JP2015214525A - PRODUCTION METHOD OF α-HETEROCYCLYL ACETIC ACID COMPOUND - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method of α-heterocyclyl acetic acid compound which uses an α,β-unsaturated carboxylic acid as a raw material and is useful as an intermediate for synthesis of medicines.SOLUTION: A production method of α-heterocyclyl acetic acid compound comprises converting an α,β-unsaturated carboxylic acid compound of formula (1) into a compound of formula (2) in the presence of phenylboronic acid and a tertiary amine having a hydrogen bond donating part within the molecule. In formulae (1) and (2), n is 1 or 2; Rand Rare H, a halogen atom, an optionally substituted 1-8C alkyl group or an optionally substituted phenyl group; Rand Rmay bind to each other to form an optionally substituted benzene ring; ** represents an asymmetric carbon atom.

Description

  The present invention relates to a method for producing an α-heterocyclylacetic acid compound useful as an intermediate for pharmaceutical synthesis.

  Α-Heterocyclylacetic acid is useful as an intermediate for the production of physiologically active substances such as pharmaceuticals and agricultural chemicals such as peripentonine C and raxofelast represented by the following structural formula, and various synthetic studies have been conducted.

  For example, as disclosed in Patent Document 1 and Non-Patent Documents 1 and 2, α, β-unsaturated ketone or α, β-unsaturated ester is used as a raw material, and α -Methods for producing heterocyclyl acetic acid derivatives have been reported.

WO2014 / 046172

J. et al. Am. Chem. Soc. , 2011, vol. 133, p16711-16713 Angew. Chem. Int. Ed. , 2013, vol. 52, p11114-11118

  An object of the present invention is to provide a method for producing an α-heterocyclylacetic acid compound in high yield from α, β-unsaturated carboxylic acid as a raw material.

As a result of intensive studies to solve the above problems, the present inventors have made intramolecular Michael addition using a compound represented by the following general formula (1) by causing two specific compounds to act as a catalyst. As a result of the reaction, it was found that an α-heterocyclylacetic acid compound can be produced with high yield, and the present invention has been completed.
That is, the present invention is as follows.
[1] General formula (1):

(Where
n represents 1 or 2;
R ¹ and R ² independently represent a hydrogen atom, a halogen atom, an optionally substituted C _1-8 alkyl group, or an optionally substituted phenyl group, or R ¹ and R ² May be combined with CH-CH to which is bonded to form an optionally substituted benzene ring. )
A compound represented by general formula (3):
Ar-B (OH) ₂ (3)
(Where
Ar represents an optionally substituted phenyl group. )
In the presence of a boronic acid represented by formula (hereinafter also referred to as compound (3)) and a tertiary amine compound having a hydrogen bond donating site in the molecule, general formula (2):

(In the formula, ** represents an asymmetric carbon atom, and other symbols are as defined above.)
A method for producing a compound represented by the general formula (2), which is converted to a compound represented by the formula (hereinafter also referred to as a compound (2)).
[2] The hydrogen bond donating site is

(Where
R ^a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Y represents an oxygen atom, a sulfur atom, or NR ^b (wherein R ^b represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or N═CNHR ^a may be combined with ^a to form an optionally substituted nitrogen-containing heterocyclic ring);
* Indicates a binding site. )
The production method according to the above [1], which is a partial structure represented by
[3] The tertiary amine compound has the general formula (4):

(Where
R ^a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Y represents an oxygen atom, a sulfur atom, or NR ^b (wherein R ^b represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or N═CNHR ^a may be combined with ^a to form an optionally substituted nitrogen-containing heterocyclic ring);
R ^c , R ^d , R ^e and R ^{f each} independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ^c and R ^d are bonded to each other. Together with CH—CH, which may form an optionally substituted saturated carbocycle, together with CH—N to which R ^d and R ^f are bonded, A saturated nitrogen-containing heterocycle may be formed, or together with CH-N to which R ^d and R ^e are bonded, a saturated nitrogen-containing heterocycle that may be substituted may be formed. Often, R ^e and R ^f may be combined with the nitrogen atom to which they are bonded to form an optionally substituted saturated nitrogen-containing heterocycle. )
The manufacturing method of said [1] description which is a tertiary amine compound (henceforth a compound (4)) represented by these.
[4] A tertiary amine compound is

The production method of the above-mentioned [1], which is selected from the above.
[5] The production method according to any one of [1] to [4], wherein the tertiary amine compound is an asymmetric catalyst, and the compound represented by the general formula (2) is an optically active compound.

[6] General formula (1):

(In the formula, n, R ¹ and R ² have the same meanings as the above [1].)
A compound represented by the general formula (3a):
Ar ^a -B (OH) ₂ (3a)
(In the formula, Ar ^a represents a phenyl group substituted at the 2-position with CH ₂ —NR ⁴ R ⁵ , and R ⁴ and R ⁵ independently represent a C _1-8 alkyl group, or R ⁴ And a nitrogen atom to which R ⁵ is bonded may form a saturated nitrogen-containing heterocyclic ring which may be substituted.
In the presence of a boronic acid represented by formula (2) (hereinafter also referred to as compound (3a)):

(Each symbol in the formula is as defined above.)
A method for producing a compound represented by the general formula (2), wherein the compound is converted to a compound represented by the formula (2).

  According to the present invention, an α-heterocyclylacetic acid compound can be produced with high yield.

Hereinafter, the present invention will be described in detail.
In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

As used herein, "hydrocarbon _group" generally refers to the _{C 1-16} hydrocarbon group, as the _{"C 1-16} hydrocarbon group", for _{example, C 1-10 alkyl, C 2-10} alkenyl Group, C _2-10 alkynyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group, C _6-14 aryl group, C _7-16 aralkyl group, etc. Can be mentioned.

In the present specification, examples of the “C _1-10 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, heptyl, octyl, nonyl, decyl and the like. Of these, a C _1-6 alkyl group is preferable, and a C _1-4 alkyl group is more preferable.
In the present specification, examples of the “C _1-8 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, heptyl, octyl and the like. Among _them, preferred is _{C 1-6 alkyl, C 1-4} alkyl group is more preferable.
Examples of the “C _1-6 alkyl (group)” in the present specification 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. Especially, _C1-4 alkyl (group) is preferable and _C1-2 alkyl (group) is more preferable.

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, neopentyl Examples include oxy and hexyloxy. Among these, C _1-4 alkoxy (group) is preferable.

In the present specification, examples of the “C _2-10 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, 5-hexenyl, 1-heptenyl, 1-octenyl and the like Is mentioned. Of these, a C _2-6 alkenyl group is preferable.
Examples of the “C _2-6 alkenyl (group)” in the present specification include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples include 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, examples of the “C _2-10 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C _2-6 alkynyl group is preferable.
Examples of the “C _2-6 alkynyl (group)” in the present specification include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, Examples include 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.

In the present specification, examples of the “C _3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, a C _3-6 cycloalkyl group is preferable.
Examples of the “C _3-8 cycloalkyl (group)” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, a C _3-6 cycloalkyl group is preferable.

In the present specification, examples of the “C _3-10 cycloalkenyl group” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl. Etc. Of these, a C _4-6 cycloalkenyl group is preferable.
Examples of the “C _3-8 cycloalkenyl (group)” in the present specification include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexene-1. -Yl and the like. Of these, a C _4-6 cycloalkenyl group is preferable.

In the present specification, examples of the “C _4-10 cycloalkadienyl group” include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene- 1-yl and the like can be mentioned. Of these, a C _4-6 cycloalkadienyl group is preferable.
Examples of the “C _4-8 cycloalkadienyl (group)” in the present specification include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclo And hexadien-1-yl. Of these, a C _4-6 cycloalkadienyl group is preferable.

In the present specification, examples of the “C _6-14 aryl group” include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, a C _6-10 aryl group is preferable.

In the present specification, examples of the “C _7-16 aralkyl group” include benzyl, 1-phenylethyl, 2-phenylethyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like. Of these, a C _7-13 aralkyl group is preferable.

  In the present specification, “heterocyclic group” means “aromatic heterocyclic group” or “non-aromatic heterocyclic group”.

In the present specification, the “aromatic heterocyclic group” means aromaticity containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Means a monocyclic or polycyclic (fused) heterocyclic group shown.
In the present specification, examples of the “monocyclic aromatic heterocyclic group” include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (1,2,4-triazolyl, 1,2,3- Triazolyl), tetrazolyl, triazinyl and the like, such as a 5- to 8-membered monocyclic aromatic heterocyclic group. Of these, a 5- or 6-membered monocyclic aromatic heterocyclic group is preferable.

  In the present specification, the “fused aromatic heterocyclic group” means that the monocyclic aromatic heterocyclic group is condensed with a monocyclic aromatic ring (preferably a benzene ring or a monocyclic aromatic heterocyclic ring). Quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl , Pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, thienopyridyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, thienopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, thienopyrimidinyl, and the like.

In the present specification, the “non-aromatic heterocyclic group” means aromaticity containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Means a monocyclic or polycyclic (fused) heterocyclic group.
In the present specification, examples of the `` monocyclic non-aromatic heterocyclic group '' include azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, Dioxolyl, dioxolanyl, dihydrooxadiazolyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl (eg, 2,3,4,4) And 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as 5-tetrahydro-1H-1,2,3-triazol-1-yl). Of these, a 5- or 6-membered monocyclic non-aromatic heterocyclic group is preferable.

  In the present specification, the “fused non-aromatic heterocyclic group” means that the monocyclic non-aromatic heterocyclic group is a monocyclic aromatic ring (eg, benzene ring, monocyclic aromatic heterocyclic ring) or Means a group fused with a monocyclic non-aromatic ring (eg, cycloalkane, monocyclic non-aromatic heterocycle), such as dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl , Dihydrobenzodioxinyl, dihydrobenzodioxepinyl, tetrahydrobenzofuranyl, chromenyl, dihydrochromenyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, dihydrophthalazinyl, etc. It is done.

In the present specification, the “cyclic amino group” includes at least one nitrogen atom in addition to a carbon atom as a ring-constituting atom, and a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. It means a monocyclic or polycyclic (fused) heterocyclic group which may contain four.
In the present specification, examples of the “monocyclic cyclic amino group” include 4- to 8-membered aromatic monocyclic cyclic amino groups such as pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl;
Azetidin-1-yl, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, piperazin-1-yl, hexamethyleneimin-1-yl, oxazolidine-3-yl, thiazolidin-3-yl, imidazolidine-1- Examples thereof include 4- to 8-membered non-aromatic monocyclic cyclic amino groups such as yl and pyrazolidin-1-yl. Of these, a 5- or 6-membered aromatic or non-aromatic monocyclic cyclic amino group is preferable.
In the present specification, the “fused cyclic amino group” means a group obtained by condensing the monocyclic cyclic amino group with a monocyclic aromatic ring (preferably a benzene ring or a monocyclic aromatic heterocyclic ring), or Means a group obtained by partial saturation of the group, for example, indol-1-yl, isoindol-2-yl, indolin-1-yl, isoindoline-2-yl, tetrahydroquinolin-1-yl, tetrahydroisoquinoline -2-yl and the like. Of these, a 5- or 6-membered aromatic or non-aromatic monocyclic cyclic amino group condensed with a benzene ring is preferable.

In the present specification, the “nitrogen-containing heterocycle” refers to a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, which contains at least one nitrogen atom in addition to a carbon atom as a ring-constituting atom. Means a monocyclic or polycyclic (fused) heterocycle which may contain ˜4.
In the present specification, as the “monocyclic nitrogen-containing heterocycle”, a 4- to 8-membered aromatic monocyclic heterocycle such as pyrrole, pyrazole, imidazole, etc .;
Examples thereof include 4- to 8-membered non-aromatic monocyclic heterocycles such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, and pyrazolidine. Of these, a 5- or 6-membered aromatic or non-aromatic monocyclic nitrogen-containing heterocyclic ring is preferable.
In the present specification, the “fused nitrogen-containing heterocycle” is a group in which the monocyclic nitrogen-containing heterocycle is condensed with a monocyclic aromatic ring (preferably, a benzene ring or a monocyclic aromatic heterocycle). Or a group obtained by partial saturation of the group, for example, indole, isoindole, indoline, isoindoline, tetrahydroquinoline (eg, 1,2,3,4-tetrahydroquinoline), tetrahydroisoquinoline (eg, 1 , 2,3,4-tetrahydroisoquinoline), dihydroquinazoline (eg, 3,4-dihydroquinazoline), 1,1-dioxide dihydrobenzothiadiazine (eg, 1,1-dioxide-3,4-dihydro-) 1,2,4-benzothiadiazine) and the like. Of these, a 5- or 6-membered aromatic or non-aromatic monocyclic nitrogen-containing heterocyclic ring condensed with a benzene ring is preferable.

In the present specification, the “saturated carbocycle” means a saturated monocyclic or polycyclic (condensed) carbocycle composed of only carbon atoms as ring-constituting atoms, specifically, cyclopropane, Examples thereof include C _3-10 cycloalkanes such as cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane, and condensed rings thereof (decahydronaphthalene and the like).

  In the present specification, the “saturated nitrogen-containing heterocycle” is a 4- to 8-membered saturated single atom such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine and the like. Examples thereof include cyclic nitrogen-containing heterocycles.

In the present specification, “optionally substituted C _1-6 alkyl group”, “optionally substituted phenyl group”, “optionally substituted benzene ring”, “optionally substituted carbon” Hydrogen group "," optionally substituted heterocyclic group "," optionally substituted nitrogen-containing heterocyclic ring "," optionally substituted saturated carbocycle "and" optionally substituted nitrogen-containing " Examples of the “substituent” of the “heterocycle” include the following substituent A.
[Substituent A]
C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _4-8 cycloalkadienyl group, C _{6-6 A 14} aryl group, a C _7-16 aralkyl group, a heterocyclic group;
Hydroxy group, C _1-6 alkoxy group (C _1-6 alkyloxy group), C _2-6 alkenyloxy group, C _2-6 alkynyloxy group, C _3-8 cycloalkyloxy group, C _3-8 cycloalkenyl group An oxy group, a C _4-8 cycloalkadienyloxy group, a C _6-14 aryloxy group, a C _7-16 aralkyloxy group, a heterocyclic oxy group;
Formyl group, C _1-6 alkyl-carbonyl group, C _2-6 alkenyl-carbonyl group, C _2-6 alkynyl-carbonyl group, C _3-8 cycloalkyl-carbonyl group, C _3-8 cycloalkenyl-carbonyl group, A C _4-8 cycloalkadienyl-carbonyl group, a C _6-14 aryl-carbonyl group, a C _7-16 aralkyl-carbonyl group, a heterocyclic carbonyl group;
Carboxy group, C _1-6 alkoxy (C _1-6 alkyloxy) -carbonyl group, C _2-6 alkenyloxy-carbonyl group, C _2-6 alkynyloxy-carbonyl group, C _3-8 cycloalkyloxy-carbonyl group C _3-8 cycloalkenyloxy-carbonyl group, C _4-8 cycloalkadienyloxy-carbonyl group, C _6-14 aryloxy-carbonyl group, C _7-16 aralkyloxy-carbonyl group, heterocyclic oxycarbonyl group ;
C _1-6 alkyl-carbonyloxy group, C _2-6 alkenyl-carbonyloxy group, C _2-6 alkynyl-carbonyloxy group, C _3-8 cycloalkyl-carbonyloxy group, C _3-8 cycloalkenyl-carbonyloxy A group, a C _4-8 cycloalkadienyl-carbonyloxy group, a C _6-14 aryl-carbonyloxy group, a C _7-16 aralkyl-carbonyloxy group, a heterocyclic carbonyloxy group;
Sulfanyl group, C _1-6 alkylsulfanyl group, C _2-6 alkenylsulfanyl group, C _2-6 alkynylsulfanyl group, C _3-8 cycloalkylsulfanyl group, C _3-8 cycloalkenylsulfanyl group, C _4-8 cyclo Alkadienylsulfanyl group, C _6-14 arylsulfanyl group, C _7-16 aralkylsulfanyl group, heterocyclic sulfanyl group;
Sulfino group, C _1-6 alkylsulfinyl group, C _2-6 alkenylsulfinyl group, C _2-6 alkynylsulfinyl group, C _3-8 cycloalkylsulfinyl group, C _3-8 cycloalkenylsulfinyl group, C _4-8 cyclo Alkadienylsulfinyl group, C _6-14 arylsulfinyl group, C _7-16 aralkylsulfinyl group, heterocyclic sulfinyl group;
Sulfo group, C _1-6 alkylsulfonyl group, C _2-6 alkenylsulfonyl group, C _2-6 alkynylsulfonyl group, C _3-8 cycloalkylsulfonyl group, C _3-8 cycloalkenylsulfonyl group, C _4-8 cyclo An alkadienylsulfonyl group, a C _6-14 arylsulfonyl group, a C _7-16 aralkylsulfonyl group, a heterocyclic sulfonyl group;
A C _1-6 alkylsulfonyloxy group, a C _2-6 alkenylsulfonyloxy group, a C _2-6 alkynylsulfonyloxy group, a C _3-8 cycloalkylsulfonyloxy group, a C _3-8 cycloalkenylsulfonyloxy group, a C _{4- 8} cycloalkadienylsulfonyloxy group, C _6-14 arylsulfonyloxy group, C _7-16 aralkylsulfonyloxy group, heterocyclic sulfonyloxy group;
Amino group, mono or di-C _1-6 alkylamino group, mono or di-C _2-6 alkenylamino group, mono or di-C _2-6 alkynylamino group, mono or di-C _3-8 cycloalkylamino Group, mono or di-C _3-8 cycloalkenylamino group, mono or di-C _4-8 cycloalkadienylamino group, mono or di-C _6-14 arylamino group, mono or di-C _7-16 An aralkylamino group, a mono- or di-heterocyclic amino group;
Carbamoyl group, mono or di-C _1-6 alkylcarbamoyl group, mono or di-C _2-6 alkenylcarbamoyl group, mono or di-C _2-6 alkynylcarbamoyl group, mono or di-C _3-8 cycloalkylcarbamoyl Group, mono or di-C _3-8 cycloalkenylcarbamoyl group, mono or di-C _4-8 cycloalkadienylcarbamoyl group, mono or di-C _6-14 arylcarbamoyl group, mono or di-C _7-16 An aralkylcarbamoyl group, a mono- or di-heterocyclic carbamoyl group;
Thiocarbamoyl group, mono or di-C _1-6 alkylthiocarbamoyl group, mono or di-C _2-6 alkenylthiocarbamoyl group, mono or di-C _2-6 alkynylthiocarbamoyl group, mono or di-C _3-8 A cycloalkylthiocarbamoyl group, a mono or di-C _3-8 cycloalkenylthiocarbamoyl group, a mono or di-C _4-8 cycloalkadienylthiocarbamoyl group, a mono or di-C _6-14 arylthiocarbamoyl group, a mono or Di-C _7-16 aralkylthiocarbamoyl group, mono- or di-heterocyclic thiocarbamoyl group;
A halogen atom;
A cyano group;
A nitro group;
An oxo group;
A thioxo group;
A C _1-3 arylenedioxy group;
Etc. Although the number of substituents is not particularly limited as long as it is a substitutable number, it is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different. The above substituents may be further substituted with a substituent A.

Hereinafter, each substituent of the formula will be described.
n represents 1 or 2.

R ¹ and R ² independently represent a hydrogen atom, a halogen atom, an optionally substituted C _1-8 alkyl group, or an optionally substituted phenyl group, or R ¹ and R ² May be combined with CH-CH to which is bonded to form an optionally substituted benzene ring.
Preferably, R ¹ and R ² together with CH—CH bonded together form an optionally substituted benzene ring.
More preferably, together with CH—CH to which R ¹ and R ² are bonded, from a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-3 arylenedioxy group A benzene ring that may be substituted with a selected substituent is formed.

Ar represents an optionally substituted phenyl group.
Ar is preferably
(1) a halogen atom (preferably a bromine atom), and
(2) (i) a halogen atom (preferably a fluorine atom), and
(ii) C _1-6 alkyl group (preferably, isopropyl) is a C _1-6 alkyl group (preferably substituted with a substituent selected from an amino group optionally mono- or di-substituted with, Methyl)
A phenyl group which may be substituted with a substituent selected from:
Ar is more preferably a phenyl group substituted with a C _1-6 alkyl group (preferably methyl) substituted with a halogen atom (preferably a fluorine atom).

R ^a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
R ^a is preferably an optionally substituted C _6-14 aryl group (preferably phenyl).
R ^a is more preferably
(1) a C _1-6 alkyl group (preferably methyl) _optionally substituted with a halogen atom (preferably a fluorine atom),
(2) a C _1-6 alkoxy group (preferably methoxy), and
(3) a C _6-10 aryl group (preferably phenyl) optionally substituted with a substituent selected from a nitro group.
R ^a is more preferably
(1) a C _1-6 alkyl group (preferably methyl) _optionally substituted with a halogen atom (preferably a fluorine atom), and
(2) C _1-6 alkoxy group (preferably methoxy)
A C _6-10 aryl group (preferably phenyl) which may be substituted with a substituent selected from:
R ^a is even more preferably
(1) a C _1-4 alkyl group (preferably methyl) _optionally substituted with a halogen atom (preferably a fluorine atom), and
(2) C _1-4 alkoxy group (preferably methoxy)
A phenyl group which may be substituted with a substituent selected from:

Y represents an oxygen atom, a sulfur atom or NR ^b (wherein R ^b represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or N = Together with CNHR ^a may form an optionally substituted nitrogen-containing heterocycle.
Y is preferably an oxygen atom, a sulfur atom or NR ^b (wherein R ^b together with N═CNHR ^a is an optionally substituted nitrogen-containing heterocycle (preferably dihydroquinazoline, 1 , 1-dioxide dihydrobenzothiadiazine).
Y is more preferably an oxygen atom, a sulfur atom or NR ^b (wherein R ^b is taken together with N═CNHR ^{a 5 which} is optionally substituted with an oxo group, condensed with a benzene ring, 5 or 6-membered aromatic or non-aromatic monocyclic nitrogen-containing heterocycle (preferably dihydroquinazoline, 1,1-dioxide dihydrobenzothiadiazine).
Y is even more preferably an oxygen atom, a sulfur atom or NR ^{b where} R ^b is taken together with N═CNHR ^a to give 4-oxo-1,4-dihydroquinazoline, or 1,1- Dioxide-3,4-dihydro-1,2,4-benzothiadiazine).
Y is particularly preferably an oxygen atom, a sulfur atom or NR ^b (wherein R ^b together with N═CNHR ^{a represents} 1,1-dioxide-3,4-dihydro-1,2,4. -Form benzothiadiazine).

