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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 68| Part 2| February 2012| Pages o405-o406

(3R,4R,4aS,7aR,12bS)-3-Cyclo­propyl­methyl-4a,9-dihy­dr­oxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octa­hydro-1H-4,12-methano­benzofuro[3,2-e]isoquinolin-3-ium bromide

aNanjing Haiguang Applied Chemistry Institute, Jiangsu Aosaikang Pharmaceutical Co. Ltd, Nanjing 211112, People's Republic of China, and bSchool of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
*Correspondence e-mail: min.sun619@yahoo.com

(Received 18 November 2011; accepted 7 January 2012; online 14 January 2012)

The title compound, C21H26NO4+·Br, also known as R-methyl­naltrexone (MNTX) bromide, is a selective peripher­ally acting μ-opioid receptor antagonist with a oroxymorphone skeleton, synthesized by hydroxyl protection, N-methyl­ation, deprotection and anion exchange of naltrexone. It comprises a five-ring system A/B/C/D/E. Rings C and E adopt distorted chair conformations, whereas ring D is in half-chair conformation. The C/E ring junctions are trans fused. The dihedral angle between rings D and E is 82.3 (1)°, while the dihedral angles between the planes of rings C and A, and rings D and E are respectively 81.7 (1), 75.9 (1) and 12.2 (1)°. In the crystal, mol­ecules are linked by O—H⋯Br hydrogen bonds.

Related literature

For general background to methyl­naltrexone (MNTX) bromide, see: Garnock-Jones & McKeage (2010[Garnock-Jones, K. P. & McKeage, K. (2010). Drugs, 70, 919-928.]). For ring conformations, see: Cremer & Pople (1975[Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.]). For synthesis of methyl­naltrexone bromide via hydroxyl protection, N-methyl­ation, deprotection and anion exchange, see: Doshan et al. (2010[Doshan, H. D. & Perez, J. (2010). US Patent No. 7674904.]).

[Scheme 1]

Experimental

Crystal data
  • C21H26NO4+·Br

  • Mr = 436.34

  • Monoclinic, P 21

  • a = 7.708 (3) Å

  • b = 13.187 (5) Å

  • c = 9.501 (3) Å

  • β = 97.679 (6)°

  • V = 957.1 (6) Å3

  • Z = 2

  • Mo Kα radiation

  • μ = 2.18 mm−1

  • T = 291 K

  • 0.28 × 0.24 × 0.22 mm

Data collection
  • Bruker SMART APEX CCD diffractometer

  • Absorption correction: multi-scan (SADABS; Bruker, 2000[Bruker (2000). SMART, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.581, Tmax = 0.646

  • 6955 measured reflections

  • 4179 independent reflections

  • 3259 reflections with I > 2σ(I)

  • Rint = 0.048

Refinement
  • R[F2 > 2σ(F2)] = 0.035

  • wR(F2) = 0.073

  • S = 1.04

  • 4179 reflections

  • 245 parameters

  • 2 restraints

  • H atoms treated by a mixture of independent and constrained refinement

  • Δρmax = 0.39 e Å−3

  • Δρmin = −0.44 e Å−3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), 1636 Friedel pairs

  • Flack parameter: −0.006 (7)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1X⋯Br1i 0.80 (5) 2.43 (5) 3.231 (3) 174 (5)
O4—H4X⋯Br1 0.81 (3) 2.40 (3) 3.204 (3) 174 (2)
Symmetry code: (i) x+1, y, z+1.

Data collection: SMART (Bruker, 2000[Bruker (2000). SMART, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2000[Bruker (2000). SMART, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

Supporting information


Comment top

Methylnaltrexone bromide is a selective µ-opioid receptor antagonist that has restricted ability to cross the blood-brain barrier, thus enabling reversal of opioid induced peripheral effects, such as constipation, without affecting the central effects, such as pain relief (Garnock-Jones et al., 2010).

