Two polymorphs of safinamide {systematic name: (2
S)-2-[4-(3-fluorobenzyloxy)benzylamino]propionamide}, C
17H
19FN
2O
2, a potent selective and reversible monoamine oxidase B (MAO-B) inhibitor, are described. Both forms are orthorhombic and regarded as conformational polymorphs due to the differences in the orientation of the 3-fluorobenzyloxy and propanamide groups. Both structures pack with layers in the
ac plane. In polymorph (I), the layers have discrete wide and narrow regions which are complementary when located next to adjacent layers. In polymorph (II), the layer has long flanges protruding from each side, which interdigitate when packed with the adjacent layers. N-H
O hydrogen bonds are present in both structures, whereas N-H
F hydrogen bonding is seen in polymorph (I), while N-H
N hydrogen bonding is seen in polymorph (II).
Supporting information
CCDC references: 782545; 782546
Plate-shaped single crystals of polymorph (I) were obtained by slow evaporation
of the title compound (25 mg) from benzene (10 ml) and hexane (2 ml) solutions
stirred and warmed slightly over a steam bath for 10 min. Needle-shaped
crystals of polymorph (II) were obtained by slow evaporation from ethyl
acetate (8 ml) and hexane (2 ml) solutions stirred and warmed slightly over a
steam bath for 10 min.
All N-bound H atoms were located in difference Fourier maps, and their positions
and isotropic displacement parameters were located and refined. All other H
atoms were located in a difference density map but were positioned
geometrically and included as riding atoms, with C—H = 0.93–0.98 Å, and
with Uiso(H) = 1.5Ueq(C) for methyl H or 1.2Ueq(C)
for the other H atoms. In the absence of significant anomalous scattering
effects, Friedel pairs were merged. The absolute configuration of safinamide
was known in advance.
For both compounds, data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg & Putz, 2005) and Mercury (Macrae et al., 2008)'; software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).
(I) (2
S)-2-[4-(3-fluorobenzyloxy)benzylamino]propionamide
top
Crystal data top
C17H19FN2O2 | F(000) = 640 |
Mr = 302.34 | Dx = 1.231 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 1832 reflections |
a = 5.1127 (5) Å | θ = 2.3–17.4° |
b = 17.8516 (16) Å | µ = 0.09 mm−1 |
c = 17.8746 (1) Å | T = 294 K |
V = 1631.4 (2) Å3 | Flaky plate, colourless |
Z = 4 | 0.14 × 0.10 × 0.06 mm |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 1179 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.057 |
Graphite monochromator | θmax = 25.0°, θmin = 1.6° |
ω scans | h = −6→6 |
15763 measured reflections | k = −21→21 |
1698 independent reflections | l = −21→21 |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.042 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.113 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.97 | w = 1/[σ2(Fo2) + (0.0525P)2 + 0.3868P] where P = (Fo2 + 2Fc2)/3 |
1698 reflections | (Δ/σ)max < 0.001 |
212 parameters | Δρmax = 0.15 e Å−3 |
0 restraints | Δρmin = −0.12 e Å−3 |
Crystal data top
C17H19FN2O2 | V = 1631.4 (2) Å3 |
Mr = 302.34 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 5.1127 (5) Å | µ = 0.09 mm−1 |
b = 17.8516 (16) Å | T = 294 K |
c = 17.8746 (1) Å | 0.14 × 0.10 × 0.06 mm |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 1179 reflections with I > 2σ(I) |
15763 measured reflections | Rint = 0.057 |
1698 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.042 | 0 restraints |
wR(F2) = 0.113 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.97 | Δρmax = 0.15 e Å−3 |
