WO2022186098A1 - Nouvel ester d'acide boronique aromatique stable - Google Patents

Nouvel ester d'acide boronique aromatique stable Download PDF

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WO2022186098A1
WO2022186098A1 PCT/JP2022/008131 JP2022008131W WO2022186098A1 WO 2022186098 A1 WO2022186098 A1 WO 2022186098A1 JP 2022008131 W JP2022008131 W JP 2022008131W WO 2022186098 A1 WO2022186098 A1 WO 2022186098A1
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貴詞 井川
直輝 岡
周司 赤井
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国立大学法人大阪大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention relates to novel aromatic boronic esters that are useful for various functionalizations, are not adsorbed even during silica gel chromatography, are stable and can be isolated and purified.
  • the present invention also relates to a method for producing the aromatic boronate ester.
  • Aromatic boronic acid derivatives are widely used in the field of synthetic organic chemistry as substrates for various reactions represented by Suzuki-Miyaura coupling.
  • aromatic boronic acids with an unprotected boronic acid group (-B(OH) 2 ) are easily dehydrated to give cyclic trimeric anhydrides, boroxines, or are strongly adsorbed on silica gel. It has drawbacks such as difficulty in its isolation, purification, structure determination by NMR, and functional group conversion while retaining the boronic acid group.
  • Non-Patent Document 1 Several solutions have been reported so far to solve the above drawbacks by protecting the boronic acid group of the aromatic boronic acid with a protective group.
  • an aromatic boronic acid pinacol ester is one of the most widely used protected boronic acids, and can be used as it is as a substrate for a coupling reaction.
  • the yield often decreases. technology was required (Non-Patent Document 2).
  • ArB(dan) Non-Patent Document 3
  • ArB(mida) Non-Patent Document 4
  • boronic acid derivatives obtained by dehydration condensation with diaminonaphthalene (dan) or N-methyliminodiacetic acid (mida) have been developed.
  • the instability of aromatic boronic acid pinacol esters was improved, but these boronic acid derivatives are difficult to synthesize, extremely polar, and difficult to convert functional groups later. Many problems still remain, such as the difficulty of protection.
  • the object of the present invention is to provide a novel aromatic boronic ester that is stable without being adsorbed even in silica gel chromatography, can be easily isolated and purified, and is applicable to a wide range of functional group transformations.
  • n represents an integer of 1 or greater.
  • the compound represented by or a salt thereof is extremely stable even on ordinary silica gel column chromatography or thin layer chromatography, and its decomposition is not observed, and it can be easily isolated and purified.
  • a salt thereof in the Suzuki-Miyaura coupling reaction it was found that it exhibited almost the same reactivity as the aromatic boronic acid pinacol ester and could be converted into the corresponding biaryls.
  • the present inventors have found that the same compound or a salt thereof can be applied to conversion to oxygen functional groups by NaBO 3 and conversion to nitrogen functional groups using a copper catalyst, and completed the present invention. .
  • a compound represented by (hereinafter sometimes referred to as compound (I)) or a salt thereof (hereinafter, compound (I) and a salt thereof may be collectively referred to as "the compound of the present invention").
  • R 1 and R 3 are each independently a linear C 1-4 alkyl group
  • R 2 and R 4 are each independently a linear C 2-4 alkyl
  • Each group represented by represents an aryl group or aromatic heterocyclic group which may be further substituted, and n represents an integer of 1 or more.
  • R 1 and R 3 each independently represent a linear C 1-6 alkyl group; R 2 and R 4 each independently represent a linear C 2-6 alkyl group.
  • Formula (I) comprising reacting a compound of formula (I):
  • X 1 represents a halogen atom
  • n represents an integer of 1 or greater.
  • R 1 and R 3 each independently represent a linear C 1-6 alkyl group; R 2 and R 4 each independently represent a linear C 2-6 alkyl group.
  • R 1 and R 3 each independently represent a linear C 1-6 alkyl group; R 2 and R 4 each independently represent a linear C 2-6 alkyl group.
  • R 1 and R 3 each independently represent a linear C 1-6 alkyl group; R 2 and R 4 each independently represent a linear C 2-6 alkyl group.
  • a compound represented by [12] The compound or salt thereof according to any one of [1] to [7] above is treated with the formula (VII) in the presence of a metal catalyst and a base:
  • R represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.
  • Formula (XI) comprising reacting with a compound of formula (XI):
  • the compound of the present invention has the advantage that it is extremely stable without being decomposed even on silica gel column chromatography or thin layer chromatography, and can be easily isolated and purified.
  • the compounds of the present invention exhibit almost the same reactivity as aromatic boronic acid pinacol esters, they can be applied to Suzuki-Miyaura coupling reaction and various functional group reactions, and can be used for various pharmaceuticals and functional materials. It is useful as a raw material compound or a synthetic intermediate.
  • FIG. 1 shows the results of developing compound (I-2) and compound (I-4), and their corresponding pinacol esters (Comparative Examples 7 and 2) by thin-layer chromatography (silica gel plate) (ammonium cerium molybdate staining) is shown.
  • halogen atom includes, for example, fluorine, chlorine, bromine, and iodine.
