Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270106012571/sk3005sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270106012571/sk3005Isup2.hkl |
CCDC reference: 612468
Desloratadine (100 mg) was dissolved in EtOAc (10 ml). The solution was filtered and the filtrate was allowed to crystallize by slow evaporation over a period of 2 d. Plate-like crystals of (I) were obtained from the solution and used for single-crystal X-ray diffraction studies.
Atoms H1 and H11 of the N—H and C—H groups, respectively, were located in difference Fourier maps and refined isotropically. All other H atoms were generated with idealized geometry and included in the refinement using a riding model, with C—H = 0.93 Å and Uiso(H) = 1.2Ueq(C) for aromatic H atoms, and C—H = 0.97 Å and Uiso(H) = 1.2Ueq(C) for methylene H atoms. The Flack parameter (Flack, 1983) was determined using a BASF/TWIN type of refinement. 1106 Friedel pairs were used for the analysis.
Data collection: SMART (Bruker, 1999); cell refinement: SMART; data reduction: SAINT (Bruker, 1999); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL.
C19H19ClN2 | F(000) = 328 |
Mr = 310.81 | Dx = 1.373 Mg m−3 |
Monoclinic, P21 | Melting point: 158 K |
Hall symbol: P 2yb | Mo Kα radiation, λ = 0.71073 Å |
a = 6.9336 (12) Å | Cell parameters from 2389 reflections |
b = 11.998 (2) Å | θ = 2.3–25.9° |
c = 9.4691 (16) Å | µ = 0.25 mm−1 |
β = 107.365 (2)° | T = 100 K |
V = 751.8 (2) Å3 | Plate, colourless |
Z = 2 | 0.47 × 0.24 × 0.11 mm |
Bruker SMART CCD area-detector diffractometer | 2550 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.023 |
Graphite monochromator | θmax = 26.0°, θmin = 2.3° |
ϕ and ω scans | h = −8→8 |
4424 measured reflections | k = −13→14 |
2661 independent reflections | l = −8→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)] = 0.032 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.075 | w = 1/[σ2(Fo2) + (0.035P)2 + 0.1332P] where P = (Fo2 + 2Fc2)/3 |
S = 1.05 | (Δ/σ)max < 0.001 |
2661 reflections | Δρmax = 0.21 e Å−3 |
208 parameters | Δρmin = −0.21 e Å−3 |
1 restraint | Absolute structure: Flack (1983), with 1106 Friedel pairs |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: 0.04 (5) |
C19H19ClN2 | V = 751.8 (2) Å3 |
Mr = 310.81 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 6.9336 (12) Å | µ = 0.25 mm−1 |
b = 11.998 (2) Å | T = 100 K |
c = 9.4691 (16) Å | 0.47 × 0.24 × 0.11 mm |
β = 107.365 (2)° |
Bruker SMART CCD area-detector diffractometer | 2550 reflections with I > 2σ(I) |
4424 measured reflections | Rint = 0.023 |
2661 independent reflections |
R[F2 > 2σ(F2)] = 0.032 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.075 | Δρmax = 0.21 e Å−3 |
S = 1.05 | Δρmin = −0.21 e Å−3 |
