JP7748736B2 - New stable aromatic boronic esters - Google Patents

Description

The present invention relates to a novel aromatic boronic acid ester that is useful for various functionalizations, is stable, does not adsorb even during silica gel chromatography, and can be isolated and purified. The present invention also relates to a method for producing the aromatic boronic acid ester.

Aromatic boronic acid derivatives are widely used in the field of organic synthetic chemistry as substrates for various reactions, such as the Suzuki-Miyaura coupling. However, aromatic boronic acids bearing an unprotected boronic acid group (-B(OH) ₂ ) have drawbacks, such as their facile dehydration to give cyclic trimeric anhydrides (boroxines) and their strong adsorption to silica gel, making their isolation, purification, structural determination by NMR, and functional group transformations while retaining the boronic acid group difficult. Several solutions to these drawbacks have been reported, including the protection of the boronic acid group with a protecting group (Non-Patent Document 1). Among these, aromatic boronic acid pinacol esters are one of the most commonly used boronic acid protected derivatives and can be used directly as substrates for coupling reactions. However, isolation and purification of aromatic boronic acid pinacol esters by silica gel chromatography often results in low yields, and their purification requires know-how and techniques that differ from those used for handling general organic compounds (Non-Patent Document 2). Recently, boronic acid derivatives such as ArB(dan) (Non-Patent Document 3) and ArB(mida) (Non-Patent Document 4), which are obtained by dehydration condensation with diaminonaphthalene (dan) or N-methyliminodiacetic acid (mida), have been developed, and the instability of aromatic pinacol boronic acid esters has been improved. However, these boronic acid derivatives still have many problems, such as difficulty in synthesis, extremely high polarity, difficulty in subsequent functional group transformation, and difficulty in deprotection.

Chem. Soc. Rev. 2014, 43, 412-443 Chem. Lett. 2012, 41, 972-973 J. Am. Chem. Soc. 2007, 129, 758-759 J. Am. Chem. Soc. 2007, 129, 6716-6717

The object of the present invention is to provide a novel aromatic boronic acid ester that is stable and easy to isolate and purify without being adsorbed even during silica gel chromatography, and that can be applied to a wide range of functional group transformations.

As a result of extensive research to solve the above problems, the present inventors have discovered a compound represented by formula (I):

[In the formula,

represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted;
R ¹ and R ³ each independently represent a linear C _1-6 alkyl group;
^R2 and ^R4 each independently represent a linear _C2-6 alkyl group; and n represents an integer of 1 or greater.
The inventors have found that a compound represented by the formula (I) or its salt is extremely stable even on conventional silica gel column chromatography or thin-layer chromatography, does not decompose, and can be easily isolated and purified. Furthermore, when this compound or its salt was used in the Suzuki-Miyaura coupling reaction, it exhibited reactivity almost equivalent to that of aromatic boronic acid pinacol esters and could be converted to the corresponding biaryls. Furthermore, the inventors have found that this compound or its salt can also be used in conversion to oxygen functional groups using _NaBO3 or to nitrogen functional groups using a copper catalyst, thereby completing the present invention.

That is, the present invention is as follows.
[1] Formula (I):

[In the formula,

represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted;
R ¹ and R ³ each independently represent a linear C _1-6 alkyl group;
^R2 and ^R4 each independently represent a linear _C2-6 alkyl group; and n represents an integer of 1 or greater.
(hereinafter, may be referred to as compound (I)) or a salt thereof (hereinafter, compound (I) and its salt may be collectively referred to as "the compound of the present invention").
[2]

[0023] The compound or salt thereof according to the above-mentioned [1], wherein the group represented by the following formula (I) is a C _6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or an 8- to 14-membered fused aromatic heterocyclic group, each of which may be further substituted.
[3]

The compound or salt thereof according to the above-mentioned [2], wherein the group represented by the following formula (I) is an optionally further substituted phenyl group, naphthyl group, pyridyl group, furyl group or thienyl group.
[4] The compound or salt thereof according to any one of the above [1] to [3], wherein R ¹ and R ³ are each independently a linear C _1-4 alkyl group, and R ² and R ⁴ are each independently a linear C _2-4 alkyl group.
[5] The compound or salt thereof according to the above-mentioned [4], wherein R ¹ and R ³ are a methyl group, an ethyl group, or an n-propyl group, and R ² and R ⁴ are an ethyl group or an n-propyl group.
[6] The compound or salt thereof according to the above-mentioned [4], wherein all of R ¹ , R ² , R ³ and R ⁴ are an ethyl group or an n-propyl group.
[7] The compound or salt thereof according to any one of the above [1] to [6], wherein n is an integer of 1 to 3.
[8] Formula (II):

[In the formula,

represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted, and n represents an integer of 1 or more.
or a salt thereof, and a compound represented by formula (III):

[In the formula,
R ¹ and R ³ each independently represent a linear C _1-6 alkyl group;
^R2 and ^R4 each independently represent a linear _C2-6 alkyl group.
The method of the present invention comprises the step of reacting a compound represented by formula (I):

[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula:
[9] Formula (IV):

[In the formula,

represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted;
^X1 represents a halogen atom; and n represents an integer of 1 or more.
or a salt thereof with isopropyl magnesium chloride-lithium chloride complex or n-butyllithium, and then reacted with trimethoxyborane, followed by reacting a compound represented by formula (III):

[In the formula,
R ¹ and R ³ each independently represent a linear C _1-6 alkyl group;
^R2 and ^R4 each independently represent a linear _C2-6 alkyl group.
with a compound represented by formula (I):

[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula:
[10] Formula (V):

[In the formula,

represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted;
^X2 represents a halogen atom or a trifluoromethanesulfonyloxy group; and n represents an integer of 1 or greater.
or a salt thereof, in the presence of a metal catalyst,

[In the formula,
R ¹ and R ³ each independently represent a linear C _1-6 alkyl group;
^R2 and ^R4 each independently represent a linear _C2-6 alkyl group.
with a compound represented by formula (I):

[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula:
[11] Formula (VI):

[In the formula,
R ¹ and R ³ each independently represent a linear C _1-6 alkyl group;
^R2 and ^R4 each independently represent a linear _C2-6 alkyl group.
A compound represented by the formula:
[12] The compound according to any one of the above [1] to [7] or a salt thereof is reacted with a compound of the formula (VII):

[In the formula,

represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted; and ^X3 represents a halogen atom.]
or a salt thereof with a compound represented by formula (VIII):

[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula:
[13] A method for producing a compound of formula (IX):

[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula:
[14] The compound according to any one of the above [1] to [7] or a salt thereof is reacted with a compound of the formula (X):

[In the formula,
R represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.
with a compound represented by formula (XI):

[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula:

The compounds of the present invention have the advantage of being extremely stable and easily isolated and purified, without decomposing even on silica gel column chromatography or thin-layer chromatography. Furthermore, because the compounds of the present invention exhibit reactivity roughly equivalent to that of aromatic boronic acid pinacol esters, they are applicable to Suzuki-Miyaura coupling reactions and various functionalization reactions, making them useful as raw materials or synthetic intermediates for various pharmaceuticals and functional materials.

FIG. 1 shows a photograph of the results (stained with cerium ammonium molybdate) of thin-layer chromatography (silica gel plate) of Compound (I-2), Compound (I-4), and their corresponding pinacol esters (Comparative Examples 7 and 2).

The definitions of each substituent used in this specification are described in detail below. Unless otherwise specified, each substituent has the following definition.

As used herein, "halogen atom" includes, for example, fluorine, chlorine, bromine, and iodine.

In the present specification, examples of the "hydrocarbon group" include alkyl groups (e.g., C _1-6 alkyl groups), alkenyl groups (e.g., C _2-6 alkenyl groups), alkynyl groups (e.g., C _2-6 alkynyl groups), cycloalkyl groups (e.g., C _3-10 cycloalkyl groups), cycloalkenyl groups (e.g., C _3-10 cycloalkenyl groups), aryl groups (e.g., C _6-14 aryl groups), and aralkyl groups (e.g., C _7-16 aralkyl groups).

In the present specification, the term "alkyl group" refers to a group obtained by removing one hydrogen atom from any carbon atom of a straight-chain or branched-chain alkane having one or more carbon atoms, and when there is no particular limitation on the range of the number of carbon atoms, it is a _C1-20 alkyl group, and among these, a _C1-6 alkyl group is preferable, and a _C1-4 alkyl group is more preferable.

