JP2003286264A - Method for producing 5-isoquinolinesulfonic acid - Google Patents
Method for producing 5-isoquinolinesulfonic acidInfo
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- JP2003286264A JP2003286264A JP2002085817A JP2002085817A JP2003286264A JP 2003286264 A JP2003286264 A JP 2003286264A JP 2002085817 A JP2002085817 A JP 2002085817A JP 2002085817 A JP2002085817 A JP 2002085817A JP 2003286264 A JP2003286264 A JP 2003286264A
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- Prior art keywords
- reaction
- sulfuric acid
- isoquinoline
- acid
- fuming sulfuric
- Prior art date
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- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医療原料として有
用な５−イソキノリンスルホン酸の製造方法に関する。TECHNICAL FIELD The present invention relates to a method for producing 5-isoquinolinesulfonic acid useful as a medical raw material.
【０００２】[0002]
【従来の技術】５−イソキノリンスルホン酸の従来の製
造方法として、イソキノリンに硫酸と発煙硫酸の両方を
作用させてスルホン化する方法がある (J. Org. Chem.,
27, 1962, 4571)。2. Description of the Related Art As a conventional method for producing 5-isoquinolinesulfonic acid, there is a method in which isoquinoline is reacted with both sulfuric acid and fuming sulfuric acid to be sulfonated (J. Org. Chem.,
27, 1962, 4571).
【０００３】この従来法では、まず最初に硫酸にイソキ
ノリンを添加してイソキノリン硫酸塩とし、そこへ次に
50％発煙硫酸を滴下してスルホン化する。しかし、本発
明者が追試してみたところ、イソキノリン硫酸塩が生成
するにつれて反応液が固化し、攪拌できない状態にな
る。そこに50％発煙硫酸を滴下して、反応させなければ
ならないが、この状態では、発煙硫酸が滴下された箇所
で部分的な反応発熱を生じるため、工業化のためのスケ
ールアップが難しい。また、使用する50％の発煙硫酸は
常温で固体であるため、滴下するためには加温溶解が必
要で、作業性が悪い。さらに、反応が２工程で行われる
ので、１工程法に比べて反応操作が複雑となる。In this conventional method, isoquinoline is first added to sulfuric acid to form isoquinoline sulfate, and then there is added.
Sulfonate by adding 50% fuming sulfuric acid dropwise. However, as a result of additional tests by the present inventor, as the isoquinoline sulfate is produced, the reaction solution solidifies and becomes in a state where it cannot be stirred. It is necessary to add 50% fuming sulfuric acid dropwise there to react them, but in this state, partial reaction heat generation occurs at the place where fuming sulfuric acid is dropped, so scale-up for industrialization is difficult. In addition, since 50% of fuming sulfuric acid used is solid at room temperature, it needs to be heated and dissolved in order to be added dropwise, resulting in poor workability. Furthermore, since the reaction is performed in two steps, the reaction operation becomes complicated as compared with the one-step method.
【０００４】[0004]
【発明が解決しようとする課題】上述したように、従来
法では、５−イソキノリンスルホン酸を工業的に製造す
ることが困難であった。本発明の目的は、工業的に容易
に実施可能な５−イソキノリンスルホン酸の新規かつ効
率的な製造方法を提供することにある。As described above, it has been difficult to industrially produce 5-isoquinolinesulfonic acid by the conventional method. An object of the present invention is to provide a new and efficient process for producing 5-isoquinolinesulfonic acid that can be easily carried out industrially.
【０００５】[0005]
【課題を解決するための手段】本発明者は、発煙硫酸に
いきなりイソキノリンを滴下することによって、イソキ
ノリンの硫酸塩を経由せずに、イソキノリンの５位を直
接スルホン化することができ、こうして５−イソキノリ
ンスルホン酸を従来法に匹敵する収率および純度で製造
できることを見出した。The present inventor can directly sulfonate the 5-position of isoquinoline without passing through the sulfate salt of isoquinoline by suddenly dropping isoquinoline into fuming sulfuric acid. It has been found that isoquinoline sulphonic acid can be produced with yields and purities comparable to conventional processes.
