JPH0796536B2 - Optically active β-amino acid derivative - Google Patents
Optically active β-amino acid derivativeInfo
- Publication number
- JPH0796536B2 JPH0796536B2 JP20518286A JP20518286A JPH0796536B2 JP H0796536 B2 JPH0796536 B2 JP H0796536B2 JP 20518286 A JP20518286 A JP 20518286A JP 20518286 A JP20518286 A JP 20518286A JP H0796536 B2 JPH0796536 B2 JP H0796536B2
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- JP
- Japan
- Prior art keywords
- amino acid
- acid derivative
- general formula
- reaction
- optically active
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
【発明の詳細な説明】Detailed Description of the Invention
本発明は一般式 （式中、Ｒは炭素数１〜３のアルキル基である。）で表
わされるβ−アミノ酸誘導体に関する。The present invention has the general formula (In the formula, R is an alkyl group having 1 to 3 carbon atoms).
本発明は前記一般式（Ｉ）で表わされるβ−アミノ酸誘
導体は、セルラーゼの存在下、重合させることにより、
撥水撥油性有する含フッ素ポリマーに導くことができ
る。又、本発明の前記一般式（Ｉ）で表わされるβ−ア
ミノ酸誘導体は、酸素阻害剤として使用できる可能性を
有している。In the present invention, the β-amino acid derivative represented by the general formula (I) is polymerized in the presence of cellulase,
It can lead to a fluorine-containing polymer having water and oil repellency. Further, the β-amino acid derivative represented by the general formula (I) of the present invention has a possibility of being usable as an oxygen inhibitor.
しかしながら、従来の含フッ素ポリマーは主鎖が含フッ
素アルキル又は含フッ素アルキルエーテルから成るもの
（例えばナフィオン）、或はパーフルオロアルキル基を
側鎖に持つアクリル酸ポリマーであり、機能性高分子と
しての官能基はカルボン酸或はスルホン酸及びそのエス
テルに限られていた。そのため特定の用途以外には使用
範囲が限られていた。However, the conventional fluorine-containing polymer is a polymer whose main chain is composed of a fluorine-containing alkyl or a fluorine-containing alkyl ether (for example, Nafion), or an acrylic acid polymer having a perfluoroalkyl group in its side chain, which is a functional polymer. Functional groups were limited to carboxylic acids or sulfonic acids and their esters. Therefore, the range of use was limited except for specific uses.
本発明者は、従来の欠点を克服すべく検討した結果、各
種の官能基を含む高性能高分子誘導できるβ−アミノ酸
誘導体を見出し、本発明を完成した。更に、本発明によ
れば従来導入が困難であった不斉因子をポリマーの主鎖
に導入することが可能となった。As a result of studies to overcome the conventional drawbacks, the present inventor found a β-amino acid derivative capable of deriving a high-performance polymer containing various functional groups, and completed the present invention. Furthermore, according to the present invention, it has become possible to introduce an asymmetric factor, which has been difficult to introduce conventionally, into the main chain of a polymer.
本発明の前記一般式（Ｉ）で表わされるβ−アミノ酸誘
導体は、以下の反応式に従い製造することができる。 The β-amino acid derivative represented by the general formula (I) of the present invention can be produced according to the following reaction formula.
本工程は前記一般式（II）で表わされる光学活性なマロ
ン酸モノエステル誘導体をオキサリルクロライドで処理
し、NaBH4で還元することにより、前記一般式（III）で
表わされるヒドロキシ誘導体を得るものである。本工程
の原料である前記一般式（II）で表わされるマロン酸モ
ノエステルは、J.Org.Chem.,51,1003（1986）に記載の
方法により容易に得ることができる化合物である。In this step, the optically active malonic acid monoester derivative represented by the general formula (II) is treated with oxalyl chloride and reduced with NaBH 4 to obtain the hydroxy derivative represented by the general formula (III). is there. The malonic acid monoester represented by the general formula (II), which is a raw material in this step, is a compound which can be easily obtained by the method described in J. Org. Chem., 51 , 1003 (1986).
