β-Polymorph of phenazepam: a powder study

Abstract

The title compound [systematic name: 7-bromo-5-(2-chloro­phen­yl)-1H-1,4-benzodiazepin-2(3H)-one] (β-polymorph), C₁₅H₁₀BrClN₂O, has been obtained via cryomodification of the known α-polymorph of phenazepam [Karapetyan et al. (1979 ▶). Bioorg. Khim. 5, 1684–1690]. In both polymorphs, the mol­ecules, which differ only in the dihedral angles between the aromatic rings [75.4 (2)° and 86.2 (3)° in the α- and β-polymorphs, respectively], are linked into centrosymmetric dimers via N—H⋯O hydrogen bonds. In the crystal structure of the β-polymorph, weak inter­molecular C—H⋯O hydrogen bonds further link these dimers into layers parallel to bc plane.

Related literature

For details of the synthesis via cryomodification, see: Sergeev & Komarov (2006 ▶). For the crystal structure of the α-polymorph of phenazepam, see: Karapetyan et al. (1979 ▶). For details of the indexing algorithm, see: Werner et al. (1985 ▶). The methodology of the refinement (including applied restraints) has been described in detail by Ryabova et al. (2005 ▶). For the March–Dollase orientation correction, see: Dollase (1986 ▶) and for the split-type pseudo-Voigt profile, see: Toraya (1986 ▶).

Experimental

Crystal data

• C₁₅H₁₀BrClN₂O

• M _r = 349.61

• Monoclinic,

• a = 14.8006 (19) Å

• b = 11.6756 (14) Å

• c = 8.4769 (9) Å

• β = 93.679 (17)°

• V = 1461.8 (3) ų

• Z = 4

• Cu Kα₁ radiation, λ = 1.54059 Å

• μ = 5.49 mm⁻¹

• T = 295 K

• Flat sheet, 15 × 1 mm

Data collection

• Guinier camera G670 diffractometer

• Specimen mounting: thin layer in the specimen holder of the camera

• Data collection mode: transmission

• Scan method: continuous

• 2θ_min = 5.00°, 2θ_max = 80.00°, 2θ_step = 0.01°

Refinement

• R _p = 0.013

• R _wp = 0.017

• R _exp = 0.012

• R _Bragg = 0.059

• χ² = 2.250

• 7501 data points

• 128 parameters

• 64 restraints

• H-atom parameters not refined

Data collection: G670 Imaging Plate Guinier Camera Software (Huber, 2002 ▶); cell refinement: MRIA (Zlokazov & Chernyshev, 1992 ▶); data reduction: G670 Imaging Plate Guinier Camera Software; method used to solve structure: simulated annealing (Zhukov et al., 2001 ▶); program(s) used to refine structure: MRIA; molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: MRIA and SHELXL97 (Sheldrick, 2008 ▶).

Supplementary Material

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

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N8—H8⋯O10i	0.86	2.15	2.865 (16)	141
C11—H11B⋯O10ii	0.97	2.18	3.03 (2)	145

Symmetry codes: (i) ; (ii) .

supplementary crystallographic information

Comment

Phenazepam is a benzodiazepine drug produced in Russia, which is used in the treatment of neurological disorders such as epilepsy, alcohol withdrawal syndrome and insomnia. The crystal structure of its α-polymorph has been reported by Karapetyan et al. (1979). Herewith we present the crystal structure of β-polymorph of phenazepam, which was obtained from the α-polymorph via cryomodification, i.e. through the preparation of metastable solid-phase from the vapor phase at low temperature (Sergeev & Komarov, 2006).

In β-polymorph (Fig. 1), two six-membered rings form a dihedral angle of 86.2 (3)°, while this dihedral angle is 75.4 (2)° in α-polymorph. In both polymorphs, intermolecular N—H···O hydrogen bonds (Table 1) link the molecules into centrosymmetric dimers. In the crystal structure of β-polymorph (in spite of α-polymorph), the non-classical intermolecular C—H···O hydrogen bonds (Table 1) link further these dimers into layers parallel to bc plane.

Experimental

The title β-polymorph of phenazepam has been obtained via cryomodification of α-polymorph of phenazepam. Cryomodification was realized by vapor deposition on a cold surface in vacuo at temperatures varying from 77 to 273 K following the known procedure (Sergeev & Komarov, 2006).

