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Acta Cryst. (2009). E65, o14    [ doi:10.1107/S160053680803986X ]

3-[(4-Amino-5-chloro-2-ethoxybenzamido)methyl]pyrrolo[2,1-c][1,4]oxazin-5-ium chloride monohydrate

T.-F. Tong, J. Zhao, L. Cheng and Y.-H. Zhang

Abstract top

The title compound, C17H25ClN3O3+·Cl-·H2O, is a monohydrated hydrochloride salt of a new derivative of mosapride, which is a pharmaceutical compound possessing gastrointestinal pro-kinetic activity. The chloride anion accepts hydrogen bonds from the NH group of the pyrrolooxazine fused-ring system and from the amine group, and the water molecules form hydrogen bonds that bridge between the chloride anion and the C=O bond of the amide.

Comment top

Mosapride citrate is a benzamide derivative that possesses a gastrointestinal prokinetic activity (Aoki et al. 2007). The title compound (Fig. 1) is a new mosapride derivative, and crystals of its hydrochloride salt were obtained by acidifying with hydrochloric acid then recrystallizing from methanol.

In the benzamide unit, the C=O bond distance of 1.229 (3) Å is much shorter than the C—O bond distances (1.359 (3)–1.432 (3) Å), showing it to have full double-bond character. Meanwhile, the C9—N2 distance of 1.330 (4) Å is comparable with that of C4—N1 (1.352 (4) Å), but much shorter than N2—C10 (1.441 (3) Å), N3—C13 (1.493 (4) Å), N3—C14 (1.489 (4) Å) and N3—C17 (1.492 (4) Å). Thus, the C4—N1 bond has partial double-bond character.

Related literature top

For related structures and background information concerning mosapride, see: Kakigami et al. (1998); Morie et al. (1995); Omae et al. (2002); Aoki et al. (2007).

Experimental top

A mixture of 4-amino-5-chloro-2-ethoxybenzoic acid (8.613 g, 40 mmol), (hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl)methanamine (4.8 g, 30.72 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (11.8 g, 61.8 mmol) in CH2Cl2 (60 ml) was stirred for two hours under an argon atmosphere. The products were treated with saturated NaHCO3 (200 ml) and extracted with CH2Cl2 (3 × 300 ml), then the organic layer was dried with anhydrous MgSO4 and distilled under vacuum. The white solids were collected and dried (yield 5.856 g, 54.0%). Crystals of the title compound were obtained by acidifying with hydrochloric acid then recrystallizing from methanol.

Refinement top

With the exception of the central amide group, H atoms bonded to N and O atoms were located in difference Fourier maps and refined without restraint. Other H atoms were positioned geometrically and refined using a riding model with N—H = 0.86 Å, C—H = 0.93–0.97 Å and with Uiso(H) = 1.2 times Ueq(C/N).

