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organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 67| Part 12| December 2011| Pages o3386-o3387
https://doi.org/10.1107/S1600536811048306

(2R)-4-[(9H-Fluoren-9-ylmeth­­oxy)carbon­yl]-2-methyl­piperazin-1-ium chloride

Anne Ertan,a* Parhalad Sharma,b Dokka Nagaraju,b K. Deepthib and Sulur G. Manjunathab

aPharmaceutical Development, AstraZeneca R&D, S-151 85 Södertälje, Sweden, and bPharmaceutical Development, AstraZeneca R&D, Off Bellary Road, Hebbal, Bangalore 560 024, India
*Correspondence e-mail: anne.ertan@astrazeneca.com, parhalad.sharma@astrazeneca.com

(Received 10 October 2011; accepted 14 November 2011; online 19 November 2011)

The synthesis of the title salt, C20H23N2O2+·Cl−, was carried out with a precursor of known absolute configuration (R) and the X-ray analysis confirmed that the product retained the absolute configuration. In the crystal, the dominant packing motif is a chain running along [010] generated by N—H⋯Cl hydrogen bonding. C—H⋯O and C—H⋯Cl inter­actions are also observed.

Related literature

For the use of piperazine and substituted piperazines as good linkers to pharmacophores in attempts to obtain compounds with desired pharmacokinetic and pharmacological properties, see: Cho et al. (2010[Cho, Y. S., Borland, M., Brain, C., Chen, C. H.-T., Cheng, H., Chopra, R., Chung, K., Groarke, J., He, G., Hou, Y., Kim, S., Kovats, S., Lu, Y., OReilly, M., Shen, J., Smith, T., Trakshel, G., Vogtle, M., Xu, M., Xu, M. & Sung, M. J. (2010). J. Med. Chem. 53, 7938-57.]); Wang et al. (2009[Wang, T., Yin, Z., Zhang, Z., Bender, J. A., Yang, Z., Johnson, G., Yang, Z., Zadjura, L. M., Arienzo, C. J., DiGiugno Parker, D., Gesenberg, C., Yamanaka, G. A., Gong, Y.-F., Ho, H.-T., Fang, H., Zhou, N., McAuliffe, B. V., Eggers, B. J., Fan, L., Nowicka-Sans, B., Dicker, I. B., Gao, Q., Colonno, R. J., Lin, P.-F., Meanwell, N. A. & Kadow, J. F. (2009). J. Med. Chem. 52, 7778-7787.]). For packing coefficients, see: Kitaigorodskij (1973[Kitaigorodskij, A. I. (1973). In Molecular Crystals and Molecules. New York: Academic Press.]).

[Scheme 1]

Experimental

Crystal data

  • C20H23N2O2+·Cl−

  • Mr = 358.85

  • Monoclinic, P 21

  • a = 8.3492 (3) Å

  • b = 7.4954 (2) Å

  • c = 14.9246 (3) Å

  • β = 90.6740 (18)°

  • V = 933.93 (5) Å3

  • Z = 2

  • Mo Kα radiation

  • μ = 0.22 mm−1

  • T = 293 K

  • 0.28 × 0.20 × 0.08 mm
Data collection

  • Nonius KappaCCD diffractometer

  • 4227 measured reflections

  • 4221 independent reflections

  • 3684 reflections with I > 2σ(I)

  • Rint = 0.022
Refinement

  • R[F2 > 2σ(F2)] = 0.036

  • wR(F2) = 0.086

  • S = 1.03

  • 4221 reflections

  • 227 parameters

  • 1 restraint

  • H-atom parameters constrained

  • Δρmax = 0.16 e Å−3

  • Δρmin = −0.15 e Å−3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), 1922 Friedel pairs

  • Flack parameter: −0.04 (5)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A D⋯A D—H⋯A
N1—H1A⋯Cl1i 1.06 2.08 3.117 (2) 165
N1—H1B⋯Cl1ii 0.88 2.26 3.135 (2) 171
C2—H2B⋯O8iii 0.96 2.41 3.316 (2) 157
C21—H21⋯O8iv 0.98 2.54 3.469 (2) 158
C22—H22⋯Cl1 0.96 2.72 3.622 (2) 157
Symmetry codes: (i) [-x+2, y-{\script{1\over 2}}, -z+1]; (ii) x, y-1, z; (iii) [-x+1, y-{\script{1\over 2}}, -z+1]; (iv) x+1, y, z.

