JPS622589B2 - - Google Patents
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- Publication number
- JPS622589B2 JPS622589B2 JP58001972A JP197283A JPS622589B2 JP S622589 B2 JPS622589 B2 JP S622589B2 JP 58001972 A JP58001972 A JP 58001972A JP 197283 A JP197283 A JP 197283A JP S622589 B2 JPS622589 B2 JP S622589B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- cimetidine
- guanidine
- cyano
- crystal
- 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
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Description
本発明はイミダゾール系化合物の製造方法に関
し、さらに詳しくは、式で表わされる、
Ｎ−シアノ−N′メチル−N″−｛２−〔（４−メチ
ル−５−イミダゾリル）−メチルチオ〕−エチル｝
グアニジン（シメチジンＡ）の多形体結晶を得る
新規な製造方法に関する。
上記式で表わされる化合物は、ヒスタミン
H2受容体遮断効果を有する有用な医薬品（一般
名：シメチジンcimetidine）であり、臨床には特
に抗潰瘍治療剤として用いられている。
従来より、式で表わされるシメチジンの製造
方法として、種々の方法（例えば特開昭55−2657
号、同56−127361号また特許公報昭55−50026な
ど）が知られている。しかし、これらの公知方法
は、反応経路が多く、反応条件が複雑であり、条
件設定に注意しなければならない。しかも、反応
に際し、高価な試薬を用いるなど経済的に不利で
あり、従つて工業上不適当である。
本発明者は、上記の欠点を解決すべく種々の研
究を重ねた結果、以下に述べるような経済的に優
れたまつたく新しい方法を見出し本発明方法を完
成するに至つた。しかも、本発明方法で得られる
シメチジンは、直接反応からシメチジンＡの多形
体結晶が得られ、化学上の進歩がここに要約され
ているものである。シメチジンについては、従
来、各種の結晶形が知られており、この中でシメ
チジンＡの多形体結晶が、最も実際の臨床に適し
ている結晶とされている。この結晶体を得るため
に、例えば特開昭53−40771号や特開昭56−
104868号などが報告されている。しかるに、本発
明方法によれば、これらの結晶形変換の必要がな
く、直接最終目的のシメチジンＡ多形体結晶が製
造できる。
すなわち、本発明方法は、一般式（）
（式中、Ｘはハロゲンを示す）、
で表わされる４−ハロメチル−５−メチルイミダ
ゾールと、一般式（）
（式中Ｒは、Ｈ、アルキル、−COCH3、
The present invention relates to a method for producing an imidazole compound, and more specifically, it is represented by the formula: N-cyano-N′methyl-N″-{2-[(4-methyl-5-imidazolyl)-methylthio]-ethyl}
The present invention relates to a novel manufacturing method for obtaining polymorphic crystals of guanidine (cimetidine A). The compound represented by the above formula is histamine
It is a useful drug (generic name: cimetidine) that has an H 2 receptor blocking effect, and is used clinically, especially as an anti-ulcer treatment. Conventionally, various methods have been used to produce cimetidine represented by the formula (for example, Japanese Patent Application Laid-Open No. 55-2657
No. 56-127361 and Patent Publication No. 55-50026, etc.) are known. However, these known methods involve many reaction routes and complex reaction conditions, and care must be taken in setting the conditions. Furthermore, the reaction requires expensive reagents, which is economically disadvantageous, and therefore industrially unsuitable. As a result of various studies aimed at solving the above-mentioned drawbacks, the inventors of the present invention have discovered an economically superior and robust new method as described below, and have completed the method of the present invention. Moreover, the cimetidine obtained by the method of the present invention is a polymorphic crystal of cimetidine A obtained from a direct reaction, and the chemical progress is summarized here. Conventionally, various crystal forms of cimetidine have been known, and among these, the polymorphic crystal of cimetidine A is said to be the crystal most suitable for actual clinical use. In order to obtain this crystal, for example, JP-A-53-40771 and JP-A-56-
