Methods of forming 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters and methods of using the same

  • US 9,422,313 B2
  • Filed: 11/06/2014
  • Issued: 08/23/2016
  • Est. Priority Date: 12/30/2011
  • Status: Active Grant
First Claim
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1. A method of forming and using 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;

    reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid with 2,3-dimethyl-2,3-butanediol to form a 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester; and

    subjecting the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester to a Suzuki'"'"'s coupling reaction in a medium consisting of a Suzuki'"'"'s coupling reactant, a palladium catalyst, a ligand, at least one solvent, and a base,wherein the Suzuki'"'"'s coupling reactant is a methyl 4-acetamido-3,6-dichloropicolinate to produce a 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate, orwherein the Suzuki'"'"'s coupling reactant is a methyl 6-acetamido-2-chloropyrimidine-4-carboxylate or a 6-amino-2-chloropyrimidine-4-carboxylic acid to produce a 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate.

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