R ^c , R ^d , R ^e and R ^{f each} independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ^c and R ^d are bonded to each other. Together with CH—CH, which may form an optionally substituted saturated carbocycle, together with CH—N to which R ^d and R ^f are bonded, A saturated nitrogen-containing heterocycle may be formed, or together with CH-N to which R ^d and R ^e are bonded, a saturated nitrogen-containing heterocycle that may be substituted may be formed. Often, R ^e and R ^f may be combined with the nitrogen atom to which they are bonded to form an optionally substituted saturated nitrogen-containing heterocycle.
Preferably, R ^c and R ^d are independently an optionally substituted C _6-10 aryl group (preferably phenyl) or an optionally substituted fused aromatic heterocyclic group (preferably quinolyl). ) And
R ^e and R ^f are independently an optionally substituted C _1-6 alkyl group (preferably methyl, ethyl), or
Together with CH—CH to which R ^c and R ^d are bonded to form an optionally substituted C _3-10 cycloalkane (preferably cyclohexane);
Together with CH—N to which R ^d and R ^f are bonded, forms an optionally substituted 4- to 8-membered saturated nitrogen-containing heterocycle (preferably piperidine);
Together with CH—N to which R ^d and R ^e are bonded, forms an optionally substituted 4- to 8-membered saturated nitrogen-containing heterocycle (preferably piperidine);
Together with the nitrogen atom to which R ^e and R ^f are bonded, a 4- to 8-membered saturated nitrogen-containing heterocyclic ring (preferably pyrrolidine, piperidine) which may be substituted is formed.
More preferably, R ^c and R ^d are independently a condensed aromatic optionally substituted with a C _6-10 aryl group (preferably phenyl) or a C _1-6 alkoxy group (preferably methoxy). A heterocyclic group (preferably quinolyl);
R ^e and R ^f are independently
(1) a hydroxy group, and
(2) C _1-6 alkyl group (preferably methyl) is a C _1-6 alkyl group (preferably substituted with a substituent selected from an amino group optionally mono- or di-substituted with, Methyl, ethyl) or
Together with CH—CH to which R ^c and R ^d are bonded to form a C _3-10 cycloalkane (preferably cyclohexane);
4- to 8-membered saturated nitrogen-containing heterocycle optionally substituted with a C _1-6 alkyl group (preferably ethyl) together with CH—N to which R ^d and R ^f are bonded ( Preferably, piperidine) is formed,
A 4- to 8-membered saturated nitrogen-containing heterocycle optionally substituted with a C _1-6 alkyl group (preferably ethyl), together with CH—N to which R ^d and R ^e are bonded ( Preferably, piperidine) is formed,
Together with the nitrogen atom to which R ^e and R ^f are bonded, a 4- to 8-membered saturated nitrogen-containing heterocycle (preferably pyrrolidine, piperidine) is formed.
Particularly preferably, R ^e and R ^f are independently a C _1-6 alkyl group (preferably methyl), and
Together with CH—CH to which R ^c and R ^d are bonded, a C _3-10 cycloalkane (preferably cyclohexane) is formed.

Ar ^a represents a phenyl group substituted at the 2-position with CH ₂ —NR ⁴ R ⁵ .
R ⁴ and R ⁵ independently represent a C _1-8 alkyl group or, together with the nitrogen atom to which R ⁴ and R ⁵ are bonded, optionally substituted saturated nitrogen-containing A heterocycle may be formed.
R ⁴ and R ⁵ are preferably independently a C _1-6 alkyl group (preferably methyl, isopropyl), or together with a nitrogen atom to which R ⁴ and R ⁵ are bonded. To form a 4- to 8-membered saturated nitrogen-containing heterocyclic ring (preferably piperidine) which may be substituted with a C _1-6 alkyl group (preferably methyl).
R ⁴ and R ⁵ are more preferably independently a C _1-6 alkyl group (preferably isopropyl).
Ar ^a is preferably CH ₂ —NR ⁴ R ^{5 at} the 2-position (wherein R ⁴ and R ⁵ are independently a C _1-6 alkyl group (preferably methyl, isopropyl), or A 4- to 8-membered saturated nitrogen-containing heterocyclic ring (preferably, optionally substituted with a C _1-6 alkyl group (preferably methyl), together with the nitrogen atom to which R ⁴ and R ⁵ are bonded. Is a phenyl group substituted with piperidine).
Ar ^a is more preferably substituted at the 2-position with CH ₂ —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently a C _1-6 alkyl group (preferably isopropyl)). Phenyl group.

  In the production method of the present invention, compound (1) is converted to compound (2) in the presence of compound (3) and a tertiary amine compound having a hydrogen bond donating site in the molecule (intramolecular Michael addition reaction).

  The hydrogen bond donor site in the “tertiary amine compound having a hydrogen bond donor site in the molecule” is not particularly limited.

(Wherein each symbol has the same meaning as described above).

  As a suitable partial structure,

Etc. Above all, in terms of yield,

Is preferred.

  A suitable “tertiary amine compound having a hydrogen bond donating site in the molecule” includes compound (4). As a specific example,

Etc. Above all, in terms of yield,

Is preferred.

  When the “tertiary amine compound having a hydrogen bond donating site in the molecule” is an asymmetric catalyst, the compound (2) is obtained as an optically active compound.

  Specific examples of such an optically active “tertiary amine compound having a hydrogen bond donating site in the molecule” include:

Etc. Above all, in terms of yield,

Is preferred.
For example, as an asymmetric catalyst,

Is used, S-form compound (2), that is,

Is obtained.

  In the intramolecular Michael addition reaction, the amount of the tertiary amine compound used is usually from 1 to 50 mol%, preferably from 5 to 30 mol%, based on the compound (1) in terms of yield and economy. .

  As the compound (3), for example,

And boronic acid catalyst. Above all, in terms of yield,

Is preferred.
The usage-amount of a compound (3) is 1-50 mol% normally with respect to a compound (1) from a yield and economical point, Preferably it is 5-30 mol%.

The intramolecular Michael addition reaction may be performed in the presence of an additive such as molecular sieve, aluminum oxide, silica gel or the like, if necessary.
The amount of the additive used is usually 10 to 1000% by weight, preferably 100 to 700% by weight, based on the compound (1), from the viewpoint of yield and economy.

The intramolecular Michael addition reaction is preferably performed in the presence of a solvent. Solvents used in the reaction include aromatic hydrocarbon solvents (eg, toluene, benzene, xylene); halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, dichloroethane, carbon tetrachloride); ether solvents (eg, diethyl) Ether, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether); nitrile solvent (eg, acetonitrile); amide solvent (eg, N, N-dimethylformamide), and mixed solvents thereof. Among them, although depending on the type of the compound (1), halogenated hydrocarbon solvents, aromatic hydrocarbon solvents and ether solvents are preferable from the viewpoint of reactivity and selectivity. Particularly, dichloroethane, methyl tert-butyl ether, tetrachloride. Carbon and mixtures thereof are preferred.
The intramolecular Michael addition reaction is usually performed by a method of mixing the compound (1), the compound (3), the tertiary amine compound and a solvent.
The intramolecular Michael addition reaction depends on the types of the compound (1), the compound (3) and the tertiary amine compound, but is preferably in the range of −20 to 60 ° C., more preferably in the range of 0 to 30 ° C. Done in
The reaction time depends on the types of the compound (1), compound (3) and the tertiary amine compound, and the reaction temperature, but is preferably 0.5 to 130 hours, more preferably 10 to 120 hours. is there.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  The intramolecular Michael addition reaction can also be performed in the presence of the compound (3a). That is, compound (1) is converted to compound (2) in the presence of compound (3a).

  As the compound (3a), for example,

Etc. Above all, in terms of yield,

Is preferred.
The amount of compound (3a) to be used is generally 1-50 mol%, preferably 5-20 mol%, relative to compound (1), from the viewpoint of yield and economy.

The intramolecular Michael addition reaction is preferably performed in the presence of a solvent. Solvents used in the reaction include aromatic hydrocarbon solvents (eg, toluene, benzene, xylene); halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, dichloroethane, carbon tetrachloride); ether solvents (eg, diethyl) Ether, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether); nitrile solvent (eg, acetonitrile); amide solvent (eg, N, N-dimethylformamide), and mixed solvents thereof. Among them, although depending on the type of the compound (1), a halogenated hydrocarbon solvent and a nitrile solvent are preferable from the viewpoint of reactivity and selectivity, dichloroethane and acetonitrile are more preferable, and acetonitrile is particularly preferable.
The intramolecular Michael addition reaction is usually performed by a method of mixing the compound (1), the compound (3a) and a solvent.
The intramolecular Michael addition reaction is preferably performed within a range of 10 to 130 ° C, more preferably within a range of 10 to 120 ° C, although it depends on the types of the compound (1) and the compound (3a).
Moreover, although the reaction time is based also on the kind of compound (1) and compound (3a), and reaction temperature, Preferably it is 0.5 to 72 hours, More preferably, it is 1 to 30 hours.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  The compound (1) used as a raw material for the intramolecular Michael addition reaction may be a commercially available product, or may be produced by a method known per se.

A compound that forms an optionally substituted benzene ring together with CH—CH to which R ¹ and R ² are bonded can be produced by the following method (compound (1a)).

(Each symbol in the formula is as defined above.)

  Compound (1a) can also be produced by the following method.

(Each symbol in the formula is as defined above.)
Compound (3) and compound (3a) may be commercially available products, or may be produced by a method known per se.

  Isolation of the compound (2) contained in the reaction mixture thus obtained is performed by subjecting the reaction mixture to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). be able to. The purification can be performed by subjecting the compound (2) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina and the like, and chromatography treatment such as silica gel column chromatography.

  According to such an intramolecular Michael addition reaction, the compound (2) can be obtained in a yield of 50% or more. Moreover, an optically active compound (2) can be obtained by using an optically active “tertiary amine compound having a hydrogen bond donating site in the molecule” as an asymmetric catalyst.

Hereinafter, although an example is given and the present invention is explained still more concretely, the present invention is not limited to these.
Unless otherwise specified, all non-aqueous reactions were performed in a dry glass container under an argon atmosphere. Solvents and raw materials were used without purifying commercial products. Column chromatography was performed with Cica silica gel 60 (230-400 mesh) or Fuji Silysia silica gel (NH, 100-200 mesh), gel permeation chromatography was performed with LC-9201, and flash column chromatography was performed with Cica silica gel 60 (spherical / 40-100 μm). Reaction and chromatographic fractions were analyzed using precoated silica gel plates (Merck Silica Gel 60 F ₂₅₄ ). All melting points were measured with a BUCHI M-565 melting point analyzer and were not corrected. IR spectra were measured with JASCO FT / IR-4100. Unless otherwise noted, NMR spectra were measured with CDCl ₃ . ¹ H NMR (500 or 400 MHz) spectra were measured with a JEOL ECP-500 or ECS-400 spectrometer, and chemical shifts were recorded as δ (ppm) relative to TMS (in CDCl ₃ ) as an internal standard. ¹³ C NMR (126 or 100 MHz) spectra were also measured with a JEOL ECP-500 or ECS-400 spectrometer and referenced to the remaining CHCl ₃ signal. ¹ H NMR multiplicity was reported as follows: br = broad; m = multiplet; s = singlet; d = doublet; t = triplet; q = quartet; sep = septet. Low resolution mass spectra were measured with a JMS-HX / HX 110A or MS700 mass spectrometer. High resolution mass spectra were measured with a Shimadzu LCMS-IT-TOF equipped with JMS-HX / MS700 (FAB) or ESI. The optical rotation was measured with a JASCO P-2200 polarimeter with a 1 cm path length. The concentration was gram per 100 mL. The [α] _D value was measured at 10 ⁻¹ deg cm ² / g. Enantiomeric excess was determined by high performance liquid chromatography (HPLC) analysis. Unless otherwise noted, all raw materials and solvents were obtained from Tokyo Kasei Co., Aldrich Inc. and other suppliers and used without purification. Unavailable substrates were prepared according to literature methods as shown below.

Reference example 1
(E) -5- (2-hydroxyphenyl) pent-2-enoic acid

To a solution of chroman-2-ol (730 mg, 4.80 mmol) in toluene (40 ml) tert-butyl 2- (triphenylphosphoranylidene) acetate (2.89 g, 7.67 mmol) was added at room temperature and the mixture was allowed to cool to room temperature. For 5 hours. To the mixture was added a solution of tert-butyl 2- (triphenylphosphoranylidene) acetate (367 mg, 0.96 mmol) in toluene (10 mL), and the mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: EtOAc = 6: 1) to give tert-butyl (E) -5- (2-hydroxyphenyl) pent-2-enoate (918 mg, 76%, colorless oil) Got.
¹ H NMR (CDCl ₃ ) δ: 7.14-7.06 (m, 2H), 6.94 (dt, J = 15.5, 6.9 Hz, 1H), 6.87 (dd, J = 7.4, 7.4 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.80 (d, J = 15.5 Hz, 1H), 4.98 (s, 1H), 2.76 (t, J = 7.7 Hz, 2H), 2.54-2.46 (m, 2H), 1.48 ( s, 9H) ppm; ¹³ C NMR (CDCl ₃ ) δ: 166.3, 153.5, 147.4, 130.2, 127.4, 127.3, 123.3, 120.9, 115.2, 80.2, 32.2, 28.8, 28.2 ppm; IR (ATR): 3398, 3018 , 2981, 1688 cm ^-1 ; HRMS (ESI): calcd.for C ₁₅ H ₂₀ O ₃ Na [M + Na] ⁺ 271.1305, found 271.1306.

TFA (3 mL) was added dropwise at 0 ° C. to a solution of tert-butyl (E) -5- (2-hydroxyphenyl) pent-2-enoate (918 mg, 3.70 mmol) obtained above in DCM (10 mL). . After stirring for 2.5 hours, the reaction mixture was allowed to warm to room temperature and concentrated under reduced pressure. Hexane was added to the residue, and the solvent was distilled off at 40 ° C. to remove the remaining TFA. The residue was purified by silica gel column chromatography (hexane: EtOAc = 1: 1) to give (E) -5- (2-hydroxyphenyl) pent-2-enoic acid (711 mg, quant.). : Mp116-117 ° C (EtOAc: hexane)
¹ H NMR (acetone-d ₆ ) δ: 10.46 (br s, 1H), 8.22 (s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.05-6.97 (m, 2H), 6.84 (d , J = 8.0 Hz, 1H), 6.77 (dd, J = 7.4, 7.4 Hz, 1H), 5.83 (dt, J = 15.7, 1.4 Hz, 1H), 2.79 (t, J = 7.7 Hz, 2H), 2.57 -2.52 (m, 2H) ppm; ¹³ C NMR (acetone-d ₆ ) δ: 167.4, 155.9, 149.9, 130.9, 128.1, 122.3, 120.4, 115.9, 32.9, 29.6, 29.3 ppm; IR (ATR): 3331 2945, 2861, 1667, 1626 cm ^-1 ; HRMS (ESI): calcd.for C ₁₁ H ₁₂ O ₃ Na [M + Na] ⁺ 215.0679, found 215.0671.
Reference example 2
(E) -4- (2-hydroxyphenyl) but-2-enoic acid

To a solution of _2- allylphenol (0.26 mL, 2.0 mmol) in Et ₂ O (30 mL) with stirring, tert-butyl acrylate (0.73 mL, 5.0 mmol), copper iodide (6.7 mg,. 04 mmol) and Grubbs 2 ^nd catalyst (34 mg, 0.04 mmol) were added at room temperature and the mixture was warmed to 40 ° C. After stirring for 19 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: EtOAc = 30: 1 → 4: 1) to give tert-butyl (E) -4- (2-hydroxyphenyl) but-2-enoate (430 mg, 92%) Got. White solid; mp 64-66 ° C. (EtOAc: hexane)
¹ H NMR (CDCl ₃ ) δ: 7.15-7.07 (m, 2H), 7.04 (dt, J = 15.7, 6.4 Hz, 1H), 6.88 (dd, J = 7.4, 7.4 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.73 (dt, J = 15.7, 1.6 Hz, 1H), 5.02 (s, 1H), 3.50 (dd, J = 6.6, 1.6 Hz, 2H), 1.46 (s, 9H) ppm ; ¹³ C NMR (CDCl ₃ ) δ: 166.8, 154.0, 146.3, 130.6, 128.0, 124.3, 123.4, 120.6, 115.4, 80.6, 33.1, 28.1 ppm; IR (ATR): 3308, 2986, 1676, 1641 cm ^-1 ; HRMS (ESI): calcd. For C ₁₄ H ₁₈ O ₃ Na [M + Na] ⁺ 257.1148, found 257.1143.

To a solution of tert-butyl (E) -4- (2-hydroxyphenyl) but-2-enoate (830 mg, 3.54 mmol) obtained above in DCM (5 mL) was added TFA (5 mL) at 0 ° C. with stirring. It was dripped at. After stirring for 1 hour, the reaction mixture was allowed to return to room temperature, stirred for a further 4 hours, and then concentrated under reduced pressure. Hexane was added to the residue, and the solvent was distilled off at 40 ° C. to remove residual TFA. The residue was purified by silica gel column chromatography (hexane: AcOEt = 1: 1) to obtain (E) -4- (2-hydroxyphenyl) but-2-enoic acid (612 mg, 97%). White solid; mp 107-108 ° C. (EtOAc: hexane)
¹ H NMR (acetone-d ₆ ) δ: 7.15-7.04 (m, 3H), 6.88 (d, J = 8.0 Hz, 1H), 6.83-6.75 (m, 1H), 5.80 (d, J = 14.3 Hz, 1H), 3.55 (d, J = 6.9 Hz, 2H) ppm; ¹³ C NMR (acetone-d ₆ ) δ: 167.5, 155.9, 148.5, 131.1, 128.7, 125.4, 122.4, 120.6, 116.0, 33.4 ppm; IR ( ATR):. 3403, 2981, 2922, 1671, 1638 cm -1; HRMS (ESI): calcd for C 10 H 9 O 3 [MH] - 177.0557, found 177.0550.

  The boronic acid catalyst and amine catalyst used in the following examples are shown below.

Example 1

A boronic acid catalyst (3a) (5.2 mg, 20 mol%, 0.02 mmol) was added to a solution of the compound (1) (19.2 mg, 0.1 mmol) obtained in Reference Example 1 in the solvent (1 mL) shown in Table 1. ), Amine catalyst (4a-4e) (20 mol%, 0.02 mmol) and molecular sieve 4A (100 mg) were added at room temperature. The mixture was stirred for the time shown in Table 1 and then concentrated under reduced pressure. The yield was determined by ¹ H-NMR. The enantiomeric excess (ee) was measured after treating the compound (2) with TMSCHN ₂ and carrying out methyl esterification. The results are shown in Table 1.

(S) -2- (chroman-2-yl) acetic acid white solid; mp 89-90 ° C. (MeCN);
[α] ²⁶ _D +74.0 (c 1.56, CHCl ₃ , for 93% ee);
¹ H NMR (acetone-d ₆ ) δ: 7.06-7.00 (m, 2H), 6.80 (dd, J = 7.4, 7.4 Hz, 1H), 6.57 (dd, J = 7.2, 2.0 Hz, 1H), 4.33- 4.25 (m, 1H), 2.81-2.68 (m, 1H), 2.67-2.49 (m, 3H), 2.03-1.95 (m, 1H), 1.70-1.56 (m, 1H) ppm;
¹³ C NMR (acetone-d ₆ ) δ: 171.9, 155.5, 130.4, 127.9, 122.7, 120.9, 117.3, 73.5, 40.7, 27.7, 25.1 ppm;
IR (ATR): 3040, 2927, 1696 cm ^-1 ;
HRMS (ESI): calcd. For C ₁₁ H ₁₂ NO ₃ Na [M + Na] ⁺ 215.0679, found 215.0675;
HPLC [Chiralpak OJ-3, hexane / 2-propanol = 98/2, 1.0 mL / min, λ = 254 nm, retention times: (major) 10.0 min (minor) 11.4 min].

Example 2

To a solution of compound (1) (0.1 mmol) synthesized in the same manner as in Reference Examples 1 and 2 in the solvent (1 mL) shown in Table 2, boronic acid catalyst (3a) (5.2 mg, 20 mol%, 0. 02 mmol), amine catalyst (4e) (6.4 mg, 20 mol%, 0.02 mmol) and molecular sieve 4A (100 mg) were added at the temperatures shown in Table 2. The mixture was stirred for the time shown in Table 2, then concentrated under reduced pressure, and purified by column chromatography to obtain compound (2). The enantiomeric excess (ee) was measured after treating the compound (2) with TMSCHN ₂ and carrying out methyl esterification. The results are shown in Table 2.

(S) -2- (2,3-dihydrobenzofuran-2-yl) acetic acid white solid; mp 83-84 ° C. (MeCN);
[α] ²⁶ _D +36.8 (c 0.69, CHCl ₃ , for 84% ee);
¹ H NMR (acetone-d ₆ ) δ: 7.18 (d, J = 7.4 Hz, 1H), 7.08 (dd, J = 6.9, 6.9 Hz, 1H), 6.81 (dd, J = 7.4, 1.1 Hz, 1H) , 6.70 (d, J = 8.0 Hz, 1H), 5.16-5.09 (m, 1H), 3.38-3.42 (m, 1H), 2.95-2.99 (m, 1H), 2.75-2.80 (m, 2H) ppm;
¹³ C NMR (acetone-d ₆ ) δ: 171.8, 160.1, 128.7, 127.6, 125.9, 121.2, 109.9, 80.0, 40.9, 35.8 ppm;
IR (ATR): 3049, 2962, 2923, 2856, 1703 cm ^-1 ;
HRMS (ESI): calcd. For C ₁₀ H ₁₀ O ₃ Na [M + Na] ⁺ 201.0522, found 201.0520;
HPLC [Chiralpak IB, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 6.2 min (minor) 6.8 min].

(S) -2- (5-Bromo-2,3-dihydrobenzofuran-2-yl) acetic acid white solid; mp 132-133 ° C. (MeCN);
[α] ²⁶ _D +43.5 (c 1.2, CHCl ₃ , for 78% ee);
¹ H NMR (CDCl ₃ ) δ: 7.27 (1H, s), 7.22 (1H, d, J = 8.0 Hz), 6.67 (1H, d, J = 8.0 Hz), 5.22-5.16 (1H, m), 3.45 -3.41 (1H, m), 2.95-2.92 (2H, m), 2.76-2.73 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 175.7, 158.0, 131.0, 128.4, 127.9, 112.5, 111.1, 78.9, 40.2, 35.1 ppm;
IR (ATR): 2922, 1704 cm ^-1 ;
HRMS (ESI):. Calcd for C 10 H 8 BrO 3 [MH] - 254.9662, found 254.9658 .;
HPLC [Chiralpak IC, hexane / 2-propanol = 98/2, 1.0 mL / min, λ = 254 nm, retention times: (major) 8.6 min (minor) 9.9 min].

(S) -2- (6-Bromochroman-2-yl) acetic acid white solid; mp 138-139 ° C. (MeCN);
[α] ²⁶ _D +77.5 (c 0.98, CHCl ₃ , for 94% ee);
¹ H NMR (CDCl ₃ ) δ: 7.18-7.16 (2H, m), 6.69 (1H, d, J = 9.2 Hz), 4.47-4.43 (1H, m), 2.89-2.83 (2H, m), 2.75 ( 1H, dd, J = 11.7, 8.3 Hz), 2.67 (1H, dd, J = 15.8, 5.7 Hz), 2.11-2.09 (1H, m), 1.83-1.76 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.3, 153.3, 132.0, 130.2, 123.6, 118.6, 112.4, 72.1 40.1, 26.2, 24.2 ppm;
IR (ATR): 2924, 1711 cm ^-1 ;
. HRMS (ESI): calcd for C 11 H 10 BrO 3 [MH] - 268.9819, found 268.9814;
HPLC [Chiralpak IA, hexane / 2-propanol = 99/1, 0.2 mL / min, λ = 254 nm, retention times: (major) 43.2 min (minor) 47.1 min].

(S) -2- (6-Methylchroman-2-yl) acetic acid white solid; mp 120-121 ° C. (MeCN);
[α] ²⁶ _D +58.9 (c 0.58, CHCl ₃ , for 93% ee);
¹ H NMR (CDCl ₃ ) δ: 6.89 (1H, d, J = 8.3 Hz), 6.86 (1H, s), 6.71 (1H, d, J = 8.3 Hz), 4.45-4.42 (1H, m), 2.88 -2.83 (2H, m), 2.74-2.71 (1H, m), 2.68-2.65 (1H, m), 2.24 (3H, s), 2.11-2.08 (1H, m), 1.82-1.80 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.5, 151.9, 129.8, 129.7, 127.9, 121.1, 116.6, 71.9, 40.3, 27.2, 24.3, 20.5 ppm;
IR (ATR): 2924, 1713 cm ^-1 ;
. HRMS (ESI): calcd for C 12 H 13 O 3 [MH] - 205.0870, found 205.0870;
HPLC [Chiralpak IC, hexane / 2-propanol = 98/2, 1.0 mL / min, λ = 254 nm, retention times: (major) 10.6 min (minor) 11.8 min].

(S) -2- (6-Methoxychroman-2-yl) acetic acid white solid; mp 108-109 ° C. (MeCN);
[α] ²⁵ _D +76.1 (c 0.74, CHCl ₃ , for 93% ee);
¹ H NMR (CDCl ₃ ) δ: 6.74 (1H, d, J = 9.0 Hz), 6.67 (1H, dd, J = 9.0, 2.7 Hz), 6.59 (1H, d, J = 2.7 Hz), 4.44-4.40 (1H, m), 3.74 (3H, s), 2.89-2.81 (2H, m), 2.77-2.72 (1H, m), 2.69-2.64 (1H, m), 2.12-2.07 (1H, m), 1.83 -1.77 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.5, 153.4, 148.3, 122.0, 117.4, 113.9, 113.3, 71.8, 55.7, 40.2, 27.1, 24.6 ppm;
IR (ATR): 2933, 1713 cm ^-1 ;
. HRMS (ESI): calcd for C 12 H 13 O 4 [MH] - 221.0819, found 221.08221;
HPLC [Chiralpak IC, hexane / 2-propanol = 98/2, 1.0 mL / min, λ = 254 nm, retention times: (major) 10.6 min (minor) 11.8 min].

(S) -2- (7-methoxychroman-2-yl) acetic acid white solid; mp 62-64 ° C .;
[α] ²⁵ _D +89.2 (c 0.89, CHCl ₃ , for 96% ee);
¹ H NMR (CDCl ₃ ) δ: 6.94 (1H, d, J = 8.3 Hz), 6.46 (1H, dd, J = 8.3, 2.6 Hz), 6.38 (1H, d, J = 2.6 Hz), 4.49-4.45 (1H, m), 3.76 (3H, s), 2.86-2.79 (2H, m), 2.73-2.65 (2H, m), 2.11-2.07 (1H, m), 1.82-1.78 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.3, 159.0, 154.9, 129.9, 113.5, 107.6, 101.4, 72.1, 55.3, 40.2, 27.2, 23.6 ppm;
IR (ATR): 2932, 1711 cm ^-1 ;
. HRMS (ESI): calcd for C 12 H 13 O 4 [MH] - 221.0819, found 221.0815;
HPLC [Chiralpak OJ-3, hexane / 2-propanol = 98/2, 1.0 mL / min, λ = 254 nm, retention times: (major) 17.5 min (minor) 19.7 min].

Example 3

To a solution of compound (1) (23.6 mg, 0.1 mmol) synthesized in the same manner as in Reference Example 1 in MTBE / CCl ₄ (1: 2, 1 mL), boronic acid catalyst (3a) (5.2 mg, 20 mol%, 0.02 mmol), amine catalyst (4e) (6.4 mg, 20 mol%, 0.02 mmol) and molecular sieve 4A (100 mg) were added at room temperature. The mixture was stirred for 24 hours, then concentrated under reduced pressure, and purified by column chromatography to obtain compound (2). The enantiomeric excess (ee) was measured after treating the compound (2) with TMSCHN ₂ and carrying out methyl esterification. The yield was 94% and the enantiomeric excess was 94% ee.

(S) -2- (7,8-dihydro-6H- [1,3] dioxolo [4,5-g] chroman-6-yl) acetic acid white solid; mp 122-124 ° C. (MeCN);
[α] ²⁶ _D +59.0 (c 0.40, CHCl ₃ , for 94% ee);
¹ H NMR (CDCl ₃ ) δ: 6.49 (1H, s), 6.36 (1H, s), 5.86 (2H, s), 4.43-4.37 (1H, m), 2.83-2.80 (2H, m), 2.67- 2.63 (2H, m), 2.07-2.05 (1H, m), 1.80-1.75 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.4, 148.7, 146.4, 141.5, 112.8, 108.1, 100.8, 98.7, 71.9, 40.2, 27.1, 24.3 ppm;
IR (ATR): 3251, 2925, 1715 cm ^-1 ;
HRMS (ESI): calcd.for C ₁₂ H ₁₂ O ₅ Na [M + Na] ⁺ 259.0577, found 259.0567;
HPLC [Chiralpak IC, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 10.9 min (minor) 12.7 min].

Example 4

  Boronic acid catalyst (3b) (2.4 mg, 10 mol%, 0.01 mmol) was added to a solution of compound (1) (0.1 mmol) synthesized in the same manner as in Reference Examples 1 and 2 in acetonitrile (1 mL). 3 was added at the temperature indicated. The mixture was stirred for the time shown in Table 3, then concentrated under reduced pressure, and purified by column chromatography to obtain compound (2). The results are shown in Table 3.

2- (2,3-dihydrobenzohydrofuran-2-yl) acetic acid white solid; mp 83-84 ° C. (MeCN);
¹ H NMR (acetone-d ₆ ) δ: 7.18 (d, J = 7.4 Hz, 1H), 7.08 (dd, J = 6.9, 6.9 Hz, 1H), 6.81 (dd, J = 7.4, 1.1 Hz, 1H) , 6.70 (d, J = 8.0 Hz, 1H), 5.16-5.09 (m, 1H), 3.38-3.42 (m, 1H), 2.95-2.99 (m, 1H), 2.75-2.80 (m, 2H) ppm;
¹³ C NMR (acetone-d ₆ ) δ: 171.8, 160.1, 128.7, 127.6, 125.9, 121.2, 109.9, 80.0, 40.9, 35.8 ppm;
IR (ATR): 3049, 2962, 2923, 2856, 1703 cm ^-1 ;
HRMS (ESI): calcd. For C ₁₀ H ₁₀ O ₃ Na [M + Na] ⁺ 201.0522, found 201.0520;

2- (5-bromo-2,3-dihydrobenzohydrofuran-2-yl) acetic acid white solid; mp 132-133 ° C. (MeCN);
¹ H NMR (CDCl ₃ ) δ: 7.27 (1H, s), 7.22 (1H, d, J = 8.0 Hz), 6.67 (1H, d, J = 8.0 Hz), 5.22-5.16 (1H, m), 3.45 -3.41 (1H, m), 2.95-2.92 (2H, m), 2.76-2.73 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 175.7, 158.0, 131.0, 128.4, 127.9, 112.5, 111.1, 78.9, 40.2, 35.1 ppm;
IR (ATR): 2922, 1704 cm ^-1 ;
HRMS (ESI):. Calcd for C 10 H 8 BrO 3 [MH] - 254.9662, found 254.9658 .;

2- (7-bromo-2,3-dihydrobenzohydrofuran-2-yl) acetic acid white solid; mp 102-103 ° C. (MeCN);
¹ H NMR (CDCl ₃ ) δ: 7.27 (1H, d, J = 7.5 Hz), 7.10 (1H, d, J = 7.5 Hz), 6.74 (1H, dd, J = 7.5, 7.5 Hz), 5.28-5.21 (1H, m), 3.57-3.54 (1H, m), 3.09-3.02 (2H, m), 2.80-2.77 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.0, 156.2, 131.3, 127.4, 124.0, 122.1, 102.7, 78.8, 40.2, 36.2 ppm;
IR (ATR): 2922, 1704 cm ^-1 ;
HRMS (ESI):. Calcd for C 10 H 8 BrO 3 [MH] - 254.9662, found 254.9662.

