JPS6112917B2 - - Google Patents
Info
- Publication number
- JPS6112917B2 JPS6112917B2 JP7537179A JP7537179A JPS6112917B2 JP S6112917 B2 JPS6112917 B2 JP S6112917B2 JP 7537179 A JP7537179 A JP 7537179A JP 7537179 A JP7537179 A JP 7537179A JP S6112917 B2 JPS6112917 B2 JP S6112917B2
- Authority
- JP
- Japan
- Prior art keywords
- aspartyl
- lower alkyl
- aqueous solution
- alkyl ester
- dkp
- 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.)
- Expired
Links
- 125000005907 alkyl ester group Chemical group 0.000 claims description 29
- YZQCXOFQZKCETR-UWVGGRQHSA-N Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YZQCXOFQZKCETR-UWVGGRQHSA-N 0.000 claims description 25
- 239000007864 aqueous solution Substances 0.000 claims description 24
- 239000013078 crystal Substances 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical group OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 17
- 238000011084 recovery Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000000356 contaminant Substances 0.000 claims description 3
- XYXLNYSVQVWRQL-UHFFFAOYSA-N 2-(2,5-dioxopiperazin-1-yl)acetic acid Chemical compound OC(=O)CN1CC(=O)NCC1=O XYXLNYSVQVWRQL-UHFFFAOYSA-N 0.000 claims 1
- 230000001376 precipitating effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005259 measurement Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000007863 gel particle Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- VNHJXYUDIBQDDX-UHFFFAOYSA-N L-cis-Cyclo(aspartylphenylalanyl) Chemical compound N1C(=O)C(CC(=O)O)NC(=O)C1CC1=CC=CC=C1 VNHJXYUDIBQDDX-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明はα−Ｌ−アスパルチル−Ｌ−フエニル
アラニン低級アルキルエステル、特にα−Ｌ−ア
スパルチル−Ｌ−フエニルアラニンメチルエステ
ル（以下APMと略記する）の新規な回収法に関
するものである。Detailed Description of the Invention The present invention provides a novel method for recovering α-L-aspartyl-L-phenylalanine lower alkyl ester, particularly α-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as APM). It is about law.
APMは低カロリー甘味剤として注目されてい
る有用な物質である。 APM is a useful substance that is attracting attention as a low-calorie sweetener.
α−Ｌ−アスパルチル−Ｌ−フエニルアラニン
低級アルキルエステルは製造途中あるいは熱によ
り容易に環化して甘味性のない３−ベンジル−６
−カルボキシメチル−２・５−ジケトピペラジン
（以下DKPと略記する）に変化する。 α-L-Aspartyl-L-phenylalanine lower alkyl ester is easily cyclized during production or by heat, resulting in 3-benzyl-6 having no sweet taste.
-Carboxymethyl-2,5-diketopiperazine (hereinafter abbreviated as DKP).
従つて製造工程より得られるα−Ｌ−アスパル
チル−Ｌ−フエニルアラニン低級アルキルエステ
ルは必然的にDKPを含むので、これを除去して
精製することが必要である。通常酸性の溶液とし
て得られるDKPを夾雑するα−Ｌ−アスパルチ
ル−Ｌ−フエニルアラニン低級アルキルエステル
工程液からα−Ｌ−アスパルチル−Ｌ−フエニル
アラニン低級アルキルエステルを析出させると
DKPの大部分はこれに随伴する。こうして得た
結晶を常法に従つて再結晶してもDKP含量を有
効に低減させることは困難である。 Therefore, since the α-L-aspartyl-L-phenylalanine lower alkyl ester obtained from the manufacturing process inevitably contains DKP, it is necessary to remove this and purify it. When α-L-aspartyl-L-phenylalanine lower alkyl ester is precipitated from the α-L-aspartyl-L-phenylalanine lower alkyl ester process solution which is usually obtained as an acidic solution and is contaminated with DKP,
Most of the DKP accompanies this. Even if the crystals thus obtained are recrystallized by a conventional method, it is difficult to effectively reduce the DKP content.
