JP6444054B2 - Method for producing organoboron compound - Google Patents

Description

  The present invention relates to a method for producing an organic boron compound by replacing a halogeno group of an organic halogen compound with boron derived from a pinacolboryl group.

  Aryl boronic acid esters such as pinacolate have a wide range of applications in synthetic reactions such as carbon-carbon bond reactions, carbon-nitrogen bond reactions, and carbon-oxygen bond reactions, and are highly stable to water and air and can be handled easily. Since it is easy, it is very useful as a reagent for organic synthesis reaction.

  Conventionally, as a general method for synthesizing an aryl boronic acid ester, a method of reacting a trialkyl boronic acid ester with aryl Grignard or aryl lithium as a reaction reagent is known (Non-patent Document 1). Since it is strongly basic and strongly nucleophilic, it reacts with substituents other than the target group, and the range of applicable substrates is narrow. Further, when aryllithium is used, it is necessary to perform the reaction at a low temperature such as −78 ° C., which is not a method that can be used simply.

  Therefore, at present, in order to broaden the applicability of the substrate, a boronation method of an aryl halide using a transition metal and a boronation method (C-B) method of an aromatic C—H bond are widely studied (Non-patent Document 2). However, since these methods are reactions using transition metals, there are problems such as expensive reagents and contamination of reaction products with heavy metals. In particular, there is a problem that mixing of heavy metals is not suitable for pharmaceuticals.

  Therefore, it has been desired to develop a method for producing an aryl boronic acid ester that does not have the above-described problems, and in particular, does not use heavy metals and has a wide range of applicable substrates.

Brown, H. C .; Srebnik, M .; Cole, T. E. Organometallics, 1986, 5, 2300. Ishiyama, T. and Miyaura, N. (2011) Chapter 2, in Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, 2nd Ed. Vol. 1 (ed. Hall, D. G.), Wiley-VCH Verlag GmbH, Weinheim

  As a result of intensive studies to solve the above problems, the present inventors have found that when an aryl halide and a silyl boronic acid ester are reacted in the presence of sodium alkoxide or potassium alkoxide, the aryl boronic acid ester is obtained without using a heavy metal. It has been found that it can be efficiently produced and reacts with various aryl halides (a wide range of applicable substrates), and the present invention has been completed.

（式中、Xは臭素原子又はヨウ素原子を表し、Rは、炭素数１〜２０のアルキル基、炭素数２〜２０のアルケニル基、炭素数２〜２０のアルキニル基、炭素数６〜１４のアリール基、或いは、窒素原子、酸素原子及び硫黄原子から選ばれる異性原子を１〜３個含む複素環基を表し、これらの基は、炭素数１〜６のアルキル基、炭素数２〜６のアルケニル基、炭素数１〜６のアルコキシ基、炭素数２〜７のアルコキシカルボニル基、炭素数２〜６のアルケニルオキシ基、炭素数２〜１２のアルキルカルバモイル基、炭素数６〜１４のアリール基、フルオロ基、クロロ基、又は炭素数２〜１２のアルキルアミノ基を置換基として有していてもよい。）と、下記一般式（VI）で示される化合物

（式中、３個のR³はそれぞれ独立して、炭素数１〜６のアルキル基又は炭素数６〜１０のアリール基を表し、４個のR⁴はそれぞれ独立して、炭素数１〜３のアルキル基を表す。）とを、ナトリウムアルコキシド又はカリウムアルコキシドの存在下で反応させることを特徴とする、下記一般式（VII）で示される化合物

（式中、R及びR⁴は、上記と同じ。）の製造方法」に関する。 That is, the present invention provides an “organic halogen compound represented by the following general formula (V):

(In the formula, X represents a bromine atom or an iodine atom, and R represents an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, or 6 to 14 carbon atoms. Represents an aryl group or a heterocyclic group containing 1 to 3 isomeric atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and these groups are an alkyl group having 1 to 6 carbon atoms and an alkyl group having 2 to 6 carbon atoms. An alkenyl group, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkylcarbamoyl group having 2 to 12 carbon atoms, and an aryl group having 6 to 14 carbon atoms , A fluoro group, a chloro group, or an alkylamino group having 2 to 12 carbon atoms as a substituent.) And a compound represented by the following general formula (VI)

(In the formula, three R ^{3 s} each independently represent an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms, and four R ^{4 s} each independently represent one to 1 carbon atoms. And a compound represented by the following general formula (VII), wherein the compound is reacted in the presence of sodium alkoxide or potassium alkoxide:

(Wherein R and R ⁴ are the same as above).

  Since the production method of the present invention does not require the use of heavy metals such as palladium unlike the conventional method for producing diol boron compounds (boron substitution reaction method), it is difficult for the products to be mixed with heavy metals or to be colored. This is a suitable method for the production of pharmaceuticals. In addition, since the reaction proceeds under mild conditions, there is no need for heating at a temperature close to 100 ° C. or cooling at a temperature lower than 0 ° C., so there is an advantage that the operation is easy and a new method useful for scale-up synthesis. It is. That is, the production method of the present invention is a simple method that solves the problems of the conventional methods.

  Furthermore, since the production method of the present invention has low reactivity with substituents other than bromine atoms or iodine atoms, it can be applied to substrates having various substituents.

It is the graph showing the change of the yield by reaction time of the phenylboronic acid pinacol ester obtained in Example 30 and Comparative Examples 12-22.

[Organic halogen compound represented by general formula (V)]
X in the general formula (V) represents a bromine atom or an iodine atom, and is preferably a bromine atom.
The alkyl group having 1 to 20 carbon atoms of R in the general formula (V) may be linear, branched or cyclic, but is preferably linear or branched. 1-10 are preferable, as for carbon number, 1-6 are more preferable, and carbon number 1-3 are especially preferable. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group Tert-pentyl group, neopentyl group, 2-methylbutyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, neohexyl group, 2-methylpentyl group, 3-methyl Pentyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, n-heptyl group, isoheptyl group, sec-heptyl group, tert-heptyl group, neoheptyl group, 2-methylhexyl group, 3-methylhexyl group, 2,2-dimethylpentyl group, 3-ethylpentyl group, 2,4-dimethylpentyl group, 1-ethyl-1-methylbutyl group, 1,2,3-trimethyl Butyl group, n-octyl group, iso Octyl, sec-octyl, tert-octyl, neooctyl, n-nonyl, isononyl, sec-nonyl, tert-nonyl, neononyl, n-decyl, isodecyl, sec-decyl, tert-decyl group, neodecyl group, n-undecyl group, isoundecyl group, sec-undecyl group, tert-undecyl group, neoundecyl group, n-dodecyl group, isododecyl group, sec-dodecyl group, tert-dodecyl group, neododecyl group, n-tridecyl group, isotridecyl group, sec-tridecyl group, tert-tridecyl group, neotridecyl group, n-tetradecyl group, isotetradecyl group, sec-tetradecyl group, tert-tetradecyl group, neotetradecyl group, n-pentadecyl group , Isopentadecyl group, sec-pentadecyl group, tert-pentadecyl group, neopentadecyl group, n-hexadecyl group, isohexadecyl group, sec-he Xadecyl, tert-hexadecyl, neohexadecyl, n-heptadecyl, isoheptadecyl, sec-heptadecyl, tert-heptadecyl, neoheptadecyl, n-octadecyl, isooctadecyl, sec-octadecyl, tert- Octadecyl group, neooctadecyl group, n-nonadecyl group, isononadecyl group, sec-nonadecyl group, tert-nonadecyl group, neodecyl group, n-icosyl group, isoicosyl group, sec-icosyl group, tert-icosyl group, neoicosyl group, cyclo Propyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cycloundecyl group, cyclododecyl group, and the like, such as methyl group, ethyl group, n-propyl group, Isopropyl group, n-butyl group, isobutyl group, sec- Tyl group, tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, 2-methylbutyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, sec- Hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, cyclo A propyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group are preferable, and a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are more preferable.
The alkyl group having 1 to 20 carbon atoms of R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, Substituent selected from C2-C6 alkenyloxy group, C2-C12 alkylcarbamoyl group, C6-C14 aryl group, fluoro group, chloro group, and C2-C12 alkylamino group However, those having an aryl group having 6 to 14 carbon atoms as a substituent or unsubstituted are preferable.

The alkenyl group having 2 to 20 carbon atoms of R in the general formula (V) may be linear, branched or cyclic, but is preferably linear. 2-10 are preferable and, as for carbon number, 2-6 are more preferable. Specifically, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group, 1,2-dimethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-2-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 5-heptenyl group, 6-heptenyl group, 1 -Octenyl, 2-octenyl, 1-nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosenyl, 1-cycl Butenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group and the like, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2 -Methylallyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 5- Hexenyl group, 2-methyl-2-pentenyl group, 1-cyclobutenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group are preferable, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group 2-butenyl group, 3-butenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group, 1 , 2-dimethyl-2-propenyl group, 1-hexenyl group, 2-hexyl More preferred are senyl group, 3-hexenyl group, 5-hexenyl group and 2-methyl-2-pentenyl group, more preferred are vinyl group, allyl group and 1,2-dimethyl-2-propenyl group, and 1,2-dimethyl group. A 2-propenyl group is particularly preferred.
The alkenyl group having 2 to 20 carbon atoms of R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, Substituent selected from C2-C6 alkenyloxy group, C2-C12 alkylcarbamoyl group, C6-C14 aryl group, fluoro group, chloro group, and C2-C12 alkylamino group However, an unsubstituted one is preferable.

