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Journal logoCRYSTALLOGRAPHIC
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ISSN: 2056-9890
Volume 72| Part 5| May 2016| Pages 687-691
doi:10.1107/S2056989016005843

Novel GluN2B selective NMDA receptor antagonists: relative configuration of 7-meth­­oxy-2-methyl-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ols

CROSSMARK_Color_square_no_text.svg
Bastian Tewes,a Bastian Frehland,a Roland Fröhlichb and Bernhard Wünscha,c*

aInstitut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstrasse 48, D-48149 Münster, Germany, bOrganisch-chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, D-48149-Münster, Germany, and cCells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Universität Münster, Germany
*Correspondence e-mail: wuensch@uni-muenster.de

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 4 March 2016; accepted 8 April 2016; online 15 April 2016)

The title compounds, C22H29NO2 (3) and C22H29NO2 (4) [systematic names: (1S*,2R*)-7-meth­oxy-2-methyl-3-(4-phenyl­but­yl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol and (1R*,2R*)-7-meth­oxy-2-methyl-3-(4-phenyl­but­yl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol, are diastereomers with the relative configuration of the adjacent hydroxyl and methyl groups at the seven-membered azepine ring being trans in (3) and cis in (4). In the crystals the orientation of these groups is −anti-periplanar (3) and +syn-clinal (4). In both cases, the crystals studied proved to be of a racemic mixture, with relative configurations (R*,S*)-3 and (R*,R*)-4. In both compounds, the seven-membered azepine ring has a chair-like conformation, and the 4-phenyl­butyl side chain adopts a extended conformation in (R*,S*)-3, but a twisted conformation in (R*,R*)-4. In the crystal of (S*,R*)-3, mol­ecules are linked via C—H⋯O hydrogen bonds, forming slabs parallel to the ac plane. In the crystal of (R*,R*)-4, mol­ecules are linked via O—H⋯N hydrogen bonds, forming chains propagating along the c-axis direction. The chains are linked by C—H⋯O hydrogen bonds, forming slabs parallel to the ac plane.

CCDC references: 1472946; 1472945

1. Chemical context

(S)-Glutamate is the most important excitatory neurotransmitter in the central nervous system. It inter­acts with different metabotropic and ionotropic glutamate receptors. The NMDA (N-methyl-D-aspartate) receptor is one of three ionotropic receptors, which control the influx of cations, in particular Na+ and Ca2+ ions, into neurons (Bräuner-Osborne et al., 2000[Bräuner-Osborne, H., Egebjerg, J., Nielsen, E. Ø., Madsen, U. & Krogsgaard-Larsen, P. (2000). J. Med. Chem. 43, 2609-2645.]; Kew & Kemp, 2005[Kew, J. N. C. & Kemp, J. A. (2005). Psychopharmacology, 179, 4-29.]). Physiological activation of the NMDA receptor is associated with processes like learning and memory. However, over-activation of the NMDA receptor is connected with damage of neuronal cells leading finally to neuronal cell death. Therefore, inhibition of the NMDA associated ion channel could be useful for the treatment of traumatic brain injury, cerebral ischemia, neuropathic pain, depression and neurodegenerative disorders like Alzheimer's and Parkinson's disease (Bräuner-Osborne et al., 2000[Bräuner-Osborne, H., Egebjerg, J., Nielsen, E. Ø., Madsen, U. & Krogsgaard-Larsen, P. (2000). J. Med. Chem. 43, 2609-2645.]; Kew & Kemp, 2005[Kew, J. N. C. & Kemp, J. A. (2005). Psychopharmacology, 179, 4-29.]; Paoletti et al., 2013[Paoletti, P., Bellone, C. & Zhou, Q. (2013). Nat. Rev. Neurosci. 14, 383-400.]; Wu & Zhou, 2009[Wu, L.-J. & Zhou, M. (2009). Neurotherapeutics, 6, 693-702.]).

The amino­alcohol ifenprodil inhibits selectively NMDA receptors containing GluN2B subunits (Williams, 2001[Williams, K. (2001). Curr. Drug Targets, 2, 285-298.]; Borza & Domány, 2006[Borza, I. & Domány, G. (2006). Curr. Top. Med. Chem. 6, 687-695.]; Layton et al., 2006[Layton, M. E., Kelly, M. J. III & Rodzinak, K. J. (2006). Curr. Top. Med. Chem. 6, 697-709.]; Karakas et al., 2011[Karakas, E., Simorowski, N. & Furukawa, H. (2011). Nature, 475, 249-253.]). In order to improve the affinity, selectivity and metabolic stabil­ity of ifenprodil, the β-amino­alcohol substructure of ifenprodil was incorporated into a ring system resulting in seven-membered 3-benzazepines with high GluN2B affinity, high selectivity over related receptors and high metabolic stability (Tewes et al., 2010a[Tewes, B., Frehland, B., Schepmann, D., Schmidtke, K.-U., Winckler, T. & Wünsch, B. (2010a). Chem. Med. Chem. 5, 687-695.],b[Tewes, B., Frehland, B., Schepmann, D., Schmidtke, K.-U., Winckler, T. & Wünsch, B. (2010b). Bioorg. Med. Chem. 18, 8005-8015.]; Schepmann et al., 2010[Schepmann, D., Frehland, B., Lehmkuhl, K., Tewes, B. & Wünsch, B. (2010). J. Pharm. Biomed. Anal. 53, 603-608.]; Falck et al., 2014[Falck, E., Begrow, F., Verspohl, E. & Wünsch, B. (2014). J. Pharm. Biomed. Anal. 88, 96-105.]).

2. Elucidation of the relative configuration

The 3-benzazepines (3) and (4) were prepared in a chiral pool synthesis starting with (R)-alanine. In a seven-step sequence the secondary amines (S,R)-1 and (R,R)-2 were obtained. In the last step, the secondary amines (S,R)-1 and (R,R)-2 were alkyl­ated with 1-chloro-4-phenyl­butane to afford the conformationally constrained ifenprodil analogues (3) and (4) which reveal high GluN2B affinity with Ki values of 47 nM and 41 nM, respectively (Tewes et al., 2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305]) (Fig. 1[link]).

[Scheme 1]
[Figure 1]
Figure 1
Reaction scheme. Reagents and reaction conditions: (a) 1-chloro-4-phenyl­butane, CH3CN, Bu4NI, K2CO3, Δ, 72 h.

As a result of the flexibility of the tetra­hydro-3-benzazepine system of (1)–(4), the relative configuration of the 3-benz­azepines (3) and (4) could not be determined unequivocally by inter­pretation of NMR spectra. However, crystallization of 70:30 mixtures of (S,R)-3 and (R,S)-3, as well as (R,R)-4 and (S,S)-4, led to colourless crystals which were suitable for X-ray crystal structure analysis. In both cases, the crystals proved to be of a racemic mixture, with the compounds having relative configurations (S*,R*)-3 and (R*,R*)-4.

3. Structural commentary

The mol­ecular structures of compounds (S*,R*)-3 and (R*,R*)-4 are depicted in Figs. 2[link] and 3[link], respectively. In the structure of (S*,R*)-3 (Fig. 2[link]), a trans-configuration with −anti-periplanar conformation and a torsion angle O12—C1—C2—C13 = −175.00 (12)°, of the OH group and the methyl group at the seven-membered azepine ring is shown. In (R*,R*)-4 (Fig. 3[link]) the same substituents are cis-configured, in +syn-clinal conformation with torsion angle O12—C1—C2—C13 = 73.2 (7)°.

[Figure 2]
Figure 2
The mol­ecular structure of compound (S*,R*)-3, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 3]
Figure 3
The mol­ecular structure of compound (R*,R*)-4, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.