Computing details top

Data collection: SMART (Bruker, 2000); cell refinement: SAINT (Bruker, 2000); data reduction: SAINT (Bruker, 2000); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. Molecular structure of the title compound with 30% displacement ellipsoids for non-H atoms.
3-[(4-Amino-5-chloro-2-ethoxybenzamido)methyl]pyrrolo[2,1- c][1,4]oxazin-5-ium chloride monohydrate top
Crystal data top
C17H25ClN3O3+·Cl−·H2OF(000) = 864
Mr = 408.32Dx = 1.374 Mg m−3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 735 reflections
a = 8.0984 (9) Åθ = 2.5–28.0°
b = 11.1594 (13) ŵ = 0.36 mm−1
c = 21.843 (3) ÅT = 293 K
V = 1974.0 (4) Å3Block, colourless
Z = 40.24 × 0.20 × 0.16 mm
Data collection top
Bruker APEX CCD
diffractometer		3848 independent reflections
Radiation source: fine-focus sealed tube3188 reflections with I > 2σ(I)
graphiteRint = 0.037
φ and ω scansθmax = 26.0°, θmin = 2.6°
Absorption correction: multi-scan
(SADABS; Bruker, 2000)		h = −9→9
Tmin = 0.919, Tmax = 0.945k = −10→13
10642 measured reflectionsl = −26→25
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.050H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.096 w = 1/[σ2(Fo2) + (0.0412P)2]
where P = (Fo2 + 2Fc2)/3
S = 1.06(Δ/σ)max = 0.001
3848 reflectionsΔρmax = 0.32 e Å−3
261 parametersΔρmin = −0.22 e Å−3
0 restraintsAbsolute structure: Flack (1983), 1631 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: −0.02 (7)
Crystal data top
C17H25ClN3O3+·Cl−·H2OV = 1974.0 (4) Å3
Mr = 408.32Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 8.0984 (9) ŵ = 0.36 mm−1
b = 11.1594 (13) ÅT = 293 K
c = 21.843 (3) Å0.24 × 0.20 × 0.16 mm
Data collection top
Bruker APEX CCD
diffractometer		3848 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2000)		3188 reflections with I > 2σ(I)
Tmin = 0.919, Tmax = 0.945Rint = 0.037
10642 measured reflectionsθmax = 26.0°
Refinement top
R[F2 > 2σ(F2)] = 0.050H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.096Δρmax = 0.32 e Å−3
S = 1.06Δρmin = −0.22 e Å−3
3848 reflectionsAbsolute structure: Flack (1983), 1631 Friedel pairs
261 parametersFlack parameter: −0.02 (7)
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
xyzUiso*/Ueq
C10.6257 (3)0.7564 (2)0.77046 (11)0.0307 (6)
C20.4701 (4)0.8084 (3)0.76571 (13)0.0364 (7)
C30.3807 (3)0.8034 (3)0.71361 (13)0.0376 (7)
C40.4363 (4)0.7438 (2)0.66142 (12)0.0344 (6)
C50.5913 (4)0.6900 (3)0.66594 (13)0.0368 (7)
C60.6851 (3)0.6961 (2)0.71801 (12)0.0323 (6)
C70.9124 (4)0.5928 (3)0.66895 (12)0.0443 (8)
H7A0.92610.65110.63640.053*
H7B0.84290.52830.65410.053*
C81.0757 (4)0.5452 (3)0.68833 (13)0.0455 (8)
H8A1.05900.47800.71500.068*
H8B1.13710.52010.65300.068*
H8C1.13600.60650.70960.068*
C90.7127 (4)0.7704 (2)0.82975 (12)0.0309 (6)
C100.9629 (4)0.7321 (3)0.88920 (13)0.0452 (8)
H10A0.89210.74860.92400.054*
H10B1.04310.79640.88600.054*
C111.0507 (4)0.6148 (3)0.89873 (12)0.0374 (7)
H110.96900.55040.90210.045*
C121.2222 (4)0.4781 (3)0.84947 (14)0.0523 (10)
H12A1.28800.46460.81300.063*
H12B1.13480.41860.85020.063*
C131.3298 (4)0.4625 (3)0.90549 (13)0.0408 (8)
H131.35960.37770.90900.049*
C141.1561 (4)0.6167 (3)0.95570 (11)0.0345 (7)
H14A1.23810.67980.95270.041*
H14B1.08780.63230.99130.041*
