JPS63201172A - Production of imidazole derivative - Google Patents

Production of imidazole derivative

Info

Publication number
JPS63201172A
JPS63201172A JP62032328A JP3232887A JPS63201172A JP S63201172 A JPS63201172 A JP S63201172A JP 62032328 A JP62032328 A JP 62032328A JP 3232887 A JP3232887 A JP 3232887A JP S63201172 A JPS63201172 A JP S63201172A
Authority
JP
Japan
Prior art keywords
cimetidine
formula
ammonium
methyl
imidazole
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
Application number
JP62032328A
Other languages
Japanese (ja)
Other versions
JPH0555503B2 (en
Inventor
Hiroaki Tan
丹 弘明
Tatsukazu Ishida
石田 達麗
Hiroyasu Ono
裕康 大野
Aiichiro Ori
小里 愛一郎
Noriaki Kihara
木原 則昭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsui Petrochemical Industries Ltd
Original Assignee
Mitsui Petrochemical Industries Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mitsui Petrochemical Industries Ltd filed Critical Mitsui Petrochemical Industries Ltd
Priority to JP62032328A priority Critical patent/JPS63201172A/en
Publication of JPS63201172A publication Critical patent/JPS63201172A/en
Publication of JPH0555503B2 publication Critical patent/JPH0555503B2/ja
Granted legal-status Critical Current

Links

Abstract

PURPOSE:To economically obtain cimetidine useful as a drug, especially a remedy for ulcer or an imidazole derivative or a cimetidine related compound, by reacting a cyanoguanidine derivative obtainable inexpensively and in high yield with an ammonium salt. CONSTITUTION:1mol. cyanoguanidine derivative shown by formula I (R is lower alkyl; R' is H or R) is reacted with 1-100mol. one or more ammonium salts such as ammonium formate, ammonium sodium hydrogenphosphate, etc., in a solvent, preferably formamide, etc., in the presence of a dehydrating agent such as orthoformic acid, etc., at 0-150 deg.C for 0.1-40hr optionally under pressure to give cimetidine (=N-cyano-N'-methyl-N''-{2-[(5-methyl-1H-imidazole-4-yl) methylthio]ethyl}guanidine) shown by formula II or a cimetidine related compound. The amount of the solvent used is 0.5-100pts.wt. based on 1pt.wt. compound shown by formula I.

Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、医薬品、特に潰瘍治療薬として冑用なシメチ
ジン(Cimetidine、  N−シアノ−N ’
 −/ チル−N ’ −(2−((5−/ チル−I
H−4ミダゾール−4−イル)メチルチオ)エチル〕グ
アニジン)あるいはシメチジン関連化合物の新規な製造
方法に関する。
DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides the use of cimetidine (N-cyano-N') as a medicine, particularly as a medicine for treating ulcers.
-/ Chill-N' -(2-((5-/ Chill-I
The present invention relates to a novel method for producing H-4midazol-4-yl)methylthio)ethyl]guanidine) or cimetidine-related compounds.

(従来の技術、発明が解決しようとする問題点、発明の
効果〕 従来、シメチジンあるいはシメチジン関連化合物の製造
方法についてはいくつかの提供がなされている(例えば
特開昭49−75574号、特開昭51−125074
号公報等)が、これらの諸法では高価なイミダゾール誘
導体を出発原料として用い、かつ多段階の反応を経る製
造方法であるためコストが高くつく欠点を有していた。
(Prior art, problems to be solved by the invention, effects of the invention) Several methods for producing cimetidine or cimetidine-related compounds have been proposed (for example, JP-A-49-75574, JP-A-49-75574; Showa 51-125074
However, these methods use expensive imidazole derivatives as starting materials and are production methods that involve multi-stage reactions, resulting in high costs.

