Study On The Synthesis Of Oxathiapiprolin

Oxathiapiprolin is a new type of piperidinyl thiazole isoxazoline compounds for the control of late blight and downy mildew.DuPont has optimized and screened through high throughput screening of compounds with pharmaceutically active compounds from Merck’s patent WO2005003128,and then found the Oxathiapiprolin with pharmaceutically activity.Oxathiapiprolin has a novel biological target that is oxysterol binding protein.Oxathiapiprolin has the function of prevention,treatment and inhibition of sporulation.Its efficacy is relatively stable.It is not only effective for downy mildew and late blight,but also it can prevent root rot of rhizome effectively.Compared with the multi-target sites bactericidal agents,Oxathiapiprolin has a single target and requires resistance management because of its high level of drug resistance.Oxathiapiprolin can be used in turn or in combination with fungicides of different mechanisms,thereby inhibiting drug resistance and extending efficacy.It is effective at extremely low dosage and shows excellent preventative and curative efficacy.Therefore,the application of Oxathiapiprolin is still very extensive,and it is worthy of large-scale production.So it has a great significance to develop an industrial synthetic route of Oxathiapiprolin.Based on study on reported synthetic routes of Oxathiapiprolin,we studied the optimization of reaction conditions and the methods of post-treatment.Then different synthetic routes were attempted to synthesize the target compound in this paper.We successfully synthesized the target compounds by a series of reactions,such as Wittig,acylation,protection and deprotection of amino groups,ammonia hydrolysis of ester,dehydration of amides and addition reaction of H2S.For the synthesis of compound B3,we have tried to use silica gel column separation,decompression and atmospheric distillation in the separation and purification,but we haven’t found a good method of purification.Two synthetic routes were attempted to synthesize the compound C6.The difference between the two routes is that the synthesis of the isooxazole ring is the inner ring of the molecule or the intermolecular ring,while the inner ring of the molecule is not successful.For the synthesis of compound D7,we also tried two routes.Route a has 6 steps,with a total yield of 23.7%;by contrast,route b has 8 steps,with a total yield of 16.0%.Route a is better than route b in addition to the high total yield,the separation and purification of the intermediates have not been made of silica gel column,but all compounds have been purified by crystallization.By optimization,the synthetic target compound is used as activator with NaBr,the best solvent is anhydrous ethanol,and the optimum reaction temperature is 72.All chemical structure of intermediates were confirmed by 1H-NMR.The structure and purification of target compound was confirmed by 1H NMR,MC and HPLC.