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Acta Crystallographica Section E: Crystallographic Communications logoLink to Acta Crystallographica Section E: Crystallographic Communications
. 2016 Apr 26;72(Pt 5):730–733. doi: 10.1107/S2056989016006563

Two ortho­rhom­bic polymorphs of hydro­morphone

Jaroslaw Mazurek a,*, Marcel Hoffmann a, Ana Fernandez Casares a, D Phillip Cox b, Mathew D Minardi c, Josh Sasine c
PMCID: PMC4908523  PMID: 27308029

Conditions to obtain two polymorphic forms by crystallization from solution were determined for the analgestic drug hydro­morphone. In both polymorphs, the hydro­morphone mol­ecules adopt very similar conformations with some small differences observed only in the N-methyl amine part of the mol­ecule. The crystal structures of both polymorphs feature chains of mol­ecules connected by hydrogen bonds

Keywords: crystal structure; polymorphism; hydro­morphone,hydrogen bonding

Abstract

Conditions to obtain two polymorphic forms by crystallization from solution were determined for the analgesic drug hydro­morphone [C17H19NO3; systematic name: (4R,4aR,7aR,12bS)-9-hy­droxy-3-methyl-1,2,4,4a,5,6,7a,13-octa­hydro-4,12-methano­benzofuro[3,2-e]iso­quinolin-7-one]. These two crystalline forms, designated as I and II, belong to the P212121 ortho­rhom­bic space group. In both polymorphs, the hydro­morphone mol­ecules adopt very similar conformations with some small differences observed only in the N-methyl amine part of the mol­ecule. The crystal structures of both polymorphs feature chains of mol­ecules connected by hydrogen bonds; however, in form I this inter­action occurs between the hydroxyl group and the tertiary amine N atom whereas in form II the hydroxyl group acts as a donor of a hydrogen bond to the O atom from the cyclic ether part.

Chemical context  

Drug polymorphism has been the subject of hundreds of publications and numerous excellent reviews (Byrn et al., 1999 ▸; Grant, 1999 ▸; Singhal & Curatolo, 2004 ▸; Vippagunta et al., 2001 ▸). It is well established that polymorphs with different stability may have different solubility and dissolution rates, which can affect the bioavailability. The semi-synthetic opiate drug hydro­morphone is a potent derivative of morphine and despite poor bioavailability (Parab et al., 1988 ▸) is commonly used to treat moderate to severe pain in the treatment of cancer (Sarhill et al., 2001 ▸). To improve bioavailability of this compound a polymorph screen was performed that resulted in two solvent-free forms, designated as form I and form II.graphic file with name e-72-00730-scheme1.jpg

Structural commentary  

The mol­ecular structure of hydro­morphone in both polymorphs is nearly identical (Fig. 1 ▸) with some deviations found only for the N-methyl amine part of the piperidine fragment (Fig. 2 ▸). For example the C10—C11—N12—C13 torsion angle is 178.5 (2)° for form I and 169.5 (2)° for form II. The adopted conformation is similar to the conformation observed for morphine (Bye, 1976 ▸; Scheins et al., 2005 ▸).

Figure 1.

Figure 1

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Mol­ecular structure and atom-numbering scheme for hydro­morphone in the crystals of form I (left) and form II (right). Displacement ellipsoids are shown at the 50% probability level.

Figure 2.

Figure 2

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Superposition of the hydro­morphone mol­ecules from two polymorphic forms (red form I, blue form II) generated by fitting of the aromatic ring.

Supra­molecular features  

Although both polymorphs crystallize in the same space group P212121 with the same number of mol­ecules in the asymmetric unit, they differ significantly in the packing features (Figs. 3 ▸ and 4 ▸). In form I, the hydrogen-bonded mol­ecules are arranged into chains that run along the a axis with adjacent mol­ecules in the chain related by translation. The hydroxyl group donates a hydrogen atom which is accepted by the free electron pair of the N atom (Fig. 5 ▸, Table 1 ▸). In the crystals of form II, inter­molecular hydrogen bonds also generate a chain of mol­ecules that propagates along the a axis; however, adjacent mol­ecules along this chain are related by a 21 symmetry axis. The mol­ecules are connected by O—H⋯O hydrogen bonds with the hydroxyl group as donor and the etheric O atom as acceptor (Table 2 ▸). These chains form a zigzag pattern, as illustrated in Fig. 6 ▸. The packing arrangement of mol­ecules in form II is more dense than in polymorph I, as indicated by the Kitajgorodskij (1973 ▸) packing coefficients of 0.71 and 0.69, respectively.

Figure 3.

Figure 3

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Crystal packing diagram of form I, viewed along the a axis. Hydrogen bonds are shown as blue lines.

Figure 4.

Figure 4

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Crystal packing diagram of form II, viewed along the a axis. Hydrogen bonds are shown as blue lines.

Figure 5.

