JPH0113469B2 - - Google Patents
Info
- Publication number
- JPH0113469B2 JPH0113469B2 JP55089128A JP8912880A JPH0113469B2 JP H0113469 B2 JPH0113469 B2 JP H0113469B2 JP 55089128 A JP55089128 A JP 55089128A JP 8912880 A JP8912880 A JP 8912880A JP H0113469 B2 JPH0113469 B2 JP H0113469B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- thiomethyl
- aminoethyl
- imidazole
- hydroxymethylimidazole
- 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
- 150000003548 thiazolidines Chemical class 0.000 claims description 8
- AXJZCJSXNZZMDU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol Chemical compound CC=1N=CNC=1CO AXJZCJSXNZZMDU-UHFFFAOYSA-N 0.000 claims description 5
- JEOZNMMOIBLWLV-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethanamine Chemical compound CC=1N=CNC=1CSCCN JEOZNMMOIBLWLV-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 7
- 229960003151 mercaptamine Drugs 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- UBHDUFNPQJWPRQ-UHFFFAOYSA-N (5-methyl-1h-imidazol-3-ium-4-yl)methanol;chloride Chemical compound Cl.CC=1NC=NC=1CO UBHDUFNPQJWPRQ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IAOGWYABFHUNKI-UHFFFAOYSA-N 1h-imidazole;dihydrochloride Chemical compound Cl.[Cl-].C1=C[NH+]=CN1 IAOGWYABFHUNKI-UHFFFAOYSA-N 0.000 description 5
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 5
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 5
- 229960001380 cimetidine Drugs 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- -1 2-substituted thiazolidine Chemical class 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- MXTPRJXPLFGHEE-UHFFFAOYSA-N 1-amino-2-sulfosulfanylethane Chemical compound NCCSS(O)(=O)=O MXTPRJXPLFGHEE-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- SNPQRYOQWLOTFA-UHFFFAOYSA-N 2,2-dimethyl-1,3-thiazolidine Chemical class CC1(C)NCCS1 SNPQRYOQWLOTFA-UHFFFAOYSA-N 0.000 description 2
- AGSHBVNPPGEAMB-UHFFFAOYSA-N 2-ethyl-2-methyl-1,3-thiazolidine Chemical class CCC1(C)NCCS1 AGSHBVNPPGEAMB-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical compound OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 description 1
- NKPNSVCEUIECCA-UHFFFAOYSA-N 2,2-dimethyl-1,3-thiazolidine;hydron;chloride Chemical compound Cl.CC1(C)NCCS1 NKPNSVCEUIECCA-UHFFFAOYSA-N 0.000 description 1
- CJIFBUZRANSSAI-UHFFFAOYSA-N 2-(1h-imidazol-2-ylmethylsulfanyl)ethanamine Chemical compound NCCSCC1=NC=CN1 CJIFBUZRANSSAI-UHFFFAOYSA-N 0.000 description 1
- SSMHGMCWVPQWQR-UHFFFAOYSA-N 2-(1h-imidazol-5-ylmethylsulfanyl)ethanamine;dihydrochloride Chemical compound Cl.Cl.NCCSCC1=CN=CN1 SSMHGMCWVPQWQR-UHFFFAOYSA-N 0.000 description 1
- IQGWPPQNIZBTBM-UHFFFAOYSA-N 2-aminoethanol;sulfuric acid Chemical compound NCCO.OS(O)(=O)=O IQGWPPQNIZBTBM-UHFFFAOYSA-N 0.000 description 1
- BKMYYZARHFWPCS-UHFFFAOYSA-N 2-ethyl-1,3-thiazolidine hydrochloride Chemical compound Cl.CCC1NCCS1 BKMYYZARHFWPCS-UHFFFAOYSA-N 0.000 description 1
- GTIDJXKZFKXXGF-UHFFFAOYSA-N 2-ethyl-2-methyl-1,3-thiazolidine;hydrochloride Chemical compound Cl.CCC1(C)NCCS1 GTIDJXKZFKXXGF-UHFFFAOYSA-N 0.000 description 1
- QCWJLAHDNKXFIQ-UHFFFAOYSA-N 2-methyl-2-(2-methylpropyl)-1,3-thiazolidine Chemical class CC(C)CC1(C)NCCS1 QCWJLAHDNKXFIQ-UHFFFAOYSA-N 0.000 description 1
- XJJXLHLQVUIRFW-UHFFFAOYSA-N 2-methyl-2-phenyl-1,3-thiazolidine Chemical compound C=1C=CC=CC=1C1(C)NCCS1 XJJXLHLQVUIRFW-UHFFFAOYSA-N 0.000 description 1
- NXOMVTLTYYYYPC-UHFFFAOYSA-N 2-phenyl-1,3-thiazolidine Chemical compound N1CCSC1C1=CC=CC=C1 NXOMVTLTYYYYPC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OPVNVJSKZBBMHF-UHFFFAOYSA-N C(#N)N(C(O)=NOCCSCC1=C(N=CN1)C)CC Chemical compound C(#N)N(C(O)=NOCCSCC1=C(N=CN1)C)CC OPVNVJSKZBBMHF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-M hydrosulfide Chemical compound [SH-] RWSOTUBLDIXVET-UHFFFAOYSA-M 0.000 description 1
- LBVZYUZDHIPGLN-UHFFFAOYSA-N imidazol-1-ylmethanethiol Chemical compound SCN1C=CN=C1 LBVZYUZDHIPGLN-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Description
【発明の詳細な説明】
本発明は、式(3)
で示される４−メチル−５−〔（２−アミノエチ
ル）チオメチル〕イミダゾールを製造するための
新規にして有用な方法に関するものである。[Detailed Description of the Invention] The present invention provides formula (3) The present invention relates to a new and useful method for producing 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole.
この式(3)で示されるイミダゾール誘導体は、式
(4)
で示される重要な医薬品であるシメチジンの合成
中間体として使用できるという重要な用途を有す
る化合物である。式(4)で示されるシメチジンは、
ヒスタミンH2−受容体拮抗剤として有効な化合
物であつて、特に胃及び十二指腸潰瘍治療の分野
において非常に重要な医薬品である。 The imidazole derivative represented by this formula (3) has the formula
(Four) It is a compound that has important uses as it can be used as an intermediate for the synthesis of cimetidine, an important pharmaceutical product shown in Cimetidine represented by formula (4) is
It is a compound effective as a histamine H 2 -receptor antagonist, and is a very important drug, especially in the field of gastric and duodenal ulcer treatment.
本発明の目的化合物である４−メチル−５−
〔（２−アミノエチル）チオメチル〕イミダゾール
は従来４−メチル−５−ヒドロキシメチルイミダ
ゾールとシステアミンとを反応させる方法が専ら
行われてきたが（特開昭47−42661）、４−メチル
−５−ヒドロキシメチルイミダゾールと２−アミ
ノエタンチオール硫酸から合成する方法も最近に
なつて開発されている（特開昭55−87773号）。 4-methyl-5- which is the object compound of the present invention
[(2-Aminoethyl)thiomethyl]imidazole has conventionally been produced by reacting 4-methyl-5-hydroxymethylimidazole with cysteamine (Japanese Patent Application Laid-Open No. 47-42661), but 4-methyl-5- A method for synthesizing it from hydroxymethylimidazole and 2-aminoethanethiol sulfuric acid has also been recently developed (Japanese Patent Application Laid-open No. 87773/1983).
しかしながら前者のシステアミンは、空気酸化
を受けやすく、副生成物の混入、収率の低下は避
けられない。また後者については、非常に厄介な
副生する硫酸の分離を必らず行わねばならないと
いう大きな欠点を有する。 However, the former cysteamine is susceptible to air oxidation, and contamination with by-products and a decrease in yield are unavoidable. The latter method also has a major drawback in that it requires the very troublesome separation of sulfuric acid as a by-product.
