JP2007238495A - Production method for crystal of n-alkoxycarbonylamino acid - Google Patents
Production method for crystal of n-alkoxycarbonylamino acid Download PDFInfo
- Publication number
- JP2007238495A JP2007238495A JP2006062621A JP2006062621A JP2007238495A JP 2007238495 A JP2007238495 A JP 2007238495A JP 2006062621 A JP2006062621 A JP 2006062621A JP 2006062621 A JP2006062621 A JP 2006062621A JP 2007238495 A JP2007238495 A JP 2007238495A
- Authority
- JP
- Japan
- Prior art keywords
- crystal
- crystals
- alkoxycarbonylamino acid
- alkoxycarbonylamino
- acid
- 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.)
- Granted
Links
- 0 *C(*)(C(O)=O)NC(*)=O Chemical compound *C(*)(C(O)=O)NC(*)=O 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、Ｎ−アルコキシカルボニルアミノ酸結晶の製造方法に関する。アミノ酸のアミノ基を保護したＮ−アルコキシカルボニルアミノ酸は、抗生物質、ペプチド、ポリペプチド、たんぱく質及びアミノ酸配糖体等の化学合成において、出発物質や中間体として用いられる。 The present invention relates to a method for producing N-alkoxycarbonylamino acid crystals. N-alkoxycarbonylamino acids in which the amino group of the amino acid is protected are used as starting materials and intermediates in chemical synthesis of antibiotics, peptides, polypeptides, proteins, amino acid glycosides and the like.
Ｎ−アルコキシカルボニルアミノ酸は、アミノ酸及びＮ−アルコキシカルボニル化剤とを水性媒体中で反応させ、次いで生成したＮ−アルコキシカルボニルアミノ酸を反応液から回収、単離することで製造することができる。アミノ酸とＮ−アルコキシカルボニル化剤との水性媒体中での反応は、塩基性化合物存在下、アミノ酸の水性媒体溶液にＮ−アルコキシカルボニル化剤を滴下して行う方法が報告されている（非特許文献１）。
また、反応液から生成したＮ−アルコキシカルボニルアミノ酸結晶を単離する方法については、酢酸エチルのような極性溶媒を用い反応液から生成Ｎ−アルコキシカルボニルアミノ酸を抽出・回収し、得られた有機相の溶媒を溜去した後、非極性溶媒である炭化水素溶媒を加えてＮ−アルコキシカルボニルアミノ酸結晶を析出させてから結晶を単離する方法が報告されている（非特許文献１、非特許文献２）。しかしながら、上述の方法は、溶剤全溜去後さらに異なる溶剤を大量に加える必要があるため操作効率が悪く実用的でなかった。
一方、Ｎ−アルコキシカルボニル−ｔｅｒｔ−ロイシンについては、温度４０℃以上に保持しながら、反応液から生成Ｎ−アルコキシカルボニル−ｔｅｒｔ−ロイシンを芳香族炭化水素溶媒に抽出・回収する方法や（特許文献１）、再結晶による光学活性Ｎ−アルコキシカルボニル−ｔｅｒｔ−ロイシンの精製方法（特許文献２）が報告されている。
特許文献１は、Ｎ−アルコキシカルボニル−ｔｅｒｔ−ロイシン結晶の晶析条件、操作方法についての記載は無く、また、特許文献２にもＮ−アルコキシカルボニル−ｔｅｒｔ−ロイシンを含む芳香族炭化水素溶媒溶液からのＮ−アルコキシカルボニル−ｔｅｒｔ−ロイシンの晶析の記載はなく、その結晶の回収率は６０％程度と工業的に使用できる方法ではなかった。
N-alkoxycarbonylamino acid can be produced by reacting an amino acid and an N-alkoxycarbonylating agent in an aqueous medium, and then recovering and isolating the produced N-alkoxycarbonylamino acid from the reaction solution. It has been reported that the reaction of an amino acid and an N-alkoxycarbonylating agent in an aqueous medium is performed by dropping the N-alkoxycarbonylating agent into an aqueous medium solution of an amino acid in the presence of a basic compound (non-patent document). Reference 1).
Moreover, about the method of isolating the N-alkoxycarbonylamino acid crystal | crystallization produced | generated from the reaction liquid, the produced | generated organic phase was extracted and collect | recovered from reaction liquid using polar solvents, such as ethyl acetate. A method of isolating the crystals after the N-alkoxycarbonylamino acid crystals are precipitated by adding a hydrocarbon solvent, which is a nonpolar solvent, is reported (Non-Patent Document 1, Non-Patent Documents). 2). However, the above-described method is not practical because the operation efficiency is low because it is necessary to add a large amount of a different solvent after the total distillation of the solvent.
On the other hand, for N-alkoxycarbonyl-tert-leucine, a method of extracting and recovering the produced N-alkoxycarbonyl-tert-leucine from the reaction solution into an aromatic hydrocarbon solvent while maintaining the temperature at 40 ° C. or higher (Patent Documents) 1) A method for purifying optically active N-alkoxycarbonyl-tert-leucine by recrystallization (Patent Document 2) has been reported.
