Methods of isolating 4-chloro-2-fluoro-3-substituted-phenylboronic acids

• US 8,822,730 B2
• Filed: 07/26/2012
• Issued: 09/02/2014
• Est. Priority Date: 07/26/2011
• Status: Active Grant

• Current Assignee: Corteva Agriscience LLC (Corteva, Inc.)
• Original Assignee: Dow Agrosciences LLC (Corteva, Inc.)
• Inventors: Oppenheimer, Jossian
• Primary Examiner(s): Puttlitz, Karl J
• Application Number:
  US13/559,238
• Publication Number:
  US 20130030213A1
• Time in Patent Office: 768 Days
• US Class Current: 568/1
• CPC Class Codes: C07C 17/38 Separation; Purification; Stabilisation; Use of additives
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

Provided herein are methods of isolating a 4-chloro-2-fluoro-3-substituted-phenylboronic acid. The method comprises contacting a mixture of water, a water-miscible organic solvent, and a 4-chloro-2-fluoro-3-substituted-phenylboronic acid with a salt to form a water-miscible organic solvent layer and a water layer. The 4-chloro-2-fluoro-3-substituted-phenylboronic acid is partitioned into the water-miscible organic solvent layer, which is separated from the water layer. Additional methods are disclosed, as is a 4-chloro-2-fluoro-3-substituted-phenylboronic acid produced by one of the methods, wherein the 4-chloro-2-fluoro-3-substituted-phenylboronic acid is obtained at a yield of greater than approximately 90%.

Claims

1. A method of isolating a 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid, comprising:

saturating a mixture of water, acetonitrile, and a 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid with a salt to form an acetonitrile layer and a water layer;

partitioning the 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid into the acetonitrile layer;

separating the acetonitrile layer comprising the 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid from the water layer;

utilizing the 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid in the acetonitrile for a Suzuki coupling reaction without concentration or isolation acts.

14. The method of claim 1, wherein saturating a mixture of water, acetonitrile, and a 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid with a salt comprises saturating the mixture with a salt selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bromide, potassium bromide, sodium sulfate, potassium sulfate, ammonium chloride, and combinations thereof.

15. The method of claim 1, wherein utilizing the 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid in the acetonitrile for a Suzuki coupling reaction without concentration or isolation acts comprises using the 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid in the acetonitrile for a synthesis of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-aminopicolinate or 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-amino-4-pyrimidinecarboxylic acid.

2. A method of isolating a 4-chloro-2-fluoro-3-substituted-phenylboronic acid, comprising:

adding a salt to an acetonitrile/water mixture comprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid to saturate the acetonitrile/water mixture;

partitioning the 4-chloro-2-fluoro-3-substituted-phenylboronic acid into an acetonitrile layer;

separating the acetonitrile layer comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid from a water layer; and

utilizing the 4-chloro-2-fluoro-3-substituted-phenylboronic acid in the acetonitrile for a synthesis of a herbicidal compound without concentration or isolation acts.

3. The method of claim 2, wherein adding a salt to an acetonitrile/water mixture comprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid comprises adding a saturated salt solution to the acetonitrile/water mixture.

4. The method of claim 2, wherein adding a salt to an acetonitrile/water mixture comprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid comprises adding a saturated sodium chloride solution to the acetonitrile/water mixture.

5. The method of claim 2, wherein adding a salt to an acetonitrile/water mixture comprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid comprises adding a solid salt to the acetonitrile/water mixture.

6. The method of claim 2, wherein adding a salt to an acetonitrile/water mixture comprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid comprises adding solid sodium chloride to the acetonitrile/water mixture.

7. The method of claim 2, wherein adding a salt to an acetonitrile/water mixture comprises adding a salt selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bromide, potassium bromide, sodium sulfate, potassium sulfate, ammonium chloride, and combinations thereof.

16. The method of claim 2, wherein utilizing the 4-chloro-2-fluoro-3-substituted-phenylboronic acid in the acetonitrile for a synthesis of a herbicidal compound without concentration or isolation acts comprises using the 4-chloro-2-fluoro-3-substituted-phenylboronic acid in the acetonitrile in a Suzuki coupling reaction.

17. The method of claim 2, wherein utilizing the 4-chloro-2-fluoro-3-substituted-phenylboronic acid in the acetonitrile for a synthesis of a herbicidal compound without concentration or isolation acts coin rises using the 4-chloro-2-fluoro-3-substituted-phenylboronic acid in the acetonitrile for a synthesis of 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate or 2-(4-chloro-2-fluoro-3-substituted-phenyl)-6-amino-4-pyrimidine carboxylic acid.

8. A method of synthesizing and isolating 4-chloro-2-fluoro-3-methoxyphenylboronic acid, comprising:

contacting 2-chloro-6-fluoroanisole (2,6-CFA) with n-butyl lithium to form a lithiated derivative of 2,6-CFA;

contacting the lithiated derivative of 2,6-CFA with B(OCH₃)₃ to form a boronic acid ester of 2,6-CFA;

contacting the boronic acid ester of 2,6-CFA with aqueous sodium hydroxide to form a sodium salt of the boronic acid of 2,6-CFA;

contacting the sodium salt of the boronic acid of 2,6-CFA with aqueous hydrochloric acid to form a solution of 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

adding acetonitrile to the solution of 4-chloro-2-fluoro-3-methoxyphenylboronic acid to form a mixture of acetonitrile, water, and 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

adding a salt to the mixture of acetonitrile, water, and 4-chloro-2-fluoro-3-methoxyphenylboronic acid to saturate the mixture and form an acetonitrile layer and a water layer, the 4-chloro-2-fluoro-3-methoxyphenylboronic acid partitioning to the acetonitrile layer;

separating the acetonitrile layer and the water layer; and

using the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the acetonitrile for a synthesis of a herbicidal compound without concentration or isolation acts.

9. The method of claim 8, wherein adding a salt to the mixture of acetonitrile, water, and 4-chloro-2-fluoro-3-methoxyphenylboronic acid comprises adding solid sodium chloride to the mixture.

10. The method of claim 8, wherein adding a salt to the mixture of acetonitrile, water, and 4-chloro-2-fluoro-3-methoxyphenylboronic acid comprises adding a saturated solution of sodium chloride to the mixture.

11. The method of claim 8, wherein adding a salt to the mixture of acetonitrile, water, and 4-chloro-2-fluoro-3-methoxyphenylboronic acid comprises adding a salt selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bromide, potassium bromide, sodium sulfate, potassium sulfate, ammonium chloride, and combinations thereof.

12. The method of claim 8, wherein using the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the acetonitrile for a synthesis of a herbicidal compound without concentration or isolation acts comprises utilizing the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the acetonitrile for in a Suzuki coupling reaction without concentration or drying.

13. The method of claim 8, wherein using the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the acetonitrile for a synthesis of a herbicidal compound without concentration or isolation acts comprises using the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the acetonitrile without concentration or drying for a synthesis of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-aminopicolinate or 2-(4-chloro-2-fluoro-3-methoxy phenyl)-6-amino-4-pyrimidinecarboxylic acid.