摘要 |
4-Amino-5-fluoro-3-halo-6-(substituted)picolinates are conveniently prepared from 4,5,6-trichloropicolinonitrile by a series of steps involving fluorine exchange, amination, halogen exchange, halogenation, nitrile hydrolysis, esterification, and transition metal assisted coupling. |
主权项 |
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 C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; and R1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; which comprises the following steps: a) fluorinating 4,5,6-trichloropicolinonitrile (Formula A)with a source of fluoride ion to produce 4,5,6-trifluoropicolinonitrile (Formula B) b) aminating 4,5,6-trifluoropicolinonitrile (Formula B) with ammonia to produce 4-amino-5,6-difluoropicolinonitrile (Formula C) c) hydrolyzing the nitrile substituent and exchanging the fluoro substituent in the 6-position of 4-amino-5,6-difluoropicolinonitrile (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-halopicolinamide of Formula D wherein X represents Cl, Br or I; d) esterifying the 4-amino-5-fluoro-6-halopicolinamide of Formula D with an alcohol (R1OH) and a Bronsted or Lewis acid to produce a 4-amino-5-fluoro-6-halopicolinate of Formula E wherein R1 represents C1-C12 alkyl or an unsubstituted or substituted C7-C11 arylalkyl; e) halogenating the 4-amino-5-fluoro-6-halopicolinate of Formula E with a halogen source to produce a 4-amino-5-fluoro-3,6-dihalopicolinate of Formula F wherein W and X independently represent Cl, Br or I,and R1 is as previously defined; and f) coupling the 4-amino-5-fluoro-3,6-dihalopicolinate of Formula F with an aryl, alkyl or alkenyl metal compound of the Formula G
R-Met Gwherein R is as previously defined and Met represents Zn-halide, Zn—R, tri-(C1-C4 alkyl)tin, copper, or B(OR2)(OR3), where R2 and R3 are independent of one another, hydrogen, C1-C4 alkyl, or when taken together form an ethylene or propylene group in the presence of a transition metal catalyst to produce the 4-amino-3-halo-5-fluoro-6-(substituted)picolinate of Formula I. |