organic compounds Acta Crystallographica Section E
Structure Reports Online ISSN 1600-5368
(S)-(+)-cis-40 -Benzyloxypraziquantel Alberto Cedillo-Cruz,* Marı´a Isabel Aguilar and Helgi Jung-Cook Departamento de Farmacia, Facultad de Quı´mica, Universidad Nacional Auto´noma de Me´xico, 04510 Me´xico, DF, Mexico Correspondence e-mail:
[email protected] Received 31 October 2013; accepted 20 November 2013
Experimental Crystal data
˚; Key indicators: single-crystal X-ray study; T = 130 K; mean (C–C) = 0.009 A disorder in main residue; R factor = 0.052; wR factor = 0.137; data-to-parameter ratio = 10.5.
The asymmetric unit of the title compound, C26H30N2O3 {systematic name (S)-(+)-2-[cis-4-(benzyloxy)cyclohexanecarbonyl]-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one}, consists of two independent molecules in which the O Camide group is syn to the N—C(C Olactam) moiety, making dihedral angles of 2.0 (8) and 3.7 (8) . The conformation of the 1,4-disubstituted cyclohexane ring is cis in each independent molecule, with the carbonyl group occupying an equatorial position and the benzyloxy group an axial position. In one molecule, two C and one O atom of the benzyloxy group are disordered over two sets of sites, with a refined occupancy ratio of 0.772 (8):0.228 (8). In the crystal, molecules are linked by C—H O interactions, forming ribbons parallel to the b-axis direction.
Related literature For pyrazinoisoquinolone derivatives with anthelmintic activity, see: Staudt et al. (1992); Jung et al. (2008); The´tiotLaurent et al. (2013); Duan et al. (2012); Patra et al. (2013); Wang et al. (2013); Meier & Blaschke (2001).
˚3 V = 2205.2 (5) A Z=4 Cu K radiation = 0.66 mm1 T = 130 K 0.59 0.31 0.13 mm
C26H30N2O3 Mr = 418.52 Monoclinic, P21 ˚ a = 15.007 (2) A ˚ b = 10.3322 (8) A ˚ c = 16.019 (2) A = 117.399 (13)
Data collection Oxford Diffraction Xcalibur (Atlas, Gemini) diffractometer Absorption correction: analytical [CrysAlis PRO (Agilent, 2011), based on expressions derived by
Clark & Reid (1995)] Tmin = 0.937, Tmax = 0.979 8420 measured reflections 5852 independent reflections 3845 reflections with I > 2(I) Rint = 0.057
Refinement R[F 2 > 2(F 2)] = 0.052 wR(F 2) = 0.137 S = 1.03 5852 reflections 558 parameters 4 restraints H-atom parameters constrained ˚ 3 max = 0.25 e A
˚ 3 min = 0.23 e A Absolute structure: Flack parameter determined using 868 quotients [(I+)(I)]/[(I+)+(I)] (Parsons et al., 2013) Absolute structure parameter: 0.4 (3)
Table 1 ˚ , ). Hydrogen-bond geometry (A D—H A
D—H
H A
D A
D—H A
C20—H20B O2i C20A—H20C O2Aii C20B—H20F O2Aii
0.99 0.99 0.99
2.45 2.60 2.26
3.332 (7) 3.567 (10) 3.19 (3)
149 165 156
Symmetry codes: (i) x; y þ 12; z þ 1; (ii) x; y þ 12; z.
Data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS2013 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2006) and ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012) and publCIF (Westrip, 2010).
Acta Cryst. (2013). E69, o1835–o1836
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organic compounds AC-C is grateful to CONACyT for a graduate student scholarship. The authors acknowledge M. Flores-Alamo for the data collection. Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: RZ5093).
References Agilent (2011). CrysAlis PRO. Agilent Technologies UK Ltd, Yarnton, England. Clark, R. C. & Reid, J. S. (1995). Acta Cryst. A51, 887–897. Duan, W.-W., Qiu, S.-J., Zhao, Y., Sun, H., Qiao, C. & Xia, C.-M. (2012). Bioorg. Med. Chem. Lett. 22, 1587–1590. Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.
