Pyrazolyl carboxylic acid and pyrazolyl urea derivative compounds

1. A process of making compound (IV) comprising the steps of:

(a) forming a mixture comprising diphenylphosphoryl azide and compound (XIV):

(b) adding a solvent comprising water;

(c) adding NBOC-EDA;

(d) filtering the mixture and collecting a wet cake comprising crude product; and

(e) obtaining compound (IV):

2. The process of claim 1 , wherein step (a) comprises:

(1) forming a mixture comprising toluene, triethylamine, 1.2 equivalents of diphenylphosphoryl azide, and 1.0 equivalent of compound (XIV) while maintaining the temperature of the mixture below 40° C.;

(2) adjusting the temperature of the mixture to 45° C. and agitating for at least about 1 hour;

(3) adjusting the temperature of the mixture to below 40° C.;

(4) adding 0.2 equivalents of diphenylphosphoryl azide while maintaining the temperature of the mixture below 40° C.; and

(5) adjusting the temperature of the mixture to 45° C. and agitating the mixture for at least 1 hour.

3. The process of claim 1 , wherein step (b) comprises:

(1) adjusting the temperature of the mixture to 25° C.;

(2) adding the solvent comprising water while maintaining the temperature of the mixture at about 25° C.;

(3) agitating the mixture at 25° C. for at least 10 minutes; and

(4) discarding a lower aqueous phase after phase separation.

4. The process of claim 1 , wherein step (b) comprises:

(1) adding the solvent comprising water while maintaining the temperature of the mixture at about 25° C.;

(2) agitating the mixture at 25° C. for at least 10 minutes;

(3) discarding the lower aqueous phase after phase separation;

(4) drying an organic phase by distillation at a temperature less than 40° C.

5. The process of claim 1 , wherein step (c) comprises adding NBOC-EDA in two portions.

6. The process of claim 1 , wherein step (c) comprises:

(1) adding 5.7 volumes of toluene;

(2) adding 0.19 equivalents of NBOC-EDA;

(3) adjusting the temperature to 90° C.;

(4) adding a further 0.81 equivalents of NBOC-EDA in toluene while maintaining the temperature of the mixture at 90° C.; and

(5) agitating the mixture at 90° C. for 4 to 5 hours.

7. The process of claim 1 , wherein step (d) comprises:

(1) adjusting the temperature of the mixture to 30° C.;

(2) agitating the mixture at 30° C. for at least one hour; and

(3) filtering the mixture to collect the wet cake comprising crude product.

8. The process of claim 7 , further comprising washing the wet cake with 2.3 volumes of toluene.

9. The process of claim 1 , wherein the wet cake comprising crude product is washed with a mixture of dichloromethane and ethanol.

10. The process of claim 1 , wherein step (e) comprises:

(1) concentrating an organic phase to 6 to 8 volumes;

(2) adjusting the temperature to 3° C.;

(3) agitating the mixture at 3° C. for at least one hour; and

(4) filtering the reaction mixture to collect a wet cake.

11. The process of claim 10 , wherein step (e) further comprises:

(1) washing the wet cake with 1.3 volumes of cold ethanol; and

(2) drying the product under reduced pressure with a nitrogen purge.