Synthesis And Development Of Disodinum Clodronate, Prasugrel And Pharmaceutical Intermediate

Disodinum clodronate is a new type of efficacious and analgesic drug to curing the metastatictumorofbone. The synthesis of disodinum clodronate has been studied systematically in this paper. Diisopropyl methylenediphosphonate is synthesized from triisopropyl phosphate and dibromomethane, and then the desired product is obtained from diisopropyl methylenediphosphonate, which is chloridized by 10% sodium hypochlorite solution, hydrolyzed by concentrated hydrochloric acid, salitied by sodium hydroxide solution, recrystallized by ethanol and distilled water. In the condensation reaction, using the different boiling point between dibromomethane and the by-product isopropyl bromide, an insulation fractionation device is used in the reaction, in order that the unreacted dibromomethane can back to the reaction systerm and isopropyl bromide can timely escape outside the reaction systerm and the reaction balance to right, the yield up to 97.4%. In the chlorination reaction, at the room temperature, a phase transfer catalyst is added to accelerating the reaction, which is simple and timesaving. After the salitying reaction, a high purity disodinum clodronate was obtained by recrystallizing from ethanol and distilled water, HPLC purity is up to 99%.Prasugrel is a new oral anti-platelet aggregation inhibitor for the treatment of atherosclerosis in the arteries, acute coronary syndrome. In this paper, the synthesis of prasugrel has been studied, a-cyclopropyl carbonyl-2-fluorobenzyl bromide(1) is synthesized from 1-(bromomethyl)-2-fluorobenzene and cyclopropanecarbonitrile, and then brominated by NBS;2-oxo-2,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridine p-toluene-sulfonic acid salt(2) is prepared by 4,5,6,7-tetrahydro-thieno[3,2-c] pyridine hydrochloride which is protected by the triphenyl chloride and then reaction with n-butyl lithium, tributyl borate and 30% H2O2, and finally deprotection of p-toluenesulfonic acid; The desired product is synthesized from (1) and (2), and then acetylation. This technics has the following improvements:1) deprotection of p-toluenesulfonic acid, making the purification problem of two-step reaction resolved; 2) anhydrous potassium carbonate as an alkali, making the reaction yield greatly improved and reducing the formation of by-products; 3) using anhydrous potassium carbonate instead of NaH which is expensive and easy to fire, reducing the production costs and simplifying the operation process, developed a new technology suitable for industrial production.Finally, a number of intermediates have been introduced in this paper. In the synthesis process of these intermediates some problems have been solved, and the synthesis technics optimized.