JP2004010483A - Method for purifying l-lysine aminoethyl ester trihydrochloride - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for purifying a high-purity L-lysine aminoethyl ester trihydrochloride by which the recyclability of a recrystallizing solvent for purification is excellent in a simple process. <P>SOLUTION: The method for purifying the L-lysine aminoethyl ester trihydrochloride comprises using a mixed solution of an aromatic hydrocarbon with alcohols as a solvent for crystallization. Xylene or toluene is preferred as the aromatic hydrocarbon and methanol is preferred as the alcohols. <P>COPYRIGHT: (C)2004,JPO

Description

【０００９】
Ｌ−リジンアミノエチルエステル・３塩酸塩を含む混合物は、リジン２塩酸塩とエタノールアミン塩酸塩を原料として、塩化水素ガスを触媒としてエステル化反応を行うことにより合成される。リジン・２塩酸塩とエタノールアミン塩酸塩とのモル比は、１：０．８〜５、好ましくは１：１．２〜３．０である。用いる塩化水素ガスの量は、リジン・２塩酸塩１モル当たり毎分５０〜１０００ｍｌ（常温常圧換算）である。反応は、２０．０ｋＰａ〜５３．３ｋＰａ（絶対圧換算）、好ましくは２６．７ｋＰａ〜−４０．０ｋＰａ（絶対圧換算）の減圧下、温度５０〜１６０℃、好ましくは９０〜１３０℃で３〜１５時間行われる。
【００１０】
エステル化を行うことにより得られる上記のＬ−リジンアミノエチルエステル・３塩酸塩を含む混合物には、目的物であるＬ−リジンアミノエチルエステル・３塩酸塩以外に、原料であるリジン・２塩酸塩やエタノールアミン塩酸塩及びエタノールアミン塩酸塩と塩酸が反応して生成する副生物であるクロロエチルアミン塩酸塩が含まれる。
本発明の方法は、それらの不純物を効率的に除去する方法であって、Ｌ−リジンアミノエチルエステル・３塩酸塩を含む混合物を特定の有機溶媒に加熱溶解した後に、結晶化させる方法である。
ここで、有機溶媒として用いるアルコール類と芳香族炭化水素としては、それぞれ、アルコール類としてはメタノール等があげられ、芳香族炭化水素としてはキシレン、トルエン等があげられる。
【００１１】
結晶化の際の温度は、１０〜１００℃、好ましくは４０〜８０℃で行われる。
溶媒の添加については、一度に添加してもよく、好ましくは、溶媒を分割滴下する。例えば、メタノール７５〜９５重量％、キシレン（ｏ−キシレン、ｍ−キシレン、ｐ−キシレン・工業用）またはトルエン５〜２５重量％の混合溶液の量を、混合物中に含有するＬ−リジンアミノエチルエステル・３塩酸塩重量に対し、好ましくは３〜１０倍、さらに好ましくは４〜７倍、最も好ましくは５〜６倍程度用いて溶解し、含有しているＬ−リジンアミノエチルエステル・３塩酸塩に対して好ましくは０．５〜１５重量％相当の種晶を加たえた後、１〜５時間熟成し室温まで４〜２０時間かけて冷却し、室温下で１〜５時間晶析する。
また、反応物をメタノールに溶解した後に、種晶を加えてキシレンまたはトルエンを１〜６時間かけて滴下することでも同様の効果が得られる。
なお、種晶を加える際の温度としては、特に限定されないが、６０℃から使用される晶析溶媒の沸点の範囲であることが好ましい。
【００１２】
晶析後は、結晶を濾別し、５０〜８０℃及び２．７ｋＰａ〜５．３ｋＰａ（絶対圧換算）の減圧下で乾燥し、Ｌ−リジンアミノエチルエステル・３塩酸塩の結晶を高収率および高純度で得ることができる。
得られた結晶は、晶析に使用した溶媒と同じ組成の溶媒で洗浄してもよく、その際に使用される溶媒は、結晶に対して、０．５〜５倍量（重量比）であるのが好ましい。
本発明の方法によって得られた、Ｌ−リジンアミノエチルエステル・３塩酸塩は、公知の方法（特公昭６０−２６７７５号公報）に準じて、ホスゲンと反応させることにより、リジントリイソシアネートとすることができ、該化合物は、ポリウレタンの原料（ＷＯ９６／１７８８１等）等として使用することができる。
