Granted Patent B2

US 12,624,005 · App. 17/932,334 · Granted May 12, 2026

Inventors: Belgin Canturk (Carmel, IN); Jayachandran Devaraj (Zionsville, IN); Amaruka Hazari (Carmel, IN); Christopher Kassl (Hoffman Estates, IL); Melissa Lee (Indianapolis, IN); Fangzheng Li (Carmel, IN); Christian T. Lowe (Westfield, IN); Thomas L. Siddall (Zionsville, IN); Gregory T. Whiteker (Carmel, IN); Chunming Zhang (Zionsville, IN)

Assignee: CORTEVA AGRISCIENCE LLC

C07D213/803C07D209/04C07D401/04C07F5/02C07F7/10

Abstract

Claims (92)

1 . A process for the preparation of a 4-amino-6-(heterocyclic) picolinate of Formula I:

wherein

R represents H, C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl;

W 1 represents H or F;

W 2 represents H, F, C 1 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, or C 1 -C 3 haloalkoxy;

Y represents H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and

Z represents C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl, or —NR 1 R 2 , wherein R 1 and R 2 are independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; and

Y and Z taken together are a 5-membered aromatic or non-aromatic, heterocyclic ring;

the process comprising the following steps:

a. creating a first mixture containing a compound of Formula A,

wherein

R represents H, C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl;

a compound of Formula B1 or Formula B2, or mixtures thereof,

wherein

M + represents an alkali metal cation;

R 3 represents H or C 1 -C 6 alkyl, or alternatively two R 3 may form a C 2 -C 6 alkyl linkage, which together with B and two O form a 5- to 9-atom cyclic structure;

R 4 represents C 1 -C 6 alkyl;

W 1 represents H or F;

W 2 represents H, F, C 1 , C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy or C 1 -C 3 haloalkoxy;

Y represents halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and

Z represents C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl, or —NR 1 R 2 , wherein R 1 and R 2 are independently hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; and

Y and Z taken together are a 5-membered aromatic or non-aromatic, heterocyclic ring;

one or more bases; and one or more solvents;

b. adding a palladium catalyst, and optionally a ligand to the first mixture to form a second mixture; and

c. heating the second mixture to a temperature of between about 25° C. and about 100° C.

2 . The process of claim 1 , wherein the 4-amino-6-(heterocyclic) picolinate of Formula I is isolated from the second mixture.

3 . The process of claim 2 , further comprising the steps of:

a. creating a mixture containing the 4-amino-6-(heterocyclic) picolinate of Formula I, wherein R represents H, and one of

i. an acid, an alcohol ROH, and a solvent; or

ii. an alkyl, alkynyl, or arylalkyl halide RX 1 , a base, and a solvent

wherein

R represents C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl; and

X 1 represents Cl, Br, or I; and

b. heating the mixture at a temperature from about 25° C. to about 80° C.

4 . The process of claim 3 , wherein the 4-amino-6-(heterocyclic) picolinate of Formula I, wherein R represents C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl, is isolated from the mixture.

5 . The process of claim 1 , wherein the compound of Formula A is prepared by a second process, the process comprising the steps of:

a. creating a first mixture containing a compound of Formula C 2

an acid or an acid chloride-forming compound, and an alcohol ROH, wherein R represents C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl;

b. heating the first mixture at a temperature from about 70° C. to about 90° C.;

c. isolating from the first mixture the compound of Formula D2

wherein

R represents C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl;

d. creating a second mixture containing the compound of Formula D2;

a phthaloyl halide or a phthalic anhydride;

wherein

A is independently selected from H, F, Cl, Br, I, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, and nitro;

n is 1, 2, 3, or 4; and

X 2 is Cl or Br;

a base; a solvent or solvent mixture; and optionally an acylation catalyst;

e. heating the second mixture at a temperature from about 25° C. to about 100° C.;

f. isolating from the second mixture the compound of Formula E2

wherein

R represents C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl;

