Ein effektives Verfahren zur Herstellung von 1?,25-Dihydroxy-cholecalciferol (Calcitriol) aus 1?3?,25-Trihydroxy-cholesta-5,7-dien (Procalcitriol)

Abstract

An Effective Procedure for the Synthesis of 1α,25‐Dihydroxy‐cholecalciferol (Calcitriol) Starting with 1α,3β, 25‐Trihydroxy‐cholesta‐5,7‐diene (Pro‐Calcitriol) In order to develop an effective synthesis of the important vitamin D metabolite 1α,25‐(OH)2‐cholecalciferol (calcitriol) 5a starting with pro‐calcitriol 1a the influence of reaction temperature and degree of turnover of 1a to the compositions of the photoproducts at irradiation in a 500 ml photoreactor were investigated. The combination of the highly photostable filter solution consisting of 2,7‐dimethyl‐3,6‐diaza‐cyclohepta‐1,6‐diene‐tetrafluoroborate and biphenyl in ethanol realizes the double wavelength irradiation in the range of 290 to 300 nm and > 330 nm resulting in a highly amount of the desired pre‐calcitriol 2a. The reversible photoisomers of pre‐calcitriol 2a 1α,25‐(OH)2‐lumisterol3 4a and 1α,25‐(OH)2‐tachysterol3 3a were isolated from an irradiation mixture in pure form by means of an appropriate combination of flash‐chromatography, MPLC and preparative HPLC, respectively. The isomers 2a, 3a and 4a were characterized chromatographically and spectroscopically. Photoisomerization of 1a at −45 °C using the filter solution mentioned above and recycling all reversible photoisomers resulted in highly pure 5a after thermally induced isomerization of 2a isolated from the irradiation mixture by means of flash‐chromatography on Ag+‐ impregnated silica with a yield of 68%.

Continuous-flow synthesis of activated vitamin D3 and its analogues

“…Some modification of the reported 7-step procedure 48 led to the synthesis of 25-OH provitamin D 3 (8) from 7 in a good yield. 1α-OH provitamin D 3 (9) 49 and 1α,25-(OH) 2 provitamin D 3 (10) 50 were prepared from the alkylation of the common starting material 22 with Grignard reagents 23 or 18. 7 Tosylate 22 was readily prepared from alcohol 20 51,52 in high yield.…”

“…The combined organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3% MeOH in CHCl 3 ) to give 1α,3β,25-trihydroxycholesta-5,7diene (10) 50 (213 mg, 0.551 mmol, 92%) as a white solid. 1 (2), and its analogues 11-13 Solutions of provitamin D 3 analogue 7, 8, 9, 10, or 24 in 1,4dioxane were introduced into the syringe pump.…”