JP4325097B2 - Optically active poly (N-methylbenzylmaleimide) and process for producing the same - Google Patents

Description

【００１１】
（式中、ｎは２〜１００００の範囲の数、＊印は光学活性炭素を表す。）
で示され、＋３０°以上の比旋光度（［α］４３５²⁵）を有する光学活性ポリ（Ｎ−α−メチルベンジルマレイミド）、及び下記式（２）
【００１２】
【化６】

【００１３】
で示される（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドを不斉配位子存在下、アニオン重合することを特徴とする前記光学活性ポリ（Ｎ−α−メチルベンジルマレイミド）の製造法である。
【００１４】
以下、本発明を詳細に説明する。
【００１５】
本発明の光学活性ポリ（Ｎ−α−メチルベンジルマレイミド）は、上記一般式（１）で示され、＋３０°以上の比旋光度（［α］４３５²⁵）を有する化合物であり、その数平均分子量（Ｍｎ）は、標準ポリスチレン換算で、通常３×１０³以上である。
【００１６】
本発明の光学活性ポリ（Ｎ−α−メチルベンジルマレイミド）は、上記式（２）で示される（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドを、不斉配位子存在下、アニオン重合することにより得られる。
【００１７】
本発明の方法において、原料として使用する（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドは、光学活性（Ｓ）−（−）−メチルベンジルアミン［（Ｓ）−（−）−１−フェネチルアミン］と無水マレイン酸を公知の方法により反応させることにより容易に調製することができる。得られる（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドの比旋光度（［α］４３５²⁵）は蒸留精製を繰り返すことにより−９８．１°に到達する。
【００１８】
本発明の方法においては、不斉配位子及びアニオン重合触媒を反応溶剤に添加、溶解させた後、これに原料の（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミド添加し反応させる。
【００１９】
本発明の方法において、アニオン重合触媒としては、ｎ−ブチルリチウム、フルオレニルリチウム、ジエチル亜鉛、ジメチル亜鉛等の有機金属触媒が好適なものとして挙げられ、その使用量としては、反応に具する原料（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドに対して、通常、０．１〜３０モル％の範囲で使用する。
【００２０】
本発明の方法において、アニオン重合に用いる光学活性配位子としては、下記式（３）
【００２１】
【化７】