The title compound was obtained by hydroxyl protection, N-methylation, deprotection and anion exchange of naltrexone. The molecule structure of (I) contains a five-ring system A/B/C/D/E (Fig. 1). Ring A is defined by atoms C1—C6, ring B by atoms C1/C6/C7/C18/O2, ring C by atoms C7/C8/C21/C20/C19/C18, ring D by atoms C5—C10, and ring E by atoms C9/C8/C7/C11/C12/N1. Ring C and E adopt a distorted chair conformation (Puckering parameters as defined by Cremer & Pople, 1975: Q = 0.558 (4)/ 0.604 (4) Å, θ= 158.7 (4)/ 13.4 (3) ° and ϕ= 334.6 (11)/ 145.3 (14) °, respectively), whereas ring D is in half chair conformation with puckering amplitude Q = 0.556 (4) Å, θ= 135.5 (4) ° ϕ=18.4 (5) °. The stereochemistry of the C/E ring junctions are trans fused. The dihedral angle between ring D and E is 82.3 (1)°, while the dihedral angles between the planes of ring C and the ring A, ring D and ring E are respectively 81.7 (1), 75.9 (1) and 12.2 (1)°. In the crystal structure, the molecules are linked by O—H···Br hydrogen bonds (Table 1).

Related literature top

For general background to methylnaltrexone (MNTX) bromide, see: Garnock-Jones et al. (2010). For ring conformations, see: Cremer & Pople (1975). For synthesis of methylnaltrexone bromide via hydroxyl protection, N-methylation, deprotection and anion exchange, see: Doshan et al. (2010).

Experimental top

To a solution of naltrexone (3.24 g, 9.5 mmol) in anhydrous tetrahydrofuran (THF) (200 mL) was added triethylamine (NEt3) (2.8 mL, 20 mmol) at 0 °C. After the reaction was stirred for 15 min at 0 °C, isobutyryl chloride (2.1 ml, 20 mmol) was added dropwise. Reaction mixture was stirred at 0 °C for 1 hr, then at room temperature for 18 hrs before being quenched with saturated sodium bicarbonate (NaHCO3) (aq) (140 ml) and 60 ml of H2O. The reaction was extracted with methylene chloride (CH2Cl2) (2×300 ml). The extracts were combined, washed with brine (200 ml), dried over sodium sulfate (Na2SO4) (50 g), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 3-O-isobutyryl-naltrexone (2.8 g 71.6%) as a white solid.

3-O-isobutyryl-naltrexone(1.4 g, 3.40 mmol) was transferred by spatula into a glass pressure vessel. The vessel was purged gently with nitrogen on the manifold for 5 minutes and was then evacuated under high vacuum. When the vacuum was constant, the lower part of the vessel was immersed in liquid nitrogen. Methyl iodide (2.0 g, 14.1 mmol) was dispensed into a separate flask on the manifold into a nitrogen atmosphere and frozen in liquid nitrogen. The frozen methyl iodide vessel was evacuated under high vacuum. The main manifold chamber was isolated from the high vacuum pump. The methyl iodide was allowed to warm to ambient temperature and sublime via the main chamber onto the liquid nitrogen cooled 3-O-isobutyryl-naltrexone. When sublimation was complete, nitrogen was slowly allowed to leach into the glass pressure vessel. The vessel was then sealed tight, removed from the manifold and heated in an oil bath at 88–90 °C for 17 hrs. The vessel was allowed to cool to ambient temperature before allowing nitrogen to flow into the vessel. The vessel was then evacuated under high vacuum to remove residues of unreacted methyl iodide giving a white solid. The crude material was purified by flash chromatography on silica gel to give 3-O-isobutyryl-N-methylnaltrexone iodide salt (1.68 g, 89.3%) as a white solid.

3-O-isobutyryl-N-methylnaltrexone iodide salt (1.68 g, 3.04 mmol) was dissolved in methanol (25 ml). To this mixture was added sterile water (23 ml) followed by 48% aqueous hydrobromic acid (3 ml). The resultant mixture was stirred under nitrogen and heated in an oil bath at 64–65 °C for 6.5 hrs. The mixture was concentrated on the rotary evaporator with the bath at 22–25 °C until approximately 1 ml of oily liquid remained. Acetonitrile (20 ml) was added and the mixture was reconcentrated. This was repeated a further three times, using 20 ml of acetonitrile, to give a ginger colored crisp foam (1.1 g, 83% crude yield).