Data collection: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: SCALEPACK (Otwinowski & Minor, 1997[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.]); data reduction: DENZO (Otwinowski & Minor, 1997[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.]) and SCALEPACK; program(s) used to solve structure: SIR97 (Altomare et al., 1999[Altomare, A., Burla, M. C., Camalli, M., Cascarano, G. L., Giacovazzo, C., Guagliardi, A., Moliterni, A. G. G., Polidori, G. & Spagna, R. (1999). J. Appl. Cryst. 32, 115-119.]); program(s) used to refine structure: initial refinement: maXus (MacKay et al., 2000[MacKay, S., Edwards, C., Henderson, A., Gilmore, C., Stewart, N., Shankland, K. & Donald, A. (2000). The maXus program package. Chemistry Department, The University, Glasgow, Scotland, MacScience Co., Japan, and Nonius BV, The Netherlands.]); final refinement: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and ORTEPII (Johnson, 1976[Johnson, C. K. (1976). ORTEPII. Oak Ridge National Laboratory, Tennessee, USA]); software used to prepare material for publication: PLATON and ACD/Labs (ACD, 2011[ACD (2011). ACD/Labs. Advanced Chemistry Development Inc., Toronto, Ontario, Canada.]).

Supporting information

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S1600536811048306/kp2361sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536811048306/kp2361Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S1600536811048306/kp2361Isup3.cml

checkCIF report


Comment top

Piperazine and substituted piperazines are good linkers to pharmacophores to bring out drug substance with desired pharmacokinetics and pharmacological properties (Cho et al., 2010; Wang et al., 2009). In this context there is a great need in selective mono N-protectected piperazines and efficient synthetic procedures for their preparation. As a part of our research in drug development we were in need of selective mono protection of 2-methylpiperazines. We could develop a simple procedure for the mono N-protection of 2-methylpiperazine with F-moc. The chromatographic and spectroscopic analysis indicated that the process is highly regioselective to give the mono protected product but the same techniques were inadequate to elucidate the structure (Fig. 1, Scheme I & II, ACD/Labs,1994–2011), therefore single-crystal technique was employed. The X-ray investigation of the title compound was undertaken to verify the structure and confirm the absolute stereochemistry of the intermediate made in the course of synthesis (Fig. 2). The absolute configuration around the chiral carbon atom C6 was determined to be 6R, which was expected from the synthesis using a precursor of R-configuration. The Flack's x parameter (Flack, 1983) was refined to -0.04 (5). The molecule has four hetero-atoms of which only one is protonated, the N1 atom. This potential H-bond donor participates in intermolecular H-bond interaction with the chloride ion (Table 1, Fig. 3), linking the molecules into infinite chain by N—H···Cl (chloride) interactions along the [0 1 0] direction (Fig. 3). Themolecules are efficiently packed, with no residual void for solvent inclusion (Fig. 4). The packing coefficient of I, calculated by PLATON, is 66.7% (Kitaigorodskij, 1973), reflecting an efficient molecular packing arrangement.

Related literature top

For the use of piperazine and substituted piperazines as good linkers to pharmacophores in attempts to obtain compounds with desired pharmacokinetic and pharmacological properties, see: Cho et al. (2010); Wang et al. (2009). For packing coefficients, see: Kitaigorodskij (1973).

Experimental top

The chemicals used for the synthesis are purchased from: (R)-2-methyl piperazine from Manjing Gaungtong Pharmaceutical & Chemical Co. Ltd. and F-moc chloride from Spectrochem India Ltd.

Preparation of (2R)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2- methylpiperazine-1-ium chloride

A solution of F-moc chloride (11.6 g, 0.0449 mol) in acetone (100 mL) was added drop wise to a solution of 2(R)-methyl piperazine (5.0 g, 0.0499 mol) in acetone (75 mL) at 2893 K over a period of 1.7 h. The temperature of the reaction mass was raised from 295 to 298 K and was allowed to stir for 1.5 h. The resulting solid was collected by filtration and washed with acetone to give 9.89 g (yield: 55.2% w/w) of the title compound as a white solid in form of hydrochloride salt. HPLC purity >98% and M+1: 323, melting point: 412 K (DSC thermogram).

Crystallization process

The single-crystal of (2R)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2- methylpiperazin-1-ium chloride has been grown using vapour diffusion method: (2R)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylpiperazine-1-ium chloride (0.5 g) is dissolved in methanol (20 mL) in a small vial, which is placed inside a larger vial containing a small volume of a heptane (100 mL) in which the sample is insoluble. The larger vial is then sealed but the smaller one is open for the second solvent to intrude. The unit is kept as such for a period of 72 h. The obtained solid was collected by filtration and examined under microscope. A large block-shaped crystal of compound I, grown from methanol/heptane, was used for single-crystal X-ray diffraction experiment.

