| This paper deals with the synthesis research of Secondary Hyperparathyroidism drug paricalcitol,including the introduction of Secondary Hyperparathyroidism,the review of synthetic routes reported of paricalcitol and the research of the synthetic route choosed.The hormonally active vitamin D3,1α,25-dihydroxyvitamin D3 [1α,25-(OH)2 D3], is the active form in the body,is now well recognized as an important cell-cycle,which influences cell proliferation,differentiation and apotosis and inhibit cell proliferation activity, in addition to possessing a regulatory effects on calcium and phosphorus metabolism. VitD3 and their synthetic analogs have been used in the treatment of osteoporosis, secondary hyperparathyroidism(SHPT), psoriasis, etc.Paricalcitol is a selective,third generation vitamin D receptor activator developped by Abbott. The main indication is the treatment of secondary hyperparathyroidism(SHPT). By modifying two side chain groups of calciferol can enable it selectively active the vitamin D receptor(VDR) and selectively increase the sensitivity of the calcium receptor(CaSR). This can better suppress PTH synthesis and secretion, while fewer adverse reactions like hypercalcemia psychosis occur. Its injection( trade name Zempalar) first on the market is in 1998, for the treatment of adult kidney dialysis patients with secondary hyperthyroidism. In 2004, FDA approved Zempalar injection for the treatment of 5-19 year-old kidney dialysis patients with secondary hyperparathyroidism. In 2005, FDA approved paricalcitol capsules for the prevention and treatment of SHPT.Since the literatures survey completed,we had chose asynthetic route and got through it. Starting with vitamin D2,the synthetic route of paricalcitol contains 14 steps such as tosyl protecting 3-hydroxy, cyclization, silyl protecting, ozonation, sodium borohydride reduction, acetyl selection protecting 22-hydroxy, 10-hydroxy protected by mesyl, lithium aluminum tetrahydrocannabinol reduction, the key intermediate IM-C10 a achieved by Swern oxidation, and then condensating the side chain IM-WR5 by Wittig reaction, acid hydrolysis, removing silyl protection, alkaline hydrolysis to give Paricalcitol. The yield is 5.50%, the literature’s yield is 5.67%(all counted by vitamin D2).The end product’s melting point is 163.6-164.7℃.Specific rotation [α]20D=19.217°(c0.363,EtOH)(the melting point and optical rotation of Paricalcitol are not reported by literature), The high resolution mass spectrometry,infrared spectroscopy,1H-NMR and 13C-NMR are consistent with the structure of Paricalcitol.The relative chemical purity of the refined product is 99.11%.The step of protecting the 3-hydroxy group of Vitamin D2 to give IM-A1, we replace pyridine with trimethylamine,choose the suitable temperature and the suitable ratio raw. Under these conditions, there are fewer impurities, generate less the three wastes and the after-treatments are simpler. The step of cyclization, we choose the appropriate reaction temperature.Under this reaction temperature, there are fewer impurities. Also,we improve the way of after-treatments,and after-treatment is simpler, the yield of oil is also improved. The step of generating 1 α-hydroxyl, we change the feeding policy by studying the reaction mechanism. And the reaction time is shortened. Preparation of the key intermediate IM-C10 a, we cut off column chromatography of the literature, and selected the appropriate after-treatment to obtain pure IM-C10 a, the yield is higher than the literature’s.Preparation of IM-WR5:starting with S–(+)-3-hydroxy-2-methyl-propionic acid methyl ester, through format, tosyl protection, iodide, to be a salt with triphenylphosphine. yield is 72.40%(literature yield is 66.53%).The step of synthesizing IM-WR5, by screening the solvent and temperature, we choose EA as the appropriate solvent, and 110℃ by pressurizing as the temperature of the reaction, avoid using the more toxic acetonitrile.The reaction time is shortened from 29 h to 12 h, and also aftertreatments are simpler. |
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