METHODS OF ISOLATING 4-CHLORO-2-FLUORO-3-SUBSTITUTED-PHENYLBORONIC ACIDS

• US 20130030213A1
• Filed: 07/26/2012
• Published: 01/31/2013
• 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
• Granted Patent: US 8,822,730 B2
• Time in Patent Office: Days
• US Class Current: 562/7
• 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-substituted-phenylboronic acid, comprising:

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;

partitioning the 4-chloro-2-fluoro-3-substituted-phenylboronic acid into the water miscible organic solvent layer; and

separating the water miscible organic solvent layer comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid from the water layer.

2. The method of claim 1, wherein contacting a mixture of water, a water miscible organic solvent, and a 4-chloro-2-fluoro-3-substituted-phenylboronic acid with a salt comprises contacting a mixture of water, acetonitrile, and the 4-chloro-2-fluoro-3-substituted-phenylboronic acid with the salt.

3. The method of claim 2, wherein contacting a mixture of water, a water miscible organic solvent, and a 4-chloro-2-fluoro-3-substituted-phenylboronic acid with a salt comprises contacting a mixture of water, acetonitrile, and 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid with the salt.

4. 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-phenyl-boronic acid;

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

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

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

6. The method of claim 4, 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.

7. The method of claim 4, 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.

8. The method of claim 4, 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.

9. The method of claim 4, 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.

10. The method of claim 4, further comprising recovering the 4-chloro-2-fluoro-3-substituted-phenylboronic acid from the acetonitrile layer.

11. 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 form an acetonitrile layer and a water layer; and

separating the acetonitrile layer and the water layer.

12. The method of claim 11, 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.

13. The method of claim 11, 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.

14. The method of claim 11, wherein separating the acetonitrile layer and the water layer comprises recovering the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in acetonitrile.

15. The method of claim 14, wherein recovering the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in acetonitrile comprises obtaining a yield of 4-chloro-2-fluoro-3-methoxyphenylboronic acid of greater than approximately 90%.

16. The method of claim 14, further comprising utilizing the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in acetonitrile without concentration or drying.

17. A 4-chloro-2-fluoro-3-substituted-phenylboronic acid derivative produced by a process, comprising:

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

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

separating the acetonitrile layer comprising the 4-chloro-2-fluoro-3-substituted-phenylboronic acid from an aqueous layer,

wherein the 4-chloro-2-fluoro-3-substituted-phenylboronic acid is obtained at a yield of greater than approximately 90%.