Methods and systems for forming boronic acids and intermediates thereof
First Claim
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.
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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.
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Citations
25 Claims
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1. A method of forming a 4-choloro-2-fluoro-3-methoxyphynylboronic acid, comprising:
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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.; andconverting the 4-choloro-2-fluoro-3-methoxyphynylboronate to the 4-choloro-2-fluoro-3-methoxyphynylboronic acid. - View Dependent Claims (2, 3, 4, 5, 6)
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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:
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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. - View Dependent Claims (8, 9, 10, 16, 17, 18, 19, 20, 21)
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11. A continuous tubular process of forming a 4-choloro-2-fluoro-3-methoxyphynylboronate, the process comprising:
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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. - View Dependent Claims (12, 13, 14, 15, 22, 23, 24, 25)
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Specification