Figure 5

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The chain of mol­ecules running along the a axis formed by O—H⋯N hydrogen bonds in form I.

Table 1. Hydrogen-bond geometry (Å, °) for (I) .

D—H⋯A D—H H⋯A D⋯A D—H⋯A
O1—H1A⋯N12i 0.91 (4) 1.89 (4) 2.796 (3) 171 (3)
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Symmetry code: (i) Inline graphic.

Table 2. Hydrogen-bond geometry (Å, °) for (II) .

D—H⋯A D—H H⋯A D⋯A D—H⋯A
O1—H1⋯O4i 0.84 (3) 1.96 (3) 2.791 (2) 167 (3)
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Symmetry code: (i) Inline graphic.

Figure 6.

Figure 6

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The zigzag chain of mol­ecules running along the a axis formed by O—H⋯O hydrogen bonds in form II.

Synthesis and crystallization  

10.8 mg of hydro­morphone was dissolved in 1.8 mL THF/acetone (1/1, v/v) and left to evaporate slowly under ambient conditions. After several days, colorless prism-like crystals of form I (m.p. 549.8 K) appeared that were used for diffraction studies. Crystals of form II were obtained in the following way: 19.7 mg of hydro­morphone was suspended in 0.3 mL of 50/50 mixture of ethanol and toluene. The suspension was heated to 333 K and stirred for about one h until it became clear. Subsequently, the vial was cooled rapidly to 278 K and colorless block-like crystals (m.p. 550.2 K) precipitated that were used for diffraction studies.

Refinement  

The H atoms from the methyl group in form II were included from geometry and their isotropic displacement parameters refined. The remaining H atoms were found in a Fourier difference map and freely refined. The absolute configuration of hydro­morphone was known from the synthetic route. In the absence of significant anomalous scattering effects, Friedel pairs were merged. Crystal data, data collection and structure refinement details are summarized in Table 3 ▸.

Table 3. Experimental details.

  (I) (II)
Crystal data
Chemical formula C17H19NO3 C17H19NO3
M r 285.33 285.33
Crystal system, space group Orthorhombic, P212121 Orthorhombic, P212121
Temperature (K) 296 296
a, b, c (Å) 8.9497 (6), 11.0906 (6), 14.2608 (9) 8.8802 (6), 10.6208 (8), 14.4733 (9)
V (Å3) 1415.49 (15) 1365.05 (16)
Z 4 4
Radiation type Mo Kα Mo Kα
μ (mm−1) 0.09 0.10
Crystal size (mm) 0.35 × 0.35 × 0.30 0.40 × 0.32 × 0.22
 
Data collection
Diffractometer Bruker KappaCCD Bruker KappaCCD
Absorption correction – –
No. of measured, independent and observed [I > 2σ(I)] reflections 7054, 3427, 3088 15227, 4920, 4693
R int 0.031 0.022
(sin θ/λ)max (Å−1) 0.671 0.758
 
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S 0.042, 0.096, 1.05 0.033, 0.095, 1.07
No. of reflections 3427 4920
No. of parameters 266 257
H-atom treatment All H-atom parameters refined H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.19, −0.17 0.27, −0.12
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Computer programs: COLLECT (Hooft, 1998 ▸), HKL DENZO and SCALEPACK (Otwinowski & Minor, 1997 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2014/7 (Sheldrick, 2015b ▸), Mercury (Macrae et al., 2006 ▸) and enCIFer (Allen et al., 2004 ▸).

Supplementary Material

Crystal structure: contains datablock(s) I, II. DOI: 10.1107/S2056989016006563/gk2659sup1.cif

e-72-00730-sup1.cif (827.3KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989016006563/gk2659Isup2.hkl

e-72-00730-Isup2.hkl (273.6KB, hkl)
Click here for additional data file. (2.2KB, mol)

Supporting information file. DOI: 10.1107/S2056989016006563/gk2659Isup4.mol

Structure factors: contains datablock(s) II. DOI: 10.1107/S2056989016006563/gk2659IIsup3.hkl

e-72-00730-IIsup3.hkl (391.7KB, hkl)
Click here for additional data file. (2.2KB, mol)

Supporting information file. DOI: 10.1107/S2056989016006563/gk2659IIsup5.mol

CCDC references: 1474753, 1474752

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

supplementary crystallographic information

(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Crystal data

C17H19NO3 Dx = 1.339 Mg m−3
Mr = 285.33 Melting point < 549.8 K
Orthorhombic, P212121 Mo Kα radiation, λ = 0.71073 Å
a = 8.9497 (6) Å Cell parameters from 9169 reflections
b = 11.0906 (6) Å θ = 1.0–32.6°
c = 14.2608 (9) Å µ = 0.09 mm−1
V = 1415.49 (15) Å3 T = 296 K
Z = 4 Prism, colorless
F(000) = 608 0.35 × 0.35 × 0.30 mm
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Data collection

