Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
The present invention relates to a process of providing the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in substantially free form (Compound 1).
1. A process for preparing 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;
comprising the steps of:
ib) providing compound 2a and compound 3a,
wherein,
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 4 inclusive; and
p is an integer from 0 to 5 inclusive;
iib) cross coupling compound 2a and compound 3a in a biphasic mixture comprising water, a first organic solvent, a first base, and a transition metal catalyst to produce compound 4a,
wherein, R 1 , o, and p are as defined for compounds 2a and 3a above;
iiib) oxidizing compound 4a to produce compound 5a,
wherein, R 1 , o, and p are as defined for compounds 2a and 3a above;
ivb) adding an amine group to the 6 position of the pyridyl moiety to produce compound 6a,
wherein,
R is H, C 1-6 aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; and
R 1 , o, and p are as defined for compounds 2a and 3a above.
2. The process of claim 1 , wherein the first organic solvent is an aprotic solvent.
3. The process of claim 1 , wherein the first organic solvent is toluene.
4. The process of claim 1 , wherein the first organic solvent is a protic solvent.
5. The process of claim 1 , wherein the first base is an inorganic base.
6. The process of claim 1 , wherein the first base is potassium carbonate.
7. The process of claim 1 , wherein the transition-metal catalyst is a palladium-based catalyst.
8. The process of claim 1 , wherein the palladium-based catalyst is Pd(dppf)Cl 2 .
9. The process of claim 1 , wherein the cross coupling reaction is run at between 60° C. and 100° C.
10. The process of claim 1 , wherein the oxidation reaction is carried out using a peroxide.
11. The process of claim 1 , wherein the oxidation reaction is carried out using peracetic acid.
12. The process of claim 1 , wherein the oxidation reaction is carried out in the presence of an anhydride.
13. The process of claim 1 , wherein the oxidation reaction is carried out in the presence of phthalic anhydride.
14. The process of claim 1 , wherein the oxidation reaction is run at between 25° C. and 65° C.
15. The process of claim 1 , wherein the amination reaction is carried out in the presence of a sulfonyl compound.
16. The process of claim 1 , wherein the amination reaction is carried out in the presence of methanesulfonic anhydride.
17. The process of claim 1 , wherein the amination reagent used in the amination reaction is an alcohol amine.
18. The process of claim 1 , wherein the amination reagent used in the amination reaction is ethanolamine.