In compound (S*,R*)-3 the 4-phenyl­butyl side chain adopts an extended conformation [torsion angle C16—C17—C18—C19 = 172.13 (14)°]. The CH3 and OH groups are on opposite sides of the azepine ring adopting an almost axial orientation. The bonds between atom N3 and its adjacent C atoms (C2, C16, C4) are shorter (ca. 1.47 Å) than the C—C bonds in the azepine ring (ca 1.52–1.54 Å). There is an intra­molecular O-H⋯N contact present (Table 1[link]) involving the O12 hydroxyl group and atom N3 of the 3-benzazepine ring, enclosing an S(5) ring motif.

Table 1
Hydrogen-bond geometry (Å, °) for (R*,S*)-3[link]

D—H⋯A D—H H⋯A D⋯A D—H⋯A
O12—H12⋯N3 0.83 2.17 2.6883 (17) 120
C15—H15B⋯O12i 0.97 2.59 3.295 (2) 130
C21—H21⋯O12ii 0.94 2.55 3.349 (2) 143
C22—H22⋯O14iii 0.94 2.59 3.373 (3) 141
Symmetry codes: (i) x-1, y, z; (ii) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]; (iii) x+1, y, z-1.

In compound (R*,R*)-4 the 4-phenyl­butyl side chain exists in a twisted conformation torsion angle C16—C17—C18—C19 = 76.1 (9)°]. The CH3 group is on the opposite side of the azepine ring adopting an almost axial orientation, as for (S*,R*)-3. However, here the OH group adopts a more equatorial orientation at the seven-membered azepine ring, in contrast to the OH group of (S*,R*)-3. The angles of the aliphatic part of the 3-benzazepine ring are close to the tetra­hedral angle value.

4. Supra­molecular features

In the crystal of (S*,R*)-3, mol­ecules are linked via C—H⋯O hydrogen bonds, forming slabs parallel to the ac plane (Table 1[link] and Fig. 4[link]). In the crystal of (R*,R*)-4, mol­ecules, are linked via O—H⋯N hydrogen bonds, forming chains propagating along the c-axis direction. The chains are linked by C—H⋯O hydrogen bonds, forming slabs parallel to the ac plane (Table 2[link] and Fig. 5[link]).

Table 2
Hydrogen-bond geometry (Å, °) for (R*,R*)-4[link]

D—H⋯A D—H H⋯A D⋯A D—H⋯A
O12—H12⋯N3i 0.83 1.97 2.796 (6) 172
C15—H15C⋯O14ii 0.97 2.58 3.365 (9) 138
Symmetry codes: (i) [-x+{\script{3\over 2}}, y, z+{\script{1\over 2}}]; (ii) [-x+{\script{1\over 2}}, y, z-{\script{1\over 2}}].
[Figure 4]
Figure 4
A view along the b axis of the crystal packing of compound (S*,R*)-3. The hydrogen bonds are shown as dashed lines (see Table 1[link]); for clarity, only the H atoms involved in these inter­actions are included.
[Figure 5]
Figure 5
A view along the b axis of the crystal packing of compound (R*,R*)-4. The hydrogen bonds are shown as dashed lines (see Table 2[link]; for clarity, only the H atoms involved in these inter­actions are included.

5. Synthesis and crystallization

(1S*,2R*)-7-Meth­oxy-2-methyl-3-(4-phenyl­but­yl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol: (S*,R*)-3

As described for the synthesis of (R,S)-3 (Tewes et al., 2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305]), the enanti­omer (S,R)-3 was prepared in the same manner by alkyl­ation of secondary amine (S,R)-1 [(S,R)-1:(R,S)-1 = 70:30] with 1-chloro-4-phenyl­butane. Purification by flash chromatography (2 cm, n-hexa­ne:ethyl acetate 95:5 and 1% N,N-di­methyl­ethanamine, 10 ml, Rf = 0.10) resulted in colourless crystals. The sample, contained the enanti­omers (S,R)-3 and (R,S)-3 in the ratio 70:30. Spectroscopic data are given in Tewes et al. (2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305]).

(1R*,2R*)-7-Meth­oxy-2-methyl-3-(4-phenyl­but­yl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol: (R*,R*)-4

As described for the synthesis of (S,S)-4 (Tewes et al., 2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305]), the enanti­omer (R,R)-4 was prepared in the same manner by alkyl­ation of secondary amine (R,R)-2 [(R,R)-1:(S,S)-1 = 70:30] with 1-chloro-4-phenyl­butane. Purification by flash chromatography (2 cm, n-hexa­ne:ethyl acetate 70: 30 and 1% N,N-di­methyl­ethanamine, 10 ml, Rf = 0.29) resulted in colourless crystals. The sample contained the enanti­omers (R,R)-4 and (S,S)-4 in the ratio 70:30. Spectroscopic data are given in Tewes et al. (2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305]).

In both cases, the compounds were used for recrystallization with ethyl acetate and the crystals obtained were used for the subsequent X-ray crystal structure analyses. The crystals thus obtained proved to be racemic mixtures, with the compounds having relative configurations (R*,S*)-3 and (R*,R*)-4.

6. Refinement details

Crystal data, data collection and structure refinement details are summarized in Table 3[link]. For both compounds the OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O—H = 0.83 Å, C—H = 0.94–0.99 Å with Uiso(H) = 1.5Ueq(O or C-meth­yl) and 1.2Ueq(C) for other H atoms.

Table 3
Experimental details

  (R*,S*)-3 (R*,R*)-4
Crystal data
Chemical formula C22H29NO2 C22H29NO2
Mr 339.46 339.46
Crystal system, space group Monoclinic, P21/n Orthorhombic, Pca21
Temperature (K) 223 223
a, b, c (Å) 10.3594 (2), 18.8246 (4), 10.9981 (3) 9.2049 (5), 25.4468 (17), 8.2451 (6)
α, β, γ (°) 90, 117.889 (1), 90 90, 90, 90
V (Å3) 1895.65 (8) 1931.3 (2)
Z 4 4
Radiation type Cu Kα Cu Kα
μ (mm−1) 0.59 0.58
Crystal size (mm) 0.40 × 0.25 × 0.10 0.35 × 0.05 × 0.03
 
Data collection
Diffractometer Nonius KappaCCD APEXII Nonius KappaCCD APEXII
Absorption correction Multi-scan (DENZO; Otwinowski et al., 2003[Otwinowski, Z., Borek, D., Majewski, W. & Minor, W. (2003). Acta Cryst. A59, 228-234.]) Multi-scan (DENZO; Otwinowski et al., 2003[Otwinowski, Z., Borek, D., Majewski, W. & Minor, W. (2003). Acta Cryst. A59, 228-234.])
Tmin, Tmax 0.799, 0.944 0.824, 0.983
No. of measured, independent and observed [I > 2σ(I)] reflections 8812, 3077, 2864 8312, 2885, 2164
Rint 0.034 0.082
(sin θ/λ)max (Å−1) 0.600 0.599
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.045, 0.118, 1.04 0.087, 0.231, 1.25
No. of reflections 3077 2885
No. of parameters 229 229
No. of restraints 0 1
H-atom treatment H-atom parameters constrained H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.16, −0.13 0.26, −0.25
Computer programs: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]), DENZO–SMN (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]), SHELXS97, SHELXL97 and XP in SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

Supporting information

CCDC references: 1472946; 1472945

Crystal structure: contains datablocks SR-3, RR-4, global. DOI: 10.1107/S2056989016005843/su5285sup1.cif

Structure factors: contains datablock S,R-3. DOI: 10.1107/S2056989016005843/su5285SR-3sup3.hkl

Structure factors: contains datablock R,R-4. DOI: 10.1107/S2056989016005843/su5285RR-4sup2.hkl

Supporting information file. DOI: 10.1107/S2056989016005843/su5285SR-3sup4.cml

Supporting information file. DOI: 10.1107/S2056989016005843/su5285RR-4sup5.cml

checkCIF report


Chemical context top

(S)-Glutamate is the most important excitatory neurotransmitter in the central nervous system. It inter­acts with different metabotropic and ionotropic glutamate receptors. The NMDA (N-methyl-D-aspartate) receptor is one of three ionotropic receptors, which control the influx of cations, in particular Na+ and Ca2+ ions, into neurons (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005). Physiological activation of the NMDA receptor is associated with processes like learning and memory. However, over-activation of the NMDA receptor is connected with damage of neuronal cells leading finally to neuronal cell death. Therefore, inhibition of the NMDA associated ion channel could be useful for the treatment of traumatic brain injury, cerebral ischemia, neuropathic pain, depression and neurodegenerative disorders like Alzheimer's and Parkinson's disease (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005; Paoletti et al., 2013; Wu & Zhou, 2009).