The alkynyl group having 2 to 20 carbon atoms of R in the general formula (V) may be linear or branched, but is preferably linear. 2-10 are preferable and, as for carbon number, 2-6 are more preferable. Specifically, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2- Pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 2-methyl -4-heptynyl group, 1-heptynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 5-heptynyl group, 6-heptynyl group, 1-octynyl group, 2- Octynyl group, 3-octynyl group, 4-octynyl group, 5-octynyl group, 6-octynyl group, 7-octynyl group, 1-noninyl group, 2-noninyl group, 3-noninyl group, 4-noninyl group, 5- Noninyl group, 6-noninyl group, 7-noninyl group, 8-noninyl group, 1-decynyl group, 3-decynyl group, 5-decynyl group, 7-decynyl group, 9 -Decynyl group, 1-undecynyl group, 3-undecynyl group, 5-undecynyl group, 7-undecynyl group, 9-undecynyl group, 1-dodecynyl group, 3-dodecynyl group, 5-dodecynyl group, 7-dodecynyl group, 9 -Dodecynyl group, 11-dodecynyl group, tridecynyl group, tetradecynyl group, pentadecynyl group, hexadecynyl group, heptadecynyl group, octadecynyl group, nonadecynyl group, icosinyl group and the like, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-3- Butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 2-methyl-4-heptynyl group, 1-heptynyl group, 2-heptynyl group, 3-heptyl Nyl group, 4-heptynyl group, 5-heptynyl group, 6-heptynyl group, 1-octynyl group, 2-octynyl group, 3-octynyl group, 4-octynyl group, 5-octynyl group, 6-octynyl group 7-octynyl group, 1-noninyl group, 2-noninyl group, 3-noninyl group, 4-noninyl group, 5-noninyl group, 6-noninyl group, 7-noninyl group, 8-noninyl group, 1-decynyl group , 3-decynyl group, 5-decynyl group, 7-decynyl group and 9-decynyl group are preferred, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group and 3-butynyl group 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group, 3 More preferred are -hexynyl group, 4-hexynyl group and 5-hexynyl group.
The alkynyl group having 2 to 20 carbon atoms of R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, Substituent selected from C2-C6 alkenyloxy group, C2-C12 alkylcarbamoyl group, C6-C14 aryl group, fluoro group, chloro group, and C2-C12 alkylamino group However, an unsubstituted one is preferable.

Examples of the aryl group having 6 to 14 carbon atoms of R in the general formula (V) include a phenyl group, a naphthyl group, and an anthracenyl group.
The aryl group having 6 to 14 carbon atoms of R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, Substituent selected from C2-C6 alkenyloxy group, C2-C12 alkylcarbamoyl group, C6-C14 aryl group, fluoro group, chloro group, and C2-C12 alkylamino group The alkyl group having 1 to 6 carbon atoms, the alkenyl group having 2 to 6 carbon atoms, the alkoxy group having 1 to 6 carbon atoms, the alkoxycarbonyl group having 2 to 7 carbon atoms, and 2 to 2 carbon atoms. Preferred are those having a substituent selected from an alkenyloxy group having 6 carbon atoms, an alkylcarbamoyl group having 2 to 12 carbon atoms, a fluoro group, a chloro group, and an alkylamino group having 2 to 12 carbon atoms, or unsubstituted. .

  As the heterocyclic group containing 1 to 3 isomeric atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom of R in the general formula (V), it may have aromaticity, usually 3 to 20 members. And preferably a group derived from a 3 to 14-membered, more preferably 5 to 10-membered monocyclic heterocyclic ring or polycyclic heterocyclic ring. In the case of a group derived from a monocyclic heterocyclic ring, those having 5 to 6 members are preferable, and in the case of a group derived from a polycyclic heterocyclic ring, those having 9 to 10 members, particularly 9 members are preferable. Groups derived from cyclic heterocycles are preferred. These may be condensed in a chain, branched or cyclic form, and they may have a planar structure or a three-dimensional structure.

  The group derived from the heterocyclic ring generally has 1 to 3, preferably 1 to 2, more preferably 1 nitrogen atom, oxygen atom or sulfur atom, and among these, those having a nitrogen atom are preferable.

  Examples of the monocyclic heterocycle include 3-membered heterocycles having one heteroatom such as an oxirane ring and an aziridine ring, such as a furan ring, a thiophene ring, a pyrrole ring, a 2H-pyrrole ring, a pyrroline ring, and a 2-pyrroline ring. , 5-membered heterocycle having one heteroatom such as pyrrolidine ring, such as 1,3-dioxolane ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, imidazoline ring, 2-imidazoline ring, imidazole 5-membered heterocycle having two heteroatoms such as lysine ring, pyrazole ring, pyrazoline ring, 3-pyrazolin ring and pyrazolidine ring, for example, three heteroatoms such as furazane ring, triazole ring, thiadiazole ring and oxadiazole ring 5-membered heterocyclic ring having, for example, pyran ring, 2H-pyran ring, pyridine ring, piperidine ring, etc. 6-membered heterocycle having 1 heteroatom, for example, 6-membered heterocycle having 2 heteroatoms such as thiopyran ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperazine ring, morpholine ring, 1,2,4-triazine ring 6-membered heterocycle having 3 heteroatoms such as

  Examples of the polycyclic heterocycle include those obtained by condensing 2 to 3 monocyclic heterocycles or monocyclic heterocycles and 1 to 2 aromatic rings such as benzene ring and naphthalene ring. And bicyclic heterocycles, tricyclic heterocycles, and the like.

  Examples of the bicyclic heterocyclic ring include benzofuran ring, isobenzofuran ring, 1-benzothiophene ring, 2-benzothiophene ring, indole ring, 3-indole ring, isoindole ring, indolizine ring, indoline ring, isoindoline. Heterocycles having one heteroatom such as a ring, 2H-chromene ring, chroman ring, isochroman ring, 1H-2-benzopyran ring, quinoline ring, isoquinoline ring, 4H-quinolidine ring, such as benzoimidazole ring, benzothiazole ring, Heterocycles having two heteroatoms such as 1H-indazole ring, 1,8-naphthyridine ring, quinoxaline ring, quinazoline ring, quinazolidine ring, cinnoline ring, phthalazine ring, for example, four heteroatoms such as purine ring and pteridine ring The heterocyclic ring etc. which have are mentioned.

  Examples of the tricyclic heterocycle include heterocycles having one heteroatom such as carbazole ring, 4aH-carbazole ring, xanthene ring, phenanthridine ring, acridine ring, such as β-carboline ring, perimidine ring, 1, Examples include 7-phenanthroline ring, 1,10-phenanthroline ring, thianthrene ring, phenoxathiin ring, phenoxazine ring, phenothiazine ring, and heterocycle having two heteroatoms such as phenazine ring.

Preferred examples of the heterocyclic group containing 1 to 3 isomeric atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom of R in the general formula (V) include a group derived from the above monocyclic heterocyclic ring and the above bicyclic ring. Examples thereof include a group derived from a system heterocycle, among which an indole ring, isoindole ring, indoline ring, isoindoline ring, quinoline ring, isoquinoline ring, 4H-quinolidine ring and the like are preferable.
The heterocyclic group containing 1 to 3 isomeric atoms selected from the nitrogen atom, oxygen atom and sulfur atom of R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and 1 to 6 carbon atoms. An alkoxy group having 2 to 7 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkylcarbamoyl group having 2 to 12 carbon atoms, an aryl group having 6 to 14 carbon atoms, a fluoro group, a chloro group, and Although it may have a substituent selected from an alkylamino group having 2 to 12 carbon atoms, one having an alkyl group having 1 to 6 carbon atoms as a substituent or an unsubstituted one is preferable.

  The alkyl group having 1 to 6 carbon atoms, which is a substituent of R in the general formula (V), may be linear, branched or cyclic, and preferably has 1 to 4 carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group Tert-pentyl group, neopentyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, neohexyl group, etc., including methyl group, ethyl group, n-propyl group, isopropyl group, n- A butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like are preferable.

  The alkenyl group having 2 to 6 carbon atoms which is a substituent of R in the general formula (V) may be linear, branched or cyclic, and preferably has 2 to 4 carbon atoms. Specifically, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methylallyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 5-hexenyl group, 2-methyl-2-pentenyl group, 1- And cyclobutenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group, etc., vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2 -A methyl allyl group etc. are preferable.

  The alkoxy group having 1 to 6 carbon atoms which is a substituent of R in the general formula (V) may be linear, branched or cyclic, and preferably has 1 to 4 carbon atoms. Specifically, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, sec-pentyloxy group, tert-pentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, sec-hexyloxy group, tert-hexyloxy group, neohexyloxy group, etc. Group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like are preferable.

The alkoxycarbonyl group having 2 to 7 carbon atoms, which is a substituent of R in the general formula (V),
It may be linear, branched or cyclic, and preferably has 2 to 5 carbon atoms. Specifically, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n- Pentyloxycarbonyl group, isopentyloxycarbonyl group, sec-pentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, n-hexyloxycarbonyl group, isohexyloxycarbonyl group, sec-hexyloxycarbonyl group Tert-hexyloxycarbonyl group, neohexyloxycarbonyl group, etc., methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxy Aryloxycarbonyl group, sec- butoxycarbonyl group, etc. tert- butoxycarbonyl group are preferred.

  The alkenyloxy group having 2 to 6 carbon atoms which is a substituent of R in the general formula (V) may be linear, branched or cyclic, and preferably has 2 to 4 carbon atoms. Specifically, for example, vinyloxy group, allyloxy group, 1-propenyloxy group, isopropenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 2-methylallyloxy group, 1-pentenyloxy group 2-pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 2-methyl-2-butenyloxy group, 1-hexenyloxy group, 2-hexenyloxy group, 3-hexenyloxy group, 5-hexenyloxy group Group, 2-methyl-2-pentenyloxy group, 1-cyclobutenyloxy group, 1-cyclopentenyloxy group, 1-cyclohexenyloxy group and the like, vinyloxy group, allyloxy group, 1-propenyloxy group, An isopropenyloxy group, a 1-butenyloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a 2-methylallyloxy group, and the like are preferable.

