JP3316917B2 - New phenylalanine salt crystals and their production - Google Patents
New phenylalanine salt crystals and their productionInfo
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- JP3316917B2 JP3316917B2 JP06197293A JP6197293A JP3316917B2 JP 3316917 B2 JP3316917 B2 JP 3316917B2 JP 06197293 A JP06197293 A JP 06197293A JP 6197293 A JP6197293 A JP 6197293A JP 3316917 B2 JP3316917 B2 JP 3316917B2
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Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規光学活性フェニル
アラニン モノメチル硫酸塩結晶及びその製造法に関す
る。The present invention relates to a novel optically active phenylalanine monomethyl sulfate crystal and a method for producing the same.
【０００２】[0002]
【従来の技術】従来のＬ−フェニルアラニン（以下Ｌ−
Ｐｈｅと略記する）製造に於て、その品質面で問題とさ
れる不純物が２つあげられる。その１つが、発酵法で製
造する場合は発酵液に共存するＬ−チロシン（以下Ｌ−
Ｔｙｒと略記する）の混入であり、もう１つが、Ｌ−Ｐ
ｈｅの光学異性体であるＤ−フェニルアラニン（以下Ｄ
−Ｐｈｅと略記する）である。2. Description of the Related Art Conventional L-phenylalanine (hereinafter referred to as L-phenylalanine).
In manufacturing, there are two impurities which are problematic in terms of quality. When one of them is manufactured by a fermentation method, L-tyrosine (hereinafter referred to as L-tyrosine) coexisting in the fermentation solution is used.
Tyr) and the other is LP
D-phenylalanine (hereinafter referred to as D)
-Phe).
【０００３】前者の不純物Ｌ−Ｔｙｒに関しては、その
淘汰性の良いとされるいくつかのＬ−Ｐｈｅ誘導体結晶
も見いだされている（例えば、特開昭６０ー１３７４６
のＬ−フェニルアラニン１ナトリウム５水和物、特開昭
５６ー７９６５２のＬ−フェニルアラニン１／２硫酸塩
１／２水和物）。しかし、それらは、いずれもＬ−Ｐｈ
ｅ誘導体結晶の溶解度が極めて高くなるため、晶析母液
へのＬ−Ｐｈｅの損失が多くなり収率が低下する問題が
ある。そこで、高収率を得るために、Ｌ−Ｐｈｅ濃度を
高くして晶析しているが、その結果、晶析させるスラリ
ー濃度が高くなり、晶析スラリーの攪拌動力の増大、分
離結晶に付着した母液中の不純物の混入といった問題が
生じる。With respect to the former impurity L-Tyr, some L-Phe derivative crystals which are considered to have good selectivity have been found (for example, Japanese Patent Application Laid-Open No. Sho 60-13746).
L-phenylalanine monosodium pentahydrate, L-phenylalanine 1/2 sulfate 1/2 hemihydrate disclosed in JP-A-56-79652). However, they are all L-Ph
Since the solubility of the e derivative crystal becomes extremely high, there is a problem that the loss of L-Phe to the crystallization mother liquor increases and the yield decreases. Therefore, in order to obtain a high yield, crystallization is performed by increasing the L-Phe concentration. As a result, the concentration of the slurry to be crystallized increases, the stirring power of the crystallization slurry increases, and the crystallization slurry adheres to the separated crystals. There is a problem that impurities in the mother liquor are mixed.
【０００４】もう一方の不純物Ｄ−Ｐｈｅは、Ｌ−Ｐｈ
ｅを含む発酵液を処理する段階での、高温条件、アルカ
リ性条件下で、Ｌ−Ｐｈｅがラセミ化して生じるもので
ある。又、Ｌ−Ｐｈｅを原料として用いた各種物質の製
造に於て、目的物質となり得なかったＬ−Ｐｈｅ誘導体
は、加水分解等の方法で置換基を脱離させ、生成したＬ
−Ｐｈｅを回収し、再度原料として用いる方法が経済的
に有利であるために、工業的に行われることが多いが、
製造工程中及び回収工程中でのラセミ化によっても生じ
る。[0004] The other impurity D-Phe is L-Ph
L-Phe is generated by racemization under high temperature conditions and alkaline conditions at the stage of treating a fermentation solution containing e. Further, in the production of various substances using L-Phe as a raw material, the L-Phe derivative which could not be a target substance was produced by removing a substituent by a method such as hydrolysis.
