# US 8,785,651 B2 · Method for manufacturing a boronic acid ester compound > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,651 B2 - Document ID: US8785651B2 - Status: Granted - Kind: B2 - Application number: 13/142,536 - Filed: 2009-03-24 - Published: 2012-05-17 - Granted: 2014-07-22 - Earliest claimed: 2009-03-24 - Assignees: Sumitomo Chemical Company, Limited; Genentech, Inc. - Applicants: Takashi Miki; Yasuharu Shimasaki; Srinivasan Babu; Zhigang Cheng; Mark E. Reynolds; Qingping Tian - Inventors: Takashi Miki; Yasuharu Shimasaki; Srinivasan Babu; Zhigang Cheng; Mark E. Reynolds; Qingping Tian - Web page: https://patentgrep.com/patent/US8785651B2 ## CPC - C07F 5/025: {Boronic and borinic acid compounds} - C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22) ## Abstract The present invention relates to a method for manufacturing a boronic acid ester compound, characterized by reacting an aryl halide compound and a diboron ester compound in the presence of a nitrogen-containing organic base, a nickel catalyst, a phosphine compound and a solvent. According to the manufacturing method of the present invention, even if a nickel catalyst is used as the catalyst, a desired boronic acid ester compound can be obtained in a sufficiently high yield. Furthermore, even if aryl chloride or aryl bromide having relatively low price and low reactivity, was used as the aryl halide compound, a desired boronic acid ester compound can be obtained in a sufficiently high yield. ## Claims ### Claim 1 A method for preparing a boronic acid ester compound represented by formula (3): wherein Ar represents an optionally substituted aromatic hydrocarbon group, or an optionally substituted aromatic heterocyclic group; R represents a an optionally substituted alkylene group, or an optionally substituted arylene group; characterized by reacting a compound represented by formula (1): Ar—X (1) wherein Ar is as defined above, X represents a halogen atom, an optionally substituted alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group; with a compound represented by formula (2): wherein R is as defined above; in the presence of a nitrogen-containing organic base, a nickel catalyst, a phosphine compound and a solvent. ### Claim 2 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein Ar is an optionally substituted aromatic hydrocarbon group, an optionally substituted nitrogen-containing aromatic heterocyclic group, an optionally substituted sulfur-containing aromatic heterocyclic group, or an optionally substituted oxygen-containing aromatic heterocyclic group. ### Claim 3 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein Ar is an optionally substituted aromatic hydrocarbon group, or an optionally substituted nitrogen-containing aromatic heterocyclic group. ### Claim 4 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein Ar is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted indolyl group, or an optionally substituted indazolyl group. ### Claim 5 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the nickel catalyst is a 0-valent or divalent nickel complex. ### Claim 6 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the nickel catalyst is at least one nickel complex selected from the group consisting of a nickel(0)-alkene complex, a nickel(0)-phosphine complex, a nickel(0)-phosphite complex, an inorganic acid salt of nickel(II), an organic acid salt of nickel(II), a nickel(II) halide, and a nickel(II) halide-phosphine complex. ### Claim 7 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the nickel catalyst is bis(1,5-cyclooctadiene)nickel(0), nickel(II) nitrate or nickel(II) chloride. ### Claim 8 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the nitrogen-containing organic base is a tertiary amine compound or a cyclic amidine compound. ### Claim 9 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the nitrogen-containing organic base is a trialkylamine compound, a cyclic tertiary amine compound or a cyclic amidine compound. ### Claim 10 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the nitrogen-containing organic base is triethylamine, diisopropylethylamine, N-methylmorpholine or 1,8-diazabicyclo[5.4.0]-7-undecene. ### Claim 11 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the phosphine compound is a triarylphosphine. ### Claim 12 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the phosphine compound is triphenylphosphine. ### Claim 13 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the solvent is an alcohol solvent, or a mixed solvent of an alcohol solvent and at least one solvent selected from the group consisting of a hydrocarbon solvent, an ether solvent, an ester solvent, a ketone solvent, an amide solvent, a nitrile solvent, a sulfoxide solvent and a halogenated hydrocarbon solvent. ### Claim 14 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the solvent is an alcohol solvent, or a mixed solvent of an alcohol solvent and at least one solvent selected from the group consisting of a hydrocarbon solvent, an ether solvent, and an ester solvent. ### Claim 15 (depends on 13) The method for preparing the boronic acid ester compound according to claim 13, wherein the alcohol solvent is methanol or ethanol. ### Claim 16 (depends on 13) The method for preparing the boronic acid ester compound according to claim 13, wherein the alcohol solvent is methanol. ### Claim 17 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the compound represented by formula (2) is bis(pinacolate)diboron. ### Claim 18 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein X is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a toluenesulfonyloxy group or a benzenesulfonyloxy group. ### Claim 19 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein X is a chlorine atom, a bromine atom, or an iodine atom. ### Claim 20 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein Ar is an aromatic heterocyclic group selected from the group consisting of the following: where the wavy lines indicate the bonding position of Ar, and the above groups may be substituted. ### Claim 21 (depends on 20) The method for preparing the boronic acid ester compound according to claim 20, wherein the aromatic heterocyclic group is substituted with one or more groups selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a cyano group, a trifluoromethyl group, a hydroxymethyl group, a carboxy group, a carbamoyl group, an N,N-dimethylcarbamoyl group, a nitro group, an amino group, an N-methylamino group, N-acetylamino group, a hydroxy group, a methoxy group, a sulfanyl group, a methylsulfonyl group, and a group represented by the formula —NHC(═O)NHCH3. ### Claim 22 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the compound represented by formula (1) is the compound represented by the following formula: ### Claim 23 (depends on 1) The method for preparing the boronic acid ester compound according to claim 1, wherein the compound represented by formula (3) is the compound represented by the following formula: