JP4005168B2 - Process for producing optically active 2-aryloxypropionic acid - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明は従来使用されてきた酒石酸やその誘導体と異なり光学異性体の両方の異性体を利用でき、目的化合物のいずれの光学異性体を得ることが容易にできる産業上の多様なニーズに対応可能な酸性分割剤の製造方法、特に、光学活性な２−アリールオキシプロピオン酸の製造方法に関するものである。
本発明によって合成された光学活性２−アリールオキシプロピオン酸（Ｉ）はそれ自体が医薬、農薬、液晶等の分野で用いられ、有用なキラル源として不斉化合物の合成に用いられる。さらに、光学活性塩基類を得るための光学分割剤としての用途が期待される重要な化合物である。医薬、農薬、食品および液晶等の分野での光学活性化合物の必要性が高まっている現在、これらの光学活性化合物を得るひとつの方法である光学分割法において必要な光学分割剤を提供することは極めて重要となっている。
【０００２】
【従来の技術】
ＲＳ−２−アリールオキシプロピオン酸は工業的に利用される化合物であり、その光学活性体、すなわちＳ−、およびＲ−２−アリールオキシプロピオン酸（Ｉ）もそれぞれ公知である。しかし、従来これら両異性体を効率よく得る方法がなかった。これは、従来の技術が主として基礎分野にとどまり、それらの工業的規模での応用がなされなかったためと考えられる。しかし、光学活性２−アリールオキシプロピオン酸（Ｉ）の誘導体は植物ホルモンの作用を有し、またペニシラン酸のアミノ基修飾に用いられる等有用な用途が開発されている。
一方、本発明者らが知る限り光学活性２−アリールオキシプロピオン酸（１）を光学分割剤として利用している文献は少数である（ベルギー国特許６５５７０９号）。
本発明者らは先に（特願平８−２０４９７７）においてＲ−およびＳ−１−ベンジルアミノ−３−フェノキシ−２−プロパノールの製造法を出願し、またＲ−およびＳ−１−ベンジルアミノ−３−フェノキシ−２−プロパノールによるＲＳ−２−フェノキシプロピオン酸の光学分割法を出願した。（特願平８−３３９８７６）。
【０００３】
光学活性２−アリールオキシプロピオン酸 (Ｉ) を得る方法にはラセミ体を光学分割する方法と光学活性物質を原料とする化学合成法がある。以下に示すように、光学分割法としては（１）〜（３）、化学合成法としては（４）が挙げられる。
（１）ＲＳ−２−アリールオキシプロピオン酸のヨヒンビンによる光学分割
(E.Fourneau,Bull.Soc.Chim.France.,31,988,(1922).)
（２）ＲＳ−２−アリールオキシプロピオン酸のデヒドロアビエチルアミンによる光学分割
(W.J.Gottstein,J.Org.Chem., 30,1267,(1965),)
（３）ＲＳ−２−アリールオキシプロピオン酸の酵素による光学分割
(A.Ornella,Farmaco, 50,221,(1995),)
（４）ＲまたはＳ−２−ハロゲノプロピオン酸（Ｖ）とフェノール類 (VI-1,VI-2)による化学合成（式３）
(G.Bettoni,J.Med.Chem., 30,1267,(1987), 特公昭６４−１０５０６号公報）
【０００４】
このうち（１）および（２）は古くから知られているアルカロイド、アミノ酸誘導体を用いる古典的なものである。この方法は分割剤が高価で大量供給が困難であり、なおかつ人体に対する毒性が強いため工業的に用いることはできない。また、酵素を用いる（３）の方法は近年著しい進歩を遂げているものの、酵素の大量供給体制が不備であり、現時点で経済的に有効であるとは言い難い。
（４）の光学活性２−ハロゲノプロピオン酸（Ｖ）を用いる化学合成法は一般にＷｉｌｌｉａｍｓｏｎ反応として知られている。原料に用いられる光学活性２−ハロゲノプロピオン酸（Ｖ）の中でＳ−２−クロロプロピオン酸は比較的よく知られている。この化合物は現在農薬原料として微生物による合成がおこなわれている。
しかし、Ｓ−２−クロロプロピオン酸は高価であり入手しやすいとは言えない。しかも、Ｗｉｌｌｉａｍｓｏｎ反応で得られる光学活性２−アリールオキシプロピオン酸 (Ｉ) はＲ−体のみである。
このため合成の容易な光学活性２−クロロプロピオン酸エチル（ III ） からの製造法も提案されている。例えば、前記の特公昭６４−１０５０６号公報に開示されている方法は、加熱下で反応系内を減圧しながらフェノール類のアルカリ金属塩水溶液中に２−ハロゲノプロピオン酸エステルと水酸化ナトリウム水溶液を同時に滴下することにより光学活性なアリールオキシアルカン酸のアルカリ金属塩を得ることを特徴としている。しかしこの方法では、反応系内を減圧にしなければならず、操作が複雑であり目的とする生成物の光学純度も充分とはいい難い。
【０００５】
【発明が解決しようとする課題】
本発明は上記従来技術の欠点を解消するために開発されたもので、緩和された条件で単純かつ実際的操作で光学純度の高い２−アリールオキシプロピオン酸（Ｉ）の製造方法を提供することを目的とするものである。
本発明はまたＲＳ−２−メチルピペラジンの光学分割に好結果を与えるＲまたはＳ−２−フェノキシプロピオン酸（特願平８−７８４７６号）に代表される光学活性２−アリールオキシプロピオン酸 (Ｉ) の有用な製造方法を提供することを目的とする。
とりわけ、本発明は安価な光学活性２−ヒドロキシプロピオン酸エステル(II)より容易に合成が可能な光学活性２−ハロゲノプロピオン酸エステル(III) または光学活性２−ヒドロキシプロピオン酸エステルのスルホン酸誘導体(IV)を原料としてフェノール類（VI-1,VI-2)と反応させて光学活性２−アリールオキシプロピオン酸（Ｉ）の両方の光学異性体をエステルの加水分解反応を新たに実施することなく製造方法を提供することを目的とする。
【０００６】
【課題を解決するための手段】
上記の目的は以下の各発明により効率良く達成されることが分かった。すなわち、
（１）Ｒ又はＳ−２−ハロゲノプロピオン酸エステルと下記一般式〔ＶＩ−１〕または〔ＶＩ−２〕で示されるフェノール類を混合させ、これに常圧で水酸化アルカリまたはその溶液を４０〜６０℃で加えて、更に８０〜９０℃で加熱することを特徴とする、出発原料と逆の立体配置をもつ光学活性な２−アリールオキシプロピオン酸の製造方法、
【化２】
（３）Ｓ−２−ヒドロキシプロピオン酸エチルより合成されるＳ−２−クロロプロピオン酸エチルを用いる上記（１）に記載の光学活性な２−アリールオキシプロピオン酸の製造方法。
上記（１）又は（２）の方法において、水酸化アルカリまたはその溶液の温度を４０〜６０℃とするのは、４０℃未満では反応液が固まり攪拌不能となり、６０℃を越えると、目的物がラセミ化を起こす。加熱温度を８０〜９０℃とするのは８０℃未満では反応が十分進行しないためであり、９０℃を越えると、水分の流失が始まるからである。
【０００７】
本発明の方法で得られる光学活性な２−アリールオキシプロピオン酸（Ｉ）は次の一般式で表される。
【０００８】
【化１】
【０００９】
【化２】
【００１０】
前述したように２−メチルピペラジンの光学分割に光学活性２−フェノキシプロピオン酸の需要があり、また光学活性２−アリールオキシプロピオン酸（Ｉ）の有用物への転換の可能性も考えられたので、Ｒ−体、Ｓ−体いずれもが得られる合成法を研究した結果、安価な光学活性２−ヒドロキシプロピオン酸エステル(II)より公知の方法で得ることができ、なおかつ２−位の立体配置の保持、反転が容易にコントロールできる光学活性２−ハロゲノプロピオン酸エステル(III) および光学活性２−ヒドロキシプロピオン酸スルホン酸誘導体(IV)を出発原料としてＲ−およびＳ−アリールオキシプロピオン酸（Ｉ）のいずれもが得られることを見いだし本発明を完成した。この間の反応を反応式で示すと次のとおりである。
【００１１】
【化３】
【００１２】
本発明は一般的に以下のように実施される。
（１）ＲまたはＳ−２−ハロゲノプロピオン酸エステル(III) とフェノール類(VI-1,VI-2) を混合し、必要ならばアルコール、ケトン、エーテル、アミド、炭化水素などの有機溶媒を加える。これに水酸化アルカリまたはその溶液を４０〜６０℃で滴下し、これを８０〜９０℃で加熱攪拌する。反応終了後生じたアルコールを留去したのち塩酸、硫酸などの強酸を用いて溶液を酸性として結晶を分離して粗結晶を得る。またはジクロロメタン、トルエンなどの有機溶媒で抽出、水洗、乾燥する。有機溶媒を留去して粗結晶を得る。粗結晶はトルエン、ヘキサン、シクロヘキサン等の炭化水素系溶媒で精製し、目的物（Ｉ）を得る。
（２）ＲまたはＳ−２−ヒドロキシプロピオン酸エステルスルホン酸誘導体 8IV) とフェノール類(VI-1,VI-2) を混合し、（１）と同様の操作をおこない目的物（Ｉ）を得る。
【００１３】
すでに述べたように、下記一般式で示すように、光学活性２−アリールオキシプロピオン酸（Ｉ）は光学活性２−ハロゲノプロピオン酸（Ｖ）と、下記一般式で示されるフェノール類 (VI-1,VI-2)との反応でも得ることができる。その原料である光学活性２−ハロゲノプロピオン酸（Ｖ）は光学活性２−ハロゲノプロピオン酸エステル(III) を加水分解して得られると考えられる。
【００１４】
【化５】