  • the "hydrocarbon group” includes an alkyl group (e.g., C 1-6 alkyl group), an alkenyl group (e.g., C 2-6 alkenyl group), an alkynyl group (e.g., C 2-6 alkynyl group). ), cycloalkyl group (e.g., C 3-10 cycloalkyl group), cycloalkenyl group (e.g., C 3-10 cycloalkenyl group), aryl group (e.g., C 6-14 aryl group), aralkyl group (e.g., C 7-16 aralkyl group).
  • alkyl group e.g., C 1-6 alkyl group
  • an alkenyl group e.g., C 2-6 alkenyl group
  • an alkynyl group e.g., C 2-6 alkynyl group
  • cycloalkyl group e.g., C 3-10 cycloalkyl group
  • alkyl group means a group obtained by removing one hydrogen atom from any carbon atom of a straight-chain or branched-chain alkane having 1 or more carbon atoms. Unless otherwise specified, it is a C 1-20 alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-4 alkyl group.
  • C 1-6 alkyl group includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-4 alkyl group includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • linear C 1-6 alkyl group includes, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and among them, linear A C 1-4 alkyl group of is preferred.
  • linear C 2-6 alkyl group includes, for example, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and among them, linear C 2-4 alkyl groups are preferred.
  • alkenyl group means a group obtained by removing one hydrogen atom from any carbon atom of a straight-chain or branched-chain alkene having 2 or more carbon atoms. Unless otherwise specified, it is a C 2-20 alkenyl group, with a C 2-6 alkenyl group being preferred.
  • C 2-6 alkenyl group includes, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • alkynyl group means a group obtained by removing one hydrogen atom from any carbon atom of a linear or branched alkyne having 2 or more carbon atoms, particularly Unless otherwise specified, it is a C 2-20 alkynyl group, with a C 2-6 alkynyl group being preferred.
  • C 2-6 alkynyl group includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
  • cycloalkyl group means a cyclic alkyl group, and unless there is a particular limitation on the carbon number range, it is a C 3-10 cycloalkyl group, especially C 3-8 cycloalkyl groups are preferred.
  • C 3-10 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2. 2]octyl, bicyclo[3.2.1]octyl and adamantyl.
  • C 3-8 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl group means a cyclic alkenyl group, and unless there is a particular limitation on the carbon number range, it is a C 3-10 cycloalkenyl group, especially C 3-8 cycloalkenyl groups are preferred.
  • C 3-8 cycloalkenyl group includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • aryl group refers to a monocyclic or polycyclic (condensed) hydrocarbon group exhibiting aromaticity, preferably a C 6-14 aryl group.
  • C 6-14 aryl group includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and biphenylyl.
  • aralkyl group means a group in which an alkyl group is substituted with an aryl group, and although the carbon number range is not particularly limited, it is preferably a C 7-16 aralkyl group.
  • C 7-16 aralkyl group includes, for example, benzyl, 1-phenylethyl, 2-phenylethyl, (naphthyl-1-yl)methyl, (naphthyl-2-yl)methyl, 1- (naphthyl-1-yl)ethyl, 1-(naphthyl-2-yl)ethyl, 2-(naphthyl-1-yl)ethyl, 2-(naphthyl-2-yl)ethyl, biphenylylmethyl, phenylpropyl be done.
  • alkoxy group means a group in which a straight or branched chain alkyl group is bonded to an oxygen atom, and the carbon number range is not particularly limited, but is preferably a C 1-6 alkoxy group. be.
  • C 1-6 alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy. Among them, a C 1-4 alkoxy group is preferred.
  • the "C 7-16 aralkyloxy group” includes, for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, (naphthyl-1-yl)methyloxy, (naphthyl-2-yl ) methyloxy, 1-(naphthyl-1-yl)ethyloxy, 1-(naphthyl-2-yl)ethyloxy, 2-(naphthyl-1-yl)ethyloxy, 2-(naphthyl-2-yl)ethyloxy, biphenylyl Examples include methyloxy and phenylpropyloxy.
  • heterocyclic group includes, for example, (i) an aromatic (ii) non-aromatic heterocyclic groups; and (iii) 7- to 10-membered heterocyclic bridged ring groups.
  • aromatic heterocyclic group includes, for example, a 5- to 14-membered ring containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms. (preferably 5- to 10-membered) aromatic heterocyclic groups.
  • aromatic heterocyclic group examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, , 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, 5- or 6-membered monocyclic aromatic heterocyclic groups such as triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
  • non-aromatic heterocyclic group includes, for example, 3 to 14 heteroatoms containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring-constituting atoms.
  • a membered (preferably 4- to 10-membered) non-aromatic heterocyclic group can be mentioned.
  • non-aromatic heterocyclic group examples include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl,
  • preferred examples of the "7- to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.
  • the "acyl group” includes a formyl group, a hydrocarbon-carbonyl group (C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl -carbonyl groups (e.g. cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl groups (e.g.
  • 2-cyclohexenecarbonyl C 6-14 aryl-carbonyl groups, C 7 -16 aralkyl-carbonyl group), heterocyclic carbonyl group (e.g., 5- to 14-membered aromatic heterocyclic carbonyl group such as nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, etc.
  • heterocyclic carbonyl group e.g., 5- to 14-membered aromatic heterocyclic carbonyl group such as nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, etc.
  • alkoxy-carbonyl group e.g., C 1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl
  • aryloxy-carbonyl group e.g., phenyloxycarbonyl, C 6-14 aryloxy-carbonyl groups such as naphthyloxycarbonyl
  • aralkyloxy-carbonyl groups e.g.
