4-((6-(2-(2,4-DIFLUOROPHENYL)-1,1-DIFLUORO-2-HYDROXY-3-(5-MERCAPTO-1H-1,2,4-TRIAZOL-1-YL)PROPYL)PYRIDIN-3-YL)OXY)BENZONITRILE AND PROCESSES OF PREPARATION
Provided herein is a process for the preparation of 4-((6-(2-(2,4-difluorophenyl)-1, 1-difluoro-2-hydroxy-3-(5-mercapto-1H-1,2,4-triazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile from 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-3-hydrazinyl-2-hydroxypropyl)pyridin-3-yl)oxy)benzonitrile.
1 . A method of making a compound of Formula I comprising:
contacting a compound of Formula II
with a base, elemental sulfur and an acid.
2 . The method of claim 1 , wherein the base is selected from the group including LiHMDS, NaHMDS, KHMDS, LDA, LTMP and mixtures thereof.
3 . The method of claim 1 , wherein the base is selected from the group including lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, and mixtures thereof.
4 . The method of claim 1 , wherein the base is selected from the group including lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
5 . The method of claim 1 , further comprising a solvent selected from the group including THF, DME, ether, MTBE, 2-Me-THF, dioxane, hexane, toluene, and mixtures thereof.
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 wherein the contacting is carried out between about 150° C. and about −80° C.
8 . The method of claim 1 wherein the contacting is carried out between about 100° C. and about −30° C.
9 . The method of claim 1 , further comprising the step of contacting a compound of Formula III
with a nitrogen containing cyclization reagent and optionally an acid, to prepare the compound of Formula II.
10 . A method of making a compound of Formula II comprising:
the step of contacting a compound of Formula III
with a nitrogen containing cyclization reagent and optionally an acid.
11 . The method of claim 9 , wherein the nitrogen containing cyclization reagent comprises 1,3,5-triazine.
12 . The method of claim 9 , wherein the nitrogen containing cyclization reagent comprises an (E)-N-((((dimethylamino)methylene)amino)methylene)-N-methylmethanaminium halide of Formula V
wherein X is Cl or Br.
13 . The method of claim 9 , wherein the nitrogen containing cyclization reagent comprises N,N′,N′-methanetriyltriformamide of Formula VI.
14 . The method of claim 9 , wherein the nitrogen containing cyclization reagent comprises a formamidine salt of Formula VII
wherein X=OAc, Cl, Br, or I.
15 . The method of claim 9 , wherein the optional acid may be selected from the group including HCl, formic acid, acetic acid, and trifluoroacetic acid.
16 . The method of claim 9 wherein the contacting is carried out between about 50° C. and about 200° C.
17 . The method of claim 9 wherein the contacting is carried out between about 50° C. and about 100° C.
18 . The method of claim 9 wherein the contacting is carried out between about 20° C. and about 60° C.
19 . The method of claim 9 , wherein the nitrogen containing cyclization reagent comprises formamide.
20 . The method of claim 19 wherein the contacting is carried out at one of the following ranges: between about 100° C. and about 200° C., and between about 140° C. and about 180° C.
21 . (canceled)