METHODS OF FORMING 4-CHLORO-2-FLUORO-3-SUBSTITUTED-PHENYLBORONIC ACID PINACOL ESTERS AND METHODS OF USING THE SAME

• US 20130172565A1
• Filed: 12/20/2012
• Published: 07/04/2013
• 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 MI
• Granted Patent: US 8,912,339 B2
• Time in Patent Office: Days
• 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 forming a 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester, comprising:

contacting a 1-chloro-3-fluoro-2-substituted benzene with an alkyl lithium to form a lithiated 1-chloro-3-fluoro-2-substituted benzene;

contacting the lithiated 1-chloro-3-fluoro-2-substituted benzene with an electrophilic boronic acid derivative to form a 4-chloro-2-fluoro-3-substituted-phenylboronate;

reacting the 4-chloro-2-fluoro-3-substituted-phenylboronate with an aqueous base to form a (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate;

reacting the (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate with an acid to form a 4-chloro-2-fluoro-3-substituted-phenylboronic acid; and

reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid with 2,3-dimethyl-2,3-butanediol.

2. The method of claim 1, reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid with 2,3-dimethyl-2,3-butanediol comprises obtaining a yield of the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester of greater than or equal to about 90%.

3. The method of claim 1, wherein contacting the 1-chloro-3-fluoro-2-substituted benzene with the alkyl lithium comprises introducing an alkyl lithium into a solution comprising the 1-chloro-3-fluoro-2-substituted benzene and an anhydrous solvent to form a reaction mixture comprising the lithiated 1-chloro-3-fluoro-2-substituted benzene.

4. The method of claim 3, wherein contacting the lithiated 1-chloro-3-fluoro-2-substituted benzene with the electrophilic boronic acid derivative comprises adding the electrophilic boronic acid derivative to the reaction mixture to form a phenyl boronate solution comprising the 4-chloro-2-fluoro-3-substituted-phenylboronate.

5. The method of claim 4, wherein reacting the 4-chloro-2-fluoro-3-substituted-phenylboronate with the aqueous base comprises adding the aqueous base to the phenyl boronate solution to form a first multi-phase solution comprising a first aqueous phase and a first organic phase, the first aqueous phase comprising the (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate.

6. The method of claim 5, wherein reacting the (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate with an acid comprises:

separating the first aqueous phase and the first organic phase; and

adding the acid to the first aqueous phase to form a phenyl boronic acid solution comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid.

7. The method of claim 6, wherein reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid with the 2,3-dimethyl-2,3-butanediol comprises:

adding a water miscible solvent to the phenyl boronic acid solution to form a second multi-phase solution comprising a second aqueous phase and a second organic phase, the second organic phase comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid;

separating the second aqueous phase and the second organic phase; and

introducing the 2,3-dimethyl-2,3-butanediol into the second organic phase to form a pinacol ester solution comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester.

8. The method of claim 7, wherein adding a water miscible solvent solution to the phenyl boronic acid solution comprises adding at least one of 4-methyl-2-pentanone, acetonitrile, and ethyl acetate to the phenyl boronic acid solution.

9. A method of forming 2-(4-chloro-2-fluoro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, comprising:

contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole;

contacting the 6-chloro-2-fluoro-3-lithioanisole with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate;

reacting the dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyOtrihydroxyborate;

reacting the potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid; and

reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid with 2,3-dimethyl-2,3-butanediol.

10. The method of claim 9, wherein reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid with the 2,3-dimethyl-2,3-butanediol comprises obtaining a yield of the 2-(4-chloro-2-fluoro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of greater than or equal to about 90%.

11. The method of claim 9, wherein contacting the 2-chloro-6-fluoroanisole with the n-butyl lithium comprises introducing n-butyl lithium into a solution comprising the 2-chloro-6-fluoroanisole and at least one of 1,2-dimethoxyethane, diethyl ether, tetrahydrofuran, and dioxane to form a reaction mixture comprising the 6-chloro-2-fluoro-3-lithioanisole.

12. The method of claim 11, wherein contacting the 6-chloro-2-fluoro-3-lithioanisole with the trimethyl borate comprises adding the trimethyl borate to the reaction mixture to form a phenyl boronate solution comprising the dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate.

13. The method of claim 12, wherein reacting the dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate with the aqueous potassium hydroxide comprises adding the aqueous potassium hydroxide to the phenyl boronate solution to form a first multi-phase solution comprising a first aqueous phase and a first organic phase, the first aqueous phase comprising the potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate.

14. The method of claim 13, wherein reacting the potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate with the aqueous hydrochloric acid comprises:

separating the first aqueous phase and the first organic phase; and

adding the aqueous hydrochloric acid to the first aqueous phase to form a phenyl boronic acid solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid.

15. The method of claim 14, wherein reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid with the 2,3-dimethyl-2,3-butanediol comprises:

adding at least one of 4-methyl-2-pentanone, acetonitrile, and ethyl acetate to the phenyl boronic acid solution to form a second multi-phase solution comprising a second aqueous phase and a second organic phase, the second organic phase comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

separating the second aqueous phase and the second organic phase; and

introducing the 2,3-dimethyl-2,3-butanediol into the second organic phase to form a pinacol ester solution comprising the 2-(4-chloro-2-fluoro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

16. 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 to produce a 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate.

17. The method of claim 16, wherein reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester with the methyl 4-acetamido-3,6-dichloropicolinate comprises reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester with the methyl 4-acetamido-3,6-dichloropicolinate in the presence of a palladium catalyst, a ligand, a base, and a solvent, the solvent comprising at least one of 4-methyl-2-pentanone, acetonitrile, ethyl acetate, and water.

18. The method of claim 16, 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.

19. The method of claim 18, 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%.

20. The method of claim 16, 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:

adding a palladium catalyst, a ligand, and a base to a deoxygenated mixture comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester, 4-acetamido-3,6-dichloropicolinate, 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.

21. A 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester produced by introducing 2,3-dimethyl-2,3-butanediol into a solution comprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid, wherein the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester is obtained at a yield of greater than approximately 90%.