JP3715662B2 - Process for producing optically active β-hydroxycarboxylic acid and its enantiomer ester - Google Patents
Process for producing optically active β-hydroxycarboxylic acid and its enantiomer ester Download PDFInfo
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Description
【０００１】
【産業上の利用分野】
本発明は、医薬、農薬等の有用な合成中間体となる光学活性β−ヒドロキシカルボン酸及びその対掌体エステルの製造法に関する。
【０００２】
【従来の技術】
近年、医薬、農薬等の生理活性物質の合成中間体としての光学活性体の需要が急速に高まっており、様々な手法を用いた光学活性体の合成研究が盛んに行われている。脂肪族カルボン酸に属する光学活性β−ヒドロキシカルボン酸及びその対掌体エステルは、分子内に２種類の官能基を持ち、種々の光学活性物質へ誘導可能である産業的に極めて有用な物質群である。
【０００３】
従来、光学活性β−ヒドロキシカルボン酸の製造法としては、化学的又は微生物的方法としてβ−ケト酸エステルの不斉還元法、光学分割法、１，３−ジオールの酸化法、脂肪酸のβ−水酸化法、直接発酵法等が報告されている。この中で、微生物の代謝経路を利用した各種光学活性β−ヒドロキシカルボン酸の生産が、工業的規模で実施されている（特公昭５９−２１５９９号公報、特公昭５９−２１６００号公報、特公昭６０−１６２３５号公報、特公昭６１−１２６７６号公報等）。これらの微生物の代謝経路を利用した方法は、各種脂肪酸、アルコールを原料として使用し、脂肪酸の主代謝経路であるβ−酸化酵素系や、類縁の分岐状アミノ酸代謝経路と共通すると思われる酵素系を利用するものである。
【０００４】
【発明が解決しようとする課題】
しかしながら、前述した微生物の代謝経路を利用する方法においては、補酵素の再生系が必要であり、エネルギー源としてＡＴＰが必須となるため、代謝系を活性化するため、好気的条件下にグルコース等のエネルギー源を補給しながら培養する必要がある。従って、培養に時間がかかる、高濃度生産が困難である、無菌状態が必要である、菌体の再利用が困難である、といった問題点を有している。これらの問題点を克服できるような光学活性β−ヒドロキシカルボン酸及びその対掌体エステルの製造方法が望まれていた。
【０００５】
【課題を解決するための手段】
本発明者等は、前記課題を解決するため鋭意検討した結果、β−ヒドロキシカルボン酸エステルのラセミ体に、エステル結合を不斉加水分解する能力を有する微生物の培養物、菌体又は菌体処理物を作用させることにより、光学純度の高い光学活性β−ヒドロキシカルボン酸及びその対掌体エステルを効率よく生産可能であることを見いだし、本発明を完成するに至った。
【０００６】
即ち、本発明は、β−ヒドロキシカルボン酸エステルのラセミ体に、エステル結合を不斉加水分解する能力を有する微生物の培養物、菌体又は菌体処理物を作用させることを特徴とする光学活性β−ヒドロキシカルボン酸及びその対掌体エステルの製造法である。
本発明において基質として使用可能なβ−ヒドロキシカルボン酸エステルとしては、例えば、次式（Ｉ）：
【０００７】
【化１】
又は次式（II）：
【０００９】
【化２】
（式中、Ｒ1 及びＲ2 は、同一又は相異なり、アルキル基を表す。）
で示される化合物が挙げられる。
β−ヒドロキシカルボン酸エステルとして前記式（Ｉ）又は前記式（II）で示される化合物を用いた場合、得られる光学活性β−ヒドロキシカルボン酸は、それぞれ、次式（Ｉ’）：
【００１１】
【化３】
又は次式（II’）：
【００１３】
【化４】
（式中、Ｒ1 は前記と同義である。）
で示される化合物である。
前記式において、Ｒ1 又はＲ2 で表されるアルキル基としては、好ましくは炭素数１〜６のアルキル基、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、sec-ブチル基、ｔ−ブチル基が挙げられる。