α−Ｌ−アスパルチル−Ｌ−フエニルアラニン
低級アルキルエステルからDKPを除去する従来
法としては、例えばイオン交換樹脂による方法
（特許昭52−35660号）、DKPを含有するα−Ｌ−
アスパルチル−Ｌ−フエニルアラニン低級アルキ
ルエステルを鉱酸水溶液中に溶解し、不溶物とし
て残るDKPの過等の操作により分離し、液
を中和してα−Ｌ−アスパルチル−Ｌ−フエニル
アラニン低級アルキルエステルを固形物として単
離する方法（特開昭48−67243号）等が知られて
いる。 Conventional methods for removing DKP from α-L-aspartyl-L-phenylalanine lower alkyl ester include, for example, a method using an ion exchange resin (Japanese Patent No. 52-35660), and α-L- containing DKP.
Aspartyl-L-phenylalanine lower alkyl ester is dissolved in an aqueous mineral acid solution, DKP remaining as an insoluble substance is separated by an excessive operation, and the liquid is neutralized to produce α-L-aspartyl-L-phenylalanine. A method for isolating a lower alkyl ester as a solid substance (Japanese Patent Application Laid-open No. 48-67243) is known.
本発明者らは工業的により容易かつ効果的な精
製法について鋭意研究した結果、DKPを含むα
−Ｌ−アスパルチル−Ｌ−フエニルアラニン低級
アルキルエステルの水性溶液に塩基性物質を加え
たのち、α−Ｌ−アスパルチル−Ｌ−フエニルア
ラニン低級アルキルエステルの結晶析出を行なう
と、DKPが効果的に除去されることを見出し、
本発明を完成するに至つた。 As a result of intensive research into industrially easier and more effective purification methods, the present inventors found that α
- When a basic substance is added to an aqueous solution of L-aspartyl-L-phenylalanine lower alkyl ester and crystallization of α-L-aspartyl-L-phenylalanine lower alkyl ester is performed, DKP becomes effective. found that it is removed by
The present invention has now been completed.
即ち本発明は、少なくとも夾雑物として３−ベ
ンジル−６−カルボキシメチル−２・５−ジケト
ピペラジンを含む水性溶液からα−Ｌ−アスパル
チル−Ｌ−フエニルアラニン低級アルキルエステ
ルを晶析させるに当り、この水性溶液に塩基性物
質を加えて、その液性をPH4.5を越え、かつ８以
下の値とした後、結晶析出させ、析出した結晶を
単離することを特徴とするα−Ｌ−アスパルチル
−Ｌ−フエニルアラニン低級アルキルエステルの
回収法を提供するものである。 That is, the present invention provides a method for crystallizing α-L-aspartyl-L-phenylalanine lower alkyl ester from an aqueous solution containing at least 3-benzyl-6-carboxymethyl-2,5-diketopiperazine as a contaminant. , α-L is characterized in that a basic substance is added to this aqueous solution to make the liquid property to a value exceeding 4.5 and 8 or less, and then crystals are precipitated, and the precipitated crystals are isolated. - Provides a method for recovering aspartyl-L-phenylalanine lower alkyl ester.
本発明の回収法が適用できるα−Ｌ−アスパル
チル−Ｌ−フエニルアラニンの低級アルキルエス
テルはそのC1ないしC3アルコールとのエステ
ル、特にメチルエステルである。 The lower alkyl ester of α-L-aspartyl-L-phenylalanine to which the recovery method of the present invention can be applied is its ester with a C 1 to C 3 alcohol, especially its methyl ester.
α−Ｌ−アスパルチル−Ｌ−フエニルアラニン
低級アルキルエステル水性溶液の溶媒としては水
または、水および水と均一に混和する有機溶媒の
混合液で使用する。この様な混合液を用いる場
合、本発明の方法で精製回収される化合物の大き
な用途が甘味剤であり、しかもその製造において
最終工適である精製回収工程でこの溶媒は使用さ
れるので、毒性の低い有機溶媒を用いるのが好ま
しい。従つてエタノール等の低級アルコールを有
機溶媒の最も好ましい例として挙げることができ
る。水と有機溶媒との混合比およびα−Ｌ−アス
パルチル−Ｌ−フエニルアラニン低級アルキルエ
ステルに対する溶媒の使用量は通常の結晶析出の
場合と同様にして決定してよい。 As the solvent for the α-L-aspartyl-L-phenylalanine lower alkyl ester aqueous solution, water or a mixture of water and an organic solvent that is uniformly miscible with water is used. When using such a mixed solution, the compound purified and recovered by the method of the present invention is mainly used as a sweetening agent, and the solvent is used in the final purification and recovery step in its production, so it is not toxic. It is preferable to use organic solvents with low . Therefore, lower alcohols such as ethanol can be cited as the most preferred example of the organic solvent. The mixing ratio of water and organic solvent and the amount of solvent to be used relative to α-L-aspartyl-L-phenylalanine lower alkyl ester may be determined in the same manner as in the case of ordinary crystal precipitation.
DKPを含むα−Ｌ−アスパルチル−Ｌ−フエ
ニルアラニン低級アルキルエステルの水性溶液、
例えば工程液は通常酸性であり、DKPを含むα
−Ｌ−アスパルチル−Ｌ−フエニルアラニン低級
アルキルエステルの結晶を溶解した液も通常PH
4.5以下の酸性を示す。本発明はこの様な溶液に
塩基性物質を加えて水性溶液の液性をPH4.5を越
え、かつ８以下の値に調節するものである。塩基
性物質を加える前の液性がPH4.5以上の場合でも
塩基性物質を加えることによつてDKPは効果的
に除去される。 an aqueous solution of α-L-aspartyl-L-phenylalanine lower alkyl ester comprising DKP;
For example, the process fluid is usually acidic and contains DKP.
-L-Aspartyl-L-phenylalanine lower alkyl ester crystals are usually dissolved at pH
Shows acidity below 4.5. In the present invention, a basic substance is added to such a solution to adjust the pH of the aqueous solution to a value exceeding 4.5 and 8 or less. DKP can be effectively removed by adding a basic substance even if the pH of the liquid before adding the basic substance is 4.5 or higher.
塩基性物質添加後の水性溶媒の液性がPH4.5以
下ではDKPの除去が充分でなく、また８を越え
ると、α−Ｌ−アスパルチル−Ｌ−フエニルアラ
ニン低級アルキルエステルの分解が起り易く、ま
たその溶解度も大きくなるので回収率が低下す
る。 If the pH of the aqueous solvent after addition of the basic substance is below 4.5, DKP will not be removed sufficiently, and if it exceeds 8, decomposition of α-L-aspartyl-L-phenylalanine lower alkyl ester will easily occur. , and its solubility also increases, resulting in a decrease in recovery rate.
本発明で使用する塩基性物質としては格別の限
定はないが、水酸化ナトリウム、炭酸水素ナトリ
ウム、炭酸ナトリウム、水酸化カリウム、アンモ
ニア等の無機塩基、トリエチルアミン、メチルア
ミン、トリスヒドロキシメチルアミノメタン等の
有機塩基、無機もしくは有機の弱酸と水酸化ナト
リウム等の強塩基とから成る塩等を例示すること
ができる。 The basic substances used in the present invention are not particularly limited, but include inorganic bases such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, ammonia, triethylamine, methylamine, trishydroxymethylaminomethane, etc. Examples include organic bases, salts consisting of inorganic or organic weak acids, and strong bases such as sodium hydroxide.
これらの塩基性物質は弱塩基性物質の場合に
は、そのまま使用してもよいがα−Ｌ−アスパル
チル−Ｌ−フエニルアラニン低級アルキルエステ
ルが塩基性の条件下で比較的簡単に分解するの
で、局部的にPHが高くなることを避けるために水
溶液として使用するのが好ましい。塩基性物質の
溶液を用いるとき、その濃度が低過ぎると、それ
だけ多量の水溶液を用いることになり、溶媒の留
去を行なわないとα−Ｌ−アスパルチル−Ｌ−フ
エニルアラニン低級アルキルエステルの回収率が
低くなるおそれがあり、濃すぎると、局部的PH上
昇によるα−Ｌ−アスパルチル−Ｌ−フエニルア
ラニン低級アルキルエステルの分解があり得るの
でいずれも好ましくない。これらのことを考慮に
入れると一般的には0.01N〜5N、好ましくは
0.05N〜1N程度の溶液を用いるのがよい。しかし
これらの値は何ら限定的でなく、強塩基の場合に
はなるべくうすい濃度のものを用いるのがよく、
弱塩基の場合には濃い溶液もしくはそのままで用
いることができる。これらの塩基性物質の添加に
際しては局部的に混合物が強塩基性になることを
避けるため、水性溶液を撹拌しながら除々に添加
することが好ましい。 If these basic substances are weak basic substances, they may be used as they are, but α-L-aspartyl-L-phenylalanine lower alkyl ester decomposes relatively easily under basic conditions. , it is preferable to use it as an aqueous solution to avoid locally high pH. When using a solution of a basic substance, if the concentration is too low, a large amount of aqueous solution will be used, and unless the solvent is distilled off, it will be difficult to recover α-L-aspartyl-L-phenylalanine lower alkyl ester. If the concentration is too high, the α-L-aspartyl-L-phenylalanine lower alkyl ester may be decomposed due to a local increase in pH, so both are unfavorable. Taking these things into consideration, it is generally 0.01N to 5N, preferably
It is best to use a solution of about 0.05N to 1N. However, these values are not limiting in any way, and in the case of a strong base, it is best to use one with a dilute concentration as much as possible.
In the case of a weak base, it can be used in a concentrated solution or as it is. When adding these basic substances, it is preferable to add them gradually while stirring the aqueous solution in order to prevent the mixture from becoming locally strongly basic.
α−Ｌ−アスパルチル−Ｌ−フエニルアラニン
低級アルキルエステル溶液に塩基性物質を添加す
る際の温度は、この物質が熱によつて分解し易い
ので低温であることがより好ましい。しかしなが
ら上記PH範囲内で処理時間が短い場合には高温で
あつても比較的その分解は少ない。従つて溶媒の
凝固点から沸点までの温度範囲で選んでよいが、
通常０゜〜80℃適度である。 The temperature at which the basic substance is added to the α-L-aspartyl-L-phenylalanine lower alkyl ester solution is preferably low because this substance is easily decomposed by heat. However, if the treatment time is short within the above pH range, the decomposition is relatively small even at high temperatures. Therefore, the temperature can be selected within the temperature range from the freezing point to the boiling point of the solvent, but
The temperature is usually between 0° and 80°C.
本発明では、この様にして水性溶媒に塩基物質
を添加したあと、慣用の晶析法と同様にしてα−
Ｌ−アスパルチル−Ｌ−フエニルアラニン低級ア
ルキルエステル結晶の析出を行なうものである。
従つて塩基性物質の添加を比較的高温で行ない、
直ちに（勿論その前に不溶成分を分離するための
過等を行なつてもよいが）冷却して結晶を析出
させ、これを採取するのが最も能率的である。ま
た溶媒留去によつて結晶析出を行なつてもよい。 In the present invention, after adding the basic substance to the aqueous solvent in this way, α-
This is to precipitate L-aspartyl-L-phenylalanine lower alkyl ester crystals.
Therefore, by adding the basic substance at a relatively high temperature,
It is most efficient to immediately cool the crystals (although, of course, a sieve to separate insoluble components may be performed before that) to precipitate crystals and collect them. Crystal precipitation may also be carried out by distilling off the solvent.
上述の説明から明らかな様に、本発明の方法に
よれば、夾雑物としてDKPを含むα−Ｌ−アス
パルチル−Ｌ−フエニルアラニン低級アルキルエ
ステルの水性溶液、例えば工程液から簡単に
DKP含量の少ないα−Ｌ−アスパルチル−Ｌ−
フエニルアラニン低級アルキルエステル結晶を得
ることができるので、本発明は工業的にも有利な
方法である。またDKPを含むα−Ｌ−アスパル
チル−Ｌ−フエニルアラニン低級アルキルエステ
ルの再結晶による精製に応用して、通常の再結晶
法では効果的に除去することのできないDKPを
容易に除くことができる。 As is clear from the above description, according to the method of the present invention, α-L-aspartyl-L-phenylalanine lower alkyl ester containing DKP as a contaminant can be easily extracted from an aqueous solution, for example, a process liquid.
α-L-Aspartyl-L- with low DKP content
Since phenylalanine lower alkyl ester crystals can be obtained, the present invention is an industrially advantageous method. It can also be applied to the purification of α-L-aspartyl-L-phenylalanine lower alkyl ester containing DKP by recrystallization to easily remove DKP, which cannot be effectively removed by normal recrystallization methods. .
以下実施例により本発明をさらに詳しく説明す
る。 The present invention will be explained in more detail with reference to Examples below.
実施例 １
DKPを含む4400ｇの粗製APM（DKP含有率
9.09％）を水72mlに加えた混合物を80％に加熱
し、均一溶液とした。PHは4.50となつた。この溶
液にNaHCO3水溶液（0.1N）24.0mlを加えてPHを
5.92としたのち、約３時間室温に放置して結晶を
析出させた。さらに10℃に一夜間保つたあとスラ
リーを過し、結晶を約100mlの冷水で洗浄し
た。得られた湿結晶を酢酸ナトリウム水溶液
（0.8％）に溶解し、高速液体クロマトグラフイ分
析により、APMの回収率およびDKPの含有量を
それぞれ求めた。APMの分析に用いた測定装置
および測定条件は下記のとおりである。Example 1 4400 g of crude APM containing DKP (DKP content
A mixture of 9.09%) added to 72 ml of water was heated to 80% to form a homogeneous solution. The pH was 4.50. Add 24.0ml of NaHCO 3 aqueous solution (0.1N) to this solution to adjust the pH.
After adjusting the temperature to 5.92, the mixture was left at room temperature for about 3 hours to precipitate crystals. After further keeping at 10°C overnight, the slurry was filtered and the crystals were washed with about 100ml of cold water. The obtained wet crystals were dissolved in an aqueous sodium acetate solution (0.8%), and the recovery rate of APM and the content of DKP were determined by high performance liquid chromatography analysis. The measurement device and measurement conditions used for APM analysis are as follows.
装 置：高速液体クロマトグラフ
（東洋曹達工業株式会社製、TSK−
HLC802、商標）
カラム：内径7.5mm×長さ200mm
充填剤：デンプン系ゲル粒径５μ
（東洋曹達工業株式会社製、TSK−
GEL、LS−170、P5、商標）
溶離液：酢酸ナトリウム水溶液（0.8重量％）
流 速：0.8ml／分
圧損失：20Kg/cm2
検出器：UV検出器（254nｍ）
またDKPの分析に用いた測定装置および測定
条件は下記の通りである。Equipment: High performance liquid chromatograph (manufactured by Toyo Soda Kogyo Co., Ltd., TSK-
HLC802, trademark) Column: Internal diameter 7.5 mm x length 200 mm Packing agent: Starch gel particle size 5 μ (manufactured by Toyo Soda Kogyo Co., Ltd., TSK-
GEL, LS-170, P5, trademark) Eluent: Sodium acetate aqueous solution (0.8% by weight) Flow rate: 0.8ml/partial pressure loss: 20Kg/cm 2 Detector: UV detector (254nm) Also used for analysis of DKP The measurement equipment and measurement conditions used are as follows.
装 置：高速液体クロマトグラフ
（東洋曹達工業株式会社製、TSK−
HLC802、商標）
カラムおよび充填剤：
カチオン交換樹脂系ゲル粒径10μ（東洋
曹達工業株式会社製、TSK−GEL、
IEX−212、P10、商標）を充填した内径
４mm×長さ100mmのカラムと、デンプン
系ゲル、粒径５μ（東洋曹達工業株式会
社製、TSK−GEL、LS−170、P5、商
標）を充填した内径7.5mm×長さ400mmの
カラムを連結したもの
溶離液：酢酸ナトリウム水溶液（0.8重量％）
流 速：0.8ml／分
圧損失：55Kg/cm2
検出器：UV検出器（256nｍ）
この様にして求めたAPMの回収率は55.5％で
あり、その中のDKPの含有率は1.05％であつた。Equipment: High performance liquid chromatograph (manufactured by Toyo Soda Kogyo Co., Ltd., TSK-
HLC802, trademark) Column and packing material: Cation exchange resin gel particle size 10μ (manufactured by Toyo Soda Kogyo Co., Ltd., TSK-GEL,
A column with an inner diameter of 4 mm and a length of 100 mm filled with IEX-212, P10, trademark) and starch gel, particle size 5μ (manufactured by Toyo Soda Kogyo Co., Ltd., TSK-GEL, LS-170, P5, trademark) Eluent: Sodium acetate aqueous solution (0.8% by weight) Flow rate: 0.8ml/partial pressure loss: 55Kg/cm 2 Detector: UV detector (256nm) The recovery rate of APM was 55.5%, and the content of DKP was 1.05%.
