JP4407191B2 - Process for producing optically active halogenohydroxypropyl compound and glycidyl compound - Google Patents
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Description
本発明は医薬、農薬等の合成中間体として有用な光学活性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 invention relates to a process for producing optically active 1-halogeno-2-hydroxypropyl compounds and optically active glycidyl compounds useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like.
エピハロヒドリンから1−ハロゲノ−2−ヒドロキシプロピル化合物を経てグリシジル化合物へ導くことを基盤とする製造法は、古くから様々に報告されている。
しかしながら、その殆どは、ラセミ体のエピハロヒドリンをラセミ体のグリシジル化合物に導く方法に関するものであり、光学活性体のエピハロヒドリンを光学活性体のグリシジル化合物に導く方法に関する報告例は数少ない。その理由の一つとしては、エピハロヒドリン上の活性位である1位のハロゲノメチレン位と3位のエポキシ環末端位に顕著な活性の差がなく、扱いにくいことが挙げられる。
Various production methods have been reported for a long time based on epihalohydrin derived from a 1-halogeno-2-hydroxypropyl compound to a glycidyl compound.
However, most of them relate to a method for converting a racemic epihalohydrin into a racemic glycidyl compound, and there are few reports on a method for converting an optically active epihalohydrin into an optically active glycidyl compound. One reason is that there is no significant difference in activity between the halogenomethylene position at the 1st position and the terminal position of the epoxy ring at the 3rd position, which are active positions on the epihalohydrin, and it is difficult to handle.
つまり、下記反応式に示すように、求核種との反応において理論上ではa経路による求核反応が優先し、[I]または[II]を選択的に与えるとされているが、実際、この選択性は完全でなく、b経路による反応を経て[III]を副生し、結果として目的生成物[II]の光学純度が低下する。 In other words, as shown in the following reaction formula, in the reaction with the nucleophilic species, the nucleophilic reaction by the a route is theoretically given priority and [I] or [II] is selectively given. The selectivity is not perfect, and [III] is produced as a by-product through the reaction by the b route, and as a result, the optical purity of the target product [II] is lowered.
反応式
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
Several techniques for overcoming the above problems have been studied. For example, (i) an optically active epihalohydrin and 4-carbamoylmethylphenol are reacted in an aqueous solvent in the presence of an alkali hydroxide and a quaternary ammonium salt. (Ii) a method of reacting optically active epihalohydrin and benzyl alcohol in the presence of boron trifluoride diethyl ether complex (see Patent Document 1), etc., all of which are raw materials Compared with epihalohydrin, the optical purity of the product glycidyl compound is reduced by about 1 to 2%, and there is still room for improvement.
Further, according to the method of reacting optically active epichlorohydrin and water in the presence of the optically active cobalt (III) complex and then treating with potassium carbonate (see Patent Document 2), the optically active glycidol is obtained with 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 cumbersome but also uneconomical.
本発明は、従来技術の上記問題点に鑑み、光学活性エピハロヒドリンから、その光学純度を損なうことがなく、かつ高収率で光学活性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を製造する方法を提供することにある。 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 in high yield without impairing their optical purity. It is to provide a way to do.
本発明者らは上記の問題点を解決すべく種々検討を重ねた結果、後記式で示されるノンキラルな金属錯体触媒(2)を用いることによって、高収率かつ高光学純度で光学活性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を製造する新たな方法を見出し本発明を完成するに至った。
本発明はすなわち、下記式(1)
で表される光学活性エピハロヒドリンに、下記式(2)
で表される金属錯体触媒存在下、下記式(3)
で表される求核剤を反応させて、下記式(4)
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)
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。
As a result of various studies to solve the above-mentioned problems, the present inventors have used a non-chiral metal complex catalyst (2) represented by the following formula to obtain an optically active 1- with high yield and high optical purity. A new method for producing a halogeno-2-hydroxypropyl compound and an optically active glycidyl compound was found and the present invention was completed.
That is, the present invention provides the following formula (1)
In the optically active epihalohydrin represented by the following formula (2)
In the presence of a metal complex catalyst represented by the following formula (3)
A nucleophile represented by the following formula (4)
Wherein the optically active 1-halogeno-2-hydroxypropyl compound represented by the formula is regioselectively produced, and then a basic agent is allowed to act on the compound to formula (5)
The manufacturing method of an optically active 1-halogeno-2-hydroxypropyl compound and an optically active glycidyl compound including the method of manufacturing the optically active glycidyl compound represented by these.
本発明を実施することにより、原料である光学活性エピハロヒドリンの光学純度を保持しつつ高収率で、光学活性1−ハロゲノ−2−ヒドロキシプロピル化合物または光学活性グリシジル化合物を製造することができる。 By carrying out the present invention, an optically active 1-halogeno-2-hydroxypropyl compound or an optically active glycidyl compound can be produced in a high yield while maintaining the optical purity of the optically active epihalohydrin as a raw material.
以下、本発明を更に詳細に説明する。
まず、光学活性エピハロヒドリン(1)に、金属錯体触媒(2)存在下、求核剤(3)を反応させて、光学活性1−ハロゲノ−2−ヒドロキシプロピル化合物(4)を得る工程について以下に説明する。
Hereinafter, the present invention will be described in more detail.
First, the step of reacting the optically active epihalohydrin (1) with the nucleophile (3) in the presence of the metal complex catalyst (2) to obtain the optically active 1-halogeno-2-hydroxypropyl compound (4) is described below. explain.
式(1)において、Xが、塩素原子または臭素原子である光学活性エピハロヒドリンが好ましく用いられる。
式(2)の金属錯体触媒において、Y1が水素原子であり、Y2およびY3が、互いに一緒になり、それらが結合する炭素原子と共に、例えば置換基を有していてもよいベンゼン環、シクロヘキセン環などの環を形成する該金属錯体触媒が好ましく、そして特に好ましい金属錯体触媒は、下記式(6)で示される。
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 combined with each other, and together with the carbon atom to which they are bonded, for example, a benzene ring optionally having a substituent The metal complex catalyst that forms a ring such as a cyclohexene ring is preferred, and a particularly preferred metal complex catalyst is represented by the following formula (6).