【００１５】
前記式（Ｉ）で示されるβ−ヒドロキシカルボン酸エステルとしては、例えばβ−ヒドロキシイソ酪酸メチル（３−ヒドロキシ−２−メチルプロピオン酸メチル）が挙げられる。
前記式（II）で示されるβ−ヒドロキシカルボン酸エステルとしては、例えばは、β−ヒドロキシ酪酸メチル、β−ヒドロキシ吉草酸メチル、β−ヒドロキシイソカプロン酸メチルが挙げられる。
【００１６】
本発明で用いる微生物は、β−ヒドロキシカルボン酸エステルのラセミ体を不斉加水分解する能力を有するものであれば特に制限はない。代表的なものとして、シュードモナス（Pseudomonas)属、ロードコッカス（Rhodococcus)属又はエセリキア（Escherichia)属に属する微生物が挙げられる。具体的には、シュードモナス・プチダ（Pseudomonas putida)MR-2068(FERM BP-3846)、ロードコッカス・エリスロポリス（Rhodococcus erythropolis)IFO 12320、ロードコッカス・エリスロポリス（Rhodococcus erythropolis)IFO 12538、エセリキア・コリ（Escherichia coli)MR-2103(FERM BP-3835)が挙げられる。エセリキア・コリ（Escherichia coli)MR-2103(FERM BP-3835)は、シュードモナス・プチダ（Pseudomonas putida)MR-2068(FERM BP-3846)由来のエステラーゼ遺伝子で形質転換された株である。
【００１７】
本発明で用いる微生物の培養は、液体培地でも固体培地でも行うことができる。培地としては、微生物が通常資化しうる炭素源、窒素源、ビタミン、ミネラル等の成分を適宜配合したものが用いられる。微生物の加水分解能を向上させるため、培地にエステルを少量添加することも可能である。培養は微生物が生育可能である温度、ｐＨで行われるが、使用する菌株の最適培養条件で行うことが好ましい。微生物の生育を促進させるため、通気攪拌を行ってもよい。
【００１８】
加水分解反応を行うに際しては、培養の開始時又は途中で培地にエステルを添加してもよく、予め微生物を培養した後、培養液にエステルを添加してもよい。また増殖した微生物の菌体を遠心分離等により採取し、これをエステルを含む反応媒体に加えてもよい。菌体としては、アセトン、トルエン等で処理した菌体を用いてもよい。
【００１９】
また、菌体の代わりに、培養液等の培養物、菌体破砕物、菌体抽出物、粗酵素、精製酵素等の菌体処理物を用いてもよく、更に、酵素又は微生物を適当な担体に固定化し、反応を行った後に回収再利用することも可能である。
反応媒体としては、例えばイオン交換水、緩衝液が用いられる。反応媒体又は培養液中のエステル濃度としては、0.１〜50重量％が好ましく、更に好ましくは５〜30重量％である。メタノール、アセトン、界面活性剤等を反応系に添加することも可能である。反応液のｐＨは、２〜11、好ましくは５〜８の範囲である。反応が進行するに従い生成したカルボン酸により反応液のｐＨが低下してくるが、この場合は適当な中和剤で最適ｐＨに維持することが好ましい。反応温度は５〜70℃が好ましく、30〜60℃が更に好ましい。
【００２０】
このようにして、β−ヒドロキシカルボン酸エステルのラセミ体に、エステル結合を不斉加水分解する能力を有する微生物の培養物、菌体又は菌体処理物を作用させることにより、光学活性β−ヒドロキシカルボン酸及びその対掌体エステルを製造することができる。生成物の分離精製は、酢酸エチル、クロロホルム、エーテル等の有機溶媒による抽出等により、容易に行うことができる。
【００２１】
【実施例】
以下、本発明を実施例により更に詳しく説明するが、本発明の範囲はこれらに限定されるものではない。
（実施例１） β−ヒドロキシカルボン酸エステルのラセミ体を不斉加水分解する能力を有する微生物のスクリーニング法
