JP2007332050A - Manufacturing method of optically active n-tert-butylcarbamoyl-l-tert-leucine - Google Patents
Manufacturing method of optically active n-tert-butylcarbamoyl-l-tert-leucine Download PDFInfo
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Abstract
Description
本発明は、式1で示される光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法に関する。詳しくは、式1で示される光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液から、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を得るに際して、該有機溶媒溶液を水共存下で蒸留し、得られた水に置換された混合液より光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を分離取得することを特徴とする、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法に関する。
本発明の方法によって得られる光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンは、ＨＩＶやＨＣＶのプロテアーゼ阻害剤等の医薬品原料として重要な中間体であり（例えば、特許文献１，２参照）、Ｌ−ｔｅｒｔ−ロイシンとｔｅｒｔ−ブチルイソシアネートとの縮合反応により得られることが報告されている（例えば、特許文献３参照）。そこで、特許文献３に従いＬ−ｔｅｒｔ−ロイシンとｔｅｒｔ−ブチルイソシアネートを縮合させ、その反応液から目的物質の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを有機溶媒で抽出し、該抽出液の濃縮物から光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを単離する実験を試みた。しかしながら、縮合反応は定量的に進ものの、得られる濃縮物は水飴状の固形物となり、例えばこの固形物をシリカゲルやアルミナを用いたカラムクロマトによって精製した後、再結晶させようとしても、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンのカラム担体との反応やカルバモイル部位の分解誘起により新たな分解が起こり、結晶状の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを得ることはできなかった。このように、文献記載の方法では、結晶状の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを得ることができないことが判明した。 The optically active N-tert-butylcarbamoyl-L-tert-leucine obtained by the method of the present invention is an important intermediate as a raw material for pharmaceuticals such as HIV and HCV protease inhibitors (see, for example, Patent Documents 1 and 2). ) And L-tert-leucine and tert-butyl isocyanate have been reported to be obtained (for example, see Patent Document 3). Therefore, according to Patent Document 3, L-tert-leucine and tert-butyl isocyanate are condensed, and the optically active N-tert-butylcarbamoyl-L-tert-leucine of the target substance is extracted from the reaction solution with an organic solvent. Attempts were made to isolate optically active N-tert-butylcarbamoyl-L-tert-leucine from the liquid concentrate. However, although the condensation reaction proceeds quantitatively, the resulting concentrate becomes a syrupy solid. For example, even if the solid is purified by column chromatography using silica gel or alumina and then recrystallized, the optically active New decomposition occurs due to reaction of N-tert-butylcarbamoyl-L-tert-leucine with the column carrier and induction of decomposition of the carbamoyl moiety to obtain crystalline optically active N-tert-butylcarbamoyl-L-tert-leucine I couldn't. As described above, it was found that the method described in the literature cannot obtain crystalline optically active N-tert-butylcarbamoyl-L-tert-leucine.
ところで、ほとんどのアミノ酸、またはアミノ酸誘導体は水への溶解性が高いため、一般的にはアミノ酸、またはアミノ酸誘導体を含む水溶液に適当な有機溶媒を加えこれらの物質を優先的に析出させて回収精製する手法がとられる（例えば、特許文献４，５参照）。しかしながら、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンはほとんど水に溶解しないため、通常のアミノ酸のように、その水溶液を調製し貧溶媒となる有機溶媒を加え優先的に析出させ分離回収する精製方法を取ることは困難であった。
一方、水への溶解性が低いアミノ酸誘導体を、該物質を溶解し得る有機溶媒に一旦溶かした後、有機溶媒溶液を酸水溶液、またはアルカリ水溶液で洗浄することにより不純物を除去した後、有機溶媒を留去し水に置換させてアミノ酸アミドの結晶を析出させる方法（例えば、特許文献６参照）もあるが、適用されるアミノ酸誘導体はＮ−アシルアミノ酸アミドのような比較的安定性の高い物質に限られており、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンのように、分子内にカルバモイルのような分解し易い
構造を有する物質を対象とする場合についてはなんら示されていない。
By the way, since most amino acids or amino acid derivatives are highly soluble in water, generally, an appropriate organic solvent is added to an aqueous solution containing amino acids or amino acid derivatives, and these substances are preferentially precipitated for purification. (See, for example, Patent Documents 4 and 5). However, optically active N-tert-butylcarbamoyl-L-tert-leucine hardly dissolves in water. Therefore, like ordinary amino acids, its aqueous solution is prepared, and an organic solvent that becomes a poor solvent is added to preferentially precipitate and separate. It was difficult to take a purification method to recover.
