The crystal structure of the antihypertensive and cardiovascular protective ramipril {systematic name: 1-[2-(1-ethoxycarbonyl-3-phenylpropylamino)propionyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid}, C23H32N2O5, has been determined. Within the crystal structure, strong hydrogen bonds connect the molecules into chains along the [100] direction. The preferred crystal growth along these chains causes a crystal morphology of very thin needles which previously prevented the crystal structure determination.
Supporting information
CCDC reference: 165672
Key indicators
- Single-crystal X-ray study
- T = 293 K
- Mean (C-C) = 0.008 Å
- R factor = 0.064
- wR factor = 0.085
- Data-to-parameter ratio = 11.8
checkCIF results
No syntax errors found
ADDSYM reports no extra symmetry
Alert Level A:
DIFF_019 Alert A _diffrn_standards_number is missing
Number of standards used in measurement.
| Author response: Data was collected with an area detector
|
DIFF_020 Alert A _diffrn_standards_interval_count and
_diffrn_standards_interval_time are missing. Number of measurements
between standards or time (min) between standards.
| Author response: Data was collected with an area detector
|
Alert Level B:
RINTA_01 Alert B The value of Rint is greater than 0.15
Rint given 0.166
| Author response: Only small and poorly reflecting needles can be crystallized,
but the compound is comercially very important, which might justify
the publication, though the quality of the structure determination
meets not the usual standards.
See _publ_section_exptl_refinement and _publ_section_comment.
|
THETM_01 Alert B The value of sine(theta_max)/wavelength is less than 0.575
Calculated sin(theta_max)/wavelength = 0.5568
| Author response: See _publ_section_exptl_refinement and _publ_section_comment.
|
Alert Level C:
STRVAL_01
From the CIF: _refine_ls_abs_structure_Flack -2.000
From the CIF: _refine_ls_abs_structure_Flack_su 1.900
Alert C Flack parameter is too small
General Notes
REFLT_03
From the CIF: _diffrn_reflns_theta_max 23.31
From the CIF: _reflns_number_total 3291
Count of symmetry unique reflns 1937
Completeness (_total/calc) 169.90%
TEST3: Check Friedels for noncentro structure
Estimate of Friedel pairs measured 1354
Fraction of Friedel pairs measured 0.699
Are heavy atom types Z>Si present no
ALERT: MoKa measured Friedel data cannot be used to
determine absolute structure in a light-atom
study EXCEPT under VERY special conditions.
It is preferred that Friedel data is merged in such cases.
2 Alert Level A = Potentially serious problem
2 Alert Level B = Potential problem
1 Alert Level C = Please check
The sample was recystallized several times from ethanol–diisopropyl ether for
further purification. In the final crystallization step, an ethanolic
solution, which was almost saturated at 313 K, was slowly cooled to room
temperature.
Data was originally collected to 54° 2θ with a SMART 1 K CCD area
detector, but reflections were observed only up to about 1 Å/45° 2θ.
Refinement was therefore done with data up to 0.9 Å/47° 2θ. All H atoms
were found in the electron-density difference map, but most of them were
placed in idealized geometry with fixed isotropic displacement parameters.
Only the coordinates and isotropic displacement parameters of the H atom of
the carboxylic acid group (H1) and of the H atom of the amino group (H2),
which are involved in hydrogen bonds, were refined.
Data collection: SMART (Bruker, 1999); cell refinement: SAINT+ (Bruker, 1999); data reduction: SAINT+; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-PC XP (Bruker, 1998); software used to prepare material for publication: SHELXL97.