  • C 7-16 aralkyloxy-carbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl groups, mono- or di-hydrocarbon-carbamoyl group (mono- or di-C 1-6 alkyl-carbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl), mono- or di- —C 2-6 alkenyl-carbamoyl group (e.g.
  • diallycarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (e.g. cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 aralkyl-carbamoyl groups (e.g., benzylcarbamoyl, phenethylcarbamoyl)), heterocyclic carbamoyl groups (e.g., 5- to 14-membered aromatic heteroaromatic groups such as pyridylcarbamoyl).
  • cycloalkyl-carbamoyl group e.g. cyclopropylcarbamoyl
  • mono- or di-C 6-14 aryl-carbamoyl e.g., phenylcarbamoyl
  • cyclic carbamoyl group thiocarbamoyl group, mono- or di-hydrocarbon-thiocarbamoyl group (mono- or di-C 1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , mono- or di-C 2-6a alkenyl-thiocarbamoyl group (e.g. diallylthiocarbamoyl), mono- or di-C 3-10 cycloalkyl-thiocarbamoyl group (e.g.
  • aryl-thiocarbamoyl group e.g., phenylthiocarbamoyl
  • mono- or di-C 7-16 aralkyl-thiocarbamoyl group e.g., benzyl
  • C 1-6 alkyl-carbonyl group eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl
  • C 3-10 cycloalkyl-carbonyl group eg, cyclobutanecarbonyl, cyclo pentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl
  • C 6-14 aryl-carbonyl groups eg, benzoyl, 1-naphthoyl, 2-naphthoyl
  • C 7-16 aralkyl-carbonyl groups eg, phenylacetyl, phenylpropionyl
  • C 1-6 alkoxy-carbonyl groups e.g.
  • acyloxy group means a group in which an acyl group is bonded to an oxygen atom, preferably formyloxy group, C 1-6 alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, hexanoyloxy, heptanoyl), C 3-10 cycloalkyl-carbonyloxy groups (e.g.
  • cyclobutanecarbonyloxy cyclopentanecarbonyloxy, cyclohexanecarbonyloxy, cycloheptanecarbonyloxy
  • C 6-14 aryl-carbonyloxy group e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy
  • C 7-16 aralkyl-carbonyloxy group C 1-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy), C 6-14 aryloxy-carbonyloxy group (e.g., benzyloxycarbonyloxy), C 7-16 aralkyloxy-
  • C 1-6 alkylsulfanyl group means a group in which a straight or branched chain C 1-6 alkyl group is bonded to a sulfur atom, for example, methylsulfanyl, ethylsulfanyl, propylsulfanyl , isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, hexylsulfanyl.
  • a C 1-4 alkylsulfanyl group is preferred.
  • C 1-6 alkylsulfonyloxy group means a group in which a C 1-6 alkylsulfonyl group is bonded to an oxygen atom, such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, hexylsulfonyloxy.
  • a C 1-4 alkylsulfonyloxy group is preferred.
  • trisubstituted silyl group means three substituents selected from the group consisting of the same or different C 1-6 alkyl groups, C 6-14 aryl groups and C 1-6 alkoxy groups means a silyl group substituted with, for example, a trialkylsilyl group such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group (preferably a triC 1-6 alkylsilyl group), A tert-butyldiphenylsilyl group and a triphenylsilyl group can be mentioned.
  • a trialkylsilyl group such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group (preferably a triC 1-6 alkylsilyl group)
  • substituted means unsubstituted or substituted with a substituent at any substitutable position (an arbitrary hydrogen atom is replaced with a substituent) .
  • substituted is not particularly limited, but includes substituents selected from the following (substituent group Z 1 ) or (substituent group Z 2 ). ) may be further substituted with a substituent selected from
  • Substituent group Z (1) a halogen atom, (2) a cyano group, (3) a nitro group, (4) a hydroxy group, (5) a carboxy group, (6) an azide group, (7) a C 1-6 alkyl group, (8) a C 3-10 cycloalkyl group, (9) a C 6-14 aryl group, (10) a C 1-6 alkoxy group, (11) a formyl group, (12) C 1-6 alkyl-carbonyl group, (13) a C 1-6 alkoxy-carbonyl group, (14) a C 1-6 alkylsulfonyl group, (15) C 1-6 alkyl-carbonyloxy group, (16) a C 1-6 alkylsulfanyl group, (17) a trisubstituted silyl group, (18) a C 1-6 alkylsulfonyloxy group, and (19) C 6-14 arylsulfonyloxy group.
  • the optionally substituted "substituent” is preferably a substituent selected from the following (substituent group Z 3 ) or (substituent group Z 4 ).