1698 reflections | Δρmin = −0.12 e Å−3 |
212 parameters | |
Special details top
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 (Å2) top | x | y | z | Uiso*/Ueq | |
C1 | 0.2831 (8) | 0.0072 (2) | 1.01349 (19) | 0.0624 (9) | |
C2 | 0.1661 (9) | 0.0617 (2) | 1.0556 (2) | 0.0774 (12) | |
H2 | 0.2099 | 0.1118 | 1.0491 | 0.093* | |
C3 | −0.0151 (10) | 0.0411 (3) | 1.1070 (3) | 0.0911 (14) | |
C4 | −0.0915 (10) | −0.0304 (3) | 1.1186 (3) | 0.0955 (15) | |
H4 | −0.2194 | −0.0420 | 1.1538 | 0.115* | |
C5 | 0.0249 (10) | −0.0846 (3) | 1.0772 (3) | 0.0917 (14) | |
H5 | −0.0216 | −0.1345 | 1.0842 | 0.110* | |
C6 | 0.2108 (9) | −0.0663 (2) | 1.0250 (2) | 0.0808 (12) | |
H6 | 0.2892 | −0.1040 | 0.9970 | 0.097* | |
C7 | 0.4762 (9) | 0.0250 (2) | 0.9525 (2) | 0.0747 (11) | |
H7A | 0.6222 | −0.0096 | 0.9549 | 0.090* | |
H7B | 0.3932 | 0.0197 | 0.9040 | 0.090* | |
C8 | 0.7410 (8) | 0.1249 (2) | 0.9092 (2) | 0.0636 (10) | |
C9 | 0.8390 (9) | 0.1955 (2) | 0.9215 (2) | 0.0745 (12) | |
H9 | 0.7849 | 0.2226 | 0.9632 | 0.089* | |
C10 | 1.0159 (9) | 0.2264 (2) | 0.8728 (2) | 0.0758 (11) | |
H10 | 1.0810 | 0.2741 | 0.8824 | 0.091* | |
C11 | 1.1003 (7) | 0.1884 (2) | 0.8094 (2) | 0.0639 (10) | |
C12 | 1.0019 (9) | 0.1185 (2) | 0.7984 (2) | 0.0753 (11) | |
H12 | 1.0576 | 0.0914 | 0.7570 | 0.090* | |
C13 | 0.8210 (8) | 0.0858 (2) | 0.8468 (2) | 0.0755 (11) | |
H13 | 0.7553 | 0.0382 | 0.8371 | 0.091* | |
C14 | 1.2953 (8) | 0.2220 (2) | 0.7559 (2) | 0.0771 (12) | |
H14A | 1.4632 | 0.2246 | 0.7811 | 0.093* | |
H14B | 1.3147 | 0.1881 | 0.7139 | 0.093* | |
C15 | 0.9785 (7) | 0.30437 (19) | 0.69276 (18) | 0.0531 (9) | |
H15 | 0.8547 | 0.2726 | 0.7201 | 0.064* | |
C16 | 0.9790 (6) | 0.28013 (19) | 0.61121 (18) | 0.0485 (8) | |
C17 | 0.8823 (10) | 0.3847 (2) | 0.6968 (3) | 0.0930 (15) | |
H17A | 0.8687 | 0.3998 | 0.7482 | 0.140* | |
H17B | 0.7138 | 0.3883 | 0.6734 | 0.140* | |
H17C | 1.0036 | 0.4169 | 0.6714 | 0.140* | |
F1 | −0.1339 (8) | 0.09638 (19) | 1.14651 (19) | 0.1656 (16) | |
N1 | 1.2348 (6) | 0.2958 (2) | 0.72683 (16) | 0.0657 (9) | |
H1N | 1.261 (10) | 0.328 (2) | 0.763 (2) | 0.110 (17)* | |
N2 | 1.2062 (6) | 0.2778 (2) | 0.57748 (18) | 0.0611 (8) | |
H2N | 1.344 (8) | 0.285 (2) | 0.607 (2) | 0.067 (11)* | |
H3N | 1.219 (7) | 0.2644 (16) | 0.5328 (17) | 0.056 (10)* | |
O1 | 0.5665 (6) | 0.09873 (14) | 0.96168 (14) | 0.0758 (8) | |
O2 | 0.7690 (4) | 0.26650 (14) | 0.57990 (12) | 0.0624 (7) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.067 (2) | 0.064 (2) | 0.056 (2) | −0.001 (2) | −0.002 (2) | 0.0046 (18) |
C2 | 0.092 (3) | 0.061 (2) | 0.080 (3) | −0.010 (2) | 0.012 (3) | −0.006 (2) |
C3 | 0.102 (4) | 0.088 (3) | 0.083 (3) | 0.005 (3) | 0.031 (3) | −0.022 (3) |
C4 | 0.099 (4) | 0.116 (4) | 0.072 (3) | −0.021 (3) | 0.023 (3) | 0.008 (3) |
C5 | 0.112 (4) | 0.074 (3) | 0.089 (3) | −0.025 (3) | 0.007 (3) | 0.009 (3) |
C6 | 0.097 (3) | 0.069 (3) | 0.077 (3) | −0.005 (3) | 0.008 (3) | −0.005 (2) |
C7 | 0.081 (3) | 0.069 (2) | 0.074 (2) | −0.005 (2) | 0.012 (3) | −0.007 (2) |
C8 | 0.061 (2) | 0.077 (3) | 0.053 (2) | −0.003 (2) | 0.005 (2) | 0.0117 (19) |
C9 | 0.089 (3) | 0.079 (3) | 0.055 (2) | −0.016 (2) | 0.014 (2) | −0.003 (2) |
C10 | 0.083 (3) | 0.084 (3) | 0.060 (2) | −0.022 (3) | 0.003 (2) | 0.001 (2) |
C11 | 0.053 (2) | 0.090 (3) | 0.048 (2) | 0.003 (2) | −0.0041 (19) | 0.008 (2) |
C12 | 0.069 (3) | 0.099 (3) | 0.058 (2) | 0.010 (3) | 0.010 (2) | −0.007 (2) |
C13 | 0.076 (3) | 0.074 (3) | 0.076 (3) | −0.002 (2) | 0.011 (3) | −0.007 (2) |
C14 | 0.050 (2) | 0.127 (3) | 0.054 (2) | 0.001 (3) | −0.0032 (19) | 0.019 (2) |