1-[2-(1-ethoxycarbonyl-3-phenylpropylamino)propionyl]octahydrocyclopenta[
b]- pyrrole-2-carboxylic acid
top
Crystal data top
C23H32N2O5 | Dx = 1.205 Mg m−3 |
Mr = 416.51 | Melting point: 109°C K |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
a = 7.4845 (11) Å | Cell parameters from 2316 reflections |
b = 13.937 (2) Å | θ = 2.4–18.2° |
c = 22.012 (3) Å | µ = 0.09 mm−1 |
V = 2296.0 (6) Å3 | T = 293 K |
Z = 4 | Needle, colourless |
F(000) = 896 | 0.7 × 0.05 × 0.03 mm |
Data collection top
Bruker AXS four-circle diffractometer | 1640 reflections with I > 2σ(I) |
Radiation source: rotating anode | Rint = 0.166 |
Graphite monochromator | θmax = 23.3°, θmin = 2.4° |
ω scans | h = −4→8 |
15851 measured reflections | k = −15→15 |
3291 independent reflections | l = −24→24 |
Refinement top
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)] = 0.064 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.085 | w = 1/[σ2(Fo2) + (0.0263P)2] where P = (Fo2 + 2Fc2)/3 |
S = 0.92 | (Δ/σ)max < 0.001 |
3291 reflections | Δρmax = 0.13 e Å−3 |
279 parameters | Δρmin = −0.14 e Å−3 |
0 restraints | Absolute structure: Flack (1983) |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −2.0 (19) |
Crystal data top
C23H32N2O5 | V = 2296.0 (6) Å3 |
Mr = 416.51 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 7.4845 (11) Å | µ = 0.09 mm−1 |
b = 13.937 (2) Å | T = 293 K |
c = 22.012 (3) Å | 0.7 × 0.05 × 0.03 mm |
Data collection top
Bruker AXS four-circle diffractometer | 1640 reflections with I > 2σ(I) |
15851 measured reflections | Rint = 0.166 |
3291 independent reflections | θmax = 23.3° |
Refinement top
R[F2 > 2σ(F2)] = 0.064 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.085 | Δρmax = 0.13 e Å−3 |
S = 0.92 | Δρmin = −0.14 e Å−3 |
3291 reflections | Absolute structure: Flack (1983) |
279 parameters | Absolute structure parameter: −2.0 (19) |
0 restraints | |
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. |
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. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O01 | 0.8534 (4) | 0.2836 (3) | 0.11780 (14) | 0.0676 (10) | |
H1 | 0.939 (7) | 0.336 (4) | 0.101 (2) | 0.109 (19)* | |
O02 | 0.9727 (5) | 0.1845 (2) | 0.04956 (14) | 0.0710 (10) | |
O03 | 0.7016 (4) | −0.0561 (2) | −0.00152 (12) | 0.0675 (10) | |
O04 | 0.8473 (4) | 0.2369 (2) | −0.17916 (14) | 0.0729 (10) | |
O05 | 0.6397 (4) | 0.1236 (2) | −0.19571 (14) | 0.0803 (11) | |
N01 | 0.7448 (5) | 0.0376 (2) | 0.08079 (16) | 0.0547 (10) | |
N02 | 0.5954 (6) | 0.1032 (3) | −0.07252 (18) | 0.0526 (12) | |
H2 | 0.589 (5) | 0.049 (2) | −0.0805 (16) | 0.039 (15)* | |
C01 | 0.7351 (6) | 0.1286 (3) | 0.11407 (18) | 0.0584 (12) | |
H01 | 0.6144 | 0.1553 | 0.1105 | 0.070* | |
C02 | 0.7694 (8) | 0.0984 (4) | 0.1801 (2) | 0.0944 (17) | |
H021 | 0.8316 | 0.1487 | 0.2021 | 0.113* | |
H022 | 0.6579 | 0.0846 | 0.2008 | 0.113* | |
C03 | 0.8840 (9) | 0.0091 (4) | 0.1756 (2) | 0.0900 (17) | |