【０００６】本発明は、発煙硫酸にイソキノリンを滴下
して反応させることを特徴とする、５−イソキノリンス
ルホン酸の製造方法である。好適態様によると、迅速な
反応が可能で、かつ容易に攪拌可能となるように、発煙
硫酸の濃度は５〜30％であり。The present invention is a method for producing 5-isoquinolinesulfonic acid, characterized in that isoquinoline is added dropwise to fuming sulfuric acid for reaction. According to a preferred embodiment, the concentration of fuming sulfuric acid is 5 to 30% so that rapid reaction is possible and easy stirring is possible.
【０００７】本発明に係る５−イソキノリンスルホン酸
の製造方法は、操作性が大幅に改善され、工業的実施が
容易である。The method for producing 5-isoquinolinesulfonic acid according to the present invention has a greatly improved operability and is easy to carry out industrially.
【０００８】[0008]
【発明の実施の形態】本発明の５−イソキノリンスルホ
ン酸の製造方法で原料として用いるイソキノリンは、タ
ール分留品と合成品のいずれでも差し障りはない。純度
は必ずしも高純度品である必要はないが、純度95％以上
のイソキノリンを使用することが好ましい。BEST MODE FOR CARRYING OUT THE INVENTION The isoquinoline used as a raw material in the method for producing 5-isoquinolinesulfonic acid of the present invention may be either a tar fractionated product or a synthetic product. The purity does not necessarily have to be a high purity product, but isoquinoline having a purity of 95% or more is preferably used.
【０００９】発煙硫酸は濃硫酸に三酸化硫黄 (ＳＯ3)を
吸収させたものであり、発煙硫酸の濃度とはＳＯ3 含有
量を意味する。本発明でイソキノリンとの反応に用いる
発煙硫酸は、５〜60％の濃度のものでよいが、好ましく
は濃度が５〜30％の発煙硫酸を使用する。発煙硫酸の濃
度が５％以下では、反応が遅く、実用的ではない。濃度
が30％以上の発煙硫酸は、工業的に入手が容易でない
上、常温で固体となり、取扱いが容易でない。Fuming sulfuric acid is obtained by absorbing sulfur trioxide (SO 3 ) in concentrated sulfuric acid, and the concentration of fuming sulfuric acid means the SO 3 content. The fuming sulfuric acid used in the reaction with isoquinoline in the present invention may have a concentration of 5 to 60%, but preferably a fuming sulfuric acid having a concentration of 5 to 30% is used. When the concentration of fuming sulfuric acid is 5% or less, the reaction is slow and it is not practical. Fuming sulfuric acid having a concentration of 30% or more is not easily industrially available, and is solid at room temperature, which is not easy to handle.
【００１０】発煙硫酸の使用量は、反応液が攪拌可能で
あれば特に制限はないが、通常はイソキノリンに対して
質量で３〜15倍の量を用いる。本発明の方法によれば、
反応器に発煙硫酸を装入しておき、この発煙硫酸に対し
て、イソキノリンを滴下する。それにより、反応系を常
に液体または流動状態に保持して、攪拌を続けながら反
応を進行させることができるので、工業的な実施も容易
である。The amount of fuming sulfuric acid used is not particularly limited as long as the reaction solution can be stirred, but is usually used in an amount of 3 to 15 times the mass of isoquinoline. According to the method of the present invention,
Fuming sulfuric acid was charged in the reactor, and isoquinoline was added dropwise to the fuming sulfuric acid. As a result, the reaction system can be maintained in a liquid or fluid state at all times and the reaction can be allowed to proceed while continuing stirring, which facilitates industrial implementation.
