Improved Process For The Synthesis Of Chloro Morpholine And Its Derivatives

The special properties of thiazole ring compounds with hetero atoms on its structure shows, is widely used in various fields. In recent years, people pay attention to two kinds of organic compounds 1,3,4-thiadiazol and 1,2,5-thiadizole ring because of their significant advantages show in the pharmaceutical.3- chloro -4- morpholinyl-1,2,5- thiadizole (Chloro Morpholine in short) is a important synthetic intermediate synthesis for β-adrenergic blocking agent timolol and other similar drugs. Therefore, this paper had select and optimize the synthetic routes of Chloro Morpholine and two derivatives, in order to determine the most suitable synthetic route for the industrialized production.The synthetic route of Chlorine Morpholine include the following steps:First, liquid cyanide, formaldehyde and ammonium chloride react to synthesize the methyleneaminoacetonitrile. Then we can get aminoacetonitrile sulfate by reaction of methyleneaminoacetonitrile and sulfuric acid solution in methanol. The aminoacetonitrile sulfate reacts with sulfur dichloride in chlorine to synthesize the compound 3,4-dichloride-1,2,5-thiadizole. Last,3,4-dichloride-1,2,5-thiadizole and morpholine react to obtain final product Chlorine Morpholine. Two derivatives can be synthesized flow the steps below:Chlorine Morpholine reacts with epichlorohydrin or 2,2-dimethyl-1,3-dioxolane-4-methanol, then we can obtain the two derivatives: 4-{4-[Oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-y1}-morpholine; 3-[4-(4-Morpholinyl)-1,2,5-thiadiazol-3-yloxy]-1,2-propanediol.This paper has optimized each step of the reaction conditions and found a suitable synthetic route by large number of documents as theoretical support and experiments as technical support. In order to get a green environmental industrial production processe,we have examed the reagent selection, solvent selection, reagent ratio, reaction temperature, reaction time and other factors on the reaction.Finally, this paper determined the most suitable synthetic route for industrial production by improving and optimizing each step reaction in the synthesis route.In this paper, we have improved product yield, reduced production costs and pollution.