C15 | 0.0468 (19) | 0.068 (2) | 0.0442 (18) | −0.0126 (19) | 0.0045 (18) | 0.0015 (16) |
C16 | 0.0349 (18) | 0.064 (2) | 0.0464 (17) | −0.0063 (17) | 0.0023 (17) | 0.0032 (16) |
C17 | 0.108 (4) | 0.083 (3) | 0.088 (3) | 0.001 (3) | 0.008 (3) | −0.017 (2) |
F1 | 0.199 (4) | 0.140 (3) | 0.158 (3) | 0.003 (3) | 0.095 (3) | −0.049 (2) |
N1 | 0.0521 (18) | 0.101 (3) | 0.0444 (16) | −0.025 (2) | −0.0038 (16) | 0.0012 (17) |
N2 | 0.0380 (16) | 0.104 (3) | 0.0412 (18) | −0.0050 (17) | −0.0007 (17) | −0.0040 (17) |
O1 | 0.090 (2) | 0.0674 (17) | 0.0704 (16) | −0.0125 (15) | 0.0170 (16) | 0.0035 (13) |
O2 | 0.0353 (13) | 0.0974 (18) | 0.0545 (14) | −0.0076 (13) | −0.0045 (12) | −0.0080 (13) |
Geometric parameters (Å, º) top
C1—C2 | 1.368 (5) | C10—H10 | 0.9300 |
C1—C6 | 1.379 (5) | C11—C12 | 1.360 (5) |
C1—C7 | 1.504 (5) | C11—C14 | 1.506 (5) |
C2—C3 | 1.356 (6) | C12—C13 | 1.394 (5) |
C2—H2 | 0.9300 | C12—H12 | 0.9300 |
C3—C4 | 1.350 (6) | C13—H13 | 0.9300 |
C3—F1 | 1.357 (5) | C14—N1 | 1.450 (5) |
C4—C5 | 1.357 (6) | C14—H14A | 0.9700 |
C4—H4 | 0.9300 | C14—H14B | 0.9700 |
C5—C6 | 1.371 (6) | C15—N1 | 1.453 (5) |
C5—H5 | 0.9300 | C15—C17 | 1.518 (5) |
C6—H6 | 0.9300 | C15—C16 | 1.521 (5) |
C7—O1 | 1.405 (4) | C15—H15 | 0.9800 |
C7—H7A | 0.9700 | C16—O2 | 1.235 (4) |
C7—H7B | 0.9700 | C16—N2 | 1.309 (4) |
C8—C9 | 1.374 (5) | C17—H17A | 0.9600 |
C8—O1 | 1.376 (4) | C17—H17B | 0.9600 |
C8—C13 | 1.378 (5) | C17—H17C | 0.9600 |
C9—C10 | 1.371 (5) | N1—H1N | 0.88 (4) |
C9—H9 | 0.9300 | N2—H2N | 0.88 (4) |
C10—C11 | 1.389 (5) | N2—H3N | 0.84 (3) |
| | | |
C2—C1—C6 | 118.5 (4) | C10—C11—C14 | 121.9 (4) |
C2—C1—C7 | 122.4 (4) | C11—C12—C13 | 122.7 (4) |
C6—C1—C7 | 119.0 (4) | C11—C12—H12 | 118.6 |
C3—C2—C1 | 118.6 (4) | C13—C12—H12 | 118.6 |
C3—C2—H2 | 120.7 | C8—C13—C12 | 119.1 (4) |
C1—C2—H2 | 120.7 | C8—C13—H13 | 120.5 |
C4—C3—C2 | 124.0 (4) | C12—C13—H13 | 120.5 |
C4—C3—F1 | 118.6 (5) | N1—C14—C11 | 116.7 (3) |
C2—C3—F1 | 117.4 (4) | N1—C14—H14A | 108.1 |
C3—C4—C5 | 117.6 (4) | C11—C14—H14A | 108.1 |
C3—C4—H4 | 121.2 | N1—C14—H14B | 108.1 |
C5—C4—H4 | 121.2 | C11—C14—H14B | 108.1 |
C4—C5—C6 | 120.3 (4) | H14A—C14—H14B | 107.3 |
C4—C5—H5 | 119.8 | N1—C15—C17 | 111.8 (3) |
C6—C5—H5 | 119.8 | N1—C15—C16 | 111.7 (3) |
C5—C6—C1 | 121.0 (4) | C17—C15—C16 | 108.4 (3) |
C5—C6—H6 | 119.5 | N1—C15—H15 | 108.3 |
C1—C6—H6 | 119.5 | C17—C15—H15 | 108.3 |
O1—C7—C1 | 109.2 (3) | C16—C15—H15 | 108.3 |
O1—C7—H7A | 109.8 | O2—C16—N2 | 123.8 (3) |
C1—C7—H7A | 109.8 | O2—C16—C15 | 119.3 (3) |
O1—C7—H7B | 109.8 | N2—C16—C15 | 116.9 (3) |
C1—C7—H7B | 109.8 | C15—C17—H17A | 109.5 |
H7A—C7—H7B | 108.3 | C15—C17—H17B | 109.5 |
C9—C8—O1 | 116.0 (3) | H17A—C17—H17B | 109.5 |
C9—C8—C13 | 119.1 (4) | C15—C17—H17C | 109.5 |
O1—C8—C13 | 124.9 (4) | H17A—C17—H17C | 109.5 |
C8—C9—C10 | 120.5 (4) | H17B—C17—H17C | 109.5 |
C8—C9—H9 | 119.7 | C14—N1—C15 | 116.0 (3) |
C10—C9—H9 | 119.7 | C14—N1—H1N | 107 (3) |
C9—C10—C11 | 121.7 (4) | C15—N1—H1N | 112 (3) |
C9—C10—H10 | 119.1 | C16—N2—H2N | 115 (2) |
C11—C10—H10 | 119.1 | C16—N2—H3N | 121 (3) |
C12—C11—C10 | 116.8 (4) | H2N—N2—H3N | 123 (4) |
C12—C11—C14 | 121.2 (4) | C8—O1—C7 | 116.9 (3) |
| | | |
C6—C1—C2—C3 | 0.2 (6) | C10—C11—C12—C13 | 1.2 (6) |
C7—C1—C2—C3 | 176.9 (4) | C14—C11—C12—C13 | −179.9 (3) |
C1—C2—C3—C4 | −1.2 (8) | C9—C8—C13—C12 | 0.8 (6) |
C1—C2—C3—F1 | −178.1 (4) | O1—C8—C13—C12 | −179.2 (3) |
C2—C3—C4—C5 | 1.4 (8) | C11—C12—C13—C8 | −1.2 (6) |
F1—C3—C4—C5 | 178.3 (5) | C12—C11—C14—N1 | 128.0 (4) |
C3—C4—C5—C6 | −0.8 (7) | C10—C11—C14—N1 | −53.1 (5) |
C4—C5—C6—C1 | 0.0 (7) | N1—C15—C16—O2 | 162.4 (3) |
C2—C1—C6—C5 | 0.3 (6) | C17—C15—C16—O2 | −74.0 (4) |
C7—C1—C6—C5 | −176.5 (4) | N1—C15—C16—N2 | −20.1 (5) |
C2—C1—C7—O1 | 16.8 (5) | C17—C15—C16—N2 | 103.5 (4) |
C6—C1—C7—O1 | −166.5 (4) | C11—C14—N1—C15 | −52.8 (5) |
O1—C8—C9—C10 | 179.4 (4) | C17—C15—N1—C14 | 153.6 (3) |
C13—C8—C9—C10 | −0.6 (6) | C16—C15—N1—C14 | −84.7 (4) |
C8—C9—C10—C11 | 0.6 (6) | C9—C8—O1—C7 | −176.3 (4) |
C9—C10—C11—C12 | −0.9 (6) | C13—C8—O1—C7 | 3.7 (5) |
C9—C10—C11—C14 | −179.8 (4) | C1—C7—O1—C8 | −178.4 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···F1i | 0.88 (4) | 2.17 (4) | 3.046 (4) | 174 (5) |
N2—H2N···N1 | 0.88 (4) | 2.23 (4) | 2.693 (4) | 113 (3) |
N2—H2N···O2ii | 0.88 (4) | 2.25 (4) | 2.885 (4) | 128 (3) |
N2—H3N···O2iii | 0.84 (3) | 2.10 (3) | 2.940 (3) | 177 (3) |
C2—H2···O1 | 0.93 | 2.41 | 2.729 (5) | 100 |
C14—H14A···Cg2ii | 0.97 | 2.98 | 3.873 (4) | 153 |
Symmetry codes: (i) x+3/2, −y+1/2, −z+2; (ii) x+1, y, z; (iii) x+1/2, −y+1/2, −z+1. |
(II) 2(
S)-[4-(3-Fluorobenzyloxy) benzylamino] propionamide
top
Crystal data top
C17H19FN2O2 | F(000) = 640 |
Mr = 302.34 | Dx = 1.277 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 5921 reflections |
a = 6.6297 (9) Å | θ = 2.8–26.1° |
b = 8.1015 (12) Å | µ = 0.09 mm−1 |
c = 29.268 (4) Å | T = 294 K |
V = 1572.0 (4) Å3 | Needle, colourless |
Z = 4 | 0.15 × 0.10 × 0.05 mm |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 1573 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.025 |
Graphite monochromator | θmax = 25.0°, θmin = 1.4° |
ω scans | h = −7→7 |
15166 measured reflections | k = −9→9 |
1636 independent reflections | l = −34→34 |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.043 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.121 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.22 | w = 1/[σ2(Fo2) + (0.0658P)2 + 0.2636P] where P = (Fo2 + 2Fc2)/3 |
1636 reflections | (Δ/σ)max < 0.001 |
212 parameters | Δρmax = 0.19 e Å−3 |
0 restraints | Δρmin = −0.17 e Å−3 |
Crystal data top
C17H19FN2O2 | V = 1572.0 (4) Å3 |
Mr = 302.34 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 6.6297 (9) Å | µ = 0.09 mm−1 |
b = 8.1015 (12) Å | T = 294 K |
c = 29.268 (4) Å | 0.15 × 0.10 × 0.05 mm |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 1573 reflections with I > 2σ(I) |
15166 measured reflections | Rint = 0.025 |
1636 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.043 | 0 restraints |
wR(F2) = 0.121 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.22 | Δρmax = 0.19 e Å−3 |
1636 reflections | Δρmin = −0.17 e Å−3 |
212 parameters | |
Special details top
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 (Å2) top | x | y | z | Uiso*/Ueq | |
C1 | −0.1171 (5) | 0.4371 (4) | −0.02528 (9) | 0.0495 (7) | |
C2 | −0.2923 (5) | 0.3716 (4) | −0.04292 (9) | 0.0520 (7) | |
H2 | −0.4162 | 0.3948 | −0.0295 | 0.062* | |
C3 | −0.2811 (5) | 0.2712 (4) | −0.08073 (10) | 0.0541 (8) | |
C4 | −0.1047 (6) | 0.2333 (4) | −0.10173 (11) | 0.0619 (9) | |
H4 | −0.1017 | 0.1654 | −0.1273 | 0.074* | |
C5 | 0.0688 (6) | 0.2983 (5) | −0.08393 (12) | 0.0687 (10) | |
H5 | 0.1921 | 0.2738 | −0.0975 | 0.082* | |
C6 | 0.0627 (5) | 0.4006 (5) | −0.04589 (11) | 0.0630 (9) | |
H6 | 0.1817 | 0.4446 | −0.0343 | 0.076* | |
C7 | −0.1350 (5) | 0.5511 (4) | 0.01517 (10) | 0.0561 (8) | |
H7A | −0.2003 | 0.6529 | 0.0060 | 0.067* | |
H7B | −0.2169 | 0.4996 | 0.0387 | 0.067* | |
C8 | 0.0697 (5) | 0.6838 (4) | 0.07106 (10) | 0.0524 (8) | |
C9 | 0.2585 (6) | 0.6969 (4) | 0.09069 (11) | 0.0621 (9) | |