【００１１】この添加順序を逆にして、反応器にイソキ
ノリンを装入し、そこに発煙硫酸を滴下すると、途中で
反応物が固化し、攪拌が困難となる。そこにさらに発煙
硫酸を滴下しても、その後は反応が局部的にしか起こら
ず、反応による発熱の制御も困難となる。従って、この
方法では、目的とする５−イソキノリンスルホン酸を効
率よく製造することはできない。When this order of addition is reversed and isoquinoline is charged into the reactor and fuming sulfuric acid is added dropwise thereto, the reaction product solidifies midway, making stirring difficult. Even if fuming sulfuric acid is further dropped there, the reaction only occurs locally thereafter, and it becomes difficult to control the heat generation due to the reaction. Therefore, this method cannot efficiently produce the desired 5-isoquinolinesulfonic acid.
【００１２】反応は−10〜150 ℃の範囲で実施可能であ
るが、望ましくは−10〜100 ℃で実施する。−10℃以下
では、反応時間が長くなり、経済的でない。100 ℃以上
では、異性体である８−イソキノリンスルホン酸 (８
体) の生成が増加する。実際の反応温度は、発煙硫酸の
濃度に応じて、上記範囲内で、発煙硫酸が固化しない温
度に設定する。より好ましい反応温度は10〜50℃であ
る。スルホン化反応は発熱性であるので、必要に応じて
反応器を冷却して、反応温度を制御する。The reaction can be carried out in the range of -10 to 150 ° C, preferably -10 to 100 ° C. If the temperature is -10 ° C or lower, the reaction time becomes long, which is not economical. Above 100 ° C, the isomer 8-isoquinolinesulfonic acid (8
Body) production increases. The actual reaction temperature is set within the above range depending on the concentration of fuming sulfuric acid so that the fuming sulfuric acid does not solidify. The more preferable reaction temperature is 10 to 50 ° C. Since the sulfonation reaction is exothermic, the reactor is cooled as necessary to control the reaction temperature.
【００１３】イソキノリンの滴下時間も含めた反応時間
は、通常 0.5〜10時間の範囲である。イソキノリンの滴
下は、例えば10分〜２時間程度で行い、その後も反応液
の攪拌を続けて反応を完了させればよい。The reaction time including the dropping time of isoquinoline is usually in the range of 0.5 to 10 hours. The dropping of isoquinoline may be performed, for example, for about 10 minutes to 2 hours, and then the reaction solution may be continuously stirred to complete the reaction.
【００１４】反応後、反応液を水中に投入すると、生成
物の５−イソキノリンスルホン酸が析出するので、濾過
または遠心分離等により生成物を回収する。反応液は多
量の発煙硫酸を含有しているので、反応液の水中への投
入は、急激な発熱を避けるように慎重に行う (例、滴下
により) 。回収された５−イソキノリンスルホン酸は、
必要に応じて再結晶等の方法で精製を実施してもよい。
しかし、実施例に示すように通常は、水洗だけでも十分
に高純度の生成物が得られることが多い。After the reaction, when the reaction solution is poured into water, the product 5-isoquinolinesulfonic acid precipitates, and the product is recovered by filtration or centrifugation. Since the reaction solution contains a large amount of fuming sulfuric acid, pour the reaction solution into water carefully so as to avoid a rapid heat generation (eg, by dropping). The recovered 5-isoquinolinesulfonic acid is
If necessary, purification may be performed by a method such as recrystallization.
However, as shown in the examples, usually, washing with water alone often gives sufficiently pure products.
【００１５】[0015]
【実施例】以下、実施例により本発明を例示する。実施
例中、％は特に指定しない限り質量％である。EXAMPLES The present invention will be illustrated below with reference to examples. In the examples,% is% by mass unless otherwise specified.
【００１６】(実施例１)温度計および攪拌棒および水冷
装置を備えた300 mlのガラスフラスコに、25％発煙硫酸
200 g を仕込み、攪拌を開始した。この発煙硫酸に、イ
ソキノリン (合成品) 25.0 g(0.194 mol) を、30℃以下
の温度を保持するように30分間かけて滴下した。滴下終
了後、温度を20〜30℃に保持して反応液の攪拌を５時間
続け、反応を完了した。この間、反応液は液状を保ち、
固化することはなかった。(Example 1) In a 300 ml glass flask equipped with a thermometer, a stir bar and a water cooling device, 25% fuming sulfuric acid was added.
200 g was charged and stirring was started. To this fuming sulfuric acid, 25.0 g (0.194 mol) of isoquinoline (synthetic product) was added dropwise over 30 minutes so as to maintain the temperature at 30 ° C or lower. After completion of the dropping, the temperature was maintained at 20 to 30 ° C. and the stirring of the reaction solution was continued for 5 hours to complete the reaction. During this time, the reaction liquid remains liquid,
It never solidified.
【００１７】その後、反応液を、水300 g を入れた500
mlのフラスコに滴下し、滴下終了後に０℃まで冷却し
た。析出した結晶を濾取し、水洗した後、減圧下60℃で
乾燥して、５−イソキノリンスルホン酸28.4 gを得た。
高速液体クロマトグラフィーによる測定値から面積百分
率法 (以下、ＬＣ面積百分率法という) により求めた純
度は99.3％、８体の含有率は0.2 ％、収率は69.9 mol％
であった。Then, the reaction solution was added to 500 g of 300 g of water.
The solution was added dropwise to a ml flask and cooled to 0 ° C after the completion of the addition. The precipitated crystals were collected by filtration, washed with water, and dried at 60 ° C. under reduced pressure to give 5-isoquinolinesulfonic acid (28.4 g).
The purity determined by the area percentage method (hereinafter referred to as LC area percentage method) from the values measured by high performance liquid chromatography was 99.3%, the content of 8 compounds was 0.2%, and the yield was 69.9 mol%.
Met.
【００１８】(実施例２)反応温度を80℃に変更した以外
は実施例１に記載したのと同様の手順で、５−イソキノ
リンスルホン酸27.1 gを得た。ＬＣ面積百分率法による
純度は98.1％、８体の含有率は1.3 ％、収率は65.5 mol
％であった。(Example 2) By the same procedure as described in Example 1 except that the reaction temperature was changed to 80 ° C, 27.1 g of 5-isoquinolinesulfonic acid was obtained. The purity by LC area percentage method is 98.1%, the content of 8 compounds is 1.3%, the yield is 65.5 mol.
%Met.
【００１９】(実施例３)反応温度を105 ℃、滴下終了後
の反応時間を２時間に変更した以外は実施例１に記載し
たのと同様の手順で、５−イソキノリンスルホン酸26.1
gを得た。ＬＣ面積百分率法による純度は97.2％、８体
の含有率は2.5 ％、収率は62.6 mol％であった。Example 3 5-Isoquinolinesulfonic acid 26.1 was prepared in the same procedure as described in Example 1 except that the reaction temperature was changed to 105 ° C. and the reaction time after completion of the dropping was changed to 2 hours.
got g. The purity measured by the LC area percentage method was 97.2%, the content of the 8 compounds was 2.5%, and the yield was 62.6 mol%.
【００２０】(比較例１)本例は上述した従来法による５
−イソキノリンスルホン酸の合成を例示する。温度計、
攪拌棒、および水冷装置を備えた300 mlのフラスコに濃
硫酸22 ml を仕込み、攪拌を開始した。この濃硫酸に、
水冷冷却下、イソキノリン52 g(0.403 mol) を20分間か
けて滴下した。滴下途中で反応液が固化し、攪拌不能と
なったが、そのままイソキノリンの滴下を続けた。Comparative Example 1 This example is based on the above-mentioned conventional method.
-Exemplifies the synthesis of isoquinoline sulfonic acid. thermometer,
22 ml of concentrated sulfuric acid was charged into a 300 ml flask equipped with a stir bar and a water cooling device, and stirring was started. In this concentrated sulfuric acid,
Under cooling with water, 52 g (0.403 mol) of isoquinoline was added dropwise over 20 minutes. The reaction liquid solidified during the dropping and stirring became impossible, but the dropping of isoquinoline was continued as it was.