  • a C 6-14 aryl group optionally substituted with 1 to 3 substituents, (10) a C 1-6 alkoxy group optionally substituted with a halogen atom, (11) a formyl group, (12) a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom, (13) a C 1-6 alkoxy-carbonyl group optionally substituted with a halogen atom, (14) a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom, (15) a C 1-6 alkyl-carbonyloxy group optionally substituted with a halogen atom, (16) (a) a C 1-6 alkyl group optionally substituted with a halogen atom, (b) a C 3-10 cycloalkyl group optionally substituted with a halogen atom, (c) selected from the group consisting of a halogen atom, a cyano group, a nitro group
  • a C 6-14 aryl group optionally substituted with 1 to 3 substituents, (9) a C 1-6 alkoxy group optionally substituted with a halogen atom, (10) a formyl group, (11) a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom, (12) a C 1-6 alkoxy-carbonyl group optionally substituted with a halogen atom, (13) a C 1-6 alkylsulfonyl group optionally substituted with a halogen atom, (14) a C 1-6 alkyl-carbonyloxy group optionally substituted with a halogen atom, (15) (a) a C 1-6 alkyl group optionally substituted with a halogen atom, (b) a C 3-10 cycloalkyl group optionally substituted with a halogen atom; (c) selected from the group consisting of a halogen atom, a cyano group, a nitro group
  • the number of "substituents” that may be substituted is not particularly limited as long as it can be substituted, but is preferably 1 to 6, more preferably 1 to 3. When multiple substituents are present, each substituent may be the same or different.
  • optionally substituted aryl group (phenyl group) "optionally substituted heterocyclic group” or “optionally substituted aromatic heterocyclic group (5- or 6-membered
  • the optionally substituted “substituent” in “a monocyclic aromatic heterocyclic group or an 8- to 14-membered condensed aromatic heterocyclic group” is a substituent selected from the above (substituent group Z).
  • a substituent selected from optionally substituted (substituent group Z 1 ) or (substituent group Z 3 ) is exemplified.
  • the optionally substituted "substituent" in the “optionally substituted alkyl group” may be further substituted with a substituent selected from the above (substituent group Z) ( Substituent group Z 2 ) or a substituent selected from (substituent group Z 4 ).
  • C 1-6 alkyl group optionally substituted with halogen atoms includes, for example, C 1 optionally substituted with 1 to 6, preferably 1 to 3 halogen atoms.
  • -6 alkyl groups include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropropyl fluoropentyl, hexyl, 6,6,6-trifluorobutyl, is
  • C 1-6 alkoxy group optionally substituted with halogen atoms includes, for example, C 1 optionally substituted with 1 to 6, preferably 1 to 3 halogen atoms.
  • -6 alkoxy groups include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl oxy and hexyloxy.
  • C 1-6 alkylsulfanyl group optionally substituted with halogen atoms is, for example, C optionally substituted with 1 to 6, preferably 1 to 3 halogen atoms
  • a 1-6 alkylthio group can be mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
  • C 1-6 alkyl-carbonyl group optionally substituted with halogen atoms may be substituted with, for example, 1 to 6, preferably 1 to 3 halogen atoms. and C 1-6 alkyl-carbonyl groups. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • C 1-6 alkyl-carbonyloxy group optionally substituted with halogen atoms is, for example, substituted with 1 to 6, preferably 1 to 3 halogen atoms.
  • good C 1-6 alkyl-carbonyloxy groups include acetoxy, chloroacetoxy, trifluoroacetoxy, trichloroacetoxy, propanoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
  • C 1-6 alkylsulfonyl group optionally substituted by halogen atoms is, for example, C optionally substituted by 1 to 6, preferably 1 to 3 halogen atoms
  • a 1-6 alkylsulfonyl group can be mentioned.
  • Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
  • C 1-6 alkylsulfonyloxy group optionally substituted with halogen atoms may be substituted with, for example, 1 to 6, preferably 1 to 3 halogen atoms. and C 1-6 alkylsulfonyloxy groups. Specific examples include methylsulfonyloxy, difluoromethylsulfonyloxy, trifluoromethylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, 4,4,4-trifluorobutylsulfonyloxy, pentylsulfonyloxy. oxy, hexylsulfonyloxy;
  • salt thereof refers to a salt produced by reacting with a base or an acid when the compound has an acidic group or a basic group. salts, salts with inorganic bases, salts with organic bases, ammonium salts, salts with amino acids, and the like.
  • the group represented by represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted.
  • a C 6-14 aryl group is preferably a C 6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group or an 8- to 14-membered condensed aromatic heterocyclic group, more preferably phenyl group, naphthyl group, or 5- or 6-membered monocyclic aromatic heterocyclic group, more preferably phenyl group, naphthyl group, pyridyl group, furyl group or thienyl group, particularly preferably phenyl group, It is a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may further have a substituent at a substitutable position.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 6, more preferably 1 to 3. When multiple substituents are present, each substituent may be the same or different.
  • the "substituent” that may be further substituted may be further substituted with a substituent selected from the above-described substituent group (for example, (substituent group Z) (substituent group Z 1 ), or a substituent selected from (substituent group Z 3 )).
  • R 1 and R 3 each independently represent a linear C 1-6 alkyl group.
  • R 1 and R 3 are preferably each independently a linear C 1-4 alkyl group, more preferably a methyl group, an ethyl group or an n-propyl group, still more preferably ethyl is the base.
  • R 2 and R 4 each independently represent a linear C 2-6 alkyl group.
  • R 2 and R 4 are preferably linear C 2-4 alkyl groups, more preferably ethyl groups or n-propyl groups, still more preferably ethyl groups.
  • n an integer of 1 or more.
  • n is preferably an integer of 1 to 3, more preferably 1 or 2.
  • Each of the groups represented by may be further substituted with a substituent selected from (substituent group Z) (substituent group Z 1 ) (preferably, (substituted a C 6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or an 8- to 14-membered condensed aromatic heterocyclic group optionally substituted with a substituent selected from group Z 3 )); is a cyclic group; R 1 and R 3 are each independently a linear C 1-4 alkyl group; R 2 and R 4 are each independently a linear C 2-4 alkyl group, and n is an integer from 1 to 3; Compound (I).