しかし、光学活性２−ハロゲノプロピオン酸エステル(III) の加水分解は分解やラセミ化が起こりやすく、高純度の光学活性２−ハロゲノプロピオン酸（Ｖ）を得ることは困難である。また、これ以外にも光学活性２−ハロゲノプロピオン酸（Ｖ）を得る方法には光学活性ナフチルエチルアミンによる光学分割、光学活性アラニンのジアゾニウム塩を置換する方法があるがいずれも原料、分割剤が高価で経済的とはいい難い。
【００１５】
一方、本発明者らの製造法は安価な光学活性２−ヒドロキシプロピオン酸エステル(II)より合成でき、反応時の立体配置の反転、保持の容易な光学活性２−ハロゲノプロピオン酸エステル(III) および２−ヒドロキシプロピオン酸エステルスルホン酸誘導体(IV)より直接目的物（Ｉ）を合成できるため工業的、経済的なメリットは非常に大きいと考えられる。
【００１６】
【発明の実施の形態】
本発明において、光学活性２−アリールオキシプロピオン酸（Ｉ）は具体的には以下のようにして得られる。
フェノール類 (VI-1,VI-2)１当量と光学活性２−ハロゲノプロピオン酸エステル(III) または光学活性２−ヒドロキシプロピオン酸エステルスルホン酸誘導体(IV)０．５〜５．０当量を混合する。必要ならば溶媒としてアルコール、ケトン、エーテル、アミド、炭化水素等の有機溶媒を加える。
これに水酸化アルカリまたはその溶液１．０〜６．０当量を常圧で加えて４０〜６０℃に加熱する。その後８０〜９０℃に加熱攪拌後、生じたアルコール、および使用した有機溶媒をのぞき、溶液を酸性にして、粗結晶を分離、または有機溶媒で抽出する。結晶または抽出溶液を乾燥後、溶媒は減圧留去して、目的物（Ｉ）を得る。必要ならば炭化水素系溶媒で再結晶をおこなう。
【００１７】
【実施例】
以下、本発明を実施例により更に具体的に説明する。
（実施例１）
Ｓ−２−クロロプロピオン酸ブチル３０．０ｇ（０．１８２ｍｏｌ）およびフェノール１６．０ｇ（０．１７０ｍｏｌ）を混合する。
これに、５０％水酸化ナトリウム水溶液２８．２ｇ（０．３５２ｍｏｌ）を６０℃以下を保ちながら滴下する。終了後、溶液を５時間かけて９０℃まで加温する。９０℃で１時間攪拌したのち脱イオン水４０ｍｌを加える。溶媒を減圧留去したのち脱イオン水１５０ｍｌを加え残さを溶解し、３５％塩酸２５ｍｌを加える。室温まて冷却後、溶液をジクロロメタン７５ｍｌで二回抽出する。有機層は脱イオン水７５ｍｌで洗浄後、硫酸ナトリウムで乾燥した。ジクロロメタンを留去して、Ｒ−２−フェノキシプロピオン酸を得た。
（実施例２）
Ｒ−２−クロロプロピオン酸ブチル３０．０ｇ（０．１８２ｍｏｌ）およびフェノール１６．０ｇ（０．１７０ｍｏｌ）を混合し、（実施例１）と同様な操作をおこない、Ｓ−２−フェノキシプロピオン酸を得た。
収量 ２７．２ｇ 収率 ９２．７％
ｍ．Ｐ ８５．５〜８７．０℃
旋光度〔α〕D −３４．５°（Ｃ．０．５ ＥｔＯＨ ２５℃）
光学純度 ８５．０％ｅｅ
（ダイセル社製ＨＰＬＣカラム ＣｈｉｒａｌｃｅｌＯＤで測定）
ＮＭＲシグナル（実施例１）と同様
【００１９】
（実施例３）
Ｒ−２−クロロプロピオン酸エチル２５．４ｇ（０．１８２ｍｏｌ）およびフェノール１６．０ｇ（０．１７０ｍｏｌ）を混合し、（実施例１）と同様な操作をおこない、Ｓ−２−フェノキシプロピオン酸を得た。
収量 ２６．４ｇ 収率 ９３．７％
ｍ．Ｐ ８５．５〜８７．０℃
旋光度〔α〕D −３３．６°（Ｃ．０．５ ＥｔＯＨ ２５℃）
光学純度 ８５．０％ｅｅ
（ダイセル社製ＨＰＬＣカラム ＣｈｉｒａｌｃｅｌＯＤで測定）
ＮＭＲシグナル（実施例１）と同様
【００２０】
（実施例４）
Ｒ−２−クロロプロピオン酸ブチル３０．０ｇ（０．１８２ｍｏｌ）および４−クロロフェノール２１．９ｇ（０．１７０ｍｏｌ）を混合し、（実施例１）と同様な操作をおこない、Ｓ−２−（４′−クロロフェノキシ）−プロピオン酸を得た。
収量 ２９．２ｇ 収率 ８５．８％
ｍ．Ｐ １０１．０〜１０２．０℃
旋光度〔α〕D −３３．２°（Ｃ．０．５ ＥｔＯＨ ２５℃）
【００２１】
（実施例５）
Ｒ−２−クロロプロピオン酸ブチル３０．０ｇ（０．１８２ｍｏｌ）および４−ニトロフェノール２３．６ｇ（０．１７０ｍｏｌ）を混合し、（実施例１）と同様な操作をおこない、Ｓ−２−（４′−ニトロフェノキシ）−プロピオン酸を得た。
収量 ３２．５ｇ 収率 ８４．５％
ｍ．Ｐ １０１．０〜１０２．０℃
旋光度〔α〕D ＋４５．０°（Ｃ．０．５ ＭｅＯＨ ２５℃）
【００２２】
（実施例６）
Ｒ−２−クロロプロピオン酸ブチル３０．０ｇ（０．１８２ｍｏｌ）および２−ナフトール２４．５ｇ（０．１７０ｍｏｌ）を混合し、（実施例１）と同様な操作をおこない、Ｓ−２−（２′−ナフトキシ）−プロピオン酸を得た。
収量 ２９．０ｇ 収率 ７９．３％
ｍ．Ｐ １１６．０〜１１７．０℃
旋光度〔α〕D −７５．３°（Ｃ．０．５ ＭｅＯＨ ２５℃）
【００２３】
（実施例７）
