Substituted benzimidazoles and methods of preparation

1. A method for preparing a compound or pharmaceutically acceptable salt thereof that is {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)-amine

the method comprising:

(a) reacting a compound of Formula (II) with a compound of Formula (III) to provide a compound of Formula (IV)

wherein b is 0, R 2 is methyl, Q is NH 2 or NO 2 ; one of L 1 or L 2 is halo and the other of L 1 or L 2 is OH or an anion thereof; Z is cyano, COOR 5 , CH 2 OR 5 , CHO, or imidazol-2-yl substituted with CF 3 and wherein R 5 is hydrogen or a hydroxy protecting group;

(b) when in the compound of Formula (IV) Z is cyano, COOR 5 or CH 2 OR 5 , reacting said compound with a reducing agent to provide a compound of Formula (IV) wherein Z is CHO;

(c) when in the compound of Formula (IV) Z is cyano, reacting the cyano functionality with an alkoxide to form an imidate, reacting the imidate with ammonium to form an amidino functionality and reacting said amidino functionality with a compound of Formula (Va) under imidazole ring forming conditions; or when in the compound of Formula (IV) Z is CHO, reacting said compound with a compound of Formula (Vb) to provide a compound of Formula (VI)

wherein b is 0, c is 1, R 4 is CF 3 , X a in Formula (Va) is a leaving group and one of R 4p and R 4q in Formula (Vb) is H and the other of R 4p and R 4q is CF 3 , and X b is ═O or ═NHOH;

(d) when in the compound of Formula (VI) Q is NO 2 , reacting said compound with a reducing agent to a compound of Formula (VI) wherein Q is NH 2 ;

(e) reacting the compound of Formula (VI) wherein Q is NH 2 with a compound of Formula (VII) to provide a compound of Formula (VIII) or a tautomer thereof wherein a is 1, b is 0, c is 1, R 1 is 4-CF 3 , R 2 is methyl, and R 4 is CF 3

(f) reacting the compound of Formula (VIII) or a tautomer thereof with a desulfurizing agent to provide {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)-amine or its tautomer; and

(g) optionally reacting {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)-amine or a tautomer thereof with an acid to give a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein part (a) is carried out with organic or inorganic base in polar solvent.

3. The method of claim 2 wherein the inorganic base is selected from the group consisting of NaOH, KOH, CaCO 3 , and K 2 CO 3 .

4. The method of claim 2 wherein the polar solvent is selected from the group consisting of dimethylsulfoxide and dimethylformamide.

5. The method of claim 1 wherein part (b) comprises reacting a compound of Formula (IV) when Z is COOR 5 with a reducing agent.

6. The method of claim 5 wherein R 5 is tert-butyl.

7. The method of claim 5 wherein the reducing agent is diisobutylaluminum hydride.

8. The method of claim 1 wherein part (c) is carried out with NH 4 OH in polar solvent.

9. The method of claim 8 wherein the polar solvent is a mixture of ethyl acetate and ethanol.

10. The method of claim 1 wherein part (d) comprises reacting a compound of Formula (VI) when Q is NO 2 with sodium dithionite.

11. The method of claim 1 wherein part (e) is carried out in acetonitrile.

12. The method of claim 1 wherein the desulfurizing agent in part (f) is selected from the group consisting of FeCl 3 , 2-chloro-1-methylpyridinium iodide, 2-chloro-1,3-dimethylimidazolium chloride, and POCl 3 .