-The method of recovering Phe and using it again as a raw material is economically advantageous, so that it is often carried out industrially,
Racemization also occurs during the manufacturing and recovery steps.
【０００５】このようにして、生成したＤ−Ｐｈｅは、
通常の晶析条件では、Ｌ−Ｐｈｅから効率よく除去する
ことが困難である。それは、溶液中のＤ−Ｐｈｅが結晶
として析出する場合には、共存するＬ−Ｐｈｅと一対に
なり、ラセミ化合物であるＤＬ−Ｐｈｅ結晶を形成し、
その溶解度は、一般にＬ−Ｐｈｅのそれよりもはるかに
低いことに起因する。[0005] The D-Phe thus generated is:
Under normal crystallization conditions, it is difficult to efficiently remove L-Phe. When D-Phe in the solution precipitates as crystals, it forms a pair with the coexisting L-Phe to form a racemic DL-Phe crystal,
Its solubility is generally due to being much lower than that of L-Phe.
【０００６】[0006]
【発明が解決しようとする課題】本発明の課題は、操作
が簡便で且つ不純物としてのＬ−Ｔｙｒ，Ｄ−Ｐｈｅの
淘汰性の高いＬ−Ｐｈｅの塩を見いだすことにある。SUMMARY OF THE INVENTION An object of the present invention is to find a salt of L-Phe which is easy to operate and has high selectivity for L-Tyr and D-Phe as impurities.
【０００７】[0007]
【課題を解決するための手段】上記課題を解決する為に
鋭意検討した結果、驚くべきことにモノメチル硫酸（以
下ＣＨ3ＳＯ4Ｈと略記する）とＬ−Ｐｈｅを含む水性溶
液から晶析操作により得られた結晶が、今まで知られて
いないＬ−フェニルアラニン モノメチル硫酸塩（以
下、Ｌ−Ｐｈｅ・ＣＨ3ＳＯ4Ｈ塩 と略記する）である
こと、又、光学的に純度の低いＬ−ＰｈｅとＣＨ3ＳＯ4
Ｈ塩の晶析系からも、光学純度の極めて高いＬ−Ｐｈｅ
・ＣＨ3ＳＯ4Ｈ塩が得られること、さらには、Ｌ−Ｔｙ
ｒの淘汰性も極めて高いことを見いだし、本発明を完成
した。As a result of intensive studies to solve the above problems, surprisingly, the crystallization operation from an aqueous solution containing monomethyl sulfate (hereinafter abbreviated as CH 3 SO 4 H) and L-Phe is performed. Is L-phenylalanine monomethyl sulfate (hereinafter, abbreviated as L-Phe.CH 3 SO 4 H salt), and L-phenylalanine having a low optical purity. Phe and CH 3 SO 4
From the crystallization system of H salt, L-Phe with extremely high optical purity
CH 3 SO 4 H salt is obtained, and furthermore, L-Ty
The inventors have also found that r has a very high selectivity, and have completed the present invention.
【０００８】又、ラセミ体ＤＬ−ＰｈｅとＣＨ3ＳＯ4Ｈ
を含む水性溶液から晶析によって得た結晶も、Ｌ−Ｐｈ
ｅから得られた結晶と同一の粉末Ｘ線回折スペクトル、
赤外線吸収スペクトルであることから、ＤＬ−Ｐｈｅ・
ＣＨ3ＳＯ4Ｈ塩はラセミ混合物であることが判明した。
このことは、光学的に不純なＬ−Ｐｈｅを効率よく光学
精製するうえで、重要な知見である。In addition, racemic DL-Phe and CH 3 SO 4 H
Crystals obtained by crystallization from an aqueous solution containing
e) the same powder X-ray diffraction spectrum as the crystals obtained from
Because of the infrared absorption spectrum, DL-Phe.
The CH 3 SO 4 H salt was found to be a racemic mixture.
This is an important finding in efficiently optically purifying optically impure L-Phe.
