The present invention relates to a preparation method of a drug pentobarbital (1) for sedation, hypnosis, pre-anesthesia administration and anti-convulsion, and provides a new preparation process for preparing high-purity pentobarbital (I) from diethyl ethylmalonate, wherein the process comprises three steps: A, bromination; B, alkylation; and C, cyclization, acidification, and purification. According to the present invention, the method has advantages of simple operation, short production cycle, low energy consumption, mother liquor circulation, less three-waste, stable process, good product quality, high product purity, isomer impurity content of less than 0.1%, high yield and low production cost, and is suitable for industrial production.