【００２１】イソキノリンの滴下完了後、50％発煙硫酸
110 mlを、30℃以下の温度を保持するよう20分間かけて
滴下した。発煙硫酸の滴下途中で反応液の流動性が増
し、攪拌可能となったが、滴下完了後は非常に粘稠な反
応液となった。発煙硫酸の滴下完了後、反応液を４時間
攪拌して、反応を完了した。After the addition of isoquinoline was completed, 50% fuming sulfuric acid was added.
110 ml was added dropwise over 20 minutes to keep the temperature below 30 ° C. The fluidity of the reaction solution increased during the dropping of fuming sulfuric acid and stirring became possible, but after the completion of dropping, the reaction solution became a very viscous liquid. After the addition of fuming sulfuric acid was completed, the reaction solution was stirred for 4 hours to complete the reaction.
【００２２】この反応液は、粘稠なため、フラスコから
の抜き出し作業がやりにくかった。フラスコから抜き出
した反応液を、水700 mlの中に滴下した後、５℃まで冷
却した。析出した結晶を濾取し、水洗した後、乾燥し
て、５−イソキノリンスルホン酸60.2 gを得た。ＬＣ面
積百分率法による純度は98.9％、８体の含有率は0.3
％、収率は70.7 mol％であった。Since this reaction solution was viscous, it was difficult to extract it from the flask. The reaction liquid extracted from the flask was dropped into 700 ml of water and then cooled to 5 ° C. The precipitated crystals were collected by filtration, washed with water, and dried to give 5-isoquinolinesulfonic acid (60.2 g). The purity by LC area percentage method is 98.9%, the content rate of 8 bodies is 0.3
%, And the yield was 70.7 mol%.
【００２３】(比較例２)温度計、攪拌棒、および油浴装
置を備えた300 mlのフラスコに濃硫酸200 g を仕込み、
攪拌を開始した。イソキノリン25.0 g(0.194 mol) を10
分間かけて滴下した。イソキノリンの滴下終了後、反応
液を100 ℃に加熱し、５時間攪拌を継続したが、５−イ
ソキノリンスルホン酸の生成は認められなかった。Comparative Example 2 200 g of concentrated sulfuric acid was charged into a 300 ml flask equipped with a thermometer, a stir bar and an oil bath.
Stirring was started. Isoquinoline 25.0 g (0.194 mol) 10
It was dripped over a period of minutes. After completion of the dropwise addition of isoquinoline, the reaction solution was heated to 100 ° C. and stirring was continued for 5 hours, but formation of 5-isoquinolinesulfonic acid was not observed.
【００２４】本発明の方法において、発煙硫酸の代わり
に濃硫酸を用いても、目的とするイソキノリンのスルホ
ン化は起こらないことがわかる。
(比較例３)温度計、攪拌棒、および水冷装置を備えた30
0 mlのガラスフラスコに、イソキノリン25.0 g(0.194 m
ol) を仕込み、攪拌を開始した。このイソキノリンに、
25％発煙硫酸200 g を30℃以下の温度を保持するように
滴下したが、滴下途中で反応液が固化し、攪拌が不能と
なった。It can be seen that in the method of the present invention, the intended sulfonation of isoquinoline does not occur even if concentrated sulfuric acid is used instead of fuming sulfuric acid. (Comparative Example 3) 30 equipped with a thermometer, a stirring bar , and a water cooling device
In a 0 ml glass flask, place 25.0 g (0.194 m) of isoquinoline.
ol) was charged and stirring was started. In this isoquinoline,
200 g of 25% fuming sulfuric acid was added dropwise so as to maintain the temperature at 30 ° C or lower, but the reaction liquid solidified during the addition, and stirring was impossible.
【００２５】本発明の方法において、添加順序を変更し
て、イソキノリンに発煙硫酸を滴下しても、円滑に反応
を進めることができないことがわかる。In the method of the present invention, it can be seen that even if the order of addition is changed and fuming sulfuric acid is added dropwise to isoquinoline, the reaction cannot proceed smoothly.