50mMトリス塩酸緩衝液(pH7.5) に１％(w/w) 濃度の (Ｒ) −（−）−３−ヒドロキシ−２−メチルプロピオン酸メチル（和光純薬社製) 又は（Ｓ）−（＋）−３−ヒドロキシ−２−メチルプロピオン酸メチル（和光純薬社製) 及び0.01％(w/w) のブロモクレゾールパープルを添加し、基質溶液とした。各種保存菌株をＬＢ培地（１％ポリペプトン、0.5 ％酵母エキス、0.5 ％ NaCl ）で培養し、遠心分離により集菌した。得られた菌体を１mlの (Ｒ) 体又は（Ｓ）体を含む基質溶液に懸濁し、30℃にて８時間酵素反応を行った。反応終了後、ブロモクレゾールパープル（pH指示薬）の色調を青色から黄色に変化させる能力を有するものを加水分解能力を有する株とした。そのなかで（Ｒ）体又は（Ｓ）体のみを加水分解するものを不斉加水分解能を有する株とした。
【００２２】
スクリーニング結果を表１に示す。
【００２３】
【表１】
（実施例２） 光学活性β−ヒドロキシイソ酪酸及びその対掌体エステルの製造
エセリキア・コリ（Escherichia coli)MR-2103(FERM BP-3835)を50μg/mlのアンピシリンを含むＬＢ培地（１％ポリペプトン、0.5 ％酵母エキス、0.5 ％ NaCl ）50mlに植菌し、37℃で20時間振盪培養した。培養終了後、培養液を遠心分離し、得られた菌体の全量をイオン交換水で洗浄した後、50mM燐酸緩衝液(pH7.0) 50mlに懸濁した。この菌体懸濁液に、（±）−β−ヒドロキシイソ酪酸メチル５g を加え、30℃で24時間反応させた。この間、反応液のｐＨは、10％ NaOH 水溶液を用いて7.0 に調整した。反応終了後、遠心分離により菌体を除き、β−ヒドロキシイソ酪酸メチルを酢酸エチルで抽出した。次いで、水相のｐＨを希硫酸で2.0 に下げた後、水相中のβ−ヒドロキシイソ酪酸を酢酸エチルで抽出した。各抽出液に無水硫酸ナトリウムを加えて脱水し、溶媒を蒸発除去した。得られたβ−ヒドロキシイソ酪酸メチル及びβ−ヒドロキシイソ酪酸の比旋光度を測定した（PM101 型旋光度計、ユニオン技研社製) 。測定結果及び収量を表２に示す。この結果より、光学活性β−ヒドロキシイソ酪酸及び対掌体エステルが生成していることがわかる。
【００２５】
【表２】
【発明の効果】
本発明の製造方法により、光学純度の高い光学活性β−ヒドロキシカルボン酸及びその対掌体エステルを効率よく生産することが可能である。生成したカルボン酸とエステルの分離、精製も容易であり、工業的に有利な方法である。[0001]
[Industrial application fields]
The present invention relates to a process for producing an optically active β-hydroxycarboxylic acid and its enantiomer ester, which are useful synthetic intermediates for pharmaceuticals, agricultural chemicals and the like.
[0002]
[Prior art]
In recent years, the demand for optically active substances as synthetic intermediates of physiologically active substances such as pharmaceuticals and agricultural chemicals is rapidly increasing, and active researches on the synthesis of optically active substances using various techniques have been actively conducted. An optically active β-hydroxycarboxylic acid belonging to an aliphatic carboxylic acid and its enantiomer ester have two types of functional groups in the molecule and can be derived into various optically active substances. It is.