Bruker KappaCCD diffractometer 3088 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube Rint = 0.031
Horizonally mounted graphite crystal monochromator θmax = 28.5°, θmin = 3.4°
CCD scans h = −11→11
7054 measured reflections k = −11→14
3427 independent reflections l = −17→19
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Refinement

Refinement on F2 Primary atom site location: difference Fourier map
Least-squares matrix: full Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.042 Hydrogen site location: difference Fourier map
wR(F2) = 0.096 All H-atom parameters refined
S = 1.05 w = 1/[σ2(Fo2) + (0.0361P)2 + 0.2726P] where P = (Fo2 + 2Fc2)/3
3427 reflections (Δ/σ)max = 0.005
266 parameters Δρmax = 0.19 e Å−3
0 restraints Δρmin = −0.17 e Å−3
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq
O1 0.91711 (18) 0.7664 (2) 0.17051 (12) 0.0513 (5)
H1A 0.993 (4) 0.774 (3) 0.213 (2) 0.069 (10)*
C2 0.7893 (2) 0.7337 (2) 0.21531 (15) 0.0337 (4)
C3 0.6543 (2) 0.73164 (19) 0.16755 (13) 0.0318 (4)
O4 0.63079 (17) 0.74990 (16) 0.07223 (10) 0.0409 (4)
C5 0.4813 (3) 0.7006 (2) 0.05538 (15) 0.0369 (5)
H5A 0.439 (3) 0.745 (2) 0.0007 (18) 0.034 (6)*
C6 0.4906 (3) 0.5664 (3) 0.03355 (16) 0.0455 (6)
O7 0.6063 (3) 0.5185 (2) 0.00966 (16) 0.0692 (6)
C8 0.3484 (4) 0.4980 (3) 0.0485 (2) 0.0555 (7)
H8A 0.362 (4) 0.413 (3) 0.031 (2) 0.073 (10)*
H8B 0.271 (4) 0.541 (3) 0.006 (2) 0.063 (9)*
C9 0.3038 (3) 0.5078 (2) 0.1523 (2) 0.0464 (6)
H9A 0.387 (4) 0.480 (3) 0.193 (2) 0.057 (8)*
H9B 0.220 (3) 0.455 (3) 0.166 (2) 0.055 (8)*
C10 0.2671 (2) 0.6384 (2) 0.17446 (16) 0.0334 (4)
H10A 0.175 (3) 0.660 (2) 0.1390 (16) 0.034 (6)*
C11 0.2315 (2) 0.6636 (2) 0.27875 (16) 0.0365 (5)
H11A 0.147 (3) 0.610 (2) 0.2993 (18) 0.043 (7)*
N12 0.1698 (2) 0.78799 (19) 0.28457 (13) 0.0381 (4)
C13 0.1274 (3) 0.8219 (3) 0.3807 (2) 0.0555 (7)
H13A 0.072 (4) 0.750 (3) 0.410 (2) 0.068 (9)*
H13B 0.216 (4) 0.844 (3) 0.417 (2) 0.054 (8)*
H13C 0.060 (4) 0.893 (3) 0.373 (2) 0.073 (10)*
C14 0.2738 (3) 0.8808 (2) 0.24843 (19) 0.0426 (6)
H14A 0.221 (3) 0.956 (3) 0.251 (2) 0.051 (8)*
H14B 0.359 (3) 0.888 (2) 0.291 (2) 0.046 (7)*
C15 0.3324 (3) 0.8528 (2) 0.15154 (17) 0.0377 (5)
H15A 0.251 (3) 0.862 (3) 0.105 (2) 0.048 (7)*
H15B 0.414 (3) 0.912 (2) 0.1341 (18) 0.043 (7)*
C16 0.3942 (2) 0.72389 (19) 0.14723 (13) 0.0291 (4)
C17 0.5225 (2) 0.70844 (19) 0.21381 (14) 0.0289 (4)
C18 0.5145 (2) 0.6740 (2) 0.30675 (14) 0.0315 (4)
C19 0.3642 (2) 0.6356 (3) 0.34492 (17) 0.0417 (5)
H19A 0.364 (3) 0.548 (3) 0.356 (2) 0.058 (9)*
H19B 0.341 (3) 0.672 (3) 0.406 (2) 0.058 (8)*
C20 0.6499 (2) 0.6686 (2) 0.35428 (14) 0.0335 (4)
H20A 0.655 (3) 0.640 (2) 0.4198 (18) 0.039 (6)*
C21 0.7821 (2) 0.6994 (2) 0.30952 (15) 0.0350 (5)
H21A 0.871 (3) 0.693 (2) 0.3430 (17) 0.038 (6)*
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23
O1 0.0239 (8) 0.0907 (15) 0.0393 (9) −0.0080 (8) 0.0014 (7) 0.0059 (9)
C2 0.0235 (9) 0.0427 (12) 0.0349 (10) 0.0002 (9) 0.0009 (8) −0.0005 (9)
C3 0.0293 (10) 0.0393 (11) 0.0269 (9) −0.0021 (8) 0.0004 (8) 0.0035 (8)
O4 0.0315 (8) 0.0656 (11) 0.0256 (7) −0.0051 (7) 0.0000 (6) 0.0068 (7)
C5 0.0321 (10) 0.0511 (13) 0.0276 (9) −0.0006 (10) −0.0047 (9) 0.0035 (9)
C6 0.0490 (14) 0.0573 (15) 0.0301 (10) 0.0061 (12) −0.0004 (11) −0.0045 (10)
O7 0.0662 (14) 0.0728 (14) 0.0687 (14) 0.0171 (11) 0.0256 (11) −0.0007 (11)
C8 0.0547 (16) 0.0505 (16) 0.0615 (17) −0.0015 (14) −0.0071 (14) −0.0212 (14)
C9 0.0390 (13) 0.0362 (12) 0.0640 (16) −0.0067 (10) −0.0001 (12) −0.0024 (11)
C10 0.0262 (9) 0.0360 (11) 0.0380 (11) −0.0030 (8) −0.0044 (9) 0.0015 (9)
C11 0.0257 (10) 0.0438 (12) 0.0398 (11) −0.0059 (9) 0.0004 (9) 0.0046 (10)
N12 0.0266 (8) 0.0487 (11) 0.0389 (9) −0.0015 (8) 0.0005 (8) −0.0058 (8)
C13 0.0374 (13) 0.084 (2) 0.0448 (14) −0.0071 (15) 0.0034 (12) −0.0195 (14)
C14 0.0357 (12) 0.0383 (13) 0.0536 (14) 0.0002 (10) 0.0000 (11) −0.0055 (10)
C15 0.0339 (11) 0.0353 (11) 0.0438 (12) 0.0003 (9) −0.0037 (10) 0.0064 (9)
C16 0.0257 (9) 0.0340 (10) 0.0275 (9) −0.0015 (8) −0.0034 (8) 0.0024 (8)
C17 0.0247 (9) 0.0340 (10) 0.0281 (9) −0.0015 (8) −0.0033 (8) 0.0024 (8)
C18 0.0281 (9) 0.0391 (11) 0.0274 (9) −0.0019 (8) 0.0000 (8) 0.0040 (8)
C19 0.0291 (11) 0.0599 (15) 0.0363 (12) −0.0029 (10) 0.0027 (10) 0.0144 (11)
C20 0.0335 (11) 0.0414 (11) 0.0256 (9) −0.0002 (9) −0.0037 (8) 0.0035 (8)
C21 0.0260 (9) 0.0441 (12) 0.0350 (10) −0.0003 (9) −0.0074 (9) −0.0006 (9)
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Geometric parameters (Å, º)