The foam (1.1 g) was dispersed in water (12 ml)/methanol (4 ml). Some dark oil remained undissolved. The clear supernatant liquid was decanted and applied to the prepared anion exchange resin column. The residue was washed twice with methanol (0.4 mL)/water (6 ml). The supernatant liquors were applied to the column. The colunm was eluted with 4.2 L of sterile water and fractions of ~20 ml were collected. The yield of the white solid N-methylnaltrexone bromide 814.4 mg (64%).

Refinement top

The H atom of the hydroxy groups were located from the difference map and refined isotropically. The remaining H atoms were placed in geometrical positions and constrained to ride on their parent atoms with C–H distances in the range 0.93–0.98 Å, and refined with Uiso(H) = 1.5Ueq(C) for methyl H and 1.2Ueq(C) for other H atoms.

Computing details top

Data collection: SMART (Bruker, 2000); cell refinement: SAINT (Bruker, 2000); data reduction: SAINT (Bruker, 2000); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.
(3R,4R,4aS,7aR,12bS)-3-Cyclopropylmethyl- 4a,9-dihydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-3-ium bromide top
Crystal data top
C21H26NO4+·BrF(000) = 452
Mr = 436.34Dx = 1.514 Mg m3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ybCell parameters from 2706 reflections
a = 7.708 (3) Åθ = 2.3–24.6°
b = 13.187 (5) ŵ = 2.18 mm1
c = 9.501 (3) ÅT = 291 K
β = 97.679 (6)°Block, colourless
V = 957.1 (6) Å30.28 × 0.24 × 0.22 mm
Z = 2
Data collection top
Bruker SMART APEX CCD
diffractometer
4179 independent reflections
Radiation source: sealed tube3259 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.048
phi and ω scansθmax = 28.5°, θmin = 2.2°
Absorption correction: multi-scan
(SADABS; Bruker, 2000)
h = 710
Tmin = 0.581, Tmax = 0.646k = 1217
6955 measured reflectionsl = 1211
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.035H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.073 w = 1/[σ2(Fo2) + (0.020P)2]
where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max = 0.001
4179 reflectionsΔρmax = 0.39 e Å3
245 parametersΔρmin = 0.44 e Å3
2 restraintsAbsolute structure: Flack (1983), 1636 Friedel pairs
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.006 (7)
Crystal data top
C21H26NO4+·BrV = 957.1 (6) Å3
Mr = 436.34Z = 2
Monoclinic, P21Mo Kα radiation
a = 7.708 (3) ŵ = 2.18 mm1
b = 13.187 (5) ÅT = 291 K
c = 9.501 (3) Å0.28 × 0.24 × 0.22 mm
β = 97.679 (6)°
Data collection top
Bruker SMART APEX CCD
diffractometer
4179 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2000)
3259 reflections with I > 2σ(I)
Tmin = 0.581, Tmax = 0.646Rint = 0.048
6955 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.035H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.073Δρmax = 0.39 e Å3
S = 1.04Δρmin = 0.44 e Å3
4179 reflectionsAbsolute structure: Flack (1983), 1636 Friedel pairs
245 parametersAbsolute structure parameter: 0.006 (7)
2 restraints
Special details top

