Methods and systems for forming boronic acids and intermediates thereof

Patent metadata

Field	Value
Publication number	US-9145428-B2
Application number	US-201213618128-A
Country	US
Kind code	B2
Filing date	Sep 14, 2012
Priority date	Sep 14, 2011
Publication date	Sep 29, 2015
Grant date	Sep 29, 2015

Abstract

Methods for forming boronic acids, and intermediates thereof, are disclosed. The method may include mixing a 1-chloro-2-substituted-3-fluorobenzene starting material with an alkyllithium in a first reactor to form a reaction mixture. The 1-chloro-2-substituted-3-fluorobenzene starting material may react with the alkyllithium to form a lithiated intermediate. The reaction mixture may be continuously transferred to a second reactor and a borate may be continuously introduced to form a boronate. The boronic acids may be formed by treating the boronate with aqueous potassium hydroxide followed by acidification. Such methods may provide continuous formation of the boronic acids and may reduce an amount of a reactive intermediate present during processing as well as cycle times. Systems for forming the boronic acids are also disclosed.

First claim

What is claimed is:

1. A method of forming a 4-choloro-2-fluoro-3-methoxyphynylboronic acid, comprising:
minimizing decomposition of a 6-chloro-2-fluoro-3-lithioanisole by applying a continuous process of forming a 4-choloro-2-fluoro-3-methoxyphynylboronate, wherein the process comprises:
(i) continuously adding a 2-chloro-6-fluoroanisole and at least one alkyllithium to a first reactor to form the 6-chloro-2-fluoro-3-lithioanisole, while continuously transferring the formed 6-chloro-2-fluoro-3-lithioanisole from the first reactor into a second reactor; and
(ii) continuously adding a borate to the second reactor, wherein the borate reacts with the 6-chloro-2-fluoro-3-lithioanisole to form the 4-choloro-2-fluoro-3-methoxyphynylboronate, while continuously transferring the formed 4-choloro-2-fluoro-3-methoxyphynylboronate from the second reactor into a receiving container to maintain a reaction mixture volume within the second reactor,
wherein the first and the second reactors are maintained at a temperature of less than about −50° C.; and

converting the 4-choloro-2-fluoro-3-methoxyphynylboronate to the 4-choloro-2-fluoro-3-methoxyphynylboronic acid.

2. The method of claim 1 , wherein continuously adding a 2-chloro-6-fluoroanisole and at least one alkyllithium to a first reactor comprises continuously adding the 2-chloro-6-fluoroanisole and at least one of a butyllithium, a methyllithium, and a propyllithium to the first reactor.

3. The method of claim 1 , wherein continuously adding a 2-chloro-6-fluoroanisole and at least one alkyllithium to a first reactor comprises continuously adding the 2-chloro-6-fluoroanisole and at least one of n-butyllithium, t-butyllithium, and sec-butyllithium to the first reactor.

4. The method of claim 1 , wherein continuously adding a borate to the second reactor comprises continuously adding trimethyl borate to the second reactor.

5. The method of claim 1 , wherein converting the 4-choloro-2-fluoro-3-methoxyphynyl boronate to the 4-choloro-2-fluoro-3-methoxyphynylboronic acid comprises:
exposing the 4-choloro-2-fluoro-3-methoxyphynylboronate to aqueous potassium hydroxide; and
performing an acidification process.

6. The method of claim 1 , wherein continuously adding a borate to the second reactor comprises continuously adding at least one of trimethyl borate and triisopropyl borate to the second reactor.

7. A method of continuously forming a 4-choloro-2-fluoro-3-methoxyphynylboronate while minimizing decomposition of a 6-chloro-2-fluoro-3-lithioanisole intermediate compound, the method comprising:
continuously adding a 2-chloro-6-fluoroanisole and at least one alkyllithium to a first reactor to form the 6-chloro-2-fluoro-3-lithioanisole, while the formed 6-chloro-2-fluoro-3-lithioanisole continuously leaves the first reactor and enters a second reactor; and
continuously adding a borate to the second reactor, wherein the borate reacts with the 6-chloro-2-fluoro-3-lithioanisole in the second reactor to form the 4-choloro-2-fluoro-3-methoxyphynylboronate, while the formed 4-choloro-2-fluoro-3-methoxyphynylboronate continuously leaves the second reactor and enters into a receiving container.

8. The method of claim 7 , wherein the first and the second reactors are maintained at a temperature of less than about −30° C.

9. The method of claim 7 , wherein the first and the second reactors are maintained at a temperature of less than about −50° C.