Refinement

During the exposure, the specimen was spun in its plane to improve particle statistics. The triclinic unit-cell dimensions were determined with the indexing program TREOR (Werner et al., 1985), M₂₀=37, using the first 35 peak positions. A number of weak unindexed lines (d-spacings of most significant ones were 8.54, 8.31, 6.90, 5.25 and 5.04 Å) demonstrated that the sample contained a small amount of α-polymorph. The crystal structure of β-polymorph was solved by simulated annealing procedure (Zhukov et al., 2001) and refined following the methodology described in (Ryabova et al., 2005). All non-H atoms were isotropically refined. H atoms were placed in geometrically calculated positions and not refined. The diffraction profiles and the differences between the measured and calculated profiles after the final two-phases Rietveld refinement are shown in Fig. 2. On the results of two-phases Rietveld refinement the ratio of β- and α-polymorphs in the sample was estimated as 1.000 (2) to 0.045 (2), respectively. For the α-polymorph, the atomic coordinates and displacement parameters were fixed to literature values (Karapetyan et al., 1979), so only scale factor and profile parameters were refined.

Figures

Fig. 1.

The molecular structure of β-polymorph with the atomic numbering and 50% displacement spheres.

Fig. 2.

The Rietveld plot, showing the observed and difference profiles for the sample under study. The vertical bars above the difference profile show the reflection positions for α-polymorph (bottom) and β-polymorph (top).

Crystal data

C15H10BrClN2O	F(000) = 696
Mr = 349.61	Dx = 1.589 Mg m−3
Monoclinic, P21/c	Cu Kα1 radiation, λ = 1.54059 Å
Hall symbol: -P 2ybc	µ = 5.49 mm−1
a = 14.8006 (19) Å	T = 295 K
b = 11.6756 (14) Å	Particle morphology: no specific habit
c = 8.4769 (9) Å	light grey
β = 93.679 (17)°	flat sheet, 15 × 1 mm
V = 1461.8 (3) Å3	Specimen preparation: Prepared at 77 K and 6.6 10-6 kPa
Z = 4

Data collection

Guinier camera G670 diffractometer	Data collection mode: transmission
Radiation source: line-focus sealed tube	Scan method: continuous
Curved Germanium (111)	2θmin = 5.00°, 2θmax = 80.00°, 2θstep = 0.01°
Specimen mounting: thin layer in the specimen holder of the camera

Refinement

Refinement on Inet	Profile function: split-type pseudo-Voigt (Toraya, 1986)
Least-squares matrix: full with fixed elements per cycle	128 parameters
Rp = 0.013	64 restraints
Rwp = 0.017	0 constraints
Rexp = 0.012	H-atom parameters not refined
RBragg = 0.059	Weighting scheme based on measured s.u.'s
χ2 = 2.250	(Δ/σ)max = 0.004
7501 data points	Background function: Chebyshev polynomial up to the 5th order
Excluded region(s): none	Preferred orientation correction: March-Dollase (Dollase, 1986); direction of preferred orientation 001, texture parameter r = 0.93(1).

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Br1	0.77280 (15)	0.40430 (17)	−0.3314 (2)	0.0470 (11)*
C2	0.8173 (12)	0.4317 (13)	−0.1182 (18)	0.074 (9)*
C3	0.8911 (12)	0.3743 (12)	−0.044 (2)	0.075 (8)*
H3	0.9200	0.3154	−0.0943	0.090*
C4	0.9202 (11)	0.4080 (13)	0.109 (2)	0.063 (9)*
H4	0.9684	0.3696	0.1616	0.076*
C5	0.8784 (12)	0.4986 (15)	0.1866 (18)	0.076 (8)*
C6	0.8023 (12)	0.5539 (13)	0.110 (2)	0.076 (9)*
C7	0.7727 (11)	0.5187 (16)	−0.0430 (18)	0.071 (8)*
H7	0.7228	0.5540	−0.0945	0.085*
N8	0.9112 (9)	0.5266 (11)	0.3406 (13)	0.064 (6)*
H8	0.9247	0.4696	0.4020	0.077*
C9	0.9248 (12)	0.6346 (12)	0.406 (2)	0.072 (8)*
O10	0.9656 (7)	0.6458 (8)	0.5370 (13)	0.057 (5)*
C11	0.8837 (11)	0.7351 (13)	0.311 (2)	0.070 (8)*
H11A	0.8966	0.8060	0.3674	0.084*
H11B	0.9113	0.7396	0.2101	0.084*
N12	0.7856 (8)	0.7217 (10)	0.2827 (16)	0.062 (7)*
C13	0.7513 (11)	0.6468 (13)	0.1858 (19)	0.061 (8)*
C14	0.6501 (11)	0.6452 (14)	0.1602 (18)	0.071 (9)*
C15	0.6074 (12)	0.7367 (12)	0.077 (2)	0.074 (8)*
H15	0.6425	0.7953	0.0384	0.089*
C16	0.5134 (11)	0.7411 (11)	0.051 (2)	0.075 (8)*
H16	0.4864	0.8028	−0.0033	0.090*
C17	0.4600 (11)	0.6530 (13)	0.106 (2)	0.073 (9)*
H17	0.3976	0.6540	0.0834	0.087*
C18	0.5002 (12)	0.5633 (14)	0.1936 (17)	0.074 (9)*
H18	0.4646	0.5067	0.2356	0.089*
C19	0.5943 (12)	0.5595 (13)	0.2180 (16)	0.065 (8)*
Cl20	0.6428 (3)	0.4396 (4)	0.3145 (5)	0.054 (2)*

