Binary isobaric vapor-liquid equilibrium (VLE) data for methanol (MeOH) + 2-(methoxymethoxy)-butane (SMMB), 2-butanol (SBOH) + (+/-)-di-sec-butoxymethane (DSBM), and SMMB + DSBM at 101.3 kPa were measured. The saturated vapor pressures for SMMB and DSBM in the corresponding temperature range were determined and then regressed to obtain the Antoine parameters by Aspen Plus. The thermodynamic consistency of all of the VLE data was confirmed by the Van Ness differential test and the pure component consistency test. T-x-y diagrams of the three systems were plotted. Related binary interaction parameters were obtained through the correlation using Wilson, NRTL, and UNIQUAC models. The circular reaction approach was proposed and designed to solve the separation of the azeotropic composition (SBOH + SMMB). Then, the separation process for the quinary system of MeOH + methylal (DMM) + SBOH + SMMB + DSBM was proposed and simulated in Aspen Plus. The purity of the main product DSBM was 99.14 wt %.