4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)pyridin-3-yl and processes of preparation

1. A method of making a compound of Formula I

comprising the steps of:

contacting a compound of Formula III

with a trialkylsulfoxonium halide and a base to prepare the compound of Formula II, and

contacting a compound of Formula II

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

2. The method of claim 1 , wherein the base is one of potassium carbonate, cesium carbonate, and sodium t-butoxide.

3. The method of claim further comprising a solvent selected from the group including dimethylsulfoxide, dimethylformamide, sulfolane, tetrahydrofuran, water, N-methyl-2-pyrrolidone, and mixtures thereof.

4. The method of claim 1 , wherein the contacting the compound of Formula II is carried out between about room temperature and about 100° C.

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

6. The method of claim 1 , wherein the base is selected from the group including sodium hydride, potassium carbonate, cesium carbonate, and sodium tert-butoxide.

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

8. The method of claim 1 , wherein the contacting the compound of Formula III is carried out between about −20° C. and about 100° C.

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

contacting a compound of Formula IV

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 III.

10. The method of claim 9 , further comprising an aprotic solvent i-s 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 V

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

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 VI

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

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 VI 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 VI 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 VII

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

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.