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Acta Crystallogr Sect E Struct Rep Online. 2008 March 1; 64(Pt 3): o587.
Published online 2008 February 13. doi:  10.1107/S160053680800408X
PMCID: PMC2960833

7-Chloro-11a-phenyl-2,3,5,10,11,11a-hexa­hydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione

Abstract

The title compound, C18H15ClN2O2, is a potential human immunodeficiency virus type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. The pyrrolidine ring adopts an envelope and the diazepine ring a boat conformation. In the crystal structure, two isomers (R and S) form centrosymmetric dimers via N—H(...)O hydrogen bonds.

Related literature

For details of the pharmacological properties of this family of compounds, see: De Clercq (1996 [triangle]). For the crystal structures of some analogues of the title compound, see: Karapetyan et al. (2002 [triangle]); Tamazyan et al. (2002 [triangle], 2007 [triangle]). For reference structural data, see Allen et al. (1987 [triangle]).

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Object name is e-64-0o587-scheme1.jpg

Experimental

Crystal data

  • C18H15ClN2O2
  • M r = 326.77
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-0o587-efi1.jpg
  • a = 8.9749 (18) Å
  • b = 9.2184 (18) Å
  • c = 9.912 (2) Å
  • α = 86.90 (3)°
  • β = 71.35 (3)°
  • γ = 88.27 (3)°
  • V = 775.8 (3) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.26 mm−1
  • T = 293 (2) K
  • 0.35 × 0.32 × 0.28 mm

Data collection

  • Enraf–Nonius CAD-4 diffractometer
  • Absorption correction: none
  • 7347 measured reflections
  • 4514 independent reflections
  • 3148 reflections with I > 2σ(I)
  • R int = 0.035
  • 3 standard reflections frequency: 180 min intensity decay: none

Refinement

  • R[F 2 > 2σ(F 2)] = 0.046
  • wR(F 2) = 0.121
  • S = 1.02
  • 4514 reflections
  • 268 parameters
  • All H-atom parameters refined
  • Δρmax = 0.27 e Å−3
  • Δρmin = −0.31 e Å−3

Data collection: DATCOL in CAD-4 (Enraf–Nonius, 1988 [triangle]); cell refinement: LS in CAD-4; data reduction: HELENA (Spek, 1997 [triangle]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]) and ORTEPII (Johnson, 1976 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680800408X/sj2462sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S160053680800408X/sj2462Isup2.hkl

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

Acknowledgments

This research was carried out under the framework of the Armenian Science and Education Foundation (ANSEF grant No. PS-chemorg-907). The authors express their thanks to ANSEF.

supplementary crystallographic information

Comment

Interest in X-ray structural investigation of title compound, (I), Fig. 1, is stimulated by its potentially HIV-1 RT inhibition properties. These compounds belong to a family of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

All intramolecular interatomic distances in molecule are in good agreement with their mean statistical values (Allen et al., 1987). In the crystal structure dimers are formed by (R and S) optical isomers of molecules of (I) via O12···H4i—N4i and O12i···H4—N4 double hydrogen bonding (Table 1, Fig.2).

Experimental

A solution of 2-phenyl-2-pyrrolidinecarboxylic acid (0.01 mol) and 6-chloro-1,4-dihydro-2H-3,1-benzoxazine-2,4-dione (0.01 mol) in dry DMF (5 ml) was boiled for 4 h. After cooling in an ice bath the title compound formed as a colourless precipitate and was separated by filtration and washed with ethylacetate. The compound as synthesized was a racemic mixture. Crystals were grown from an ethanol solution of the compound.

Refinement

Hydrogen atoms were located in a difference map and refined freely with isotropic thermal parameters.

