(3R,4R,4aS,7aR,12bS)-3-Cyclo-propyl-methyl-4a,9-dihy-droxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octa-hydro-1H-4,12-methano-benzofuro[3,2-e]isoquinolin-3-ium bromide.

The title compound, C(21)H(26)NO(4) (+)·Br(-), also known as R-methyl-naltrexone (MNTX) bromide, is a selective peripher-ally acting μ-opioid receptor antagonist with a oroxymorphone skeleton, synthesized by hydroxyl protection, N-methyl-ation, 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, mol-ecules are linked by O-H⋯Br hydrogen bonds.

Related literature

For general background to methyl­naltrexone (MNTX) n class="Chemical">bromide, see: Garnock-Jones & McKeage (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

Crystal data

C21H26NO4 +·n class="Chemical">Br−

M = 436.34

Monoclinic,

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 ▶) T min = 0.581, T max = 0.646

6955 measured reflections

4179 independent reflections

3259 reflections with I > 2σ(I)

R int = 0.048

Refinement

R[F 2 > 2σ(F 2)] = 0.035

wR(F 2) = 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 ▶), 1636 Friedel pairs

Flack parameter: −0.006 (7)

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

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812000645/bg2437sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812000645/bg2437Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

C21H26NO4+·Br−	F(000) = 452
Mr = 436.34	Dx = 1.514 Mg m−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 2706 reflections
a = 7.708 (3) Å	θ = 2.3–24.6°
b = 13.187 (5) Å	µ = 2.18 mm−1
c = 9.501 (3) Å	T = 291 K
β = 97.679 (6)°	Block, colourless
V = 957.1 (6) Å3	0.28 × 0.24 × 0.22 mm
Z = 2

Bruker SMART APEX CCD diffractometer	4179 independent reflections
Radiation source: sealed tube	3259 reflections with I > 2σ(I)
graphite	Rint = 0.048
phi and ω scans	θmax = 28.5°, θmin = 2.2°
Absorption correction: multi-scan (SADABS; Bruker, 2000)	h = −7→10
Tmin = 0.581, Tmax = 0.646	k = −12→17
6955 measured reflections	l = −12→11

Refinement on F2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.035	H 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 reflections	Δρmax = 0.39 e Å−3
245 parameters	Δρmin = −0.44 e Å−3
2 restraints	Absolute structure: Flack (1983), 1636 Friedel pairs
Primary atom site location: structure-invariant direct methods	Flack parameter: −0.006 (7)

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.

