Study On The Synthesis Of Minodronic Acid

- Feb 23, 2019-

  Osteoporosis is a class of bone metabolic diseases caused by many types of factors. The disease is characterized by degeneration of bone tissue and low bone density, which causes the bone to become brittle and lead to fracture. It is a chronic disease. There is usually no special situation before a fracture occurs. The proportion of women with this disease is relatively high, which is common in postmenopausal women and the elderly. With the increase of the elderly population in China, the incidence rate is on the rise. 

   Minodronic acid belongs to the 3rd generation bisphosphonate compound, and the intermediate have Ethyl trans-4-oxo-2-butenoate CAS 2960-66-9,etc. This product is a new type jointly developed by Astellas and Ono. Heterocyclic bisphosphonate, trade name Bonoteo, is effective in reducing bone resorption and was first approved for sale in Japan in 2009 for the treatment of osteoporosis, the drug through the transformation of the loose bone to the cortical bone and bone The effect of quality comes into play. It can effectively inhibit the bone resorption ability of osteoclasts and further reduce the circulation of bone metabolism, which can have a good therapeutic effect on the treatment of osteoporosis. Compared with other bisphosphonate formulations, minodronic acid can significantly improve postmenopausal, significantly increased bone mass loss and osteoporosis in the elderly. Moreover, the dose of the drug was significantly decreased (allindronate was 10 mg/day and minodronic acid was 1 mg/day), which improved patient compliance and significantly reduced bisphosphonate formulation. Causes common gastrointestinal side effects. 

  Based on the relevant literature and data, this paper designed the synthesis route of minodronic acid, and carried out the research. The optimized route is: 2, 2-dimethoxyacetaldehyde and triethyl phosphonoacetate reaction, synthesis 4 , 4-dimethoxy-2-butenoic acid ethyl ester, after cyclization, hydrolysis, and phosphorus tribromide reaction, hydrolysis to prepare minodronic acid. Through the analysis of infrared spectrum and nuclear magnetic spectrum, the structure of the synthesized intermediates and final products is determined. Through optimization, the process is simple, the equipment requirements are not high, the production cost is low, the environmental pollution is small, and the starting material price Low cost, easy to obtain, suitable for industrial production, can meet the use of pharmaceutical preparations.