【００２６】[0026]
【発明の効果】従来法では、イソキノリンから、最初に
硫酸、次に50％発煙硫酸を作用させる２段階の反応で５
−イソキノリンスルホン酸を製造する。しかし、この方
法は、最初の硫酸との反応により反応液が固化し、攪拌
不能となる；使用する50％発煙硫酸が室温で固体で、加
温しないと滴下できない；最終的に得られる反応液が非
常に粘稠で、取り出しが困難、といった難点があり、作
業性が極めて悪く、工業的実施には適していない。According to the conventional method, isoquinoline is used in a two-step reaction in which sulfuric acid is reacted first and then 50% fuming sulfuric acid.
To produce isoquinoline sulfonic acid. However, in this method, the reaction liquid solidifies by the first reaction with sulfuric acid and cannot be stirred; the 50% fuming sulfuric acid used is solid at room temperature and cannot be added dropwise without heating; the reaction liquid finally obtained Is very viscous and difficult to take out, the workability is extremely poor, and it is not suitable for industrial implementation.
【００２７】これに対し、本発明によれば、イソキノリ
ンに室温で液状の５〜30％発煙硫酸を作用させることに
より、１段階の反応で５−イソキノリンスルホン酸を製
造することができる。しかも、反応途中で反応液が固化
することがなく、最終的に得られる反応液も粘稠ではな
いため、作業性がよく、工業的な実施が容易である。さ
らに、実施例１〜３と比較例１の反応結果を対比すると
わかるように、本発明の方法によれば、生成物の純度や
収率も、従来法に比べて遜色ない結果が得られる。On the other hand, according to the present invention, 5-isoquinolinesulfonic acid can be produced by a one-step reaction by allowing 5 to 30% of fuming sulfuric acid which is liquid at room temperature to act on isoquinoline. Moreover, since the reaction liquid does not solidify during the reaction and the finally obtained reaction liquid is not viscous, workability is good and industrial implementation is easy. Further, as can be seen by comparing the reaction results of Examples 1 to 3 and Comparative Example 1, the method of the present invention provides results in which the purity and yield of the product are comparable to those of the conventional method.
【００２８】従って、本発明は、これまで有効な工業的
な製造方法が確立していなかった５−イソキノリンスル
ホン酸の工業的な製造を可能にするものであり、その工
業的な意義は大きい。Therefore, the present invention enables the industrial production of 5-isoquinolinesulfonic acid for which an effective industrial production method has not been established, and its industrial significance is great.
Claims (2)
させることを特徴とする、５−イソキノリンスルホン酸
の製造方法。1. A method for producing 5-isoquinolinesulfonic acid, which comprises adding isoquinoline dropwise to fuming sulfuric acid for reaction.
１に記載の５−イソキノリンスルホン酸の製造方法。2. The method for producing 5-isoquinolinesulfonic acid according to claim 1, wherein the concentration of fuming sulfuric acid is 5 to 30%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006063017A (en) * | 2004-08-27 | 2006-03-09 | Asahi Kasei Fainkemu Kk | Method for producing 5-isoquinoline sulfonic acid |
| CN101863880A (en) * | 2010-06-12 | 2010-10-20 | 陶灵刚 | Fasudil hydrochloride compound and novel method thereof |
-
2002
- 2002-03-26 JP JP2002085817A patent/JP4277476B2/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006063017A (en) * | 2004-08-27 | 2006-03-09 | Asahi Kasei Fainkemu Kk | Method for producing 5-isoquinoline sulfonic acid |
| JP4707349B2 (en) * | 2004-08-27 | 2011-06-22 | 旭化成ファインケム株式会社 | Process for producing 5-isoquinolinesulfonic acid |
| CN101863880A (en) * | 2010-06-12 | 2010-10-20 | 陶灵刚 | Fasudil hydrochloride compound and novel method thereof |
| CN101863880B (en) * | 2010-06-12 | 2012-08-01 | 陶灵刚 | Fasudil hydrochloride compound and novel method thereof |
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