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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

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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

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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 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

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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*

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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

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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

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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)

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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

Figure

Table 1. The dihedral angles C8—O2—C9—C14 and N2—

References

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