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Acta Crystallogr Sect E Struct Rep Online. 2008 December 1; 64(Pt 12): o2294.
Published online 2008 November 8. doi:  10.1107/S1600536808036106
PMCID: PMC2960090

tert-Butyl 4-carbamoyl-3-methoxy­imino-4-methyl­piperidine-1-carboxyl­ate

Abstract

The title compound, C13H23N3O4, was prepared starting from ethyl N-benzyl-3-oxopiperidine-4-carboxyl­ate through a nine-step reaction, including hydrogenation, Boc (tert-butoxy­carbon­yl) protection, methyl­ation, oximation, hydrolysis, esterification and ammonolysis. In the crystal structure, mol­ecules are linked by inter­molecular N—H(...)O hydrogen bonds to form a porous three-dimensional network with solvent-free hydro­phobic channels extending along the c axis.

Related literature

For the synthesis and properties of quinolone derivatives, see: Ray et al. (2005 [triangle]); Ball et al. (1998 [triangle]); Bryskier (1997 [triangle]); De Sarro & De Sarro (2001 [triangle]); Anderson & Osheroff (2001 [triangle]); Dang et al. (2007 [triangle]); Wang et al. (2008 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-o2294-scheme1.jpg

Experimental

Crystal data

  • C13H23N3O4
  • M r = 285.34
  • Tetragonal, An external file that holds a picture, illustration, etc.
Object name is e-64-o2294-efi1.jpg
  • a = 22.813 (2) Å
  • c = 12.0742 (16) Å
  • V = 6283.8 (11) Å3
  • Z = 16
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 293 (2) K
  • 0.48 × 0.46 × 0.45 mm

Data collection

  • Bruker SMART APEX CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 1996 [triangle]) T min = 0.957, T max = 0.963
  • 16003 measured reflections
  • 2763 independent reflections
  • 1794 reflections with I > 2σ(I)
  • R int = 0.049

Refinement

  • R[F 2 > 2σ(F 2)] = 0.039
  • wR(F 2) = 0.113
  • S = 1.01
  • 2763 reflections
  • 181 parameters
  • H-atom parameters constrained
  • Δρmax = 0.19 e Å−3
  • Δρmin = −0.12 e Å−3

Data collection: SMART (Bruker, 1998 [triangle]); cell refinement: SAINT (Bruker, 1999 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808036106/rz2260sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808036106/rz2260Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

We are grateful to the National Research Center of Drug and Metabolite Analysis and the Pharmacology Laboratory of the Institute of Medicinal Biotechnology for support.

supplementary crystallographic information

Comment

Quinolones, a class of synthetic antibacterial compounds based on a 4-quinolone skeleton, have been the landmark discovery in the treatment of bacterial infections in both community and hospital setting (Ray et al., 2005; Ball et al., 1998; Bryskier, 1997). The most intensive structural variations have been carried out on the basic group at the C-7 position, partially due to the ease of their introduction through a nucleophilic aromatic substitution reaction on the corresponding halide. Piperazine, aminopyrolidine and their derivatives have been the most successfully employed side chains, as evidenced by the compounds currently on the market (De Sarro & De Sarro, 2001; Anderson & Osheroff, 2001; Dang et al., 2007). Recently, as part of an ongoing study aimed to find potent and broad-spectrum antibacterial agents displaying strong Gram-positive activity, we have focused our attention on the synthesis of C-7 substituted quinolones (Wang et al., 2008). We report here the crystal structure of the title compound, which is a key intermediate of 3-methoxyimino-4-amino-4-methylpiperidine.

