JP2013063950A - Method for manufacturing unsymmetrical tertiary alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply manufacturing unsymmetrical tertiary alcohol having an annular skeleton in high yield without using a high toxicity metal compound.SOLUTION: The unsymmetrical tertiary alcohol shown in formula (5) is generated by making a ketone intermediate by adding a liquid including a specific organometallic compound at a speed of 0.01-0.5 equivalence/time into a liquid including an acid halogen compound having an annular skeleton, and, in addition, by reacting the specific organometallic compound with the intermediate. In the formula, the ring Z shows a nonaromatic or aromatic ring of a monocyclic or multiple ring. Moreover, Rand Rare a hydrocarbon group, and are different groups.

Description

  The present invention relates to a method for producing an asymmetric tertiary alcohol and a method for producing a carboxylic acid asymmetric tertiary alcohol ester using the asymmetric tertiary alcohol. More specifically, an asymmetric tertiary in which a monocyclic or polycyclic non-aromatic or aromatic ring is bonded to a carbon atom to which a hydroxyl group is bonded, and two different groups are bonded. The present invention relates to a method for producing alcohol and a method for producing a carboxylic acid asymmetric tertiary alcohol ester using the asymmetric tertiary alcohol. Such asymmetric tertiary alcohols and carboxylic acid asymmetric tertiary alcohol esters are useful as raw materials for functional polymers such as photosensitive resins and fine chemicals such as pharmaceuticals.

  As a method for producing an asymmetric tertiary alcohol, a ketone is obtained by reacting an alkyl manganese halide and an acid halide, and an alkyl lithium or alkyl magnesium halide is reacted with the obtained ketone to obtain a target asymmetric tertiary alcohol. Methods have been reported (Non-Patent Documents 1 and 2). However, in this method, in addition to using a stoichiometric amount of a highly toxic manganese compound, it is necessary to prepare an alkylmanganese halide by further reacting an alkyllithium synthesized from an alkane with a manganese halide, which makes the process complicated. . Conventionally, there is no industrially efficient method for producing a carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton.

  As a method for producing an asymmetric ketone, there has been reported a method for obtaining a target asymmetric ketone by reacting an acyl chloride with a Grignard reagent in the presence of a catalytic amount of a metal halide (Non-patent Document 3). In this document, when the addition time of the Grignard reagent is fast, the reduced product of the target ketone (secondary alcohol) is the main by-product, and when the addition time of the Grignard reagent is slow, It is described that esters of acids are the main by-products. This document does not describe a method for producing an asymmetric tertiary alcohol.

Tetrahedron Letters, 1988, 29 (30), 3659-3622. Tetrahedron Letters, 1986, 27 (37), 4441-4444 Tetrahedron, 61 (2005), 83-88

An object of the present invention is to provide a method capable of easily producing an asymmetric tertiary alcohol having a cyclic skeleton in a high yield without using a highly toxic metal compound.
Another object of the present invention is to provide a method capable of producing an asymmetric tertiary alcohol having a cyclic skeleton from a readily available raw material with high selectivity and yield.
Still another object of the present invention is to provide an industrially efficient process for producing a carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton.

  As a result of intensive studies to achieve the above object, the present inventors have responded by adding a liquid mixture containing a specific organometallic compound to a liquid mixture containing a carboxylic acid derivative having a cyclic skeleton at a predetermined rate. After producing a ketone, it was found that when a specific organometallic compound is reacted with the ketone, an asymmetric tertiary alcohol having a cyclic skeleton can be obtained industrially efficiently in a high yield, and the present invention has been completed. .

［式中、環Ｚは単環又は多環の非芳香族性又は芳香族性環を示す。Ｘは、ハロゲン原子、−ＯＣＯＲ^a（式中、Ｒ^aは炭化水素基を示す）、又は−ＯＲ^b（式中、Ｒ^bは炭化水素基を示す）を示す］
で表される化合物を含む液中に、下記式（２）
Ｒ¹−Ｍ¹ （２）
［式中、Ｒ¹は炭化水素基を示す。Ｍ¹は配位子を有していてもよい金属原子、又は−Ｍ^aＹ（式中、Ｍ^aはマンガン以外の金属原子、Ｙはハロゲン原子を示す）を示す］
で表される有機金属化合物を含む液を、０．０１〜０．５当量／時間の速度で添加して、下記式（３）

［式中、環Ｚ、Ｒ¹は前記に同じ］
で表されるケトンを生成させる工程Ａ、及び前記式（３）で表されるケトンに、下記式（４）
Ｒ²−Ｍ² （４）
［式中、Ｒ²は炭化水素基を示す。但し、Ｒ¹とＲ²は異なる基である。Ｍ²は配位子を有していてもよい金属原子、又は−Ｍ^bＹ（式中、Ｍ^bはマンガン以外の金属原子、Ｙはハロゲン原子を示す）を示す］
で表される有機金属化合物を反応させて、下記式（５）

（式中、環Ｚ、Ｒ¹、Ｒ²は前記に同じ）
で表される非対称第３級アルコールを生成させる工程Ｂとを少なくとも含む非対称第３級アルコールの製造方法を提供する。 That is, the present invention provides the following formula (1):

[Wherein, ring Z represents a monocyclic or polycyclic non-aromatic or aromatic ring. X represents a halogen atom, —OCOR ^a (wherein R ^a represents a hydrocarbon group), or —OR ^b (wherein R ^b represents a hydrocarbon group)]
In a liquid containing the compound represented by formula (2)
R ¹ -M ¹ (2)
[Wherein R ¹ represents a hydrocarbon group. M ¹ represents a metal atom optionally having a ligand, or —M ^a Y (wherein M ^a represents a metal atom other than manganese, and Y represents a halogen atom)]
A liquid containing an organometallic compound represented by formula (3) is added at a rate of 0.01 to 0.5 equivalent / hour, and the following formula (3)

[Wherein, ring Z and R ¹ are the same as above]
Step A for producing a ketone represented by the formula (3) and the ketone represented by the formula (3)
R ² -M ² (4)
[Wherein R ² represents a hydrocarbon group. However, R ¹ and R ² are different groups. M ² represents a metal atom optionally having a ligand, or —M ^b Y (wherein M ^b represents a metal atom other than manganese, and Y represents a halogen atom)]
Is reacted with an organometallic compound represented by the following formula (5):

(Wherein, ring Z, R ¹ and R ² are the same as above)
And a process B for producing an asymmetric tertiary alcohol represented by the formula:

  In the step A, after adding the liquid containing the organometallic compound represented by the formula (2) to the liquid containing the compound represented by the formula (1), a compound having active hydrogen may be added.

  The reaction in Step A and / or the reaction in Step B may be performed in the presence of an ionic compound containing a Group 8 to Group 11 element in the periodic table.

  The reaction in step A and / or the reaction in step B may be performed in the presence of a Lewis acid.

  After the step B, it may further include a step of removing water by subjecting the produced reaction mixture containing the asymmetric tertiary alcohol represented by the formula (5) to an azeotropic dehydration operation.

（式中、環Ｚは単環又は多環の非芳香族性又は芳香族性環を示す。Ｒ¹、Ｒ²は、それぞれ、炭化水素基を示す。但し、Ｒ¹とＲ²は異なる基である）
で表される非対称第３級アルコールを製造した後、該非対称第３級アルコールを、下記式（６）
Ｒ³ＣＯＯＨ （６）
（式中、Ｒ³は炭化水素基、複素環式基又はこれらが結合した基を示す）
で表されるカルボン酸又はその反応性誘導体と反応させて、下記式（７）

（式中、環Ｚ、Ｒ¹、Ｒ²、Ｒ³は前記に同じ）
で表される環状骨格を有するカルボン酸非対称第３級アルコールエステルを得ることを特徴とするカルボン酸非対称第３級アルコールエステルの製造方法を提供する。 The present invention also provides the following formula (5) by the above method.