Issues such as No. 104868 have been reported. However, according to the method of the present invention, there is no need for these crystal form conversions, and the final target cimetidine A polymorph crystals can be directly produced. That is, in the method of the present invention, the general formula () (wherein, X represents halogen), 4-halomethyl-5-methylimidazole represented by the general formula () (In the formula, R is H, alkyl, -COCH3 ,
【式】を示す）
で表わされるＮ−シアノ−N′−メチル−N″−（２
−メルカプトエチル）−グアニジンあるいはＮ−
シアノ−N′−メチル−N″−〔（２−アシルチオ）
エチル〕−グアニジンとを、イソプロピルアルコ
ール中で光照射することを特徴とする、一般式
（）
で表わされるＮ−シアノ−N′−メチル−N″−｛２
−〔（４−メチル−５−イミダゾリル）メチルチ
オ〕−エチル｝−グアニジン（シメチジンＡ）の多
形体結晶の製造法に関するものである。
本反応は、単に上記の化合物ととの各１モ
ルをイソプロピルアルコール中で高圧水銀灯によ
り光照射するだけで反応が進行し、定量的に目的
物が得られる。イソプロピルアルコールのかわ
りに普通の有機溶媒、すなわち、ベンゼン、トル
エン、テトラヒドロフラン、塩化メチレン、エタ
ノールなどを用いても勿論シメチジンが得られる
が、シメチジンＡの多形体結晶を得るためには、
前述のようにイソプロピルアルコールの使用がよ
い。また本反応は光照射するものであるから、繰
り返し半永久的にその装置を使用できる利点があ
る。
原料の化合物は、いずれのハロゲン体も利用
でき、また化合物についても、Ｎ−シアノ−
N′−メチル−N″−（２−メルカプトエチル）−グ
アニジンのほか、Ｎ−シアノ−N′−メチル−
N″−〔（２−アシルチオ）エチル〕−グアニジンが
利用でき、至極便利である。
光照射は一般に80℃でおこない１時間〜４時間
で完了する。反応後、混合物からある程度のイソ
プロピルアルコールを留去し、そのまま静置する
ことで目的のシメチジンＡの多形体結晶が定量的
に得られる。
以下、実施例を示し、本発明をさらに詳細に説
明する。
実施例 １
４−クロルメチル−５−メチルイミダゾール
4.35ｇとＮ−シアノ−N′−メチル−N″−（２−メ
ルカプトエチル）−グアニジン5.27ｇとをイソプ
ロピルアルコール105mlに溶解し、窒素気流中、
高圧水銀灯にて光照射しつつ、120分80℃に加熱
撹拌した。ついで反応混合物を約60℃にて低減圧
下に溶媒を約2/3ほど留去し、そのまま静置する
とプリズム晶が析出した。これを過、乾燥する
とシメチジンＡの純多形体結晶（融点142−143
℃）8.23ｇが得られた。
赤外線吸収スペクトル（KBr）：1400cm-1と
1385cm-1（非常に強く広いピーク）、1205cm-1
（強く鋭いピーク）、1155cm-1（中程度の強さの鋭
いピーク）、1180cm-1にはピークが認められなか
つた。
元素分析値：C10H16N6Sとして、
計算値（％）：Ｃ，47.60；Ｈ，6.39；Ｎ，
33.30；Ｓ，12.71
実験値（％）：Ｃ，47.62；Ｈ，6.31；Ｎ，
33.25；Ｓ，12.80
実施例 ２
４−ブロムメチル−５−メチルイミダゾール
5.8ｇとＮ−シアノ−N′−メチル−N″−（２−メ
ルカプトエチル）−グアニジン5.3ｇとをイソプロ
ピルアルコール110mlに溶解し、窒素気流中、高
圧水銀灯にて光照射しつつ、120分80℃に加熱撹
拌した。ついで反応混合物を上記実施例１と同様
に処理し、得られたプリズム晶を過、乾燥し
た。シメチジンＡの純多形体結晶（融点142−143
℃）8.22ｇを得た。この結晶の赤外線吸収スペク
トルには実施例１で得られた結晶のそれと同一で
あり、混融しても融点降下を示さなかつた。
実施例 ３
４−ヨードメチル−５−メチルイミダゾール
7.5ｇとＮ−シアノ−N′−メチル−N″−（２−メ
ルカプトエチル）−グアニジン5.3ｇとをイソプロ
ピルアルコール110mlに溶解し、窒素気流中高圧
水銀灯にて光照射しつつ、120分80℃に加熱撹拌
した。ついで反応液を上記実施例１と同様に処理
し、得られたプリズム晶を過、乾燥した。シメ
チジンＡの純多形体結晶（融点142−143℃）8.22
ｇを得た。この結晶の赤外線吸収スペクトルは実
施例１で得られた結晶のそれと同一であり、混融
しても融点降下を示さなかつた。
実施例 ４
４−クロルメチル−５−メチルイミダゾール
4.3ｇとＮ−シアノ−N′−メチル−N″−〔２−（ア
セチルチオ）エチル〕−グアニジン6.7ｇとをイソ
プロピルアルコール120mlに溶解し、窒素気流
中、高圧水銀灯にて光照射しつつ、120分80℃に
加熱撹拌した。ついで、反応液を実施例１と同様
に処理し、得られたプリズム晶を過、乾燥し
た。シメチジンＡの純多形体結晶（融点142−143
℃）8.23ｇを得た。この結晶の赤外線吸収スペク
トルは、実施例１で得た結晶のそれと同一であ
り、また混融するも融点降下を示さなかつた。
実施例 ５
４−ブロムメチル−５−メチルイミダゾール
5.8ｇとＮ−シアノ−N′−メチル−N″−〔２−（プ
