The title compound, raloxifene hydrochloride, C
28H
28NO
4S
+·Cl
-, belongs to the benzothiophene class of antiosteoporotic drugs. In the molecular cation, the 2-phenol ring sustains a dihedral angle of 45.3 (1)° relative to the benzo[
b]thiophene system. The benzo[
b]thiophene and phenyl ring planes are twisted with respect to the carbonyl plane, with the smallest twist component occurring between the phenyl and carbonyl planes. The N atom bears the positive charge in the molecular cation and the piperidine ring adopts an almost perfect chair conformation. The Cl
- anion is involved in the formation of N-H
Cl and O-H
Cl intermolecular hydrogen bonds, which lead to the formation of a layer of molecular cations.
Supporting information
CCDC reference: 173383
The compound was obtained from LABORATORIOS GADOR S·A., Buenos Aires,
Argentina. Crystals suitable for X-ray diffraction were obtained through slow
evaporation from a water solution.
All H atoms were located in a Fourier difference map and were refined freely
with individual isotropic displacement parameters. C—H bond distances range
from 0.88 (3) Å for C26—H26 to 1.02 (2) Å for C46—H462. Data collection
was performed at the Instituto de Física de São Carlos, Universidade de
São Paulo, SP, Brazil.
Data collection: COLLECT (Nonius, 1997-2000); cell refinement: HKL SCALEPACK (Otwinowski & Minor, 1997); data reduction: HKL DENZO and Scalepak; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: PARST (Nardelli, 1995), CSD (Allen et al., 1983) and WinGX (Farrugia, 1999).
Crystal data top
C28H28NO4S+·Cl− | Dx = 1.335 Mg m−3 |
Mr = 510.02 | Melting point: 531 K |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
a = 13.4836 (3) Å | Cell parameters from 42516 reflections |
b = 13.1345 (3) Å | θ = 1.0–27.5° |
c = 14.6532 (3) Å | µ = 0.27 mm−1 |
β = 102.0570 (13)° | T = 120 K |
V = 2537.84 (10) Å3 | Prism, yellow |
Z = 4 | 0.36 × 0.18 × 0.08 mm |
F(000) = 1072 | |
Data collection top
Nonius KappaCCD diffractometer | Rint = 0.1 |
ϕ scans and ω scans with κ offsets | θmax = 27.5°, θmin = 1.5° |
55970 measured reflections | h = −17→17 |
5835 independent reflections | k = −15→17 |
4580 reflections with I > 2σ(I) | l = −19→19 |
Refinement top
Refinement on F2 | All H-atom parameters refined |
Least-squares matrix: full | w = 1/[σ2(Fo2) + (0.081P)2 + 0.3926P] where P = (Fo2 + 2Fc2)/3 |
R[F2 > 2σ(F2)] = 0.044 | (Δ/σ)max = 0.002 |
wR(F2) = 0.142 | Δρmax = 0.30 e Å−3 |
S = 1.09 | Δρmin = −0.35 e Å−3 |
5835 reflections | Extinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
429 parameters | Extinction coefficient: 0.017 (2) |
0 restraints | |
Crystal data top
C28H28NO4S+·Cl− | V = 2537.84 (10) Å3 |
Mr = 510.02 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 13.4836 (3) Å | µ = 0.27 mm−1 |
b = 13.1345 (3) Å | T = 120 K |
c = 14.6532 (3) Å | 0.36 × 0.18 × 0.08 mm |
β = 102.0570 (13)° | |
Data collection top
Nonius KappaCCD diffractometer | 4580 reflections with I > 2σ(I) |
55970 measured reflections | Rint = 0.1 |
5835 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.044 | 0 restraints |
wR(F2) = 0.142 | All H-atom parameters refined |
S = 1.09 | Δρmax = 0.30 e Å−3 |