【００２２】
で示される（−）−スパルテイン（以下Ｓｐと略す）、又は下記式（４）
【００２３】
【化８】

【００２４】
で示される（４Ｓ）−２，２’−（１−エチルプロピリデン）ビス［４−（１−フェニルエチル）−４，５−ジハイドロオキサゾール］（以下Ｂｎｂｏｘと略す）が好適なものとして挙げられる。光学活性配位子は、反応に使用するアニオン重合触媒に対して理論的には等モル量の使用で良いが、安定した反応を行うため、好ましくは１．０２〜１．５モル量使用される。
【００２５】
本発明の方法に適用可能な反応溶剤としては、反応に不活性なものであればあらゆるものが使用可能であり、特に限定するものではないが、具体的には、ジエチルエーテル、ジ−ｎ−プロピルエーテル、ジ−ｉ−プロピルエーテル、ジ−ｎ−ブチルエーテル、ジ−ｔ−ブチルエーテル、テトラヒドロフラン（以下ＴＨＦと略す）等のエーテル系溶剤、ベンゼン、トルエン、キシレン、エチルベンゼン、メシチレン等の芳香族炭化水素系溶剤等が好適なものとして挙げられる。
【００２６】
本発明の方法において、溶剤の使用量は、特に限定するものではないが、反応に具する（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドに対して重量で２〜１００倍程度使用する。
【００２７】
本発明の方法において、反応温度は、反応条件により異なるため特に限定するものではないが、通常−７８℃〜１００℃の範囲で実施可能である。
【００２８】
本発明の方法において、反応時間は、触媒及び反応温度の違いにより異なるため、特に限定するのではないが、通常１時間〜２４０時間の範囲内で反応は完結する。
【００２９】
反応終了後、反応液を、ヘキサン、へプタン、メタノール、エタノール、イソプロパノール等の生成物の溶解度が低い溶剤に滴下晶析させることにより、本発明の光学活性ポリマレイミド誘導体を粉末として取り上げる。純度を向上させるために、さらにＴＨＦやトルエン等の溶剤に再溶解させ、再度メタノール等の溶剤に投入し、再晶析を行っても良い。
【００３０】
【発明の効果】
本発明によれば、光学活性化合物の分離剤等の用途が期待される新規な（＋）旋光性の高い光学活性ポリ（Ｎ−α−メチルベンジルマレイミド）を簡便な製造法により提供することができるため、工業的にも極めて有意義である。
【００３１】
【実施例】
以下、実施例により本発明を具体的に説明するが、本発明はこれら実施例のみに限定されるものではない。
【００３２】
なお、本発明の光学活性ポリマレイミド誘導体合成において使用する光学活性配位子：（４Ｓ）−２，２’−（１−エチルプロピリデン）ビス［４−（１−フェニルエチル）−４，５−ジハイドロオキサゾール］（Ｂｎｂｏｘ）は、Ｓ．Ｅ．Ｄｅｎｍａｒｋ，ｅｔ．ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，６０，４８８４（１９９５）に記載の方法により調製したものを用いた。
【００３３】
平均分子量は、ゲルパーミエーションクロマトグラフィー（東ソー製高速ＧＰＣシステム）により標準ポリスチレン換算で算出、比旋光度はＪＡＳＣＯ製ＤＩＰ−１８１により測定した。
【００３４】
調製した光学活性ポリマレイミド誘導体の分離能の測定には、東ソー製マルチポンプＣＣＰＭ、紫外可視検出器ＵＶ−８０２０、インテグレーターＣＨＲＯＭＡＴＯＣＯＲＤＥＲ２１を用いた。
【００３５】
参考例１ （Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドの調製
調製に当たっては、Ｐ．Ｙ．Ｒｅｄｄｙ，ｅｔ．ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，６２，２６５２（１９９７）記載の方法に従った。
【００３６】
冷却コンデンサー、滴下ロート及び攪拌子を備えた５００ｍｌの丸底３つ口フラスコに、無水マレイン酸４．０ｇ（４０．８ｍｍｏｌ）及び乾燥ベンゼン２４０ｍｌを入れ、攪拌することにより溶解させた後、氷浴上で０℃に冷却した。
【００３７】
次いで、これに（Ｓ）−（−）−１−フェネチルアミン５．２ｍｌ（４０．８ｍｍｏｌ）を乾燥ベンゼン１００ｍｌに溶解させた溶液を滴下ロートを用い添加した後、室温に戻し、１時間攪拌を行った。
【００３８】
さらに反応液を激しく攪拌しながら、これに塩化亜鉛５．５６ｇ（４０．８ｍｍｏｌ）を加え、油浴上で８０℃に加熱し、ヘキサメチルジシラザン１１．５ｍｌ（５４．５ｍｍｏｌ）を乾燥ベンゼン８０ｍｌに溶解させた溶液を滴下ロートを用い滴下し、さらに加熱還流下、５時間反応を行った。
【００３９】
反応終了後、室温に冷却し、０．５Ｎ塩酸で洗浄し、酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄し、飽和食塩水で洗浄し、無水硫酸マグネシウム上で乾燥し、濃縮することにより、粗製（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドを得た。得られた粗製（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミドを、引き続きカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝４／１，ｖｏｌ／ｖｏｌ）で精製、次いで蒸留精製（１１４℃／８．３×１０^-3ｍｍＨｇ）することにより白色固体６．９ｇを得た（収率８４％）。
【００４０】
融点（℃）：３３〜３５℃
比旋光度［α］４３５²⁵＝−９８．１°（Ｃ＝１．０，ＴＨＦ）
実施例１
マグネット攪拌子を入れた２５ｍｌのナス型フラスコに、ジエチル亜鉛３０．９ｍｇ（０．２５ｍｍｏｌ）、（−）−スパルテイン７０．３ｍｇ（０．３０ｍｍｏｌ）及びトルエン５ｍｌを仕込み、攪拌しながら０℃で３０分攪拌を行った後、これに参考例１で得られた（Ｓ）−（−）−Ｎ−α−メチルベンジルマレイミド５０３ｍｇ（２．５０ｍｍｏｌ）を添加、さらに同温度で７２時間反応を行った。
【００４１】
反応終了後、反応液を５０ｍｌのメタノールに投入し、次いで析出物をろ取、室温度で減圧下、乾燥することにより目的物の光学活性ポリ（Ｎ−α−メチルベンジルマレイミド）０．５ｇを微黄色粉末として得た（収率１００％）。
【００４２】
数平均分子量（Ｍｎ）＝１２．７×１０³，Ｍｗ／Ｍｎ＝１０．０
比旋光度［α］４３５²⁵＝２４２．２°（Ｃ＝１．０，ＣＨＣｌ₃）
［ＴＨＦ溶解分の比旋光度［α］４３５²⁵＝２０６．０°（Ｃ＝１．０，ＴＨＦ）］
実施例２、実施例３
実施例１と同じ反応装置を用い、表１中に示した条件下、反応を行った。結果を表１中に示した。なお、表１中に記載されていない条件については実施例１と同じ条件で実施した。
【００４３】
参考例１〜参考例３
実施例１と同じ反応装置を用い、表１中に示した条件下、反応を行った。結果を表１中に示す。なお、表１中に記載されていない条件については実施例１と同じ条件で実施した。
【００４４】
【表１】