(Wherein, .R ^1, R ² ring Z is showing a non-aromatic or aromatic monocyclic or polycyclic, respectively, a hydrocarbon group. However, R ¹ and R ² different groups Is)
Then, the asymmetric tertiary alcohol is represented by the following formula (6):
R ³ COOH (6)
(Wherein R ³ represents a hydrocarbon group, a heterocyclic group or a group to which these are bonded)
Is reacted with a carboxylic acid represented by the following formula (7):

(Wherein, ring Z, R ¹ , R ² and R ³ are the same as above)
A method for producing a carboxylic acid asymmetric tertiary alcohol ester characterized in that a carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton represented by formula (1) is obtained.

  In this production method, the alcohol may be added after reacting the asymmetric tertiary alcohol represented by the formula (5) with the carboxylic acid represented by the formula (6) or a reactive derivative thereof.

According to the production method of the present invention, an asymmetric tertiary alcohol having a cyclic skeleton can be easily produced in a high yield without using a highly toxic metal compound. Also, an asymmetric tertiary alcohol having a cyclic skeleton can be produced from a readily available raw material with high selectivity and yield.
In addition, a carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton can be produced industrially efficiently.

[Production of asymmetric tertiary alcohol]
In the method for producing an asymmetric tertiary alcohol of the present invention, a liquid containing an organometallic compound represented by the formula (2) is added to a solution containing the compound represented by the formula (1) by 0.01 to 0.00. Step A in which a ketone represented by the formula (3) is produced by adding at a rate of 5 equivalents / hour, and the organometallic compound represented by the formula (4) is added to the ketone represented by the formula (3). And at least a step B of generating an asymmetric tertiary alcohol represented by the formula (5). In the present specification, “asymmetric” tertiary alcohol means a tertiary alcohol in which two different groups are introduced into the carbonyl carbon of the compound of formula (1) used as a raw material.

[Compound represented by Formula (1)]
In the compound represented by the formula (1), the ring Z represents a monocyclic or polycyclic non-aromatic or aromatic ring. X represents a halogen atom, —OCOR ^a (wherein R ^a represents a hydrocarbon group), or —OR ^b (wherein R ^b represents a hydrocarbon group).

  The non-aromatic ring in the ring Z includes an alicyclic hydrocarbon ring (non-aromatic hydrocarbon ring) and a non-aromatic heterocyclic ring. The alicyclic hydrocarbon ring includes monocyclic hydrocarbon ring and polycyclic hydrocarbon ring [spiro hydrocarbon ring, ring assembly hydrocarbon ring, bridged cyclic hydrocarbon ring (including condensed cyclic hydrocarbon ring) The non-aromatic heterocyclic ring includes a monocyclic heterocyclic ring and a polycyclic heterocyclic ring (such as a bridged cyclic heterocyclic ring).

Examples of the monocyclic hydrocarbon ring include C _3-12 cycloalkane rings such as cyclopentane, cyclohexane, cycloheptane, and cyclooctane ring; C _3-12 cycloalkene rings such as cyclohexene ring. Spiro hydrocarbon rings include, for example, C _5-16 spiro hydrocarbon rings such as spiro [4.4] nonane, spiro [4.5] decane, and spirobicyclohexane rings. Examples of the ring assembly hydrocarbon ring include ring assembly hydrocarbon rings including C _3-12 cycloalkane rings such as bicyclohexane and biperhydronaphthalene ring.

As the bridged cyclic hydrocarbon ring, for example, bicyclic such as pinane, bornane, norpinane, norbornane, bicyclooctane ring (bicyclo [2.2.2] octane ring, bicyclo [3.2.1] octane ring, etc.) Hydrocarbon ring; Tricyclic hydrocarbon ring such as homobredan, adamantane, tricyclo [5.2.1.0 ^2,6 ] decane, tricyclo [4.3.1.1 ^2,5 ] undecane ring; tetracyclo [4 4.0.1, ^2,5 . 1 ^7,10 ] dodecane, and tetracyclic hydrocarbon rings such as perhydro-1,4-methano-5,8-methanonaphthalene ring.

  The bridged cyclic hydrocarbon ring includes dimer hydrogenates [eg, cycloalkadiene dimer hydrogenates such as cyclopentadiene, cyclohexadiene, cycloheptadiene (eg, perhydro-4). , 7-methanoindene, etc.), dimers of butadiene (vinylcyclohexene) and hydrogenated products thereof, etc.].

  The bridged cyclic hydrocarbon ring includes a condensed cyclic hydrocarbon ring such as perhydronaphthalene (decalin), perhydroanthracene, perhydrophenanthrene, perhydroacenaphthene, perhydrofluorene, perhydroindene, perhydroindene. A condensed ring in which a plurality of 5- to 8-membered cycloalkane rings such as a phenalene ring are condensed is also included.

Preferred bridged cyclic hydrocarbon rings include norbornane, bornane, adamantane, bicyclooctane, tricyclo [5.2.1.0 ^2,6 ] decane, decalin ring and the like.

  Examples of the monocyclic non-aromatic heterocycle include oxygen atom-containing heterocycles such as oxolane, oxane, oxepane, and oxocan ring; nitrogen atom-containing heterocycles such as perhydroazepine ring. Examples of the polycyclic non-aromatic heterocyclic ring include a bridged cyclic heterocyclic ring.

  The aromatic ring includes an aromatic hydrocarbon ring and an aromatic heterocycle. Examples of the aromatic hydrocarbon ring include monocyclic or polycyclic aromatic hydrocarbon rings such as benzene, naphthalene, anthracene, phenanthrene, and phenalene ring. Examples of the aromatic heterocycle include one or more heteroatoms such as oxygen atom, nitrogen atom, sulfur atom such as furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, acridine, phenazine ring, or the like. A monocyclic or polycyclic aromatic heterocyclic ring containing a plurality of them can be mentioned.

  Preferred ring Z is a polycyclic non-aromatic ring (hydrocarbon ring or heterocyclic ring), and in particular, a bridged cyclic ring (bridged cyclic hydrocarbon ring or bridge) containing 2 to 4 rings such as an adamantane ring. Cyclic heterocycle) is preferred. The ring Z is preferably a monocyclic or polycyclic non-aromatic or aromatic ring having 5 or more carbon atoms (for example, 5 to 18, particularly 6 to 14).

Ring Z may have a substituent. The substituent is not particularly limited as long as it does not impair the reaction. Representative examples of the substituent include, for example, a halogen atom (bromine, chlorine, fluorine atom, etc.), an alkyl group (C _1-4 alkyl group such as methyl, ethyl, butyl, t-butyl group, etc.), a protecting group, etc. Examples include a protected hydroxyl group and an amino group protected with a protecting group.

Examples of the protecting group for the hydroxyl group include protecting groups commonly used in the field of organic synthesis, such as alkyl groups (for example, C _1-4 alkyl groups such as methyl and t-butyl groups), cycloalkyl groups (for example, cyclohexyl). Group), aralkyl group (eg benzyl group, etc.), substituted methyl group (eg methoxymethyl, methoxythiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl group etc.), substituted ethyl group (eg , 1-ethoxyethyl, 1-methyl-1-methoxyethyl, etc.), acyl group (for example, C _1-6 aliphatic acyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl group; acetoacetyl group Benzoyl, naphthoyl and other aromatic acyl groups), alkoxycarbonyl groups For example, methoxycarbonyl, ethoxycarbonyl, C _1-4 alkoxycarbonyl group such as t- butoxycarbonyl group), an aralkyloxycarbonyl group (e.g., benzyloxycarbonyl group, etc. p- methoxybenzyloxycarbonyl group) can be exemplified. Preferred protecting groups for hydroxyl groups include C _1-4 alkyl groups, substituted methyl groups, substituted ethyl groups, acyl groups, C _1-4 alkoxycarbonyl groups, and the like.

Examples of the amino-protecting group include an alkyl group, a cycloalkyl group, an aralkyl group, an acyl group, an alkoxycarbonyl group, and an aralkyloxycarbonyl group exemplified as the protective group for the hydroxyl group. Preferred protecting groups for amino groups include C _1-4 alkyl groups, C _1-6 aliphatic acyl groups, aromatic acyl groups, C _1-4 alkoxycarbonyl groups and the like.

