JP2004075683A - Method for producing optically active halogenohydroxypropyl compound and glycidyl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active 1-halogeno-2-hydroxypropyl compound or an optically active glycidyl compound with high optical purity in high yield. <P>SOLUTION: The method comprises a position-selective production of the optically active 1-halogeno-2-hydroxypropyl compound by reacting a nucleophilic reagent such as water, phenol or the like in the presence of a metal complex catalyst expressed by formula (6), (in the formula n is 0, 1 or 2, Z<SP>1</SP>, Z<SP>2</SP>, Z<SP>3</SP>or Z<SP>4</SP>are each H, a halogen atom, nitro group or a (substituted) alkyl group or the like, A is a ion pair, and M is a metal ion), to an optically active epihalohydrin and then reacting a basic reagent to obtain the optically active glycidyl compound. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention relates to a method for producing an optically active 1-halogeno-2-hydroxypropyl compound and an optically active glycidyl compound, which are useful as intermediates for synthesis of pharmaceuticals, agricultural chemicals and the like.

Various production methods based on leading epihalohydrin to a glycidyl compound via a 1-halogeno-2-hydroxypropyl compound have been reported for a long time.
However, most of them relate to a method of converting racemic epihalohydrin into a racemic glycidyl compound, and there are few reports on a method of converting optically active epihalohydrin to an optically active glycidyl compound. One of the reasons is that there is no remarkable difference in activity between the 1-position halogenomethylene position, which is the active position on epihalohydrin, and the 3-position epoxy ring terminal position, and it is difficult to handle.

That is, as shown in the following reaction formula, in the reaction with a nucleophilic species, the nucleophilic reaction by the a-path has a higher priority in theory and selectively gives [I] or [II]. The selectivity is not perfect, and [III] is produced as a by-product through the reaction by the route b. As a result, the optical purity of the target product [II] decreases.

（上記式において、Ｘ'はハロゲン原子、Ｎｕ’は求核種の残基である。）
　上記の問題を克服するための手法も幾つか検討されており、例えば、（i）光学活性エピハロヒドリンと４−カルバモイルメチルフェノールとを含水溶媒中、水酸化アルカリおよび第４級アンモニウム塩存在下で反応させる方法（特許文献１参照）、（ii）光学活性エピハロヒドリンとベンジルアルコールとを三フッ化ホウ素ジエチルエーテル錯体存在下で反応させる方法（特許文献１参照）などが挙げられるが、いずれも原料であるエピハロヒドリンに比べて生成物であるグリシジル化合物の光学純度が１〜２％程度低下しており、依然、改良の余地が残されている。
　また、光学活性エピクロロヒドリンと水とを光学活性コバルト（III）錯体存在下で反応させた後、炭酸カリウムで処理する方法（特許文献２参照）によれば、光学活性グリシドールを高光学純度で得ることができるが、この方法により反応を行なうには、原料であるエピクロロヒドリンの立体異性体ごとに特定の立体配置をもつ高価な光学活性コバルト（III）錯体触媒を調製して使用しなければならず、煩雑であるのみならず、非経済的である。 Reaction formula

(In the above formula, X ′ is a halogen atom, and Nu ′ is a residue of a nucleophilic species.)
Several methods for overcoming the above-mentioned problems have been studied. For example, (i) reaction of optically active epihalohydrin with 4-carbamoylmethylphenol in a water-containing solvent in the presence of an alkali hydroxide and a quaternary ammonium salt. (See Patent Document 1), (ii) a method of reacting optically active epihalohydrin with benzyl alcohol in the presence of a boron trifluoride diethyl ether complex (see Patent Document 1), and the like. The optical purity of the product glycidyl compound is lower by about 1 to 2% than that of epihalohydrin, and there is still room for improvement.
According to a method of reacting optically active epichlorohydrin with water in the presence of an optically active cobalt (III) complex and then treating with potassium carbonate (see Patent Document 2), the optically active glycidol has high optical purity. In order to carry out the reaction by this method, an expensive optically active cobalt (III) complex catalyst having a specific configuration for each stereoisomer of epichlorohydrin as a raw material is prepared and used. Not only is it cumbersome, but also uneconomical.

Japanese Patent Publication No. 6-37482 Heterocycles, 31, 1715 (1990) J. Am. Chem. Soc. 124, 1307 (2002)

In view of the above problems of the prior art, the present invention produces optically active 1-halogeno-2-hydroxypropyl compounds and optically active glycidyl compounds from optically active epihalohydrins without impairing their optical purity and in high yield. It is to provide a way to do it.