2661 reflections | Absolute structure: Flack (1983), with 1106 Friedel pairs |
208 parameters | Absolute structure parameter: 0.04 (5) |
1 restraint |
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. |
x | y | z | Uiso*/Ueq | ||
Cl1 | 1.30938 (7) | −0.26310 (4) | 0.25228 (5) | 0.02176 (14) | |
N1 | 1.0382 (3) | 0.35354 (15) | 0.23443 (18) | 0.0183 (4) | |
N2 | 0.3026 (3) | 0.21123 (17) | −0.0094 (2) | 0.0217 (5) | |
C1 | 1.0218 (3) | 0.27342 (18) | 0.3292 (2) | 0.0151 (4) | |
C2 | 1.1542 (3) | 0.44150 (19) | 0.2915 (2) | 0.0206 (5) | |
C3 | 1.2556 (3) | 0.45345 (19) | 0.4397 (2) | 0.0209 (5) | |
C4 | 1.2392 (3) | 0.37022 (18) | 0.5353 (2) | 0.0176 (5) | |
C5 | 1.1214 (3) | 0.27722 (18) | 0.4815 (2) | 0.0162 (4) | |
C6 | 1.0939 (3) | 0.18222 (18) | 0.5774 (2) | 0.0178 (4) | |
C7 | 1.2008 (3) | 0.07625 (19) | 0.5542 (2) | 0.0169 (4) | |
C8 | 1.1423 (3) | 0.02314 (18) | 0.4010 (2) | 0.0143 (4) | |
C9 | 1.2325 (3) | −0.07951 (18) | 0.3917 (2) | 0.0151 (4) | |
C10 | 1.1965 (3) | −0.13316 (19) | 0.2576 (2) | 0.0171 (5) | |
C11 | 1.0735 (3) | −0.08755 (19) | 0.1277 (2) | 0.0170 (4) | |
C12 | 0.9822 (3) | 0.01259 (19) | 0.1379 (2) | 0.0167 (4) | |
C13 | 1.0077 (3) | 0.06879 (18) | 0.2721 (2) | 0.0140 (4) | |
C14 | 0.8931 (3) | 0.17469 (18) | 0.2692 (2) | 0.0146 (4) | |
C15 | 0.6896 (3) | 0.17988 (18) | 0.2193 (2) | 0.0154 (4) | |
C16 | 0.5509 (3) | 0.0826 (2) | 0.1640 (2) | 0.0184 (4) | |
C17 | 0.4130 (3) | 0.10602 (19) | 0.0057 (2) | 0.0194 (5) | |
C18 | 0.4355 (3) | 0.3050 (2) | 0.0511 (2) | 0.0214 (5) | |
C19 | 0.5733 (3) | 0.28702 (19) | 0.2100 (2) | 0.0187 (5) | |
H1 | 0.214 (3) | 0.206 (2) | 0.034 (2) | 0.018 (6)* | |
H2 | 1.1673 | 0.4990 | 0.2260 | 0.025* | |
H3 | 1.3352 | 0.5178 | 0.4751 | 0.025* | |
H4 | 1.3084 | 0.3764 | 0.6380 | 0.021* | |
H6A | 0.9477 | 0.1666 | 0.5559 | 0.021* | |
H6B | 1.1464 | 0.2048 | 0.6825 | 0.021* | |
H7A | 1.1802 | 0.0197 | 0.6244 | 0.020* | |
H7B | 1.3474 | 0.0924 | 0.5827 | 0.020* | |
H9 | 1.3195 | −0.1127 | 0.4785 | 0.018* | |
H11 | 1.054 (3) | −0.1273 (19) | 0.039 (2) | 0.015 (6)* | |
H12 | 0.8977 | 0.0453 | 0.0497 | 0.020* | |
H16A | 0.4670 | 0.0697 | 0.2307 | 0.022* | |
H16B | 0.6318 | 0.0146 | 0.1640 | 0.022* | |
H17A | 0.4968 | 0.1067 | −0.0626 | 0.023* | |
H17B | 0.3145 | 0.0443 | −0.0250 | 0.023* | |
H18A | 0.3515 | 0.3720 | 0.0494 | 0.026* | |
H18B | 0.5211 | 0.3198 | −0.0138 | 0.026* | |
H19A | 0.6686 | 0.3502 | 0.2396 | 0.022* | |
H19B | 0.4904 | 0.2840 | 0.2789 | 0.022* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0233 (2) | 0.0149 (3) | 0.0290 (3) | 0.0025 (2) | 0.0108 (2) | −0.0017 (2) |
N1 | 0.0201 (8) | 0.0158 (10) | 0.0183 (8) | 0.0005 (8) | 0.0047 (7) | 0.0004 (8) |
N2 | 0.0170 (8) | 0.0229 (13) | 0.0233 (9) | −0.0007 (8) | 0.0033 (7) | −0.0006 (8) |