[0003]
Conventionally, as a method for producing optically active β-hydroxycarboxylic acid, as a chemical or microbial method, asymmetric reduction method of β-keto acid ester, optical resolution method, 1,3-diol oxidation method, fatty acid β- Hydroxylation method, direct fermentation method, etc. have been reported. Among these, production of various optically active β-hydroxycarboxylic acids utilizing the metabolic pathway of microorganisms has been carried out on an industrial scale (Japanese Patent Publication Nos. 59-21599, 59-21600, and Shoko). No. 60-16235, Japanese Patent Publication No. 61-12676, etc.). The method using metabolic pathways of these microorganisms uses various fatty acids and alcohols as raw materials, and is considered to be common with β-oxidase system which is the main metabolic pathway of fatty acids and related branched amino acid metabolic pathways. Is to be used.
[0004]
[Problems to be solved by the invention]
However, in the method using the metabolic pathway of microorganisms described above, a coenzyme regeneration system is required, and ATP is essential as an energy source. Therefore, in order to activate the metabolic system, glucose under aerobic conditions is required. It is necessary to culture while supplementing energy sources such as. Therefore, there are problems that it takes time to culture, high concentration production is difficult, sterility is necessary, and it is difficult to reuse cells. A method for producing an optically active β-hydroxycarboxylic acid and its enantiomer ester capable of overcoming these problems has been desired.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained a culture, a fungus body, or a fungus body treatment of a microorganism having the ability to asymmetrically hydrolyze an ester bond into a racemic beta-hydroxycarboxylic acid ester. It has been found that an optically active β-hydroxycarboxylic acid having high optical purity and its enantiomer ester can be produced efficiently by allowing the product to act, and the present invention has been completed.
[0006]
That is, the present invention is an optical activity characterized by allowing a culture, a microbial cell or a treated product of a microorganism having an ability to asymmetrically hydrolyze an ester bond to act on a racemic form of a β-hydroxycarboxylic acid ester. This is a method for producing β-hydroxycarboxylic acid and its enantiomer ester.
Examples of the β-hydroxycarboxylic acid ester that can be used as a substrate in the present invention include the following formula (I):
[0007]
[Chemical 1]
Or the following formula (II):
[0009]
[Chemical formula 2]
(In the formula, R 1 and R 2 are the same or different and represent an alkyl group.)
The compound shown by these is mentioned.
When the compound represented by the formula (I) or the formula (II) is used as the β-hydroxycarboxylic acid ester, the obtained optically active β-hydroxycarboxylic acid is represented by the following formula (I ′):
[0011]
[Chemical 3]
Or the following formula (II '):
[0013]
[Formula 4]
(In the formula, R 1 has the same meaning as described above.)
It is a compound shown by these.
In the above formula, the alkyl group represented by R 1 or R 2 is preferably an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. Group, sec-butyl group and t-butyl group.
[0015]
Examples of the β-hydroxycarboxylic acid ester represented by the formula (I) include methyl β-hydroxyisobutyrate (methyl 3-hydroxy-2-methylpropionate).
Examples of the β-hydroxycarboxylic acid ester represented by the formula (II) include methyl β-hydroxybutyrate, methyl β-hydroxyvalerate, and methyl β-hydroxyisocaproate.
[0016]
The microorganism used in the present invention is not particularly limited as long as it has an ability to asymmetrically hydrolyze the racemic β-hydroxycarboxylic acid ester. Representative examples include microorganisms belonging to the genus Pseudomonas, the genus Rhodococcus or the genus Escherichia. Specifically, Pseudomonas putida MR-2068 (FERM BP-3846), Rhodococcus erythropolis IFO 12320, Rhodococcus erythropolis IFO 12538, Escherichia coli ( Escherichia coli) MR-2103 (FERM BP-3835). Escherichia coli MR-2103 (FERM BP-3835) is a strain transformed with an esterase gene derived from Pseudomonas putida MR-2068 (FERM BP-3846).
[0017]
The microorganism used in the present invention can be cultured in a liquid medium or a solid medium. As a culture medium, what mix | blended suitably components, such as a carbon source, a nitrogen source, a vitamin, a mineral which a microorganism can normally utilize, is used. In order to improve the hydrolytic ability of microorganisms, a small amount of ester can be added to the medium. The culture is performed at a temperature and pH at which the microorganism can grow, but it is preferably performed under the optimal culture conditions of the strain to be used. In order to promote the growth of microorganisms, aeration and agitation may be performed.