As the alkyl carbamoyl group having 2 to 12 carbon atoms which is a substituent of R in the general formula (V), two hydrogen atoms of the carbamoyl (—CONH ₂ ) group have 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. Specific examples include N, N-methylethylcarbamoyl group, N, Nn-methylpropylcarbamoyl group, N, N-methylisopropylcarbamoyl group, N, N-methyl, and the like. -n-butylcarbamoyl group, N, N-methyl-tert-butylcarbamoyl group, N, N-methyl-n-hexylcarbamoyl group, N, N-methylcyclohexylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dicyclohexylcarbamoyl group and the like can be mentioned.

  As a C6-C14 aryl group which is a substituent of R in General formula (V), a phenyl group, a naphthyl group, an anthracenyl group etc. are mentioned, for example.

As a C2-C12 alkylamino group which is a substituent of R in General formula (V), _two hydrogen atoms of an amino group (-NH2) are C1-C6, Preferably C1-C3 Specifically, for example, N, N-methylethylamino group, N, N-methyl-n-propylamino group, N, N-methylisopropylamino group, N, N-methyl-n-butylamino group, N, N-methyl-tert-butylamino group, N, N-methyl-n-hexylamino group, N, N-methylcyclohexylamino group, N, N-methylethylamino Group, N, N-dicycloamino group, N, N-dimethylamino group and the like.

  R in the general formula (V) may have an aryl group having 6 to 14 carbon atoms as a substituent, an alkyl group having 1 to 20 carbon atoms; an alkenyl group having 2 to 20 carbon atoms; An alkynyl group; an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, C6-C14 which may have a C2-C12 alkylcarbamoyl group, a C6-C14 aryl group, a fluoro group, a chloro group, or a C2-C12 alkylamino group as a substituent. Or a heterocyclic group optionally having as a substituent an alkyl group having 1 to 6 carbon atoms containing 1 to 3 isomeric atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples of these include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, sec- Pentyl group, tert-pentyl group, neopentyl group, 2-methylbutyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, neohexyl group, 2-methylpentyl group, 3 -Methylpentyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenylmethyl group, phenylethyl Group, phenyl-n-propyl group, phenyl-n-butyl group, phenyl-n-pentyl group, phenyl-n-hexyl group, vinyl group, allyl group, 1-propenyl group, iso Lopenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-butenyl Group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 5-hexenyl group, 2-methyl-2-pentenyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2 -Butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 1-hexynyl Group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, phenyl group, naphthyl group, anthracenyl group, group derived from indole ring, group derived from isoindole ring, group derived from indoline ring, Group derived from isoindoline ring, group derived from quinoline ring, iso Norin ring-derived group, 4H-quinolidine ring-derived group, N-methylindole ring-derived group, N-ethylindole ring-derived group, Nn-propylindole ring-derived group, N-methylisoindole ring-derived group , Group derived from N-ethylisoindole ring, group derived from Nn-propylisoindole ring, methylphenyl group, dimethylphenyl group, trimethylphenyl group, ethylphenyl group, propylphenyl group, tripropylphenyl group, triisopropylphenyl group Allylphenyl group, 1-propenylphenyl group, methoxyphenyl group, ethoxyphenyl group, propoxyphenyl group, methoxycarbonylphenyl group, ethoxycarbonylphenyl group, propoxycarbonylphenyl group, butoxycarbonylphenyl group, allyloxyphenyl group, 1- Propenyloxyphenyl , Dimethylcarbamoyl phenyl group, diethylcarbamoyl phenyl group, dipropylcarbamoylphenyl group, fluorophenyl group, chlorophenyl group, dimethylaminophenyl group, diethylaminophenyl group, dipropylamino and a phenyl group.

（式中、Xは臭素原子又はヨウ素原子を表し、ｐ₁は０〜５の整数を表し、ｐ₁個のR¹は、それぞれ独立して炭素数１〜６のアルキル基、炭素数２〜６のアルケニル基、炭素数１〜６のアルコキシ基、炭素数２〜７のアルコキシカルボニル基、炭素数２〜６のアルケニルオキシ基、炭素数２〜１２のアルキルカルバモイル基、炭素数６〜１４のアリール基、フルオロ基、クロロ基、又は炭素数２〜１２のアルキルアミノ基を表す。）、下記一般式（II）で示される化合物

（式中、X及びR^１は上記と同じ。ｐ₂は０〜７の整数を表す。）、下記一般式（III）で示される化合物

（式中、X及びR^１は上記と同じ。ｐ₃は０〜９の整数を表す。）、下記一般式（IV）で示される化合物

（式中、Xは上記と同じ。R²は炭素数１〜６のアルキル基を表す。）、炭素数６〜１４のアリール基を置換基として有する又は無置換の炭素数１〜２０のアルキルブロマイド、炭素数６〜１４のアリール基を置換基として有する又は無置換の炭素数１〜２０のアルキルヨード、炭素数２〜２０のアルケニルブロマイド、炭素数２〜２０のアルケニルヨード、炭素数２〜２０のアルキニルブロマイド、或いは、炭素数２〜２０のアルキニルヨード等が挙げられる。これらの中でも、一般式（I）で示される化合物、一般式（III）で示される化合物、一般式（IV）で示される化合物、炭素数６〜１４のアリール基を置換基として有する又は無置換の炭素数１〜２０のアルキルブロマイド、炭素数２〜２０のアルケニルブロマイドが好ましく、一般式（I）で示される化合物が特に好ましい。 As the organic halogen compound represented by the general formula (V), a compound represented by the following general formula (I)

(In the formula, X represents a bromine atom or an iodine atom, p ₁ represents an integer of 0 to 5, and p ₁ R ^{1 s} are each independently an alkyl group having 1 to 6 carbon atoms or 2 to 2 carbon atoms. 6 alkenyl groups, alkoxy groups having 1 to 6 carbon atoms, alkoxycarbonyl groups having 2 to 7 carbon atoms, alkenyloxy groups having 2 to 6 carbon atoms, alkylcarbamoyl groups having 2 to 12 carbon atoms, and 6 to 14 carbon atoms An aryl group, a fluoro group, a chloro group, or an alkylamino group having 2 to 12 carbon atoms), a compound represented by the following general formula (II)

(Wherein X and R ¹ are the same as described above; p ₂ represents an integer of 0 to 7), a compound represented by the following general formula (III)

(Wherein X and R ¹ are the same as described above; p ₃ represents an integer of 0 to 9), a compound represented by the following general formula (IV)

(In the formula, X is the same as above. R ² represents an alkyl group having 1 to 6 carbon atoms.), An aryl group having 6 to 14 carbon atoms as a substituent or an unsubstituted alkyl group having 1 to 20 carbon atoms. Bromide, C6-C14 aryl group as a substituent or unsubstituted alkyl iodo having 1 to 20 carbon atoms, C2-C20 alkenyl bromide, C2-C20 alkenyl iodide, C2-C2 Examples thereof include 20 alkynyl bromides or alkynyl iodides having 2 to 20 carbon atoms. Among these, the compound represented by the general formula (I), the compound represented by the general formula (III), the compound represented by the general formula (IV), an aryl group having 6 to 14 carbon atoms as a substituent or unsubstituted 1 to 20 alkyl bromide and C 2 to C 20 alkenyl bromide are preferred, and the compound represented by formula (I) is particularly preferred.

P < ₁ > in general formula (I) is an integer of 0-5, 0-3 are preferable and 0 or 1 is more preferable.

R ¹ in the general formula (I), an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, 2 carbon atoms Specific examples and preferred examples of -6 alkenyloxy groups, C2-C12 alkylcarbamoyl groups, C6-C14 aryl groups, and C2-C12 alkylamino groups are given in general formula (V): The same thing as what was described as a substituent of R is mentioned.

Specific examples of the compound represented by the general formula (I) include the following compounds, among which bromide compounds are preferable.

P < ₂ > in general formula (II) is an integer of 0-7, 0-3 are preferable and 0 is more preferable.

Specific examples and preferred examples of R ¹ in formula (II) are the same as those for R ¹ in formula (I).

  Preferred examples of the compound represented by the general formula (II) include those in which the phenylene group in the general formula I is substituted with a naphthylene group, among which bromonaphthylene or iodonaphthylene is preferable, and bromonaphthylene is particularly preferable.

P < ₃ > in general formula (III) is an integer of 0-9, 0-3 are preferable and 0 is more preferable.

Specific examples and preferred examples of R ¹ in the general formula (III) are the same as those for R ¹ in the general formula (I).

  Preferred examples of the compound represented by the general formula (III) include those in which the phenylene group in the general formula I is substituted with an anthracenylene group. Among them, bromoanthracene or iodoanthracene is preferable, and bromoanthracene is particularly preferable.

Examples of the alkyl group having 1 to 6 carbon atoms of R ² in the general formula (IV) include the same as the alkyl group having 1 to 6 carbon atoms which is the substituent of R in the general formula (V). The preferred ones are the same.

  Preferable examples of the compound represented by the general formula (IV) include the following, among which bromide compounds are preferable.

  As a C1-C14 aryl group which has a C6-C14 aryl group as a substituent, or an unsubstituted C1-C20 alkyl bromide, it has a C6-C14 aryl group as a substituent, or is unsubstituted C1-C10 Alkyl bromide is preferable, and an aryl bromide having 6 to 14 carbon atoms as a substituent or an unsubstituted alkyl bromide having 1 to 6 carbon atoms is more preferable. Examples of the aryl group as the substituent include a phenyl group, a naphthyl group, and an anthracenyl group, and a phenyl group is preferable.