H03 | 0.8515 | −0.0358 | 0.2080 | 0.108* | |
C04 | 0.8450 (7) | −0.0370 (3) | 0.1131 (2) | 0.0692 (15) | |
H04 | 0.7715 | −0.0947 | 0.1180 | 0.083* | |
C05 | 1.0878 (10) | 0.0224 (5) | 0.1744 (3) | 0.119 (2) | |
H051 | 1.1194 | 0.0833 | 0.1560 | 0.143* | |
H052 | 1.1366 | 0.0201 | 0.2152 | 0.143* | |
C06 | 1.1574 (8) | −0.0604 (5) | 0.1366 (3) | 0.115 (2) | |
H062 | 1.2775 | −0.0480 | 0.1220 | 0.138* | |
H061 | 1.1565 | −0.1199 | 0.1594 | 0.138* | |
C07 | 1.0250 (7) | −0.0628 (3) | 0.0852 (2) | 0.0769 (15) | |
H071 | 1.0207 | −0.1262 | 0.0671 | 0.092* | |
H072 | 1.0575 | −0.0168 | 0.0541 | 0.092* | |
C08 | 0.8697 (7) | 0.2008 (3) | 0.0902 (2) | 0.0520 (12) | |
C09 | 0.6838 (5) | 0.0214 (3) | 0.0242 (2) | 0.0515 (13) | |
C10 | 0.5754 (5) | 0.1012 (3) | −0.00601 (18) | 0.0483 (12) | |
H10 | 0.6131 | 0.1632 | 0.0106 | 0.058* | |
C11 | 0.3784 (5) | 0.0845 (3) | 0.00971 (18) | 0.0705 (14) | |
H111 | 0.3414 | 0.0232 | −0.0056 | 0.106* | |
H112 | 0.3069 | 0.1341 | −0.0084 | 0.106* | |
H113 | 0.3635 | 0.0859 | 0.0530 | 0.106* | |
C12 | 0.7651 (6) | 0.1439 (3) | −0.09581 (17) | 0.0468 (11) | |
H12 | 0.7865 | 0.2047 | −0.0747 | 0.056* | |
C13 | 0.7382 (8) | 0.1659 (4) | −0.1625 (2) | 0.0581 (14) | |
C14 | 0.8554 (8) | 0.2576 (4) | −0.2443 (2) | 0.0966 (19) | |
H141 | 0.8798 | 0.3253 | −0.2503 | 0.116* | |
H142 | 0.7409 | 0.2432 | −0.2628 | 0.116* | |
C15 | 0.9973 (9) | 0.1995 (4) | −0.2738 (2) | 0.125 (2) | |
H151 | 1.1101 | 0.2128 | −0.2548 | 0.188* | |
H152 | 1.0037 | 0.2157 | −0.3162 | 0.188* | |
H153 | 0.9697 | 0.1326 | −0.2695 | 0.188* | |
C16 | 0.9326 (5) | 0.0823 (3) | −0.08925 (17) | 0.0499 (12) | |
H161 | 1.0351 | 0.1199 | −0.1018 | 0.060* | |
H162 | 0.9483 | 0.0666 | −0.0466 | 0.060* | |
C17 | 0.9309 (6) | −0.0108 (3) | −0.12562 (19) | 0.0674 (13) | |
H171 | 0.8300 | −0.0495 | −0.1129 | 0.081* | |
H172 | 0.9154 | 0.0041 | −0.1683 | 0.081* | |
C18 | 1.1002 (7) | −0.0677 (3) | −0.1175 (2) | 0.0586 (13) | |
C19 | 1.2530 (9) | −0.0455 (3) | −0.14919 (19) | 0.0693 (14) | |
H19 | 1.2520 | 0.0061 | −0.1760 | 0.083* | |
C20 | 1.4077 (8) | −0.0979 (5) | −0.1421 (3) | 0.0842 (17) | |
H20 | 1.5082 | −0.0830 | −0.1651 | 0.101* | |
C21 | 1.4137 (11) | −0.1717 (5) | −0.1014 (3) | 0.100 (2) | |
H21 | 1.5191 | −0.2057 | −0.0952 | 0.119* | |
C22 | 1.2611 (11) | −0.1951 (4) | −0.0696 (3) | 0.0953 (19) | |
H22 | 1.2632 | −0.2462 | −0.0425 | 0.114* | |
C23 | 1.1063 (8) | −0.1441 (4) | −0.0777 (2) | 0.0825 (16) | |
H23 | 1.0043 | −0.1611 | −0.0560 | 0.099* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O01 | 0.080 (3) | 0.060 (2) | 0.062 (2) | −0.0136 (19) | 0.0148 (19) | −0.009 (2) |
O02 | 0.086 (3) | 0.058 (2) | 0.069 (2) | −0.0111 (18) | 0.025 (2) | −0.0078 (19) |
O03 | 0.088 (3) | 0.0458 (18) | 0.069 (2) | −0.0039 (17) | −0.0168 (17) | −0.0041 (18) |
O04 | 0.089 (3) | 0.079 (2) | 0.051 (2) | 0.003 (2) | 0.005 (2) | 0.0188 (18) |
O05 | 0.095 (3) | 0.099 (3) | 0.046 (2) | −0.003 (2) | −0.0097 (19) | −0.013 (2) |
