WO2015137175A1 - Procédé de production d'un composé ester d'acide arylboronique - Google Patents

Procédé de production d'un composé ester d'acide arylboronique Download PDF

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Publication number
WO2015137175A1
WO2015137175A1 PCT/JP2015/056037 JP2015056037W WO2015137175A1 WO 2015137175 A1 WO2015137175 A1 WO 2015137175A1 JP 2015056037 W JP2015056037 W JP 2015056037W WO 2015137175 A1 WO2015137175 A1 WO 2015137175A1
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Prior art keywords
compound
acid ester
producing
nickel complex
boronic acid
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PCT/JP2015/056037
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English (en)
Japanese (ja)
Inventor
節 丹羽
孝充 細谷
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国立研究開発法人理化学研究所
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Priority to JP2016507454A priority Critical patent/JPWO2015137175A1/ja
Publication of WO2015137175A1 publication Critical patent/WO2015137175A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • the present invention relates to a method for producing an aryl boronic acid ester compound from a fluoroaryl compound by a one-step reaction process.
  • the present invention has been made in view of the above-described conventional circumstances, and should provide a method capable of producing an aryl boronic acid ester compound from various fluorinated aryl compounds by a one-step reaction process. It is an issue.
  • the present inventors tried to obtain an aryl boronic acid ester compound by cross-coupling a fluorinated aryl compound and a boration reagent.
  • a cross-coupling reaction has not been known, but it has been found that the coupling reaction can be performed by setting specific reaction conditions, and the production method of the present invention has been completed.
  • the method for producing an aryl boronic acid ester compound of the present invention comprises a fluorinated aryl compound, diboron pinacol ester or pinacol borane, a zerovalent nickel complex, a phosphine ligand, and a monovalent or divalent copper compound. And cross-coupling in an aprotic solvent in the presence of a base.
  • an aryl boronic acid ester compound of the present invention even when a fluorinated aryl compound to which a particularly strong electron withdrawing group is not bonded is used as a substrate, cross-coupling with diboron pinacol ester or pinacol borane Since the reaction proceeds, it can be used as a general-purpose production method for aryl boronic acid ester compounds.
  • any compound in which fluorine is directly bonded to a benzene ring and does not have a functional group that hinders the coupling reaction in the production method of the present invention can be used.
  • fluorobenzene and derivatives thereof, fluorobiphenyl and derivatives thereof, fluoronaphthalene and derivatives thereof, and the like can be used.
  • the present inventors have confirmed that an aryl boronic acid ester compound can be obtained even if an ether moiety, an ester moiety or an amino group is present in the fluorinated aryl compound.
  • (Bpin) 2 As the diboron pinacol ester, (Bpin) 2 , (Bcat) 2 and the like can be used.
  • the pinacol borane can be used HBpin.
  • Ni (cod) 2 bis (cyclooctadiene) nickel (abbreviation Ni (cod) 2 ) or the like can be used as the zero-valent nickel complex.
  • phosphine ligand it is preferable to use phosphines having at least one alkyl group.
  • phosphines having at least one alkyl group For example, trialkylphosphine, triarylphosphine, or diaryldiphosphine can be used.
  • the trialkylphosphine include P (cC 6 H 11 ) 3 and P (cC 5 H 9 ) 3 .
  • the triarylphosphine include P (Ph) 3 and P (p-MeO C 6 H 4 ) 3 .
  • diaryldiphosphines include 1,1-bis (diphenylphosphino) methane (DPPM), 1,2-bis (diphenylphosphino) ethane (DPPE), and 1,3-bis (diphenylphosphino).
  • DPPM 1,1-bis (diphenylphosphino) methane
  • DPPE 1,2-bis (diphenylphosphino) ethane
  • DPPF 1,3-bis (diphenylphosphino).
  • DPPP 1,1′-bis (diphenylphosphino) ferrocene
  • 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (XPhos) can also be used.
  • a monovalent or divalent copper compound can be used as the copper compound, and a monovalent copper compound is preferred.
  • the monovalent copper compound include CuI, CuBr, CuCl, CuOAc, CuBF 4 (MeCN) 4 , and CuPF 4 (MeCN) 4 .
  • the divalent copper compound include CuCl 2 , CuBr 2 , CuF 2 , and Cu (OAc) 2 .
  • alkali metal alkoxides such as CsF, KOtBu, NaOtBu, and the like can be used.
  • toluene, xylene, hexane, tBuOMe, cC 5 H 9 OMe, THF, dimethoxyethylene, DMF, and the like can be used as the aprotic solvent.
  • Particularly preferred are low-polarity aprotic solvents such as toluene and xylene.
  • a divalent nickel complex can be used instead of a zero valent nickel complex.
  • the divalent nickel complex is reduced to a zero valent nickel complex.
  • a reducing agent that can be used is required. That is, a fluorinated aryl compound, diboron pinacol ester or pinacol borane, a divalent nickel complex, a reducing agent capable of reducing the divalent nickel complex, a phosphine ligand, and a monovalent or divalent copper
  • NiCl 2 (dme), Ni (acac) 2 , etc. can be used as the divalent nickel complex.
  • a typical metal hydride such as alkylaluminum such as DIBAL or a zerovalent nickel complex such as Ni (cod) 2 can be used.
  • a fluorinated aryl compound is used as a raw material.
  • Numerous pharmaceuticals composed of fluorinated aryl compounds have been developed (for example, Atorvastatin, a blood cholesterol lowering agent, Iloperodon, an antidepressant, etc.), and aryl boronic acid ester compounds can be obtained from these compounds.
  • the aryl boronic acid ester compound can be used as a reagent for the Suzuki-Miyaura coupling reaction, and therefore is a convenient intermediate material in compound synthesis. For example, the following usage can be considered.
  • PET positron emission tomography
  • a tracer labeled with a short-lived radionuclide that emits a positron such as 18 F or 11 C is administered in vivo.
  • This is a method of imaging the distribution by a computer.
  • the PET method is used as a useful measurement technique in various fields such as biology, drug development, and medicine because it can trace the movement of a substance in a living body over time, non-invasively and quantitatively.