（式中、Ｘはハロゲン原子を意味する。）
で表される光学活性エピハロヒドリンに、下記式（２）

（式中、ｎは０、１または２の整数を意味し、Ｙ¹、Ｙ²およびＹ³は、同一または異なって、水素原子、ハロゲン原子、ニトロ基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、アシル基、またはアルコキシカルボニル基を意味し、また、Ｙ¹とＹ²、あるいはＹ²とＹ³は、互いに一緒になり、それらが結合する炭素原子と共に環を形成してもよく、Ａは対イオンを意味し、そしてＭは金属イオンを意味する。）
で表される金属錯体触媒存在下、下記式（３）

（式中、Ｎｕは置換基を有するヘテロ原子を意味し、そしてＱは水素原子または置換基を有するケイ素原子を意味する。）
で表される求核剤を反応させて、下記式（４）

（式中、ＸおよびＮｕは前掲と同じものを意味する。）
で表される光学活性１−ハロゲノ−２−ヒドロキシプロピル化合物を位置選択的に製造する方法、並びに、続いて該化合物に塩基性試剤を作用させて下記式（５）

（式中、Ｎｕは前掲と同じものを意味する。）
で表される光学活性グリシジル化合物を製造する方法を含む、光学活性１−ハロゲノ−２−ヒドロキシプロピル化合物および光学活性グリシジル化合物の製造法に関する。 The present inventors have conducted various studies in order to solve the above-mentioned problems, and as a result, by using a non-chiral metal complex catalyst (2) represented by the following formula, the optical activity 1- with high yield and high optical purity was obtained. The present inventors have found a new method for producing a halogeno-2-hydroxypropyl compound and an optically active glycidyl compound, and have completed the present invention.
The present invention provides the following formula (1)

(In the formula, X means a halogen atom.)
The optically active epihalohydrin represented by the following formula (2)

(Wherein, n represents an integer of 0, 1 or 2; Y ¹ , Y ² and Y ³ are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a substituted or unsubstituted alkyl group, Or an unsubstituted aryl group, acyl group or alkoxycarbonyl group, and Y ¹ and Y ² or Y ² and Y ³ together form a ring together with the carbon atom to which they are attached. Where A represents a counter ion and M represents a metal ion.)
In the presence of a metal complex catalyst represented by the following formula (3)

(In the formula, Nu means a substituted heteroatom, and Q means a hydrogen atom or a substituted silicon atom.)
By reacting a nucleophile represented by the following formula (4)

(In the formula, X and Nu mean the same as those described above.)
A method for regioselectively producing an optically active 1-halogeno-2-hydroxypropyl compound represented by the following formula, and then reacting the compound with a basic reagent to obtain the following formula (5)

(In the formula, Nu means the same as above.)
And a method for producing an optically active 1-halogeno-2-hydroxypropyl compound and an optically active glycidyl compound, including a method for producing an optically active glycidyl compound represented by the formula:

に よ り By carrying out the present invention, an optically active 1-halogeno-2-hydroxypropyl compound or an optically active glycidyl compound can be produced in high yield while maintaining the optical purity of the optically active epihalohydrin as a raw material.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.
First, a step of reacting an optically active epihalohydrin (1) with a nucleophile (3) in the presence of a metal complex catalyst (2) to obtain an optically active 1-halogeno-2-hydroxypropyl compound (4) will be described below. explain.

In the formula (1), an optically active epihalohydrin in which X is a chlorine atom or a bromine atom is preferably used.
In the metal complex catalyst of the formula (2), Y ¹ is a hydrogen atom, Y ² and Y ³ are taken together, and together with the carbon atom to which they are bonded, for example, a benzene ring which may have a substituent. And a metal complex catalyst forming a ring such as a cyclohexene ring is preferable, and a particularly preferable metal complex catalyst is represented by the following formula (6).

（式中、ｎは０、１または２の整数を意味し、Ｚ¹、Ｚ²、Ｚ³およびＺ⁴は、同一または異なって、水素原子、ハロゲン原子、ニトロ基、直鎖、置換もしくは無置換のアルキル基、置換もしくは無置換のアラルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルキルオキシ基、置換もしくは無置換のアラルキルオキシ基、または置換もしくは無置換のアリールオキシ基を意味し、また、Ｚ¹とＺ²、Ｚ²とＺ³、あるいはＺ³とＺ⁴は、互いに一緒になり、それらが結合する炭素原子と共に環を形成してもよく、Ａは対イオンを意味し、そしてＭは金属イオンを意味する。）

(In the formula, n represents an integer of 0, 1 or 2, and Z ¹ , Z ² , Z ³ and Z ⁴ are the same or different and are each a hydrogen atom, a halogen atom, a nitro group, a straight chain, substituted or unsubstituted. Means a substituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aralkyloxy group, or a substituted or unsubstituted aryloxy group And Z ¹ and Z ² , Z ² and Z ³ , or Z ³ and Z ⁴ may be taken together to form a ring together with the carbon atom to which they are attached, and A represents a counter ion And M represents a metal ion.)

