(2R,6S)-tert-Butyl 2-(benzhydryl­carbamo­yl)-6-methyl­morpholine-4-carboxyl­ate

Haiyang Wang; Guangxin Xia; Xuejun Liu; Jingkang Shen

doi:10.1107/S1600536811017764

. 2011 May 20;67(Pt 6):o1437. doi: 10.1107/S1600536811017764

(2R,6S)-tert-Butyl 2-(benzhydrylcarbamoyl)-6-methylmorpholine-4-carboxylate

Haiyang Wang ^a, Guangxin Xia ^b, Xuejun Liu ^b, Jingkang Shen ^a,^*

PMCID: PMC3120296 PMID: 21754815

Abstract

The title compound, C₂₄H₃₀N₂O₄, was obtained by the reaction of (2R,6S)-4-(tert-butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid with diphenylmethanamine in dimethylformamide solution. The morpholine ring is in a chair conformation. In the crystal, weak intermolecular C—H⋯O hydrogen bonds link molecules into chains along the b axis.

Related literature

For a review of the biological relevance and synthesis of C-substituted morpholine derivatives, see: Wijtmans et al. (2004 ▶). For applications of morpholine derivatives as drugs, see: Dando & Perry (2004 ▶); Hajos et al. (2004 ▶); Hale et al. (1998 ▶); Versiani et al. (2002 ▶). For agrochemical fungicides and bactericides containing a morpholine skeleton, see: Dieckmann et al. (1993 ▶). For applications of morpholines as chiral auxiliaries in asymmetric synthesis, see: Dave & Sasaki (2004 ▶); Enders et al. (1994 ▶).

Experimental

Crystal data

C₂₄H₃₀N₂O₄
M _r = 410.50
Monoclinic,
a = 27.248 (4) Å
b = 5.8241 (8) Å
c = 14.275 (2) Å
β = 94.192 (3)°
V = 2259.3 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 293 K
0.37 × 0.24 × 0.16 mm

Data collection

Bruker SMART APEX CCD diffractometer
5956 measured reflections
2310 independent reflections
1934 reflections with I > 2σ(I)
R _int = 0.110

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.109
S = 0.96
2310 reflections
279 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.15 e Å⁻³
Δρ_min = −0.23 e Å⁻³

Data collection: SMART (Bruker, 2002 ▶); cell refinement: SAINT (Bruker, 2002 ▶); 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 I, global. DOI: 10.1107/S1600536811017764/cv5082sup1.cif

e-67-o1437-sup1.cif^{(22.8KB, cif)}

Supplementary material file. DOI: 10.1107/S1600536811017764/cv5082Isup2.cdx

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811017764/cv5082Isup3.hkl

e-67-o1437-Isup3.hkl^{(113.5KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811017764/cv5082Isup4.cml

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

Enhanced figure: interactive version of Fig. 1

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C19—H19⋯O1ⁱ	0.93	2.54	3.332 (4)	144

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Symmetry code: (i) Inline graphic .

Acknowledgments

HW is indebted to Professor Jianshu Xie for supporting this project and for critical review of the manuscript. We gratefully acknowledge financial support from the Shanghai Pharmaceutical Group Co. Ltd GX is grateful to the Shanghai Postdoctoral Sustentation Fund, China (grant No. 07R214213) for financial support.

supplementary crystallographic information

Comment

Morpholines are an important class of heterocyclic compounds found in many naturally occurring or synthetically organic molecules (Wijtmans et al., 2004). Especially, the morpholine moiety has found widespread use in medicinal chemistry, and many drugs contain this subunit. For example, antidepressant drug Reboxetine (Hajos et al., 2004; Versiani et al., 2002), Aprepitant in combination with other agents to prevent and control nausea and vomiting caused by chemotherapy (Dando & Perry, 2004; Hale et al., 1998). The morpholine skeleton is also used to construct a number of agrochemical fungicides and bactericides, such as Fenpropimorph and tridemorph (Dieckmann et al., 1993). Furthermore, morpholines have been applied as chiral auxiliaries in asymmetric synthesis (Dave & Sasaki, 2004; Enders et al., 1994). Herewith we report the crystal structure of the title compound (I).

In (I) (Fig. 1), the morpholine ring is in a chair conformation. Weak intermolecular C—H···O hydrogen bonds (Table 1) link the molecules related by translation along axis b into chains.

Experimental

The schematic representation of the synthesis is given in Fig. 2. To a solution of EDC (125 mg, 0.54 mmol) and HOAt (74 mg, 0.54 mmol) in DMF (2 ml) was added diphenylmethanamine (82 mg, 0.45 mmol) and (2R,6S)-4-(tert-butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid (132 mg, 0.54 mmol) and the mixture stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was then washed successively with saturated aqueous sodium bicarbonate, brine and then dried (MgSO4). The solution was evaporated to dryness in vacuo and the residue purified by flash column chromatography to give the title compound (124 mg) as a colourless solid. Crystals suitable for X-ray structure analysis were obtained by slow evaporation of a solution in EtOAc at room temperature.