In the present specification, examples of the "C _1-6 alkyl group" include 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.

In the present specification, examples of the "C _1-4 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

In the present specification, examples of the "straight-chain C _1-6 alkyl group" include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, and among these, a straight-chain C _1-4 alkyl group is preferable.

In the present specification, examples of the "straight-chain C _2-6 alkyl group" include ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, and among these, a straight-chain C _2-4 alkyl group is preferable.

In the present specification, the term "alkenyl group" refers to a group obtained by removing one hydrogen atom from any carbon atom of a straight-chain or branched-chain alkene having two or more carbon atoms, and unless there is any particular limitation on the range of the number of carbon atoms, is a _C2-20 alkenyl group, and of these, a _C2-6 alkenyl group is preferred.

In the present specification, examples of the "C _alkenyl group" include 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.

In the present specification, the term "alkynyl group" refers to a group in which one hydrogen atom has been removed from any carbon atom of a straight-chain or branched-chain alkyne having two or more carbon atoms, and when there is no particular limitation on the range of the number of carbon atoms, it is a _C2-20 alkynyl group, and of these, a _C2-6 alkynyl group is preferred.

In the present specification, examples of the "C _alkynyl group" include 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 and 4-methyl-2-pentynyl.

In the present specification, the term "cycloalkyl group" means a cyclic alkyl group, and when there is no particular limitation on the range of carbon atoms, it is a C _3-10 cycloalkyl group, and among these, a C _3-8 cycloalkyl group is preferred.

In the present specification, examples of the "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the "C _3-8 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, the term "cycloalkenyl group" means a cyclic alkenyl group, and when there is no particular limitation on the range of the number of carbon atoms, it is a C _3-10 cycloalkenyl group, and among these, a C _3-8 cycloalkenyl group is preferred.

In the present specification, examples of the "C _3-8 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

In the present specification, the term "aryl group" refers to a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity, and among these, a C _6-14 aryl group is preferred.

In the present specification, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and biphenylyl.

In the present specification, the term "aralkyl group" refers to a group in which an aryl group is substituted on an alkyl group, and although there are no particular limitations on the range of carbon atoms, it is preferably a C _7-16 aralkyl group.

In the present specification, examples of the "C _aralkyl group" include 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 and phenylpropyl.

In the present specification, the term "alkoxy group" refers to a group in which a linear or branched alkyl group is bonded to an oxygen atom, and although there are no particular limitations on the range of carbon atoms, it is preferably a C _1-6 alkoxy group.

[0023] In the present specification, examples of the "C _1-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy and hexyloxy. Of these, a C _1-4 alkoxy group is preferable.

In the present specification, examples of the "C _aralkyloxy group" include 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, biphenylylmethyloxy and phenylpropyloxy.

In this specification, examples of the term "heterocyclic group" include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered bridged heterocyclic groups, each of which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.

In this specification, examples of the term "aromatic heterocyclic group" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring-constituting atoms.

Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.;
Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl Examples of fused aromatic heterocyclic groups include 8- to 14-membered fused aromatic heterocyclic groups (fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups) such as phenyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In this specification, examples of "non-aromatic heterocyclic groups" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring-constituting atoms.

Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydrofuranyl, and the like. 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as dihydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, etc.;
Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

In this specification, suitable examples of "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the "acyl group" include a formyl group, a hydrocarbon-carbonyl group (C _1-6 alkyl-carbonyl group, C _2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C _3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C _3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C _6-14 aryl-carbonyl group, a C _7-16 aralkyl-carbonyl groups), heterocyclylcarbonyl groups (e.g., 5- to 14-membered aromatic heterocyclylcarbonyl groups such as nicotinoyl, isonicotinoyl, thenoyl, and furoyl, and 3- to 14-membered non-aromatic heterocyclylcarbonyl groups such as morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl), alkoxy-carbonyl groups (e.g., C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl and ethoxycarbonyl), aryloxy-carbonyl groups (e.g., C _6-14 aryloxy-carbonyl groups such as phenyloxycarbonyl and naphthyloxycarbonyl), aralkyloxy-carbonyl groups (e.g., C _7-16 aralkyloxy-carbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl), carbamoyl groups, mono- or di-hydrocarbon-carbamoyl groups (mono- or di-C _1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl), mono- or di-C _2-6 alkenyl-carbamoyl groups (e.g., diallylcarbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl groups (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 heterocyclic carbamoyl groups such as pyridylcarbamoyl), thiocarbamoyl groups, mono- or di-hydrocarbon-thiocarbamoyl groups (mono- or di-C _1-6 alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl)), and aromatic heterocyclic thiocarbamoyl groups (e.g., 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups such as pyridylthiocarbamoyl). Among these, preferred are a formyl group, a C _1-6 alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl), a C _3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C _6-14 aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl), a C _7-16 aralkyl-carbonyl group (e.g., phenylacetyl, phenylpropionyl), a C _1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl), C _6-14 aryloxy-carbonyl groups, C _7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), carbamoyl groups, and mono- or di-C _1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl).

In the present specification, the term "acyloxy group" means a group in which an acyl group is bonded to an oxygen atom, and is preferably a formyloxy group, a C _1-6 alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, hexanoyloxy, heptanoyl), a C _3-10 cycloalkyl-carbonyloxy group (e.g., cyclobutanecarbonyloxy, cyclopentanecarbonyloxy, cyclohexanecarbonyloxy, cycloheptanecarbonyloxy), a C _6-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), a C _7-16 aralkyl-carbonyloxy group, a C _1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy), C _6-14 aryloxy-carbonyloxy groups (e.g., benzyloxycarbonyloxy), C _7-16 aralkyloxy-carbonyloxy groups, carbamoyloxy groups, mono- or di-C _1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, N-ethyl-N-methylcarbamoyloxy).

In the present specification, the term "C _1-6 alkylsulfanyl group" means a group in which a linear or branched C _1-6 alkyl group is bonded to a sulfur atom, and examples thereof include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, and hexylsulfanyl. Of these, a C _1-4 alkylsulfanyl group is preferred.

In the present specification, the term "C _1-6 alkylsulfonyl group" means a group in which a linear or branched C _1-6 alkyl group is bonded to a sulfonyl group (-S(=O) ₂ -), and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, and hexylsulfonyl. Of these, a C _1-4 alkylsulfonyl group is preferred.

In the present specification, the term "C _1-6 alkylsulfonyloxy group" means a group in which a C _1-6 alkylsulfonyl group is bonded to an oxygen atom, and examples thereof include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, and hexylsulfonyloxy. Of these, a C _1-4 alkylsulfonyloxy group is preferable.

As used herein, the term "C _6-14 arylsulfonyl group" means a group in which a C _6-14 aryl group is bonded to the sulfur atom of a sulfonyl group (-S(=O) ₂ -), and examples thereof include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, the term "C _6-14 arylsulfonyloxy group" means a group in which a C _6-14 aryl group is bonded to the sulfur atom of a sulfonyloxy group (-S(=O) ₂ -O-), and examples thereof include phenylsulfonyloxy, 1-naphthylsulfonyloxy and 2-naphthylsulfonyloxy.

As used herein, the term "tri-substituted silyl group" refers to a silyl group substituted with three substituents, which may be the same or different, selected from the group consisting of a _C1-6 alkyl group, a _C6-14 aryl group, and a _C1-6 alkoxy group. Examples include trialkylsilyl groups such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, and a tert-butyldimethylsilyl group (preferably a tri- _C1-6 alkylsilyl group), a tert-butyldiphenylsilyl group, and a triphenylsilyl group.

In this specification, the term "optionally substituted" means unsubstituted or substituted with a substituent at any substitutable position (any hydrogen atom is replaced with a substituent). The "substituent" is not particularly limited, but includes a substituent selected from the following (substituent group ^Z1 ) or (substituent group ^Z2 ), and each substituent may be further substituted with a substituent selected from the following (substituent group Z).