本発明は、両者の持つ大きな欠点を取り除くた
めになされたものであり、システアミン、２−ア
ミノエタンチオール硫酸に代わる好適な原料を求
めて研究を重ねた結果、式(2)で示される２，２−
２置換チアゾリジンが好適であることをつきと
め、完成されたものである。すなわち、本発明
は、次の反応式で示される４−メチル−５−〔（２
−アミノエチル）チオメチル〕イミダゾールの製
造方法である。 The present invention was made to eliminate the major drawbacks of both cysteamine and 2-aminoethanethiol sulfuric acid, and as a result of repeated research in search of a suitable raw material to replace cysteamine and 2-aminoethanethiol sulfuric acid, 2, 2-
It was discovered that 2-substituted thiazolidine was suitable and was completed. That is, the present invention provides 4-methyl-5-[(2
-aminoethyl)thiomethyl]imidazole.
（式中、R1、R2はそれぞれアルキル基若しくは
フエニル基を表わし、又はR1、R2は一緒になつ
て環を形成する。）
本発明における原料化合物である２，２−２置
換チアゾリジンは、そのイオウ原子がチオエーテ
ル結合を形成しているため、空気酸化を受けにく
い物質であるし、また反応によつて副生するケト
ンは、減圧濃縮によつて容易に除去することがで
きる。また、最近になつて、２，２−２置換チア
ゾリジンは、モノエタノールアミンの硫酸エステ
ルと、ケトン、水硫化物から、安価に製造するこ
とも開発され（特開昭56−81574）原料化合物と
しては非常に有利である。さらに、この２，２−
２置換チアゾリジンを加水分解することによつ
て、従来の合成原料であつたシステアミンを容易
に製造することができることも判明した（特開昭
56−8358号）。 (In the formula, R 1 and R 2 each represent an alkyl group or a phenyl group, or R 1 and R 2 are taken together to form a ring.) 2,2-2-substituted thiazolidine which is a raw material compound in the present invention Because its sulfur atoms form a thioether bond, it is a substance that is not susceptible to air oxidation, and the ketone produced by the reaction can be easily removed by vacuum concentration. In addition, recently, it has been developed that 2,2-disubstituted thiazolidine can be produced inexpensively from monoethanolamine sulfate, ketone, and hydrosulfide (Japanese Patent Application Laid-open No. 81574/1983) as a raw material compound. is very advantageous. Furthermore, this 2,2-
It was also found that cysteamine, which was a conventional synthetic raw material, could be easily produced by hydrolyzing disubstituted thiazolidine (Japanese Patent Application Laid-open No.
56-8358).
これに対して本発明方法は、システアミンの合
成原料である２，２−２置換チアゾリジンを使用
するにもかかわらず、加水分解工程を取り除くこ
とを可能にしたわけであつて、その効果は、一工
程削減による効率向上にとどまらず、収率、品質
の上昇につながり、非常に顕著なものが得られ
る。本発明方法を採用することによつて、前記し
た従来法の有する欠点がすべて解決されることは
いうまでもない。 In contrast, the method of the present invention makes it possible to eliminate the hydrolysis step even though it uses 2,2-2-substituted thiazolidine, which is a raw material for cysteamine synthesis, and the effect is that it is possible to eliminate the hydrolysis step in one step. Not only does the reduction improve efficiency, but it also leads to an increase in yield and quality, which is very noticeable. It goes without saying that by employing the method of the present invention, all of the drawbacks of the conventional methods described above are solved.
