JPS59130273A - Preparation of imidazole compound - Google Patents
Preparation of imidazole compoundInfo
- Publication number
- JPS59130273A JPS59130273A JP58004632A JP463283A JPS59130273A JP S59130273 A JPS59130273 A JP S59130273A JP 58004632 A JP58004632 A JP 58004632A JP 463283 A JP463283 A JP 463283A JP S59130273 A JPS59130273 A JP S59130273A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- crown
- imidazole
- cyano
- formula
- 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 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title description 11
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims abstract description 9
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 3
- 150000001340 alkali metals Chemical group 0.000 claims abstract description 3
- 229910052784 alkaline earth metal Chemical group 0.000 claims abstract 2
- 150000001342 alkaline earth metals Chemical group 0.000 claims abstract 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims description 18
- 229960001380 cimetidine Drugs 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 9
- 150000003983 crown ethers Chemical class 0.000 abstract description 9
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000767 anti-ulcer Effects 0.000 abstract description 2
- 229910052752 metalloid Inorganic materials 0.000 abstract 2
- 150000002357 guanidines Chemical class 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000005905 mesyloxy group Chemical group 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 abstract 1
- 239000000047 product Substances 0.000 description 9
- 238000000862 absorption spectrum Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- XKEHLMZHBXCJGZ-UHFFFAOYSA-N 1,4,7,10,13,16,19-heptaoxacyclohenicosane Chemical compound C1COCCOCCOCCOCCOCCOCCO1 XKEHLMZHBXCJGZ-UHFFFAOYSA-N 0.000 description 1
- GAIOTNZPXCFNJU-UHFFFAOYSA-N 1-(2-chloroethyl)-3-cyano-2-methylguanidine Chemical compound N#CNC(=NC)NCCCl GAIOTNZPXCFNJU-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- XTNKKKZZEGJQDP-UHFFFAOYSA-N 2-[(n-cyano-n'-methylcarbamimidoyl)amino]ethyl 4-methylbenzenesulfonate Chemical compound N#CNC(=NC)NCCOS(=O)(=O)C1=CC=C(C)C=C1 XTNKKKZZEGJQDP-UHFFFAOYSA-N 0.000 description 1
- KEWLVUBYGUZFKX-UHFFFAOYSA-N 2-ethylguanidine Chemical compound CCNC(N)=N KEWLVUBYGUZFKX-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 101150084411 crn1 gene Proteins 0.000 description 1
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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■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）
の製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an imidazole compound, and more particularly, the present invention relates to a method for producing an imidazole compound, and more particularly, to a method for producing an imidazole compound, N-cyano-N'-methyl-N''-(2-((4-methyl-5 -imidazolyl)-methylthio]-ethyl)guanidine (cimetidine)
Relating to a manufacturing method.
上記式■で表わされる化合物は、ヒスタ之ン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。The compound represented by the above formula
cimetidine) and is used clinically, particularly as an anti-ulcer therapeutic agent.
従来より、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号または特許公報昭５５−５０００２６号
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、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、工業
上不適当である。Conventionally, N-cyano-N/-methyl-N″-(2-((4-methyl-5-imidazolyl)-
As a method for producing methylthio]-ethyl)guanidine,
Various methods (for example, JP-A-55-2657, JP-A-56-
No. 127361 or Patent Publication No. 55-500026) are known. However, these known methods
There are many reaction routes, the reaction conditions are complicated, and moreover, expensive reagents are used during the reaction, which is economically disadvantageous, making it industrially unsuitable.
