JPS5892664A - Preparation of imidazole derivative - Google Patents
Preparation of imidazole derivativeInfo
- Publication number
- JPS5892664A JPS5892664A JP56190160A JP19016081A JPS5892664A JP S5892664 A JPS5892664 A JP S5892664A JP 56190160 A JP56190160 A JP 56190160A JP 19016081 A JP19016081 A JP 19016081A JP S5892664 A JPS5892664 A JP S5892664A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- imidazolyl
- ethyl
- methylthio
- 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
- 150000002460 imidazoles Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 150000007524 organic acids Chemical class 0.000 claims abstract description 9
- -1 cyanogen halide Chemical class 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims abstract 4
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- OFFPEAOWWDXZOY-UHFFFAOYSA-N 2-methyl-1-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethyl]guanidine Chemical compound CN=C(N)NCCSCC=1N=CNC=1C OFFPEAOWWDXZOY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 15
- CHJJGSNFBQVOTG-UHFFFAOYSA-N methylguanidine Chemical compound CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 9
- 238000010992 reflux Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 125000002883 imidazolyl group Chemical group 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000001476 alcoholic effect Effects 0.000 abstract description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- APZXPRHPPCTRHN-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1h-imidazole Chemical compound CC=1NC=NC=1CCl APZXPRHPPCTRHN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960001380 cimetidine Drugs 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GCYDEHNKSNMNMN-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanethiol Chemical compound CC=1NC=NC=1CS GCYDEHNKSNMNMN-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IGSAPGNIBICQPA-UHFFFAOYSA-N 2-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethyl]guanidine Chemical compound CC=1NC=NC=1CSCCNC(N)=N IGSAPGNIBICQPA-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- FKCBLVCOSCZFHV-UHFFFAOYSA-N acetonitrile;ethanol Chemical compound CCO.CC#N FKCBLVCOSCZFHV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229960001195 imidapril Drugs 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000013076 target 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
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
本発明はイミダゾール誘導体の製造方法に関し更に詳細
には式ＣＩ）
で表わされるＮ−シアノ−Ｎ′−メチル−Ｎ“−（２−
（（４−メチル−５−イミダチリル〕メチルチオ〕エチ
ルコグアニジンの新規な製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing imidazole derivatives, and more particularly relates to a method for producing imidazole derivatives, and more particularly, the present invention relates to a method for producing imidazole derivatives, and more particularly, N-cyano-N'-methyl-N"-(2-
(Relating to a novel method for producing (4-methyl-5-imidacyl)methylthio]ethylcoguanidine.
本発明の方法により製造される式（Ｉ）で表わされる化
合物は、一般名をシメチジンといい、ヒスタミン−一受
容体拮抗作用に基づく胃酸分泌抑制作用を示し、医薬と
して就中、抗潰瘍治療剤として有用なものである。The compound represented by formula (I) produced by the method of the present invention has a generic name of cimetidine, exhibits gastric acid secretion suppressing action based on histamine-1 receptor antagonism, and is used as a medicine, especially as an anti-ulcer therapeutic agent. It is useful as a.
従来より、当該化合物を製造する方法としては、例えは
■ イミダゾリル誘導体を、塩基性条件下にてメルカプ
タンと反応させる方法（％開昭５１−１２５０７４号）
。Conventionally, methods for producing this compound include, for example, (1) a method in which an imidazolyl derivative is reacted with a mercaptan under basic conditions (% 1987-125074);
.
■ イミダゾリル誘導体を、イソチオウレア或いはイソ
シアネートと反応させる方法（％開昭４７−４２６６１
号、同４９−７５５７４号）■ イソチオウレアを強塩
基の存在下、シアナミドと反応させる方法（％開昭５１
−５４５６１号〕などが知られている。■ A method of reacting an imidazolyl derivative with isothiourea or isocyanate (% 47-42661
No. 49-75574) ■ Method of reacting isothiourea with cyanamide in the presence of a strong base (%
-54561] and the like are known.
しかしながら、これら公知の方法は例えば原料化合物の
不安定性、反応条件の困難性と共に収率も必ずしも満足
するものではなく、好ましい方法とはいえない。However, these known methods do not necessarily satisfy the yield, for example, the instability of the starting compounds, the difficulty of the reaction conditions, and cannot be said to be preferable methods.