  • Each of the groups represented by may be further substituted with a substituent selected from (substituent group Z) (substituent group Z 1 ) (preferably, (substituted a phenyl group, a naphthyl group, or a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with a substituent selected from group Z 3 );
  • R 1 and R 3 are each independently a linear C 1-4 alkyl group;
  • R 2 and R 4 are each independently a linear C 2-4 alkyl group, and n is an integer from 1 to 3;
  • Compound (I) is preferably, (substituted a phenyl group, a naphthyl group, or a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with a substituent selected from group Z 3 );
  • R 1 and R 3 are each independently a linear C 1-4 alkyl group;
  • R 2 and R 4 are each independently a linear C 2-4
  • R 1 and R 3 are each independently a linear C 1-4 alkyl group;
  • R 2 and R 4 are each independently a linear C 2-4 alkyl group, and n is an integer from 1 to 3;
  • Compound (I) is a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each optionally substituted with a substituent selected from the above (substituent group Z 3 ),
  • R 1 and R 3 are each independently a linear C 1-4 alkyl group;
  • R 2 and R 4 are each independently a linear C 2-4 alkyl group, and n is an integer from 1 to 3;
  • Compound (I) is a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each optionally substituted with a substituent selected from the above (substituent group Z 3 ),
  • R 1 and R 3 are a methyl group, an ethyl group or an n-propyl group, R 2 and R 4 are an ethyl group or an n-propyl group, and n is 1 or 2; Compound (I).
  • R 1 , R 2 , R 3 and R 4 are ethyl groups or n-propyl groups, and n is 1 or 2; Compound (I).
  • compound (I) include the compounds of Examples I-1 to I-21.
  • salts include, for example, salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic Examples include salts with amino acids, salts with acidic amino acids, and the like.
  • salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; and aluminum salts.
  • salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Salts with toluenesulfonic acid and the like are included.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.
  • Compound (I) includes solvates (eg, hydrates, ethanolates, dimethylsulfoxide solutes, etc.) and non-solvates (eg, non-hydrates, etc.) within its scope.
  • solvates eg, hydrates, ethanolates, dimethylsulfoxide solutes, etc.
  • non-solvates eg, non-hydrates, etc.
  • Compound (I) may be a compound labeled or substituted with an isotope (eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.).
  • an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
  • isomers such as enantiomers or diastereomers may exist. All such isomers and mixtures thereof are included within the scope of this invention. Further, isomers may be produced due to conformation or tautomerism, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • the raw materials and reagents used in each step of the manufacturing method below, as well as the resulting compound, may each form a salt.
  • Such salts include, for example, the same salts as those of compound (I) described above.
  • the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or other desired salt by a method known per se.
  • the compound obtained in each step can be used in the next reaction after being obtained as a reaction solution or as a crude product, or the compound obtained in each step can be concentrated from the reaction mixture in accordance with a conventional method. , crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography, and the like.
  • the raw materials and reagent compounds for each process are commercially available, the commercially available products can be used as they are.
  • reaction in each step is a method known per se, for example, 5th edition Jikken Kagaku Koza, vols. 13-19 (edited by The Chemical Society of Japan); Chemistry Society ed.); Fine Organic Chemistry Revised 2nd Edition (L. F. Tietze, Th.
  • the protection or deprotection reaction of the functional group is performed by a method known per se, for example, Wiley-Interscience 2007 "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts by P. J. Kocienski), or according to the method described in Examples.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, known synthetic techniques and separation techniques (concentration, solvent extraction, column chromatography, recrystallization, etc.) Each can be obtained as a single item by
  • Optical isomers can be produced by methods known per se. Specifically, optical isomers are obtained by using optically active synthetic intermediates or by optically resolving the racemic form of the final product according to a conventional method.
  • This production method is a method for producing compound (I), which includes a step of reacting compound (II) with compound (III) in a solvent that does not adversely affect the reaction.
  • the amount of compound (III) to be used is generally 1 mol-1.5 mol, preferably 1 mol-1.2 mol, per 1 mol of the boronic acid group of compound (II).
  • the solvent is not particularly limited, but ether solvents such as diethyl ether, methyl tert-butyl ether, 1,4-dioxane, cyclopentyl methyl ether, and 4-methyltetrahydropyran; halogenated hydrocarbons such as chloroform and dichloromethane; toluene , aromatic hydrocarbons such as benzene, etc., which separate from water, among which dichloromethane is preferred.
  • the reaction temperature is usually 0° C. to 100° C., preferably room temperature (15° C. to 30° C.).
  • the reaction time is usually 2 to 24 hours, preferably 8 to 24 hours.
  • a catalytic amount of acetic acid may also be added to accelerate the reaction.
  • This production method comprises a step of reacting compound (IV) with isopropylmagnesium chloride-lithium chloride complex (i-PrMgCl-LiCl) or n-butyllithium (n-BuLi) in a solvent that does not adversely affect the reaction (step 1)
  • a method for producing compound (I) comprising a step (step 3) of reacting with compound (III) via a step of reacting with trimethoxyborane (B(OMe) 3 ) (step 2).
  • Step 1 The amount of isopropylmagnesium chloride-lithium chloride complex (i-PrMgCl—LiCl) or n-butyllithium (n-BuLi) to be used is generally 1 mol-1.5 per 1 mol of X 1 group in compound (IV). mol, preferably 1.2 mol.
