JP4277476B2 - Process for producing 5-isoquinolinesulfonic acid - Google Patents
Process for producing 5-isoquinolinesulfonic acid Download PDFInfo
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Description
【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。
【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)。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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。
【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300 mlのガラスフラスコに、イソキノリン25.0 g(0.194 mol) 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。
【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。
【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。
【００２７】
これに対し、本発明によれば、イソキノリンを室温で液状の５〜30％発煙硫酸に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。
【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。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 5-isoquinolinesulfonic acid useful as a medical raw material.
[0002]
[Prior art]
As a conventional method for producing 5-isoquinolinesulfonic acid, there is a method of sulfonation by allowing both sulfuric acid and fuming sulfuric acid to act on isoquinoline (J. Org. Chem., 27, 1962, 4571).
[0003]
In this conventional method, isoquinoline is first added to sulfuric acid to form isoquinoline sulfate, and then 50% fuming sulfuric acid is added dropwise thereto for sulfonation. However, when the present inventor made additional trials, as the isoquinoline sulfate was formed, the reaction solution solidified and became unable to be stirred. 50% fuming sulfuric acid must be dropped there for reaction, but in this state, partial reaction heat is generated at the location where the fuming sulfuric acid is dropped, so it is difficult to scale up for industrialization. In addition, since 50% fuming sulfuric acid used is solid at room temperature, warming and dissolution are required for dripping, and workability is poor. Furthermore, since the reaction is performed in two steps, the reaction operation is complicated as compared with the one-step method.
[0004]
[Problems to be solved by the invention]
As described above, in the conventional method, it was difficult to industrially produce 5-isoquinolinesulfonic acid. An object of the present invention is to provide a novel and efficient method for producing 5-isoquinolinesulfonic acid which can be easily carried out industrially.
[0005]
[Means for Solving the Problems]
The present inventor can sulphonate isoquinoline directly by dripping isoquinoline into fuming sulfuric acid without passing through the sulfate of isoquinoline, thus making 5-isoquinoline sulfonic acid comparable to the conventional method. It was found that it can be produced with the yield and purity.
[0006]
The present invention is a method for producing 5-isoquinoline sulfonic acid, characterized in that isoquinoline is dropped and reacted with fuming sulfuric acid.
According to a preferred embodiment, the concentration of fuming sulfuric acid is 5-30% so that rapid reaction is possible and stirring is easy.
[0007]
The method for producing 5-isoquinoline sulfonic acid according to the present invention is greatly improved in operability and easy to implement industrially.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
The isoquinoline used as a raw material in the method for producing 5-isoquinoline sulfonic acid according to the present invention can be either a tar fraction product or a synthetic product. The purity is not necessarily a high-purity product, but it is preferable to use isoquinoline having a purity of 95% or more.
[0009]
Fuming sulfuric acid is obtained by absorbing sulfur trioxide (SO 3 ) into concentrated sulfuric acid, and the concentration of fuming sulfuric acid means the SO 3 content. The fuming sulfuric acid used for the reaction with isoquinoline in the present invention may have a concentration of 5 to 60%, but preferably 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 not practical. Fuming sulfuric acid having a concentration of 30% or more is not easily available industrially, becomes solid at room temperature, and is not easy to handle.
[0010]
The amount of fuming sulfuric acid is not particularly limited as long as the reaction solution can be stirred, but usually 3 to 15 times the mass of isoquinoline is used.
According to the method of the present invention, fuming sulfuric acid is charged into a reactor, and isoquinoline is dropped into the fuming sulfuric acid. Thereby, the reaction system can always be maintained in a liquid or fluid state, and the reaction can be continued while stirring, so that industrial implementation is also easy.
[0011]
If this addition order is reversed and isoquinoline is charged into the reactor and fuming sulfuric acid is added dropwise thereto, the reaction product solidifies in the middle, making stirring difficult. Even if fuming sulfuric acid is further dropped there, the reaction occurs only locally thereafter, and it becomes difficult to control the heat generation by the reaction. Therefore, this method cannot efficiently produce the desired 5-isoquinoline sulfonic acid.
[0012]
The reaction can be carried out in the range of −10 to 150 ° C., preferably 10 to 100 ° C. Below -10 ° C, the reaction time is long and not economical. Above 100 ° C, the production of the isomeric 8-isoquinoline sulfonic acid (eight bodies) increases. The actual reaction temperature is set to a temperature within which the fuming sulfuric acid does not solidify, depending on the concentration of fuming sulfuric acid. A 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]
The reaction time including the dropping time of isoquinoline is usually in the range of 0.5 to 10 hours. The dropwise addition of isoquinoline may be performed, for example, for about 10 minutes to 2 hours, and the reaction liquid may be continuously stirred to complete the reaction thereafter.
[0014]
When the reaction solution is poured into water after the reaction, the product 5-isoquinolinesulfonic acid is precipitated, and the product is recovered by filtration or centrifugation. Since the reaction solution contains a large amount of fuming sulfuric acid, the reaction solution should be poured carefully into the water to avoid sudden exotherm (eg, by dripping). The recovered 5-isoquinoline sulfonic acid may be purified by a method such as recrystallization as necessary. However, as shown in the examples, usually, a sufficiently high purity product is often obtained only by washing with water.