【００４５】
比較例１〜比較例３
実施例１と同じ反応装置を用い、表１中に示した条件下、反応を行った。結果を表１中に示す。なお、表１中に記載されていない条件については実施例１と同じ条件で実施した。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel optically active polymaleimide derivative and a method for producing the same.
[0002]
The optically active polymaleimide derivative is expected to be used as a separating agent for optically active compounds.
[0003]
[Prior art]
It is known that an optically active polymaleimide polymer having a certain degree of specific rotation can be produced by radical polymerization or anionic polymerization using optically active (R)-(+)-N-α-methylbenzylmaleimide as a raw material ( T. Oishi et al., J. Polym. Chem. Ed., 22, 2789-2800 (1984)).
[0004]
On the other hand, a method for obtaining an optically active polymaleimide derivative by asymmetric anionic polymerization of an achiral maleimide derivative is also known (T. Oishi et al., Chemistry Letters, 1998, 791-792).
[0005]
[Problems to be solved by the invention]
However, in the radical polymerization method using optically active (R)-(+)-N-α-methylbenzylmaleimide as a raw material and using azoisobutyl nitrile, the specific rotation ([α] 435 ²⁵ ) is + 30 ° or less. In addition, only those having a number average molecular weight (Mn) of about 3000 in terms of standard polystyrene are obtained.
[0006]
Also, in the anionic polymerization method using the same raw material and using butyl lithium, only those having a specific rotation of 0 to -100 ° and a molecular weight (Mn) of 3 × 10 ³ or less can be obtained. The optically active polymaleimide derivative obtained in 1) was not satisfactory in terms of optical purity and molecular weight when considering use in applications such as a separating agent.
[0007]
On the other hand, in the method of using an achiral maleimide derivative to obtain an optically active polymaleimide derivative by asymmetric anionic polymerization, an optically active polymer having a certain degree of specific rotation can be obtained, but the molecular weight is as low as about 1 × 10 ³ , No example of applying this method using an optically active maleimide derivative as a raw material is known.
[0008]
[Means for Solving the Problems]
As a result of intensive studies aimed at the development of optically active poly (N-α-methylbenzylmaleimide) having higher optical purity and molecular weight, the present inventor has obtained optically active (S)-(−)-N-α-methyl. It has been found that optically active poly (N-α-methylbenzylmaleimide) having high specific rotation and high molecular weight can be obtained by anionic polymerization in the presence of an asymmetric ligand using benzylmaleimide as a raw material. It came to complete.
[0009]
That is, the present invention provides the following general formula (1)
[0010]
[Chemical formula 5]

[0011]
(In the formula, n represents a number in the range of 2 to 10,000, and * represents optically active carbon.)
And optically active poly (N-α-methylbenzylmaleimide) having a specific optical rotation ([α] 435 ²⁵ ) of + 30 ° or more, and the following formula (2)
[0012]
[Chemical 6]