5835 reflections | Δρmin = −0.35 e Å−3 |
429 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 | |
S1 | 0.44561 (3) | 0.64332 (4) | 0.46501 (3) | 0.04437 (16) | |
O7 | 0.07769 (11) | 0.50024 (14) | 0.36978 (12) | 0.0634 (4) | |
H7 | 0.072 (3) | 0.541 (3) | 0.315 (3) | 0.116 (12)* | |
O24 | 0.83901 (11) | 0.88169 (13) | 0.74108 (12) | 0.0627 (4) | |
H24 | 0.895 (2) | 0.855 (2) | 0.719 (2) | 0.090 (10)* | |
O30 | 0.36514 (11) | 0.67186 (13) | 0.76953 (10) | 0.0610 (4) | |
O34 | 0.73883 (11) | 0.41684 (12) | 0.98063 (9) | 0.0568 (4) | |
N41 | 0.91353 (11) | 0.32103 (12) | 1.11867 (10) | 0.0386 (3) | |
H41 | 0.9376 (16) | 0.2724 (18) | 1.1633 (16) | 0.054 (6)* | |
C2 | 0.48797 (13) | 0.65797 (13) | 0.58553 (12) | 0.0387 (4) | |
C3 | 0.41872 (12) | 0.62382 (14) | 0.63359 (12) | 0.0382 (4) | |
C4 | 0.32688 (12) | 0.58570 (13) | 0.57403 (12) | 0.0385 (4) | |
C5 | 0.23879 (13) | 0.54647 (15) | 0.59754 (13) | 0.0438 (4) | |
H5 | 0.2318 (16) | 0.5433 (16) | 0.6642 (16) | 0.050 (5)* | |
C6 | 0.15817 (14) | 0.51699 (15) | 0.52846 (14) | 0.0472 (4) | |
H6 | 0.0942 (18) | 0.4900 (18) | 0.5428 (15) | 0.059 (6)* | |
C7 | 0.16299 (13) | 0.52634 (14) | 0.43429 (13) | 0.0457 (4) | |
C8 | 0.24937 (14) | 0.56207 (14) | 0.40810 (13) | 0.0441 (4) | |
H8 | 0.2540 (16) | 0.5658 (17) | 0.3412 (17) | 0.057 (6)* | |
C9 | 0.33121 (13) | 0.59141 (13) | 0.47930 (12) | 0.0390 (4) | |
C21 | 0.58223 (12) | 0.71454 (13) | 0.62272 (12) | 0.0398 (4) | |
C22 | 0.67246 (14) | 0.69809 (16) | 0.59332 (13) | 0.0451 (4) | |
H22 | 0.6778 (17) | 0.6503 (17) | 0.5508 (17) | 0.054 (6)* | |
C23 | 0.75932 (13) | 0.75253 (16) | 0.63245 (14) | 0.0479 (4) | |
H23 | 0.8224 (17) | 0.7391 (17) | 0.6122 (15) | 0.052 (6)* | |
C24 | 0.75702 (14) | 0.82442 (15) | 0.70058 (14) | 0.0473 (4) | |
C25 | 0.66721 (16) | 0.84238 (17) | 0.72918 (18) | 0.0577 (5) | |
H25 | 0.6681 (18) | 0.8917 (19) | 0.7756 (17) | 0.063 (7)* | |
C26 | 0.58129 (15) | 0.78839 (16) | 0.69039 (16) | 0.0526 (5) | |
H26 | 0.5252 (19) | 0.8033 (19) | 0.7090 (17) | 0.063 (7)* | |
C30 | 0.43037 (13) | 0.62908 (14) | 0.73686 (12) | 0.0411 (4) | |
C31 | 0.51762 (13) | 0.57844 (14) | 0.79920 (12) | 0.0394 (4) | |
C32 | 0.57643 (14) | 0.50452 (15) | 0.76778 (13) | 0.0452 (4) | |
H32 | 0.5682 (17) | 0.4927 (18) | 0.7031 (17) | 0.060 (6)* | |
C33 | 0.65047 (15) | 0.45243 (16) | 0.82973 (13) | 0.0489 (5) | |
H33 | 0.6897 (18) | 0.4005 (19) | 0.8076 (17) | 0.061 (6)* | |
C34 | 0.66709 (13) | 0.47447 (15) | 0.92428 (12) | 0.0436 (4) | |
C35 | 0.61256 (15) | 0.55134 (16) | 0.95638 (13) | 0.0493 (5) | |
H35 | 0.6234 (19) | 0.567 (2) | 1.0228 (19) | 0.071 (7)* | |
C36 | 0.53708 (15) | 0.60061 (16) | 0.89394 (13) | 0.0475 (4) | |
H36 | 0.498 (2) | 0.6509 (18) | 0.9163 (18) | 0.067 (7)* | |
C37 | 0.75367 (16) | 0.43115 (17) | 1.07855 (13) | 0.0484 (5) | |
H371 | 0.6903 (19) | 0.4372 (18) | 1.0996 (17) | 0.063 (7)* | |
H372 | 0.7918 (17) | 0.4951 (18) | 1.0935 (15) | 0.056 (6)* | |
C38 | 0.80592 (15) | 0.33923 (17) | 1.12753 (14) | 0.0474 (4) | |
H381 | 0.8080 (18) | 0.3458 (17) | 1.1962 (18) | 0.060 (7)* | |
H382 | 0.7686 (18) | 0.280 (2) | 1.1055 (17) | 0.062 (7)* | |
C42 | 0.92441 (16) | 0.27960 (17) | 1.02585 (13) | 0.0473 (4) | |