本発明における２，２−２置換チアゾリジンと
４−メチル−５−ヒドロキシメチルイミダゾール
の反応は、水の存在しない氷酢酸中でも十分に進
行するという新規な知見が得られたが、これによ
れば、２，２−２置換チアゾリジンは、４−メチ
ル−５−ヒドロキシメチルイミダゾールと反応を
起こした結果、開環するということになり、本発
明に係る反応はまつたく新規な化学反応であると
いい得るのである。 A novel finding was obtained that the reaction between 2,2-2-substituted thiazolidine and 4-methyl-5-hydroxymethylimidazole in the present invention proceeds satisfactorily even in glacial acetic acid in the absence of water. 2,2-2-substituted thiazolidine undergoes ring opening as a result of reaction with 4-methyl-5-hydroxymethylimidazole, and the reaction according to the present invention can be said to be a completely new chemical reaction. It is.
すなわち本発明に係る反応は、加水分解反応で
はない点で非常に特異的であり、前記した２，２
−２置換チアゾリジンからシステアミンを経由し
てイミダゾールと反応させる方法とは根本的に異
なるものである。 In other words, the reaction according to the present invention is very specific in that it is not a hydrolysis reaction, and is
This method is fundamentally different from the method in which a -2-substituted thiazolidine is reacted with imidazole via cysteamine.
本発明方法では、４−メチル−５−ヒドロキシ
メチルイミダゾールは塩の形、例えば鉱酸塩、あ
るいは遊離塩基で、遊離塩基又は例えば鉱酸塩と
いつた塩の形にした２，２−２置換チアゾリジン
と反応させることができる。 In the process of the invention, 4-methyl-5-hydroxymethylimidazole is used in the form of a salt, e.g. a mineral acid salt, or in a free base, with a 2,2-2 substituted Can be reacted with thiazolidine.
２，２−２置換チアゾリジンとしては、２，２
−ジメチルチアゾリジン、２−メチル−２−エチ
ルチアゾリジン、２−メチル−２−イソブチルチ
アゾリジン、スピロシクロヘキサン−１，2′−チ
アゾリジン、２−メチル−２−フエニルチアゾリ
ジンなどが広く使用されるが、特に好ましくは、
２，２−ジメチルチアゾリジン、２−メチル−２
−エチルチアゾリジンである。 As the 2,2-2-substituted thiazolidine, 2,2
-Dimethylthiazolidine, 2-methyl-2-ethylthiazolidine, 2-methyl-2-isobutylthiazolidine, spirocyclohexane-1,2'-thiazolidine, 2-methyl-2-phenylthiazolidine, etc. are widely used, but especially Preferably,
2,2-dimethylthiazolidine, 2-methyl-2
-Ethylthiazolidine.
溶媒としては一般に有機合成において使用され
る酸性溶媒が使用できるが、特に好ましくは、酢
酸、又はハロゲン化水素酸である。 As the solvent, acidic solvents commonly used in organic synthesis can be used, but acetic acid or hydrohalic acid is particularly preferred.
反応時間は、条件によつても異なるが、通常、
１〜10時間であり、反応終了後、減圧濃縮乾固
し、イソプロピルアルコールまたは、アセトンに
分散、冷却、過すると、白色結晶の４−メチル
−５−〔（２−アミノエチル）チオメチル〕イミダ
ゾール・２ハロゲン酸塩が得られる。 The reaction time varies depending on the conditions, but usually
After the reaction is completed, it is concentrated to dryness under reduced pressure, dispersed in isopropyl alcohol or acetone, cooled, and filtered to give white crystals of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole. A dihalogen salt is obtained.
次に本発明の実施例とシメチジン合成の参考例
を示す。 Next, examples of the present invention and reference examples of cimetidine synthesis will be shown.