Figures

Fig. 1.
A view of molecule with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are omitted for clarity.
Fig. 2.
The formation dimers of molecules via hydrogen bonding. For clarity only those H atoms participating in hydrogen bonding are depicted. Symmetry code: (i) 2 - x, -y, 2 - z

Crystal data

C18H15ClN2O2Z = 2
Mr = 326.77F(000) = 340
Triclinic, P1Dx = 1.399 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 8.9749 (18) ÅCell parameters from 22 reflections
b = 9.2184 (18) Åθ = 12.6–16.6°
c = 9.912 (2) ŵ = 0.26 mm1
α = 86.90 (3)°T = 293 K
β = 71.35 (3)°Prism, colourless
γ = 88.27 (3)°0.35 × 0.32 × 0.28 mm
V = 775.8 (3) Å3

Data collection

Enraf–Nonius CAD-4 diffractometerRint = 0.035
Radiation source: fine-focus sealed tubeθmax = 30.0°, θmin = 2.2°
graphiteh = −12→12
θ/2θ scansk = −12→12
7347 measured reflectionsl = −13→13
4514 independent reflections3 standard reflections every 180 min
3148 reflections with I > 2σ(I) intensity decay: none

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.046Hydrogen site location: difference Fourier map
wR(F2) = 0.121All H-atom parameters refined
S = 1.02w = 1/[σ2(Fo2) + (0.0496P)2 + 0.2193P] where P = (Fo2 + 2Fc2)/3
4514 reflections(Δ/σ)max < 0.001
268 parametersΔρmax = 0.27 e Å3
0 restraintsΔρmin = −0.31 e Å3

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.
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)