Patent Document 1 does not describe crystallization conditions and operation methods of N-alkoxycarbonyl-tert-leucine crystals, and Patent Document 2 also discloses an aromatic hydrocarbon solvent solution containing N-alkoxycarbonyl-tert-leucine. There was no description of crystallization of N-alkoxycarbonyl-tert-leucine from No. 1, and the crystal recovery rate was about 60%, which was not an industrially usable method.
本発明の目的は、取扱い性に優れた結晶として簡便に収率良く得るＮ−アルコキシカルボニルアミノ酸結晶の製造方法を提供することにある。 An object of the present invention is to provide a method for producing an N-alkoxycarbonylamino acid crystal that is easily obtained in a good yield as a crystal excellent in handleability.
本発明は以下の通りである。
（１）少なくとも下記（Ａ）〜（Ｃ）工程を有するＮ−アルコキシカルボニルアミノ酸結晶の製造方法。
（Ａ）Ｎ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液を冷却晶析する工程
（Ｂ）その後、Ｎ−アルコキシカルボニルアミノ酸結晶が析出している芳香族炭化水素溶媒溶液をＮ−アルコキシカルボニルアミノ酸結晶の一部が残存する温度まで昇温した後に冷却する工程
（Ｃ）次いで、Ｎ−アルコキシカルボニルアミノ酸結晶を単離する工程
（２）粒子径１００μｍ以上である結晶が８０質量％以上であるＮ−アルコキシカルボニルアミノ酸結晶。
The present invention is as follows.
(1) A method for producing an N-alkoxycarbonylamino acid crystal having at least the following steps (A) to (C).
(A) Step of cooling and crystallizing an aromatic hydrocarbon solvent solution containing N-alkoxycarbonylamino acid (B) Thereafter, the aromatic hydrocarbon solvent solution in which N-alkoxycarbonylamino acid crystals are precipitated is converted to N-alkoxycarbonylamino acid. The step of cooling after raising the temperature to a temperature at which a part of the crystals remains (C) The step of isolating N-alkoxycarbonylamino acid crystals (2) The N having a particle diameter of 100 μm or more is 80% by mass or more -Alkoxycarbonylamino acid crystals.
本発明によれば、取扱い性に優れた結晶として簡便に収率良く得るＮ−アルコキシカルボニルアミノ酸結晶の製造方法を提供することができる。また、本発明の方法により得られるＮ−アルコキシカルボニルアミノ酸結晶は、適度な粒度分布を有し、飛散によるロスや容器の移し替え時のロスを大幅に減らすことが可能であるため取り扱い性に優れている。 ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the N-alkoxy carbonyl amino acid crystal | crystallization obtained simply as a crystal | crystallization excellent in the handleability with a sufficient yield can be provided. In addition, the N-alkoxycarbonylamino acid crystal obtained by the method of the present invention has an appropriate particle size distribution, and is excellent in handleability because it can greatly reduce loss due to scattering and loss during container transfer. ing.
以下、本発明について詳細に説明する。
本発明に係るＮ−アルコキシカルボニルアミノ酸は、アミノ酸及びＮ−アルコキシカルボニル化剤とを水性媒体中で反応させることにより得ることができる。
１．Ｎ−アルコキシカルボニルアミノ酸
Ｎ−アルコキシカルボニルアミノ酸は、下記一般式（Ｉ）で示される化合物である。
Hereinafter, the present invention will be described in detail.
The N-alkoxycarbonylamino acid according to the present invention can be obtained by reacting an amino acid and an N-alkoxycarbonylating agent in an aqueous medium.
1. N-alkoxycarbonylamino acid N-alkoxycarbonylamino acid is a compound represented by the following general formula (I).
上記一般式（Ｉ）中、Ｒ１及びＲ２は、同一又は異なっており、水素原子、または任意の置換基を示す。
任意の置換基としては、例えば、低級アルキル基、置換低級アルキル基、低級アルケニル基、シクロアルキル基、置換シクロアルキル基、芳香族基、置換芳香族基、複素環基、又は置換複素環基等が好ましい。
R3は、アルコキシ基であり、炭素数１〜８の直鎖又は分岐アルコキシ基、ベンジルオキシ基又はフェネチルオキシ基等が好ましく、メトキシ基、エトキシ基、プロポキシ基、ｉｓｏ−プロポキシ基、ブトキシ基、ｉｓｏ−ブトキシ基、ｔｅｒｔ−ブトキシ基又はベンジルオキシ基等が特に好ましい。
例えば、Ｎ−アルコキシカルボニル−ｔｅｒｔ−ロイシンが挙げられる。好ましくは、Ｎ−ｔｅｒｔ−ブトキシカルボニル−ｔｅｒｔ−ロイシン、Ｎ−エトキシカルボニル−ｔｅｒｔ−ロイシン又はＮ−メトキシカルボニル−ｔｅｒｔ−ロイシン（以下、ＭＬＴＬ）であり、特に好ましくはＭＬＴＬである。
In the general formula (I), R 1 and R 2 are the same or different and represent a hydrogen atom or an arbitrary substituent.
Examples of the optional substituent include a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, a heterocyclic group, and a substituted heterocyclic group. Is preferred.
R3 is an alkoxy group, preferably a linear or branched alkoxy group having 1 to 8 carbon atoms, a benzyloxy group or a phenethyloxy group, and is a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso -Butoxy group, tert-butoxy group, benzyloxy group and the like are particularly preferable.
