CN101417985A - Method for synthesizing 2-amino thizaoline - Google Patents
Method for synthesizing 2-amino thizaoline Download PDFInfo
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- CN101417985A CN101417985A CNA2008100798980A CN200810079898A CN101417985A CN 101417985 A CN101417985 A CN 101417985A CN A2008100798980 A CNA2008100798980 A CN A2008100798980A CN 200810079898 A CN200810079898 A CN 200810079898A CN 101417985 A CN101417985 A CN 101417985A
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Abstract
The invention relates to a method for synthesizing 2-aminothiazoline, which comprises the following steps: firstly, performing chlorinated reaction between ethanolamine and thionyl chloride in an organic solvent to generate 2-chloro-ethylamine hydrochloride; and secondly, performing cyclization reaction between the 2-chloro-ethylamine hydrochloride and thiourea to generate the 2-aminothiazoline. Compared with the prior art, the method does not need introduce hydrogen chloride gas and concentrated hydrochloric acid to synthesize ethanolamine hydrochloride, thereby reducing reaction reagents and the reaction steps; besides, the process route is more advanced, environment-friendly and safer, and the cyclization yield reaches more than 70 percent.
Description
Technical field
The present invention relates to a kind of synthetic method of thiazolamine quinoline.
Background technology
Thiazolamine quinoline, English name are 2-Aminothiazoline, and its structural formula is as follows:
This compound is mainly used in synthetic semisynthetic antibiotics cefotiam and anti-leprosy medicine Thiazosulfone as medicine intermediate, and this compound still is the main component of space anti-radiation protective agent and makeup sun-screening agent simultaneously.
The synthetic method of existing thiazolamine quinoline is to be starting raw material with the thanomin, generate ethanolamine hydrochloric salt with hydrogenchloride or hydrochloric acid reaction, generate the 2-chloroethyl amine hydrochloride with the sulfur oxychloride reaction again, last and Sodium Thiocyanate 99 carries out annulation, through extracting, concentrate, make (Doherty D.G., et al J.Am.1957 (79) 5667).
In this synthesis technique, need earlier thanomin to be dissolved in methylene dichloride during preparation 2-chloroethyl amine hydrochloride, feed hydrogen chloride gas (vapor phase process) or make ethanolamine hydrochloric salt, and then carry out chlorination to generate the 2-chloroethyl amine hydrochloride with sulfur oxychloride, phosphorus trichloride or five chlorethoxyfos with 30% hydrochloric acid reaction (liquid phase method).For example narrated among the JP83-41842 with vapor phase process and fed the method that pure hydrogen chloride gas carries out building-up reactions, its technology shortcoming is that operation easier is bigger to the equipment requirements height, and the reaction times reaches 36h.Zhu Yifeng etc. (fine chemistry industry, 1998 (15) 48) adopt liquid phase method, promptly prepare ethanolamine hydrochloric salt with thanomin and concentrated hydrochloric acid under 1: 1 condition, obtain the 2-chloroethyl amine hydrochloride with the sulfur oxychloride chloro again.This method is done for the moisture content in the reaction solution is removed when preparation thanomin hydrochloric acid, needs the heating distillation dehydration, and remaining small amount of water also need add toluene again, takes out of with the water azeotropic, and operation steps is many and consume energy higher.
Summary of the invention
The objective of the invention is to overcome the shortcoming of prior art, the thiazolamine quinoline that a kind of technology is reasonable, yield is higher synthetic method is provided.
Thiazolamine quinoline synthetic method of the present invention is earlier thanomin and sulfur oxychloride directly to be carried out chlorination generation 2-chloroethyl amine hydrochloride in organic solvent, carry out annulation with 2-chloroethyl amine hydrochloride and thiocarbamide again and generate the thiazolamine quinoline, its reaction formula is as follows:
In chlorination, the organic solvent that uses is methylene dichloride, chloroform, toluene, dimethylbenzene, orthodichlorobenzene, ethyl acetate, ethylene dichloride etc., and its consumption is 3～10 times of thanomin quality.In above-mentioned organic solvent, with thanomin: the mol ratio of sulfur oxychloride=1: 1.1～1.5 feeds intake, and generates the 2-chloroethyl amine hydrochloride in 10～15 hours in 40～75 ℃ of reactions.
Alternative cyclizing agent can be thiocarbamide, Sodium Thiocyanate 99 or potassium sulfocyanate in the annulation, wherein thiocarbamide is a kind of more satisfactory thiazolamine quinoline cyclizing agent, the thiazolamine quinoline yield that uses it is than the Sodium Thiocyanate 99 height, so the preferred thiocarbamide of the present invention is as cyclizing agent.
Suitable annulation condition is with the 2-chloroethyl amine hydrochloride: the mol ratio of thiocarbamide=1: 2.5～3 feeds intake, and reacts 20～24 hours down at 70～100 ℃.
Thiazolamine quinoline synthetic method of the present invention is to adopt thanomin and sulfur oxychloride directly to carry out chlorination in organic solvent, utilize the 2-chloroethyl amine of a part hydrogenchloride that produces in sulfur oxychloride and the thanomin reaction process and generation to form hydrochloride, do not need to feed hydrogen chloride gas or add concentrated hydrochloric acid synthesizing alcohol amine hydrochlorate.Compared with prior art, synthetic method of the present invention has reduced reaction reagent on the one hand, shortened reactions steps, operational path is more advanced, reasonable, got rid of on the other hand and used transportation difficulty and dangerous bigger pure chlorination chlorine body or this step reaction of concentrated hydrochloric acid synthesizing alcohol amine hydrochlorate, made and produce Environmental Safety more.
The present invention adopts 2-chloroethyl amine hydrochloride and thiocarbamide reaction to generate the thiazolamine quinoline, and side reaction is few, need not aftertreatment and just can obtain highly purified thiazolamine quinoline, and the cyclization yield reaches more than 70%.
Compared with prior art, thiazolamine quinoline synthetic method production cost of the present invention is low, and is not high to equipment requirements, operation easily, and safe and reliable, solvent can be recycled, and has bigger implementary value and economic results in society.
Embodiment
Embodiment 1
Preparation 2-chloroethyl amine hydrochloride
In having the dry reaction bottle of reflux, stirring and thermometer, add 250mL chloroform and 46.5g (0.76mol) thanomin, open and stir, make its mixing, be cooled to 10 ℃, slowly be added dropwise to 121g (1.02mol) sulfur oxychloride, in 3 hours, dropwise, be warming up to reflux temperature, react after 15 hours, steam and remove chloroform and excessive sulfur oxychloride, slowly cooling makes and separates out crystallization, continue to be cooled to 5 ℃, filter, vacuum-drying obtains the crystallization of 85.6g2-chloroethylamine hydrochloride white plates.
Mp:146.3～147.1 ℃ (literature value is 147.5～148 ℃), yield 97%, purity 99.2% (GC method), IR (KBr): υ
-NH3500cm
-1, 3116cm
-1, 1582cm
-1υ
C-N1110cm
-1
Synthetic 2-aminothiazole quinoline
With 85.6g (0.74mol) 2-chloroethyl amine hydrochloride 200mL water dissolution, add 160g (2.10mol) thiocarbamide, be heated to backflow, react after 24 hours, be cooled to 70 ℃, regulate pH=9, earlier respectively with 200mL dichloromethane extraction 2 times with 40% sodium hydroxide solution, use the 100mL dichloromethane extraction again 1 time, united extraction liquid behind anhydrous sodium sulfate drying, concentrates, filters, vacuum-drying obtains thiazolamine quinoline white crystals 57.2g.
Mp:78.3～80 ℃ (80～82 ℃ of literature values), yield 76% (2-chloroethyl amine hydrochloride relatively), purity 99.2% (HPLC normalization method).