  Examples of the halogen atom in X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a chlorine atom, a bromine atom, and an iodine atom are preferable.

The hydrocarbon group in R ^a and R ^b includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and a group obtained by connecting a plurality of these groups.

Examples of the aliphatic hydrocarbon group include C ₁ such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, octyl, decyl, vinyl, allyl, and 2-propynyl group. _-10 aliphatic hydrocarbon groups (linear or branched alkyl groups, alkenyl groups, and alkynyl groups). Preferred aliphatic hydrocarbon groups are C _1-6 (especially C _1-4 ) aliphatic hydrocarbon groups.

  Examples of the alicyclic hydrocarbon group include 3- to 12-membered alicyclic hydrocarbon groups (cycloalkyl group, cycloalkenyl group, etc.) such as cyclopentyl and cyclohexyl groups.

Examples of the aromatic hydrocarbon group include C _6-20 aromatic hydrocarbon groups (aryl groups) such as phenyl and naphthyl groups. Examples of the group in which a plurality of different hydrocarbon groups are linked include C _7-16 aralkyl groups such as benzyl and 2-phenylethyl groups, C _3-12 cycloalkyl-C such as cyclopentylmethyl and cyclohexylmethyl groups. Examples include _1-6 alkyl groups.

  The hydrocarbon group may have a substituent. The substituent is not particularly limited as long as it does not inhibit the reaction. For example, a halogen atom, a substituted oxy (or thio) group (for example, methoxy, methylthio, methoxyethoxy, 2- (trimethylsilyl) ethoxy, benzyloxy group Etc.), an acyl group (for example, benzoyl group, etc.) and the like.

Preferred R ^a and R ^b include a C _1-6 alkyl group, a C _3-12 cycloalkyl group, a C _6-20 aryl group, etc., particularly a C _1-4 alkyl group, a C _5-6 cycloalkyl group, phenyl Group etc. are included.

[Organometallic Compound Represented by Formula (2)]
In said formula (2), R < ¹ > shows a hydrocarbon group. M ¹ represents a metal atom which may have a ligand, or —M ^a Y (wherein M ^a represents a metal atom other than manganese, and Y represents a halogen atom).

Examples of the hydrocarbon group for R ¹ include the same hydrocarbon groups as those described above for R ^a and R ^b . Preferred R ¹ includes a C _1-6 alkyl group, a C _3-12 cycloalkyl group, a C _3-12 cycloalkyl-C _1-6 alkyl group, a C _6-20 aryl group, a C _7-16 aralkyl group, and the like. included. Among these, R ¹ is preferably a C _1-4 alkyl group such as a methyl group, an ethyl group, a propyl group, or an isopropyl group.

Examples of the metal atom in M ¹ include alkali metals such as lithium, and transfer metal atoms such as cerium, titanium, and copper. The metal atom may have a ligand. Examples of the ligand include a halogen atom such as a chlorine atom, an alkoxy group such as an isopropoxy group, a dialkylamino group such as a diethylamino group, an alkali metal atom such as a cyano group, an alkyl group, and a lithium atom.

Examples of M ^a include magnesium and zinc. Examples of the halogen atom represented by Y include chlorine, bromine and iodine atoms.

  Representative examples of the organometallic compound represented by the formula (2) include organotitanium compounds such as dimethyldiisopropoxytitanium (such as art complexes of organotitanium); methylmagnesium bromide, ethylmagnesium bromide, butylmagnesium bromide, etc. Organic magnesium compounds (such as Grignard reagent); organic zinc compounds (such as organic zinc halides) such as methyl zinc bromide, ethyl zinc bromide, and butyl zinc bromide; and organic lithium compounds such as methyl lithium and butyl lithium.

[Organometallic Compound Represented by Formula (4)]
In the formula (4), R ² represents a hydrocarbon group. However, R ¹ and R ² are different groups. M ² represents a metal atom optionally having a ligand, or —M ^b Y (wherein M ^b represents a metal atom other than manganese, and Y represents a halogen atom).

Examples of the hydrocarbon group for R ² include the same hydrocarbon groups as those described above for R ^a and R ^b . Preferred R ² includes a C _1-6 alkyl group, a C _3-12 cycloalkyl group, a C _3-12 cycloalkyl-C _1-6 alkyl group, a C _6-20 aryl group, a C _7-16 aralkyl group, and the like. included. Among them, R ² is preferably a C _1-4 alkyl group such as a methyl group, an ethyl group, a propyl group, or an isopropyl group.

Examples of the metal atom in M ² include alkali metals such as lithium, and transfer metal atoms such as cerium, titanium, and copper. The metal atom may have a ligand. Examples of the ligand include a halogen atom such as a chlorine atom, an alkoxy group such as an isopropoxy group, a dialkylamino group such as a diethylamino group, an alkali metal atom such as a cyano group, an alkyl group, and a lithium atom.

Examples of M ^b include magnesium and zinc. Y is the same as described above.

  Representative examples of the organometallic compound represented by the formula (4) include organotitanium compounds such as dimethyldiisopropoxytitanium (such as art complexes of organotitanium); methylmagnesium bromide, ethylmagnesium bromide, butylmagnesium bromide, etc. Organic magnesium compounds (such as Grignard reagent); organic zinc compounds (such as organic zinc halides) such as methyl zinc bromide, ethyl zinc bromide, and butyl zinc bromide; and organic lithium compounds such as methyl lithium and butyl lithium.

[reaction]
The reaction is carried out in two steps (two steps). That is, first, the compound represented by the formula (1) and the organometallic compound represented by the formula (2) are reacted to produce a ketone represented by the formula (3) (first stage reaction; step) A), and then the produced ketone and the organometallic compound represented by the formula (4) are reacted to produce an asymmetric tertiary alcohol represented by the formula (5) (second stage reaction; step B). ).

［式中、環Ｚ、Ｒ¹は前記に同じ］
で表される対称第３級アルコールが多く副生する。式（２）で表される有機金属化合物を含む液の添加速度は、好ましくは０．０５〜０．４当量／時間、さらに好ましくは０．１〜０．３当量／時間である。 In the present invention, in the first-stage reaction (step A), the liquid containing the organometallic compound represented by the formula (2) is usually added to the liquid containing the compound represented by the formula (1). -0.5 equivalent / hour, preferably 0.02-0.4 equivalent / hour, more preferably 0.03-0.3 equivalent / hour, and the addition rate is represented by the formula (3) It is important to produce a ketone. The “equivalent” means the equivalent of the organometallic compound represented by the formula (2) with respect to the compound represented by the formula (1) (preparation standard) used as a raw material. When the addition rate of the liquid containing the organometallic compound represented by the formula (2) is too slow, the reaction time becomes long and the production efficiency decreases. On the other hand, when the addition rate of the liquid containing the organometallic compound represented by the formula (2) is too fast, a reduced form of ketone (alcohol or the like) represented by the formula (3) or the following formula (8)

[Wherein, ring Z and R ¹ are the same as above]
A large amount of the symmetric tertiary alcohol represented by The addition rate of the liquid containing the organometallic compound represented by the formula (2) is preferably 0.05 to 0.4 equivalent / hour, more preferably 0.1 to 0.3 equivalent / hour.

  As the liquid containing the compound represented by the formula (1), a mixed liquid of the compound represented by the formula (1) and a solvent can be used. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include linear or cyclic ethers such as diethyl ether, dibutyl ether, dimethoxyethane, and tetrahydrofuran; aliphatic hydrocarbons such as hexane, heptane, and octane. An aromatic hydrocarbon such as benzene, toluene and xylene; an alicyclic hydrocarbon such as cyclohexane; and a mixed solvent thereof. A preferable solvent includes the ether or a mixed solvent of the ether and another solvent (hydrocarbon or the like). The concentration of ether in the solvent is preferably 10% by weight or more.

  As the liquid containing the organometallic compound represented by the formula (2), a mixed liquid of the organometallic compound represented by the formula (2) and a solvent can be used. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include the same solvents as the solvent of the compound represented by the formula (1). A preferable solvent includes the ether or a mixed solvent of the ether and another solvent (hydrocarbon or the like). The concentration of ether in the solvent is preferably 10% by weight or more.