An example is N-alkoxycarbonyl-tert-leucine. N-tert-butoxycarbonyl-tert-leucine, N-ethoxycarbonyl-tert-leucine or N-methoxycarbonyl-tert-leucine (hereinafter referred to as MLTL) is preferable, and MLTL is particularly preferable.
２．Ｎ−アルコキシカルボニルアミノ酸の調製
Ｎ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液は、例えば、水性媒体中でＮ−アルコキシカルボニルアミノ酸を合成後、極性有機溶剤によりＮ−アルコキシカルボニルアミノ酸を抽出回収し、次いで極性有機溶剤を芳香族炭化水素溶媒に置換して調製する方法、合成後、Ｎ−アルコキシカルボニルアミノ酸を芳香族炭化水素溶媒に抽出回収して得る方法、またはいずれかの方法で得られたＮ−アルコキシカルボニルアミノ酸結晶を芳香族炭化水素溶媒に再溶解させる方法等によって調製することができる。
2. Preparation of N-alkoxycarbonylamino acid An aromatic hydrocarbon solvent solution containing N-alkoxycarbonylamino acid is prepared by, for example, synthesizing N-alkoxycarbonylamino acid in an aqueous medium, and then extracting and recovering N-alkoxycarbonylamino acid with a polar organic solvent. Then, a method of preparing by replacing the polar organic solvent with an aromatic hydrocarbon solvent, a method of extracting and recovering N-alkoxycarbonylamino acid in an aromatic hydrocarbon solvent after synthesis, or any method obtained N-alkoxycarbonylamino acid crystals can be prepared by a method such as redissolving in an aromatic hydrocarbon solvent.
なお、Ｎ−アルコキシカルボニルアミノ酸結晶の単離前に、純度向上や単離収率向上を目的として、Ｎ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液を、少量の水、あるいは無機塩を含む水で洗浄する、共沸脱水等の脱水処理を行う等の操作を行っても良い。脱水処理後のＮ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液の水分濃度は、結晶成長、結晶純度、収率等が向上する点で０．５質量％以下とすることが好ましく、０．１質量％以下とすることがより好ましく、０．０５質量％以下とすることが特に好ましい。
芳香族炭化水素溶媒としては、ベンゼン、トルエン、トリメチルベンゼン、キシレン等が挙げられる。これら溶媒は収率、操作効率などの点から好ましい。ベンゼン、トルエン、キシレンを用いることがより好ましく、トルエンを用いることが特に好ましい。
Before the isolation of the N-alkoxycarbonylamino acid crystals, the aromatic hydrocarbon solvent solution containing the N-alkoxycarbonylamino acid contains a small amount of water or an inorganic salt for the purpose of improving the purity or improving the isolation yield. Operations such as washing with water and dehydration treatment such as azeotropic dehydration may be performed. The water concentration of the aromatic hydrocarbon solvent solution containing N-alkoxycarbonylamino acid after the dehydration treatment is preferably 0.5% by mass or less from the viewpoint of improving crystal growth, crystal purity, yield, etc. The content is more preferably 1% by mass or less, and particularly preferably 0.05% by mass or less.
Examples of the aromatic hydrocarbon solvent include benzene, toluene, trimethylbenzene, xylene and the like. These solvents are preferable from the viewpoints of yield and operational efficiency. It is more preferable to use benzene, toluene, and xylene, and it is particularly preferable to use toluene.
Ｎ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液のＮ−アルコキシカルボニルアミノ酸濃度は、２〜５０質量％とすることが好ましい。この範囲内であると操作が容易である。濃度は、５〜４０質量％とすることがより好ましく、１０〜３０質量％とすることが特に好ましい。 The concentration of N-alkoxycarbonylamino acid in the aromatic hydrocarbon solvent solution containing N-alkoxycarbonylamino acid is preferably 2 to 50% by mass. If it is within this range, the operation is easy. The concentration is more preferably 5 to 40% by mass, and particularly preferably 10 to 30% by mass.
３．冷却晶析工程
次に、上述のごとく調製したＮ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液を冷却して結晶を析出させる。
冷却速度は、結晶成長、結晶純度などの点から２５℃／hr以下とすることが好ましい。また、２０℃／hr以下とすることがより好ましく、１５℃／hr以下とすることが特に好ましい。
芳香族炭化水素溶媒溶液からＮ−アルコキシカルボニルアミノ酸の析出してくる析出温度は、Ｎ−アルコキシカルボニルアミノ酸の種類、濃度等により異なる。通常は、−１０〜８０℃のである。例えば、Ｎ−アルコキシカルボニルアミノ酸がＭＬＴＬの場合の析出温度は、濃度１５〜３０質量％のとき４５〜６５℃である。
3. Cooling Crystallization Step Next, the aromatic hydrocarbon solvent solution containing N-alkoxycarbonylamino acid prepared as described above is cooled to precipitate crystals.
The cooling rate is preferably 25 ° C./hr or less from the standpoints of crystal growth and crystal purity. Moreover, it is more preferable to set it as 20 degrees C / hr or less, and it is especially preferable to set it as 15 degrees C / hr or less.