Refinement top

Data collection, structure solution and refinement:

Diffraction data for compound 1 was collected at RT using a Nonius Kappa-CCD diffractometer (Nonius, 1998), with graphite-monochromated Mo Kα radiation (0.71073 Å). Details of X-ray experiment are summarized in Supplementary Material. The structure was solved by direct methods (Altomare et al., 1999, SIR97) and refined with F2 against all reflections. The title compound 1 had one molecule in the asymmetric unit. The absolute configuration at the chiral C6 carbon atom was determined to be R. The number of Friedel pairs measured was 1922. All non-H atoms were anisotropically refined. Although identified in late difference Fourier maps, the aromatic- and methyl-H atoms were calculated due to poor bond angles and constrained to ideal geometry positions with distance 0.96-0.98 Å, from the parent atoms. The H1A and H1B atoms, found from difference Fourier map, were refined a few cycles with isotropic displacement parameters but were constrained in the final cycles of refinement to 1.06 and 0.86 Å from their parent atoms. Due to the fact that both these H-atoms are involved in H-bonds, the refined positions were kept in the final structure model. The H atoms were refined using a riding model, with Uiso(H) = 1.2Ueq(C). Six low integer reflections shadowed by the beam stop were omitted from the final calculations. The highest residual electron density peak was located close to carbon C11 atom and the deepest hole close to carbon C10 atom. The original structure model was obtained (Altomare, SIR97) and refined initially within maXus software suite (MacKay et al., 2000) but the final refinement of the structure was done with SHELXL97 (Sheldrick, 2008).

Structure description top

Piperazine and substituted piperazines are good linkers to pharmacophores to bring out drug substance with desired pharmacokinetics and pharmacological properties (Cho et al., 2010; Wang et al., 2009). In this context there is a great need in selective mono N-protectected piperazines and efficient synthetic procedures for their preparation. As a part of our research in drug development we were in need of selective mono protection of 2-methylpiperazines. We could develop a simple procedure for the mono N-protection of 2-methylpiperazine with F-moc. The chromatographic and spectroscopic analysis indicated that the process is highly regioselective to give the mono protected product but the same techniques were inadequate to elucidate the structure (Fig. 1, Scheme I & II, ACD/Labs,1994–2011), therefore single-crystal technique was employed. The X-ray investigation of the title compound was undertaken to verify the structure and confirm the absolute stereochemistry of the intermediate made in the course of synthesis (Fig. 2). The absolute configuration around the chiral carbon atom C6 was determined to be 6R, which was expected from the synthesis using a precursor of R-configuration. The Flack's x parameter (Flack, 1983) was refined to -0.04 (5). The molecule has four hetero-atoms of which only one is protonated, the N1 atom. This potential H-bond donor participates in intermolecular H-bond interaction with the chloride ion (Table 1, Fig. 3), linking the molecules into infinite chain by N—H···Cl (chloride) interactions along the [0 1 0] direction (Fig. 3). Themolecules are efficiently packed, with no residual void for solvent inclusion (Fig. 4). The packing coefficient of I, calculated by PLATON, is 66.7% (Kitaigorodskij, 1973), reflecting an efficient molecular packing arrangement.

For the use of piperazine and substituted piperazines as good linkers to pharmacophores in attempts to obtain compounds with desired pharmacokinetic and pharmacological properties, see: Cho et al. (2010); Wang et al. (2009). For packing coefficients, see: Kitaigorodskij (1973).

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPAK (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: initial refinement: maXus (MacKay et al., 2000); final refinement: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009) and ORTEPII (Johnson, 1976); software used to prepare material for publication: PLATON (Spek, 2009) and ACD/Labs (ACD, 2011).