そこで本発明者は、上記の欠点を解決すべく種種研究し
喪結果、入手が容易な原料化合物を用いて、経済的に安
価な方法で収率よく式（Ｉ）で表わされる本発明の目的
化合物を得ることを見出し、本発明を完成した。Therefore, in order to solve the above-mentioned drawbacks, the present inventor has carried out various studies, and based on the results, the object of the present invention is to obtain a compound represented by the formula (I) in an economically inexpensive manner in good yield by using easily available raw material compounds. They discovered that a compound can be obtained and completed the present invention.
即ち、本発明ｉ式（ＩＩ）
で表わされるｙ−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
を、不活性有機溶媒中有機酸の存在下にてシアノ化ハロ
ゲンと反応させて式（１）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
）を製造する方法に関するものである。That is, in the present invention, y-methyl-N'-(2-((4-methyl-5-imidazolyl)methylthio)ethyl)guanidine represented by formula (II) is dissolved in an inert organic solvent in the presence of an organic acid. N-cyano-N represented by formula (1) by reacting with cyanated halogen
The present invention relates to a method for producing '-methyl-N''-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (cimetidine).
本発明の出発物質として使用される式（ＩＩ）で表わさ
れる化合物は、以下に示す反応工程を経て製造される。The compound represented by formula (II) used as a starting material in the present invention is produced through the reaction steps shown below.
先ず公知化合物である４−クロルメチル−５−メチルイ
ミダゾール（ｖ）を出発物質として用い、このものをア
ルカル性溶媒中にてチオ尿素と反応させ４−メルカプト
メチル−５−メチルイミダゾール（ＩＶ）とし、次いで
ナトリウムエトキシ−の存在下でジクロルエタンと反応
させ、４−メチル−５−（（２−クロルエチル〕チオメ
チル〕イミダゾール（ＩＩ［）を得る。引続きこの化合
物を、アルコール性溶媒中にてメチルグアニジンと反応
させることによ９式（ｎ）の化合物を製造することが出
来る。First, the known compound 4-chloromethyl-5-methylimidazole (v) is used as a starting material, and this is reacted with thiourea in an alkaline solvent to form 4-mercaptomethyl-5-methylimidazole (IV). It is then reacted with dichloroethane in the presence of sodium ethoxy to give 4-methyl-5-((2-chloroethyl]thiomethyl]imidazole (II[). This compound is subsequently reacted with methylguanidine in an alcoholic solvent. By doing so, a compound of formula 9 (n) can be produced.
（Ｖ） （ＩＶ）
１
（ｚ） ＮＨ
上記の反応により得られる本発明の原料化合物は、極め
て容易に且つ安価な物質を使用して製造することが出、
来るので利用価値も高いものと考えられる。(V) (IV) 1 (z) NH The raw material compound of the present invention obtained by the above reaction can be produced extremely easily and using inexpensive materials;
It is thought that the value of use is high because it comes in many forms.
次に、本発明に於ける目的化合物である式ＣＩ）フ
で表わされる化合物を製造するには、式（ＩＩ）で表わ
される化合物を、不活性Ｖ後浴媒中有機酸の存在下にて
シアン化ハロゲンと反応させることにより容易に製造す
ることが出来る。Next, in order to produce the compound represented by formula CI), which is the target compound of the present invention, the compound represented by formula (II) is added to the compound represented by formula (II) in the presence of an organic acid in an inert V post-bath medium. It can be easily produced by reacting with halogen cyanide.
本反応に於ける一方の反応物質であるシアン化ハロゲン
トシては、シアン化デロム、シアン化クロルが特に都合
が良い。As the halogen cyanide which is one of the reactants in this reaction, delom cyanide and chlorine cyanide are particularly convenient.
本反応は、通常不活性有機溶媒中有機酸の存在下にて行
われるが、不活性有機溶媒としては、メタノール、エタ
ノール、ベンゼン、トルエン、テトラヒｒロフラン、ジ
オキサン、Ｎ、Ｎ−ジメチルホルムアミＰ、ヘキサメチ
ルホスファミド、アセトニトリルなどが用いられる。又
、有機酸としテｔ！、ｐ−）ルエンスルホン酸、トリフ
ルオロ酢酸、酢酸、プロピオン酸、シュウ酸などが適宜
選択組合せて用いられる。This reaction is usually carried out in the presence of an organic acid in an inert organic solvent. Examples of inert organic solvents include methanol, ethanol, benzene, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide , hexamethylphosphamide, acetonitrile, etc. are used. Also, as an organic acid! , p-)luenesulfonic acid, trifluoroacetic acid, acetic acid, propionic acid, oxalic acid, and the like are used in appropriate combinations.