O1—C2 1.360 (3) C11—C19 1.548 (3)
O1—H1A 0.91 (4) C11—H11A 1.01 (3)
C2—C3 1.387 (3) N12—C13 1.472 (3)
C2—C21 1.398 (3) N12—C14 1.480 (3)
C3—C17 1.376 (3) C13—H13A 1.03 (4)
C3—O4 1.390 (2) C13—H13B 0.98 (3)
O4—C5 1.465 (3) C13—H13C 1.00 (4)
C5—C6 1.523 (4) C14—C15 1.510 (3)
C5—C16 1.546 (3) C14—H14A 0.96 (3)
C5—H5A 1.00 (3) C14—H14B 0.98 (3)
C6—O7 1.212 (3) C15—C16 1.534 (3)
C6—C8 1.498 (4) C15—H15A 0.99 (3)
C8—C9 1.537 (4) C15—H15B 1.01 (3)
C8—H8A 0.99 (3) C16—C17 1.500 (3)
C8—H8B 1.03 (3) C17—C18 1.381 (3)
C9—C10 1.519 (3) C18—C20 1.390 (3)
C9—H9A 1.00 (3) C18—C19 1.512 (3)
C9—H9B 0.97 (3) C19—H19A 0.99 (3)
C10—C16 1.531 (3) C19—H19B 0.98 (3)
C10—C11 1.546 (3) C20—C21 1.387 (3)
C10—H10A 1.00 (2) C20—H20A 0.99 (3)
C11—N12 1.488 (3) C21—H21A 0.93 (3)
C2—O1—H1A 110 (2) C14—N12—C11 113.08 (18)
O1—C2—C3 120.43 (18) N12—C13—H13A 108.1 (19)
O1—C2—C21 124.26 (19) N12—C13—H13B 110.6 (17)
C3—C2—C21 115.31 (18) H13A—C13—H13B 111 (3)
C17—C3—C2 120.96 (17) N12—C13—H13C 105 (2)
C17—C3—O4 111.48 (17) H13A—C13—H13C 111 (3)
C2—C3—O4 127.56 (18) H13B—C13—H13C 110 (3)
C3—O4—C5 104.13 (15) N12—C14—C15 113.2 (2)
O4—C5—C6 110.4 (2) N12—C14—H14A 106.6 (17)
O4—C5—C16 105.03 (16) C15—C14—H14A 112.8 (17)
C6—C5—C16 111.35 (19) N12—C14—H14B 109.2 (16)
O4—C5—H5A 106.7 (14) C15—C14—H14B 108.4 (16)
C6—C5—H5A 110.2 (14) H14A—C14—H14B 106 (2)
C16—C5—H5A 113.0 (14) C14—C15—C16 110.72 (18)
O7—C6—C8 122.9 (3) C14—C15—H15A 109.5 (16)
O7—C6—C5 122.2 (3) C16—C15—H15A 109.6 (17)
C8—C6—C5 114.8 (2) C14—C15—H15B 110.0 (15)
C6—C8—C9 108.8 (2) C16—C15—H15B 109.6 (15)
C6—C8—H8A 110 (2) H15A—C15—H15B 107 (2)
C9—C8—H8A 110 (2) C17—C16—C10 109.73 (16)
C6—C8—H8B 104.6 (18) C17—C16—C15 110.92 (17)
C9—C8—H8B 110.7 (18) C10—C16—C15 107.40 (17)
H8A—C8—H8B 112 (3) C17—C16—C5 97.53 (16)
C10—C9—C8 108.9 (2) C10—C16—C5 119.10 (18)
C10—C9—H9A 109.6 (18) C15—C16—C5 111.80 (17)
C8—C9—H9A 110.5 (18) C3—C17—C18 123.80 (18)
C10—C9—H9B 111.4 (18) C3—C17—C16 109.37 (17)
C8—C9—H9B 110.3 (18) C18—C17—C16 126.82 (18)
H9A—C9—H9B 106 (2) C17—C18—C20 115.76 (18)
C9—C10—C16 112.16 (19) C17—C18—C19 118.01 (18)
C9—C10—C11 114.6 (2) C20—C18—C19 125.99 (18)
C16—C10—C11 106.56 (17) C18—C19—C11 113.97 (18)
C9—C10—H10A 107.5 (14) C18—C19—H19A 109.8 (18)
C16—C10—H10A 109.8 (14) C11—C19—H19A 107.0 (18)
C11—C10—H10A 106.0 (14) C18—C19—H19B 113.1 (19)
N12—C11—C10 107.31 (18) C11—C19—H19B 107.2 (18)
N12—C11—C19 115.9 (2) H19A—C19—H19B 105 (2)
C10—C11—C19 113.08 (19) C21—C20—C18 120.57 (18)
N12—C11—H11A 104.9 (15) C21—C20—H20A 118.2 (16)
C10—C11—H11A 109.1 (15) C18—C20—H20A 121.2 (16)
C19—C11—H11A 106.1 (15) C20—C21—C2 123.27 (19)
C13—N12—C14 108.0 (2) C20—C21—H21A 118.1 (15)
C13—N12—C11 112.6 (2) C2—C21—H21A 118.5 (15)
C10—C11—N12—C13 178.5 (2)
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(I) (4R,4aR,7aR,12bS)-9-Hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] . Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A
O1—H1A···N12i 0.91 (4) 1.89 (4) 2.796 (3) 171 (3)
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Symmetry code: (i) x+1, y, z.