A is independently selected from H, F, Cl, Br, I, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, and nitro; and

n is 1, 2, 3, or 4;

g. creating a third mixture containing the compound of Formula E2;

a fluorinating compound or a fluorinating mixture of compounds; and a solvent;

h. heating the third mixture at a temperature from about 25° C. to about 110° C.;

i. isolating from the third mixture a compound of Formula F2

wherein

R represents H, C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl;

A is independently selected from H, F, Cl, Br, I, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, and nitro; and

n is 1, 2, 3, or 4;

j. creating a fourth mixture containing the compound of Formula F2;

hydrobromic acid (HBr); acetic acid; and water;

k. heating the fourth mixture at a temperature from about 50° C. to about 110° C.;

l. Isolating from the fourth mixture the compound of Formula A or the hydrobromide (HBr) salt thereof

wherein

R represents H.

6 . The process of claim 5 , the process further comprising the steps of:

a. creating another mixture containing the compound of Formula A, wherein R represents H; and one of

i. an acid, an alcohol ROH, and a solvent; or

ii. an alkyl, alkynyl, or arylalkyl halide RX 1 , a base, and a solvent

wherein

R represents C 1 -C 12 alkyl, C 3 -C 12 alkynyl, C 1 -C 3 alkyl substituted with CN, or C 6 -C 12 arylalkyl; and

X 1 represents C 1 , Br, or I; and

b. heating the mixture at a temperature from about 25° C. to about 80° C.

7 . The process of claim 6 , wherein the compound of Formula A

wherein

R represents C 1 -C 12 alkyl, C 1 -C 3 alkyl substituted with CN, C 3 -C 12 alkynyl, or C 6 -C 12 arylalkyl;

is isolated.

8 . The process of claim 1 , wherein the compound of Formula A is cyanomethyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate.

9 . The process of claim 1 , wherein the compound of Formula A is 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid.

10 . The process of claim 1 , wherein the compound of Formula B1 or Formula B2 is selected from the group consisting of (1-(tert-butyldimethylsilyl)-7-fluoro-1H-indol-6-yl) boronic acid, lithium (1-(tert-butyldimethylsilyl)-7-fluoro-1H-indol-6-yl)trimethoxyborate, lithium (1-(tert-butyldimethylsilyl)-7-fluoro-1H-indol-6-yl)triisopropoxyborate, (7-fluoro-1H-indol-6-yl) boronic acid, 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and mixtures thereof.

11 . The process of claim 1 , wherein the one or more solvents is selected from the group consisting of methyl isobutyl ketone (MIBK), dimethoxyethane (DME), acetonitrile (MeCN), tetrahydrofuran (THF), methanol (MeOH), benzyl alcohol, toluene, water, and mixtures thereof.

12 . The process of claim 11 , wherein the one or more solvents is acetonitrile and water.

13 . The process of claim 1 , wherein the first mixture is deoxygenated prior to addition of the palladium catalyst and optionally, the ligand.

14 . The process of claim 1 , wherein the ligand is selected from the group consisting of tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tri (o-tolyl)phosphine, 1,2-bis(diphenylphosphino) ethane, 1,3-bis(diphenylphosphaneyl) propane, 1,4-bis(diphenylphosphino) butane, 1,1′-ferrocenediyl-bis(diphenylphosphine) (dppf), 4-diphenylphosphinomethyl polystyrene resin crosslinked, sodium diphenylphosphinobenzene-3-sulfonate with 2% DVB, tri (p-tolyl)phosphine, and (+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.

15 . The process of claim 14 , wherein the ligand is triphenylphosphine.

16 . The process of claim 1 , wherein the palladium catalyst is selected from the group consisting of palladium acetate (Pd(OAc) 2 ) and dichlorobis(triphenylphosphine) palladium (II) (PdCl 2 (PPh 3 ) 2 ).

17 . The process of claim 1 , wherein the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium acetate, sodium acetate, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, sodium tetraborate, potassium hydroxide, sodium hydroxide, cesium fluoride, potassium fluoride, triethylamine, triisopropylamine, diisopropylamine, diethylamine, and diisopropylethylamine.

18 . The process of claim 17 , wherein the base is sodium hydroxide.

Assignments (2)

Continuity (2)

References Cited (9)