また、本発明の方法で得られるＬ−リジンアミノエチルエステル・３塩酸塩は、高純度であるため、ホスゲンとの反応速度が速い。
【００１３】
【実施例】
本発明を以下の実施例により詳細に説明するが、本発明はこれらの実施例により限定されるものではない。
実施例のＨＰＬＣ条件は、以下の方法で分析を行った。
【００１４】
分析機器（島津製作所社製ＨＰＬＣ）
・ポンプ：ＬＣ−１０Ａｉ
・データ処理装置：ｃｌａｓｓ−ＬＣ１０
・カラムオーブン：ＣＴＯ−１０Ａ
・検出器：ＲＩＤ−１０Ａ
・オートサンプラー：ＳＩＬ−１０Ａｉ
【００１５】
分析条件
・カラムオーブン温度：３０℃
・流量：０．７ｍｌ／ｍｉｎ
・移動相：過塩素酸（７０％）を５２０ｍｍοｌ／リットルの濃度に正確に蒸留水を用いて調製する。調製後、脱気して使用する。
・カラム：ＣＲＯＷＮＰＡＫ　ＣＲ（＋），（ダイセル化学工業社製）
・内部標準液：ο−トルイジンを３ｍｇ／ｍｌの濃度に正確に移動相で調製する。
・サンプル調製：サンプルを約１００ｍｇ正確に測り取る。その中に、内部標準液を５ｍｌのホールピッペトで正確に測り取り添加する。混合した後、ＨＰＬＣへ５μｌ注入し分析を開始する。
・計算方法：内部標準法
・濾過速度の測定：真空中を４．０〜５．０ｋＰａ（絶対圧換算）に制御した状態で、晶析溶液を桐山ロート（φ６０ｍｍ）に投入した時点から母液が出なくなるまでの濾過時間と濾別した母液量を測定し、下記の計算を用いて濾過速度を算出した。
【００１６】
【数１】

【００１７】
参考例
リジン・１塩酸塩１８２ｇ（１モル）を濃塩酸（３５％）３１５ｇ（３モル）と混合し溶解する。その後に、冷却し、内温を２０〜５０℃に保持しながら、エタノールアミン１９５ｇ（２モル）を添加した。
この混合物を掻き混ぜ機を付けた１リットルの反応フラスコに入れ、３３．３ｋＰａ（絶対圧換算）で水を留去させながら、１１５℃で塩化水素ガス［塩化水素ガスの量はリジン・２塩酸塩１モル当り毎分１０００ｍｌ（常温常圧換算）］を導入して５時間、エステル化反応行い、エステル化率約６５％の反応物を得た。
また、前記と同様に、エステル化反応を１０時間、行うことにより、エステル化率７５％の反応物を得た。
ここで、エステル化率とは、以下の式で表わされる値のことである。
【００１８】
エステル化率（％）＝（Ａ／Ｂ）×１００
Ａ：生成したＬ−リジンアミノエチルエステル・３塩酸塩のモル数
Ｂ：原料で使用されたリジン・１塩酸塩のモル数
【００１９】
実施例１
参考例で得られた、エステル化率６５％の反応物４００ｇ（Ｌ−リジンアミノエチルエステル・３塩酸塩が、４８％含有物）に対し、メタノール７３３ｇ，キシレン２０５ｇの混合液を加えて６０℃まで加熱し、溶解後、６０℃で種晶を加え、６０℃から４０℃まで４時間かけて冷却し、４０℃から室温（２０℃）まで６時間かけて冷却した。
析出した結晶を濾別し、晶析時と同一組成のメタノール／キシレン混合液３２１．３ｇを用いて結晶を洗浄し、湿結晶を得た。
この結晶を６０℃及び２．７ｋＰａ〜５．３ｋＰａ（絶対圧換算）の減圧下で乾燥し、Ｌ−リジンアミノエチルエステル・３塩酸塩の結晶を１５５ｇ得た。
この際の収率は８０％であり、結晶の純度は、高速液体クロマトグラフィー（以下、ＨＰＬＣと略す）分析により測定した結果、９９％以上であった。また、結晶の形状は、顕微鏡による観察の結果１×１００μｍ程度（長径）の針状結晶であった。
【００２０】
実施例２
参考例で得られたエステル化率７５％の反応物４００ｇ（Ｌ−リジンアミノエチルエステル・３塩酸塩、５６％含有物）に対し、メタノール８４５ｇ、キシレン１１８ｇの混合液を加えて６０℃まで加熱し溶解後、６０℃で種晶を加え、６０℃から４０℃まで４時間かけて冷却し、４０℃から室温（２０℃）まで６時間かけて冷却した。
得られた結晶を濾別し、晶析時と同一組成のメタノール／キシレン混合液３２１．３ｇを用いて結晶を洗浄し、湿結晶を得た。
この湿結晶を、６０℃及び、２．７ｋＰａ〜５．３ｋＰａ（絶対圧換算）の減圧下で乾燥し、Ｌ−リジンアミノエチルエステル・３塩酸塩の結晶を１８０ｇ得た。
この際の収率は８０％であり、結晶の純度は、ＨＰＬＣにより測定した結果、９９％以上であった。また、結晶の形状は、顕微鏡による観察の結果、１×１００μｍ程度（長径）の針状結晶であった。
【００２１】
比較例１
実施例２と同様、エステル化率７５％の反応物（Ｌ−リジンアミノエチルエステル・３塩酸塩が５６％含有物）４００ｇに対し、メタノール８４５ｇ、エタノール１００ｇの混合液を加えて、６０℃まで加熱し、溶解後、６０℃で種晶を加えて結晶の析出が確認後に熟成を行い、エタノール１０９ｇをゆっくり滴下した。その後、室温まで冷却して晶析した。
得られた結晶を濾別し、晶析時と同一組成のメタノール／エタノール混合液３２１．３ｇを用いて結晶を洗浄し、湿結晶を得た。
この湿結晶を６０℃及び２．７ｋＰａ〜５．３ｋＰａ（絶対圧換算）の減圧下で乾燥し、Ｌ−リジンアミノエチルエステル・３塩酸塩の結晶を１４６ｇ得た。
この際の収率は、６５％であり、結晶の純度は、ＨＰＬＣにより測定した結果、９８％以上であった。また、結晶の形状は、顕微鏡による観察の結果、１×１０μｍ程度（長径）の微細な針状結晶であった。
【００２２】
実施例１〜２及び比較例１におけるＬ−リジンアミノエチルエステル・３塩酸塩の結晶のＨＰＬＣ分析結果や濾別効果（固液分離）について評価した結果を表−１に示す。
【００２３】
【表１】

【００２４】
【発明の効果】
本発明の精製法は、晶析の溶媒として芳香族炭化水素とアルコール類の混合溶液を用いることにより、固液分離が簡便で迅速に、且、高純度のＬ−リジンアミノエチルエステル・３塩酸塩を得ることができ、また用いた晶析用溶媒はリサイクル性に優れる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for purifying L-lysine aminoethyl ester trihydrochloride. The resulting L-lysine aminoethyl ester trihydrochloride is phosgenated to give an isosonate, which can be used as a raw material for polyurethane.
[0002]
[Prior art]
As a method for producing L-lysine aminoethyl ester trihydrochloride, there is a method proposed in JP-A-55-105649. In this method, when performing esterification by heating and reacting an amino acid hydrochloride and an amino alcohol hydrochloride, hydrogen chloride gas is absorbed into the reaction system in the absence of an organic solvent that forms an azeotropic compound with water, and esterification is performed. It is stated that, as a purification method, a method of purifying a mixed solvent of alcohols (methanol, ethanol, propanol, isopropanol) as a recrystallization solvent is effective.
[0003]
However, in the above-mentioned recrystallization method, impurities cannot be sufficiently removed, and recrystallization is repeatedly performed, so that the steps are lengthened, the cost is increased, and the production efficiency is reduced. Having. Further, when recovering the filtered washing liquid for recycling, a mixed solvent of lower alcohols having little difference in boiling point has a drawback in that it is difficult to separate each alcohol by purified distillation, and it is difficult to reuse the alcohol.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for purifying L-lysine aminoethyl ester trihydrochloride having high purity and excellent recyclability of a recrystallization solvent for purification in a simple step.
