organic papers
Acta Cryst.(2006). E62, o2551–o2552 doi:10.1107/S1600536806019428 Umbreenet al. C
25H19N3O4
o2551
Acta Crystallographica Section E Structure Reports
Online
ISSN 1600-5368
(
S
)-4-[2-(3-Cyanobenzamido)-3-hydroxy-propyl]phenyl 3-cyanobenzoate
Sumaira Umbreen, Sabine Foro* and Boris Schmidt
Clemens-Scho¨pf-Institut fu¨r Organische Chemie und Biochemie, Technische Universita¨t Darm-stadt, Petersenstraße 22, D-64287 DarmDarm-stadt, Germany
Correspondence e-mail: foro@tu-darmstadt.de
Key indicators
Single-crystal X-ray study T= 299 K
Mean(C–C) = 0.005 A˚ Rfactor = 0.038 wRfactor = 0.079 Data-to-parameter ratio = 8.4
For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.
Received 17 May 2006 Accepted 24 May 2006
#2006 International Union of Crystallography All rights reserved
Non-planar molecules of the title compound, C25H19N4O3, are
linked by intermolecular N—H O, O—H N and C— H O hydrogen bonds to form a three-dimensional network.
Comment
The accumulation of -amyloid peptide (A) in the brain is thought to be a primary cause for the progression of Alzhei-mer’s disease (Selkoe, 2001). Since Ais generated from the cleavage of-amyloid precursor protein (APP) by proteolytic enzymes, - and -secretases (Sinha & Lieberburg, 1999), these two secretases represent potential therapeutic targets (Schmidtet al., 2005). The identification of-secretase (Vassar et al., 1999) prompted us to develop effective inhibitors against this enzyme. -Secretase belongs to an aspartyl protease family, similar to HIV protease. The majority of potent inhi-bitors of BACE are still peptide-based transition state analo-gues according to several reviews (Schmidt, 2003; Schmidt et al., 2005, 2006). Hydroxyethylenes, statines, norstatines, bis-statines, hydroxyethylamines and hydroxyethylureas were employed. The hydroxyethylenes delivered the first highly potent inhibitors. The compound (S )-4-[2-(3-cyano-benzoamido)-3-hydroxypropyl]phenyl 3-cyanobenzoate (I), is an important precurser for hydroxyethylene amides. In the reaction of 3-cyanobenzoic acid withl-tyrosinol, we obtained compound (I) as the major and unexpected product. X-ray studies of the title compound, (I), have been carried out to obtain detailed structural information and the results are presented here.
[image:1.610.205.462.534.655.2]The three intermolecular N—H O, O—H N and C— H O hydrogen bonds form a three-dimensional network. Details of the hydrogen-bonding geometry are given in Table 1. The dihedral angles C8—O2—C9—C14 and N2— C18—C19—C24 are 95.5 (3) and 34.2 (4), respectively
Experimental
Ethyl-3-(30-dimethylaminopropyl)carbodiimide hydrochloride
(979 mg, 5.11 mmol) andN-hydroxybenzotriazole hydrate (828 mg, 6.13 mmol) were added to a solution of 3-cyanobenzoic acid (751 mg, 5.11 mmol) dissolved in CH2Cl2(10 ml). The resulting mixture was
stirred at ambient temperature for 5 min, then treated withl
-tyro-sinol (1.02 ml, 6.13 mmol) and triethylamine (1.42 ml, 10.22 mmol) for 6 h. CH2Cl2(20 ml) was added, and the solution was washed with
HCl (0.1N, 530 ml), NaHCO3saturated solution (330 ml) and
brine (130 ml), dried over Na2SO4and concentrated to obtain the
title compound, (I), as colourless crystals (1.5 g, 69%). Single crystals of (I) suitable for X-ray data collection were obtained by slow evaporation of a methanol/dichloromethane (2:8) solution.
