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

Juxian Wang; Mingliang Liu; Jue Cao; Yucheng Wang

doi:10.1107/S1600536808036106

. 2008 Nov 8;64(Pt 12):o2294. doi: 10.1107/S1600536808036106

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

Juxian Wang ^a, Mingliang Liu ^a, Jue Cao ^a, Yucheng Wang ^a,^*

PMCID: PMC2960090 PMID: 21581272

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 ▶); Ball et al. (1998 ▶); Bryskier (1997 ▶); De Sarro & De Sarro (2001 ▶); Anderson & Osheroff (2001 ▶); Dang et al. (2007 ▶); Wang et al. (2008 ▶). graphic file with name e-64-o2294-scheme1.jpg

Experimental

Crystal data

C₁₃H₂₃N₃O₄
M _r = 285.34
Tetragonal,
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 ▶) 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
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.12 e Å⁻³

Data collection: SMART (Bruker, 1998 ▶); cell refinement: SAINT (Bruker, 1999 ▶); data reduction: SAINT; 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.

Supplementary Material

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

e-64-o2294-sup1.cif^{(20KB, cif)}

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

e-64-o2294-Isup2.hkl^{(136KB, hkl)}

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H3A⋯O4ⁱ	0.86	2.11	2.9607 (18)	173
N3—H3B⋯O3ⁱⁱ	0.86	2.34	3.1334 (19)	153

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Symmetry codes: (i) Inline graphic ; (ii) .

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)⁺.