  The usage-amount of the organometallic compound represented by Formula (2) is 0.5-5 equivalent with respect to the compound represented by Formula (1) used as a raw material, Preferably it is 0.8-1.5. Equivalent, more preferably 0.9 to 1.2 equivalent. If the amount of the organometallic compound represented by the formula (2) is too small, the yield tends to decrease, and if too large, side reaction occurs and the selectivity tends to decrease. The reaction temperature is, for example, -40 ° C to 60 ° C, preferably -10 ° C to 40 ° C, more preferably -5 ° C to 20 ° C. If the reaction temperature is too low, the yield tends to decrease, whereas if it is too high, side reactions occur and the selectivity tends to decrease.

  In the present invention, a liquid containing an organometallic compound represented by formula (2) is added to a liquid containing a compound represented by formula (1), and then a compound having active hydrogen is added to the reaction mixture. The reaction may be stopped.

  Although it does not specifically limit as a compound which has active hydrogen, For example, water; Alcohol, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 1-hexanol, cyclohexyl alcohol (Eg, alcohol having 1 to 4 carbon atoms); phenols such as phenol and cresol; formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, succinic acid, malonic acid, adipic acid, maleic acid, fumaric acid, benzoic acid Carboxylic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, boric acid and the like; and mixtures thereof. As the compound having active hydrogen, water, alcohol (for example, alcohol having 1 to 4 carbon atoms), organic acid, inorganic acid, and a mixture thereof are preferable.

  The temperature at which the compound having active hydrogen is added is in the same range as the reaction temperature. The addition amount of the compound having active hydrogen is not limited as long as it can be deactivated by decomposing the unreacted organometallic compound represented by the formula (2) or the adduct of the organometallic compound. An amount may be used.

  The reaction mixture or a mixture obtained by adding a compound having active hydrogen to the reaction mixture is subjected to physical treatment such as liquidity adjustment, dilution, concentration, and solvent exchange as necessary, followed by extraction and washing with water. The ketone represented by the formula (3) can be obtained by purification such as distillation. This ketone is subjected to the second stage reaction (step B). In addition, without purifying the ketone represented by the formula (3), the reaction mixture or a mixture obtained by adding a compound having active hydrogen to the reaction mixture was subjected to the physical treatment as it was. Later, it can also be subjected to the second stage reaction (step B).

  In the second-stage reaction (step B), the ketone represented by formula (3) is reacted with the organometallic compound represented by formula (4) to form an asymmetric tertiary alcohol represented by formula (5). Is generated. In this case, the liquid containing the organometallic compound represented by the formula (4) may be added (dropped) to the liquid containing the ketone represented by the formula (3). You may add (drop) the liquid containing the ketone represented by Formula (3) in the liquid containing the organometallic compound represented. From the viewpoint of yield and the like, a method of adding (dropping) a liquid containing a ketone represented by formula (3) to a liquid containing an organometallic compound represented by formula (4) is preferable.

  Examples of the liquid containing the ketone represented by the formula (3) include a mixed liquid of the ketone represented by the formula (3) and a solvent. Moreover, as a liquid containing the organometallic compound represented by Formula (4), the liquid mixture of the organometallic compound represented by Formula (4) and a solvent is mentioned. As these solvents, the solvents exemplified above can be used.

  In the second stage reaction, the amount of the organometallic compound represented by formula (4) is, for example, 0.5 to 10 equivalents relative to the compound represented by formula (1) used as a raw material, preferably 0.8 to 8 equivalents, more preferably 0.9 to 5 equivalents. If the amount of the organometallic compound represented by formula (4) is too small, the yield tends to decrease, and conversely if too large, side reactions occur and the selectivity decreases or the post-treatment is complicated. Prone. The reaction temperature is, for example, -50 ° C to 50 ° C, preferably -20 ° C to 40 ° C, more preferably -10 ° C to 30 ° C. If the reaction temperature is too low, the yield tends to decrease, whereas if it is too high, side reactions occur and the selectivity tends to decrease.

  After completion of the second stage reaction, an adduct of an organometallic compound is usually added by adding an aqueous solution containing an acid (eg, an inorganic acid such as hydrochloric acid or sulfuric acid; an organic acid such as acetic acid) or a salt (eg, ammonium chloride). (Quenching), adjusting the liquidity as necessary, and subjecting it to conventional separation and purification means such as filtration, concentration, extraction, distillation, crystallization, recrystallization, column chromatography, etc. An asymmetric tertiary alcohol represented by a certain formula (5) can be obtained.

  It is not always necessary to isolate and purify the asymmetric tertiary alcohol represented by the formula (5). For example, a mixed solution containing the asymmetric tertiary alcohol represented by the formula (5) after quenching may be used as necessary. Then, after liquid adjustment, washing with water, etc., it is subjected to an azeotropic dehydration operation in the presence of a solvent azeotropic with water to remove water, and then used (for example, carboxylic acid asymmetric tertiary alcohol described later) Ester). When such an azeotropic dehydration operation is performed, since asymmetric tertiary alcohol can be used for the reaction without purification such as precision distillation, the operation can be simplified and the process can be shortened. Become. Examples of the solvent azeotropic with water include toluene, xylene, ethylbenzene, and octane. The azeotropic dehydration operation can be performed by a conventional method.

[Metal catalyst]
The first stage reaction and the second stage reaction can be carried out in the presence of a metal catalyst, if necessary. By making a metal catalyst exist in a reaction system, a yield and a selectivity can be improved. In the first stage reaction, the metal catalyst can be contained, for example, in a liquid containing the compound represented by the formula (1).

  Examples of the metal catalyst include (i) an ionic compound containing Group 8 to Group 11 elements of the periodic table, and (ii) Lewis acid. The ionic compound (i) and Lewis acid (ii) containing Group 8 to Group 11 elements of the periodic table can be used alone or in combination of two or more. Even if only the ionic compound (i) containing an element from Group 8 to Group 11 of the periodic table is used as the metal catalyst or only Lewis acid (ii) is used, the effect can be obtained. The combined use of the ionic compound (i) containing a Group 11 element and the Lewis acid (ii) can greatly improve the yield of the target compound. In the present specification, a boron compound is also included in the metal catalyst.

  In the ionic compound (i) containing Group 8 to Group 11 elements of the periodic table, Group 8 elements include iron, ruthenium, and osmium, and Group 9 elements include cobalt, rhodium, and iridium. The Group 10 elements include nickel, palladium, and platinum, and the Group 11 elements include copper, silver, and gold. Among these, elements of the fourth period (iron, cobalt, nickel, copper) are preferable, and copper is particularly preferable.

  Examples of ionic compounds containing these elements include halides such as chlorides, bromides, and iodides of Group 8 to Group 11 elements (metal elements) of the periodic table; nitrates, sulfates, phosphates, and boric acids. Examples thereof include inorganic acid salts such as salts and perchlorates; carboxylates such as acetates, and organic acid salts such as sulfonates such as p-toluenesulfonate. Among these, halides such as chloride are preferable.

  As the ionic compound (i) containing Group 8 to Group 11 elements of the periodic table, a particularly preferable compound is copper chloride. The valence of copper in copper chloride may be 1 or 2.

As the Lewis acid (ii), a well-known Lewis acid can be used. For example, a periodic table group 3 element compound (such as a rare earth metal compound) such as cerium triflate; a titanium compound such as TiCl ₄ ; a zirconium compound such as ZrCl ₄ ; Group 4 element compounds of the periodic table; Group 12 element compounds of the periodic table such as zinc compounds such as ZnCl ₂ , ZnBr ₂ , ZnI ₂ ; Boron compounds such as boron trifluoride etherate; Aluminum compounds such as AlCl ₃ and AlBr ₃ Periodic table group 13 element compounds; periodic table group 14 element compounds such as tin compounds such as SnCl ₂ and SnCl ₄ ; and periodic table group 15 element compounds such as antimony compounds and bismuth compounds. As the Lewis acid, a halide or trifluoromethanesulfonate of Group 3 element, Group 4 element, Group 12 element, Group 13 element, Group 14 element, Group 15 element of the periodic table is preferable. Among these, titanium compounds such as TiCl ₄ , zirconium compounds such as ZrCl ₄ , zinc compounds such as ZnCl ₂ , and aluminum compounds such as AlCl ₃ and AlBr ₃ are particularly preferable.

