Process for the preparation of 2-aminomethylpyridine derivative

1. Process for the preparation of a 2-aminomethylpyridine derivative of general formula (I) or a salt thereof:

in which:

n represents 0, 1, 2 or 3,

X is halogen atom,

Y may be the same or different and may be a halogen atom, a halogenoalkyl, a alkoxycarbonyl or a alkylsulphonyl;

said process comprising:

(A)—a first step according to reaction scheme 1:

in which benzophenone (BP) is reacted with glycine alkyl ester hydrochloride (GAE.HCl) at reflux in a non polar solvent, said solvent being capable of forming an azeotrope with water, in the presence of an acid catalyst and a trialkylamine base, in a BP/GAE.HCl molar ratio of from 1 to 4, to provide a benzophenone glycine imine derivative (BPGI);

(B)—a second step according to reaction scheme 2;

in which:

X, Y and n are as defined above,

z is a leaving group,

comprising the reaction of the benzophenone glycine imine derivative (BPGI) solution obtained in step one with a pyridine derivative (Py-z) in the presence of a dry inorganic base, in the presence of a catalyst and an aprotic polar solvent, the mixture being heated at reflux, to provide a pyridine glycine imine derivative (PyGI);

(C)—a third step according to reaction scheme 3;

in which X, Y and n are as defined above

comprising the addition to the previous pyridine glycine imine derivative (PyGI) solution of an aqueous hydrochloric acid at up to 25° C., in a HCl/PyGI molar ratio of at least 1, to provide a pyridine glycine ester hydrochloride derivative (PyGE.HCl);

(D)—a fourth step comprising the conversion of the pyridine glycine ester hydrochloride derivative (PyGE.HCl) into a compound of general formula (I) by heating under reflux of water.

2. Process according to claim 1 , characterised in that X is chlorine.

3. Process according to claim 1 , characterised in that n is 1.

4. Process according to claim 1 , characterised in that Y is haloalkyl.

5. Process according to claim 4 , characterised in that Y is trifluoromethyl.

6. Process according to claim 1 , characterised in that X is chlorine, n is 1 and Y is trifluoromethyl.

7. Process according to claim 6 , characterised in that compound of general formula (I) is 2-aminomethyl-3-chloro-5-trifluoromethylpyridine.

8. Process according to claim 1 , characterised in that, in the first step, the acid catalyst is paratoluenesulfonic acid catalyst.

9. Process according to claim 1 , characterised in that, in the first step, the solvent capable of forming an azeotrope with water is toluene or ethylbenzene.

10. Process according to claim 1 , characterised in that the trialkylamine base is N,N-diisopropyl N-ethylamine.

11. Process according to claim 1 , characterised in that, in the second step, z is a halogen atom.

12. Process according to claim 11 , characterised in that z is a chlorine atom.

13. Process according to claim 1 , characterised in that, in the second step, the dry inorganic base is K 2 CO 3 or NaH.

14. Process according to claim 1 , characterised in that, in the second step, the catalyst is a phase transfer catalyst.

15. Process according to claim 14 , characterised in that the phase transfer catalyst is Net 4 Br.

16. Process according to claim 1 , characterised in that, in the second step, the polar solvent is propionitrile.

17. Process according to claim 1 , characterised in that, in the third step, the temperature is of from 20 to 25° C.

18. Process according to claim 1 , characterised in that, in the third step the HCl/PyGI molar ratio is of from 1 to 5.

19. Process for the preparation of

in which:

n represents 0, 1, 2 or 3,

X is halogen atom,

Y may be the same or different and may a halogen atom, a halogenoalkyl, a alkoxycarbonyl or a alkylsulphonyl;

said process comprising:

(A)—a first step according to reaction scheme 1;

in which benzophenone (BP) is reacted with glycine alkyl ester hydrochloride (GAE.HCl) at reflux in the presence of an acid catalyst and a trialkylamine base, in a non polar solvent, said solvent being capable of forming an azeotrope with water, in a BP/GAE.HCl molar ratio of 1 to 4, to provide a benzophenone glycine imine derivative (BPGI);

(B)—a second step according to reaction scheme 2;

in which:

X, Y and n are as defined above,

z is a leaving group,

comprising the reaction of the benzophenone glycine imine derivative (BPGI) solution obtained in step one with a pyridine derivative (Py-z) in the presence of a dry inorganic base, in which is added a catalyst and an aprotic polar solvent, the mixture being heated at reflux, to provide a pyridine glycine imine derivative (PyGI);

(C)—a third step according to reaction scheme 3;

comprising the addition to the previous pyridine glycine imine derivative (PyGI) solution of an aqueous hydrochloric acid at up to 25° C., in a HCl/PyGI molar ratio of at least 1, to provide a pyridine glycine ester hydrochloride derivative (PyGE.HCl).