The amino­alcohol ifenprodil inhibits selectively NMDA receptors containing GluN2B subunits (Williams, 2001; Borza & Domány, 2006; Layton et al., 2006; Karakas et al., 2011). In order to improve the affinity, selectivity and metabolic stability of ifenprodil, the β-amino­alcohol substructure of ifenprodil was incorporated into a ring system resulting in seven-membered 3-benzazepines with high GluN2B affinity, high selectivity over related receptors and high metabolic stability (Tewes et al., 2010a,b; Schepmann et al., 2010; Falck et al., 2014).

Elucidation of the relative configuration top

The 3-benzazepines (3) and (4) were prepared in a chiral pool synthesis starting with (R)-alanine. In a seven-step sequence the secondary amines (S,R)-1 and (R,R)-2 were obtained. In the last step, the secondary amines (S,R)-1 and (R,R)-2 were alkyl­ated with 1-chloro-4-phenyl­butane to afford the conformationally constrained ifenprodil analogues (3) and (4) which reveal high GluN2b affinity with Ki values of 47 nM and 41 nM, respectively (Tewes et al., 2015) (Fig. 1).

As a result of the flexibility of the tetra­hydro-3-benzazepine system of (1)–(4), the relative configuration of the 3-benzazepines (3) and (4) could not be determined unequivocally by inter­pretation of NMR spectra. However, crystallization of 70:30 mixtures of (S,R)-3 and (R,S)-3, as well as (R,R)-4 and (S,S)-4, led to colourless crystals which were suitable for X-ray crystal structure analysis. In both cases, the crystals proved to be of a racemic mixture, with the compounds having relative configurations (S*,R*)-3 and (R*,R*)-4.

Structural commentary top

The molecular structures of compounds (S*,R*)-3 and (R*,R*)-4 are depicted in Figs. 2 and 3, respectively. In the structure of (S*,R*)-3 (Fig. 2), a trans-orientation, or -anti-periplanar with torsion angle O12—C1—C2—C13 = -175.00 (12)°, of the OH group and the methyl group at the seven-membered azepine ring is shown. In (R*,R*)-4 (Fig. 3) the same substituents are cis-configured, or +syn-clinal with torsion angle O12—C1—C2—C13 = 73.2 (7)°.

In compound (S*,R*)-3 the 4-phenyl­butyl side chain adopts an extended conformation [torsion angle C16—C17—C18—C19 = 172.13 (14)°]. The CH3 and OH groups are on opposite sides of the azepine ring adopting an almost axial orientation. The bonds between atom N3 and its adjacent C atoms (C2, C16, C4) are shorter (ca. 1.47 Å) than the C—C bonds in the azepine ring (ca 1.52–1.54 Å). There is an intra­molecular O—H···N contact present (Table 1) involving the O12 hydroxyl group and atom N3 of the 3-benzazepine ring, enclosing an S(5) ring motif.

In compound (R*,R*)-4 the 4-phenyl­butyl side chain exists in a twisted conformation torsion angle C16—C17—C18—C19 = 76.1 (9)°]. The CH3 group is on the opposite side of the azepine ring adopting an almost axial orientation, as for (S*,R*)-3. However, here the OH group adopts a more equatorial orientation at the seven-membered azepine ring, in contrast to the OH group of (S*,R*)-3. The angles of the aliphatic part of the 3-benzazepine ring are close to the tetra­hedral angle value.

Supra­molecular features top

In the crystal of (S*,R*)-3, molecules are linked via C—H···O hydrogen bonds, forming slabs parallel to the ac plane (Table 1 and Fig. 4). In the crystal of (R*,R*)-4, molecules, are linked via O—H···N hydrogen bonds, forming chains propagating along the c-axis direction. The chains are linked by C—H···O hydrogen bonds, forming slabs parallel to the ac plane (Table 2 and Fig. 5).

Synthesis and crystallization top

\ \ (1S*,2R*)-7-Meth­oxy-2-methyl-3-\ (4-\ phenyl­butyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol: (S*,R*)-3

As described for the synthesis of (R,S)-3 (Tewes et al., 2015), the enanti­omer (S,R)-3 was prepared in the same manner by alkyl­ation of secondary amine (S,R)-1 [(S,R)-1:(R,S)-1 = 70:30] with 1-chloro-4-phenyl­butane. Purification by flash chromatography (2 cm, n-hexane:ethyl acetate 95:5 and 1% N,N-di­methyl­ethanamine, 10 ml, Rf = 0.10) resulted in colourless crystals. The sample, contained the enanti­omers (S,R)-3 and (R,S)-3 in the ratio 70:30. Spectroscopic data are given in Tewes et al. (2015).

(1R*,2R*)-7-Meth­oxy-2-methyl-3-\ (4-phenyl­butyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol: (R*,R*)-4

As described for the synthesis of (S,S)-4 (Tewes et al., 2015), the enanti­omer (R,R)-4 was prepared in the same manner by alkyl­ation of secondary amine (R,R)-2 [(R,R)-1:(S,S)-1 = 70:30] with 1-chloro-4-phenyl­butane. Purification by flash chromatography (2 cm, n-hexane:ethyl acetate 70 : 30 and 1% N,N-di­methyl­ethanamine, 10 ml, Rf = 0.29) resulted in colourless crystals. The sample contained the enanti­omers (R,R)-4 and (S,S)-4 in the ratio 70:30. Spectroscopic data are given in Tewes et al. (2015).

In both cases, the compounds were used for recrystallization with ethyl acetate and the crystals obtained were used for the subsequent X-ray crystal structure analyses. The crystals thus obtained proved to be racemic mixtures, with the compounds having relative configurations (R*,S*)-3 and (R*,R*)-4.

Refinement details top

Crystal data, data collection and structure refinement details are summarized in Table 3. For both compounds the OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O—H = 0.83 Å, C—H = 0.94–0.99 Å with Uiso(H) = 1.5Ueq(O or C-methyl) and 1.2Ueq(C) for other H atoms.

Structure description top

(S)-Glutamate is the most important excitatory neurotransmitter in the central nervous system. It inter­acts with different metabotropic and ionotropic glutamate receptors. The NMDA (N-methyl-D-aspartate) receptor is one of three ionotropic receptors, which control the influx of cations, in particular Na+ and Ca2+ ions, into neurons (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005). Physiological activation of the NMDA receptor is associated with processes like learning and memory. However, over-activation of the NMDA receptor is connected with damage of neuronal cells leading finally to neuronal cell death. Therefore, inhibition of the NMDA associated ion channel could be useful for the treatment of traumatic brain injury, cerebral ischemia, neuropathic pain, depression and neurodegenerative disorders like Alzheimer's and Parkinson's disease (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005; Paoletti et al., 2013; Wu & Zhou, 2009).

The amino­alcohol ifenprodil inhibits selectively NMDA receptors containing GluN2B subunits (Williams, 2001; Borza & Domány, 2006; Layton et al., 2006; Karakas et al., 2011). In order to improve the affinity, selectivity and metabolic stability of ifenprodil, the β-amino­alcohol substructure of ifenprodil was incorporated into a ring system resulting in seven-membered 3-benzazepines with high GluN2B affinity, high selectivity over related receptors and high metabolic stability (Tewes et al., 2010a,b; Schepmann et al., 2010; Falck et al., 2014).

The 3-benzazepines (3) and (4) were prepared in a chiral pool synthesis starting with (R)-alanine. In a seven-step sequence the secondary amines (S,R)-1 and (R,R)-2 were obtained. In the last step, the secondary amines (S,R)-1 and (R,R)-2 were alkyl­ated with 1-chloro-4-phenyl­butane to afford the conformationally constrained ifenprodil analogues (3) and (4) which reveal high GluN2b affinity with Ki values of 47 nM and 41 nM, respectively (Tewes et al., 2015) (Fig. 1).

As a result of the flexibility of the tetra­hydro-3-benzazepine system of (1)–(4), the relative configuration of the 3-benzazepines (3) and (4) could not be determined unequivocally by inter­pretation of NMR spectra. However, crystallization of 70:30 mixtures of (S,R)-3 and (R,S)-3, as well as (R,R)-4 and (S,S)-4, led to colourless crystals which were suitable for X-ray crystal structure analysis. In both cases, the crystals proved to be of a racemic mixture, with the compounds having relative configurations (S*,R*)-3 and (R*,R*)-4.

The molecular structures of compounds (S*,R*)-3 and (R*,R*)-4 are depicted in Figs. 2 and 3, respectively. In the structure of (S*,R*)-3 (Fig. 2), a trans-orientation, or -anti-periplanar with torsion angle O12—C1—C2—C13 = -175.00 (12)°, of the OH group and the methyl group at the seven-membered azepine ring is shown. In (R*,R*)-4 (Fig. 3) the same substituents are cis-configured, or +syn-clinal with torsion angle O12—C1—C2—C13 = 73.2 (7)°.

In compound (S*,R*)-3 the 4-phenyl­butyl side chain adopts an extended conformation [torsion angle C16—C17—C18—C19 = 172.13 (14)°]. The CH3 and OH groups are on opposite sides of the azepine ring adopting an almost axial orientation. The bonds between atom N3 and its adjacent C atoms (C2, C16, C4) are shorter (ca. 1.47 Å) than the C—C bonds in the azepine ring (ca 1.52–1.54 Å). There is an intra­molecular O—H···N contact present (Table 1) involving the O12 hydroxyl group and atom N3 of the 3-benzazepine ring, enclosing an S(5) ring motif.

In compound (R*,R*)-4 the 4-phenyl­butyl side chain exists in a twisted conformation torsion angle C16—C17—C18—C19 = 76.1 (9)°]. The CH3 group is on the opposite side of the azepine ring adopting an almost axial orientation, as for (S*,R*)-3. However, here the OH group adopts a more equatorial orientation at the seven-membered azepine ring, in contrast to the OH group of (S*,R*)-3. The angles of the aliphatic part of the 3-benzazepine ring are close to the tetra­hedral angle value.

In the crystal of (S*,R*)-3, molecules are linked via C—H···O hydrogen bonds, forming slabs parallel to the ac plane (Table 1 and Fig. 4). In the crystal of (R*,R*)-4, molecules, are linked via O—H···N hydrogen bonds, forming chains propagating along the c-axis direction. The chains are linked by C—H···O hydrogen bonds, forming slabs parallel to the ac plane (Table 2 and Fig. 5).

Synthesis and crystallization top

\ \ (1S*,2R*)-7-Meth­oxy-2-methyl-3-\ (4-\ phenyl­butyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol: (S*,R*)-3

As described for the synthesis of (R,S)-3 (Tewes et al., 2015), the enanti­omer (S,R)-3 was prepared in the same manner by alkyl­ation of secondary amine (S,R)-1 [(S,R)-1:(R,S)-1 = 70:30] with 1-chloro-4-phenyl­butane. Purification by flash chromatography (2 cm, n-hexane:ethyl acetate 95:5 and 1% N,N-di­methyl­ethanamine, 10 ml, Rf = 0.10) resulted in colourless crystals. The sample, contained the enanti­omers (S,R)-3 and (R,S)-3 in the ratio 70:30. Spectroscopic data are given in Tewes et al. (2015).

(1R*,2R*)-7-Meth­oxy-2-methyl-3-\ (4-phenyl­butyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol: (R*,R*)-4

As described for the synthesis of (S,S)-4 (Tewes et al., 2015), the enanti­omer (R,R)-4 was prepared in the same manner by alkyl­ation of secondary amine (R,R)-2 [(R,R)-1:(S,S)-1 = 70:30] with 1-chloro-4-phenyl­butane. Purification by flash chromatography (2 cm, n-hexane:ethyl acetate 70 : 30 and 1% N,N-di­methyl­ethanamine, 10 ml, Rf = 0.29) resulted in colourless crystals. The sample contained the enanti­omers (R,R)-4 and (S,S)-4 in the ratio 70:30. Spectroscopic data are given in Tewes et al. (2015).

In both cases, the compounds were used for recrystallization with ethyl acetate and the crystals obtained were used for the subsequent X-ray crystal structure analyses. The crystals thus obtained proved to be racemic mixtures, with the compounds having relative configurations (R*,S*)-3 and (R*,R*)-4.

Refinement details top

Crystal data, data collection and structure refinement details are summarized in Table 3. For both compounds the OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O—H = 0.83 Å, C—H = 0.94–0.99 Å with Uiso(H) = 1.5Ueq(O or C-methyl) and 1.2Ueq(C) for other H atoms.