[0015]
【Example】
The following examples illustrate the invention. In Examples,% is% by mass unless otherwise specified.
[0016]
(Example 1)
A 300 ml glass flask equipped with a thermometer, a stir bar, and a water cooling device was charged with 200 g of 25% fuming sulfuric acid, 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 a temperature of 30 ° C. or lower. After completion of dropping, the temperature was kept at 20 to 30 ° C. and stirring of the reaction solution was continued for 5 hours to complete the reaction. During this time, the reaction solution remained liquid and did not solidify.
[0017]
Thereafter, the reaction solution was added dropwise to a 500 ml flask containing 300 g of water, and cooled to 0 ° C. after completion of the addition. The precipitated crystals were collected by filtration, washed with water, and then dried at 60 ° C. under reduced pressure to obtain 28.4 g of 5-isoquinolinesulfonic acid. The purity determined by the area percentage method (hereinafter referred to as the LC area percentage method) from the measured value by high performance liquid chromatography was 99.3%, the content of 8 bodies was 0.2%, and the yield was 69.9 mol%.
[0018]
(Example 2)
Except that the reaction temperature was changed to 80 ° C., 27.1 g of 5-isoquinolinesulfonic acid was obtained by the same procedure as described in Example 1. The purity by LC area percentage method was 98.1%, the content of 8 compounds was 1.3%, and the yield was 65.5 mol%.
[0019]
Example 3
26.1 g of 5-isoquinolinesulfonic acid was obtained in the same procedure as described in Example 1 except that the reaction temperature was 105 ° C. and the reaction time after completion of dropping was changed to 2 hours. The purity by LC area percentage method was 97.2%, the content of 8 compounds was 2.5%, and the yield was 62.6 mol%.
[0020]
(Comparative Example 1)
This example illustrates the synthesis of 5-isoquinoline sulfonic acid by the conventional method described above. A 300 ml flask equipped with a thermometer, a stir bar, and a water cooling device was charged with 22 ml of concentrated sulfuric acid, and stirring was started. To this concentrated sulfuric acid, 52 g (0.403 mol) of isoquinoline was added dropwise over 20 minutes under cooling with water. During the dropping, the reaction solution solidified and became impossible to stir, but the addition of isoquinoline was continued as it was.
[0021]
After completion of the addition of isoquinoline, 110 ml of 50% fuming sulfuric acid was added dropwise over 20 minutes so as to maintain a temperature of 30 ° C. or lower. During the dropping of the fuming sulfuric acid, the fluidity of the reaction liquid increased and stirring became possible, but after the completion of the dropping, the reaction liquid became a very viscous reaction liquid. After completion of dropwise addition of fuming sulfuric acid, the reaction solution was stirred for 4 hours to complete the reaction.
[0022]
Since this reaction solution was viscous, it was difficult to extract 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 obtain 60.2 g of 5-isoquinolinesulfonic acid. The purity by LC area percentage method was 98.9%, the content of 8 compounds was 0.3%, and the yield was 70.7 mol%.
[0023]
(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 apparatus, and stirring was started. 25.0 g (0.194 mol) of isoquinoline was added dropwise over 10 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 no formation of 5-isoquinoline sulfonic acid was observed.
[0024]
In the method of the present invention, it can be seen that the intended sulfonation of isoquinoline does not occur even when concentrated sulfuric acid is used instead of fuming sulfuric acid.
(Comparative Example 3)
Isoquinoline (25.0 g, 0.194 mol) was charged into a 300 ml glass flask equipped with a thermometer, a stir bar , and a water cooling device, and stirring was started. To this isoquinoline, 200 g of 25% fuming sulfuric acid was added dropwise so as to maintain a temperature of 30 ° C. or lower. However, the reaction solution solidified during the addition and stirring was impossible.
[0025]
In the method of the present invention, it can be seen that even if the addition order is changed and fuming sulfuric acid is added dropwise to isoquinoline, the reaction cannot proceed smoothly.
[0026]
【The invention's effect】
In the conventional method, 5-isoquinolinesulfonic acid is produced from isoquinoline in a two-stage reaction in which sulfuric acid is first reacted with 50% fuming sulfuric acid. However, in this method, the reaction solution is solidified 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 solution finally obtained However, it is very viscous and difficult to take out, and the workability is extremely poor, which is not suitable for industrial implementation.
[0027]
In contrast, according to the present invention, by acting on 5-30% fuming sulfuric acid liquid at room temperature isoquinoline can be prepared 5-isoquinoline sulfonic acid in a single step reaction. In addition, since the reaction solution does not solidify during the reaction and the reaction solution finally obtained is not viscous, workability is good and industrial implementation is easy. Furthermore, as can be seen by comparing the reaction results of Examples 1 to 3 and Comparative Example 1, according to the method of the present invention, the product purity and yield are comparable to those of the conventional method.
[0028]
Therefore, the present invention enables industrial production of 5-isoquinolinesulfonic acid, for which no effective industrial production method has been established so far, and its industrial significance is great.
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