JPH033668B2 - - Google Patents
Info
- Publication number
- JPH033668B2 JPH033668B2 JP57143569A JP14356982A JPH033668B2 JP H033668 B2 JPH033668 B2 JP H033668B2 JP 57143569 A JP57143569 A JP 57143569A JP 14356982 A JP14356982 A JP 14356982A JP H033668 B2 JPH033668 B2 JP H033668B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- compound
- formula
- ethanol
- imidazolylmethyl
- 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
Links
- 150000001875 compounds Chemical class 0.000 claims description 19
- 150000002460 imidazoles Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- -1 methyl-5-imidazolylmethyl Chemical group 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 2
- IVSSOOPRPJEGBZ-UHFFFAOYSA-N n-methyl-1-(5-methyl-1h-imidazol-4-yl)methanamine Chemical compound CNCC=1N=CNC=1C IVSSOOPRPJEGBZ-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical class [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
【発明の詳細な説明】
本発明はイミダゾール誘導体、特に下式〔〕
で示されるＮ−シアノ−N′−メチル−N′−（４−
メチル−５−イミダゾリルメチル）−N″−メルカ
プトエチルグアニジンおよびその製造法に関す
る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to imidazole derivatives, particularly the following formula []
N-cyano-N'-methyl-N'-(4-
The present invention relates to methyl-5-imidazolylmethyl)-N''-mercaptoethylguanidine and its production method.
イミダゾール誘導体は薬理学的に極めて重要な
分野を占める化合物である。本発明に係る上記イ
ミダゾール誘導体は、分子内の失印(a)部分の結合
の分断と分子内転位反応とを生起させることがで
き、例えばジメチジン（cimetidine）と称される
強力な胃酸分泌抑制作用をもつ抗潰瘍剤の合成に
有用な化合物である。 Imidazole derivatives are compounds that occupy an extremely important pharmacological field. The above-mentioned imidazole derivative according to the present invention is capable of causing cleavage of the bond of the unmarked (a) moiety in the molecule and intramolecular rearrangement reaction, and has a strong gastric acid secretion suppressing effect called, for example, dimetidine. It is a useful compound for the synthesis of anti-ulcer agents.
本発明によれば、
式〔〕：
で示されるＮ−シアノ−N′−メチル−N′−（４−
メチル−５−イミダゾリルメチル）−Ｓ−メチル
−イソチオウレアと
式〔〕：NH2CH2CH2SH 〔〕
で示されるシステアミンもしくはその塩酸塩とを
反応させることにより目的とする上記化合物
〔〕を得る。 According to the invention, the formula []: N-cyano-N'-methyl-N'-(4-
The desired compound [] can be obtained by reacting methyl-5-imidazolylmethyl)-S-methyl-isothiourea with cysteamine or its hydrochloride represented by the formula []: NH 2 CH 2 CH 2 SH []. obtain.
上記反応は、好ましくは、メタノール、エタノ
ール、ジエチレングリコール、ジオキサンなどの
有機極性溶媒中、水素化ナトリウム、水素化カリ
ウム、ナトリウムメチラート、カリウムメチラー
ト、ナトリウムエチラート、カリウムエチラート
などのアルカリ金属塩基の存在下、不活性雰囲気
中で行なわれる。 The above reaction is preferably carried out using an alkali metal base such as sodium hydride, potassium hydride, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, etc. in an organic polar solvent such as methanol, ethanol, diethylene glycol, dioxane, etc. in the presence of an inert atmosphere.
反応温度は室温が好ましい。反応時間は１〜３
時間である。 The reaction temperature is preferably room temperature. Reaction time is 1-3
It's time.
原料化合物の仕込量はすべて化学量論的量であ
るのが好ましい。 It is preferable that all raw material compounds are charged in stoichiometric amounts.