N01 | 0.079 (3) | 0.046 (2) | 0.039 (2) | −0.005 (2) | −0.006 (2) | 0.006 (2) |
N02 | 0.063 (3) | 0.041 (3) | 0.054 (3) | 0.002 (3) | −0.006 (2) | −0.010 (2) |
C01 | 0.085 (4) | 0.054 (3) | 0.037 (3) | −0.011 (3) | 0.012 (3) | 0.000 (3) |
C02 | 0.151 (5) | 0.081 (4) | 0.051 (3) | −0.013 (4) | 0.012 (4) | 0.002 (3) |
C03 | 0.138 (6) | 0.090 (5) | 0.042 (3) | −0.023 (4) | −0.022 (4) | 0.020 (3) |
C04 | 0.082 (4) | 0.061 (4) | 0.064 (4) | −0.011 (3) | −0.012 (3) | 0.018 (3) |
C05 | 0.153 (7) | 0.118 (5) | 0.088 (5) | −0.020 (5) | −0.069 (5) | 0.009 (4) |
C06 | 0.120 (5) | 0.110 (5) | 0.114 (5) | −0.006 (4) | −0.049 (5) | 0.038 (4) |
C07 | 0.084 (4) | 0.068 (3) | 0.079 (4) | −0.004 (3) | −0.022 (4) | 0.024 (3) |
C08 | 0.059 (4) | 0.054 (3) | 0.043 (3) | −0.003 (3) | −0.007 (3) | 0.000 (3) |
C09 | 0.056 (3) | 0.045 (3) | 0.053 (3) | −0.007 (3) | −0.001 (3) | 0.013 (3) |
C10 | 0.059 (3) | 0.053 (3) | 0.033 (3) | −0.007 (3) | 0.001 (2) | −0.006 (2) |
C11 | 0.055 (3) | 0.083 (3) | 0.073 (3) | −0.005 (3) | 0.006 (3) | 0.001 (3) |
C12 | 0.053 (3) | 0.045 (3) | 0.043 (3) | −0.001 (3) | −0.005 (3) | −0.010 (2) |
C13 | 0.071 (4) | 0.062 (4) | 0.042 (4) | 0.020 (3) | 0.005 (3) | −0.003 (3) |
C14 | 0.115 (5) | 0.113 (5) | 0.062 (4) | 0.018 (4) | 0.010 (4) | 0.031 (3) |
C15 | 0.140 (6) | 0.166 (6) | 0.069 (4) | 0.015 (5) | 0.021 (4) | 0.003 (4) |
C16 | 0.053 (3) | 0.052 (3) | 0.045 (3) | 0.007 (3) | −0.006 (2) | −0.001 (2) |
C17 | 0.069 (3) | 0.069 (3) | 0.064 (3) | 0.014 (3) | −0.010 (3) | −0.015 (3) |
C18 | 0.063 (4) | 0.050 (3) | 0.062 (4) | 0.011 (3) | −0.007 (3) | −0.024 (3) |
C19 | 0.079 (4) | 0.060 (3) | 0.069 (3) | 0.014 (4) | −0.003 (4) | −0.021 (3) |
C20 | 0.072 (5) | 0.077 (4) | 0.104 (5) | 0.003 (4) | 0.002 (4) | −0.041 (4) |
C21 | 0.106 (6) | 0.065 (5) | 0.128 (6) | 0.027 (4) | −0.038 (5) | −0.035 (4) |
C22 | 0.110 (6) | 0.062 (4) | 0.113 (5) | 0.021 (5) | −0.015 (5) | 0.004 (3) |
C23 | 0.091 (5) | 0.069 (4) | 0.088 (4) | 0.011 (4) | −0.002 (4) | −0.014 (4) |
Geometric parameters (Å, º) top
O01—C08 | 1.311 (5) | C09—C10 | 1.529 (5) |
O01—H1 | 1.04 (6) | C10—C11 | 1.532 (5) |
O02—C08 | 1.202 (5) | C10—H10 | 0.9800 |
O03—C09 | 1.226 (5) | C11—H111 | 0.9600 |
O04—C13 | 1.334 (5) | C11—H112 | 0.9600 |
O04—C14 | 1.463 (4) | C11—H113 | 0.9600 |
O05—C13 | 1.194 (5) | C12—C13 | 1.513 (5) |
N01—C09 | 1.347 (4) | C12—C16 | 1.527 (5) |
N01—C01 | 1.466 (4) | C12—H12 | 0.9800 |
N01—C04 | 1.467 (5) | C14—C15 | 1.485 (6) |
N02—C10 | 1.472 (5) | C14—H141 | 0.9700 |
N02—C12 | 1.482 (5) | C14—H142 | 0.9700 |
N02—H2 | 0.77 (3) | C15—H151 | 0.9600 |
C01—C08 | 1.518 (5) | C15—H152 | 0.9600 |
C01—C02 | 1.534 (5) | C15—H153 | 0.9600 |
C01—H01 | 0.9800 | C16—C17 | 1.524 (4) |
C02—C03 | 1.515 (6) | C16—H161 | 0.9700 |
C02—H021 | 0.9700 | C16—H162 | 0.9700 |
C02—H022 | 0.9700 | C17—C18 | 1.506 (5) |
C03—C05 | 1.537 (6) | C17—H171 | 0.9700 |
C03—C04 | 1.546 (6) | C17—H172 | 0.9700 |
C03—H03 | 0.9800 | C18—C19 | 1.374 (6) |