Ｒ−２−ヒドロキシプロピオン酸エチル−ｐ−トルエンスルホン酸エステル４０．０ｇ（０．１４７ｍｏｌ）およびフェノール１２．９ｇ（０．１３７ｍｏｌ）を混合し、（実施例１）と同様の操作をおこなってＲ−２−フェノキシプロピオン酸を得た。
収量 １８．０ｇ 収率 ７８．９％
ｍ．Ｐ ８６．５〜８７．５℃
旋光度〔α〕D −３０．８°（Ｃ．０．５ ＥｔＯＨ ２５℃）
光学純度 ７６．３％ｅｅ
（ダイセル社製ＨＰＬＣカラム ＣｈｉｒａｌｃｅｌＯＤで測定）
ＮＭＲシグナル（実施例１）と同様
【００２４】
（実施例８）
Ｒ−２−クロロプロピオン酸エチル２５．４ｇ（０．１８２ｍｏｌ）およびフェノール１６．０ｇ（０．１７０ｍｏｌ）、２−メチル−２−プロパノール１２０ｍｌを混合し、（実施例１）と同様な操作をおこない、Ｓ−２−フェノキシプロピオン酸を得た。
収量 ２６．０ｇ 収率 ９２．０％
ｍ．Ｐ ８５．５〜８６．２℃
旋光度〔α〕D −３４．３°（Ｃ．０．５ ＥｔＯＨ ２５℃）
光学純度 ８５．８％ｅｅ
（ダイセル社製ＨＰＬＣカラム ＣｈｉｒａｌｃｅｌＯＤで測定）
ＮＭＲシグナル（実施例１）と同様[0001]
BACKGROUND OF THE INVENTION
The present invention can use both optical isomers unlike tartaric acid and its derivatives that have been conventionally used, and can meet various industrial needs that can easily obtain any optical isomer of the target compound. The present invention relates to a method for producing an acidic resolving agent, in particular, a method for producing optically active 2-aryloxypropionic acid.
The optically active 2-aryloxypropionic acid (I) synthesized according to the present invention is itself used in the fields of pharmaceuticals, agricultural chemicals, liquid crystals and the like, and is used as a useful chiral source for the synthesis of asymmetric compounds. Furthermore, it is an important compound expected to be used as an optical resolution agent for obtaining optically active bases. At present, the need for optically active compounds in the fields of pharmaceuticals, agricultural chemicals, foods, liquid crystals, etc. is increasing. To provide optically resolving agents necessary for optical resolution, which is one method for obtaining these optically active compounds. It is extremely important.
[0002]
[Prior art]
RS-2-aryloxypropionic acid is an industrially utilized compound, and its optically active form, ie, S- and R-2-aryloxypropionic acid (I) are also known. However, there has been no method for efficiently obtaining both isomers. This is presumably because the conventional techniques remain mainly in the basic field and have not been applied on an industrial scale. However, the optically active 2-aryloxypropionic acid (I) derivative has an action of a plant hormone, and useful applications such as use for amino group modification of penicillanic acid have been developed.