[0018]
When performing the hydrolysis reaction, an ester may be added to the medium at the start or during the cultivation, or the microorganism may be cultured in advance and then the ester may be added to the culture solution. In addition, the cells of the grown microorganisms may be collected by centrifugation or the like and added to a reaction medium containing an ester. As the cells, cells treated with acetone, toluene, or the like may be used.
[0019]
Further, instead of the cells, a culture such as a culture solution, a crushed cell, a cell extract, a crude enzyme, a purified enzyme, or a treated product of a cell may be used. It is also possible to immobilize on a carrier and collect and reuse after the reaction.
As the reaction medium, for example, ion exchange water or a buffer solution is used. The ester concentration in the reaction medium or the culture solution is preferably 0.1 to 50% by weight, more preferably 5 to 30% by weight. It is also possible to add methanol, acetone, surfactant, etc. to the reaction system. The pH of the reaction solution is in the range of 2-11, preferably 5-8. The pH of the reaction solution is lowered by the carboxylic acid produced as the reaction proceeds. In this case, it is preferable to maintain the optimum pH with a suitable neutralizing agent. The reaction temperature is preferably 5 to 70 ° C, more preferably 30 to 60 ° C.
[0020]
In this way, the optically active β-hydroxy is obtained by allowing a culture, a microbial cell or a treated product of a microorganism having the ability to asymmetrically hydrolyze an ester bond to act on the racemic form of β-hydroxycarboxylic acid ester. Carboxylic acid and its enantiomer ester can be produced. Separation and purification of the product can be easily performed by extraction with an organic solvent such as ethyl acetate, chloroform or ether.
[0021]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention in more detail, the scope of the present invention is not limited to these.
(Example 1) Screening method for microorganisms capable of asymmetric hydrolysis of racemic β-hydroxycarboxylic acid ester
1% (w / w) concentration of (R)-(−)-3-hydroxy-2-methylpropionate methyl (manufactured by Wako Pure Chemical Industries) or (S) − in 50 mM Tris-HCl buffer (pH 7.5) Methyl (+)-3-hydroxy-2-methylpropionate (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.01% (w / w) bromocresol purple were added to obtain a substrate solution. Various stocks were cultured in LB medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl) and collected by centrifugation. The obtained bacterial cells were suspended in 1 ml of a substrate solution containing (R) or (S) and subjected to an enzyme reaction at 30 ° C. for 8 hours. After completion of the reaction, a strain having the ability to change the color tone of bromocresol purple (pH indicator) from blue to yellow was defined as a strain having hydrolysis ability. Among them, a strain that hydrolyzes only the (R) isomer or the (S) isomer was designated as a strain having asymmetric hydrolysis ability.
[0022]
The screening results are shown in Table 1.
[0023]
[Table 1]
(Example 2) Production of optically active β-hydroxyisobutyric acid and its enantiomer ester Escherichia coli MR-2103 (FERM BP-3835) in LB medium (50% / ml ampicillin) (1% polypeptone) , 0.5% yeast extract, 0.5% NaCl) was inoculated into 50 ml, and cultured with shaking at 37 ° C. for 20 hours. After completion of the culture, the culture solution was centrifuged, and the whole amount of the obtained bacterial cells was washed with ion-exchanged water and then suspended in 50 ml of 50 mM phosphate buffer (pH 7.0). To this cell suspension, 5 g of methyl (±) -β-hydroxyisobutyrate was added and reacted at 30 ° C. for 24 hours. During this time, the pH of the reaction solution was adjusted to 7.0 using a 10% NaOH aqueous solution. After completion of the reaction, the cells were removed by centrifugation, and methyl β-hydroxyisobutyrate was extracted with ethyl acetate. Next, after the pH of the aqueous phase was lowered to 2.0 with dilute sulfuric acid, β-hydroxyisobutyric acid in the aqueous phase was extracted with ethyl acetate. Each extract was dehydrated by adding anhydrous sodium sulfate, and the solvent was removed by evaporation. Specific rotations of the obtained methyl methyl β-hydroxyisobutyrate and β-hydroxyisobutyric acid were measured (PM101 polarimeter, manufactured by Union Giken Co., Ltd.). The measurement results and yield are shown in Table 2. From this result, it can be seen that optically active β-hydroxyisobutyric acid and enantiomer ester are formed.
