A Modified Synthesis of the Antiosteoporosis Drug Alfacalcidol via a Key Photochemical Transformation of 1α-5,6-trans-Vitamin D3
Received: 28 July 2013
Accepted after revision; 28 August 2013
14 October 2013 (online)
Alfacalcidol (1α-hydroxyvitamin D3) is an important clinical drug for the treatment of osteoporosis. Its practical synthesis has been intensively pursued across academia. The difficulties of separating 5,6-cis and 5,6-trans isomers in the current process was avoided by photochemical transformation of the 5,6-trans isomer into the 5,6-cis isomer. Employing vitamin D3 as a starting material, alfacalcidol was obtained by a five-step reaction sequence of esterification, cyclization, oxidation, solvolysis ring-opening, and subsequent photochemical reaction. The overall yield has been greatly improved from 17% to 31%.
References and Notes
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- 16 Phototransformation of 5,6-trans-1α-Hydroxyvitamin D3 (5b) to 5,6-cis-1α-Hydroxyvitamin D3 (5a) A solution of of the crystalline solid (0.5 g, 1.2 mmol) from the last step in anhydrous MeOH (80 mL) containing anthracene (18.0 mg, 0.1 mmol) was thoroughly degassed. A medium-pressure 500 W ultraviolet lamp was placed such that the outside of the water-cooled jacket was 15 cm from the reaction vessel. Ice water was passed in the jacket of the quartz tube to keep the reaction cool. The mixture was irradiated for 4.0 h under argon protection at r.t., until all of 5a was converted into 5b and then concentrated in vacuo. The residue was eluted by PE–EtOAc (4:6) to separate 5a, and further recrystallization from EtOAc and cyclohexane afforded 0.37 g (75% yield) of a white crystalline solid (5a) Analytcal Data IR (KBr): 3406, 1643, 1629, 1059, 909 cm–1. 1H NMR (500MHz, CDCl3): δ = 0.55 (3 H, s, 18-CH3), 0.87 (6 H, dd, J 1 = 2.3 Hz, J 2 = 6.6 Hz, 26-CH3, 27-CH3), 0.92 (3 H, d, J = 6.5 Hz, 21-CH3), 2.32 (1 H, dd, J 1 = 6.6 Hz, J 2 = 13.4 Hz, H-4β), 2.60 (1 H, dd, J 1 = 3.3 Hz, J 2 = 13.4 Hz, H-4α), 2.83 (1 H, dd, J 1 = 3.8 Hz, J 2 = 11.8 Hz, H-14), 4.24 (1 H, m, H-3α), 4.44 (1 H, dd, J 1 = 4.3 Hz, J 2 = 7.8 Hz, H-1β), 5.01 (1 H, s, H-19E), 5.33 (1 H, t, J = 1.5 Hz, H-19Z), 6.02 (1 H, d, J = 11.3 Hz, H-7), 6.39 (1 H, d, J = 11.3 Hz, H-6).