In this paper, process improvements of the synthesis of Tenofovir disoproxil fumarate started from (R)-propylene carbonate was optimized. The process improvements were included in simply microwave-assisted acid hydrolysis of phosphonate ester, alkylation promoted with magnesium ethoxide, and iodine methyl isopropyl carbonate as an efficiently esterification reagent. The overall yield of the process of synthesis of Tenofovir disoproxil fumarate was not only improved from 24% to 33.5%, but also the identified process were more environmentally friendly, lower cost, and more suitable for productive and robust production.