10. The method of claim 7 , wherein the first and the second reactors are maintained at a temperature of less than about −60° C.

11. A continuous tubular process of forming a 4-choloro-2-fluoro-3-methoxyphynylboronate, the process comprising:
continuously feeding a starting material mixture comprising a 2-chloro-6-fluoroanisole and an alkyllithium into a first reaction zone of a tubular reactor apparatus to form a reaction mixture comprising an 6-chloro-2-fluoro-3-lithioanisole intermediate, while continuously withdrawing the formed reaction mixture comprising the 6-chloro-2-fluoro-3-lithioanisole intermediate from the first reaction zone into a second reaction zone of the tubular reactor; and
continuously feeding a borate to the reaction mixture in the second reaction zone to form the 4-choloro-2-fluoro-3-methoxyphynylboronateboronate, while continuously withdrawing the 4-choloro-2-fluoro-3-methoxyphynylboronateboronate from the second reaction zone of the tubular reactor apparatus into a receiving container.

12. The method of claim 11 , wherein the tubular reactor apparatus is maintained at a temperature of less than about −30° C.

13. The method of claim 11 , wherein the tubular reactor apparatus is maintained at a temperature of less than about −40° C.

14. The method of claim 11 , wherein the tubular reactor apparatus is maintained at a temperature of less than about −50° C.

15. The method of claim 11 , wherein the first and the second zone of the tubular reactor apparatus comprise stainless steel tubing.

16. The method of claim 7 , wherein continuously adding a 2-chloro-6-fluoroanisole to a first reactor comprises continuously adding the 2-chloro-6-fluoroanisole to the first reactor below a surface of liquid contained in the first reactor.

17. The method of claim 7 , wherein continuously adding at least one alkyllithium to a first reactor comprises continuously adding the at least one alkyllithium to the first reactor over a surface of liquid contained in the first reactor.

18. The method of claim 7 , wherein continuously adding at least one alkyllithium to a first reactor comprises continuously adding the at least one alkyllithium to the first reactor below a surface of liquid contained in the first reactor.

19. The method of claim 7 , wherein the receiving container is at room temperature.

20. The method of claim 7 , further comprising converting the 4-choloro-2-fluoro-3-methoxyphynylboronate collected in the receiving container to a 4-choloro-2-fluoro-3-methoxyphynylboronic acid.

21. The method of claim 20 , wherein converting the 4-choloro-2-fluoro-3-methoxyphynylboronate collected in the receiving container to a 4-choloro-2-fluoro-3-methoxyphynylboronic acid comprises:
transferring at least a portion of the 4-choloro-2-fluoro-3-methoxyphynylboronate in the receiving container to a reaction container;
reacting the 4-choloro-2-fluoro-3-methoxyphynylboronate in the reactor container with an aqueous potassium hydroxide, followed by performing an acidification process to provide the 4-choloro-2-fluoro-3-methoxyphynylboronic acid.

22. The method of claim 11 , further comprising:
cooling the 2-chloro-6-fluoroanisole in a pre-cooling zone of the tubular reactor apparatus prior to mixing the 2-chloro-6-fluoroanisole with the alkyllithium to provide the starting material mixture.

23. The method of claim 11 , further comprising:
mixing the 2-chloro-6-fluoroanisole and the alkyllithium in a first mixing zone of the tubular reactor apparatus to provide the starting material mixture that is subsequently continuously fed into the first reaction zone of the tubular reactor apparatus.

24. The method of claim 11 , further comprising converting the 4-choloro-2-fluoro-3-methoxyphynylboronate collected in the receiving container to a 4-choloro-2-fluoro-3-methoxyphynylboronic acid.

25. The method of claim 24 , wherein converting the 4-choloro-2-fluoro-3-methoxyphynylboronate collected in the receiving container to a 4-choloro-2-fluoro-3-methoxyphynylbor

Assignees

• Emonds Mark V M
• Menning Catherine A
• Blaylock D Wayne
• Dow Agrosciences Llc

Inventors

• Emonds Mark V M
• Menning Catherine A
• Blaylock D Wayne

Classifications

• B01J2219/00873

  Heat exchange · CPC title

• B01J2219/00099

  the reactor being immersed in the heat exchange medium · CPC title

• B01J19/24

  Stationary reactors without moving elements inside (B01J19/08, B01J19/26 take precedence; with stationary particles B01J8/02) · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• B01J2219/00813

  Fluidic connections · CPC title