C04—C07 | 1.523 (6) | C18—C23 | 1.381 (6) |
C04—H04 | 0.9800 | C19—C20 | 1.378 (6) |
C05—C06 | 1.513 (6) | C19—H19 | 0.9300 |
C05—H051 | 0.9700 | C20—C21 | 1.365 (7) |
C05—H052 | 0.9700 | C20—H20 | 0.9300 |
C06—C07 | 1.505 (6) | C21—C22 | 1.378 (7) |
C06—H062 | 0.9700 | C21—H21 | 0.9300 |
C06—H061 | 0.9700 | C22—C23 | 1.371 (7) |
C07—H071 | 0.9700 | C22—H22 | 0.9300 |
C07—H072 | 0.9700 | C23—H23 | 0.9300 |
| | | |
C08—O01—H1 | 114 (2) | C09—C10—H10 | 109.1 |
C13—O04—C14 | 116.1 (4) | C11—C10—H10 | 109.1 |
C09—N01—C01 | 126.3 (4) | C10—C11—H111 | 109.5 |
C09—N01—C04 | 120.2 (4) | C10—C11—H112 | 109.5 |
C01—N01—C04 | 113.4 (4) | H111—C11—H112 | 109.5 |
C10—N02—C12 | 116.0 (3) | C10—C11—H113 | 109.5 |
C10—N02—H2 | 102 (3) | H111—C11—H113 | 109.5 |
C12—N02—H2 | 110 (3) | H112—C11—H113 | 109.5 |
N01—C01—C08 | 111.5 (4) | N02—C12—C13 | 107.4 (4) |
N01—C01—C02 | 103.2 (3) | N02—C12—C16 | 117.1 (3) |
C08—C01—C02 | 113.5 (4) | C13—C12—C16 | 108.3 (3) |
N01—C01—H01 | 109.5 | N02—C12—H12 | 107.9 |
C08—C01—H01 | 109.5 | C13—C12—H12 | 107.9 |
C02—C01—H01 | 109.5 | C16—C12—H12 | 107.9 |
C03—C02—C01 | 104.9 (4) | O05—C13—O04 | 125.2 (5) |
C03—C02—H021 | 110.8 | O05—C13—C12 | 125.2 (5) |
C01—C02—H021 | 110.8 | O04—C13—C12 | 109.6 (5) |
C03—C02—H022 | 110.8 | O04—C14—C15 | 110.5 (4) |
C01—C02—H022 | 110.8 | O04—C14—H141 | 109.5 |
H021—C02—H022 | 108.8 | C15—C14—H141 | 109.5 |
C02—C03—C05 | 117.6 (5) | O04—C14—H142 | 109.5 |
C02—C03—C04 | 107.1 (4) | C15—C14—H142 | 109.5 |
C05—C03—C04 | 102.8 (5) | H141—C14—H142 | 108.1 |
C02—C03—H03 | 109.6 | C14—C15—H151 | 109.5 |
C05—C03—H03 | 109.6 | C14—C15—H152 | 109.5 |
C04—C03—H03 | 109.6 | H151—C15—H152 | 109.5 |
N01—C04—C07 | 115.1 (4) | C14—C15—H153 | 109.5 |
N01—C04—C03 | 103.5 (4) | H151—C15—H153 | 109.5 |
C07—C04—C03 | 106.9 (4) | H152—C15—H153 | 109.5 |
N01—C04—H04 | 110.4 | C17—C16—C12 | 115.0 (3) |
C07—C04—H04 | 110.4 | C17—C16—H161 | 108.5 |
C03—C04—H04 | 110.4 | C12—C16—H161 | 108.5 |
C06—C05—C03 | 105.0 (5) | C17—C16—H162 | 108.5 |
C06—C05—H051 | 110.7 | C12—C16—H162 | 108.5 |
C03—C05—H051 | 110.7 | H161—C16—H162 | 107.5 |
C06—C05—H052 | 110.7 | C18—C17—C16 | 112.3 (3) |
C03—C05—H052 | 110.7 | C18—C17—H171 | 109.1 |
H051—C05—H052 | 108.8 | C16—C17—H171 | 109.1 |
C07—C06—C05 | 101.7 (5) | C18—C17—H172 | 109.1 |
C07—C06—H062 | 111.4 | C16—C17—H172 | 109.1 |
C05—C06—H062 | 111.4 | H171—C17—H172 | 107.9 |
C07—C06—H061 | 111.4 | C19—C18—C23 | 117.9 (5) |
C05—C06—H061 | 111.4 | C19—C18—C17 | 121.5 (5) |
H062—C06—H061 | 109.3 | C23—C18—C17 | 120.6 (6) |
C06—C07—C04 | 105.9 (4) | C18—C19—C20 | 121.5 (5) |
C06—C07—H071 | 110.6 | C18—C19—H19 | 119.2 |
C04—C07—H071 | 110.6 | C20—C19—H19 | 119.2 |
C06—C07—H072 | 110.6 | C21—C20—C19 | 120.1 (6) |
C04—C07—H072 | 110.6 | C21—C20—H20 | 120.0 |
H071—C07—H072 | 108.7 | C19—C20—H20 | 120.0 |
O02—C08—O01 | 124.8 (4) | C20—C21—C22 | 119.0 (7) |
O02—C08—C01 | 124.0 (5) | C20—C21—H21 | 120.5 |
O01—C08—C01 | 111.2 (4) | C22—C21—H21 | 120.5 |