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Jung, H., Ca´rdenas, G., Sciutto, E. & Fleury, A. (2008). Curr. Top. Med. Chem. 8, 424–433. Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39, 453–457. Meier, H. & Blaschke, G. (2001). J. Pharm. Biomed. Anal. 26, 409–415. Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Patra, M., Ingram, K., Pierroz, V., Ferrari, S., Spingler, B., Gasser, R. B., Keiser, J. & Gasser, G. (2013). Chem. Eur. J. 19, 2232–2235. Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Staudt, U., Schmahl, G., Blaschke, G. & Mehlhorn, H. (1992). Parasitol. Res. 78, 392–397. The´tiot-Laurent, S. A. L., Boissier, J., Robert, A. & Meunier, B. (2013). Angew. Chem. Int. Ed. 52, 7936–7956. Wang, W.-L., Song, L.-J., Chen, X., Yin, X.-R., Fan, W.-H., Wang, G.-P., Yu, C.X. & Feng, B. (2013). Molecules, 18, 9163–9178. Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.
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supplementary materials
supplementary materials Acta Cryst. (2013). E69, o1835–o1836
[doi:10.1107/S1600536813031735]
(S)-(+)-cis-4′-Benzyloxypraziquantel Alberto Cedillo-Cruz, María Isabel Aguilar and Helgi Jung-Cook 1. Comment The importance of pyrazinoisoquinolone derivatives as anthelmintics is well established (Jung et al., 2008; ThétiotLaurent et al., 2013). Extensive number of derivatives has been synthesized, nevertheless at the date there are none with an activity comparable to that of praziquantel (Duan et al., 2012; Patra et al., 2013; Wang et al., 2013). Such compounds usually have an asymmetric carbon atom and only one of the enantiomers presents anthelmintic activity, often the enantiomer with (R)-(-)-configuration (Staudt et al., 1992). Herein, we report the synthesis and crystal structure of the title compound, (S)-(+)-cis-4 -benzyloxypraziquantel (Fig. 1), as a key intermediate for the synthesis of (S)-(+)-cis-4 -hydroxypraziquantel, one of the main metabolites of praziquantel (Meier & Blaschke, 2001). The most stable conformation for (S)-(+)-cis-4′-benzyloxypraziquantel is observed where the O═ Camide group is syn to the N–C(C═Olactam) moiety with a dihedral angle of 2.0 (8) and 3.7 (8)° for the two independent molecules per asymmetric unit. Furthermore, the conformation of the 1,4-disubstituted cyclohexane is cis, where the carbonyl moiety occupies an equatorial position and the benzyloxy moiety occupies an axial position. In the crystal (Fig. 2), molecules are linked by intermolecular C—H···O hydrogen interactions (Table 1) to form ribbons parallel to the b axis. 2. Experimental To a solution of (S)-(+)-praziquanamine (505.5 mg, 2.50 mmol) and 4-methylmorpholine (1.4 ml, 12.73) in dichloromethane (35 ml) under nitrogen atmosphere, a solution of cis-4-(benzyloxy)cyclohexanecarbonyl chloride (586 mg, 2.50 mmol) in dichloromethane (15 ml) was added dropwise at 0°C. After stirring at room temperature for 2 h, dichloromethane (50 ml) was added. The organic layer was successively washed with 1 M HCl (3 · 50 ml), saturated solution of NaHCO3 (3 · 50 ml), water (3 · 50 ml) and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, ethyl acetate 100%). A white powder was obtained (935.7 mg, 89% yield). m.p. 405–408 K. Single-crystals suitable for X-ray diffraction were prepared by evaporation of a solution of the title compound in methanol at room temperature. 3. Refinement All H atoms were geometrically positioned and refined using a riding model, with C–H = 0.95 Å for aromatic CH, 0.99 Å for secondary CH2, 1.00 Å for tertiary CH, respectively, and with Uiso(H) = 1.2Ueq(C). The absolute configuration was not established by anomalous dispersion effects, nevertheless the absolute configuration could be assigned from the known configuration of the chiral centers. In one molecule the C20A, C21A and O3A atoms of the benzyloxy group are disordered over two sets of sites with refined site occupancies of 0.772 (8):0.228 (8). During the refinement, the C21B– C26A, C21B–C22A and C21B–C20B bond lengths were constrained to be 1.38 (1), 1.38 (2) and 1.50 (1) Å, respectively. In the last cycles of refinement, 14 outliers were omitted.