In the above formula (6), Z ¹ , Z ² , Z ³ and Z ⁴ are, for example, a halogen atom such as a hydrogen atom, a fluorine atom, chlorine, bromine or iodine, a nitro group, methyl, ethyl, n-propyl, isopropyl C1-C6 linear or branched alkyl groups such as 2,2-dimethylpropyl, n-butyl, sec-butyl, tert-butyl, n-heptyl and n-hexyl, and carbon numbers such as cyclopentyl and cyclohexyl 3 to 7 cyclic alkyl groups, substituted alkyl groups such as trifluoromethyl and perfluoro-tert-butyl, substituted or unsubstituted aralkyl groups such as benzyl, 4-methylbenzyl and cumenyl, phenyl, 4-methylphenyl, Substituted or unsubstituted aryl groups such as -naphthyl and 2-naphthyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy; Substituted or unsubstituted alkyloxy groups such as cis, perfluoro-tert-butoxy, substituted or unsubstituted aralkyloxy groups such as benzyloxy and 4-methylbenzyloxy, and substituted or unsubstituted phenoxy and 4-methylphenoxy; Aryloxy group. Z ¹ and Z ² , Z ² and Z ³ , or Z ³ and Z ⁴ may be taken together to form a ring such as a benzene ring and a cyclohexene ring together with the carbon atom to which they are bonded. Good. Further, the ring may have a substituent.
A preferred group in Z ^{1 to} Z ⁴ is that Z ¹ , Z ² , Z ³ and Z ⁴ are all hydrogen atoms, Z ¹ , Z ² and Z ³ are hydrogen atoms, and Z ⁴ is a tert-butyl group. alternatively at Z ¹ and Z ³ is a hydrogen atom, and Z ² and Z ⁴ are tert- butyl group.
It is also a preferable example that the metal complex catalyst is immobilized on an insoluble carrier such as a polymer, silica gel, alumina, or zeolite via an ether bond or a methylene chain.

Examples of the counter ion represented by A in the metal complex catalyst of the formula (2) or the formula (6) include halogen atoms such as nitrate, fluoride, chloride and bromide, substituted alkoxides such as pentafluoro-tert-butoxide, and pentane. Substituted or unsubstituted alkyl carbonates such as fluorophenoxide, 2,4,6-trinitrophenoxide, etc., acetate, n-butylate, trifluoroacetate, trichloroacetate, phenylacetate, 4-nitrophenylacetate; Substituted or unsubstituted arylcarbonate such as substituted or unsubstituted aralkyl carbonate, benzoate, pentafluorobenzoate, 2,4-dinitrobenzoate such as 3,5-difluorophenyl acetate And substituted or unsubstituted arylsulfonates such as methanesulfonate, trifluoromethanesulfonate, (±) -camphorsulfonate and the like, and benzenesulfonate, p-toluenesulfonate and 3-nitrobenzenesulfonate. Preferred counterions are acetate, n-butyrate, (±) -camphorsulfonate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate.

In the metal complex catalyst of the formula (2) or the formula (6), the metal ion represented by M is not particularly limited. For example, an aluminum ion, a titanium ion, a vanadium ion, a chromium ion, a manganese ion, and an iron ion , Cobalt ion, nickel ion, copper ion, zinc ion, molybdenum ion, ruthenium ion, rhodium ion, tungsten ion, etc., preferably vanadium ion, chromium ion, manganese ion, iron ion, cobalt ion, nickel ion, molybdenum Ions, ruthenium ions, or tungsten ions. Each metal ion corresponds to any one of the oxidation states (II) to (IV). Particularly preferred are chromium ion (III) and cobalt ion (III).

（式中、ｎ、Ｚ¹、Ｚ²、Ｚ³およびＺ⁴は、式（６）と同じものを意味する。）
で表されるコバルト（II）錯体を、前掲のＡで示される電子吸引性置換基に水素原子が結合したものに相当する酸試剤の存在下、適当な溶媒中、室温で空気酸化することにより容易に調製することができる。
　この際、酸試剤の使用量はコバルト（II）錯体に対して１〜１０当量、好ましくは１〜２当量である。また、コバルト（II）錯体は、公知の反応、すなわち、アルキルジアミン類１当量とサリチルアルデヒド類２当量とをカップリングして得られるサレン配位子と酢酸コバルト（II）四水和物とを混合する錯体形成反応から容易に調製することができる。
　その他の本発明に用いられる金属錯体は、公知の方法で容易に調製することができる。
　本発明における金属錯体触媒の使用量は、光学活性エピハロヒドリンに対して０．１〜１０モル％、好ましくは１〜５モル％である。また、コバルト（III）錯体については、前掲した方法にてコバルト（II）錯体から空気酸化した後、その溶液を精製せずにそのまま反応に用いることもできる。さらに、金属錯体触媒の単独使用で本反応を進行させることが充分に可能であるが、Ｎ，Ｎ−ジイソプロピルエチルアミン、トリイソブチルアミン等の嵩高い３級アミンを０．１〜１００モル％量添加すると反応が促進される。 For example, the cobalt (III) complex is represented by the following formula (8)

(In the formula, n, Z ¹ , Z ² , Z ³ and Z ⁴ mean the same as in formula (6).)
By air oxidation at room temperature in a suitable solvent in the presence of an acid reagent corresponding to a hydrogen atom bonded to the electron-withdrawing substituent represented by A described above. It can be easily prepared.
At this time, the amount of the acid reagent to be used is 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the cobalt (II) complex. Further, the cobalt (II) complex is formed by a known reaction, that is, a salen ligand obtained by coupling one equivalent of an alkyldiamine and two equivalents of salicylaldehyde with a cobalt (II) acetate tetrahydrate. It can be easily prepared from mixed complexation reactions.
Other metal complexes used in the present invention can be easily prepared by a known method.
The amount of the metal complex catalyst used in the present invention is 0.1 to 10 mol%, preferably 1 to 5 mol%, based on the optically active epihalohydrin. In addition, the cobalt (III) complex can be used in the reaction without purification after the air is oxidized from the cobalt (II) complex by the method described above. Further, it is sufficiently possible to advance this reaction by using a metal complex catalyst alone, but a bulky tertiary amine such as N, N-diisopropylethylamine or triisobutylamine is added in an amount of 0.1 to 100 mol%. Then, the reaction is accelerated.