xyzUiso*/Ueq
C20.70626 (17)0.27403 (17)1.00932 (16)0.0333 (3)
C30.66409 (19)0.11255 (18)1.04089 (17)0.0389 (3)
C50.91077 (18)0.04305 (16)0.85230 (16)0.0343 (3)
C60.9468 (2)−0.05252 (19)0.74145 (19)0.0432 (4)
C71.0802 (2)−0.0350 (2)0.6255 (2)0.0488 (4)
C81.1788 (2)0.0798 (2)0.61835 (19)0.0470 (4)
C91.1492 (2)0.1717 (2)0.72885 (19)0.0418 (4)
C101.01455 (17)0.15430 (16)0.84775 (16)0.0332 (3)
C110.99809 (17)0.25083 (15)0.96767 (16)0.0319 (3)
C140.8259 (2)0.37447 (19)1.17444 (18)0.0391 (3)
C150.6494 (2)0.3646 (2)1.24567 (19)0.0493 (4)
C160.5879 (2)0.3677 (2)1.11921 (19)0.0448 (4)
C170.71935 (17)0.32632 (16)0.85722 (16)0.0335 (3)
C180.8016 (2)0.45256 (19)0.79868 (18)0.0405 (4)
C190.8104 (2)0.5045 (2)0.6632 (2)0.0519 (4)
C200.7365 (3)0.4332 (2)0.5842 (2)0.0571 (5)
C210.6523 (3)0.3101 (2)0.6421 (2)0.0562 (5)
C220.6436 (2)0.2556 (2)0.7781 (2)0.0439 (4)
Cl1.33908 (7)0.10803 (8)0.46554 (6)0.0735 (2)
H40.745 (2)−0.072 (2)0.987 (2)0.052 (6)*
H60.874 (2)−0.135 (2)0.747 (2)0.047 (5)*
H71.101 (3)−0.097 (2)0.551 (2)0.062 (6)*
H91.219 (2)0.246 (2)0.725 (2)0.049 (5)*
H180.851 (2)0.504 (2)0.853 (2)0.048 (5)*
H190.864 (3)0.590 (3)0.625 (2)0.065 (7)*
H200.745 (3)0.481 (2)0.482 (3)0.064 (6)*
H210.599 (3)0.259 (2)0.595 (2)0.058 (6)*
H220.584 (2)0.174 (2)0.816 (2)0.051 (6)*
H14A0.856 (2)0.473 (2)1.1500 (19)0.040 (5)*
H15A0.608 (3)0.445 (3)1.311 (2)0.065 (6)*
H16A0.596 (2)0.467 (2)1.080 (2)0.052 (6)*
H14B0.886 (2)0.328 (2)1.233 (2)0.048 (5)*
H15B0.623 (2)0.270 (2)1.301 (2)0.054 (6)*
H16B0.484 (3)0.331 (2)1.139 (2)0.055 (6)*
N10.85316 (15)0.29356 (14)1.04452 (13)0.0327 (3)
N40.77286 (16)0.01605 (16)0.96731 (15)0.0390 (3)
O121.11592 (13)0.28878 (12)0.99545 (13)0.0410 (3)
O130.54222 (16)0.07208 (16)1.12946 (15)0.0604 (4)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C20.0302 (7)0.0378 (8)0.0323 (7)−0.0007 (6)−0.0102 (5)−0.0035 (6)
C30.0373 (8)0.0440 (9)0.0352 (8)−0.0102 (6)−0.0106 (6)−0.0001 (6)
C50.0389 (8)0.0298 (7)0.0351 (7)0.0016 (6)−0.0134 (6)0.0008 (6)
C60.0543 (10)0.0354 (8)0.0433 (9)0.0004 (7)−0.0199 (8)−0.0040 (7)
C70.0610 (11)0.0468 (10)0.0399 (9)0.0125 (8)−0.0178 (8)−0.0093 (8)
C80.0423 (9)0.0553 (11)0.0373 (8)0.0095 (8)−0.0055 (7)0.0000 (8)
C90.0352 (8)0.0438 (9)0.0437 (9)0.0006 (7)−0.0092 (7)0.0006 (7)
C100.0324 (7)0.0316 (7)0.0359 (7)0.0017 (5)−0.0118 (6)−0.0001 (6)
C110.0342 (7)0.0263 (7)0.0361 (7)−0.0030 (5)−0.0131 (6)0.0040 (5)
C140.0480 (9)0.0360 (8)0.0367 (8)0.0009 (7)−0.0174 (7)−0.0070 (7)
C150.0494 (10)0.0602 (12)0.0365 (9)0.0050 (9)−0.0102 (7)−0.0112 (8)
C160.0394 (9)0.0540 (11)0.0407 (9)0.0087 (8)−0.0115 (7)−0.0118 (8)
C170.0310 (7)0.0363 (8)0.0343 (7)0.0047 (6)−0.0119 (6)−0.0050 (6)
C180.0417 (9)0.0405 (9)0.0418 (9)−0.0001 (7)−0.0168 (7)−0.0032 (7)
C190.0563 (11)0.0507 (11)0.0463 (10)−0.0007 (9)−0.0147 (8)0.0080 (8)
C200.0711 (13)0.0641 (13)0.0382 (9)0.0087 (10)−0.0213 (9)−0.0014 (9)
C210.0687 (13)0.0618 (12)0.0508 (11)0.0060 (10)−0.0354 (10)−0.0148 (9)
C220.0462 (9)0.0440 (9)0.0467 (9)−0.0005 (7)−0.0215 (8)−0.0068 (8)
Cl0.0554 (3)0.0986 (5)0.0498 (3)0.0051 (3)0.0065 (2)−0.0053 (3)
N10.0349 (6)0.0337 (6)0.0318 (6)−0.0002 (5)−0.0134 (5)−0.0037 (5)
N40.0418 (7)0.0314 (7)0.0417 (7)−0.0078 (5)−0.0106 (6)0.0026 (6)
O120.0371 (6)0.0362 (6)0.0532 (7)−0.0047 (4)−0.0189 (5)−0.0019 (5)
O130.0519 (8)0.0631 (9)0.0522 (8)−0.0217 (7)0.0050 (6)−0.0049 (6)

Geometric parameters (Å, °)

