JPH037671B2 - - Google Patents
Info
- Publication number
- JPH037671B2 JPH037671B2 JP57213634A JP21363482A JPH037671B2 JP H037671 B2 JPH037671 B2 JP H037671B2 JP 57213634 A JP57213634 A JP 57213634A JP 21363482 A JP21363482 A JP 21363482A JP H037671 B2 JPH037671 B2 JP H037671B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- imidazolyl
- reaction
- guanidine
- 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 5
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229960001380 cimetidine Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- -1 alkali metal alkoxides Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000005881 detosylation reaction Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、シアノグアニジン誘導体、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−H″−〔２
−｛（４−メチル−５−イミダゾリル）−メチルチ
オ｝エチル〕グアニジンおよびその製造法に関す
る。
上記化合物は、シメチジン（cimetidine）と
称されるヒスタミンH2受容体遮断効果にすぐれ
た抗漬瘍剤の合成に有用な化合物である。
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−N″−（２−
メチルカプトエチル）グアニジンと、式：
The present invention provides cyanoguanidine derivatives, particularly N-cyano-N'-methyl-N''-(4
-Methyl-5-imidazolyl)methyl-H″-[2
-{(4-Methyl-5-imidazolyl)-methylthio}ethyl]guanidine and its production method. The above compound is useful for the synthesis of an anti-ulcer agent called cimetidine, which has excellent histamine H 2 receptor blocking effects. According to the invention, the formula []: N-cyano-N'-methyl-N''-(4-
Methyl-5-imidazolyl)methyl-N″-(2-
Methylcaptoethyl)guanidine and the formula:
【式】 〔式中、TS−は【formula】 [In the formula, TS− is
【式】を表わ
し、１または３位に位置する〕
で示される１−トシル−４(5)−メチル−５(4)−ア
セトキシメチルイミダゾ−ルを溶媒中、塩基性条
件下に反応させることにより得られる。
塩基性条件は、水酸化ナトリウム、水酸化カリ
ウム、アルカリ金属のアルコキサイド、アルカリ
金属の水素化物などによつて与えられる。
反応溶媒は、ジメチルホルムアミドDMF、メ
タノ−ルやエタノ−ルなどのアルコ−ルなどであ
る。収率の点からはメタノ−ル、エタノ−ルなど
のアルコ−ルが好ましい。もつとも、塩基として
水素化ナトリウムNaHなどのアルカリ金属水素
化物を使用する場合は、DMFでも好収率で目的
化合物が得られる。
反応温度は20〜80℃の範囲が適当であり、一夜
で反応の完結をみる。
保護基であるトシル基は、反応過程、または反
応生成物の抽出時に脱離するので、脱トシル化工
程は不要である。
本発明の化合物はシメチジンの合成に有用で
あり、、化合物に塩基性条件下で下記化合物
（Ｎ−シアノ−N′−メチル−N″−（２−メルカプ
トエチル）−グアニジン
を作用させれば、シメチジン、すなわち下式で示
されるＮ−メチル−N′−シアノ−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
を容易に得ることができる。
実施例
エタノ−ル20mlにＮ−シアノ−N″−メチル−
N″−（４−メチル−５−イミダゾリル）メチル−
N″−（２−メルカプトエチル）グアニジン1.14g
（0.00452モル）を加え、これにナトリウムエトキ
シド0.307g（0.00452モル）を添加する。ついで、
１−トシル−４(5)−メチル−５(4)−アセトキシメ
チルイミダゾ−ル1.39g（0.00452モル）を加え、
一夜撹拌する。反応終了後、溶媒を留去し、残渣
を5N−水酸化ナトリウムと酢酸エチルで抽出す
る。酢酸エチル相を乾燥後留去し、担体としてワ
コ−ゲルＣ−300を用いカラムクロマトグラフイ
に付す。溶離液としてアセトンを使用する。目的
分画をアセトニトリルから結晶化させる。
TLC（メルク社製キ−ゼルゲル60F254使用）：
Rf0.4〔酢酸エチル：メタノ−ル：28％アンモニア
水容液（10：１：１）〕。
赤外吸収スペクトル：第１図に示す。Reacting 1-tosyl-4(5)-methyl-5(4)-acetoxymethylimidazole represented by [Formula] and located at the 1 or 3 position in a solvent under basic conditions. It is obtained by Basic conditions are provided by sodium hydroxide, potassium hydroxide, alkali metal alkoxides, alkali metal hydrides, and the like. Reaction solvents include dimethylformamide DMF and alcohols such as methanol and ethanol. From the viewpoint of yield, alcohols such as methanol and ethanol are preferred. However, when an alkali metal hydride such as sodium hydride NaH is used as a base, the target compound can be obtained in good yield even with DMF. The appropriate reaction temperature is in the range of 20 to 80°C, and the reaction is completed overnight. Since the protective tosyl group is removed during the reaction process or during extraction of the reaction product, a detosylation step is not necessary. The compound of the present invention is useful for the synthesis of cimetidine. , cimetidine, i.e., N-methyl-N′-cyano-N″-[2-{(4
-Methyl-5-imidazolyl)methylthio}ethyl]guanidine can be easily obtained. Example N-cyano-N″-methyl- in 20 ml of ethanol
N″-(4-methyl-5-imidazolyl)methyl-
N″-(2-mercaptoethyl)guanidine 1.14g
(0.00452 mol) and to this is added 0.307 g (0.00452 mol) of sodium ethoxide. Then,
Add 1.39 g (0.00452 mol) of 1-tosyl-4(5)-methyl-5(4)-acetoxymethylimidazole,
Stir overnight. After the reaction is completed, the solvent is distilled off, and the residue is extracted with 5N sodium hydroxide and ethyl acetate. After drying, the ethyl acetate phase was distilled off and subjected to column chromatography using Wako Gel C-300 as a carrier. Use acetone as eluent. Crystallize the desired fraction from acetonitrile. TLC (using Merck Kieselgel 60F 254 ):
Rf0.4 [ethyl acetate: methanol: 28% ammonia aqueous solution (10:1:1)]. Infrared absorption spectrum: Shown in Figure 1.
第１図は赤外吸収スペクトルを示す。 FIG. 1 shows an infrared absorption spectrum.
Claims (1)
条件下に反応させることを特徴とする 式： で示されるシアノグアニジン誘導体の製造法。[Claims] 1 Formula: A cyanoguanidine derivative represented by 2 formula: Compound and formula shown by: A formula characterized by reacting a compound represented by [in the formula] and located at the 1 or 3 position under basic conditions: A method for producing a cyanoguanidine derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57213634A JPS59104363A (en) | 1982-12-06 | 1982-12-06 | Cyanoguanidine derivative and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57213634A JPS59104363A (en) | 1982-12-06 | 1982-12-06 | Cyanoguanidine derivative and its production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59104363A JPS59104363A (en) | 1984-06-16 |
| JPH037671B2 true JPH037671B2 (en) | 1991-02-04 |
Family
ID=16642396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57213634A Granted JPS59104363A (en) | 1982-12-06 | 1982-12-06 | Cyanoguanidine derivative and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59104363A (en) |
-
1982
- 1982-12-06 JP JP57213634A patent/JPS59104363A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59104363A (en) | 1984-06-16 |
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