Bayesian Optimization of a Continuous Flow Synthetic Process for N-Benzyl-p-toluenesulfonamide
N-Benzyl-p-toluenesulfonamide(1)is an inhibitor of skeletal muscle myosin Ⅱ that specifically inhibits contraction of skeletal muscle fast fibers.A continuous flow synthesis system was developed for 1 and the main reaction parameters were optimized with a Bayesian optimization algorithm.After 10 rounds of Latin hypercube sampling and 10 rounds of Bayesian optimization iterations,two sets of optimal reaction conditions were obtained.① The reaction temperature was 3.8 ℃,the residence time was 14.6 min,the dosage of acid binding agent(N,N-diisopropylethylamine)was 1.5 equiv.and the concentration of p-toluenesulfonyl chloride(2)was 0.26 mol/L,which corresponded to a product yield of 91.4％(based on 2)with a purity of 99.5％.(2)The reaction temperature was 7.5 ℃,the residence time was 18.5 min,the dosage of DIEA was 1.6 equiv.and the concentration of 2 was 0.37 mol/L,which corresponded to a product yield of 92.3％with a purity of 99.7％.The Bayesian optimization can greatly improve the efficiency of searching optimal conditions.The reaction time of the optimized process is greatly reduced,and the solvent is single and economical,which is valuable for industrial application.
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