(Substituent group Z ¹ )
(1) a halogen atom,
(2) a cyano group,
(3) a nitro group,
(4) a hydroxy group,
(5) a carboxy group,
(6) sulfo group,
(7) phospho group,
(8) an azide group,
(9) an oxo group,
(10) hydrocarbon groups,
(11) acyl group,
(12) heterocyclic groups,
(13) a C _alkoxy group,
(14) a C _{cycloalkyloxy} group,
(15) a _C2-6 alkenyloxy group,
(16) a C _alkynyloxy group,
(17) a C _aryloxy group,
(18) a C _7-16 aralkyloxy group,
(19) an acyloxy group,
(20) (a) a hydrocarbon group;
(b) an acyl group,
(c) a C _1-6 alkylsulfonyl group, and
(d) an amino group which may be mono- or di-substituted by a substituent selected from the group consisting of C _6-14 arylsulfonyl groups;
(21) a C _1-6 alkylsulfanyl group,
(22) a C _1-6 alkylsulfonyl group,
(23) a C _arylsulfonyl group,
(24) a _diC alkylphosphino group,
(25) a _diC arylphosphino group,
(26) a trisubstituted silyl group,
(27) C _1-6 alkylsulfonyloxy group, and
(28) A C _6-14 arylsulfonyloxy group.

(Substituent group Z ² )
(1) a halogen atom,
(2) a cyano group,
(3) a nitro group,
(4) a hydroxy group,
(5) a carboxy group,
(6) sulfo group,
(7) phospho group,
(8) an azide group,
(9) an oxo group,
(10) a C _cycloalkyl group,
(11) a C _aryl group,
(12) acyl group,
(13) heterocyclic groups,
(14) a C _alkoxy group,
(15) a C _{cycloalkyloxy} group,
(16) a _C2-6 alkenyloxy group,
(17) a C _alkynyloxy group,
(18) a C _aryloxy group,
(19) a C _7-16 aralkyloxy group,
(20) an acyloxy group,
(21) (a) a hydrocarbon group;
(b) an acyl group,
(c) a C _1-6 alkylsulfonyl group, and
(d) an amino group which may be mono- or di-substituted by a substituent selected from the group consisting of C _6-14 arylsulfonyl groups;
(22) a C _1-6 alkylsulfanyl group,
(23) a C _1-6 alkylsulfonyl group,
(24) a C _arylsulfonyl group,
(25) a _diC alkylphosphino group,
(26) a _diC arylphosphino group,
(27) a trisubstituted silyl group,
(28) C _1-6 alkylsulfonyloxy group, and
(29) A C _6-14 arylsulfonyloxy group.

(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 _aryl group,
(10) a C _alkoxy group,
(11) formyl group,
(12) a C _1-6 alkyl-carbonyl group,
(13) a C _alkoxy -carbonyl group,
(14) a C _1-6 alkylsulfonyl group,
(15) a 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) A C _6-14 arylsulfonyloxy group.

Among these, the optionally substituted "substituent" is preferably a substituent selected from the following (substituent group Z ³ ) or (substituent group Z ⁴ ).

(Substituent group Z ³ )
(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 optionally substituted by a halogen atom,
(8) (a) a halogen atom,
(b) a C _1-6 alkyl group optionally substituted with a halogen atom, and
(c) a C _3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a C _1-6 alkoxy group optionally substituted by a halogen atom;
(9) (a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a C _1-6 alkyl group optionally substituted by a halogen atom;
(e) a C _1-6 alkoxy group optionally substituted by a halogen atom,
(f) a formyl group,
(g) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom, and
(h) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a C _1-6 alkyl-carbonyloxy group optionally substituted by a halogen atom;
(10) a C _1-6 alkoxy group optionally substituted by a halogen atom,
(11) formyl group,
(12) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom,
(13) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom,
(14) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom,
(15) a C _1-6 alkyl-carbonyloxy group optionally substituted by 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 by a halogen atom;
(c) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(d) a formyl group,
(e) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom,
(f) a C _1-6 alkoxy-carbonyl group optionally substituted with a halogen atom or a C _6-14 aryl group,
(g) a C _6-14 aryl-carbonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(h) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom, and
(i) an amino _{group optionally mono- or di-substituted by a substituent selected from the group consisting of a C 6-14 arylsulfonyl} group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C 1-6 alkoxy group optionally substituted by a halogen atom;
(17) a C _1-6 alkylsulfanyl group optionally substituted by a halogen atom,
(18) trisubstituted silyl groups,
(19) A C _1-6 alkylsulfonyloxy group optionally substituted by a halogen atom, and
(20) A C _6-14 arylsulfonyloxy group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted with a halogen atom, and a C _1-6 alkoxy group optionally substituted with a halogen atom.

(Substituent group Z ⁴ )
(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) a halogen atom,
(b) a C _1-6 alkyl group optionally substituted with a halogen atom, and
(c) a C _3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a C _1-6 alkoxy group optionally substituted by a halogen atom;
(8) (a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a C _1-6 alkyl group optionally substituted by a halogen atom;
(e) a C _1-6 alkoxy group optionally substituted by a halogen atom,
(f) a formyl group,
(g) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom, and
(h) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a C _1-6 alkyl-carbonyloxy group optionally substituted by a halogen atom;
(9) a C _1-6 alkoxy group optionally substituted by a halogen atom,
(10) formyl group,
(11) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom,
(12) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom,
(13) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom,
(14) a C _1-6 alkyl-carbonyloxy group optionally substituted by 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 by a halogen atom;
(c) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(d) a formyl group,
(e) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom or a C _6-14 aryl group,
(f) a C _alkoxy -carbonyl group optionally substituted by a halogen atom,
(g) a C _6-14 aryl-carbonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(h) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom, and
(i) an amino group optionally mono- or di-substituted by _{a substituent selected from the group consisting of a C 6-14 arylsulfonyl} group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C 1-6 alkoxy group optionally substituted by a halogen atom;
(16) a C _1-6 alkylsulfanyl group optionally substituted by a halogen atom,
(17) a trisubstituted silyl group,
(18) a C _1-6 alkylsulfonyloxy group optionally substituted by a halogen atom, and
(19) A C _6-14 arylsulfonyloxy group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted with a halogen atom, and a C _1-6 alkoxy group optionally substituted with a halogen atom.

The number of "substituents" that may be substituted is not particularly limited as long as it is a substitutable number, but is preferably 1 to 6, and more preferably 1 to 3. When multiple substituents are present, the substituents may be the same or different.

In the present specification, examples of the "optionally substituted substituent" in the "optionally substituted aryl group (phenyl group)", "optionally substituted heterocyclic group" or "optionally substituted aromatic heterocyclic group (5- or 6-membered monocyclic aromatic heterocyclic group or 8- to 14-membered fused aromatic heterocyclic group)" include (substituent group Z 1 ) which may be further substituted with a substituent selected from the above (substituent group Z) ^{, or a substituent selected from (substituent group Z 3 )} .

In the present specification, examples of the "substituent" in the "optionally substituted alkyl group" that may be substituted include (substituent group Z2) which may be further substituted with a substituent selected from the above (substituent group ^Z ), or a substituent selected from (substituent group ^Z4 ).

[0033] In the present specification, examples of the " _C1-6 alkyl group optionally substituted with one or more halogen atoms" include a _C1-6 alkyl group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples 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-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl.

[0033] In the present specification, examples of the "C _1-6 alkoxy group optionally substituted with one or more halogen atoms" include a C _1-6 alkoxy group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

[0033] In the present specification, examples of the "C _1-6 alkylsulfanyl group optionally substituted with one or more halogen atoms" include a C _1-6 alkylthio group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[0033] In the present specification, examples of the "C _1-6 alkyl-carbonyl group optionally substituted with one or more halogen atoms" include a C _1-6 alkyl-carbonyl group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

[0033] In the present specification, examples of the "C _1-6 alkyl-carbonyloxy group optionally substituted with one or more halogen atoms" include a C _1-6 alkyl-carbonyloxy group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples include acetoxy, chloroacetoxy, trifluoroacetoxy, trichloroacetoxy, propanoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.

[0033] In the present specification, examples of the "C _1-6 alkylsulfonyl group optionally substituted with one or more halogen atoms" include a C _1-6 alkylsulfonyl group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[0033] In the present specification, examples of the "C _1-6 alkylsulfonyloxy group optionally substituted with one or more halogen atoms" include a C _1-6 alkylsulfonyloxy group optionally substituted with 1 to 6, preferably 1 to 3, halogen atoms. Specific examples include methylsulfonyloxy, difluoromethylsulfonyloxy, trifluoromethylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, 4,4,4-trifluorobutylsulfonyloxy, pentylsulfonyloxy and hexylsulfonyloxy.

In this specification, "its salt" refers to a salt formed by reacting a compound having an acidic or basic group with a base or acid, such as a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, an ammonium salt, or a salt with an amino acid.

(Compound (I) of the present invention)
Each group in compound (I) will be explained below.

The group represented by represents an aryl group or an aromatic heterocyclic group, each of which may be further substituted.