Crystal data
C25H19N3O4
Mr= 425.43
Monoclinic,C2 a= 32.665 (9) A˚ b= 4.778 (1) A˚ c= 15.015 (4) A˚
= 113.19 (2)
V= 2154.1 (9) A˚3
Z= 4
Dx= 1.312 Mg m
3
MoKradiation
= 0.09 mm1 T= 299 (2) K Nneedle, colourless 0.500.080.02 mm
Data collection
Oxford Diffraction Xcalibur diffractometer with Sapphire CCD detector
!and’scans
Absorption correction: analytical (CrysAlis RED; Oxford
Diffraction, 2004) Tmin= 0.974,Tmax= 0.998 7760 measured reflections 2438 independent reflections 1261 reflections withI> 2(I) Rint= 0.052
max= 26.4
Refinement
Refinement onF2 R[F2> 2(F2)] = 0.038
wR(F2) = 0.079 S= 0.88 2438 reflections 289 parameters
H-atom parameters constrained w= 1/[2(F
o2) + (0.0294P)2] whereP= (Fo2+ 2Fc2)/3 (/)max< 0.001
max= 0.15 e A˚3 min=0.14 e A˚
3
Table 1
Hydrogen-bond geometry (A˚ ,).
D—H A D—H H A D A D—H A
N2—H2N O4i
0.86 2.14 2.889 (4) 145
O3—H3O N1ii 0.82 2.19 3.007 (5) 173
C11—H11 O1iii
0.93 2.53 3.414 (4) 159
Symmetry codes: (i)x;y1;z; (ii)xþ1 2;y
1
2;z; (iii)xþ 1 2;yþ
1 2;zþ1.
H atoms were positioned with idealized geometry and were refined using a riding model, with C—H in the range 0.93–0.98 A˚ , O—H = 0.82 A˚ and N—H = 0.86 A˚.Uiso(H) values were set equal to 1.2Ueqof
the parent atom. In the absence of significant anamalous dispersion effects, Friedel pairs were merged and thef00term set to zero. The
absolute configuration was assigned according to the known absolute configuration of the eductl-tyrosinol.
Data collection: CrysAlis CCD (Oxford Diffraction, 2003); cell refinement: CrysAlis RED (Oxford Diffraction, 2004); data reduc-tion:CrysAlis RED; program(s) used to solve structure:SHELXS97
(Sheldrick, 1997); program(s) used to refine structure:SHELXL97
(Sheldrick, 1997); molecular graphics:PLATON(Spek, 2003); soft-ware used to prepare material for publication:SHELXL97.
The authors thank Professor Dr Hartmut Fuess, FG Strukturforschung, FB Material- und Geowissenschaften, Technische Universita¨t Darmstadt, Petersenstr. 23, 64287 Darmstadt, for diffractometer time.
References
Oxford Diffraction (2003).CrysAlis CCD. Oxford Diffraction Ltd., Ko¨ln, Germany.
Oxford Diffraction (2004).CrysAlis RED. Oxford Diffraction Ltd., Ko¨ln, Germany.
Schmidt, B. (2003).Chembiochem,4, 367–378.
Schmidt, B., Baumann, S., Braun, H. A. & Larbig, G. (2006).Curr. Top. Med. Chem.6, 377–392.
Schmidt, B., Braun, H. A. & Narlawar, R. (2005).Curr. Med. Chem.12, 1677– 1695.
Selkoe, D. J. (2001).Nat. Phys. Rev.81, 741–766.
Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Go¨ttingen, Germany.
Sinha, S. & Lieberburg, I. (1999).Proc. Natl Acad. Sci. USA,96, 11049–11053. Spek, A. L. (2003).J. Appl. Cryst.36, 7–13.
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J.et al.(1999).Science,286, 753–766.
