Dissertation > Industrial Technology > Chemical Industry > Basic Organic Chemistry Industry > The production of heterocyclic compounds > Containing five pairs or more different atoms of heterocyclic

Study on the Synthetic Process of 2-(2-Amino-4-Thiazolyl)-2-Methox Yi-Minoacetic, Thiobenzothiazole Ester

Author XiaoHaiHuan
Tutor LiZhenQiu
School Qingdao University of Science and Technology
Course Chemical processes
Keywords pharmaceutical intermediate ethyl acetoacetate (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid benzothiazyl disuflide 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester
Type Master's thesis
Year 2009
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2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester(MAEM) was synthesized by using (Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid and benzothiazyl disuflide (DM) as merterials. They were pharmaceutical intermediates. The synthesis of (Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminocetic acid, DM and MAEM was studied in this thesis. The following three parts were contained.1:Improved synthetic process of (Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino -acetic acid.Continuous charging method was adopted in this experiments. 4-Bromoacetoa -cetic acid ethyl ester was synthesized by ethyl acetoacetate and bromine as material with acidic condition, and then oximation, cyclization, methylation. The effects of different solvents and reaction orders on the synthesis were mainly studied. The optimum solvent was ethanol and tetrahydrofuran mixed solvents, and the optimum reaction orders was bromide reaction, oximation, cyclization, methylation. Bromide reaction mechanism was analyzed in this paper. The optimum bromide reaction temperature was-5~0℃, and the reaction time was 8h. Experiments showed that the optimum oximation molar ratio between 4-bromoacetoacetic acid ethyl ester and ethy nitrite was 1 to 1.4 for 4 to 5h of optimum reaction time and 5℃as optimum reaction temperature. The thesis analysed cyclization reaction mechanism. In the process of cyclization reaction the optimum temperature was 20℃, the reaction time was 8h. Thiourea was put in the oxime product by batch feeding mode. Ethyl (Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetate was synthesized. Experiments showed that optimum reaction temperature was 20~25℃and the optimum molar ratio of Ethyl (Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetate/dimethyl sulfate was 1:1.2 for Methylation reaction. Optimum reaction conditions of hydrolysis were: optimum reaction temperature was 50℃, the reaction time was 90 minutes, the molar ratio of sodium hydroxide to (Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino -acetic acid ethyl ester was 2.5:1. (Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid was characterized by IR spectrum and 1HNMR.2.The synthesis of DM with oxygen oxidation method.The synthesis of DM was focused with 2-mercaptobenzothiazole (M) refined as material, ammonia as solvent and oxygen as oxidizer in this paper. The optimized technical conditions was obtained.The optimized process conditions were as follows: ammonia 45g 5%, temperature 50~60℃, pressure 0.7MPa, the account of catalyst was 0.2% of material M. The average yield was 87.1% and its average melting point was 177.6℃. It could meet the standard of pharmaceutical grade. The product’s structure was testified exactly by IR. Industrialization feasibility of oxygen oxidation method pilot process was studied and product effect was well.3: Study on improved synthetic process of MAEMMAEM was synthesized by using (Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino -acetic acid and DM as raw merterials, 1,2-Dichloroethane as reaction solvent and triethylamine as catalyst. The effect of different temperatures and solvents on the synthesis of MAEM was reviewed. The optimum process conditions conclued by orthogonal test were as follows: the molar ratio of (Z)-2-(2-amino-4-thiazolyl)-2 -methoxyiminoacetic acid/benzothiazyl disuflide/triethylamine/triphenylphosphine was 1:1.1:1.2:1.1, and the reaction temperature was 10~15℃. The yield was 85.3%, and the product was charactorized by IR and 1HNMR.

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