O03—C09—N01 | 122.6 (4) | C23—C22—C21 | 120.8 (6) |
O03—C09—C10 | 119.9 (4) | C23—C22—H22 | 119.6 |
N01—C09—C10 | 117.3 (4) | C21—C22—H22 | 119.6 |
N02—C10—C09 | 113.1 (4) | C22—C23—C18 | 120.6 (6) |
N02—C10—C11 | 109.0 (3) | C22—C23—H23 | 119.7 |
C09—C10—C11 | 107.6 (3) | C18—C23—H23 | 119.7 |
N02—C10—H10 | 109.1 | | |
| | | |
C09—N01—C01—C08 | −74.4 (5) | C04—N01—C09—C10 | 178.2 (3) |
C04—N01—C01—C08 | 100.3 (4) | C12—N02—C10—C09 | −76.2 (4) |
C09—N01—C01—C02 | 163.4 (4) | C12—N02—C10—C11 | 164.2 (3) |
C04—N01—C01—C02 | −21.9 (5) | O03—C09—C10—N02 | −35.6 (5) |
N01—C01—C02—C03 | 28.0 (5) | N01—C09—C10—N02 | 149.4 (4) |
C08—C01—C02—C03 | −92.8 (5) | O03—C09—C10—C11 | 84.7 (5) |
C01—C02—C03—C05 | 89.8 (5) | N01—C09—C10—C11 | −90.3 (4) |
C01—C02—C03—C04 | −25.2 (5) | C10—N02—C12—C13 | −163.9 (4) |
C09—N01—C04—C07 | 65.4 (5) | C10—N02—C12—C16 | 74.0 (5) |
C01—N01—C04—C07 | −109.7 (4) | C14—O04—C13—O05 | −5.5 (6) |
C09—N01—C04—C03 | −178.5 (4) | C14—O04—C13—C12 | 171.8 (4) |
C01—N01—C04—C03 | 6.4 (5) | N02—C12—C13—O05 | −29.5 (6) |
C02—C03—C04—N01 | 12.1 (5) | C16—C12—C13—O05 | 97.8 (5) |
C05—C03—C04—N01 | −112.5 (5) | N02—C12—C13—O04 | 153.3 (3) |
C02—C03—C04—C07 | 134.0 (4) | C16—C12—C13—O04 | −79.4 (4) |
C05—C03—C04—C07 | 9.4 (5) | C13—O04—C14—C15 | −89.9 (5) |
C02—C03—C05—C06 | −149.4 (4) | N02—C12—C16—C17 | 64.8 (4) |
C04—C03—C05—C06 | −32.1 (5) | C13—C12—C16—C17 | −56.8 (5) |
C03—C05—C06—C07 | 42.6 (5) | C12—C16—C17—C18 | 179.5 (4) |
C05—C06—C07—C04 | −36.1 (5) | C16—C17—C18—C19 | −80.5 (5) |
N01—C04—C07—C06 | 130.8 (4) | C16—C17—C18—C23 | 99.3 (5) |
C03—C04—C07—C06 | 16.6 (5) | C23—C18—C19—C20 | 0.6 (6) |
N01—C01—C08—O02 | −0.9 (6) | C17—C18—C19—C20 | −179.6 (4) |
C02—C01—C08—O02 | 115.1 (5) | C18—C19—C20—C21 | −2.3 (7) |
N01—C01—C08—O01 | 176.4 (4) | C19—C20—C21—C22 | 2.7 (8) |
C02—C01—C08—O01 | −67.6 (5) | C20—C21—C22—C23 | −1.4 (9) |
C01—N01—C09—O03 | 177.7 (4) | C21—C22—C23—C18 | −0.3 (8) |
C04—N01—C09—O03 | 3.3 (6) | C19—C18—C23—C22 | 0.7 (7) |
C01—N01—C09—C10 | −7.4 (6) | C17—C18—C23—C22 | −179.1 (4) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O01—H1···N02i | 1.04 (6) | 1.58 (6) | 2.601 (5) | 168 (4) |
N02—H2···O03 | 0.78 (3) | 2.43 (3) | 2.829 (5) | 114 (3) |
C03—H03···O05ii | 0.98 | 2.45 | 3.388 (6) | 161 |
Symmetry codes: (i) x+1/2, −y+1/2, −z; (ii) −x+3/2, −y, z+1/2. |
Experimental details
Crystal data |
Chemical formula | C23H32N2O5 |
Mr | 416.51 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 293 |
a, b, c (Å) | 7.4845 (11), 13.937 (2), 22.012 (3) |
V (Å3) | 2296.0 (6) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.09 |
Crystal size (mm) | 0.7 × 0.05 × 0.03 |
|
Data collection |
Diffractometer | Bruker AXS four-circle diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 15851, 3291, 1640 |
Rint | 0.166 |
θmax (°) | 23.3 |
(sin θ/λ)max (Å−1) | 0.557 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.064, 0.085, 0.92 |
No. of reflections | 3291 |