ロピルチオ）エチル〕−グアニジン7.5ｇとをイソ
プロピルアルコール120mlに溶解し、窒素気流
中、高圧水銀灯にて光照射しつつ、120分80℃に
加熱、撹拌した。ついで反応液を実施例１と同様
に処理し、得られたプリズム晶を過、乾燥し
た。シメチジンＡの純多形体結晶（融点142−143
℃）8.21ｇを得た。この結晶の赤外線吸収スペク
トルは実施例１で得た結晶のそれと同一であり、
混融するも融点降下を示さなかつた。
実施例 ６
４−クロルメチル−５−メチルイミダゾール
4.3ｇとＮ−シアノ−N′−メチル−N″−〔２−ベ
ンゾイルチオ）エチル〕−グアニジン8.7ｇとをイ
ソプロピルアルコール120mlに溶解し、窒素気流
中、高圧水銀灯にて光照射しつつ、120分80℃に
加熱撹拌した。ついで、反応液を実施例１と同様
に処理し、得られたプリズム晶を過乾燥した。
シメチジンＡの純多形体結晶（融点142−143℃）
8.2ｇを得た。この結晶の赤外線吸収スペクトル
は実施例１で得られた結晶のそれと同一であり、
混融するも融点降下を示さなかつた。N-cyano-N'-methyl-N''-(2
-mercaptoethyl)-guanidine or N-
Cyano-N′-methyl-N″-[(2-acylthio)
General formula () characterized by irradiating light with ethyl]-guanidine in isopropyl alcohol. N-cyano-N′-methyl-N″-{2
The present invention relates to a method for producing polymorphic crystals of -[(4-methyl-5-imidazolyl)methylthio]-ethyl}-guanidine (cimetidine A). In this reaction, the reaction proceeds by simply irradiating 1 mole of each of the above compounds in isopropyl alcohol with a high-pressure mercury lamp, and the desired product can be obtained quantitatively. Cimetidine can of course be obtained by using ordinary organic solvents such as benzene, toluene, tetrahydrofuran, methylene chloride, ethanol, etc. in place of isopropyl alcohol, but in order to obtain polymorphic crystals of cimetidine A,
As mentioned above, it is preferable to use isopropyl alcohol. Furthermore, since this reaction involves light irradiation, there is an advantage that the apparatus can be used repeatedly and semi-permanently. Any halogen compound can be used as the raw material compound, and N-cyano-
In addition to N'-methyl-N''-(2-mercaptoethyl)-guanidine, N-cyano-N'-methyl-
N″-[(2-acylthio)ethyl]-guanidine is available and extremely convenient. Light irradiation is generally carried out at 80°C and completed in 1 to 4 hours. After the reaction, some isopropyl alcohol is distilled from the mixture. The desired polymorphic crystal of cimetidine A can be quantitatively obtained by removing the polymorph and leaving it as it is.Hereinafter, the present invention will be explained in more detail with reference to Examples.Example 1 4-chloromethyl-5-methyl imidazole
4.35 g and 5.27 g of N-cyano-N'-methyl-N''-(2-mercaptoethyl)-guanidine were dissolved in 105 ml of isopropyl alcohol, and in a nitrogen stream,
The mixture was heated and stirred at 80°C for 120 minutes while being irradiated with light using a high-pressure mercury lamp. Then, about 2/3 of the solvent was distilled off from the reaction mixture under reduced pressure at about 60° C., and when it was left to stand, prism crystals precipitated. When this is filtered and dried, pure polymorphic crystals of cimetidine A (melting point 142-143) are obtained.
℃) 8.23g was obtained. Infrared absorption spectrum (KBr): 1400cm -1
1385cm -1 (very strong and wide peak), 1205cm -1