実施例 １
酢酸25c.c.に４−メチル−５−ヒドロキシメチル
イミダゾール塩酸塩4.5ｇと２，２−ジメチルチ
アゾリジン塩酸塩4.6ｇを加え、還流下２時間反
応させ、減圧下で酢酸を除去した後、イソプロピ
ルアルコール50c.c.を加えて、分散、冷却、過、
乾燥すると、白色結晶の４−メチル−５−〔（２−
アミノエチル）チオメチル〕イミダゾール・２塩
酸塩5.9ｇ（収率81.2％）が得られる。薄層クロ
マトグラフイーとI.Rで標準品と一致した。Example 1 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 4.6 g of 2,2-dimethylthiazolidine hydrochloride were added to 25 c.c. of acetic acid, reacted under reflux for 2 hours, and acetic acid was removed under reduced pressure. After that, add 50 c.c. of isopropyl alcohol, disperse, cool, filter,
When dried, white crystals of 4-methyl-5-[(2-
5.9 g (yield: 81.2%) of (aminoethyl)thiomethyl]imidazole dihydrochloride is obtained. Thin layer chromatography and IR results matched the standard product.
実施例 ２
酢酸25c.c.に４−メチル−５−ヒドロキシメチル
イミダゾール塩酸塩4.5ｇと、２−メチル−２−
エチルチアゾリジン塩酸塩5.0ｇを加え、還流下
２時間反応させ、減圧下で酢酸を除去した後、イ
ソプロピルアルコール50c.c.を加えて、分散、冷
却、過、乾燥すると、白色結晶の４−メチル−
５−〔（２−アミノエチル）チオメチル〕イミダゾ
ール・２塩酸塩5.9ｇ（収率81.2％）が得られる。Example 2 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 2-methyl-2-
Add 5.0 g of ethylthiazolidine hydrochloride, react under reflux for 2 hours, remove acetic acid under reduced pressure, add 50 c.c. of isopropyl alcohol, disperse, cool, filter, and dry. 4-methyl −
5.9 g (yield: 81.2%) of 5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride is obtained.
薄層クロマトグラフイーとI.Rで標準品と一致
した。 Thin layer chromatography and IR results matched the standard product.
実施例 ３
濃塩酸80c.c.に４−メチル−５−ヒドロキシメチ
ルイミダゾール塩酸塩4.5ｇと２−メチル−２−
イソブチルチアゾリジン塩酸塩5.9ｇを加え、還
流下２時間反応させた後、減圧下で十分に水を除
去し、イソプロピルアルコール50c.c.を加え、分
散、冷却、過、乾燥すると、白色結晶の４−メ
チル−５〔（２−アミノエチル）チオメチル〕イミ
ダゾール・２塩酸塩4.7ｇ（収率64.8％）が得ら
れる。Example 3 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 2-methyl-2- in 80 c.c. of concentrated hydrochloric acid
After adding 5.9 g of isobutylthiazolidine hydrochloride and reacting under reflux for 2 hours, water was thoroughly removed under reduced pressure, and 50 c.c. of isopropyl alcohol was added, dispersed, cooled, filtered, and dried to form white crystals. -Methyl-5[(2-aminoethyl)thiomethyl]imidazole dihydrochloride 4.7g (yield 64.8%) is obtained.
薄層クロマトグラフイーとI.Rで標準品と一致
した。 Thin layer chromatography and IR results matched the standard product.
実施例 ４
48％臭化水素酸60c.c.に、４−メチル−５−ヒド
ロキシメチルイミダゾール塩酸塩4.5ｇとスピロ
シクロヘキサン−１，2′−チアゾリジン塩酸塩
5.8ｇを加え、還流下２時間反応させた後、減圧
下で十分に水分を除去し、アセトン50c.c.を加え、
分散、冷却、過、乾燥すると、白色結晶の４−
メチル−５−〔（２−アミノエチル）チオメチル〕
イミダゾール・２塩酸塩5.4ｇ（収率74.4％）が
得られる。薄層クロマトグラフイーとI.Rが標準
品と一致した。Example 4 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and spirocyclohexane-1,2'-thiazolidine hydrochloride in 60 c.c. of 48% hydrobromic acid.
After adding 5.8 g and reacting under reflux for 2 hours, water was thoroughly removed under reduced pressure, and 50 c.c. of acetone was added.
