Crystal structure of hydrocortisone 17-butyrate

In the title compound, C25H36O6, the two central cyclohexane rings exhibit a chair conformation. The terminal cyclohexene and cyclopentane rings are in half-chair and envelope conformations (with the C atom bearing the methyl substituent as the flap), respectively. The methyl group of the butyrate chain is disordered over two orientations, with a refined occupancy ratio of 0.742 (6):0.258 (6). Intramolecular O—H⋯O and C—H⋯O hydrogen bonds are observed. In the crystal, molecules are linked by O—H⋯O hydrogen bonds into chains running parallel to the a axis.


S1. Comment
Hydrocortisone 17-butyrate is an important cortical hormone drug derived from the esterification reaction of hydrocortisone at the hydroxyl group of C-17. Due to the introduction of the alkyl chain, hydrocortisone 17-butyrate showed increased lipophicity and affinity for receptors, which lead to increased pharmacological activity (Haapasaari et al., 1995;Lerche et al., 2010;D′Erme & Gola, 2012). Compared with hydrocortisone, it showed increased anti-inflammatory activity, immunosuppressive properties, and low side effect. Due to the outstanding characteristics of hydrocortisone 17butyrate, it has drawn great attention of the experts from the fields of chemistry, pharmacy and medicine. The synthesis and properties have been investigated quite extensively, while its molecular structure has not been reported. Here we present the single-crystal X-ray diffraction study of hydrocortisone 17-butyrate.
The molecular structure of the title compound is shown in Figure 1

S2. Experimental
The title compound was obtained following a patent report (Sun et al., 2009). At 0-5°C, butyryl chloride (1.5 mmol, 0.16 mL) was added dropwise to a CH 2 Cl 2 (10 mL) solution containing hydrocortisone 21-acetate (1 mmol, 0.4 g), Et 3 N (4 mL) and 4-dimethylaminopyridine (0.05 mmol, 6 mg). The mixture was then stirred at 0°C for 3 hours before being treated with HCl to reach a pH of 2. The mixture was then washed with H 2 O to reach neutrality, and extracted using CH 2 Cl 2 . The organic phase was combined, dried, and evaporated. Crystallization of the residue in MeOH produced hydrocortisone 17-butyrate 21-acetate. The CH 2 Cl 2 solution of hydrocortisone 17-butyrate 21-acetate was added slowly to a MeOH (10 mL) solution of K 2 CO 3 (0.1 g) at -10°C for selective hydrolysis. The mixture was then neutralized by CH 3 COOH, washed with H 2 O, and extracted with CH 2 Cl 2 . The organic phase was combined, dried and evaporated.
Crystallization of the residue in MeOH at 0°C produced pure hydrocortisone 17-butyrate. Crystals suitable for X-ray analysis were obtained by slow evaporation of a MeOH (20 mL) solution of hydrocortisone 17-butyrate (5 mg) at room temperature.
supporting information

S3. Refinement
The C25 methyl carbon atom is disordered over two orientations with refined occupancy ratio 0.742 (6):0.258 (6). The disordered atoms were refined by constraining the C24-C25 and C24-C25A bond lengths to be 1.52 (1) Å and by restraining the anisotropic displacement ellipsoids to be equal. The hydroxyl H atom bound to O4 was located in a difference Fourier map and refined freely. All other H atoms were placed in calculated positions and refined as riding, with C-H = 0.93-0.97 Å, O-H = 0.82 Å, and with U iso (H) = 1.2U eq (C) or 1.5U eq (C) for methyl and hydroxyl H atoms.
A rotating model was applied to the methyl and hydroxyl groups. One outlier (0 1 1) was omitted in the last cycles of refinement.

Figure 1
The  Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (