Processes for producing cycloalkylcarboxamido-pyridine benzoic acids

1. A process for preparing a compound of formula 1:

comprising the step of:

ia) reacting a compound of formula 6a:

wherein,

R is H, C 1-6 aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl;

R 1 is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;

o is an integer from 0 to 3 inclusive; and

p is an integer from 0 to 5 inclusive;

with a compound of formula 7a:

wherein,

A is a fused cycloalkyl, or heterocycloalkyl ring;

R 1 is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 -haloalkyl, —C 1-4 -haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;

m is an integer from 0 to 3 inclusive;

n is an integer from 1 to 4 inclusive; and

X is a halo or OH;

in an organic solvent in the presence of a second base,

wherein compound 7a is prepared by the following steps

ic) reducing Compound 10a in an organic solvent:

wherein,

A is a fused cycloalkyl or heterocycloalkyl ring;

R 1 is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 -haloalkyl, —C 1-4 -haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;

R K is methyl; and

m is an integer from 0 to 3 inclusive,

with a reducing agent to produce Compound 11a:

wherein, ring A, R 1 , and m are as defined in Compound 10a above;

iic) reacting Compound 11a with a halogenating agent in an organic solvent to produce Compound 12a:

wherein, ring A, R 1 , and m are as defined in Compound 10a above, and Hal is a halide;

iiic) reacting Compound 12a with a cyanide to produce Compound 13a:

wherein, ring A, R 1 , and m are as defined in Compound 10a above;

ivc) reacting Compound 13a with a compound of formula 13aa in the presence of a base:

wherein,

Hal is a halide; and

q is an integer from 0 to 3 inclusive; to produce a compound of formula 14a:

wherein,

r is an integer from 1 to 4 inclusive; and

ring A, R 1 , and m are as defined in Compound 10a above;

vc) sequentially reacting Compound 14a with a hydroxide base and acid to form Compound 15a, which is compound 7a when X═OH:

wherein, r, ring A, R 1 , and m are as defined in Compound 14a above; and

vic) reacting Compound 15a with a halogenating agent in an organic solvent to form Compound 16a, which is compound 7a when X=halide:

wherein,

Hal is halide; and

r, ring A, R 1 , and m are as defined in Compound 14a above.

2. The process of claim 1 , wherein the reaction between compound 6a and compound 7a is carried out in the presence of a catalytic amine.

3. The process of claim 1 , wherein the reaction between compound 6a and compound 7a is carried out in the presence of a catalytic amount of dimethylaminopyridine.

4. The process of claim 1 , wherein when R 1 on the phenyl ring in formula 1 is an ester, the process further comprises de-esterifying the compound of formula 1 in a biphasic mixture comprising water, an organic solvent, and an acid to give an acid salt.

5. The process of claim 4 , wherein the organic solvent is acetonitrile.

6. The process of claim 4 , the acid is an inorganic acid.

7. The process of claim 4 , wherein the acid is hydrochloric acid.

8. The process of claim 4 , wherein the de-esterification reaction is run at between 20° C. and 60° C.

9. The process of claim 4 , wherein the acid salt is converted to the free form, Form I, by slurrying or dissolving the acid salt in a solvent for an effective amount of time.

10. The process of claim 9 , wherein the solvent is selected from water or a 50% methanol/water mixture.

11. The process of claim 9 , wherein the solvent is water.

12. The process of claim 9 , wherein the effective amount of time is between 2 and 24 hours.

13. The process of claim 9 , further comprising the step of filtering the slurry of the compound of formula I in Form I, or concentrating the solution of the compound of formula I in Form I to effect recrystallization and filtering the recrystallized compound of formula I in Form I.

14. The process of claim 1 , wherein the compound of formula 7a is

15. The process of claim 1 , wherein the compound of formula 6a is

16. The process of claim 4 , wherein the compound of formula I is

17. The process of claim 9 , wherein the compound of formula I is