  • the solvent is not particularly limited, but includes ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane, among which tetrahydrofuran is preferred.
  • the reaction temperature is usually -78°C to -10°C, preferably -78°C to -40°C.
  • the reaction time is usually 0.5 to 24 hours, preferably 1 to 12 hours.
  • Step 2 The amount of trimethoxyborane (B(OMe) 3 ) to be used is generally 1.5 mol-3 mol, preferably 2 mol, per 1 mol of X 1 group of compound (IV).
  • the solvent the solvent used in step 1 is preferred.
  • the reaction temperature is generally 0° C. to 60° C., preferably room temperature (15° C. to 30° C.).
  • the reaction time is usually 2 to 24 hours, preferably 8 to 24 hours.
  • the reaction mixture of step 2 can be directly subjected to step 3 after work-up.
  • the amount of compound (III) to be used is generally 1-1.5 mol, preferably 1 mol-1.2 mol, per 1 mol of X 1 group of compound (IV).
  • the solvent is not particularly limited, but ether solvents such as diethyl ether, methyl tert-butyl ether, 1,4-dioxane, cyclopentyl methyl ether, and 4-methyltetrahydropyran; halogenated hydrocarbons such as chloroform and dichloromethane; toluene , aromatic hydrocarbons such as benzene, etc., which separate from water, among which dichloromethane is preferred.
  • the reaction temperature is generally 0° C. to 60° C., preferably room temperature (15° C. to 30° C.).
  • the reaction time is usually 2 to 24 hours, preferably 8 to 24 hours.
  • This production method is a method for producing compound (I), which includes a step (step 1) of reacting compound (V) with compound (VI) in the presence of a metal catalyst in a solvent that does not adversely affect the reaction.
  • the amount of compound (VI) to be used is generally 1 mol-2 mol, preferably 1.5 mol, per 1 mol of X 2 group of compound (V).
  • Metal catalysts include palladium(II) acetate, palladium(II) chloride, [1,3-bis(diphenylphosphino)propane]palladium(II) dichloride (PdCl 2 (dppp)), 1,1-bis(diphenyl palladium catalysts such as phosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II); zinc catalysts such as dimethylzinc, diethylzinc; iron catalysts such as ferric iron(III) (Fe(acac) 3 ), iron(II) chloride; Ni 2 (Icy) 4 ( ⁇ -( ⁇ 2 :
  • the amount of the metal catalyst to be used is generally 0.001 mol to 0.5 mol, preferably 0.01 mol to 0.2 mol, more preferably 1 mol of X 2 groups in compound (V). is 0.01 to 0.1 mol.
  • the solvent can be arbitrarily selected depending on the type of metal catalyst used, but ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane system solvents; halogenated hydrocarbons such as chloroform and dichloromethane; nitrile solvents such as acetonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; Among them, tetrahydrofuran and dimethylsulfoxide are preferred.
  • a base may be added as necessary.
  • bases include sodium tert-butoxide, potassium methoxide, sodium methoxide, magnesium tert-butoxide, potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine. , potassium fluoride, cesium fluoride, etc. Among them, potassium acetate and sodium acetate are preferable.
  • the amount of the base to be used is generally 1 mol to 10 mol, preferably 1 mol to 5 mol, more preferably 1.5 to 3 mol, per 1 mol of X 2 group of compound (V). .
  • the reaction temperature is generally 0°C to 100°C, preferably 60°C to 100°C, more preferably 80°C.
  • the reaction time is usually 1 to 12 hours, preferably 1 to 3 hours.
  • Compound (VI) used in production method (3) can be produced by a method represented by the following Reaction Scheme 4 or a method analogous thereto.
  • Reaction formula 4
  • This production method includes a step of dehydration condensation of tetrahydroxydiboron (compound (XII)) with compound (III) in the presence of a base in a solvent that does not adversely affect the reaction.
  • the amount of compound (III) to be used is generally 2 mol-3 mol, preferably 2 mol, per 1 mol of compound (XII).
  • bases include sodium tert-butoxide, potassium methoxide, sodium methoxide, magnesium tert-butoxide, potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine.
  • potassium acetate is preferred.
  • the amount of the base to be used is generally 2 mol-5 mol, preferably 2 mol-3 mol, per 1 mol of compound (XII).
  • the solvent include, but are not particularly limited to, aromatic hydrocarbon solvents such as benzene, toluene, and xylene. Among them, toluene is preferred.
  • the reaction temperature is preferably the heating reflux temperature of the solvent, and this step is usually carried out using a Dean-Stark apparatus.
  • the reaction time is usually 2 to 36 hours, preferably 12 to 24 hours.
  • Compound (I) obtained by the above production methods (1) to (3) is extremely stable as compared to the corresponding boronic acid pinacol ester, and therefore can be subjected to silica gel chromatography (silica gel) as described in the test examples described later. column chromatography, thin-layer silica gel chromatography, etc.) can be easily purified with a good recovery rate.
  • compound (I) can stably exist and is acidic. It was confirmed to exhibit high stability under the conditions.
  • Compound (I) is not only superior in stability as compared with the corresponding boronic acid pinacol ester, but also can be widely used in various functionalization reactions like the corresponding boronic acid pinacol ester. Typical examples of various functionalization methods using compound (I) are described below, but applicable functionalization methods are not limited to these. Compound (I) is generally applicable to various conventionally known functionalization reactions using pinacol boronic acid esters.
  • the amount of compound (VII) to be used is generally 0.5 mol-0.7 mol, preferably 0.7 mol, per 1 mol of the boron ester group of compound (I).
  • Metal catalysts include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0).
  • the amount of the metal catalyst to be used is generally 0.001 mol to 0.5 mol, preferably 0.005 mol to 0.1 mol, and more preferably 1 mol of the boron ester group of compound (I). is 0.005 to 0.05 mol.
  • the solvent can be arbitrarily selected depending on the type of metal catalyst used, but ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane system solvents; chloroform, halogenated hydrocarbons such as dichloromethane; nitrile solvents such as acetonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; aromatic hydrocarbon solvents such as toluene and xylene; and mixed solvents of these organic solvents and water.
  • ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane system solvents
  • chloroform, halogenated hydrocarbons such
  • bases include potassium hydroxide, potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, rubidium carbonate, and the like.
  • tripotassium phosphate is preferred.
  • the amount of the base to be used is generally 1 mol to 10 mol, preferably 1 mol to 5 mol, more preferably 1.5 to 3 mol, per 1 mol of the boron ester group of compound (I).
  • the reaction temperature is generally 60°C to 120°C, preferably 90°C to 120°C, more preferably 110°C.
  • the reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.
  • the amount of the peracid to be used is generally 1 mol-2 mol, preferably 1 mol-1.5 mol, per 1 mol of the boron ester group of compound (I).
  • peracids include sodium perborate (NaBO 3 ), sodium periodate (under acidic conditions), hydrogen peroxide, and the like. Among them, sodium perborate (NaBO 3 ) and its hydrates are preferred.
  • the solvent can be arbitrarily selected depending on the type of peracid used, but ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane system solvents; chloroform, halogenated hydrocarbons such as dichloromethane; nitrile solvents such as acetonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; aromatic hydrocarbon solvents such as toluene and xylene; and mixed solvents of these organic solvents and water.
  • the reaction temperature is usually 0° C. to 100° C., preferably room temperature (15° C. to 30° C.).
  • the reaction time is generally 1 to 48 hours, preferably 8 to 24 hours.
  • Compound (XI) can be produced by reacting compound (I) with compound (X) in the presence of a metal catalyst and a base according to the method shown in Reaction Scheme 7 below or a method analogous thereto. Reaction formula 7
  • the amount of compound (X) to be used is generally 0.5 mol-2 mol, preferably 0.5 mol-1 mol, per 1 mol of the boron ester group of compound (I).
  • Metal catalysts include copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (II) nitrate, copper (I) bis(trifluoromethanesulfonate), bis Copper catalysts such as copper (I) (trifluoroacetate); nickel catalysts such as nickel (II) chloride, nickel (II) acetate, and nickel (II) nitrate; Copper acetate is more preferred.
  • the amount of the metal catalyst to be used is generally 0.001 mol to 0.5 mol, preferably 0.005 mol to 0.1 mol, and more preferably 1 mol of the boron ester group of compound (I). is 0.01 to 0.05 mol.
  • the solvent can be arbitrarily selected depending on the type of metal catalyst used, but ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane system solvents; chloroform, halogenated hydrocarbons such as dichloromethane; nitrile solvents such as acetonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; aromatic hydrocarbon solvents such as toluene and xylene; and mixed solvents of these organic solvents and water.
  • ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane system solvents
  • chloroform, halogenated hydrocarbons such
  • Examples of the base include potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, rubidium carbonate, and the like. Among them, cesium fluoride is preferred.
  • the amount of the base to be used is generally 0.5 mol to 10 mol, preferably 0.5 mol to 3 mol, more preferably 0.5 to 1 mol, per 1 mol of the boron ester group of compound (I). 1 mol.
  • the reaction temperature is generally 15°C to 100°C, preferably 20°C to 60°C, more preferably 40°C.
  • the reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.
  • room temperature means a temperature of 15 to 30°C unless otherwise specified.
  • the ratios shown for mixed solvents are volume ratios unless otherwise specified. % indicates % by weight unless otherwise specified.
  • the zinc powder was stirred in 1.0 M hydrochloric acid under a nitrogen stream for 30 minutes, washed with distilled water and diethyl ether, dried under reduced pressure for 6 hours, and stored in an argon atmosphere to be used as active zinc powder.
  • a dichloromethane (0.40 L) suspension of active zinc powder 13 g, 0.20 mol
  • a 1.0 M titanium tetrachloride dichloromethane solution (0.10 L, 0.10 mol)
  • pivalonitrile 40 mL, 0 .40 mol
  • a dichloromethane solution (50 mL, 50 mmol) of 1.0 M titanium tetrachloride was added to a dichloromethane (0.20 L) suspension of active zinc powder (6.5 g, 0.10 mol) prepared by the same method as in Production Example 1. After that, pivalonitrile (22 mL, 0.20 mol) was slowly added dropwise at 0°C. After stirring the reaction suspension for another 30 minutes at room temperature, a solution of 4-heptanone (7.0 mL, 50 mmol) in dichloromethane (0.15 L) was slowly added dropwise at 0°C.
  • reaction mixture was stirred at room temperature for 16 hours, and saturated aqueous ammonium chloride solution was added at room temperature to quench the reaction.
