Minodronate, chemical name 1_hydroxy_2_[(imidazo[1,2_a]pyridine-3-yl]ethylidene-1,1-diphosphonic acid, developed by Japan Yamauchi Co., Ltd. A novel heterocyclic bisphosphonate for the treatment of hypercalcemia caused by osteoporosis and malignant tumors, which inhibits bone resorption activities of disodium neocardium, alendronate and pamidron 2, 10 and 100 times the acid disodium. This product has significant benefits in the incidence of spinal fractures, and has a significant reduction in gastrointestinal side effects, and has now been identified as an effective new drug against osteoporosis. , prevention of fractures. The development of this drug will undoubtedly provide a safer, more effective and convenient treatment for patients with clinical diseases.
Considering the good social and economic benefits of Minophosphate and the reaction yield, industrialization conditions and environmental protection policies, it is necessary to have an effective method for synthesizing Compound I that can be safely and easily controlled.
The disclosed preparation methods are:
1. Using imidazo[1,2-a]pyridine as starting material, reacting with paraformaldehyde and dimethylamine hydrochloride to give 3-[(N,N-dimethylamino)methyl]imidazo[ 1,2-a]pyridine, which reacts with an alkyl halide to form a quaternary ammonium salt, which is directly hydrolyzed under basic conditions after being substituted by a cyano group, and then reacted with phosphorus trichloride and phosphorous acid in a suitable solvent to obtain a target compound.
The synthetic method uses the sodium citrate, which is dangerous to operate, has a long reaction step, is cumbersome to operate, and is not suitable for industrial production.
2. When ethyl 4-aldehyde-based butyrate is prepared, anhydrous and oxygen-free are required, and the reaction temperature is -80 ° C, which is difficult to achieve. When preparing 3-bromo-4-aldehyde-based butyrate, the reagents involved are liquid bromine and carbon tetrachloride, which are highly toxic and are not suitable for mass production in the pharmaceutical industry.
In view of the shortcomings of the existing methods, it is difficult to achieve large-scale production. On the basis of a large number of experiments, it provides an effective avoidance of the use of highly toxic chemical reagents, mild reaction conditions, strong controllability, and short reaction steps. A method for preparing minodronic acid with a high rate and low cost and suitable for industrial production. The main raw material prepared was Ethyl trans-4-oxo-2-butenoate. The minodronic acid is prepared by first condensing the compound II and the compound III into the compound IV, and then ring-closing the compound IV with the 2-aminopyridine to obtain the compound V. The compound V is hydrolyzed to the compound VI, and finally phosphorylated to the compound I. The method avoids the use of highly toxic chemical reagents such as sodium cyanide or bromine, the reaction conditions are mild and controllable, the reaction steps are short, the yield is high, and the cost is low, which is suitable for industrial production.