2- (chroman-2-yl) acetic acid white solid; mp 89-90 ° C. (MeCN);
¹ H NMR (acetone-d ₆ ) δ: 7.06-7.00 (m, 2H), 6.80 (dd, J = 7.4, 7.4 Hz, 1H), 6.57 (dd, J = 7.2, 2.0 Hz, 1H), 4.33- 4.25 (m, 1H), 2.81-2.68 (m, 1H), 2.67-2.49 (m, 1H), 2.03-1.95 (m, 1H), 1.70-1.56 (m, 1H) ppm;
¹³ C NMR (acetone-d ₆ ) δ: 171.9, 155.5, 130.4, 127.9, 122.7, 120.9, 117.3, 73.5, 40.7, 27.7, 25.1 ppm;
IR (ATR): 3040, 2927, 1696 cm ^-1 ;
HRMS (ESI): calcd. For C ₁₁ H ₁₂ NO ₃ Na [M + Na] ⁺ 215.0679, found 215.0675;

2- (6-Bromochroman-2-yl) acetic acid white solid; mp 138-139 ° C. (MeCN);
¹ H NMR (CDCl ₃ ) δ: 7.18-7.16 (2H, m), 6.69 (1H, d, J = 9.2 Hz), 4.47-4.43 (1H, m), 2.89-2.83 (2H, m), 2.75 ( 1H, dd, J = 11.7, 8.3 Hz), 2.67 (1H, dd, J = 15.8, 5.7 Hz), 2.11-2.09 (1H, m), 1.83-1.76 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.3, 153.3, 132.0, 130.2, 123.6, 118.6, 112.4, 72.1 40.1, 26.2, 24.2 ppm;
IR (ATR): 2924, 1711 cm ^-1 ;
. HRMS (ESI): calcd for C 11 H 10 BrO 3 [MH] - 268.9819, found 268.9814;

2- (6-Methylchroman-2-yl) acetic acid white solid; mp 120-121 ° C. (MeCN);
¹ H NMR (CDCl ₃ ) δ: 6.89 (1H, d, J = 8.3 Hz), 6.86 (1H, s), 6.71 (1H, d, J = 8.3 Hz), 4.45-4.42 (1H, m), 2.88 -2.83 (2H, m), 2.74-2.71 (1H, m), 2.68-2.65 (1H, m), 2.24 (3H, s), 2.11-2.08 (1H, m), 1.82-1.80 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.5, 151.9, 129.8, 127.9, 121.1, 116.6, 71.9, 40.3, 27.2, 24.3, 20.5 ppm;
IR (ATR): 2924, 1713 cm ^-1 ;
. HRMS (ESI): calcd for C 12 H 13 O 3 [MH] - 205.0870, found 205.0870;

2- (6-methoxychroman-2-yl) acetic acid white solid; mp 108-109 ° C. (MeCN);
¹ H NMR (CDCl ₃ ) δ: 6.74 (1H, d, J = 9.0 Hz), 6.67 (1H, dd, J = 9.0, 2.7 Hz), 6.59 (1H, d, J = 2.7 Hz), 4.44-4.40 (1H, m), 3.74 (3H, s), 2.89-2.81 (2H, m), 2.77-2.72 (1H, m), 2.69-2.64 (1H, m), 2.12-2.07 (1H, m), 1.83 -1.77 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.5, 153.4, 148.3, 122.0, 117.4, 113.9, 113.3, 71.8, 55.7, 40.2, 27.1, 24.6 ppm;
IR (ATR): 2933, 1713 cm ^-1 ;
. HRMS (ESI): calcd for C 12 H 13 O 4 [MH] - 221.0819, found 221.08221;

2- (7-Methoxychroman-2-yl) acetic acid

White solid; mp 62-64 ° C;
¹ H NMR (CDCl ₃ ) δ: 6.94 (1H, d, J = 8.3 Hz), 6.46 (1H, dd, J = 8.3, 2.6 Hz), 6.38 (1H, d, J = 2.6 Hz), 4.49-4.45 (1H, m), 3.76 (3H, s), 2.86-2.79 (2H, m), 2.73-2.65 (2H, m), 2.11-2.07 (1H, m), 1.82-1.78 (1H, m) ppm;
¹³ C NMR (CDCl ₃ ) δ: 176.3, 159.0, 154.9, 129.9, 113.5, 107.6, 101.4, 72.1, 55.3, 40.2, 27.2, 23.6 ppm;
IR (ATR): 2932, 1711 cm ^-1 ;
. HRMS (ESI): calcd for C 12 H 13 O 4 [MH] - 221.0819, found 221.0815;

  According to the present invention, an α-heterocyclylacetic acid compound can be produced with high yield, and therefore it is very useful for the synthesis of pharmaceuticals such as peripentonine C and raxofelast, and agricultural chemicals.

Claims (5)

General formula (1):

(Where
n represents 1 or 2;
R ¹ and R ² independently represent a hydrogen atom, a halogen atom, an optionally substituted C _1-8 alkyl group, or an optionally substituted phenyl group, or
R ¹ and R ² may be combined with CH-CH to which R ¹ and R ² are bonded to form an optionally substituted benzene ring. )
A compound represented by general formula (3):
Ar-B (OH) ₂ (3)
(Where
Ar represents an optionally substituted phenyl group. )
In the presence of a boronic acid represented by formula (III) and a tertiary amine compound having a hydrogen bond donating site in the molecule, the general formula (2):

(In the formula, ** represents an asymmetric carbon atom, and other symbols are as defined above.)
A process for producing a compound represented by the general formula (2), wherein the compound is converted to Hydrogen bond donating site

(Where
R ^a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Y represents an oxygen atom, a sulfur atom, or NR ^b (wherein R ^b represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or N═CNHR ^a may be combined with ^a to form an optionally substituted nitrogen-containing heterocyclic ring);
* Indicates a binding site. )
The manufacturing method of Claim 1 which is a partial structure represented by these. A tertiary amine compound has the general formula (4):

(Where
R ^a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
Y represents an oxygen atom, a sulfur atom, or NR ^b (wherein R ^b represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or N═CNHR ^a may be combined with ^a to form an optionally substituted nitrogen-containing heterocyclic ring);
R ^c , R ^d , R ^e and R ^{f each} independently represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ^c and R ^d are bonded to each other. Together with CH—CH, which may form an optionally substituted saturated carbocycle, together with CH—N to which R ^d and R ^f are bonded, A saturated nitrogen-containing heterocycle may be formed, or together with CH-N to which R ^d and R ^e are bonded, a saturated nitrogen-containing heterocycle that may be substituted may be formed. Often, R ^e and R ^f may be combined with the nitrogen atom to which they are bonded to form an optionally substituted saturated nitrogen-containing heterocycle. )
The manufacturing method of Claim 1 which is a tertiary amine compound represented by these. Tertiary amine compounds are

The manufacturing method of Claim 1 selected from these.   The production method according to any one of claims 1 to 4, wherein the tertiary amine compound is an asymmetric catalyst and the compound represented by the general formula (2) is an optically active compound.