Embodiment 2
In having the dry reaction bottle of reflux, stirring and thermometer, add 300mL toluene and 46.5g (0.76mol) thanomin, open and stir, make its mixing, be cooled to 10 ℃, slowly be added dropwise to 119g (1mol) sulfur oxychloride, in 3 hours, dropwise, kept back flow reaction 10 hours, normal pressure steams and removes toluene and unreacted sulfur oxychloride, is decompressed to 60 ℃ of solvent evaporated again.
Residue in reaction flask adds water 200mL, and thiocarbamide 165g (2.17mol) was heated to back flow reaction 20 hours, be cooled to 70 ℃, add 40% sodium hydroxide solution and regulate pH=9, earlier respectively with 200mL dichloromethane extraction 2 times, use the 100mL dichloromethane extraction again 1 time, united extraction liquid, anhydrous sodium sulfate drying, concentrate, filter, vacuum-drying obtains thiazolamine quinoline white crystals 56.6g, yield 72.8% (with respect to thanomin), purity 99.2%, 77.5～79 ℃ of fusing points.
Embodiment 3
In having the dry reaction bottle of reflux, stirring and thermometer, add 220mL methylene dichloride and 46.5g (0.76mol) thanomin, open and stir, make its mixing, be cooled to 10 ℃, slowly be added dropwise to 135g (1.13mol) sulfur oxychloride, in 3 hours, dropwise, kept back flow reaction 12 hours, normal pressure steams and removes methylene dichloride and sulfur oxychloride, and underpressure distillation is to doing.
Residue in reaction flask adds water 200mL, and thiocarbamide 172g (2.26mol) was heated to back flow reaction 22 hours, be cooled to 70 ℃, add 40% sodium hydroxide solution and regulate pH=9, earlier respectively with 200mL dichloromethane extraction 2 times, use the 100mL dichloromethane extraction again 1 time, united extraction liquid, anhydrous sodium sulfate drying, concentrate, filter, vacuum-drying obtains thiazolamine quinoline white crystals 57.2g, yield 73.6% (with respect to thanomin), purity 99.3%, 78～79 ℃ of fusing points.
Embodiment 4
In having the dry reaction bottle of reflux, stirring and thermometer, add 270mL dimethylbenzene and 46.5g (0.76mol) thanomin, open and stir, make its mixing, be cooled to 10 ℃, slowly be added dropwise to 100g (0.84mol) sulfur oxychloride, in 3 hours, dropwise, kept back flow reaction 15 hours, steam and remove dimethylbenzene, add water 200mL, thiocarbamide 157g (2.07mol) was heated to back flow reaction 24 hours, and post-processing operation is with embodiment 2, obtain thiazolamine quinoline white crystals 57.7g, yield 73% (with respect to thanomin), purity 99.3%, 77～79 ℃ of fusing points.
Embodiment 5
Having reflux, add 320mL ethyl acetate and 46.5g (0.76mol) thanomin in the dry reaction bottle of stirring and thermometer, open and stir, make its mixing, be cooled to 10 ℃, slowly be added dropwise to 113g (0.95mol) sulfur oxychloride, in 3 hours, dropwise, kept back flow reaction 12 hours, steam and remove ethyl acetate and excessive sulfur oxychloride, add water 200mL, thiocarbamide 145g (1.91mol) was heated to back flow reaction 22 hours, and post-processing operation is with embodiment 2, obtain thiazolamine quinoline white crystals 56.2g, yield 72.3% (with respect to thanomin), purity 99%, 77.2～79 ℃ of fusing points.
Embodiment 6
Having reflux, add 240mL ethylene dichloride and 46.5g (0.76mol) thanomin in the dry reaction bottle of stirring and thermometer, open and stir, make its mixing, be cooled to 10 ℃, slowly be added dropwise to 126g (1.06mol) sulfur oxychloride, in 3 hours, dropwise, kept back flow reaction 13.5 hours, steam and remove ethylene dichloride, add water 200mL, thiocarbamide 155g (2.04mol) was heated to back flow reaction 21 hours, and post-processing operation is with embodiment 2, obtain thiazolamine quinoline white crystals 56.7g, yield 73% (with respect to thanomin), purity 99.1%, 77.6～79 ℃ of fusing points.