C8 | 0.0132 (9) | 0.0145 (11) | 0.0162 (10) | −0.0022 (9) | 0.0062 (8) | −0.0003 (8) |
C9 | 0.0127 (9) | 0.0151 (12) | 0.0171 (10) | 0.0004 (9) | 0.0040 (7) | 0.0033 (8) |
C10 | 0.0133 (9) | 0.0113 (12) | 0.0293 (11) | −0.0021 (9) | 0.0103 (8) | 0.0005 (9) |
C14 | 0.0203 (10) | 0.0127 (12) | 0.0111 (9) | 0.0005 (9) | 0.0049 (8) | 0.0005 (8) |
C18 | 0.0175 (10) | 0.0218 (14) | 0.0231 (11) | 0.0045 (10) | 0.0034 (9) | 0.0034 (9) |
C5 | 0.0120 (9) | 0.0172 (12) | 0.0195 (10) | 0.0038 (9) | 0.0051 (8) | −0.0024 (9) |
C4 | 0.0140 (9) | 0.0163 (12) | 0.0211 (10) | 0.0048 (9) | 0.0028 (8) | −0.0056 (9) |
C1 | 0.0114 (9) | 0.0162 (11) | 0.0172 (9) | 0.0033 (8) | 0.0038 (7) | −0.0018 (8) |
C13 | 0.0126 (9) | 0.0136 (11) | 0.0163 (9) | −0.0036 (9) | 0.0050 (7) | −0.0002 (8) |
C15 | 0.0180 (10) | 0.0153 (12) | 0.0120 (9) | −0.0005 (9) | 0.0029 (8) | −0.0010 (8) |
C7 | 0.0177 (9) | 0.0168 (12) | 0.0155 (9) | 0.0018 (9) | 0.0039 (8) | 0.0021 (8) |
C11 | 0.0165 (10) | 0.0155 (12) | 0.0180 (10) | −0.0042 (9) | 0.0037 (8) | −0.0029 (9) |
C6 | 0.0182 (10) | 0.0188 (12) | 0.0165 (10) | 0.0014 (9) | 0.0057 (8) | −0.0013 (8) |
C2 | 0.0195 (10) | 0.0178 (12) | 0.0264 (11) | −0.0003 (10) | 0.0097 (9) | 0.0021 (9) |
C17 | 0.0171 (10) | 0.0216 (13) | 0.0171 (10) | −0.0008 (10) | 0.0017 (8) | 0.0003 (9) |
C12 | 0.0133 (10) | 0.0173 (12) | 0.0173 (10) | −0.0027 (9) | 0.0012 (8) | 0.0013 (8) |
C3 | 0.0162 (10) | 0.0152 (13) | 0.0314 (12) | −0.0003 (10) | 0.0071 (9) | −0.0053 (9) |
C19 | 0.0153 (10) | 0.0187 (12) | 0.0212 (10) | −0.0001 (9) | 0.0042 (8) | −0.0017 (9) |
C16 | 0.0165 (9) | 0.0186 (12) | 0.0203 (10) | −0.0016 (9) | 0.0059 (8) | 0.0006 (9) |
Cl1—C10 | 1.752 (2) | C4—H4 | 0.9500 |
C14—C15 | 1.349 (3) | C13—C12 | 1.403 (3) |
C14—C1 | 1.490 (3) | C15—C16 | 1.503 (3) |
C14—C13 | 1.494 (3) | C15—C19 | 1.506 (3) |
N2—C18 | 1.458 (3) | C7—C6 | 1.521 (3) |
N2—C17 | 1.461 (3) | C7—H7A | 0.9900 |
N2—H1 | 0.84 (2) | C7—H7B | 0.9900 |
C10—C9 | 1.378 (3) | C11—C12 | 1.375 (3) |
C10—C11 | 1.384 (3) | C11—H11 | 0.94 (2) |
C9—C8 | 1.396 (3) | C6—H6A | 0.99 |
C9—H9 | 0.9500 | C6—H6B | 0.99 |
C8—C13 | 1.407 (3) | C2—C3 | 1.376 (3) |
C8—C7 | 1.524 (3) | C2—H2 | 0.95 |
N1—C2 | 1.339 (3) | C17—C16 | 1.545 (3) |
N1—C1 | 1.343 (3) | C17—H17A | 0.99 |
C18—C19 | 1.538 (3) | C17—H17B | 0.99 |
C18—H18A | 0.9900 | C12—H12 | 0.95 |
C18—H18B | 0.9900 | C3—H3 | 0.9500 |
C5—C4 | 1.387 (3) | C19—H19A | 0.99 |
C5—C1 | 1.401 (3) | C19—H19B | 0.99 |
C5—C6 | 1.505 (3) | C16—H16A | 0.99 |
C4—C3 | 1.375 (3) | C16—H16B | 0.99 |
C15—C14—C1 | 122.80 (18) | C6—C7—H7B | 107.6 |
C15—C14—C13 | 122.69 (18) | C8—C7—H7B | 107.6 |
C1—C14—C13 | 114.49 (16) | H7A—C7—H7B | 107.0 |
C18—N2—C17 | 112.13 (16) | C12—C11—C10 | 117.23 (19) |
C18—N2—H1 | 109.8 (16) | C12—C11—H11 | 124.2 (13) |
