Synthesis of 20-Epi-eldecalcitol [20-Epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-Epi-ED-71]

Novel, Practical, and Scalable Approach for the Synthesis of Eldecalcitol

“…The combined organic layers were dried over MgSO 4 , filtered, and concentrated at 30 °C to give the oil product 6 (782 g), which was used in the next step without further purification. LC (7). To a solution of 6 (1000 g, 3.81 mol), DMAP (46.5 g, 0.38 mol), and TEA (771 g, 7.63 mol) in DCM (12 L) was added TBDPSCl (1467 g, 5.34 mol) dropwise at −5−0 °C under a nitrogen atmosphere.…”

“…However, the stereoselective construction of the A-ring fragment represented a formidable challenge, several of which are shown in Figure . One synthetic route to the A-ring (12 steps, 10.4%) eneyne fragment started from a symmetrical epoxide 1 (obtained by (−)-diethyl d -tartrate, five steps, 65.4%), in which several different types of C–C elongation, cyclization, and redox reactions were involved. − ,− Although the overall yield is acceptable, this route lacks the ability to construct the stereocenter at the C-1 position of the A-ring, leading to purification difficulties.…”

“…Calcitriol (1,25-(OH) 2 D 3 , 1 , Figure ), a biologically active metabolite of vitamin D 3 in vivo, exhibits a variety of physiological activities via interaction with specific subtypes of vitamin D receptor (VDR), regulating the expression of numerous genes involved in calcium/phosphate homeostasis, cellular proliferation and differentiation, and immune response. − For decades, many efforts have been made on the structural optimization of calcitriol to achieve more potent drugs for the treatment of osteoporosis, psoriasis, secondary hyperparathyroidism, cancer, and other diseases with excessive cell proliferation. − Among them, one successful invention was the discovery of eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy)­vitamin D 3 , ED-71 , 2 , Figure ), which has been used worldwide for the treatment of osteoporosis since it was licensed in 2011 …”

Vitamin D and Its Synthetic Analogs

“…20-epi-Eldecalcitol ( 84 ), a 20-epi derivative of the antiosteoporotic drug eldecalcitol ( 12 ) (Table 1 and Figure 1), was synthesized through a convergent approach by Pd-catalyzed ring-closure of an enyne and coupling with vinyl bromide. 55 Since 20-epi-1,25(OH) 2 D 3 , a diasteromer of 1,25(OH) 2 D 3 possessing an inverted C-21 methyl-substituent at C-20, shows enhanced biological activities compared to 1,25(OH) 2 D 3 , compound 84 displays a 50-fold increased inhibition of U937 human leukemia cell proliferation. 56…”