JPH01299274A - Production of 4-methyl-5-((2-aminoethyl)-thiometyl)-imidazole - Google Patents
Production of 4-methyl-5-((2-aminoethyl)-thiometyl)-imidazoleInfo
- Publication number
- JPH01299274A JPH01299274A JP63128193A JP12819388A JPH01299274A JP H01299274 A JPH01299274 A JP H01299274A JP 63128193 A JP63128193 A JP 63128193A JP 12819388 A JP12819388 A JP 12819388A JP H01299274 A JPH01299274 A JP H01299274A
- Authority
- JP
- Japan
- Prior art keywords
- imidazole
- methyl
- methylimidazole
- aminoethyl
- sulfuric acid
- 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
- JEOZNMMOIBLWLV-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethanamine Chemical compound CC=1N=CNC=1CSCCN JEOZNMMOIBLWLV-UHFFFAOYSA-N 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 3
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 abstract description 28
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 18
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 abstract description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 abstract description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 4
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 abstract description 2
- 229960001380 cimetidine Drugs 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 abstract 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 5
- 229960003151 mercaptamine Drugs 0.000 description 5
- AXJZCJSXNZZMDU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol Chemical compound CC=1N=CNC=1CO AXJZCJSXNZZMDU-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- MPGQQQKGAXDBDN-UHFFFAOYSA-N 1,3-thiazolidin-3-ium;chloride Chemical compound Cl.C1CSCN1 MPGQQQKGAXDBDN-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
- QMAYEPIYAFAKEH-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethanamine;sulfuric acid Chemical compound OS(O)(=O)=O.CC=1NC=NC=1CSCCN QMAYEPIYAFAKEH-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は４−メチル−５−［（２−アミノエチル）−チ
オメチル］−イミダゾールを４−メチルイミダゾールよ
り一段で得る新規な製法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel process for producing 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole from 4-methylimidazole in one step.
本発明で得られる４−メチル−５−［（２−アミノエチ
ル）−チオメチル］−イミダゾールはヒスタミンＨ２−
受容体拮抗剤として知られているシメチジンの合成中間
体として重要な用途を有する化合物である。4-Methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole obtained in the present invention is histamine H2-
This compound has important uses as a synthetic intermediate for cimetidine, which is known as a receptor antagonist.
（従来の技術）
従来４−メチル−５−［（２−アミノエチル）−チオメ
チル］−イミダゾールを得る方法としては、
■ ４−メチル−５−ヒドロキシルメチル−イミダゾー
ルを濃塩酸中でシステアミンと反応させる方法（特開昭
５３−１１９８６７号）、および■ 濃塩酸中の４−メ
チルイミダゾールをシステアミン及びホルムアルデヒド
も［（はチアゾリジンと反応させる方法（特開昭５４−
１３２５６８号）等が知られている。(Prior art) Conventional methods for obtaining 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole include: ■ Reacting 4-methyl-5-hydroxylmethyl-imidazole with cysteamine in concentrated hydrochloric acid. method (JP-A No. 53-119867), and (1) method of reacting 4-methylimidazole in concentrated hydrochloric acid with cysteamine and formaldehyde [( is a method of reacting with thiazolidine (JP-A No. 54-1989).
No. 132568), etc. are known.
（発明が解決しようとする課題）
特開昭５３−１１９８６７号の４−メチル−５−ヒドロ
キシルメチル−イミダゾールを濃塩酸中でシステアミン
と反応させる方法の欠点は４−メチル−５−ヒドロキシ
ルメチル−イミダゾールがら出発することである。なぜ
ならば４−メチル−５−ヒドロキシルメチル−イミダゾ
ールは４−メチルイミダゾールを塩酸中でホルムアルデ
ヒドと反応させる方法や、４−メチルイミダゾール−５
−カルボン酸エステルの還元等で得られるが煩雑な手段
を要し収率も低いという欠点を有する。(Problems to be Solved by the Invention) The disadvantage of the method of reacting 4-methyl-5-hydroxylmethyl-imidazole with cysteamine in concentrated hydrochloric acid as disclosed in JP-A-53-119867 is that 4-methyl-5-hydroxylmethyl-imidazole It is to leave with a feeling. This is because 4-methyl-5-hydroxylmethyl-imidazole can be obtained by reacting 4-methylimidazole with formaldehyde in hydrochloric acid, or by reacting 4-methylimidazole-5 with formaldehyde in hydrochloric acid.
- It can be obtained by reduction of carboxylic acid ester, etc., but it has the disadvantage that it requires complicated means and the yield is low.