The substituent represented by Nu in the nucleophile of the formula (3) is not particularly limited as long as it is a hetero atom having a substituent, and examples thereof include an oxygen atom, a sulfur atom, a selenium atom, a nitrogen atom, and a phosphorus atom. Or a hetero atom such as an arsenic atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted aralkylcarbonyl And those substituted by a substituted or unsubstituted arylcarbonyl group. Examples of the substituent represented by Q include a hydrogen atom, and a linear or branched alkylsilyl group such as trimethylsilyl, triethylsilyl, and triisopropylsilyl.

（式中、Ｒは、水素原子、直鎖、分岐もしくは環状のアルキル基、直鎖、分岐もしくは環状のアルキルカルボニル基、置換もしくは無置換のアラルキル基、置換もしくは無置換のアラルキルカルボニル基、置換もしくは無置換のアリール基、または置換もしくは無置換のアリールカルボニル基を意味する。）
　Ｒで示される基の具体例としては、例えば、水素原子、メチル、エチル、イソプロピル、シクロペンチル、シクロヘキシルなどの直鎖、分岐もしくは環状のアルキル基、ベンジル、３−ブロモベンジル、４−メトキシベンジルなどの置換もしくは無置換のアラルキル基、フェニル、トリル、４−フルオロフェニル、２−アリルオキシフェニルなどの置換もしくは無置換のアリール基、アセチル、プロピオニル、ブチリル、ピバロイルなどの直鎖もしくは分岐のアルキルカルボニル基、フェニルアセチル、２−ブロモフェニルアセチルなどの置換もしくは無置換のアラルキルカルボニル基、ベンゾイル、２，４，６−トリメチルベンゾイル、４−フェニルベンゾイルなどの置換もしくは無置換のアリールカルボニル基が挙げられる。
　求核剤の使用量は、光学活性エピハロヒドリン（１）に対して０．５〜２．０当量、好ましくは０．８〜１．２当量である。 Preferred nucleophiles are represented by the following formula (7).

(Wherein R is a hydrogen atom, a linear, branched or cyclic alkyl group, a linear, branched or cyclic alkylcarbonyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aralkylcarbonyl group, It means an unsubstituted aryl group or a substituted or unsubstituted arylcarbonyl group.)
Specific examples of the group represented by R include, for example, a hydrogen atom, a linear, branched or cyclic alkyl group such as methyl, ethyl, isopropyl, cyclopentyl and cyclohexyl, and benzyl, 3-bromobenzyl and 4-methoxybenzyl. Substituted or unsubstituted aralkyl groups, phenyl, tolyl, 4-fluorophenyl, substituted or unsubstituted aryl groups such as 2-allyloxyphenyl, acetyl, propionyl, butyryl, linear or branched alkylcarbonyl groups such as pivaloyl, Examples include a substituted or unsubstituted aralkylcarbonyl group such as phenylacetyl and 2-bromophenylacetyl, and a substituted or unsubstituted arylcarbonyl group such as benzoyl, 2,4,6-trimethylbenzoyl and 4-phenylbenzoyl.
The nucleophile is used in an amount of 0.5 to 2.0 equivalents, preferably 0.8 to 1.2 equivalents, based on the optically active epihalohydrin (1).

Solvents used in performing this reaction include diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, tert-butyl methyl ether, ether solvents such as cyclopentyl methyl ether, chloroform, dichloromethane, 1,2-dichloroethane and the like. Chlorinated solvents, hydrocarbon solvents such as hexane, heptane, benzene, and toluene, ester solvents such as ethyl acetate and butyl acetate, ketone solvents such as acetone and 2-butanone, dimethylformamide, dimethyl sulfoxide, and acetonitrile. An aprotic polar solvent or a mixed solvent thereof may be mentioned, and an ether solvent such as tetrahydrofuran or tert-butyl methyl ether is preferable. The amount of these solvents used is not particularly limited. This reaction can be carried out without a solvent.

This reaction is carried out at a temperature in the range of -80 ° C to the reflux temperature of the solvent, preferably at -50 to 50 ° C, more preferably at 0 to 30 ° C. Further, it may be under normal pressure or under pressure.
After completion of the reaction, the reaction solution can be used in the next step without any particular treatment. After extraction and washing with water, the excess solvent is distilled off under reduced pressure, and the residue is subjected to purification treatment such as distillation, recrystallization, silica gel column chromatography, etc., so that the optically active 1-halogeno-2-object as the target substance is obtained. Hydroxypropyl compound (4) can also be obtained.