In the molecule of the title compound (Fig. 1), the N1—C6 (1.352 (2) Å) and N3—C12 (1.323 (2) Å) bond lengths are significantly shorter than the normal C—N single bond (1.47 Å), indicating some conjugation with the C6═O2 and C12═O4 carbonyl groups, respectively. The six-membered piperidine ring adopts a boat conformation, with N1 and C3 displaced by 0.533 (2) and 0.632 (2) Å, respectively, from the mean-plane through C1, C2, C4 and C5. In the crystal structure, molecules are linked by intermolecular N—H···O hydrogen bonds (Table 1) to form a porous three-dimensional network with solvent-free hydrophobic channels extending along the c axis (Fig. 2).

Experimental

To a solution of ethyl N-Boc-3-methoxyimino-4-methylpiperidine-4-carboxylate (12.71 g, 40.5 mmol) in ethanol (50 ml) was added dropwise a solution of sodium hydroxide (2.75 g, 68.85 mmol) in water (5 ml) at room temperature. After stirring for 4.5 h, ethanol was removed under reduced pressure. After addition of water (20 ml), acetic acid (5 ml, 86.5 mmol) and triethylamine (17 ml, 122 mmol), the mixture was stirred for 10 min and extracted with CH2Cl2 (3 × 40 ml). The combined organic extracts were washed with saturated brine (3 × 20 ml) and dried over anhydrous sodium sulfate. The reaction mixture was then cooled to 259-261 K, and isobutyl chloroformate (13.1 ml, 101.8 mmol) was added. After 0.5 h, the reaction mixture was washed with 1 N HCl (4 × 20 ml) and saturated brine (4 × 40 ml), and dried over anhydrous sodium sulfate. The resulting yellow residue was purified by column chromatography, with petroleum ether/diethyl ether (3:1 v/v) as eluent to afford the title compound (4.92 g, 42.6%; mp: 140–142 °C). Single crystals suitable for X-ray analysis were obtained by slow evaporation of an ethanol/ethyl acetoacetate solution (1:1 v/v). 1H NMR (CDCl3, δ): 1.37-1.46 (12H, m, CH3), 1.50-1.57 (1H, m, C5), 2.43-2.49 (1H, m, C5), 3.38-3.53 (2H, m, C6), 3.89 (3H, s, OCH3), 4.17-4.45 (2H, m, C2), 5.57 (1H, br, CONH), 6.00 (1H, br, CONH). MS (ESI, m/z): 286 (M+1)+.

Refinement

All H atoms were placed at calculated positions, with C—H = 0.95–0.98 Å, N—H = 0.86 Å, and included in the final cycles of refinement using a riding model, with Uiso(H) = 1.2 Ueq(C, N) or 1.5 Ueq(C) for methyl H atoms. The crystal structure contains voids of about 105 Å3 connected to form channels along the c axis, which may accommodate solvent molecules. However, significant residual densities in the void could not be observed in the difference Fourier map.

Figures

Fig. 1.
The molecular structure of the title compound, showing 40% probability displacement ellipsoids and the atom-numbering scheme.
Fig. 2.
Crystal packing of the title compound viewed along the c axis.

Crystal data

C13H23N3O4Z = 16
Mr = 285.34F000 = 2464
Tetragonal, I41/aDx = 1.206 Mg m3
Hall symbol: -I 4adMo Kα radiation λ = 0.71073 Å
a = 22.813 (2) ÅCell parameters from 3595 reflections
b = 22.813 (2) Åθ = 2.5–22.6º
c = 12.0742 (16) ŵ = 0.09 mm1
α = 90ºT = 293 (2) K
β = 90ºBlock, colorless
γ = 90º0.48 × 0.46 × 0.45 mm
V = 6283.8 (11) Å3

Data collection

Bruker SMART APEX CCD diffractometer2763 independent reflections
Radiation source: fine-focus sealed tube1794 reflections with I > 2σ(I)
Monochromator: graphiteRint = 0.049
T = 293(2) Kθmax = 25.0º
[var phi] and ω scansθmin = 1.8º
Absorption correction: multi-scan(SADABS; Sheldrick, 1996)h = −27→27
Tmin = 0.957, Tmax = 0.963k = −27→18
16003 measured reflectionsl = −14→14

