A synthesis is reported of 17-hydroxyprogesterone, labeled with four atoms of deuterium
at ring C and suitable for use as an internal standard for isotope dilution mass spectrometry.
Base-catalyzed equilibration of methyl 3 alpha-acetoxy-12-oxo-cholanate (III) with
2H2O, followed by reduction of the 12-oxo group by the modified Wolff-Kisher method
using [2H]diethylene glycol and [2H]hydrazine hydrate afforded [11,11,12,12,23,23(-2)H]lithocholic
acid (V). The Meystre-Miescher degradation of the side chain of V yielded 3 alpha-hydroxy-5
beta-[11,11,12,12(-2)H]pregnan-20-one (X). Oxidation of the 3,20-enol-diacetate of
X with perbenzoic acid followed by saponification afforded 3 alpha,17-dihydroxy-5
beta-[11,11,12,12(-2)H]pregnan-20-one (XI). Oxidation of XI with N-bromoacetamide
yielded 17-hydroxy-5 beta-[11,11,12,12(-2)H]pregnane-3,20-dione (XII). Bromination
of XII followed by dehydrobromination yielded 17-hydroxy-[11,11,12,12(-2)H] progesterone
(XIV), consisting of 0.3% 2H0-, 1.1% 2H1-, 8.6% 2H2-, 37.1% 2H3-, 52.1% 2H4-, and
0.8% 2H5-species.