[0013]
(S)-(-)-N-α-methylbenzylmaleimide represented by the formula (I) is anionically polymerized in the presence of an asymmetric ligand, to produce the optically active poly (N-α-methylbenzylmaleimide) Is the law.
[0014]
Hereinafter, the present invention will be described in detail.
[0015]
The optically active poly (N-α-methylbenzylmaleimide) of the present invention is a compound represented by the above general formula (1) and having a specific optical rotation ([α] 435 ²⁵ ) of + 30 ° or more. The molecular weight (Mn) is usually 3 × 10 ³ or more in terms of standard polystyrene.
[0016]
The optically active poly (N-α-methylbenzylmaleimide) of the present invention comprises (S)-(−)-N-α-methylbenzylmaleimide represented by the above formula (2) in the presence of an asymmetric ligand. It can be obtained by anionic polymerization.
[0017]
In the method of the present invention, (S)-(−)-N-α-methylbenzylmaleimide used as a raw material is optically active (S)-(−)-methylbenzylamine [(S)-(−)-1]. -Phenethylamine] and maleic anhydride can be easily prepared by reacting by a known method. The specific rotation ([α] 435 ²⁵ ) of the obtained (S)-(−)-N-α-methylbenzylmaleimide reaches −98.1 ° by repeated distillation purification.
[0018]
In the method of the present invention, an asymmetric ligand and an anionic polymerization catalyst are added and dissolved in a reaction solvent, and then (S)-(−)-N-α-methylbenzylmaleimide as a raw material is added thereto and reacted. .
[0019]
In the method of the present invention, examples of the anionic polymerization catalyst include organic metal catalysts such as n-butyllithium, fluorenyllithium, diethylzinc, dimethylzinc and the like, and the amount used is suitable for the reaction. It is normally used in the range of 0.1 to 30 mol% with respect to the raw material (S)-(-)-N-α-methylbenzylmaleimide.
[0020]
In the method of the present invention, the optically active ligand used for anionic polymerization is represented by the following formula (3):
[0021]
[Chemical 7]

[0022]
(-)-Sparteine (hereinafter abbreviated as Sp) represented by the following formula (4)
[0023]
[Chemical 8]