	x	y	z	Uiso*/Ueq
Br1	−0.27040 (4)	0.31792 (5)	0.03917 (3)	0.05094 (11)
C1	0.5410 (4)	0.4248 (3)	0.5393 (4)	0.0436 (9)
C2	0.5975 (4)	0.4559 (3)	0.6764 (4)	0.0506 (10)
C3	0.4825 (5)	0.5137 (3)	0.7423 (4)	0.0519 (10)
H3	0.5192	0.5375	0.8336	0.062*
C4	0.3139 (5)	0.5383 (3)	0.6787 (3)	0.0464 (9)
H4	0.2389	0.5748	0.7287	0.056*
C5	0.2590 (4)	0.5076 (3)	0.5394 (3)	0.0392 (8)
C6	0.3776 (4)	0.4540 (3)	0.4748 (3)	0.0372 (8)
C7	0.3529 (4)	0.4120 (3)	0.3254 (3)	0.0358 (8)
C8	0.1586 (4)	0.3871 (3)	0.2814 (3)	0.0330 (7)
C9	0.0565 (4)	0.4882 (3)	0.3026 (3)	0.0320 (7)
H9	−0.0676	0.4745	0.2710	0.038*
C10	0.0725 (4)	0.5145 (2)	0.4634 (3)	0.0405 (8)
H10A	0.0292	0.5828	0.4737	0.049*
H10B	−0.0013	0.4687	0.5088	0.049*
C11	0.4099 (4)	0.4890 (3)	0.2210 (3)	0.0425 (9)
H11A	0.5342	0.5021	0.2444	0.051*
H11B	0.3901	0.4611	0.1257	0.051*
C12	0.3096 (4)	0.5877 (3)	0.2249 (3)	0.0398 (8)
H12A	0.3397	0.6316	0.1499	0.048*
H12B	0.3468	0.6213	0.3147	0.048*
C13	0.0381 (4)	0.67932 (19)	0.2407 (3)	0.0406 (8)
H13A	0.0929	0.7008	0.3338	0.049*
H13B	0.0694	0.7280	0.1719	0.049*
C14	−0.1571 (4)	0.6804 (3)	0.2385 (3)	0.0432 (8)
H14	−0.2058	0.6347	0.3045	0.052*
C15	−0.2726 (5)	0.7068 (3)	0.1044 (4)	0.0565 (11)
H15A	−0.2176	0.7162	0.0192	0.068*
H15B	−0.3881	0.6764	0.0887	0.068*
C16	−0.2390 (5)	0.7841 (3)	0.2174 (4)	0.058
H16A	−0.3338	0.8006	0.2710	0.070*
H16B	−0.1632	0.8405	0.2015	0.070*
C17	0.0470 (4)	0.5559 (3)	0.0514 (3)	0.0395 (8)
H17A	0.0618	0.6163	−0.0020	0.059*
H17B	−0.0747	0.5377	0.0404	0.059*
H17C	0.1132	0.5016	0.0173	0.059*
C18	0.4825 (3)	0.3216 (4)	0.3524 (3)	0.0451 (7)
H18	0.5266	0.3014	0.2645	0.054*
C19	0.3966 (5)	0.2325 (3)	0.4176 (4)	0.0465 (9)
C20	0.2143 (5)	0.2074 (3)	0.3494 (4)	0.0488 (9)
H20A	0.1708	0.1484	0.3946	0.059*
H20B	0.2141	0.1927	0.2494	0.059*
C21	0.0982 (4)	0.2997 (3)	0.3677 (3)	0.0398 (9)
H21A	−0.0232	0.2836	0.3347	0.048*
H21B	0.1078	0.3184	0.4671	0.048*
N1	0.1112 (3)	0.5747 (2)	0.2073 (3)	0.0335 (6)
O1	0.7622 (3)	0.4286 (3)	0.7404 (3)	0.0719 (10)
H1X	0.762 (6)	0.403 (4)	0.817 (5)	0.086*
O2	0.6235 (3)	0.3609 (2)	0.4553 (2)	0.0548 (8)
O3	0.4644 (4)	0.1902 (2)	0.5242 (3)	0.0638 (9)
O4	0.1381 (3)	0.35700 (17)	0.1374 (2)	0.0393 (6)
H4X	0.037 (4)	0.344 (3)	0.108 (3)	0.047*

	U11	U22	U33	U12	U13	U23
Br1	0.04321 (15)	0.0671 (2)	0.04230 (17)	−0.0020 (2)	0.00507 (11)	−0.0091 (2)
C1	0.0374 (18)	0.051 (3)	0.040 (2)	0.0021 (17)	−0.0021 (15)	0.0060 (17)
C2	0.0402 (18)	0.064 (3)	0.044 (2)	−0.0095 (18)	−0.0098 (15)	0.0156 (18)
C3	0.061 (2)	0.061 (3)	0.0297 (18)	−0.021 (2)	−0.0071 (16)	0.0019 (17)
C4	0.061 (2)	0.046 (2)	0.0322 (18)	−0.0040 (18)	0.0057 (15)	0.0002 (16)
C5	0.0437 (18)	0.044 (2)	0.0299 (16)	−0.0031 (16)	0.0036 (13)	0.0046 (15)
C6	0.0340 (17)	0.048 (2)	0.0286 (17)	−0.0016 (16)	0.0022 (13)	0.0085 (16)
C7	0.0337 (16)	0.046 (2)	0.0284 (16)	0.0083 (14)	0.0059 (12)	0.0059 (15)
C8	0.0318 (15)	0.041 (2)	0.0260 (15)	0.0057 (14)	0.0041 (12)	0.0001 (14)
C9	0.0282 (14)	0.040 (2)	0.0283 (15)	0.0008 (13)	0.0045 (12)	0.0048 (14)
C10	0.0440 (18)	0.048 (2)	0.0305 (16)	0.0079 (16)	0.0079 (13)	−0.0009 (15)
C11	0.0295 (15)	0.058 (3)	0.0409 (18)	0.0000 (16)	0.0082 (13)	0.0117 (17)
C12	0.0274 (15)	0.050 (2)	0.0413 (18)	−0.0081 (15)	0.0020 (13)	0.0094 (16)
C13	0.0469 (18)	0.033 (2)	0.0417 (17)	0.0000 (16)	0.0036 (14)	−0.0012 (15)
C14	0.0475 (19)	0.042 (2)	0.0420 (18)	0.0075 (16)	0.0127 (15)	0.0091 (16)
C15	0.050 (2)	0.072 (3)	0.047 (2)	0.011 (2)	0.0065 (16)	0.022 (2)
C16	0.062	0.052	0.066	0.029	0.031	0.019
C17	0.0460 (19)	0.045 (2)	0.0257 (16)	0.0010 (16)	−0.0012 (13)	0.0055 (15)
C18	0.0359 (14)	0.064 (2)	0.0348 (14)	0.016 (2)	0.0037 (11)	0.008 (2)
C19	0.056 (2)	0.048 (3)	0.0360 (19)	0.0243 (19)	0.0088 (16)	0.0002 (18)
C20	0.062 (2)	0.039 (2)	0.047 (2)	0.0038 (19)	0.0162 (18)	0.0040 (17)
C21	0.0403 (15)	0.042 (3)	0.0380 (15)	0.0039 (16)	0.0074 (12)	0.0049 (16)
N1	0.0306 (12)	0.0356 (17)	0.0337 (14)	−0.0007 (12)	0.0020 (10)	0.0028 (12)
O1	0.0516 (15)	0.105 (3)	0.0531 (16)	−0.0082 (16)	−0.0165 (13)	0.0250 (17)
O2	0.0337 (11)	0.083 (2)	0.0459 (13)	0.0126 (12)	−0.0002 (10)	0.0088 (12)
O3	0.081 (2)	0.059 (2)	0.0489 (16)	0.0221 (18)	−0.0009 (15)	0.0115 (15)
O4	0.0431 (11)	0.0443 (17)	0.0300 (11)	0.0049 (10)	0.0029 (9)	−0.0029 (9)

