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US-12624005-B2 - Synthesis of 4-amino-6-(heterocyclic)picolinates

US12624005B2US 12624005 B2US12624005 B2US 12624005B2US-12624005-B2

Abstract

The present disclosure relates to improved processes for preparing 4-amino-6-(heterocyclic)picolinates.

Inventors

  • Belgin CANTURK
  • Chunming Zhang
  • Jayachandran Devaraj
  • Amaruka Hazari
  • CHRISTOPHER KASSL
  • Melissa Lee
  • Fangzheng Li
  • Christian T. Lowe
  • Thomas L. Siddall
  • Gregory T. Whiteker

Assignees

  • CORTEVA AGRISCIENCE LLC

Dates

Publication Date
20260512
Application Date
20210317

Claims (18)

  1. 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. 2 . The process of claim 1 , wherein the 4-amino-6-(heterocyclic) picolinate of Formula I is isolated from the second mixture.
  3. 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. 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. 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. 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. 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. 8 . The process of claim 1 , wherein the compound of Formula A is cyanomethyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate.
  9. 9 . The process of claim 1 , wherein the compound of Formula A is 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid.
  10. 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. 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. 12 . The process of claim 11 , wherein the one or more solvents is acetonitrile and water.
  13. 13 . The process of claim 1 , wherein the first mixture is deoxygenated prior to addition of the palladium catalyst and optionally, the ligand.
  14. 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. 15 . The process of claim 14 , wherein the ligand is triphenylphosphine.
  16. 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. 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. 18 . The process of claim 17 , wherein the base is sodium hydroxide.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International (PCT) Patent Application Serial No. PCT/US21/22716, filed Mar. 17, 2021, and entitled “IMPROVED SYNTHESIS OF 4-AMINO-6-(HETEROCYCLIC) PICOLINATES,” which claims priority to U.S. Provisional Application Ser. No. 62/991,291, filed on Mar. 18, 2020, the entire disclosure of which is hereby expressly incorporated by reference. FIELD The present disclosure concerns improved processes for the preparation of 4-amino-6-(heterocyclic)picolinates. More particularly, the present disclosure concerns an improved process for the preparation of 4-amino-6-(heterocyclic)picolinates from 6-bromo-4-aminopicolinates. BACKGROUND 4-amino-6-(heterocyclic)picolinates, such as arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinates, are high value herbicides recently developed and marketed by Dow AgroSciences LLC. PCT Patent Application Publication WO 2018208582 A1, U.S. Patent Application Publication 20120190857 A1, and U.S. Pat. Nos. 7,314,849 B2, 8,609,853 B2, 8,609,855 B2, 8,754,231 B2, 8,836,688 B2, 9,637,505 B2, 10,087,164 B2, 10,544,121 B2, and 10,570,114 B2 (the disclosure of each is explicitly incorporated by reference herein) describe inter alia certain 4-amino-6-aryl- and -6-heteroarylpicolinates and syntheses thereof. The syntheses of these molecules involve reacting a 6-chloropicolinic acid or 6-chloropicolinate head with an aryl or a heteroaryl boronic acid or boronate tail. The reaction scheme for 4-amino-6-arylpicolinates is shown in Scheme 1. It would be useful to have a higher yielding process route to these 6-aryl- and 6-heteroaryl-4-aminopicolinate compounds. SUMMARY The present disclosure concerns an improved process for the preparation of 4-amino-6-(heterocyclic)picolinates and picolinonitriles of Formula I. In some embodiments, the disclosure concerns a process for the preparation of 4-amino-6-(heterocyclic)picolinates of Formula I wherein R represents H, C1-C12 alkyl, C3-C12 alkynyl, C1-C3 alkyl substituted with CN, or C6-C12 arylalkyl;W1 represents H or F;W2 represents H, F, Cl, C1-C3 alkyl, or C1-C3 alkoxy;Y represents H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3alkoxy, C1-C3 haloalkoxy, —CN, or —NO2; andZ represents H, F, Cl, C1-C4 alkyl, C1-C3alkoxy, C1-C4 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy-substituted C1-C3 alkyl, or —NR1R2, wherein R1 and R2 are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; orY and Z or Z and W2 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, C1-C12 alkyl, C3-C12 alkynyl, C1-C3 alkyl substituted with CN, or C6-C12 arylalkyl; a compound of Formula B1 or Formula B2, or mixtures thereof, wherein M+ represents an alkali metal cation;R3 represents H or C1-C6 alkyl, or alternatively two R3 may form a C2-C6 alkyl linkage, which together with B and two O form a 5- to 9-atom cyclic structure;R4 represents C1-C6 alkyl;W1 represents H or F;W2 represents H, F, Cl, C1-C3 alkyl, or C1-C3 alkoxy;Y represents H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3alkoxy, C1-C3 haloalkoxy, —CN, or —NO2; andZ represents H, F, Cl, C1-C4 alkyl, C1-C3alkoxy, C1-C4 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy-substituted C1-C3 alkyl, or —NR1R2, wherein R1 and R2 are independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; orY and Z or Z and W2 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; andc) heating the second mixture to a temperature of between about 25° C. and about 100° C. Specific examples of the heterocyclic group in Formula I can be found in PCT International Application Publication Nos. WO 2014151005 and WO 2014151009, the disclosures of which are explicitly incorporated herein by reference and include, but are not limited to, the following examples T1 to T36: R5, if applicable to the A group, is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, halocyclopropyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, amino, C1-C4 alkylamino, C2-C4 haloalkylamino, OH, or CN; R6, R6′, and R6″, if applicable to the A group, are independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, halocyclopropyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, amino, C1-C4 alkylamino or C2-C4 haloalkylamino, OH, CN, or NO2; R7 and R7′ are independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, halocyclopropyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, amino, C1-C4 alkylamino, C1-C4 hal