The group represented by the formula (I) is preferably a C _6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or an 8- to 14-membered fused aromatic heterocyclic group, more preferably a phenyl group, a naphthyl group, or a 5- or 6-membered monocyclic aromatic heterocyclic group, even more preferably a phenyl group, a naphthyl group, a pyridyl group, a furyl group, or a thienyl group, and particularly preferably a phenyl group, a naphthyl group, a pyridyl group, a furyl group, or a thienyl group, each of which optionally further has a substituent at a substitutable position. The number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 6, more preferably 1 to 3. When multiple substituents are present, the respective substituents may be the same or different. Examples of "substituents" that may be further substituted include substituents selected from the above-mentioned substituent group (for example, (substituent group Z ¹ ) or (substituent group Z ³ ) which may be further substituted with a substituent selected from (substituent group Z)).

R ¹ and R ³ each independently represent a linear C _1-6 alkyl group.

Preferably, R ¹ and R ³ are each independently a linear C _1-4 alkyl group, more preferably a methyl group, an ethyl group or an n-propyl group, and even more preferably an ethyl group.

^R2 and ^R4 each independently represent a linear _C2-6 alkyl group.

^R2 and ^R4 are preferably a linear _C2-4 alkyl group, more preferably an ethyl group or an n-propyl group, and even more preferably an ethyl group.

n represents an integer of 1 or greater.

n is preferably an integer from 1 to 3, more preferably 1 or 2.

A suitable compound (I) is shown below.

[Compound (I)-A]
In formula (I),

is a C 6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group or an _{8- to 14-} membered fused aromatic heterocyclic group, each of which may be further substituted with a substituent selected from (substituent group Z ¹ ) (preferably a substituent selected from (substituent group Z ³ )), which may further be substituted with a substituent selected from (substituent group Z),
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).

[Compound (I)-B]
In formula (I),

is a phenyl group, a naphthyl group, or a 5- or 6-membered monocyclic aromatic heterocyclic group, each of which may be further substituted with a substituent selected from (substituent group Z ¹ ) (preferably a substituent selected from (substituent group Z ³ )), which may be further substituted with a substituent selected from (substituent group Z);
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).

[Compound (I)-C]
In formula (I),

is a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may be further substituted by 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).

[Compound (I)-D]
In formula (I),

is a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may be further substituted by 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;
^R2 and ^R4 are ethyl or n-propyl groups, and n is 1 or 2;
Compound (I).

[Compound (I)-E]
In formula (I),

is a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may be further substituted by a substituent selected from the above (substituent group Z ³ ),
R ¹ , R ² , R ³ and R ⁴ are all ethyl or n-propyl groups, and n is 1 or 2;
Compound (I).

Specific examples of suitable compounds (I) include the compounds of Examples I-1 to I-21.

When compound (I) is in the form of a salt, examples of such salts include the salts with the aforementioned inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic amino acids, and salts with acidic amino acids.

Suitable examples of 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; aluminum salts, etc.

Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.

Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

Suitable examples of salts with organic acids include salts with 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-toluenesulfonic acid, etc.

Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.

Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

Compound (I) encompasses within its scope solvates (e.g., hydrates, ethanol solvates, dimethyl sulfoxide solvates, etc.) and non-solvates (e.g., non-hydrates, etc.).

Compound (I) may be a compound labeled or substituted with an isotope (e.g., ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, etc.).

When compound (I) has an asymmetric center, it may exist in the form of isomers such as enantiomers or diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention. Furthermore, isomers may be produced due to conformation or tautomerism, and such isomers and mixtures thereof are also included in compound (I) of the present invention.

(Method for producing the compound of the present invention)
The method for producing the compound of the present invention (hereinafter sometimes referred to as "the production method of the present invention") will be explained below.

The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include those similar to the salts of compound (I) described above.

If 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, if the compound obtained in each step is a salt, it can be converted into the free form or another type of desired salt by a method known per se.

The compounds obtained in each step can be used in the next reaction either as the reaction solution or as a crude product, or they can be isolated and/or purified from the reaction mixture by conventional separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and chromatography.

If the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as is.

Unless otherwise specified, the reactions in each step are carried out in accordance with methods known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc., 1989, or the like, or the method described in the Examples.

In each step, the protection or deprotection of functional groups is carried out according to known methods, such as those described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene and Peter G. M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (P. J. Kocienski), published by Thieme in 2004, or methods described in the Examples.

When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, each can be obtained as a single product by known synthesis or separation methods (concentration, solvent extraction, column chromatography, recrystallization, etc.).

Optical isomers can be produced by methods known per se. Specifically, optically active synthetic intermediates are used, or optical isomers are obtained by optically resolving the final racemic compound using conventional methods.

As examples of the manufacturing method of the present invention, representative manufacturing methods (1) to (3) as well as the manufacturing examples and examples described below are described below, but the manufacturing methods are not limited to these.

(Manufacturing method (1))
Compound (I) can be produced by the method shown in the following reaction scheme 1 or a method analogous thereto.
Reaction Scheme 1

(The symbols in the formula have the same meanings as above.)

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) used is usually 1 mole to 1.5 moles, preferably 1 mole to 1.2 moles, per mole of the boronic acid group of compound (II).
The solvent is not particularly limited, but examples thereof include 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; and aromatic hydrocarbons such as toluene and benzene, which are solvents that separate from water. Of these, 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.
In order to accelerate the reaction, a catalytic amount of acetic acid may be added.

(Manufacturing method (2))
Compound (I) can be produced by the method shown in the following reaction scheme 2 or a method analogous thereto.
Reaction Scheme 2

(The symbols in the formula have the same meanings as above.)

This production method is a method for producing compound (I), comprising a step (step 1) of reacting compound (IV) with isopropyl magnesium chloride-lithium chloride complex (i-PrMgCl-LiCl) or n-butyllithium (n-BuLi) in a solvent that does not adversely influence the reaction, a step (step 2) of reacting compound (IV) with trimethoxyborane (B(OMe) ₃ ), and a step (step 3) of reacting compound (III).

(Step 1)
The amount of isopropyl magnesium chloride-lithium chloride complex (i-PrMgCl-LiCl) or n-butyllithium (n-BuLi) used is usually 1 mole to 1.5 moles, preferably 1.2 moles, per mole of ^X group in compound (IV).
The solvent is not particularly limited, but examples thereof include ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane, and among these, tetrahydrofuran is preferred.
The reaction temperature is usually from -78°C to -10°C, preferably from -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 ) used is usually 1.5 to 3 moles, preferably 2 moles, per mole of X ¹ group in compound (IV).
The solvent is preferably the solvent used in step 1.
The reaction temperature is usually 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 subjected to step 3 as it is after post-treatment.

(Step 3)
The amount of compound (III) used is usually 1 to 1.5 moles, preferably 1 to 1.2 moles, per mole of ^one group X in compound (IV).
The solvent is not particularly limited, but examples thereof include 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; and aromatic hydrocarbons such as toluene and benzene, which are solvents that separate from water. Of these, dichloromethane is preferred.
The reaction temperature is usually 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.

(Manufacturing method (3))
Compound (I) can be produced by the method shown in the following reaction scheme 3 or a method analogous thereto.
Reaction Scheme 3

(The symbols in the formula have the same meanings as above.)

This production method is a method for producing compound (I), which includes a step (step 1) of reacting compound (V) with compound (VI) in a solvent that does not adversely affect the reaction in the presence of a metal catalyst.