Next, the step of subjecting the optically active 1-halogeno-2-hydroxypropyl compound (4) obtained in the preceding step to a ring closure reaction in the presence of a base reagent to obtain an optically active glycidyl compound (5) will be described.
Examples of usable base reagents include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, and alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, and cesium carbonate. Alkali metal alkoxides such as sodium carbonate, sodium methoxide, sodium ethoxide, sodium benzyl oxide, sodium phenoxide and potassium tert-butoxide; alkali metals such as sodium and potassium; hydrogenation such as sodium hydride and potassium hydride Alkali metal, alkali metal or alkaline earth metal amides such as sodium amide and magnesium amide, 1,1,3,3-tetramethylguanidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1 , 8-diazabicyclo [5.4.0] -7-undecene and the like. However, for the compound represented by the formula (4) containing a carbonyl group in the substituent Nu, the above-mentioned hydroxide of an alkali metal or alkaline earth metal cannot be used because it is hydrolyzed.
The amount of the base reagent to be used is 1 equivalent or more, preferably 1.1 to 2.0 equivalents, relative to the optically active 1-halogeno-2-hydroxypropyl compound (4).
The reaction can be sufficiently advanced by using a single base reagent alone, but crown ethers such as 4-dimethylaminopyridine, 15-crown-5 and 18-crown-6, sodium iodide, iodide The reaction is promoted by adding a reagent such as an alkali metal iodide salt such as potassium or an alkali metal bromide salt such as sodium bromide or potassium bromide in an amount of 0.1 to 10 mol%.

Solvents that can be used in this reaction are divided into water-soluble solvents and water-insoluble solvents. Examples of the water-soluble solvents include ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, and 1,4-dioxane, dimethylformamide, and dimethylformamide. Sulfoxide, aprotic polar solvent such as acetonitrile, or a mixed solvent thereof, and examples of the water-insoluble solvent include diethyl ether, diisopropyl ether, ether solvents such as tert-butyl methyl ether, chloroform, dichloromethane, 1, Examples include a chlorine-based solvent such as 2-dichloroethane, a hydrocarbon-based solvent such as hexane, heptane, benzene, and toluene, or a mixed solvent thereof. The amount of these solvents used is not particularly limited.

The water-insoluble solvent can also be used in the reaction as a two-phase solvent with an aqueous solution containing a basic reagent. However, the compound represented by the formula (4) containing a carbonyl group in the substituent Nu cannot be used because it is hydrolyzed. Examples of the basic reagents that can be prepared as an aqueous solution include, among those mentioned above, hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium carbonate, potassium carbonate, and calcium carbonate. And a carbonate of an alkali metal or an alkaline earth metal, and preferred are sodium hydroxide and potassium hydroxide. In the case of a reaction in a two-phase solvent, the use of a phase transfer catalyst significantly accelerates the reaction. Examples of usable phase transfer catalysts include tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltributylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, and N-benzylquinium chloride. Quaternary ammonium salts such as quaternary ammonium salts, quaternary phosphonium salts such as tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, benzyltriphenylphosphonium chloride and benzyltriphenylphosphonium bromide, 12-crown-4 , 15-crown-5, 18-crown-6, etc. N'eteru and the like. The amount of addition is preferably 0.1 to 10 mol% based on the substrate.

This reaction is carried out at a temperature in the range of -80 to 50C. However, when a two-phase solvent of a water-insoluble solvent and an aqueous solution containing a basic reagent is used, it is preferably carried out at a temperature in the range of 0 to 50 ° C. because of the possibility of freezing. This reaction may be carried out under normal pressure or under pressure.
After completion of the reaction, the desired optically active glycidyl is obtained by performing extraction, liquid separation by washing with water, distillation of the excess solvent under reduced pressure, and purification of the residue by distillation, recrystallization and silica gel column chromatography. Compound (5) can be obtained.

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples. In the examples, quantitative analysis by gas chromatography refers to quantification of the amount of products using gas chromatography by an internal standard method (internal standard substance: m-dimethoxybenzene), and optical purity analysis by gas chromatography refers to optical activity. Optical purity measurement using a capillary column (G-TA / GL Sciences Inc.) and optical purity analysis by high-performance liquid chromatography are optical purity measurements using an optically active column (CHIRALCEL @ OD-H / Daicel Inc.) means.

Example 1
Production of (S) -3-chloro-1,2-propanediol 119 mg (0.216 mmol) of N, N'-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) To a mixture of 2.0 mL of tetrahydrofuran (hereinafter abbreviated as THF) was added 60.3 mg (0.260 mmol) of (±) -camphorsulfonic acid, and the mixture was stirred at room temperature for 1 hour while filling the inside with air. Subsequently, 1.00 g (10.8 mmol, optical purity 99% ee) of (S) -epichlorohydrin and 234 μL (13.0 mmol) of H ₂ O were added to this solution, that is, a THF solution of the cobalt (III) complex. It was added sequentially and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was subjected to quantitative analysis and optical purity analysis by gas chromatography. As a result, the amount of the title (S) -3-chloro-1,2-propanediol produced was 1.14 g (yield 95.4). %) And the optical purity was 99% ee.

Example 2
Production of (R) -3-chloro-1,2-propanediol 119 mg (0.216 mmol) of N, N'-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) To a mixture of 2.0 mL of tetrahydrofuran, 60.3 mg (0.260 mmol) of (±) -camphorsulfonic acid was added, and the mixture was stirred at room temperature for 1 hour while filling the inside with air. Subsequently, 1.00 g (10.8 mmol, optical purity 99% ee) of (R) -epichlorohydrin and 234 μL (13.0 mmol) of H ₂ O were added to this solution (a THF solution of a cobalt (III) complex). It was added sequentially and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was subjected to quantitative analysis and optical purity analysis by gas chromatography, and as a result, the amount of the title (R) -3-chloro-1,2-propanediol produced was 1.12 g (yield 93.7). %) And the optical purity was 99% ee.

