JPS59130272A - Preparation of imidazole compound - Google Patents
Preparation of imidazole compoundInfo
- Publication number
- JPS59130272A JPS59130272A JP58004631A JP463183A JPS59130272A JP S59130272 A JPS59130272 A JP S59130272A JP 58004631 A JP58004631 A JP 58004631A JP 463183 A JP463183 A JP 463183A JP S59130272 A JPS59130272 A JP S59130272A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- methyl
- compound shown
- cimetidine
- light rays
- 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.)
- Granted
Links
- -1 imidazole compound Chemical class 0.000 title claims abstract description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title description 10
- 239000013078 crystal Substances 0.000 claims abstract description 21
- 229960001380 cimetidine Drugs 0.000 claims abstract description 16
- GCYDEHNKSNMNMN-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanethiol Chemical compound CC=1NC=NC=1CS GCYDEHNKSNMNMN-UHFFFAOYSA-N 0.000 claims abstract description 5
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims abstract 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 12
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 6
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 7
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052753 mercury Inorganic materials 0.000 abstract description 4
- 230000001678 irradiating effect Effects 0.000 abstract description 3
- 102000003710 Histamine H2 Receptors Human genes 0.000 abstract description 2
- 108090000050 Histamine H2 Receptors Proteins 0.000 abstract description 2
- 230000000767 anti-ulcer Effects 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000005905 mesyloxy group Chemical group 0.000 abstract 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 abstract 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- GAIOTNZPXCFNJU-UHFFFAOYSA-N 1-(2-chloroethyl)-3-cyano-2-methylguanidine Chemical compound N#CNC(=NC)NCCCl GAIOTNZPXCFNJU-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FNMHARGLJLWHAA-UHFFFAOYSA-N 1-(2-bromoethyl)-3-cyano-2-methylguanidine Chemical compound N#CNC(=NC)NCCBr FNMHARGLJLWHAA-UHFFFAOYSA-N 0.000 description 1
- CLYRBADKYTXVTQ-UHFFFAOYSA-N 1-cyano-3-(2-iodoethyl)-2-methylguanidine Chemical compound N#CNC(=NC)NCCI CLYRBADKYTXVTQ-UHFFFAOYSA-N 0.000 description 1
- FOWRNONMFJXAJD-UHFFFAOYSA-N 2-[(n-cyano-n'-methylcarbamimidoyl)amino]ethyl methanesulfonate Chemical compound N#CNC(=NC)NCCOS(C)(=O)=O FOWRNONMFJXAJD-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
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６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）の多形体績″晶を得る新規な製造方法に関するも
のである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an imidazole compound, and more specifically, to a method for producing an imidazole compound, and more particularly, to a method for producing an imidazole compound, N-cyano-N'-
The present invention relates to a novel method for producing polymorphic crystals of methyl-N"-(2-[:(4-methyl-5-imidazolyl)-methylthio]-ethyl)guanidine (cymetidine A).
上記式６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益な医薬品（一般名：シメチジンＣ
１ｍｅｔｉｄｉｎｅ ）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。The compound represented by the above formula 6 is a useful drug (generic name: cimetidine C) having a histamine H2 receptor blocking effect.
1methidine) and is used clinically, especially as an anti-ulcer therapeutic agent.
従来より、式３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５
６−１２７３６１号また特許公報昭５５−５００２６号
など）が知られている。Conventionally, various methods have been used to produce cimetidine represented by formula 3 (for example, Japanese Patent Application Laid-open Nos. 55-2657 and 1983).
No. 6-127361, Japanese Patent Publication No. 55-50026, etc.) are known.
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な
ど欠点が多い。しかも、反応に際して高価な試薬を用い
るなど経済的に不利であり、従って工業的に不適当であ
る。However, these known methods have many drawbacks, such as a large number of reaction routes, complicated reaction conditions, and the need to be careful in setting the conditions. Moreover, it is economically disadvantageous, such as using expensive reagents during the reaction, and is therefore industrially unsuitable.
本発明者らは、上記の欠点を解決すべく種々の研究を重
ねた結果、次の工程図に示すような、まった〈従来の例
にない新しいより工業的に優れた方法を見出すに至り、
本発明方法を完成した。As a result of repeated research in order to solve the above-mentioned drawbacks, the inventors of the present invention have discovered a completely new and industrially superior method that has never been seen before, as shown in the following process diagram. ,
The method of the present invention has been completed.