The amount of compound (VI) used is usually 1 to 2 moles, preferably 1.5 moles, per mole of X ² group of compound (V). Examples of the metal catalyst include palladium catalysts such as palladium(II) acetate, palladium(II) chloride, [1,3-bis(diphenylphosphino)propane]palladium(II) dichloride (PdCl ₂ (dppp)), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), and dichlorobis(tricyclohexylphosphine)palladium(II); zinc catalysts such as dimethylzinc and diethylzinc; iron catalysts such as trisacetylacetonatoiron(III) (Fe(acac) ₃ ) and iron(II) chloride; and tetrakis(1,3-dicyclohexylimidazolin-2-ylidene)(1,5-cyclooctadiene)nickel(0) [Ni ₂ (Icy) ₄ (μ-(η ² :η ² )-COD)], bis(1,3-dicyclohexylimidazolin-2-ylidene)(ethylene)nickel(0) [Ni(Icy) ₂ (η ² -C ₂ H ₄ )], tetrakis(1,3-dicyclohexylimidazolin-2-ylidene)(cyclooctene)nickel(0) [Ni(Icy) ₂ (η ² cobalt catalysts such as oxazolidinylferrocenylphosphine cobalt(II), diphenylphosphinoferrocene cobalt(II) chloride, and tris(acetylacetonato)cobalt(III); cerium catalysts such as cerium(III) chloride; copper catalysts such as copper(I) iodide, copper(I) chloride, copper(I) bromide, and phenanthroline copper(I) iodide; and manganese catalysts such as manganese(II) iodide, manganese(II) bromide, manganese(II) chloride, and manganese(IV) dioxide. Palladium catalysts are preferred, and [1,3-bis(diphenylphosphino)propane]palladium(II) dichloride (PdCl ₂ (dppp)) is more preferred.
Furthermore, if necessary, a phosphine ligand such as 2-bis(cyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), or 3,6-dimethoxy-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (BrettPhos), or an NHC ligand precursor such as 1,3-bis(2,6-diisopropylphenyl)imidazolium salt may be added.
The amount of the metal catalyst used is usually 0.001 to 0.5 moles, preferably 0.01 to 0.2 moles, more preferably 0.01 to 0.1 moles, per mole of ^X2 group in compound (V).
The solvent can be arbitrarily selected depending on the type of metal catalyst used and the like, and examples thereof include ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; nitrile solvents such as acetonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxide solvents such as dimethyl sulfoxide, and among these, tetrahydrofuran and dimethyl sulfoxide are preferred.
In this step, a base may be added as needed.
Examples of the base include sodium tert-butoxide, potassium methoxide, sodium methoxide, magnesium tert-butoxide, potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogencarbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, and cesium fluoride, and among these, potassium acetate and sodium acetate are preferred.
The amount of the base used is usually 1 to 10 moles, preferably 1 to 5 moles, more preferably 1.5 to 3 moles, per mole of X ² group of compound (V).
The reaction temperature is usually 0°C to 100°C, preferably 60°C to 100°C, and 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 the method shown in the following reaction scheme 4 or a method similar thereto.
Reaction Scheme 4

(The symbols in the formula have the same meanings as above.)

This production method includes a step of dehydrating and condensing 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) used is usually 2 to 3 moles, preferably 2 moles, per mole of compound (XII).
Examples of the base include sodium tert-butoxide, potassium methoxide, sodium methoxide, magnesium tert-butoxide, potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogencarbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, rubidium carbonate, and the like, and among these, potassium acetate is preferred.
The amount of the base used is usually 2 to 5 moles, preferably 2 to 3 moles, per mole of compound (XII).
The solvent is not particularly limited, but examples thereof include aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and among these, toluene is preferred.
The reaction temperature is preferably the 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 compared to the corresponding pinacol boronate ester. Therefore, as described in the test examples below, it can be easily purified with good recovery rates by silica gel chromatography (silica gel column chromatography, thin-layer silica gel chromatography, etc.). Furthermore, it was confirmed that compound (I) remains stable even under deprotection reaction conditions for the corresponding pinacol boronate ester to boronic acid (i.e., deprotection reaction conditions using hydrochloric acid-sodium periodate), and exhibits high stability under acidic conditions.

(Various functionalization methods using compound (I) of the present invention)
Compound (I) is not only more stable than the corresponding pinacol boronate ester, but can also be used in a wide variety of functionalization reactions, similar to the corresponding pinacol boronate ester. Representative 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 boronate esters.

(Biaryl Coupling Reaction (Suzuki-Miyaura Coupling Reaction))
Compound (VIII) can be produced by reacting compound (VII) with compound (I) in the presence of a metal catalyst and a base according to the method shown in the following reaction scheme 5 or a method similar thereto.
Reaction Scheme 5

(The symbols in the formula have the same meanings as above.)

The amount of compound (VII) used is usually 0.5 to 0.7 moles, preferably 0.7 moles, per mole of the boryl ester group of compound (I).
Examples of the metal catalyst include palladium catalysts such as palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride.diphenylphosphinoferrocene (PdCl ₂ (dppf)), and palladium on carbon(0); copper catalysts such as copper(I) iodide, copper(I) bromide, copper(I) chloride, and copper(II) chloride; nickel catalysts such as bis(1,5-cyclooctadiene)nickel(0) and bis(acetylacetonato)nickel(II); and ruthenium catalysts such as dichloro(p-cymene)ruthenium(II) dimer and ruthenium alumina. Palladium catalysts are preferred, and palladium(II) acetate is more preferred.
Furthermore, if necessary, a phosphine ligand such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (BrettPhos), tri-t-butylphosphine, tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos), or (S)-1-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (JosiPhos) may be added.
The amount of the metal catalyst used is usually 0.001 to 0.5 moles, preferably 0.005 to 0.1 moles, and more preferably 0.005 to 0.05 moles, per mole of the boryl ester group of compound (I).
The solvent can be arbitrarily selected depending on the type of metal catalyst used and other factors, and examples thereof include ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; 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 dimethyl sulfoxide; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and mixed solvents of these organic solvents with water, and among these, a mixed solvent of toluene and water is preferred.
Examples of the base include potassium hydroxide, potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, rubidium carbonate, and the like, and among these, tripotassium phosphate is preferred.
The amount of the base used is usually 1 to 10 moles, preferably 1 to 5 moles, more preferably 1.5 to 3 moles, per mole of the boryl ester group of compound (I).
The reaction temperature is usually 60°C to 120°C, preferably 90°C to 120°C, and more preferably 110°C.
The reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.

(Oxidation reaction)
Compound (IX) can be produced by reacting compound (I) with a peracid according to the method shown in the following reaction scheme 6 or a method similar thereto.
Reaction Scheme 6

(The symbols in the formula have the same meanings as above.)

The amount of peracid used is usually 1 to 2 moles, preferably 1 to 1.5 moles, per mole of the boryl ester group of compound (I).
Examples of peracids include sodium perborate (NaBO ₃ ), sodium periodate (under acidic conditions), and hydrogen peroxide, and among these, sodium perborate (NaBO ₃ ) or its hydrate is preferred.
The solvent can be arbitrarily selected depending on the type of peracid used and other factors, and examples thereof include ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; 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 dimethyl sulfoxide; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and mixed solvents of these organic solvents with water, and among these, a mixed solvent of tetrahydrofuran and water 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 1 to 48 hours, preferably 8 to 24 hours.

(Amination reaction)
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 the following reaction scheme 7 or a method analogous thereto.
Reaction Scheme 7

(The symbols in the formula have the same meanings as above.)

The amount of compound (X) used is usually 0.5 to 2 moles, preferably 0.5 to 1 mole, per mole of the boryl ester group of compound (I).
Examples of the metal catalyst include copper catalysts such as copper(II) acetate, copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(II) nitrate, copper(I) bis(trifluoromethanesulfonate), and copper(I) bis(trifluoroacetate); and nickel catalysts such as nickel(II) chloride, nickel(II) acetate, and nickel(II) nitrate. Of these, copper catalysts are preferred, and copper acetate is more preferred.
The amount of the metal catalyst used is usually 0.001 to 0.5 moles, preferably 0.005 to 0.1 moles, more preferably 0.01 to 0.05 moles, per mole of the boryl ester group of compound (I).
The solvent can be arbitrarily selected depending on the type of metal catalyst used and other factors, and examples thereof include ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; 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 dimethyl sulfoxide; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and mixed solvents of these organic solvents with water, and among these, acetonitrile is preferred.
Examples of the base include potassium acetate, sodium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogencarbonate, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, rubidium carbonate, and the like, and among these, cesium fluoride is preferred.
The amount of the base used is usually 0.5 to 10 moles, preferably 0.5 to 3 moles, more preferably 0.5 to 1 mole, per mole of the boryl ester group of compound (I).
The reaction temperature is usually 15°C to 100°C, preferably 20°C to 60°C, and more preferably 40°C.
The reaction time is usually 1 to 48 hours, preferably 12 to 24 hours.

The present invention is further explained in detail by the following manufacturing examples, examples, and test examples, but these do not limit the present invention and may be modified without departing from the scope of the present invention.