On the other hand, as far as the present inventors know, there are few documents using the optically active 2-aryloxypropionic acid (1) as an optical resolution agent (Belgian Patent No. 655709).
The present inventors previously filed a method for producing R- and S-1-benzylamino-3-phenoxy-2-propanol in Japanese Patent Application No. Hei 8-204977, and R- and S-1-benzylamino. An application was made for an optical resolution method of RS-2-phenoxypropionic acid with -3-phenoxy-2-propanol. (Japanese Patent Application No. 8-339876).
[0003]
There are two methods for obtaining optically active 2-aryloxypropionic acid (I): a method of optically resolving a racemate and a chemical synthesis method using an optically active substance as a raw material. As shown below, examples of the optical resolution method include (1) to (3), and examples of the chemical synthesis method include (4).
(1) Optical resolution of RS-2-aryloxypropionic acid with yohimbine
(E.Fourneau, Bull.Soc.Chim.France., 31 ,, 988, (1922).)
(2) Optical resolution of RS-2-aryloxypropionic acid with dehydroabiethylamine
(WJGottstein, J. Org. Chem., 30 , 1267, (1965),)
(3) Enzymatic resolution of RS-2-aryloxypropionic acid by enzyme
(A. Ornella, Farmaco, 50 , 221, (1995),)
(4) Chemical synthesis of R or S-2-halogenopropionic acid (V) and phenols (VI-1, VI-2) (Formula 3)
(G. Bettoni, J. Med. Chem., 30 , 1267, (1987), Japanese Patent Publication No. 64-10506)
[0004]
Of these, (1) and (2) are classical ones using alkaloids and amino acid derivatives that have been known for a long time. This method cannot be used industrially because the resolving agent is expensive and difficult to supply in large quantities and is highly toxic to the human body. In addition, although the method (3) using an enzyme has made remarkable progress in recent years, it is difficult to say that it is economically effective at the present time because the enzyme mass supply system is inadequate.