Example 3
Preparation of (R) -glycidylphenyl ether A mixture of 173 mg (0.532 mmol) of N, N'-disalicylideneethylenediaminatocobalt (II) and 13 mL of dichloromethane was added with 148 mg of (±) -camphorsulfonic acid (0.1 mg). 638 mmol), and the mixture was stirred at room temperature for 1 hour while filling the inside with air, and the reaction solution was concentrated to dryness under reduced pressure to obtain a black-brown crude cobalt (III) complex. Subsequently, 5.0 mL of tert-butyl methyl ether was added to disperse the crude cobalt (III) complex, and then 2.50 mL of (S) -epichlorohydrin (31.9 mmol, optical purity 99% ee) and phenol 2.50 g (26.6 mmol) were sequentially added, and the mixture was stirred at room temperature for 24 hours under a nitrogen gas atmosphere. After completion of the reaction, the reaction solution was diluted by adding 20 mL of tert-butyl methyl ether, washed sequentially with 10 mL of 6% aqueous sodium hydroxide and 10 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (S)-. 5.75 g of 1-chloro-3-phenoxy-2-propanol was obtained.
5.75 g of the above crude (S) -1-chloro-3-phenoxy-2-propanol was dissolved in 10 mL of isopropanol, and 6.64 g (39.8 mmol) of 24% aqueous sodium hydroxide was added under ice-cooling, and the mixture was stirred at room temperature. Stir for 1 hour. After completion of the reaction, the reaction solution was diluted by adding 50 mL of tert-butyl methyl ether, washed successively with 20 mL of water, 20 mL of saturated aqueous ammonium chloride, and 20 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (R). 3.96 g of -glycidyl phenyl ether was obtained. As a result of quantitative analysis by gas chromatography, the production amount of the title (R) -glycidylphenyl ether was 3.80 g (yield 95.4%), and as a result of optical purity analysis by high performance liquid chromatography, The optical purity was 99% ee.

Example 4
Preparation of (S) -glycidylphenyl ether To a mixture of 173 mg (0.532 mmol) of N, N'-disalicylideneethylenediaminatocobalt (II) and 13 mL of dichloromethane was added 148 mg of (±) -camphorsulfonic acid (0. 638 mmol), and the mixture was stirred at room temperature for 1 hour while filling the inside with air, and the reaction solution was concentrated to dryness under reduced pressure to obtain a black-brown crude cobalt (III) complex. Subsequently, after adding 5.0 mL of tert-butyl methyl ether to disperse the crude cobalt (III) complex, 2.50 mL of (R) -epichlorohydrin (31.9 mmol, optical purity 99% ee) and phenol 2.50 g (26.6 mmol) were sequentially added, and the mixture was stirred at room temperature for 24 hours under a nitrogen gas atmosphere. After completion of the reaction, the reaction solution was diluted by adding 20 mL of tert-butyl methyl ether, washed sequentially with 10 mL of 6% aqueous sodium hydroxide and 10 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (R)-. 5.44 g of 1-chloro-3-phenoxy-2-propanol were obtained.
5.44 g of the above crude (R) -1-chloro-3-phenoxy-2-propanol was dissolved in 10 mL of isopropanol, and 6.64 g (39.8 mmol) of a 24% aqueous sodium hydroxide solution was added under ice-cooling. Stir for 1 hour. After completion of the reaction, the reaction solution was diluted by adding 50 mL of tert-butyl methyl ether, washed sequentially with 20 mL of water, 20 mL of saturated ammonium chloride solution, and 20 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (S). 3.80 g of glycidyl phenyl ether were obtained. As a result of quantitative analysis by gas chromatography, the amount of the title (S) -glycidylphenyl ether produced was 3.71 g (yield 93.0%), and as a result of optical purity analysis by high performance liquid chromatography, The optical purity was 99% ee.

Example 5
Production of (R) -glycidylphenyl ether To a mixture of 138 mg (0.425 mmol) of N, N'-disalicylideneethylenediaminatocobalt (II) and 10 mL of dichloromethane, 33 μL (0.510 mmol) of methanesulfonic acid was added. After stirring at room temperature for 1 hour while filling the system with air, the reaction solution was concentrated to dryness under reduced pressure to obtain a black-brown crude cobalt (III) complex. Subsequently, after adding 4.0 mL of tert-butyl methyl ether to disperse the crude cobalt (III) complex, 2.00 mL of (S) -epichlorohydrin (25.5 mmol, optical purity 99% ee) and phenol were added. 2.00 g (21.3 mmol) were sequentially added, and the mixture was stirred at room temperature under a nitrogen gas atmosphere for 24 hours. After completion of the reaction, the reaction solution was diluted by adding 20 mL of tert-butyl methyl ether, washed sequentially with 10 mL of 6% aqueous sodium hydroxide and 10 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (S)-. 4.85 g of 1-chloro-3-phenoxy-2-propanol was obtained.
4.85 g of the above crude (S) -1-chloro-3-phenoxy-2-propanol was dissolved in 10 mL of isopropanol, and 4.50 g (25.5 mmol) of 24% aqueous sodium hydroxide was added under ice-cooling, and the mixture was added at room temperature. Stir for 1 hour. After completion of the reaction, the reaction solution was diluted by adding 50 mL of tert-butyl methyl ether, washed successively with 20 mL of water, 20 mL of saturated aqueous ammonium chloride, and 20 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (R). 3.24 g of -glycidyl phenyl ether was obtained. As a result of quantitative analysis by gas chromatography, the production amount of the title (R) -glycidylphenyl ether was 3.07 g (yield 96.1%), and as a result of optical purity analysis by high performance liquid chromatography, The optical purity was 99% ee.