（Ｒ＝Ｂｒ、 ＣＩ、 Ｉ、 ＯＭｓ、 ０Ｔｓ）（２
）
（３）
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、ここに化学
的進歩と独創性が要約されているといっても過言ではな
い。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の各形体結晶が、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の多形体結晶が製造
できる。(R=Br, CI, I, OMs, 0Ts) (2
(3) Moreover, cimetidine obtained by the method of the present invention is a polymorphic crystal of cimetidine A obtained through a direct reaction, and it is no exaggeration to say that the chemical progress and originality are summarized here. Conventionally, various crystal forms of cimetidine have been known, and among these, cimetidine A crystal forms are considered to be the most suitable for actual clinical use. In order to obtain this crystal, for example, JP-A-53-40771 and JP-A-56-104868 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.
すなわち、前述の工程図に示すように、式１で表わされ
る４−メチル−５−メルカゾトメチルーイミダゾール・
ダイマー〔ビス（４−メチル−５−メルカゾトメチルー
イミダゾール）〕と、一般式２で表わされる（式中、Ｒ
はハロゲンおよびＯＭｓ 、 ＯＴｓ基を示す）、Ｎ−
シアノ−Ｎ′−メチル−Ｎ“−（２−置換エチル）−グ
アニジン誘導体とを、インゾロぎルアルコール中で光照
射することを特徴とする、式６で表わされるＮ−シアノ
−Ｎ′−メチルーＮ“−（２−Ｃ（４−メチル−５−イ
ミダゾリル）メチルチオツーエチル）グアニジン（シメ
チジンＡ）の多形体結晶を製造する方法に関するもので
ある。That is, as shown in the process diagram above, 4-methyl-5-mercazotomethyl-imidazole represented by formula 1
dimer [bis(4-methyl-5-mercazotomethyl-imidazole)], represented by general formula 2 (wherein R
represents halogen and OMs, OTs groups), N-
cyano-N'-methyl-N"-(2-substituted ethyl)-guanidine derivative represented by formula 6, which is characterized in that it is irradiated with light in inzologyl alcohol. The present invention relates to a method for producing polymorphic crystals of N"-(2-C(4-methyl-5-imidazolyl)methylthiotwoethyl)guanidine (cymetidine A).
本反応は、上記の化合物１０１モルと化合物２０２モル
を使用し、イソプロピルアルコール中テ高圧水銀灯で光
照射するだけで、目的の化合物３０２モルが定量的に生
成する。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ｒ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。しかし、シメチジンＡの多形体
結晶を得るために、イソゾロビルアルコール中で反応さ
せるのが最も有利である。さらに、本反応は、光照射す
るものであるから繰り返し操作ができ、半永久的にその
装置を使用できる点も有益と云える。原料化合物１に対
して化合物２け、その置換体釜れも同様に使用できる。In this reaction, 101 moles of the above compound and 202 moles of the compound are used, and 302 moles of the target compound are quantitatively produced by simply irradiating isopropyl alcohol with light from a high-pressure mercury lamp. Cimetidine can of course also be obtained by using common organic solvents such as benzene, toluene, tetrahydrofuran, methylene chloride, and ethanol instead of isopropyl alcohol. However, in order to obtain polymorphic crystals of cimetidine A, it is most advantageous to carry out the reaction in isozorobyl alcohol. Furthermore, since this reaction involves light irradiation, it can be repeated and the apparatus can be used semi-permanently, which is advantageous. It is also possible to use two substituted compounds per one raw material compound.
光照射は、一般にる。Light irradiation is generally used.
以下、実施例を示し、本発明をさらに詳細に説明する。EXAMPLES Hereinafter, the present invention will be explained in further detail by showing examples.
〈実施例１〉
ビス（４−メチル−５−メルカプトメチルイミダゾール
） ４．２５．９とＮ−シアノ−Ｎ′−メチル−Ｎ“−
（２−クロロエチル）グアニジン５．３ｇとをインプロ
ピルアルコール１２０ｄに溶解し、窒素気流中、高圧水
銀灯にて光照射しつつ、１８０分８０℃に加熱・攪拌さ
せた。ついで反応液を約６０℃にて減圧下に溶媒を約％
はど留去し、そのまま静置すると結晶が析出した。これ
を濾過・乾燥し、純シメチジンへの多形体結晶（ｍｐ、
１４２−１４３℃） ８．２７ Ｉｉを得た。<Example 1> Bis(4-methyl-5-mercaptomethylimidazole) 4.25.9 and N-cyano-N'-methyl-N"-
(2-chloroethyl)guanidine (5.3 g) was dissolved in 120 d of inpropyl alcohol, and heated and stirred at 80° C. for 180 minutes while irradiating with light from a high-pressure mercury lamp in a nitrogen stream. Then, the reaction solution was heated to about 60°C under reduced pressure to add about % of the solvent.