本発明は、従来法における上記欠点を解消したイミダゾ
ール誘導体の新規な製造方法を提供するものであり、そ
の特徴とするところは、安価でかつ高収率で得られる原
料を用い最終段階でイミダゾール環を形成させることに
よって経済的にシメチジンあるいはシメチジン関連化合
物を得ることができるよう改良した点にある。
The present invention provides a new method for producing imidazole derivatives that eliminates the above-mentioned drawbacks of conventional methods.The present invention is characterized by the use of raw materials that are inexpensive and can be obtained in high yields, and in which the imidazole ring is removed in the final step. The present invention has been improved so that cimetidine or a cimetidine-related compound can be economically obtained by forming the following.

〔発明の構成〕[Structure of the invention]

すなわち、本発明は、一般式(1) 〔式中Rは低級アルキル基であり、R′は水素又は低級
アルキル基である。〕で示されるシアノグアニジン誘導
体とアンモニウム塩を反応させることを特徴とする一般
式(n) (式中、RS R’は前述と同じである。〕で表わされ
るイミダゾール誘導体の製造方法をその要旨とする0本
発明に係る式(I)で表わされるシアノグアニジン誘導
体中、Rに用いられる低級アルキル基としては、メチル
基、エチル基、n−プロと714、イソプロピル基、n
−ブチル基、5ec−ブチル基、イソブチル基等を挙げ
ることができ、好ましくはメチル基である。R′に用い
られる置換基としては水素又は低級アルキル基があり、
低級アルキル基としては、メチル基、エチル基、n−プ
ロピル基、n−ブチル基を挙げることができ、好ましく
は水素又はメチル基である0式(I)で表わされるシア
ノグアニジン誘導体は、本出願人により同日出願された
特許出願「シアノグアニジン誘導体及びその製造法」に
記載の如く得ることができる。
That is, the present invention is directed to the general formula (1) [wherein R is a lower alkyl group and R' is hydrogen or a lower alkyl group]. The gist of this invention is a method for producing an imidazole derivative represented by the general formula (n) (wherein RSR' is the same as above), which is characterized by reacting a cyanoguanidine derivative represented by the following with an ammonium salt. In the cyanoguanidine derivative represented by formula (I) according to the present invention, examples of the lower alkyl group used for R include methyl group, ethyl group, n-pro and 714, isopropyl group, n
-butyl group, 5ec-butyl group, isobutyl group, etc., and preferably methyl group. Substituents used for R' include hydrogen or lower alkyl groups,
Examples of the lower alkyl group include methyl group, ethyl group, n-propyl group, and n-butyl group, and the cyanoguanidine derivative represented by formula (I), which is preferably hydrogen or methyl group, is applicable to the present application. It can be obtained as described in the patent application ``Cyanoguanidine Derivatives and Process for Producing the Same'' filed on the same day.

また本願発明で用いられるアンモニウム塩としては、例
えば、弱酸のアンモニウム塩が挙げられ、弱酸としては
ギ酸、酢酸、プロピオン酸、ブタン酸、炭酸、安息香酸
、リン酸などが挙げられる。
Examples of ammonium salts used in the present invention include ammonium salts of weak acids, and examples of weak acids include formic acid, acetic acid, propionic acid, butanoic acid, carbonic acid, benzoic acid, and phosphoric acid.

好ましくは、ギ酸アンモニウム、酢酸アンモニウム、リ
ン酸−水素ナトリウムアンモニウムである。
Preferred are ammonium formate, ammonium acetate, and sodium ammonium hydrogen phosphate.

これらのアンモニウム塩は各単独で用いるほか、二種以
上を混合使用してもよい。
These ammonium salts may be used alone or in combination of two or more.

アンモニウム塩の使用量は通常式(1)のシアノグアニ
ジン誘導体1モルに対して工ないし100モルであり、
好ましくは2ないし20モルである。
The amount of ammonium salt used is usually 1 to 100 mol per 1 mol of the cyanoguanidine derivative of formula (1),
Preferably it is 2 to 20 moles.

