Synthesis and crystal structure of (22R)-6 alpha,9 alpha-difluoro-11 beta-hydroxy-21-palmitoyloxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione (rofleponide 21-palmitate)

The 21-palmitate of the stereochemically pure glucocorticosteroid rofleponi de [(22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-p ropylmethylenedioxypregn-4-ene-3,20-dione], C41H64O7F2, was synthesised, an d its solid-state conformation and absolute configuration were determined a t T = 163 +/- 2 K using single-crystal X-ray diffraction. The structure has an orthorhornbic (P2(1)2(1)2(1), No. 19) unit cell with a = 8.007(2) Angst rom, b = 17.399(5) Angstrom, c = 27.927(6) Angstrom, V-c = 3891(2) Angstrom (3), containing four molecules [D-c = 1.2069(5) g cm(-3), F(000) = 1536]. T he R configuration for the chiral centre at C(22), created during the synth esis of rofleponide, is deduced using the knowledge of the absolute configu ration of the hydrocortisone-related part of the molecule. The long-chained angular 17 beta-substituent is partially disordered, exhibiting at least t wo different conformations: it is approximately equatorially connected to t he cyclopentane D ring and axially to the dioxolane E ring in the 'a' confo rmer, but has a bisectional attachment to both five-membered rings in the ' b' conformer. The O(11)H ... O(3) hydrogen bond links the steroid molecules so as to form endless parallel strings. The final structure model, compris ing two major disorder sites for each of the eleven most disordered non-hyd rogen atoms and also for the hydrogens linked to them, was refined to R = 0 .061 for 1332 observations with I > 2 sigma(I).