H421 | 0.9118 (17) | 0.3346 (16) | 0.9804 (16) | 0.051 (6)* | |
H422 | 0.8745 (19) | 0.225 (2) | 1.0106 (17) | 0.068 (7)* | |
C43 | 1.03302 (18) | 0.24586 (18) | 1.03217 (17) | 0.0579 (5) | |
H431 | 1.052 (2) | 0.199 (2) | 1.077 (2) | 0.074 (8)* | |
H432 | 1.0379 (18) | 0.217 (2) | 0.9706 (18) | 0.069 (7)* | |
C44 | 1.10570 (19) | 0.3332 (2) | 1.0600 (2) | 0.0686 (7) | |
H441 | 1.094 (2) | 0.388 (2) | 1.012 (2) | 0.077 (8)* | |
H442 | 1.173 (2) | 0.310 (2) | 1.0627 (19) | 0.081 (8)* | |
C45 | 1.09063 (17) | 0.3810 (2) | 1.15027 (19) | 0.0641 (6) | |
H451 | 1.110 (2) | 0.337 (2) | 1.197 (2) | 0.076 (9)* | |
H452 | 1.132 (2) | 0.443 (2) | 1.164 (2) | 0.083 (8)* | |
C46 | 0.98120 (15) | 0.41034 (16) | 1.14587 (16) | 0.0523 (5) | |
H461 | 0.9703 (19) | 0.433 (2) | 1.2073 (19) | 0.071 (7)* | |
H462 | 0.9579 (17) | 0.4633 (18) | 1.0950 (17) | 0.055 (6)* | |
Cl1 | 0.94827 (4) | 0.16604 (4) | 1.28512 (3) | 0.05178 (17) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
S1 | 0.0425 (3) | 0.0548 (3) | 0.0352 (2) | −0.00617 (19) | 0.00673 (18) | 0.00249 (18) |
O7 | 0.0500 (8) | 0.0718 (10) | 0.0578 (9) | −0.0174 (7) | −0.0130 (7) | −0.0029 (8) |
O24 | 0.0410 (8) | 0.0669 (10) | 0.0755 (11) | −0.0123 (7) | 0.0012 (7) | −0.0084 (8) |
O30 | 0.0432 (7) | 0.0972 (12) | 0.0416 (8) | 0.0216 (7) | 0.0062 (6) | 0.0008 (7) |
O34 | 0.0597 (8) | 0.0715 (9) | 0.0352 (7) | 0.0275 (7) | 0.0008 (6) | 0.0024 (6) |
N41 | 0.0414 (8) | 0.0400 (8) | 0.0330 (7) | 0.0037 (6) | 0.0048 (6) | 0.0046 (6) |
C2 | 0.0358 (8) | 0.0430 (9) | 0.0355 (8) | 0.0008 (7) | 0.0032 (6) | 0.0018 (7) |
C3 | 0.0332 (8) | 0.0441 (9) | 0.0347 (8) | 0.0021 (7) | 0.0010 (6) | 0.0023 (7) |
C4 | 0.0352 (8) | 0.0407 (9) | 0.0365 (8) | 0.0014 (7) | 0.0006 (6) | 0.0058 (7) |
C5 | 0.0393 (9) | 0.0488 (10) | 0.0414 (10) | −0.0015 (7) | 0.0043 (7) | 0.0099 (8) |
C6 | 0.0381 (9) | 0.0477 (10) | 0.0526 (11) | −0.0056 (8) | 0.0021 (8) | 0.0099 (8) |
C7 | 0.0404 (9) | 0.0420 (10) | 0.0477 (10) | −0.0033 (7) | −0.0066 (7) | −0.0001 (8) |
C8 | 0.0449 (9) | 0.0467 (10) | 0.0369 (9) | −0.0007 (8) | 0.0000 (7) | −0.0017 (7) |
C9 | 0.0378 (8) | 0.0386 (9) | 0.0387 (9) | −0.0002 (7) | 0.0033 (7) | 0.0026 (7) |
C21 | 0.0336 (8) | 0.0425 (9) | 0.0414 (9) | −0.0003 (7) | 0.0037 (7) | 0.0028 (7) |
C22 | 0.0426 (9) | 0.0513 (11) | 0.0416 (10) | −0.0008 (8) | 0.0095 (7) | −0.0024 (8) |
C23 | 0.0332 (8) | 0.0604 (12) | 0.0495 (10) | −0.0003 (8) | 0.0076 (7) | 0.0062 (9) |
C24 | 0.0352 (9) | 0.0494 (10) | 0.0530 (11) | −0.0051 (7) | −0.0005 (7) | 0.0057 (8) |
C25 | 0.0466 (11) | 0.0553 (12) | 0.0710 (14) | −0.0069 (9) | 0.0118 (10) | −0.0206 (10) |
C26 | 0.0373 (9) | 0.0527 (11) | 0.0690 (13) | −0.0017 (8) | 0.0139 (9) | −0.0129 (10) |
C30 | 0.0340 (8) | 0.0518 (10) | 0.0355 (9) | 0.0001 (7) | 0.0027 (7) | 0.0012 (7) |
C31 | 0.0361 (8) | 0.0464 (9) | 0.0332 (8) | −0.0002 (7) | 0.0017 (6) | 0.0000 (7) |
C32 | 0.0489 (10) | 0.0548 (11) | 0.0301 (8) | 0.0077 (8) | 0.0043 (7) | −0.0018 (7) |
C33 | 0.0526 (11) | 0.0563 (11) | 0.0372 (9) | 0.0148 (9) | 0.0082 (8) | −0.0017 (8) |
C34 | 0.0393 (9) | 0.0523 (11) | 0.0361 (9) | 0.0074 (8) | 0.0013 (7) | 0.0017 (7) |