H9 | 0.3667 | 0.6383 | 0.0786 | 0.074* | |
C10 | 0.2863 (6) | 0.7973 (4) | 0.12828 (11) | 0.0632 (9) | |
H10 | 0.4138 | 0.8053 | 0.1413 | 0.076* | |
C11 | 0.1288 (6) | 0.8859 (4) | 0.14691 (9) | 0.0548 (8) | |
C12 | −0.0589 (5) | 0.8686 (4) | 0.12731 (10) | 0.0580 (8) | |
H12 | −0.1675 | 0.9256 | 0.1398 | 0.070* | |
C13 | −0.0904 (5) | 0.7689 (4) | 0.08958 (10) | 0.0570 (8) | |
H13 | −0.2185 | 0.7595 | 0.0769 | 0.068* | |
C14 | 0.1626 (6) | 1.0039 (4) | 0.18580 (9) | 0.0611 (9) | |
H14A | 0.2914 | 1.0585 | 0.1816 | 0.073* | |
H14B | 0.0584 | 1.0879 | 0.1851 | 0.073* | |
C15 | 0.1719 (4) | 1.0422 (3) | 0.26796 (9) | 0.0375 (6) | |
H15 | 0.0413 | 1.0983 | 0.2703 | 0.045* | |
C16 | 0.3358 (4) | 1.1737 (3) | 0.26122 (8) | 0.0339 (5) | |
C17 | 0.2095 (7) | 0.9497 (4) | 0.31239 (9) | 0.0648 (10) | |
H17A | 0.1037 | 0.8706 | 0.3172 | 0.097* | |
H17B | 0.2116 | 1.0266 | 0.3373 | 0.097* | |
H17C | 0.3368 | 0.8936 | 0.3107 | 0.097* | |
F1 | −0.4535 (3) | 0.2103 (3) | −0.09842 (8) | 0.0809 (7) | |
N1 | 0.1607 (3) | 0.9244 (3) | 0.23036 (7) | 0.0337 (5) | |
H1N | 0.262 (4) | 0.853 (3) | 0.2338 (8) | 0.027 (6)* | |
N2 | 0.2709 (4) | 1.3273 (3) | 0.25989 (9) | 0.0446 (6) | |
H2N | 0.144 (6) | 1.344 (4) | 0.2631 (10) | 0.049 (8)* | |
H3N | 0.359 (5) | 1.402 (4) | 0.2545 (9) | 0.038 (7)* | |
O1 | 0.0592 (3) | 0.5858 (3) | 0.03269 (7) | 0.0640 (6) | |
O2 | 0.5132 (3) | 1.1349 (2) | 0.25693 (8) | 0.0516 (5) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.0547 (17) | 0.0506 (16) | 0.0433 (14) | −0.0022 (15) | −0.0081 (12) | 0.0073 (13) |
C2 | 0.0493 (16) | 0.0571 (17) | 0.0494 (15) | −0.0001 (16) | −0.0037 (13) | 0.0053 (14) |
C3 | 0.0588 (19) | 0.0533 (17) | 0.0503 (16) | −0.0040 (16) | −0.0146 (14) | 0.0018 (14) |
C4 | 0.075 (2) | 0.0593 (19) | 0.0518 (16) | 0.0074 (19) | −0.0025 (16) | −0.0040 (15) |
C5 | 0.061 (2) | 0.076 (2) | 0.070 (2) | 0.007 (2) | 0.0067 (17) | −0.0030 (19) |
C6 | 0.0503 (17) | 0.072 (2) | 0.0667 (19) | −0.0060 (18) | −0.0071 (15) | −0.0006 (17) |
C7 | 0.0550 (18) | 0.0638 (19) | 0.0495 (15) | −0.0036 (17) | −0.0088 (14) | 0.0007 (15) |
C8 | 0.0618 (19) | 0.0500 (16) | 0.0455 (14) | −0.0076 (16) | −0.0086 (14) | 0.0056 (13) |
C9 | 0.062 (2) | 0.0597 (19) | 0.0650 (18) | −0.0002 (18) | −0.0130 (17) | −0.0039 (16) |
C10 | 0.068 (2) | 0.0573 (18) | 0.0643 (18) | −0.0047 (18) | −0.0253 (17) | 0.0024 (16) |
C11 | 0.077 (2) | 0.0401 (14) | 0.0472 (15) | −0.0121 (16) | −0.0145 (15) | 0.0089 (13) |
C12 | 0.070 (2) | 0.0553 (17) | 0.0488 (15) | −0.0038 (17) | 0.0002 (15) | 0.0003 (15) |
C13 | 0.0548 (19) | 0.0652 (19) | 0.0510 (16) | −0.0104 (17) | −0.0089 (14) | 0.0022 (14) |
C14 | 0.093 (3) | 0.0394 (14) | 0.0510 (15) | −0.0149 (18) | −0.0150 (17) | 0.0076 (12) |
C15 | 0.0326 (13) | 0.0297 (12) | 0.0502 (13) | 0.0001 (10) | 0.0053 (12) | −0.0002 (11) |
C16 | 0.0304 (12) | 0.0290 (11) | 0.0423 (12) | 0.0010 (10) | −0.0028 (10) | −0.0031 (10) |
C17 | 0.103 (3) | 0.0461 (16) | 0.0452 (15) | −0.016 (2) | 0.0050 (17) | 0.0025 (13) |
F1 | 0.0726 (13) | 0.0881 (15) | 0.0820 (13) | −0.0113 (12) | −0.0212 (11) | −0.0177 (12) |
N1 | 0.0293 (10) | 0.0271 (9) | 0.0447 (11) | −0.0036 (9) | −0.0022 (9) | 0.0033 (9) |
N2 | 0.0288 (12) | 0.0276 (11) | 0.0774 (16) | −0.0024 (9) | 0.0038 (11) | 0.0032 (11) |
O1 | 0.0612 (13) | 0.0750 (15) | 0.0559 (12) | −0.0052 (13) | −0.0101 (10) | −0.0126 (11) |
O2 | 0.0314 (9) | 0.0310 (9) | 0.0925 (15) | 0.0028 (8) | −0.0001 (9) | −0.0058 (10) |
Geometric parameters (Å, º) top
C1—C6 | 1.368 (5) | C10—H10 | 0.9300 |
C1—C2 | 1.378 (4) | C11—C12 | 1.378 (5) |
C1—C7 | 1.506 (4) | C11—C14 | 1.503 (4) |
