JPH033664B2 - - Google Patents
Info
- Publication number
- JPH033664B2 JPH033664B2 JP57057727A JP5772782A JPH033664B2 JP H033664 B2 JPH033664 B2 JP H033664B2 JP 57057727 A JP57057727 A JP 57057727A JP 5772782 A JP5772782 A JP 5772782A JP H033664 B2 JPH033664 B2 JP H033664B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- compound
- reaction
- cyano
- present
- 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
- -1 4-methyl-5-imidazolyl Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- WNDQPKIYIFNJOU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methyl n-methylcarbamate Chemical compound CNC(=O)OCC=1N=CNC=1C WNDQPKIYIFNJOU-UHFFFAOYSA-N 0.000 claims description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 5
- 229960001380 cimetidine Drugs 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000002994 raw material Substances 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
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 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
- UFEJKYYYVXYMMS-UHFFFAOYSA-N methylcarbamic acid Chemical compound CNC(O)=O UFEJKYYYVXYMMS-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 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、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″−
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に関する。Detailed Description of the Invention The present invention relates to cyanoguanidine derivatives, particularly N-cyano-N'-methyl-N''-
2-[[(4-methyl-5-imidazolyl)methyl]
The present invention relates to a method for producing thio]ethylguanidine.
本発明の目的化合物〔〕は一般名をシメチジ
ン（cimetidine）と称せられ、ヒスタミンのH2
一受容体遮断効果を有し抗潰瘍剤として広く知ら
れているものである。 The object compound of the present invention [ ] has a generic name called cimetidine, and has the H 2
It has a receptor blocking effect and is widely known as an anti-ulcer agent.
従来、シメチジンの製造法については種々提案
されているが（特開昭54−59275号、同51−
54561、同51−125074号、同50−32174号、特開昭
56−1309号等）、いずれも反応試剤として高価な
システアミン（HSCH2CH2NH2）を必要とし、
かつその反応生成物はクロマトグラフイーによる
分離精製を要する等、工業的な製造法とは言えな
い。また、４−メチル−５−メルカプトメチルイ
ミダゾールを原料とする製造法（特開昭54−
130566号）では、該原料がアルカリ性条件下で酸
化され易いため収率の抵下を免れ得ず、多量の副
生成が分離精製を困難にするという欠点がある。 Until now, various methods for producing cimetidine have been proposed (Japanese Patent Application Laid-open Nos. 54-59275 and 51-59).
54561, No. 51-125074, No. 50-32174, JP-A-Sho
56-1309, etc.), all of which require expensive cysteamine (HSCH 2 CH 2 NH 2 ) as a reaction reagent,
Moreover, the reaction product requires separation and purification by chromatography, so it cannot be called an industrial production method. In addition, a manufacturing method using 4-methyl-5-mercaptomethylimidazole as a raw material (Japanese Patent Application Laid-open No.
No. 130566) has the drawback that the raw material is easily oxidized under alkaline conditions, resulting in a decrease in yield, and a large amount of by-products make separation and purification difficult.
本発明は、上記欠点を克服すべくなされたもの
であり、１反応工程にて高収率で目的化合物
〔〕を製造する方法を提供する。 The present invention has been made to overcome the above-mentioned drawbacks, and provides a method for producing the target compound in high yield in one reaction step.
本発明方法によれば、下式〔〕
で示される４−メチル−５−（Ｎ−メチルカルバ
モイルオキシ）メチル−イミダゾールと、下式
〔〕
で示されるＮ−シアノ−N′、Ｓ−エチレンイソ
チオウレアとを、塩基性条件下に反応させて目的
化合物であるシメチジン〔〕を得る。 According to the method of the present invention, the following formula [] 4-methyl-5-(N-methylcarbamoyloxy)methyl-imidazole represented by the following formula [] The desired compound, cimetidine, is obtained by reacting N-cyano-N', S-ethyleneisothiourea represented by the formula under basic conditions.
上記反応における塩基性条件は、例えば水酸化
ナトリウム、水酸化カリウム、水酸化カルシウム
などのアルカリ金属またはアルカリ土類金属の水
酸化物、あるいはナトリウムエトキシド、カリウ
ムエトキシドなどのアルカリ金属アルコキサイド
などによつてもたらされる。反応は、溶媒中、常
圧もしくは加圧条件下、加熱もしくは常温で行な
われる。反応溶媒の例としては、水、メタノー
ル、エタノール、アセトン、アセトニトリル、ジ
メチルホルムアミド（DMF）、ジメチルスルホキ
シド（DMSO）など、あるいはこれらの混合溶
媒が挙げられる。 The basic conditions in the above reaction are, for example, hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, or alkali metal alkoxides such as sodium ethoxide and potassium ethoxide. It will be brought to you. The reaction is carried out in a solvent, under normal pressure or pressurized conditions, with heating or at room temperature. Examples of the reaction solvent include water, methanol, ethanol, acetone, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and a mixed solvent thereof.
