METHODS FOR THE PREPARATION OF 5-BROMO-2-(3-CHLORO-PYRIDIN-2-YL)-2H-PYRAZOLE-3-CARBOXYLIC ACID

1 . A method of preparing a compound of Formula V, wherein

each of R 5 -R 10 is independently selected from hydrogen and halogen; and

R 12 is an organic acid, the method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

R 4 is a halogen; and

each of R 5 -R 10 is independently selected from hydrogen and halogen;

B) a solvent;

C) a carbonyl-containing compound;

D) a compound comprising a metal; and

E) optionally an additive; and

II) reacting the mixture.

2 . The method of claim 1 , wherein the compound comprising a metal is selected from a Grignard reagent and a lithium-containing compound.

3 . The method of claim 2 , wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, and combinations thereof.

4 . The method of claim 3 , wherein the Grignard reagent is iPrMgCl.

5 . The method of claim 2 , wherein the lithium-containing compound is nBuLi.

6 . The method of claim 1 , wherein the solvent is selected from THf, toluene, 1,4-dioxane, Me-THf, and combinations thereof.

7 . The method of claim 6 , wherein the solvent is THF.

8 . The method of claim 1 , wherein the carbonyl-containing compound is selected from dimethyl carbonate, N,N-dimethyacetamide, carbon dioxide, and combinations thereof.

9 . The method of claim 8 , wherein the carbonyl-containing compound is carbon dioxide.

10 . The method of claim 1 , wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 60° C.

11 . The method of claim 10 , wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 30° C.

12 . The method of claim 1 , wherein R 5 , and R 6 of Formula III are each independently hydrogen.

13 . The method of claim 1 , wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

each of R 4 , R 5 , and R 6 is independently selected from hydrogen and halogen;

wherein at least one of R 4 , R 5 , and R 6 is hydrogen; and

wherein the compound of Formula II is prepared according to a method comprising

i) forming a mixture comprising

 a) a compound of Formula I, wherein

 each of R 1 , R 2 , and R 3 is independently a halogen;

 b) optionally a dehalogenation reagent;

 c) a reducing agent; and

 d) a solvent; and

ii) reacting the mixture;

B) a compound of Formula IV, wherein

each of R 7 -R 11 is independently selected from hydrogen and halogen;

C) a solvent;

D) an inorganic base; and

E) optionally an additive; and

II) reacting the mixture.

14 . The method of claim 13 , wherein the inorganic base is selected from powder sodium hydroxide, powder potassium hydroxide, potassium carbonate, potassium phosphate, powder sodium methoxide, powder potassium t-butoxide, and combinations thereof.

15 . The method of claim 13 , wherein the solvent C) is selected from heavy aromatic solvents, heavy aromatic solvent S150, heavy aromatic solvent S200, acetonitrile (MeCN), toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), diglyme, triglyme, sulfolane and combinations thereof

16 . The method of claim 13 , wherein the additive is selected from potassium iodide, a phase transfer catalyst, and combinations thereof.

17 . The method of claim 16 , wherein the phase transfer catalyst is selected from butyl ammonium chloride, tetra butyl ammonium bromide, aliquat-336, 18-crown-6, and combinations thereof.

18 . A method of preparing a compound of Formula II, wherein

each of R 4 , R 5 , and R 6 is independently selected from hydrogen and halogen; and

wherein at least one of R 4 , R 5 , and R 6 is hydrogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula I, wherein

each of R 1 , R 2 , and R 3 is independently a halogen; and

wherein the compound of Formula I is prepared according to a method comprising

 i) forming a mixture comprising

 a) pyrazole or a pyrazole derivative;

 b) a halogenation reagent;

 c) a reaction solvent comprising water and an organic solvent; and

 d) optionally an inorganic base; and

 ii) reacting the mixture;

B) optionally a dehalogenation reagent;

C) a reducing agent; and

D) a solvent; and

II) reacting the mixture.

19 . The method of claim 18 , wherein the solvent D) is selected from acetic acid, water, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and combinations thereof.

20 . The method of claim 18 , wherein the reducing agent is selected from sodium sulfite, sodium bisulfite, sodium hyposulfite, sodium thiosulfate, sodium hydrosulfide, sodium sulfate, and combinations thereof.