Example 6
Preparation of (R) -glycidyl methyl ether A mixture of 70.2 mg (0.216 mmol) of N, N'-disalicylideneethylenediaminatocobalt (II) and 5.0 mL of dichloromethane was mixed with (±) -camphorsulfonic acid. After 60.3 mg (0.260 mmol) was added and the system was stirred at room temperature for 1 hour while filling the inside with air, the reaction solution was concentrated to dryness under reduced pressure to obtain a black-brown crude cobalt (III) complex. Subsequently, 2.0 mL of tert-butyl methyl ether was added to disperse the crude cobalt (III) complex, and then 1.0 g (10.8 mmol, optical purity 99% ee) of (S) -epichlorohydrin and methanol 527 μL (13.0 mmol) were sequentially added, and the mixture was stirred at room temperature under a nitrogen gas atmosphere for 72 hours. After completion of the reaction, the reaction solution was diluted by adding 20 mL of tert-butyl methyl ether, washed sequentially with 10 mL of 6% aqueous sodium hydroxide and 10 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (S)-. 1.54 g of 1-chloro-3-methoxy-2-propanol was obtained.
1.54 g of the above crude (S) -1-chloro-3-methoxy-2-propanol was dissolved in 5.0 mL of isopropanol, and 2.70 g (16.2 mmol) of 24% aqueous sodium hydroxide was added under ice-cooling. Stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted by adding 20 mL of tert-butyl methyl ether, washed sequentially with 10 mL of water, 10 mL of saturated ammonium chloride solution and 10 mL of saturated saline, and the organic layer was concentrated under reduced pressure to obtain crude (R). 2.90 g of glycidyl methyl ether were obtained. As a result of quantitative analysis by gas chromatography, the production amount of the title (R) -glycidyl methyl ether was 0.763 g (yield: 80.2%), and as a result of optical purity analysis by high performance liquid chromatography, The optical purity was 99% ee.

Example 7
Production of (R) -glycidyl acetate A mixture of 70.2 mg (0.216 mmol) of N, N'-disalicylideneethylenediaminatocobalt (II) and 5.0 mL of dichloromethane was added to 23 μL of trifluoromethanesulfonic acid (0. After adding 260 mmol) and stirring the mixture at room temperature for 1 hour while filling the inside with air, the reaction solution was concentrated to dryness under reduced pressure to obtain a crude black-brown cobalt (III) complex. Subsequently, 2.0 mL of tert-butyl methyl ether was added to disperse the crude cobalt (III) complex, and then 1.0 g (10.8 mmol, optical purity 99% ee) of (S) -epichlorohydrin and acetic acid were added. 742 μL (13.0 mmol) were sequentially added, and the mixture was stirred at room temperature under a nitrogen gas atmosphere for 48 hours. After completion of the reaction, 8.0 mL of tert-butyl methyl ether was added to the reaction solution for dilution, and 1.46 g (13.0 mmol) of potassium tert-butoxide was added under ice-cooling, followed by stirring for 1 hour. After completion of the reaction, 116 mg (2.16 mmol) of ammonium chloride was added and the mixture was stirred for 30 minutes, the precipitate was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.38 g of crude (R) -glycidyl acetate. As a result of quantitative analysis by gas chromatography, the amount of the title (R) -glycidyl acetate produced was 0.795 g (yield 63.4%). Was 99% ee.

Example 8
Preparation of (R) -glycidyl acetate A mixture of 119 mg (0.216 mmol) of N, N'-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) and 5.0 mL of dichloromethane was prepared. Then, 23 μL (0.260 mmol) of trifluoromethanesulfonic acid was added, the mixture was stirred at room temperature for 1 hour while filling the inside with air, and the reaction solution was concentrated to dryness under reduced pressure to obtain a crude black-green cobalt (III) complex. Was. Subsequently, after adding 2.0 mL of tert-butyl methyl ether to disperse the crude cobalt (III) complex, 1.0 g (10.8 mmol, optical purity 99% ee) of (S) -epichlorohydrin and acetic acid were added. 742 μL (13.0 mmol) were sequentially added, and the mixture was stirred at room temperature under a nitrogen gas atmosphere for 24 hours. After completion of the reaction, 8.0 mL of tert-butyl methyl ether was added to the reaction solution for dilution, and 1.46 g (13.0 mmol) of potassium tert-butoxide was added under ice-cooling, followed by stirring for 1 hour. After completion of the reaction, 116 mg (2.16 mmol) of ammonium chloride was added, and the mixture was stirred for 30 minutes. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.36 g of crude (R) -glycidyl acetate. As a result of quantitative analysis by gas chromatography, the production amount of the title (R) -glycidyl acetate was 0.802 g (yield 63.9%), and the result of optical purity analysis by gas chromatography was 99%. ee.