On the other hand, after the amino acid derivative having low solubility in water is once dissolved in an organic solvent capable of dissolving the substance, the organic solvent solution is washed with an acid aqueous solution or an alkaline aqueous solution to remove impurities, and then the organic solvent There is also a method in which amino acid amide crystals are precipitated by distilling off and replacing with water (see, for example, Patent Document 6), but the amino acid derivative to be applied is a relatively stable substance such as N-acyl amino acid amide. However, there is no description about a case where a substance having a structure easily decomposed such as carbamoyl in the molecule, such as optically active N-tert-butylcarbamoyl-L-tert-leucine, is disclosed. .
式1で示される光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンは光学活性体であるＬ−ｔｅｒｔ−ロイシンとｔｅｒｔ−ブチルイソシアネートの縮合により生成させることができる（例えば、特許文献３参照）。本発明で使用するＬ−ｔｅｒｔ−ロイシンおよびｔｅｒｔ−ブチルイソシアネートは、その製法および品質等に特に制限はない。例えば、従来知られているＤＬ−ｔｅｒｔ−ロイシンアミドの光学分割手法によりＬ−ｔｅｒｔ−ロイシンを得ることができる（例えば、特許文献４，７、非特許文献１，２参照）。また、ｔｅｒｔ−ブチルイソシアネートも、既知の反応により得ることができる（例えば、非特許文献３，４参照）。 The optically active N-tert-butylcarbamoyl-L-tert-leucine represented by the formula 1 can be produced by condensation of optically active L-tert-leucine and tert-butyl isocyanate (for example, see Patent Document 3). ). L-tert-leucine and tert-butyl isocyanate used in the present invention are not particularly limited in their production method and quality. For example, L-tert-leucine can be obtained by a conventionally known optical resolution method of DL-tert-leucine amide (see, for example, Patent Documents 4 and 7, Non-Patent Documents 1 and 2). Moreover, tert-butyl isocyanate can also be obtained by a known reaction (for example, refer nonpatent literatures 3 and 4).
本発明の目的は、性状的に優れた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を分離取得するための工業的に実施可能な製造方法を提供することにある。 An object of the present invention is to provide an industrially feasible production method for separating and obtaining crystals of optically active N-tert-butylcarbamoyl-L-tert-leucine excellent in properties.
本発明者らは上記課題を解決すべく鋭意検討した結果、式１で示す光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液から結晶状の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを分離取得するに際して、水存在下で該有機溶媒溶液を蒸留し水溶媒系に置換する方法をとることによって、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの分解を抑え、化学純度、光学純度ともに優れた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを高収率で得られることを見出し、本発明を完成するに至った。すなわち、本発明は、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液から、結晶状の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを効率的に得るための（１）〜（７）に示す製造方法に関する。
（１）式1で示す光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液から、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を得るに際して、該有機溶媒溶液を水共存下で蒸留し、得られた水に置換された混合液より光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を分離取得することを特徴とする、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法。
（３）式1で示す光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液を水共存下で蒸留する際、留出分より回収した水を還流させながら行う、（２）に記載の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法。
（４）式１で示す光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液を水共存下で蒸留する際、３０〜７０℃の温度で蒸留を行う、（１）に記載の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法。
（５）水に置換された混合液中に含まれる有機溶媒量が、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンに対して０．１〜１０重量倍の範囲となるように蒸留する、（１）に記載の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法。
（６）水に置換された混合液中に含まれる水の量が、その中に含まれる光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンに対して、１〜１００倍重量の範囲となるように蒸留する、（１）に記載の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法。
（７）式1で示す光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液の有機溶媒が酢酸エチルである、（１）〜（６）の何れかに記載の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの製造方法。
As a result of intensive studies to solve the above problems, the inventors of the present invention obtained a crystalline optically active N-tert-butylene from an organic solvent solution containing the optically active N-tert-butylcarbamoyl-L-tert-leucine represented by Formula 1. When separating and obtaining rucarbamoyl-L-tert-leucine, an optically active N-tert-butylcarbamoyl-L-tert-leucine is obtained by distilling the organic solvent solution in the presence of water and replacing it with an aqueous solvent system. It was found that an optically active N-tert-butylcarbamoyl-L-tert-leucine excellent in both chemical purity and optical purity can be obtained in high yield, and the present invention has been completed. That is, the present invention is for efficiently obtaining crystalline optically active N-tert-butylcarbamoyl-L-tert-leucine from an organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine. It relates to the manufacturing method shown to (1)-(7).