C151.4860 (4)0.5363 (3)0.90920 (16)0.0545 (9)
H15A1.46930.61510.89160.065*
H15B1.57590.49690.88780.065*
C161.5225 (5)0.5453 (4)0.97717 (17)0.0689 (11)
H16A1.61820.49710.98760.083*
H16B1.54430.62780.98860.083*
C171.3705 (4)0.4991 (3)1.01002 (14)0.0511 (9)
H17A1.38910.41911.02590.061*
H17B1.34060.55161.04360.061*
Cl10.92851 (11)0.35057 (8)0.99188 (4)0.0554 (3)
Cl20.18901 (10)0.87543 (9)0.70977 (4)0.0614 (3)
N10.3486 (4)0.7381 (3)0.60884 (12)0.0482 (7)
H1A0.266 (5)0.780 (3)0.5990 (16)0.072*
H1B0.394 (4)0.717 (3)0.5755 (15)0.072*
N20.8652 (3)0.7270 (2)0.83413 (10)0.0438 (7)
H2A0.90790.69410.80230.053*
N31.2391 (3)0.4983 (2)0.96212 (11)0.0363 (6)
O10.8390 (2)0.64810 (19)0.72151 (8)0.0410 (5)
O20.6491 (3)0.8222 (2)0.87342 (8)0.0453 (6)
O31.1512 (3)0.59417 (19)0.84669 (9)0.0478 (6)
O1W0.3524 (4)0.8923 (3)0.92869 (14)0.0712 (8)
H20.426 (3)0.845 (2)0.8005 (12)0.038 (8)*
H50.627 (3)0.648 (3)0.6312 (12)0.043 (8)*
H3C1.161 (3)0.443 (2)0.9736 (11)0.031 (8)*
H1WA0.368 (4)0.954 (3)0.9456 (15)0.049 (12)*
H1WB0.444 (6)0.887 (4)0.9073 (18)0.103 (16)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0306 (16)0.0293 (15)0.0321 (14)−0.0011 (13)0.0022 (12)0.0019 (12)
C20.0337 (18)0.0426 (18)0.0329 (16)0.0061 (14)0.0033 (13)−0.0059 (14)
C30.0220 (15)0.0445 (18)0.0461 (17)0.0067 (13)−0.0004 (13)0.0014 (15)
C40.0289 (15)0.0347 (16)0.0395 (16)0.0000 (14)−0.0011 (14)0.0037 (13)
C50.0427 (19)0.0369 (17)0.0308 (15)−0.0003 (14)0.0093 (14)−0.0037 (13)
C60.0295 (16)0.0310 (16)0.0364 (15)0.0031 (13)0.0027 (13)0.0048 (13)
C70.046 (2)0.0475 (19)0.0396 (17)0.0091 (16)0.0043 (15)−0.0063 (15)
C80.0380 (19)0.0496 (19)0.0488 (18)0.0063 (17)0.0112 (16)−0.0018 (15)
C90.0303 (16)0.0275 (15)0.0350 (15)0.0027 (12)0.0025 (13)0.0008 (13)
C100.045 (2)0.0479 (19)0.0430 (18)0.0126 (16)−0.0087 (15)−0.0073 (15)
C110.0368 (16)0.0376 (17)0.0380 (15)0.0030 (15)−0.0034 (14)−0.0028 (14)
C120.052 (2)0.063 (2)0.0426 (18)0.0179 (19)−0.0069 (16)−0.0193 (17)
C130.0390 (19)0.0365 (17)0.0468 (17)0.0072 (15)−0.0058 (15)−0.0087 (14)
C140.0361 (16)0.0335 (16)0.0338 (14)0.0030 (14)−0.0013 (13)−0.0051 (13)
C150.038 (2)0.054 (2)0.071 (2)0.0050 (16)0.0032 (18)−0.0074 (19)
C160.043 (2)0.077 (3)0.087 (3)−0.0011 (19)−0.016 (2)−0.024 (2)
C170.059 (2)0.0451 (19)0.0486 (19)0.0065 (17)−0.0229 (17)−0.0012 (16)
Cl10.0476 (5)0.0593 (5)0.0594 (5)−0.0128 (4)−0.0147 (4)0.0070 (4)
Cl20.0388 (5)0.0819 (7)0.0635 (5)0.0261 (5)−0.0107 (4)−0.0162 (5)
N10.0410 (17)0.067 (2)0.0367 (15)0.0077 (15)−0.0072 (13)−0.0028 (14)
N20.0434 (16)0.0529 (16)0.0350 (13)0.0173 (13)−0.0074 (12)−0.0107 (12)
N30.0367 (15)0.0338 (14)0.0385 (14)−0.0018 (12)−0.0079 (11)0.0017 (12)
O10.0352 (12)0.0515 (13)0.0364 (10)0.0138 (10)0.0004 (9)−0.0086 (10)
O20.0358 (12)0.0588 (15)0.0415 (11)0.0069 (11)0.0012 (10)−0.0108 (11)
O30.0531 (14)0.0558 (14)0.0346 (10)0.0229 (12)−0.0035 (10)−0.0039 (10)
O1W0.0479 (18)0.088 (2)0.078 (2)0.0005 (17)0.0099 (15)−0.0155 (18)
Geometric parameters (Å, °) top
C1—C21.391 (4)C11—H110.980
C1—C61.413 (4)C12—O31.419 (4)
C1—C91.483 (4)C12—C131.512 (4)
C2—C31.350 (4)C12—H12A0.970
C2—H20.93 (3)C12—H12B0.970
C3—C41.394 (4)C13—N31.493 (4)
C3—Cl21.750 (3)C13—C151.511 (4)
C4—N11.352 (4)C13—H130.980
