Improved and efficient synthesis of 1alpha-hydroxy-[6-(2)H] and 1alpha-hydroxy-[6,19,19-(2)H]vitamin D3 derivatives.
Improved and efficient procedures for deuterium-labeling at the 6,19,19 positions of 1alpha-hydroxyvitamin D3 derivatives via its sulfur dioxide-adduct by using a base-catalyzed H-D exchange reaction are described. Application of the known procedure using tBuOK/DMF-D2O, which is effective for labeling vitamin D3 derivatives, to 1alpha-hydroxy compounds gave only poor results because of isomerization and decomposition. We found that this procedure is improved by the use of iPrONa/iPrOD. During this study, we also found that the 6-monodeuterated product was selectively obtained when MeONa/CD3OD was employed instead of iPrONa/iPrOD. On the other hand, simple addition of 1,3-dimethyl-2-imidazolidinone as a co-solvent to the above conditions was effective for 1alpha,25-dihydroxy compounds. These improved procedures were successfully applied to the synthesis of 1alpha-hydroxy-[6,19,19-(2)H]vitamin D3 derivatives 4 and 1alpha-hydroxy-[6-(2)H]vitamin D3 derivatives 6 from the corresponding 1alpha-hydroxyvitamin D3 derivatives 1 via its sulfur dioxide-adducts 2, 3 and 5 in good over-all yield with high deuterium incorporation.
Iwasaki
H
H
Tsukuba Research Laboratory, NOF Corporation, Ibaraki, Japan.
Hosotani
R
R
Nakano
Y
Y
Konno
K
K
Takayama
H
H
D003903:Deuterium; D006887:Hydroxycholecalciferols / Q000138:chemical synthesis / Q000737:chemistry*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure
D006887:Hydroxycholecalciferols; D003903:Deuterium; C008088:alfacalcidol