(1) When an optically active N-tert-butylcarbamoyl-L-tert-leucine crystal is obtained from an organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine represented by the formula 1, A solvent solution is distilled in the presence of water, and optically active N-tert-butylcarbamoyl-L-tert-leucine crystals are separated and obtained from the resulting mixed liquid substituted with water. -Method for producing tert-butylcarbamoyl-L-tert-leucine.
(3) When an organic solvent solution containing the optically active N-tert-butylcarbamoyl-L-tert-leucine represented by the formula 1 is distilled in the presence of water, the water collected from the distillate is refluxed (2 ) For producing optically active N-tert-butylcarbamoyl-L-tert-leucine.
(4) When an organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine represented by Formula 1 is distilled in the presence of water, distillation is performed at a temperature of 30 to 70 ° C. A process for producing the optically active N-tert-butylcarbamoyl-L-tert-leucine as described.
(5) Distillation so that the amount of the organic solvent contained in the mixed liquid substituted with water is in the range of 0.1 to 10 times by weight with respect to optically active N-tert-butylcarbamoyl-L-tert-leucine. The method for producing optically active N-tert-butylcarbamoyl-L-tert-leucine according to (1).
(6) The amount of water contained in the mixed liquid substituted with water is in the range of 1 to 100 times the weight of the optically active N-tert-butylcarbamoyl-L-tert-leucine contained therein. The method for producing optically active N-tert-butylcarbamoyl-L-tert-leucine according to (1), wherein the distillation is performed as follows.
(7) The optical activity according to any one of (1) to (6), wherein the organic solvent in the organic solvent solution containing the optically active N-tert-butylcarbamoyl-L-tert-leucine represented by formula 1 is ethyl acetate. A method for producing N-tert-butylcarbamoyl-L-tert-leucine.
本発明の方法によれば、ＨＩＶやＨＣＶのプロテアーゼ阻害剤等の医薬品原料として重要な光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを、簡便な方法で高純度かつ高収率に製造し提供することが可能となる。 According to the method of the present invention, optically active N-tert-butylcarbamoyl-L-tert-leucine, which is important as a raw material for drugs such as HIV and HCV protease inhibitors, is produced in a simple method with high purity and high yield. Can be provided.
本発明の対象となる光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液は、例えば、原料のＬ−ｔｅｒｔ−ロイシンを含むアルカリ水溶液に、反応が急激に進まないようにｔｅｒｔ−ブチルイソシアネートを少しずつ滴下しながら反応させ、次いで該水溶液に酸を加えて中和した後、生成した光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを該物質可溶の性質を有する有機溶媒で抽出することによって得られる（特許文献３）。 The organic solvent solution containing the optically active N-tert-butylcarbamoyl-L-tert-leucine, which is the subject of the present invention, is prepared, for example, so that the reaction does not rapidly proceed to an alkaline aqueous solution containing the raw material L-tert-leucine. The reaction is carried out while dropwise adding tert-butyl isocyanate little by little, and then neutralization is performed by adding an acid to the aqueous solution, and the resulting optically active N-tert-butylcarbamoyl-L-tert-leucine is dissolved in the substance. It obtains by extracting with the organic solvent which has (patent document 3).
このような有機溶媒としては、ｎ−ブタノール、イソブタノール等のアルコール類、酢酸エチル、酢酸ブチル等の有機カルボン酸エステル類、ジエチルエーテル、ジイソプロピルエーテル、メチル−ｔｅｒｔ−ブチルエーテル等のエーテル類等の溶媒が挙げられる。このうち、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの溶解性が高く沸点も比較的低い点で、酢酸エチルが好適に使用できる。 Examples of such organic solvents include alcohols such as n-butanol and isobutanol, organic carboxylic acid esters such as ethyl acetate and butyl acetate, solvents such as ethers such as diethyl ether, diisopropyl ether, and methyl-tert-butyl ether. Is mentioned. Of these, ethyl acetate can be preferably used in terms of the high solubility and high boiling point of optically active N-tert-butylcarbamoyl-L-tert-leucine.
上記したように、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンは分子内に不安定なカルバモイル基を有することから、結晶を得るにあたって使用した有機溶媒を除去しようとする場合、できる限り低い温度で蒸留する条件を取る必要がある。それに伴って、有機溶媒中での飽和溶解度も低下することから、蒸留により濃度が若干上昇しただけで光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの急激な析出と凝集が起こり易くなる。この場合、副生塩や未反応の不純物も巻き込む形で結晶が析出してしまうため、得られる光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの純度が低下してしまうだけではなく、同時に析出した不純物が介在することによって、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンが凝集固形化し微粒子状の結晶とならない現象を招く。このような光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの急激な析出と凝集を防ぐには、溶媒の留去に連動させ、主要な不純物である塩を析出させないように、水を共存させるような条件下で徐々に溶媒を水に置換させながら、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶成長をはかる方法をとる必要がある。 As described above, since optically active N-tert-butylcarbamoyl-L-tert-leucine has an unstable carbamoyl group in the molecule, it is possible to remove the organic solvent used for obtaining crystals as much as possible. It is necessary to adopt conditions for distillation at a low temperature. Along with this, the saturation solubility in an organic solvent is also lowered, so that the optically active N-tert-butylcarbamoyl-L-tert-leucine is likely to be rapidly precipitated and aggregated only when the concentration is slightly increased by distillation. . In this case, since crystals precipitate in a form involving by-product salts and unreacted impurities, not only the purity of the obtained optically active N-tert-butylcarbamoyl-L-tert-leucine is reduced, Simultaneously with the deposited impurities, the optically active N-tert-butylcarbamoyl-L-tert-leucine is aggregated and solidified, resulting in a phenomenon in which fine crystals are not formed. In order to prevent such rapid precipitation and aggregation of optically active N-tert-butylcarbamoyl-L-tert-leucine, water is used so that the main impurity salt does not precipitate in conjunction with the evaporation of the solvent. It is necessary to take a method for crystal growth of optically active N-tert-butylcarbamoyl-L-tert-leucine while gradually substituting the solvent with water under the coexisting conditions.
本発明の特徴である、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液を蒸留し水系に置換する方法としては以下に示すＡ、Ｂ２法が考えられる。
Ａ．光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液に、あらかじめ有機溶媒に対して同体積以上の水を共存させた状態から有機溶媒を留去させて溶媒を水に置換する方法。
Ｂ．光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液から有機溶媒を留去させながら、留去した溶媒の体積に応じた水を随時有機溶媒溶液に足して、溶媒を水に置換する方法。
以上の２法のうち、Ａ法は、Ｂ法の様に留去した有機溶媒量に見合った水を逐次添加する必要性がない点で簡便ではあるが、蒸留釜の容積を少なくとも倍増させなければならない点で経済的でなく現実的ではない。よって、選択肢としてはＢ法の方が好ましい。
なお、使用する有機溶媒が水との共沸混合物を形成する場合には、蒸留によって失われた水の分だけ多く水を添加するか、蒸留液より分離回収した水を添加する水の中に追加する上記の変法を採用することができる。
このような蒸留方法を取ることによって、取り扱い易い光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶スラリーが得られるとともに、結晶性状、化学純度、光学純度ともに優れた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを高い収率で得ることが可能となる。図１にこのような蒸留操作法を行うための装置を模式的に示す。
The following methods A and B2 can be considered as a method of distilling an organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine and replacing it with an aqueous system, which is a feature of the present invention.
A. An organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine is distilled in advance from the state where water of the same volume or more is previously present in the organic solvent to replace the solvent with water. how to.
B. While distilling off the organic solvent from the organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine, water corresponding to the volume of the distilled solvent was added to the organic solvent solution as needed, and the solvent was washed with water. How to replace
Of the above two methods, method A is simple in that it is not necessary to sequentially add water corresponding to the amount of the organic solvent distilled off as in method B, but the volume of the distillation kettle must be doubled at least. It is not economical nor realistic in terms of having to be. Therefore, Method B is preferable as an option.
If the organic solvent to be used forms an azeotrope with water, add as much water as lost by distillation, or add water separated and recovered from the distillate into the water. Additional variations of the above can be employed.
By taking such a distillation method, a crystal slurry of easy-to-handle optically active N-tert-butylcarbamoyl-L-tert-leucine can be obtained, and optically active N-tert having excellent crystal properties, chemical purity and optical purity. -Butylcarbamoyl-L-tert-leucine can be obtained in high yield. FIG. 1 schematically shows an apparatus for performing such a distillation operation method.
蒸留釜に光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液を張り込み、蒸留を行う。蒸留温度は３０〜７０℃、好ましくは６０〜７０℃の温度範囲が望ましい。蒸留温度が７０℃よりも高いと光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの分解が起こり好ましくない。なお、蒸留時の圧力は、望ましい蒸留温度が得られる圧力を適宜選択すればよい。 Distillation is performed by placing an organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine in a distillation kettle. The distillation temperature is 30 to 70 ° C, preferably 60 to 70 ° C. When the distillation temperature is higher than 70 ° C., the optically active N-tert-butylcarbamoyl-L-tert-leucine is decomposed, which is not preferable. In addition, what is necessary is just to select the pressure at the time of distillation suitably the pressure from which desirable distillation temperature is obtained.
なお、水への溶媒置換が進に従って蒸留釜中に光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの白色結晶が析出して来るが、その際、結晶性状に優れた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを晶析させるためには、結晶間での過度の凝集を防ぐため蒸留中の混合液を撹拌混合させる必要がある。混合液は複合渦を形成した状態で撹拌される状態が望ましく、例えば、放射流型翼を用いた撹拌装置の場合では、レイノルズ数が１，０００以上となる流動状態で攪拌を続けると性状的に優れた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を得ることができる。 As the solvent substitution into water progresses, white crystals of optically active N-tert-butylcarbamoyl-L-tert-leucine precipitate in the distillation kettle. At that time, optically active N- with excellent crystal properties In order to crystallize tert-butylcarbamoyl-L-tert-leucine, it is necessary to stir and mix the liquid mixture during distillation in order to prevent excessive aggregation between crystals. It is desirable that the mixed liquid is stirred in a state where a composite vortex is formed. For example, in the case of a stirring device using a radial flow type blade, if stirring is continued in a fluidized state where the Reynolds number is 1,000 or more, the properties In addition, an optically active N-tert-butylcarbamoyl-L-tert-leucine crystal having excellent properties can be obtained.
蒸留操作は、水に置換された混合液中に残存する有機溶媒が二層分離を起こさない程度、かつ、塩等の不純物を十分に溶解させることのできる程度まで蒸留し停止させる。残存有機溶媒が至適範囲を超えて存在する場合には、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの晶析が不十分となり収率が低下する。逆に、残存有機溶媒が至適範囲に満たない場合には、未反応の、原料のＬ−ｔｅｒｔ−ロイシンやｔｅｒｔ−ブチルイソシアネート等が結晶に付着し得られる光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの純度が低下する。
例えば、有機溶媒が酢酸エチルである場合には、その中に含まれる酢酸エチルの濃度が０．１〜１０％の範囲になったところで溶媒置換操作を終了させればよく、さらには１〜５％の濃度範囲で溶媒置換操作を終了させるのがより好ましい。
The distillation operation is stopped by distillation to such an extent that the organic solvent remaining in the mixed liquid substituted with water does not cause two-layer separation and can sufficiently dissolve impurities such as salts. When the residual organic solvent is present beyond the optimum range, the crystallization of optically active N-tert-butylcarbamoyl-L-tert-leucine becomes insufficient and the yield decreases. On the contrary, when the residual organic solvent is less than the optimum range, optically active N-tert-butylcarbamoyl from which unreacted raw material L-tert-leucine, tert-butylisocyanate, etc. can be attached to the crystal The purity of L-tert-leucine decreases.
For example, when the organic solvent is ethyl acetate, the solvent replacement operation may be terminated when the concentration of ethyl acetate contained therein is in the range of 0.1 to 10%. It is more preferable to end the solvent replacement operation in a concentration range of%.
このようにして、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む有機溶媒溶液を水共存下で蒸留することにより、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの白色結晶を含むスラリー混合物が得られる。このスラリー混合物を室温付近まで除冷し、結晶を熟成させた後、必要に応じ結晶を水洗しながら濾過や遠心分離等の通常の手段で結晶を分離し、真空または通風等の通常の方法で乾燥する。これにより、光学純度および化学純度ともに優れた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを高収率で得ることができる。 In this way, by distilling the organic solvent solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine in the presence of water, optically active N-tert-butylcarbamoyl-L-tert-leucine was whitened. A slurry mixture containing crystals is obtained. After cooling the slurry mixture to near room temperature and ripening the crystals, the crystals are separated by usual means such as filtration or centrifugation while washing the crystals with water as necessary, and then by a usual method such as vacuum or ventilation. dry. Thereby, optically active N-tert-butylcarbamoyl-L-tert-leucine excellent in both optical purity and chemical purity can be obtained in high yield.
次に、本発明を実施例および比較例をもってより具体的に説明する。ただし、本発明はこれらの例によって制限されるものではない。
実施例１
Ｌ−ｔｅｒｔ−ロイシン１１ｇ（８４ｍｍｏｌ）を１規定のＮａＯＨ水溶液９２ｍＬに溶解した溶液、およびテトラヒドロフラン４０ｍＬを３００ｍＬのフラスコに取り、攪拌下、ｔｅｒｔ−ブチルイソシアネート１０ｇ（１０１ｍｍｏｌ）を、液温が３０℃を超えないようにしながらゆっくりと滴下した後、室温にて２時間反応させた。得られた反応液を各回３０ｍＬの酢酸エチルで３回洗浄した後、クエン酸５．９ｇ（３１ｍｍｏｌ）を添加し中和した。この中和した溶液を各回１００ｍＬの酢酸エチルで３回抽出した後、得られた酢酸エチル溶液を各回２０ｍＬの水で３回洗浄し、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシン１７ｇ（７６ｍｍｏｌ）を含む酢酸エチル溶液２８０ｍＬを得た。
次ぎに、図１の装置模式図に従い、２００ｍＬのフラスコを蒸留釜に、１５０ｍＬのガラス容器を留分受器として使用し、上記のようにして得られた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシン１７ｇ(７６ｍｍｏｌ)を含む酢酸エチル溶液２８０ｍＬと水１００ｍＬを蒸留釜に入れ、７０℃、２０ｍｍＨｇの減圧条件下、共沸ガスより冷却回収した水を連続的に留分受器より蒸留釜に還流させながら、生じたスラリー混合液中に含まれる酢酸エチル濃度が２ｗｔ％に到達するまで蒸留を行った。
次に、このスラリー混合液を２５℃まで放冷した後、２時間静置して結晶の熟成を行い、析出した沈殿物を濾取し真空乾燥を行った。その結果、１６．６ｇ（７２ｍｍｏｌ）の光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの結晶を得た。反応に仕込んだＬ−ｔｅｒｔ−ロイシンからの単離収率は８６ｍｏｌ％であった。この結晶を液体クロマトグラフィーによって分析した結果、化学純度は９９％以上、および光学純度は１０％ｅｅであった。
Next, the present invention will be described more specifically with reference to examples and comparative examples. However, the present invention is not limited by these examples.
Example 1
A solution of 11 g (84 mmol) of L-tert-leucine in 92 mL of 1N NaOH aqueous solution and 40 mL of tetrahydrofuran are placed in a 300 mL flask, and 10 g (101 mmol) of tert-butylisocyanate is added with stirring to a liquid temperature of 30 ° C. The solution was allowed to react slowly at room temperature for 2 hours after slowly dropping while preventing the temperature from exceeding. The obtained reaction solution was washed three times with 30 mL of ethyl acetate each time, and then neutralized by adding 5.9 g (31 mmol) of citric acid. This neutralized solution was extracted 3 times with 100 mL of ethyl acetate each time, and then the obtained ethyl acetate solution was washed 3 times with 20 mL of water each time to obtain 17 g of optically active N-tert-butylcarbamoyl-L-tert-leucine. 280 mL of ethyl acetate solution containing (76 mmol) was obtained.