Computing details top

For both compounds, data collection: COLLECT (Nonius, 1998); cell refinement: COLLECT (Nonius, 1998); data reduction: DENZO–SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. Reaction scheme. Reagents and reaction conditions: (a) 1-chloro-4-phenylbutane, CH3CN, Bu4NI, K2CO3, Δ, 72 h.
[Figure 2] Fig. 2. The molecular structure of compound (S*,R*)-3, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 3] Fig. 3. The molecular structure of compound (R*,R*)-4, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 4] Fig. 4. A view along the b axis of the crystal packing of compound (S*,R*)-3. The hydrogen bonds are shown as dashed lines (see Table 1); for clarity, only the H atoms involved in these interactions are included.
[Figure 5] Fig. 5. A view along the b axis of the crystal packing of compound (R*,R*)-4. The hydrogen bonds are shown as dashed lines (see Table 2; for clarity, only the H atoms involved in these interactions are includedOoops···.).
(SR-3) (1S*,2R*)-7-Methoxy-2-methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol top
Crystal data top
C22H29NO2F(000) = 736
Mr = 339.46Dx = 1.189 Mg m−3
Monoclinic, P21/nCu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2ynCell parameters from 1877 reflections
a = 10.3594 (2) Åθ = 0.9–68.3°
b = 18.8246 (4) ŵ = 0.59 mm−1
c = 10.9981 (3) ÅT = 223 K
β = 117.889 (1)°Plate, colourless
V = 1895.65 (8) Å30.40 × 0.25 × 0.10 mm
Z = 4
Data collection top
Nonius KappaCCD APEXII
diffractometer		3077 independent reflections
Radiation source: fine-focus sealed tube2864 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.034
ω and \ scansθmax = 67.6°, θmin = 5.1°
Absorption correction: multi-scan
(DENZO; Otwinowski et al., 2003)		h = 0→12
Tmin = 0.799, Tmax = 0.944k = 0→21
8812 measured reflectionsl = −13→11
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.045Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.118H-atom parameters constrained
S = 1.04 w = 1/[σ2(Fo2) + (0.056P)2 + 0.5327P]
where P = (Fo2 + 2Fc2)/3
3077 reflections(Δ/σ)max < 0.001
229 parametersΔρmax = 0.16 e Å−3
0 restraintsΔρmin = −0.13 e Å−3
Crystal data top
C22H29NO2V = 1895.65 (8) Å3
Mr = 339.46Z = 4
Monoclinic, P21/nCu Kα radiation
a = 10.3594 (2) ŵ = 0.59 mm−1
b = 18.8246 (4) ÅT = 223 K
c = 10.9981 (3) Å0.40 × 0.25 × 0.10 mm
β = 117.889 (1)°
Data collection top
Nonius KappaCCD APEXII
diffractometer		3077 independent reflections
Absorption correction: multi-scan
(DENZO; Otwinowski et al., 2003)		2864 reflections with I > 2σ(I)
Tmin = 0.799, Tmax = 0.944Rint = 0.034
8812 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0450 restraints
wR(F2) = 0.118H-atom parameters constrained
S = 1.04Δρmax = 0.16 e Å−3
3077 reflectionsΔρmin = −0.13 e Å−3
229 parameters
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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
xyzUiso*/Ueq
C10.66460 (15)0.15839 (8)0.42463 (15)0.0438 (4)
H10.74770.14340.51280.053*
C20.64344 (16)0.10045 (8)0.31824 (16)0.0461 (4)
H20.74220.08940.33050.055*
N30.56166 (13)0.13021 (7)0.17856 (13)0.0450 (3)
C40.40433 (16)0.13908 (9)0.12903 (16)0.0489 (4)
H4A0.36430.09430.14220.059*
H4B0.35750.14890.03010.059*
C50.36506 (16)0.19818 (9)0.20015 (16)0.0470 (4)
H5A0.41880.24090.19960.056*
H5B0.26080.20860.14470.056*
C60.39431 (15)0.18510 (7)0.34623 (15)0.0417 (3)
C70.27908 (16)0.19112 (8)0.37801 (16)0.0448 (4)
H70.18500.20200.30780.054*
C80.30111 (17)0.18140 (8)0.51121 (17)0.0456 (4)
C90.43943 (18)0.16572 (9)0.61484 (17)0.0500 (4)
H90.45560.15950.70570.060*
C100.55380 (17)0.15931 (8)0.58400 (16)0.0475 (4)
H100.64740.14830.65490.057*
C110.53452 (15)0.16869 (7)0.45093 (15)0.0421 (3)
O120.70726 (11)0.22260 (6)0.38429 (11)0.0492 (3)
H120.67940.22180.30020.074*
C130.5846 (2)0.03100 (9)0.3454 (2)0.0621 (5)
H13A0.48910.03930.33890.093*
H13B0.65090.01380.43680.093*
H13C0.5763−0.00420.27770.093*
O140.19492 (12)0.18687 (7)0.55197 (13)0.0607 (3)
C150.04982 (18)0.20161 (11)0.4508 (2)0.0653 (5)
H15A0.04730.24670.40690.098*
H15B−0.01310.20410.49390.098*
H15C0.01590.16420.38220.098*
C160.59495 (18)0.09299 (9)0.07866 (17)0.0528 (4)
H16A0.51500.1010−0.01420.063*
H16B0.60040.04180.09700.063*
C170.73646 (17)0.11704 (9)0.08386 (17)0.0497 (4)
H17A0.81690.10680.17540.060*
H17B0.73290.16860.07030.060*
C180.76778 (17)0.08148 (9)−0.02367 (17)0.0492 (4)
H18A0.78550.0307−0.00250.059*
H18B0.68190.0861−0.11410.059*
C190.89835 (18)0.11362 (8)−0.02919 (18)0.0511 (4)
H19A0.98300.10830.06190.061*
H19B0.88040.1647−0.04640.061*
C200.93912 (16)0.08411 (8)−0.13445 (15)0.0439 (4)
C211.04410 (18)0.11928 (9)−0.15571 (17)0.0521 (4)
H211.08580.1611−0.10620.063*
C221.0888 (2)0.09450 (12)−0.24730 (19)0.0661 (5)
H221.16050.1193−0.25960.079*
C231.0292 (2)0.03362 (12)−0.32099 (19)0.0683 (5)
H231.06080.0162−0.38260.082*
C240.9229 (2)−0.00145 (10)−0.30370 (19)0.0638 (5)
H240.8802−0.0426−0.35540.077*
C250.87799 (18)0.02311 (8)−0.21089 (18)0.0533 (4)
H250.8056−0.0017−0.19960.064*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0332 (7)0.0498 (8)0.0415 (8)0.0023 (6)0.0116 (7)−0.0005 (6)
C20.0356 (7)0.0512 (8)0.0452 (9)0.0044 (6)0.0135 (7)−0.0032 (6)
N30.0365 (6)0.0552 (7)0.0404 (7)0.0007 (5)0.0155 (6)−0.0060 (5)
C40.0364 (8)0.0644 (10)0.0401 (8)0.0007 (6)0.0130 (7)−0.0025 (7)
C50.0350 (7)0.0598 (9)0.0402 (9)0.0078 (6)0.0127 (7)0.0047 (6)
C60.0362 (7)0.0444 (7)0.0416 (8)0.0008 (6)0.0157 (7)−0.0010 (6)
C70.0342 (7)0.0486 (8)0.0465 (9)0.0010 (6)0.0145 (7)0.0003 (6)
C80.0427 (8)0.0463 (8)0.0524 (9)−0.0032 (6)0.0259 (8)0.0006 (6)
C90.0482 (9)0.0588 (9)0.0422 (9)0.0015 (7)0.0205 (8)0.0050 (7)
C100.0393 (8)0.0554 (9)0.0404 (8)0.0039 (6)0.0125 (7)0.0047 (6)
C110.0362 (7)0.0444 (8)0.0413 (8)0.0005 (6)0.0145 (7)−0.0007 (6)
O120.0407 (6)0.0532 (6)0.0529 (7)−0.0060 (4)0.0212 (6)−0.0065 (5)
C130.0674 (11)0.0498 (9)0.0614 (11)0.0020 (8)0.0236 (10)0.0011 (8)
O140.0451 (6)0.0837 (8)0.0618 (8)0.0015 (5)0.0321 (6)0.0090 (6)
C150.0398 (9)0.0861 (13)0.0710 (13)−0.0001 (8)0.0267 (9)−0.0064 (9)
C160.0457 (9)0.0631 (10)0.0487 (9)−0.0033 (7)0.0213 (8)−0.0118 (7)
C170.0466 (9)0.0521 (9)0.0500 (9)0.0022 (6)0.0225 (8)−0.0040 (7)
C180.0442 (8)0.0551 (9)0.0473 (9)0.0006 (6)0.0206 (8)−0.0021 (7)
C190.0508 (9)0.0485 (8)0.0558 (10)−0.0009 (7)0.0264 (8)−0.0040 (7)
C200.0388 (8)0.0473 (8)0.0413 (8)0.0073 (6)0.0152 (7)0.0063 (6)