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.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 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 (Å2) top
xyzUiso*/Ueq
Br10.27040 (4)0.31792 (5)0.03917 (3)0.05094 (11)
C10.5410 (4)0.4248 (3)0.5393 (4)0.0436 (9)
C20.5975 (4)0.4559 (3)0.6764 (4)0.0506 (10)
C30.4825 (5)0.5137 (3)0.7423 (4)0.0519 (10)
H30.51920.53750.83360.062*
C40.3139 (5)0.5383 (3)0.6787 (3)0.0464 (9)
H40.23890.57480.72870.056*
C50.2590 (4)0.5076 (3)0.5394 (3)0.0392 (8)
C60.3776 (4)0.4540 (3)0.4748 (3)0.0372 (8)
C70.3529 (4)0.4120 (3)0.3254 (3)0.0358 (8)
C80.1586 (4)0.3871 (3)0.2814 (3)0.0330 (7)
C90.0565 (4)0.4882 (3)0.3026 (3)0.0320 (7)
H90.06760.47450.27100.038*
C100.0725 (4)0.5145 (2)0.4634 (3)0.0405 (8)
H10A0.02920.58280.47370.049*
H10B0.00130.46870.50880.049*
C110.4099 (4)0.4890 (3)0.2210 (3)0.0425 (9)
H11A0.53420.50210.24440.051*
H11B0.39010.46110.12570.051*
C120.3096 (4)0.5877 (3)0.2249 (3)0.0398 (8)
H12A0.33970.63160.14990.048*
H12B0.34680.62130.31470.048*
C130.0381 (4)0.67932 (19)0.2407 (3)0.0406 (8)
H13A0.09290.70080.33380.049*
H13B0.06940.72800.17190.049*
C140.1571 (4)0.6804 (3)0.2385 (3)0.0432 (8)
H140.20580.63470.30450.052*
C150.2726 (5)0.7068 (3)0.1044 (4)0.0565 (11)
H15A0.21760.71620.01920.068*
H15B0.38810.67640.08870.068*
C160.2390 (5)0.7841 (3)0.2174 (4)0.058
H16A0.33380.80060.27100.070*
H16B0.16320.84050.20150.070*
C170.0470 (4)0.5559 (3)0.0514 (3)0.0395 (8)
H17A0.06180.61630.00200.059*
H17B0.07470.53770.04040.059*
H17C0.11320.50160.01730.059*
C180.4825 (3)0.3216 (4)0.3524 (3)0.0451 (7)
H180.52660.30140.26450.054*
C190.3966 (5)0.2325 (3)0.4176 (4)0.0465 (9)
C200.2143 (5)0.2074 (3)0.3494 (4)0.0488 (9)
H20A0.17080.14840.39460.059*
H20B0.21410.19270.24940.059*
C210.0982 (4)0.2997 (3)0.3677 (3)0.0398 (9)
H21A0.02320.28360.33470.048*
H21B0.10780.31840.46710.048*
N10.1112 (3)0.5747 (2)0.2073 (3)0.0335 (6)
O10.7622 (3)0.4286 (3)0.7404 (3)0.0719 (10)
H1X0.762 (6)0.403 (4)0.817 (5)0.086*
O20.6235 (3)0.3609 (2)0.4553 (2)0.0548 (8)
O30.4644 (4)0.1902 (2)0.5242 (3)0.0638 (9)
O40.1381 (3)0.35700 (17)0.1374 (2)0.0393 (6)
H4X0.037 (4)0.344 (3)0.108 (3)0.047*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Br10.04321 (15)0.0671 (2)0.04230 (17)0.0020 (2)0.00507 (11)0.0091 (2)
C10.0374 (18)0.051 (3)0.040 (2)0.0021 (17)0.0021 (15)0.0060 (17)
C20.0402 (18)0.064 (3)0.044 (2)0.0095 (18)0.0098 (15)0.0156 (18)
C30.061 (2)0.061 (3)0.0297 (18)0.021 (2)0.0071 (16)0.0019 (17)
C40.061 (2)0.046 (2)0.0322 (18)0.0040 (18)0.0057 (15)0.0002 (16)
C50.0437 (18)0.044 (2)0.0299 (16)0.0031 (16)0.0036 (13)0.0046 (15)
C60.0340 (17)0.048 (2)0.0286 (17)0.0016 (16)0.0022 (13)0.0085 (16)
C70.0337 (16)0.046 (2)0.0284 (16)0.0083 (14)0.0059 (12)0.0059 (15)
C80.0318 (15)0.041 (2)0.0260 (15)0.0057 (14)0.0041 (12)0.0001 (14)
C90.0282 (14)0.040 (2)0.0283 (15)0.0008 (13)0.0045 (12)0.0048 (14)
C100.0440 (18)0.048 (2)0.0305 (16)0.0079 (16)0.0079 (13)0.0009 (15)
