JPH0717614B2 - Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole - Google Patents
Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazoleInfo
- Publication number
- JPH0717614B2 JPH0717614B2 JP63243800A JP24380088A JPH0717614B2 JP H0717614 B2 JPH0717614 B2 JP H0717614B2 JP 63243800 A JP63243800 A JP 63243800A JP 24380088 A JP24380088 A JP 24380088A JP H0717614 B2 JPH0717614 B2 JP H0717614B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- thiomethyl
- imidazole
- aminoethyl
- reaction
- 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 - Lifetime
Links
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 238000006243 chemical reaction Methods 0.000 claims description 52
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 50
- 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 23
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 12
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 11
- 239000011707 mineral Substances 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 238000000909 electrodialysis Methods 0.000 claims description 6
- 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 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 21
- 239000002994 raw material Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 239000012528 membrane Substances 0.000 description 6
- VFWUYASTZCOUKN-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethanamine;dihydrochloride Chemical compound Cl.Cl.CC=1N=CNC=1CSCCN VFWUYASTZCOUKN-UHFFFAOYSA-N 0.000 description 5
- RYKANBBWRLXVDN-UHFFFAOYSA-N 5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.CC1=CNC=N1 RYKANBBWRLXVDN-UHFFFAOYSA-N 0.000 description 5
- 238000005341 cation exchange Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- MPGQQQKGAXDBDN-UHFFFAOYSA-N 1,3-thiazolidin-3-ium;chloride Chemical compound Cl.C1CSCN1 MPGQQQKGAXDBDN-UHFFFAOYSA-N 0.000 description 3
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 3
- 239000003011 anion exchange membrane Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000003014 ion exchange membrane Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- AXJZCJSXNZZMDU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol Chemical compound CC=1N=CNC=1CO AXJZCJSXNZZMDU-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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- -1 [(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride Chemical compound 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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］−イミダゾールを製造する新規な製法に関す
る。TECHNICAL FIELD The present invention relates to a novel process for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole.
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。The 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole obtained in the present invention is a compound having an important use as a synthetic intermediate of cimetidine known as a histamine H 2 -receptor antagonist. is there.
（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たとえば、特開
昭54-132568号明細書に、過剰の濃塩酸中130℃の反応温
度、10時間の反応時間で４−メチルイミダゾールとチア
ゾリジンを反応させた後、減圧下で塩酸を留去した後、
アルコール、氷酢酸による再結晶または洗浄により、４
−メチル−５−［（２−アミノエチル）−チオメチル］
−イミダゾールを収率68％で得ている。(Prior Art) As a conventional method for obtaining 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole, for example, JP-A-54-132568 discloses a reaction in excess concentrated hydrochloric acid at 130 ° C. After reacting 4-methylimidazole and thiazolidine at a temperature of 10 hours for reaction, hydrochloric acid was distilled off under reduced pressure,
4 by recrystallization or washing with alcohol, glacial acetic acid
-Methyl-5-[(2-aminoethyl) -thiomethyl]
-Imidazole is obtained with a yield of 68%.
（発明が解決しようとする課題） 前記従来の過剰の濃塩酸中、４−メチルイミダゾールと
チアゾリジンを反応させる方法では目的物である４−メ
チル−５−ヒドロキシルメチル−イミダゾールの逐次反
応が進行し、収率が低いこと、また生成物の４−メチル
−５−［（２−アミノエチル）−チオメチル］−イミダ
ゾールを含む反応液中には、４−メチルイミダゾールと
チアゾリジン、塩酸等の未反応原料の他に逐次反応と考
えられる反応による副成物を含むため、高品質の生成物
を単離しょうとするとき精製効率が低いと共に、未反応
原料の再使用が実質上不可能であるという欠点がある。(Problems to be solved by the invention) In the conventional excess concentrated hydrochloric acid, in the method of reacting 4-methylimidazole and thiazolidine, the sequential reaction of 4-methyl-5-hydroxylmethyl-imidazole, which is the target, proceeds, The yield is low, and in the reaction solution containing the product 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole, 4-methylimidazole and thiazolidine, hydrochloric acid and other unreacted raw materials Since it also contains by-products from reactions that are considered to be sequential reactions, the purification efficiency is low when trying to isolate high-quality products, and the disadvantages that reuse of unreacted raw materials is virtually impossible is there.
