Efficient photochemical formation of 1 alpha-hydroxyprevitamin D3.

Abstract

Control of the band width of the irradiating light between 280 and 310 nm and of the temperature of the reaction permits formation of la-hydroxyprevitamin D3 in yields of over 80%, at 40-60% conversion of the la-hydroxyprovitamin D3. The procedures developed permit doubling the photochemical yield of the la-hydroxyvitamin D3 compounds which are the major circulatory forms of vitamin D3.The utility of la-hydroxyvitamin D derivatives in the treatment of various medical disorders arising from faulty calcium metabolic processes has led to the preparation of a wide variety of hydroxylated sidechain derivatives (for reviews of the physiology of vitamin D, see refs. 1-3). In the preparation of these materials, the major attention often has been directed only to the preparation of the material, without optimization of the overall yield. It was early found by Barton (4) that the standard irradiation condition utilized to prepare previtamin D3 (preD3) in good yield gave a much lower yield (15-25%) when applied to the preparation of la-OHpreD3 and its side chain-hydre ylated derivatives.7-dehydrocholesterol in dry ether was irradiated at the given temperature with 300-nm light from a CMX-4 laser (6 kV per pulse; 15 pulses per sec; 5 mW; rhodamine 6-G in methanol) and the reaction was monitored by HPLC with progesterone as the standard. Under the HPLC conditions used, la-hydroxyprovitamin D3 and la-hydroxylumisterol could not be separated, and therefore the sum of the two compounds is reported here. At 0C, the formation of la-OHpreD3 leveled off at a maximal yield of about 22%; the amount of the provitamin continued to decrease, 60% having been consumed at this leveling-off stage (Fig. 1A). About 3% of la-hydroxytachysterol3 had been found, a material not reported by Kobayashi (5) but reported by other workers (6). The formation ofundesirable byproducts (i.e., decomposition ofmaterials) continued at a steady rate and, at the leveling-off point for la-OHpreD3 formation, these products amounted to 45% of the total reaction mixture (Fig. 1B).When the laser irradiation was conducted at -21°C, quite a different reaction profile was found. The formation of la-HO la-Hydroxyprevitamin D3 la-Hydroxyprovitamin D3 It was noted that UV light in the ranges below 275 nm and above 310 nm, especially between 310 and 330 nm, gave rise to undesirable products.The problem of synthesis recently has been investigated in detail at room temperature by Kobayashi and his collaborators (5) using monochromatic UV light obtained from a spectroirradiator for analytical irradiations and using a newly reported filter solution (light between 280 and 310 nm) for preparative irradiation. These studies showed that the maximal yield of lahydroxyvitamin D was obtained by using their filter solution III, the results being 39% la-OHD3, 20% starting la-hydroxyprovitamin D3 (1-OHproD3) and 41% undesirable byproducts (i.e., a 50% yield of vitamin D based upon recovered preD3 precursors). EXPERIMENTALThe effect of bandwidth of the incident light and of the ...