本工程は前記ａ工程で得られた前記一般式（III）で表
わされるヒドロキシ酸誘導体をTsClと反応させ前記一般
式（IV）で表わされる化合物を製造するものである。 反応を行うにあたっては溶媒を用いることが好ましく、
例えばピリジン、ピペラジン等を好適に使用することが
できる。 反応は−10〜50℃で円滑に進行する。In this step, the hydroxy acid derivative represented by the general formula (III) obtained in the step a is reacted with TsCl to produce the compound represented by the general formula (IV). In carrying out the reaction, it is preferable to use a solvent,
For example, pyridine, piperazine and the like can be preferably used. The reaction proceeds smoothly at -10 to 50 ° C.
本工程は前記ｂ工程で得られた前記一般式（IV）で表わ
される化合物をアジ化ナトリウムと反応させることによ
り前記一般式（Ｖ）で表わされるアジドを製造するもの
である。 通常、反応は、イソプロピルアルコール中で行うことが
できるが、その他エタノール、ブタノール等の溶媒を用
いてもさしつかいない。 反応は溶媒の還流温度即ち60〜80℃の範囲を選択するこ
とにより円滑に反応が進行する。In this step, the azide represented by the general formula (V) is produced by reacting the compound represented by the general formula (IV) obtained in the b step with sodium azide. Usually, the reaction can be carried out in isopropyl alcohol, but other solvents such as ethanol and butanol may be used. The reaction proceeds smoothly by selecting the reflux temperature of the solvent, that is, the range of 60 to 80 ° C.
本工程は前記ｃ工程で得られた前記一般式（Ｖ）で表わ
されるアジドを還元し、前記一般式（VI）で表わされる
アミノ酸エステルを製造するものである。 還元するにあたっては、例えば、水酸化ホウ素ナトリウ
ム、ジイソブチルアルミニウムハイドライドなどの還元
剤を使用することができる。 還元剤の種類によっても異なるが反応はエタノール、イ
ソプロパノール、プロパノール等などの溶媒中で行うこ
とができる。 反応は50〜80℃で円滑に進行する。In this step, the azide represented by the general formula (V) obtained in the step c is reduced to produce the amino acid ester represented by the general formula (VI). Upon the reduction, a reducing agent such as sodium borohydride or diisobutylaluminum hydride can be used. The reaction can be carried out in a solvent such as ethanol, isopropanol, propanol, etc., though it depends on the type of reducing agent. The reaction proceeds smoothly at 50-80 ° C.
本工程は前記ｄ工程で得られた前記一般式（VI）で表わ
されるアミノ酸エステルを加水分解酵素の存在下、に反
応させ、前記一般式（Ｉ）で表わされるβ−アミノ酸誘
導体を製造するものである。 本工程で用いる加水分解酵素としては、例えばリーパー
ゼ−MT、セルラーゼ、などが使用できる。 反応を行うにあたっては、緩衝溶液中で行うのが好まし
く、例えば、KH2PO4−Na2HPO4緩衝溶液を好適に使用で
きる。 反応温度は、30〜45℃の範囲が目的物が効率良く得られ
る点で好ましい。 以下実施例により本発明を更に詳細に説明する。 参考例 １ DMF（3.4ml）をCH2Cl2（40ml）に溶かし、更にオキサリ
ルクロライド（8ml）を注入した。０℃１時間攪拌後、
減圧下に溶媒を留去し、系内を窒素置換した。得られた
白色の固体にCH3CN（30ml）、THF（100ml）を加えて、
−30℃まで冷却した。これに（Ｓ）−（−）−２−メチ
ル−２−フルオロマロン酸モノエチル（40mmol）を加
え、１時間攪拌した。次に反応液を−78℃まで冷却した
のち、NaBH4（3.5g,93mmol）のDMF溶液（20ml）をゆっ
くり注入した。−20℃に保ち４時間攪拌したのち、3N−
HCl（50ml）を加えて反応を終了した。酢酸エチルで抽
出を行ない、1N−HCl水溶液、５％ NaHCO3水溶液、水、
飽和食塩水で順次洗浄しMgSO4で乾燥した。蒸留にて
（Ｓ）−（−）−３−ヒドロキシ−２−フルオロ−２−
メチルプロパン酸エチルを得た。収率69％［α］D/MeOH
−8.97（c1.81）bp.84−85℃/8mmHg. 参考例 ２ 同様に反応を行ない（Ｒ）−（−）−Me体、（Ｒ）−
（＋）−Ｈ体を得た。その結果を参考例１の結果とあわ
せ、表１に示した。 参考例 ３ （Ｓ）−（−）−３−ヒドロキシ−２−フルオロホフホ
メチルプロパン酸エチル（2.0g,13mmol）をピリジン（2
0ml）に溶かし、TsCl（3.0g,16mmol）を加えて、室温で
３時間攪拌した。単離は、カラムクロマトグラフィーに
てヘキサン−ジエチルエーテル（5:1）を用いて行っ
た。収率95％．［α］D/MeOH−1.97（c1.34）＞99％ee 参考例 ４ 同様に反応を行ない（Ｒ）−（−）−Me体、（Ｒ）−
（＋）−Ｈ体を得た。その結果を参考例３の結果とあわ
せ、表２に示した。 参考例 ５ （Ｓ）−（−）−３−ヒドロキシ−２−フルオロ−２−