C35 | 0.0539 (11) | 0.0569 (11) | 0.0325 (9) | 0.0123 (9) | −0.0015 (8) | −0.0065 (8) |
C36 | 0.0484 (10) | 0.0525 (11) | 0.0376 (9) | 0.0128 (9) | 0.0000 (7) | −0.0068 (8) |
C37 | 0.0465 (10) | 0.0609 (12) | 0.0351 (9) | 0.0135 (9) | 0.0021 (7) | 0.0012 (8) |
C38 | 0.0426 (10) | 0.0583 (12) | 0.0405 (10) | 0.0068 (9) | 0.0071 (8) | 0.0083 (8) |
C42 | 0.0540 (11) | 0.0505 (11) | 0.0372 (9) | 0.0007 (9) | 0.0091 (8) | −0.0029 (8) |
C43 | 0.0657 (13) | 0.0612 (13) | 0.0501 (12) | 0.0170 (11) | 0.0191 (10) | 0.0024 (10) |
C44 | 0.0494 (12) | 0.0839 (18) | 0.0765 (17) | 0.0072 (12) | 0.0221 (11) | 0.0132 (13) |
C45 | 0.0436 (11) | 0.0716 (15) | 0.0721 (16) | −0.0056 (11) | 0.0010 (10) | −0.0044 (13) |
C46 | 0.0482 (11) | 0.0490 (11) | 0.0565 (12) | −0.0029 (9) | 0.0036 (9) | −0.0094 (9) |
Cl1 | 0.0514 (3) | 0.0605 (3) | 0.0406 (3) | 0.0017 (2) | 0.00322 (19) | 0.00827 (19) |
Geometric parameters (Å, º) top
S1—C9 | 1.7387 (18) | C25—C26 | 1.376 (3) |
S1—C2 | 1.7496 (18) | C25—H25 | 0.94 (3) |
O7—C7 | 1.371 (2) | C26—H26 | 0.88 (3) |
O7—H7 | 0.95 (4) | C30—C31 | 1.487 (2) |
O24—C24 | 1.366 (2) | C31—C36 | 1.389 (2) |
O24—H24 | 0.95 (3) | C31—C32 | 1.391 (3) |
O30—C30 | 1.222 (2) | C32—C33 | 1.382 (3) |
O34—C34 | 1.363 (2) | C32—H32 | 0.94 (2) |
O34—C37 | 1.419 (2) | C33—C34 | 1.387 (3) |
N41—C46 | 1.489 (3) | C33—H33 | 0.96 (2) |
N41—C42 | 1.500 (2) | C34—C35 | 1.388 (3) |
N41—C38 | 1.503 (2) | C35—C36 | 1.379 (3) |
N41—H41 | 0.92 (2) | C35—H35 | 0.98 (3) |
C2—C3 | 1.358 (2) | C36—H36 | 0.95 (3) |
C2—C21 | 1.475 (2) | C37—C38 | 1.503 (3) |
C3—C4 | 1.447 (2) | C37—H371 | 0.97 (3) |
C3—C30 | 1.490 (2) | C37—H372 | 0.99 (2) |
C4—C5 | 1.402 (2) | C38—H381 | 1.00 (3) |
C4—C9 | 1.403 (2) | C38—H382 | 0.95 (3) |
C5—C6 | 1.377 (3) | C42—C43 | 1.514 (3) |
C5—H5 | 1.00 (2) | C42—H421 | 0.97 (2) |
C6—C7 | 1.400 (3) | C42—H422 | 0.98 (3) |
C6—H6 | 0.99 (2) | C43—C44 | 1.509 (4) |
C7—C8 | 1.382 (3) | C43—H431 | 0.90 (3) |
C8—C9 | 1.405 (2) | C43—H432 | 1.00 (3) |
C8—H8 | 1.00 (2) | C44—C45 | 1.516 (4) |
C21—C26 | 1.389 (3) | C44—H441 | 1.00 (3) |
C21—C22 | 1.390 (3) | C44—H442 | 0.95 (3) |
C22—C23 | 1.390 (3) | C45—C46 | 1.513 (3) |
C22—H22 | 0.90 (2) | C45—H451 | 0.90 (3) |
C23—C24 | 1.379 (3) | C45—H452 | 0.98 (3) |
C23—H23 | 0.97 (2) | C46—H461 | 0.99 (3) |
C24—C25 | 1.382 (3) | C46—H462 | 1.02 (2) |
| | | |
C9—S1—C2 | 91.85 (8) | C33—C32—C31 | 120.77 (17) |
C7—O7—H7 | 110 (2) | C33—C32—H32 | 119.7 (14) |
C24—O24—H24 | 105.9 (19) | C31—C32—H32 | 119.4 (14) |
C34—O34—C37 | 118.13 (14) | C32—C33—C34 | 119.77 (18) |
C46—N41—C42 | 110.98 (16) | C32—C33—H33 | 120.2 (14) |
C46—N41—C38 | 113.61 (16) | C34—C33—H33 | 120.0 (15) |
C42—N41—C38 | 114.52 (15) | O34—C34—C33 | 115.82 (16) |
C46—N41—H41 | 104.5 (14) | O34—C34—C35 | 123.92 (16) |
C42—N41—H41 | 107.7 (14) | C33—C34—C35 | 120.26 (17) |
C38—N41—H41 | 104.6 (14) | C36—C35—C34 | 119.09 (17) |
C3—C2—C21 | 127.42 (16) | C36—C35—H35 | 119.7 (15) |
C3—C2—S1 | 111.86 (13) | C34—C35—H35 | 121.1 (15) |
C21—C2—S1 | 120.19 (13) | C35—C36—C31 | 121.59 (18) |
C2—C3—C4 | 113.33 (15) | C35—C36—H36 | 119.1 (16) |
C2—C3—C30 | 124.99 (15) | C31—C36—H36 | 119.3 (16) |
C4—C3—C30 | 121.60 (15) | O34—C37—C38 | 109.24 (16) |
