The invention discloses a preparation method of a multi-substituted quinazoline derivative and belongs to the technical field of pharmaceutical synthesis and chemical product synthesis. The preparation method comprises the following steps of: adding diaryl hyper-valent iodine salt and copper salt to a reactor; changing the nitrogen gas by three times and adding a solvent; adding nitrile by two steps; heating up until the reaction is finished after the adding is finished; cooling the reaction system, adding water or a salt solution for quenching the reaction; adding dichloromethane and K2CO3 for stirring and treating; extracting by dichloromethane by three times; combining organic phases; adding magnesium sulfate for drying and filtering; evaporating and concentrating filtrate to obtain a crude product in a rotary manner; and separating the crude product by eluent to obtain the product. The preparation method of the multi-substituted quinazoline derivative has the beneficial effects that the preparation method is scientific and reasonable, capable of synthesizing the multi-substituted quinazoline derivative which is difficult to synthesize by other methods. Moreover, the synthesis method has the characteristics of being simple in structure, high in yield, easy for realization of products and the like.