一方、従来の特開昭５４−１３２５６８号の濃塩酸中の
４−メチルイミダゾールをシステアミン及びホルムアル
デヒドも［（はチアゾリジンと反応させる方法は従来の
特開昭５３−１１９８６７号の４−メチル−５−ヒドロ
キシルメチル−イミダゾールを濃塩酸中でシステアミン
と反応させる方法の改良方法として４−メチルイミダゾ
ールから一段で４−メチル−５−［（２−アミノエチル
）−チオメチル］−イミダゾールを得る方法を開示して
いるが、濃塩酸中で反応するため、反応基質の濃度が低
く、反応速度が低いため生産効率が悪いという欠点を有
する。On the other hand, the conventional method of reacting 4-methylimidazole with cysteamine and formaldehyde in concentrated hydrochloric acid, as disclosed in JP-A-54-132,568, and 4-methyl-5- Discloses a method for obtaining 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole in one step from 4-methylimidazole as an improved method of reacting hydroxylmethyl-imidazole with cysteamine in concentrated hydrochloric acid. However, since the reaction is carried out in concentrated hydrochloric acid, the concentration of the reaction substrate is low and the reaction rate is low, resulting in poor production efficiency.
本発明者は従来の方法の欠点を改良すべく鋭意研究を行
なった結果、４−メチルイミダゾールとチアゾリジンを
硫酸中で反応させることにより短時間の反応で４−メチ
ル−５−［（２−アミノエチル）−チオメチル］−イミ
ダゾールが高収率で得られれることを見い出し本発明に
至った。As a result of intensive research to improve the shortcomings of the conventional methods, the inventors of the present invention discovered that 4-methyl-5-[(2-amino It was discovered that ethyl)-thiomethyl]-imidazole can be obtained in high yield, leading to the present invention.
（課題を解決するための手段）
本発明は４−メチルイミダゾールとチアゾリジンを硫酸
中で反応させることを特徴とする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
法に関するものである。(Means for Solving the Problems) The present invention is characterized in that 4-methylimidazole and thiazolidine are reacted in sulfuric acid.
The present invention relates to a method for producing 2-aminoethyl)-thiomethyl]-imidazole.
４−メチルイミダゾールとチアゾリジンとの反応を実施
する方法としては、４−メチルイミダゾールとチアゾリ
ジンを混合して調製したものを硫酸中で１００〜１８０
℃、好ま［（は１２０〜１５０℃で反応を行なうのがよ
く、反応時間は硫酸の量、濃度および反応温度によって
異なるが通常２〜２０時間である。As a method for carrying out the reaction between 4-methylimidazole and thiazolidine, a mixture of 4-methylimidazole and thiazolidine is mixed and prepared at a concentration of 100 to 180% in sulfuric acid.
The reaction is preferably carried out at 120 to 150°C, and the reaction time varies depending on the amount and concentration of sulfuric acid and the reaction temperature, but is usually 2 to 20 hours.
本発明で使用する硫酸量は４−メチルイミダゾールに対
し２〜８倍モル、経済性および生産性の面より２〜５倍
モルが好ましい。The amount of sulfuric acid used in the present invention is preferably 2 to 8 times mole relative to 4-methylimidazole, and preferably 2 to 5 times mole from the viewpoint of economy and productivity.
本発明により生成する４−メチル−５−［（２−アミノ
エチル）−チオメチル］−イミダゾールはｆｉ＆酸塩と
して得られる。生成物の単離は過剰の酸を中和した後、
減圧下で濃縮乾固し、エタノール等の低級アルコールや
酢酸等で再結晶することにより行なわれる。また１−１
０パノール、２−ブタノール等のアルコールを用いて濃
縮乾固物を熱時洗浄することによっても得られる。遊離
塩基として単離する場合はたとえばアルカリにて中和後
溶剤抽出することにより容易に得ることができる。The 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole produced according to the invention is obtained as the fi&acid salt. The product is isolated after neutralizing the excess acid.
This is done by concentrating to dryness under reduced pressure and recrystallizing from a lower alcohol such as ethanol or acetic acid. Also 1-1
It can also be obtained by washing the concentrated and dried product with alcohol such as 0-panol and 2-butanol under hot conditions. When isolated as a free base, it can be easily obtained, for example, by neutralizing with an alkali and then extracting with a solvent.
（実 施 例）
次に、実施例により本発明を具体的に説明するが、これ
らは単なる例示であり、本発明がこれら実施例に限定さ
れるものではない。(Examples) Next, the present invention will be specifically explained with reference to Examples, but these are merely illustrative and the present invention is not limited to these Examples.
実施例−１
８０重量％硫酸水溶液４３．０ｇに、４−メチルイミダ
ゾール８．２ｇ、チアゾリジン８．９ｇを３０℃以下に
冷却しながらゆっくり溶解した。Example-1 8.2 g of 4-methylimidazole and 8.9 g of thiazolidine were slowly dissolved in 43.0 g of an 80% by weight aqueous sulfuric acid solution while cooling to 30° C. or lower.
この混合物を閉鎖されたグラスライニング製オートクレ
ーブ中で１４０℃で７時間かく拌しながら加熱した０反
応液に２０重量％水酸化ナトリウム水溶液１００．０ｇ
、３０℃以下に保ちながらゆっくり加えた０次に減圧下
で濃縮乾固した。Ｊ！！渣にエタノール６５．０ｇを加
え、１時間加熱環流した。その後残渣を熱時ろ過した。This mixture was heated at 140°C for 7 hours with stirring in a closed glass-lined autoclave.To the reaction solution, 100.0g of a 20% by weight sodium hydroxide aqueous solution was added.