When the residue was distilled off and left to stand, crystals precipitated. This is filtered and dried to obtain pure cimetidine as polymorphic crystals (mp,
142-143°C) 8.27 Ii was obtained.
この結晶の赤外線吸収スペクトル（ＫＢｒ）は、１４０
０ｃＩｒＬ−”と１３８５ｃｍ−”に非常に強く広いピ
ークを示し、１２０５ｃＩＩＬ−１に強く鋭い−一りを
示し、さらに１１５５ｃＩｒＬ−１に中程度の強さの鋭
い−一りを示した。また、１１８０ｃｍ−１にはぎ−り
が認められなかった。The infrared absorption spectrum (KBr) of this crystal is 140
Very strong and broad peaks were observed at 0cIrL-'' and 1385cm-'', a strong and sharp peak was observed at 1205cIIL-1, and a moderately strong sharp peak was observed at 1155cIrL-1. Further, no peeling was observed at 1180 cm-1.
元素分析値’ ”１ＯＨ１６Ｎ６ｓとして、計算値（（
６）： ｃ、 ４７，６０ ； Ｈ，６，５９； Ｎ、
３３，３０；Ｓ 、１２．７１゜
実験値（（６）： ｃ、 ４７．５７ ； ）１．６，
４３ ； Ｎ、 ３３．３６；８．１２，８０゜
〈実施例２〉
上記実施例１の反応で、Ｎ−７アノーＮ′−メチル−Ｎ
“−（２−クロルエチル）グアニジンにかえてＮ−シア
ノ−Ｎ′−メチル−Ｎ“−（２−ブロムエチル）グアニ
ジン６．８ｇを用いて同様に反応、ノち同じように処理
して純シメチジンＡの多形体結晶（ｍｐ−１４２−１４
３°Ｏ） ８，２５．９を得た。このものは、すべての
点で実施例１で得られたものと同一であった。Elemental analysis value '''1OH16N6s, calculated value ((
6): c, 47,60; H, 6,59; N,
33,30; S, 12.71° Experimental value ((6): c, 47.57; ) 1.6,
43; N, 33.36; 8.12, 80゜〈Example 2〉 In the reaction of Example 1 above, N-7anoN'-methyl-N
The same reaction was carried out using 6.8 g of N-cyano-N'-methyl-N"-(2-bromoethyl)guanidine instead of "-(2-chloroethyl)guanidine, and pure cimetidine A was treated in the same manner. polymorphic crystals (mp-142-14
3°O) 8,25.9 was obtained. This was identical in all respects to that obtained in Example 1.
〈実施例３・〉
上記実施例１の反応でＮ−シアノ−Ｎ′−メチル−Ｎ“
−（２−クロルエチル）グアニジンのかわりに、Ｎ−シ
アノ−Ｎ′−メチル−Ｎ“−（２−ヨードエチル）グア
ニジン８．４ｇを用いて反応、のち同じように処理し、
純シメチジンＡの多形体結晶（ｍｐ、１４２−１４３°
０ ） ８，２０ ｇを得た。このものは、実施例１で
得たものとすべての点において同一であった。<Example 3> In the reaction of Example 1 above, N-cyano-N'-methyl-N"
-(2-Chlorethyl)guanidine was replaced with 8.4 g of N-cyano-N'-methyl-N''-(2-iodoethyl)guanidine, and then treated in the same manner.
Polymorphic crystals of pure cimetidine A (mp, 142-143°
0) 8.20 g was obtained. This was identical in all respects to that obtained in Example 1.