  The amount of the ionic compound (i) containing Group 8 to Group 11 elements in the periodic table is usually 0.0001 to 0.2 mol, preferably 1 mol to 1 mol of the compound represented by the formula (1). 0.0005 to 0.1 mol, more preferably 0.005 to 0.07 mol. The amount of Lewis acid (ii) used is usually 0.0001 to 0.2 mol, preferably 0.0005 to 0.1 mol, based on 1 mol of the compound represented by formula (1). Preferably, it is 0.005-0.07 mol.

  According to the method of the present invention, a general organometallic reagent having low toxicity such as a Grignard reagent can be used as it is, and it is not necessary to perform an isolation operation in the middle, and two kinds of organometallic reagents are continuously reacted. Thus, an asymmetric tertiary alcohol having a cyclic skeleton can be easily produced with high yield and selectivity. In Step A, the organometallic compound represented by the formula (2) is added to the liquid containing the compound represented by the formula (1) at a predetermined addition rate. Alcohol and the like) and by-products such as the compound represented by the formula (8) can be remarkably suppressed. For this reason, in the ketone represented by the formula (3) which is an intermediate without distillation, the content of the reduced form of the ketone which is an impurity is 0.5% by weight or less (preferably 0.1% by weight). %), The content of the compound represented by the formula (8) as an impurity is 0.5% by weight or less (preferably 0.1% by weight or less), and the total content thereof is 1% by weight or less. be able to. Further, in step B, the ketone represented by the formula (3) can be efficiently converted into an asymmetric tertiary alcohol having a target cyclic skeleton, so that the asymmetric third having the target cyclic skeleton can be obtained without distillation. In the secondary alcohol, the content of the ketone represented by the formula (3) can be 0.8% by weight or less (preferably 0.4% by weight or less). Therefore, according to the present invention, it is possible to obtain an asymmetric tertiary alcohol having a practical level of cyclic skeleton without performing precise distillation.

  The asymmetric tertiary alcohol having a cyclic skeleton obtained by the above method is useful as a raw material for functional polymers such as photosensitive resins and fine chemicals such as pharmaceuticals.

[Production of carboxylic acid asymmetric tertiary alcohol ester]
In the method for producing a carboxylic acid asymmetric tertiary alcohol ester of the present invention, the asymmetric tertiary alcohol represented by the formula (5) obtained by the above method is converted to the carboxylic acid represented by the formula (6) or a carboxylic acid thereof. By reacting with a reactive derivative, a carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton represented by the formula (7) is obtained. In the reaction, a base, an acid, a dehydrating condensing agent, or the like can be used as necessary to improve the reaction rate. In addition, as asymmetric tertiary alcohol represented by Formula (5) used as a raw material, what was obtained by methods other than the said manufacturing method may be used.

Examples of the hydrocarbon group for R ³ in formula (6) include those exemplified as the hydrocarbon groups for R ^a and R ^b . Examples of the heterocyclic group for R ³ include heterocyclic groups having at least one heteroatom selected from nitrogen, oxygen and sulfur atoms such as pyridyl, furyl and thienyl groups. R ³ is preferably a heterocyclic group having at least one heteroatom selected from a hydrocarbon group having 1 to 20 carbon atoms, a nitrogen atom, an oxygen atom and a sulfur atom. Among them, R ³ is preferably a hydrocarbon group having a polymerizable unsaturated bond, for example, an alkenyl group having 2 to 10 carbon atoms such as a vinyl group, a propenyl group, or an isopropenyl group.

  As typical examples of the carboxylic acid represented by the formula (6), formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid , Saturated aliphatic carboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid (saturated aliphatic monocarboxylic acid, saturated aliphatic dicarboxylic acid, etc.); acrylic acid, methacrylic acid, propiolic acid, crotonic acid, Unsaturated aliphatic carboxylic acids such as isocrotonic acid, oleic acid, maleic acid, fumaric acid (unsaturated aliphatic monocarboxylic acid, unsaturated aliphatic dicarboxylic acid, etc.); benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid Carbocyclic carboxylic acids such as acids, toluic acid, cinnamic acid; nicotinic acid, isonicotinic acid, furan carboxylic acid, thiophene carboxylic acid Such heterocyclic carboxylic acids. In addition, when dicarboxylic acid is used for reaction, the corresponding diester can produce | generate. Of these, unsaturated aliphatic carboxylic acids, particularly acrylic acid and methacrylic acid are preferred.

  Examples of the reactive derivative of the carboxylic acid represented by the formula (6) include carboxylic acid anhydrides; carboxylic acid halides such as carboxylic acid chloride and carboxylic acid bromide.

  In a preferred embodiment of the method for producing a carboxylic acid tertiary alcohol ester, an asymmetric tertiary alcohol represented by the formula (5) is converted into a halide (carboxylic acid) of the carboxylic acid represented by the formula (6) in the presence of a base. Carboxylic acid halides such as chloride and carboxylic acid bromide) to obtain a carboxylic acid tertiary alcohol ester having a cyclic skeleton represented by the formula (7).

As the base, for example, the following formula (9) or (10)
R ^c MgX ¹ (9)
R ^c Li (10)
(Wherein R ^c represents an alkyl group or a haloalkyl group, and X ¹ represents a halogen atom)
And organic amine compounds and tertiary amines. These bases can be used alone or in combination of two or more. In particular, when the organometallic compound represented by the formula (9) or (10) is used in combination with a tertiary amine, the target carboxylic acid asymmetric tertiary alcohol ester can be obtained in high yield.

Examples of the alkyl group for R ^c include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl groups. Among these, a C _1-4 alkyl group is particularly preferable. As the haloalkyl group in R ^c , one or more hydrogen atoms constituting the alkyl group such as trifluoromethyl and 2,2,2-trifluoroethyl group are replaced with halogen atoms (fluorine atoms, chlorine atoms, etc.). And the like.

Examples of the halogen atom for X ¹ include a chlorine atom, a bromine atom, and an iodine atom.

  Representative examples of the organometallic compound represented by the formula (9) include organomagnesium compounds such as methylmagnesium bromide, ethylmagnesium bromide, butylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, butylmagnesium chloride (Grineer reagent, etc. ). Moreover, organic lithium compounds, such as methyllithium, ethyllithium, and butyllithium, are mentioned as a typical example of the organometallic compound represented by Formula (10). The organomagnesium compound can also be used in combination with a copper halide.

  As the organometallic compound, it is particularly preferable to use a compound represented by the above formula (9) in that it is easy to handle, can be safely scaled up, and is suitable for industrialization.

  Examples of the tertiary amine include aliphatic amines, aromatic amines, alicyclic amines, and heterocyclic amines. The tertiary amine may contain a hydroxyl group, a nitro group or the like in the molecule. In addition to monoamines, polyamines such as diamines may be used.

  Specific examples of the tertiary amine include trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, triisopropylamine, tributylamine, N-methyl-diethylamine, N-ethyl-dimethylamine, N-ethyl-diamilamine and the like. Aliphatic amines; aromatic amines such as N, N-dimethylaniline and diethylaniline; alicyclic amines such as N, N-dimethyl-cyclohexylamine and N, N-diethyl-cyclohexylamine; N, N-dimethylamino Heterocyclic amines such as pyridine, N-methylmorpholine, diazabicycloundecene (DBU), diazabicyclononene (DBN), N-methylpyridine, N-methylpyrrolidine; diamines such as tetramethylethylenediamine and triethylenediamine All Rukoto can.

  As the tertiary amine, aliphatic amines such as trimethylamine and triethylamine and heterocyclic amines such as N-methylmorpholine are preferable, and aliphatic amines such as trimethylamine and triethylamine improve the yield of the target compound. It is preferable in that

  The amount of base used (total amount) is, for example, 0.2 to 15 equivalents, preferably 1.6 to 10 equivalents, more preferably 1 to the asymmetric tertiary alcohol represented by the formula (5) used as a raw material. .9-7 equivalents. When the organometallic compound represented by the formula (9) or (10) and a tertiary amine are used in combination as the base, the amount of the organometallic compound represented by the formula (9) or (10) is used. Is, for example, 0.1 to 5 equivalents, preferably 0.8 to 3 equivalents, more preferably 0.9 to 2 equivalents, relative to the asymmetric tertiary alcohol represented by the formula (5) used as a raw material. The amount of the tertiary amine used is, for example, 0.1 to 10 equivalents, preferably 0.8 to 7 equivalents, more preferably the asymmetric tertiary alcohol represented by the formula (5) used as a raw material. 1 to 5 equivalents. If the amount of the base is too small, the yield of the target product tends to decrease. Moreover, when there is too much quantity of a base, it will become easy to produce a side reaction.

  The amount of the carboxylic acid halide (carboxylic acid halide) represented by the formula (6) is, for example, 0.1 to 5 equivalents relative to the asymmetric tertiary alcohol represented by the formula (5) used as a raw material. , Preferably 0.8-3 equivalents, more preferably 0.9-2 equivalents. When the usage-amount of carboxylic acid halide is less than the said range, there exists a tendency for the yield of the target ester to fall. On the other hand, when the amount of the carboxylic acid halide used exceeds the above range, a by-product derived from the carboxylic acid halide [for example, a carboxylic acid halide having a polymerizable unsaturated group such as (meth) acrylic acid halide is used as the carboxylic acid halide. In such a case, the carboxylic acid halide polymer and the like] tend to increase.

  In the present invention, from the viewpoint of reaction yield, the total amount of base used [equivalent to the asymmetric tertiary alcohol represented by formula (5) used as a raw material] -halide of carboxylic acid represented by formula (6) Is preferably 1.8 equivalents or more (e.g., 1.8 to 8 equivalents), more preferably 2. equivalent amount (equivalent to the asymmetric tertiary alcohol represented by the formula (5) used as a raw material). It is 0 equivalent or more (for example, 2.0 to 6 equivalent). If this value is too low, the yield of the target carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton tends to decrease.

  Moreover, when using carboxylic acid halide which has polymerizable unsaturated groups, such as (meth) acrylic acid halide, as carboxylic acid halide, it is preferable to react in presence of a polymerization inhibitor. By adding a polymerization inhibitor, a carboxylic acid halide used in the reaction and an ester [(meth) acrylic acid ester, etc.] having a polymerizable unsaturated group, which is the target product, are polymerized to produce an oligomer as a by-product. Can be prevented. When an ester having a polymerizable unsaturated group [(meth) acrylic acid ester, etc.] having an extremely low oligomer content as an impurity is used as a raw material for a resist polymer, a resist film is formed using the obtained polymer. Since a uniform and homogeneous resist film can be formed and a fine pattern can be formed with excellent sensitivity and resolution, it is possible to cope with the recent miniaturization of substrate circuits.

  The polymerization inhibitor is not particularly limited, and those generally used can be used, but one of the two ortho positions of the phenolic hydroxyl group on the benzene ring is unsubstituted and the other is substituted with a hydrocarbon group. It is preferable to use the phenols. By using phenols having such a specific structure, polymerization of raw materials and products having a polymerizable unsaturated group such as a (meth) acryloyl group can be suppressed, and oligomer by-product can be prevented.

  Examples of the hydrocarbon group at the ortho position of the phenolic hydroxyl group on the benzene ring include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl groups; Examples thereof include cycloalkyl groups such as propyl, cyclopentyl and cyclohexyl groups; aryl groups such as phenyl and naphthyl groups; aralkyl groups such as benzyl groups and the like. As said hydrocarbon group, C1-C10 alkyl groups, such as methyl, ethyl, isopropyl, and t-butyl group, are preferable, and t-butyl group is especially preferable.

  In the phenols, the meta-position and the para-position of the phenolic hydroxyl group may or may not have a substituent, but the two substituents of the phenolic hydroxyl group do not have the substituent. A position adjacent to the ortho-position preferably has a hydrocarbon group as a substituent. Examples of the hydrocarbon group include the same examples as described above, but an alkyl group having 1 to 3 carbon atoms such as a methyl group is particularly preferable.

  Preferable examples of the phenols include compounds having a 4-hydroxy-2,5-dialkylphenyl group. Examples of the alkyl group include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl groups. The 5-position alkyl group is particularly preferably a t-butyl group, and the 2-position alkyl group is preferably an alkyl group having 1 to 3 carbon atoms, particularly a methyl group.

  Representative examples of the compound having a 4-hydroxy-2,5-dialkylphenyl group include, for example, 4,4′-thiobis (6-t-butyl-m-cresol), 4,4′-butylidenebis (6 -T-butyl-m-cresol), 1,1,3-tris (5-t-butyl-4-hydroxy-2-methylphenyl) butane and the like. These polymerization inhibitors can be used alone or in combination of two or more.

  The amount of the polymerization inhibitor used is, for example, 0.001 to 0.1 mol, preferably 0.005 to 0.05 mol, per 1 mol of the asymmetric tertiary alcohol represented by the formula (5) used as a raw material. Degree.

  The reaction between the asymmetric tertiary alcohol represented by formula (5) and the carboxylic acid halide represented by formula (6) (carboxylic acid halide) is preferably carried out in an organic solvent. The organic solvent may be any solvent inert to the reaction. For example, ethers such as diethyl ether, tert-butyl methyl ether (MTBE), 1,2-dimethoxyethane, tetrahydrofuran (THF); heptane, hexane, Examples thereof include aliphatic hydrocarbons such as octane; aromatic hydrocarbons such as benzene, toluene and xylene; alicyclic hydrocarbons such as cyclohexane. These can be used alone or in combination of two or more. Among these, it is preferable to use a combination of tetrahydrofuran and toluene or tetrahydrofuran and tert-butyl methyl ether, and particularly preferable to use a combination of tetrahydrofuran and toluene in terms of excellent solubility of the organometallic compound. .

  The reaction temperature can be appropriately selected within a range of, for example, about −100 ° C. to 150 ° C. depending on the kind of the organometallic compound and the reaction component. For example, when the compound represented by the formula (9) is used as the organometallic compound, the reaction temperature is, for example, 0 ° C. to 50 ° C., preferably 0 ° C. to 25 ° C., particularly preferably 0 ° C. to 15 ° C. . When the compound represented by the formula (10) is used as the organometallic compound, the reaction temperature is, for example, about -20 ° C to 10 ° C, preferably about -10 ° C to 5 ° C. When the reaction temperature is out of the above range, the yield tends to decrease.

  The reaction can be performed by a conventional method such as a batch system, a semi-batch system, or a continuous system. In general, an organometallic compound represented by formula (9) or (10) (or a solution containing this) is sequentially added to a solution containing an asymmetric tertiary alcohol represented by formula (5) as a raw material. Then, a carboxylic acid halide (carboxylic acid halide) represented by formula (6) (or a solution containing the carboxylic acid halide) is sequentially added to the system, and then a tertiary amine is sequentially added. . When adding the said polymerization inhibitor, it is preferable to add in the system at the appropriate time before adding the halide (carboxylic acid halide) of carboxylic acid represented by Formula (6).

  In the present invention, it is preferable to add the alcohol after reacting the asymmetric tertiary alcohol represented by the formula (5) with the carboxylic acid represented by the formula (6) or a reactive derivative thereof. After the reaction, by adding an alcohol, a reactive derivative of carboxylic acid represented by the unreacted formula (6) (such as a carboxylic acid halide) can be converted into an ester. When no alcohol is added, the by-product derived from the reactive derivative of the carboxylic acid represented by the unreacted formula (6) (such as a carboxylic acid halide) causes the carboxylic acid asymmetric structure having the target cyclic skeleton. The quality of the tertiary alcohol ester may deteriorate. For example, a carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton tends to become cloudy or the purity tends to decrease. Examples of the alcohol include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butanol.