C210.0472 (9)0.0595 (9)0.0452 (9)−0.0030 (7)0.0179 (8)0.0050 (7)
C220.0559 (10)0.0947 (14)0.0531 (11)−0.0001 (9)0.0299 (9)0.0124 (10)
C230.0643 (11)0.0977 (15)0.0456 (10)0.0195 (10)0.0281 (9)0.0025 (9)
C240.0610 (11)0.0631 (11)0.0583 (11)0.0095 (8)0.0205 (9)−0.0109 (8)
C250.0485 (9)0.0517 (9)0.0611 (10)0.0016 (7)0.0267 (8)−0.0014 (7)
Geometric parameters (Å, º) top
C1—O121.4271 (18)C9—C101.382 (2)
C1—C111.517 (2)C10—C111.393 (2)
C1—C21.539 (2)O14—C151.418 (2)
C2—N31.474 (2)C16—C171.510 (2)
C2—C131.530 (2)C17—C181.520 (2)
N3—C41.4664 (19)C18—C191.509 (2)
N3—C161.4736 (19)C19—C201.511 (2)
C4—C51.521 (2)C20—C211.383 (2)
C5—C61.509 (2)C20—C251.389 (2)
C6—C71.397 (2)C21—C221.372 (3)
C6—C111.402 (2)C22—C231.372 (3)
C7—C81.385 (2)C23—C241.371 (3)
C8—O141.3721 (18)C24—C251.385 (2)
C8—C91.383 (2)
O12—C1—C11112.51 (12)C10—C9—C8119.56 (14)
O12—C1—C2108.58 (12)C9—C10—C11121.94 (14)
C11—C1—C2114.35 (12)C10—C11—C6118.37 (13)
N3—C2—C13116.16 (13)C10—C11—C1118.72 (13)
N3—C2—C1109.33 (12)C6—C11—C1122.88 (13)
C13—C2—C1112.66 (13)C8—O14—C15118.41 (13)
C4—N3—C16112.60 (12)N3—C16—C17113.02 (13)
C4—N3—C2115.30 (12)C16—C17—C18113.29 (13)
C16—N3—C2112.04 (12)C19—C18—C17112.11 (13)
N3—C4—C5114.23 (13)C18—C19—C20117.42 (14)
C6—C5—C4117.34 (13)C21—C20—C25117.73 (15)
C7—C6—C11119.38 (14)C21—C20—C19118.49 (14)
C7—C6—C5118.92 (13)C25—C20—C19123.78 (14)
C11—C6—C5121.68 (13)C22—C21—C20121.55 (17)
C8—C7—C6121.11 (14)C21—C22—C23120.28 (17)
O14—C8—C9115.27 (14)C24—C23—C22119.27 (17)
O14—C8—C7125.09 (14)C23—C24—C25120.67 (18)
C9—C8—C7119.63 (14)C24—C25—C20120.47 (16)
O12—C1—C2—N3−44.25 (15)C7—C6—C11—C1177.61 (13)
C11—C1—C2—N382.30 (15)C5—C6—C11—C1−3.9 (2)
O12—C1—C2—C13−175.00 (12)O12—C1—C11—C10−114.59 (15)
C11—C1—C2—C13−48.45 (18)C2—C1—C11—C10120.93 (15)
C13—C2—N3—C452.51 (18)O12—C1—C11—C667.47 (18)
C1—C2—N3—C4−76.33 (15)C2—C1—C11—C6−57.01 (19)
C13—C2—N3—C16−78.04 (16)C9—C8—O14—C15−178.90 (15)
C1—C2—N3—C16153.12 (12)C7—C8—O14—C151.9 (2)
C16—N3—C4—C5−158.97 (13)C4—N3—C16—C17147.99 (14)
C2—N3—C4—C570.75 (17)C2—N3—C16—C17−80.09 (17)
N3—C4—C5—C6−72.96 (18)N3—C16—C17—C18−177.17 (14)
C4—C5—C6—C7−123.71 (15)C16—C17—C18—C19172.13 (14)
C4—C5—C6—C1157.74 (19)C17—C18—C19—C20−178.61 (13)
C11—C6—C7—C80.2 (2)C18—C19—C20—C21170.56 (14)
C5—C6—C7—C8−178.36 (13)C18—C19—C20—C25−10.0 (2)
C6—C7—C8—O14179.40 (14)C25—C20—C21—C22−1.1 (2)
C6—C7—C8—C90.2 (2)C19—C20—C21—C22178.45 (15)
O14—C8—C9—C10−179.82 (14)C20—C21—C22—C230.2 (3)
C7—C8—C9—C10−0.6 (2)C21—C22—C23—C241.0 (3)
C8—C9—C10—C110.5 (2)C22—C23—C24—C25−1.4 (3)
C9—C10—C11—C60.0 (2)C23—C24—C25—C200.5 (3)
C9—C10—C11—C1−178.04 (14)C21—C20—C25—C240.7 (2)
C7—C6—C11—C10−0.3 (2)C19—C20—C25—C24−178.77 (16)
C5—C6—C11—C10178.20 (14)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O12—H12···N30.832.172.6883 (17)120
C15—H15B···O12i0.972.593.295 (2)130
C21—H21···O12ii0.942.553.349 (2)143
C22—H22···O14iii0.942.593.373 (3)141
Symmetry codes: (i) x−1, y, z; (ii) x+1/2, −y+1/2, z−1/2; (iii) x+1, y, z−1.
(RR-4) (1R*,2R*)-7-Methoxy-2-methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol top
Crystal data top
C22H29NO2F(000) = 736
Mr = 339.46Dx = 1.167 Mg m−3
Orthorhombic, Pca21Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2c -2acCell parameters from 2216 reflections
a = 9.2049 (5) Åθ = 0.9–70.1°
b = 25.4468 (17) ŵ = 0.57 mm−1
c = 8.2451 (6) ÅT = 223 K
V = 1931.3 (2) Å3Needle, colourless
Z = 40.35 × 0.05 × 0.03 mm
Data collection top
Nonius KappaCCD APEXII
diffractometer		2885 independent reflections
Radiation source: fine-focus sealed tube2164 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.082
ω and φ scansθmax = 67.5°, θmin = 3.5°
Absorption correction: multi-scan
(DENZO; Otwinowski et al., 2003)		h = −10→10
Tmin = 0.824, Tmax = 0.983k = −30→30
8312 measured reflectionsl = −9→9
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.087Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.231H-atom parameters constrained
S = 1.25 w = 1/[σ2(Fo2) + (0.0636P)2 + 2.9552P]
where P = (Fo2 + 2Fc2)/3
2885 reflections(Δ/σ)max < 0.001
229 parametersΔρmax = 0.26 e Å−3
1 restraintΔρmin = −0.24 e Å−3
Crystal data top
C22H29NO2V = 1931.3 (2) Å3
Mr = 339.46Z = 4
Orthorhombic, Pca21Cu Kα radiation
a = 9.2049 (5) ŵ = 0.57 mm−1
b = 25.4468 (17) ÅT = 223 K
c = 8.2451 (6) Å0.35 × 0.05 × 0.03 mm
Data collection top
Nonius KappaCCD APEXII
diffractometer		2885 independent reflections
Absorption correction: multi-scan
(DENZO; Otwinowski et al., 2003)		2164 reflections with I > 2σ(I)
Tmin = 0.824, Tmax = 0.983Rint = 0.082
8312 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0871 restraint
wR(F2) = 0.231H-atom parameters constrained
S = 1.25Δρmax = 0.26 e Å−3
2885 reflectionsΔρmin = −0.24 e Å−3
229 parameters
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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
xyzUiso*/Ueq
C10.6240 (7)0.2962 (3)−0.1209 (7)0.0427 (15)
H10.71540.3049−0.17800.051*
C20.5358 (6)0.2577 (3)−0.2273 (7)0.0415 (16)
H20.58460.2233−0.21570.050*
N30.5442 (5)0.2708 (2)−0.4043 (6)0.0447 (13)
C40.4711 (8)0.3205 (3)−0.4472 (7)0.0514 (18)
H4A0.37090.3191−0.40740.062*
H4B0.46700.3233−0.56560.062*
C50.5428 (8)0.3701 (3)−0.3805 (7)0.0524 (18)
H5A0.51330.4002−0.44720.063*
H5B0.64840.3665−0.38980.063*
C60.5040 (7)0.3814 (3)−0.2034 (7)0.0416 (16)
C70.4270 (7)0.4272 (3)−0.1680 (7)0.0471 (16)
H70.39900.4500−0.25200.057*
C80.3912 (8)0.4391 (3)−0.0060 (8)0.0554 (18)
C90.4298 (8)0.4036 (3)0.1137 (8)0.062 (2)
H90.40460.41050.22210.075*
C100.5042 (8)0.3586 (3)0.0767 (7)0.0537 (19)
H100.52860.33520.16050.064*
C110.5447 (6)0.3465 (3)−0.0823 (7)0.0427 (16)
O120.6590 (5)0.26820 (19)0.0243 (5)0.0512 (12)
H120.74850.26760.03650.077*
C130.3828 (7)0.2497 (3)−0.1623 (9)0.0564 (18)
H13A0.32540.2810−0.18230.085*
H13B0.38700.2430−0.04660.085*
H13C0.33830.2199−0.21650.085*
O140.3170 (6)0.4827 (2)0.0418 (6)0.0726 (16)
C150.2708 (10)0.5186 (3)−0.0778 (9)0.071 (2)
H15A0.35430.5312−0.13800.106*
H15B0.22210.5480−0.02640.106*
H15C0.20400.5012−0.15140.106*
C160.4847 (7)0.2273 (3)−0.5048 (9)0.0536 (18)
H16A0.49470.2372−0.61920.064*
H16B0.38060.2242−0.48190.064*
C170.5525 (7)0.1746 (3)−0.4821 (8)0.0526 (17)
H17A0.52220.1603−0.37710.063*
H17B0.65840.1785−0.48010.063*
C180.5110 (8)0.1357 (3)−0.6165 (8)0.0556 (18)
H18A0.53240.0998−0.58000.067*
H18B0.40630.1380−0.63690.067*
C190.5930 (12)0.1465 (4)−0.7735 (10)0.090 (3)
H19A0.56820.1819−0.81140.108*
