Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof

1. A process for preparing a compound of Formula (I):

wherein:

R 1a , R 1b , R 1c , R 1d , and R 1e are each, independently, H, F, or Cl;

R 2 is methyl;

R 3 is Cl or Br;

R 4 is methoxy;

R 5 , at each occurrence, is H;

the process comprising:

a) reacting a compound of Formula (II):

with a compound of Formula (III):

wherein Z is an isocyanate group (—NCO) or isocyanate equivalent to form said compound of Formula (I); or

b) reacting a compound of Formula (II) with an isocyanate-generating reagent to form a compound of Formula (IIa):

wherein Y is an isocyanate group or isocyanate equivalent; and reacting said compound of Formula (IIa) with a compound of Formula (IIIa):

to form said compound of Formula (I).

2. The process of claim 1 wherein;

R 1a is F;

R 1b is H;

R 1c is F;

R 1d is H;

R 1e is H;

R 2 is methyl;

R 3 is Br;

R 4 is methoxy; and

R 5 , at each occurrence, is H.

3. The process of claim 1 wherein:

R 1a is H;

R 1b is H;

R 1c is Cl;

R 1d is H;

R 1e is H;

R 2 is methyl;

R 3 is Br;

R 4 is methoxy; and

R 5 , at each occurrence, is H.

4. The process of claim 1 wherein the process comprises reacting a compound of Formula (II):

with a compound of Formula (III):

wherein Z is an isocyanate group to form said compound of Formula (I).

5. The process of claim 4 wherein said reacting is carried out in an organic solvent.

6. The process of claim 5 wherein said organic solvent comprises an aromatic solvent.

7. The process of claim 5 wherein said organic solvent comprises toluene.

8. The process of claim 5 wherein said reacting is carried out at a reduced temperature.

9. The process of claim 8 wherein said reduced temperature is about 10 to about 20° C.

10. The process of claim 5 wherein said compound of Formula (III) is added in molar excess relative to the amount of Formula (II).

11. The process of claim 1 wherein said compound of Formula (II) is prepared by the process comprising deprotecting a compound of Formula (IV):

wherein:

Pr is an amino protecting group; and

R N is H;

or Pr and R N together with the N atom to which they are attached form a cyclic amino protecting group;

with a deprotecting agent to form said compound of Formula (II).

12. The process of claim 11 wherein said compound of Formula (IV) is prepared by the process comprising halogenating a compound of Formula (V):

with a halogenating reagent selected from a chlorinating reagent and a brominating reagent to form said compound of Formula (IV).

13. The process of claim 12 wherein said compound of Formula (V) is prepared by the process comprising cyclizing a compound of Formula (VI):

wherein R 2a and R 2b are each, independently, C 1-4 alkyl, with an alkylhydrazine having the formula NH 2 NH—R 2 to form said compound of Formula (V).

14. The process of claim 13 wherein said compound of Formula (VI) is prepared by the processes comprising condensing a compound of Formula (VII):

with an acetal of Formula (VIII):

wherein R and R′ are each, independently, C 1-6 akyl, arylalkyl or alkylaryl, or R and R′ together with the O atoms to which they are attached and the intervening CH group form a 5- or 6-membered heterocycloalkyl group to form said compound of Formula (VI).

15. A process for preparing a compound of Formula (II):

wherein:

R 2 is methyl;

R 3 is Cl or Br;

R 4 is methoxy;

R 5 , at each occurrence, is H;

comprising reacting a compound of Formula (IV):

wherein:

Pr is an amino protecting group; and

R N is H;

or Pr and R N together with the N atom to which they are attached form a cyclic amino protecting group;

with a base to form said compound of Formula (II).

16. The process of claim 15 wherein Pr is an acyl group.

17. The process of claim 15 wherein Pr is —C(O)Me.

18. The process of claim 15 wherein said base is sodium hydroxide.

19. The process of claim 15 wherein said reacting is carried out in an organic solvent.

20. The process of claim 19 wherein said organic solvent comprises an alcohol.

21. The process of claim 20 wherein said organic solvent comprises methanol.

22. A process for the preparation of a compound of Formula (IV):

wherein:

R 2 is methyl;

R 3 is Cl or Br;

R 4 is methoxy;

R 5 , at each occurrence, is H;

Pr is an amino protecting group; and

R N is H;

or Pr and R N together with the N atom to which they are attached form a cyclic amino protecting group;

comprising reacting a compound of Formula (V):

with a reagent selected from a chlorinating reagent and a brominating reagent to form said compound of Formula (IV).

23. The process of claim 22 wherein said halogenating reagent is a brominating reagent.

24. The process of claim 23 wherein said halogenating reagent comprises N-bromosuccinimide.

25. The process of claim 24 wherein said reacting is carried out in an organic solvent.

26. The process of claim 25 wherein said organic solvent comprises an alcohol.

27. The process of claim 26 wherein said organic solvent comprises methanol.

28. A process for preparing a compound of Formula (V):

wherein:

R 2 is methyl;

R 3 is Cl or Br;

R 4 is methoxy;

R 5 , at each occurrence, is H;

Pr is an amino protecting group; and

R N is H;

or Pr and R N together with the N atom to which they are attached form a cyclic amino protecting group;

comprising reacting a compound of Formula (VI):

wherein R 2a and R 2b are each, independently, C 1-4 alkyl, with an alkylhydrazine having the formula NH 2 NH—R 2 to form said compound of Formula (V).

29. The process of claim 28 wherein said reacting is carried out in the presence of an organic solvent.

30. The process of claim 29 wherein said organic solvent comprises an alcohol.

31. The process of claim 29 wherein said organic solvent comprises methanol.

32. The process of claim 28 wherein said reacting is carried out in the presence of an acid.

33. The process of claim 32 wherein said acid comprises HCl.

34. A compound of Formula (IV) or (V):

wherein:

R 2 is methyl;

R 3 is Cl or Br;

R 4 is methoxy;

R 5 , at each occurrence, is H;

Pr is an amino protecting group;

R N is H; and

or Pr and R N together with the N atom to which they are attached form a cyclic amino protecting group.

35. The compound of claim 34 wherein said compound has Formula (IV) and R 2 is methyl; R 3 is Br; R 4 is methoxy; R 5 , at each occurrence, is H; and Pr is —C(O)Me.

36. The compound of claim 34 wherein said compound has Formula (V) and R 2 is methyl; R 4 is methoxy; R 5 , at each occurrence, is H; and Pr is —C(O)Me.

37. The process of claim 19 wherein said reacting is carried out at about 0 to about 100° C.