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Volume 68 
Part 11 
Pages o436-o438  
November 2012  

Received 24 August 2012
Accepted 22 September 2012
Online 18 October 2012

Oxycodone N-oxide

aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA, and bDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, USA
Correspondence e-mail: pacrooks@uams.edu

The title compound, (5R,9R,13S,14S,17R)-14-hydroxy-3-methoxy-17-methyl-4,5-epoxymorphinan-6-one N-oxide, C18H21NO5, has been prepared in a diastereomerically pure form by the reaction of oxycodone with 3-chloroperbenzoic acid and subsequent crystallization of the product from chloroform. The crystal packing shows that the molecule exhibits intramolecular O-H...O [D...A = 2.482 (2) Å] hydrogen bonding. In addition, there are weak intermolecular C-H...O interactions which, along with van der Waals forces, stabilize the structure. The new chiral center at the 17-position is demonstrated to be R.

Comment

Oxycodone is a semisynthetic codeine derivative that has been used as both an analgesic and an antitussive agent. In the mid-1990s, oxycontin was introduced as a slow-release formulation of oxycodone for use in patients with moderate to severe chronic pain associated with such ailments as arthritis, vertebral disc disease and cancer (Moore et al., 2003[Moore, K. A., Ramcharitar, V., Levine, B. & Flower, D. (2003). J. Anal. Toxicol. 27, 346-352.]). Oxycodone metabolites excreted in the urine and faeces of several mammalian species, including man, have been reported (Ishida et al., 1982[Ishida, T., Oguri, K. & Yoshimura, H. (1982). J. Pharmacobiodyn. 5, 521-525.]; Moore et al., 2003[Moore, K. A., Ramcharitar, V., Levine, B. & Flower, D. (2003). J. Anal. Toxicol. 27, 346-352.]). There are seven known metabolites of oxycodone: oxycodone N-oxide, (I)[link], oxymorphone, (II)[link], 6[alpha]-oxycodol, (III)[link], 6[beta]-oxycodol, (IV)[link], 6[alpha]-oxycodol N-oxide, (V)[link], noroxycodone, (VI)[link], and 7[beta]-hydroxy-6[beta]-oxycodol, (VII)[link] (see Scheme[link]). In order to confirm the absolute stereochemistry of oxycodone N-oxide at the N atom in the 17-position, we synthesized (I)[link] by the reaction of oxycodone with 3-chloroperbenzoic acid, employing nonaqueous solvents, to afford a diastereomerically pure compound with subsequent crystallization of the product from chloroform. Depending on the orientation of the N-CH3 group, two diastereoisomers of oxycodone N-oxide are possible. However, in the present study, we obtained exclusively a single diastereoisomer, according to NMR analysis of the product. To establish the orientation of the N-CH3 group in this synthetic N-oxide derivative of oxycodone, and to study the detailed conformation of this molecule, its X-ray structure determination was carried out and the results are presented here.

[Scheme 1]

In an earlier study, a conformational analysis of several morphinan-6-one alkaloids was carried out using two-dimensional NMR techniques (Caldwell et al., 1993[Caldwell, G. W., Gauthier, A. D., Mills, J. E. & Greco, M. N. (1993). Magn. Reson. Chem. 31, 309-317.]). In support of these NMR studies, an X-ray crystallographic analysis of oxycodone N-oxide, (I)[link], was also carried out. The present study of (I)[link] and the Caldwell study are the same compound, but the X-ray analyses were undertaken at different temperatures, 90 and 293 K, respectively.

