Synthesis Of Ergocalciferol Analogues

In the past, people think the analogues of ergocalciferol were only nutrient that regulated the balance of calcium metabolism; in 1981, Japanese scientists confirmed that analogues of ergocalciferol had the function that inducted cell differentiation and cell proliferation. Analogues of ergocalciferol receptor, not only exists in small intestine, bone and kidney, but also in various organizations as well as a variety of human cancer cells. Today, the drugs of ergocalciferol analogues can target tissue, physiological role is diversity, it is widely used to treat osteoporosis, parathyroid (ARF), psoriasis, cancer and immune diseases. However, Because ergocalciferol analogues in the treatment of hypercalcemia often lead to hypercalcemia and hyperphosphatemia, its application was limited, and 19-methylene missing ergocalciferol analogues compounds in animal experiments and clinical studies have shown the pharmacological effects of relatively selective were safe and effective for its inhibition the secretion of parathyroid hormone and parathyroid gland hyperplasia and rarely cause hypercalcemia and hyperphosphatemia.This paper concentrates on studing the synthesis of ergocalciferol analogues and the key steps of synthesis. New 19-nor ergocalciferol analogues were synthesized by two routines, The content included as following:1. Using similar synthetic method, alfacalcidol and doxercalciferol were synthesized.2. As a model reaction,19-nor ergocalciferol was synthesized. After the synthesis of 3, 5-cycle ergocalciferol, la-OH formed by allylic oxidation, protected through ester, then used potassium permanganate oxidation to generate diol, with lead tetraacetate instead of sodium periodate generated la-OAc-10-oxo compound, followed by reaction with similar to 19-nor ergocalciferol, final crude product was obtained. This route was complex, low yield. Therefore, we attempted another synthesis, starting from 10-oxo ergocalciferol, by triflating reagent to obtain 10-OTf-l-alene ergotcalciferol, reduced to get 1-alene ergotcalciferol by Pd(OAc)2, then by 9-BBN to obtain la-OH compound, and finally through the hydrolysis method to get target product.3. On the research of dihydroxylation of the 3,5-cycle ergocalciferol, we employed potassium permanganate as the oxidant instead of osmium tetroxide which is toxic and expensive, and achieved good and similar result.4. Respectively investigated the synthesis condition on the triflate of 10-oxo-3,5-cycle ergocalciferol by employing different alkali including 2,6-Lutidine,Sodium Hydride,LDA,LiHMDS, experiment showed the best reagent was LiHMDS, it got the less by-product and higher yield.