Empowering the Medicinal Applications of Bisphosphonates by Unveiling their Synthesis Details

Abstract

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.

Keywords: P-reactants; bisphosphonates; pharmaceutical applications; reactional solvents; research-driven studies; synthesis improvement.

Figure 1

Structures of inorganic pyrophosphate and commercially available BPs in their acidic form.

Figure 2

Morphological comparison between a (left) normal/healthy and an (right) osteoporotic bone. (Constructed with the content on the database Servier Medical Art [31]).

Figure 3

Application of BPs in: (A) Bone imaging–a Single-photon emission computed tomography (SPECT/CT) scan using a HAP-binding molecule with ^99mTc; (B) selective removal of uranyl ions from blood. Adapted with permission from Bhushan, K.R.; Misra, P.; Liu, F.; Mathur, S.; Lenkinski, R.E.; Frangioni, J.V. Detection of breast cancer microcalcifications using a dual-modality SPECT/NIR fluorescent probe. J. Am. Chem. Soc. 2008, 130, 17648–17649. Copyright 2008, American Chemical Society; and Wang, L.; Yang, Z.; Gao, J.; Xu, K.; Gu, H.; Zhang, B.; Zhang, X.; Xu, B. A biocompatible method of decorporation: bisphosphonate-modified magnetite nanoparticles to remove uranyl ions from blood. J. Am. Chem. Soc. 2006, 128, 13358–13359. Copyright 2006, American Chemical Society.

Scheme 1

Generic reaction procedures, with distinct approaches, for the synthesis of BPs.

Scheme 2

Reactional scheme for the synthesis of pamidronate sodium, alendronate sodium, risedronic acid and zoledronic acid, through MWAS. An appropriate carboxylic acid, phosphorous acid and phosphorous trichloride were used in a ratio of 1:3:3, with sulfolane as solvent.

Scheme 3

Possible mechanism for the formation of BPs while using MSA as solvent and phosphorous trichloride as the sole P-reactant (A). Secondary reactions that led to the formation of intermediate molecules are also shown (B,C).

Scheme 4

Possible mechanism for the formation of BPs while using sulfolane as solvent and phosphorous trichloride and phosphorous acid as P-reactants (A). Secondary reactions that led to the formation of intermediate molecules are also shown (B,C).