  Preferable specific examples of the alkyl bromide having an aryl group having 6 to 14 carbon atoms as a substituent or an unsubstituted alkyl group having 1 to 20 carbon atoms include, for example, methyl bromide, ethyl bromide, n-propyl bromide, isopropyl bromide, and n-butyl. Bromide, isobutyl bromide, sec-butyl bromide, tert-butyl bromide, n-pentyl bromide, isopentyl bromide, sec-pentyl bromide, tert-pentyl bromide, neopentyl bromide, 2-methylbutyl bromide, 1-ethylpropyl bromide, n-hexyl bromide, isohexyl bromide, sec-hexyl bromide, tert-hexyl bromide, neohexyl bromide, 2-methylpentyl bromide, 3-methylpentyl bromide, 1,2-dimethylbutyl bromide, 2,2-dimethyl Tyl bromide, 1-ethylbutyl bromide, 2-ethylbutyl bromide, cyclopropyl bromide, cyclobutyl bromide, cyclopentyl bromide, cyclohexyl bromide, phenylmethyl bromide, phenylethyl bromide, phenyl-n-propyl bromide, phenylisopropyl bromide, phenyl- n-butyl bromide, phenyl isobutyl bromide, phenyl-sec-butyl bromide, phenyl-tert-butyl bromide, phenyl-n-pentyl bromide, phenyl isopentyl bromide, phenyl-sec-pentyl bromide, phenyl-tert-pentyl bromide, phenyl Neopentyl bromide, 4-phenyl-2-methylbutyl bromide, 3-phenyl-1-ethylpropyl bromide, phenyl-n-hexyl bromide, phen Ruisohexyl bromide, phenyl-sec-hexyl bromide, phenyl-tert-hexyl bromide, phenyl neohexyl bromide, 5-phenyl-2-methylpentyl bromide, 5-phenyl-3-methylpentyl bromide, 4-phenyl-1, 2-dimethylbutyl bromide, 4-phenyl-2,2-dimethylbutyl bromide, 4-phenyl-1-ethylbutyl bromide, 4-phenyl-2-ethylbutyl bromide, phenylcyclopropyl bromide, phenylcyclobutyl bromide, phenylcyclopentyl Bromide, phenylcyclohexyl bromide, etc., such as methyl bromide, ethyl bromide, n-propyl bromide, isopropyl bromide, phenyl methyl bromide, phenyl ethyl bromide, phenyl-n-propyl bromide, phenyl iso B pills bromide and the like are preferable, phenyl bromide, phenylethyl bromide, phenyl -n- propyl bromide, phenyl isopropyl bromide are preferred.

  As a C1-C14 aryl group which has a C6-C14 aryl group as a substituent, or an unsubstituted C1-C20 alkyl iodo, it has a C6-C14 aryl group as a substituent, or is unsubstituted C1-C10 And an alkyliodine having 1 to 6 carbon atoms as a substituent or an unsubstituted alkyliodine having 1 to 6 carbon atoms is more preferable. Examples of the aryl group as the substituent include a phenyl group, a naphthyl group, and an anthracenyl group, and a phenyl group is preferable.

  Preferable specific examples of the alkyliodine having a C6-C14 aryl group as a substituent or unsubstituted C1-C20 include, for example, methyliodine, ethyliodide, n-propyliodine, isopropyliodide, n-butyliodine, isobutyl Iodo, sec-butyliodide, tert-butyliodine, n-pentyliodide, isopentyliodine, sec-pentyliodide, tert-pentyliodine, neopentyliodine, 2-methylbutyliodine, 1-ethylpropyliodine, n-hexyliodine, Isohexyl iodide, sec-hexyl iodide, tert-hexyl iodide, neohexyl iodide, 2-methylpentyl iodide, 3-methylpentyl iodide, 1,2-dimethylbutyl iodide, 2,2-dimethylbutyl iodide, 1-ethylbutyl Iodo, 2-ethylbutyliodide, cyclopropyliodine, cyclobutyliodine , Cyclopentyliodine, cyclohexyliodine, phenylmethyliodine, phenylethyliodine, phenyl-n-propyliodine, phenylisopropyliodine, phenyl-n-butyliodine, phenylisobutyliodine, phenyl-sec-butyliodine, phenyl-tert-butyliodine, phenyl- n-pentyliodine, phenylisopentyliodine, phenyl-sec-pentyliodine, phenyl-tert-pentyliodine, phenylneopentyliodine, 4-phenyl-2-methylbutyliodine, 3-phenyl-1-ethylpropyliodine, phenyl -n-hexyliodine, phenylisohexyliodine, phenyl-sec-hexyliodine, phenyl-tert-hexyliodine, phenylneohexyliodide, 5-phenyl-2-methylpentyliodide, 5-phenyl-3-methylpentyliodide, 4-phenyl-1,2-di Butylbutyl iodide, 4-phenyl-2,2-dimethylbutyliodide, 4-phenyl-1-ethylbutyliodide, 4-phenyl-2-ethylbutyliodine, phenylcyclopropyliodine, phenylcyclobutyliodine, phenylcyclopentyliodide, Phenyl cyclohexyl iodo etc. are mentioned.

  As a C2-C20 alkenyl bromide, a C2-C10 alkenyl bromide is preferable and a C2-C6 alkenyl bromide is more preferable. Preferred examples include vinyl bromide, allyl bromide, 1-propenyl bromide, isopropenyl bromide, 1-butenyl bromide, 2-butenyl bromide, 3-butenyl bromide, 2-methylallyl bromide, 1-pentenyl bromide. 2-pentenyl bromide, 3-pentenyl bromide, 4-pentenyl bromide, 2-bromo-3-methylbutene, 1-hexenyl bromide, 2-hexenyl bromide, 3-hexenyl bromide, 5-hexenyl bromide, 2-methyl-2- Examples include pentenyl bromide, 1-cyclobutenyl bromide, 1-cyclopentenyl bromide, 1-cyclohexenyl bromide, and 2-bromo-3-methylbutene is preferred.

  As a C2-C20 alkenyl iodide, a C2-C10 alkenyl iodide is preferable and a C2-C6 alkenyl iodine is more preferable. Preferable specific examples include, for example, vinyl iodide, allyl iodide, 1-propenyl iodide, isopropenyl iodide, 1-butenyl iodide, 2-butenyl iodide, 3-butenyl iodide, 2-methylallyl iodide, 1-pentenyl iodide, 2-pentenyl iodide, 3-pentenyl iodide, Pentenyliodine, 4-pentenyliodine, 2-methyl-2-butenyliodine, 1-hexenyliodine, 2-hexenyliodine, 3-hexenyliodine, 5-hexenyliodine, 2-methyl-2-pentenyliodine, 1-cyclobutenyl Examples include iodo, 1-cyclopentenyl iodo, 1-cyclohexenyl iodo and the like.

  As a C2-C20 alkynyl bromide, a C2-C10 alkynyl bromide is preferable and a C2-C6 alkynyl bromide is more preferable. Preferable specific examples include, for example, ethynyl bromide, 1-propynyl bromide, 2-propynyl bromide, 1-butynyl bromide, 2-butynyl bromide, 3-butynyl bromide, 1-methyl-2-propynyl bromide, 1-pentyl Nyl bromide, 2-pentynyl bromide, 3-pentynyl bromide, 4-pentynyl bromide, 1-methyl-3-butynyl bromide, 1-hexynyl bromide, 2-hexynyl bromide, 3-hexynyl bromide, 4 -Hexynyl bromide, 5-hexynyl bromide, 2-methyl-4-heptynyl bromide and the like.

  As a C2-C20 alkynyl iodide, a C2-C10 alkynyl iodine is preferable and a C2-C6 alkynyl iodine is more preferable. Preferable specific examples include, for example, ethynyl iodide, 1-propynyl iodide, 2-propynyl iodide, 1-butynyl iodide, 2-butynyl iodide, 3-butynyl iodide, 1-methyl-2-propynyl iodide, 1-pentynyl iodide, 2-pentyl iodide Nyliodo, 3-pentynyliodine, 4-pentynyliodine, 1-methyl-3-butynyliodine, 1-hexynyliodine, 2-hexynyliodine, 3-hexynyliodine, 4-hexynyliodine, 5-hexynyliodide, 2-methyl-4-to Putinyl iodine and the like can be mentioned.

  The organic halogen compound represented by the general formula (V) may be either a commercially available product or a product produced by a method known per se.

[Compound represented by formula (VI)]
The alkyl group having 1 to 6 carbon atoms of R ^{3 in} the compound represented by the general formula (VI) may be linear, branched or cyclic, preferably 1 to 3 carbon atoms, more preferably 1 carbon atom. Can be mentioned. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group Tert-pentyl group, neopentyl group, 2-methylbutyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, neohexyl group, 2-methylpentyl group, 3-methyl Examples include pentyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. Of these, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are preferable, and a methyl group is more preferable.

Examples of the aryl group having 6 to 10 carbon atoms of R ^{3 in} the compound represented by the general formula (VI) include a phenyl group and a naphthyl group.

The three R ³ groups may be the same or different, but are preferably composed of two different groups, for example, one is an aryl group and the remaining two are selected from an alkyl group. The same group or the same group in which one is an alkyl group and the remaining two are selected from an aryl group is preferable. More specifically, for example, a combination of one phenyl group and the remaining two methyl groups, one methyl group and the remaining two phenyl groups is preferable.

Examples of the alkyl group having 1 to 3 carbon atoms of R ^{4 in} the compound represented by the general formula (VI) include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and a methyl group is preferable. The four R ^{4 s} may be the same or different from each other, but all are preferably the same.

