Granted Patent B2

US 8,575,395 · App. 13/226,061 · Granted Nov 5, 2013

Inventors: Vijayavitthal Thippannachar Mathad (Maharashtra, IN); Navnath Chintaman Niphade (Maharashtra, IN); Gorakshanath Balasaheb Shinde (Maharashtra, IN); Sharad Subhash Ippar (Maharashtra, IN); Shrikant Prataprao Deshmukh (Maharashta, IN); Raghavendra Kumar Panchangam (Maharashtra, IN)

Assignees: Amneal Pharmaceuticals, LLC; Megafine Pharma (P) Ltd.

Abstract

Claims (59)

1. A method for the preparation of a compound of Formula (I) or salts thereof,

the method comprising:

a. reacting a compound of the Formula (II) and a compound of Formula (III) to form a compound of Formula (IV);

wherein

Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, and nitro groups;

b. treating the compound of Formula (IV) obtained from step (a) with a compound of Formula (V) to form a compound of Formula (VI);

wherein;

Ar is as described above,

X is chloro, bromo or iodo; and

c. treating the compound of Formula (VI) with water and/or acid solution to obtain a compound of Formula (I) or salts thereof;

2. The method according to claim 1 , wherein the step (a) is carried out at a temperature from about 10° C. to 150° C.

3. The method according to claim 2 wherein the step (a) is carried out in the presence of a solvent.

4. The method according to claim 3 , wherein the solvent is selected from the group consisting of hydrocarbons, alcohols, C 1 -C 10 ether, C 5 -C 8 cyclic ether, C 2 -C 10 aliphatic ester, C 2 -C 8 aliphatic amides, sulfoxide, C 1 -C 8 chlorinated hydrocarbon, 1-ethyl-3-methyl imidazolium ethylsulfate, and mixtures thereof.

5. The method according to claim 1 wherein, the compound of Formula (III) is selected from benzaldehyde, salisaldehyde, p-hydroxylbenzaldehyde, o-chlorobenzaldehyde, p-methoxy benzaldehyde, o-methoxy benzaldehyde, and p-nitrobenzaldehyde.

6. The method according to claim 1 , further comprising isolating the compound of Formula (I) or a salt thereof in a crystalline form.

7. The method according to claim 1 , wherein the step (b) is carried out at a temperature of 80° C. to 180° C.

8. The method as according to claim 7 , wherein the step (b) is carried out in the presence of a solvent.

9. The method according to claim 8 , wherein the solvent is selected from the group consisting of hydrocarbons, alcohols, C 1 -C 10 ethers, C 5 -C 8 cyclic ethers, C 2 -C 10 aliphatic esters, C 2 -C 8 aliphatic amides, sulfoxides, C 1 -C 8 chlorinated hydrocarbons, 1-ethyl-3-methyl imidazolium ethyl sulfate, and mixtures thereof.

10. The method according to claim 1 , wherein the step (c) is carried out at a temperature of about 20° C. to 60° C.

11. The method according to claim 10 , wherein the step (c) is carried out in the presence of a solvent.

12. The method according to claim 11 , wherein the solvent is selected from the group consisting of hydrocarbons, alcohols, C 1 -C 10 ethers, C 5 -C 8 cyclic ethers, C 2 -C 10 aliphatic esters, C 2 -C 8 aliphatic amides, sulfoxides, C 1 -C 8 chlorinated hydrocarbons, 1-ethyl-3-methyl imidazolium ethyl sulfate, and mixtures thereof.

13. The method according to claim 1 , further comprising isolation of the compound of Formula (I) or salts thereof by:

I. cooling the reaction mass of step (c) and diluting it with water and a water-immiscible organic solvent;

II. adjusting the pH of the reaction mixture of Step I to a pH of about 10;

III. separating the organic layer comprising the compounds of Formula (I) or salts thereof, Formula (II) and Formula (III), from the aqueous layer comprising the compound of Formula (V);

IV. washing the organic layer separated in Step III with water;

V. further washing the organic layer of Step IV with a solution of sodium meta-bisulphite to remove the compound of Formula (III);

VI. diluting the organic layer of Step V with water and adjusting the pH to about 1 to about 5;

VII. separating the organic layer of Step VI comprising the compound of Formula (I) or salts thereof from the aqueous layer comprising the compound of Formula (II);

VIII. washing the organic layer obtained from Step VII with water and adjusting the pH of the organic layer to about 8 to about 10; and

IX. separating the organic layer mostly comprising the compound of Formula (I) or a salt thereof, and recovering the compound of Formula (I) or salt thereof by removing the solvent from the organic layer.

14. The method according to claim 13 , wherein the water-immiscible organic solvent is selected from the group consisting of hydrocarbons, esters, ethers, chlorinated hydrocarbons and mixtures thereof.

15. The method according to claim 1 , further comprising isolation of a hydrochloride salt of the compound of Formula (I) by

I. cooling the reaction mass of step (c) and diluting it with water and a water-immiscible organic solvent;

II. adjusting the pH of the reaction mixture of step I to a pH of around 10;

III. separating the organic layer comprising the compounds of Formula (I) or salts thereof, Formula (II) and Formula (III), from the aqueous layer comprising the compound of Formula (V);

IV. washing the organic layer separated in step III with water;

V. further washing the organic layer of step IV with a solution of sodium metabisulfite to remove the compound of Formula (III);

VI. diluting the organic layer of step V with water and adjusting the pH to about 1 to about 5 by adding hydrochloric acid to obtain a hydrochloride salt of the compound of Formula (I);

VII. separating the organic layer of step VI and further washing it with water; and

VIII. removing the solvent from the organic layer to obtain a hydrochloride salt of the compound of Formula (I).

16. The method according to claim 15 , wherein the water-immiscible solvent is selected from the group consisting of hydrocarbons, esters, ethers, chlorinated hydrocarbons, and mixtures thereof.

17. A compound of the Formula (VI),

wherein,

Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, or nitro group; and

X is chloro, bromo or iodo.

18. A method of preparing the compound of claim 17 , comprising

a. reacting a compound of Formula (II) and a compound of Formula (III) to obtain a compound of Formula (IV);

wherein

Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, and nitro groups; and

b. treating the compound of Formula (IV) with a compound of Formula (V) to obtain a compound of Formula (VI),

wherein

Ar is as defined above, and

X is chloro, bromo, or iodo.

19. The method according to claim 18 , wherein the step (a) is carried out at a temperature of 10° C. to 150° C.

20. The method according to claim 19 , wherein the step (a) is carried out in the presence of a solvent.

21. The method according to claim 20 , wherein the solvent is selected from the group consisting of a hydrocarbons, alcohols, C 1 -C 10 ethers, C 5 -C 8 cyclic ethers, C 2 -C 10 aliphatic esters, C 2 -C 8 aliphatic amides, sulfoxides, C 1 -C 8 chlorinated hydrocarbons, 1-ethyl-3-methyl imidazolium ethylsulfate, and mixtures thereof.

22. The method according to claim 18 , wherein the compound of Formula (III) is selected from benzaldehyde, salisaldehyde, p-hydroxy benzaldehyde, o-chlorobenzaldehyde, p-methoxy benzaldehyde, o-methoxy benzaldehyde, and p-nitrobenzaldehyde.

23. A method of preparing a compound of Formula (I) or a salt thereof, comprising reacting the compound of claim 17 to produce the compound of Formula (I).

Assignments (14)

Priority Claims (1)

Continuity (2)