The invention discloses a preparation method of an impurity reference substance of ambroxol hydrochloride. The method comprises the following steps: firstly, dissolving ambroxol hydrochloride in an appropriate amount of dichloromethane solution, and then adding a certain amount of bicarbonate Sodium aqueous solution, stirred evenly, to obtain free ambroxol, organic phase separation, drying, concentration, concentrated solution was dissolved in alcohol solution, then refluxed with excess orthoformate, after condensation, (1R, 4R)‑4‑ (6,8-dibromo-3,4-dihydroquinazoline)-cyclohexanol crude product, the crude product was purified by silica gel column chromatography to obtain pure product. The present invention creatively uses orthoformate as a condensing agent. Compared with other condensing agents reported in literature, orthoformate has the advantages of good stability, high safety, low cost, high product yield, and easy purification.