(Strong and sharp peak), 1155cm -1 (moderately strong and sharp peak), and no peak was observed at 1180cm -1 . Elemental analysis value: C 10 H 16 N 6 S Calculated value (%): C, 47.60; H, 6.39; N,
33.30; S, 12.71 Experimental value (%): C, 47.62; H, 6.31; N,
33.25; S, 12.80 Example 2 4-bromomethyl-5-methylimidazole
5.8 g and 5.3 g of N-cyano-N'-methyl-N''-(2-mercaptoethyl)-guanidine were dissolved in 110 ml of isopropyl alcohol and heated for 120 minutes while irradiating with a high-pressure mercury lamp in a nitrogen stream.80 C. The reaction mixture was then treated in the same manner as in Example 1 above, and the resulting prismatic crystals were filtered and dried.Cimetidine A pure polymorph crystals (melting point 142-143
℃) 8.22g was obtained. The infrared absorption spectrum of this crystal was the same as that of the crystal obtained in Example 1, and the melting point did not decrease even when mixed. Example 3 4-iodomethyl-5-methylimidazole
7.5 g and 5.3 g of N-cyano-N'-methyl-N''-(2-mercaptoethyl)-guanidine were dissolved in 110 ml of isopropyl alcohol, and heated at 80°C for 120 minutes under irradiation with a high-pressure mercury lamp in a nitrogen stream. The reaction solution was then treated in the same manner as in Example 1 above, and the obtained prism crystals were filtered and dried. Pure polymorphic crystals of cimetidine A (melting point 142-143°C) 8.22
I got g. The infrared absorption spectrum of this crystal was the same as that of the crystal obtained in Example 1, and the melting point did not decrease even when mixed. Example 4 4-chloromethyl-5-methylimidazole
4.3 g and 6.7 g of N-cyano-N'-methyl-N''-[2-(acetylthio)ethyl]-guanidine were dissolved in 120 ml of isopropyl alcohol, and while irradiated with a high-pressure mercury lamp in a nitrogen stream, the solution was heated to 120 g. The reaction solution was heated and stirred at 80°C for minutes.Then, the reaction solution was treated in the same manner as in Example 1, and the obtained prism crystals were filtered and dried.Cimetidine A pure polymorphic crystals (melting point 142-143
℃) 8.23g was obtained. The infrared absorption spectrum of this crystal was the same as that of the crystal obtained in Example 1, and even though it was mixed, it did not show a drop in melting point. Example 5 4-bromomethyl-5-methylimidazole
5.8 g and 7.5 g of N-cyano-N'-methyl-N''-[2-(propylthio)ethyl]-guanidine were dissolved in 120 ml of isopropyl alcohol, and while irradiated with a high-pressure mercury lamp in a nitrogen stream, the solution was heated to 120 g. The reaction solution was heated to 80°C and stirred for 30 minutes.Then, the reaction solution was treated in the same manner as in Example 1, and the obtained prismatic crystals were filtered and dried.