Preferred examples of the compound represented by the general formula (VI) include the following.

  The compound represented by the general formula (VI) may be either a commercially available product or a compound produced by a method known per se.

（式中、R及びR⁴は、上記と同じ。）
一般式（VII）におけるRの具体例及び好ましい具体例は、一般式（V）のRと同じものが挙げられる。 [Compound represented by formula (VII) according to the present invention]

(In the formula, R and R ⁴ are the same as above.)
Specific examples and preferred specific examples of R in the general formula (VII) include the same as R in the general formula (V).

Specific examples and preferred specific examples of R ⁴ in the general formula (VII) include the same as R ^{4 in the} general formula (VI).

（式中、Rは上記と同じ。） Specific examples of the compound represented by the general formula (VII) include the following general formulas [VI-1] to [VI-6], and [VI-1] is particularly preferable.

(In the formula, R is the same as above.)

[Sodium alkoxide or potassium alkoxide according to the present invention]
Examples of the sodium alkoxide according to the present invention include those having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specifically, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium Propoxide, sodium n-butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert-butoxide, sodium n-pentyl oxide, sodium isopentyl oxide, sodium sec-pentyl oxide, sodium tert-pentyl oxide, sodium neopentyl oxide, Examples include sodium n-hexyl oxide, sodium isohexyl oxide, sodium sec-hexyl oxide, sodium tert-hexyl oxide, sodium neohexyl oxide, sodium methoxide, sodium Tokishido, sodium n- propoxide, sodium isopropoxide, sodium n- butoxide, sodium tert- butoxide, and more preferably sodium methoxide.

  Examples of the potassium alkoxide according to the present invention include those having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and specifically include potassium methoxide, potassium ethoxide, potassium n-propoxide, potassium isopropanol. Propoxide, potassium n-butoxide, potassium isobutoxide, potassium sec-butoxide, potassium tert-butoxide, potassium n-pentyl oxide, potassium isopentyl oxide, potassium sec-pentyl oxide, potassium tert-pentyl oxide, potassium neopentyl oxide, Examples include potassium n-hexyl oxide, potassium isohexyl oxide, potassium sec-hexyl oxide, potassium tert-hexyl oxide, potassium neohexyl oxide, potassium methoxide, potassium ethoxide, potassium n-propoxide, potassium Isopropoxide, potassium n-butoxide, potassium tert-butoxide and the like are preferable.

[Production method of the compound represented by the general formula (VII) of the present invention (production method of the present invention)]
The production method of the present invention is performed by reacting the organic halogen compound represented by the general formula (V) with the compound represented by the general formula (VI) in the presence of sodium alkoxide or potassium alkoxide. As a result of this reaction, the bromine atom or iodine atom in the compound represented by the general formula (V) is substituted with the diol boron group in the compound represented by the general formula (VI), and the compound represented by the general formula (VII) Is manufactured.

  The amount of the compound represented by the general formula (VI) in the process for producing the compound represented by the general formula (VII) of the present invention is usually 1 to 5 equivalents, preferably with respect to the compound represented by the general formula (V). Is 1 to 2 equivalents, more preferably 1 to 1.5 equivalents, still more preferably 1.2 to 1.5 equivalents.

  The amount of sodium methoxide or potassium methoxide used in the process for producing the compound represented by the general formula (VII) of the present invention is usually 1 to 5 equivalents, preferably 1 with respect to the compound represented by the general formula (V). ˜2 equivalents, more preferably 1 to 1.5 equivalents, still more preferably 1 to 1.2 equivalents.

  The method for producing the compound represented by the general formula (VII) of the present invention is preferably carried out in an organic solvent. The organic solvent is preferably an ether solvent, and specific examples include diethyl ether, ethylene glycol diethyl ether, dibutyl ether, tert-butyl methyl ether, dioxane, dioxolane, dimethoxyethane, diethoxyethane, tetrahydrofuran and the like. It is done. Of these, dimethoxyethane, tetrahydrofuran and dioxane are preferred. The amount of the organic solvent to be used is generally 1 to 50 mL, preferably 1 to 10 mL, more preferably 5 to 10 mL with respect to 1 mmol of the compound represented by the general formula (V).

  The reaction temperature in the production method of the compound represented by the general formula (VII) of the present invention is usually 0 to 100 ° C, preferably 20 to 60 ° C, more preferably 20 to 40 ° C. Reaction time should just be time for which all the compounds shown by general formula (V) react, and are 0.5 to 5 hours normally, Preferably it is 0.5 to 3 hours, More preferably, it is 1-2 hours.

  Specific examples of the method for producing the compound represented by the general formula (VII) of the present invention include 1 to the compound represented by the general formula (V) and the compound represented by the general formula (V). 2 equivalents of the compound represented by the general formula (VI) in the presence of 1 to 1.5 equivalents of sodium methoxide or potassium methoxide with respect to the compound represented by the general formula (V) What is necessary is just to make it react for 0.5 to 3 hours at 0-90 degreeC in 100 mL. More specifically, for example, 1 mmol of bromobenzene and 1-2 mmol of (dimethylphenylsilyl) boronic acid pinacol ester in the presence of sodium methoxide or 1-1.5 mmol of potassium methoxide in 10-20 mL of an ether organic solvent. By reacting at 20 to 40 ° C. for 1 to 2 hours, phenylboronic acid pinacol ester or a derivative thereof can be obtained.

Example 1 Method for producing 4-methoxyphenylboronic acid pinacol ester 42.1 mg (0.6 mmol) of potassium methoxide (KOMe) (manufactured by ALDRICH), 5 ml of 1,2-dimethoxyethane (DME), and (under argon atmosphere) 196.7 mg (0.75 mmol) of dimethylphenylsilyl) boronic acid pinacol ester (manufactured by ALDRICH) was added, and the mixture was stirred at 30 ° C. for 10 minutes. Thereafter, 93.5 mg (0.50 mmol) of 4-bromoanisole (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise and reacted for 1 hour, and then the reaction mixture was analyzed using gas chromatography (GC). Confirmed completion.

  After the reaction, the reaction mixture was cooled to 0 ° C., tetrabutylammonium fluoride (TBAF) (1.0 M, 800 μl) was added, and the mixture was stirred for 3 hours. Thereafter, 100 ml of water was added to the mixed solution, and then the target product was extracted with 50 ml of diethyl ether. The organic layer was washed twice with 50 ml of water and then dried by adding magnesium sulfate. After filtering the magnesium sulfate, the diethyl ether in the filtrate was distilled off. The obtained crude product was purified with a boron-impregnated silica gel column chromatography with an eluent of 0-5% hexane / diethyl ether to obtain 4-methoxyphenylboronic acid pinacol ester as colorless oil. The yield calculated from GC was 92%, and the yield at the time of isolation was 77%.

上記反応の条件［ハロゲン化アリールのハロゲンの種類（X）、使用溶媒、使用塩基、及び反応温度］、GCから算出した収率、及びホウ素化生成物対シリル化生成物の比（B／Si）について表1に示す。 The reaction scheme of this reaction is shown below. The silylated product in parentheses represents a by-product other than the target product.

Conditions for the above reaction [halogen type of aryl halide (X), solvent used, base used, and reaction temperature], yield calculated from GC, and ratio of boronated product to silylated product (B / Si ) Is shown in Table 1.

The physical property data of the obtained 4-methoxyphenylboronic acid pinacol ester is shown below.
[Physical property data]
¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.33 (s, 12H), 3.83 (s, 3H), 6.90 (dt, J = 2.3, 8.7 Hz, 2H), 7.75 (dt, J = 2.1, 8.7 ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.9 (CH ₃ ), 55.2 (CH ₃ ), 83.6 (C), 113.4 (CH), 136.6 (CH), 162.2 (C); HRMS-APCI m / z [M + H] + calcd C ₁₃ H ₂₀ O ₃ ¹⁰ B, 234.15363; found, 234.15370.

Example 2 Production method of 4-methoxyphenylboronic acid pinacol ester using tetrahydrofuran as a solvent Implementation was performed except that tetrahydrofuran (THF) (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of the solvent DME used in Example 1. In the same manner as in Example 1, 4-methoxyphenylboronic acid pinacol ester was obtained.
The reaction conditions [halogen type of aryl halide (X), solvent used, base used, and reaction temperature], yield calculated from GC, and B / Si are shown in Table 1 together with those of Example 1. Shown in The physical property data of the obtained product was the same as in Example 1.

Comparative Example 1-4 Method for producing 4-methoxyphenylboronic acid pinacol ester using various organic solvents Toluene, dichloromethane (CH ₂ Cl ₂ ) and N, N-dimethylformamide were used in place of the solvent DME used in Example 1. (DMF) or methanol (MeOH) was used, and the same method as in Example 1 was used.

  Conditions of the reaction [type of halogen of aryl halide (X), solvent used, base used, reaction temperature], yield calculated from GC, and B / Si are shown together with those of Examples 1 and 2. Shown in 1. The physical property data of the obtained product was the same as in Example 1.

From the results in Table 1, it was found that when an ether solvent such as 1,2-dimethoxyethane (DME) or tetrahydrofuran (THF) was used, the reaction proceeded efficiently and the target product was obtained with a high yield of 85% or more. . On the other hand, when toluene, dichloromethane (CH ₂ Cl ₂ ), N, N-dimethylformamide (DMF), and methanol were used, the yield was very low. In particular, it was found that the reaction did not proceed with DMF and methanol.

Example 3-4 Effect on reaction due to difference in reaction temperature Except that the reaction temperature of Example 1 was changed to 50 ° C. and 0 ° C., it was carried out in the same manner as in Example 1, and 4-methoxyphenylboronic acid pinacol ester was obtained. Obtained.