  • Tetrahydroxydiboron (0.38 g, 4.2 mmol), 3,4-diethylhexane-3,4-diol (1.5 g, 8.4 mmol) and potassium acetate (1.0 g, 11 mmol) were added under a nitrogen stream. Diluted in toluene (40 mL) and heated to reflux using a Dean-Stark apparatus for 16 hours. Thereafter, the reaction mixture was allowed to cool to room temperature, filtered through celite, and the solvent was distilled off to obtain 4,4,4',4',5,5,5',5'-octaethyl-2,2'.
  • Examples I-1 to I-21 (synthesis of compounds (I-1) to (I-21)) (Manufacturing method 1) General method for producing 3,4-diethylhexane-3,4-diol ester of boronic acid (1) Under a nitrogen stream, a dichloromethane suspension (0.10 M) of arylboronic acid (boronic acid group: 1.0 mol) and 3,4-diethylhexane-3,4-diol (1.0 mol) was prepared at room temperature for 16 hours. After stirring, water was added to stop the reaction. The reaction mixture was extracted three times with dichloromethane and dried over anhydrous magnesium sulfate.
  • trimethoxyborane (2.0 mol) was added dropwise, and after stirring overnight at room temperature, a saturated aqueous ammonium chloride solution was added to stop the reaction.
  • the reaction mixture was extracted three times with ethyl acetate and dried over anhydrous magnesium sulfate. After distilling off the solvent, 3,4-diethylhexane-3,4-diol (1.0 mol) and dichloromethane were added to the residue, and the mixture was stirred at room temperature.
  • the resulting reaction solution was diluted with ethyl acetate, filtered through silica gel, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3,4-diethylhexane-3,4-diol ester of arylboronic acid.
  • Examples I-1 to I-21 were synthesized according to or according to Production Method 1, Production Method 2, or Production Method 3.
  • Tables 1-1 to 1-5 below show the chemical structure, yield and physical property data of each example compound.
  • Test example 1 Stability evaluation of compound (I) against silica gel chromatography
  • Comparison of compound (I-1), compound (I-18) and compound (I-19) with phenylboronic acid pinacol ester (Comparative Example 1)
  • Experiment 100 mg each of pure compound (I-1), compound (I-18), compound (I-19) and phenylboronic acid pinacol ester (Comparative Example 1) were separately added to an eggplant flask as test compounds. It was dissolved in dichloromethane (1.0 mL) and silica gel (about 600 mg) was added. The solvent was distilled off from this suspension under reduced pressure using an evaporator, and the test compound was adsorbed onto silica gel (from mixing to adsorption within about 5 minutes).
  • Test example 2 Stability evaluation of compound (I) against deprotection reaction conditions of pinacol ester Pinacol ester of p-tolylboronic acid (Comparative Example 7) is usually prepared in a mixed solvent of THF-water under acidic conditions of hydrochloric acid (1N hydrochloric acid), It was deprotected by sodium iodate and converted to arylboronic acid (yield: 62%). When compound (I-2) was subjected to the same deprotection conditions, deprotection hardly proceeded and compound (I-2) was recovered in a yield of 87%. In addition, it was confirmed to be stable under acidic conditions (acidic conditions with hydrochloric acid) and basic conditions (in the presence of sodium hydroxide and lithium hydroxide).
  • Test Example 3 (various functionalization reactions using compound (I)) [1] Suzuki-Miyaura coupling reaction using compound (I) (manufacturing method 4) Compound (I) (boryl group: 1.5 mol), aryl halide (Compound (VII)) (1.0 mol), palladium acetate (1.0 mol%), SPhos (2. 0 mol %) and a toluene/water (10/1) solution (1.0 M) of tripotassium phosphate (2.0 mol) were heated at 110° C. and stirred for 24 hours.
  • Compound (I) (boryl group: 1.5 mol), aryl halide (Compound (VII)) (1.0 mol), palladium acetate (1.0 mol%), SPhos (2. 0 mol %) and a toluene/water (10/1) solution (1.0 M) of tripotassium phosphate (2.0 mol) were heated at 110° C. and stirred for 24 hours.
  • the present invention it is possible to provide a novel aromatic boronic ester that is extremely stable without being decomposed or adsorbed even on silica gel column chromatography or thin layer chromatography, and that can be easily isolated and purified. .
  • the compound of the present invention exhibits reactivity equivalent to or superior to that of the conventionally widely used aromatic boronic acid pinacol ester, it can be applied to Suzuki-Miyaura coupling reactions and various functionalization reactions. and is extremely useful as a raw material compound or synthetic intermediate for various pharmaceuticals and functional materials.

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Abstract

L'invention vise à fournir un nouvel ester d'acide boronique aromatique qui est utile dans divers types de fonctionnalisation et peut être isolé et purifié sans être adsorbé même dans une chromatographie sur gel de silice.　La présente invention concerne un composé représenté par la formule (I) : [dans la formule, chaque symbole est tel que décrit dans la description], ou un sel de celui-ci, et son procédé de production.
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CN116655674A (zh) * 2023-01-16 2023-08-29 中国科学院兰州化学物理研究所 一种合成高丰度硼10同位素的联硼酸酯的方法
CN116655674B (zh) * 2023-01-16 2024-04-16 中国科学院兰州化学物理研究所 一种合成高丰度硼10同位素的联硼酸酯的方法

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