C1—O2	1.374 (4)	C13—C14	1.502 (5)
C1—C2	1.379 (5)	C13—N1	1.539 (4)
C1—C6	1.380 (4)	C13—H13A	0.9700
C2—O1	1.380 (4)	C13—H13B	0.9700
C2—C3	1.381 (5)	C14—C15	1.495 (4)
C3—C4	1.396 (5)	C14—C16	1.508 (5)
C3—H3	0.9300	C14—H14	0.9800
C4—C5	1.395 (4)	C15—C16	1.478 (6)
C4—H4	0.9300	C15—H15A	0.9700
C5—C6	1.364 (5)	C15—H15B	0.9700
C5—C10	1.524 (4)	C16—H16A	0.9700
C6—C7	1.512 (4)	C16—H16B	0.9700
C7—C11	1.524 (5)	C17—N1	1.518 (4)
C7—C8	1.536 (4)	C17—H17A	0.9600
C7—C18	1.555 (5)	C17—H17B	0.9600
C8—O4	1.413 (3)	C17—H17C	0.9600
C8—C21	1.523 (5)	C18—O2	1.457 (4)
C8—C9	1.575 (4)	C18—C19	1.520 (6)
C9—N1	1.549 (4)	C18—H18	0.9800
C9—C10	1.555 (4)	C19—O3	1.212 (4)
C9—H9	0.9800	C19—C20	1.504 (5)
C10—H10A	0.9700	C20—C21	1.534 (5)
C10—H10B	0.9700	C20—H20A	0.9700
C11—C12	1.517 (5)	C20—H20B	0.9700
C11—H11A	0.9700	C21—H21A	0.9700
C11—H11B	0.9700	C21—H21B	0.9700
C12—N1	1.526 (4)	O1—H1X	0.80 (5)
C12—H12A	0.9700	O4—H4X	0.82 (3)
C12—H12B	0.9700
O2—C1—C2	128.2 (3)	C14—C13—H13B	108.9
O2—C1—C6	112.3 (3)	N1—C13—H13B	108.9
C2—C1—C6	119.4 (4)	H13A—C13—H13B	107.7
C1—C2—O1	119.6 (4)	C15—C14—C13	119.7 (3)
C1—C2—C3	116.8 (3)	C15—C14—C16	59.0 (2)
O1—C2—C3	123.6 (3)	C13—C14—C16	114.3 (3)
C2—C3—C4	123.3 (3)	C15—C14—H14	117.0
C2—C3—H3	118.4	C13—C14—H14	117.0
C4—C3—H3	118.4	C16—C14—H14	117.0
C5—C4—C3	119.3 (3)	C16—C15—C14	61.0 (2)
C5—C4—H4	120.3	C16—C15—H15A	117.7
C3—C4—H4	120.3	C14—C15—H15A	117.7
C6—C5—C4	116.2 (3)	C16—C15—H15B	117.7
C6—C5—C10	117.7 (3)	C14—C15—H15B	117.7
C4—C5—C10	125.4 (3)	H15A—C15—H15B	114.8
C5—C6—C1	124.8 (3)	C15—C16—C14	60.1 (2)
C5—C6—C7	127.2 (3)	C15—C16—H16A	117.8
C1—C6—C7	107.9 (3)	C14—C16—H16A	117.8
C6—C7—C11	110.9 (3)	C15—C16—H16B	117.8
C6—C7—C8	109.2 (2)	C14—C16—H16B	117.8
C11—C7—C8	108.7 (2)	H16A—C16—H16B	114.9
C6—C7—C18	97.4 (2)	N1—C17—H17A	109.5
C11—C7—C18	112.5 (3)	N1—C17—H17B	109.5
C8—C7—C18	117.5 (3)	H17A—C17—H17B	109.5
O4—C8—C21	107.8 (3)	N1—C17—H17C	109.5
O4—C8—C7	107.6 (2)	H17A—C17—H17C	109.5
C21—C8—C7	111.9 (2)	H17B—C17—H17C	109.5
O4—C8—C9	111.6 (2)	O2—C18—C19	109.1 (2)
C21—C8—C9	112.2 (2)	O2—C18—C7	104.1 (4)
C7—C8—C9	105.6 (3)	C19—C18—C7	110.8 (2)
N1—C9—C10	114.7 (3)	O2—C18—H18	110.9
N1—C9—C8	111.7 (2)	C19—C18—H18	110.9
C10—C9—C8	109.8 (2)	C7—C18—H18	110.9
N1—C9—H9	106.7	O3—C19—C20	122.1 (4)
C10—C9—H9	106.7	O3—C19—C18	122.3 (3)
C8—C9—H9	106.7	C20—C19—C18	115.3 (3)
C5—C10—C9	113.5 (2)	C19—C20—C21	107.6 (3)
C5—C10—H10A	108.9	C19—C20—H20A	110.2
C9—C10—H10A	108.9	C21—C20—H20A	110.2
C5—C10—H10B	108.9	C19—C20—H20B	110.2
C9—C10—H10B	108.9	C21—C20—H20B	110.2
H10A—C10—H10B	107.7	H20A—C20—H20B	108.5
C12—C11—C7	111.3 (3)	C8—C21—C20	108.3 (3)
