2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-substituted-pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ols and processes for their preparation

1. A method of making compounds of Formula III, including the step of:

contacting compounds of Formula IIa with a preformed organometallic reagent,

wherein

R 1 is

or

Br; and

R 2 and R 3 are selected from —OCH 3 , —CH 3 , —CH 2 CH 3 or joined together to form a morpholine ring.

2. The method of claim 1 , wherein the preformed organometallic reagent is formed by a metal halogen exchange reaction of 1-bromo-2,4-difluorobenzene with one of magnesium, n-butyllithium, and isopropylmagnesium chloride.

3. The method of claim 1 , wherein the step of contacting compounds of Formula Ha with the preformed organometallic reagent further includes an aprotic solvent.

4. The method of claim 3 , wherein the aprotic solvent is one of diethyl ether and tetrahydrofuran.

5. The method of claim 1 wherein the step of contacting compounds of Formula IIa with the preformed organometallic reagent is carried out at about 0° C.

6. The method of claim 1 , further comprising the step of:

contacting compounds of Formula II with an amine, a Lewis acid, and a solvent

7. The method of claim 6 , wherein the amine is selected from N,O-dimethylhydroxylamine, dimethylamine, diethylamine and morpholine.

8. The method of claim 6 , wherein the Lewis acid is dimethylaluminum chloride.

9. The method of claim 6 , wherein the solvent is dichloromethane.

10. The method of claim 6 , wherein the step of contacting compounds of Formula II with the amine, the Lewis acid, and the solvent is carried out in such a manner as to maintain a temperature below about 15° C.

11. The method of claim 6 , further comprising the step of:

contacting compounds of the Formula I with ethyl 2-bromo-2,2-difluoroacetate and a metal

12. The method of claim 11 , wherein the metal is copper.

13. The method of claim 11 , wherein the step of contacting I with ethyl 2-bromo-2,2-difluoroacetate and a metal further includes a solvent.

14. The method of claim 13 , wherein the solvent is selected from dimethyl sulfoxide, dimethylformamide, and mixtures thereof.

15. The method of claim 11 , further comprising the step of:

Contacting 6-bromopyridin-3-ol with one of 5-chloro-2-fluoropyridine and 2-fluoro-5-(trifluoromethyl)pyridine.

16. The method of claim 15 , wherein the step of contacting 6-bromopyridin-3-ol with one of 5-chloro-2-fluoropyridine and 2-fluoro-5-(trifluoromethyl)pyridine further includes a base.

17. The method of claim 16 , wherein the base is one of cesium carbonate and potassium carbonate.

18. The method of claim 15 , wherein the step of contacting 6-bromopyridin-3-ol with one of 5-chloro-2-fluoropyridine and 2-fluoro-5-(trifluoromethyl)pyridine further includes a solvent.

19. The method of claim 18 , wherein the solvent is one of dimethyl sulfoxide and dimethylformamide.

20. The method of claim 15 wherein the step of contacting 6-bromopyridin-3-ol with one of 5-chloro-2-fluoropyridine and 2-fluoro-5-(trifluoromethyl)pyridine is carried out between 65° C. and 100° C.

21. The method of claim 11 , further comprising the step of:

Contacting 6-bromopyridin-3-ol with 2,2,2-trifluoroethyl trifluoromethanesulfonate.