Study On Continuous Flow Green Catalytic Amide Bond Synthesis

The amide bond is the most basic functional group in organic synthesis.It not only exists in more than 30 % of small molecule drugs,but also is the main chemical bond(peptide bond)in all polypeptide and protein structures.At present,the industrial synthesis of amide bonds mainly uses stoichiometric coupling reagents and activation reagents.These methods have the disadvantages of poor atomic economy,high environmental toxicity,and high price of some reagents.The method of catalytic direct amidation in response to the concept of ’green chemistry’ has received extensive attention.Therefore,the development of a class of amidation catalysts with mild reaction conditions and a wide range of substrates has great application value.At the same time,continuous flow chemistry can also be combined with it to replace the traditional kettle reaction,so as to avoid the excessive consumption of raw material resources and human resources in the kettle reaction.In this paper,an efficient and practical boric acid catalyst was selected.A simple continuous flow device was built to select the appropriate catalyst for immobilization,and the fluidization reaction was realized.By establishing a template reaction of 4-methylphenylacetic acid and benzylamine,the thianthrene-1-boronic acid with the best reaction effect was screened from 14 heterocyclic boronic acid structures,and the reaction conditions were optimized.The optimum reaction conditions were determined as follows: the amount of catalyst was 10mol%,the reaction temperature was 40℃ in dry dichloromethane.Using this condition to test in 21 aliphatic substrates,it was found that 18 substrates had good yield,the highest yield reached 98%.For the gram-level reaction,it also had a yield of 76%,and for the treatment of small molecule drug rivaroxaban intermediates synthesis also has70 % yield.After increasing the reaction temperature,thianthracene-1-boronic acid also has a good catalytic effect on challenging aromatic substrates and amino acid substrates.It has a catalytic effect on the selected 20 aromatic substrates,with a maximum yield of93% and a minimum of 30%.There are also 57%-88% product conversion rates for amino acid substrates with three conventional protective groups.At the same time,among the above screened catalysts,quinoline-3-boronic acid with good catalytic effect and easy structure was selected for the next continuous flow reaction.A simple flow reaction equipment was built.The effects of reaction temperature,time and flow rate on the flow reaction were investigated from the aspects of fixing a substrate and fixing a catalyst.The optimum reaction conditions were as follows : the reaction was carried out at a flow rate of 0.1 m L/min at 120℃.On this basis,the experimental results were compared,and it was found that the catalytic effect of fixed substrate was better than that of fixed catalyst,and the reaction effect of benzoic acid substrate was better than that of amino acid substrate.Finally,the catalytic performance of the catalyst immobilized on the resin carrier was also investigated.The results showed that the quinoline-3-boronic acid catalyst bound to the Merrifield resin could be recycled five times,and its activity did not decrease significantly.