C110.0295 (15)0.058 (3)0.0409 (18)0.0000 (16)0.0082 (13)0.0117 (17)
C120.0274 (15)0.050 (2)0.0413 (18)0.0081 (15)0.0020 (13)0.0094 (16)
C130.0469 (18)0.033 (2)0.0417 (17)0.0000 (16)0.0036 (14)0.0012 (15)
C140.0475 (19)0.042 (2)0.0420 (18)0.0075 (16)0.0127 (15)0.0091 (16)
C150.050 (2)0.072 (3)0.047 (2)0.011 (2)0.0065 (16)0.022 (2)
C160.0620.0520.0660.0290.0310.019
C170.0460 (19)0.045 (2)0.0257 (16)0.0010 (16)0.0012 (13)0.0055 (15)
C180.0359 (14)0.064 (2)0.0348 (14)0.016 (2)0.0037 (11)0.008 (2)
C190.056 (2)0.048 (3)0.0360 (19)0.0243 (19)0.0088 (16)0.0002 (18)
C200.062 (2)0.039 (2)0.047 (2)0.0038 (19)0.0162 (18)0.0040 (17)
C210.0403 (15)0.042 (3)0.0380 (15)0.0039 (16)0.0074 (12)0.0049 (16)
N10.0306 (12)0.0356 (17)0.0337 (14)0.0007 (12)0.0020 (10)0.0028 (12)
O10.0516 (15)0.105 (3)0.0531 (16)0.0082 (16)0.0165 (13)0.0250 (17)
O20.0337 (11)0.083 (2)0.0459 (13)0.0126 (12)0.0002 (10)0.0088 (12)
O30.081 (2)0.059 (2)0.0489 (16)0.0221 (18)0.0009 (15)0.0115 (15)
O40.0431 (11)0.0443 (17)0.0300 (11)0.0049 (10)0.0029 (9)0.0029 (9)
Geometric parameters (Å, º) top
C1—O21.374 (4)C13—C141.502 (5)
C1—C21.379 (5)C13—N11.539 (4)
C1—C61.380 (4)C13—H13A0.9700
C2—O11.380 (4)C13—H13B0.9700
C2—C31.381 (5)C14—C151.495 (4)
C3—C41.396 (5)C14—C161.508 (5)
C3—H30.9300C14—H140.9800
C4—C51.395 (4)C15—C161.478 (6)
C4—H40.9300C15—H15A0.9700
C5—C61.364 (5)C15—H15B0.9700
C5—C101.524 (4)C16—H16A0.9700
C6—C71.512 (4)C16—H16B0.9700
C7—C111.524 (5)C17—N11.518 (4)
C7—C81.536 (4)C17—H17A0.9600
C7—C181.555 (5)C17—H17B0.9600
C8—O41.413 (3)C17—H17C0.9600
C8—C211.523 (5)C18—O21.457 (4)
C8—C91.575 (4)C18—C191.520 (6)
C9—N11.549 (4)C18—H180.9800
C9—C101.555 (4)C19—O31.212 (4)
C9—H90.9800C19—C201.504 (5)
C10—H10A0.9700C20—C211.534 (5)
C10—H10B0.9700C20—H20A0.9700
C11—C121.517 (5)C20—H20B0.9700
C11—H11A0.9700C21—H21A0.9700
C11—H11B0.9700C21—H21B0.9700
C12—N11.526 (4)O1—H1X0.80 (5)
C12—H12A0.9700O4—H4X0.82 (3)
C12—H12B0.9700
O2—C1—C2128.2 (3)C14—C13—H13B108.9
O2—C1—C6112.3 (3)N1—C13—H13B108.9
C2—C1—C6119.4 (4)H13A—C13—H13B107.7
C1—C2—O1119.6 (4)C15—C14—C13119.7 (3)
C1—C2—C3116.8 (3)C15—C14—C1659.0 (2)
O1—C2—C3123.6 (3)C13—C14—C16114.3 (3)
C2—C3—C4123.3 (3)C15—C14—H14117.0
C2—C3—H3118.4C13—C14—H14117.0
C4—C3—H3118.4C16—C14—H14117.0
C5—C4—C3119.3 (3)C16—C15—C1461.0 (2)
C5—C4—H4120.3C16—C15—H15A117.7
C3—C4—H4120.3C14—C15—H15A117.7
C6—C5—C4116.2 (3)C16—C15—H15B117.7
C6—C5—C10117.7 (3)C14—C15—H15B117.7
C4—C5—C10125.4 (3)H15A—C15—H15B114.8
C5—C6—C1124.8 (3)C15—C16—C1460.1 (2)
C5—C6—C7127.2 (3)C15—C16—H16A117.8
C1—C6—C7107.9 (3)C14—C16—H16A117.8
C6—C7—C11110.9 (3)C15—C16—H16B117.8
C6—C7—C8109.2 (2)C14—C16—H16B117.8
C11—C7—C8108.7 (2)H16A—C16—H16B114.9
C6—C7—C1897.4 (2)N1—C17—H17A109.5
C11—C7—C18112.5 (3)N1—C17—H17B109.5
C8—C7—C18117.5 (3)H17A—C17—H17B109.5
O4—C8—C21107.8 (3)N1—C17—H17C109.5
O4—C8—C7107.6 (2)H17A—C17—H17C109.5
C21—C8—C7111.9 (2)H17B—C17—H17C109.5
O4—C8—C9111.6 (2)O2—C18—C19109.1 (2)
C21—C8—C9112.2 (2)O2—C18—C7104.1 (4)