C5—C4—C9 | 118.36 (16) | O34—C37—H371 | 112.6 (14) |
C5—C4—C3 | 129.87 (16) | C38—C37—H371 | 105.7 (14) |
C9—C4—C3 | 111.77 (15) | O34—C37—H372 | 107.2 (13) |
C6—C5—C4 | 120.13 (17) | C38—C37—H372 | 114.1 (13) |
C6—C5—H5 | 119.0 (12) | H371—C37—H372 | 108.2 (19) |
C4—C5—H5 | 120.8 (12) | C37—C38—N41 | 116.83 (17) |
C5—C6—C7 | 120.51 (18) | C37—C38—H381 | 108.8 (13) |
C5—C6—H6 | 122.1 (13) | N41—C38—H381 | 106.0 (14) |
C7—C6—H6 | 117.4 (13) | C37—C38—H382 | 109.6 (14) |
O7—C7—C8 | 121.84 (18) | N41—C38—H382 | 107.1 (14) |
O7—C7—C6 | 116.91 (18) | H381—C38—H382 | 108.3 (19) |
C8—C7—C6 | 121.23 (16) | N41—C42—C43 | 109.10 (16) |
C7—C8—C9 | 117.62 (17) | N41—C42—H421 | 108.4 (13) |
C7—C8—H8 | 121.3 (13) | C43—C42—H421 | 106.7 (13) |
C9—C8—H8 | 121.1 (13) | N41—C42—H422 | 106.3 (15) |
C4—C9—C8 | 122.10 (16) | C43—C42—H422 | 114.1 (15) |
C4—C9—S1 | 111.18 (12) | H421—C42—H422 | 112.1 (19) |
C8—C9—S1 | 126.66 (14) | C44—C43—C42 | 111.06 (19) |
C26—C21—C22 | 117.96 (17) | C44—C43—H431 | 104.6 (18) |
C26—C21—C2 | 118.68 (16) | C42—C43—H431 | 111.8 (18) |
C22—C21—C2 | 123.36 (17) | C44—C43—H432 | 112.1 (15) |
C21—C22—C23 | 120.60 (18) | C42—C43—H432 | 107.7 (14) |
C21—C22—H22 | 121.8 (15) | H431—C43—H432 | 110 (2) |
C23—C22—H22 | 117.6 (15) | C43—C44—C45 | 110.7 (2) |
C24—C23—C22 | 120.43 (18) | C43—C44—H441 | 111.1 (16) |
C24—C23—H23 | 119.9 (13) | C45—C44—H441 | 106.3 (16) |
C22—C23—H23 | 119.7 (13) | C43—C44—H442 | 109.0 (18) |
O24—C24—C23 | 123.57 (18) | C45—C44—H442 | 113.5 (17) |
O24—C24—C25 | 117.08 (19) | H441—C44—H442 | 106 (2) |
C23—C24—C25 | 119.34 (18) | C46—C45—C44 | 112.1 (2) |
C26—C25—C24 | 120.2 (2) | C46—C45—H451 | 108.4 (19) |
C26—C25—H25 | 122.6 (15) | C44—C45—H451 | 109.5 (18) |
C24—C25—H25 | 117.3 (15) | C46—C45—H452 | 108.0 (17) |
C25—C26—C21 | 121.49 (19) | C44—C45—H452 | 110.0 (17) |
C25—C26—H26 | 117.5 (17) | H451—C45—H452 | 109 (2) |
C21—C26—H26 | 121.0 (17) | N41—C46—C45 | 110.40 (18) |
O30—C30—C31 | 120.43 (16) | N41—C46—H461 | 106.3 (15) |
O30—C30—C3 | 119.15 (15) | C45—C46—H461 | 111.5 (15) |
C31—C30—C3 | 120.34 (15) | N41—C46—H462 | 105.3 (13) |
C36—C31—C32 | 118.38 (16) | C45—C46—H462 | 110.7 (13) |
C36—C31—C30 | 118.70 (16) | H461—C46—H462 | 112 (2) |
C32—C31—C30 | 122.77 (15) | | |
| | | |
C9—S1—C2—C3 | 0.71 (14) | C24—C25—C26—C21 | 0.5 (4) |
C9—S1—C2—C21 | −171.56 (14) | C22—C21—C26—C25 | −1.5 (3) |
C21—C2—C3—C4 | 170.53 (16) | C2—C21—C26—C25 | 178.7 (2) |
S1—C2—C3—C4 | −1.1 (2) | C2—C3—C30—O30 | 124.1 (2) |
C21—C2—C3—C30 | −6.1 (3) | C4—C3—C30—O30 | −52.3 (3) |
S1—C2—C3—C30 | −177.67 (14) | C2—C3—C30—C31 | −58.9 (3) |
C2—C3—C4—C5 | −178.71 (18) | C4—C3—C30—C31 | 124.70 (19) |
C30—C3—C4—C5 | −2.0 (3) | O30—C30—C31—C36 | −15.2 (3) |
C2—C3—C4—C9 | 0.9 (2) | C3—C30—C31—C36 | 167.90 (17) |
C30—C3—C4—C9 | 177.68 (16) | O30—C30—C31—C32 | 160.3 (2) |
C9—C4—C5—C6 | −1.6 (3) | C3—C30—C31—C32 | −16.6 (3) |
C3—C4—C5—C6 | 178.01 (19) | C36—C31—C32—C33 | 1.8 (3) |
C4—C5—C6—C7 | −0.4 (3) | C30—C31—C32—C33 | −173.67 (19) |
C5—C6—C7—O7 | −176.73 (18) | C31—C32—C33—C34 | −0.5 (3) |
C5—C6—C7—C8 | 2.1 (3) | C37—O34—C34—C33 | −175.51 (19) |
O7—C7—C8—C9 | 177.03 (17) | C37—O34—C34—C35 | 4.7 (3) |
C6—C7—C8—C9 | −1.8 (3) | C32—C33—C34—O34 | 177.60 (19) |