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の
鉱酸中での反応を詳しく解析した結果、反応系内の４−
メチル−５−［（２−アミノエチル）−チオメチル］−
イミダゾールのモル濃度が４−メチルイミダゾールと４
−メチル−５−［（２−アミノエチル）−チオメチル］
−イミダゾールを合せたモル数に対し、70モル％に達す
るまで、即ち４−メチルイミダゾールの転化率が70モル
％に達するまでは生成物の４−メチル−５−［（２−ア
ミノエチル）−チオメチル］−イミダゾールの選択率は
ほぼ定量的であるが、より転化率を上げると生成物の４
−メチル−５−［（２−アミノエチル）−チオメチル］
−イミダゾールの逐次反応と考えられる反応が進行し、
選択率が低下することを見い出した。As a result of intensive studies to improve the drawbacks of the conventional method, the present inventor analyzed in detail the reaction of 4-methylimidazole and thiazolidine in a mineral acid, and as a result,
Methyl-5-[(2-aminoethyl) -thiomethyl]-
The molar concentration of imidazole is 4-methylimidazole and 4
-Methyl-5-[(2-aminoethyl) -thiomethyl]
The product 4-methyl-5-[(2-aminoethyl) -up to 70 mol%, that is, until the conversion of 4-methylimidazole reaches 70 mol%, based on the combined number of moles of imidazole. The selectivity of thiomethyl] -imidazole is almost quantitative, but the higher the conversion, the more
-Methyl-5-[(2-aminoethyl) -thiomethyl]
-A reaction considered to be a sequential reaction of imidazole proceeds,
It has been found that the selectivity decreases.
（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鉱酸
中の反応系で反応させ、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に
際し、反応系内の４−メチル−５−［（２−アミノエチ
ル）−チオメチル］−イミダゾールのモル濃度が４−メ
チルイミダゾールと４−メチル−５−［（２−アミノエ
チル）−チオメチル］−イミダゾールを合せたモル数に
対し、70モル％以下に保ちながら反応液を反応系外へ抜
き出し、反応液から４−メチル−５−［（２−アミノエ
チル）−チオメチル］−イミダゾールを含む液を分離
し、残部は反応系へ再循環して用い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) In the present invention, 4-methylimidazole and thiazolidine are reacted in a reaction system in a mineral acid to produce 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole. In this case, the molar concentration of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole in the reaction system was 4-methylimidazole and 4-methyl-5-[(2-aminoethyl) -thiomethyl]-. The reaction solution was withdrawn to the outside of the reaction system while keeping it at 70 mol% or less based on the total number of moles of imidazole combined, and a solution containing 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole was removed from the reaction solution. The present invention relates to a process for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole, which is characterized in that it is separated and the rest is recycled to the reaction system for use.
本発明において、反応系内の４−メチル−５−［（２−
アミノエチル）−チオメチル］−イミダゾールのモル濃
度が４−メチルイミダゾールと４−メチル−５−［（２
−アミノエチル）−チオメチル］−イミダゾールを合せ
たモル数に対し、70モル％以下、好ましくは60〜40モル
％に保つ意味は実質的に逐次反応による副生物を生成さ
せないことにありプロセス上特段の意味を有するもので
ある。またこの反応系をこの条件に保つには反応器内で
の反応温度および反応液の滞留時間の制御により行うこ
とができる。またバッチ反応の場合は反応の終了を意味
する。In the present invention, 4-methyl-5-[(2-
Aminoethyl) -thiomethyl] -imidazole has a molar concentration of 4-methylimidazole and 4-methyl-5-[(2
-Aminoethyl) -thiomethyl] -imidazole based on the total number of moles combined is kept at 70 mol% or less, preferably 60 to 40 mol% because substantially no by-products are produced by the sequential reaction. Has the meaning of. Further, this reaction system can be maintained under this condition by controlling the reaction temperature and the residence time of the reaction liquid in the reactor. In the case of a batch reaction, it means the end of the reaction.
本発明の方法で用いられる４−メチルイミダゾールは遊
離塩基または塩酸、臭化水素酸、硫酸、リン酸等の鉱酸
で中和した塩の状態で用いられる。4-Methylimidazole used in the method of the present invention is used in the form of a salt neutralized with a free base or a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
本発明の方法で用いられるチアゾリジンは遊離塩基また
は鉱酸塩として用いられる。The thiazolidine used in the method of the present invention is used as a free base or a mineral acid salt.
本発明の方法で用いられる鉱酸としては塩酸、臭化水素
酸などのハロゲン化水素酸や硫酸、リン酸等が使用でき
る。As the mineral acid used in the method of the present invention, hydrohalic acid such as hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid and the like can be used.
また原料の４−メチルイミダゾールとチアゾリジンのモ
ル比は0.9〜1.1であり、好ましくは等モルである。The molar ratio of the starting materials, 4-methylimidazole and thiazolidine, is 0.9 to 1.1, preferably equimolar.
原料の４−メチルイミダゾールに対して鉱酸は２〜８倍
モル、経済性および生産性の面からは２〜５倍モルの使
用量が好ましい。It is preferable to use the mineral acid in an amount of 2 to 8 times by mole, and 2 to 5 times by mole in terms of economy and productivity, with respect to 4-methylimidazole as a raw material.
本発明の４−メチルイミダゾールと、チアゾリジンを鉱
酸中の反応系で反応を実施する好ましい方法としては、
４−メチルイミダゾール塩酸塩水溶液とチアゾリジン塩
酸塩水溶液を鉱酸中に連続的に供給し、100〜180℃、好
ましくは120〜150℃の温度で反応を行なうのがよい。反
応液の滞留時間は鉱酸の量、濃度および反応温度により
異なるが通常30分〜10時間である。As a preferred method for carrying out the reaction of 4-methylimidazole of the present invention and thiazolidine in a reaction system in a mineral acid,
It is preferred that the 4-methylimidazole hydrochloride aqueous solution and the thiazolidine hydrochloride aqueous solution be continuously fed into the mineral acid to carry out the reaction at a temperature of 100 to 180 ° C, preferably 120 to 150 ° C. The residence time of the reaction solution varies depending on the amount and concentration of the mineral acid and the reaction temperature, but is usually 30 minutes to 10 hours.
本発明で反応系外へ抜き出した反応液から生成物である
４−メチル−５−［（２−アミノエチル）−チオメチ
ル］−イミダゾールと未反応原料を分離する方法として
はカラム分離法や電気透析法が挙げられ、特に電気透析
法が好ましい。The method of separating 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole which is a product and unreacted raw material from the reaction liquid extracted from the reaction system in the present invention is a column separation method or electrodialysis. Method, and electrodialysis method is particularly preferable.
本発明で用いられる電気透析装置は通常用いられるもの
で陽イオン交換膜と陰イオン交換膜を交互に多数配列
し、両端に一対の電極を配置したものである。陽極側に
陰イオン交換膜、陰極側に陽イオン交換膜の室では電離
した陽イオンが陰極に向って移動し、陽イオン交換膜を
通過し、隣室に移り陰イオン交換膜で透過を阻止され
る。この際適当な交換膜たとえばAC-110（旭化成（株）
製）などを用いることにより生成物より分子量の小さな
原料は陽イオン交換膜を透過し、分子量の大きな生成物
である４−メチル−５−［（２−アミノエチル）−チオ
メチル］−イミダゾール透過を阻止され分離が行なわれ
る。The electrodialyzer used in the present invention is a commonly used one, in which a large number of cation exchange membranes and anion exchange membranes are alternately arranged, and a pair of electrodes is arranged at both ends. In the chamber with the anion exchange membrane on the anode side and the cation exchange membrane on the cathode side, ionized cations move toward the cathode, pass through the cation exchange membrane, move to the adjacent chamber, and are blocked from permeation by the anion exchange membrane. It At this time, a suitable exchange membrane such as AC-110 (Asahi Kasei Co., Ltd.)
A raw material having a smaller molecular weight than the product permeates through the cation exchange membrane by using such a product, and permeation of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole, which is a product with a large molecular weight, through the cation exchange membrane. Blocked and separated.
生成物４−メチル−５−［（２−アミノエチル）−チオ
メチル］−イミダゾールを含む内部液はそのまま次工程
に使用される。また必要なら内部液を濃縮後１−プロパ
ノール等の貧溶媒中で晶析することにより結晶として得
ることができる。The internal liquid containing the product 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole is directly used in the next step. If necessary, the internal solution may be concentrated and then crystallized in a poor solvent such as 1-propanol to obtain crystals.