C12—C11—H11A	109.4	C8—C21—H21A	110.0
C7—C11—H11A	109.4	C20—C21—H21A	110.0
C12—C11—H11B	109.4	C8—C21—H21B	110.0
C7—C11—H11B	109.4	C20—C21—H21B	110.0
H11A—C11—H11B	108.0	H21A—C21—H21B	108.4
C11—C12—N1	114.0 (3)	C17—N1—C12	108.4 (2)
C11—C12—H12A	108.7	C17—N1—C13	105.5 (2)
N1—C12—H12A	108.7	C12—N1—C13	105.4 (2)
C11—C12—H12B	108.7	C17—N1—C9	111.8 (2)
N1—C12—H12B	108.7	C12—N1—C9	111.5 (2)
H12A—C12—H12B	107.6	C13—N1—C9	113.8 (2)
C14—C13—N1	113.5 (3)	C2—O1—H1X	114 (3)
C14—C13—H13A	108.9	C1—O2—C18	104.3 (2)
N1—C13—H13A	108.9	C8—O4—H4X	112 (2)
O2—C1—C2—O1	5.5 (6)	C8—C9—C10—C5	47.6 (3)
C6—C1—C2—O1	−178.7 (4)	C6—C7—C11—C12	−57.6 (3)
O2—C1—C2—C3	−174.4 (4)	C8—C7—C11—C12	62.5 (3)
C6—C1—C2—C3	1.3 (6)	C18—C7—C11—C12	−165.5 (3)
C1—C2—C3—C4	2.1 (6)	C7—C11—C12—N1	−52.0 (4)
O1—C2—C3—C4	−177.8 (4)	N1—C13—C14—C15	−92.0 (4)
C2—C3—C4—C5	−3.0 (6)	N1—C13—C14—C16	−158.8 (2)
C3—C4—C5—C6	0.3 (5)	C13—C14—C15—C16	−102.1 (4)
C3—C4—C5—C10	170.4 (3)	C13—C14—C16—C15	111.3 (3)
C4—C5—C6—C1	3.3 (6)	C6—C7—C18—O2	−35.8 (3)
C10—C5—C6—C1	−167.6 (4)	C11—C7—C18—O2	80.5 (3)
C4—C5—C6—C7	−179.8 (3)	C8—C7—C18—O2	−152.0 (2)
C10—C5—C6—C7	9.3 (5)	C6—C7—C18—C19	81.4 (3)
O2—C1—C6—C5	172.2 (4)	C11—C7—C18—C19	−162.3 (3)
C2—C1—C6—C5	−4.2 (6)	C8—C7—C18—C19	−34.8 (4)
O2—C1—C6—C7	−5.2 (4)	O2—C18—C19—O3	−14.9 (5)
C2—C1—C6—C7	178.4 (3)	C7—C18—C19—O3	−129.0 (3)
C5—C6—C7—C11	90.1 (4)	O2—C18—C19—C20	159.1 (3)
C1—C6—C7—C11	−92.6 (4)	C7—C18—C19—C20	45.1 (4)
C5—C6—C7—C8	−29.7 (5)	O3—C19—C20—C21	112.0 (4)
C1—C6—C7—C8	147.6 (3)	C18—C19—C20—C21	−62.0 (4)
C5—C6—C7—C18	−152.3 (4)	O4—C8—C21—C20	61.1 (3)
C1—C6—C7—C18	25.1 (4)	C7—C8—C21—C20	−57.1 (3)
C6—C7—C8—O4	174.7 (3)	C9—C8—C21—C20	−175.6 (2)
C11—C7—C8—O4	53.6 (4)	C19—C20—C21—C8	66.2 (3)
C18—C7—C8—O4	−75.7 (3)	C11—C12—N1—C17	−77.1 (3)
C6—C7—C8—C21	−67.0 (4)	C11—C12—N1—C13	170.2 (2)
C11—C7—C8—C21	171.8 (3)	C11—C12—N1—C9	46.3 (3)
C18—C7—C8—C21	42.6 (3)	C14—C13—N1—C17	69.2 (3)
C6—C7—C8—C9	55.4 (3)	C14—C13—N1—C12	−176.2 (2)
C11—C7—C8—C9	−65.7 (3)	C14—C13—N1—C9	−53.7 (3)
C18—C7—C8—C9	165.0 (2)	C10—C9—N1—C17	−164.4 (2)
O4—C8—C9—N1	−55.3 (3)	C8—C9—N1—C17	69.9 (3)
C21—C8—C9—N1	−176.5 (2)	C10—C9—N1—C12	74.1 (3)
C7—C8—C9—N1	61.3 (3)	C8—C9—N1—C12	−51.7 (3)
O4—C8—C9—C10	176.3 (2)	C10—C9—N1—C13	−45.0 (3)
C21—C8—C9—C10	55.1 (3)	C8—C9—N1—C13	−170.7 (2)
C7—C8—C9—C10	−67.1 (3)	C2—C1—O2—C18	156.9 (4)
C6—C5—C10—C9	−18.0 (4)	C6—C1—O2—C18	−19.2 (4)
C4—C5—C10—C9	172.1 (3)	C19—C18—O2—C1	−83.5 (3)
N1—C9—C10—C5	−79.1 (3)	C7—C18—O2—C1	34.8 (3)

D—H···A

—···

—···

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	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) .