Figures top
[Figure 1] Fig. 1. Scheme I and II showing the two possible mono protected products, not possible to elucidate their structures by chromatographic or spectroscopic analysis.
[Figure 2] Fig. 2. View of the title compound showing the atom-labelling scheme. Displacement ellipsoids of non-H atoms are drawn at the 50% probability level. ORTEPII (Johnson, 1976).
[Figure 3] Fig. 3. Part of the molecular H-bond scheme with the molecules joined as chains containg equivalent symmetry translated units along the [1 0 0] direction. Dotted lines indicate H-bond interactions. The view is along the [1 0 0] direction. PLATON (Spek, 2009).
[Figure 4] Fig. 4. Spacefill packing diagram of the molecules in the unit cell along the [1 0 0] direction reflecting an efficient molecular packing arrangement. PLATON (Spek, 2009).
(2R)-4-[(9H-Fluoren-9-ylmethoxy)carbonyl]-2-methylpiperazin-1-ium chloride top
Crystal data top
C20H23N2O2+·Cl−F(000) = 380
Mr = 358.85Dx = 1.276 Mg m−3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ybCell parameters from 2263 reflections
a = 8.3492 (3) Åθ = 1.0–27.5°
b = 7.4954 (2) ŵ = 0.22 mm−1
c = 14.9246 (3) ÅT = 293 K
β = 90.6740 (18)°Block, colourless
V = 933.93 (5) Å30.28 × 0.20 × 0.08 mm
Z = 2
Data collection top
Nonius KappaCCD
diffractometer		3684 reflections with I > 2σ(I)
Radiation source: fine-focusRint = 0.022
Graphite monochromatorθmax = 27.5°, θmin = 3.0°
φ and ω scans with κ offsetsh = −10→10
4227 measured reflectionsk = −9→9
4221 independent reflectionsl = −19→19
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.036 w = 1/[σ2(Fo2) + (0.037P)2 + 0.176P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.086(Δ/σ)max < 0.001
S = 1.03Δρmax = 0.16 e Å−3
4221 reflectionsΔρmin = −0.15 e Å−3
227 parametersExtinction correction: SHELXL97 (Sheldrick, 2008), FC*=KFC[1+0.001XFC2Λ3/SIN(2Θ)]-1/4
1 restraintExtinction coefficient: 0.075 (4)
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), 1922 Friedel pairs
Secondary atom site location: difference Fourier mapAbsolute structure parameter: −0.04 (5)
Crystal data top
C20H23N2O2+·Cl−V = 933.93 (5) Å3
Mr = 358.85Z = 2
Monoclinic, P21Mo Kα radiation
a = 8.3492 (3) ŵ = 0.22 mm−1
b = 7.4954 (2) ÅT = 293 K
c = 14.9246 (3) Å0.28 × 0.20 × 0.08 mm
β = 90.6740 (18)°
Data collection top
Nonius KappaCCD
diffractometer		3684 reflections with I > 2σ(I)
4227 measured reflectionsRint = 0.022
4221 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.036H-atom parameters constrained
wR(F2) = 0.086Δρmax = 0.16 e Å−3
S = 1.03Δρmin = −0.15 e Å−3
4221 reflectionsAbsolute structure: Flack (1983), 1922 Friedel pairs
227 parametersAbsolute structure parameter: −0.04 (5)
1 restraint
Special details top

Experimental. Crystals were crystallized from methanol/heptane by vapour diffusion.

Number of collected frames: 212 Number of repeats: 1 Crystal-Detector distance (mm): 30 Exposure time (sec) per frame: 5 Phi-rotation (°) step: 2

