The invention provides a synthesis method of 4 - cycloheximide methyl substituted benzofuran derivatives. Belong to organic synthesis technical field. After the Lewis-methyl benzofuran 5 - carboxylic acid is obtained -2 -methoxy -3 -methylbenzofuran 5 - carboxylic acid and then subjected to a hydrolysis reaction under basic conditions to obtain -2 -methoxy -3 -methylbenzofuran 5 - carboxylic acid, and then reacted with -2 - aniline in the presence of a condensing agent and a base to obtain -3 -methoxy R - methyl 5 -2 - R -phenyl benzofuran -3 - N formamide. After demethyl reaction 5 - hydroxyl -2 - methyl - N-R -phenyl benzofuran -3 - formamide was obtained, and finally, formaldehyde was added. Of the cycloheximide Mannich resulted in the final product.