本発明者らは、上記の欠点を解決すべく種々研究を重ね
た結果、次に述べるような経済性に優れたまったく新し
い独創的な方法を見出し、本発明を完成した。すなわち
、一般式■（式中、ＭはＮａ、Ｋなどのアルカリ金属、
またはＯａ、ＭｇおよびＺｎなどの金属を示す）、で表
わされる
ＣＨ，、０Ｈ２Ｓ’Ｍ
４−メチル−５−（メタロイＶチオ）メチルイミダゾー
ルと、一般式■（式中、Ｒは、ハロゲン、ＯＭｓおよび
ＯＴｓを示す）。The inventors of the present invention have conducted various studies to solve the above-mentioned drawbacks, and as a result, have discovered a completely new and original method with excellent economical efficiency as described below, and have completed the present invention. That is, the general formula ■ (wherein M is an alkali metal such as Na or K,
or metals such as Oa, Mg and Zn), CH,,0H2S'M 4-methyl-5-(metalloyVthio)methylimidazole and the general formula and OTs).
で表わされるＮ−シアノ−Ｎ′−メチル−１ｇ／／−（
２−置換エチル）−グアニジン誘導体とを、クラウンエ
ーテルの存在下、有機溶媒中で処理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）の製造法に関するも
のである。N-cyano-N'-methyl-1g//-(
N-cyano-N'-methyl-N''-(2-substituted ethyl)-guanidine derivative represented by the formula
-[(4-methyl-5-imidazolyl)methylthio]-
This invention relates to a method for producing (ethyl)guanidine (cimetidine).
さらにまた、上記の反応において、有機溶媒として、イ
ソプロぎルアルコールを用いると、反応終了後、直接シ
メチジンへの多形体結晶が製造できることも本発明方法
の特徴である。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。Furthermore, another feature of the method of the present invention is that when isoprogyl alcohol is used as the organic solvent in the above reaction, polymorphic crystals of cimetidine can be produced directly after the reaction is completed. 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.
この結晶を得るために、例えば、特開昭５３−４０７７
１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、直接シメチジンＡ多形体結晶が得られ
る点、非常に有益である。In order to obtain this crystal, for example, JP-A-53-4077
No. 1 and JP-A-56-104868 have been reported. However, the method of the present invention is very advantageous in that cimetidine A polymorphic crystals can be directly obtained without the need for these crystal form conversions.
本発明方法によれば、単に上記化合物■の１モルと化合
物■の１モルとを、有機溶媒中で適当量（０，０１モル
〜１モル）のクラウンエーテルの存在下で処理するだけ
で容易に、しかも定量的に目的の化合物■が製造できる
。クラウンエーテルとしては、１５−クラウン−５、ベ
ンゾ−１５−クラウン−５，１８−クラウン−６、シシ
クロヘキシル−１８−クラウン−６、ジベンゾ−１８−
クラウン−６、ジペンゾ−２４−クラウン−８、ジシク
ロへキシル−２４−クラウン−８，２１−クラウン−７
、また二環性ジアミノポリエーテルなどが利用できる。According to the method of the present invention, it is easy to treat 1 mole of the above compound (1) and 1 mole of compound (2) in an organic solvent in the presence of an appropriate amount (0.01 mole to 1 mole) of crown ether. The target compound (2) can be produced quickly and quantitatively. Crown ethers include 15-crown-5, benzo-15-crown-5,18-crown-6, cyclohexyl-18-crown-6, dibenzo-18-
Crown-6, Dipenzo-24-crown-8, Dicyclohexyl-24-crown-8,21-crown-7
, bicyclic diamino polyether, etc. can also be used.
このクラウンエーテルは反応後回収し再使用できるのも
至極便利である。It is also extremely convenient that this crown ether can be recovered and reused after the reaction.