The numbering system of the non-H atoms and the overall configuration of the title compound are shown in Fig. 1[link], which shows that the absolute configuration of the chiral C centers in the molecule is identical to that of the starting material, oxycodone. The new chiral center at the 17-position is demonstrated to be R. The five-membered ring is distorted and the ethanamine ring has a typical chair conformation, with the newly formed N-O bond projected in an axial orientation. The conformation of the cyclohexanone ring is a twisted chair, caused by the presence of the 4,5-ether bridge, which is also responsible for the overall rigidity of the molecule. The observed C3-O19 [1.372 (2) Å] and O19-C20 [1.447 (2) Å] bond lengths are comparable with values found for methoxy O-CH3 bonds. There is an asymmetry of the exocyclic angles at C3 for (I)[link] [O19-C3-C4 = 126.72 (19)° and O19-C3-C2 = 117.16 (16)°], as is typical of anisoles (Seip & Seip, 1973[Seip, H. M. & Seip, R. (1973). Acta Chem. Scand. 27, 4024-4027.]). This asymmetry of the angles at C3 is caused by the tendency of the methoxy group to be coplanar with the benzene ring, due to conjugation of the O19 lone pair with the benzene ring of (I)[link], which is in agreement with earlier observations of the 4-methoxybenzyl group (Domiano et al., 1979[Domiano, P., Nardelli, M., Balsamo, A., Macchia, B. & Macchia, F. (1979). Acta Cryst. B35, 1363-1372.]). Most of the bond lengths and angles are in agreement with reported values (Caldwell et al., 1993[Caldwell, G. W., Gauthier, A. D., Mills, J. E. & Greco, M. N. (1993). Magn. Reson. Chem. 31, 309-317.]), although values for the torsion angles are not available for comparison.

The X-ray structure of protonated oxymorphone, (II)[link] (amine salt), has already been reported (Darling et al., 1982[Darling, S. D., Kolb, V. M., Mandel, G. S. & Mandel, N. S. (1982). J. Pharm. Sci. 71, 763-767.]). We compared our results from (I)[link] with these findings. Most of the bond lengths, bond angles and torsion angles for the non-H atoms of (I)[link] are in agreement with the literature values for protonated (II)[link]. The C2-C3, C11-C12, C13-C5, C7-C8, C8-C14, C14-C9, C10-C11 and C15-C16 bonds are considerably longer (0.034-0.053 Å) in (I)[link] compared with the values observed for protonated (II)[link]. Also, the N17-C9 bond is longer by 0.037 Å. Comparison of the bond angles for (I)[link] and protonated (II)[link] suggests that they are essentially very similar, except for C9-C14-O23, which is larger by nearly 8°. This may be the result of strong intramolecular hydrogen bonding, resulting in some stretching of the molecule. This accounts for the increases in the above-mentioned bond lengths and bond angle. Furthermore, the C8-C14-C13-C5, C14-C13-C5-C6, C14-C13-C15-C16 and C13-C15-C16-N17 torsion angles in (I)[link] are slightly larger than the values reported for protonated (II)[link]. Changes in some of the bond lengths, bond angles and torsion angles away from the site of the newly formed N-O bond suggest long-range substituent effects. The positive charge on the N atom also has an effect, which can be transmitted throughout the molecule via long-range inductive and electrostatic field effects.

The H atom attached to atom O23 is involved in an intramolecular hydrogen bond with atom O24 (Table 1[link]). In addition, there are weak intermolecular C-H...O interactions (Table 1[link]) which, along with van der Waals forces, stabilize the structure.

[Figure 1]
Figure 1
A view of the asymmetric unit of (I)[link], showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. The dashed line indicates the intramolecular hydrogen bond.

Experimental

To a stirred solution of oxycodone (0.315 g, 1 mmol) [(5R,9R,13S,14S,17R)-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one; Zalucky & Hite, 1961[Zalucky, T. B. & Hite, G. (1961). J. Med. Pharm. Chem. 3, 615-617.]] in chloroform (30 ml), maintained at 273-278 K, was added 3-chloroperbenzoic acid (0.259 g, 1.5 mmol) in small portions. After complete addition of 3-chloroperbenzoic acid, stirring was continued at room temperature for 12 h. The solution was passed through basic alumina (110-200 mesh) and traces of unreacted oxycodone were removed by washing with chloroform. Elution with methanol-chloroform (1:3 v/v) afforded oxycodone N-oxide. The crude product was crystallized from chloroform as colorless crystals, which were suitable for X-ray analysis. 1H NMR (CDCl3): [delta] 1.56-1.74 (m, 2H), 1.94-2.01 (m, 1H), 2.20-2.27 (m, 1H), 3.08-3.30 (m, 6H), 3.31 (s, 3H), 3.60 (d, 1H), 3.90 (s, 3H), 4.77 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 12.34 (s, 1H); 13C NMR (CDCl3): [delta] 26.1, 29.0, 33.2, 35.2, 50.2, 57.1, 59.8, 62.0, 72.5, 76.0, 90.1, 116.0, 120.2, 120.4, 129.4, 144.1, 145.5, 207.8.