C7—C8—C9105.6 (3)C19—C18—C7110.8 (2)
N1—C9—C10114.7 (3)O2—C18—H18110.9
N1—C9—C8111.7 (2)C19—C18—H18110.9
C10—C9—C8109.8 (2)C7—C18—H18110.9
N1—C9—H9106.7O3—C19—C20122.1 (4)
C10—C9—H9106.7O3—C19—C18122.3 (3)
C8—C9—H9106.7C20—C19—C18115.3 (3)
C5—C10—C9113.5 (2)C19—C20—C21107.6 (3)
C5—C10—H10A108.9C19—C20—H20A110.2
C9—C10—H10A108.9C21—C20—H20A110.2
C5—C10—H10B108.9C19—C20—H20B110.2
C9—C10—H10B108.9C21—C20—H20B110.2
H10A—C10—H10B107.7H20A—C20—H20B108.5
C12—C11—C7111.3 (3)C8—C21—C20108.3 (3)
C12—C11—H11A109.4C8—C21—H21A110.0
C7—C11—H11A109.4C20—C21—H21A110.0
C12—C11—H11B109.4C8—C21—H21B110.0
C7—C11—H11B109.4C20—C21—H21B110.0
H11A—C11—H11B108.0H21A—C21—H21B108.4
C11—C12—N1114.0 (3)C17—N1—C12108.4 (2)
C11—C12—H12A108.7C17—N1—C13105.5 (2)
N1—C12—H12A108.7C12—N1—C13105.4 (2)
C11—C12—H12B108.7C17—N1—C9111.8 (2)
N1—C12—H12B108.7C12—N1—C9111.5 (2)
H12A—C12—H12B107.6C13—N1—C9113.8 (2)
C14—C13—N1113.5 (3)C2—O1—H1X114 (3)
C14—C13—H13A108.9C1—O2—C18104.3 (2)
N1—C13—H13A108.9C8—O4—H4X112 (2)
O2—C1—C2—O15.5 (6)C8—C9—C10—C547.6 (3)
C6—C1—C2—O1178.7 (4)C6—C7—C11—C1257.6 (3)
O2—C1—C2—C3174.4 (4)C8—C7—C11—C1262.5 (3)
C6—C1—C2—C31.3 (6)C18—C7—C11—C12165.5 (3)
C1—C2—C3—C42.1 (6)C7—C11—C12—N152.0 (4)
O1—C2—C3—C4177.8 (4)N1—C13—C14—C1592.0 (4)
C2—C3—C4—C53.0 (6)N1—C13—C14—C16158.8 (2)
C3—C4—C5—C60.3 (5)C13—C14—C15—C16102.1 (4)
C3—C4—C5—C10170.4 (3)C13—C14—C16—C15111.3 (3)
C4—C5—C6—C13.3 (6)C6—C7—C18—O235.8 (3)
C10—C5—C6—C1167.6 (4)C11—C7—C18—O280.5 (3)
C4—C5—C6—C7179.8 (3)C8—C7—C18—O2152.0 (2)
C10—C5—C6—C79.3 (5)C6—C7—C18—C1981.4 (3)
O2—C1—C6—C5172.2 (4)C11—C7—C18—C19162.3 (3)
C2—C1—C6—C54.2 (6)C8—C7—C18—C1934.8 (4)
O2—C1—C6—C75.2 (4)O2—C18—C19—O314.9 (5)
C2—C1—C6—C7178.4 (3)C7—C18—C19—O3129.0 (3)
C5—C6—C7—C1190.1 (4)O2—C18—C19—C20159.1 (3)
C1—C6—C7—C1192.6 (4)C7—C18—C19—C2045.1 (4)
C5—C6—C7—C829.7 (5)O3—C19—C20—C21112.0 (4)
C1—C6—C7—C8147.6 (3)C18—C19—C20—C2162.0 (4)
C5—C6—C7—C18152.3 (4)O4—C8—C21—C2061.1 (3)
C1—C6—C7—C1825.1 (4)C7—C8—C21—C2057.1 (3)
C6—C7—C8—O4174.7 (3)C9—C8—C21—C20175.6 (2)
C11—C7—C8—O453.6 (4)C19—C20—C21—C866.2 (3)
C18—C7—C8—O475.7 (3)C11—C12—N1—C1777.1 (3)
C6—C7—C8—C2167.0 (4)C11—C12—N1—C13170.2 (2)
C11—C7—C8—C21171.8 (3)C11—C12—N1—C946.3 (3)
C18—C7—C8—C2142.6 (3)C14—C13—N1—C1769.2 (3)
C6—C7—C8—C955.4 (3)C14—C13—N1—C12176.2 (2)
C11—C7—C8—C965.7 (3)C14—C13—N1—C953.7 (3)
C18—C7—C8—C9165.0 (2)C10—C9—N1—C17164.4 (2)
O4—C8—C9—N155.3 (3)C8—C9—N1—C1769.9 (3)
C21—C8—C9—N1176.5 (2)C10—C9—N1—C1274.1 (3)
C7—C8—C9—N161.3 (3)C8—C9—N1—C1251.7 (3)
O4—C8—C9—C10176.3 (2)C10—C9—N1—C1345.0 (3)
C21—C8—C9—C1055.1 (3)C8—C9—N1—C13170.7 (2)
C7—C8—C9—C1067.1 (3)C2—C1—O2—C18156.9 (4)
C6—C5—C10—C918.0 (4)C6—C1—O2—C1819.2 (4)
C4—C5—C10—C9172.1 (3)C19—C18—O2—C183.5 (3)
N1—C9—C10—C579.1 (3)C7—C18—O2—C134.8 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1X···Br1i0.80 (5)2.43 (5)3.231 (3)174 (5)
O4—H4X···Br10.81 (3)2.40 (3)3.204 (3)174 (2)
Symmetry code: (i) x+1, y, z+1.