The chemical synthesis method using the optically active 2-halogenopropionic acid (V) of (4) is generally known as Williamson reaction. Of the optically active 2-halogenopropionic acids (V) used as raw materials, S-2-chloropropionic acid is relatively well known. This compound is currently synthesized by microorganisms as a raw material for agricultural chemicals.
However, it cannot be said that S-2-chloropropionic acid is expensive and easily available. Moreover, the optically active 2-aryloxypropionic acid (I) obtained by the Williamson reaction is only the R-form.
Therefore, a production method from optically active ethyl 2-chloropropionate ( III ) , which is easy to synthesize, has also been proposed. For example, in the method disclosed in the above Japanese Patent Publication No. 64-10506, a 2-halogenopropionic acid ester and an aqueous sodium hydroxide solution are added to an aqueous solution of an alkali metal salt of phenol while reducing the pressure in the reaction system under heating. It is characterized by obtaining an alkali metal salt of an optically active aryloxyalkanoic acid by dropping simultaneously. However, in this method, the inside of the reaction system must be depressurized, the operation is complicated, and the optical purity of the target product is difficult to say.
[0005]
[Problems to be solved by the invention]
The present invention was developed to eliminate the above-mentioned drawbacks of the prior art, and provides a method for producing 2-aryloxypropionic acid (I) having high optical purity by simple and practical operation under relaxed conditions. It is intended.
The present invention also provides optically active 2-aryloxypropionic acid (I) represented by R or S-2-phenoxypropionic acid (Japanese Patent Application No. Hei 8-78476) which gives good results for the optical resolution of RS-2-methylpiperazine. It is an object of the present invention to provide a useful production method.
In particular, the present invention relates to an optically active 2-halogenopropionic acid ester (III) or a sulfonic acid derivative of an optically active 2-hydroxypropionic acid ester (III) that can be easily synthesized from an inexpensive optically active 2-hydroxypropionic acid ester (II) ( Without reacting both optical isomers of optically active 2-aryloxypropionic acid (I) with ester hydrolysis using phenol (VI-1, VI-2) as raw material An object is to provide a manufacturing method.
[0006]
[Means for Solving the Problems]
It has been found that the above object can be efficiently achieved by the following inventions. That is,
(1) R or S-2-halogenopropionic acid ester and a phenol represented by the following general formula [VI-1] or [VI-2] are mixed, and an alkali hydroxide or a solution thereof is added thereto at normal pressure. A method for producing an optically active 2-aryloxypropionic acid having a configuration opposite to that of the starting material, characterized by being added at -60 ° C and further heating at 80-90 ° C;
[Chemical formula 2]
In the method of (1) or (2) above, the temperature of the alkali hydroxide or its solution is set to 40 to 60 ° C. When the temperature is lower than 40 ° C., the reaction solution is hardened and cannot be stirred. Causes racemization. The reason why the heating temperature is set to 80 to 90 ° C. is that the reaction does not proceed sufficiently when the heating temperature is less than 80 ° C., and when the heating temperature exceeds 90 ° C., the loss of moisture starts.
[0007]
The optically active 2-aryloxypropionic acid (I) obtained by the method of the present invention is represented by the following general formula.
[0008]
[Chemical 1]
[0009]
[Chemical 2]
[0010]
As described above, there is a demand for optically active 2-phenoxypropionic acid in the optical resolution of 2-methylpiperazine, and the possibility of conversion of optically active 2-aryloxypropionic acid (I) to a useful product was also considered. As a result of studying synthetic methods for obtaining both R-form and S-form, it can be obtained by a known method from an inexpensive optically active 2-hydroxypropionic acid ester (II), and has a 2-position configuration. R- and S-aryloxypropionic acid (I) starting from optically active 2-halogenopropionic acid ester (III) and optically active 2-hydroxypropionic acid sulfonic acid derivative (IV) that can be easily controlled for retention and inversion As a result, the present invention was completed. The reaction during this time is shown by the reaction formula as follows.
[0011]
[Chemical 3]
[0012]
The present invention is generally implemented as follows.