メチルプロパン酸エチルのトシレート体（20mmol）、Na
N3（55mmol）をイソプロパノール（100ml）に溶かし、1
5時間還流したのち、反応液に水を加え、生じた油状物
を塩化メチレンで抽出した。溶媒を留去したのち目的物
を得た。同様に反応を行ない（Ｒ）−Me体、（Ｒ）−Ｈ
体を得た。その結果を表３に示した。 実施例 １ 参考例５で得られたアジド（10mmol）、NaBH4（33mmo
l）をエタノール（30ml）に溶かし５時間還流したの
ち、飽和塩化アンモニウム溶液を加え、生じた油状物を
ジエチルエーテルで抽出した。溶媒を留去したのち得ら
れたβ−アミノ酸誘導体をカラムクロマトグラフィーに
てヘキサン−ジエチルエーテル（10:1）溶液を用いて単
離した。その結果を表４に示した。 参考例 ６ セルラーゼ（5g,ヤクルト社製）をKH2PO4−Na2HPO4緩衝
溶液（pH8.0,100ml）に懸濁させ、40−41℃で15分間攪
拌した。この液にα−フルオロ−β−アラニン（20mmo
l）を加え、40−41℃で５日間攪拌しながら重合反応し
たのち、重合生成物を酢酸エチルで抽出した。精製はカ
ラムクロマトグラフィーにて行った。その結果を表５に
示した。 In this step, the amino acid ester represented by the general formula (VI) obtained in the step d is reacted in the presence of a hydrolase to produce a β-amino acid derivative represented by the general formula (I). Is. As the hydrolase used in this step, for example, lipase-MT, cellulase, etc. can be used. The reaction is preferably carried out in a buffer solution, for example, a KH 2 PO 4 —Na 2 HPO 4 buffer solution can be preferably used. The reaction temperature is preferably in the range of 30 to 45 ° C. because the target product can be obtained efficiently. Hereinafter, the present invention will be described in more detail with reference to Examples. Reference Example 1 DMF (3.4 ml) was dissolved in CH 2 Cl 2 (40 ml), and oxalyl chloride (8 ml) was further injected. After stirring at 0 ° C for 1 hour,
The solvent was distilled off under reduced pressure, and the system was replaced with nitrogen. CH 3 CN (30 ml) and THF (100 ml) were added to the obtained white solid,
Cooled to -30 ° C. Monoethyl (S)-(-)-2-methyl-2-fluoromalonate (40 mmol) was added thereto, and the mixture was stirred for 1 hour. Then, the reaction solution was cooled to −78 ° C., and then NaBH 4 (3.5 g, 93 mmol) in DMF solution (20 ml) was slowly injected. After stirring at -20 ℃ for 4 hours, 3N-
The reaction was terminated by adding HCl (50 ml). Subjected to extraction with ethyl acetate, 1N-HCl solution, 5% NaHCO 3 solution, water,
It was washed successively with saturated brine and dried over MgSO 4 . By distillation (S)-(-)-3-hydroxy-2-fluoro-2-
Ethyl methylpropanoate was obtained. Yield 69% [α] D / MeOH
-8.97 (c1.81) bp.84-85 ° C / 8mmHg. Reference Example 2 The same reaction was carried out (R)-(-)-Me form, (R)-
A (+)-H form was obtained. The results are shown in Table 1 together with the results of Reference Example 1. Reference Example 3 Ethyl (S)-(-)-3-hydroxy-2-fluorophophphomethylpropanoate (2.0 g, 13 mmol) was added to pyridine (2
This was dissolved in 0 ml), TsCl (3.0 g, 16 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Isolation was performed by column chromatography using hexane-diethyl ether (5: 1). Yield 95%. [Α] D /MeOH-1.97 (c1.34)> 99% ee Reference Example 4 The same reaction is carried out (R)-(−)-Me form, (R)-
A (+)-H form was obtained. The results are shown in Table 2 together with the results of Reference Example 3. Reference example 5 (S)-(-)-3-hydroxy-2-fluoro-2-