  • the aryl boronic acid ester compound produced by the method of the present invention introduces a C—C bond by a coupling reaction using a transition metal catalyst or is oxidized to a hydroxyl group. , Amination, iodination, bromination, chlorination, azidation, etc., etherification using the Chan-Evans-Lam coupling reaction, and reaction with carbon monoxide to convert the carbonyl group It can be converted into various compounds such as by introduction.
  • Example 1 In Example 1, 4-fluorobiphenyl (1) was used as a fluorinated aryl compound serving as a substrate, and B 2 (pin) 2 was used as a diboron pinacol ester to produce the corresponding boronate ester (3).
  • Ni (COD) 2 bis (cyclooctadiene) nickel (0)
  • PCy 3 Tricyclohexylphosphine (28.0 mg, 0.1 mmol, 50 mol%), sealed with a lid with a septum, and taken out from the glove box.
  • Toluene (0.5 mL) was added to the vial and stirred at room temperature for 10 minutes to prepare a nickel phosphine complex toluene solution (0.5 mL).
  • the total amount of the nickel phosphine complex toluene solution prepared previously (0.5 mL) was added, and the mixture was stirred at room temperature for 5 minutes, and then heated and stirred at 80 ° C. for 24 hours using a heat block.
  • saturated aqueous ammonium chloride solution (2 mL) and diethyl ether (2 mL) were added, and the mixture was stirred at room temperature for 15 min.
  • the reaction mixture was extracted with diethyl ether using a separatory funnel (5 mL ⁇ 3), and the organic layers were combined, washed with a saturated aqueous sodium chloride solution (5 mL), and dried over anhydrous sodium sulfate.
  • Example 2 to 11 In Examples 2 to 11, the following fluorinated biphenyl compounds were used in place of 4-fluorobiphenyl in Example 1. “Bn” in the formula represents a benzyl group. Other conditions were the same as in Example 1 (however, in Example 11, 30 mol% of Ni (COD) 2 , 9 equivalents of CsF, 150 mol% of tricyclohexylphosphine, and 60 mol% of CuI were used). The details are omitted.
  • Example 12 the corresponding boronic acid ester (5) was produced using 4-fluoroanisole (4) as the fluorinated aryl compound as a substrate and B 2 (pin) 2 as the diboron pinacol ester. That is, in a glove box substituted with argon, bis (cyclooctadiene) nickel (0) (15.4 mg, 0.06 mmol, 30 mol%) and tricyclohexylphosphine (84.1 mg, 0.3 mmol, 150 mol) were placed in a 5 mL vial. %), Seal with a lid with a septum, and remove from the glove box.
  • Toluene (0.6 mL) was added to the vial and stirred at room temperature for 10 minutes to prepare a nickel phosphine complex toluene solution (0.6 mL).
  • bis (pinacolato) diboron (101.6 mg, 0.4 mmol, 2.0 equiv.)
  • Copper iodide (22.8 mg, 0.12 mmol, 60 mol%)
  • fluoride in a glove box substituted with argon
  • cesium 272.9 mg, 1.8 mmol, 9.0 equiv.
  • Example 13 to 24 In Examples 13 to 24, the following fluorinated aryl compounds were used in place of 4-fluorobiphenyl (1) in Example 1. Other conditions are the same as those in the first embodiment, and the details are omitted.
  • TBS represents a tert-butyldimethylsilyl group
  • TIPS triisopropylsilyl group
  • Boc represents a tert-butoxycarbonyl group.
  • Comparative Examples 1 to 4 In Comparative Examples 1 to 4, various silver compounds (see Table 2) were used instead of the copper compound, and the corresponding boronate ester (3) was produced in the same manner as in Examples 25 to 34 except for the other conditions. The experimental procedure is the same as in Example 1, and the description is omitted.
  • Example 35 to 37 4-fluorobiphenyl (1) was used as the fluorinated aryl compound as a substrate, B 2 (pin) 2 was used as the diboron pinacol ester, and various bases (see Table 3) were used. The other conditions were fixed as follows to produce the corresponding boronate ester (3).
  • the experimental procedure is the same as in Example 1, and the description is omitted.
  • Example 38 to 41 a boronate ester (3) was produced under the following conditions using a phosphine ligand (see Table 4) other than tricyclohexylphosphine (PCy 3 ).
  • Example 42 to 49 In Examples 42 to 49, a boronic ester (3) was produced under the following conditions using a nonpolar solvent other than toluene (see Table 5).
  • the boronic acid ester (3) was not obtained using any activator other than the copper compound.
  • Example 50 to 52 In Examples 50 to 52, a divalent nickel complex was used instead of the nickel complex Ni (cod) 2 used in Example 1 (or a zero-valent nickel complex and a divalent nickel complex were used in combination), Further, diisobutylaluminum DIBAL was added as a reducing agent (see Table 7). Other conditions and procedures are the same as those in the first embodiment, and a description thereof will be omitted.
  • Example 53 In Example 53, instead of (Bpin) 2 which is diboron pinacol ester used in Example 1, HBpin which is pinacol borane was used, and other conditions and procedures were carried out in the same manner as in Example 1. .
  • a fluorine substituent composed of 19 F which is a normal non-radioactive isotope
  • a fluorine substituent composed of 18 F which is a radioisotope.
  • it can be used as a raw material for the synthesis of PET probes and an intermediate material for drug discovery.
  • aryl boronic acid ester compounds can be produced from various fluorinated aryl compounds by a one-step reaction process.
  • the aryl boronic acid ester compound serves as a substrate for the Suzuki-Miyaura coupling reaction, and can be used as a raw material for the synthesis of PET probes and an intermediate material for drug discovery.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention a pour but de résoudre le problème consistant à fournir un procédé de production d'un composé ester d'acide arylboronique à partir de divers composés fluorure d'aryle, par une étape de réaction dans une seule phase. La solution selon l'invention porte sur un couplage croisé d'un composé fluorure d'aryle et d'un ester de pinacol diboré ou de pinacolborane, lequel est réalisé dans un solvant aprotique, en présence d'un complexe de nickel à valence nulle, d'un ligand phosphine, d'un composé du cuivre monovalent ou divalent (de préférence monovalent), et d'une base. Du fluorobenzène ou ses dérivés, du fluorobiphényle ou ses dérivés, et analogues peuvent être utilisés comme composés fluorure d'aryle. Du Ni(cod)2 ou analogue peut être utilisé comme complexe de nickel de valence nulle. Une trialkyl-phosphine, une triaryl-phosphine, ou une diaryl-diphosphine peut être utilisée comme ligand phosphine.
PCT/JP2015/056037 2014-03-10 2015-03-02 Procédé de production d'un composé ester d'acide arylboronique WO2015137175A1 (fr)