【０００９】本発明の晶析に供せられるＣＨ3ＳＯ4Ｈの
量は、対応するＬ−Ｐｈｅに対し等モル以上あればよ
い。ＣＨ3ＳＯ4Ｈ量が少ないと、晶析収率の低下を招く
が、ＣＨ3ＳＯ4ＨがＬ−Ｐｈｅより等モル以下の場合に
は、Ｌ−Ｐｈｅ・ＣＨ3ＳＯ4Ｈ塩結晶とＬ−Ｐｈｅ結晶
とが共存した状態で得られることもある。この場合も、
後述する方法で容易に、この混合結晶から、遊離したＬ
−Ｐｈｅを得ることができる。逆に、ＣＨ3ＳＯ4Ｈが多
くなるにつれ生成する塩の溶解度は著しく減少する傾向
を示し晶析収率は増大するが、必要以上に多くすること
は経済的でない。The amount of CH 3 SO 4 H to be subjected to the crystallization of the present invention may be at least equimolar to the corresponding L-Phe. When the amount of CH 3 SO 4 H is small, the crystallization yield is reduced, but when the amount of CH 3 SO 4 H is less than or equal to L-Phe, L-Phe · CH 3 SO 4 H salt crystals It may be obtained in a state where L-Phe crystals coexist. Again,
The L released from this mixed crystal can be easily obtained by the method described later.
-Phe can be obtained. Conversely, as the amount of CH 3 SO 4 H increases, the solubility of the formed salt tends to decrease significantly and the crystallization yield increases, but increasing the amount more than necessary is not economical.
【００１０】使用するＣＨ3ＳＯ4Ｈはメタノールと硫酸
から容易に調製されるが、ＣＨ3ＳＯ4Ｈと塩基との塩を
硫酸、塩酸等の酸で遊離させたものも使用できる。この
ような塩としては、ナトリウム、カリウム等のアルカリ
金属塩、カルシウム等のアルカリ土類金属塩、アンモニ
ア、トリエチルアミン等のアミン塩等があげられる。The CH 3 SO 4 H to be used is easily prepared from methanol and sulfuric acid, but a salt of CH 3 SO 4 H and a base liberated with an acid such as sulfuric acid or hydrochloric acid can also be used. Examples of such salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and amine salts such as ammonia and triethylamine.
【００１１】本発明は、望ましくは水溶媒中で晶析させ
るが、水と混和する他の有機溶媒が含まれていても、問
題ない。他の有機溶媒としては、メタノール、エタノー
ル等のアルコール類、アセトン等のケトン類、蟻酸、酢
酸等のカルボン酸類、アセトニトリル等のニトリル類が
あげられる。In the present invention, the crystallization is preferably carried out in an aqueous solvent, but there is no problem even if other organic solvents miscible with water are contained. Other organic solvents include alcohols such as methanol and ethanol, ketones such as acetone, carboxylic acids such as formic acid and acetic acid, and nitriles such as acetonitrile.
【００１２】晶析方法は、濃縮晶析、冷却晶析等通常の
晶析方法で可能であるが、温度による溶解度の差が大き
いので、冷却晶析が効率良い。又、Ｌ−Ｐｈｅ・ＣＨ3
ＳＯ4Ｈ塩の溶解度が、一般に水に比べて有機溶媒に低
いことから、Ｌ−ＰｈｅとＣＨ3ＳＯ4Ｈを含む水溶液
を、水と混和する有機溶媒と混合することによっても得
られる。更には、ＣＨ3ＳＯ4Ｈが塩基との塩の場合は酸
による中和晶析も可能である。The crystallization method can be a conventional crystallization method such as concentration crystallization and cooling crystallization. However, since the difference in solubility depending on the temperature is large, cooling crystallization is efficient. Also, L-Phe.CH 3
Since the solubility of the SO 4 H salt is generally lower in organic solvents than in water, it can also be obtained by mixing an aqueous solution containing L-Phe and CH 3 SO 4 H with an organic solvent miscible with water. Further, when CH 3 SO 4 H is a salt with a base, neutralization crystallization with an acid is also possible.
【００１３】本結晶を得るには、晶析系にＣＨ3ＳＯ4Ｈ
とＬ−Ｐｈｅとが存在すれば良く、両者の混合順序には
影響されない。例えば、モノメチル硫酸ナトリウム塩
（以下、ＣＨ3ＳＯ4Ｎａと略記する）を硫酸で中和した
後、結晶状のＬ−Ｐｈｅを添加しても、Ｌ−Ｐｈｅを硫
酸水溶液に加え溶解させたものにＣＨ3ＳＯ4Ｈ、あるい
はモノメチル硫酸ナトリウムを加えて晶析させても、い
ずれもＬ−Ｐｈｅ・ＣＨ3ＳＯ4Ｈ塩が得られる。In order to obtain the present crystal, CH 3 SO 4 H is added to the crystallization system.
And L-Phe need only be present, and are not affected by the mixing order of the two. For example, monomethyl sulfate sodium salt (hereinafter abbreviated as CH 3 SO 4 Na) is neutralized with sulfuric acid, and then L-Phe is added to and dissolved in a sulfuric acid aqueous solution even when crystalline L-Phe is added. And L 3 -Phe.CH 3 SO 4 H salt can be obtained by adding CH 3 SO 4 H or sodium monomethyl sulfate to the mixture for crystallization.
【００１４】晶析時のＬ−Ｐｈｅの濃度は、対応するＣ
Ｈ3ＳＯ4Ｈの量及び、水と混和する有機溶剤を含む水性
溶媒を用いた場合、その有機溶媒の種類と含有量に、溶
解度が大きく影響されるために、特に限定されないが、
０．１ｇ／ｄｌ以上の濃度であれば晶析は可能である。
溶媒として実質的に有機溶媒を含まない場合、望ましく
は、１ｇ／ｄｌ以上で晶析するのがよい。At the time of crystallization, the concentration of L-Phe
When the amount of H 3 SO 4 H and an aqueous solvent containing an organic solvent miscible with water are used, the type and the content of the organic solvent greatly affect the solubility.
Crystallization is possible if the concentration is 0.1 g / dl or more.
When substantially no organic solvent is contained as a solvent, crystallization is preferably performed at 1 g / dl or more.
【００１５】晶析時の温度は、低温で晶析するほど溶解
度が下がり晶析率が増加する為、６０℃以下、望ましく
は３０℃以下に保つ。The temperature during crystallization is maintained at 60 ° C. or lower, preferably 30 ° C. or lower, because the lower the temperature, the lower the solubility and the higher the crystallization rate.
【００１６】このようにして得られたＬ−Ｐｈｅ・ＣＨ
3ＳＯ4Ｈ塩は、その水溶液を陰イオン交換樹脂を用いて
ＣＨ3ＳＯ4Ｈを除去するか、水酸化ナトリウム、水酸化
カリウム、炭酸ナトリウム、炭酸水素ナトリウム、アン
モニア等の通常用いられる塩基で中和して、晶析に賦す
ること等で容易に遊離のＬ−Ｐｈｅを得ることができ
る。The thus obtained L-Phe.CH
The 3 SO 4 H salt is prepared by removing CH 3 SO 4 H from the aqueous solution using an anion exchange resin, or using a commonly used base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, ammonia and the like. Free L-Phe can be easily obtained by neutralizing and subjecting to crystallization.
【００１７】尚、上記の説明及び以下の実施例はＬ−Ｐ
ｈｅ・ＣＨ3ＳＯ4Ｈ塩を目的物質として記述している
が、対掌体であるＤ−Ｐｈｅ・ＣＨ3ＳＯ4Ｈ塩が目的物
質の場合も同様であることは、言うまでもない。The above description and the following embodiments are based on LP
Although he · CH 3 SO 4 H salt is described as the target substance, it goes without saying that the same applies when the enantiomer D-Phe · CH 3 SO 4 H salt is the target substance.
【００１８】[0018]
【実施例】以下、実施例により、詳細に説明するThe present invention will be described in detail below with reference to examples.
【００１９】[0019]
【実施例１】ＣＨ3ＳＯ4Ｎａ １３．４ｇ（０．１ｍｏ
ｌ）、Ｌ−Ｐｈｅ ４．１３ｇ（２５ｍｍｏｌ）を水３
５ｍｌに加え、硫酸でｐＨ＝０に調整した。これを、約
７０℃で加熱溶解した後、冷却した。析出した結晶を吸
引濾過分離し、少量の冷水で洗浄、減圧乾燥した。得量
５．７８ｇ。本結晶は各種物性測定の結果Ｌ−Ｐｈｅ
・ＣＨ3ＳＯ4Ｈであった。それらの物性測定結果は、表
１、図１、図２及び図３に示した。Example 1 13.4 g of CH 3 SO 4 Na (0.1 mol)
l), 4.13 g (25 mmol) of L-Phe
5 ml, and adjusted to pH = 0 with sulfuric acid. This was heated and melted at about 70 ° C., and then cooled. The precipitated crystals were separated by suction filtration, washed with a small amount of cold water, and dried under reduced pressure. 5.78 g. This crystal showed L-Phe as a result of various physical property measurements.
- it was CH 3 SO 4 H. The measurement results of the physical properties are shown in Table 1, FIG. 1, FIG. 2, and FIG.
【００２０】[0020]
【表１】 [Table 1]
【００２１】[0021]
【実施例２】ＤＬ−Ｐｈｅ ４．１３ｇ（２５ｍｍｏ
ｌ）を用いる以外は実施例１と同様にした。結晶得量
４．５７ｇ。本結晶のＩＲスペクトル及び粉末Ｘ線回折
は実施例１で得られた結晶のそれと同一であった。又、
融点は、１７３〜１７４．５℃であった。Example 2 4.13 g (25 mmo) of DL-Phe
Same as Example 1 except that l) was used. Crystal yield
4.57 g. The IR spectrum and powder X-ray diffraction of this crystal were the same as those of the crystal obtained in Example 1. or,
The melting point was 173-174.5 ° C.
【００２２】[0022]
【実施例３】Ｌ−Ｐｈｅ ３．７２ｇ（２２．５ｍｍｏ
ｌ）、Ｄ−Ｐｈｅ ０．４１ｇ（２．５ｍｍｏｌ）（Ｄ
−Ｐｈｅ／Ｌ−Ｐｈｅ＝１１％）を用いる以外は実施例
１と同様にした。結晶得量 ５．０１ｇ。得られた結晶
を光学活性カラムを用いたＨＰＬＣで分析したところ、
Ｄ−Ｐｈｅは、Ｌ−Ｐｈｅに対し１％含まれるのみであ
った。Example 3 3.72 g (22.5 mmo) of L-Phe
l), 0.41 g (2.5 mmol) of D-Phe (D
-Phe / L-Phe = 11%), except that Example 1 was used. Crystal yield 5.01 g. When the obtained crystals were analyzed by HPLC using an optically active column,
D-Phe was only 1% contained in L-Phe.
【００２３】[0023]
【比較例１】Ｌ−Ｐｈｅ ３．７２ｇ（２２．５ｍｍｏ
ｌ）、Ｄ−Ｐｈｅ ０．４１ｇ（２．５ｍｍｏｌ）（Ｄ
−Ｐｈｅ／Ｌ−Ｐｈｅ＝１１％）を水５０ｍｌに懸濁さ
せ、これに硫酸を加えて溶解させた。この溶液を５０％
水酸化ナトリウム水溶液でｐＨを６に調整し、析出した
結晶を４０℃で濾過分離した。結晶得量 ２．９８ｇ。
得られた結晶を光学活性カラムを用いたＨＰＬＣで分析
したところ、Ｄ−Ｐｈｅは、Ｌ−Ｐｈｅに対し１４．７
％含まれていた。Comparative Example 1 L-Phe 3.72 g (22.5 mmo
l), 0.41 g (2.5 mmol) of D-Phe (D
-Phe / L-Phe = 11%) was suspended in 50 ml of water, and sulfuric acid was added thereto to dissolve the suspension. 50% of this solution
The pH was adjusted to 6 with an aqueous sodium hydroxide solution, and the precipitated crystals were separated by filtration at 40 ° C. Crystal yield 2.98 g.
When the obtained crystals were analyzed by HPLC using an optically active column, D-Phe was 14.7 relative to L-Phe.
% Was included.
【００２４】[0024]
【実施例４】ＣＨ3ＳＯ4Ｎａ ６．３９ｇ（０．０４８
ｍｏｌ）、Ｌ−Ｐｈｅ １．９７ｇ（１１．９ｍｍｏ
ｌ）、Ｌ−Ｔｙｒ ９８ｍｇ（５ｗｔ％対Ｌ−Ｐｈｅ）
を水１５ｍｌに加え、硫酸でｐＨ＝０に調整した。これ
を、約７０℃で加熱溶解した後、冷却した。析出した結
晶を吸引濾過分離し、少量の冷水で洗浄、減圧乾燥し
た。結晶得量 ２．６２ｇ。 本結晶中にはＬ−Ｐｈｅ
１．５４ｇ（９．３ｍｍｏｌ）、Ｌ−Ｔｙｒは２８．
６ｍｇ（１．９ｗｔ％対Ｌ−Ｐｈｅ）含まれていた。Example 4 6.39 g (0.048 g) of CH 3 SO 4 Na
mol), 1.97 g (11.9 mmol) of L-Phe
l), L-Tyr 98mg (5wt% vs. L-Phe)
Was added to 15 ml of water, and the pH was adjusted to 0 with sulfuric acid. This was heated and melted at about 70 ° C., and then cooled. The precipitated crystals were separated by suction filtration, washed with a small amount of cold water, and dried under reduced pressure. Crystal yield 2.62 g. This crystal contains L-Phe
1.54 g (9.3 mmol), L-Tyr 28.
6 mg (1.9 wt% vs. L-Phe) was contained.
【００２５】[0025]
【比較例２】Ｌ−Ｐｈｅ １．９７ｇ（１１．９ｍｍｏ
ｌ）、Ｌ−Ｔｙｒ９８ｍｇ（５ｗｔ％対Ｐｈｅ）を水３
０ｍｌに加え、８０℃で加熱溶解した後、４０℃まで徐
冷した。析出した結晶を吸引濾過分離し、少量の水で洗
浄、減圧乾燥した。結晶得量０．６５ｇ。本結晶中には
Ｌ−Ｐｈｅ ０．５９ｇ（３．６ｍｍｏｌ）、Ｌ−Ｔｙ
ｒは５５ｍｇ（９．４ｗｔ％対Ｌ−Ｐｈｅ）含まれてい
た。Comparative Example 2 1.97 g of L-Phe (11.9 mmo)
l), L-Tyr 98 mg (5 wt% vs. Phe) was added to water 3
After adding to 0 ml and dissolving by heating at 80 ° C, the mixture was gradually cooled to 40 ° C. The precipitated crystals were separated by suction filtration, washed with a small amount of water, and dried under reduced pressure. Crystal yield 0.65 g. 0.59 g (3.6 mmol) of L-Phe and L-Ty
r was contained at 55 mg (9.4 wt% vs. L-Phe).
【００２６】[0026]
【実施例５】ＣＨ3ＳＯ4Ｎａ ３．１９ｇ（２３．８ｍ
ｍｏｌ）、Ｌ−Ｐｈｅ １．９７ｇ（１１．９ｍｍｏ
ｌ）を水１０ｍｌと酢酸５ｍｌの混合液に加え、これを
硫酸でｐＨを０．６に調整して得られた溶液を氷冷し、
析出した結晶を吸引濾過分離した。結晶得量 １．７８
ｇ。本結晶中にはＬ−Ｐｈｅが１．０１ｇ含まれてい
た。Example 5 3.19 g (23.8 m) of CH 3 SO 4 Na
mol), 1.97 g (11.9 mmol) of L-Phe
l) was added to a mixture of 10 ml of water and 5 ml of acetic acid, and the pH was adjusted to 0.6 with sulfuric acid.
The precipitated crystals were separated by suction filtration. Crystal yield 1.78
g. The crystal contained 1.01 g of L-Phe.
【００２７】[0027]
【実施例６】Ｌ−Ｐｈｅ・ＣＨ3ＳＯ4Ｈ塩 ２．３８ｇ
を水 ９ｍｌに溶解させた液をアセトン ５０ｍｌに滴
下すると、混合液は白濁した。冷蔵庫内で結晶を熟成さ
せた後、吸引濾過分離した。乾燥後の結晶重量 １．８
６ｇ。Example 6 2.38 g of L-Phe.CH 3 SO 4 H salt
Was added dropwise to 50 ml of acetone, and the mixture became cloudy. After the crystals were aged in a refrigerator, they were separated by suction filtration. Crystal weight after drying 1.8
6g.
【００２８】[0028]
【実施例７】メタノール ３３ｍｌに９５％硫酸 ５．
８ｍｌを加え、加熱還流した。その後、メタノールを減
圧下留去した後、全体が１５ｍｌになるまで水を加えＣ
Ｈ3ＳＯ4Ｈ溶液を調製した。これに、Ｌ−Ｐｈｅ ２．
７ｇとＤ−Ｐｈｅ ０．３ｇを加え（ＤーＰｈｅ／Ｌ−
Ｐｈｅ＝１１．１％）、加熱して溶解した後、氷冷し
た。析出した結晶を吸引濾過により分離し、少量の冷水
で洗浄した。結晶得量３．７３ｇ。 光学活性カラムを
用いたＨＰＬＣ分析の結果、本結晶中には、Ｌ−Ｐｈｅ
が１．６６ｇ、Ｄ−Ｐｈｅが０．０４９ｇ含まれていた
（ＤーＰｈｅ／Ｌ−Ｐｈｅ＝２．９％）。又、ＣＨ3Ｓ
Ｏ4Ｈ溶液中に残存するメタノールによりエステル化さ
れたＬ−フェニルアラニンメチルエステルが４１ｍｇ含
まれていた。Example 7 95% sulfuric acid in 33 ml of methanol
8 ml was added, and the mixture was heated under reflux. Thereafter, methanol was distilled off under reduced pressure, and water was added until the total volume became 15 ml.