本発明においては、溶媒を使用しなくても行うことがで
きるが、溶媒を用いることが好ましい、この場合の溶媒
としては、例えば、メタノール、エタノール、n−プロ
パフール、イソプロパツールなどのアルコール系溶媒、
ジエチルエーテル、ジオキサン、テトラヒドロフランな
どのエーテル系の溶媒、N、N−ジメチルホルムアミド
、N、N−ジエチルホルムアミド、N−メチルホルムア
ミド、ホルムアミド、アセトアミドなどの脂肪族アミド
系溶媒などが好ましい、これらの溶媒の使用量は式(1
)のシアノグアニジン誘導体1重量部に対し、0.5な
いし100重量部、好ましくは2ないし50重量部であ
る0反応温度は0℃ないし150℃、好ましくは40℃
ないし110℃であり、必要に応じて加圧下で行うこと
ができる。また、生じる低沸点物質を適時除きながら行
うのも好ましい、さらに、オルトギ酸メチル、オルト酢
酸メチル、ホルムアミジン誘導体などの脱水剤を共存さ
せてもよい。反応時間は反応温度により異なり0.1な
いし40時間、好ましくは0.5ないし20時間である
0反応後、目的物である式(II)で表わされるイミダ
ゾール誘導体を得るには、反応混合物中の溶媒を減圧下
に留去後、再結晶あるいはクロマトグラフィーなどの通
常用いられる一般的な精製手段を用いることができる。
Although the present invention can be carried out without using a solvent, it is preferable to use a solvent. Examples of the solvent in this case include alcoholic solvents such as methanol, ethanol, n-propafur, and isopropanol. ,
Ether solvents such as diethyl ether, dioxane, and tetrahydrofuran, aliphatic amide solvents such as N,N-dimethylformamide, N,N-diethylformamide, N-methylformamide, formamide, and acetamide are preferred. The usage amount is calculated using the formula (1
) is 0.5 to 100 parts by weight, preferably 2 to 50 parts by weight, per 1 part by weight of the cyanoguanidine derivative.The reaction temperature is 0°C to 150°C, preferably 40°C.
The temperature is between 110° C. and 110° C., and can be carried out under pressure if necessary. It is also preferable to carry out the reaction while removing low-boiling substances produced as appropriate. Furthermore, a dehydrating agent such as methyl orthoformate, methyl orthoacetate, or formamidine derivatives may be present. The reaction time varies depending on the reaction temperature and is from 0.1 to 40 hours, preferably from 0.5 to 20 hours. After the reaction, to obtain the target imidazole derivative represented by formula (II), After the solvent is distilled off under reduced pressure, commonly used purification means such as recrystallization or chromatography can be used.

〔実施例〕〔Example〕

以下、本発明の方法を実施例によって具体的に説明する
Hereinafter, the method of the present invention will be specifically explained using examples.

実施例I N−シアノ−N’−(2−(3ホルムアミノ−2−オキ
ソブチルチオ)エチル)−N#−メチルグアニジン13
6■、ギ酸アンモニウム320mg、オルトギ酸メチル
0.6m、リン酸−水素ナトリウムアンモニウム4水和
物209■gにホルムアミド2.5mを加え、100℃
で2時間攪拌した0反応混合物を冷却後、不溶物を除い
て、減圧下に溶媒を除いた。得られた残渣をシリカゲル
カラムクロマトグラフィー(溶出溶媒クロロホルム−エ
タノール−5=1)にて精製し、次いで、イソプロパノ
−ルーエタノール(60: 40)で再結晶して目的の
シメチジンを110 rag得た(収率87%)。
Example I N-cyano-N'-(2-(3formamino-2-oxobutylthio)ethyl)-N#-methylguanidine 13
6. Add 2.5 m of formamide to 320 mg of ammonium formate, 0.6 m of methyl orthoformate, and 209 g of ammonium sodium hydrogen phosphate tetrahydrate, and heat at 100°C.
After cooling the reaction mixture, which had been stirred for 2 hours, insoluble materials were removed and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-ethanol-5=1), and then recrystallized from isopropanol-ethanol (60:40) to obtain 110 rag of the desired cimetidine ( yield 87%).