上記式(6)において、Z1、Z2、Z3およびZ4は、例えば、水素原子、フッ素原子、塩素、臭素、ヨウ素などのハロゲン原子、ニトロ基、メチル、エチル、n−プロピル、イソプロピル、2,2−ジメチルプロピル、n−ブチル、sec−ブチル、tert−ブチル、n−へプチル、n−ヘキシルなどの炭素数1〜6の直鎖もしくは分岐アルキル基、シクロペンチル、シクロヘキシルなどの炭素数3〜7の環状アルキル基、トリフルオロメチル、パーフルオロ−tert−ブチルなどの置換アルキル基、ベンジル、4−メチルベンジル、クメニルなどの置換もしくは無置換のアラルキル基、フェニル、4−メチルフェニル、1−ナフチル、2−ナフチルなどの置換もしくは無置換のアリール基、メトキシ、エトキシ、tert−ブトキシ、トリフルオロメトキシ、パーフルオロ−tert−ブトキシなどの置換もしくは無置換のアルキルオキシ基、ベンジルオキシ、4−メチルベンジルオキシなどの置換もしくは無置換のアラルキルオキシ基、フェノキシ、4−メチルフェノキシなどの置換もしくは無置換のアリールオキシ基が挙げられる。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、例えば、ベンゼン環、シクロヘキセン環などの環を形成してもよい。また、該環は置換基を有していてもよい。
Z1〜Z4における好ましい基は、Z1、Z2、Z3、Z4がいずれも水素原子、Z1、Z2、Z3が水素原子であり、そしてZ4がtert−ブチル基、あるいはZ1およびZ3が水素原子であり、そしてZ2およびZ4がtert−ブチル基である。
また、該金属錯体触媒を、ポリマー、シリカゲル、アルミナ、ゼオライトなどの不溶性担体に、エーテル結合やメチレン鎖を介して固定化して用いることも好ましい例の1つである。
In the above formula (6), Z 1 , Z 2 , Z 3 and Z 4 are, for example, a hydrogen atom, a fluorine atom, a halogen atom such as chlorine, bromine or iodine, a nitro group, methyl, ethyl, n-propyl, isopropyl , 2,2-dimethylpropyl, n-butyl, sec-butyl, tert-butyl, n-heptyl, n-hexyl, etc., straight or branched alkyl groups having 1 to 6 carbon atoms, cyclopentyl, cyclohexyl, etc. 3-7 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, 1 -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, substituted or unsubstituted such as phenoxy and 4-methylphenoxy Of the aryloxy group. Z 1 and Z 2 , Z 2 and Z 3 , or Z 3 and Z 4 may be combined with each other to form a ring such as a benzene ring or a cyclohexene ring together with the carbon atom to which they are bonded. Good. The ring may have a substituent.
Preferred groups in Z 1 to Z 4 are as follows: 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, Z 1 and Z 3 are hydrogen atoms, and Z 2 and Z 4 are tert-butyl groups.
It is also a preferred example that the metal complex catalyst is used by being immobilized on an insoluble carrier such as a polymer, silica gel, alumina, or zeolite via an ether bond or a methylene chain.
式(2)または式(6)の金属錯体触媒においてAで示される対イオンとしては、例えば、ナイトレート、フルオリド、クロライド、ブロマイドなどのハロゲン原子、ペンタフルオロ−tert−ブトキシドなどの置換アルコキシド、ペンタフルオロフェノキシド、2,4,6−トリニトロフェノキシドなどの置換アリールオキシド、アセテート、n−ブチレート、トリフルオロアセテート、トリクロロアセテートなどの置換もしくは無置換のアルキルカルボネート、フェニルアセテート、4−ニトロフェニルアセテート、3,5−ジフルオロフェニルアセテートなどの置換もしくは無置換のアラルキルカルボネート、ベンゾエート、ペンタフルオロベンゾエート、2,4−ジニトロベンゾエートなどの置換もしくは無置換のアリールカルボネート、メタンスルホネート、トリフルオロメタンスルホネート、(±)−カンファースルホネートなどの置換もしくは無置換のアルキルスルホネート、ベンゼンスルホネート、p−トルエンスルホネート、3−ニトロベンゼンスルホネートなどの置換もしくは無置換のアリールスルホネートが挙げられる。好ましい対イオンは、アセテート、n−ブチレート、(±)−カンファースルホネート、メタンスルホネート、p−トルエンスルホネート、およびトリフルオロメタンスルホネートである。 Examples of the counter ion represented by A in the metal complex catalyst of the formula (2) or (6) include halogen atoms such as nitrate, fluoride, chloride, bromide, substituted alkoxides such as pentafluoro-tert-butoxide, penta Substituted aryloxides such as fluorophenoxide, 2,4,6-trinitrophenoxide, substituted or unsubstituted alkyl carbonates such as acetate, n-butyrate, trifluoroacetate, trichloroacetate, phenylacetate, 4-nitrophenylacetate, Substituted or unsubstituted aralkyl carbonates such as 3,5-difluorophenyl acetate, substituted or unsubstituted aryl carbonates such as benzoate, pentafluorobenzoate, and 2,4-dinitrobenzoate , Methanesulfonate, trifluoromethanesulfonate, substituted or unsubstituted alkylsulfonate such as (±) -camphorsulfonate, benzenesulfonate, p-toluenesulfonate, and substituted or unsubstituted arylsulfonate such as 3-nitrobenzenesulfonate. Preferred counter ions are acetate, n-butyrate, (±) -camphor sulfonate, methane sulfonate, p-toluene sulfonate, and trifluoromethane sulfonate.
式(2)または式(6)の金属錯体触媒において、Mで示される金属イオンは、特に限定されるものではなく、例えば、アルミニウムイオン、チタンイオン、バナジウムイオン、クロムイオン、マンガンイオン、鉄イオン、コバルトイオン、ニッケルイオン、銅イオン、亜鉛イオン、モリブデンイオン、ルテニウムイオン、ロジウムイオン、タングステンイオンなどが挙げられ、好ましくはバナジウムイオン、クロムイオン、マンガンイオン、鉄イオン、コバルトイオン、ニッケルイオン、モリブデンイオン、ルテニウムイオン、またはタングステンイオンである。また、各々の金属イオンは、(II)〜(IV)のいずれかの酸化状態に相当する。特に好ましくはクロムイオン(III)、コバルトイオン(III)である。 In the metal complex catalyst of formula (2) or formula (6), the metal ion represented by M is not particularly limited. For example, aluminum ion, titanium ion, vanadium ion, chromium ion, manganese ion, 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 An ion, a ruthenium ion, or a tungsten ion. Each metal ion corresponds to any oxidation state (II) to (IV). Particularly preferred are chromium ion (III) and cobalt ion (III).
