4-((6-(2-(2,4-DIFLUOROPHENYL)-1,1-DIFLUORO-2-OXOETHYL)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 mixture formed by combining 1-bromo-2,4-difluorobenzene with a metal or an organometallic reagent, and

an acid.

2 . The method of claim 1 , 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.

3 . The method of claim 1 , wherein the metal is magnesium and the organometallic reagent is an alkyllithium or an alkylmagnesium halide.

4 . The method of claim 3 wherein the alkyllithium is n-butyllithium, and the alkylmagnesium halide is isopropylmagnesium chloride.

5 . The method of claim 1 , wherein the contacting is carried out between about −80° C. and about 50° C.

6 . The method of claim 1 , 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.

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

contacting a compound of Formula III

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

8 . The method of claim 7 , wherein the metal is copper.

9 . The method of claim 7 , further comprising a solvent selected from the group including DMSO, DMF, THF, NMP, and mixtures thereof.

10 . The method of claim 7 , wherein the contacting is carried out between about room temperature and about 100° C.

11 . The method of claim 7 , further comprising the step of:

contacting a compound of Formula IV

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

12 . The method of claim 11 wherein the base is selected from cesium carbonate and potassium carbonate.

13 . The method of claim 11 , wherein the step of contacting the compound of Formula IV with 4-fluorobenzonitrile or 4-nitrobenzonitrile, and a base further includes a solvent.

14 . The method of claim 13 , wherein the solvent is selected from the group including dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidone, and mixtures thereof.

15 . The method of claim 11 , wherein the step of contacting the compound of Formula IV with 4-fluorobenzonitrile or 4-nitrobenzonitrile, and a base is carried out between about room temperature and about 120° C.

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

contacting a compound of Formula V

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

17 . The method of claim 16 , wherein the magnesium-halogen exchange reagent is isopropylmagnesium chloride.

18 . The method of claim 16 , wherein the borate is selected from the group including B(OMe) 3 , B(OEt) 3 and B(Oi-Pr) 3 .

19 . The method of claim 16 , wherein the oxidizing agent is selected from the group including hydrogen peroxide, peracetic acid, and a mixture of hydrogen peroxide and acetic acid.

20 . The method of claim 16 , further comprising a solvent selected from the group including THF, 2-methyltetrahydrofuran, methyl t-butyl ether, dioxane, and mixtures thereof.

21 . A method of making a compound of Formula IV

comprising the step of contacting a compound of Formula V

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

22 . The method of claim 21 , wherein the magnesium-halogen exchange reagent is isopropylmagnesium chloride.

23 . The method of claim 21 , wherein the borate is selected from the group including B(OMe) 3 , B(OEt) 3 , and B(Oi-Pr) 3 .

24 . The method of claim 21 , wherein the oxidizing agent is selected from the group including hydrogen peroxide, peracetic acid, and a mixture of hydrogen peroxide and acetic acid.

25 . The method of claim 21 , further comprising a solvent selected from the group including tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, dioxane, and mixtures thereof.

26 . A compound consisting of: