JPH0333706B2 - - Google Patents
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- Publication number
- JPH0333706B2 JPH0333706B2 JP57150014A JP15001482A JPH0333706B2 JP H0333706 B2 JPH0333706 B2 JP H0333706B2 JP 57150014 A JP57150014 A JP 57150014A JP 15001482 A JP15001482 A JP 15001482A JP H0333706 B2 JPH0333706 B2 JP H0333706B2
- Authority
- JP
- Japan
- Prior art keywords
- sulfonic acid
- pantetheine
- exchange resin
- resin
- salt
- 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 - Lifetime
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、パンテテイン−Ｓ−スルホン酸およ
びその塩の精製法に関し、更に詳細には特定のイ
オン交換樹脂を用いしかもそれらを特に組み合わ
せて用いることを重要なポイントとする精製法に
関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying pantetheine-S-sulfonic acid and its salts, and more particularly, the important point is to use specific ion exchange resins and to use them in particular combinations. It concerns purification methods.
パンテテイン−Ｓ−スルホン酸およびその塩
は、生理的意義の重要性が特に注目されている腸
内細菌，ビヒズス菌の増殖も促進する因子すなわ
ちビヒズス因子として知られている。また、パン
テテイン−Ｓ−スルホン酸およびその塩は、現在
臨床医薬として使用されているパンテチンと全く
同様に、生体内におけるエネルギー代謝・脂質代
謝・アセチル化作用に重要な役割を有するコエン
ザイムＡの前駆物質として有用な化合物であるこ
とも知られている。すなわち、パンテテイン−Ｓ
−スルホン酸は、医薬としても非常に有用な物質
であり、そのうえ、パンテチンに比べるとコスト
が低い点で極めて有用性が高いものである。 Pantetheine-S-sulfonic acid and its salts are known as bihudus factors, that is, factors that also promote the growth of bihudus bacteria, an enteric bacterium that has attracted particular attention for its physiological significance. In addition, pantetheine-S-sulfonic acid and its salts are precursors of coenzyme A, which plays an important role in energy metabolism, lipid metabolism, and acetylation in the body, just like pantethine, which is currently used as a clinical drug. It is also known to be a useful compound as That is, pantetheine-S
-Sulfonic acid is a very useful substance as a medicine, and is also very useful because it is less expensive than pantethine.
パンテテイン−Ｓ−スルホン酸およびその塩の
工業的製法としては、次式で示すように、パント
テン酸カルシウムと２−アミノエタンチオール硫
酸とからジシクロヘキシルカルボジイミドを縮合
剤として合成する方法が確立されている。 As an industrial method for producing pantetheine-S-sulfonic acid and its salts, a method has been established in which calcium pantothenate and 2-aminoethanethiol sulfuric acid are synthesized using dicyclohexylcarbodiimide as a condensing agent, as shown in the following formula.
しかしながら、パンテテイン−Ｓ−スルホン酸
およびその塩は、吸湿性が高いうえに水以外の通
常の有機溶媒には非常にとけにくいため、再結晶
により、未反応のパントテン酸カルシウムと２−
アミノエタンチオール硫酸を除くことは困難であ
る。 However, pantetheine-S-sulfonic acid and its salts have high hygroscopicity and are very difficult to dissolve in ordinary organic solvents other than water.
It is difficult to remove aminoethanethiol sulfate.
ある化合物を特に医薬として用いる場合、その
化合物は充分に精製することが必要であつて、不
純物を含まない極めて高純度のものにしておくこ
とが絶対に必要である。 When a certain compound is used especially as a medicine, it is necessary to sufficiently purify the compound, and it is absolutely necessary to keep the compound free from impurities and of extremely high purity.
そこで、イオン交換法に着目して反応液を強酸
性陽イオン交換樹脂により処理したけれども、高
純度のパンテテイン−Ｓ−スルホン酸およびその
塩を得ることはできなかつた。すなわち、パンテ
テイン−Ｓ−スルホン酸は酸性のスルホン酸基を
有しているうえに、未反応のパントテン酸も酸性
のカルボン酸基をもつているため陽イオン交換樹
脂を用いて未反応のパントテン酸を除去すること
はできない。またもう一方の未反応物である２−
アミノエタンチオール硫酸はアミノ基を有しては
いるが、分子内にスルホン酸基をも有していて、
分子内塩を形成するためスルホン酸基を有する陽
イオン交換樹脂が中性塩分解能を有するにもかか
わらず、分子内のスルホン酸基と交換基を同じく
する。このスルホン酸基型陽イオン交換樹脂に交
換捕捉されないのである。 Therefore, focusing on the ion exchange method, the reaction solution was treated with a strongly acidic cation exchange resin, but it was not possible to obtain highly pure pantetheine-S-sulfonic acid and its salt. In other words, pantetheine-S-sulfonic acid has an acidic sulfonic acid group, and unreacted pantothenic acid also has an acidic carboxylic acid group, so a cation exchange resin is used to remove unreacted pantothenic acid. cannot be removed. Also, the other unreacted product, 2-
Although aminoethanethiol sulfate has an amino group, it also has a sulfonic acid group in the molecule,
In order to form an intramolecular salt, the sulfonic acid group and the exchange group in the molecule are made the same, even though the cation exchange resin having a sulfonic acid group has the ability to decompose a neutral salt. It is not exchanged and captured by this sulfonic acid group type cation exchange resin.
しかしながら、パンテテイン−Ｓ−スルホン酸
の精製法の確立は急務であるが、上記したように
再結晶法は好適ではない。そして、イオン交換法
にも上記のように欠点があつて、強酸性陽イオン
交換樹脂を用いたのでは所期の目的は達成し得な
かつたのではあるけれども、本発明者らは、スル
ホン酸基とカルボン酸基に対する陰イオン交換樹
脂の選択性のちがい、および、弱塩基性陰イオン
交換樹脂が中性塩分解能をもたない点に着目し、
イオン交換樹脂法を再検討して、イオン交換樹脂
の選択のみならずそれらの組み合わせについても
深く研究した結果、あらかじめ強酸性陽イオン交
換樹脂に通液した反応液に弱塩基性陰イオン交換
樹脂を添加したところ、パンテテイン−Ｓ−スル
ホン酸のみが選択的に交換捕捉され、パントテン
酸と２−アミノエタンチオール硫酸はいずれも交
換捕捉されないことをつきとめ、効率よくパンテ
テイン−Ｓ−スルホン酸およびその塩を精製でき
ることを発見し、本発明を完成した。 However, although there is an urgent need to establish a method for purifying pantetheine-S-sulfonic acid, the recrystallization method is not suitable as described above. Although the ion exchange method also has drawbacks as mentioned above, and the intended purpose could not be achieved by using a strongly acidic cation exchange resin, the present inventors Focusing on the difference in selectivity of anion exchange resins for groups and carboxylic acid groups, and the fact that weakly basic anion exchange resins do not have the ability to decompose neutral salts,
After reexamining the ion exchange resin method and deeply researching not only the selection of ion exchange resins but also their combinations, we decided to add a weakly basic anion exchange resin to the reaction solution that had been passed through a strongly acidic cation exchange resin in advance. When added, it was found that only pantetheine-S-sulfonic acid was selectively exchanged and captured, while neither pantothenic acid nor 2-aminoethanethiol sulfate was exchanged and captured, and pantetheine-S-sulfonic acid and its salts were efficiently captured. They discovered that it could be purified and completed the present invention.
すなわち、本発明は、パンテテイン−Ｓ−スル
ホン酸および／または該塩を含有する液を強酸性
陽イオン交換樹脂に通液して不純物を吸着除去す
るとともに該塩にあつてはそれを遊離の酸とな
し、次いで樹脂に吸着されないで流出してくる流
出液を弱塩基性陰イオン交換樹脂と接触せしめて
パンテテイン−Ｓ−スルホン酸を樹脂に吸着捕捉
せしめ、そしてこれをアルカリによつて溶出する
ことを特徴とするパンテテイン−Ｓ−スルホン酸
およびその塩の精製法、である。 That is, the present invention adsorbs and removes impurities by passing a solution containing pantetheine-S-sulfonic acid and/or its salt through a strongly acidic cation exchange resin, and in the case of the salt, converts it into a free acid. Then, the effluent that flows out without being adsorbed by the resin is brought into contact with a weakly basic anion exchange resin to adsorb and trap pantetheine-S-sulfonic acid on the resin, and then it is eluted with an alkali. A method for purifying pantetheine-S-sulfonic acid and its salts, characterized by:
本発明においては、これら双方のイオン交換樹
脂を併用することが必須の要件であつて、どちら
か一方のイオン交換樹脂のみを使用したのでは所
期の目的は達成されない。本発明を実施するに
は、反応液を先ず強酸性陽イオン交換樹脂で処理
した後、弱塩基性陰イオン交換樹脂で処理する。
処理の方法としては、通液したり、浸漬したり、
これらを組合わせたりすることができる。 In the present invention, it is essential to use both of these ion exchange resins, and the intended purpose cannot be achieved if only one of the ion exchange resins is used. To carry out the present invention, the reaction solution is first treated with a strongly acidic cation exchange resin and then treated with a weakly basic anion exchange resin.
Treatment methods include passing through liquid, immersing,
These can be combined.
例えば、パンテテイン−Ｓ−スルホン酸の合成
反応液を濃縮し、溶媒を水におきかえ不溶分を
去したのち、液を強酸性陽イオン交換樹脂に通
液する。流出液にPH２になるように弱塩基性陰イ
オン交換樹脂を添加しパンテテイン−Ｓ−スルホ
ン酸を交換捕捉させる。パンテテイン−Ｓ−スル
ホン酸を捕捉している樹脂をカラムにつめ、、共
にPH２にした液を流し、さらに水洗する。アルカ
リ溶液にして溶出し、溶出液をただちに強酸性陽
イオン交換樹脂に通液すれば遊離のパンテテイン
−Ｓ−スルホン酸が得られ、これを希望する塩に
相当するアルカリで中和すればパンテテイン−Ｓ
−スルホン酸の希望する塩の水溶液が得られる。
この水溶液を濃縮乾燥すればパンテテイン−Ｓ−
スルホン酸塩を高純度で得ることができる。 For example, the synthesis reaction solution for pantetheine-S-sulfonic acid is concentrated, the solvent is replaced with water to remove insoluble matter, and then the solution is passed through a strongly acidic cation exchange resin. A weakly basic anion exchange resin is added to the effluent to adjust the pH to 2, and pantetheine-S-sulfonic acid is exchanged and captured. The resin capturing pantetheine-S-sulfonic acid is packed into a column, and a solution adjusted to pH 2 is poured into the column, followed by washing with water. Elution is carried out in an alkaline solution, and the eluate is immediately passed through a strongly acidic cation exchange resin to obtain free pantetheine-S-sulfonic acid.If this is neutralized with an alkali corresponding to the desired salt, pantetheine-S-sulfonic acid is obtained. S
- An aqueous solution of the desired salt of sulfonic acid is obtained.
If this aqueous solution is concentrated and dried, pantetheine-S-
Sulfonate salts can be obtained with high purity.
本発明において使用する強酸性陽イオン交換樹
脂とは交換基としてスルホン酸を有するイオン交
換樹脂をいい、弱塩基性陰イオン交換樹脂とは第
１〜３級アミンを交換基とする樹脂を示すもので
あつて、第４級アンモニウムでは本発明の目的は
達成されない。第１〜３級のアミンはそれを単独
で交換基として有していてもよいし、それらが適
宜混合されたものでもよい。強酸性陽イオン交換
樹脂・弱塩基性陰イオン交換樹脂共に市販のもの
を適宜使用することができる。 The strongly acidic cation exchange resin used in the present invention refers to an ion exchange resin having a sulfonic acid as an exchange group, and the weakly basic anion exchange resin refers to a resin having a primary to tertiary amine as an exchange group. However, the object of the present invention cannot be achieved with quaternary ammonium. The primary to tertiary amines may have it alone as an exchange group, or they may be appropriately mixed. Commercially available strong acidic cation exchange resins and weakly basic anion exchange resins can be used as appropriate.
次に本発明を実施例について説明する。 Next, the present invention will be explained with reference to examples.
実施例
パントテン酸カルシウム23.8ｇと２−アミノエ
タンチオール硫酸15.7ｇを水30mlに溶解し、ピリ
ジン50mlに溶解した１−ヒドロキシベンゾトリア
ゾール13.5ｇとピリジン150mlを加え、氷浴で10
℃まで冷却する。Example 23.8 g of calcium pantothenate and 15.7 g of 2-aminoethanethiol sulfuric acid were dissolved in 30 ml of water, 13.5 g of 1-hydroxybenzotriazole dissolved in 50 ml of pyridine and 150 ml of pyridine were added, and the mixture was heated in an ice bath for 10 min.
Cool to ℃.
ピリジン50mlに溶解したジシクロヘキシルカル
ボジイミド20.6ｇを加え、氷浴中で１時間、その
後室温に戻して一晩、撹拌反応させる。次いで反
応溶媒のピリジンを減圧濃縮により除去し、水に
溶解して不溶分を去する。液をスルホン酸基
型陽イオン交換樹脂（商品名：ダイヤイオン
SKIB〔H+〕）150mlに通液する。流出液に第１、
第２級アミン型陰イオン交換樹脂（商品名：ダイ
ヤイオンWA21〔OH-〕）を添加しPH２とする。こ
の陰イオン交換樹脂をカラムにつめ先にPH２とし
た液を流し、さらに水洗したのち２％NaOH水
溶液500mlで溶出する。溶出液はただちにスルホ
ン酸基型陽イオン交換樹脂（商品名：ダイヤイオ
ンSKIB〔H+〕）に通液する。流出液をそのまま定
量すれば遊離のパンテテイン−Ｓ−スルホン酸が
26.2ｇ含まれている。さらにCaCO3で中和したの
ち濃縮乾燥すればパンテテイン−Ｓ−スルホン酸
カルシウムの白色粉末状結晶27.7ｇ（収率73.5
％）を得る。 Add 20.6 g of dicyclohexylcarbodiimide dissolved in 50 ml of pyridine, and react with stirring in an ice bath for 1 hour, then return to room temperature overnight. Next, the reaction solvent pyridine is removed by concentration under reduced pressure, and the solution is dissolved in water to remove insoluble matter. The solution is sulfonic acid group type cation exchange resin (product name: Diaion
Pour the solution into 150ml of SKIB [H + ]). First to the effluent,
Add secondary amine type anion exchange resin (trade name: Diaion WA21 [OH - ]) to adjust the pH to 2. This anion exchange resin was poured into a column with a solution adjusted to pH 2, and after further washing with water, it was eluted with 500 ml of a 2% NaOH aqueous solution. The eluate is immediately passed through a sulfonic acid group type cation exchange resin (trade name: Diaion SKIB [H + ]). If the effluent is directly quantified, free pantetheine-S-sulfonic acid will be detected.
Contains 26.2g. Furthermore, after neutralizing with CaCO 3 and concentrating and drying, 27.7 g of white powdery crystals of calcium pantetheine-S-sulfonate (yield 73.5
%).
元素分析値 C22H42O14N4S4Caとして Ｃ Ｈ Ｎ 計算値(%) 35.00 5.61 7.42 測定値(%) 34.89 5.71 7.37 〔α〕20 D＋14.4゜（C1.95，H2O）Elemental analysis value C 22 H 42 O 14 N 4 S 4 As Ca C H N Calculated value (%) 35.00 5.61 7.42 Measured value (%) 34.89 5.71 7.37 [α] 20 D +14.4゜ (C1.95, H 2 O)
Claims (1)
は該塩を含有する液を強酸性陽イオン交換樹脂に
通液して不純物を吸着除去するとともに該塩にあ
つてはそれを遊離の酸となし、次いで樹脂に吸着
されないで流出してくる流出液を弱塩基性陰イオ
ン交換樹脂と接触せしめてパンテテイン−Ｓ−ス
ルホン酸を樹脂に吸着捕捉せしめ、そしてこれを
アルカリによつて溶出することを特徴とするパン
テテイン−Ｓ−スルホン酸およびその塩の精製
法。1 A solution containing pantetheine-S-sulfonic acid and/or its salt is passed through a strongly acidic cation exchange resin to adsorb and remove impurities, and in the case of the salt, it is converted into a free acid, and then passed through a resin. Pantetheine, which is characterized by contacting the effluent that flows out without being adsorbed by the resin with a weakly basic anion exchange resin to adsorb and capture pantetheine-S-sulfonic acid on the resin, and then eluting it with an alkali. - A method for purifying S-sulfonic acid and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15001482A JPS5939868A (en) | 1982-08-31 | 1982-08-31 | Purification of pantetheine-s-sulfonic acid and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15001482A JPS5939868A (en) | 1982-08-31 | 1982-08-31 | Purification of pantetheine-s-sulfonic acid and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5939868A JPS5939868A (en) | 1984-03-05 |
| JPH0333706B2 true JPH0333706B2 (en) | 1991-05-20 |
Family
ID=15487587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15001482A Granted JPS5939868A (en) | 1982-08-31 | 1982-08-31 | Purification of pantetheine-s-sulfonic acid and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5939868A (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6014026B2 (en) * | 1979-09-05 | 1985-04-11 | 相互薬工株式会社 | Method for producing pantetheine-S-sulfonic acid and its salts |
| JPS5849540B2 (en) * | 1980-10-17 | 1983-11-05 | 相互薬工株式会社 | Purification method of compound having both amino group and sulfonic acid group |
-
1982
- 1982-08-31 JP JP15001482A patent/JPS5939868A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5939868A (en) | 1984-03-05 |
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