The reaction was monitored by thin layer chromatography using Merck 60 F254 silica gel plates (0.25 mm thick).
All melting points (mp) are uncorrected and were measured using a Yanaco MP-S3.
Infrared absorption (IR) spectra were measured by the thin film method using a Shimadzu FTIR IR Affinity 1S.
High-resolution mass spectrometry (HRMS) was measured using a JEOL JMS-S3000 (MALDI) or a JEOL JMS-700 (EI, CI, FAB).
¹ H and ¹³ C-NMR spectra were measured using a JEOL JNM-ECA500, a JEOL ECS400, and a JEOL ECS300 in deuterated chloroform as the solvent. ¹ H-NMR data are reported as chemical shifts (δ ppm), multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, dd = double doublet, dt = double triplet, brs = broad singlet), coupling constants (Hz), integrals, and assignments.
Flash chromatography was performed using silica gel 60N from Kanto Chemical Co., Ltd. (Tokyo, Japan).
In the thin layer chromatography, UV absorption (wavelength: 254 nm) of the compound was observed, and anisaldehyde or cerium ammonium molybdate was used as a color reagent.
Reagents and materials used in the following Preparations, Examples, and Test Examples are commercially available unless otherwise specified.
Unless otherwise specified, "room temperature" refers to a temperature of 15 to 30°C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified.

The following abbreviations are used in the following examples:
Mp: Melting point
M: Molar concentration
N: Normality
CDCl ₃ : deuterated chloroform
¹ H NMR: proton nuclear magnetic resonance
¹³ C NMR: Carbon nuclear magnetic resonance
_CH2Cl2 : _{dichloromethane}
CH ₃ CN: acetonitrile
t-BuCN: pivalonitrile
Et ₃ N: Triethylamine
TiCl ₄ : Titanium tetrachloride
EtMgBr: Ethyl magnesium bromide
AcOK: Potassium acetate
i-PrMgCl-LiCl: Isopropyl magnesium chloride-lithium chloride complex
HRMS: High resolution mass spectrometry
THF: tetrahydrofuran
SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
DMSO: dimethyl sulfoxide
PdCl ₂ (dppp) : [1,3-bis(diphenylphosphino)propane]palladium(II) dichloride

Production Example 1
Synthesis of 3,4-diethylhexane-3,4-diol

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 under an argon atmosphere to be used as activated zinc powder.
To a suspension of activated zinc powder (13 g, 0.20 mol) in dichloromethane (0.40 L) was added a 1.0 M solution of titanium tetrachloride in dichloromethane (0.10 L, 0.10 mol), and then pivalonitrile (40 mL, 0.40 mol) was slowly added dropwise at 0°C. The reaction suspension was stirred for an additional 30 minutes at room temperature, and then a solution of diethyl ketone (11 mL, 0.10 mol) in dichloromethane (0.25 L) was slowly added dropwise at 0°C. After the addition, the reaction mixture was stirred at room temperature for 16 hours, and then saturated aqueous ammonium chloride solution was added at room temperature to quench the reaction. The reaction solution was filtered through Celite, extracted three times with dichloromethane, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 9:1) to obtain 3,4-diethylhexane-3,4-diol (6.2 g, yield 71%) as a colorless solid.
Mp 25.7-26.1℃;
¹ H NMR (400MHz, CDCl ₃ ) δ: 0.94 (12H, t, J= 7.5 Hz), 1.58-1.65 (8H, m), 1.98 (2H, s);
^13C NMR (100MHz, CDCl ₃ ) δ: 9.0, 27.3, 78.8.

Production Example 2
Synthesis of 4,5-dipropyloctane-4,5-diol

To a suspension of activated zinc powder (6.5 g, 0.10 mol) in dichloromethane (0.20 L) prepared by the same method as in Preparation Example 1, a 1.0 M solution of titanium tetrachloride in dichloromethane (50 mL, 50 mmol) was added, and then pivalonitrile (22 mL, 0.20 mol) was slowly added dropwise at 0°C. The reaction suspension was stirred for an additional 30 minutes at room temperature, and then a solution of 4-heptanone (7.0 mL, 50 mmol) in dichloromethane (0.15 L) was slowly added dropwise at 0°C. After the addition, the 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. The reaction solution was filtered through Celite, extracted three times with dichloromethane, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=90:10) to obtain 4,5-dipropyloctane-4,5-diol (3.0 g, yield 52%) as a colorless solid.
Mp 75.1-76.3 °C;
¹ H NMR (300MHz, CDCl ₃ ) δ: 0.91 (12H, t, J= 7.0 Hz), 1.31-1.57 (16H, m), 1.91 (2H, s);
^13C NMR (100MHz, CDCl ₃ ) δ: 15.1, 17.8, 38.0, 78.7.

Production Example 3
Synthesis of 3,4-dimethylhexane-3,4-diol

Under a nitrogen stream, a solution of diacetyl (4.4 mL, 50 mmol) in THF (0.10 L) was cooled to 0°C, and a 3.0 M solution of ethylmagnesium bromide in THF (4.2 mL, 0.13 mol) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for an additional 18 hours, and then the reaction was quenched with saturated aqueous ammonium chloride. The reaction solution was extracted three times with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 80:20) to obtain 3,4-dimethylhexane-3,4-diol (diastereomeric ratio; 1.9:1) (2.0 g, yield 27%) as a colorless oil.
¹ H NMR (300MHz, CDCl ₃ ) δ: 0.96 (6H, t, J= 7.5 Hz), 1.12 (12/3H, d, J= 0.5 Hz), 1.14 (6/3H, d, J= 0.5 Hz), 1.37-1.49 (8/3H, m), 1.61-1.70 (4/3H, m), 1.78 (2H, brs);
¹³ C NMR (100MHz, CDCl ₃ ) δ: 7.96 (2/3C), 8.02 (1/3C), 20.0 (2/3C), 20.5 (1/3C), 28.1 (1/3C), 28.5 (2/3C), 77.2.

Production Example 4
Synthesis of 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bis(1,3,2-dioxaborolane)

Under a nitrogen stream, 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 diluted in toluene (40 mL) and heated to reflux for 16 hours using a Dean-Stark apparatus. The reaction mixture was then allowed to cool to room temperature, filtered through Celite, and the solvent was evaporated to give 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bis(1,3,2-dioxaborolane) (1.5 g, yield 99%) as a colorless solid.
Mp 62.7-64.5 °C;
¹ H NMR (300MHz, CDCl ₃ ) δ: 0.90 (24H, t, J= 7.5 Hz), 1.60-1.75 (16H, m);
^13C NMR (100MHz, CDCl ₃ ) δ: 8.9, 26.4, 88.3.

Examples I-1 to I-21 (Synthesis of Compounds (I-1) to (I-21))
(Production Method 1)
General method for preparing 3,4-diethylhexane-3,4-diol esters of boronic acids (1)
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 stirred at room temperature for 16 hours under a nitrogen stream, and then water was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the 3,4-diethylhexane-3,4-diol ester of arylboronic acid.

(Production Method 2)
General method for preparing 3,4-diethylhexane-3,4-diol esters of boronic acids (2)
Under a nitrogen stream, a 1.0 M solution of i-PrMgCl-LiCl in THF (1.2 equivalents) was slowly added dropwise to a THF solution of an aryl halide (halogen atom: 1.0 mol) at −40°C, followed by stirring at the same temperature for 12 hours (or a 2.7 M solution of n-butyllithium in THF (1.2 mol) was slowly added dropwise at −78°C, followed by stirring at the same temperature for 1 hour). Subsequently, trimethoxyborane (2.0 mol) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was then quenched by adding saturated aqueous ammonium chloride. 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, followed by stirring at room temperature. The resulting solution was concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the 3,4-diethylhexane-3,4-diol ester of arylboronic acid.

(Production Method 3)
General method for preparing 3,4-diethylhexane-3,4-diol esters of boronic acids (3)
In a Schlenk tube, PdCl ₂ (dppp)-CH ₂ Cl ₂ (5.0 mol %), potassium acetate (3.0 mol), and 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bis(1,3,2-dioxaborolane) (1.5 mol) were added, and the mixture was placed under an argon atmosphere. A DMSO solution (1.0 M) of aryl halide (halogen atom: 1.0 mol) was then added, and the mixture was stirred at 80°C, after which the reaction mixture was allowed to cool to room temperature. The resulting reaction mixture was diluted with ethyl acetate, filtered through silica gel, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3,4-diethylhexane-3,4-diol ester of arylboronic acid.