なお、例えば、コバルト(III)錯体は、下記式(8)
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 has the following formula (8):
A cobalt (II) complex represented by the formula (1) is air-oxidized at room temperature in an appropriate solvent in the presence of an acid reagent corresponding to a hydrogen atom bonded to the electron-withdrawing substituent represented by A above. It can be easily prepared.
Under the present circumstances, the usage-amount of an acid reagent is 1-10 equivalent with respect to a cobalt (II) complex, Preferably it is 1-2 equivalent. Further, the cobalt (II) complex comprises a known reaction, that is, a salen ligand obtained by coupling 1 equivalent of an alkyl diamine and 2 equivalents of a salicyl aldehyde and cobalt (II) acetate tetrahydrate. It can be easily prepared from the complex formation reaction to be mixed.
Other metal complexes used in the present invention can be easily prepared by known methods.
The usage-amount of the metal complex catalyst in this invention is 0.1-10 mol% with respect to optically active epihalohydrin, Preferably it is 1-5 mol%. Moreover, about a cobalt (III) complex, after carrying out air oxidation from a cobalt (II) complex by the method mentioned above, the solution can also be used for reaction as it is, without refine | purifying. Furthermore, although it is possible to proceed with this reaction by using a metal complex catalyst alone, 0.1 to 100 mol% of a bulky tertiary amine such as N, N-diisopropylethylamine or triisobutylamine is added. Then the reaction is promoted.
式(3)の求核剤においてNuで示される置換基は、置換基を有するヘテロ原子ならば、特に限定されることはなく、例えば、酸素原子、硫黄原子、セレン原子、窒素原子、リン原子、または砒素原子などのヘテロ原子に、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カルボニル基、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カルボニル基などが置換したものが挙げられる。また、Qで示される置換基としては、水素原子、トリメチルシリル、トリエチルシリル、トリイソプロピルシリルなどの直鎖もしくは分岐のアルキルシリル基が挙げられる。 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 Group, a substituted or unsubstituted arylcarbonyl group, and the like. In addition, examples of the substituent represented by Q include a linear or branched alkylsilyl group such as a hydrogen atom, trimethylsilyl, triethylsilyl, triisopropylsilyl and the like.
好ましい求核剤は、下記式(7)で示される。
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。
A preferred nucleophile is represented by the following formula (7).
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, benzyl, 3-bromobenzyl, 4-methoxybenzyl and the like. A substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group such as phenyl, tolyl, 4-fluorophenyl, and 2-allyloxyphenyl; a linear or branched alkylcarbonyl group such as acetyl, propionyl, butyryl, and pivaloyl; Examples thereof include substituted or unsubstituted aralkylcarbonyl groups such as phenylacetyl and 2-bromophenylacetyl, and substituted or unsubstituted arylcarbonyl groups such as benzoyl, 2,4,6-trimethylbenzoyl and 4-phenylbenzoyl.
The amount of the nucleophile used is 0.5 to 2.0 equivalents, preferably 0.8 to 1.2 equivalents, relative to the optically active epihalohydrin (1).
本反応を行う際に使用される溶媒としては、ジエチルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、tert−ブチルメチルエーテル、シクロペンチルメチルエーテルなどのエーテル系溶媒、クロロホルム、ジクロロメタン、1,2−ジクロロエタンなどの塩素系溶媒、ヘキサン、ヘプタン、ベンゼン、トルエンなどの炭化水素系溶剤、酢酸エチル、酢酸ブチルなどのエステル系溶媒、アセトン、2−ブタノンなどのケトン系溶媒、ジメチルホルムアミド、ジメチルスルホキシド、アセトニトリルなどの非プロトン性極性溶媒、またはこれらの混合溶媒などが挙げられ、好ましくはテトラヒドロフラン、tert−ブチルメチルエーテルなどのエーテル系溶媒である。これらの溶媒の使用量は特に制限はない。また、本反応は無溶媒でも行うことが可能である。 Solvents used in carrying out this reaction include ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, chloroform, dichloromethane, 1,2-dichloroethane, etc. Chlorinated solvents, hexane, heptane, benzene, toluene and other hydrocarbon solvents, ethyl acetate, butyl acetate and other ester solvents, acetone, 2-butanone and other ketone solvents, dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. Examples include aprotic polar solvents or mixed solvents thereof, and ether solvents such as tetrahydrofuran and tert-butyl methyl ether are preferred. The amount of these solvents used is not particularly limited. In addition, this reaction can be performed without a solvent.
本反応は、−80℃〜溶媒の還流温度の範囲で行なわれ、好ましくは−50〜50℃、さらに好ましくは0〜30℃で行なわれる。また、常圧でも加圧下でもよい。
反応終了後、反応液は特に処理を施さないで次の工程に使用できる。また、抽出、水洗操作後、過剰の溶媒を減圧下留去し、残渣を蒸留、再結晶、シリカゲルカラムクロマトグラフィーなどの精製処理を施すことにより、目的物である光学活性1−ハロゲノ−2−ヒドロキシプロピル化合物(4)を得ることもできる。
This reaction is carried out in the range of −80 ° C. to the reflux temperature of the solvent, preferably −50 to 50 ° C., more preferably 0 to 30 ° C. Moreover, normal pressure or under pressure may be used.
After completion of the reaction, the reaction solution can be used in the next step without any particular treatment. Further, after extraction and washing operations, excess solvent is distilled off under reduced pressure, and the residue is subjected to purification treatment such as distillation, recrystallization, silica gel column chromatography, and the like, so that the target optically active 1-halogeno-2- A hydroxypropyl compound (4) can also be obtained.