[0005]
[Means for Solving the Problems]
As a result of intensive studies, the present inventors have found that the above-mentioned disadvantages of the conventional technique can be overcome by devising the composition of the solvent for crystallization, and have accomplished the present invention.
That is, the present invention relates to the following (1) to (3).
(1) A method for purifying L-lysine aminoethyl ester trihydrochloride, wherein a mixed solution of an aromatic hydrocarbon and an alcohol is used as a crystallization solvent.
(2) The method for purifying L-lysineaminoethyl ester trihydrochloride according to (1), wherein the aromatic hydrocarbon is xylene or toluene.
(3) The method for purifying L-lysineaminoethyl ester trihydrochloride according to (1), wherein the alcohol is methanol.
[0006]
According to the method of the present invention, L-lysineaminoethyl ester trihydrochloride can be purified in a simple step, quickly, with high purity, and with high yield. Further, the recrystallization solvent used in the present invention is easily separated by distillation or the like and has excellent recyclability.
Furthermore, the crystals of L-lysineaminoethyl ester trihydrochloride obtained by the purification method of the present invention have a large crystal diameter and do not become clogged in a filtration membrane or the like at the time of filtration. fast.
Therefore, the purification method of the present invention is excellent in production efficiency because the obtained L-lysine aminoethyl ester trihydrochloride has a high filtration rate.
[0007]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
L-Lysine aminoethyl ester trihydrochloride purified by the method of the present invention is represented by the following structural formula.
[0008]
Embedded image

[0009]
The mixture containing L-lysine aminoethyl ester · 3 hydrochloride is synthesized by performing an esterification reaction using lysine dihydrochloride and ethanolamine hydrochloride as raw materials and using hydrogen chloride gas as a catalyst. The molar ratio of lysine dihydrochloride to ethanolamine hydrochloride is from 1: 0.8 to 5, preferably from 1: 1.2 to 3.0. The amount of hydrogen chloride gas used is 50 to 1000 ml per minute (converted to normal temperature and normal pressure) per mole of lysine dihydrochloride. The reaction is carried out under a reduced pressure of 20.0 kPa to 53.3 kPa (in terms of absolute pressure), preferably 26.7 kPa to -40.0 kPa (in terms of absolute pressure), at a temperature of 50 to 160 ° C., preferably 90 to 130 ° C. Performed for 15 hours.
[0010]
The mixture containing the L-lysine aminoethyl ester trihydrochloride obtained by the esterification contains, in addition to the target L-lysine aminoethyl ester trihydrochloride, the raw material lysine dihydrochloride. Salts and ethanolamine hydrochloride, and chloroethylamine hydrochloride, which is a by-product formed by the reaction of ethanolamine hydrochloride with hydrochloric acid, are included.
The method of the present invention is a method for efficiently removing these impurities, and is a method for heating and dissolving a mixture containing L-lysine aminoethyl ester trihydrochloride in a specific organic solvent and then crystallizing the mixture. .
Here, the alcohols and aromatic hydrocarbons used as the organic solvent include, for example, methanol and the like, and the aromatic hydrocarbons include xylene and toluene, respectively.
[0011]
The crystallization is performed at a temperature of 10 to 100 ° C, preferably 40 to 80 ° C.
As for the addition of the solvent, the solvent may be added all at once, and preferably, the solvent is added dropwise. For example, L-lysineaminoethyl containing 75 to 95% by weight of methanol, xylene (o-xylene, m-xylene, p-xylene for industrial use) or 5 to 25% by weight of toluene in a mixture. L-Lysine aminoethyl ester / 3 hydrochloric acid dissolved and used preferably in an amount of about 3 to 10 times, more preferably about 4 to 7 times, and most preferably about 5 to 6 times the weight of the ester / 3 hydrochloride. After adding 0.5 to 15% by weight of a seed crystal to the salt, the mixture is aged for 1 to 5 hours, cooled to room temperature over 4 to 20 hours, and crystallized at room temperature for 1 to 5 hours. .
The same effect can be obtained by dissolving the reaction product in methanol, adding seed crystals, and dropping xylene or toluene over 1 to 6 hours.
The temperature at which the seed crystal is added is not particularly limited, but is preferably in the range of 60 ° C. to the boiling point of the crystallization solvent used.
[0012]
After the crystallization, the crystals are separated by filtration, and dried under reduced pressure of 50 to 80 ° C. and 2.7 kPa to 5.3 kPa (in absolute pressure) to obtain crystals of L-lysine aminoethyl ester trihydrochloride in high yield. It can be obtained in high purity and purity.
The obtained crystal may be washed with a solvent having the same composition as the solvent used for crystallization, and the solvent used at that time is 0.5 to 5 times (weight ratio) with respect to the crystal. Preferably it is.
The L-lysine aminoethyl ester trihydrochloride obtained by the method of the present invention is converted to lysine triisocyanate by reacting with phosgene according to a known method (Japanese Patent Publication No. 60-27675). The compound can be used as a raw material of polyurethane (WO96 / 17881, etc.).
Moreover, since the L-lysine aminoethyl ester trihydrochloride obtained by the method of the present invention has high purity, the reaction rate with phosgene is high.
[0013]
【Example】
The present invention will be described in detail with reference to the following examples, but the present invention is not limited to these examples.
The HPLC conditions of the examples were analyzed by the following method.
[0014]
Analytical instruments (HPLC manufactured by Shimadzu Corporation)
・ Pump: LC-10Ai
-Data processing device: class-LC10
・ Column oven: CTO-10A
・ Detector: RID-10A
・ Autosampler: SIL-10Ai
[0015]
Analysis conditions and column oven temperature: 30 ° C
・ Flow rate: 0.7ml / min
Mobile phase: Perchloric acid (70%) is prepared using distilled water exactly to a concentration of 520 mmol / l. After preparation, use after degassing.
・ Column: CROWNPAK CR (+), (manufactured by Daicel Chemical Industries, Ltd.)
-Internal standard solution: Prepare o-toluidine in a mobile phase exactly to a concentration of 3 mg / ml.
-Sample preparation: accurately measure about 100 mg of sample. In it, the internal standard solution is accurately measured with a 5 ml whole pipet and added. After mixing, 5 μl is injected into the HPLC to start the analysis.
-Calculation method: Internal standard method-Filtration rate measurement: The mother liquor was obtained from the time when the crystallization solution was put into a Kiriyama funnel (φ60 mm) while controlling the vacuum at 4.0 to 5.0 kPa (absolute pressure conversion). The filtration time until no more liquid was obtained and the amount of mother liquor separated by filtration were measured, and the filtration speed was calculated using the following calculation.
[0016]
(Equation 1)

[0017]
Reference Example 182 g (1 mol) of lysine monohydrochloride is mixed with 315 g (3 mol) of concentrated hydrochloric acid (35%) and dissolved. Thereafter, while cooling and maintaining the internal temperature at 20 to 50 ° C, 195 g (2 mol) of ethanolamine was added.
This mixture was placed in a 1-liter reaction flask equipped with a stirrer, and while distilling off water at 33.3 kPa (in absolute pressure), hydrogen chloride gas [the amount of hydrogen chloride gas was lysine / dihydrochloric acid at 115 ° C.] An esterification reaction was carried out for 5 hours by introducing 1000 ml per minute (equivalent to normal temperature and normal pressure) per 1 mol of salt, and a reaction product having an esterification rate of about 65% was obtained.
In addition, similarly to the above, the esterification reaction was performed for 10 hours to obtain a reaction product having an esterification rate of 75%.
Here, the esterification ratio is a value represented by the following equation.
[0018]
Esterification rate (%) = (A / B) × 100
A: number of moles of L-lysine aminoethyl ester trihydrochloride produced B: number of moles of lysine monohydrochloride used as a raw material
Example 1
A mixture of 733 g of methanol and 205 g of xylene was added to 400 g of the reaction product (containing 48% of L-lysine aminoethyl ester / 3 hydrochloride) having an esterification rate of 65% obtained in Reference Example, and the mixture was heated to 60 ° C. After heating and dissolving, seed crystals were added at 60 ° C., cooled from 60 ° C. to 40 ° C. over 4 hours, and cooled from 40 ° C. to room temperature (20 ° C.) over 6 hours.