(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Crystal data

C17H19NO3 Dx = 1.388 Mg m−3
Mr = 285.33 Melting point < 550.2 K
Orthorhombic, P212121 Mo Kα radiation, λ = 0.71073 Å
a = 8.8802 (6) Å Cell parameters from 7368 reflections
b = 10.6208 (8) Å θ = 0.4–32.6°
c = 14.4733 (9) Å µ = 0.10 mm−1
V = 1365.05 (16) Å3 T = 296 K
Z = 4 Block, colorless
F(000) = 608 0.40 × 0.32 × 0.22 mm
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Data collection

Bruker KappaCCD diffractometer 4693 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube Rint = 0.022
Horizonally mounted graphite crystal monochromator θmax = 32.6°, θmin = 3.8°
CCD scans h = −13→13
15227 measured reflections k = −16→16
4920 independent reflections l = −21→16
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Refinement

Refinement on F2 Primary atom site location: difference Fourier map
Least-squares matrix: full Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.033 Hydrogen site location: mixed
wR(F2) = 0.095 H atoms treated by a mixture of independent and constrained refinement
S = 1.07 w = 1/[σ2(Fo2) + (0.0623P)2 + 0.0509P] where P = (Fo2 + 2Fc2)/3
4920 reflections (Δ/σ)max = 0.011
257 parameters Δρmax = 0.27 e Å−3
0 restraints Δρmin = −0.12 e Å−3
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq
O1 0.93240 (13) 0.77706 (10) 0.49050 (9) 0.0470 (3)
H1 1.015 (3) 0.792 (2) 0.517 (2) 0.069 (8)*
C2 0.94522 (14) 0.66225 (11) 0.44868 (8) 0.0314 (2)
C3 0.82077 (12) 0.60798 (11) 0.40680 (7) 0.02819 (19)
O4 0.67658 (10) 0.65856 (9) 0.39772 (7) 0.03425 (18)
C5 0.60923 (12) 0.58599 (11) 0.32226 (8) 0.0299 (2)
H5 0.500 (2) 0.586 (2) 0.3283 (14) 0.039 (4)*
C6 0.64963 (14) 0.64991 (13) 0.23020 (10) 0.0362 (2)
O7 0.68419 (15) 0.76008 (11) 0.22794 (10) 0.0516 (3)
C8 0.6488 (2) 0.56607 (16) 0.14696 (10) 0.0455 (3)
H8A 0.549 (3) 0.528 (2) 0.1420 (15) 0.048 (5)*
H8B 0.681 (3) 0.615 (2) 0.0937 (18) 0.058 (6)*
C9 0.75507 (16) 0.45421 (14) 0.16230 (8) 0.0366 (3)
H9A 0.856 (2) 0.486 (2) 0.1784 (15) 0.048 (5)*
H9B 0.759 (3) 0.396 (3) 0.1098 (19) 0.065 (7)*
C10 0.69690 (13) 0.37489 (11) 0.24255 (7) 0.0289 (2)
H10 0.601 (2) 0.3431 (18) 0.2251 (13) 0.035 (4)*
C11 0.79909 (14) 0.26306 (11) 0.26841 (8) 0.0322 (2)
H11 0.810 (2) 0.2131 (17) 0.2157 (12) 0.033 (4)*
N12 0.71416 (14) 0.18458 (10) 0.33458 (8) 0.0359 (2)
C13 0.7868 (2) 0.06280 (15) 0.35203 (14) 0.0513 (4)
H13A 0.8072 0.0217 0.2943 0.075 (8)*
H13B 0.8796 0.0760 0.3847 0.090 (9)*
H13C 0.7212 0.0110 0.3885 0.081 (8)*