次に、前工程で得られた光学活性1−ハロゲノ−2−ヒドロキシプロピル化合物(4)を、塩基試剤存在下、閉環反応に付し、光学活性グリシジル化合物(5)を得る工程について説明する。
使用できる塩基試剤としては、水酸化ナトリウム、水酸化カリウム、水酸化カルシウムなどのアルカリ金属またはアルカリ土類金属の水酸化物、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなどのアルカリ金属またはアルカリ土類金属の炭酸塩、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムベンジルオキシド、ナトリウムフェノキシド、カリウムtert−ブトキシドなどのアルカリ金属アルコキシド、ナトリウム、カリウムなどのアルカリ金属、水素化ナトリウム、水素化カリウムなどの水素化アルカリ金属、ナトリウムアミド、マグネシウムアミドなどのアルカリ金属もしくはアルカリ土類金属アミド、1,1,3,3−テトラメチルグアニジン、1,5−ジアザビシクロ[4.3.0]ノン−5−エン、1,8−ジアザビシクロ[5.4.0]−7−ウンデセンなどのアミン類が挙げられる。ただし、置換基Nu中にカルボニル基を含む式(4)で示される化合物については、加水分解されるため前掲のアルカリ金属またはアルカリ土類金属の水酸化物は使用できない。
塩基試剤の使用量は、光学活性1−ハロゲノ−2−ヒドロキシプロピル化合物(4)に対して1当量以上であり、好ましくは1.1〜2.0当量である。
なお、塩基試剤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、4−ジメチルアミノピリジン、15−クラウン−5、18−クラウン−6などのクラウンエーテル、ヨウ化ナトリウム、ヨウ化カリウムなどのヨウ化アルカリ金属塩、臭化ナトリウム、臭化カリウムなどの臭化アルカリ金属塩などの試薬を0.1〜10モル%量添加すると反応が促進される。
Next, the step of obtaining the optically active glycidyl compound (5) by subjecting the optically active 1-halogeno-2-hydroxypropyl compound (4) obtained in the previous step to a ring-closing reaction in the presence of a base reagent will be described.
Base reagents that can be used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, alkali metals such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, or alkaline earth. Metal carbonates, sodium methoxide, sodium ethoxide, sodium benzyloxide, sodium phenoxide, alkali metal alkoxides such as potassium tert-butoxide, alkali metals such as sodium and potassium, hydrogenation such as sodium hydride and potassium hydride Alkali metal or alkaline earth metal amide such as sodium amide, 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, since the compound represented by the formula (4) containing a carbonyl group in the substituent Nu is hydrolyzed, the alkali metal or alkaline earth metal hydroxide described above cannot be used.
The usage-amount of a base reagent is 1 equivalent or more with respect to an optically active 1-halogeno-2-hydroxypropyl compound (4), Preferably it is 1.1-2.0 equivalent.
In addition, although it is possible enough to advance this reaction only by using a base reagent, crown ethers such as 4-dimethylaminopyridine, 15-crown-5, 18-crown-6, sodium iodide, iodide The reaction is promoted by adding 0.1 to 10 mol% of a reagent such as an alkali metal iodide such as potassium or an alkali metal bromide such as sodium bromide or potassium bromide.
本反応に使用できる溶媒は水溶性溶媒と非水溶性溶媒とに分けられ、水溶性溶媒としては、1,2−ジメトキシエタン、テトラヒドロフラン、1,4−ジオキサンなどのエーテル系溶剤、ジメチルホルムアミド、ジメチルスルホキシド、アセトニトリルなどの非プロトン性極性溶媒、またはこれらの混合溶媒が挙げられ、非水溶性溶媒としては、ジエチルエーテル、ジイソプロピルエーテル、tert−ブチルメチルエーテルなどのエーテル系溶媒、クロロホルム、ジクロロメタン、1,2−ジクロロエタンなどの塩素系溶媒、ヘキサン、ヘプタン、ベンゼン、トルエンなどの炭化水素系溶剤、またはこれらの混合溶媒が挙げられる。なお、これらの溶媒の使用量は特に制限はない。 Solvents that can be used in this reaction are classified into water-soluble solvents and water-insoluble solvents. Examples of water-soluble solvents include ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethyl Examples include aprotic polar solvents such as sulfoxide and acetonitrile, or mixed solvents thereof. Examples of the non-aqueous solvent include ether solvents such as diethyl ether, diisopropyl ether, and tert-butyl methyl ether, chloroform, dichloromethane, 1, Examples include chlorinated solvents such as 2-dichloroethane, hydrocarbon solvents such as hexane, heptane, benzene, and toluene, or a mixed solvent thereof. In addition, the usage-amount of these solvents does not have a restriction | limiting in particular.
非水溶性溶媒は、塩基性試剤を含む水溶液との二相系溶媒としても反応に使用することもできる。ただし、置換基Nu中にカルボニル基を含む式(4)で示される化合物については、加水分解されるため使用できない。水溶液として調製できる塩基性試剤としては、前掲したものの中で、水酸化ナトリウム、水酸化カリウム、水酸化カルシウムなどのアルカリ金属またはアルカリ土類金属の水酸化物、炭酸ナトリウム、炭酸カリウム、炭酸カルシウムなどのアルカリ金属またはアルカリ土類金属の炭酸塩が挙げられ、好ましくは水酸化ナトリウム、水酸化カリウムである。また、二相系溶媒中での反応の場合、相関移動触媒を使用すると反応が著しく促進される。使用できる相関移動触媒としては、テトラブチルアンモニウムクロリド、テトラブチルアンモニウムブロミド、ベンジルトリメチルアンモニウムブロミド、ベンジルトリエチルアンモニウムクロリド、ベンジルトリブチルアンモニウムクロリド、メチルトリオクチルアンモニウムクロリド、テトラオクチルアンモニウムブロミド、N−ベンジルキニウムクロリドなどの4級アンモニウム塩、テトラブチルホスホニウムクロリド、テトラブチルホスホニウムブロミド、テトラフェニルホスホニウムクロリド、テトラフェニルホスホニウムブロミド、ベンジルトリフェニルホスホニウムクロリド、ベンジルトリフェニルホスホニウムブロミドなどの4級ホスホニウム塩、12−クラウン−4、15−クラウン−5、18−クラウン−6などのクラウンエーテルが挙げられる。添加量は基質に対して0.1〜10モル%量が好ましい。 The water-insoluble solvent can 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 basic agents that can be prepared as an aqueous solution include those listed above, hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, etc. And alkali metal or alkaline earth metal carbonates, preferably 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. Usable phase transfer catalysts include tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltributylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, N-benzylquinium chloride. Quaternary ammonium salts such as tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, benzyltriphenylphosphonium chloride, benzyltriphenylphosphonium bromide and the like quaternary phosphonium salts, 12-crown-4 , 15-crown-5, 18-crown-6, etc. N'eteru and the like. The addition amount is preferably 0.1 to 10 mol% with respect to the substrate.
本反応は、−80〜50℃の範囲で行なわれる。ただし、非水溶性溶媒と塩基性試剤を含む水溶液との二相系溶媒を使用する場合は、凍結のおそれがあるため、0〜50℃の範囲で好ましく行なわれる。また、本反応は常圧でも加圧下でもよい。
反応終了後、抽出、水洗による分液操作、過剰の溶媒の減圧下留去、そして、残渣の蒸留、再結晶、シリカゲルカラムクロマトグラフィーなどの精製処理を施すことにより、目的物である光学活性グリシジル化合物(5)を得ることができる。
This reaction is carried out in the range of −80 to 50 ° C. However, when a two-phase solvent comprising a water-insoluble solvent and an aqueous solution containing a basic reagent is used, it is preferably carried out in the range of 0 to 50 ° C. because there is a risk of freezing. In addition, this reaction may be performed under normal pressure or under pressure.
After completion of the reaction, the target optically active glycidyl is obtained by subjecting it to extraction, separation operation by washing with water, distilling off excess solvent under reduced pressure, and purifying the residue by distillation, recrystallization, silica gel column chromatography, etc. Compound (5) can be obtained.
以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、実施例において、ガスクロマトグラフィーによる定量分析とは内部標準法(内部標準物質:m−ジメトキシベンゼン)によるガスクロマトグラフィーを用いた生成物量の定量、ガスクロマトグラフィーによる光学純度分析とは光学活性キャピラリーカラム(G−TA/ジーエルサイエンス社製)を用いた光学純度の測定、高速液体クロマトグラフィーによる光学純度分析とは光学活性カラム(CHIRALCEL OD−H/ダイセル社製)を用いた光学純度の測定を意味する。 EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples. In Examples, quantitative analysis by gas chromatography is quantitative determination of the amount of product using gas chromatography by an internal standard method (internal standard substance: m-dimethoxybenzene), and optical purity analysis by gas chromatography is optical activity. Measurement of optical purity using capillary column (G-TA / GL Science) and optical purity analysis by high performance liquid chromatography are measurement of optical purity using optically active column (CHIRALCEL OD-H / Daicel). means.
実施例1
(S)-3−クロロ−1,2−プロパンジオールの製造
N,N’−ビス(3,5−ジ−tert−ブチルサリチリデン)エチレンジアミナトコバルト(II)119mg(0.216mmol)とテトラヒドロフラン(以下THFと略記する。)2.0mLの混合液に、(±)−カンファースルホン酸60.3mg(0.260mmol)を加え、系内を空気で満たしつつ室温で1時間撹拌した。続いて、この溶液、すなわちコバルト(III)錯体のTHF溶液に、(S)-エピクロロヒドリン1.00g(10.8mmol,光学純度99%e.e.)、H2O 234μL(13.0mmol)を順次加え、室温で20時間撹拌した。反応終了後、反応液をガスクロマトグラフィーにて定量分析および光学純度分析した結果、標題の(S)-3−クロロ−1,2−プロパンジオールの生成量は1.14g(収率95.4%)であり、そして光学純度は99%e.e.であった。
Example 1
Preparation of (S) -3-chloro-1,2-propanediol N, N′-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) 119 mg (0.216 mmol) 6 ± mg (0.260 mmol) of (±) -camphorsulfonic acid was added to a mixed solution of 2.0 mL of tetrahydrofuran (hereinafter abbreviated as THF), and stirred at room temperature for 1 hour while filling the system with air. Subsequently, 1.00 g (10.8 mmol, optical purity 99% ee) of (S) -epichlorohydrin and 234 μL of H 2 O (13.0 mmol) were added to this solution, that is, a THF solution of a cobalt (III) complex. Sequentially added 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 title (S) -3-chloro-1,2-propanediol produced was 1.14 g (yield 95.4). %) And the optical purity was 99% ee.
実施例2
(R)-3−クロロ−1,2−プロパンジオールの製造
N,N’−ビス(3,5−ジ−tert−ブチルサリチリデン)エチレンジアミナトコバルト(II)119mg(0.216mmol)とテトラヒドロフラン2.0mLの混合液に、(±)−カンファースルホン酸60.3mg(0.260mmol)を加え、系内を空気で満たしつつ室温で1時間撹拌した。続いて、この溶液(コバルト(III)錯体のTHF溶液)に、(R)-エピクロロヒドリン1.00g(10.8mmol,光学純度99%e.e.)およびH2O 234μL(13.0mmol)を順次加え、室温で20時間撹拌した。反応終了後、反応液をガスクロマトグラフィーにて定量分析および光学純度分析した結果、標題の(R)-3−クロロ−1,2−プロパンジオールの生成量は1.12g(収率93.7%)であり、そして光学純度は99%e.e.であった。
Example 2
Preparation of (R) -3-chloro-1,2-propanediol N, N′-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) 119 mg (0.216 mmol) To a mixed solution of 2.0 mL of tetrahydrofuran, 60.3 mg (0.260 mmol) of (±) -camphorsulfonic acid was added and stirred at room temperature for 1 hour while filling the system with air. Subsequently, 1.00 g (10.8 mmol, optical purity 99% ee) of (R) -epichlorohydrin and 234 μL of H 2 O (13.0 mmol) were added to this solution (THF solution of cobalt (III) complex). Sequentially added 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 (R) -3-chloro-1,2-propanediol produced was 1.12 g (yield 93.7). %) And the optical purity was 99% ee.
実施例3
(R)-グリシジルフェニルエーテルの製造
N,N’−ジサリチリデンエチレンジアミナトコバルト(II)173mg(0.532mmol)とジクロロメタン13mLの混合液に、(±)−カンファースルホン酸148mg(0.638mmol)を加えて系内を空気で満たしつつ室温で1時間撹拌した後、反応液を減圧下濃縮乾固して黒褐色の粗コバルト(III)錯体を得た。続いて、tert−ブチルメチルエーテル5.0mLを加えて粗コバルト(III)錯体を分散させた後、(S)-エピクロロヒドリン2.50mL(31.9mmol,光学純度99%e.e.)およびフェノール2.50g(26.6mmol)を順次加え、窒素ガス雰囲気下、室温で24時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル20mLを加えて希釈し、6%水酸化ナトリウム水10mL、飽和食塩水10mLにて順次洗浄し、有機層を減圧下濃縮して粗(S)-1−クロロ−3−フェノキシ−2−プロパノール5.75gを得た。
上記の粗(S)-1−クロロ−3−フェノキシ−2−プロパノール5.75gをイソプロパノール10mLに溶解し、氷冷下24%水酸化ナトリウム水6.64g(39.8mmol)を加え、室温で1時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル50mLを加えて希釈し、水20mL、飽和塩化アンモニウム水20mL、飽和食塩水20mLにて順次洗浄し、有機層を減圧下濃縮して粗(R)-グリシジルフェニルエーテル3.96gを得た。ガスクロマトグラフィーにて定量分析した結果、標題の(R)-グリシジルフェニルエーテルの生成量は3.80g(収率95.4%)であり、そして高速液体クロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 3
Preparation of (R) -glycidyl phenyl ether To a mixture of 173 mg (0.532 mmol) of N, N′-disalicylideneethylenediaminatocobalt (II) and 13 mL of dichloromethane, 148 mg of (±) -camphorsulfonic acid (0. 638 mmol) was added and the system was filled with air and stirred at room temperature for 1 hour, and then the reaction solution was concentrated to dryness under reduced pressure to obtain a dark 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 (31.9 mmol, optical purity 99% ee) of (S) -epichlorohydrin and phenol 2.50 g (26.6 mmol) was 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 mixture was diluted with 20 mL of tert-butyl methyl ether, washed successively with 6 mL of 6% aqueous sodium hydroxide and 10 mL of saturated brine, and the organic layer was concentrated under reduced pressure to give 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. Stir for 1 hour. After completion of the reaction, the reaction solution is diluted with 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 brine, and the organic layer is concentrated under reduced pressure to give a 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) -glycidyl phenyl ether was 3.80 g (yield 95.4%), and optical purity analysis was performed by high performance liquid chromatography. The optical purity was 99% ee.
実施例4
(S)-グリシジルフェニルエーテルの製造
N,N’−ジサリチリデンエチレンジアミナトコバルト(II)173mg(0.532mmol)とジクロロメタン13mLの混合液に、(±)−カンファースルホン酸148mg(0.638mmol)を加えて系内を空気で満たしつつ室温で1時間撹拌した後、反応液を減圧下濃縮乾固して黒褐色の粗コバルト(III)錯体を得た。続いて、tert−ブチルメチルエーテル5.0mLを加えて粗コバルト(III)錯体を分散させた後、(R)-エピクロロヒドリン2.50mL(31.9mmol,光学純度99%e.e.)およびフェノール2.50g(26.6mmol)を順次加え、窒素ガス雰囲気下、室温で24時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル20mLを加えて希釈し、6%水酸化ナトリウム水10mL、飽和食塩水10mLにて順次洗浄し、有機層を減圧下濃縮して粗(R)-1−クロロ−3−フェノキシ−2−プロパノール5.44gを得た。
上記の粗(R)-1−クロロ−3−フェノキシ−2−プロパノール5.44gをイソプロパノール10mLに溶解し、氷冷下24%水酸化ナトリウム水6.64g(39.8mmol)を加え、室温で1時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル50mLを加えて希釈し、水20mL、飽和塩化アンモニウム水20mL、飽和食塩水20mLにて順次洗浄し、有機層を減圧下濃縮して粗(S)-グリシジルフェニルエーテル3.80gを得た。ガスクロマトグラフィーにて定量分析した結果、標題の(S)-グリシジルフェニルエーテルの生成量は3.71g(収率93.0%)であり、そして高速液体クロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 4
Preparation of (S) -glycidyl phenyl ether To a mixture of 173 mg (0.532 mmol) of N, N′-disalicylideneethylenediaminatocobalt (II) and 13 mL of dichloromethane, 148 mg of (±) -camphorsulfonic acid (0. 638 mmol) was added and the system was filled with air and stirred at room temperature for 1 hour, and then the reaction solution was concentrated to dryness under reduced pressure to obtain a dark 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 (31.9 mmol, optical purity 99% ee) of (R) -epichlorohydrin and phenol 2.50 g (26.6 mmol) was 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 mixture was diluted with 20 mL of tert-butyl methyl ether, washed successively with 6 mL of 6% aqueous sodium hydroxide and 10 mL of saturated brine, and the organic layer was concentrated under reduced pressure to give crude (R)- 5.44 g of 1-chloro-3-phenoxy-2-propanol was obtained.
The above crude (R) -1-chloro-3-phenoxy-2-propanol (5.44 g) was dissolved in 10 mL of isopropanol, and 6.64 g (39.8 mmol) of 24% aqueous sodium hydroxide was added under ice-cooling. Stir for 1 hour. After completion of the reaction, the reaction solution is diluted with 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 brine, and the organic layer is concentrated under reduced pressure to give crude (S) -3.80 g of glycidyl phenyl ether was obtained. As a result of quantitative analysis by gas chromatography, the production amount of the title (S) -glycidyl phenyl ether was 3.71 g (yield 93.0%), and optical purity analysis was performed by high performance liquid chromatography. The optical purity was 99% ee.
実施例5
(R)-グリシジルフェニルエーテルの製造
N,N’−ジサリチリデンエチレンジアミナトコバルト(II)138mg(0.425mmol)とジクロロメタン10mLの混合液に、メタンスルホン酸33μL(0.510mmol)を加えて系内を空気で満たしつつ室温で1時間攪拌した後、反応液を減圧下濃縮乾固して黒褐色の粗コバルト(III)錯体を得た。続いて、tert−ブチルメチルエーテル4.0mLを加えて粗コバルト(III)錯体を分散させた後、(S)-エピクロロヒドリン2.00mL(25.5mmol,光学純度99%e.e.)そしてフェノール2.00g(21.3mmol)を順次加え、窒素ガス雰囲気下、室温で24時間攪拌した。反応終了後、反応液にtert−ブチルメチルエーテル20mLを加えて希釈し、6%水酸化ナトリウム水10mL、飽和食塩水10mLにて順次洗浄し、有機層を減圧下濃縮して粗(S)-1−クロロ−3−フェノキシ−2−プロパノール4.85gを得た。
上記の粗(S)-1−クロロ−3−フェノキシ−2−プロパノール4.85gをイソプロパノール10mLに溶解し、氷冷下24%水酸化ナトリウム水4.50g(25.5mmol)を加え、室温で1時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル50mLを加えて希釈し、水20mL、飽和塩化アンモニウム水20mL、飽和食塩水20mLにて順次洗浄し、有機層を減圧下濃縮して粗(R)-グリシジルフェニルエーテル3.24gを得た。ガスクロマトグラフィーにて定量分析した結果、標題の(R)-グリシジルフェニルエーテルの生成量は3.07g(収率96.1%)であり、そして高速液体クロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 5
Preparation of (R) -glycidyl phenyl ether To a mixture of 138 mg (0.425 mmol) of N, N′-disalicylideneethylenediaminatocobalt (II) and 10 mL of dichloromethane was added 33 μL (0.510 mmol) of methanesulfonic acid. The mixture was stirred at room temperature for 1 hour while the system was filled with air, and then the reaction solution was concentrated to dryness under reduced pressure to obtain a dark brown crude cobalt (III) complex. Subsequently, 4.0 mL of tert-butyl methyl ether was added to disperse the crude cobalt (III) complex, and then 2.00 mL of (S) -epichlorohydrin (25.5 mmol, optical purity 99% ee) and phenol 2.00 g (21.3 mmol) was 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 mixture was diluted with 20 mL of tert-butyl methyl ether, washed successively with 6 mL of 6% aqueous sodium hydroxide and 10 mL of saturated brine, and the organic layer was concentrated under reduced pressure to give 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. Stir for 1 hour. After completion of the reaction, the reaction solution is diluted with 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 brine, and the organic layer is concentrated under reduced pressure to give a 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) -glycidyl phenyl ether was 3.07 g (yield 96.1%), and optical purity analysis was performed by high performance liquid chromatography. The optical purity was 99% ee.
実施例6
(R)-グリシジルメチルエーテルの製造
N,N’−ジサリチリデンエチレンジアミナトコバルト(II)70.2mg(0.216mmol)とジクロロメタン5.0mLの混合液に、(±)−カンファースルホン酸60.3mg(0.260mmol)を加えて系内を空気で満たしつつ室温で1時間撹拌した後、反応液を減圧下濃縮乾固して黒褐色の粗コバルト(III)錯体を得た。続いて、tert−ブチルメチルエーテル2.0mLを加えて粗コバルト(III)錯体を分散させた後、(S)-エピクロロヒドリン1.0g(10.8mmol,光学純度99%e.e.)およびメタノール527μL(13.0mmol)を順次加え、窒素ガス雰囲気下、室温で72時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル20mLを加えて希釈し、6%水酸化ナトリウム水10mL、飽和食塩水10mLにて順次洗浄し、有機層を減圧下濃縮して粗(S)-1−クロロ−3−メトキシ−2−プロパノール1.54gを得た。
上記の粗(S)-1−クロロ−3−メトキシ−2−プロパノール1.54gをイソプロパノール5.0mLに溶解し、氷冷下24%水酸化ナトリウム水2.70g(16.2mmol)を加え、室温で1時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル20mLを加えて希釈し、水10mL、飽和塩化アンモニウム水10mL、飽和食塩水10mLにて順次洗浄し、有機層を減圧下濃縮して粗(R)-グリシジルメチルエーテル2.90gを得た。ガスクロマトグラフィーにて定量分析した結果、標題の(R)-グリシジルメチルエーテルの生成量は0.763g(収率80.2%)であり、そして高速液体クロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 6
Preparation of (R) -glycidyl methyl ether (±) -camphorsulfonic acid was added to a mixture of 70.2 mg (0.216 mmol) of N, N′-disalicylideneethylenediaminatocobalt (II) and 5.0 mL of dichloromethane. After 60.3 mg (0.260 mmol) was added and the system was filled with air and stirred at room temperature for 1 hour, the reaction solution was concentrated to dryness under reduced pressure to obtain a dark 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 were dispersed. 527 μL (13.0 mmol) was sequentially added, and the mixture was stirred at room temperature for 72 hours under a nitrogen gas atmosphere. After completion of the reaction, the reaction mixture was diluted with 20 mL of tert-butyl methyl ether, washed successively with 6 mL of 6% aqueous sodium hydroxide and 10 mL of saturated brine, and the organic layer was concentrated under reduced pressure to give crude (S)- 1.54 g of 1-chloro-3-methoxy-2-propanol was obtained.
The above crude (S) -1-chloro-3-methoxy-2-propanol (1.54 g) was dissolved in isopropanol (5.0 mL), and 2.70 g (16.2 mmol) of 24% aqueous sodium hydroxide was added under ice cooling. Stir at room temperature for 1 hour. After completion of the reaction, the reaction solution is diluted with 20 mL of tert-butyl methyl ether, washed successively with 10 mL of water, 10 mL of saturated aqueous ammonium chloride and 10 mL of saturated brine, and the organic layer is concentrated under reduced pressure to give a crude (R) -2.90 g of glycidyl methyl ether was 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 optical purity analysis was performed by high performance liquid chromatography. The optical purity was 99% ee.
実施例7
(R)-グリシジルアセテートの製造
N,N’−ジサリチリデンエチレンジアミナトコバルト(II)70.2mg(0.216mmol)とジクロロメタン5.0mLの混合液に、トリフルオロメタンスルホン酸23μL(0.260mmol)を加えて系内を空気で満たしつつ室温で1時間撹拌した後、反応液を減圧下濃縮乾固して黒褐色の粗コバルト(III)錯体を得た。続いて、tert−ブチルメチルエーテル2.0mLを加えて粗コバルト(III)錯体を分散させた後、(S)-エピクロロヒドリン1.0g(10.8mmol,光学純度99%e.e.)および酢酸742μL(13.0mmol)を順次加え、窒素ガス雰囲気下、室温で48時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル8.0mLを加えて希釈し、氷冷下カリウムtert−ブトキシド1.46g(13.0mmol)を加え、1時間撹拌した。反応終了後、塩化アンモニウム116mg(2.16mmol)を加えて30分間撹拌し、沈殿物をろ過、ろ液を減圧下濃縮して粗(R)−グリシジルアセテート1.38gを得た。ガスクロマトグラフィーにて定量分析した結果、標題の(R)-グリシジルアセテートの生成量は0.795g(収率63.4%)であり、そしてガスクロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 7
Preparation of (R) -glycidyl acetate To a mixed solution of 70.2 mg (0.216 mmol) of N, N′-disalicylideneethylenediaminatocobalt (II) and 5.0 mL of dichloromethane was added 23 μL of trifluoromethanesulfonic acid (0. 260 mmol) was added and the system was filled with air and stirred at room temperature for 1 hour, and then the reaction solution was concentrated to dryness under reduced pressure to obtain a dark 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 acetic acid were dispersed. 742 μL (13.0 mmol) was sequentially added, and the mixture was stirred at room temperature for 48 hours under a nitrogen gas atmosphere. After completion of the reaction, the reaction solution was diluted by adding 8.0 mL of tert-butyl methyl ether, and 1.46 g (13.0 mmol) of potassium tert-butoxide was added with ice cooling, followed by stirring for 1 hour. After completion of the reaction, 116 mg (2.16 mmol) of ammonium chloride was added and 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 production amount of the title (R) -glycidyl acetate was 0.795 g (yield 63.4%). Was 99% ee.