H19B0.69750.1459−0.75100.108*
C200.5606 (9)0.1078 (3)−0.9069 (9)0.062 (2)
C210.6546 (10)0.0668 (4)−0.9347 (10)0.077 (2)
H210.73800.0627−0.87020.092*
C220.6251 (13)0.0308 (4)−1.0606 (13)0.090 (3)
H220.68930.0027−1.07910.108*
C230.5073 (14)0.0361 (4)−1.1541 (12)0.094 (3)
H230.48970.0119−1.23790.112*
C240.4124 (12)0.0765 (4)−1.1288 (12)0.092 (3)
H240.33010.0805−1.19520.110*
C250.4391 (10)0.1116 (4)−1.0039 (12)0.080 (3)
H250.37220.1388−0.98470.095*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.042 (3)0.055 (4)0.030 (3)0.004 (3)−0.002 (3)0.008 (3)
C20.033 (3)0.061 (4)0.030 (3)−0.007 (3)0.001 (3)0.007 (3)
N30.050 (3)0.060 (4)0.023 (2)0.004 (3)0.004 (2)0.003 (2)
C40.061 (5)0.063 (5)0.030 (3)0.007 (4)−0.007 (3)−0.001 (3)
C50.073 (5)0.063 (5)0.022 (3)0.005 (4)0.009 (3)0.004 (3)
C60.047 (4)0.051 (4)0.027 (3)−0.003 (3)0.001 (3)0.000 (3)
C70.057 (4)0.060 (4)0.025 (3)0.001 (3)0.000 (3)0.001 (3)
C80.059 (4)0.067 (5)0.039 (4)0.010 (4)0.001 (3)0.001 (4)
C90.073 (5)0.080 (6)0.033 (4)0.014 (4)0.001 (4)0.000 (4)
C100.059 (4)0.074 (5)0.028 (4)0.014 (4)0.002 (3)0.004 (3)
C110.043 (3)0.061 (5)0.024 (3)−0.004 (3)0.005 (3)0.004 (3)
O120.050 (2)0.072 (3)0.032 (2)0.007 (2)−0.0035 (19)0.013 (2)
C130.044 (4)0.079 (5)0.046 (4)−0.005 (4)0.004 (3)0.001 (4)
O140.096 (4)0.078 (4)0.044 (3)0.030 (3)0.002 (3)−0.007 (3)
C150.090 (6)0.063 (5)0.059 (5)0.020 (5)−0.014 (4)−0.009 (4)
C160.049 (4)0.069 (5)0.043 (4)0.004 (4)−0.005 (3)−0.012 (4)
C170.051 (4)0.061 (5)0.046 (4)0.002 (3)0.000 (3)−0.002 (4)
C180.065 (4)0.058 (5)0.044 (4)−0.011 (4)0.003 (3)0.003 (3)
C190.126 (9)0.088 (7)0.055 (5)−0.024 (6)0.027 (5)−0.016 (5)
C200.082 (6)0.063 (5)0.040 (4)−0.012 (4)0.006 (4)0.000 (4)
C210.073 (5)0.096 (7)0.062 (5)0.001 (5)0.006 (4)0.004 (5)
C220.111 (8)0.065 (6)0.095 (7)0.006 (6)0.033 (6)−0.016 (5)
C230.125 (9)0.091 (7)0.065 (6)−0.030 (7)0.012 (6)−0.024 (6)
C240.097 (7)0.114 (9)0.065 (6)−0.021 (7)−0.017 (5)0.002 (6)
C250.083 (6)0.075 (6)0.080 (6)0.012 (5)0.008 (5)0.006 (5)
Geometric parameters (Å, º) top
C1—O121.429 (7)C13—H13C0.9700
C1—C111.509 (9)O14—C151.410 (9)
C1—C21.545 (9)C15—H15A0.9700
C1—H10.9900C15—H15B0.9700
C2—N31.498 (7)C15—H15C0.9700
C2—C131.521 (9)C16—C171.492 (9)
C2—H20.9900C16—H16A0.9800
N3—C41.477 (8)C16—H16B0.9800
N3—C161.486 (8)C17—C181.535 (10)
C4—C51.525 (9)C17—H17A0.9800
C4—H4A0.9800C17—H17B0.9800
C4—H4B0.9800C18—C191.524 (10)
C5—C61.531 (8)C18—H18A0.9800
C5—H5A0.9800C18—H18B0.9800
C5—H5B0.9800C19—C201.507 (11)
C6—C111.387 (9)C19—H19A0.9800
C6—C71.395 (9)C19—H19B0.9800
C7—C81.408 (9)C20—C211.374 (11)
C7—H70.9400C20—C251.378 (11)
C8—O141.361 (8)C21—C221.410 (13)
C8—C91.384 (9)C21—H210.9400
C9—C101.369 (9)C22—C231.338 (14)
C9—H90.9400C22—H220.9400
C10—C111.397 (8)C23—C241.365 (14)
C10—H100.9400C23—H230.9400
O12—H120.8300C24—C251.383 (13)
C13—H13A0.9700C24—H240.9400
C13—H13B0.9700C25—H250.9400
O12—C1—C11110.8 (5)H13B—C13—H13C109.5
O12—C1—C2106.2 (5)C8—O14—C15118.5 (6)
C11—C1—C2113.8 (5)O14—C15—H15A109.5
O12—C1—H1108.6O14—C15—H15B109.5
C11—C1—H1108.6H15A—C15—H15B109.5
C2—C1—H1108.6O14—C15—H15C109.5
N3—C2—C13114.9 (5)H15A—C15—H15C109.5
N3—C2—C1112.7 (5)H15B—C15—H15C109.5
C13—C2—C1111.8 (5)N3—C16—C17116.4 (5)
N3—C2—H2105.5N3—C16—H16A108.2
C13—C2—H2105.5C17—C16—H16A108.2
C1—C2—H2105.5N3—C16—H16B108.2
C4—N3—C16109.7 (5)C17—C16—H16B108.2
C4—N3—C2113.6 (5)H16A—C16—H16B107.3
C16—N3—C2111.1 (5)C16—C17—C18112.7 (6)
N3—C4—C5115.2 (5)C16—C17—H17A109.0
N3—C4—H4A108.5C18—C17—H17A109.0
C5—C4—H4A108.5C16—C17—H17B109.0
N3—C4—H4B108.5C18—C17—H17B109.0
C5—C4—H4B108.5H17A—C17—H17B107.8
H4A—C4—H4B107.5C19—C18—C17111.9 (6)
C4—C5—C6113.5 (5)C19—C18—H18A109.2
C4—C5—H5A108.9C17—C18—H18A109.2
C6—C5—H5A108.9C19—C18—H18B109.2
C4—C5—H5B108.9C17—C18—H18B109.2
C6—C5—H5B108.9H18A—C18—H18B107.9
H5A—C5—H5B107.7C20—C19—C18113.8 (7)
C11—C6—C7121.4 (5)C20—C19—H19A108.8
C11—C6—C5120.2 (6)C18—C19—H19A108.8
C7—C6—C5118.4 (5)C20—C19—H19B108.8
C6—C7—C8119.8 (6)C18—C19—H19B108.8
C6—C7—H7120.1H19A—C19—H19B107.7
C8—C7—H7120.1C21—C20—C25117.9 (8)
O14—C8—C9117.0 (6)C21—C20—C19119.6 (9)
O14—C8—C7124.5 (6)C25—C20—C19122.6 (8)
C9—C8—C7118.4 (7)C20—C21—C22119.6 (9)
C10—C9—C8121.0 (6)C20—C21—H21120.2
C10—C9—H9119.5C22—C21—H21120.2
C8—C9—H9119.5C23—C22—C21121.0 (9)
C9—C10—C11121.8 (6)C23—C22—H22119.5
C9—C10—H10119.1C21—C22—H22119.5
C11—C10—H10119.1C22—C23—C24120.4 (9)
C6—C11—C10117.5 (6)C22—C23—H23119.8
C6—C11—C1121.5 (5)C24—C23—H23119.8
C10—C11—C1120.9 (6)C23—C24—C25119.1 (10)
C1—O12—H12109.5C23—C24—H24120.5
C2—C13—H13A109.5C25—C24—H24120.5
C2—C13—H13B109.5C20—C25—C24122.0 (9)
H13A—C13—H13B109.5C20—C25—H25119.0
C2—C13—H13C109.5C24—C25—H25119.0
H13A—C13—H13C109.5
O12—C1—C2—N3−155.6 (5)C9—C10—C11—C6−1.4 (10)
C11—C1—C2—N382.3 (6)C9—C10—C11—C1−178.8 (7)
O12—C1—C2—C1373.2 (7)O12—C1—C11—C6177.6 (6)
C11—C1—C2—C13−49.0 (7)C2—C1—C11—C6−62.8 (7)
C13—C2—N3—C462.0 (7)O12—C1—C11—C10−5.1 (8)
C1—C2—N3—C4−67.7 (7)C2—C1—C11—C10114.5 (7)
C13—C2—N3—C16−62.1 (7)C9—C8—O14—C15−177.4 (7)
C1—C2—N3—C16168.2 (5)C7—C8—O14—C150.6 (11)
C16—N3—C4—C5−167.4 (5)C4—N3—C16—C17177.1 (6)
C2—N3—C4—C567.6 (7)C2—N3—C16—C17−56.6 (7)
N3—C4—C5—C6−80.9 (7)N3—C16—C17—C18−166.4 (6)
C4—C5—C6—C1163.5 (8)C16—C17—C18—C1976.1 (9)
C4—C5—C6—C7−116.2 (7)C17—C18—C19—C20177.5 (7)
C11—C6—C7—C81.0 (10)C18—C19—C20—C21−98.4 (10)
C5—C6—C7—C8−179.2 (6)C18—C19—C20—C2581.5 (11)
C6—C7—C8—O14179.8 (7)C25—C20—C21—C220.7 (12)
C6—C7—C8—C9−2.2 (10)C19—C20—C21—C22−179.3 (8)
O14—C8—C9—C10179.8 (7)C20—C21—C22—C230.3 (14)
C7—C8—C9—C101.6 (11)C21—C22—C23—C24−0.3 (16)
C8—C9—C10—C110.2 (12)C22—C23—C24—C25−0.7 (16)
C7—C6—C11—C100.7 (9)C21—C20—C25—C24−1.7 (13)
C5—C6—C11—C10−179.0 (6)C19—C20—C25—C24178.3 (8)
C7—C6—C11—C1178.1 (6)C23—C24—C25—C201.8 (15)
C5—C6—C11—C1−1.7 (9)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O12—H12···N3i0.831.972.796 (6)172
C15—H15C···O14ii0.972.583.365 (9)138
Symmetry codes: (i) −x+3/2, y, z+1/2; (ii) −x+1/2, y, z−1/2.
Hydrogen-bond geometry (Å, º) for (SR-3) top
D—H···AD—HH···AD···AD—H···A
O12—H12···N30.832.172.6883 (17)120
C15—H15B···O12i0.972.593.295 (2)130
C21—H21···O12ii0.942.553.349 (2)143
C22—H22···O14iii0.942.593.373 (3)141
Symmetry codes: (i) x−1, y, z; (ii) x+1/2, −y+1/2, z−1/2; (iii) x+1, y, z−1.
Hydrogen-bond geometry (Å, º) for (RR-4) top
D—H···AD—HH···AD···AD—H···A
O12—H12···N3i0.831.972.796 (6)172
C15—H15C···O14ii0.972.583.365 (9)138
Symmetry codes: (i) −x+3/2, y, z+1/2; (ii) −x+1/2, y, z−1/2.