The mixture was slowly added to the solution while keeping the temperature below 30°C, and then concentrated to dryness under reduced pressure. J! ! 65.0 g of ethanol was added to the residue, and the mixture was heated under reflux for 1 hour. The residue was then filtered hot.
ろ液をさらに冷却し、析出した沈殿をろ過し、減圧下で
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］−イミダゾール硫酸塩２２．１
ｇ（収率８２．０％）を得た。The filtrate was further cooled and the precipitate was filtered and dried under reduced pressure to give white crystals of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole sulfate 22.1
g (yield 82.0%) was obtained.
実施例−２
８０重量％硫酸水溶液３０．６ｇに、４−メチルイーミ
ダゾール８．２ｇ、チアゾリジン塩酸塩１２．５ｇを３
０℃以下に冷却しながらゆっくり溶解した。この混合物
を閉鎖されたグラスライニング製オートクレーブ中、１
２０℃で１０時間かく拌しながら加熱した７反応液に５
０重量％水酸化ナトリウム水溶液５０．０ｇを３０℃以
下に冷却しながらゆっくり加えた。よく撹拌後、３０分
間靜１後、上層のみを取り出し、その油状物質を３６重
量％塩化水素水溶液２０．３ｇに溶解させた。Example-2 8.2 g of 4-methylimidazole and 12.5 g of thiazolidine hydrochloride were added to 30.6 g of an 80% by weight aqueous sulfuric acid solution.
It was slowly dissolved while cooling to below 0°C. This mixture was placed in a closed glass-lined autoclave for 1 hour.
Add 5 to the reaction solution heated at 20°C for 10 hours with stirring.
50.0 g of 0% by weight aqueous sodium hydroxide solution was slowly added while cooling to 30° C. or below. After stirring well and leaving the mixture for 30 minutes, only the upper layer was taken out, and the oily substance was dissolved in 20.3 g of a 36% by weight aqueous hydrogen chloride solution.
濃縮乾固後、残渣をエタノール６５．０ｇに完全に溶解
させた後、冷却し、析出した沈殿をろ過し、減圧下で乾
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］−イミダゾール塩酸塩２０．５ｇ
（収率８４．１％）を得た。After concentration to dryness, the residue was completely dissolved in 65.0 g of ethanol, cooled, and the deposited precipitate was filtered and dried under reduced pressure to give white crystals of 4-methyl-5-[(2-aminoethyl). -Thiomethyl]-imidazole hydrochloride 20.5g
(yield 84.1%).
（発明の効果）
本発明は、４−メチルイミダゾールとチアゾリジンを硫
酸中で反応させることにより４−メチル−５−［（２−
アミノエチル）−チオメチル］−イミダゾールを高収率
、高純度で容易に得られる工業的に有利な方法である。(Effect of the invention) The present invention provides 4-methyl-5-[(2-
This is an industrially advantageous method for easily obtaining aminoethyl)-thiomethyl]-imidazole in high yield and purity.
Claims (1)
で反応させることを特徴とする４−メチル−５−［（２
−アミノエチル）−チオメチル］−イミダゾールの製法
。(1) 4-methyl-5-[(2
-aminoethyl)-thiomethyl]-imidazole.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63101243A JPH01272570A (en) | 1988-04-26 | 1988-04-26 | Production of 4-methyl-5-((2-aminoethyl)-thiomethyl)-imidazole |
| JP63128193A JPH01299274A (en) | 1988-05-27 | 1988-05-27 | Production of 4-methyl-5-((2-aminoethyl)-thiometyl)-imidazole |
| US07/342,798 US4916233A (en) | 1988-04-26 | 1989-04-25 | Method for production of 4-methyl-5-(2-aminoethyl)-thiomethyl)-imidazole |
| KR1019890005523A KR900016142A (en) | 1988-04-26 | 1989-04-26 | Preparation of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole |
| EP19890304158 EP0339970A3 (en) | 1988-04-26 | 1989-04-26 | Method for production of 4-methyl-5-((2-aminoethyl)-thiomethyl)-imidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63128193A JPH01299274A (en) | 1988-05-27 | 1988-05-27 | Production of 4-methyl-5-((2-aminoethyl)-thiometyl)-imidazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01299274A true JPH01299274A (en) | 1989-12-04 |
Family
ID=14978754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63128193A Pending JPH01299274A (en) | 1988-04-26 | 1988-05-27 | Production of 4-methyl-5-((2-aminoethyl)-thiometyl)-imidazole |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01299274A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1646054A1 (en) * | 2003-07-11 | 2006-04-12 | Ube Industries, Ltd. | Acid-base mixture and ion conductor composed of such mixture |
-
1988
- 1988-05-27 JP JP63128193A patent/JPH01299274A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1646054A1 (en) * | 2003-07-11 | 2006-04-12 | Ube Industries, Ltd. | Acid-base mixture and ion conductor composed of such mixture |
| EP1646054A4 (en) * | 2003-07-11 | 2010-05-19 | Ube Industries | Acid-base mixture and ion conductor composed of such mixture |
| US8308970B2 (en) | 2003-07-11 | 2012-11-13 | Ube Industries, Ltd. | Acid-base mixture and ion conductor comprising the same |
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