The precipitated crystals were separated by filtration and washed with 321.3 g of a methanol / xylene mixed solution having the same composition as that at the time of crystallization to obtain wet crystals.
The crystals were dried at 60 ° C. and a reduced pressure of 2.7 kPa to 5.3 kPa (in terms of absolute pressure) to obtain 155 g of crystals of L-lysine aminoethyl ester · 3 hydrochloride.
The yield at this time was 80%, and the purity of the crystals was 99% or more as a result of measurement by high performance liquid chromatography (hereinafter abbreviated as HPLC) analysis. The shape of the crystal was a needle-like crystal of about 1 × 100 μm (major axis) as observed by a microscope.
[0020]
Example 2
A mixture of 845 g of methanol and 118 g of xylene was added to 400 g of the reaction product (L-lysineaminoethyl ester / 3-hydrochloride, containing 56%) having an esterification rate of 75% obtained in Reference Example, and heated to 60 ° C. After dissolution, a seed crystal was added at 60 ° C., cooled from 60 ° C. to 40 ° C. over 4 hours, and cooled from 40 ° C. to room temperature (20 ° C.) over 6 hours.
The obtained crystals were separated by filtration and washed with 321.3 g of a methanol / xylene mixed solution having the same composition as at the time of crystallization to obtain wet crystals.
The wet crystals were dried at 60 ° C. and under a reduced pressure of 2.7 kPa to 5.3 kPa (in terms of absolute pressure) to obtain 180 g of crystals of L-lysine aminoethyl ester trihydrochloride.
The yield at this time was 80%, and the purity of the crystal was 99% or more as a result of measurement by HPLC. As a result of observation with a microscope, the shape of the crystal was a needle-like crystal of about 1 × 100 μm (long diameter).
[0021]
Comparative Example 1
In the same manner as in Example 2, a mixture of 845 g of methanol and 100 g of ethanol was added to 400 g of a reaction product (containing 56% of L-lysineaminoethyl ester / 3 hydrochloride) having an esterification rate of 75%, and the mixture was heated to 60 ° C. After heating and dissolution, seed crystals were added at 60 ° C., and after crystallization was confirmed, aging was performed, and 109 g of ethanol was slowly dropped. Then, it cooled to room temperature and crystallized.
The obtained crystals were separated by filtration, and the crystals were washed with 321.3 g of a methanol / ethanol mixed solution having the same composition as at the time of crystallization to obtain wet crystals.
The wet crystals were dried at 60 ° C. and a reduced pressure of 2.7 kPa to 5.3 kPa (in terms of absolute pressure) to obtain 146 g of crystals of L-lysine aminoethyl ester · 3 hydrochloride.
At this time, the yield was 65%, and the purity of the crystal was 98% or more as measured by HPLC. As a result of observation with a microscope, the shape of the crystal was a fine needle-like crystal of about 1 × 10 μm (long diameter).
[0022]
Table 1 shows the results of HPLC analysis of the crystals of L-lysineaminoethyl ester.3 hydrochloride and the results of evaluating the filtration effect (solid-liquid separation) in Examples 1 and 2 and Comparative Example 1.
[0023]
[Table 1]

[0024]
【The invention's effect】
The purification method of the present invention uses a mixed solution of an aromatic hydrocarbon and an alcohol as a crystallization solvent, so that solid-liquid separation is simple and rapid, and high-purity L-lysineaminoethyl ester / 3-hydrochloric acid is used. A salt can be obtained, and the crystallization solvent used is excellent in recyclability.

Claims (3)

A method for purifying L-lysine aminoethyl ester trihydrochloride, wherein a mixed solution of an aromatic hydrocarbon and an alcohol is used as a crystallization solvent. The method for purifying L-lysine aminoethyl ester · 3 hydrochloride according to claim 1, wherein the aromatic hydrocarbon is xylene or toluene. The method for purifying L-lysine aminoethyl ester · 3 hydrochloride according to claim 1, wherein the alcohol is methanol.