本発明に用いられるイミダゾール誘導体〔〕
は、＊印の炭素がカルボニル基より求核攻撃を受
け易く、求核攻撃により遊離するＮ−メチルカル
バミン酸は容易に脱炭酸を受けて、CO2と
NH2CH3に分離する。一方、環状イソチオウレ
ア誘導体〔〕は、上記化合物〔〕に対する求
核試剤として、その＊印の炭素に求核的に作用
し、それにより生ずるメチルアミンが反応に関与
することによつて目的化合物であるシメチジン
〔〕が１反応工程にて高収率で得られる。 Imidazole derivative used in the present invention [] The carbon marked with * is more susceptible to nucleophilic attack than the carbonyl group, and the N-methylcarbamic acid liberated by the nucleophilic attack is easily decarboxylated and converted into CO 2 and
Separate into NH2CH3 . On the other hand, the cyclic isothiourea derivative [ ] acts nucleophilically on the carbon marked with * as a nucleophilic reagent for the above compound [ ], and the methylamine generated thereby participates in the reaction to form the target compound. A certain cimetidine [ ] can be obtained in high yield in one reaction step.
なお、環状イソチオウレア誘導体〔〕は、メ
ルカプト基が保護された化学構造であり、塩基性
条件下においても耐酸化性を有するので、化合物
〔〕との反応において従来法のような副反応生
成物を生じることがなく、目的化合物〔〕の分
離精製も容易である。 The cyclic isothiourea derivative [] has a chemical structure with a protected mercapto group and has oxidation resistance even under basic conditions, so it does not produce side reaction products when reacting with the compound [] as in conventional methods. The separation and purification of the target compound [] is also easy.
次に実施例について説明するが、本発明方法は
これに限定されるものではない。 Next, examples will be described, but the method of the present invention is not limited thereto.
実施例（化合物〔〕＋化合物〔〕→化合物
〔〕）
エタノール50mlに水酸化ナトリウム２ｇ（0.05
モル）を溶解し、これにＮ−シアノ−N′、Ｓ−
エチレンイソチオウレア（化合物〔〕）6.4ｇ
（0.05モル）を加え、20分間攪拌し、ついで４−
メチル−５−（Ｎ−メチルカルバモイルオキシ）
メチル−イミダゾール（化合物〔〕）8.45ｇ
（0.05モル）を一度に加え、60〜70℃で１時間攪
拌する。Example (Compound [] + Compound [] → Compound []) 2 g of sodium hydroxide in 50 ml of ethanol (0.05
mol), and to this dissolve N-cyano-N', S-
Ethyleneisothiourea (compound []) 6.4g
(0.05 mol) and stirred for 20 minutes, then 4-
Methyl-5-(N-methylcarbamoyloxy)
Methyl-imidazole (compound []) 8.45g
(0.05 mol) at once and stirred at 60-70°C for 1 hour.
反応液を留去したのち、2N水酸化ナトリウム
水溶液と酢酸エチルで振とうし、酢酸エチル相を
乾燥留去する。残渣をアセトニトリルとエーテル
の混合溶媒から結晶化させて目的とするシメチジ
ン〔〕を得る。6.9ｇ（55％）。融点：139〜141
℃。 After the reaction solution was distilled off, the mixture was shaken with a 2N aqueous sodium hydroxide solution and ethyl acetate, and the ethyl acetate phase was dried and distilled off. The residue is crystallized from a mixed solvent of acetonitrile and ether to obtain the desired cimetidine. 6.9g (55%). Melting point: 139-141
℃.
Claims (1)
オキシ）メチル−イミダゾールと、Ｎ−シアノ−
N′、Ｓ−エチレンイソチオウレアとを、塩基性
条件下に反応させて、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ることを特
徴とするシアノグアニジン誘導体の製造法。1 4-Methyl-5-(N-methylcarbamoyloxy)methyl-imidazole and N-cyano-
N′,S-ethyleneisothiourea is reacted under basic conditions to produce N-cyano-N′-methyl-N″-2-[[(4-methyl-5-imidazolyl).
A method for producing a cyanoguanidine derivative, which comprises obtaining methyl]thio]ethylguanidine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57057727A JPS58174370A (en) | 1982-04-06 | 1982-04-06 | Production of cyanogyanidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57057727A JPS58174370A (en) | 1982-04-06 | 1982-04-06 | Production of cyanogyanidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58174370A JPS58174370A (en) | 1983-10-13 |
| JPH033664B2 true JPH033664B2 (en) | 1991-01-21 |
Family
ID=13063956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57057727A Granted JPS58174370A (en) | 1982-04-06 | 1982-04-06 | Production of cyanogyanidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58174370A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1762899A1 (en) | 2005-09-12 | 2007-03-14 | Ricoh Company, Ltd. | Latent electrostatic image bearing member, and the method for producing the same, image forming method, image forming apparatus, and process cartridge |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2607369B2 (en) * | 1987-02-20 | 1997-05-07 | 興和株式会社 | New heterocyclic compounds |
-
1982
- 1982-04-06 JP JP57057727A patent/JPS58174370A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1762899A1 (en) | 2005-09-12 | 2007-03-14 | Ricoh Company, Ltd. | Latent electrostatic image bearing member, and the method for producing the same, image forming method, image forming apparatus, and process cartridge |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58174370A (en) | 1983-10-13 |
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