When dispersed, cooled, filtered and dried, white crystals of 4-
Methyl-5-[(2-aminoethyl)thiomethyl]
5.4 g (yield 74.4%) of imidazole dihydrochloride is obtained. Thin layer chromatography and IR were consistent with the standard product.
実施例 ５
濃塩酸80c.c.に、４−メチル−５−ヒドロキシメ
チルイミダゾール塩酸塩4.5ｇと２−メチル−２
−フエニルチアゾリジン5.4ｇを加え、還流下２
時間反応させた後、減圧下で十分に水分を除去
し、アセトン50c.c.を加え、分散、冷却、過、乾
燥すると、白色結晶の４−メチル−５−〔（２−ア
ミノエチル）チオメチル〕イミダゾール・２塩酸
塩4.7ｇ（収率64.8％）が得られる。Example 5 In 80 c.c. of concentrated hydrochloric acid, 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 2-methyl-2
- Add 5.4 g of phenylthiazolidine and reflux for 2 hours.
After reacting for an hour, water was thoroughly removed under reduced pressure, 50 c.c. of acetone was added, dispersed, cooled, filtered, and dried, resulting in white crystals of 4-methyl-5-[(2-aminoethyl)thiomethyl ] 4.7 g (yield 64.8%) of imidazole dihydrochloride is obtained.
薄層クロマトグラフイーとI.Rが標準品と一致
した。 Thin layer chromatography and IR were consistent with the standard product.
実施例 ６
４−メチル−５−〔（２−アミノエチル）チオメ
チル〕イミダゾール
酢酸30c.c.に、２−メチル−２−エチルチアゾリ
ジン塩酸塩4.6ｇを加える。これに、４−メチル
−５−ヒドロキシメチルイミダゾール塩酸塩4.5
ｇを加え、還流下10時間反応させ、減圧下で酢酸
を除去した後、イソプロピルアルコール50c.c.を加
えて分散、冷却、過、乾燥すると、白色結晶の
４−メチル−５−〔（２−アミノエチル）チオメチ
ル〕イミダゾール・２塩酸塩7.0ｇ（収率95.9％）
が得られる。Example 6 4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole To 30 c.c. of acetic acid is added 4.6 g of 2-methyl-2-ethylthiazolidine hydrochloride. To this, 4-methyl-5-hydroxymethylimidazole hydrochloride 4.5
After adding 10 g of 4-methyl-5- -aminoethyl)thiomethyl]imidazole dihydrochloride 7.0g (yield 95.9%)
is obtained.
薄層クロマトグラフイーとI.Rが標準品と一致
した。 Thin layer chromatography and IR were consistent with the standard product.
参考例
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〕−Ｏ−エチ
ルイソ尿素
実施例６で得た４−メチル−５−〔（２−アミノ
エチル）チオメチル〕イミダゾール・２塩酸塩
4.9ｇに水40c.c.、炭酸カリウム2.8ｇ、Ｏ−エチル
−５−メチルシアノチオイミドカルボネート2.9
ｇとエタノール40c.c.の溶液を加え、60℃で２時間
反応させ、減圧下でエタノールを除去し、冷却、
過、乾燥すると、白色結晶の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〕−Ｏ−エチルイソ尿素、4.8ｇ
（収率89.7％）が得られる。Reference example N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-O-ethylisourea 4-Methyl-5-[(2-aminoethyl) obtained in Example 6 Thiomethyl imidazole dihydrochloride
4.9g, 40c.c. of water, 2.8g of potassium carbonate, 2.9g of O-ethyl-5-methylcyanothioimide carbonate
Add a solution of g and 40 c.c. of ethanol, react at 60°C for 2 hours, remove ethanol under reduced pressure, cool,
When filtered and dried, white crystals of N-cyano-
N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-O-ethyl isourea, 4.8 g
(Yield 89.7%) is obtained.
薄層クロマトグラフイーとI.Rが標準品と一致
した。 Thin layer chromatography and IR were consistent with the standard product.