有機溶媒としては、ベンゼン、トルエン、キシレン、ア
セトニトリル、ベンゾニトリル、メタノール、ＤＭＳＯ
なと普通のものが利用できるが、前述のように反応にイ
ソゾロビルアルコールヲ用イル場合、最終的にシメチジ
ンＡ多形体結晶が得られ有益である。反応は、室温で攪
拌するだけで進行するが反応終結を早めるため極く短時
間（５分〜６分）、溶媒の沸点下に還流または加熱（８
００〜１００°Ｃ）すると良い。クラウンエーテルの触
媒的効果は、次のように説明できる。すなわち、Ｓ−メ
タル化合物（Ｉ）のメタルは容易にクラウンエーテルに
よって捕捉され、残りは活性化アニョン（Ｓ−残基）と
なり、従って他の化合物と容易に結合する。クラウンエ
ーテルは反応終了後、定量的に回収できる。Organic solvents include benzene, toluene, xylene, acetonitrile, benzonitrile, methanol, DMSO
However, as mentioned above, when isozolobyl alcohol is used in the reaction, cimetidine A polymorphic crystals can be finally obtained, which is advantageous. The reaction proceeds simply by stirring at room temperature, but in order to hasten the completion of the reaction, it is refluxed or heated below the boiling point of the solvent for a very short time (5 to 6 minutes).
00-100°C). The catalytic effect of crown ethers can be explained as follows. That is, the metal of the S-metal compound (I) is easily captured by the crown ether, and the remainder becomes an activated anion (S-residue) and therefore easily binds to other compounds. Crown ether can be quantitatively recovered after the reaction is completed.
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 more detail by showing examples.
〈実施例１〉
４−メチル−５−（ボッタシウムチオ）メチルーイミダ
ヂール５．６ｇとＮ−シアノ−Ｎ′−メチル−Ｎ”−（
２１０ルエチル）−グアニジン８．７ｇとを、インゾロ
ぎシアルコール８０１＋１Ａ！ＩＩｎ加え、さらにジシ
クロへキシル−１８−クラウン−６０，５９を加えて、
混合物を５分間還流した。<Example 1> 5.6 g of 4-methyl-5-(bottaciumthio)methyl-imidadyl and N-cyano-N'-methyl-N''-(
210 ethyl) - 8.7 g of guanidine and inzologisial alcohol 801 + 1A! Add IIn and further add dicyclohexyl-18-crown-60,59,
The mixture was refluxed for 5 minutes.
ついで、この反応液からそのまま１０〜’１Ｏｔｎｌの
インゾロぎルアルコールを留去し、反応液を静危した。Then, 10 to 1 Otnl of inzologyl alcohol was distilled off from the reaction solution as it was, and the reaction solution was allowed to stand still.
析出した結晶な濾過・乾燥し純シメチジンへの多形体結
晶８．２８９ （ｍｐ、 １４２− Ｉ Ａ ３℃）を
得た。The precipitated crystalline product was filtered and dried to obtain polymorphic crystals of pure cimetidine (8.289 mp, 142-IA 3°C).
シメチジンＡのろ液をさらに濃縮し、ジシクロへキシル
−１８−クラウン−６０，４９ｇを回収した。インゾロ
ぎルアルコールの回収量は７５ＩＩＩｌテあった。The cimetidine A filtrate was further concentrated to recover 60.49 g of dicyclohexyl-18-crown. The amount of inzologyl alcohol recovered was 75IIIl.
この実験で得られたシメチジンＡの赤外線吸収スペクト
ル（ＫＢｒ）は、１４００ｃｒｎ−１と１３８５ｃＩｎ
−１に非常に強くはげ広い２−りを示し、１２０５側−
１に強く鎖いＶ−りを、さらに１１５５ｍ−１に中程度
の強さの鋭いｆ−りを示したが、１１８０（−ｍ−１に
はピークが認められなかった。The infrared absorption spectrum (KBr) of cimetidine A obtained in this experiment is 1400 crn-1 and 1385 cIn
-1 shows very strong baldness and wide 2-ri, 1205 side-
A strongly chained V-resistance was observed at 1155m-1, and a medium-strength sharp f-resistance was observed at 1155m-1, but no peak was observed at 1180(-m-1).