(1) Mix R or S-2-halogenopropionate (III) with phenols (VI-1, VI-2), and if necessary, remove organic solvents such as alcohols, ketones, ethers, amides and hydrocarbons. Add. An alkali hydroxide or its solution is dripped at this at 40-60 degreeC, and this is heated and stirred at 80-90 degreeC. After the reaction, the resulting alcohol is distilled off, and then the solution is acidified with a strong acid such as hydrochloric acid or sulfuric acid to separate the crystals to obtain crude crystals. Alternatively, it is extracted with an organic solvent such as dichloromethane and toluene, washed with water and dried. The organic solvent is distilled off to obtain crude crystals. The crude crystals are purified with a hydrocarbon solvent such as toluene, hexane, cyclohexane and the like to obtain the desired product (I).
(2) R or S-2-hydroxypropionic ester sulfonic acid derivative 8IV) and phenols (VI-1, VI-2) are mixed, and the same operation as (1) is performed to obtain the target product (I). .
[0013]
As already described, as shown by the following general formula, optically active 2-aryloxypropionic acid (I) is optically active 2-halogenopropionic acid (V) and phenols represented by the following general formula (VI-1 , VI-2). The optically active 2-halogenopropionic acid (V) as the raw material is considered to be obtained by hydrolyzing the optically active 2-halogenopropionic acid ester (III).
[0014]
[Chemical formula 5]
However, hydrolysis of the optically active 2-halogenopropionic acid ester (III) is likely to be decomposed or racemized, and it is difficult to obtain high-purity optically active 2-halogenopropionic acid (V). In addition, there are other methods for obtaining optically active 2-halogenopropionic acid (V), including optical resolution with optically active naphthylethylamine and a method of substituting diazonium salt of optically active alanine. It is hard to say that it is economical.
[0015]
On the other hand, the production method of the present inventors can be synthesized from an inexpensive optically active 2-hydroxypropionic acid ester (II), and the optically active 2-halogenopropionic acid ester (III) can be easily inverted and maintained at the time of reaction. In addition, since the target compound (I) can be directly synthesized from the 2-hydroxypropionic ester sulfonic acid derivative (IV), it is considered that the industrial and economic advantages are very large.
[0016]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the optically active 2-aryloxypropionic acid (I) is specifically obtained as follows.
1 equivalent of phenols (VI-1, VI-2) and 0.5-5.0 equivalents of optically active 2-halogenopropionic acid ester (III) or optically active 2-hydroxypropionic acid sulfonic acid derivative (IV) To do. If necessary, an organic solvent such as alcohol, ketone, ether, amide, or hydrocarbon is added as a solvent.
Alkali hydroxide or a 1.0-6.0 equivalent thereof is added to this at normal pressure and heated to 40-60 ° C. Then, after heating and stirring at 80 to 90 ° C., the resulting alcohol and the organic solvent used are removed, the solution is acidified, and the crude crystals are separated or extracted with an organic solvent. After drying the crystal or extraction solution, the solvent is distilled off under reduced pressure to obtain the desired product (I). If necessary, recrystallization is performed with a hydrocarbon solvent.
[0017]
【Example】
Hereinafter, the present invention will be described more specifically with reference to examples.
Example 1
30.0 g (0.182 mol) of butyl S-2-chloropropionate and 16.0 g (0.170 mol) of phenol are mixed.
To this, 28.2 g (0.352 mol) of 50% aqueous sodium hydroxide solution is added dropwise while maintaining the temperature at 60 ° C. or lower. After completion, the solution is warmed to 90 ° C. over 5 hours. After stirring for 1 hour at 90 ° C., 40 ml of deionized water is added. After distilling off the solvent under reduced pressure, 150 ml of deionized water is added to dissolve the residue, and 25 ml of 35% hydrochloric acid is added. After cooling to room temperature, the solution is extracted twice with 75 ml of dichloromethane. The organic layer was washed with 75 ml of deionized water and then dried over sodium sulfate. Dichloromethane was distilled off to obtain R-2-phenoxypropionic acid.
(Example 2)
By mixing 30.0 g (0.182 mol) of butyl R-2-chloropropionate and 16.0 g (0.170 mol) of phenol, the same operation as in Example 1 was performed, and S-2-phenoxypropionic acid was added. Obtained.