本発明に於いては、式（ＩＩ）で表わされる化合物１モ
ルに対しシアン化ハロゲン１〜５モル程度使用すること
ができ、又、有機酸の使用量としてはＬｌ、５〜２モル
程度が好ましい。反応温度は、１０〜１２０℃、通常室
温から溶媒の還流温度で行うことが好ましい。In the present invention, about 1 to 5 moles of cyanide halogen can be used per 1 mole of the compound represented by formula (II), and the amount of organic acid used is about 5 to 2 moles. preferable. The reaction temperature is preferably 10 to 120°C, usually from room temperature to the reflux temperature of the solvent.
反応終了彼、目的物質を反応混合物より分離、精製する
には何ら格別な方法を用いる必要はなく、かかる目的の
為に通常用いられる周知の手段、例えば溶媒抽出、洗浄
、結晶化或いはカラムクロマトグラフィーなどにより容
易に達成することが出来る。Upon completion of the reaction, it is not necessary to use any special method to separate and purify the target substance from the reaction mixture; well-known means commonly used for such purposes, such as solvent extraction, washing, crystallization, or column chromatography. This can be easily achieved by
以下に実施例を示し、本発明を更に詳細に説明する。EXAMPLES The present invention will be explained in more detail by way of Examples below.
実施例１
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（式（■））
の−製造方法
４−メｆルー５−（（２−クロルエチル）チオメチルク
イミダゾールｉ ｏ、ｏ ｇ ＠エタノール４００ゴに
溶解し、室温上攪拌しながらメチルグアニジン１０．０
ｇを加える。この溶液を約６時間加熱還流した後、減圧
下に濃縮し、生成物をシリカゲル６０．９０カラムを用
いエタノールを展開溶出液としてカラムクロマトグラフ
ィーを行い、エタノールで再結晶することにより、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ｂ、７ｇｔ得た。Example 1 N-methyl-N'-(2-((4-methyl-5-imidazolyl)methylthio]ethyl]guanidine (formula (■))
-Production method of 4-Mef-5-((2-chloroethyl)thiomethylquimidazoleio,og @ ethanol 400 g Dissolved in 10.0 g of methyl guanidine while stirring at room temperature.
Add g. After heating this solution under reflux for about 6 hours, it was concentrated under reduced pressure, and the product was subjected to column chromatography using a silica gel 60.90 column with ethanol as the developing eluent, and recrystallized with ethanol.
Methyl-N/-(2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine b, 7 gt was obtained.
実施例２
Ｎ−シアノ−Ｎ′−メチル−Ｎ“−（２−（（４−メチ
ル−５−イミダプリル）メチルチオ）エチル〕グアニジ
ン（Ｉ）の製造方法。Example 2 Method for producing N-cyano-N'-methyl-N''-(2-((4-methyl-5-imidapril)methylthio)ethyl]guanidine (I).