  The amount of the alcohol added is usually 0.1 to 10 equivalents, preferably 0.2 to 7 equivalents, more preferably 0, relative to the asymmetric tertiary alcohol represented by the formula (5) used in the reaction. .4 to 4 equivalents. The temperature at which the alcohol is added is in the same range as the reaction temperature. The reaction time after addition of alcohol is, for example, 0.1 to 12 hours, preferably 0.3 to 6 hours.

  Water is added to the reaction mixture of the asymmetric tertiary alcohol represented by the formula (5) and the carboxylic acid represented by the formula (6) or a reactive derivative thereof, or the alcohol-treated product thereof as necessary. Then, for example, by using separation and purification means such as liquidity adjustment, filtration, concentration, extraction, washing, distillation, crystallization, recrystallization, column chromatography, adsorption treatment, etc., the target carboxylic acid asymmetric tertiary alcohol Esters can be obtained.

  Further, when adding a polymerization inhibitor, by-products of the oligomer can be remarkably suppressed, for example, after completion of the reaction, the reaction product is subjected to extraction using water and an organic solvent, and the resulting organic layer For example, the target reaction product can be obtained simply by concentration and distillation. According to this production method, a carboxylic acid asymmetric tertiary alcohol ester having a high-purity cyclic skeleton [for example, (meth) having a cyclic skeleton, with an excellent yield (for example, 80% or more, preferably 85% or more). Acrylic acid asymmetric tertiary alcohol ester] can be obtained.

  The thus obtained carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton [for example, (meth) acrylic acid asymmetric tertiary alcohol ester having a cyclic skeleton] is a functional polymer monomer, an intermediate raw material for fine chemicals, etc. Can be used as In particular, a compound having a polymerizable unsaturated bond and having an alcohol moiety eliminated by an acid to generate a free carboxylic acid can be used as a monomer raw material for a photosensitive resin as an acid-sensitive compound. When a resist film is formed using a polymer obtained by polymerizing such a monomer, a uniform and homogeneous resist film can be obtained, and a desired fine pattern can be obtained with high accuracy.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. In Examples and the like, purity and impurity content are area% values (values calculated excluding the solvent) by gas chromatography (GC).

Production Example 1
1250% (6.9 mol) of 1-adamantanecarboxylic acid and 2.6 g (0.005 eq) of N, N-dimethylformamide were dissolved in 4110 g of toluene, and the temperature was raised to 70 ° C. in an N ₂ atmosphere. Thereto, 867 g (7.1 mol) of thionyl chloride was added dropwise over 3 hours, and after completion of the addition, the dropping funnel was washed out with 19 g of toluene. Thereafter, the mixture was aged at 70 ° C. for 1 hour, heated to 100 ° C., and further aged for 1 hour. After cooling to room temperature, the solvent was distilled off until the amount of 1-adamantanecarbonyl chloride was 60% by weight to obtain the target 1-adamantanecarbonyl chloride [the following formula (1a)] in a yield of 98% (purity 99 .9%).

Example 1
20.2 g (0.03 eq) of CuCl and 27.8 g (0.03 eq) of ZnCl _{2 were} stirred in 2363 g of THF (tetrahydrofuran) at room temperature for 30 minutes in an N ₂ atmosphere. A solution obtained by adding 798 g of THF to 2248 g of 1-adamantanecarbonyl chloride / toluene solution synthesized in Production Example 1 (1-adamantanecarbonyl chloride: 1350 g, 6.8 mol) was further stirred at room temperature for 30 minutes. After cooling to 0 ° C., 6370 g (1.0 eq) of 1.07 mol / kg ethyl magnesium bromide / THF solution was added dropwise over 4 hours (the dropping rate of ethyl magnesium bromide was 0.25 eq / hour). Aged for 30 minutes. Further, 318 g (0.05 eq) of a 1.07 mol / kg ethylmagnesium bromide / THF solution was added dropwise, and the mixture was aged at 0 ° C. for 30 minutes. Further, 318 g (0.05 eq) of a 1.07 mol / kg ethylmagnesium bromide / THF solution was added dropwise, and the mixture was aged at 0 ° C. for 30 minutes. In the range of −5 ° C. to 5 ° C., 7185 g of 0.66M sulfuric acid aqueous solution was added to stop the reaction. After separation into an organic layer and an aqueous layer, 3389 g of a 5 wt% aqueous sodium hydroxide solution was added to the organic layer, and the mixture was stirred and separated. Further, 4509 g of 5 wt% aqueous sodium hydroxide solution was added to the separated organic layer, and the mixture was stirred and separated. As a result of analyzing the separated organic layer by gas chromatography (GC), the yield of 1- (1-adamantyl) propan-1-one [the following formula (3a)] was 94% and the purity was 98. It was 5%. The content of 1- (1-adamantyl) propan-1-one reductant (1-adamantyl-1-propanol) as an impurity is less than 0.1%, 3-adamantyl-3-pentanol [the following formula The content of (8a)] (diethyl form) was less than 0.1%.

Example 2
To the organic layer obtained in Example 1, 5428 g of toluene was added, followed by washing twice with a 1 wt% aqueous sodium chloride solution (4136 g). After distilling off the solvent, the target 1- (1-adamantyl) propan-1-one was obtained with a recovery rate of 84% (purity 99.6%) by performing simple distillation.

Example 3
To a reaction vessel in an N ₂ atmosphere, 1.66 mol / kg methylmagnesium chloride / THF solution 7050 g (2.5 eq) was charged and cooled to 0 ° C. Thereto was added dropwise 1- (1-adamantyl) propan-1-one 900 g / THF 1800 g synthesized in Example 1 over 30 minutes, and after completion of the dropwise addition, the mixture was aged for 3 hours while gradually warming to room temperature. Within the range of 0 to 5 ° C., 8821 g of a 0.8 M sulfuric acid aqueous solution was added to stop the reaction. After separation into an organic layer and an aqueous layer, 3600 g of a 5 wt% aqueous sodium hydroxide solution was added to the organic layer, and the mixture was stirred and separated. Further, 4500 g of 5 wt% aqueous sodium hydroxide solution was added to the separated organic layer, and after stirring, the mixture was separated, and 2-adamantyl-2-butanol (purity 98.6%) was obtained in a yield of 98% [formula (5a )].

Example 4
The organic layer obtained in Example 3 was washed twice with 3153 g of a 1 wt% aqueous sodium chloride solution. About the obtained organic layer, the solvent was distilled off until 2-adamantyl-2-butanol became 50 weight%. 7905 g of toluene was added thereto, and the solvent was distilled off until the amount of 2-adamantyl-2-butanol was 12.7% by weight (azeotropic dehydration).

Example 5
In a reaction vessel in an N ₂ atmosphere, 6805 g of a 12.7 wt% solution of 2-adamantyl-2-butanol obtained in Example 4, 845 g of toluene, 4,4-butylidenebis- (6-tert-butyl-m as a polymerization inhibitor) -Cresol) 15.3 g was charged. Thereto, 5573 g (1.38 eq) of 1.07 mol / kg ethylmagnesium bromide / THF solution was added dropwise at about 30 ° C. After completion of the addition, the inside of the dropping funnel was washed away with 900 g of toluene. The temperature was raised to 50 ° C. and aged for 1 hour. Thereafter, the solution was cooled to 0 ° C., and a solution obtained by diluting 813 g (1.8 eq) of methacrylic acid chloride in 2250 g of toluene was slowly dropped into the reaction vessel while maintaining a temperature around 0 ° C. Thereafter, 1749 g (4.0 eq) of triethylamine was dropped, and the temperature was raised to 10 ° C. and reacted for 20 hours. The temperature was cooled to 0 ° C. or lower, 9000 g of toluene was added, 277 g of methanol was added within the range of 0 to 5 ° C., and the mixture was stirred at the same temperature for 1.5 hours.
In another reaction vessel, 15300 g of 0.5 M sulfuric acid was placed, and after cooling to 0 ° C., the reaction solution quenched with methanol was added dropwise within a range of 0 to 5 ° C. After separating into an organic layer and an aqueous layer, 6750 g of 1N sodium hydroxide aqueous solution was added to the organic layer, and the organic layer was stirred. Thereafter, liquid separation was performed to obtain 24670 g of a toluene-THF solution of 2-adamantyl-2-methacryloyloxybutane. To the obtained 2-adamantyl-2-methacryloyloxybutane in toluene-THF, 4.8 g of methoquinone (4000 ppm vs. 2-adamantyl-2-methacryloyloxybutane theoretical yield) was added, and the solvent was distilled off. Furthermore, the operation of adding 2388 g of toluene and distilling off the solvent was repeated twice. Thereafter, 2800 g of toluene was added so that 2-adamantyl-2-methacryloyloxybutane was 30% by weight, and 358 g (30% by weight) of an adsorbent (trade name “KYOWARD 500SN”, manufactured by Kyowa Chemical Industry Co., Ltd.). To 2-adamantyl-2-methacryloyloxybutane) and stirred at 40 ° C. for 5 hours. After cooling to room temperature, the solution was filtered while washing with 1130 g of toluene, then washed 3 times with 5325 g of ion-exchanged water, 1430 g of toluene was added, and then the solvent was distilled off. As a result of analysis by high performance liquid chromatography, the yield of 2-adamantyl-2-methacryloyloxybutane [the following formula (7a)] was 88%.