The compounds of Examples I-1 to I-21 were synthesized according to or in accordance with 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
Evaluation of the Stability of Compound (I) Against Silica Gel Chromatography [1] Comparative Experiment of Compounds (I-1), (I-18), and (I-19) with Phenylboronic Acid Pinacol Ester (Comparative Example 1) Pure Compounds (I-1), (I-18), (I-19), and phenylboronic acid pinacol ester (Comparative Example 1), each 100 mg, were dissolved in dichloromethane (1.0 mL) separately in a recovery flask, and silica gel (approximately 600 mg) was added. The solvent was removed from this suspension under reduced pressure using an evaporator, and the test compound was adsorbed onto the silica gel (the entire process from mixing to adsorption took approximately 5 minutes). This was placed on a silica gel column (inner diameter 20 mm) approximately 10 cm high (pretreated or not with 1% triethylamine) and eluted with ethyl acetate (in the presence or absence of 1% triethylamine) (retention time: approximately 1 minute). The solvent was distilled off from the obtained fraction under reduced pressure, and after confirming by ¹ H NMR that the chemical structure was maintained, the fraction was weighed. The results are shown in Table 2 below.

[2] Comparative Experiment of Compounds (I-4), (I-20), and (I-21) with 1,4-Phenylenediboronic Acid Pinacol Ester (Comparative Example 2) 50 mg of each of pure Compounds (I-4), (I-20), (I-21), and 1,4-phenylenediboronic Acid Pinacol Ester (Comparative Example 2) were dissolved in dichloromethane (1.0 mL) separately in a recovery flask, and silica gel (approximately 600 mg) was added. The solvent was removed from this suspension under reduced pressure using an evaporator, and the test compound was adsorbed onto the silica gel (the entire process from mixing to adsorption took approximately 5 minutes). This was placed on a silica gel column (inner diameter 20 mm) approximately 10 cm high and eluted with ethyl acetate (with or without triethylamine) (retention time: approximately 1 minute). The solvent was removed from the resulting fraction under reduced pressure, and after confirming the maintenance of the chemical structure by ¹ H NMR, the fraction was weighed. The results obtained are shown in Table 3 below.

[3] Comparative Experiments of Compounds (I-10), (I-11), (I-13), and (I-15) with the Corresponding Heteroarylboronic Acid Pinacol Esters (Comparative Examples 3, 4, 5, and 6) 50 mg of each of pure Compounds (I-10), (I-11), (I-13), and (I-15), and the corresponding heteroarylboronic acid pinacol esters (Comparative Examples 3, 4, 5, and 6), as test compounds, were dissolved in dichloromethane (1.0 mL) separately in a recovery flask, and silica gel (approximately 600 mg) was added. The solvent was removed from this suspension under reduced pressure using an evaporator, and the test compounds were adsorbed onto the silica gel (the entire process from mixing to adsorption took approximately 5 minutes). This was placed on top of a silica gel column (inner diameter 20 mm) approximately 10 cm high, and eluted with ethyl acetate (retention time: approximately 1 minute). The solvent was distilled off from the obtained fraction under reduced pressure, and after confirming by ¹ H NMR that the chemical structure was maintained, the fraction was weighed. The results are shown in Table 4 below.

Tables 2, 3, and 4 confirm that compound (I) is extremely stable on silica gel compared to the corresponding pinacol ester.

Furthermore, thin-layer chromatography of compound (I-2) and compound (I-4) and their corresponding pinacol esters, p-tolylboronic acid pinacol ester (Comparative Example 7) and 1,4-phenylenediboronic acid pinacol ester (Comparative Example 2), revealed that while tailing was observed for both of the corresponding pinacol esters, compound (I-2) and compound (I-4) were observed as clean spots, confirming the stability of compound (I) on silica gel (see Figure 1). This result is in good agreement with the results in Tables 2, 3, and 4.

Test Example 2
Evaluation of the stability of compound (I) under deprotection reaction conditions of pinacol ester The pinacol ester of p-tolylboronic acid (Comparative Example 7) was deprotected with sodium periodate under acidic conditions of hydrochloric acid (1N hydrochloric acid) in a THF-water mixed solvent, and converted to an 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 87% yield. It was also confirmed that compound (I-2) was stable under acidic conditions (hydrochloric acid) and basic conditions (in the presence of sodium hydroxide or lithium hydroxide).

The results of Test Examples 1 and 2 showed that compound (I) exhibits remarkable stability compared to the corresponding boronic acid pinacol ester and can be easily and efficiently isolated and purified by silica gel chromatography.

Test Example 3 (Various functionalization reactions using compound (I))
[1] Suzuki-Miyaura coupling reaction using compound (I) (Production Method 4)
Under a nitrogen stream, in a Schlenk tube, a toluene/water (10/1) solution (1.0 M) of compound (I) (boryl group: 1.5 mol), aryl halide (compound (VII)) (1.0 mol), palladium acetate (1.0 mol%), SPhos (2.0 mol%), and tripotassium phosphate (2.0 mol) was heated and stirred at 110° C. for 24 hours. The reaction mixture was returned to room temperature, diluted with ethyl acetate, and filtered through silica gel. The solvent was distilled off under reduced pressure using an evaporator, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain a biaryl compound.
Various biaryl compounds were synthesized according to or in accordance with Production Method 4. Tables 5-1 to 5-3 below show the chemical structures, yields, and physical property data of each raw material compound and biaryl compound.

[2] Oxygen Functional Group Introduction Reaction Using Compound (I) (Compound (I-2)) 4-Methylphenylboronic acid 3,4-diethylhexane-3,4-diol ester (Compound (I-2)) (27 mg, 0.10 mmol), a THF/H ₂ O=1/1 solution (1.0 mL), and NaBO ₃ ·4H ₂ O (77 mg, 0.50 mmol) were added and stirred at room temperature for 12 hours. After filtration through Celite, the mixture was separated into saturated brine and ethyl acetate. After dehydration over magnesium sulfate, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=95/5) to obtain p-cresol (10 mg; yield 96%) as a colorless oil.
¹ H NMR (400MHz, CDCl ₃ ) δ: 2.28 (3H, s), 4.66 (1H, brs), 6.73 (2H, d, J= 8.5 Hz), 7.04 (2H, d, J= 8.5 Hz);
^13C NMR (100MHz, CDCl ₃ ) δ: 20.5, 115.0, 129.96, 130.04, 153.2.

[3] Nitrogen Functional Group Introduction Reaction Using Compound (I) (Compound (I-2)) CsF (15 mg, 0.10 mmol) was placed in a slotted test tube, flame-dried, and allowed to cool. Then, Cu(OAc) ₂ (2.0 mg, 0.010 mmol) was added to replace the oxygen. Then, 4-methylphenylboronic acid 3,4-diethylhexane-3,4-diol ester (Compound (I-2)) (55 mg, 0.20 mmol) and butylamine (10 μL, 0.10 mmol) were diluted with acetonitrile, added via syringe, and stirred at 40°C for 24 hours. The reaction solution was filtered through silica gel, and the solvent was removed under reduced pressure using an evaporator. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 90:10) to obtain N-butyl-4-methylaniline (11 mg; yield 67%) as a brown oil.
¹ H NMR (400MHz, CDCl ₃ ) δ: 0.94 (3H, t, J= 7.0 Hz), 1.37-1.46 (2H, m), 1.57-1.64 (2H, m), 2.24 (3H, s), 3.09 (2H, t, J= 7.0 Hz), 6.58 (2H, d, J= 8.0 Hz), 6.99 (2H, d, J= 8.0 Hz);
^13C NMR (100MHz, CDCl ₃ ) δ: 13.8, 20.2, 20.5, 31.0, 45.4, 114.5, 126.8, 128.8, 129.8.

The results obtained in Test Example 3 [2] and [3] are shown in Table 6 below. The values in parentheses in the yield column in Table 6 indicate the yield when the corresponding pinacol ester is used as a raw material.

The results of Test Example 3 [1] to [3] confirmed that in various functionalization reactions, compound (I) exhibits reactivity equivalent to or superior to that of the corresponding boronic acid pinacol ester.

The present invention provides novel aromatic boronic acid esters that are extremely stable and can be easily isolated and purified without being decomposed or adsorbed even on silica gel column chromatography or thin-layer chromatography. Furthermore, the compounds of the present invention exhibit reactivity equivalent to or superior to that of the conventionally widely used aromatic boronic acid pinacol esters. Therefore, they are applicable to Suzuki-Miyaura coupling reactions and various functionalization reactions, and are extremely useful as raw materials or synthetic intermediates for various pharmaceuticals and functional materials.

This application is based on Patent Application No. 2021-031904 filed in Japan on March 1, 2021, the contents of which are incorporated in their entirety into this specification.