  The reaction conditions [halogen type (X) of aryl halide, solvent used, base used, reaction temperature], yield calculated from GC, and B / Si are shown in Table 2 together with those of Example 1. Shown in The physical property data of the obtained product was the same as in Example 1.

  From the results in Table 2, it was found that the reaction at 30 ° C. was most efficient, but the target product was obtained at a high yield of 80% or higher even at 50 ° C. or 0 ° C. In addition, in the case of 0 degreeC, it turned out that the ratio of the silylated product with respect to a boronation product raises a little compared with 30 degreeC and 50 degreeC.

Example 5-6 Method for Producing 4-Methoxyphenylboronic Acid Pinacol Ester Using Various Bases Use of Example 1 Sodium methoxide (NaOMe) or potassium tert-butoxide (KO ^t Bu) was used in place of KOMe. Except that, 4-methoxyphenylboronic acid pinacol ester was obtained in the same manner as in Example 1.
Table 3 shows the reaction conditions [halogen type (X) of aryl halide, solvent used, base used, reaction temperature], yield calculated from GC, and B / Si. The physical property data of the obtained product was the same as in Example 1.

Comparative Example 5-10 Method for Producing 4-Methoxyphenylboronic Acid Pinacol Ester Using Various Bases Used in Example 1 Lithium methoxide (LiOMe), potassium acetate (KOAc), potassium carbonate (K ₂ ) instead of KOMe This was carried out in the same manner as in Example 1 except that CO ₃ ), potassium fluoride (KF), or diazabicycloundecene (DBU) (manufactured by Wako Pure Chemical Industries, Ltd.) was used. Moreover, in the comparative example 10, it carried out by the method similar to Example 1 except not using a base.
The reaction conditions [halogen type (X) of aryl halide, solvent used, base used, and reaction temperature], yield calculated from GC, and B / Si were combined with those of Examples 5 and 6. Table 3 shows.

From the results in Table 3, it was found that boron substitution reaction proceeds when sodium methoxide and potassium tert-butoxide are used as bases. On the other hand, when lithium methoxide (LiOMe), potassium acetate (KOAc), potassium carbonate (K ₂ CO ₃ ), potassium fluoride (KF), or diazabicycloundecene (DBU) is used as the base, the reaction I found out that it was not going.
From the results of Examples 1, 2, 5 and 6, it was found that boron substitution reaction proceeds efficiently when sodium alkoxide or potassium alkoxide is used.

Example 7 Production Method of Diol Boron Compound Using Iodide as Starting Material 4- methoxyphenyl was prepared in the same manner as in Example 1 except that 4-iodoanisole was used instead of 4- bromoanisole in Example 1. Boronic acid pinacol ester was obtained.
Table 4 shows the reaction conditions [halogen type of aryl halide (X), solvent used, base used, reaction temperature], yield calculated from GC, and B / Si together with those of Example 1. Shown in The physical property data of the obtained product was the same as in Example 1.

Comparative Example 11 Production Method of Diol Boron Compound Using Chloride as Starting Material 4-methoxyphenyl was prepared in the same manner as in Example 7 except that 4-chloroanisole was used instead of 4- iodoanisole in Example 7. Boronic acid pinacol ester was obtained.
The reaction conditions [halogen type (X) of aryl halide, solvent used, base used, and reaction temperature], yield calculated from GC, and B / Si were combined with those of Examples 1 and 7. Table 4 shows. The physical property data of the obtained product was the same as in Example 1.

  From the results in Table 4, it was found that when bromine and iodine are substituents, the boron substitution reaction proceeds efficiently. On the other hand, it was found that even if it is a halogen atom, when the substituent is chlorine, the boron substitution reaction does not proceed so much.

Example 8 Production Method of Diol Boron Compound by Difference in Solvent Amount According to the same method as in Example 1 except that 5 ml of solvent DME used in Example 1 was changed to 0.5 ml, 4-methoxyphenylboronic acid pinacol An ester was obtained.

  Table 5 shows the reaction conditions [type of halogen of aryl halide (X), solvent used, base used, reaction temperature], yield calculated from GC, and B / Si together with those of Example 1. Shown in The physical property data of the obtained product was the same as in Example 1.

Examples 9-23 Production method of diol boron compound using various starting materials The same method as in Example 1 except that various aryl bromides shown in Table 6 were used instead of the starting material 4- bromoanisole of Example 1. The boronic acid pinacol ester was obtained.
The yield at the time of isolation of the reaction and the yield calculated from GC or NMR are shown in Table 6, respectively.

  From the results in Table 6, it was found that the boron substitution reaction proceeded efficiently even when various starting materials (substrates) were used.

The physical property data of the boronic acid pinacol ester obtained in Examples 9-23 are as follows.
[Physical property data]
P-Tolylboronic acid pinacol ester obtained in Example 9: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.33 (s, 12H), 2.36 (s, 3H), 7.18 (d, J = 7.3 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 21.7 (CH ₃ ), 24.8 (CH ₃ ), 83.6 (C), 128.5 (CH), 134.8 (CH), 141.4 (C); HRMS-EI m / z [M-Me] + calcd C ₁₂ H ₁₆ O ₂ ¹⁰ B, 202.12797; found, 202.12779; anal. Calcd for C13H19BO2: C, 71.59, H, 8.78; found, C, 71.61, H, 8.92.

M-Tolylboronic acid pinacol ester obtained in Example 10: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 12H), 2.35 (s, 3H), 7.24-7.30 (m, 2H), 7.58-7.65 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 21.3 (CH ₃ ), 24.8 (CH ₃ ), 83.7 (C), 127.7 (CH), 131.8 (CH), 132.0 (CH), 135.3 (CH), 137.1 (C); HRMS-APCI m / z [M + H] + calcd C ₁₃ H ₂₀ O ₂ ¹⁰ B, 218.15872; found, 218.15869; anal. Calcd for C ₁₃ H ₁₉ BO ₂ : C, 71.59, H, 8.78; found, C, 71.61, H, 8.97.

O-Tolylboronic acid pinacol ester obtained in Example 11: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 12H), 2.54 (s, 3H), 7.14-7.18 (m, 2H), 7.31 (dt, J = 1.6, 7.6 Hz, 1H), 7.76 (dd, J = 1.5, 7.7 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 22.2 (CH ₃ ), 24.8 (CH ₃ ), 83.3 (C), 124.7 (CH), 129.7 (CH), 130.8 (CH), 135.8 (CH), 144.8 (C); HRMS-ESI m / z [M + H] + calcd for C ₁₃ H ₂₀ ¹⁰ BO ₂ , 218.15872; found, 218.15859; anal. Calcd for C ₁₃ H ₁₉ BO ₂ : C, 71.59, H, 8.78; found, C, 71.77, H, 8.95.

Phenylboronic acid pinacol ester obtained in Example 12: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.35 (s, 12H), 7.33-7.41 (m, 2H), 7.46 (tt, J = 2.0, 7.5 Hz, 1H), 7.76-7.84 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.9 (CH ₃ ), 83.7 (C), 127.7 (CH), 131.2 (CH), 134.7 (CH); HRMS-ESI m / z [M + H] + calcd for C ₁₂ H ₁₈ O ₂ ¹⁰ B, 204.14307; found, 204.14297; anal. Calcd for C ₁₂ H ₁₇ BO ₂ : C, 70.63, H, 8.40; found, C, 70.52, H, 8.63.

4-fluorophenylboronic acid pinacol ester obtained in Example 13: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 12H), 7.05 (tt, J = 2.3, 9.2 Hz, 2H), 7.76-7.83 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.8 (CH ₃ ), 83.9 (C), 114.8 (d, J = 20.1 Hz, CH), 136.9 (d, J = 8.6 Hz, CH), 165.1 (d, J = 252.0 Hz, C); HRMS-ESI m / z [M + H] + calcd for C ₁₂ H ₁₇ ¹⁰ B FO ₂ , 222.13365; found, 222.13355.

4-chlorophenylboronic acid pinacol ester obtained in Example 14: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 12H), 7.34 (dt, J = 1.8, 8.7 Hz, 2H), 7.70 −7.75 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.8 (CH ₃ ), 84.0 (C), 128.0 (CH), 136.1 (CH), 137.5 (C); HRMS-ESI m / z [M + H] + calcd for C ₁₂ H ₁₇ ¹⁰ BClO ₂ , 238.10410; found, 238.10370; anal. calcd for C ₁₂ H ₁₆ BClO ₂ : C, 60.43, H, 6.76; Found, C, 60.25, H, 6.81.

Tert-Butyl (4-boronic acid pinacol ester) benzoate obtained in Example 15: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.36 (s, 12H), 1.60 (s, 9H), 7.81- 7.87 (m, 2H), 7.93-7.98 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.9 (CH ₃ ), 28.2 (CH ₃ ), 81.1 (C), 84.1 (C) , 128.4 (CH), 134.2 (C), 134.5 (CH), 165.8 (C); HRMS-ESI m / z [M + Na] + calcd for C ₁₇ H ₂₅ O4 ¹⁰ BNa, 326.17744; found, 326.17768; calcd for C ₁₇ H ₂₅ BO ₄ : C, 67.12, H, 8.28; found, C, 67.09, H, 8.37.

Ethyl (4-boronic acid pinacol ester) benzoate obtained in Example 16: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.36 (s, 12H), 1.40 (t, J = 7.3 Hz, 3H) , 4.38 (q, J = 7.3 Hz, 2H), 7.84-7.89 (m, 2H), 8.00-8.05 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 14.3 (CH ₃ ), 24.9 (CH ₃ ), 61.0 (CH ₂ ), 84.1 (C), 128.5 (CH), 132.6 (C), 134.6 (CH), 166.6 (C); HRMS-ESI m / z [M + H] + calcd for C ₁₅ H ₂₂ O ₄ ¹⁰ B, 276.16420; found, 276.16446; anal. calcd for C ₁₅ H ₂₁ BO ₄ : C, 65.24, H, 7.67; found, C, 65.32, H, 7.81.