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

Refinement. Refinement on F2 for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The observed criterion of F2 > σ(F2) is used only for calculating -R-factor-obs 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
O80.44893 (17)0.0878 (2)0.65110 (9)0.0556 (5)
O90.61979 (15)0.06962 (17)0.76938 (8)0.0404 (4)
N10.86676 (19)−0.2463 (2)0.55195 (9)0.0431 (5)
N40.61615 (18)−0.1517 (3)0.66869 (10)0.0468 (5)
C20.7114 (2)−0.1768 (3)0.51533 (12)0.0512 (6)
C30.5787 (2)−0.2213 (3)0.57921 (13)0.0540 (7)
C50.7678 (2)−0.2172 (3)0.70499 (11)0.0438 (6)
C60.9062 (2)−0.1750 (3)0.64313 (11)0.0397 (5)
C71.0634 (2)−0.2547 (3)0.67673 (14)0.0532 (7)
C80.5532 (2)0.0098 (3)0.69198 (11)0.0398 (5)
C100.5939 (2)0.2555 (2)0.78753 (11)0.0380 (5)
C110.70593 (19)0.3087 (2)0.86403 (10)0.0336 (5)
C120.6628 (2)0.2475 (2)0.95797 (11)0.0358 (5)
C130.5230 (2)0.2774 (3)1.00485 (13)0.0446 (6)
C140.5175 (3)0.2224 (3)1.09407 (13)0.0529 (7)
C150.6472 (3)0.1385 (3)1.13435 (13)0.0571 (7)
C160.7860 (3)0.1070 (3)1.08760 (13)0.0514 (7)
C170.7936 (2)0.1632 (2)0.99900 (11)0.0389 (5)
C180.9257 (2)0.1579 (2)0.93493 (11)0.0370 (5)
C191.0795 (2)0.0892 (3)0.94323 (15)0.0504 (7)
C201.1808 (2)0.0990 (3)0.87068 (16)0.0555 (7)
C211.1300 (2)0.1765 (3)0.79113 (15)0.0528 (7)
C220.9768 (2)0.2495 (3)0.78302 (12)0.0429 (5)
C230.87605 (19)0.2402 (2)0.85559 (11)0.0349 (5)
Cl10.82783 (6)0.33785 (7)0.55846 (3)0.0512 (2)
H1A0.95740−0.205300.507000.0520*
H1B0.86370−0.363700.549000.0520*
H2A0.71940−0.049500.509400.0620*
H2B0.68890−0.228700.457700.0620*
H3A0.56490−0.348400.581300.0650*
H3B0.48160−0.166700.557700.0650*
H5A0.78820−0.161000.761800.0520*
H5B0.76240−0.344200.713000.0520*
H60.91990−0.048000.639700.0480*
H7A1.08780−0.207800.735200.0640*
H7B1.14880−0.226500.636700.0640*
H7C1.05130−0.381900.680400.0640*
H10A0.615300.325200.735100.0460*
H10B0.484600.272500.804900.0460*
H110.710900.453000.857700.0400*
H130.434800.335400.975100.0540*
H140.422000.240301.128200.0640*
H150.641900.101801.195900.0690*
H160.875200.048801.116400.0620*
H191.112800.038800.999600.0610*
H201.286900.049800.873900.0670*
H211.204900.175600.741200.0630*
H220.943200.309100.729000.0510*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O80.0442 (8)0.0714 (10)0.0508 (7)0.0151 (7)−0.0161 (6)−0.0121 (7)
O90.0444 (7)0.0403 (7)0.0363 (6)0.0044 (6)−0.0068 (5)−0.0027 (5)
N10.0498 (9)0.0414 (8)0.0382 (8)−0.0015 (7)0.0020 (6)−0.0056 (7)
N40.0417 (8)0.0550 (9)0.0435 (8)0.0051 (8)−0.0024 (6)−0.0121 (8)
C20.0568 (12)0.0583 (12)0.0383 (8)0.0044 (10)−0.0124 (8)−0.0084 (9)
C30.0476 (11)0.0600 (13)0.0542 (11)0.0000 (9)−0.0064 (9)−0.0203 (10)
C50.0476 (10)0.0462 (12)0.0375 (9)0.0095 (8)0.0009 (7)−0.0003 (7)
C60.0433 (9)0.0379 (9)0.0378 (8)0.0011 (8)−0.0045 (7)−0.0016 (8)
C70.0459 (11)0.0595 (12)0.0541 (11)0.0070 (10)−0.0048 (9)0.0006 (10)
C80.0344 (9)0.0496 (11)0.0355 (8)−0.0001 (8)0.0007 (7)−0.0041 (8)
C100.0345 (9)0.0386 (9)0.0407 (9)0.0062 (7)−0.0036 (7)−0.0001 (8)
C110.0320 (8)0.0346 (10)0.0340 (8)0.0027 (7)−0.0021 (6)−0.0003 (6)
C120.0392 (9)0.0299 (8)0.0384 (8)−0.0017 (7)0.0004 (7)−0.0035 (7)
C130.0439 (10)0.0404 (10)0.0497 (10)−0.0027 (8)0.0080 (8)−0.0064 (8)
C140.0638 (13)0.0478 (12)0.0476 (11)−0.0169 (10)0.0196 (9)−0.0120 (9)
C150.0811 (16)0.0547 (13)0.0357 (9)−0.0228 (12)0.0046 (10)0.0017 (9)