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.039H-atom parameters constrained
wR(F2) = 0.113  w = 1/[σ2(Fo2) + (0.0607P)2] where P = (Fo2 + 2Fc2)/3
S = 1.01(Δ/σ)max < 0.001
2763 reflectionsΔρmax = 0.19 e Å3
181 parametersΔρmin = −0.12 e Å3
Primary atom site location: structure-invariant direct methodsExtinction correction: none

Special details

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)

xyzUiso*/Ueq
N10.38925 (6)0.53733 (7)0.27764 (13)0.0504 (4)
N20.29390 (6)0.58484 (6)0.05570 (12)0.0430 (4)
N30.41951 (6)0.51996 (6)−0.00791 (13)0.0484 (4)
H3A0.44320.4941−0.03420.058*
H3B0.38300.5189−0.02530.058*
O10.46173 (5)0.48101 (5)0.33671 (11)0.0554 (4)
O20.37946 (6)0.43856 (6)0.26866 (13)0.0694 (4)
O30.24359 (5)0.55589 (5)0.09853 (10)0.0501 (4)
O40.49117 (5)0.56448 (5)0.08658 (12)0.0570 (4)
C10.33172 (8)0.54686 (10)0.23109 (17)0.0558 (5)
H1A0.30800.56920.28280.067*
H1B0.31260.50940.21890.067*
C20.33613 (7)0.57937 (7)0.12372 (14)0.0400 (4)
C30.39477 (7)0.60751 (7)0.09840 (14)0.0405 (4)
C40.41585 (8)0.63467 (8)0.20750 (15)0.0502 (5)
H4A0.45310.65410.19490.060*
H4B0.38790.66420.23090.060*
C50.42325 (9)0.58985 (8)0.30031 (16)0.0558 (5)
H5A0.46430.57960.30740.067*
H5B0.41050.60690.36980.067*
C60.40799 (8)0.48163 (10)0.29224 (16)0.0503 (5)
C70.49544 (8)0.42673 (9)0.34839 (16)0.0544 (5)
C80.50169 (11)0.39737 (11)0.2370 (2)0.0890 (8)
H8A0.46430.38240.21380.134*
H8B0.52920.36570.24260.134*
H8C0.51550.42540.18370.134*
C90.55329 (9)0.44949 (10)0.3911 (2)0.0709 (6)
H9A0.57030.47540.33720.106*
H9B0.57940.41720.40410.106*
H9C0.54710.47040.45900.106*
C100.46678 (10)0.38805 (11)0.4341 (2)0.0861 (8)
H10A0.46190.40960.50170.129*
H10B0.49100.35440.44750.129*
H10C0.42910.37550.40760.129*
C110.19775 (8)0.55590 (9)0.01807 (17)0.0588 (6)
H11A0.18180.59470.01150.088*
H11B0.16740.52930.04080.088*
H11C0.21320.5437−0.05220.088*
C120.43929 (8)0.56124 (7)0.05932 (14)0.0401 (4)
C130.39064 (9)0.65416 (8)0.00759 (16)0.0529 (5)
H13A0.37610.6366−0.05930.079*
H13B0.42880.6705−0.00570.079*
H13C0.36440.68470.03080.079*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
N10.0401 (9)0.0565 (10)0.0546 (10)0.0059 (8)−0.0052 (7)0.0066 (8)
N20.0373 (9)0.0459 (9)0.0457 (9)0.0019 (7)0.0041 (7)−0.0026 (7)
N30.0342 (8)0.0456 (9)0.0655 (11)0.0027 (7)0.0014 (7)−0.0195 (8)
O10.0444 (8)0.0558 (8)0.0661 (9)0.0102 (6)−0.0121 (6)0.0019 (7)
O20.0574 (9)0.0617 (10)0.0890 (11)−0.0071 (7)−0.0152 (8)0.0097 (8)
O30.0346 (7)0.0627 (8)0.0529 (8)−0.0010 (6)0.0000 (6)0.0073 (6)
O40.0338 (7)0.0607 (9)0.0766 (10)0.0034 (6)−0.0029 (6)−0.0254 (7)
C10.0360 (11)0.0753 (14)0.0560 (13)0.0088 (9)0.0019 (9)0.0136 (10)
C20.0345 (10)0.0412 (10)0.0442 (10)0.0093 (8)0.0030 (8)−0.0041 (8)
C30.0398 (10)0.0369 (10)0.0447 (10)0.0042 (8)0.0025 (8)−0.0042 (8)
C40.0525 (12)0.0423 (11)0.0559 (12)0.0054 (9)−0.0005 (9)−0.0119 (9)
C50.0593 (13)0.0571 (13)0.0509 (12)0.0100 (10)−0.0094 (10)−0.0106 (10)
C60.0433 (12)0.0622 (14)0.0453 (12)0.0027 (10)−0.0009 (9)0.0055 (10)
C70.0512 (12)0.0570 (13)0.0549 (13)0.0139 (9)0.0011 (10)0.0058 (10)
C80.0959 (19)0.0966 (19)0.0744 (17)0.0334 (15)−0.0017 (14)−0.0162 (14)
C90.0470 (13)0.0821 (16)0.0837 (17)0.0128 (11)−0.0020 (11)0.0093 (13)
C100.0726 (16)0.0894 (18)0.0962 (19)0.0002 (13)−0.0024 (14)0.0364 (15)
C110.0409 (11)0.0714 (14)0.0641 (13)−0.0025 (9)−0.0097 (10)0.0085 (11)
C120.0345 (10)0.0393 (10)0.0467 (11)−0.0006 (8)0.0024 (8)−0.0035 (8)
C130.0551 (12)0.0464 (11)0.0571 (12)0.0021 (9)0.0057 (9)0.0021 (9)

Geometric parameters (Å, °)

N1—C61.352 (2)C4—H4B0.9700
N1—C11.444 (2)C5—H5A0.9700
N1—C51.453 (2)C5—H5B0.9700
N2—C21.272 (2)C7—C101.509 (3)
N2—O31.4217 (17)C7—C91.509 (3)
N3—C121.323 (2)C7—C81.509 (3)
N3—H3A0.8600C8—H8A0.9600
N3—H3B0.8600C8—H8B0.9600
O1—C61.339 (2)C8—H8C0.9600
O1—C71.465 (2)C9—H9A0.9600
O2—C61.213 (2)C9—H9B0.9600
O3—C111.427 (2)C9—H9C0.9600
O4—C121.2308 (19)C10—H10A0.9600
C1—C21.497 (2)C10—H10B0.9600
C1—H1A0.9700C10—H10C0.9600
C1—H1B0.9700C11—H11A0.9600
C2—C31.515 (2)C11—H11B0.9600
C3—C131.531 (2)C11—H11C0.9600
C3—C41.533 (2)C13—H13A0.9600
C3—C121.539 (2)C13—H13B0.9600
C4—C51.526 (3)C13—H13C0.9600
C4—H4A0.9700
C6—N1—C1118.66 (17)O1—C7—C10109.46 (16)
C6—N1—C5125.56 (16)O1—C7—C9101.60 (15)
C1—N1—C5115.73 (16)C10—C7—C9110.25 (18)
C2—N2—O3109.33 (14)O1—C7—C8109.82 (17)
C12—N3—H3A120.0C10—C7—C8113.1 (2)
C12—N3—H3B120.0C9—C7—C8111.98 (17)
H3A—N3—H3B120.0C7—C8—H8A109.5
C6—O1—C7121.90 (15)C7—C8—H8B109.5
N2—O3—C11110.11 (13)H8A—C8—H8B109.5
N1—C1—C2110.52 (15)C7—C8—H8C109.5
N1—C1—H1A109.5H8A—C8—H8C109.5
C2—C1—H1A109.5H8B—C8—H8C109.5
N1—C1—H1B109.5C7—C9—H9A109.5
C2—C1—H1B109.5C7—C9—H9B109.5
H1A—C1—H1B108.1H9A—C9—H9B109.5
N2—C2—C1123.83 (16)C7—C9—H9C109.5
N2—C2—C3119.79 (16)H9A—C9—H9C109.5
C1—C2—C3116.37 (15)H9B—C9—H9C109.5
C2—C3—C13112.63 (14)C7—C10—H10A109.5
C2—C3—C4105.95 (14)C7—C10—H10B109.5
C13—C3—C4110.71 (14)H10A—C10—H10B109.5
C2—C3—C12110.73 (13)C7—C10—H10C109.5
C13—C3—C12107.33 (14)H10A—C10—H10C109.5
C4—C3—C12109.49 (14)H10B—C10—H10C109.5
C5—C4—C3113.25 (14)O3—C11—H11A109.5
C5—C4—H4A108.9O3—C11—H11B109.5