Claims (7)
- The synthetic method of 1 one kinds of thiazolamine quinolines, be under 40～75 ℃, thanomin and sulfur oxychloride directly to be carried out chlorination generation 2-chloroethyl amine hydrochloride in organic solvent, under 70～100 ℃, carry out annulation again and generate the thiazolamine quinoline with 2-chloroethyl amine hydrochloride and thiocarbamide.
- The synthetic method of 2 thiazolamine quinolines according to claim 1 is characterized in that in the described chlorination, and thanomin is 1: 1.1～1.5 with the amount of substance ratio of sulfur oxychloride.
- The synthetic method of 3 thiazolamine quinolines according to claim 1 is characterized in that in the described annulation, and the 2-chloroethyl amine hydrochloride is 1: 2.5～3 with the amount of substance ratio of thiocarbamide.
- The synthetic method of 4 thiazolamine quinolines according to claim 1, the reaction times that it is characterized in that described chlorination is 10～15 hours.
- The synthetic method of 5 thiazolamine quinolines according to claim 1, the reaction times that it is characterized in that described annulation is 20～24 hours.
- The synthetic method of 6 thiazolamine quinolines according to claim 1 is characterized in that described organic solvent is a kind of in methylene dichloride, chloroform, toluene, dimethylbenzene, orthodichlorobenzene, ethyl acetate, the ethylene dichloride.
- The synthetic method of 7 thiazolamine quinolines according to claim 6, the consumption that it is characterized in that described organic solvent are 3～10 times of thanomin quality.
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| CN2008100798980A CN101417985B (en) | 2008-11-24 | 2008-11-24 | Method for synthesizing 2-amino thizaoline |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633702A (en) * | 2012-03-22 | 2012-08-15 | 广州九益生物技术有限公司 | Beta-amino ethyl thiosulfuric acid and synthesis method thereof |
| CN111574381A (en) * | 2020-04-17 | 2020-08-25 | 杭州盛弗泰新材料科技有限公司 | Method for preparing 2-chloroethylamine hydrochloride |
| CN116554120A (en) * | 2023-07-10 | 2023-08-08 | 山东国邦药业有限公司 | Preparation method of 2-amino-2-thiazoline |
-
2008
- 2008-11-24 CN CN2008100798980A patent/CN101417985B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633702A (en) * | 2012-03-22 | 2012-08-15 | 广州九益生物技术有限公司 | Beta-amino ethyl thiosulfuric acid and synthesis method thereof |
| CN111574381A (en) * | 2020-04-17 | 2020-08-25 | 杭州盛弗泰新材料科技有限公司 | Method for preparing 2-chloroethylamine hydrochloride |
| CN111574381B (en) * | 2020-04-17 | 2023-01-10 | 杭州盛弗泰新材料科技有限公司 | Method for preparing 2-chloroethylamine hydrochloride |
| CN116554120A (en) * | 2023-07-10 | 2023-08-08 | 山东国邦药业有限公司 | Preparation method of 2-amino-2-thiazoline |
| CN116554120B (en) * | 2023-07-10 | 2023-10-20 | 山东国邦药业有限公司 | Preparation method of 2-amino-2-thiazoline |
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Inventor after: Su Wei Inventor after: Chen Wancheng Inventor after: Gao Zhiwei Inventor after: Chu Piming Inventor after: Su Binlin Inventor after: Kang Futang Inventor before: Su Binlin Inventor before: Chen Wancheng Inventor before: Gao Zhiwei Inventor before: Chu Piming Inventor before: Su Wei Inventor before: Kang Futang |
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Address after: 030500 Shanxi province Jiaocheng Cross Ridge Road from the 307 National Road 1000 meters Patentee after: Shanxi xintianyuan Pharmaceutical Co. Ltd. Address before: 030500 Shanxi province Jiaocheng Cross Ridge Road from the 307 National Road 1000 meters Patentee before: Shanxi Xintianyuan Pharm. & Chem. Co., Ltd. |