[0025]
[Table 2]
【The invention's effect】
By the production method of the present invention, it is possible to efficiently produce an optically active β-hydroxycarboxylic acid having high optical purity and its enantiomer ester. Separation and purification of the produced carboxylic acid and ester are easy, and this is an industrially advantageous method.
Claims (1)
で示されるβ−ヒドロキシカルボン酸エステルのラセミ体に、エステル結合を不斉加水分解する能力を有する、シュードモナス（Pseudomonas）属、若しくはロードコッカス（Rhodococcus）属に属する微生物、又はエセリキア・コリ（Escherichia coli）MR-2103 (FERM BP-3835)の培養物、菌体又は菌体処理物を作用させることを特徴とする、式（Ｉ’）
で示される光学活性β−ヒドロキシカルボン酸及びその対掌体エステルの製造法。Formula (I)
Or a microorganism belonging to the genus Pseudomonas or Rhodococcus having the ability to asymmetrically hydrolyze ester bonds, or Escherichia coli ) MR-2103 (FERM BP-3835) culture, fungus body, or treated cell product is acted on, formula (I ′)
A process for producing an optically active β-hydroxycarboxylic acid represented by the formula:
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13059094A JP3715662B2 (en) | 1994-06-13 | 1994-06-13 | Process for producing optically active β-hydroxycarboxylic acid and its enantiomer ester |
| DE69513827T DE69513827T2 (en) | 1994-06-13 | 1995-06-13 | METHOD FOR PRODUCING OPTICALLY ACTIVE ALPHA-SUBSTITUTED CARBONIC ACID DERIVATIVES |
| ES95921160T ES2141354T3 (en) | 1994-06-13 | 1995-06-13 | PROCEDURE FOR THE OBTAINING OF OPTICALLY ACTIVE CARBOXYLIC ACID DERIVATIVES, WITH ALPHA SUBSTITUTION. |
| EP95921160A EP0765857B1 (en) | 1994-06-13 | 1995-06-13 | Process for producing optically active alpha-substituted carboxylic acid derivatives |
| PCT/JP1995/001176 WO1995034525A1 (en) | 1994-06-13 | 1995-06-13 | OPTICALLY ACTIVE α-SUBSTITUTED CARBOXYLIC ACID DERIVATIVE AND PROCESS FOR PRODUCING THE SAME |
| US08/750,761 US5773240A (en) | 1994-06-13 | 1995-06-13 | Optically active α-substituted carboxylic acid derivatives and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13059094A JP3715662B2 (en) | 1994-06-13 | 1994-06-13 | Process for producing optically active β-hydroxycarboxylic acid and its enantiomer ester |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005218296A Division JP2005323612A (en) | 2005-07-28 | 2005-07-28 | METHOD FOR PRODUCING OPTICALLY ACTIVE beta-HYDROXYCARBOXYLIC ACID AND ITS ANTIPODE ESTER |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07327692A JPH07327692A (en) | 1995-12-19 |
| JP3715662B2 true JP3715662B2 (en) | 2005-11-09 |
Family
ID=15037850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13059094A Expired - Fee Related JP3715662B2 (en) | 1994-06-13 | 1994-06-13 | Process for producing optically active β-hydroxycarboxylic acid and its enantiomer ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3715662B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1281766B1 (en) | 2001-07-16 | 2008-06-04 | Canon Kabushiki Kaisha | Process for producing polyester, process for producing substituted alpha-hydroxy acid, and Clostridium beijerinckii strain HICA432 |
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1994
- 1994-06-13 JP JP13059094A patent/JP3715662B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07327692A (en) | 1995-12-19 |
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