4-((6-(2-(2,4-DIFLUOROPHENYL)-1,1-DIFLUORO-2-HYDROXY-3-(1H-1,2,4-TRIAZOL-1-YL)PROPYL)PYRIDIN-3-YL)OXY)BENZONITRILE AND PROCESSES OF PREPARATION

1 . A method of making a compound of Formula I

comprising the step of contacting a compound of Formula II

with a trialkylsulfoxonium halide, a base, and 1H-1,2,4-triazole.

2 . The method of claim 1 , wherein the trialkylsulfoxonium halide is one of trimethylsulfoxonium iodide, trimethylsulfoxonium bromide and trimethylsulfoxonium chloride.

3 . The method of claim 1 , wherein the base may be selected from the group including metal carbonates, metal alkoxides and metal bicarbonates.

4 . The method of claim 1 , wherein the base is potassium carbonate or sodium tert-butoxide.

5 . The method of claim 1 further comprising a solvent selected from the group including dimethylsulfoxide (DMSO), dimethylformamide (DMF), sulfolane, tetrahydrofuran (THF), water, N-methyl-2-pyrrolidone (NMP), and mixtures thereof.

6 . The method of claim 1 further comprising a solvent selected from the group including THF, water, DMSO, and mixtures thereof.

7 . The method of claim 1 wherein the contacting is carried out from about −20° C. to about 100° C.

8 . The method of claim 1 wherein the contacting is carried out from about 20° C. to about 80° C.

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

contacting a compound of Formula III

with a mixture formed by combining 1-bromo-2,4-difluorobenzene with a metal or an organometallic reagent, and

an acid,

to prepare the compound of Formula II.

10 . The method of claim 9 , further comprising an aprotic solvent selected from the group including diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, toluene, dioxane, methyl t-butyl ether, and mixtures thereof.

11 . The method of claim 9 wherein the metal is magnesium and the organometallic reagent is an alkyllithium, or an alkylmagnesium halide.

12 . The method of claim 11 wherein the alkyllithium is n-butyllithium, and the alkylmagnesium halide is isopropylmagnesium chloride.

13 . The method of claim 9 , wherein the contacting is carried out between about −80° C. and about 50° C.

14 . The method of claim 9 , wherein the acid is selected from the group including HCl, HBr, H 2 SO 4 , H 3 PO 4 , HNO 3 , acetic acid, and trifluoroacetic acid.

15 . The method of claim 9 , further comprising the step of:

contacting a compound of Formula IV

with ethyl 2-bromo-2,2-difluoroacetate and a metal to prepare the compound of Formula III.

16 . The method of claim 15 , wherein the metal is copper.

17 . The method of claim 15 , further comprising a solvent selected from the group including DMSO, DMF, THF, NMP, and mixtures thereof.

18 . The method of claim 15 wherein the contacting is carried out between about room temperature and about 100° C.

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

contacting a compound of Formula V

with 4-fluorobenzonitrile or 4-nitrobenzonitrile, and a base to prepare the compound of Formula IV.

20 . The method of claim 19 wherein the base is selected from cesium carbonate and potassium carbonate.

21 . The method of claim 19 , wherein the step of contacting the compound of Formula V with 4-fluorobenzonitrile or 4-nitrobenzonitrile, and a base further includes a solvent.

22 . The method of claim 21 , wherein the solvent is selected from the group including dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof.

23 . The method of claim 19 wherein the step of contacting the compound of Formula V with 4-fluorobenzonitrile or 4-nitrobenzonitrile, and a base is carried out between about room temperature and about 120° C.

24 . The method of claim 19 , further comprising the step of:

contacting a compound of Formula VI

with a magnesium-halogen exchange reagent, a borate, and an oxidizing agent to prepare the compound of Formula V.

25 . The method of claim 24 , wherein the magnesium-halogen exchange reagent is iso-propylmagnesium chloride.

26 . The method of claim 24 , wherein the borate is selected from the group including B(OMe) 3 , B(OEt) 3 and B(Oi-Pr) 3 .

27 . The method of claim 24 , wherein the oxidizing agent is selected from the group including hydrogen peroxide, peracetic acid, and a mixture of hydrogen peroxide and acetic acid.

28 . The method of claim 24 , further comprising a solvent selected from the group including THF, 2-methyltetrahydrofuran, methyl t-butyl ether, dioxane, and mixtures thereof.