C5—C4—C9—C8 | 1.9 (3) | C32—C33—C34—C35 | −2.6 (3) |
C3—C4—C9—C8 | −177.74 (16) | O34—C34—C35—C36 | −175.9 (2) |
C5—C4—C9—S1 | 179.31 (14) | C33—C34—C35—C36 | 4.4 (3) |
C3—C4—C9—S1 | −0.37 (19) | C34—C35—C36—C31 | −3.1 (3) |
C7—C8—C9—C4 | −0.3 (3) | C32—C31—C36—C35 | 0.0 (3) |
C7—C8—C9—S1 | −177.21 (14) | C30—C31—C36—C35 | 175.67 (19) |
C2—S1—C9—C4 | −0.17 (14) | C34—O34—C37—C38 | 160.14 (18) |
C2—S1—C9—C8 | 177.05 (17) | O34—C37—C38—N41 | 67.5 (2) |
C3—C2—C21—C26 | −39.1 (3) | C46—N41—C38—C37 | 53.5 (2) |
S1—C2—C21—C26 | 131.89 (17) | C42—N41—C38—C37 | −75.4 (2) |
C3—C2—C21—C22 | 141.2 (2) | C46—N41—C42—C43 | 60.5 (2) |
S1—C2—C21—C22 | −47.9 (2) | C38—N41—C42—C43 | −169.18 (17) |
C26—C21—C22—C23 | 1.5 (3) | N41—C42—C43—C44 | −58.8 (2) |
C2—C21—C22—C23 | −178.71 (17) | C42—C43—C44—C45 | 55.2 (3) |
C21—C22—C23—C24 | −0.6 (3) | C43—C44—C45—C46 | −52.9 (3) |
C22—C23—C24—O24 | −179.02 (19) | C42—N41—C46—C45 | −58.5 (2) |
C22—C23—C24—C25 | −0.4 (3) | C38—N41—C46—C45 | 170.78 (18) |
O24—C24—C25—C26 | 179.1 (2) | C44—C45—C46—N41 | 54.5 (3) |
C23—C24—C25—C26 | 0.5 (3) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N41—H41···Cl1 | 0.92 (2) | 2.25 (2) | 3.136 (2) | 161 (2) |
O7—H7···Cl1i | 0.95 (4) | 2.19 (4) | 3.112 (2) | 165 (3) |
O24—H24···Cl1ii | 0.95 (4) | 2.15 (3) | 3.038 (2) | 156 (3) |
C36—H36···O30 | 0.95 (3) | 2.51 (2) | 2.794 (2) | 97 (2) |
C38—H381···O30iii | 1.00 (3) | 2.50 (3) | 3.012 (3) | 111 (2) |
C42—H421···O34 | 0.97 (2) | 2.57 (2) | 3.043 (3) | 110 (2) |
Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x+2, −y+1, −z+2; (iii) −x+1, −y+1, −z+2. |
Experimental details
Crystal data |
Chemical formula | C28H28NO4S+·Cl− |
Mr | 510.02 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 120 |
a, b, c (Å) | 13.4836 (3), 13.1345 (3), 14.6532 (3) |
β (°) | 102.0570 (13) |
V (Å3) | 2537.84 (10) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.27 |
Crystal size (mm) | 0.36 × 0.18 × 0.08 |
|
Data collection |
Diffractometer | Nonius KappaCCD diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 55970, 5835, 4580 |
Rint | 0.1 |
(sin θ/λ)max (Å−1) | 0.650 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.044, 0.142, 1.09 |
No. of reflections | 5835 |
No. of parameters | 429 |
H-atom treatment | All H-atom parameters refined |
Δρmax, Δρmin (e Å−3) | 0.30, −0.35 |
Selected geometric parameters (Å, º) topS1—C9 | 1.7387 (18) | N41—C42 | 1.500 (2) |
S1—C2 | 1.7496 (18) | N41—C38 | 1.503 (2) |
O7—C7 | 1.371 (2) | C2—C3 | 1.358 (2) |
O24—C24 | 1.366 (2) | C2—C21 | 1.475 (2) |
O30—C30 | 1.222 (2) | C3—C30 | 1.490 (2) |
O34—C34 | 1.363 (2) | C30—C31 | 1.487 (2) |
O34—C37 | 1.419 (2) | C37—C38 | 1.503 (3) |
N41—C46 | 1.489 (3) | | |
| | | |
C9—S1—C2 | 91.85 (8) | C36—C31—C30 | 118.70 (16) |
C34—O34—C37 | 118.13 (14) | C32—C31—C30 | 122.77 (15) |
C46—N41—C42 | 110.98 (16) | O34—C37—C38 | 109.24 (16) |
C46—N41—C38 | 113.61 (16) | C37—C38—N41 | 116.83 (17) |
C42—N41—C38 | 114.52 (15) | N41—C42—C43 | 109.10 (16) |
C2—C3—C30 | 124.99 (15) | C44—C43—C42 | 111.06 (19) |
C4—C3—C30 | 121.60 (15) | C43—C44—C45 | 110.7 (2) |
O30—C30—C31 | 120.43 (16) | C46—C45—C44 | 112.1 (2) |
O30—C30—C3 | 119.15 (15) | N41—C46—C45 | 110.40 (18) |