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）
上で得た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〕−Ｏ
−エチルイソ尿素4.0ｇに、エタノール45c.c.、水
45c.c.、氷冷下５℃以下でモノメチルアミン40％水
溶液56c.c.を加え、冷却したままで一夜撹拌し、減
圧濃縮乾固の後、アセトニトリル20c.c.を加えて、
冷却、過、乾燥すると、白色結晶のシメチジ
ン、すなわち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3.0ｇ（収率78.9％）が
得られる。N-cyano-N'-methyl-N''-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (cimetidine) N-cyano-N'-[2-((4 -Methyl-5-imidazolyl)methylthio)ethyl]-O
-4.0 g of ethyl isourea, 45 c.c. of ethanol, and water
45 c.c., add 56 c.c. of a 40% monomethylamine aqueous solution at below 5°C under ice-cooling, stir overnight while cooling, concentrate to dryness under reduced pressure, and then add 20 c.c. of acetonitrile.
Upon cooling, filtering and drying, white crystalline cimetidine, N-cyano-N'-methyl-N''-[2
3.0 g (yield 78.9%) of -((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine is obtained.
薄層クロマトグラフイーとI.Rが標準品と一致
した。 Thin layer chromatography and IR were consistent with the standard product.
Claims (1)
ミダゾールに 式(2) （式中、R1、R2はそれぞれアルキル基、若しく
はフエニル基を表わし、又はR1、R2は一緒にな
つて環を形成する。） で示される２，２−２置換チアゾリジンを反応さ
せることを特徴とする式(3) で示される４−メチル−５−〔（２−アミノエチ
ル）チオメチル〕イミダゾールの製造方法。[Claims] 1 Formula (1) For 4-methyl-5-hydroxymethylimidazole represented by formula (2) (In the formula, R 1 and R 2 each represent an alkyl group or a phenyl group, or R 1 and R 2 are taken together to form a ring.) A 2,2-2-substituted thiazolidine represented by Equation (3) is characterized by A method for producing 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8912880A JPS5714576A (en) | 1980-07-02 | 1980-07-02 | Preparation of imidazole derivative |
| GB8119385A GB2079276B (en) | 1980-07-02 | 1981-06-23 | 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole production |
| DE19813125990 DE3125990A1 (en) | 1980-07-02 | 1981-07-01 | Process for preparing imidazole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8912880A JPS5714576A (en) | 1980-07-02 | 1980-07-02 | Preparation of imidazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5714576A JPS5714576A (en) | 1982-01-25 |
| JPH0113469B2 true JPH0113469B2 (en) | 1989-03-06 |
Family
ID=13962240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8912880A Granted JPS5714576A (en) | 1980-07-02 | 1980-07-02 | Preparation of imidazole derivative |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS5714576A (en) |
| DE (1) | DE3125990A1 (en) |
| GB (1) | GB2079276B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU8361782A (en) * | 1981-05-26 | 1982-12-02 | Bridge Chemicals Ltd. | Preparation of 4-(2-aminoethylthiomethyl)-5-methylimidazole |
| JPS6090857U (en) * | 1983-11-29 | 1985-06-21 | 株式会社ミニパイロ電機 | LED lamp |
| JPS62178237U (en) * | 1986-05-02 | 1987-11-12 | ||
| JPH01272570A (en) * | 1988-04-26 | 1989-10-31 | Nippon Shokubai Kagaku Kogyo Co Ltd | Production of 4-methyl-5-((2-aminoethyl)-thiomethyl)-imidazole |
-
1980
- 1980-07-02 JP JP8912880A patent/JPS5714576A/en active Granted
-
1981
- 1981-06-23 GB GB8119385A patent/GB2079276B/en not_active Expired
- 1981-07-01 DE DE19813125990 patent/DE3125990A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB2079276A (en) | 1982-01-20 |
| JPS5714576A (en) | 1982-01-25 |
| DE3125990A1 (en) | 1982-02-04 |
| GB2079276B (en) | 1984-07-25 |
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