実施例2〜4 実施例1において、ギ酸アンモニウム、オルトギ酸メチ
ル、リン酸−水素ナトリウムアンモニウムを添加する代
わりに表1記載の添加物を用いる以外は実施例工と同様
の方法で反応を行ったところ、シメチジンが表1の収率
で得られた。
Examples 2 to 4 The reaction was carried out in the same manner as in Example 1, except that the additives listed in Table 1 were used instead of ammonium formate, methyl orthoformate, and ammonium sodium hydrogen phosphate. However, cimetidine was obtained in the yield shown in Table 1.

実施例5 N−(2−(3−アセトアミノ−2−オキソブチルチオ
)エチル)−N′−シアノ−N“−メチルグアニジン1
42m、酢酸アンモニウム390■g1オルト酢酸メチ
ル0.63m、リン酸−水素ナトリウムアンモニウム4
水和物209−gにホルムアミド2.5mを加え100
℃で2時間攪拌した6反応混合物を冷却後不溶物を除い
て減圧下に溶媒を除いた。得られた残渣をシリカゲルカ
ラムクロマトグラフィー(溶出溶媒クロロホルム−エタ
ノール−5: 1)にて精製し、次いでイソプロパノ−
ルーエーテル(50:50)で再結晶して目的のN−シ
アノ−N’−(2−(2,5−ジメチル−I■−イミダ
ゾール−4−イル)メチルチオ)エチル〕−N#−メチ
ルグアニジンを97■g得た(収率73%)。
Example 5 N-(2-(3-acetamino-2-oxobutylthio)ethyl)-N'-cyano-N"-methylguanidine 1
42 m, ammonium acetate 390 g 1 methyl orthoacetate 0.63 m, sodium ammonium phosphate 4
Add 2.5 m of formamide to 209 g of hydrate to make 100
After cooling the reaction mixture, which was stirred for 2 hours at °C, insoluble materials were removed and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-ethanol-5:1), and then purified with isopropano-ethanol.
Recrystallization from hydrogen ether (50:50) yields the desired N-cyano-N'-(2-(2,5-dimethyl-I-imidazol-4-yl)methylthio)ethyl]-N#-methylguanidine. 97 g (yield 73%) was obtained.

Claims (1)

【特許請求の範囲】 一般式〔 I 〕 ▲数式、化学式、表等があります▼〔 I 〕 〔式中Rは低級アルキル基であり、R′は水素又は低級
アルキル基である。〕で示されるシアノグアニジン誘導
体とアンモニウム塩を反応させることを特徴とする一般
式〔II〕 ▲数式、化学式、表等があります▼〔II〕 〔式中、R、R′は前述と同じである。〕で示されるイ
ミダゾール誘導体の製造方法。
[Claims] General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R is a lower alkyl group, and R' is hydrogen or a lower alkyl group. [II] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [II] [In the formula, R and R' are the same as above. . ] A method for producing an imidazole derivative.
JP62032328A 1987-02-17 1987-02-17 Production of imidazole derivative Granted JPS63201172A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP62032328A JPS63201172A (en) 1987-02-17 1987-02-17 Production of imidazole derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP62032328A JPS63201172A (en) 1987-02-17 1987-02-17 Production of imidazole derivative

Publications (2)

Publication Number Publication Date
JPS63201172A true JPS63201172A (en) 1988-08-19
JPH0555503B2 JPH0555503B2 (en) 1993-08-17

Family

ID=12355875

Family Applications (1)

Application Number Title Priority Date Filing Date
JP62032328A Granted JPS63201172A (en) 1987-02-17 1987-02-17 Production of imidazole derivative

Country Status (1)

Country Link
JP (1) JPS63201172A (en)

Also Published As

Publication number Publication date
JPH0555503B2 (en) 1993-08-17

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