C17—N2—H1 | 109.0 (17) | C10—C11—H11 | 118.6 (13) |
C9—C10—C11 | 121.9 (2) | C5—C6—C7 | 112.99 (16) |
C9—C10—Cl1 | 118.84 (16) | C5—C6—H6A | 109.0 |
C11—C10—Cl1 | 119.25 (17) | C7—C6—H6A | 109.0 |
C10—C9—C8 | 120.57 (18) | C5—C6—H6B | 109.0 |
C10—C9—H9 | 119.7 | C7—C6—H6B | 109.0 |
C8—C9—H9 | 119.7 | H6A—C6—H6B | 107.8 |
C9—C8—C13 | 118.86 (18) | N1—C2—C3 | 123.8 (2) |
C9—C8—C7 | 115.59 (17) | N1—C2—H2 | 118.1 |
C13—C8—C7 | 125.55 (18) | C3—C2—H2 | 118.1 |
C2—N1—C1 | 117.04 (17) | N2—C17—C16 | 113.96 (17) |
N2—C18—C19 | 114.31 (18) | N2—C17—H17A | 108.8 |
N2—C18—H18A | 108.7 | C16—C17—H17A | 108.8 |
C19—C18—H18A | 108.7 | N2—C17—H17B | 108.8 |
N2—C18—H18B | 108.7 | C16—C17—H17B | 108.8 |
C19—C18—H18B | 108.7 | H17A—C17—H17B | 107.7 |
H18A—C18—H18B | 107.6 | C11—C12—C13 | 123.22 (19) |
C4—C5—C1 | 117.4 (2) | C11—C12—H12 | 118.4 |
C4—C5—C6 | 123.66 (18) | C13—C12—H12 | 118.4 |
C1—C5—C6 | 118.96 (18) | C4—C3—C2 | 118.6 (2) |
C3—C4—C5 | 119.84 (19) | C4—C3—H3 | 120.7 |
C3—C4—H4 | 120.1 | C2—C3—H3 | 120.7 |
C5—C4—H4 | 120.1 | C15—C19—C18 | 109.99 (17) |
N1—C1—C5 | 123.38 (19) | C15—C19—H19A | 109.7 |
N1—C1—C14 | 118.35 (17) | C18—C19—H19A | 109.7 |
C5—C1—C14 | 118.26 (18) | C15—C19—H19B | 109.7 |
C12—C13—C8 | 118.04 (19) | C18—C19—H19B | 109.7 |
C12—C13—C14 | 118.01 (17) | H19A—C19—H19B | 108.2 |
C8—C13—C14 | 123.95 (17) | C15—C16—C17 | 110.08 (17) |
C14—C15—C16 | 125.43 (19) | C15—C16—H16A | 109.6 |
C14—C15—C19 | 123.06 (19) | C17—C16—H16A | 109.6 |
C16—C15—C19 | 111.50 (16) | C15—C16—H16B | 109.6 |
C6—C7—C8 | 118.99 (16) | C17—C16—H16B | 109.6 |
C6—C7—H7A | 107.6 | H16A—C16—H16B | 108.2 |
C8—C7—H7A | 107.6 |
D—H···A | D—H | H···A | D···A | D—H···A |
C11—H11···N1i | 0.940 (18) | 2.485 (18) | 3.357 (3) | 154.4 (18) |
Symmetry code: (i) −x+2, y−1/2, −z. |
Experimental details
Crystal data | |
Chemical formula | C19H19ClN2 |
Mr | 310.81 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 100 |
a, b, c (Å) | 6.9336 (12), 11.998 (2), 9.4691 (16) |
β (°) | 107.365 (2) |
V (Å3) | 751.8 (2) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.25 |
Crystal size (mm) | 0.47 × 0.24 × 0.11 |
Data collection | |
Diffractometer | Bruker SMART CCD area-detector diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4424, 2661, 2550 |
Rint | 0.023 |
(sin θ/λ)max (Å−1) | 0.618 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.032, 0.075, 1.05 |
No. of reflections | 2661 |
No. of parameters | 208 |
No. of restraints | 1 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.21, −0.21 |
Absolute structure | Flack (1983), with 1106 Friedel pairs |
Absolute structure parameter | 0.04 (5) |
Computer programs: SMART (Bruker, 1999), SMART, SAINT (Bruker, 1999), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXTL (Bruker, 1997), SHELXTL.