Yield 27.2g Yield 92.7%
m. P 85.5-87.0 ° C
Optical rotation [α] D -34.5 ° (C.0.5 EtOH 25 ° C.)
Optical purity 85.0% ee
(Measured with Daicel HPLC column Chiralcel OD)
Similar to NMR signal (Example 1)
(Example 3)
25.4 g (0.182 mol) of ethyl R-2-chloropropionate and 16.0 g (0.170 mol) of phenol were mixed, and the same operation as in (Example 1) was carried out to obtain S-2-phenoxypropionic acid. Obtained.
Yield 26.4 g Yield 93.7%
m. P 85.5-87.0 ° C
Optical rotation [α] D −33.6 ° (C.0.5 EtOH 25 ° C.)
Optical purity 85.0% ee
(Measured with Daicel HPLC column Chiralcel OD)
Same as NMR signal (Example 1)
(Example 4)
3-2-g (0.182 mol) of butyl R-2-chloropropionate and 21.9 g (0.170 mol) of 4-chlorophenol were mixed, and the same operation as in (Example 1) was performed. 4'-Chlorophenoxy) -propionic acid was obtained.
Yield 29.2g Yield 85.8%
m. P 101.0-102.0 ° C
Optical rotation [α] D −33.2 ° (C.0.5 EtOH 25 ° C.)
[0021]
(Example 5)
3-2-g (0.182 mol) of butyl R-2-chloropropionate and 23.6 g (0.170 mol) of 4-nitrophenol were mixed, and the same operation as in Example 1 was performed. 4'-Nitrophenoxy) -propionic acid was obtained.
Yield 32.5 g Yield 84.5%
m. P 101.0-102.0 ° C
Optical rotation [α] D + 45.0 ° (C.0.5 MeOH 25 ° C.)
[0022]
(Example 6)
R-2-chloropropionate butyl (30.0 g, 0.182 mol) and 2-naphthol (24.5 g, 0.170 mol) were mixed, and the same operation as in Example 1 was performed. '-Naphthoxy) -propionic acid was obtained.
Yield 29.0 g Yield 79.3%
m. P 116.0-117.0 ° C
Optical rotation [α] D −75.3 ° (C.0.5 MeOH 25 ° C.)
[0023]
(Example 7)
R-2-hydroxypropionic acid ethyl-p-toluenesulfonate 40.0 g (0.147 mol) and phenol 12.9 g (0.137 mol) were mixed, and the same operation as in Example 1 was performed. -2-Phenoxypropionic acid was obtained.
Yield 18.0 g Yield 78.9%
m. P 86.5-87.5 ° C
Optical rotation [α] D -30.8 ° (C.0.5 EtOH 25 ° C.)
Optical purity 76.3% ee
(Measured with Daicel HPLC column Chiralcel OD)
Similar to NMR signal (Example 1)
(Example 8)
25.4 g (0.182 mol) of ethyl R-2-chloropropionate, 16.0 g (0.170 mol) of phenol, and 120 ml of 2-methyl-2-propanol were mixed, and the same operation as in Example 1 was performed. S-2-phenoxypropionic acid was obtained.
Yield 26.0 g Yield 92.0%
m. P 85.5-86.2 ° C
Optical rotation [α] D −34.3 ° (C.0.5 EtOH 25 ° C.)
Optical purity 85.8% ee
(Measured with Daicel HPLC column Chiralcel OD)
Same as NMR signal (Example 1)
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP08813197A JP4005168B2 (en) | 1997-04-07 | 1997-04-07 | Process for producing optically active 2-aryloxypropionic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP08813197A JP4005168B2 (en) | 1997-04-07 | 1997-04-07 | Process for producing optically active 2-aryloxypropionic acid |
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| Publication Number | Publication Date |
|---|---|
| JPH10279521A JPH10279521A (en) | 1998-10-20 |
| JP4005168B2 true JP4005168B2 (en) | 2007-11-07 |
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| JP08813197A Expired - Lifetime JP4005168B2 (en) | 1997-04-07 | 1997-04-07 | Process for producing optically active 2-aryloxypropionic acid |
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| CN109111355A (en) * | 2018-08-31 | 2019-01-01 | 浙江工业大学 | A kind of chemical synthesis process of (R) -2- phenoxy propionic acid |
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