METHODS FOR THE PREPARATION OF ETHYL 3-BROMO-1-(3-CHLOROPYRIDIN-2-YL)-1H-PYRAZOLE-5-CARBOXYLATE

1 . A method of preparing a compound of Formula (II)

wherein R 5 is halogen;

each R 6 is independently C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, CN, NO 2 , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, C 3 -C 6 (alkyl)cycloalkylamino, C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylaminocarbonyl, C 3 -C 8 dialkylaminocarbonyl or C 3 -C 6 trialkylsilyl;

R 7 is H or C 1 -C 4 alkyl;

Y is N or CR 8 ;

R s is H or R 9 , wherein R 9 is independently C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, CN, NO 2 , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, C 3 -C 6 (alkyl)cycloalkylamino, C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylaminocarbonyl, C 3 -C 8 dialkylaminocarbonyl or C 3 -C 6 trialkylsilyl; and

m is 0, 1, 2, or 3, with the proviso that when Y is CH then m is at least 1, the method comprising:

I) forming a mixture comprising

A) a compound of Formula (I)

wherein R 1 is halogen;

each R 2 is independently C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, CN, NO 2 , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, C 3 -C 6 (alkyl)cycloalkylamino, C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylaminocarbonyl, C 3 -C 8 dialkylaminocarbonyl or C 3 -C 6 trialkylsilyl;

R 3 is H or C 1 -C 4 alkyl;

X is N or CR 4 ;

R 4 is H or R 2 ; and

n is 0, 1, 2, or 3, with the proviso that when X is CH then n is at least 1;

B) an organic solvent; and

C) an inorganic base;

II) optionally heating the mixture;

III) irradiating the mixture; and

IV) adding an oxidizing agent to the mixture.

2 . The method of claim 1 wherein m is 1, 2, or 3.

3 . The method of claim 1 wherein R s is Cl or Br.

4 . The method of claim 1 wherein R 6 is independently Cl or Br.

5 . The method of claim 4 wherein one R 6 is at the 3-position.

6 . The method of claim 1 wherein R 7 is C 1 -C 4 alkyl.

7 . The method of claim 1 wherein Y is N.

8 . The method of claim 1 wherein the compound of Formula (II) is ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, having the following structure:

9 . The method of claim 1 , further comprising isolating the compound of Formula (II).

10 . The method of claim 1 wherein n is 1, 2, or 3.

11 . The method of claim 1 wherein R 1 is Cl or Br.

12 . The method of claim 1 wherein R 2 is independently Cl or Br.

13 . The method of claim 12 wherein one R 2 is at the 3-position.

14 . The method of claim 1 wherein R 3 is C 1 -C 4 alkyl.

15 . The method of claim 1 wherein X is N.

16 . The method of claim 1 wherein the compound of Formula (I) is ethyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate, having the following structure:

17 . The method of claim 1 wherein the organic solvent is selected from acetonitrile, N,N-dimethylformamide, dimethylacetamide, chloroform, acetone, propionitrile, chlorobutane, chlorobenzene, tetrachloromethane, dichlorobenzene, dichloromethane, 1,2-dichloroethane, and combinations thereof.

18 . The method of claim 1 wherein the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, ammonium bicarbonate, trisodium phosphate, tripotassium phosphate, caesium carbonate, triethylamine, pyridine, N-methylimidazole, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, potassium hydroxide, and combinations thereof.

19 . The method of claim 1 wherein the inorganic base is in the form of a solid or an aqueous solution.

20 . The method of claim 1 wherein the mixture is a two-phase mixture.