Method for preparing N-phenylpyrazole-1-carboxamides

1. A method for preparing a compound of Formula 1

wherein

X is O;

Z is N;

R 1 is H, CH 3 , Cl or Br;

R 2 is H, Br, Cl or CN;

R 3 is H, C 1 -C 4 alkyl or C 4 -C 10 cycloalkylalkyl;

R 4 is Cl, or Br; or

C 1 -C 4 alkyl substituted with Q;

R 5 is F, Cl or Br;

R 6 is H, F or Cl;

Q is a 5- or 6-membered aromatic heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 haloalkyl;

comprising:

combining (1) a carboxylic acid compound of Formula 2,

wherein Z, R 4 , R 5 , R 6 , R 7 , and Q are as defined for the compound of Formula 1; and

(2) an aniline compound of Formula 3,

wherein X, R 1 , R 2 and R 3 are as defined for the compound of Formula 1;

(3) a sulfonyl chloride to form the compound of Formula 1; wherein the method comprises a continuous process comprising combining the compound of Formula 2, the compound of Formula 3, the sulfonyl chloride continuously in a reaction zone; and removing the compound of Formula 1 continuously in an isolation step further wherein the reaction zone comprises one or more continuous reaction vessels; and

(4) optionally in the presence of a base or solvent.

2. The method of claim 1 wherein the sulfonyl chloride is of Formula 4

R 8 S(O) 2 Cl   4

wherein R 8 is C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, or phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl and nitro.

3. The method of claim 2 wherein the sulfonyl chloride is methanesulfonyl chloride.

4. The method of claim 1 wherein the carboxylic acid of Formula 2 is combined with the aniline of Formula 3 to form a mixture, and then the mixture is combined with the sulfonyl chloride.

5. The method of claim 1 further comprising a base, wherein the base is combined with the compounds of Formulae 2 and 3 to form the mixture before combining with the sulfonyl chloride.

6. The method of claim 5 wherein the base is selected from 2-picoline, 3-picoline, 2,6-lutidine and pyridine.

7. The method of claim 1 further comprising a solvent, wherein the solvent is combined with the compounds of Formulae 2 and 3 and the sulfonyl chloride.

8. The method of claim 1 wherein a compound of Formula 1 is prepared, and the compound is selected from the group consisting of:

3-bromo-N-[4-chloro-2-methyl-6-[(methylamino) carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide,

3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino) carbonyl]phenyl]-1H-pyrazole-5-carboxamide,

1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino) carbonyl]phenyl]-3-[[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl]-1H-pyrazole-5-carboxamide, and

3-bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl]amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide.

9. The method of claim 1 , wherein the reaction vessels are selected from the group consisting of continuous stirred tank reactors, plug flow reactors, and combinations thereof.

10. The method of claim 9 , wherein the reaction zone comprises two continuous reaction vessels in series.

11. The method of claim 9 , wherein the reaction zone comprises one continuous reaction vessel.

12. The method of claim 9 , wherein each of the one or more reaction vessels in the reaction zone is operated at an independent residence time and temperature.

13. The method of claim 9 , wherein an average residence time for moieties in each reaction vessel in the reaction zone is 2 hours or less.

14. The method of claim 9 , wherein the isolation step comprises:

quenching a reaction mass comprising the compound of Formula 1 obtained from the reaction zone in a quench zone to precipitate the compound of Formula 1; and

separating the compound of Formula 1 from the quenched reaction mass by filtration to form collected solid compound of Formula 1.

15. The method of claim 14 , wherein quenching the reaction mass comprises continuously adding an antisolvent to the reaction mass in the quench zone.

16. The method of claim 14 , wherein the quench zone consists of one or more continuous quench vessels.

17. The method of claim 9 , wherein the isolation step yields a filtrate, and wherein the filtrate is recycled back into the reaction zone.

18. The method of claim 1 , wherein the molar ratio of the compound of Formula 2 to the compound of Formula 3 is from about 1.2:1 to about 1:1.2.

19. The method of claim 1 , wherein the carboxylic acid compound of Formula 2, the aniline compound of Formula 3 and sulfonyl chloride are combined at a temperature between about −70 and about 100° C.