なお、本発明に使用される原料化合物〔〕は
本発明者等によつて見出された化合物であり、こ
のものは、
式〔〕：
で示される４−メチル−５−メチルアミノメチル
−イミダゾールと、
式〔〕：
で示されるジメチルシアノジオイミドカーボネー
トをエタノールなどの有機極性溶媒中、トリエチ
ルアミンなどの有機塩基の存在下に室温で反応さ
せることにより得られる。 The raw material compound [] used in the present invention is a compound discovered by the present inventors, and has the following formula: 4-methyl-5-methylaminomethyl-imidazole represented by the formula []: It can be obtained by reacting dimethylcyanodioimide carbonate represented by in an organic polar solvent such as ethanol in the presence of an organic base such as triethylamine at room temperature.
次に本発明の実施例について説明する。 Next, examples of the present invention will be described.
実施例
窒素気流下において、Ｎ−シアノ−N′−メチ
ル−N′−（４−メチル−５−イミダゾリルメチ
ル）−Ｓ−メチル−イソチオウレア（化合物
〔〕。このものゝ合成は後記参考例参照。）285mg
（9.8×10-4モル）をエタノール10mlに溶かし、一
方50％水素化ナトリウム（NaH）108mg（1.88×
10-3モル）をエタノール10mlに溶かし、システア
ミン・塩酸塩（化合物〔〕）を加えて溶液を調
製し、これを上記エタノール溶液に一度に加え、
室温で１時間撹拌して、目的とするＮ−シアノ−
N′−メチル−N′−（４−メチル−５−イミダゾリ
ルメチル）−N″−メルカプトエチルグアニジン
〔〕を得る。Example Under a nitrogen stream, N-cyano-N'-methyl-N'-(4-methyl-5-imidazolylmethyl)-S-methyl-isothiourea (compound []). For the synthesis of this compound, refer to the reference example below. ) 285mg
(9.8 × 10 -4 mol) was dissolved in 10 ml of ethanol, while 108 mg of 50% sodium hydride (NaH) (1.88
10 -3 mol) in 10 ml of ethanol, add cysteamine hydrochloride (compound []) to prepare a solution, add this to the above ethanol solution all at once,
Stir at room temperature for 1 hour to obtain the desired N-cyano-
N'-Methyl-N'-(4-methyl-5-imidazolylmethyl)-N''-mercaptoethylguanidine [] is obtained.
目的化合物〔〕は酸素、熱等に対して極めて
不安定であるので、次のように２，４−ジニトロ
ベンゼン誘導体に変換したのち、その構造確認を
行つた。 Since the target compound [] is extremely unstable to oxygen, heat, etc., it was converted into a 2,4-dinitrobenzene derivative as follows, and then its structure was confirmed.
上記反応液を未精製のまゝ、これに少量の水と
水酸化ナトリウムおよび２倍モルの２，４−ジニ
トロクロルベンゼンを加え、撹拌する。１時間
後、溶媒を留去し、残渣に1N塩酸を加え、沈澱
物を去する。液に2N水酸化ナトリウム溶液
を加えると、結晶が生成する。結晶をエタノール
から再結晶させ、融点208℃の結晶を得る。その
赤外吸収スペクトル、核磁気共鳴スペクトルは次
のとおりである。 A small amount of water, sodium hydroxide, and twice the mole of 2,4-dinitrochlorobenzene are added to the unpurified reaction solution and stirred. After 1 hour, the solvent was distilled off, 1N hydrochloric acid was added to the residue, and the precipitate was removed. When 2N sodium hydroxide solution is added to the solution, crystals form. The crystals are recrystallized from ethanol to obtain crystals with a melting point of 208°C. Its infrared absorption spectrum and nuclear magnetic resonance spectrum are as follows.
IR、νKBr nax（cm-1）：2170、1590、1530、1430、
1403、1340、1300付近に吸収を示す。 IR, ν KBr nax (cm -1 ): 2170, 1590, 1530, 1430,
It shows absorption near 1403, 1340, and 1300.
NMR、δd6−DMSO（ppm）：11.85(b)、8.83(d)、
8.43(d)、8.23(d)、8.05、7.94、7.45（ｓ）、4.33、
3.65（ｍ）、4.48（ｄ、ｍ）、2.92（Ｓ）、2.21（Ｓ）
。 NMR, δd6 -DMSO (ppm): 11.85(b), 8.83(d),
8.43(d), 8.23(d), 8.05, 7.94, 7.45(s), 4.33,
3.65 (m), 4.48 (d, m), 2.92 (S), 2.21 (S)
.