C31—C30—C3 | 120.34 (15) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N41—H41···Cl1 | 0.92 (2) | 2.25 (2) | 3.136 (2) | 161 (2) |
O7—H7···Cl1i | 0.95 (4) | 2.19 (4) | 3.112 (2) | 165 (3) |
O24—H24···Cl1ii | 0.95 (4) | 2.15 (3) | 3.038 (2) | 156 (3) |
C36—H36···O30 | 0.95 (3) | 2.51 (2) | 2.794 (2) | 97 (2) |
C38—H381···O30iii | 1.00 (3) | 2.50 (3) | 3.012 (3) | 111 (2) |
C42—H421···O34 | 0.97 (2) | 2.57 (2) | 3.043 (3) | 110 (2) |
Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x+2, −y+1, −z+2; (iii) −x+1, −y+1, −z+2. |
Many non-steroidal compounds (antiestrogens or selective estrogen receptor modulators) are clinically used for the management of osteoporosis in women because they cause estrogen-like effects in a number of physiological systems without an increase in the risk of cancer. They act by binding with high affinity to the estrogen receptor, a nuclear transcription factor which controls the differentiation of the precursors of the macrophage cells that resorb bone tissue, the osteoclasts. The estrogen receptor action has been better understood following novel X-ray crystallographic studies on different ligand/receptor complexes (Brzozowski et al., 1997; Pike et al., 1999, and references therein). The accepted model states that the tissue-selective agonistic and/or antagonistic effects of the antiestrogens depend on the structural feature of each drug and are originated by the conformational change that takes place in the estrogen receptor upon binding of each individual ligand (McDonnell, 2000; Rodan & Martin, 2000). The mixed agonist/antagonist antiosteoporotic Raloxifene hydrochloride is efficacious in preventing bone loss, and exerts beneficial effects on the cardiovascular system and breast tissue in the absence of significant secondary events in mammary tissue and the uterus (Bryant & Dere, 1998; Bryant et al., 1999; Goldstein et al., 2000).
A number of antiestrogens have been crystallographically studied, including the Raloxifene closely related compound [(3-(4-(tetrahydropyrrolyl-ethoxy)benzoyl)-2-p-hydroxyphenyl)-6- hydroxybenzo[b]thiophene acetone solvate] (Kym et al., 1993). Data of the latter compound were retrieved from the Cambridge Structural Database (Allen et al., 1983) [refcode PIDXIJ; Kym et al., 1993], and then used to compare the structures of both antiestrogens.
The X-ray solid-state analysis of Raloxifene hydrochloride was undertaken as a part of our ongoing study on crystal and molecular structures of different chemical compounds that affect osseous metabolism and are used as therapeutic agents to treat a variety of bone disorders (Vega et al., 1996, 1998). \sch
The asymmetric unit of Raloxifene hydrochloride, (I), consists of the benzo[b]thiophene, i.e. the five-membered heterocycle fused across the C4—C9 bond to the benzo ring, which is substituted at the 2-position with the phenol and at the 3-position with the basic arm containing the phenyl and piperidine rings (see figure 1). The molecule bears a net positive charge due to proton transfer from HCl to the N atom of the piperidine ring (N41), so hereinafter it will be referred to as the molecular cation.