C14 0.68139 (17) 0.24994 (12) 0.42125 (9) 0.0367 (2)
H14A 0.617 (3) 0.1946 (18) 0.4586 (14) 0.044 (5)*
H14B 0.769 (3) 0.2710 (19) 0.4580 (15) 0.046 (5)*
C15 0.59734 (14) 0.37270 (12) 0.40416 (8) 0.0323 (2)
H15A 0.496 (2) 0.3593 (17) 0.3840 (13) 0.034 (4)*
H15B 0.592 (2) 0.4201 (18) 0.4616 (15) 0.044 (5)*
C16 0.67804 (11) 0.45335 (10) 0.33092 (7) 0.02580 (18)
C17 0.83077 (12) 0.49110 (10) 0.36541 (7) 0.02626 (19)
C18 0.96269 (12) 0.42399 (11) 0.35670 (8) 0.02859 (19)
C19 0.95925 (15) 0.30434 (12) 0.30011 (10) 0.0356 (2)
H19A 1.020 (3) 0.318 (2) 0.2452 (17) 0.055 (6)*
H19B 1.006 (3) 0.233 (3) 0.3363 (19) 0.071 (7)*
C20 1.09004 (13) 0.47869 (12) 0.39737 (8) 0.0325 (2)
H20 1.191 (2) 0.4392 (19) 0.3896 (13) 0.039 (4)*
C21 1.07953 (14) 0.59403 (12) 0.44358 (8) 0.0334 (2)
H21 1.170 (2) 0.6333 (17) 0.4688 (15) 0.043 (5)*
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23
O1 0.0399 (5) 0.0442 (5) 0.0569 (6) −0.0038 (4) −0.0079 (5) −0.0219 (5)
C2 0.0304 (5) 0.0351 (5) 0.0289 (5) −0.0049 (4) −0.0020 (4) −0.0040 (4)
C3 0.0249 (4) 0.0316 (5) 0.0281 (4) −0.0005 (4) 0.0002 (4) −0.0050 (4)
O4 0.0277 (4) 0.0350 (4) 0.0400 (4) 0.0037 (3) −0.0007 (3) −0.0119 (3)
C5 0.0232 (4) 0.0327 (5) 0.0337 (5) 0.0021 (3) −0.0005 (4) −0.0050 (4)
C6 0.0263 (5) 0.0402 (6) 0.0421 (6) 0.0046 (4) −0.0030 (4) 0.0064 (5)
O7 0.0452 (6) 0.0432 (6) 0.0663 (7) −0.0039 (5) −0.0079 (5) 0.0138 (5)
C8 0.0511 (8) 0.0538 (8) 0.0316 (5) 0.0087 (7) −0.0034 (5) 0.0080 (5)
C9 0.0400 (6) 0.0445 (6) 0.0254 (4) 0.0030 (5) 0.0035 (4) −0.0002 (4)
C10 0.0285 (5) 0.0334 (5) 0.0248 (4) −0.0008 (4) 0.0007 (3) −0.0048 (3)
C11 0.0352 (5) 0.0305 (5) 0.0310 (5) 0.0001 (4) 0.0044 (4) −0.0064 (4)
N12 0.0415 (6) 0.0285 (4) 0.0378 (5) −0.0021 (4) 0.0036 (4) −0.0025 (4)
C13 0.0601 (10) 0.0338 (6) 0.0602 (9) 0.0061 (6) 0.0052 (7) 0.0034 (6)
C14 0.0438 (6) 0.0357 (6) 0.0306 (5) −0.0041 (5) 0.0038 (5) 0.0024 (4)
C15 0.0314 (5) 0.0369 (5) 0.0285 (4) −0.0044 (4) 0.0065 (4) −0.0038 (4)
C16 0.0228 (4) 0.0295 (4) 0.0251 (4) −0.0013 (3) 0.0012 (3) −0.0042 (3)
C17 0.0237 (4) 0.0291 (4) 0.0260 (4) −0.0012 (3) −0.0001 (3) −0.0029 (3)
C18 0.0248 (4) 0.0308 (5) 0.0301 (4) 0.0018 (4) 0.0008 (3) 0.0003 (4)
C19 0.0296 (5) 0.0331 (5) 0.0441 (6) 0.0039 (4) 0.0046 (5) −0.0060 (4)
C20 0.0240 (4) 0.0387 (5) 0.0350 (5) 0.0014 (4) −0.0020 (4) 0.0045 (4)
C21 0.0272 (5) 0.0412 (6) 0.0320 (5) −0.0054 (4) −0.0056 (4) 0.0014 (4)
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Geometric parameters (Å, º)