Figure 1
supporting information
sup-1 Acta Cryst. (2006). E62, o2551–o2552
supporting information
Acta Cryst. (2006). E62, o2551–o2552 [https://doi.org/10.1107/S1600536806019428]
(
S
)-4-[2-(3-Cyanobenzamido)-3-hydroxypropyl]phenyl 3-cyanobenzoate
Sumaira Umbreen, Sabine Foro and Boris Schmidt
(S)-4-[2-(3-Cyanobenzamido)-3-hydroxypropyl]phenyl 3-cyanobenzoate
Crystal data C25H19N3O4
Mr = 425.43
Monoclinic, C2 Hall symbol: C 2y a = 32.665 (9) Å b = 4.778 (1) Å c = 15.015 (4) Å β = 113.19 (2)° V = 2154.1 (9) Å3
Z = 4
F(000) = 888 Dx = 1.312 Mg m−3
Mo Kα radiation, λ = 0.71073 Å Cell parameters from 681 reflections θ = 2.5–17.0°
µ = 0.09 mm−1
T = 299 K
Long needle, colourless 0.50 × 0.08 × 0.02 mm
Data collection
Oxford Diffraction Xcalibur
diffractometer with Sapphire CCD detector Radiation source: fine-focus sealed tube Graphite monochromator
Rotation method data acquisition using ω and φ scans
Absorption correction: analytical
(CrysAlis RED; Oxford Diffraction, 2004) Tmin = 0.974, Tmax = 0.998
7760 measured reflections 2438 independent reflections 1261 reflections with I > 2σ(I) Rint = 0.052
θmax = 26.4°, θmin = 4.2°
h = −40→40 k = −4→5 l = −18→18
Refinement Refinement on F2
Least-squares matrix: full R[F2 > 2σ(F2)] = 0.038
wR(F2) = 0.079
S = 0.88 2438 reflections 289 parameters 1 restraint
Primary atom site location: structure-invariant direct methods
Secondary atom site location: difference Fourier map
Hydrogen site location: inferred from neighbouring sites
H-atom parameters constrained w = 1/[σ2(F
o2) + (0.0294P)2]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max < 0.001
Δρmax = 0.15 e Å−3
Δρmin = −0.14 e Å−3
Special details
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)
x y z Uiso*/Ueq
O1 0.14379 (8) 0.3447 (7) 0.35007 (19) 0.0812 (9) O3 0.43176 (8) 0.1263 (6) 0.48333 (17) 0.0761 (8)
H3O 0.4404 0.0802 0.4411 0.091*
O4 0.34124 (8) 0.8483 (5) 0.25373 (16) 0.0581 (7) N1 −0.03983 (12) 0.5075 (12) 0.3194 (3) 0.1269 (19) O2 0.16193 (7) 0.6439 (5) 0.25713 (15) 0.0582 (7) N2 0.36583 (8) 0.4191 (6) 0.31506 (18) 0.0426 (7)
H2N 0.3705 0.2502 0.3017 0.051*
N3 0.40966 (14) −0.1541 (10) 0.0017 (3) 0.1072 (14) C1 −0.01539 (14) 0.5824 (12) 0.2880 (3) 0.0941 (17) C2 0.01557 (12) 0.6760 (11) 0.2481 (3) 0.0671 (12) C3 0.00342 (14) 0.8705 (11) 0.1752 (3) 0.0822 (13)
H3 −0.0253 0.9428 0.1506 0.099*