元素分析値：Ｃ１ｏＨ□６８Ｎ６として、計算値（係）
：Ｃ１４７，６０； Ｈ，６，３９； Ｎ、３３．３０
；Ｓ、１２．７１、
実験値（絢：Ｃ１４７，６５； １（，６，４２； Ｎ
、３５．２４ ；ｓ、１２．８ａ
さらに、この上の実験をアセトニトリルＦ３Ｏｍｅ中で
行い、同様に処理してのち、シメチジン８．２ 、！ｉ
’ （ｍｐ、 １４１−１４３’Ｏ）を得た。Elemental analysis value: Calculated value (as C1oH□68N6)
:C147,60; H,6,39; N,33.30
;S, 12.71, Experimental value (Aya: C147,65; 1(,6,42; N
, 35.24; s, 12.8a Furthermore, the above experiment was carried out in acetonitrile F3Ome, and after the same treatment, cimetidine 8.2,! i
' (mp, 141-143'O) was obtained.
〈実施例２〉
４−メチル−５−（ソジウム チオ）メチル−イミダゾ
ール５．０ｇ、Ｎ−シアノ−Ｎ′−メチル−Ｎ″−（２
−クロルエチル）−グアニジン８．７ｇ、インゾロざル
アルコール８０ｍ１および１８−クラウン−６０，５ｇ
を用いて実施例１と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°Ｃ） ８
．２．６ ｇを得た。<Example 2> 5.0 g of 4-methyl-5-(sodium thio)methyl-imidazole, N-cyano-N'-methyl-N''-(2
-chloroethyl)-guanidine 8.7 g, inzorozal alcohol 80 ml and 18-crown-60,5 g
After reaction treatment in the same manner as in Example 1, polymorphic crystals of pure cimetidine A (mp, 142-143°C) 8
．． 2.6 g was obtained.
このものは、実施例１で得たものと同一の赤外線吸収ス
ペクトルを示し、混融しても融点降下を示さなかった。This product showed the same infrared absorption spectrum as that obtained in Example 1, and showed no drop in melting point even when mixed.
〈実施例ろ〉
４−メチル−５−（リチウムチオ）メチル−イミダゾー
ル４．５ｇ、Ｎ−シアノ−Ｎ′−メチル−ＩＪ”−（２
−ブロムエチル）−〃゛アニジフ６．８ｇシクロヘキシ
ル−１５−クラウン−５０，５９、イソプロピルアルコ
ール８０ｍｅを用いて実施例１と同様に反応、処理して
のち、純シメチジンＡの多形体結晶８．．２３［（ｍｐ
、 １４２−１４６００ ）を得た。このものの赤外線
吸収スペクトルは、実施例１で得たものと同一であり、
また混融して融点降下を示さなかった。<Example 2> 4.5 g of 4-methyl-5-(lithiumthio)methyl-imidazole, N-cyano-N'-methyl-IJ''-(2
-bromoethyl)-゛Anidif (6.8 g) cyclohexyl-15-crown-50,59 and isopropyl alcohol (80 me) were reacted and treated in the same manner as in Example 1, followed by polymorphic crystals of pure cimetidine A.8. ．． 23 [(mp.
, 142-14600) was obtained. The infrared absorption spectrum of this product is the same as that obtained in Example 1,
In addition, the mixture melted and did not show a decrease in melting point.
〈実施例４〉
４−メチル−５−（ジンクチオ）メチル−イミダゾール
６．５ｇ、Ｎ−シアノ−Ｎ′−メチル−Ｎ／／−（２−
７ｒロムエチル）−グアニジン６．８ｇ、ジペンゾ−２
４−クラウン−８０，５，９１イソプロピルアルコ一ル
８０ｍ１の混合物を実施例１と同様に反応・処″理して
のち、純シメチジンへの多形体結晶８．２１１ （ｍｐ
、 １４２−１４３°Ｃ）を得た。このものの赤外線吸
収スペクトルは、実施例１で得たもののそれと同一であ
り、また混融して融点降下を示さなかった。<Example 4> 6.5 g of 4-methyl-5-(zincthio)methyl-imidazole, N-cyano-N'-methyl-N//-(2-
7r romethyl)-guanidine 6.8g, dipenzo-2
After reacting and treating a mixture of 80 ml of 4-crown-80,5,91 isopropyl alcohol in the same manner as in Example 1, 8.211 ml of polymorphic crystals (mp
, 142-143°C). The infrared absorption spectrum of this product was the same as that of the product obtained in Example 1, and it was mixed and did not show a drop in melting point.
〈実施例５〉
４−メチル−５−（ソジウムチオ）メチル−、イミダゾ
ール５．０．！ｉｌ、Ｎ−シアノーＮ′−メチル−、／
／−（２−ヨーｒエチル）−グアニジン８．４ｇ、ジシ
クロへキシル−１８−クラウン−６０，５９、イソゾロ
ぎルアルコール８０ｍ１の混合物を実施例１と同様に反
応・処理してのち、純シメチジンへの多形体結晶８．２
２．！？ （ｍｐ、、 １４．２−１４３°Ｇ）を得た
。<Example 5> 4-Methyl-5-(sodiumthio)methyl-, imidazole 5.0. ! il, N-cyano N'-methyl-, /
A mixture of 8.4 g of /-(2-iorrethyl)-guanidine, dicyclohexyl-18-crown-60,59, and 80 ml of isozologyl alcohol was reacted and treated in the same manner as in Example 1, and then pure cimetidine was obtained. Polymorph crystals to 8.2
2. ! ? (mp, 14.2-143°G) was obtained.
このものの赤外線吸収スペクトルは、実施例１で得たも
ののそれと同一であり、混融にも融点降下を示さなかっ
た。The infrared absorption spectrum of this product was the same as that of the one obtained in Example 1, and no melting point depression was observed even during blending.
〈実施例６〉
４−メチル−５−（ｆ：ツタシウムチオ）メチル−イミ
ダゾール５．６ 、！９、Ｎ−シアノ−Ｎ′−メチル−
Ｎ”−（２−メシルオキシエチル）−グアニシン１１．
２！ｑ、ジシクロへキシル−１８−クラウン−６０，５
ｇ、インプロピルアルコール８［］ｍｌの混合物を実施
例１とまったく同様に反応・処理してのち、純シメチジ
ンＡの結晶８−２５ 、！ｉ’（ｍｐ、１４２−１４３
°Ｃ）を得た。<Example 6> 4-Methyl-5-(f: Tutaciumthio)methyl-imidazole 5.6,! 9, N-cyano-N'-methyl-
N”-(2-mesyloxyethyl)-guanisine 11.
2! q, dicyclohexyl-18-crown-60,5
After reacting and treating a mixture of 8 [] ml of inpropyl alcohol in exactly the same manner as in Example 1, pure cimetidine A crystals 8-25,! i'(mp, 142-143
°C) was obtained.
このものの赤外線吸収スペクトルは、実施例１で得たも
ののそれと同一であり、また混融するも融点降下を示さ
なかった。The infrared absorption spectrum of this product was the same as that of that obtained in Example 1, and even though it was mixed, it did not show a drop in melting point.
さらにまた、上述の反応をブチロニトリル８［１ｍｌ中
でおこない、同様に処理してのち、シメチジｙ（ｍｐ、
１４１−１’４３°ｃ ）８．２’、！ｉ＋を得た。Furthermore, the above reaction was carried out in 1 ml of butyronitrile 8, and after the same treatment, Shimetidi y (mp,
141-1'43°c ) 8.2',! I got i+.
〈実施例７〉
４−メチル−５−（ポツタシウムチオ）メチル−イミダ
ゾール５．６ｇ、Ｎ−シアノ−Ｎ′−メチル−Ｎ”−（
２−トシルオキシエチル）−グアニジン９．５ 、！９
、ジシクロへキシル−１８−クラウン−／Ｓ０．５ｇ
、イソゾロぎルアルコール８．（Ｊｍｌの混合物を実施
例１とまったく同様に反応・処理してのち、純シメチジ
ンＡの結晶８．２４１ （ｍｐ。<Example 7> 5.6 g of 4-methyl-5-(potassiumthio)methyl-imidazole, N-cyano-N'-methyl-N"-(
2-Tosyloxyethyl)-guanidine 9.5,! 9
, dicyclohexyl-18-crown-/S0.5g
, isozologyl alcohol8. (After reacting and treating the mixture of Jml in exactly the same manner as in Example 1, 8.241 crystals of pure cimetidine A (mp.
１４２−１４３°Ｇ）を得た。142-143°G) was obtained.
このものの赤外線吸収スペクトルは、実施例１で得たも
ののそれと同一であり、また混融して融点降下を示さな
かった。The infrared absorption spectrum of this product was the same as that of the product obtained in Example 1, and it was mixed and did not show a drop in melting point.
代理人 浅 村 皓 外４名Agent Asamura Hao 4 other people
Claims (1)
す） で表わされる４−メチル−５−（メタロイドチオ）メチ
ル−イミダゾールと、。 一般式■ （式中、Ｒはハロゲン、メシルオキシおよびトシルオキ
シを示す） で表わされる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、クラウンエーテ
ルの存在下に有機溶媒中で処理することを特徴とする、 式■ ＨＮ Ｎ ＼（ 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）の製造法。 【２） 有機溶媒としてイソゾロぎルアルコールヲ用
いることを特徴とする特許請求の範囲第１項記載の式■
で表わされる化合物の多形体結晶の製造法。(1) 4-methyl-5-(metalloidthio)methyl-imidazole represented by the general formula (1) (wherein M represents an alkali metal or an alkaline earth metal); N-cyano-N'-methyl-N''-(2-
N-cyano-N′-methyl-N″-( represented by the formula ■ HN N \( 2
-[(4-methyl-5-imidazolyl)methylthio]-
Method for producing ethyl) guanidine (cimetidine). [2] Formula (■) according to claim 1, characterized in that isozorogyl alcohol is used as the organic solvent.
A method for producing polymorphic crystals of a compound represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58004632A JPS59130273A (en) | 1983-01-14 | 1983-01-14 | Preparation of imidazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58004632A JPS59130273A (en) | 1983-01-14 | 1983-01-14 | Preparation of imidazole compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59130273A true JPS59130273A (en) | 1984-07-26 |
| JPS622591B2 JPS622591B2 (en) | 1987-01-20 |
Family
ID=11589384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58004632A Granted JPS59130273A (en) | 1983-01-14 | 1983-01-14 | Preparation of imidazole compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59130273A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113234018A (en) * | 2021-05-11 | 2021-08-10 | 石家庄市普力制药有限公司 | Production method of cimetidine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5340771A (en) * | 1976-09-21 | 1978-04-13 | Smith Kline French Lab | Novel polymorph of heterocyclic compound |
| JPS5440547A (en) * | 1977-09-07 | 1979-03-30 | Seikosha Kk | Device for adjusting output frequency of frequency divider |
| JPS54130566A (en) * | 1977-12-28 | 1979-10-09 | Om Lab Sa | Manufacture of guanidine derivative |
-
1983
- 1983-01-14 JP JP58004632A patent/JPS59130273A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5340771A (en) * | 1976-09-21 | 1978-04-13 | Smith Kline French Lab | Novel polymorph of heterocyclic compound |
| JPS5440547A (en) * | 1977-09-07 | 1979-03-30 | Seikosha Kk | Device for adjusting output frequency of frequency divider |
| JPS54130566A (en) * | 1977-12-28 | 1979-10-09 | Om Lab Sa | Manufacture of guanidine derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113234018A (en) * | 2021-05-11 | 2021-08-10 | 石家庄市普力制药有限公司 | Production method of cimetidine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS622591B2 (en) | 1987-01-20 |
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