Ethyl methyl propanoate tosylate (20mmol), Na
Dissolve N 3 (55 mmol) in isopropanol (100 ml) and add 1
After refluxing for 5 hours, water was added to the reaction solution, and the resulting oily matter was extracted with methylene chloride. After evaporating the solvent, the desired product was obtained. The same reaction is performed (R) -Me form, (R) -H
Got the body The results are shown in Table 3. Example 1 Azide (10 mmol) obtained in Reference Example 5, NaBH 4 (33 mmo
l) was dissolved in ethanol (30 ml) and refluxed for 5 hours, saturated ammonium chloride solution was added, and the resulting oily matter was extracted with diethyl ether. After the solvent was distilled off, the β-amino acid derivative obtained was isolated by column chromatography using a hexane-diethyl ether (10: 1) solution. The results are shown in Table 4. Reference Example 6 Cellulase (5 g, manufactured by Yakult) was suspended in KH 2 PO 4 —Na 2 HPO 4 buffer solution (pH 8.0, 100 ml) and stirred at 40 to 41 ° C. for 15 minutes. Add α-fluoro-β-alanine (20mmo
l) was added and the polymerization reaction was carried out at 40-41 ° C. for 5 days with stirring, and then the polymerization product was extracted with ethyl acetate. Purification was performed by column chromatography. The results are shown in Table 5.
Claims (1)
は炭素数１〜３のアルキル基である。）。1. A general formula An optically active β-amino acid derivative represented by
Is an alkyl group having 1 to 3 carbon atoms. ).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20518286A JPH0796536B2 (en) | 1986-09-02 | 1986-09-02 | Optically active β-amino acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20518286A JPH0796536B2 (en) | 1986-09-02 | 1986-09-02 | Optically active β-amino acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6360954A JPS6360954A (en) | 1988-03-17 |
| JPH0796536B2 true JPH0796536B2 (en) | 1995-10-18 |
Family
ID=16502772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20518286A Expired - Lifetime JPH0796536B2 (en) | 1986-09-02 | 1986-09-02 | Optically active β-amino acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0796536B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855455A (en) * | 1988-01-22 | 1989-08-08 | W. R. Grace & Co.-Conn. | Preparation of amino acid derivatives |
| DE60039299D1 (en) | 1999-05-14 | 2008-08-07 | Kaneka Corp | METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE AZETIDIN-2-CARBOXYLIC ACIDS |
| WO2003089402A1 (en) * | 2002-04-19 | 2003-10-30 | Daikin Industries, Ltd. | PROCESS FOR PRODUCING α-FLUORO-β-ALANINE COMPOUND AND PRODUCING INTERMEDIATE THEREFOR |
-
1986
- 1986-09-02 JP JP20518286A patent/JPH0796536B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| 日本化学会誌（１９８５）第１０巻第２００１〜２００９頁 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6360954A (en) | 1988-03-17 |
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