Experimental details

(SR-3)(RR-4)
Crystal data
Chemical formulaC22H29NO2C22H29NO2
Mr339.46339.46
Crystal system, space groupMonoclinic, P21/nOrthorhombic, Pca21
Temperature (K)223223
a, b, c (Å)10.3594 (2), 18.8246 (4), 10.9981 (3)9.2049 (5), 25.4468 (17), 8.2451 (6)
α, β, γ (°)90, 117.889 (1), 9090, 90, 90
V (Å3)1895.65 (8)1931.3 (2)
Z44
Radiation typeCu KαCu Kα
µ (mm−1)0.590.57
Crystal size (mm)0.40 × 0.25 × 0.100.35 × 0.05 × 0.03
Data collection
DiffractometerNonius KappaCCD APEXIINonius KappaCCD APEXII
Absorption correctionMulti-scan
(DENZO; Otwinowski et al., 2003)		Multi-scan
(DENZO; Otwinowski et al., 2003)
Tmin, Tmax0.799, 0.9440.824, 0.983
No. of measured, independent and
observed [I > 2σ(I)] reflections		8812, 3077, 2864 8312, 2885, 2164
Rint0.0340.082
(sin θ/λ)max (Å−1)0.6000.599
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.045, 0.118, 1.04 0.087, 0.231, 1.25
No. of reflections30772885
No. of parameters229229
No. of restraints01
H-atom treatmentH-atom parameters constrainedH-atom parameters constrained
Δρmax, Δρmin (e Å−3)0.16, −0.130.26, −0.24

Computer programs: COLLECT (Nonius, 1998), DENZO–SMN (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

 

Acknowledgements

Financial support by the Deutsche Forschungsgemeinschaft is gratefully acknowledged.

References

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ISSN: 2056-9890
Volume 72| Part 5| May 2016| Pages 687-691
doi:10.1107/S2056989016005843
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