℃) 8.21 g was obtained. The infrared absorption spectrum of this crystal is the same as that of the crystal obtained in Example 1,
Even though the mixture was mixed, the melting point did not decrease. Example 6 4-chloromethyl-5-methylimidazole
4.3 g and 8.7 g of N-cyano-N'-methyl-N''-[2-benzoylthio)ethyl]-guanidine were dissolved in 120 ml of isopropyl alcohol, and while irradiated with a high-pressure mercury lamp in a nitrogen stream, the solution was heated to 120 g. The mixture was stirred and heated to 80° C. The reaction solution was then treated in the same manner as in Example 1, and the obtained prism crystals were overdried.
Pure polymorphic crystal of cimetidine A (melting point 142-143℃)
8.2g was obtained. The infrared absorption spectrum of this crystal is the same as that of the crystal obtained in Example 1,
Even though the mixture was mixed, the melting point did not decrease.
Claims (1)
ゾールと、一般式（） （式中、ＲはＨ、アルキル、−COCH3、
【式】を示す） で表わされるＮ−シアノ−N′−メチル−N″（２
−メルカプトエチル）−グアニジンあるいはＮ−
シアノ−N′−メチル−N″−〔（２−アシルチオ）
エチル〕−グアニジンとを、イソプロピルアルコ
ール中で光照射することを特徴とする、 一般式（） で表わされるＮ−シアノ−N′−メチル−N″−｛２
−〔（４−メチル−５−イミダゾリル）メチルチ
オ〕−エチル｝グアニジン（シメチジンＡ）の多
形体結晶の製造法。[Claims] 1 General formula () (In the formula, X represents halogen) 4-halomethyl-5-methylimidazole represented by the general formula () (In the formula, R is H, alkyl, -COCH3 ,
N-cyano-N'-methyl-N'' (2
-mercaptoethyl)-guanidine or N-
Cyano-N′-methyl-N″-[(2-acylthio)
General formula () characterized by irradiating light with ethyl]-guanidine in isopropyl alcohol. N-cyano-N′-methyl-N″-{2
- A method for producing polymorphic crystals of [(4-methyl-5-imidazolyl)methylthio]-ethyl}guanidine (cimetidine A).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58001972A JPS59128375A (en) | 1983-01-10 | 1983-01-10 | Preparation of imidazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58001972A JPS59128375A (en) | 1983-01-10 | 1983-01-10 | Preparation of imidazole compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59128375A JPS59128375A (en) | 1984-07-24 |
| JPS622589B2 true JPS622589B2 (en) | 1987-01-20 |
Family
ID=11516469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58001972A Granted JPS59128375A (en) | 1983-01-10 | 1983-01-10 | Preparation of imidazole compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59128375A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372596A (en) * | 2019-07-30 | 2019-10-25 | 河北康泰药业有限公司 | Cimetidine synthesis technology |
| CN114394939A (en) * | 2022-01-27 | 2022-04-26 | 河北科技大学 | A kind of synthetic method of cimetidine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1533380A (en) * | 1974-09-02 | 1978-11-22 | Smith Kline French Lab | Process for the preparation of heterocyclic substituted thioureas and h-cyanoguanidines |
| NZ184893A (en) * | 1976-09-21 | 1980-11-28 | Smith Kline French Lab | Pure crystalline form of cimetidine a(n-methyl-n-cyano-n-(-2-(5-methyl-4imidazolyl) methylthio) ethyl)-guanidine andpharmaceutical compositions containing it |
-
1983
- 1983-01-10 JP JP58001972A patent/JPS59128375A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59128375A (en) | 1984-07-24 |
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