No. of parameters | 279 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.13, −0.14 |
Absolute structure | Flack (1983) |
Absolute structure parameter | −2.0 (19) |
Selected geometric parameters (Å, º) topO01—C08 | 1.311 (5) | C03—C04 | 1.546 (6) |
O01—H1 | 1.04 (6) | C04—C07 | 1.523 (6) |
O02—C08 | 1.202 (5) | C05—C06 | 1.513 (6) |
O03—C09 | 1.226 (5) | C06—C07 | 1.505 (6) |
O04—C13 | 1.334 (5) | C09—C10 | 1.529 (5) |
O04—C14 | 1.463 (4) | C10—C11 | 1.532 (5) |
O05—C13 | 1.194 (5) | C12—C13 | 1.513 (5) |
N01—C09 | 1.347 (4) | C12—C16 | 1.527 (5) |
N01—C01 | 1.466 (4) | C14—C15 | 1.485 (6) |
N01—C04 | 1.467 (5) | C16—C17 | 1.524 (4) |
N02—C10 | 1.472 (5) | C17—C18 | 1.506 (5) |
N02—C12 | 1.482 (5) | C18—C19 | 1.374 (6) |
N02—H2 | 0.77 (3) | C18—C23 | 1.381 (6) |
C01—C08 | 1.518 (5) | C19—C20 | 1.378 (6) |
C01—C02 | 1.534 (5) | C20—C21 | 1.365 (7) |
C02—C03 | 1.515 (6) | C21—C22 | 1.378 (7) |
C03—C05 | 1.537 (6) | C22—C23 | 1.371 (7) |
| | | |
C13—O04—C14 | 116.1 (4) | O03—C09—C10 | 119.9 (4) |
C09—N01—C01 | 126.3 (4) | N01—C09—C10 | 117.3 (4) |
C09—N01—C04 | 120.2 (4) | N02—C10—C09 | 113.1 (4) |
C01—N01—C04 | 113.4 (4) | N02—C10—C11 | 109.0 (3) |
C10—N02—C12 | 116.0 (3) | C09—C10—C11 | 107.6 (3) |
N01—C01—C08 | 111.5 (4) | N02—C12—C13 | 107.4 (4) |
N01—C01—C02 | 103.2 (3) | N02—C12—C16 | 117.1 (3) |
C08—C01—C02 | 113.5 (4) | C13—C12—C16 | 108.3 (3) |
C03—C02—C01 | 104.9 (4) | O05—C13—O04 | 125.2 (5) |
C02—C03—C05 | 117.6 (5) | O05—C13—C12 | 125.2 (5) |
C02—C03—C04 | 107.1 (4) | O04—C13—C12 | 109.6 (5) |
C05—C03—C04 | 102.8 (5) | O04—C14—C15 | 110.5 (4) |
N01—C04—C07 | 115.1 (4) | C18—C17—C16 | 112.3 (3) |
N01—C04—C03 | 103.5 (4) | C19—C18—C23 | 117.9 (5) |
C07—C04—C03 | 106.9 (4) | C19—C18—C17 | 121.5 (5) |
C06—C05—C03 | 105.0 (5) | C23—C18—C17 | 120.6 (6) |
C07—C06—C05 | 101.7 (5) | C18—C19—C20 | 121.5 (5) |
C06—C07—C04 | 105.9 (4) | C21—C20—C19 | 120.1 (6) |
O02—C08—O01 | 124.8 (4) | C20—C21—C22 | 119.0 (7) |
O02—C08—C01 | 124.0 (5) | C23—C22—C21 | 120.8 (6) |
O01—C08—C01 | 111.2 (4) | C22—C23—C18 | 120.6 (6) |
O03—C09—N01 | 122.6 (4) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O01—H1···N02i | 1.04 (6) | 1.58 (6) | 2.601 (5) | 168 (4) |
N02—H2···O03 | 0.78 (3) | 2.43 (3) | 2.829 (5) | 114 (3) |
C03—H03···O05ii | 0.98 | 2.45 | 3.388 (6) | 161 |
Symmetry codes: (i) x+1/2, −y+1/2, −z; (ii) −x+3/2, −y, z+1/2. |
Ramipril, (I), is an ACE inhibitor, which can dramatically improve cardiovascular outcomes (Hall et al., 1997; Yusuf et al., 2000). The active pharmaceutical ingredient is contained in numerous drugs with trade names such as Delix, Altace, Triace, Triatec, Delmuno, Unimax, Acovil and Vesdil. Crystals of ramipril adopt the morphology of long very thin needles and during drug development in the eighties, all attempts to determine the crystal structure remained unsuccessful. The absolute configuration (all S) was confirmed by structure determinations of derivatives (Paulus, Geiger