[0024]
(4S) -2,2 ′-(1-ethylpropylidene) bis [4- (1-phenylethyl) -4,5-dihydrooxazole] (hereinafter abbreviated as Bnbox) represented by It is done. The optically active ligand may theoretically be used in an equimolar amount with respect to the anionic polymerization catalyst used in the reaction, but is preferably used in an amount of 1.02 to 1.5 mol in order to perform a stable reaction. The
[0025]
Any reaction solvent applicable to the method of the present invention can be used as long as it is inert to the reaction, and is not particularly limited. Specifically, diethyl ether, di-n- Ether solvents such as propyl ether, di-i-propyl ether, di-n-butyl ether, di-t-butyl ether, tetrahydrofuran (hereinafter abbreviated as THF), aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Examples of suitable solvents include system solvents.
[0026]
In the method of the present invention, the amount of solvent used is not particularly limited, but about 2 to 100 times by weight with respect to (S)-(−)-N-α-methylbenzylmaleimide included in the reaction. To do.
[0027]
In the method of the present invention, the reaction temperature is not particularly limited because it varies depending on the reaction conditions, but it can usually be carried out in the range of −78 ° C. to 100 ° C.
[0028]
In the method of the present invention, the reaction time varies depending on the difference in catalyst and reaction temperature, and is not particularly limited, but the reaction is usually completed within a range of 1 hour to 240 hours.
[0029]
After completion of the reaction, the optically active polymaleimide derivative of the present invention is taken up as a powder by crystallizing the reaction solution dropwise in a solvent having low product solubility such as hexane, heptane, methanol, ethanol, isopropanol. In order to improve the purity, it may be further re-dissolved in a solvent such as THF or toluene, and then charged again in a solvent such as methanol for recrystallization.
[0030]
【The invention's effect】
According to the present invention, it is possible to provide a novel (+) optically active optically active poly (N-α-methylbenzylmaleimide) that is expected to be used as a separating agent for optically active compounds by a simple production method. Since it is possible, it is very significant industrially.
[0031]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited only to these Examples.
[0032]
The optically active ligand used in the synthesis of the optically active polymaleimide derivative of the present invention: (4S) -2,2 ′-(1-ethylpropylidene) bis [4- (1-phenylethyl) -4,5 -Dihydrooxazole] (Bnbox) E. Denmark, et. al. , J .; Org. Chem. 60, 4884 (1995).
[0033]
The average molecular weight was calculated in terms of standard polystyrene by gel permeation chromatography (high-speed GPC system manufactured by Tosoh Corporation), and the specific rotation was measured by DIP-181 manufactured by JASCO.
[0034]
For the determination of the separation ability of the prepared optically active polymaleimide derivative, Tosoh multi-pump CCPM, UV-visible detector UV-8020 and integrator CHROMATOCODER21 were used.
[0035]
Reference Example 1 In the preparation of (S)-(−)-N-α-methylbenzylmaleimide, P.I. Y. Reddy, et. al. , J .; Org. Chem. 62, 2652 (1997).
[0036]
In a 500 ml round bottom three-necked flask equipped with a cooling condenser, a dropping funnel and a stirrer, 4.0 g (40.8 mmol) of maleic anhydride and 240 ml of dry benzene were placed and dissolved by stirring. Cooled to 0 ° C. above.
[0037]
Next, a solution obtained by dissolving 5.2 ml (40.8 mmol) of (S)-(−)-1-phenethylamine in 100 ml of dry benzene was added thereto using a dropping funnel, and then returned to room temperature and stirred for 1 hour. It was.
[0038]
Further, while vigorously stirring the reaction solution, 5.56 g (40.8 mmol) of zinc chloride was added thereto, heated to 80 ° C. on an oil bath, and 11.5 ml (54.5 mmol) of hexamethyldisilazane was added to 80 ml of dry benzene. The solution dissolved in was added dropwise using a dropping funnel, and further reacted for 5 hours under reflux with heating.
[0039]
After completion of the reaction, cool to room temperature, wash with 0.5N hydrochloric acid, extract with ethyl acetate, wash with saturated aqueous sodium bicarbonate, wash with saturated brine, dry over anhydrous magnesium sulfate and concentrate. Gave crude (S)-(−)-N-α-methylbenzylmaleimide. The obtained crude (S)-(−)-N-α-methylbenzylmaleimide was subsequently purified by column chromatography (n-hexane / ethyl acetate = 4/1, vol / vol), followed by distillation purification (114 ° C. /8.3×10 ⁻³ mmHg) to obtain 6.9 g of a white solid (yield 84%).
[0040]
Melting point (° C): 33-35 ° C
Specific rotation [α] 435 ²⁵ = −98.1 ° (C = 1.0, THF)
Example 1
A 25 ml eggplant-shaped flask containing a magnetic stir bar was charged with 30.9 mg (0.25 mmol) of diethylzinc, 70.3 mg (0.30 mmol) of (-)-sparteine and 5 ml of toluene at 0 ° C. with stirring. After stirring for 30 minutes, 503 mg (2.50 mmol) of (S)-(−)-N-α-methylbenzylmaleimide obtained in Reference Example 1 was added thereto, followed by further reaction at the same temperature for 72 hours. It was.
[0041]
After completion of the reaction, the reaction solution was poured into 50 ml of methanol, and then the precipitate was collected by filtration and dried at room temperature under reduced pressure to obtain 0.5 g of the objective optically active poly (N-α-methylbenzylmaleimide). Obtained as a slightly yellow powder (yield 100%).
[0042]
Number average molecular weight (Mn) = 12.7 × 10 ³ , Mw / Mn = 10.0
Specific rotation [α] 435 ²⁵ = 242.2 ° (C = 1.0, CHCl ₃ )
[Specific rotation of THF dissolved component [α] 435 ²⁵ = 206.0 ° (C = 1.0, THF)]
Example 2 and Example 3
Using the same reaction apparatus as in Example 1, the reaction was performed under the conditions shown in Table 1. The results are shown in Table 1. In addition, about the conditions which are not described in Table 1, it implemented on the same conditions as Example 1. FIG.
[0043]
Reference Example 1 to Reference Example 3
Using the same reaction apparatus as in Example 1, the reaction was performed under the conditions shown in Table 1. The results are shown in Table 1. In addition, about the conditions which are not described in Table 1, it implemented on the same conditions as Example 1. FIG.
[0044]
[Table 1]

[0045]
Comparative Examples 1 to 3
Using the same reaction apparatus as in Example 1, the reaction was performed under the conditions shown in Table 1. The results are shown in Table 1. In addition, about the conditions which are not described in Table 1, it implemented on the same conditions as Example 1. FIG.

Claims (2)

The following general formula (1)

(In the formula, n represents a number in the range of 2 to 10,000, and * represents optically active carbon.)
And optically active poly (N-α-methylbenzylmaleimide) having a specific optical rotation ([α] ₄₃₅ ²⁵ ) of + 242.2 ° to 466.2 ° . Following formula (2)

(S)-(−)-N-α-methylbenzylmaleimide represented by the formula below is reacted with an anion in the presence of diethylzinc and (−)-sparteine in a toluene solvent at a reaction temperature ranging from −35 ° C. to 0 ° C. The method for producing optically active poly (N-α-methylbenzylmaleimide) according to claim 1, which is polymerized.