(4-boronic acid pinacol ester) N, N-diethylbenzoic acid obtained in Example 17: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.30-1.15 (m, 3H), 1.15-1.10 (m , 3H), 1.35 (s, 12H), 3.30−3.10 (m, 2H), 3.64−3.40 (m, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz, ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 12.9 (CH ₃ ), 14.2 (CH ₃ ), 24.8 (CH ₃ ), 39.2 (CH ₂ ) 43.2 (CH ₂ ), 84.0 (C), 125.4 (CH), 134.7 (CH), 139.8 (C), 171.1 (C); HRMS-ESI m / z [M + H] + calcd for C ₁₇ H ₂₇ O ₃ N ¹⁰ B, 303.21148; found, 303.21192.

(4-boronic acid pinacol ester) N, N-diethylaniline obtained in Example 18: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.32 (s, 12H), 2.98 (s, 6H), 6.69 (dt, J = 2.3, 9.2 Hz, 2H), 7.69 (dt, J = 2.3, 9.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.9 (CH ₃ ), 40.2 (CH ₃ ), 83.3 (C), 111.3 (CH), 136.2 (CH), 152.6 (C); HRMS-EI m / z [M-Me] + calcd for C ₁₃ H ₁₉ ¹⁰ BNO ₂ , 231.15452; found, 231.15344; anal. calcd for C ₁₄ H ₂₂ BNO ₂ : C, 68.04, H, 8.97, N, 5.67, found, C, 68.04, H, 9.00, N, 5.46.

1-methyl (5-boronic acid pinacol ester) indole obtained in Example 19: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.37 (s, 12H), 3.79 (s, 3H), 6.50 (dd , J = 0.9, 3.2 Hz, 1H), 7.04 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 0.9, 8.2 Hz, 1H), 8.16 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.9 (CH ₃ ), 32.8 (CH ₃ ), 83.4 (C) 101.6 (CH), 108.6 (CH), 127.6 (CH), 128.2 (C), 128.8 (CH), 128.9 (CH), 138.6 (C); HRMS-EI m / z [M-Me] + calcd for C ₁₅ H ₂₀ ¹⁰ BNO ₂ , 256.16234; found, 256.16149.

2- (3-Methyl-2-butenyl) boronic acid pinacol ester obtained in Example 20: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.27 (s, 12H), 1.67 (s, 3H), 1.72 (s, 3H), 1.98 (d, J = 1.8 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 16.5 (CH ₃ ), 21.2 (CH ₃ ), 24.4 (CH ₃ ), 24.8 (CH ₃ ), 82.7 (C), 148.2 (C); HRMS-EI m / z [M-Me] + calcd for C ₁₁ H ₂₁ ¹⁰ BO ₂ , 195.16709; found, 195.16723.

(2,6-Dimethylphenyl) boronic acid pinacol ester obtained in Example 21: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.39 (s, 12H), 2.39 (s, 6H), 6.94 (d , J = 7.8 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 22.2 (CH ₃ ), 24.9 (CH ₃ ), 83.6 (C) , 126.4 (CH), 129.1 (CH), 141.7 (C); HRMS-EI m / z [M-Me] + calcd for C ₁₄ H ₂₁ ¹⁰ BO ₂ , 231.16709; found, 231.16664; anal. Calcd for C14H21BO2: C, 72.44, H, 9.12: found, C, 72.25, H, 9.13.

9-anthraceneboronic acid pinacol ester obtained in Example 22: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.57 (s, 12H), 7.40-7.52 (m, 4H), 7.95-8.20 (m, 2H), 8.38−8.52 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 25.2 (CH ₃ ), 84.4 (C) 124.9 (CH), 125.8 (CH), 128.3 (CH), 128.8 (CH), 129.5 (CH), 131.1 (C), 135.9 (C); HRMS-EI m / z [M-Me] + calcd for C ₂₀ H ₂₁ ¹⁰ BO ₂ , 303.16709; found, 303.16766.

(2,4,6-Triisopropylphenyl) boronic acid pinacol ester obtained in Example 23: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.21 (d, J = 7.0 Hz, 6H), 1.25 ( d, J = 7.0 Hz, 12 H), 1.37 (s, 12H), 2.84 (sep, J = 7.1 Hz, 1H), 2.96 (sep, J = 7.0, 2H), 6.93 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.0 (CH ₃ ), 24.4 (CH ₃ ), 24.9 (CH ₃ ), 34.0 (CH), 34.5 (CH), 83.6 (C), 119.6 (CH), 149.7 (C), 151.8 (C); HRMS-ESI m / z [M + H] + calcd for C ₂₁ H ₃₆ ¹⁰ BO ₂ , 330.28392; found, 330.28359.

Example 24 Production Method of Phenethylboronic Acid Pinacol Ester Example 1 except that starting material 4-bromoanisole of Example 1 was changed to (2-bromoethyl) benzene, solvent DME to dioxane, and reaction temperature 30 ° C. to 100 ° C. 1 to obtain phenethylboronic acid pinacol ester.
Table 7 shows the reaction conditions [starting material, solvent used, base used, and reaction temperature], yield calculated from NMR, and B / Si.
In addition, the physical property data of the obtained phenethyl boronic acid pinacol ester are shown below.
[Physical property data]
¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.14 (t, J = 8.4 Hz, 2H), 1.22 (s, 12H), 2.75 (t, J = 8.4 Hz, 2H), 7.10-7.29 (m, ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 12.5 (br, BCH ₂ ), 24.9 (CH ₃ ), 30.1 (CH ₂ ), 83.2 (C), 125.6 (CH), 128.1 (CH ₂ ), 128.3 (CH), 144.5 (C); HRMS-EI m / z [M] + calcd C ₁₄ H ₂₁ ¹⁰ BO ₂ , 231.16709; found, 231.16694.

Example 25 (4-Allyloxyphenyl) boronic acid pinacol ester production method The same procedure as in Example 1 except that 4-allyloxyphenyl bromide was used instead of the starting material 4-bromoanisole of Example 1. , (4-allyloxyphenyl) boronic acid pinacol ester was obtained.
The starting materials for the reaction and the yields calculated from NMR are shown in Table 8.
The physical property data of the obtained (4-allyloxyphenyl) boronic acid pinacol ester is shown below.

[Physical property data]
¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.33 (s, 12H), 4.47-4.63 (m, 2H), 5.29 (dd, J = 1.5, 11.0 Hz, 1H), 5.41 (dd, J = 1.5 , 17.6 Hz, 1H), 6.05 (ddt, J = 5.6, 10.6, 17.0 Hz, 1H), 6.83-6.95 (m, 2H), 7.67-7.80 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): Δ = 24.8 (CH ₃ ), 68.4 (CH ₂ ), 83.5 (C), 114.0 (CH), 117.6 (CH ₂ ), 133.0 (CH), 136.4 (CH), 161.1 (C); HRMS-EI m / z [M] + calcd C 15 H 21 10 BO 3, 259.16201; found, 259.16174; anal calcd for C15H21BO3:. C, 69.26, H, 8.14; found, C, 69.24, H, 8.32.

Example 26 Method for producing 2- (3-butenyl) phenylboronic acid pinacol ester Same as Example 1 except that o- (3-butenyl) bromobenzene was used instead of the starting material 4-bromoanisole of Example 1. To give 2- (3-butenyl) phenylboronic acid pinacol ester.
The starting material of the reaction and the yield calculated from NMR are shown in Table 8 together with those of Example 25.
The physical property data of the obtained 2- (3-butenyl) phenylboronic acid pinacol ester is shown below.

[Physical property data]
¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.34 (s, 12H), 2.25-2.35 (m, 2H), 2.96 (t, J = 8.1 Hz, 2H), 4.91-4.98 (m, 1H), 5.03 (dq, J = 1.8, 17.5 Hz, 1H), 5.89 (ddt, J = 6.9, 10.4, 17.4 Hz, 1H), 7.14-7.21 (m, 2H), 7.34 (dt, J = 1.5, 7.7 Hz, 1H), 7.74-7.80 (m, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 24.8 (CH ₃ ), 35.4 (CH ₂ ), 37.5 (CH ₂ ), 83.3 (C), 114.3 ( CH ₂ ), 125.1 (CH), 129.2 (CH), 130.8 (CH), 136.1 (CH), 138.7 (CH), 149.0 (C); HRMS-ESI m / z [M + H] + calcd for C ₁₆ H ₂₄ ¹⁰ BO ₂ , 258.19002; found, 258.18970; anal. Calcd for C ₁₆ H ₂₃ BO ₂ : C, 74.47, H, 8.98; found, C, 74.47, H, 9.24.

Example 27 Continuous reaction of boron substitution reaction and Suzuki-Miyaura coupling Under argon atmosphere, KOMe 42.1 mg (0.6 mmol), DME 5 ml, and (dimethylphenylsilyl) boronic acid pinacol ester 196.7 mg (0.75 mmol) Stir at 0 ° C. for 10 minutes. Then, 93.5 mg (0.50 mmol) of 4-bromoanisole was added dropwise and reacted for 1 hour, and then the reaction mixture was analyzed by gas chromatography (GC) to confirm whether the reaction was complete.