O1—C2 1.3660 (15) C11—C19 1.5574 (18)
O1—H1 0.84 (3) C11—H11 0.934 (17)
C2—C3 1.3860 (15) N12—C14 1.4629 (17)
C2—C21 1.3975 (18) N12—C13 1.467 (2)
C3—C17 1.3813 (14) C13—H13A 0.9600
C3—O4 1.3948 (14) C13—H13B 0.9600
O4—C5 1.4643 (14) C13—H13C 0.9600
C5—C6 1.5379 (18) C14—C15 1.5225 (19)
C5—C16 1.5407 (16) C14—H14A 0.98 (2)
C5—H5 0.98 (2) C14—H14B 0.97 (2)
C6—O7 1.2101 (18) C15—C16 1.5398 (15)
C6—C8 1.498 (2) C15—H15A 0.958 (19)
C8—C9 1.533 (2) C15—H15B 0.97 (2)
C8—H8A 0.97 (2) C16—C17 1.4998 (14)
C8—H8B 0.97 (2) C17—C18 1.3770 (15)
C9—C10 1.5249 (17) C18—C20 1.4010 (16)
C9—H9A 0.98 (2) C18—C19 1.5122 (16)
C9—H9B 0.98 (3) C19—H19A 0.97 (2)
C10—C16 1.5356 (14) C19—H19B 1.01 (3)
C10—C11 1.5409 (17) C20—C21 1.3988 (18)
C10—H10 0.954 (19) C20—H20 1.00 (2)
C11—N12 1.4767 (16) C21—H21 0.98 (2)
C2—O1—H1 107.5 (18) C13—N12—C11 112.62 (12)
O1—C2—C3 119.90 (11) N12—C13—H13A 109.5
O1—C2—C21 123.87 (11) N12—C13—H13B 109.5
C3—C2—C21 116.22 (10) H13A—C13—H13B 109.5
C17—C3—C2 120.81 (11) N12—C13—H13C 109.5
C17—C3—O4 111.37 (9) H13A—C13—H13C 109.5
C2—C3—O4 127.81 (10) H13B—C13—H13C 109.5
C3—O4—C5 104.03 (8) N12—C14—C15 111.38 (10)
O4—C5—C6 108.58 (10) N12—C14—H14A 107.6 (12)
O4—C5—C16 104.99 (9) C15—C14—H14A 108.4 (12)
C6—C5—C16 112.43 (9) N12—C14—H14B 114.9 (13)
O4—C5—H5 109.9 (12) C15—C14—H14B 106.6 (12)
C6—C5—H5 108.1 (12) H14A—C14—H14B 107.7 (17)
C16—C5—H5 112.8 (13) C14—C15—C16 111.10 (10)
O7—C6—C8 123.66 (14) C14—C15—H15A 112.6 (11)
O7—C6—C5 120.62 (14) C16—C15—H15A 108.1 (11)
C8—C6—C5 115.67 (11) C14—C15—H15B 109.2 (12)
C6—C8—C9 109.94 (11) C16—C15—H15B 108.9 (12)
C6—C8—H8A 107.9 (13) H15A—C15—H15B 106.8 (17)
C9—C8—H8A 104.6 (13) C17—C16—C10 108.88 (9)
C6—C8—H8B 108.7 (15) C17—C16—C15 109.91 (9)
C9—C8—H8B 110.4 (15) C10—C16—C15 108.80 (9)
H8A—C8—H8B 115 (2) C17—C16—C5 98.12 (8)
C10—C9—C8 109.26 (11) C10—C16—C5 118.14 (9)
C10—C9—H9A 108.6 (13) C15—C16—C5 112.34 (9)
C8—C9—H9A 109.0 (13) C18—C17—C3 124.03 (10)
C10—C9—H9B 104.8 (15) C18—C17—C16 126.91 (10)
C8—C9—H9B 113.6 (16) C3—C17—C16 109.05 (9)
H9A—C9—H9B 111.5 (19) C17—C18—C20 115.70 (10)
C9—C10—C16 111.81 (10) C17—C18—C19 117.86 (10)
C9—C10—C11 114.29 (10) C20—C18—C19 126.32 (10)
C16—C10—C11 106.27 (9) C18—C19—C11 114.49 (9)
C9—C10—H10 107.3 (11) C18—C19—H19A 107.6 (14)
C16—C10—H10 108.4 (11) C11—C19—H19A 108.1 (15)
C11—C10—H10 108.6 (12) C18—C19—H19B 110.0 (16)
N12—C11—C10 106.97 (10) C11—C19—H19B 108.4 (16)
N12—C11—C19 115.74 (11) H19A—C19—H19B 108 (2)
C10—C11—C19 113.10 (9) C21—C20—C18 120.67 (11)
N12—C11—H11 105.2 (11) C21—C20—H20 118.9 (12)
C10—C11—H11 107.5 (11) C18—C20—H20 120.3 (12)
C19—C11—H11 107.8 (12) C2—C21—C20 122.43 (11)
C14—N12—C13 110.99 (12) C2—C21—H21 117.6 (11)
C14—N12—C11 112.94 (9) C20—C21—H21 119.8 (12)
C10—C11—N12—C13 169.5 (2)
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(II) (4R,4aR,7aR,12bS)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one. Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A
O1—H1···O4i 0.84 (3) 1.96 (3) 2.791 (2) 167 (3)
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Symmetry code: (i) x+1/2, −y+3/2, −z+1.