C3—C4—H4A108.9H11A—C11—H11B109.5
C5—C4—H4B108.9O3—C11—H11C109.5
C3—C4—H4B108.9H11A—C11—H11C109.5
H4A—C4—H4B107.7H11B—C11—H11C109.5
N1—C5—C4110.80 (15)O4—C12—N3122.35 (15)
N1—C5—H5A109.5O4—C12—C3120.75 (15)
C4—C5—H5A109.5N3—C12—C3116.84 (15)
N1—C5—H5B109.5C3—C13—H13A109.5
C4—C5—H5B109.5C3—C13—H13B109.5
H5A—C5—H5B108.1H13A—C13—H13B109.5
O2—C6—O1125.26 (19)C3—C13—H13C109.5
O2—C6—N1124.14 (18)H13A—C13—H13C109.5
O1—C6—N1110.60 (17)H13B—C13—H13C109.5
C2—N2—O3—C11−173.54 (15)C1—N1—C5—C4−40.4 (2)
C6—N1—C1—C2−118.26 (19)C3—C4—C5—N1−20.9 (2)
C5—N1—C1—C259.1 (2)C7—O1—C6—O28.3 (3)
O3—N2—C2—C10.3 (2)C7—O1—C6—N1−172.16 (15)
O3—N2—C2—C3−178.79 (13)C1—N1—C6—O20.0 (3)
N1—C1—C2—N2167.35 (16)C5—N1—C6—O2−177.08 (19)
N1—C1—C2—C3−13.5 (2)C1—N1—C6—O1−179.54 (15)
N2—C2—C3—C1316.4 (2)C5—N1—C6—O13.4 (3)
C1—C2—C3—C13−162.72 (16)C6—O1—C7—C10−68.6 (2)
N2—C2—C3—C4137.60 (16)C6—O1—C7—C9174.80 (16)
C1—C2—C3—C4−41.54 (19)C6—O1—C7—C856.1 (2)
N2—C2—C3—C12−103.77 (18)C2—C3—C12—O4−142.74 (17)
C1—C2—C3—C1277.10 (19)C13—C3—C12—O493.96 (19)
C2—C3—C4—C559.91 (19)C4—C3—C12—O4−26.3 (2)
C13—C3—C4—C5−177.69 (15)C2—C3—C12—N340.0 (2)
C12—C3—C4—C5−59.54 (19)C13—C3—C12—N3−83.25 (19)
C6—N1—C5—C4136.72 (18)C4—C3—C12—N3156.51 (15)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N3—H3A···O4i0.862.112.9607 (18)173
N3—H3B···O3ii0.862.343.1334 (19)153

Symmetry codes: (i) −x+1, −y+1, −z; (ii) y−1/4, −x+3/4, z−1/4.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: RZ2260).

References

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