et al., 1987; Paulus, Henning & Urbach, 1987), taking into account, that L-alanine was one of the educts. In 1987, the last attempt to determine the crystal structure failed, since the collected diffraction data of the largest crystal found (0.7 × 0.05 × 0.03 mm) was too weak. A new data collection on the same crystal applying a rotating anode operated at 50 kV and 120 mA still yielded a data set with reflections observed only up to about 1.0 Å, but the structure was solved with direct methods, immediately.
Ramipril crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit (Fig. 1). Since there are no atoms higher than oxygen present in the crystal structure, it was not possible to reconfirm the absolute configuration (Flack & Bernadinelli, 1999) and the absolute structure with ramipril in ab all-S configuration was chosen for refinement. All bond lengths and angles (Table 1) are in the usual range of values (Orpen et al., 1994). The first five-membered ring (N01, C01–C04) is twisted on C01—C02 and the second five-membered ring (C03–C07) is twisted on C5—C6. A Cremer & Pople puckering analysis (Cremer & Pople, 1975) yields Q = 0.275 Å and ϕ = 61.48°, and Q = 0.4407 Å and ϕ = 121.64°, respectively. Despite of the coexistence of a carboxylic acid group and an amino group, the neutral molecule and not the zwitter ionic tautomer is found in the crystal. The carboxylic acid group adopts the frequently observed synplanar (s-cis) conformation (Leiserowitz, 1976; Gandour, 1981). An intramolecular hydrogen bond between the amino hydrogen H2 and the amido oxygen O03 is formed with contact distances N02···O03 2.829 (5) Å and H2···O03 2.43 (3) Å and an angle N02—H2···O03 114 (3)°. Within the crystal structure, the molecules are connected to chains via strong –COOH···NH– hydrogen bonds between the caboxylic acid groups and the amino groups of adjacent molecules. The molecules within these chains are symmetry related by the 21 screw axis parallel to the crystallographic a axis. These hydrogen-bonded chains account for a preferred crystal growth in [10 0] direction and for the corresponding crystal morphology with the long needle axis coinciding with this direction. The intermolecular hydrogen bond exhibits distances O01···N02i 2.601 (5) Å and H1···N02i 1.58 (6) Å, and an angle O01—H1···N02 168 (4)° [symmetry code: (i) x + 1/2, 1/2 - y, -z]. In addition, a short intermolecular distance C03—H03···O05ii to the carbonyl oxygen of the ester group is found [C03···O5ii 3.388 (6) Å, H03···O05 2.45 Å and C03—H03···O5ii 161°; symmetry code: (ii) 3/2 - x, -y, z + 1/2 which might be discussed as a weak intermolecular C—H···O hydrogen bond (Desiraju, 1996; Desiraju & Steiner, 1998).
The experimentally determined powder diffraction pattern of the sample agrees with the one calculated from the crystal structure model, which proves that the determined crystal structure represents the crystalline phase of the sample.