References

  1. Allen, F. H., Johnson, O., Shields, G. P., Smith, B. R. & Towler, M. (2004). J. Appl. Cryst. 37, 335–338.
  2. Bye, E. (1976). Acta Chem. Scand. Ser. B, 30, 549–554.
  3. Byrn, S. R., Pfeiffer, R. R. & Stowell, J. G. (1999). In Solid-State Chemistry of Drugs. West Lafayette, Indiana: Ssci Inc.
  4. Grant, D. J. (1999). Drugs Pharm. Sci. 95, 1–33.
  5. Hooft, R. W. W. (1998). COLLECT. Nonius BV, Delft, The Netherlands.
  6. Kitajgorodskij, A. I. (1973). In Molecular Crystals and Molecules. New York: Academic Press.
  7. Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39, 453–457.
  8. 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.
  9. Parab, P. V., Ritschel, W. A., Coyle, D. E., Gregg, R. V. & Denson, D. D. (1988). Biopharm. Drug Dispos. 9, 187–199. [DOI] [PubMed]
  10. Sarhill, N., Walsh, D. & Nelson, K. A. (2001). Support. Care Cancer, 9, 84–96. [DOI] [PubMed]
  11. Scheins, S., Messerschmidt, M. & Luger, P. (2005). Acta Cryst. B61, 443–448. [DOI] [PubMed]
  12. Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.
  13. Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.
  14. Singhal, D. & Curatolo, W. (2004). Adv. Drug Deliv. Rev. 56, 335–347. [DOI] [PubMed]
  15. Vippagunta, S. R., Brittain, H. G. & Grant, D. J. (2001). Adv. Drug Deliv. Rev. 48, 3–26. [DOI] [PubMed]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Crystal structure: contains datablock(s) I, II. DOI: 10.1107/S2056989016006563/gk2659sup1.cif

e-72-00730-sup1.cif (827.3KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989016006563/gk2659Isup2.hkl

e-72-00730-Isup2.hkl (273.6KB, hkl)
Click here for additional data file. (2.2KB, mol)

Supporting information file. DOI: 10.1107/S2056989016006563/gk2659Isup4.mol

Structure factors: contains datablock(s) II. DOI: 10.1107/S2056989016006563/gk2659IIsup3.hkl

e-72-00730-IIsup3.hkl (391.7KB, hkl)
Click here for additional data file. (2.2KB, mol)

Supporting information file. DOI: 10.1107/S2056989016006563/gk2659IIsup5.mol

CCDC references: 1474753, 1474752

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

Articles from Acta Crystallographica Section E: Crystallographic Communications are provided here courtesy of International Union of Crystallography

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