JPS6345266A - Production of imidazole derivative - Google Patents
Production of imidazole derivativeInfo
- Publication number
- JPS6345266A JPS6345266A JP61189797A JP18979786A JPS6345266A JP S6345266 A JPS6345266 A JP S6345266A JP 61189797 A JP61189797 A JP 61189797A JP 18979786 A JP18979786 A JP 18979786A JP S6345266 A JPS6345266 A JP S6345266A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- cimetidine
- reacting
- mercaptoethylguanidine
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 150000002460 imidazoles Chemical class 0.000 title claims description 4
- -1 aminomethylimidazole compound Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims 2
- 229960001380 cimetidine Drugs 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 238000010992 reflux Methods 0.000 abstract description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 abstract 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract 2
- OXPFWTHSDWUOEZ-UHFFFAOYSA-N 1-[(5-methyl-1h-imidazol-4-yl)methyl]piperidine Chemical compound N1C=NC(CN2CCCCC2)=C1C OXPFWTHSDWUOEZ-UHFFFAOYSA-N 0.000 abstract 1
- GAPFINWZKMCSBG-UHFFFAOYSA-N 2-(2-sulfanylethyl)guanidine Chemical compound NC(=N)NCCS GAPFINWZKMCSBG-UHFFFAOYSA-N 0.000 abstract 1
- 208000025865 Ulcer Diseases 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 231100000397 ulcer Toxicity 0.000 abstract 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- 150000001875 compounds Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- XPOZILPQFAIBOC-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanamine Chemical compound CC=1NC=NC=1CN XPOZILPQFAIBOC-UHFFFAOYSA-N 0.000 description 1
- ZORWZOOZJGMSTE-UHFFFAOYSA-N 1-cyano-2-methyl-3-(2-sulfanylethyl)guanidine Chemical compound N#CNC(=NC)NCCS ZORWZOOZJGMSTE-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- PDWPOXKSTFGRIT-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.CC=1NC=NC=1CCl PDWPOXKSTFGRIT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000003710 Histamine H2 Receptors Human genes 0.000 description 1
- 108090000050 Histamine H2 Receptors Proteins 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000002747 voluntary effect Effects 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（１）、
で表わされるＮ−シアノ−Ｎ′−メチル−Ｎ″−（２−
（５−メチル−４−イミダゾリルメチルチオ）エチル〕
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 specifically, to a method for producing imidazole derivatives, more specifically, N-cyano-N'-methyl-N''-(2-
(5-methyl-4-imidazolylmethylthio)ethyl]
This invention relates to a new method for producing guanidine.
本発明方法により製造される式（１）で表わされる化合
物は、−役名をシメチジンといい、ヒスタミンＨ２受容
体拮抗作用に基づく胃酸分泌抑制作用を示し、抗潰瘍治
療剤として広く使用されている。The compound represented by formula (1) produced by the method of the present invention is called cimetidine, exhibits gastric acid secretion suppressive action based on histamine H2 receptor antagonism, and is widely used as an anti-ulcer therapeutic agent.
従来から種々のシメチジンの製法が報告されている。米
国特許第４．０１３．６７８号におけろ製法によれば、
シメチジンは塩基の存在下４−クロロメチル−５−メチ
ルイミダゾール塩酸塩をＮ−ンアノーＮ′−メチル＝Ｎ
″−（２−メルカプトエチル）グアニジンと反応させて
製造される。又、特開昭５９−７１７２におけろ製法に
よれば、４−アミノメチル−５−メチルイミダゾールを
アルキル化剤により凹板アンモニウム塩を経由して、次
いでこれにＮ−シアノ−Ｎ′−メチルーＮ″−（２−メ
ルカプトエチル）グアニジンを反応させてシメチジンを
製造する方法が記載されている。Various methods for producing cimetidine have been reported. According to the process in U.S. Patent No. 4.013.678,
Cimetidine converts 4-chloromethyl-5-methylimidazole hydrochloride into N-anor N'-methyl=N in the presence of a base.
It is produced by reacting with ``-(2-mercaptoethyl)guanidine.Also, according to the Ro process in JP-A-59-7172, 4-aminomethyl-5-methylimidazole is converted to concave ammonium by alkylating agent. A method for producing cimetidine via a salt and then reacting this with N-cyano-N'-methyl-N''-(2-mercaptoethyl)guanidine is described.
しかしながら、これらの製造法は原料の製造法嘆
の問題や反応工程の繁雑さなど々多くの問題点があった
。However, these production methods have many problems, such as problems with the production method of raw materials and complicated reaction steps.
そこで本発明者は、上記の欠点を解決すべく脱ぎ研究し
、本発明を完成した。Therefore, the inventor conducted extensive research to solve the above-mentioned drawbacks, and completed the present invention.
即ち、本発明は、式（ＩＩ）
基、低級アルケニル基、もしくはアラルキル基を示し、
また両者は隣接する窒素原子と共に環を形成しても良い
）
はその酸付加塩を式（ｊｌｌ）
ＣＮ
＋１ＳＣＩｔ２Ｃ１ｌｔＮｌｌＣＮｌｌＣＩ＋３ （
ｉｌｌ ）て示されろメルカプトエチルグアニジン化合
物と反応させろことを特徴とする式（１）て表イつされ
るシメチジンの製法に関するものである。That is, the present invention represents a group of formula (II), a lower alkenyl group, or an aralkyl group,
In addition, both may form a ring together with the adjacent nitrogen atom), and the acid addition salt thereof is expressed by the formula (jll) CN +1SCIt2C1ltNlllCNllCI+3 (
The present invention relates to a method for producing cimetidine represented by formula (1), characterized in that it is reacted with a mercaptoethylguanidine compound represented by formula (1).
