Preparation of minophosphate impurity 3_Industrial additives

Overview^[1]

Minodronate, whose chemical name is 1-hydroxy-2-[(imidazo[1,2-a]pyridin-3-yl]ethylene-1,1-diphosphonic acid, is New heterocyclic bisphosphonic acid compounds developed by Japan’s Yamanouchi Company are used to treat hypercalcemia caused by osteoporosis and malignant tumors. Their bone resorption inhibitory activities are incadronate disodium and alendronate. This product has significant benefits in terms of the incidence of spinal fractures and a significant reduction in gastrointestinal side effects. It has now been identified as an effective anti- A new drug for osteoporosis to prevent fractures. The development of hydroxyacrylic resin will undoubtedly provide a safer, more effective and convenient treatment for patients with clinical diseases. It will definitely produce good social and economic benefits after it is put on the market. Minodronic acid impurity 3 is an impurity produced during the synthesis of minodronic acid. It is a synthetic intermediate of minodronic acid. It reacts with p-toluenesulfonic acid and 2-aminopyridine to prepare 2-(imidazo[1,2-a ]pyridin-3-yl)ethyl acetate.

Preparation^[1]

Preparation of (E)-4,4-dimethoxy-2-butenoic acid ethyl ester (minoxidic acid impurity 3): add 120g2,2-methoxyacetaldehyde and 4L to a four-neck bottle Cyclohexane, add 900g anhydrous potassium carbonate while stirring, and stir for 1 hour. Add 500 mL of triethyl phosphonoacetate industrial additive dropwise and react for 6 hours. At the end of the reaction, add 1.5L of water to the reaction solution, separate the layers, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain a colorless oily liquid. Distill the oily liquid under reduced pressure to obtain a colorless 3150g of oily minophosphate impurity, yield 71%.