C2—N11.4858 (19)C14—C151.517 (3)
C2—C171.527 (2)C14—H14A0.956 (19)
C2—C31.538 (2)C14—H14B0.99 (2)
C2—C161.539 (2)C15—C161.522 (3)
C3—O131.217 (2)C15—H15A0.99 (2)
C3—N41.356 (2)C15—H15B1.00 (2)
C5—C101.395 (2)C16—H16A0.97 (2)
C5—C61.396 (2)C16—H16B0.96 (2)
C5—N41.407 (2)C17—C221.387 (2)
C6—C71.375 (3)C17—C181.393 (2)
C6—H61.010 (19)C18—C191.380 (3)
C7—C81.385 (3)C18—H180.95 (2)
C7—H70.93 (2)C19—C201.378 (3)
C8—C91.374 (3)C19—H190.94 (2)
C8—Cl1.7370 (19)C20—C211.376 (3)
C9—C101.398 (2)C20—H201.06 (2)
C9—H90.93 (2)C21—C221.392 (3)
C10—C111.490 (2)C21—H210.92 (2)
C11—O121.2391 (18)C22—H220.92 (2)
C11—N11.340 (2)N4—H40.85 (2)
C14—N11.472 (2)
N1—C2—C17113.17 (12)C14—C15—C16102.64 (15)
N1—C2—C3106.65 (12)C14—C15—H15A111.5 (13)
C17—C2—C3113.09 (13)C16—C15—H15A113.8 (13)
N1—C2—C16101.84 (12)C14—C15—H15B110.0 (12)
C17—C2—C16111.26 (13)C16—C15—H15B109.7 (12)
C3—C2—C16110.18 (14)H15A—C15—H15B109.1 (18)
O13—C3—N4121.24 (16)C15—C16—C2104.63 (14)
O13—C3—C2122.47 (16)C15—C16—H16A107.3 (12)
N4—C3—C2116.26 (13)C2—C16—H16A107.6 (12)
C10—C5—C6119.46 (15)C15—C16—H16B115.7 (13)
C10—C5—N4123.50 (14)C2—C16—H16B109.7 (13)
C6—C5—N4116.96 (15)H16A—C16—H16B111.4 (18)
C7—C6—C5120.84 (17)C22—C17—C18118.84 (15)
C7—C6—H6119.9 (11)C22—C17—C2121.50 (15)
C5—C6—H6119.3 (11)C18—C17—C2119.56 (14)
C6—C7—C8119.40 (17)C19—C18—C17120.52 (17)
C6—C7—H7120.2 (14)C19—C18—H18119.7 (12)
C8—C7—H7120.4 (14)C17—C18—H18119.8 (12)
C9—C8—C7120.77 (17)C20—C19—C18120.54 (19)
C9—C8—Cl120.40 (15)C20—C19—H19119.1 (14)
C7—C8—Cl118.82 (15)C18—C19—H19120.3 (14)
C8—C9—C10120.23 (17)C21—C20—C19119.41 (18)
C8—C9—H9120.2 (12)C21—C20—H20124.0 (12)
C10—C9—H9119.6 (12)C19—C20—H20116.5 (12)
C5—C10—C9119.18 (15)C20—C21—C22120.71 (19)
C5—C10—C11123.97 (14)C20—C21—H21123.0 (13)
C9—C10—C11116.69 (14)C22—C21—H21116.3 (14)
O12—C11—N1121.43 (14)C17—C22—C21119.96 (18)
O12—C11—C10120.38 (14)C17—C22—H22120.9 (13)
N1—C11—C10118.18 (13)C21—C22—H22119.1 (13)
N1—C14—C15103.15 (14)C11—N1—C14121.27 (13)
N1—C14—H14A110.2 (11)C11—N1—C2126.30 (12)
C15—C14—H14A110.6 (11)C14—N1—C2112.36 (12)
N1—C14—H14B109.6 (11)C3—N4—C5128.71 (14)
C15—C14—H14B112.6 (11)C3—N4—H4113.7 (14)
H14A—C14—H14B110.4 (15)C5—N4—H4116.9 (14)
N1—C2—C3—O13118.43 (17)C3—C2—C17—C2223.3 (2)
C17—C2—C3—O13−116.54 (18)C16—C2—C17—C22−101.29 (18)
C16—C2—C3—O138.7 (2)N1—C2—C17—C18−38.96 (19)
