Synthesis Research Of Maxacalcitol

In the paper, two alternative synthetic route have been developed using commercially available vitamin D2 as the starting material. In addition, as a key intermediate, the asymmetric synthesis of 20(S)-alcohol with the chiral auxiliary (R-CBS) was described for the first time.One of the analogs shown to exert a selective action on the parathyroid glands was la,25-dihydroxy-22-oxavitamin D3 (Maxacalcitol), which was developed by Chugai pharmaceuticals in Japan. It has been shown to be highly effective in stimulating monocytic differentiation of human promyelocytic leukemic HL-60 cells. Additionally, the clinical trials indicate that Maxacalcitol not only appears to be safe, suppressing PTH (Secondary hyperparathyroidism) and exhibiting positive effects on bone formation, but it is also less calcemic than 1,25(OH)2 D3. The strategy was employed by Chugai pharmaceuticals to prepare Maxacalcitol on the industrial scale. The byproduct or isomer caused by the co-occurrence of side reactions is difficult to eliminate, leading to tedious work procedures and high production costs.We prepared epimeric SO2 adducts through Di els-Alder reaction by bubbling SO2 gas into the dual-solvent system. Then the resulting sulfone was ozonized. An oxygenation procedure was taken to produce isomers. In order to obtain the desired 20(S)-alcohol with high purity, an asymmetric synthetic strategy was employed. The (R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone using borane tetrahydrofuran complex as the reducing agent. Due to the fact that the epoxide exhibits high reactivity toward primary and secondary alcohols under Williamson conditions to give the corresponding ether,3-(bromomethyl)-2,2-dimethyloxirane was chosen as the alkylating agent to react with the secondary alcohol to afford the epoxy-ether, which subsequently reacted with the boron reagents to give tertiary alcohol. Selenium dioxide and N-methylmorpholine-N-oxide (NMO) produced Cl position alcohol. Triplet-sensitized photoisomerization is well-known for the conversion of trans-vitamin D compounds to cis-vitamin D compounds, and the photoisomerization afforded the target Maxacalcitol as a white solid. The strategy promoted the yield of Maxacalcitol(13.9%). Therefore, the simple operation procedure and the low production costs of this developed synthetic route will benefit the industrial production of Maxacalcitol.