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JP2016507454A JPWO2015137175A1 (ja) 2014-03-10 2015-03-02 アリールボロン酸エステル化合物の製造方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859761A (zh) * 2016-04-26 2016-08-17 丽水学院 一种芳香硼酸酯化合物合成方法

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WO2009131107A1 (fr) * 2008-04-22 2009-10-29 ユニマテック株式会社 Composé d’ester de l’acide borique fluoré et procédé de production
JP2010241764A (ja) * 2009-04-09 2010-10-28 Unimatec Co Ltd 含フッ素ボロン酸エステル化合物の製造方法
WO2011068181A1 (fr) * 2009-12-04 2011-06-09 独立行政法人理化学研究所 Procédé de fluorométhylation rapide et procédé de préparation d'un traceur pet utilisant celui-ci
WO2012121345A1 (fr) * 2011-03-10 2012-09-13 国立大学法人大阪大学 Procédé de préparation d'oléfines fluorées substituées avec des groupes organiques

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WO2008023780A1 (fr) * 2006-08-25 2008-02-28 Gifu University Procédé de méthylation rapide, coffret pour préparer un traceur pet et procédé de fabrication d'un traceur pet
WO2009131107A1 (fr) * 2008-04-22 2009-10-29 ユニマテック株式会社 Composé d’ester de l’acide borique fluoré et procédé de production
JP2010241764A (ja) * 2009-04-09 2010-10-28 Unimatec Co Ltd 含フッ素ボロン酸エステル化合物の製造方法
WO2011068181A1 (fr) * 2009-12-04 2011-06-09 独立行政法人理化学研究所 Procédé de fluorométhylation rapide et procédé de préparation d'un traceur pet utilisant celui-ci
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859761A (zh) * 2016-04-26 2016-08-17 丽水学院 一种芳香硼酸酯化合物合成方法
CN105859761B (zh) * 2016-04-26 2018-06-26 丽水学院 一种芳香硼酸酯化合物合成方法

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