The H 3 SO 4 H solution was prepared. In addition, L-Phe 2.
7 g and D-Phe 0.3 g were added (D-Phe / L-
(Phe = 11.1%), and after heating to dissolve, the mixture was ice-cooled. The precipitated crystals were separated by suction filtration and washed with a small amount of cold water. 3.73 g of crystal yield. As a result of HPLC analysis using an optically active column, L-Phe
1.66 g and 0.049 g of D-Phe (D-Phe / L-Phe = 2.9%). Also, CH 3 S
The O 4 H solution contained 41 mg of L-phenylalanine methyl ester esterified with residual methanol.
【００２９】[0029]
【発明の効果】本発明の方法によれば、簡便な操作及び
安価な物質を用い、高収率で高純度な光学活性Ｐｈｅを
製造することができる。According to the method of the present invention, high-purity optically active Phe can be produced in a high yield using simple operations and inexpensive substances.
【図１】実施例１で得られた結晶の粉末Ｘ線回折図（Ｃ
ｕＫα線）FIG. 1 is a powder X-ray diffraction pattern (C) of the crystals obtained in Example 1.
uKα ray)
【図２】実施例１で得られた結晶のＩＲチャ−ト（ＫＢ
ｒ法）FIG. 2 is an IR chart (KB) of the crystal obtained in Example 1.
r method)
【図３】実施例１で得られた結晶のＮＭＲチャ−ト（溶
媒：重水）FIG. 3 is an NMR chart of a crystal obtained in Example 1 (solvent: heavy water).
フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 229/36 C07C 227/42 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)Continuation of the front page (58) Field surveyed (Int. Cl. 7 , DB name) C07C 229/36 C07C 227/42 CA (STN) REGISTRY (STN)
Claims (2)
硫酸塩結晶1. An optically active phenylalanine monomethyl sulfate crystal
含む溶液を有機溶媒の存在下又は不存在下で水溶媒中で
晶析操作に晒すことを特徴とする光学活性フェニルアラ
ニン モノメチル硫酸塩の製造法2. A method for producing optically active phenylalanine monomethyl sulfate, comprising subjecting a solution containing monomethyl sulfate and phenylalanine to crystallization in an aqueous solvent in the presence or absence of an organic solvent.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP06197293A JP3316917B2 (en) | 1993-02-25 | 1993-03-22 | New phenylalanine salt crystals and their production |
| US08/190,450 US5466864A (en) | 1993-02-25 | 1994-02-02 | Method for recovering L-phenylalanine |
| DE69403109T DE69403109T2 (en) | 1993-02-25 | 1994-02-08 | Process for the recovery of L-phenylalanine |
| EP94101925A EP0612717B1 (en) | 1993-02-25 | 1994-02-08 | Method for recovering L-phenylalanine |
| CA002115883A CA2115883A1 (en) | 1993-02-25 | 1994-02-17 | Method for recovering l-phenylalanine |
| US08/441,737 US5616766A (en) | 1993-02-25 | 1995-05-16 | Method for recovering L-phenylalanine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5-36880 | 1993-02-25 | ||
| JP3688093 | 1993-02-25 | ||
| JP06197293A JP3316917B2 (en) | 1993-02-25 | 1993-03-22 | New phenylalanine salt crystals and their production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06306029A JPH06306029A (en) | 1994-11-01 |
| JP3316917B2 true JP3316917B2 (en) | 2002-08-19 |
Family
ID=26375971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP06197293A Expired - Lifetime JP3316917B2 (en) | 1993-02-25 | 1993-03-22 | New phenylalanine salt crystals and their production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3316917B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5380743B2 (en) * | 2008-06-19 | 2014-01-08 | 住友化学株式会社 | Process for producing optically active 4-amino-3-substituted phenylbutanoic acid |
-
1993
- 1993-03-22 JP JP06197293A patent/JP3316917B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06306029A (en) | 1994-11-01 |
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