N1—C2—C3—N4−59.63 (17)C3—C2—C17—C18−160.38 (14)
C17—C2—C3—N465.40 (18)C16—C2—C17—C1875.00 (18)
C16—C2—C3—N4−169.39 (14)C22—C17—C18—C19−1.4 (2)
C10—C5—C6—C7−2.5 (2)C2—C17—C18—C19−177.78 (16)
N4—C5—C6—C7−179.40 (15)C17—C18—C19—C200.7 (3)
C5—C6—C7—C8−0.6 (3)C18—C19—C20—C210.6 (3)
C6—C7—C8—C93.3 (3)C19—C20—C21—C22−1.2 (3)
C6—C7—C8—Cl−175.46 (14)C18—C17—C22—C210.8 (3)
C7—C8—C9—C10−2.9 (3)C2—C17—C22—C21177.10 (16)
Cl—C8—C9—C10175.88 (13)C20—C21—C22—C170.5 (3)
C6—C5—C10—C92.9 (2)O12—C11—N1—C14−6.6 (2)
N4—C5—C10—C9179.60 (14)C10—C11—N1—C14172.75 (13)
C6—C5—C10—C11−172.22 (14)O12—C11—N1—C2170.27 (13)
N4—C5—C10—C114.5 (2)C10—C11—N1—C2−10.4 (2)
C8—C9—C10—C5−0.3 (2)C15—C14—N1—C11−165.56 (14)
C8—C9—C10—C11175.20 (15)C15—C14—N1—C217.18 (18)
C5—C10—C11—O12141.38 (15)C17—C2—N1—C11−50.6 (2)
C9—C10—C11—O12−33.9 (2)C3—C2—N1—C1174.38 (18)
C5—C10—C11—N1−38.0 (2)C16—C2—N1—C11−170.11 (15)
C9—C10—C11—N1146.80 (14)C17—C2—N1—C14126.50 (14)
N1—C14—C15—C16−34.22 (19)C3—C2—N1—C14−108.52 (14)
C14—C15—C16—C239.5 (2)C16—C2—N1—C146.98 (17)
N1—C2—C16—C15−28.50 (18)O13—C3—N4—C5172.76 (16)
C17—C2—C16—C15−149.37 (15)C2—C3—N4—C5−9.1 (2)
C3—C2—C16—C1584.38 (18)C10—C5—N4—C343.9 (2)
N1—C2—C17—C22144.75 (15)C6—C5—N4—C3−139.36 (17)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N4—H4···O12i0.85 (2)2.35 (2)2.997 (2)133 (2)

Symmetry codes: (i) −x+2, −y, −z+2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: SJ2462).

References

  • Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & Taylor, R. (1987). J. Chem. Soc. Perkin Trans. 2, pp. S1–19.
  • De Clercq, E. (1996). Rev. Med. Virol.6, 97–117. [PubMed]
  • Enraf–Nonius (1988). CAD-4 Manual Version 5.0. Enraf–Nonius, Delft, The Netherlands.
  • Johnson, C. K. (1976). ORTEPII Report ORNL-5138. Oak Ridge National Laboratory, Tennessee, USA.
  • Karapetyan, H., Tamazyan, R., Martirosyan, A., Hovhannesyan, V. & Gasparyan, S. (2002). Acta Cryst. C58, o399–o401. [PubMed]
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Spek, A. L. (1997). HELENA University of Utrecht, The Netherlands.
  • Tamazyan, R., Ayvazyan, A., Martirosyan, A., Martirosyan, V. & Schinazi, R. (2007). Acta Cryst. E63, o3967.
  • Tamazyan, R., Karapetyan, H., Martirosyan, A., Hovhannesyan, V. & Gasparyan, S. (2002). Acta Cryst. C58, o386–o388. [PubMed]

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