Methods of forming 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters and methods of using the same

• US 8,912,339 B2
• Filed: 12/20/2012
• Issued: 12/16/2014
• Est. Priority Date: 12/30/2011
• Status: Active Grant

• Current Assignee: Corteva Agriscience LLC (Corteva, Inc.)
• Original Assignee: Dow Agrosciences LLC (Corteva, Inc.)
• Inventors: Oppenheimer, Jossian
• Primary Examiner(s): CHANDRAKUMAR, NIZAL S
• Application Number:
  US13/722,471
• Publication Number:
  US 20130172565A1
• Time in Patent Office: 726 Days
• Field of Search: 546/310, 558/288
• US Class Current: 546/310
• CPC Class Codes: C07D 213/807 by oxidation of pyridines or condensed pyridines
• CPC Class Codes: C07F 1/02 Lithium compounds
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids

Abstract

Methods include formation of 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters. The method comprises contacting a 1-chloro-3-fluoro-2-substituted benzene with an alkyl lithium to form a lithiated 1-chloro-3-fluoro-2-substituted benzene. The lithiated 1-chloro-3-fluoro-2-substituted benzene is contacted with an electrophilic boronic acid derivative to form a 4-chloro-2-fluoro-3-substituted-phenylboronate. The 4-chloro-2-fluoro-3-substituted-phenylboronate is reacted with an aqueous base to form a (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate. The (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate is reacted with an acid to form a 4 chloro-2-fluoro-3-substituted-phenylboronic acid. The 4-chloro-2-fluoro-3-substituted-phenylboronic acid is reacted with 2,3-dimethyl-2,3-butanediol to form 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters. Methods of using 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters to produce 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinates are also disclosed.

Claims

1. A method of using a 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester comprising:

reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester with methyl 4-acetamido-3,6-dichloropicolinate in a medium consisting essentially of a palladium catalyst, a ligand, a base, and at least one solvent to produce a 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate.

2. The method of claim 1, wherein the solvent comprises at least one of 4-methyl-2-pentanone, acetonitrile, ethyl acetate, and water.

3. The method of claim 1, wherein reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester with the methyl 4-acetamido-3,6-dichloropicolinate to produce the 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate comprises reacting 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with the methyl 4-acetamido-3,6-dichloropicolinate to produce methyl 4-acetamido-3-chloro-6-(4-chloro-2-fluoro-methoxyphenyl)picolinate.

4. The method of claim 3, wherein reacting the 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with the methyl 4-acetamido-3,6-dichloropicolinate to produce methyl 4-acetamido-3-chloro-6-(4-chloro-2-fluoro-methoxyphenyl)picolinate comprises obtaining a yield of the methyl 4-acetamido-3-chloro-6-(4-chloro-2-fluoro-methoxyphenyl)picolinate of greater than about 85%.

5. The method of claim 1, wherein reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester with the methyl 4-acetamido-3,6-dichloropicolinate to produce the 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate comprises:

reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester with the 4-acetamido-3,6-dichloropicolinate in a deoxygenated medium consisting essentially of a palladium catalyst, a ligand, a base, and at least one solvent to form a coupling reaction mixture;

agitating the coupling reaction mixture at a temperature within a range of from about 40°

C. to about 70°

C. to form a multi-phase solution comprising an aqueous phase and an organic phase, the organic phase comprising the 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate; and

separating the organic phase from the aqueous phase.