The main objective of the present study is to propose a methodology to evaluate alternatives for the synthesis of the second-generation bioethanol production process from lignocellulosic feedstock, in order to reduce amount of waste, energy consumption and production costs. The methodology is based on modelling, synthesis, design and simulation, where the heat integration in the 2G bioethanol production process is a key tool to evaluate the process in technical, economic and environmental terms. As a case study, wheat straw is considered as raw material, and the simulations are performed using a modular process simulator. For the assessment and comparison of the biorefinery alternatives, the selected evaluation criteria are ethanol yield, unit production cost, energy consumption, CO2 emissions and water consumption. The results show the best process alternatives that can lead to greater sustainable ethanol production, supporting better decision making in the synthesis and design of biorefineries.