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５．０ｇをア
セトニトリル１００ｄに溶解し、ｐ−トルエンスルホン
ｌＩ！２．Ｏｆｌ 、シアン化テロＡ ２．ＯＳを攪拌
下に加えた。この反応液を約５時間加熱還流した後、減
圧下に濃縮し、生成物をシリカゲル６０ｇのカラムを用
い、アセトニトリル−エタノール（容積比１：１）＝ｉ
展開溶出液としてカラムクロマトグラフィーを行い、エ
タノールテ再結晶することによシＮ−シアノー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〕グアニジンを得た。このものの
融点は１３９．５〜１４２℃であり、元素分析値は以下
の通りであった。Ｃ１゜Ｈ１６Ｎ６Ｂとして実施例３
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
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５．０ｇをエ
タノール５０１／に溶解し、ｐ−トルエンスルホン＠
ｉ、ｓ ｇ 、シアン化ソロム４．０９ｔｔＡ加して約
４時間加熱還流する。次いで減圧下で製綱し、残留物全
エタノールから２回再結晶することにより、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〕グアニジンを得た。こ
のものの融点は、１４０〜１４１℃であった。5.0 g of N-methyl-N'-(2-((4-methyl-5-imidazolyl)methylthio)ethyl)guanidine was dissolved in 100 d of acetonitrile, p-toluenesulfone lI!2.Ofl, cyanide telo A 2 .OS was added under stirring.The reaction solution was heated under reflux for about 5 hours, concentrated under reduced pressure, and the product was purified using a 60 g silica gel column with acetonitrile-ethanol (1:1 volume ratio) = i
Column chromatography was performed as a developing eluate, and recrystallization was performed using ethanol to obtain 2-(2-((4-methyl-5-imidazolyl)methylthio)ethyl)guanidine. The melting point of this product was 139.5-142°C, and the elemental analysis values were as follows.Example 3 N-cyano-N'-methyl-N''-(2-(( Method for producing 4-methyl-5-imidazolyl)methylthio)ethyl]guanidine Dissolve 5.0 g of N-methyl-N'-(2-((4-methyl-5-imidazolyl)methylthio)ethyl)guanidine in ethanol 501/ p-Toluenesulfone@
i, s g and 4.09 ttA of cyanide were added, and the mixture was heated under reflux for about 4 hours. Next, the steel was made under reduced pressure, and the residue was recrystallized twice from total ethanol to obtain N-cyano-N'-methyl-N"-[2((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine. The melting point of this product was 140-141°C.
代理人 浅 村 皓 外４名Agent Asa Mura Hao 4 other people
Claims (1)
−５−イミダゾリル）メチルチオ）エチル〕グアニジン
を、不活性有機溶媒中有機酸の存在下にてシアン化ハロ
ゲンと反応させることを特徴と メする、
グ式（Ｉ）
浴で表わされるＮ−シアノ−
Ｎ′−メチル−Ｎ“−Ｃ２−１４−メチル−５−イきダ
ゾリル）メチ ′式（Ｉ［［） で表わされる４−メチル−５−（（２−クロルチル）チ
オメチル〕イミ、ダゾールにメチルグアジンを反応させ
、式（ＩＩ） で懺わされるＮ−メチル−Ｎ’−（２−（（４−チル−
５−イミダゾリル）メチルチオ）エチル〕アニジンを得
、次いでこの化合物を不活性有機媒中有機酸の存在下に
てシアン化ハロゲンと反させることｔ−Ｓ徴とする、式
（Ｉ） 罰＼グＮ で懺わされるＮ−シアノ−Ｎ′−／チルーＮ“−ルチオ
）エチル〕グアニシンの製造方法。(1) N-methyl-N'-(2-((4-methyl-5-imidazolyl)methylthio)ethyl)guanidine represented by the formula (If) was prepared by cyanogen in the presence of an organic acid in an inert organic solvent. Characterized by reaction with halogen chloride,
Formula (I)
N-cyano- represented by bath
4-Methyl-5-((2-chlorotyl)thiomethyl)imie, dazole and methylguazine represented by the formula (I to give N-methyl-N'-(2-((4-thyl-
5-Imidazolyl)methylthio)ethyl]anidine is obtained and then reacting this compound with halogen cyanide in the presence of an organic acid in an inert organic medium gives the t-S characteristic of formula (I). A method for producing N-cyano-N'-/thi-N''-ruthio)ethyl]guanisine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56190160A JPS6056708B2 (en) | 1981-11-27 | 1981-11-27 | Method for producing imidazole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56190160A JPS6056708B2 (en) | 1981-11-27 | 1981-11-27 | Method for producing imidazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5892664A true JPS5892664A (en) | 1983-06-02 |
| JPS6056708B2 JPS6056708B2 (en) | 1985-12-11 |
Family
ID=16253417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56190160A Expired JPS6056708B2 (en) | 1981-11-27 | 1981-11-27 | Method for producing imidazole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6056708B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100401283B1 (en) * | 1998-07-13 | 2003-12-31 | 주식회사유한양행 | Ras-mutant cell growth inhibitor anidine derivatives |
-
1981
- 1981-11-27 JP JP56190160A patent/JPS6056708B2/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100401283B1 (en) * | 1998-07-13 | 2003-12-31 | 주식회사유한양행 | Ras-mutant cell growth inhibitor anidine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6056708B2 (en) | 1985-12-11 |
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