C160.0641 (13)0.0472 (12)0.0425 (10)−0.0114 (10)−0.0101 (9)0.0081 (8)
C170.0441 (10)0.0325 (8)0.0399 (9)−0.0059 (7)−0.0046 (7)0.0014 (7)
C180.0365 (9)0.0302 (8)0.0440 (9)0.0007 (7)−0.0061 (7)−0.0009 (7)
C190.0427 (11)0.0424 (11)0.0659 (12)0.0049 (9)−0.0119 (9)0.0038 (9)
C200.0333 (10)0.0463 (12)0.0866 (16)0.0063 (9)−0.0055 (10)−0.0070 (11)
C210.0379 (10)0.0565 (12)0.0641 (13)−0.0028 (9)0.0104 (9)−0.0160 (10)
C220.0392 (9)0.0469 (10)0.0425 (9)−0.0032 (8)0.0013 (7)−0.0044 (8)
C230.0323 (8)0.0325 (8)0.0397 (8)0.0004 (7)−0.0030 (6)−0.0025 (7)
Cl10.0585 (3)0.0495 (3)0.0457 (2)0.0006 (2)0.0055 (2)−0.0020 (2)
Geometric parameters (Å, º) top
O8—C81.208 (2)C19—C201.384 (3)
O9—C81.353 (2)C20—C211.384 (3)
O9—C101.436 (2)C21—C221.395 (3)
N1—C21.495 (2)C22—C231.381 (2)
N1—C61.495 (2)C2—H2A0.9600
N4—C31.464 (3)C2—H2B0.9600
N4—C51.457 (2)C3—H3A0.9600
N4—C81.366 (3)C3—H3B0.9600
N1—H1A1.0600C5—H5A0.9600
N1—H1B0.8800C5—H5B0.9600
C2—C31.508 (3)C6—H60.9600
C5—C61.521 (2)C7—H7A0.9600
C6—C71.522 (3)C7—H7B0.9600
C10—C111.521 (2)C7—H7C0.9600
C11—C231.517 (2)C10—H10A0.9600
C11—C121.522 (2)C10—H10B0.9600
C12—C171.397 (2)C11—H111.0900
C12—C131.386 (2)C13—H130.9600
C13—C141.395 (3)C14—H140.9600
C14—C151.384 (3)C15—H150.9600
C15—C161.380 (3)C16—H160.9600
C16—C171.390 (3)C19—H190.9600
C17—C181.469 (2)C20—H200.9600
C18—C231.394 (2)C21—H210.9800
C18—C191.388 (2)C22—H220.9600
Cl1···N1i3.1353 (16)H1B···H3A2.5500
Cl1···C223.6222 (19)H2A···H62.5500
Cl1···N1ii3.1167 (16)H2A···Cl13.1300
Cl1···H2A3.1300H2B···O8vii2.4100
Cl1···H222.7200H3A···H1B2.5500
Cl1···H1Bi2.2600H3A···H5B2.5500
Cl1···H1Aii2.0800H3B···O82.3800
Cl1···H7Bii2.9600H3B···Cl1vii3.0900
Cl1···H3Biii3.0900H5A···H14x2.5300
O8···C2iii3.316 (2)H5A···H7A2.5600
O9···C223.276 (2)H5A···O92.2300
O8···H10B2.6900H5B···H7C2.4800
O8···H2Biii2.4100H5B···H3A2.5500
O8···H21iv2.5400H6···H2A2.5500
O8···H10A2.5700H7A···H5A2.5600
O8···H3B2.3800H7A···C213.0200
O9···H5A2.2300H7B···H1A2.5000
N1···N42.829 (2)H7B···Cl1v2.9600
N1···Cl1v3.1167 (16)H7C···H1B2.5000
N1···Cl1vi3.1353 (16)H7C···H5B2.4800
N4···N12.829 (2)H7C···H22vi2.5900
C2···O8vii3.316 (2)H10A···O82.5700
C17···C19viii3.470 (3)H10B···O82.6900
C19···C17ix3.470 (3)H10B···C21iv3.0500
C22···O93.276 (2)H10B···H20iv2.5700
C22···Cl13.6222 (19)H10B···C15xii3.1000
C5···H14x2.9800H10B···C133.0000
C10···H223.0800H10B···C20iv3.0200
C11···H19viii3.0600H11···C14xii2.8700
C12···H19viii2.9400H11···H14xii2.4300
C13···H10B3.0000H13···C16xii2.8900
C14···H20viii2.9800H13···C15xii2.8800
C14···H11x2.8700H14···H5Axii2.5300
C15···H13x2.8800H14···H11x2.4300
C15···H10Bx3.1000H14···C5xii2.9800
C16···H13x2.8900H16···C22ix2.9600
C16···H193.0800H19···C11ix3.0600
C17···H19viii2.9200H19···C12ix2.9400
C18···H19viii3.0400H19···C163.0800
C20···H10Bxi3.0200H19···C18ix3.0400
C21···H10Bxi3.0500H19···C17ix2.9200
C21···H7A3.0200H20···C14ix2.9800
C22···H16viii2.9600H20···H10Bxi2.5700
H1A···Cl1v2.0800H21···O8xi2.5400
H1A···H7B2.5000H22···H7Ci2.5900
H1B···H7C2.5000H22···Cl12.7200
H1B···Cl1vi2.2600H22···C103.0800
C8—O9—C10114.92 (14)C3—C2—H2B110.00
C2—N1—C6112.89 (14)H2A—C2—H2B109.00
C3—N4—C5113.24 (16)N4—C3—H3A110.00
C3—N4—C8117.98 (16)N4—C3—H3B109.00
C5—N4—C8122.64 (17)C2—C3—H3A109.00
C2—N1—H1B108.00C2—C3—H3B109.00
C6—N1—H1A109.00H3A—C3—H3B109.00
C2—N1—H1A107.00N4—C5—H5A109.00
H1A—N1—H1B106.00N4—C5—H5B110.00