The deposition temperature at which N-alkoxycarbonylamino acid precipitates from the aromatic hydrocarbon solvent solution varies depending on the type and concentration of N-alkoxycarbonylamino acid. Usually, it is -10-80 degreeC. For example, the precipitation temperature when the N-alkoxycarbonylamino acid is MLTL is 45 to 65 ° C. when the concentration is 15 to 30% by mass.
４．昇温工程
次に、結晶析出後、Ｎ−アルコキシカルボニルアミノ酸結晶が析出している芳香族炭化水素溶媒溶液を析出したＮ−アルコキシカルボニルアミノ酸結晶が完全に再溶解しない温度まで昇温し、Ｎ−アルコキシカルボニルアミノ酸結晶の一部を残存させて再溶解する。
一部が残存するＮ−アルコキシカルボニルアミノ酸結晶の量は、結晶成長の点で析出した結晶に対し０．５〜４０％とすることが好ましく、１〜２０％とすることが特に好ましい。
析出しているＮ−アルコキシカルボニルアミノ酸結晶の一部が残存した芳香族炭化水素溶媒溶液の昇温後の温度を０．１〜３時間保持しても良く、又は、直ちに再冷却しても良い。保持の間、結晶が析出している状態を維持できれば良く、攪拌等を行っても良い。
溶液に析出しているＮ−アルコキシカルボニルアミノ酸結晶の一部が残存した後、再度、該溶液を冷却する。冷却速度は、上述の条件と同じである。
4). Next, after the crystals are precipitated, the temperature is raised to a temperature at which the N-alkoxycarbonylamino acid crystals from which the aromatic hydrocarbon solvent solution in which the N-alkoxycarbonylamino acid crystals are precipitated are precipitated are not completely redissolved. A part of the alkoxycarbonylamino acid crystal remains and redissolves.
The amount of the partially remaining N-alkoxycarbonylamino acid crystal is preferably 0.5 to 40%, particularly preferably 1 to 20%, based on the crystal deposited in terms of crystal growth.
The temperature after raising the temperature of the aromatic hydrocarbon solvent solution in which some of the precipitated N-alkoxycarbonylamino acid crystals remain may be maintained for 0.1 to 3 hours, or may be immediately recooled. . It is only necessary to maintain the state in which crystals are precipitated during the holding, and stirring or the like may be performed.
After some of the N-alkoxycarbonylamino acid crystals precipitated in the solution remain, the solution is cooled again. The cooling rate is the same as that described above.
５．結晶の単離工程
Ｎ−アルコキシカルボニルアミノ酸結晶の単離は、ろ過又は遠心分離等により単離することができる。
単離温度は操作性、取り扱いに優れた結晶が収率良く得られれば特に制限されないが、−１０〜５０℃とすることが好ましい。この範囲内であると結晶の収率及び純度が高い点で好ましい。温度は、０〜４０℃とすることが特に好ましい。
5). Crystal Isolation Step N-alkoxycarbonylamino acid crystals can be isolated by filtration or centrifugation.
The isolation temperature is not particularly limited as long as crystals excellent in operability and handling can be obtained in good yield, but it is preferably −10 to 50 ° C. Within this range, the crystal yield and purity are preferred. The temperature is particularly preferably 0 to 40 ° C.
上述のようにして、Ｎ−アルコキシカルボニルアミノ酸の結晶を単離することにより粒度分布が粒子径１００μｍ以上、好ましくは、粒子径１０５〜３００μｍの範囲である結晶を８０質量％以上得ることができる。この範囲内の結晶であると結晶の取扱い性が良く好ましい。 By isolating N-alkoxycarbonylamino acid crystals as described above, 80% by mass or more of crystals having a particle size distribution of 100 μm or more, preferably a particle size of 105 to 300 μm, can be obtained. A crystal within this range is preferable because of its good handleability.
以下、本発明を実施例及び比較例により具体的に説明する。
なお、検出は、高速液体クロマトグラフィー（ＨＰＬＣ）を用いて行った。
＜Ｌ−ｔｅｒｔ−ロイシンのＨＰＬＣ分析条件＞
試料調製： 反応液を純水で希釈する
カラム： イナートシル ＯＤＳ−３Ｖ ＧＬサイエンス社製
移動層： ０．１％ リン酸水溶液（ｖ／ｖ）
流速： １ｍＬ／ｍｉｎ
検出： ＲＩ
Ｌ−ｔｅｒｔ−ロイシンの保持時間： 約８．７分
＜ＭＬＴＬのＨＰＬＣ分析条件＞
試料調製：反応液を移動層で希釈する
カラム： イナートシル ＯＤＳ−３Ｖ ＧＬサイエンス社製
移動層： ０．１％ リン酸水溶液（ｖ／ｖ）：アセトニトリル（７０：３０）
流速： １ｍＬ／ｍｉｎ
検出： ＵＶ（２１０ｎｍ）
各化合物の保持時間： ＭＬＴＬ 約７．７分
Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples.
The detection was performed using high performance liquid chromatography (HPLC).
<HPLC analysis conditions for L-tert-leucine>
Sample preparation: Column for diluting reaction solution with pure water: Inertosyl ODS-3V GL Sciences
Moving layer: 0.1% phosphoric acid aqueous solution (v / v)
Flow rate: 1mL / min
Detection: RI
L-tert-leucine retention time: about 8.7 minutes <MLTL HPLC analysis conditions>
Sample preparation: Column for diluting reaction solution in moving bed: Inertosyl ODS-3V GL Sciences
Moving layer: 0.1% phosphoric acid aqueous solution (v / v): acetonitrile (70:30)
Flow rate: 1mL / min
Detection: UV (210nm)
Retention time of each compound: MLTL about 7.7 minutes
＜ＭＬＴＬ結晶の化学純度のＨＰＬＣ分析条件＞
試料調製： 結晶を移動層に溶解し、０．５％ｗ／ｖ溶液を調整する
カラム： イナートシル ＯＤＳ−３Ｖ ＧＬサイエンス社製
移動層： ０．１％ リン酸水溶液（ｖ／ｖ）：アセトニトリル（７０：３０）
流速： １ｍＬ／ｍｉｎ
検出： ＵＶ（２１０ｎｍ）
<HPLC analysis conditions for chemical purity of MLTL crystals>
Sample preparation: Column in which 0.5% w / v solution is prepared by dissolving crystals in moving bed: Inertosyl ODS-3V GL Sciences
Moving layer: 0.1% phosphoric acid aqueous solution (v / v): acetonitrile (70:30)
Flow rate: 1mL / min
Detection: UV (210nm)
結晶の粒度分布は、下記の方法で行った。
＜ＭＬＴＬ結晶の粒度分布測定方法＞
装置：Ｒｏ−Ｔａｐ式フルイ振とう機 ＤＡ型 ＣＭＴ社製
機具：受器 ステンレス製、Φ２００ｍｍ
ふるい ステンレス製、Φ２００ｍｍ、目開き４５μｍ
ふるい ステンレス製、Φ２００ｍｍ、目開き７５μｍ
ふるい ステンレス製、Φ２００ｍｍ、目開き１０６μｍ
ふるい ステンレス製、Φ２００ｍｍ、目開き３００μｍ
受器、ふるいを積み上げ、目開き３００μｍのふるいの上に秤量したＭＬＴＬ結晶約２０ｇを移し、振とう機でふるいを１０分間振とうさせる。
ふるい上に残った結晶質量を算出し、粒度分布を求める。
The particle size distribution of the crystals was determined by the following method.
<Method for Measuring Particle Size Distribution of MLTL Crystal>
Equipment: Ro-Tap type sieve shaker DA type CMT equipment: Receiver Stainless steel, Φ200mm
Sieve made of stainless steel, Φ200mm, opening 45μm
Sieve made of stainless steel, Φ200mm, aperture 75μm
Sieve made of stainless steel, Φ200mm, aperture 106μm
Sieve made of stainless steel, Φ200mm, opening 300μm
The receiver and the sieve are stacked, and about 20 g of the weighed MLTL crystal is transferred onto a sieve having an opening of 300 μm, and the sieve is shaken for 10 minutes with a shaker.
The crystal mass remaining on the sieve is calculated to determine the particle size distribution.
結晶の溶媒付着量は、下記の方法で行った。
＜ＭＬＴＬ結晶の溶媒付着量測定方法＞
真空乾燥操作の質量減少量から計算する。
The amount of the solvent adhered to the crystal was measured by the following method.
<Measurement method of solvent adhesion amount of MLTL crystal>
Calculated from the weight loss of vacuum drying operation
[調製例１] ＭＬＴＬの調製
Ｌ−ｔｅｒｔ−ロイシン（東京化成（株）製）１３１．１ｇ（１．００ｍｏｌ）を２９３．３ｇ（１．１０ｍｏｌ）の１５％ｗｔNaOH水溶液に添加後、攪拌して溶解させた。次いで、これを攪拌しながらクロロギ酸メチル１０３．８ｇ（１．１０ｍｏｌ）を２時間かけて加えた。
Ｎ−アルコキシカルボニル化反応中は２０℃で反応液のｐＨが１２．２〜１２．６になるように適宜２５％ｗｔＮａＯＨ水溶液を加えた。その後、ＨＰＬＣ分析によりＬ−ｔｅｒｔ−ロイシンが９９％以上消費されたことを確認し反応を終了した。この時、ＭＬＴＬ生成量はＨＰＬＣ分析より１８７．３ｇ（収率９９％）であった。
このＭＬＴＬ水溶液にトルエン４００ｇを加え、次いで、３６％塩酸を水相のｐＨが１．５になるまで加えた。ｐＨを１．５に調整後、この溶液を５０℃で０．５時間、撹拌により混合した。その後、静置して分相し、ＭＬＴＬを含むトルエン溶液５９５．０ｇを回収した。このトルエン溶液の内温を５０℃に保持しながら３８ｇの水で洗浄した。水洗浄後回収したＭＬＴＬを含むトルエン溶液の水分濃度をカールフィッシャー水分測定器で測定したところ、水分濃度は１．４質量％であった。このＭＬＴＬ含むトルエン溶液にさらにトルエン８００ｇを加え、内温を５５〜６５℃に保持しながら全体量が９００ｇになるまで減圧濃縮した。これにトルエン８００ｇを加え、同様の条件で全体量が９３５ｇになるまで減圧濃縮し共沸脱水した。共沸脱水後トルエン溶液の水分濃度は０．００９質量％であった。トルエン溶液を内温が７０℃になるまで加温した後、熱時ろ過して微量不溶分を除去した。ろ液としてＭＬＴＬを含むトルエン溶液９３０ｇ（ＭＬＴＬ濃度２０質量％）を回収した。
[Preparation Example 1] Preparation of MLTL After adding 131.1 g (1.00 mol) of L-tert-leucine (manufactured by Tokyo Chemical Industry Co., Ltd.) to 293.3 g (1.10 mol) of 15% wt NaOH aqueous solution, the mixture was stirred. Dissolved. Next, 103.8 g (1.10 mol) of methyl chloroformate was added over 2 hours while stirring.
During the N-alkoxycarbonylation reaction, a 25% wt NaOH aqueous solution was appropriately added so that the pH of the reaction solution was 12.2 to 12.6 at 20 ° C. Thereafter, HPLC analysis confirmed that 99% or more of L-tert-leucine had been consumed, and the reaction was completed. At this time, the MLTL production was 187.3 g (99% yield) from HPLC analysis.
To this MLTL aqueous solution was added 400 g of toluene, and then 36% hydrochloric acid was added until the pH of the aqueous phase reached 1.5. After adjusting the pH to 1.5, the solution was mixed by stirring at 50 ° C. for 0.5 hour. Then, it left still and phase-separated and 595.0 g of toluene solutions containing MLTL were collect | recovered. The toluene solution was washed with 38 g of water while maintaining the internal temperature at 50 ° C. When the water concentration of the toluene solution containing MLTL collected after washing with water was measured with a Karl Fischer moisture meter, the water concentration was 1.4% by mass. 800 g of toluene was further added to the toluene solution containing MLTL, and the mixture was concentrated under reduced pressure until the total amount reached 900 g while maintaining the internal temperature at 55 to 65 ° C. To this, 800 g of toluene was added, and concentrated under reduced pressure until the total amount became 935 g under the same conditions, followed by azeotropic dehydration. The water concentration of the toluene solution after azeotropic dehydration was 0.009% by mass. The toluene solution was heated until the internal temperature reached 70 ° C., and then filtered while hot to remove trace insolubles. As a filtrate, 930 g of a toluene solution containing MLTL (MLTL concentration 20 mass%) was recovered.
[実施例１]
調製例１で得られたＭＬＴＬを含むトルエン溶液を内温７０℃で攪拌しながら１５℃〜１８℃／hrの冷却速度で冷却した。内温５２℃でＭＬＴＬ結晶が析出したことを目視で確認した。その後、内温を６０℃まで昇温してから６０℃で１時間攪拌した。この時、析出したＭＬＴＬ結晶は完全に溶解せずに一部残存していることを確認した。昇温前と昇温後の上清ＭＬＴＬ濃度をＨＰＬＣで分析、一部残存したＮ−アルコキシカルボニルアミノ酸結晶の量は、結晶成長の点で析出した結晶に対し３％であった。攪拌後、１５℃〜１８℃／hrの冷却速度で該溶液を内温１０℃まで冷却し、その後、１０℃で１時間攪拌した。減圧ろ過によりＭＬＴＬ結晶を回収し、次いで少量のトルエンで結晶を洗浄した。湿結晶を真空乾燥後、１７９．７ｇのＭＬＴＬ結晶が得られた（９５％Ｙｄ．）。
得られたＭＬＴＬ結晶の粒度分布は、粒子径１０６μｍ〜２９９μｍの範囲に８０．４０質量％であった。
化学純度は９９．９％以上であり不純物はＨＰＬＣ検出限界値以下であった。溶媒付着量は、対ＭＬＴＬ質量比で２．６％であった。
[Example 1]
The toluene solution containing MLTL obtained in Preparation Example 1 was cooled at a cooling rate of 15 ° C. to 18 ° C./hr while stirring at an internal temperature of 70 ° C. It was visually confirmed that MLTL crystals were precipitated at an internal temperature of 52 ° C. Thereafter, the internal temperature was raised to 60 ° C., followed by stirring at 60 ° C. for 1 hour. At this time, it was confirmed that the precipitated MLTL crystals were not completely dissolved but partially remained. The supernatant MLTL concentration before and after the temperature increase was analyzed by HPLC, and the amount of the partially remaining N-alkoxycarbonylamino acid crystals was 3% with respect to the crystals precipitated in terms of crystal growth. After stirring, the solution was cooled to an internal temperature of 10 ° C. at a cooling rate of 15 ° C. to 18 ° C./hr, and then stirred at 10 ° C. for 1 hour. MLTL crystals were recovered by vacuum filtration, and then washed with a small amount of toluene. After the wet crystals were vacuum dried, 179.7 g of MLTL crystals were obtained (95% Yd.).
The particle size distribution of the obtained MLTL crystal was 80.40% by mass in a particle diameter range of 106 μm to 299 μm.
The chemical purity was 99.9% or more, and the impurities were below the HPLC detection limit. The amount of solvent adhesion was 2.6% in terms of MLTL mass ratio.
[参考例１]
６０℃まで昇温して同温度で１時間攪拌する操作を省略した以外は実施例１と同様の方法で行った。湿結晶を真空乾燥後、１７７．９ｇのＭＬＴＬ結晶が得られた（９４％Ｙｄ．）。
得られたＭＬＴＬ結晶の粒度分布は粒子径７５μｍ〜１０５μｍの範囲に８２．９６質量％であった。
化学純度は９９．７％であった。溶媒付着量は、対ＭＬＴＬ質量比で１５．６％であった。
[Reference Example 1]
The procedure was the same as in Example 1 except that the operation of raising the temperature to 60 ° C. and stirring at the same temperature for 1 hour was omitted. After the wet crystals were vacuum dried, 177.9 g of MLTL crystals were obtained (94% Yd.).
The particle size distribution of the obtained MLTL crystal was 82.96% by mass in the particle size range of 75 μm to 105 μm.
The chemical purity was 99.7%. The amount of solvent adhesion was 15.6% in terms of MLTL mass ratio.
[実施例２]
化学純度９９．５％のＭＬＴＬ結晶１００ｇをトルエン４００ｇ中に加え、７０℃まで昇温して結晶を溶解させた。７０℃で熱時ろ過後、得られたろ液を攪拌しながら１５℃／hrの冷却速度で冷却した。内温５５℃でＭＬＴＬ結晶が析出したことを目視で確認した。その後、内温を６０℃まで昇温し、その後、６０℃で１時間攪拌した。この時、析出したＭＬＴＬ結晶は完全に溶解せずに一部残存していることを確認した。昇温前と昇温後の上清ＭＬＴＬ濃度をＨＰＬＣで分析、一部残存したＮ−アルコキシカルボニルアミノ酸結晶の量は、結晶成長の点で析出した結晶に対し５％であった。攪拌後、１５〜２０℃／hrの冷却速度で該溶液を１０℃まで冷却、その後１０℃で１時間攪拌した。減圧ろ過によりＭＬＴＬ結晶を回収し、次いで少量のトルエンで結晶を洗浄した。湿結晶を真空乾燥後、９８ｇのＭＬＴＬ結晶が得られた（９８％Ｙｄ．）。
得られたＭＬＴＬ結晶の粒度分布は粒子径１０６μｍ〜２９９μｍの範囲に８５．１質量％であった。化学純度は９９．９％以上であり不純物はＨＰＬＣ検出限界値以下であった。溶媒付着量は、対ＭＬＴＬ質量比で２．０％であった。
[Example 2]
100 g of MLTL crystals having a chemical purity of 99.5% were added to 400 g of toluene, and the temperature was raised to 70 ° C. to dissolve the crystals. After hot filtration at 70 ° C., the obtained filtrate was cooled at a cooling rate of 15 ° C./hr while stirring. It was visually confirmed that MLTL crystals were precipitated at an internal temperature of 55 ° C. Thereafter, the internal temperature was raised to 60 ° C., and then stirred at 60 ° C. for 1 hour. At this time, it was confirmed that the precipitated MLTL crystals were not completely dissolved but partially remained. The supernatant MLTL concentration before and after the temperature increase was analyzed by HPLC, and the amount of the partially remaining N-alkoxycarbonylamino acid crystals was 5% with respect to the precipitated crystals in terms of crystal growth. After stirring, the solution was cooled to 10 ° C. at a cooling rate of 15 to 20 ° C./hr, and then stirred at 10 ° C. for 1 hour. MLTL crystals were recovered by vacuum filtration, and then washed with a small amount of toluene. After the wet crystals were vacuum dried, 98 g of MLTL crystals were obtained (98% Yd.).
The particle size distribution of the obtained MLTL crystal was 85.1% by mass in the particle size range of 106 μm to 299 μm. The chemical purity was 99.9% or more, and the impurities were below the HPLC detection limit. The solvent adhesion amount was 2.0% in terms of MLTL mass ratio.
Claims (2)
（Ａ）Ｎ−アルコキシカルボニルアミノ酸を含む芳香族炭化水素溶媒溶液を冷却晶析する工程
（Ｂ）その後、Ｎ−アルコキシカルボニルアミノ酸結晶が析出している芳香族炭化水素溶媒溶液をＮ−アルコキシカルボニルアミノ酸結晶の一部が残存する温度まで昇温した後に冷却する工程
（Ｃ）次いで、Ｎ−アルコキシカルボニルアミノ酸結晶を単離する工程 A method for producing an N-alkoxycarbonylamino acid crystal comprising at least the following steps (A) to (C).
