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

1. A process for the preparation of a 4-amino-5-fluoro-3-halo-6-(substituted)-picolinate of the Formula I

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 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; and

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

which comprises the following steps:

a) fluorinating the a 4,5,6-trichloropicolinate of Formula A

wherein R 1 is as previously defined;

with a source of fluoride ion to produce a 4,5,6-trifluoropicolinate of Formula B

wherein R 1 is as previously defined;

b) aminating 4,5,6-trifluoropicolinate of Formula B with ammonia to produce a 4-amino-5,6-difluoropicolinate of Formula C

wherein R 1 is as previously defined;

c) exchanging the fluoro substituent in the 6-position of the 4-amino-5,6-difluoro picolinate of Formula C with an iodo, bromo or chloro substituent by treating with an iodide, bromide or chloride source to produce a 4-amino-5-fluoro-6-halopicolinate of Formula D

wherein X represents Cl, Br or I,

and R 1 is as previously defined;

d) halogenating the 4-amino-5-fluoro-6-halopicolinate of Formula D with a halogen source to produce a 4-amino-3,6-dihalo-5-fluoropicolinate of Formula E

wherein W and X independently represent Cl, Br or I,

and R 1 is as previously defined; and

e) coupling the 4-amino-3,6-dihalo-5-fluoropicolinate of Formula E with an aryl, alkyl or alkenyl metal compound of the Formula F

R-Met  F

wherein R is as previously defined and Met represents 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 independent of one another, 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 produce the 4-amino-5-fluoro-3-halo-6-(substituted)picolinate of Formula I.

2. The process of claim 1 in which an amine-containing product or intermediate 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.

3. A process for the preparation of a 4-amino-5-fluoro-3-halo-6-(substituted)-picolinate of the Formula I

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 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; and

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

which comprises the following steps:

a) fluorinating a 4,5,6-trichloropicolinate of Formula A

wherein R 1 is as previously defined;

with a source of fluoride ion to produce a 4,5,6-trifluoropicolinate of Formula B

wherein R 1 is as previously defined;

b) aminating the 4,5,6-trifluoropicolinate of Formula B with ammonia to produce a 4-amino-5,6-difluoropicolinate of Formula C

wherein R 1 is as previously defined;

c) exchanging the fluoro substituent in the 6-position of the 4-amino-5,6-difluoro-picolinate of Formula C with an iodo, bromo or chloro substituent by treating with an iodide, bromide or chloride source to produce a 4-amino-5-fluoro-6-halopicolinate of Formula D

wherein X represents Cl, Br or I; and

R 1 is as previously defined;

d) coupling the 4-amino-5-fluoro-6-halopicolinate of Formula D with an aryl, alkyl or alkenyl metal compound of the Formula F

R-Met  F

wherein R is as previously defined and Met represents 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 independent of one another, 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 produce the 4-amino-5-fluoro-6-(substituted)-picolinate of Formula G.

wherein R, R 1 are as previously defined; and

e) halogenating the 4-amino-5-fluoro-6-(substituted)picolinate of Formula G with a halogen source to produce a 4-amino-5-fluoro-3-halo-6-(substituted)picolinate of Formula I.

4. The process of claim 3 in which an amine-containing product or intermediate 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.

5. A process for the preparation of a 4-amino-5-fluoro-3-halo-6-(substituted)-picolinate of the Formula I

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 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; and

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

which comprises the following steps:

a) coupling a 4,5,6-trichloropicolinate of Formula A

wherein R 1 is as previously defined;

with an aryl, alkyl or alkenyl metal compound of the Formula F

R-Met  F

wherein R is as previously defined and Met represents 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 independent of one another, 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 produce a 4,5-dichloro-6-(substituted)picolinate of Formula H

wherein R and R 1 are as previously defined;

b) fluorinating the 4,5-dichloro-6-(substituted)picolinate of Formula H with a fluoride ion source to produce a 4,5-difluoro-6-(substituted)picolinate of Formula J

wherein R 1 is as previously defined;

c) aminating the 4,5-difluoro-6-(substituted)picolinate of Formula J with ammonia to produce a 4-amino-5-fluoro-6-(substituted)picolinate of Formula K

wherein R and R 1 are as previously defined; and

d) halogenating the 4-amino-5-fluoro-6-(substituted)picolinate of Formula K with a halogen source to produce the 4-amino-5-fluoro-3-halo-6-(substituted)picolinate of Formula I.

6. The process of claim 5 in which an amine-containing product or intermediate 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.