 4 ) alcohol, and 2-3 mole of compound (III) at a temperature of about 90° C.

22. The polymorphic form of the free base of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine according to claim 9 , characterized by characteristic signals in the x-ray powder diffractogram at angles 7.3, 14.6, 18.3, 23.0, 24.8, 28.3 and 29.5.