Example 9
Preparation of (S) -3-chloro-1,2-propanediol 1- (n-butylate) N, N'-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) A mixture of 1.49 g (2.70 mmol) and 52.4 g (0.594 mol) of n-butyric acid was stirred for 1 hour while heating at 50 ° C. while the inside of the system was filled with air. Subsequently, 6.89 g (54.0 mmol) of N, N-diisopropylethylamine and 50.0 g (0.540 mol, optical purity) of S-epichlorohydrin were added to this solution, that is, a solution of the cobalt (III) complex in n-butyric acid. 99% ee) was added in sequence, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to obtain 80.0 g (yield: 82.0%) of the title (S) -3-chloro-1,2-propanediol 1- (n-butyrate). As a result of optical purity analysis by high performance liquid chromatography, the optical purity was 99% ee.

Example 10
Production of (R) -glycidyl n-butyrate 50.0 g of (S) -3-chloro-1,2-propanediol 1- (n-butyrate) obtained in Example 9 (0.277 mol, optical purity 99%) ee) was dissolved in 1,2-dichloroethane (200 mL), and potassium tert-butoxide (32.6 g, 0.291 mol) was added under ice cooling, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was transferred to a separating funnel and washed twice with 200 mL of water, and the organic layer was concentrated under reduced pressure. The obtained crude oil was distilled under reduced pressure to obtain 28.7 g (yield: 72.0%) of the title (R) -glycidyl n-butyrate. As a result of optical purity analysis by high performance liquid chromatography, the optical purity was 99% ee.

Claims (8)

The following equation (1)

(In the formula, X means a halogen atom.)
The optically active epihalohydrin represented by the following formula (2)

(Wherein, n represents an integer of 0, 1 or 2; Y ¹ , Y ² and Y ³ are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a substituted or unsubstituted alkyl group, Or an unsubstituted aryl group, acyl group or alkoxycarbonyl group, and Y ¹ and Y ² or Y ² and Y ³ together form a ring together with the carbon atom to which they are attached. Where A represents a counter ion and M represents a metal ion.)
In the presence of a metal complex catalyst represented by the following formula (3)

(In the formula, Nu means a substituted heteroatom, and Q means a hydrogen atom or a substituted silicon atom.)
By reacting a nucleophile represented by the following formula (4)

(In the formula, X and Nu mean the same as those described above.)
A method for regioselectively producing an optically active 1-halogeno-2-hydroxypropyl compound represented by the formula: The following equation (1)

(In the formula, X means the same as above.)
The optically active epihalohydrin represented by the following formula (2)

(In the formula, n, Y ¹ , Y ² , Y ³ , A and M mean the same as those described above.)
Under the metal complex catalyst represented by the following formula (3)

(In the formula, Nu and Q mean the same as above.)
Is reacted with a nucleophile represented by the following formula (4)

(In the formula, X and Nu mean the same as those described above.)
An optically active 1-halogeno-2-hydroxypropyl compound represented by the following formula is produced regioselectively, and then a basic reagent is allowed to act thereon to obtain the following formula (5)

(In the formula, Nu means the same as above.)
A method for producing an optically active glycidyl compound represented by the formula: The method according to claim 1, wherein the halogen atom represented by ΔX is a chlorine atom or a bromine atom. The method according to any one of claims 1 to 3, wherein the metal complex catalyst represented by the formula (2) is a catalyst represented by the following formula (6).

(Wherein, n represents an integer of 0, 1 or 2; Z ¹ , Z ² , Z ³ and Z ⁴ are the same or different and are each independently a hydrogen atom, a halogen atom, a nitro group, a substituted or unsubstituted Chain alkyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted alkyloxy group, substituted or unsubstituted aralkyloxy group, or substituted or unsubstituted aryloxy group And Z ¹ and Z ² , Z ² and Z ³ , or Z ³ and Z ⁴ may be taken together to form a ring together with the carbon atom to which they are attached, and A represents a counter ion. , And M represents a metal ion.) The method according to any one of claims 1 to 4, wherein the nucleophile represented by the formula (3) is represented by the following formula (7).

(Wherein R is a hydrogen atom, a linear, branched or cyclic alkyl group, a linear, branched or cyclic alkylcarbonyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aralkylcarbonyl group, It means an unsubstituted aryl group or a substituted or unsubstituted arylcarbonyl group.) The metal complex catalyst represented by the formula (2) or (6), wherein the metal ion M is a vanadium ion, a chromium ion, a manganese ion, an iron ion, a cobalt ion, a nickel ion, a molybdenum ion, a ruthenium ion or a tungsten ion. The method according to any one of claims 1 to 5. The metal complex catalyst represented by the formula (2) or (6), wherein the counter ion A is acetate, n-butyrate, (±) -camphorsulfonate, methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. 6. The production method according to any one of 6. The reaction for deriving an optically active epihalohydrin (1) to an optically active 1-halogeno-2-hydroxypropyl compound (4) is carried out in an ether-based solvent, according to any one of claims 1 to 7, wherein Manufacturing method.