Study On Synthesis Technology Of(-)-2,6-amino-4,5,6,7-Tetrahydro Benzothiazole

2,6-amino-4,5,6,7-tetrahydro-benzothiazole is a key intermediate of the pramipexole which is synthetic treatment of Parkinson’s drug. It’s directly related to the cost and application of the drug. It’s great significant for industrial production and reduce costs to carry out the synthesis of research of such intermediate.This research work is mainly launched around the design and synthesis of the biologically optics (-)2,6-amino-4,5,6,7-tetrahydro-benzothiazole, experimental design scheme mainly uses the raw material4-acetyl cyclohexanone, then through following five steps:N-acylation reaction, oxidation reaction, one-step cyclization, hydrolysis, racemic body split, then the target product (-)2,6-diamino-4,5,6,7-tetrahydro-benzothiazoleis is successfully produced under the conditions of the easier process of industrialization.The first chapter introduces the basic features and application of thiazole compounds which has important applications in agriculture, medicine, materials science and other aspects. Then it introduces the syntheticroute of thiazoles and the research of Pramipexole, specified (-)2,6-amino-4,5,6,7-tetrahydro-benzothiazole is hotspot in the field of the treatment of Parkinson’s disease drugs. Finally, it introduces the source> meaning and content of this thesis.The second chapter describes the basic properties of the intermediates synthesizing the2,6-amino-4,5,6,7-tetrahydro-benzothiazole and the route selection in synthesis process. Comprehensive analysis of literature data, combined with the yield and cost of the intermediates in the reaction process, considering the situation of raw material source, the process simplification, appropriate yield and other aspects, we select a laboratory synthetic route.The third chapter is the research of experimental mechanism. It analyzes the reaction mechanism, and introduces N-acylation reaction, oxidation, hydrolysis and chiral split. The comparison between different reagents and methods is the theoretical basis of the experiment.The fourth chapter is the experimental study which is also the focus of this article. It introduces experimental medicine, instruments and experimental process and highlights the methods of operation of the study, and the experimental conditions and the problems that may arise in the study. It raises the points of easily controlled methods, which is the important guarantee of the experimental findings. The main process is as follows: Step1:Synthesis of4-acetyl cyclohexyl alcohol (intermediate1) uses the acetic anhydride N acylated to protect amino, through the reaction in the solvents benzene acylation of trans4-amino cyclohexanol,4-acetyl amino cyclohexanol is produced. The key of the reaction is to make the raw materials-amino cyclohexanol suspended in a solvent pump. In order to make the reaction proceed smoothly, the first is to heat to about40℃and then take the dropwise acetic anhydride process control methods to ensure that the raw materials in the reaction system are always in excess, and makes acetic anhydride play as a big role in enhancing the reaction yield.Step2:Then select the line with Jones reagent to oxidize4-acetyl cyclohexanol, the reaction makes use of the principle of the aqueous phase reaction and transfer of the reaction product to the organic phase to avoid further oxidation of the reaction products. through the extraction、evaporation and crystallization, the4-acetyl cyclohexyl ketone (intermediate2) is produced.Step3:the synthesis of2-Amino-6-acetyl-4,5,6,7-tetrahydro-benzothiazole (intermediate) is made by the two intermediate system to take intermediate which doesn’t require functional group protection and then by the bromination, thiazole cyclization in glacial acetic acid, that is to say, bromination product is no need to separate and react directly with thiourea to generate the thiazole ring, we study the controlled conditions of the reaction and the main influencing factors:the reaction temperature is at54℃～55℃when appending the bromide, drop acceleration should be slow in the beginning and gradually become faster, the time of reaction ia about1.5h, the temperature is75℃～80℃when appending the thiourea, after adding the thiourea,reaction should be last1h in the107℃～108℃.Step4:the synthesis of2,6-amino-4,5,6,7-tetrahydro benzo thiazole (intermediate4) is through the high temperature hydrolysis of2-Amino-6-acetyl-4,5,6,7-tetrahydro-benzothiazole (intermediate3) and the elimination of the protection acetyl amino to get the intermediate four. Select the Strong acidic aqueous solution of hydrogen bromide to directly do the high-temperature hydrolysis, saturated with hydrogen bromide heating reflux6h, and then with appending alkali after filtering to PH>14, product intermediates IV is precipitated, its color is gray, and the melting point is225.5～250.5℃, its producing rate is about70%.Step5:the four intermediate is split by L-(+) tartaric acid, using the different characteristics of the solubility of the product generated by the tartaric acid with the body rotating around, and then remove the tartaric acid to get the active product, its color is gray, and the melting point of225.5～250.5℃, and yield is about70%.、 The Conditions of this project are easy to operate. The product synthesized is of high purity and yield, and the mild reaction condition is suitable for industrial production. Through the melting point analysis, elemental analysis and infrared spectroscopy (FI-IR) characterization Experimental raw materials and products, the structure and nature of the three substances is obvious and in line with their respective chemical structures.Chapter Ⅴ is the experimental results and the process of analysis and discussion, especially the problems and treatment measures in the reaction product characterization analysis to discuss the impact of different factors on the experimental results.Chapter Ⅵ in the thesis is mainly about conclusions and recommendations. These are the thinking of the shortcomings and waste processing in the experiment based on author’s experience.Above all, this thesis studies in detail the production technology which treats the4-amino-cyclohexanol as raw materials, and examines the various factors affecting the yield of the product in the process of synthesis to optimize the reaction conditions and improve the technological level and reduce the synthesis costs. By the experimental methods, we study the reaction time, the feeding amount, temperature, solvent selection and other factors affecting on the yield and determine the optimized synthesis process.