Vitamins, 3. Vitamin D

Bendik, Igor; Höller, Ulrich; Marty, Maurus; Schütz, Jan; Lábler, L.

doi:10.1002/14356007.o27_o06.pub2

Cited by 1 publication

(1 citation statement)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to retrosynthetic analysis, there are essentially two categories of reported synthetic routes to calcitriol (1), i.e., the semi-syntheses and the total syntheses. [15][16][17] The semi-syntheses are the dominant strategy for the large-scale preparation of calcitriol. They can be further stratified into two sub-categories that use steroid precursors and vitamin D 2 (ergocalciferol, 5) as the starting material, respectively.…”

Section: Resultsmentioning

confidence: 99%

Integrated Synthesis of Calcitriol and 26,27-Hexadeutero Calcitriol

Tang,

Cui,

et al. 2024

Pharmaceutical Fronts

View full text Add to dashboard Cite

Calcitriol (1α,25-dihydroxyvitamin D3, 1), a classical vitamin D drug, is indicated primarily in the treatment of patients with postmenopausal osteoporosis and renal osteodystrophy. In this study, a practical synthesis of calcitriol (1), from readily available commercial vitamin D2 (5) via hub intermediate 18, has been accomplished in 9% overall yield. This semi-synthetic process embedded four prominent elements of vitamin D chemistry: (1) cheletropic sulfur dioxide (SO2) adduction for the isomerization of the characteristic triene from (5Z,7E) to (5E,7E), or for the protection of the triene for selective ozonolysis of the side chain, and cheletropic extrusion of SO2 from the adduct in ethanolic sodium bicarbonate to retrieve the triene; (2) direct, regio- and stereoselective 1α-hydroxylation of 3β-TBS-protected (5E)-calciferol intermediate 19 using selenium dioxide in the presence of N-methylmorpholine N-oxide as a re-oxidant in a hot mixture of methylene chloride and methanol; (3) nickel(0)-mediated conjugate addition of the 22-iodide 23 to electron-deficient ethyl acrylate followed by Grignard reaction with methylmagnesium bromide to construct the calcitriol side chain; and (4) triplet-sensitized photoisomerization of 26 to access the bioactive (5Z,7E)-triene in calcitriol (1). The high-performance liquid chromatography purities of batches of the synthesized calcitriol (1) were consistently more than 99.9%, with related substances listed in the USP 2023 and EP 11.0 well controlled. This robust process proved amenable to pilot scale-up and industrial production. 26,27-Hexadeutero calcitriol (4), a deuterium-labeled calcitriol derivative, is useful as the internal standard in the bioanalysis for the quantification of calcitriol in serum. 4 was efficiently synthesized in an integrated manner from hub intermediate 18 in 48% yield.

show abstract

Section: Resultsmentioning

confidence: 99%