(A) Step of cooling and crystallizing an aromatic hydrocarbon solvent solution containing N-alkoxycarbonylamino acid (B) Thereafter, the aromatic hydrocarbon solvent solution in which N-alkoxycarbonylamino acid crystals are precipitated is converted to N-alkoxycarbonylamino acid. A step of cooling after raising the temperature to a temperature at which a part of the crystals remains (C) and then a step of isolating N-alkoxycarbonylamino acid crystals
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006062621A JP5318330B2 (en) | 2006-03-08 | 2006-03-08 | Method for producing N-alkoxycarbonylamino acid crystals |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006062621A JP5318330B2 (en) | 2006-03-08 | 2006-03-08 | Method for producing N-alkoxycarbonylamino acid crystals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2007238495A true JP2007238495A (en) | 2007-09-20 |
| JP5318330B2 JP5318330B2 (en) | 2013-10-16 |
Family
ID=38584379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006062621A Expired - Fee Related JP5318330B2 (en) | 2006-03-08 | 2006-03-08 | Method for producing N-alkoxycarbonylamino acid crystals |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP5318330B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010122682A1 (en) * | 2009-04-24 | 2010-10-28 | 株式会社カネカ | PROCESS FOR PRODUCTION OF N-ALKOXYCARBONYL-tert-LEUCINES |
| CN115286536A (en) * | 2022-07-05 | 2022-11-04 | 南京安淮创新药物研究院有限公司 | Crystallization and purification method of product after amino group in amino acid is grafted with protecting group |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62247802A (en) * | 1986-03-18 | 1987-10-28 | Daicel Chem Ind Ltd | Crystallization method |
| JPH026399A (en) * | 1987-12-25 | 1990-01-10 | Toray Ind Inc | Production of organic compound crystal |
| JPH09278683A (en) * | 1996-04-12 | 1997-10-28 | Mitsubishi Gas Chem Co Inc | Production of high-purity 2,6-dimethylnaphthalene |
| JP2003146962A (en) * | 2001-11-09 | 2003-05-21 | Mitsubishi Rayon Co Ltd | Method for recovering n-alkoxycarbonyl-tert-leucine |
-
2006
- 2006-03-08 JP JP2006062621A patent/JP5318330B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62247802A (en) * | 1986-03-18 | 1987-10-28 | Daicel Chem Ind Ltd | Crystallization method |
| JPH026399A (en) * | 1987-12-25 | 1990-01-10 | Toray Ind Inc | Production of organic compound crystal |
| JPH09278683A (en) * | 1996-04-12 | 1997-10-28 | Mitsubishi Gas Chem Co Inc | Production of high-purity 2,6-dimethylnaphthalene |
| JP2003146962A (en) * | 2001-11-09 | 2003-05-21 | Mitsubishi Rayon Co Ltd | Method for recovering n-alkoxycarbonyl-tert-leucine |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010122682A1 (en) * | 2009-04-24 | 2010-10-28 | 株式会社カネカ | PROCESS FOR PRODUCTION OF N-ALKOXYCARBONYL-tert-LEUCINES |
| CN115286536A (en) * | 2022-07-05 | 2022-11-04 | 南京安淮创新药物研究院有限公司 | Crystallization and purification method of product after amino group in amino acid is grafted with protecting group |
| CN115286536B (en) * | 2022-07-05 | 2023-10-27 | 南京安淮创新药物研究院有限公司 | Crystallization and purification method for product after amino group in amino acid is accessed with protecting group |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5318330B2 (en) | 2013-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2185510B1 (en) | New salts of bazedoxifene | |
| TW201429924A (en) | Production method of refined amine compound | |
| JP5318330B2 (en) | Method for producing N-alkoxycarbonylamino acid crystals | |
| JP4972643B2 (en) | Method for producing crystalline perindopril | |
| JP2003342269A (en) | Method for reducing taxane | |
| CN105418477B (en) | The method for reducing diastereoisomer impurity content in Lei Dipawei intermediate | |
| JP2007332050A (en) | Manufacturing method of optically active n-tert-butylcarbamoyl-l-tert-leucine | |
| US20120271056A1 (en) | Process for the preparation of crystalline form i of l-malic acid salt of sunitinib | |
| JP4721339B2 (en) | Method for producing N-alkoxycarbonylamino acid | |
| US20130123511A1 (en) | Process for the direct preparation of malic acid salt of sunitinib | |
| US10259770B2 (en) | Process for the preparation of ethacrynic acid | |
| JP2981323B2 (en) | Method for isolating 2-bisarylamino-9,9-dialkylfluorene | |
| CN111662233B (en) | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method | |
| CN103781767B (en) | The preparation method of S 16257-2 and synthetic intermediate thereof | |
| TWI360545B (en) | Process for the preparation of 4, 10β-diacetoxy-2α | |
| JP6856365B2 (en) | Manufacturing method of azilsartan | |
| JP2016064988A (en) | Method for manufacturing tartrate of 1-(3-benzoyloxy propyl)-7-cyano-5-[(2r)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline | |
| JP6147546B2 (en) | Method for producing telmisartan A-type crystals with reduced acetic acid | |
| JP2003146962A (en) | Method for recovering n-alkoxycarbonyl-tert-leucine | |
| JP2005068066A (en) | Method for purifying 2,6-diisopropylaniline | |
| CN113024433A (en) | Preparation method of amisulpride sulfoxide impurities | |
| JP2010184904A (en) | Method for producing acetic acid compound | |
| WO2010079605A1 (en) | Process for producing high-purity 1-benzyl-3-aminopyrrolidine | |
| JP2022028990A (en) | Production method for amide alcohol compound | |
| JPH0253782A (en) | Production of formylaminothiazoleacetic acid derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090115 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20111118 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20111124 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120112 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20120202 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130603 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130710 |
|
| LAPS | Cancellation because of no payment of annual fees |