Experimental details

Crystal data
Chemical formulaC21H26NO4+·Br
Mr436.34
Crystal system, space groupMonoclinic, P21
Temperature (K)291
a, b, c (Å)7.708 (3), 13.187 (5), 9.501 (3)
β (°) 97.679 (6)
V3)957.1 (6)
Z2
Radiation typeMo Kα
µ (mm1)2.18
Crystal size (mm)0.28 × 0.24 × 0.22
Data collection
DiffractometerBruker SMART APEX CCD
diffractometer
Absorption correctionMulti-scan
(SADABS; Bruker, 2000)
Tmin, Tmax0.581, 0.646
No. of measured, independent and
observed [I > 2σ(I)] reflections
6955, 4179, 3259
Rint0.048
(sin θ/λ)max1)0.672
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.035, 0.073, 1.04
No. of reflections4179
No. of parameters245
No. of restraints2
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.39, 0.44
Absolute structureFlack (1983), 1636 Friedel pairs
Absolute structure parameter0.006 (7)

Computer programs: SMART (Bruker, 2000), SAINT (Bruker, 2000), SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1X···Br1i0.80 (5)2.43 (5)3.231 (3)174 (5)
O4—H4X···Br10.81 (3)2.40 (3)3.204 (3)174 (2)
Symmetry code: (i) x+1, y, z+1.
 

References

First citationBruker (2000). SMART, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationCremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358.  CrossRef CAS Web of Science Google Scholar
First citationDoshan, H. D. & Perez, J. (2010). US Patent No. 7674904.  Google Scholar
First citationFlack, H. D. (1983). Acta Cryst. A39, 876–881.  CrossRef CAS Web of Science IUCr Journals Google Scholar
First citationGarnock-Jones, K. P. & McKeage, K. (2010). Drugs, 70, 919–928.  Web of Science CAS PubMed Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationSpek, A. L. (2009). Acta Cryst. D65, 148–155.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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ISSN: 2056-9890
Volume 68| Part 2| February 2012| Pages o405-o406
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