式（ｎ）のＲ，、Ｒ，において、低級アルキル基として
は、たとえば、メチル基、エチル基、プロピル基、イソ
プロピル基を意味し、低級アルケニル基としては、たと
えば、アリル基、クロチル基を色味し、アラルキル基と
しては、ベンジルＩＨ等の基を色味する。またＲ１とＲ
２が隣接する窒素原子とノ（に環を形成する例として、
ピロリジン、ピペリジンあるいはモルホリンなどの環が
あげられろ。In R and R of formula (n), the lower alkyl group means, for example, a methyl group, ethyl group, propyl group, and isopropyl group, and the lower alkenyl group means, for example, an allyl group and a crotyl group. As an aralkyl group, groups such as benzyl IH are used. Also R1 and R
As an example where 2 forms a ring with the adjacent nitrogen atom,
Examples include rings such as pyrrolidine, piperidine, or morpholine.
式（Ｉｔ）の化合物と式（ｉＩｌ）の化合物との反応は
有機溶媒中、高温、好ましくは還流温度で行なうことが
できる。The reaction between a compound of formula (It) and a compound of formula (il) can be carried out in an organic solvent at an elevated temperature, preferably at reflux temperature.
使用されろ有機溶媒としては、エタノール、プロパツー
ルのようなアルコール類、ジグライム（ジエチレングリ
コールジメチルエーテル）のようなエーテル類やツメチ
ルホルムアミド等があげられる。まｆこ、上記反応は、
溶媒を用いろことなく高温下（５０°Ｃ〜２００°Ｃ）
で反応を行なうこともできろ。Examples of organic solvents that may be used include alcohols such as ethanol and propatool, ethers such as diglyme (diethylene glycol dimethyl ether), and dimethylformamide. Mafko, the above reaction is
Under high temperature (50°C to 200°C) without using a solvent
You can also perform a reaction with
更に、この反応は、中性又は塩基性条件下で６行なうこ
とができ、塩基性条件としては、ナトリウムアルコキシ
ド、ピリノン等が用いられる。Furthermore, this reaction can be carried out under neutral or basic conditions, and sodium alkoxide, pyrinone, etc. are used as the basic conditions.
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 showing examples below.
実憔列１
４−ピペリツノメチル−５−メチルイミダゾール３９７
ｍｇ及びＮ−ンアノーＮ′−メチル−Ｈ−−（２−メル
カプトエチル）グアニジン３４８ｍｇを１４０ ’Ｃて
窒素雰囲気下３０分撹拌しｆこ。反応混合物を冷却し、
クロロ士ルムメタノール系でシリカゲル力、ラムクロマ
トグラフィーを行ｒ、−）ｆこ後、アセトニトリルで再
結晶して１１７ｍｇのシメチジンを得ｆこ。Actual sequence 1 4-piperitunomethyl-5-methylimidazole 397
348 mg of N-anor N'-methyl-H--(2-mercaptoethyl)guanidine were stirred at 140'C for 30 minutes under a nitrogen atmosphere. cool the reaction mixture;
After performing silica gel chromatography and ram chromatography using a chlorofluoride methanol system, the product was recrystallized from acetonitrile to obtain 117 mg of cimetidine.
融り１３９〜１４１℃
’ＨＮＭＲ（ＣＤ、ＯＤン
６２．２０（ｓ、３Ｈ２〈〕γ０ｈ）
２．４〜２．９ （ｍ、 ２Ｈ，−５ＣＨｔ−）２
．７８ （５，３Ｈ，）Ｎ ＣＬ）３．２〜３．
５ （＋ｎ、 ２Ｈ１ＣＨＪく）３．６８ （
５，２Ｈ，（、’、ｌ。）！１ＬＬＳ
特許出願人 日本ケミファ味式会辻手続補正書（自
発）
昭和６１年９月Ｃ日Melting 139-141℃ 'HNMR (CD, ODn 62.20 (s, 3H2〈]γ0h) 2.4-2.9 (m, 2H, -5CHt-)2
．． 78 (5,3H,)N CL) 3.2-3.
5 (+n, 2H1CHJku) 3.68 (
5,2H,(,',l.)! 1LLS Patent applicant Nippon Chemifa Aji Shikikai Tsuji procedural amendment (voluntary) September C, 1986
Claims (1)
ルキル基、低級アルケニル基もしくはアラルキル基を示
し、また両者は隣接する窒素原子と共に環を形成しても
良い） で示されるアミノメチルイミダゾール化合物又はその酸
付加塩を 式； ▲数式、化学式、表等があります▼ で示されるメルカプトエチルグアニジン化合物と反応さ
せることを特徴とする 式； ▲数式、化学式、表等があります▼ で示されるイミダゾール化合物の製造方法。[Claims] Formulas; ▲ Numerical formulas, chemical formulas, tables, etc. It is characterized by reacting an aminomethylimidazole compound or its acid addition salt represented by (which may form a ring with atoms) with a mercaptoethylguanidine compound represented by the formula; Formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing imidazole compounds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61189797A JPS6345266A (en) | 1986-08-13 | 1986-08-13 | Production of imidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61189797A JPS6345266A (en) | 1986-08-13 | 1986-08-13 | Production of imidazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6345266A true JPS6345266A (en) | 1988-02-26 |
Family
ID=16247368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61189797A Pending JPS6345266A (en) | 1986-08-13 | 1986-08-13 | Production of imidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6345266A (en) |
-
1986
- 1986-08-13 JP JP61189797A patent/JPS6345266A/en active Pending
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