C6—N1—H1B114.00C6—C5—H5A108.00
N1—C2—C3109.43 (15)C6—C5—H5B109.00
N4—C3—C2110.33 (15)H5A—C5—H5B109.00
N4—C5—C6111.56 (15)N1—C6—H6109.00
C5—C6—C7112.14 (15)C5—C6—H6109.00
N1—C6—C5108.51 (14)C7—C6—H6108.00
N1—C6—C7109.85 (16)C6—C7—H7A109.00
O9—C8—N4110.82 (15)C6—C7—H7B111.00
O8—C8—O9123.88 (19)C6—C7—H7C109.00
O8—C8—N4125.26 (17)H7A—C7—H7B110.00
O9—C10—C11107.66 (13)H7A—C7—H7C109.00
C10—C11—C12117.54 (13)H7B—C7—H7C109.00
C12—C11—C23101.91 (12)O9—C10—H10A110.00
C10—C11—C23114.66 (13)O9—C10—H10B109.00
C11—C12—C13128.75 (15)C11—C10—H10A111.00
C13—C12—C17120.70 (16)C11—C10—H10B110.00
C11—C12—C17110.36 (14)H10A—C10—H10B110.00
C12—C13—C14118.12 (18)C10—C11—H11103.00
C13—C14—C15121.0 (2)C12—C11—H11113.00
C14—C15—C16121.04 (19)C23—C11—H11107.00
C15—C16—C17118.5 (2)C12—C13—H13119.00
C12—C17—C16120.66 (17)C14—C13—H13123.00
C16—C17—C18130.86 (17)C13—C14—H14120.00
C12—C17—C18108.42 (14)C15—C14—H14119.00
C17—C18—C23108.85 (14)C14—C15—H15120.00
C19—C18—C23120.38 (16)C16—C15—H15119.00
C17—C18—C19130.77 (16)C15—C16—H16120.00
C18—C19—C20118.94 (19)C17—C16—H16121.00
C19—C20—C21120.64 (17)C18—C19—H19119.00
C20—C21—C22120.70 (18)C20—C19—H19122.00
C21—C22—C23118.58 (17)C19—C20—H20121.00
C11—C23—C22128.88 (15)C21—C20—H20119.00
C18—C23—C22120.72 (15)C20—C21—H21117.00
C11—C23—C18110.40 (14)C22—C21—H21122.00
N1—C2—H2A109.00C21—C22—H22121.00
N1—C2—H2B110.00C23—C22—H22120.00
C3—C2—H2A109.00
C10—O9—C8—O8−17.4 (2)C11—C12—C13—C14−173.75 (18)
C10—O9—C8—N4164.52 (14)C17—C12—C13—C140.6 (3)
C8—O9—C10—C11−167.41 (13)C11—C12—C17—C16175.50 (16)
C6—N1—C2—C3−57.2 (2)C11—C12—C17—C18−2.04 (17)
C2—N1—C6—C555.8 (2)C13—C12—C17—C160.2 (3)
C2—N1—C6—C7178.70 (16)C13—C12—C17—C18−177.31 (16)
C5—N4—C3—C2−57.0 (2)C12—C13—C14—C15−0.7 (3)
C8—N4—C3—C296.2 (2)C13—C14—C15—C160.1 (3)
C3—N4—C5—C656.7 (2)C14—C15—C16—C170.7 (3)
C8—N4—C5—C6−95.1 (2)C15—C16—C17—C12−0.8 (3)
C3—N4—C8—O812.5 (3)C15—C16—C17—C18176.07 (18)
C3—N4—C8—O9−169.49 (15)C12—C17—C18—C19179.93 (18)
C5—N4—C8—O8163.05 (18)C12—C17—C18—C230.59 (18)
C5—N4—C8—O9−19.0 (2)C16—C17—C18—C192.7 (3)
N1—C2—C3—N455.6 (2)C16—C17—C18—C23−176.61 (18)
N4—C5—C6—N1−54.2 (2)C17—C18—C19—C20178.81 (18)
N4—C5—C6—C7−175.72 (18)C23—C18—C19—C20−1.9 (3)
O9—C10—C11—C12−74.83 (17)C17—C18—C23—C111.10 (18)
O9—C10—C11—C2344.87 (17)C17—C18—C23—C22−178.39 (16)
C10—C11—C12—C13−56.5 (2)C19—C18—C23—C11−178.32 (16)
C10—C11—C12—C17128.77 (15)C19—C18—C23—C222.2 (3)
C23—C11—C12—C13177.33 (17)C18—C19—C20—C210.2 (3)
C23—C11—C12—C172.55 (16)C19—C20—C21—C221.3 (3)
C10—C11—C23—C18−130.26 (14)C20—C21—C22—C23−1.0 (3)
C10—C11—C23—C2249.2 (2)C21—C22—C23—C11179.91 (18)
C12—C11—C23—C18−2.18 (16)C21—C22—C23—C18−0.7 (3)
C12—C11—C23—C22177.26 (17)
Symmetry codes: (i) x, y+1, z; (ii) −x+2, y+1/2, −z+1; (iii) −x+1, y+1/2, −z+1; (iv) x−1, y, z; (v) −x+2, y−1/2, −z+1; (vi) x, y−1, z; (vii) −x+1, y−1/2, −z+1; (viii) −x+2, y+1/2, −z+2; (ix) −x+2, y−1/2, −z+2; (x) −x+1, y−1/2, −z+2; (xi) x+1, y, z; (xii) −x+1, y+1/2, −z+2.
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl1v1.062.083.117 (2)165
N1—H1B···Cl1vi0.882.263.135 (2)171
C2—H2B···O8vii0.962.413.316 (2)157
C3—H3B···O80.962.382.778 (3)104
C5—H5A···O90.962.232.665 (2)106
C21—H21···O8xi0.982.543.469 (2)158
C22—H22···Cl10.962.723.622 (2)157
Symmetry codes: (v) −x+2, y−1/2, −z+1; (vi) x, y−1, z; (vii) −x+1, y−1/2, −z+1; (xi) x+1, y, z.

Experimental details

Crystal data
Chemical formulaC20H23N2O2+·Cl−
Mr358.85
Crystal system, space groupMonoclinic, P21
Temperature (K)293
a, b, c (Å)8.3492 (3), 7.4954 (2), 14.9246 (3)
β (°) 90.6740 (18)
V (Å3)933.93 (5)
Z2
Radiation typeMo Kα
µ (mm−1)0.22
Crystal size (mm)0.28 × 0.20 × 0.08
Data collection
DiffractometerNonius KappaCCD
Absorption correction–
No. of measured, independent and
observed [I > 2σ(I)] reflections		4227, 4221, 3684
Rint0.022
(sin θ/λ)max (Å−1)0.649
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.036, 0.086, 1.03
No. of reflections4221
No. of parameters227
No. of restraints1
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å−3)0.16, −0.15
Absolute structureFlack (1983), 1922 Friedel pairs
Absolute structure parameter−0.04 (5)

Computer programs: COLLECT (Nonius, 1998), SCALEPACK (Otwinowski & Minor, 1997), DENZO and SCALEPAK (Otwinowski & Minor, 1997), SIR97 (Altomare et al., 1999), initial refinement: maXus (MacKay et al., 2000); final refinement: SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009) and ORTEPII (Johnson, 1976), PLATON (Spek, 2009) and ACD/Labs (ACD, 2011).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl1i1.06002.08003.117 (2)165.00
N1—H1B···Cl1ii0.88002.26003.135 (2)171.00
C2—H2B···O8iii0.96002.41003.316 (2)157.00
C21—H21···O8iv0.98002.54003.469 (2)158.00
C22—H22···Cl10.96002.72003.622 (2)157.00
Symmetry codes: (i) −x+2, y−1/2, −z+1; (ii) x, y−1, z; (iii) −x+1, y−1/2, −z+1; (iv) x+1, y, z.
 

Acknowledgements

Thanks to the Pharmaceutical Development Team in Bangalore for providing the material for single-crystal X-ray investigation. The authors also thank Jaikumar Keshavan and other members of AstraZeneca for all their support. This refers to ATP NO 11/0793.

References

First citationACD (2011). ACD/Labs. Advanced Chemistry Development Inc., Toronto, Ontario, Canada.  Google Scholar
 First citationAltomare, A., Burla, M. C., Camalli, M., Cascarano, G. L., Giacovazzo, C., Guagliardi, A., Moliterni, A. G. G., Polidori, G. & Spagna, R. (1999). J. Appl. Cryst. 32, 115–119.  Web of Science CrossRef CAS IUCr Journals Google Scholar
 First citationCho, Y. S., Borland, M., Brain, C., Chen, C. H.-T., Cheng, H., Chopra, R., Chung, K., Groarke, J., He, G., Hou, Y., Kim, S., Kovats, S., Lu, Y., OReilly, M., Shen, J., Smith, T., Trakshel, G., Vogtle, M., Xu, M., Xu, M. & Sung, M. J. (2010). J. Med. Chem. 53, 7938–57.  Web of Science CrossRef PubMed Google Scholar
 First citationFlack, H. D. (1983). Acta Cryst. A39, 876–881.  CrossRef CAS Web of Science IUCr Journals Google Scholar
 First citationJohnson, C. K. (1976). ORTEPII. Oak Ridge National Laboratory, Tennessee, USA  Google Scholar
 First citationKitaigorodskij, A. I. (1973). In Molecular Crystals and Molecules. New York: Academic Press.  Google Scholar
 First citationMacKay, S., Edwards, C., Henderson, A., Gilmore, C., Stewart, N., Shankland, K. & Donald, A. (2000). The maXus program package. Chemistry Department, The University, Glasgow, Scotland, MacScience Co., Japan, and Nonius BV, The Netherlands.  Google Scholar
 First citationNonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.  Google Scholar
 First citationOtwinowski, 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.  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
 First citationWang, T., Yin, Z., Zhang, Z., Bender, J. A., Yang, Z., Johnson, G., Yang, Z., Zadjura, L. M., Arienzo, C. J., DiGiugno Parker, D., Gesenberg, C., Yamanaka, G. A., Gong, Y.-F., Ho, H.-T., Fang, H., Zhou, N., McAuliffe, B. V., Eggers, B. J., Fan, L., Nowicka-Sans, B., Dicker, I. B., Gao, Q., Colonno, R. J., Lin, P.-F., Meanwell, N. A. & Kadow, J. F. (2009). J. Med. Chem. 52, 7778–7787.  Web of Science CrossRef PubMed CAS Google Scholar

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ISSN: 2056-9890
Volume 67| Part 12| December 2011| Pages o3386-o3387
https://doi.org/10.1107/S1600536811048306
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