Example 6
5 g (5000 ppm vs. 2-adamantyl-2-methacryloyloxybutane) of an antioxidant (trade name “IRGANOX”) was dissolved in 2-adamantyl-2-methacryloyloxybutane obtained in Example 5, and 0.005-0 As a result of distillation in the range of 0.01 torr and 70 to 100 ° C., 2-adamantyl-2-methacryloyloxybutane was obtained with a recovery rate of 64%.

Example 7
The same operation as in Example 1 was carried out except that the reaction scale was 50/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 50 g) (the dropping rate of ethylmagnesium bromide was 0.25 eq / Time). As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 86% and the purity was 96.3%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is less than 0.1%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) Was less than 0.1%.

Example 8
The reaction scale was 10/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 10 g), and the dropping time of the ethylmagnesium bromide / THF solution was 8 hours (the dropping rate of ethylmagnesium bromide was 0). .125 eq / hour), and the same operation as in Example 1 was performed. As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 82%, and the purity was 97.6%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is less than 0.1%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) Was less than 0.1%.

Example 9
The reaction scale was 5/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 5 g), and the same operation as in Example 1 was performed except that CuCl was not used (ethyl magnesium bromide). Is a dropping rate of 0.25 eq / hour). As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 77%, and the purity was 92.6%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is less than 0.1%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) Was less than 0.1%.

Example 10
The reaction scale was changed to 5/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 5 g), and the same operation as in Example 1 was performed except that ZnCl ₂ was not used (ethyl magnesium). The drop rate of bromide is 0.25 eq / hour). As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 75%, and the purity was 95.7%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is less than 0.1%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) Was less than 0.1%.

Example 11
The reaction scale was 575/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 575 g), and 13.7 g (0.03 eq) of CuCl ₂ was used without CuCl. The same operation as in Example 1 was performed except that the dropping time of the bromide / THF solution was 8 hours (the dropping rate of ethylmagnesium bromide was 0.125 eq / hour). As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 74%, and the purity was 95.7%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is 0.18%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) is It was less than 0.1%.

Example 12
The reaction scale was 575/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 575 g), and 13.7 g (0.03 eq) of CuCl ₂ was used without CuCl. The same operation as in Example 1 was performed except that the dropping time of the bromide / THF solution was set to 9 hours (the dropping rate of ethylmagnesium bromide was 0.111 eq / hour). As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 78%, and the purity was 96.3%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is 0.15%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) is It was less than 0.1%.

Example 13
The reaction scale was 12/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 12 g), and the dropping time of the ethylmagnesium bromide / THF solution was 16 hours (the dropping rate of ethylmagnesium bromide was 0). 0.063 eq / hour), and the same operation as in Example 1 was performed. As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 84% and the purity was 97.3%. The content of the reduced form of 1- (1-adamantyl) propan-1-one as an impurity is less than 0.1%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) Was less than 0.1%.

Comparative Example 1
The reaction scale was 50/1350 of Example 1 (that is, the amount of 1-adamantanecarbonyl chloride used was 50 g), and the dropping time of the ethylmagnesium bromide / THF solution was 80 minutes (the dropping rate of ethylmagnesium bromide was 0). .75 eq / hour), and the same operation as in Example 1 was performed. As a result, the yield of the target 1- (1-adamantyl) propan-1-one was 78%, and the purity was as low as 81.7%. The content of 1- (1-adamantyl) propan-1-one reductant as an impurity is 7.2%, and the content of 3-adamantyl-3-pentanol represented by the formula (8a) is It was 8.6%.

  The results of Examples 1, 7 to 13 and Comparative Example 1 are summarized in Table 1.

Claims (7)

Following formula (1)

[Wherein, ring Z represents a monocyclic or polycyclic non-aromatic or aromatic ring. X represents a halogen atom, —OCOR ^a (wherein R ^a represents a hydrocarbon group), or —OR ^b (wherein R ^b represents a hydrocarbon group)]
In a liquid containing the compound represented by formula (2)
R ¹ -M ¹ (2)
[Wherein R ¹ represents a hydrocarbon group. M ¹ represents a metal atom optionally having a ligand, or —M ^a Y (wherein M ^a represents a metal atom other than manganese, and Y represents a halogen atom)]
A liquid containing an organometallic compound represented by formula (3) is added at a rate of 0.01 to 0.5 equivalent / hour, and the following formula (3)

[Wherein, ring Z and R ¹ are the same as above]
Step A for producing a ketone represented by the formula (3) and the ketone represented by the formula (3)
R ² -M ² (4)
[Wherein R ² represents a hydrocarbon group. However, R ¹ and R ² are different groups. M ² represents a metal atom optionally having a ligand, or —M ^b Y (wherein M ^b represents a metal atom other than manganese, and Y represents a halogen atom)]
Is reacted with an organometallic compound represented by the following formula (5):

(Wherein, ring Z, R ¹ and R ² are the same as above)
And a process B for producing an asymmetric tertiary alcohol represented by the formula:   The asymmetry according to claim 1, wherein in step A, a compound containing an organic metal compound represented by formula (2) is added to a solution containing a compound represented by formula (1), and then a compound having active hydrogen is added. A method for producing tertiary alcohol.   The method for producing an asymmetric tertiary alcohol according to claim 1 or 2, wherein the reaction in Step A and / or the reaction in Step B is carried out in the presence of an ionic compound containing Group 8 to Group 11 elements of the periodic table.   The method for producing an asymmetric tertiary alcohol according to any one of claims 1 to 3, wherein the reaction in Step A and / or the reaction in Step B is performed in the presence of a Lewis acid.   The process of any one of Claims 1-4 which further includes the process of attaching | subjecting the reaction liquid mixture containing the asymmetrical tertiary alcohol represented by Formula (5) produced | generated to the azeotropic dehydration operation after the process B, and removing water. 2. A process for producing an asymmetric tertiary alcohol according to item 1. By the method of any one of Claims 1-5, following formula (5)

(Wherein, .R ^1, R ² ring Z is showing a non-aromatic or aromatic monocyclic or polycyclic, respectively a hydrocarbon group. However, R ¹ and R ² different groups Is)
Then, the asymmetric tertiary alcohol is represented by the following formula (6):
R ³ COOH (6)
(Wherein R ³ represents a hydrocarbon group, a heterocyclic group or a group to which these are bonded)
Is reacted with a carboxylic acid represented by the following formula (7):

(Wherein, ring Z, R ¹ , R ² and R ³ are the same as above)
A carboxylic acid asymmetric tertiary alcohol ester having a cyclic skeleton represented by the formula:   The asymmetric tertiary alcohol according to claim 6, wherein the asymmetric tertiary alcohol represented by the formula (5) is reacted with the carboxylic acid represented by the formula (6) or a reactive derivative thereof, and then the alcohol is added. A method for producing an alcohol ester.