Geometric parameters (Å, °)

Br1—C2	1.910 (15)	C11—N12	1.46 (2)
C2—C7	1.39 (2)	C11—H11A	0.9704
C2—C3	1.40 (2)	C11—H11B	0.9697
C3—C4	1.40 (2)	N12—C13	1.28 (2)
C3—H3	0.9297	C13—C14	1.50 (2)
C4—C5	1.41 (2)	C14—C19	1.41 (2)
C4—H4	0.9299	C14—C15	1.41 (2)
C5—N8	1.402 (19)	C15—C16	1.40 (2)
C5—C6	1.42 (2)	C15—H15	0.9299
C6—C7	1.41 (2)	C16—C17	1.39 (2)
C6—C13	1.49 (2)	C16—H16	0.9299
C7—H7	0.9301	C17—C18	1.40 (2)
N8—C9	1.389 (19)	C17—H17	0.9301
N8—H8	0.8600	C18—C19	1.40 (3)
C9—O10	1.23 (2)	C18—H18	0.9303
C9—C11	1.53 (2)	C19—Cl20	1.751 (16)
C7—C2—C3	121.6 (14)	C9—C11—H11A	109.4
C7—C2—Br1	114.3 (11)	N12—C11—H11B	109.4
C3—C2—Br1	124.1 (12)	C9—C11—H11B	109.4
C4—C3—C2	118.1 (15)	H11A—C11—H11B	108.0
C4—C3—H3	120.9	C13—N12—C11	121.6 (14)
C2—C3—H3	121.0	N12—C13—C6	125.6 (14)
C3—C4—C5	121.7 (15)	N12—C13—C14	116.8 (14)
C3—C4—H4	119.2	C6—C13—C14	117.3 (14)
C5—C4—H4	119.2	C19—C14—C15	117.4 (15)
N8—C5—C4	118.1 (15)	C19—C14—C13	124.2 (14)
N8—C5—C6	122.4 (15)	C15—C14—C13	118.4 (14)
C4—C5—C6	119.3 (14)	C16—C15—C14	121.2 (15)
C7—C6—C5	118.7 (15)	C16—C15—H15	119.4
C7—C6—C13	118.3 (15)	C14—C15—H15	119.4
C5—C6—C13	123.0 (14)	C17—C16—C15	120.0 (14)
C2—C7—C6	120.6 (15)	C17—C16—H16	120.0
C2—C7—H7	119.7	C15—C16—H16	120.0
C6—C7—H7	119.7	C16—C17—C18	120.0 (15)
C9—N8—C5	128.2 (13)	C16—C17—H17	120.0
C9—N8—H8	115.9	C18—C17—H17	120.0
C5—N8—H8	115.9	C19—C18—C17	119.4 (15)
O10—C9—N8	120.5 (13)	C19—C18—H18	120.3
O10—C9—C11	123.4 (13)	C17—C18—H18	120.3
N8—C9—C11	116.1 (14)	C18—C19—C14	121.9 (14)
N12—C11—C9	111.1 (13)	C18—C19—Cl20	118.0 (12)
N12—C11—H11A	109.4	C14—C19—Cl20	120.0 (13)

Hydrogen-bond geometry (Å, °)

D—H···A	D—H	H···A	D···A	D—H···A
N8—H8···O10i	0.86	2.15	2.865 (16)	141
C11—H11B···O10ii	0.97	2.18	3.03 (2)	145

Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) x, −y+3/2, z−1/2.