Synthesis Of Cis-propenylphosphonic Acid Synthesis And Applications Of The Key Intermediate Of Calcitriol

Fosfomycin a novel broad-spectrum antimicrobial agent, has a unique chemicalstructure and antibacterial activity. cis-Propenylphosphonic acid（CPPA） is a keysynthetic intermediate. In this paper, we studied the synthesis of CPPA and found asimple and efficient synthetic routine. According to the references, we studied andimproved reaction conditons as follows:（1）With phosphorous trichloride and t-butylalcohol as raw material, triethylamine acted as acid binding agent to complete thesubstitution reaction and then rearrangement under heating, next catalytichydrogenation, finally acid-catalyzed to obtain CPPA.（2）With phosphoroustrichloride and propargyl alcohol as raw material, bubbling to the reaction system toremove hydrogen chloride, we got2-propnyl phosphorodichloridite and thenrearrangement, next hydrolysis and catalytic hydrogenation to get CPPA.We also designed the two synthetic methods:（1）With phosphorous trichlorideand propargyl alcohol as raw material, bubbling to the reaction system to removehydrogen chloride, and then reacted with t-butyl alcohol, after rearrangement andcatalytic hydrogenation, finally acid-catalyzed to get CPPA.（2）With phosphoroustrichloride and propargyl alcohol as raw material, triethylamine acted as acid bindingagent, and then reacted with t-butyl alcohol, followed by rearrangement, we got manyby-products rather than di-t-butyl propadienylphosphonate. In this paper, we selectedthe first synthetic route to prepare CPPA with five steps, the total yield was79%andthe purity of CPPA analyzed by HPLC was99%.Calcitriol namely1ɑ,25-dihydroxyvitamin D₃, is the basic form of vitamn D₃playing a physiological role in the body. With vitamin D2as the starting material,using sulfur dioxide to protect the conjugated triene structure, and then oxidation,low-temperature ozonation, removal of sulfur dioxide under heating, after a total of8-steps, the key intermediate （1S,3R）-bis-（t-butyldimethylsilyloxy）-20-formyl-9,10-secopregna-5（E）,7（E）,10（19）-triene was obtained with a yield of41%. In this paper,the key intermediate was used to react with phosphorous ylide and organic copperreagent.（1S,3R）-bis-（t-butyldimethylsilyloxy）-25-hyhroxy-9,10-secocholesta-5（E）,7（E）,10（19）,22（E）-tetraene and （1S,3R）-bis-（t-butyldimethylsilyloxy）-25-hydroxy-9,10-secocholesta-5（E）,7（E）,10（19）-triene were obtained respectively.