C4 0.03374 (15) 0.9589 (10) 0.1386 (3) 0.0833 (14)
H4 0.0256 1.0913 0.0892 0.100*
C5 0.07626 (13) 0.8506 (9) 0.1752 (3) 0.0651 (11)
H5 0.0969 0.9126 0.1511 0.078*
C6 0.08848 (11) 0.6506 (9) 0.2474 (2) 0.0516 (9) C7 0.05790 (12) 0.5635 (9) 0.2847 (2) 0.0623 (12)
H7 0.0659 0.4308 0.3340 0.075*
C8 0.13328 (12) 0.5251 (9) 0.2908 (3) 0.0527 (10) C9 0.20717 (11) 0.5657 (8) 0.3051 (2) 0.0489 (10) C10 0.23322 (12) 0.7125 (8) 0.3859 (2) 0.0537 (10)
H10 0.2211 0.8555 0.4099 0.064*
C11 0.27759 (12) 0.6449 (8) 0.4311 (2) 0.0492 (9)
H11 0.2957 0.7468 0.4851 0.059*
C12 0.29584 (11) 0.4273 (8) 0.3978 (2) 0.0436 (9) C13 0.26869 (12) 0.2875 (8) 0.3151 (2) 0.0546 (10)
H13 0.2805 0.1453 0.2902 0.065*
C14 0.22412 (12) 0.3562 (8) 0.2688 (2) 0.0543 (10)
H14 0.2060 0.2599 0.2135 0.065*
C15 0.34382 (10) 0.3459 (8) 0.4516 (2) 0.0509 (9)
H15A 0.3465 0.1452 0.4460 0.061*
H15B 0.3524 0.3888 0.5198 0.061*
C16 0.37631 (10) 0.4924 (7) 0.4158 (2) 0.0440 (9)
H16 0.3726 0.6950 0.4194 0.053*
C17 0.42446 (12) 0.4191 (8) 0.4790 (3) 0.0584 (10)
H17A 0.4441 0.5091 0.4532 0.070*
H17B 0.4317 0.4903 0.5440 0.070*
supporting information
sup-3 Acta Cryst. (2006). E62, o2551–o2552
C19 0.34024 (10) 0.4933 (7) 0.1429 (2) 0.0386 (9) C20 0.30544 (11) 0.6079 (8) 0.0655 (2) 0.0504 (9)
H20 0.2880 0.7466 0.0765 0.061*
C21 0.29606 (13) 0.5203 (9) −0.0277 (3) 0.0661 (12)
H21 0.2719 0.5944 −0.0791 0.079*
C22 0.32278 (14) 0.3223 (10) −0.0442 (3) 0.0672 (12)
H22 0.3170 0.2636 −0.1071 0.081*
C23 0.35812 (13) 0.2109 (8) 0.0323 (3) 0.0550 (10) C24 0.36655 (11) 0.2921 (7) 0.1258 (2) 0.0433 (9)
H24 0.3899 0.2116 0.1773 0.052*
C25 0.38668 (16) 0.0074 (10) 0.0147 (3) 0.0730 (13)
Atomic displacement parameters (Å2)
U11 U22 U33 U12 U13 U23
Geometric parameters (Å, º)
O1—C8 1.188 (4) C11—C12 1.387 (4)
O3—C17 1.416 (5) C11—H11 0.9300
O3—H3O 0.8200 C12—C13 1.381 (4)
O4—C18 1.237 (4) C12—C15 1.505 (4)
N1—C1 1.133 (5) C13—C14 1.383 (4)
O2—C8 1.351 (4) C13—H13 0.9300
O2—C9 1.415 (4) C14—H14 0.9300
N2—C18 1.326 (4) C15—C16 1.535 (4)
N2—C16 1.456 (3) C15—H15A 0.9700
N2—H2N 0.8600 C15—H15B 0.9700
N3—C25 1.146 (5) C16—C17 1.524 (4)
C1—C2 1.435 (6) C16—H16 0.9800
C2—C3 1.369 (6) C17—H17A 0.9700
C2—C7 1.380 (5) C17—H17B 0.9700
C3—C4 1.375 (5) C18—C19 1.502 (4)
C3—H3 0.9300 C19—C20 1.379 (4)
C4—C5 1.378 (5) C19—C24 1.379 (4)
C4—H4 0.9300 C20—C21 1.374 (4)
C5—C6 1.381 (5) C20—H20 0.9300
C5—H5 0.9300 C21—C22 1.375 (5)