〈実施例４〉
ビス（４−メチル−５−メルカプトメチルイミダゾール
） ４，２５ 、！？とＮ−シアノ−Ｎ′−メチル−Ｎ
“−（２−メシルオキシエチル）グアニジン７．３ｇと
を、イソプロピルアルコール１５０ ｍｌＫ加工、窒素
気流中、高圧水銀灯にて光照射しつつ、２００分、８０
℃に加熱攪拌させた。ついで、反応液を約６０℃にて減
圧下に溶媒を約％はど留去し、そのまま静置すると結晶
が析出した。これを濾過・乾燥し、純シメチジンＡの多
形体結晶（ｍｐ、 １４２−１４６℃＞ ８．２３ ＆
を得た。<Example 4> Bis(4-methyl-5-mercaptomethylimidazole) 4,25,! ? and N-cyano-N'-methyl-N
“-(2-Mesyloxyethyl)guanidine (7.3 g) was treated with 150 ml of isopropyl alcohol and heated in a nitrogen stream with light irradiation using a high-pressure mercury lamp for 200 minutes and 80 ml of isopropyl alcohol.
The mixture was heated and stirred at ℃. Then, about % of the solvent was distilled off from the reaction solution under reduced pressure at about 60° C., and when it was left to stand, crystals were precipitated. This was filtered and dried to obtain polymorphic crystals of pure cimetidine A (mp, 142-146℃>8.23 &
I got it.
このものの赤外線吸収スペクトル（ＫＢｒ）は、実施例
１で得られたもののそれとまったく同一であり、また、
両者を混融するも融点降下を示さなかった。The infrared absorption spectrum (KBr) of this product is exactly the same as that of that obtained in Example 1, and
Even when the two were mixed together, no decrease in the melting point was observed.
〈実施例５〉
上記実施例４の反応で、Ｎ−シアノ−Ｎ′−メチ、ｎｔ
−Ｎ“−（２−メシルオキシエチル）グアニジンにか
えて、Ｎ−シアノ−Ｎ′−メチル−Ｎ“−（２−トシル
オキクエチル）グアニジン９．７ｇを用いて同様に反応
・処理してのち、純シメチジンＡの多形体結晶（ｍｐ−
１４２−１４３℃） ８，２２．９’を得た。このもの
は、すべての点で、実施例１で得たものと同一であった
。<Example 5> In the reaction of Example 4 above, N-cyano-N'-methy, nt
-N"-(2-mesyloxyethyl)guanidine was replaced with 9.7 g of N-cyano-N'-methyl-N"-(2-tosyloquiquethyl)guanidine, and the reaction and treatment were carried out in the same manner. , polymorphic crystals of pure cimetidine A (mp-
142-143°C) 8,22.9' was obtained. This was identical in all respects to that obtained in Example 1.
代理人 浅 村 皓 外４名Agent Asamura Hao 4 other people
Claims (1)
イミダゾール）（４−メチル−５−メルカプトメチルイ
ミダゾール・タイマー）と、一般式２ （式中、Ｒは、ハ０）７７、ＯＭｓ 、 ’ ＯＴｓ基
を示す）で表わされるＮ−シアノ−Ｎ′−メチル−Ｎ／
／ −（２−を換エチル）−グアニ′ジン誘導体とを、
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、 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。[Scope of Claims] Bis(4-methyl-5-mercaptomethylimidazole) (4-methyl-5-mercaptomethylimidazole timer) represented by the formula and general formula 2 (wherein R is 0) 77, OMs, ' OTs group) represented by N-cyano-N'-methyl-N/
/ -(ethyl substituted with 2-)-guani'dine derivative,
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 |
|---|---|---|---|
| JP58004631A JPS59130272A (en) | 1983-01-14 | 1983-01-14 | Preparation of imidazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58004631A JPS59130272A (en) | 1983-01-14 | 1983-01-14 | Preparation of imidazole compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59130272A true JPS59130272A (en) | 1984-07-26 |
| JPS622590B2 JPS622590B2 (en) | 1987-01-20 |
Family
ID=11589362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58004631A Granted JPS59130272A (en) | 1983-01-14 | 1983-01-14 | Preparation of imidazole compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59130272A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5808090A (en) * | 1996-02-22 | 1998-09-15 | Endo Pharmaceuticals Inc. | Process for preventing precipitation in cimetidine injection solutions |
-
1983
- 1983-01-14 JP JP58004631A patent/JPS59130272A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5808090A (en) * | 1996-02-22 | 1998-09-15 | Endo Pharmaceuticals Inc. | Process for preventing precipitation in cimetidine injection solutions |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS622590B2 (en) | 1987-01-20 |
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