Synthesis Study Of The Bisphosphonate Class Of Drugs

Osteoporsis is one of the common geratic diseases, the important cause of threatening elders' health and damaging their bodies. Its attack rate has jumped to the 7th place of the world's diseases of frequent occurrence. Therapies of osteoporsis are such as: pharmacotherapy, alimentotherapy, physicotherapy and operative treatment etc. However, pharmacotherapy is the main remedy of all. Bisphosphonates are effective drugs and focus of drug research and development of prevention and cure of osteoporsis. Up to now, over ten kinds of bisphosphonates have been developed. Six of them have appeared on the market. Here some of the bisphosphonates are listed (from low to high according to their activities ) : etidronate, clodronate, pamidronate, alendronate, incardronate and ibandronate. Their therapeutic effect ratios are 1:10:100:1000:5000:10000. Ibandronate is the most effective bisphosphonate until now. This thesis reported the synthetic processes and characterization of methylenediphosphonic acid, pamidronate, alendronate and ibandronate.Methods for bisphosphonate synthesizing follow into two categories. Synthesis of methylenediphosphonic acid is one type. Since MDP can be used as precursor of clodronate, this route is practical. Another type of synthetic process was adopted to synthesize pamidronate, alendronate and ibandronate. Synthetic processes of pamidronate and alendronate which were used in references are improved in this thesis: overall yields were raised or processes weresimplified so that they were suit for mass production. Based on the above work, we designed a synthetic route of ibandronate which can not be found in any documents until now and developed ibandronate successfully. Now, we have applied for a national patent with this process.Chemical structures of the synthetic compounds in this thesis have been analyzed and confirmed by element analysis, IR, 'H(!3C)-NMR or MS spectra. Some of the spectra are explained. Results indicate that the chemical structures of the products which are synthesized with the processes provided in this thesis are correct, their physico-chemical data accord with those reported in other documents. This thesis provides the experimental basis of pilot-plant test or mass production of bisphosphonate.