C6—C7 1.388 (4) C21—H21 0.9300
C6—C8 1.475 (5) C22—C23 1.375 (5)
C7—H7 0.9300 C22—H22 0.9300
C9—C14 1.358 (4) C23—C24 1.376 (4)
C9—C10 1.370 (4) C23—C25 1.442 (6)
C10—C11 1.375 (4) C24—H24 0.9300
C10—H10 0.9300
C17—O3—H3O 109.5 C9—C14—H14 120.4
C8—O2—C9 115.9 (3) C13—C14—H14 120.4
C18—N2—C16 123.0 (3) C12—C15—C16 114.3 (3)
C18—N2—H2N 118.5 C12—C15—H15A 108.7
C16—N2—H2N 118.5 C16—C15—H15A 108.7
N1—C1—C2 179.7 (6) C12—C15—H15B 108.7 C3—C2—C7 120.8 (4) C16—C15—H15B 108.7 C3—C2—C1 121.0 (4) H15A—C15—H15B 107.6 C7—C2—C1 118.2 (4) N2—C16—C17 110.8 (3) C2—C3—C4 120.0 (4) N2—C16—C15 110.0 (3)
C2—C3—H3 120.0 C17—C16—C15 111.3 (3)
C4—C3—H3 120.0 N2—C16—H16 108.2
C3—C4—C5 119.8 (4) C17—C16—H16 108.2
C3—C4—H4 120.1 C15—C16—H16 108.2
C5—C4—H4 120.1 O3—C17—C16 111.7 (3)
C4—C5—C6 120.5 (4) O3—C17—H17A 109.3
C4—C5—H5 119.8 C16—C17—H17A 109.3
supporting information
sup-5 Acta Cryst. (2006). E62, o2551–o2552
C5—C6—C7 119.5 (3) C16—C17—H17B 109.3 C5—C6—C8 123.9 (4) H17A—C17—H17B 107.9 C7—C6—C8 116.5 (4) O4—C18—N2 123.9 (3) C2—C7—C6 119.3 (4) O4—C18—C19 119.3 (3)
C2—C7—H7 120.3 N2—C18—C19 116.8 (3)
C6—C7—H7 120.3 C20—C19—C24 119.2 (3)
O1—C8—O2 123.1 (3) C20—C19—C18 118.7 (3) O1—C8—C6 124.7 (4) C24—C19—C18 122.1 (3) O2—C8—C6 112.1 (4) C21—C20—C19 121.1 (3) C14—C9—C10 121.6 (3) C21—C20—H20 119.5 C14—C9—O2 120.0 (3) C19—C20—H20 119.5 C10—C9—O2 118.4 (3) C20—C21—C22 119.4 (4) C9—C10—C11 118.9 (3) C20—C21—H21 120.3
C9—C10—H10 120.5 C22—C21—H21 120.3
C11—C10—H10 120.5 C21—C22—C23 120.0 (4) C10—C11—C12 121.2 (3) C21—C22—H22 120.0
C10—C11—H11 119.4 C23—C22—H22 120.0
C12—C11—H11 119.4 C24—C23—C22 120.5 (4) C13—C12—C11 118.2 (3) C24—C23—C25 119.6 (4) C13—C12—C15 121.5 (3) C22—C23—C25 119.9 (4) C11—C12—C15 120.3 (3) C23—C24—C19 119.8 (3) C12—C13—C14 120.9 (3) C23—C24—H24 120.1
C12—C13—H13 119.6 C19—C24—H24 120.1
C14—C13—H13 119.6 N3—C25—C23 179.3 (6) C9—C14—C13 119.2 (3)
C9—C10—C11—C12 −1.7 (5) C22—C23—C24—C19 −2.1 (5) C10—C11—C12—C13 2.8 (5) C25—C23—C24—C19 177.9 (3) C10—C11—C12—C15 −176.4 (3) C20—C19—C24—C23 0.7 (4) C11—C12—C13—C14 −2.2 (5) C18—C19—C24—C23 −176.7 (3) C15—C12—C13—C14 177.0 (3) C24—C23—C25—N3 −7 (38) C10—C9—C14—C13 0.6 (5) C22—C23—C25—N3 173 (100)
Hydrogen-bond geometry (Å, º)
D—H···A D—H H···A D···A D—H···A
N2—H2N···O4i 0.86 2.14 2.889 (4) 145
O3—H3O···N1ii 0.82 2.19 3.007 (5) 173
C11—H11···O1iii 0.93 2.53 3.414 (4) 159