C2—C3 | 1.375 (4) | C12—C13 | 1.384 (4) |
C2—H2 | 0.9300 | C12—H12 | 0.9300 |
C3—F1 | 1.348 (4) | C13—H13 | 0.9300 |
C3—C4 | 1.357 (5) | C14—N1 | 1.454 (3) |
C4—C5 | 1.368 (5) | C14—H14A | 0.9700 |
C4—H4 | 0.9300 | C14—H14B | 0.9700 |
C5—C6 | 1.388 (5) | C15—N1 | 1.458 (3) |
C5—H5 | 0.9300 | C15—C17 | 1.521 (4) |
C6—H6 | 0.9300 | C15—C16 | 1.535 (3) |
C7—O1 | 1.414 (4) | C15—H15 | 0.9800 |
C7—H7A | 0.9700 | C16—O2 | 1.223 (3) |
C7—H7B | 0.9700 | C16—N2 | 1.318 (3) |
C8—C13 | 1.377 (5) | C17—H17A | 0.9600 |
C8—O1 | 1.377 (4) | C17—H17B | 0.9600 |
C8—C9 | 1.382 (5) | C17—H17C | 0.9600 |
C9—C10 | 1.380 (5) | N1—H1N | 0.89 (3) |
C9—H9 | 0.9300 | N2—H2N | 0.86 (4) |
C10—C11 | 1.379 (5) | N2—H3N | 0.85 (3) |
| | | |
C6—C1—C2 | 119.1 (3) | C10—C11—C14 | 121.2 (3) |
C6—C1—C7 | 123.2 (3) | C11—C12—C13 | 121.9 (3) |
C2—C1—C7 | 117.7 (3) | C11—C12—H12 | 119.1 |
C3—C2—C1 | 118.9 (3) | C13—C12—H12 | 119.1 |
C3—C2—H2 | 120.5 | C8—C13—C12 | 119.3 (3) |
C1—C2—H2 | 120.5 | C8—C13—H13 | 120.3 |
F1—C3—C4 | 118.3 (3) | C12—C13—H13 | 120.3 |
F1—C3—C2 | 118.6 (3) | N1—C14—C11 | 113.3 (2) |
C4—C3—C2 | 123.0 (3) | N1—C14—H14A | 108.9 |
C3—C4—C5 | 117.7 (3) | C11—C14—H14A | 108.9 |
C3—C4—H4 | 121.1 | N1—C14—H14B | 108.9 |
C5—C4—H4 | 121.1 | C11—C14—H14B | 108.9 |
C4—C5—C6 | 120.7 (3) | H14A—C14—H14B | 107.7 |
C4—C5—H5 | 119.6 | N1—C15—C17 | 109.4 (2) |
C6—C5—H5 | 119.6 | N1—C15—C16 | 113.1 (2) |
C1—C6—C5 | 120.5 (3) | C17—C15—C16 | 109.6 (2) |
C1—C6—H6 | 119.7 | N1—C15—H15 | 108.2 |
C5—C6—H6 | 119.7 | C17—C15—H15 | 108.2 |
O1—C7—C1 | 109.6 (3) | C16—C15—H15 | 108.2 |
O1—C7—H7A | 109.8 | O2—C16—N2 | 123.6 (2) |
C1—C7—H7A | 109.8 | O2—C16—C15 | 121.1 (2) |
O1—C7—H7B | 109.8 | N2—C16—C15 | 115.4 (2) |
C1—C7—H7B | 109.8 | C15—C17—H17A | 109.5 |
H7A—C7—H7B | 108.2 | C15—C17—H17B | 109.5 |
C13—C8—O1 | 124.8 (3) | H17A—C17—H17B | 109.5 |
C13—C8—C9 | 119.8 (3) | C15—C17—H17C | 109.5 |
O1—C8—C9 | 115.4 (3) | H17A—C17—H17C | 109.5 |
C10—C9—C8 | 119.8 (3) | H17B—C17—H17C | 109.5 |
C10—C9—H9 | 120.1 | C14—N1—C15 | 112.8 (2) |
C8—C9—H9 | 120.1 | C14—N1—H1N | 112.3 (16) |
C11—C10—C9 | 121.4 (3) | C15—N1—H1N | 107.4 (16) |
C11—C10—H10 | 119.3 | C16—N2—H2N | 118 (2) |
C9—C10—H10 | 119.3 | C16—N2—H3N | 116.6 (19) |
C12—C11—C10 | 117.8 (3) | H2N—N2—H3N | 125 (3) |
C12—C11—C14 | 121.0 (3) | C8—O1—C7 | 117.1 (2) |
| | | |
C6—C1—C2—C3 | 0.0 (4) | C10—C11—C12—C13 | −1.4 (5) |
C7—C1—C2—C3 | 178.0 (3) | C14—C11—C12—C13 | 175.7 (3) |
C1—C2—C3—F1 | −178.6 (3) | O1—C8—C13—C12 | −177.5 (3) |
C1—C2—C3—C4 | 0.0 (5) | C9—C8—C13—C12 | 1.0 (5) |
F1—C3—C4—C5 | 178.8 (3) | C11—C12—C13—C8 | 0.2 (5) |
C2—C3—C4—C5 | 0.3 (5) | C12—C11—C14—N1 | 98.5 (4) |
C3—C4—C5—C6 | −0.5 (5) | C10—C11—C14—N1 | −84.5 (4) |
C2—C1—C6—C5 | −0.3 (5) | N1—C15—C16—O2 | −59.6 (3) |
C7—C1—C6—C5 | −178.1 (3) | C17—C15—C16—O2 | 62.8 (3) |
C4—C5—C6—C1 | 0.5 (6) | N1—C15—C16—N2 | 119.6 (3) |
C6—C1—C7—O1 | −10.9 (5) | C17—C15—C16—N2 | −118.0 (3) |
C2—C1—C7—O1 | 171.2 (3) | C11—C14—N1—C15 | −173.8 (3) |
C13—C8—C9—C10 | −1.0 (5) | C17—C15—N1—C14 | −169.3 (3) |
O1—C8—C9—C10 | 177.6 (3) | C16—C15—N1—C14 | −46.8 (3) |
C8—C9—C10—C11 | −0.1 (5) | C13—C8—O1—C7 | −9.8 (4) |
C9—C10—C11—C12 | 1.3 (5) | C9—C8—O1—C7 | 171.7 (3) |
C9—C10—C11—C14 | −175.7 (3) | C1—C7—O1—C8 | −177.6 (2) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···O2i | 0.89 (3) | 2.33 (3) | 3.212 (3) | 171 (2) |
N2—H2N···N1ii | 0.86 (4) | 2.13 (4) | 2.981 (3) | 171 (3) |
N2—H3N···O2iii | 0.85 (3) | 2.10 (3) | 2.916 (3) | 160 (3) |
C6—H6···O1 | 0.93 | 2.41 | 2.746 (4) | 101 |
C5—H5···F1iv | 0.93 | 2.41 | 3.274 (4) | 155 |
Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) −x, y+1/2, −z+1/2; (iii) −x+1, y+1/2, −z+1/2; (iv) x+1, y, z. |
Experimental details
| (I) | (II) |
Crystal data |
Chemical formula | C17H19FN2O2 | C17H19FN2O2 |
Mr | 302.34 | 302.34 |
Crystal system, space group | Orthorhombic, P212121 | Orthorhombic, P212121 |
Temperature (K) | 294 | 294 |
a, b, c (Å) | 5.1127 (5), 17.8516 (16), 17.8746 (1) | 6.6297 (9), 8.1015 (12), 29.268 (4) |
V (Å3) | 1631.4 (2) | 1572.0 (4) |
Z | 4 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.09 | 0.09 |
Crystal size (mm) | 0.14 × 0.10 × 0.06 | 0.15 × 0.10 × 0.05 |
|
Data collection |
Diffractometer | Bruker SMART APEX CCD area-detector diffractometer | Bruker SMART APEX CCD area-detector diffractometer |
Absorption correction | – | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 15763, 1698, 1179 | 15166, 1636, 1573 |
Rint | 0.057 | 0.025 |
(sin θ/λ)max (Å−1) | 0.595 | 0.595 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.042, 0.113, 0.97 | 0.043, 0.121, 1.22 |
No. of reflections | 1698 | 1636 |
No. of parameters | 212 | 212 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.15, −0.12 | 0.19, −0.17 |
Hydrogen-bond geometry (Å, º) for (I) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···F1i | 0.88 (4) | 2.17 (4) | 3.046 (4) | 174 (5) |
N2—H2N···N1 | 0.88 (4) | 2.23 (4) | 2.693 (4) | 113 (3) |
N2—H2N···O2ii | 0.88 (4) | 2.25 (4) | 2.885 (4) | 128 (3) |
N2—H3N···O2iii | 0.84 (3) | 2.10 (3) | 2.940 (3) | 177 (3) |
C2—H2···O1 | 0.93 | 2.41 | 2.729 (5) | 100 |
C14—H14A···Cg2ii | 0.97 | 2.98 | 3.873 (4) | 153 |
Symmetry codes: (i) x+3/2, −y+1/2, −z+2; (ii) x+1, y, z; (iii) x+1/2, −y+1/2, −z+1. |
Hydrogen-bond geometry (Å, º) for (II) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···O2i | 0.89 (3) | 2.33 (3) | 3.212 (3) | 171 (2) |
N2—H2N···N1ii | 0.86 (4) | 2.13 (4) | 2.981 (3) | 171 (3) |
N2—H3N···O2iii | 0.85 (3) | 2.10 (3) | 2.916 (3) | 160 (3) |
C6—H6···O1 | 0.93 | 2.41 | 2.746 (4) | 101 |
C5—H5···F1iv | 0.93 | 2.41 | 3.274 (4) | 155 |
Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) −x, y+1/2, −z+1/2; (iii) −x+1, y+1/2, −z+1/2; (iv) x+1, y, z. |
Selected geometric parameters (Å ,° ) for polymorphs (I) and (II) top | (I) | (II) |
C2-C1-C6 | 118.5 (4) | 119.1 (3) |
C2-C1-C7 | 122.4 (4) | 117.7 (3) |
C6-C1-C7 | 119.0 (4) | 123.2 (3) |
N1-C14-C11 | 116.7 (3) | 113.3 (2) |
N1-C15-C16 | 111.7 (3) | 113.1 (2) |
N1-C15-C17 | 111.8 (3) | 109.4 (2) |
C14-N1-C15 | 116.0 (3) | 112.8 (2) |
| | |
C11-C14-N1-C15 | -52.8 (5) | -173.8 (3) |
C16-C15-N1-C14 | -84.7 (4) | -46.8 (3) |
N1-C15-C16-N2 | -20.1 (5) | 119.6 (3) |
Monoamino oxidases (MAOs) are flavin adenine dinucleotide (FAD) containing enzymes localized in the outer mitochondrial membrane. Two different isoenzymatic forms have been identified, namely, MAO-A and MAO-B, which differ in their amino acid sequences, three-dimensional structures, substrate specificity and sensitivity to inhibitors. Safinamide, a derivative of the chemical class of aminoamides, has been developed by Newron Pharmaceuticals, Bresso, Italy, and was initially reported by Pharmacia & Upjohn as a potent anticonvulsant (Pevarello et al., 1998). It acts by means of multiple mechanisms of action that comprise MAO-B and dopamine uptake inhibition, sodium and calcium channel modulation, and reduction of glutamate release in the central nervous system (Caccia et al., 2006). Due to its excellent therapeutic properties and safety margin, safinamide has been developed as an antiparkinsonian and anticonvulsant agent.
Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice (Grant, 1999). The last decade has witnessed many developments in the design and characterization of polymorphs, due to the increased awareness of the possibility of multiple crystal forms of a substance, the utility that may be derived from preparing a crystal form with enhanced properties, and the potential intellectual property implications of new crystal forms.
The present study is a continuation of our investigation of the structural characterization of pharmaceutical compounds (Ravikumar & Sridhar, 2007; Ravikumar et al., 2008; Ravikumar & Sridhar, 2009). We report here the crystal structures of two polymorphic forms of safinamide, (I) and (II).
Both polymorphs (I) and (II) crystallize in space group P212121 and were assigned the known handedness (the asymmetric centre C15 has the S configuration). The molecular structures observed in polymorphs (I) and (II) are composed of a central aromatic ring substituted at C8 by a fluorobenzyloxy group and at C11 by an alaninamide group (Figs. 1 and 2). The bond lengths in the two structures are the same to within 3σ. The exocyclic bond angles involving atom C1 differ by up to 5.3° (Table 3); the sense of these deviations suggests interactions between atoms O1 and C2 [in (I)] or C6 [in (II)], possibly associated with weak intramolecular C—H···O hydrogen bonds. The slight variation in the bond angles involving the amine atom N1 may be attributed to its involvement in different types of hydrogen-bonding interactions. The significant conformational differences between polymorphs (I) and (II) are in the orientations of the fluorobenzyloxy and alaninamide groups in relation to the central aromatic ring. The fluoro-substituted phenyl ring is cisoid [C2—C1—C7—O1 = 16.8 (5)°] to the ether atom O1 in (I), while it is transoid [C2—C1—C7—O1 = 171.2 (3)°] in (II). Similarly, the alaninamide group is in a -sc,-sc,-sp orientation in (I), whereas it is -ap,sc,ac in (II).
It is noteworthy that in the crystal structure of the complex safinamide–human monoamine oxidase [Binda et al., 2007; Protein Data Bank (Berman et al., 2000) entry 2 V5Z], the extracted ligand structure (Fig. 3) shows another significant difference in the orientation of the C8 and C11 substituents (C2—C1—C7—O1 = -44.8°, and the alaninamide group is in an -ap,-ac,-sc orientation). It is interesting to note that the alaninamide chain is in an extended conformation in the extracted ligand structure and perhaps it may be speculated that a third polymorph of the title compound is possible with such features.
Substantial differences in the molecular packing of the polymorphs are observed. Both structures (I) and (II) pack with layers in the ac plane. In (I), the layers have discrete wide and narrow regions which are complementary when located next to adjacent layers. In (II), the layer has long flanges protruding from each side, which interdigitate when packed with the adjacent layers.
The amide groups are associated to form the core of the hydrogen-bonding networks in (I) (Table 1). Amide atom N2 connects two adjacent molecules by N—H···O═C hydrogen bonding involving only the amide groups, creating an R32(8) motif (Etter, 1990; Etter et al., 1990; Bernstein et al., 1995). The hydrogen-bonded amide groups are coplanar, forming a ribbon-like packing motif along the a axis (Fig. 4). Amine atom N1 forms an N—H···F interaction with an adjacent fluorobenzyl group, developing a helical hydrogen-bonded catemer along the a axis and cross-linking neighbouring ribbon-like motifs along the c axis to give the two-dimensional supramolecular hydrogen-bonded network.
Fig. 5 illustrates the packing for (II), wherein one N2—H forms an N—H···O═C interaction with another amide (Table 3). This generates a ribbon-like pattern of R22(9) motifs along the a axis. The second amide H atom bound to N2 forms an N—H···N hydrogen bond to an amine, generating an R43(11) motif in combination with N—H···O hydrogen bonds, resulting in an infinite two-dimensional supramolecular hydrogen-bonded network. A stacking interaction between pairs of aromatic and fluorobenzyl rings [centroid-to-centroid separation = 3.875 (2) Å; symmetry code: -1/2 + x, 3/2 - y, -z] occurs between adjacent layers. The F atom in (II) is involved in an intermolecular C—H···F interaction. Ether atom O1 is not involved in any intermolecular hydrogen-bonding interactions in either polymorph.
In conclusion, it can be seen that the two polymorphic structures, (I) and (II), which differ significantly in the orientation of the two substituents at C8 and C11, give rise to two different modifications of the crystal packing.