Empowering the Medicinal Applications of Bisphosphonates by Unveiling their Synthesis Details.

Bisphosphonates (BPs), well-known medicinal compounds used for osteoporosis management, are currently the target of intensive research, from basic pre-formulation studies to more advanced stages of clinical practice. The high demand by the pharmaceutical industry inherently requires an easy, efficient and quick preparation of BPs. Current synthetic procedures are, however, still far from ideal. This work presents a comprehensive compilation of reports on the synthesis of the commercially available bisphosphonates that are pharmaceutical active ingredients. Current limitations to the conventional synthesis are assessed, and paths towards their improvement are described, either through the use of alternative solvents and/or by selecting appropriate ratios of the reactants. Innovative processes, such as microwave-assisted synthesis, are presented as more environmental-friendly and effective methods. The main advantages and setbacks of all syntheses are provided as a way to clarify and promote the development of simpler and improved procedures. Only in this way one will be able to efficiently respond to the future high demand of BPs, mostly due to the increase in life span in occidental countries.