Crystal data
  • C18H21NO5

  • Mr = 331.36

  • Orthorhombic, P 21 21 21

  • a = 7.2080 (1) Å

  • b = 12.7611 (3) Å

  • c = 16.3676 (4) Å

  • V = 1505.52 (6) Å3

  • Z = 4

  • Mo K[alpha] radiation

  • [mu] = 0.11 mm-1

  • T = 90 K

  • 0.22 × 0.20 × 0.15 mm

Data collection
  • Nonius KappaCCD area-detector diffractometer

  • Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]) Tmin = 0.977, Tmax = 0.984

  • 3445 measured reflections

  • 1988 independent reflections

  • 1746 reflections with I > 2[sigma](I)

  • Rint = 0.023

Refinement
  • R[F2 > 2[sigma](F2)] = 0.034

  • wR(F2) = 0.081

  • S = 1.07

  • 1988 reflections

  • 220 parameters

  • H-atom parameters constrained

  • [Delta][rho]max = 0.24 e Å-3

  • [Delta][rho]min = -0.21 e Å-3

Table 1
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
O23-H23...O24 0.84 1.72 2.483 (2) 151
C5-H5...O23i 1.00 2.60 3.536 (2) 157
C9-H9...O23ii 1.00 2.36 3.314 (2) 160
C16-H16B...O22iii 0.99 2.40 3.227 (3) 141
C18-H18B...O19iv 0.98 2.46 3.413 (2) 165
Symmetry codes: (i) [x+{\script{1\over 2}}, -y+{\script{3\over 2}}, -z]; (ii) [x-{\script{1\over 2}}, -y+{\script{3\over 2}}, -z]; (iii) [-x+{\script{3\over 2}}, -y+2, z-{\script{1\over 2}}]; (iv) [x-{\script{1\over 2}}, -y+{\script{5\over 2}}, -z].

H atoms were found in difference Fourier maps and subsequently placed in idealized positions, with constrained distances of 0.95 (CAr-H), 0.98 (RCH3), 0.99 (R2CH2), 1.00 (R3CH) and 0.84 Å (OH). Uiso(H) values were set at 1.2Ueq(CArH, R2CH2 and R3CH) or 1.5Ueq(RCH3 and OH) of the parent atom.

Since there was no measurable anomalous signal, Friedel pairs were merged.

Data collection: COLLECT (Nonius, 1999[Nonius (1999). COLLECT. Nonius, BV, Delft, The Netherlands.]); cell refinement: SCALEPACK (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO-SMN (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: XP in SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); software used to prepare material for publication: SHELX97-2 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) and local procedures.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: UK3053 ). Services for accessing these data are described at the back of the journal.


References

Caldwell, G. W., Gauthier, A. D., Mills, J. E. & Greco, M. N. (1993). Magn. Reson. Chem. 31, 309-317.  [CrossRef] [ChemPort] [ISI]
Darling, S. D., Kolb, V. M., Mandel, G. S. & Mandel, N. S. (1982). J. Pharm. Sci. 71, 763-767.  [CrossRef] [ChemPort] [PubMed] [ISI]
Domiano, P., Nardelli, M., Balsamo, A., Macchia, B. & Macchia, F. (1979). Acta Cryst. B35, 1363-1372.  [CrossRef] [details] [ISI]
Ishida, T., Oguri, K. & Yoshimura, H. (1982). J. Pharmacobiodyn. 5, 521-525.  [CrossRef] [ChemPort] [PubMed]
Moore, K. A., Ramcharitar, V., Levine, B. & Flower, D. (2003). J. Anal. Toxicol. 27, 346-352.  [PubMed] [ChemPort]
Nonius (1999). COLLECT. Nonius, BV, Delft, The Netherlands.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.
Seip, H. M. & Seip, R. (1973). Acta Chem. Scand. 27, 4024-4027.  [CrossRef] [ChemPort]
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]
Zalucky, T. B. & Hite, G. (1961). J. Med. Pharm. Chem. 3, 615-617.  [CrossRef] [PubMed] [ChemPort]


Acta Cryst (2012). C68, o436-o438   [ doi:10.1107/S0108270112040188 ]