Acta Cryst. (2013). E69, o1835–o1836
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supplementary materials Computing details Data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO (Agilent, 2011); data reduction: CrysAlis PRO (Agilent, 2011); program(s) used to solve structure: SHELXS2013 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2006) and ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012) and publCIF (Westrip, 2010).
Figure 1 The asymmetric unit of the title compound with displacement ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Only the major component of the disordered atoms is shown.
Acta Cryst. (2013). E69, o1835–o1836
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Figure 2 Intermolecular C—H···O interactions (dotted lines) forming ribbons parallel to the b axis in the title compound. Only the major components of the disordered atoms are shown. (S)-(+)-2-[cis-4-(Benzyloxy)cyclohexanecarbonyl]-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one Crystal data C26H30N2O3 Mr = 418.52 Monoclinic, P21 a = 15.007 (2) Å b = 10.3322 (8) Å c = 16.019 (2) Å β = 117.399 (13)° V = 2205.2 (5) Å3 Z=4 F(000) = 896 Acta Cryst. (2013). E69, o1835–o1836
Dx = 1.261 Mg m−3 Melting point = 405–408 K Cu Kα radiation, λ = 1.54184 Å Cell parameters from 1613 reflections θ = 3.3–73.3° µ = 0.66 mm−1 T = 130 K Needle, colourless 0.59 × 0.31 × 0.13 mm
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supplementary materials Data collection Oxford Diffraction Xcalibur (Atlas, Gemini) diffractometer Radiation source: Enhance (Cu) X-ray Source Graphite monochromator Detector resolution: 10.4685 pixels mm-1 ω scans Absorption correction: analytical [CrysAlis PRO (Agilent, 2011), based on expressions derived by Clark & Reid (1995)]
Tmin = 0.937, Tmax = 0.979 8420 measured reflections 5852 independent reflections 3845 reflections with I > 2σ(I) Rint = 0.057 θmax = 68.3°, θmin = 5.5° h = −17→18 k = −12→7 l = −19→18
Refinement Refinement on F2 Least-squares matrix: full R[F2 > 2σ(F2)] = 0.052 wR(F2) = 0.137 S = 1.03 5852 reflections 558 parameters 4 restraints Primary atom site location: structure-invariant direct methods Secondary atom site location: difference Fourier map Hydrogen site location: inferred from neighbouring sites
H-atom parameters constrained w = 1/[σ2(Fo2) + (0.0462P)2 + 0.6847P] where P = (Fo2 + 2Fc2)/3 (Δ/σ)max < 0.001 Δρmax = 0.25 e Å−3 Δρmin = −0.23 e Å−3 Extinction correction: SHELXL2013 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 Extinction coefficient: 0.00115 (17) Absolute structure: Flack parameter determined using 868 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) Absolute structure parameter: 0.382 (265)
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 > 2σ(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)
O1 O2 N1 N2 C12 H12 C13 C16 H16C H16D C2 H2 C19
x
y
z
Uiso*/Ueq
0.6375 (3) 0.2778 (3) 0.5909 (3) 0.3976 (3) 0.5135 (3) 0.4792 0.3000 (4) 0.0377 (4) −0.0294 0.0492 0.4924 (4) 0.4226 0.2203 (4)
0.2009 (4) 0.1973 (4) 0.4128 (4) 0.3440 (4) 0.5133 (5) 0.5224 0.3110 (5) 0.4631 (6) 0.4226 0.5139 0.7477 (5) 0.7356 0.4976 (5)
0.7391 (3) 0.5624 (3) 0.7198 (3) 0.5860 (3) 0.6799 (3) 0.7203 0.5562 (4) 0.4195 (4) 0.3863 0.3729 0.6361 (3) 0.6154 0.5981 (4)
0.0452 (10) 0.0489 (11) 0.0346 (11) 0.0350 (11) 0.0289 (12) 0.035* 0.0341 (13) 0.0423 (15) 0.051* 0.051* 0.0331 (13) 0.040* 0.0351 (13)
Acta Cryst. (2013). E69, o1835–o1836
Occ. (