上記反応の出発物質及び単離時の収率について表９に示す。 After the reaction, the mixture was cooled to 0 ° C., TBAF (1.0 M, 800 μl) was added, and the mixture was stirred for 3 hours. Thereafter, 100 ml of water was added to the mixed solution, followed by extraction three times with 50 ml of diethyl ether. Magnesium sulfate was added to the organic layer for drying, and after filtration, the diethyl ether in the filtrate was distilled off.
Under nitrogen atmosphere, the reaction was mixed with 2 ml of DMF, 276 mg (1.0 mmol) of K ₂ CO ₃ , 249 mg (1.0 mmol) of 1-iodo-4-nitrobenzene, and tetrakis (triphenylphosphine) palladium (Pd (PPh _{3 4} ) 29 mg (0.025 mmol, 5 mol%) was added, and the reaction was stirred at 90 ° C. for 24 hours.
After the reaction, the reaction solution was cooled to room temperature, 100 ml of water was added to the reaction solution, and then extracted three times with 50 ml of diethyl ether. Magnesium sulfate was added to the organic layer for drying, and after filtration, the diethyl ether in the filtrate was distilled off. The resulting crude product was purified using silica gel column chromatography with hexane as an eluent to give 4-methoxy-4′-nitrobiphenyl.
The reaction scheme of this reaction is shown below.

Table 9 shows the starting materials for the above reaction and the yield at the time of isolation.

The physical property data of the obtained 4-methoxy-4′-nitrobiphenyl is shown below.
[Physical property data]
¹ H NMR (400 MHz, CDCl ₃ ): δ = 3.86 (s, 3H), 7.01 (dt, J = 2.6, 9.2 Hz, 2H), 7.56 (dt, J = 2.7, 9.2 Hz, 2H), 7.66 ( dt, J = 2.3, 9.2 Hz, 2H), 8.24 (dt, J = 2.3, 9.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 55.3 (CH ₃ ), 114.5 (CH), 124.0 (CH), 126.9 (CH), 128.5 (CH), 130.9 (C), 146.4 (C), 147.1 (C), 160.4 (C).

Examples 28-29 Boron Substitution Reaction Using Various Starting Materials and Suzuki-Miyaura Coupling Reactions Example 27 Starting Material 4-Bromoanisole Instead of the aryl bromide described in Example 28 or 29 of Table 9 A coupling product was obtained in the same manner as in Example 27 except that was used.
The starting materials for the reaction and the yield at the time of isolation are shown in Table 9 together with those of Example 28.

The physical property data of the coupling product obtained in Example 28 or 29 are as follows.
[Physical property data]
3-methyl-4′-nitrobiphenyl: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.43 (s, 3H), 7.25 (d, J = 7.3 Hz, 1H), 7.33-7.44 (m, 2H) , 7.70 (dt, J = 2.3, 9.2 Hz, 2H), 8.25 (dt, J = 2.3, 9.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 21.4 (CH ₃ ), 123.9 ( CH), 124.4 (CH), 127.7 (CH), 128.0 (CH), 129.0 (CH), 129.6 (CH), 138.6 (C), 138.8 (C), 146.9 (C), 147.7 (C).
4-fluoro-4′-nitrobiphenyl: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.15−7.22 (m, 2H), 7.55−7.63 (m, 2H), 7.69 (dt, J = 2.3, 9.2) Hz, 2H), 8.28 (dt , J = 2.3,8.7 Hz, 2H); 13 C NMR (100 MHz, CDCl 3): δ = 116.1 (d, J = 22.0 Hz, CH), 124.1 (CH), 127.6 (CH), 129.8 (d, J = 8.6 Hz, CH), 134.8 (d, J = 2.9 Hz, CH), 146.5 (C), 147.0 (C), 163.3 (d, J = 251 Hz, C).

Example 30 Change in yield of phenylboronic acid pinacol ester depending on the reaction time Under argon atmosphere, KOMe 84.2 mg (0.12 mmol), DME 5 ml, and (dimethylphenylsilyl) boronic acid pinacol ester 39.34 mg (0.15 mmol) were added. And stirred at 30 ° C. for 10 minutes. Thereafter, 15.7 mg (0.10 mmol) of bromobenzene was added dropwise, and the reaction rate of the mixture was analyzed using gas chromatography (GC). By this reaction, phenylboronic acid pinacol ester was obtained.
The obtained result (metal free) is shown in FIG.

Comparative Example 12-22 Change in Yield with Reaction Time of Phenylboronic Acid Pinacol Ester Using Transition Metal Various transition metals described in Table 10 together with the starting material KOMe of Example 10 except that the amounts described in Table 10 were added Was carried out in the same manner as in Example 10 to obtain phenylboronic acid pinacol ester.
In addition, it shows in Table 10 about the kind and addition amount of the transition metal which this reaction added.
The obtained results are shown in FIG. 1 together with the results of Example 30.

  From the results of FIG. 1, it was found that phenylboronic acid pinacol ester was obtained in a high yield by the method of the present invention in which no metal was added as compared with the case where various transition metals were added.

  According to the production method of the present invention, it is not necessary to carry out the reaction at a temperature lower than 0 ° C. as in the conventional method using a Grignard reagent or a lithium reagent, and the desired diol boron compound can be easily obtained. In addition, the production method of the present invention does not require the use of heavy metals such as palladium, and is therefore suitable for the production of pharmaceuticals.

  Furthermore, since the reaction of the present invention has low reactivity with substituents other than bromine atoms or iodine atoms, a diol boron compound derived from the compound is obtained by using the compound having various substituents as a substrate by the method of the present invention. Can do.

In FIG. 1, − ● − indicates the result (metal free) of Example 30, − ▲ − indicates the result of Comparative Example 20 ([Ir (OMe) (cod)] ₂ ), − ■ − indicates that of Comparative Example 12. The result (Cu (OAc) ₂ ), − ♦ − indicates the result of Comparative Example 14 (NiCl ₂ ), − ◯ − indicates the result of Comparative Example 22 ([RuCl ₂ (p-cymene)] ₂ ), −Δ − Indicates the result of Comparative Example 13 (CuCl), − □ − indicates the result of Comparative Example 18 (AgOAc), − ◇ − indicates the result of Comparative Example 21 ([RhCl (cod)] ₂ ),. ... are the results of palladium acetate of Comparative example _{16 (Pd (OAc) 2)} , ··· ▲ ··· are of Comparative example 17 results (CoCl _2), ··· ■ ··· Comparative example 19 The results (PtCl ₂ (cod)),...,... Represent the results of Comparative Example 15 (FeCl ₃ ), respectively.

Claims (5)

Organohalogen compounds represented by the following general formula (V)

(In the formula, X represents a bromine atom or an iodine atom, and R represents an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 14 carbon atoms, a nitrogen atom, an oxygen atom, and A bicyclic heterocyclic group formed by condensation of a monocyclic heterocyclic ring containing 1 to 3 isomeric atoms selected from sulfur atoms and one aromatic ring, or an isomer selected from nitrogen, oxygen and sulfur atoms A tricyclic heterocyclic group formed by condensation of a monocyclic heterocyclic ring containing 1 to 3 atoms and two aromatic rings is represented by an alkyl group having 1 to 6 carbon atoms, 2 to 2 carbon atoms. 6 alkenyl groups, alkoxy groups having 1 to 6 carbon atoms, alkoxycarbonyl groups having 2 to 7 carbon atoms, alkenyloxy groups having 2 to 6 carbon atoms, alkylcarbamoyl groups having 2 to 12 carbon atoms, and 6 to 14 carbon atoms An aryl group, a fluoro group, a chloro group, or an aryl group having 2 to 12 carbon atoms The Kiruamino group which may have a substituent. However, when R is bicyclic heterocyclic group or tricyclic heterocyclic group, X is the bicyclic heterocyclic group or tricyclic heterocyclic group And a compound represented by the following general formula (VI):

(In the formula, three R ^{3 s} each independently represent an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms, and four R ^{4 s} each independently represent one to 1 carbon atoms. And a compound represented by the following general formula (VII), wherein the compound is reacted in the presence of sodium alkoxide or potassium alkoxide:

(Wherein R and R ⁴ are the same as above). The organic halogen compound represented by the general formula (V) is a compound represented by the following general formula (I)

(In the formula, X represents a bromine atom or an iodine atom, p ₁ represents an integer of 0 to 5, and p ₁ R ^{1 s} are each independently an alkyl group having 1 to 6 carbon atoms or 2 to 2 carbon atoms. 6 alkenyl groups, alkoxy groups having 1 to 6 carbon atoms, alkoxycarbonyl groups having 2 to 7 carbon atoms, alkenyloxy groups having 2 to 6 carbon atoms, alkylcarbamoyl groups having 2 to 12 carbon atoms, and 6 to 14 carbon atoms An aryl group, a fluoro group, a chloro group, or an alkylamino group having 2 to 12 carbon atoms), a compound represented by the following general formula (II)

(Wherein X and R ¹ are the same as described above; p ₂ represents an integer of 0 to 7), a compound represented by the following general formula (III)

(Wherein X and R ¹ are the same as described above; p ₃ represents an integer of 0 to 9), a compound represented by the following general formula (IV)

(In the formula, X is the same as above. R ² represents an alkyl group having 1 to 6 carbon atoms.), An aryl group having 6 to 14 carbon atoms as a substituent or an unsubstituted alkyl group having 1 to 20 carbon atoms. A bromide, an aryliodine having 6 to 14 carbon atoms as an substituent or an unsubstituted alkyliodine having 1 to 20 carbons, an alkenyl bromide having 2 to 20 carbons, or an alkenyl iodo having 2 to 20 carbons; The manufacturing method according to claim 1. The production method according to claim 1, wherein the reaction is carried out in an organic solvent. The production method according to claim 3, wherein the organic solvent is an ether solvent. The production method according to claim 3, wherein the organic solvent is dimethoxyethane, tetrahydrofuran or dioxane.

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