原料を含む外部液はそのまま又は適当な濃度に濃縮また
は希釈後反応系へリサイクルすることができる。The external liquid containing the raw materials can be recycled to the reaction system as it is or after being concentrated or diluted to an appropriate concentration.
（作用） 本発明において、反応系内の４−メチル−５−［（２−
アミノエチル）−チオメチル］−イミダゾールのモル濃
度が４−メチルイミダゾールと４−メチル−５−［（２
−アミノエチル）−チオメチル］−イミダゾールを合せ
たモル数に対し、70モル％以下、好ましくは60〜40モル
％に保ちながら反応液を反応系外へ抜き出すことは実質
的に逐次反応による副成物を生成させないことにあり、
反応生成物である４−メチル−５−［（２−アミノエチ
ル）−チオメチル］−イミダゾールが高品質で得られ
る。また該反応液から未反応原料を分離し、反応系へリ
サイクルすることにより、反応原料をほぼ定量的に反応
生成物に転化できる作用を有する。(Operation) In the present invention, 4-methyl-5-[(2-
Aminoethyl) -thiomethyl] -imidazole has a molar concentration of 4-methylimidazole and 4-methyl-5-[(2
-Aminoethyl) -thiomethyl] -imidazole based on the total number of moles combined, the reaction liquid is extracted from the reaction system while maintaining the amount at 70 mol% or less, preferably 60 to 40 mol%. Not to create things,
The reaction product 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole is obtained in high quality. Further, by separating the unreacted raw material from the reaction liquid and recycling it to the reaction system, the reaction raw material can be converted almost quantitatively into a reaction product.
（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 described by way of examples, but these are merely examples and the present invention is not limited to these examples.
実施例−１ 36重量％塩酸811gに４−メチルイミダゾール164g、チア
ゾリジン塩酸塩250gを溶解した。この混合物をオートク
レーブ中、140℃にて３時間加熱かく拌した。得られた
反応液1225g中には４−メチル−５−［（２−アミノエ
チル）−チオメチル］−イミダゾール・二塩酸塩244g、
４−メチルイミダゾール塩酸塩118gの他原料および塩酸
を含み、４−メチルイミダゾールの転化率を50％であっ
た。Example-1 164 g of 4-methylimidazole and 250 g of thiazolidine hydrochloride were dissolved in 811 g of 36 wt% hydrochloric acid. The mixture was heated and stirred at 140 ° C. for 3 hours in an autoclave. In the obtained reaction solution 1225 g, 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride 244 g,
118 g of 4-methylimidazole hydrochloride was added as a starting material and hydrochloric acid was included, and the conversion rate of 4-methylimidazole was 50%.
つぎにこの反応液を内部液、水1000gを外部液、電極液
として５％硫酸ナトリウム水溶液を用い、イオン交換膜
［AC-110（旭化成（株）製］を用いた電気透析装置にか
けた。電気透析の途中で外部液を水1000gに交換しさら
に電気透析を行なった。Next, this reaction solution was applied to an electrodialyzer using an ion exchange membrane [AC-110 (manufactured by Asahi Kasei Corp.)] using an inner solution, 1000 g of water as an outer solution, and a 5% sodium sulfate aqueous solution as an electrode solution. During the dialysis, the external solution was exchanged with 1000 g of water and further electrodialysis was performed.
最終的に内部液として４−メチル−５−［（２−アミノ
エチル）−チオメチル］−イミダゾール・二塩酸塩172g
および水410gよりなる液582gを得た。また外部液として
４−メチル−５−［（２−アミノエチル）−チオメチ
ル］−イミダゾール・二塩酸塩72g、４−メチルイミダ
ゾール118gの他原料および塩酸を含む液2634gを得た。Finally, 172 g of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride as an internal solution
582 g of a liquid consisting of and 410 g of water was obtained. As an external liquid, 72 g of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride, 118 g of 4-methylimidazole and 2634 g of a liquid containing hydrochloric acid and other raw materials were obtained.
得られた内部液は減圧下濃縮後、１−プロピルアルコー
ル中に投入し、析出した結晶をろ過、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・二塩酸塩162gが得られた。The obtained internal liquid was concentrated under reduced pressure, put into 1-propyl alcohol, and the precipitated crystals were filtered and dried to give white crystals of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole. 162 g of the dihydrochloride were obtained.
実施例−２ 実施例−１で得られた外部液を減圧下1010gまで濃縮し
た。この濃縮液に４−メチルイミダゾール57g、チアゾ
リジン・塩酸塩87gおよび36重量％塩酸71gをを加えオー
トクレーブ中、140℃、２時間反応させた。得られた反
応液中には４−メチル−５−［（２−アミノエチル）−
チオメチル］−イミダゾール・二塩酸塩243g、４−メチ
ルイミダゾール・塩酸塩119gの他原料および塩酸を含
み、１回目の反応液と同組成であった。この反応液を実
施例−１と同様に電気透析することにより４−メチル−
５−［（２−アミノエチル）−チオメチル］−イミダゾ
ール・二塩酸塩170gおよび水405gよりなる内部液が得ら
れた。Example-2 The external liquid obtained in Example-1 was concentrated under reduced pressure to 1010 g. 57 g of 4-methylimidazole, 87 g of thiazolidine hydrochloride and 71 g of 36% by weight hydrochloric acid were added to this concentrated liquid, and the mixture was reacted in an autoclave at 140 ° C. for 2 hours. 4-Methyl-5-[(2-aminoethyl)-
The composition was the same as that of the first reaction liquid, containing 243 g of thiomethyl] -imidazole dihydrochloride, 119 g of 4-methylimidazole hydrochloride, and other raw materials and hydrochloric acid. By electrodialyzing this reaction solution in the same manner as in Example-1, 4-methyl-
An internal solution consisting of 170 g of 5-[(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride and 405 g of water was obtained.
外部液は減圧下濃縮後次反応に循環した。The external liquid was concentrated under reduced pressure and then circulated to the next reaction.
実施例−３ 図−１において、導管１より6.75g/minで38重量％の塩
酸、導管２より5.75g/minで４−メチルイミダゾール、
導管３より8.8g/minでチアゾリジン・塩酸塩をそれぞれ
混合槽４に供給した。混合槽４より導管５を通して21.3
g/minで140℃に保持された反応器６へ供給した。Example-3 In FIG. 1, 38 wt% hydrochloric acid at 6.75 g / min from conduit 1, 4-methylimidazole at 5.75 g / min from conduit 2,
Thiazolidine / hydrochloride was supplied to the mixing tank 4 from the conduit 3 at 8.8 g / min. 21.3 from mixing tank 4 through conduit 5
It was fed to the reactor 6 kept at 140 ° C. at g / min.
反応器６中の滞留時間は2.5時間であった。反応器６よ
り導管７を通して162g/minで抜き出した。この反応液に
は、４−メチル−５−［（２−アミノエチル）−チオメ
チル］−イミダゾール・二塩酸塩15.1重量％、４−メチ
ルイミダゾール・塩酸塩7.3重量％の他原料および塩酸
を含み、４−メチルイミダゾールの転化率50％に相当し
た。この反応液を冷却器８で50℃以下まで冷却し、導管
９を通して電極液として５％硫酸ナトリウム水溶液を用
いてイオン交換膜［AC-110（旭化成（株）製］とした電
気透析装置10の内部液として供給した。導管11を通して
水272g/minを電気透析装置10の外部液として供給した。
導管12から98g/minで、４−メチル−５−［（２−アミ
ノエチル）−チオメチル］−イミダゾール・二塩酸塩1
7.44重量％の濃度の液を得た。The residence time in reactor 6 was 2.5 hours. It was withdrawn from the reactor 6 through the conduit 7 at 162 g / min. This reaction liquid contains 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride 15.1% by weight, 4-methylimidazole hydrochloride 7.3% by weight, and other raw materials and hydrochloric acid. The conversion rate of 4-methylimidazole was equivalent to 50%. This reaction solution was cooled to 50 ° C. or lower by a cooler 8, and a 5% sodium sulfate aqueous solution was used as an electrode solution through a conduit 9 to prepare an ion exchange membrane [AC-110 (manufactured by Asahi Kasei Corporation)] of an electrodialyzer 10. It was supplied as an internal liquid, and 272 g / min of water was supplied as an external liquid of the electrodialyzer 10 through the conduit 11.
4-Methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride 1 via conduit 12 at 98 g / min
A solution with a concentration of 7.44% by weight was obtained.