参考例
（原料化合物〔〕の合成）
化合物〔〕＋化合物〔〕→化合物〔〕
４−メチル−５−メチルアミノメチル−イミダ
ゾール（化合物〔〕）198mg（1.0×10-3モル）、
ジメチルシアノジチオイミドカーボネート（化合
物〔〕）146mg（1.0×10-3モル）およびトリエ
チルアミン202mg（2.0×10-3モル）を、エタノー
ル20mlに加え撹拌する。一夜反応させたのち、溶
媒を留去し、1N−KC1と酢酸エチルで振とうす
る。水相を分取し、炭酸カリウムでアルカリ性に
調節したのち、酢酸エチルで振とうする。酢酸エ
チル層を分取し、乾燥したのち酢酸エチルを留去
すると、粘稠な油状物としてＮ−シアノ−N′−
メチル−N′−（４−メチル−５−イミダゾリルメ
チル）−Ｓ−メチル−イソチオウレア（化合物
〔〕）を得る。収量169mg（81％）。このものは、
薄層クロマトグラフイーにおいて単一スポツトで
あり、精製することなく次の反応に供することが
できる。赤外吸収スペクトルは下記のように特徴
的な波数を示す。Reference example (Synthesis of raw material compound []) Compound [] + Compound [] → Compound [] 4-methyl-5-methylaminomethyl-imidazole (compound []) 198 mg (1.0 × 10 -3 mol),
146 mg (1.0 x 10 -3 mol) of dimethyl cyanodithioimide carbonate (compound []) and 202 mg (2.0 x 10 -3 mol) of triethylamine are added to 20 ml of ethanol and stirred. After reacting overnight, the solvent was distilled off and the mixture was shaken with 1N-KC1 and ethyl acetate. The aqueous phase is separated, adjusted to alkalinity with potassium carbonate, and then shaken with ethyl acetate. The ethyl acetate layer was separated, dried, and then the ethyl acetate was distilled off to form N-cyano-N'- as a viscous oil.
Methyl-N'-(4-methyl-5-imidazolylmethyl)-S-methyl-isothiourea (compound []) is obtained. Yield 169 mg (81%). This thing is
It is a single spot in thin layer chromatography and can be used in the next reaction without purification. The infrared absorption spectrum shows characteristic wave numbers as shown below.
IR、νneat nax（cm-1）：2180、1550、1440、1403付
近
に吸収を示す。 IR, ν neat nax (cm -1 ): Shows absorption near 2180, 1550, 1440, and 1403.
Claims (1)
る 式： で示されるイミダゾール誘導体の製造法。[Claims] 1 Formula: An imidazole derivative represented by 2 formula: A compound represented by the formula: NH 2 CH 2 CH 2 SH is reacted with a compound represented by the formula: NH 2 CH 2 CH 2 SH. A method for producing an imidazole derivative shown in
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57143569A JPS5933269A (en) | 1982-08-19 | 1982-08-19 | Imidazole derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57143569A JPS5933269A (en) | 1982-08-19 | 1982-08-19 | Imidazole derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5933269A JPS5933269A (en) | 1984-02-23 |
| JPH033668B2 true JPH033668B2 (en) | 1991-01-21 |
Family
ID=15341797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57143569A Granted JPS5933269A (en) | 1982-08-19 | 1982-08-19 | Imidazole derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5933269A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1643458A2 (en) | 2004-07-20 | 2006-04-05 | Alps Electric Co., Ltd. | Passive keyless entry device |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0303570A3 (en) * | 1987-08-12 | 1990-11-07 | Ciba-Geigy Ag | Substituted isothioureas |
| JP4848219B2 (en) * | 2006-07-27 | 2011-12-28 | 日本メクトロン株式会社 | Printed wiring board and manufacturing method thereof |
-
1982
- 1982-08-19 JP JP57143569A patent/JPS5933269A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1643458A2 (en) | 2004-07-20 | 2006-04-05 | Alps Electric Co., Ltd. | Passive keyless entry device |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5933269A (en) | 1984-02-23 |
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