C4—C51.395 (4)C14—N31.489 (4)
C5—C61.369 (4)C14—H14A0.970
C5—H50.94 (3)C14—H14B0.970
C6—O11.359 (3)C15—C161.517 (4)
C7—O11.432 (3)C15—H15A0.970
C7—C81.486 (4)C15—H15B0.970
C7—H7A0.970C16—C171.515 (5)
C7—H7B0.970C16—H16A0.970
C8—H8A0.960C16—H16B0.970
C8—H8B0.960C17—N31.492 (4)
C8—H8C0.960C17—H17A0.970
C9—O21.229 (3)C17—H17B0.970
C9—N21.330 (4)N1—H1A0.84 (4)
C10—N21.441 (3)N1—H1B0.85 (3)
C10—C111.504 (4)N2—H2A0.860
C10—H10A0.970N3—H3C0.92 (3)
C10—H10B0.970O1W—H1WA0.79 (3)
C11—O31.417 (3)O1W—H1WB0.88 (4)
C11—C141.509 (4)
C2—C1—C6116.5 (3)O3—C12—H12B109.2
C2—C1—C9116.8 (2)C13—C12—H12B109.2
C6—C1—C9126.7 (2)H12A—C12—H12B107.9
C3—C2—C1122.1 (3)N3—C13—C15102.8 (2)
C3—C2—H2120.1 (17)N3—C13—C12110.9 (2)
C1—C2—H2117.8 (17)C15—C13—C12117.6 (3)
C2—C3—C4122.4 (3)N3—C13—H13108.4
C2—C3—Cl2119.8 (2)C15—C13—H13108.4
C4—C3—Cl2117.8 (2)C12—C13—H13108.4
N1—C4—C3123.2 (3)N3—C14—C11108.7 (2)
N1—C4—C5120.8 (3)N3—C14—H14A109.9
C3—C4—C5116.0 (3)C11—C14—H14A109.9
C6—C5—C4122.4 (3)N3—C14—H14B109.9
C6—C5—H5122.0 (18)C11—C14—H14B109.9
C4—C5—H5115.6 (18)H14A—C14—H14B108.3
O1—C6—C5122.4 (2)C13—C15—C16104.6 (3)
O1—C6—C1117.0 (2)C13—C15—H15A110.8
C5—C6—C1120.6 (3)C16—C15—H15A110.8
O1—C7—C8107.1 (2)C13—C15—H15B110.8
O1—C7—H7A110.3C16—C15—H15B110.8
C8—C7—H7A110.3H15A—C15—H15B108.9
O1—C7—H7B110.3C17—C16—C15106.4 (3)
C8—C7—H7B110.3C17—C16—H16A110.4
H7A—C7—H7B108.5C15—C16—H16A110.4
C7—C8—H8A109.1C17—C16—H16B110.4
C7—C8—H8B109.7C15—C16—H16B110.4
H8A—C8—H8B109.5H16A—C16—H16B108.6
C7—C8—H8C109.7N3—C17—C16104.4 (3)
H8A—C8—H8C109.5N3—C17—H17A110.9
H8B—C8—H8C109.5C16—C17—H17A110.9
O2—C9—N2120.3 (3)N3—C17—H17B110.9
O2—C9—C1121.9 (2)C16—C17—H17B110.9
N2—C9—C1117.7 (2)H17A—C17—H17B108.9
N2—C10—C11109.9 (2)C4—N1—H1A127 (3)
N2—C10—H10A109.7C4—N1—H1B121 (3)
C11—C10—H10A109.7H1A—N1—H1B106 (3)
N2—C10—H10B109.7C9—N2—C10123.8 (2)
C11—C10—H10B109.7C9—N2—H2A118.1
H10A—C10—H10B108.2C10—N2—H2A118.1
O3—C11—C10107.6 (2)C14—N3—C17112.5 (2)
O3—C11—C14109.8 (2)C14—N3—C13112.4 (2)
C10—C11—C14111.7 (2)C17—N3—C13103.4 (2)
O3—C11—H11109.2C14—N3—H3C108.4 (17)
C10—C11—H11109.2C17—N3—H3C107.6 (16)
C14—C11—H11109.2C13—N3—H3C112.4 (16)
O3—C12—C13111.9 (3)C6—O1—C7120.4 (2)
O3—C12—H12A109.2C11—O3—C12110.3 (2)
C13—C12—H12A109.2H1WA—O1W—H1WB100 (4)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl1i0.84 (4)2.66 (4)3.384 (3)146 (3)
N1—H1B···Cl1ii0.85 (3)2.45 (3)3.281 (3)169 (3)
N3—H3C···Cl10.92 (3)2.18 (3)3.077 (3)164 (2)
O1W—H1WA···Cl1iii0.79 (3)2.62 (3)3.410 (4)176 (3)
O1W—H1WB···O20.88 (4)1.95 (5)2.800 (4)161 (4)
Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x+3/2, −y+1, z−1/2; (iii) x−1/2, −y+3/2, −z+2.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N1—H1A···Cl1i0.84 (4)2.66 (4)3.384 (3)146 (3)
N1—H1B···Cl1ii0.85 (3)2.45 (3)3.281 (3)169 (3)
N3—H3C···Cl10.92 (3)2.18 (3)3.077 (3)164 (2)
O1W—H1WA···Cl1iii0.79 (3)2.62 (3)3.410 (4)176 (3)
O1W—H1WB···O20.88 (4)1.95 (5)2.800 (4)161 (4)
Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x+3/2, −y+1, z−1/2; (iii) x−1/2, −y+3/2, −z+2.
Acknowledgements top

The authors thank the Program for Young Excellent Talents in China Pharmaceutical University for financial support.

references
References top

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