実施例8
(R)-グリシジルアセテートの製造
N,N’−ビス(3,5−ジ−tert−ブチルサリチリデン)エチレンジアミナトコバルト(II)119mg(0.216mmol)とジクロロメタン5.0mLの混合液に、トリフルオロメタンスルホン酸23μL(0.260mmol)を加えて系内を空気で満たしつつ室温で1時間撹拌した後、反応液を減圧下濃縮乾固して黒緑色の粗コバルト(III)錯体を得た。続いて、tert−ブチルメチルエーテル2.0mLを加えて粗コバルト(III)錯体を分散させた後、(S)−エピクロロヒドリン1.0g(10.8mmol,光学純度99%e.e.)および酢酸742μL(13.0mmol)を順次加え、窒素ガス雰囲気下、室温で24時間撹拌した。反応終了後、反応液にtert−ブチルメチルエーテル8.0mLを加えて希釈し、氷冷下カリウムtert−ブトキシド1.46g(13.0mmol)を加え、1時間撹拌した。反応終了後、塩化アンモニウム116mg(2.16mmol)を加えて30分間撹拌し、沈殿物をろ過、ろ液を減圧下濃縮して粗(R)-グリシジルアセテート1.36gを得た。ガスクロマトグラフィーにて定量分析した結果、標題の(R)−グリシジルアセテートの生成量は0.802g(収率63.9%)、ガスクロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 8
Preparation of (R) -glycidyl acetate In a mixed solution of 119 mg (0.216 mmol) of N, N′-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) and 5.0 mL of dichloromethane Then, 23 μL (0.260 mmol) of trifluoromethanesulfonic acid was added and the system was filled with air and stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a black-green crude cobalt (III) complex. It was. 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 dispersed. 742 μL (13.0 mmol) was 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 8.0 mL of tert-butyl methyl ether, and 1.46 g (13.0 mmol) of potassium tert-butoxide was added with ice cooling, followed by stirring for 1 hour. After completion of the reaction, 116 mg (2.16 mmol) of ammonium chloride was added and 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%). As a result of optical purity analysis by gas chromatography, optical purity was 99%. It was ee.
実施例9
(S)-3−クロロ−1,2−プロパンジオール 1−(n−ブチレート)の製造
N,N’−ビス(3,5−ジ−tert−ブチルサリチリデン)エチレンジアミナトコバルト(II)1.49g(2.70mmol)とn−酪酸52.4g(0.594mol)の混合液を、系内を空気で満たしつつ、50℃に加熱下、1時間撹拌した。続いて、この溶液、すなわちコバルト(III)錯体のn−酪酸溶液に、N,N−ジイソプロピルエチルアミン6.89g(54.0mmol)およびS−エピクロロヒドリン50.0g(0.540mol,光学純度99%e.e.)を順次加え、室温で24時間撹拌した。反応終了後、反応液を減圧下蒸留して標題の(S)−3−クロロ−1,2−プロパンジオール 1−(n−ブチレート)80.0g(収率82.0%)を得た。高速液体クロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 9
Preparation of (S) -3-chloro-1,2-propanediol 1- (n-butyrate) N, N′-bis (3,5-di-tert-butylsalicylidene) ethylenediaminatocobalt (II) A mixed liquid 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 to 50 ° C. while filling the system with air. Subsequently, 6.89 g (54.0 mmol) of N, N-diisopropylethylamine and 50.0 g of S-epichlorohydrin (0.540 mol, optical purity) were added to the n-butyric acid solution of the cobalt (III) complex. 99% ee) was sequentially added and 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.
実施例10
(R)-グリシジル n−ブチレートの製造
実施例9で得られた(S)−3−クロロ−1,2−プロパンジオール 1−(n−ブチレート)50.0g(0.277mol,光学純度99%e.e.)を、1,2−ジクロロエタン200mLに溶解し、氷冷下カリウムtert−ブトキシド32.6g(0.291mol)を加え、1時間撹拌した。反応終了後、反応液を分液ロートに移して水200mLにて2回洗浄し、有機層を減圧下濃縮した。得られた粗油を減圧下蒸留して標題の(R)−グリシジル n−ブチレート28.7g(収率72.0%)を得た。高速液体クロマトグラフィーにて光学純度分析した結果、光学純度は99%e.e.であった。
Example 10
Preparation of (R) -glycidyl n-butyrate 50.0 g (0.277 mol, optical purity 99%) of (S) -3-chloro-1,2-propanediol 1- (n-butyrate) obtained in Example 9 ee) was dissolved in 200 mL of 1,2-dichloroethane, and 32.6 g (0.291 mol) of potassium tert-butoxide was added under ice cooling, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was transferred to a separatory funnel and washed twice with 200 mL of water, and the organic layer was concentrated under reduced pressure. The resulting 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)
で表される光学活性エピハロヒドリンに、下記式(2)
で表される金属錯体触媒存在下、下記式(3)
で表される求核剤を反応させて、下記式(4)
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。 Following formula (1)
In the optically active epihalohydrin represented by the following formula (2)
In the presence of a metal complex catalyst represented by the following formula (3)
A nucleophile represented by the following formula (4)
A method for regioselectively producing an optically active 1-halogeno-2-hydroxypropyl compound represented by the formula:
で表される光学活性エピハロヒドリンに、下記式(2)
で表される金属錯体触媒下、下記式(3)
で表される求核剤を反応させ、下記式(4)
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し、続いで塩基性試剤を作用させ、下記式(5)
で表される光学活性グリシジル化合物を製造する方法。 Following formula (1)
In the optically active epihalohydrin represented by the following formula (2)
Under the metal complex catalyst represented by the following formula (3)
A nucleophile represented by the following formula (4)
An optically active 1-halogeno-2-hydroxypropyl compound represented by the following formula (5):
The method to manufacture the optically active glycidyl compound represented by these.
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