Claims (5)

Formula (I):
[In the formula,
represents a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may further be substituted by 1 to 3 substituents selected from the following (substituent group Z 3 ⁾ ;
R ¹ and R ³ each independently represent a methyl group, an ethyl group, or an n-propyl group;
^R2 and ^R4 each independently represent an ethyl group or an n-propyl group; and n represents 1 or 2 .
(Substituent group Z ³ )
(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 optionally substituted by a halogen atom ,
(8) (a) a halogen atom,
(b) a C _1-6 alkyl group optionally substituted with a halogen atom , and
(c) a C _1-6 alkoxy group optionally substituted with a halogen atom
A C _3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of
(9) (a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a C _1-6 alkyl group optionally substituted by a halogen atom ;
(e) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(f) a formyl group,
(g) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom , and
(h) a C _1-6 alkyl-carbonyloxy group optionally substituted with a halogen atom
a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(10) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(11) formyl group,
(12) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(13) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom ,
(14) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom ,
(15) a C _1-6 alkyl-carbonyloxy group optionally substituted by 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 by a halogen atom ;
(c) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(d) a formyl group,
(e) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(f) a C _1-6 alkoxy-carbonyl group optionally substituted with a halogen atom or a C _6-14 aryl group,
(g) a C _6-14 aryl- carbonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(h) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom , and
(i) a C _6-14 arylsulfonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom.
an amino group which may be mono- or di-substituted with a substituent selected from the group consisting of
(17) a C _1-6 alkylsulfanyl group optionally substituted by a halogen atom ,
(18) trisubstituted silyl groups,
(19) A C _1-6 alkylsulfonyloxy group optionally substituted by a halogen atom , and
(20) A C _6-14 arylsulfonyloxy group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted with a halogen atom, and a C _1-6 alkoxy group optionally substituted with a halogen atom.]
A compound represented by the formula (I) or a salt thereof . 2. The compound or salt thereof according to claim 1 , wherein all of R ¹ , R ² , R ³ and R ⁴ are an ethyl group or an n-propyl group. Formula (II):
[In the formula,
represents a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may be further substituted by 1 to 3 substituents selected from the following (substituent group Z 3 ) , and ⁿ represents 1 or 2 .
(Substituent group Z ³ )
(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 optionally substituted by a halogen atom ,
(8) (a) a halogen atom,
(b) a C _1-6 alkyl group optionally substituted with a halogen atom , and
(c) a C _1-6 alkoxy group optionally substituted with a halogen atom
A C _3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of
(9) (a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a C _1-6 alkyl group optionally substituted by a halogen atom ;
(e) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(f) a formyl group,
(g) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom , and
(h) a C _1-6 alkyl-carbonyloxy group optionally substituted with a halogen atom
a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(10) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(11) formyl group,
(12) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(13) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom ,
(14) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom ,
(15) a C _1-6 alkyl-carbonyloxy group optionally substituted by 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 by a halogen atom ;
(c) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(d) a formyl group,
(e) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(f) a C _1-6 alkoxy-carbonyl group optionally substituted with a halogen atom or a C _6-14 aryl group,
(g) a C _6-14 aryl- carbonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(h) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom , and
(i) a C _6-14 arylsulfonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom.
an amino group which may be mono- or di-substituted with a substituent selected from the group consisting of
(17) a C _1-6 alkylsulfanyl group optionally substituted by a halogen atom ,
(18) trisubstituted silyl groups,
(19) A C _1-6 alkylsulfonyloxy group optionally substituted by a halogen atom , and
(20) A C _6-14 arylsulfonyloxy group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted with a halogen atom, and a C _1-6 alkoxy group optionally substituted with a halogen atom.]
or a salt thereof, and a compound represented by formula (III):
[In the formula,
R ¹ and R ³ each independently represent a methyl group, an ethyl group, or an n-propyl group;
^R2 and ^R4 each independently represent an ethyl group or an n-propyl group.
The method of the present invention comprises the step of reacting a compound represented by formula (I):
[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula: Formula (IV):
[In the formula,
represents a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may further be substituted by 1 to 3 substituents selected from the following (substituent group Z 3 ⁾ ;
^X1 represents a halogen atom; and n represents 1 or 2 .
(Substituent group Z ³ )
(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 optionally substituted by a halogen atom ,
(8) (a) a halogen atom,
(b) a C _1-6 alkyl group optionally substituted with a halogen atom , and
(c) a C _1-6 alkoxy group optionally substituted with a halogen atom
A C _3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of
(9) (a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a C _1-6 alkyl group optionally substituted by a halogen atom ,
(e) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(f) a formyl group,
(g) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom , and
(h) a C _1-6 alkyl-carbonyloxy group optionally substituted with a halogen atom
a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(10) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(11) formyl group,
(12) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(13) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom ,
(14) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom ,
(15) a C _1-6 alkyl-carbonyloxy group optionally substituted by 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 by a halogen atom ;
(c) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(d) a formyl group,
(e) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(f) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom or a C _6-14 aryl group,
(g) a C _6-14 aryl- carbonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(h) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom , and
(i) a C _6-14 arylsulfonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom.
an amino group which may be mono- or di-substituted with a substituent selected from the group consisting of
(17) a C _1-6 alkylsulfanyl group optionally substituted by a halogen atom ,
(18) trisubstituted silyl groups,
(19) A C _1-6 alkylsulfonyloxy group optionally substituted by a halogen atom , and
(20) A C _6-14 arylsulfonyloxy group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted with a halogen atom, and a C _1-6 alkoxy group optionally substituted with a halogen atom.]
or a salt thereof with isopropyl magnesium chloride-lithium chloride complex or n-butyllithium, and then reacted with trimethoxyborane, followed by reacting a compound represented by formula (III):
[In the formula,
R ¹ and R ³ each independently represent a methyl group, an ethyl group, or an n-propyl group;
^R2 and ^R4 each independently represent an ethyl group or an n-propyl group.
with a compound represented by formula (I):
[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula: Formula (V):
[In the formula,
represents a phenyl group, a naphthyl group, a pyridyl group, a furyl group or a thienyl group, each of which may further be substituted by 1 to 3 substituents selected from the following (substituent group Z 3 ⁾ ;
^X2 represents a halogen atom or a trifluoromethanesulfonyloxy group; and n represents 1 or 2 .
(Substituent group Z ³ )
(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 optionally substituted by a halogen atom ,
(8) (a) a halogen atom,
(b) a C _1-6 alkyl group optionally substituted with a halogen atom , and
(c) a C _1-6 alkoxy group optionally substituted with a halogen atom
A C _3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of
(9) (a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a C _1-6 alkyl group optionally substituted by a halogen atom ;
(e) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(f) a formyl group,
(g) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom , and
(h) a C _1-6 alkyl-carbonyloxy group optionally substituted with a halogen atom
a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of:
(10) a C _1-6 alkoxy group optionally substituted by a halogen atom ,
(11) formyl group,
(12) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(13) a C _1-6 alkoxy-carbonyl group optionally substituted by a halogen atom ,
(14) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom ,
(15) a C _1-6 alkyl-carbonyloxy group optionally substituted by 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 by a halogen atom ;
(c) a C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(d) a formyl group,
(e) a C _1-6 alkyl-carbonyl group optionally substituted by a halogen atom ,
(f) a C _1-6 alkoxy-carbonyl group optionally substituted with a halogen atom or a C _6-14 aryl group,
(g) a C _6-14 aryl- carbonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom;
(h) a C _1-6 alkylsulfonyl group optionally substituted by a halogen atom , and
(i) a C _6-14 arylsulfonyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted by a halogen atom, and a C _1-6 alkoxy group optionally substituted by a halogen atom.
an amino group which may be mono- or di-substituted with a substituent selected from the group consisting of
(17) a C _1-6 alkylsulfanyl group optionally substituted by a halogen atom ,
(18) trisubstituted silyl groups,
(19) A C _1-6 alkylsulfonyloxy group optionally substituted by a halogen atom , and
(20) A C _6-14 arylsulfonyloxy group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group optionally substituted with a halogen atom, and a C _1-6 alkoxy group optionally substituted with a halogen atom.]
or a salt thereof, in the presence of a metal catalyst,
[In the formula,
R ¹ and R ³ each independently represent a methyl group, an ethyl group, or an n-propyl group;
^R2 and ^R4 each independently represent an ethyl group or an n-propyl group.
with a compound represented by formula (I):
[Each symbol in the formula has the same meaning as defined above.]
A method for producing a compound represented by the formula: