Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates

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

or a salt, solvate, isotopologue, or polymorph thereof, wherein:

W represents Cl, Br or I;

R represents C 1 -C 4 alkyl, cyclopropyl, C 2 -C 4 alkenyl or phenyl substituted with from 0 to 5 substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy; and

R 1 represents C 1 -C 12 alkyl or an unsubstituted or substituted C 7 -C 11 arylalkyl; comprising:

(a) fluorinating a compound of Formula (II):

wherein A 6 is halogen or R;

with a source of fluoride ion to form a compound of Formula (III):

wherein B 6 is F or R;

and transforming the compound of Formula (III) to a compound of Formula (IV):

(b) halogenating a compound of Formula (IV) with a halogen source to form a compound of Formula (V):

and

(c) coupling a compound of Formula (VI)

wherein

X is Cl, Br, or I;

A 2 is hydrogen or R 1 ;

A 3 is hydrogen or W;

A 4 is Cl, F, NH 2 , NHCOCH 3 , or a protected amino group;

A 5 is F or Cl;

with a compound of Formula (VII)

R-Met  (VII)

wherein Met is Zn-halide, Zn—R, tri-(C 1 -C 4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are each independently, hydrogen, C 1 -C 4 alkyl, or when taken together form an ethylene or propylene group;

in the presence of a transition metal catalyst to form a compound of Formula (VIII):

wherein transformation (c) may occur prior to, between, or after transformations (a) and (b).

2. The process of claim 1 , wherein R represents C 1 -C 4 alkyl, cyclopropyl, C 2 -C 4 alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy.

3. The process of claim 1 , wherein the transformation of a compound of Formula (III) to a compound of Formula (IV) comprises:

contacting the compound of Formula (III) with an alcohol R 1 OH to form a compound of Formula (IX):

and

aminating the compound of Formula (IX) with an ammonia source to form the compound of Formula (IV).

4. The process of claim 1 , wherein the transformation of a compound of Formula (III) to a compound of Formula (IV) comprises:

contacting the compound of Formula (III) with an ammonia source to form a compound of Formula (X):

and

contacting the compound of Formula (X) with an acid HX and an alcohol R 1 OH to form the compound of Formula (IV), wherein X is I, Br, or Cl.

5. The process of claim 1 , comprising:

transformation (a), which comprises:

(a-1) fluorinating a compound of Formula (A):

with a source of fluoride ion to form a compound of Formula (B):

(a-2) contacting the compound of Formula (B) with an alcohol R 1 OH to form a compound of Formula (C):

(a-3) aminating the compound of Formula (C) with an ammonia source to form a compound of Formula (D):

and

(a-4) contacting the compound of Formula (D) with an iodide, bromide or chloride source under conditions suitable for halogen exchange to form a compound of Formula (E):

wherein X is Cl, Br, or I;

transformation (c), which comprises:

coupling the compound of Formula (E) with a compound of Formula (F)

R-Met  (F)

wherein Met is Zn-halide, Zn—R, tri-(C 1 -C 4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are each independently, hydrogen, C 1 -C 4 alkyl, or when taken together form an ethylene or propylene group;

in the presence of a transition metal catalyst to form a compound of Formula (G):

and

transformation (b), which comprises:

halogenating the compound of Formula (G) with a halogen source to form a compound of Formula (I).

6. The process of claim 1 , comprising:

transformation (a), which comprises:

(a-1) fluorinating a compound of Formula (A):

with a source of fluoride ion to form a compound of Formula (B):

(a-2) contacting the compound of Formula (B) with an alcohol R 1 OH to form a compound of Formula (C):

(a-3) aminating the compound of Formula (C) with an ammonia source to form a compound of Formula (D):

and

(a-4) contacting the compound of Formula (D) with an iodide, bromide or chloride source under conditions suitable for halogen exchange to form a compound of Formula (E):

wherein X is Cl, Br, or I;

transformation (b), which comprises:

halogenating the compound of Formula (E) with a halogen source to form a compound of Formula (H):

and

transformation (c), which comprises:

coupling the compound of Formula (H) with a compound of Formula (F)

R-Met  (F)

wherein Met is Zn-halide, Zn—R, tri-(C 1 -C 4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are each independently, hydrogen, C 1 -C 4 alkyl, or when taken together form an ethylene or propylene group;

in the presence of a transition metal catalyst to form a compound of Formula (I).

7. The process of claim 1 , comprising:

transformation (c), which comprises:

coupling a compound of Formula (J):

with a compound of Formula (F)

R-Met  (F)

wherein Met is Zn-halide, Zn—R, tri-(C 1 -C 4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are each independently, hydrogen, C 1 -C 4 alkyl, or when taken together form an ethylene or propylene group;

in the presence of a transition metal catalyst to form a compound of Formula (K):

transformation (a), which comprises:

(a-1) transforming the compound of Formula (K) to a compound of Formula (L):

under conditions suitable for the formation of acid chloride;

(a-2) fluorinating the compound of Formula (L) with a source of fluoride ion to form a compound of Formula (M):

(a-3) contacting the compound of Formula (M) with an alcohol R 1 OH to form a compound of Formula (N):

and

(a-4) aminating the compound of Formula (N) with an ammonia source to form a compound of Formula (O):

and

transformation (b), which comprises:

halogenating the compound of Formula (O) with a halogen source to form a compound of Formula (I).

8. The process of claim 1 , comprising:

transformation (c), which comprises:

(c-1) coupling a compound of Formula (P):

with a compound of Formula (F)

R-Met  (F)

wherein Met is Zn-halide, Zn—R, tri-(C 1 -C 4 alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2 and R 3 are each independently, hydrogen, C 1 -C 4 alkyl, or when taken together form an ethylene or propylene group;

in the presence of a transition metal catalyst to form a compound of Formula (Q):

and

(c-2) hydrolyzing the compound of Formula (Q) to a compound of Formula (K):

transformation (a), which comprises:

(a-1) transforming the compound of Formula (K) to a compound of Formula (L):

under conditions suitable for the formation of acid chloride;

(a-2) fluorinating the compound of Formula (L) with a source of fluoride ion to form a compound of Formula (M):

(a-3) contacting the compound of Formula (M) with a compound R 1 OH to form a compound of Formula (N):

and

(a-4) aminating the compound of Formula (N) with an ammonia source to form a compound of Formula (O):

and

transformation (b), which comprises:

halogenating the compound of Formula (O) with a halogen source to form a compound of Formula (I).

9. The process of claim 1 , further comprising protecting the NH 2 substituent in the 4-position of the pyridine structure prior to transformation (c); and further comprising a deprotecting step.

10. The process of claim 1 , wherein R is phenyl substituted with from 1 to 4 substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy.

11. The process of claim 1 , wherein an amine-containing compound of Formulas (I), (IV), (V), (VI), or (VIII) is purified by: a) protonating with an acid to form a salt, b) isolating the salt in higher purity by crystallization, precipitation or extraction, and c) neutralizing the purified salt with a base to form the purified neutral amine-containing product or intermediate.

12. The process of claim 1 , wherein the source of fluoride ion is a metal fluoride.

13. The process of claim 12 , wherein the metal fluoride is selected from sodium fluoride, potassium fluoride and cesium fluoride.

14. The process of claim 13 , wherein the metal fluoride is potassium fluoride.

15. The process of claim 1 , wherein the fluorination step in transformation (a) occurs in the presence of a catalyst selected from a crown ether, a phosphonium halide, a polyether, a phosphazenium salt, and a tetra-substituted ammonium halide.

16. The process of claim 15 , wherein the catalyst is a crown ether.

17. The process of claim 16 , wherein the crown ether is 18-crown-6.

18. The process of claim 1 , wherein the fluorination step in transformation (a) occurs in the presence of a solvent selected from an alkyl nitrile or an alkyl sulfone.

19. The process of claim 18 , wherein the solvent is acetonitrile or sulfolane.

20. The process of claim 1 , wherein the solvate is a hydrate.