The benzo[b]thiophene is essentially planar, the maximum deviation from least-squares plane through S1,C2,C3,C4,C5,C6,C7,O7,C8,C9 occurring at O7 [0.067 (1) Å]. The dihedral angle sustained between least-squares planes of the benzo[b]thiophene and of the 2-phenol [45.3 (1)°] is equal in both Raloxifene and PIDXIJ (Kym et al., 1993), suggesting that the benzo[b]thiophene and the phenol ring arrange in a structural motif which is common to both antiestrogens. As the phenol ring at the 2-position does not show any other interatomic contact than that in which is involved O24 atom, then its orientation relative to benzo[b]thiophene could be the result of minimizing the steric hindrance.
The carbonyl C30 atom assumes sp2 character and has trigonal angle configuration with bond angles sum of 360° (see table 1). The two bond angles made by the five-membered heterocycle with the carbonyl group, C2—C3—C30 124.99 (15) Å and C4—C3—C30 121.60 (15) Å, compare well with those in PIDXIJ (124.2 and 121.7 Å, respectively). Those formed by the phenyl ring and the carbonyl group, C32—C31—C30 122.77 (15) Å and C36—C31—C30 118.70 (16) Å, differ from the correspondent ones in PIDXIJ (121.2 and 119.6 Å), suggesting that the attractive interaction involving C36—H36···O30 in Raloxifene hydrochloride is higher than the one present in PIDXIJ.
According to Benassi et al. (1987), the five-membered heterocycle in benzo[b]thiophene derivatives possesses higher degree of conjugative ability than the phenyl ring, so the former is less twisted than the latter from the carbonyl plane. Besides, the same authors showed that the exocyclic C(thiophene)—C(carbonyl) bond [1.476 (2) Å] is shorter than the C(phenyl)—C(carbonyl) one [1.483 (2) Å], in direct correspondence with was observed about the bond shortening as the twist of the plane with respect to the carbonyl plane decreases (Benassi et al., 1987). However, a very different conjugative ability is observed in PIDXIJ and in Raloxifene hydrochloride. In PIDXIJ, the five-membered heterocycle is more twisted from the carbonyl plane than the phenyl ring, as can be assessed by the values of the dihedral angles 69 and 12°, respectively. Moreover, the C(thiophene)—C(carbonyl) bond (1.492 Å) is larger than the C(phenyl)—C(carbonyl) one (1.476 Å), clearly showing that the conjugative ability was transferred from the five-membered heterocycle to the phenyl ring. An intermediate situation occurs in this work, where the angular relationships involving the benzo[b]thiophene, the phenyl ring and the carbonyl planes (dihedral angles 16.9 (1) and 53.4 (1)°, respectively) indicate that the phenyl ring plane is slightly more twisted from the carbonyl plane and the five-membered heterocycle is less than 15° twisted than the correspondent ones in PIDXIJ. Although the exocyclic C(thiophene)—C(carbonyl) bond [C3—C30 1.490 (2) Å] compares well with that of PIDXIJ, the C(phenyl)—C(carbonyl) bond [C30—C31 1.487 (2) Å] is not significantly shorter than the previous one. By another way, the carbonyl group is able to rotate around the C(thiophene)—C(carbonyl) bond and the torsion angle C2—C3—C30—O30, which in Raloxifene has a value of 124.0 (2)°, in PIDXIJ is -66.2°.
The O34—C37—C38—N41 chain of atoms linking the phenyl to the terminal ring, assumes, as in PIDXIJ, a gauche conformation, the torsion angles being 67.5 (2)° and 59°, respectively. Bond lengths and angles about the atoms component of the O34—C37—C38—N41 chain show differences when comparing both structures. In Raloxifene hydrochloride the geometry of the atoms within the chain could significantly be affected by the ability of the C42 atom of the piperidine ring to be a hydrogen-bond donor to O34, in such a way that the C42—H421···O34 intramolecular contact forms a six-membered ring as is apparent in figure 1. The terminal piperidine ring suffers considerable deviation from planarity and adopts an almost perfect chair conformation, the ring puckering parameters (Cremer & Pople, 1975) being QT 0.578 (2) Å, θ 175.6 (2) Å and ϕ 221 (3)°. Asymmetry parameters (Nardelli, 1983) show the ring is close to D3 d local pseudo-symmetry.
Hydrogen bonding determines the packing of the crystal of Raloxifene hydrochloride, which comprises stacking of layers (the hydrogen-bond geometry is given in Table 2). Within a layer, the molecular cations are arranged in a chain running along crystallographic b axis due to the N41—H41···Cl1 and the O7—H7···Cl1i hydrogen bonds, and, at the same time, parallel chains are held together via the O24—H24···Cl1ii hydrogen bonds. As shown in Table 2, the intermolecular C38—H381···O30iii contacts seem to contribute to the structure interlayer stability.