Crystal structure of hydro­cortisone 17-butyrate

Yu Zhu; Wei Shen; Hai-li Wang

doi:10.1107/S1600536814023903

. 2014 Nov 5;70(Pt 12):o1239–o1240. doi: 10.1107/S1600536814023903

Crystal structure of hydrocortisone 17-butyrate

Yu Zhu ^a,^*, Wei Shen ^a, Hai-li Wang ^a

PMCID: PMC4257404 PMID: 25553020

Abstract

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.

Keywords: crystal structure, hydrocortisone derivative, hydrogen bonds, pharmacological activity

Related literature

For the pharmacological activities of the title compound, see: Haapasaari et al. (1995 ▶); Lerche et al. (2010 ▶); D’Erme & Gola (2012 ▶). For the synthesis of the title compound, see: Sun et al. (2009 ▶).

Experimental

Crystal data

C₂₅H₃₆O₆
M _r = 432.54
Orthorhombic,
a = 9.05738 (8) Å
b = 11.87633 (9) Å
c = 21.13465 (15) Å
V = 2273.42 (3) Å³
Z = 4
Cu Kα radiation
μ = 0.72 mm⁻¹
T = 291 K
0.22 × 0.2 × 0.2 mm

Data collection

Agilent Xcalibur Eos Gemini diffractometer
Absorption correction: multi-scan (CrysAlis PRO (Agilent, 2011 ▶) T _min = 0.952, T _max = 1.000
23353 measured reflections
4496 independent reflections
4389 reflections with I > 2σ(I)
R _int = 0.021

Refinement

R[F ² > 2σ(F ²)] = 0.040
wR(F ²) = 0.111
S = 1.06
4496 reflections
301 parameters
4 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.31 e Å⁻³
Δρ_min = −0.28 e Å⁻³
Absolute structure: Flack (1983 ▶), 1932 Friedel pairs
Absolute structure parameter: 0.02 (18)

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: OLEX2.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536814023903/rz5136sup1.cif

e-70-o1239-sup1.cif^{(36.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814023903/rz5136Isup2.hkl

e-70-o1239-Isup2.hkl^{(220.3KB, hkl)}

Click here for additional data file.^{(9.8KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814023903/rz5136Isup3.cml

Click here for additional data file.^{(1.7MB, tif)}

. DOI: 10.1107/S1600536814023903/rz5136fig1.tif

The molecular structure of the title compound showing 30% probability displacement ellipsoids. Only the major component of the disordered C25 methyl group is shown

CCDC reference: 1031721

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (, ).

DHA	DH	HA	D A	DHA
C19H19CO2	0.96	2.39	3.016(2)	122
O4H4O3	0.83(3)	2.06(3)	2.629(3)	126(2)
O2H2O1ⁱ	0.82	2.11	2.9192(18)	169

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors thank Ms L. R. Yang for technical assistance. This research was supported by the National Natural Science Foundation of China (No. JI210060).

supplementary crystallographic information

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 17-butyrate, 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. As expected, the chiral carbon atoms C8, C9, C11, C13, and C14 exhibit S configuration, and atoms C10 and C17 exhibit R configuration. The Flack parameter is 0.02 (18). Both central six membered rings (C5, C6, C7, C8, C9, C10, and C8, C9, C11, C12, C13, C14) exhibit chair conformation, with atoms C5 and C8 displaced by 0.6024 (16) and 0.6378 (15) Å on opposite sides from the C6, C7, C9 and C10 plane, and atoms C9 and C13 by 0.6249 (14) and 0.7014 (15) Å from the C8, C11, C12 and C14 plane. The cyclohexene ring (C1, C2, C3, C4, C5, C10) assumes a half-chair conformation, atom C2 protruding by 0.534 (2) Å from the mean plane through the remaining five atoms. The cyclopentane ring is in an envelope conformation, with atom C13 displaced by 0.6761 (15) Å from the C14, C15, C16, C17 mean plane. Intramolecular O—H···O and C—H···O hydrogen bonds are observed (Table 1). In the crystal, molecules are connected by intermolecular O—H···O hydrogen bonds to form chains parallel to the a axis.

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 CH₂Cl₂ (10 mL) solution containing hydrocortisone 21-acetate (1 mmol, 0.4 g), Et₃N (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 H₂O to reach neutrality, and extracted using CH₂Cl₂. The organic phase was combined, dried, and evaporated. Crystallization of the residue in MeOH produced hydrocortisone 17-butyrate 21-acetate. The CH₂Cl₂ solution of hydrocortisone 17-butyrate 21-acetate was added slowly to a MeOH (10 mL) solution of K₂CO₃ (0.1 g) at -10°C for selective hydrolysis. The mixture was then neutralized by CH₃COOH, washed with H₂O, and extracted with CH₂Cl₂. 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.