この液582gを濃縮し、１−プロピルアルコール1000g中
に投入し、析出した沈澱をろ過し、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・二塩酸塩162gを得た。582 g of this liquid was concentrated, poured into 1000 g of 1-propyl alcohol, and the deposited precipitate was filtered and dried under reduced pressure to give 4-methyl-5-[(2-aminoethyl)-as white crystals.
162 g of thiomethyl] -imidazole dihydrochloride were obtained.
電気透析装置10で得た外部液は、導管13より336.3g/min
で抜き出し、濃縮器14へ供給し、濃縮し、４−メチルイ
ミダゾール・塩酸塩8.4重量％、４−メチル−５−
［（２−アミノエチル）−チオメチル］−イミダゾール
・二塩酸塩5.2重量％の他原料および塩酸を含む液に調
整し、導管15を通して141g/hで反応器５へ戻した。The external liquid obtained in the electrodialysis device 10 was 336.3 g / min from the conduit 13.
It is taken out with, supplied to the concentrator 14, concentrated, and 4-methylimidazole hydrochloride 8.4% by weight, 4-methyl-5-
A liquid containing [(2-aminoethyl) -thiomethyl] -imidazole dihydrochloride (5.2 wt% other raw material) and hydrochloric acid was prepared, and the solution was returned to the reactor 5 at 141 g / h through a conduit 15.
（発明の効果） 本発明の４−メチルイミダゾールとチアゾリジンを鉱酸
中の反応系で反応させ、４−メチル−５−［（２−アミ
ノエチル）−チオメチル］−イミダゾール製造するに際
し、反応系内の４−メチル−５−［（２−アミノエチ
ル）−チオメチル］−イミダゾールのモル濃度が４−メ
チルイミダゾールと４−メチル−５−［（２−アミノエ
チル）−チオメチル］−イミダゾールを合せたモル数に
対し、70モル％以下に保ちながら反応液を反応系外へ抜
き出すことは実質的に逐次反応による副成物を生成させ
ないことにあり、反応生成物である４−メチルイミダゾ
ールと４−メチル−５−［（２−アミノエチル）−チオ
メチル］−イミダゾールを高品質で容易に得られる。ま
た該反応液から未反応原料を分離し、反応系へリサイク
ルすることにより未反応原料をほぼ定量的に反応生成物
に転化できる。未本発明は反応、分離、未反応原料の回
収再使用を含むプロセスを連続的に行なう方法を提供す
るものであり工業的に有利な方法である。(Effect of the invention) When 4-methylimidazole of the present invention and thiazolidine are reacted in a reaction system in a mineral acid to prepare 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole, the reaction system Of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole having a molar concentration of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole are combined. Withdrawing the reaction solution out of the reaction system while keeping it at 70 mol% or less with respect to the number means that by-products are not substantially produced by the sequential reaction, and the reaction products 4-methylimidazole and 4-methyl High quality and easy to obtain -5-[(2-aminoethyl) -thiomethyl] -imidazole. Further, by separating the unreacted raw material from the reaction solution and recycling it to the reaction system, the unreacted raw material can be almost quantitatively converted into a reaction product. The present invention provides a method for continuously carrying out a process including reaction, separation and recovery / reuse of unreacted raw materials, and is an industrially advantageous method.
図−１は本発明の一実施例を示す工程図である。 4:混合槽 6:反応器 8:冷却器 10:電気透析装置 14:濃縮器 FIG. 1 is a process chart showing an embodiment of the present invention. 4: Mixing tank 6: Reactor 8: Cooler 10: Electrodialysis device 14: Concentrator
フロントページの続き (56)参考文献 特開 昭54−132568（ＪＰ，Ａ) Ｄ．Ｇ．ＪＯＮＥＳ編 向坊隆監訳 現 代化学シリーズ45「化学と化学工業−基礎 研究とプロセスの開発−」（1970年６月１ 日発行）東京化学同人Ｐ．110−117Continuation of front page (56) References JP-A-54-132568 (JP, A) D. G. JONES Translated by Takashi Mukobo Current chemistry series 45 "Chemistry and chemical industry-Basic research and process development-" (Published June 1, 1970) Tokyo Kagaku Dojin P. 110-117
Claims (2)
鉱酸中の反応系で反応させ、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
るに際し、反応系内の４−メチル−５−［（２−アミノ
エチル）−チオメチル］−イミダゾールのモル濃度が４
−メチルイミダゾールと４−メチル−５−［（２−アミ
ノエチル）−チオメチル］−イミダゾールを合せたモル
数に対し、70モル％以下に保ちながら反応液を反応系外
へ抜き出し、反応液から４−メチル−５−［（２−アミ
ノエチル）−チオメチル］−イミダゾールを含む液を分
離し、残部は反応系へ再循環して用いることを特徴とす
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-Methylimidazole and thiazolidine are reacted in a reaction system in a mineral acid to give 4-methyl-5-[(2-
When producing aminoethyl) -thiomethyl] -imidazole, the molar concentration of 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole in the reaction system was 4
-Methylimidazole and 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole are combined and the reaction solution is withdrawn to the outside of the reaction system while maintaining the amount at 70 mol% or less. A liquid containing -methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole is separated, and the rest is recycled to the reaction system for use. 4-methyl-5-[(2-amino Method for producing ethyl) -thiomethyl] -imidazole.
ノエチル）−チオメチル］−イミダゾールを含む液を分
離する方法が電気透析法である請求項１記載の方法。2. The method according to claim 1, wherein the method of separating the liquid containing 4-methyl-5-[(2-aminoethyl) -thiomethyl] -imidazole from the reaction liquid is electrodialysis.
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 |
| JP63243800A JPH0717614B2 (en) | 1988-05-31 | 1988-09-30 | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-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 (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13149788 | 1988-05-31 | ||
| JP63-131497 | 1988-05-31 | ||
| JP63243800A JPH0717614B2 (en) | 1988-05-31 | 1988-09-30 | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0249773A JPH0249773A (en) | 1990-02-20 |
| JPH0717614B2 true JPH0717614B2 (en) | 1995-03-01 |
Family
ID=26466319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63243800A Expired - Lifetime JPH0717614B2 (en) | 1988-04-26 | 1988-09-30 | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0717614B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0768222B2 (en) * | 1988-06-01 | 1995-07-26 | 株式会社日本触媒 | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole |
-
1988
- 1988-09-30 JP JP63243800A patent/JPH0717614B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| Ｄ．Ｇ．ＪＯＮＥＳ編向坊隆監訳現代化学シリーズ４５「化学と化学工業−基礎研究とプロセスの開発−」（１９７０年６月１日発行）東京化学同人Ｐ．１１０−１１７ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0249773A (en) | 1990-02-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4916233A (en) | Method for production of 4-methyl-5-(2-aminoethyl)-thiomethyl)-imidazole | |
| JPS6212729A (en) | Production of isopropyl alcohol | |
| JP2503056B2 (en) | Method for producing 1,6-di (Nup3) -cyano-Nup1) -guanidino) hexane | |
| CN113227058A (en) | Improved process for preparing 4, 6-dihydroxypyrimidine | |
| US5258550A (en) | Process for preparing glycine | |
| JPH0717614B2 (en) | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole | |
| JPH0768222B2 (en) | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole | |
| JPH04334359A (en) | Production of carbodihydrazide | |
| JPH0717613B2 (en) | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole | |
| JPH01157938A (en) | Production of diemthylaminoethanol | |
| JPH0244472B2 (en) | ||
| JPH0597782A (en) | Production of bevantolol hydrochloride | |
| JPH023676A (en) | Production of aminoalkylthiol sulfate | |
| JP4024882B2 (en) | Method for producing tertiary butyl hydrazine / hydrohalide | |
| JPH04145040A (en) | Production of dipentaerythritol | |
| JPH0548229B2 (en) | ||
| JPS6127979A (en) | Preparation of hydroxyflavan compound | |
| JPH04312557A (en) | Method of manufacturing dialkylaminopropanediol | |
| JPH01149771A (en) | Production of 4-methylimidazole | |
| JPH07100699B2 (en) | Process for producing 4-methylimidazole | |
| JPS6310149B2 (en) | ||
| JP4739695B2 (en) | Process for producing 5-amino-1-substituted-1,2,4-triazole, and triazole derivative obtained by the process | |
| JPH06184072A (en) | Method for purifying alpha-hydroxyisobutyramide | |
| JPH0747579B2 (en) | Method for producing imidazoles | |
| JPH07100698B2 (en) | Process for producing 4-methylimidazole |