D—H···A | D—H | H···A | D···A | D—H···A |
C11—H11···N1i | 0.940 (18) | 2.485 (18) | 3.357 (3) | 154.4 (18) |
Symmetry code: (i) −x+2, y−1/2, −z. |
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Desloratadine, (I), is a tricyclic antihistamine and is used to treat allergies. It is sold under brand names such as Clarinex and Aerius. It has a long-lasting effect and does not cause drowsiness because it does not readily enter the central nervous system. Desloratadine is an active metabolite of loratadine, which is also on the market. It is 10–20 times more potent as an antihistamine than loratadine. The solid-state chemistry of active pharmaceutical ingredients (API) is of both academic and applied interest and is concerned with the identification and characterization of different solid forms of APIs and their use in formulations.
Commercially available desloratadine, (I), was crystallized from EtOAc and crystals suitable for X-ray studies were obtained. The crystal structure was determined and the results are presented here. The molecular geometry and atom numbering are given in Fig. 1, and the packing arrangement is shown in Fig. 2. The only hydrogen bond present in the structure is a C—H···N interaction between the phenyl atom H11 and the pyridine atom N1. This interaction gives rise to an infinite zigzag chain, with piperidine rings alternating and pointing outwards on either side of the chain. Two such adjacent chains pack by placing their piperidine fragments into the space between two fragments of the adjacent chain and vice-versa, as shown in Fig. 2. This is basically a close-packed arrangement.
The most interesting feature of the crystal structure of (I) is that the piperidine N—H group is not hydrogen bonded in a conventional sense (N—H···N), although there are two N-atom acceptors in the molecule. A search of the Cambridge Structural Database (CSD, Version?; Allen, 2002) was carried out for entries which contain only N—H as a hydrogen-bond donor and where this N—H is not hydrogen bonded to any acceptor. The constraints used in this search were as follows: R < 0.05, no errors, not polymeric, no ions, only organics. 543 hits were obtained. However, analysis showed that, in almost all these cases, the N—H group is sterically hindered. It is therefore surprising that, in the case of desloratadine, which has a sterically unhindered N—H group, no hydrogen bonds are formed. The reason for this may lie in the awkward shape of the molecule. This reasoning was supported with a computational study using Polymorph Predictor (Accelrys, Year?). The polymorph prediction was carried out with the DREIDING2.21 force-field in five space groups, P21, C2/c, P1, P21/c and P212121. Except in C2/c, the most stable structure predicted was very similar to the experimental structure, in that no N—H···N hydrogen bond is present. Crystal structure prediction in the experimental space group (P21) gave the most stable structure, which was identical to the experimental structure. This is a good validation of the force field.
Desiraju (2002) has discussed a similar issue in his article entitled `Bond free' with respect to the literature example of the oxalic acid–phthalocyanine complex (Liu et al., 2002) and also alloxan (Coombes et al., 1997; Beyer et al., 2001). He concluded that crystal structures are determined by an interplay of both space filling and hydrogen bonding, such that the free energy is a minimum, and that the very occasional appearance of a crystal structure where sterically unhindered X—H groups do not form strong X—H···A interactions is a statistical issue, brought about by the fact that a very large number of crystal structures of small organic molecules are being determined today.
To date, two polymorphs of desloratadine have been reported in a patent application (Toth et al., 2004) but no crystal structure data are available. A comparison of the powder X-ray spectrum given in the patent and that simulated from the single-crystal data of the present study showed that the single-crystal obtained by us corresponds to form 1 of desloratadine. We feel it is possible to realise experimentally the hydrogen-bonded structure obtained computationally in the C2/c space group because it is only 2 kcal mol−1 molecule−1 (1 kcal mol−1 = 4.184 kJ mol−1) less stable than the experimental P21 structure reported here.