Synthesis of putative metabolites of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)

1α,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71), an analog of active vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is under phase III clinical trials in Japan for the treatment of osteoporosis and bone fracture prevention. Since ED-71 has a substituent at the 2β-position of the A-ring, it is recognized that the metabolic pathway of ED-71 might be more complicated than 1,25(OH)2D3 because of metabolism at the 2β-position substituent in addition to the inherent metabolism of the side chain. To clarify the metabolism of hydroxypropoxy substituent of the 2β-positon and a combination of metabolism between side chain and 2β-positon, four putative metabolites of ED-71 have been prepared as authentic samples. The metabolites at the 2β-positon, the methyl ester derivative considered as an ester standard of the oxidized metabolite and the tetraol derivative as the truncated metabolite were synthesized from α-epoxide, a key intermediate of ED-71 synthesis. The combination metabolites between side chain and 2β-positon, the 24(S)- and 24(R)-pentaols were synthesized using Trost's convergent method.