Next, according to the apparatus schematic diagram of FIG. 1, a 200 mL flask was used as a distillation kettle and a 150 mL glass container was used as a fraction receiver, and the optically active N-tert-butylcarbamoyl-L obtained as described above was used. -280 mL of an ethyl acetate solution containing 17 g (76 mmol) of tert-leucine and 100 mL of water are placed in a distillation kettle, and the water recovered by cooling from the azeotropic gas is continuously distilled from a fraction receiver under a reduced pressure condition of 70 ° C and 20 mmHg. While refluxing in the kettle, distillation was performed until the ethyl acetate concentration contained in the resulting slurry mixture reached 2 wt%.
Next, the slurry mixture was allowed to cool to 25 ° C. and then allowed to stand for 2 hours to age the crystals, and the deposited precipitate was collected by filtration and vacuum dried. As a result, 16.6 g (72 mmol) of optically active N-tert-butylcarbamoyl-L-tert-leucine crystals were obtained. The isolated yield from L-tert-leucine charged in the reaction was 86 mol%. As a result of analyzing the crystals by liquid chromatography, the chemical purity was 99% or more, and the optical purity was 10% ee.
比較例１
実施例１と同様の反応操作と抽出操作により取得した光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む酢酸エチル溶液をロータリーエバポレータにて濃縮乾固した後、真空乾燥させた。光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの回収率は１００％であったが、結晶が凝集し、結晶粉末としての回収は不可能であった。また、化学純度も８６．９％と低く、不純物を取り除くことは出来なかった。
Comparative Example 1
An ethyl acetate solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine obtained by the same reaction operation and extraction operation as in Example 1 was concentrated to dryness in a rotary evaporator and then vacuum dried. The recovery rate of optically active N-tert-butylcarbamoyl-L-tert-leucine was 100%, but the crystals were aggregated and could not be recovered as crystal powder. Further, the chemical purity was as low as 86.9%, and impurities could not be removed.
比較例２
実施例１と同様の反応操作と抽出操作により取得した光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む酢酸エチル溶液をロータリーエバポレータにて濃縮乾固した後、真空乾燥させた。真空乾燥で得られた粗光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンに、水：エタノール＝３：1（体積比）の混合溶媒３５０ｍＬを加えて還流下に溶解させた後に、ゆっくりと室温へ冷却することにより再結晶を行った。析出した結晶はろ過回収し、冷エタノールにて洗浄した。得られた光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの化学純度は９９％以上であったが、収量は１１．４ｇ（５０ｍｍｏｌ）であり、反応に仕込んだＬ−ｔｅｒｔ−ロイシンからの単離収率は５９ｍｏｌ％と光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを再結晶溶媒へ多く損失した。
Comparative Example 2
An ethyl acetate solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine obtained by the same reaction operation and extraction operation as in Example 1 was concentrated to dryness in a rotary evaporator and then vacuum dried. After adding 350 mL of a mixed solvent of water: ethanol = 3: 1 (volume ratio) to the crude optically active N-tert-butylcarbamoyl-L-tert-leucine obtained by vacuum drying and dissolving under reflux, slowly And recrystallization was performed by cooling to room temperature. The precipitated crystals were collected by filtration and washed with cold ethanol. The obtained optically active N-tert-butylcarbamoyl-L-tert-leucine had a chemical purity of 99% or more, but the yield was 11.4 g (50 mmol), which was obtained from L-tert-leucine charged in the reaction. The isolation yield of was 59 mol%, and a large amount of optically active N-tert-butylcarbamoyl-L-tert-leucine was lost to the recrystallization solvent.
比較例３
実施例１と同様の操作により取得した光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンを含む酢酸エチル溶液を濃縮し、この濃縮物にヘキサン１００ｍＬを添加し光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンの晶析を試みた。しかしながら、光学活性Ｎ−ｔｅｒｔ−ブチルカルバモイル−Ｌ−ｔｅｒｔ−ロイシンが凝集し、結晶の回収は不可能であった。
Comparative Example 3
The ethyl acetate solution containing optically active N-tert-butylcarbamoyl-L-tert-leucine obtained by the same procedure as in Example 1 was concentrated, and 100 mL of hexane was added to the concentrate to add optically active N-tert-butylcarbamoyl. Attempts were made to crystallize -L-tert-leucine. However, optically active N-tert-butylcarbamoyl-L-tert-leucine aggregated, and recovery of crystals was impossible.
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| WO2018216426A1 (en) * | 2017-05-22 | 2018-11-29 | 昭和電工株式会社 | Production method for hexafluoro-1,3-butadiene |
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