なお以下の実施例の場合でもAPMの回収率お
よびAPM中のDKPの含有率の測定には別記のな
い限りすべて上記の装置および条件を用いた。 In the following Examples, the above-described apparatus and conditions were used to measure the recovery rate of APM and the content of DKP in APM, unless otherwise specified.
比較例 １
NaHCO3水溶液（0.1N）を加えなかつた以外
は、実施例１と全く同様に操作を行なつた。Comparative Example 1 The operation was carried out in exactly the same manner as in Example 1, except that the NaHCO 3 aqueous solution (0.1N) was not added.
APMの回収率は65.8％で、その中のDKPの含
有率は1.80％であつた。 The recovery rate of APM was 65.8%, and the content rate of DKP was 1.80%.
実施例 ２
6050ｇの粗製APM（DKP含有率9.09％）をメ
タノール水溶液（100ml（メタノール：水＝２：
１）に加えた混合物を55℃に加熱し、均一溶液
（PH4.8）とした。この溶液にNaHCO3水溶液
（0.1N）20.0mlを加えてPHを5.85としたのち、減
圧でメタノール66mlを留去し、結晶を析出させ
た。さらに一夜間冷蔵庫に放置したあと、スラリ
ーを過し、結晶を約100mlの冷水で洗浄した。
得られた湿結晶を実施例１と同様にして分析を行
い、APMの回収率77.3％、DKPの含有率0.16％
を得た。Example 2 6050 g of crude APM (DKP content 9.09%) was added to a methanol aqueous solution (100 ml (methanol:water = 2:
The mixture added to 1) was heated to 55°C to form a homogeneous solution (PH4.8). After adding 20.0 ml of NaHCO 3 aqueous solution (0.1N) to this solution to adjust the pH to 5.85, 66 ml of methanol was distilled off under reduced pressure to precipitate crystals. After being left in the refrigerator overnight, the slurry was filtered and the crystals were washed with about 100 ml of cold water.
The obtained wet crystals were analyzed in the same manner as in Example 1, and the recovery rate of APM was 77.3%, and the content of DKP was 0.16%.
I got it.
比較例 ２
実施例１と同じサンプルを用い、NaHCO3水溶
液を加えなかつた以外は同実施例と全く同様に操
作を行つた。APMの回収率は71.4％、DKPの含
有率は2.55％であつた。Comparative Example 2 The same sample as in Example 1 was used, and the operation was carried out in exactly the same manner as in Example 1, except that the NaHCO 3 aqueous solution was not added. The recovery rate of APM was 71.4%, and the content rate of DKP was 2.55%.
実施例 ３
1457ｇの粗製APM（DKP含有率3.85％）を水
50mlに加えた混合物を50℃に加熱し、均一溶液と
した。溶液のPHは4.4であつた。この液に
NaHCO3水溶液（0.1N）3.0mlを加えてPHを5.60
としたのち、約３時間室温に放置して結晶を析出
させた。さらに一夜間10℃に放置したあとスラリ
ーを過し、結晶を約90mlの冷水で洗浄した。得
られた湿結晶を実施例１と同様にして分析を行
い、APMの回収率32.4％、DKP含有率0.46％を
得た。Example 3 1457g of crude APM (DKP content 3.85%) was added to water.
The mixture added to 50 ml was heated to 50°C to form a homogeneous solution. The pH of the solution was 4.4. In this liquid
Add 3.0ml of NaHCO3 aqueous solution (0.1N) to bring the pH to 5.60
After that, the mixture was left at room temperature for about 3 hours to precipitate crystals. After further standing at 10°C overnight, the slurry was filtered and the crystals were washed with about 90 ml of cold water. The obtained wet crystals were analyzed in the same manner as in Example 1, and the recovery rate of APM was 32.4% and the DKP content was 0.46%.
比較例 ３
NaHCO3水溶液（0.1N）を加えなかつた以外は
実施例３と全く同様に操作を行つた。APMの回
収率22.7％、DKP含有率0.72％を得た。Comparative Example 3 The operation was carried out in exactly the same manner as in Example 3, except that the NaHCO 3 aqueous solution (0.1N) was not added. APM recovery rate of 22.7% and DKP content rate of 0.72% were obtained.
Claims (1)
カルボキシメチル−２・５−ジケトピペラジンを
含む水性溶液からα−Ｌ−アスパルチル−Ｌ−フ
エニルアラニン低級アルキルエステルを晶析させ
るに当り、この水性溶液に塩基性物質を加えてそ
の液性をPH4.5を越え、かつ８以下の値とした
後、結晶析出させ、析出した結晶を単離すること
を特徴とするα−Ｌ−アスパルチル−Ｌ−フエニ
ルアラニン低級アルキルエステルの回収法。 ２ α−Ｌ−アスパルチル−Ｌ−フエニルアラニ
ン低級アルキルエステルがα−Ｌ−アスパルチル
−Ｌ−フエニルアラニンメチルエステルである特
許請求の範囲第１項記載の回収法。 ３ 水性溶液が水溶液である特許請求の範囲第１
項または第２項記載の回収法。 ４ 水性溶液の溶媒が水および水に均一に混和す
る有機溶媒の混合液である特許請求の範囲第１項
または第２項記載の回収法。[Claims] 1. At least 3-benzyl-6- as a contaminant
When crystallizing α-L-aspartyl-L-phenylalanine lower alkyl ester from an aqueous solution containing carboxymethyl-2,5-diketopiperazine, a basic substance is added to the aqueous solution to change its liquid properties. A method for recovering α-L-aspartyl-L-phenylalanine lower alkyl ester, which comprises adjusting the pH to a value exceeding 4.5 and below 8, precipitating the crystals, and isolating the precipitated crystals. 2. The recovery method according to claim 1, wherein the α-L-aspartyl-L-phenylalanine lower alkyl ester is α-L-aspartyl-L-phenylalanine methyl ester. 3 Claim 1 in which the aqueous solution is an aqueous solution
Collection method described in Section 2 or Section 2. 4. The recovery method according to claim 1 or 2, wherein the solvent of the aqueous solution is a mixture of water and an organic solvent that is uniformly miscible with water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7537179A JPS55167266A (en) | 1979-06-15 | 1979-06-15 | Recovery of alpha-l-aspartyl-l-phenylalanine lower alkyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7537179A JPS55167266A (en) | 1979-06-15 | 1979-06-15 | Recovery of alpha-l-aspartyl-l-phenylalanine lower alkyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55167266A JPS55167266A (en) | 1980-12-26 |
| JPS6112917B2 true JPS6112917B2 (en) | 1986-04-10 |
Family
ID=13574279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7537179A Granted JPS55167266A (en) | 1979-06-15 | 1979-06-15 | Recovery of alpha-l-aspartyl-l-phenylalanine lower alkyl ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55167266A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0249373Y2 (en) * | 1985-05-10 | 1990-12-26 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58177952A (en) * | 1982-04-12 | 1983-10-18 | Ajinomoto Co Inc | Crystallization of l-alpha-aspartyl-l-phenylalanine methyl ester |
| JPH0742310B2 (en) * | 1984-01-23 | 1995-05-10 | 味の素株式会社 | Crystallization method of L-aspartyl-L-phenylalanine or its lower alkyl ester |
-
1979
- 1979-06-15 JP JP7537179A patent/JPS55167266A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0249373Y2 (en) * | 1985-05-10 | 1990-12-26 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55167266A (en) | 1980-12-26 |
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