(3R,4S,5R)-Methyl 3,5-bis­[(tert-butyl­dimethyl­sil­yl)­oxy]-4-meth­oxy­cyclo­hex-1-ene­carboxyl­ate

Ri Liu; Yu Shi; Chun-Xiu Xu; Yi-Liang Li

doi:10.1107/S1600536813007551

. 2013 Apr 5;69(Pt 5):o632. doi: 10.1107/S1600536813007551

(3R,4S,5R)-Methyl 3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methoxycyclohex-1-enecarboxylate

Ri Liu ^a, Yu Shi ^b, Chun-Xiu Xu ^a, Yi-Liang Li ^b,^*

PMCID: PMC3647833 PMID: 23723799

Abstract

The title compound, C₂₁H₄₂O₅Si₂, was synthesized from (3R,4S,5R)-methyl 3,5-bis[(tert-butyldimethylsilyl)oxy]-4-hydroxycyclohex-1-enecarboxylate by an esterification reaction. The cyclohexene ring adopts a half-chair conformation. In the crystal, molecules are linked via C—H⋯O hydrogen bonds, forming helical chains propagating along [010].

Related literature

The title compound is an intermediate in the synthesis of vandetanib {systematic name: N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine} derivatives. For vandetanib as a tyrosine kinase inhibitor, see: Heymach (2005 ▶); Morabito et al. (2009 ▶); Wells et al. (2010 ▶); Natale et al. (2009 ▶). graphic file with name e-69-0o632-scheme1.jpg

Experimental

Crystal data

C₂₁H₄₂O₅Si₂
M _r = 430.72
Monoclinic,
a = 10.760 (5) Å
b = 8.321 (4) Å
c = 14.601 (7) Å
β = 98.997 (9)°
V = 1291.3 (10) Å³
Z = 2
Mo Kα radiation
μ = 0.16 mm⁻¹
T = 113 K
0.20 × 0.18 × 0.12 mm

Data collection

Rigaku Saturn724 CCD diffractometer
Absorption correction: multi-scan (CrystalClear; Rigaku, 2007 ▶) T _min = 0.968, T _max = 0.981
13589 measured reflections
6015 independent reflections
4456 reflections with I > 2σ(I)
R _int = 0.058

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.073
S = 0.98
6015 reflections
265 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.21 e Å⁻³
Δρ_min = −0.29 e Å⁻³
Absolute structure: Flack (1983 ▶), 2745 Friedel pairs
Flack parameter: −0.04 (9)

Data collection: CrystalClear (Rigaku, 2007 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; 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: CrystalStructure (Rigaku/MSC, 2006 ▶).

Supplementary Material

Click here for additional data file.^{(32.7KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536813007551/vm2187sup1.cif

e-69-0o632-sup1.cif^{(32.7KB, cif)}

Click here for additional data file.^{(294.4KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813007551/vm2187Isup2.hkl

e-69-0o632-Isup2.hkl^{(294.4KB, hkl)}

Click here for additional data file.^{(3.1KB, cdx)}

Supplementary material file. DOI: 10.1107/S1600536813007551/vm2187Isup4.cdx

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
C7—H7B⋯O3ⁱ	0.98	2.55	3.410 (3)	147
C9—H9A⋯O3ⁱⁱ	0.98	2.59	3.527 (3)	161

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

Acknowledgments

The synthesis and evaluation of the title compound was undertaken as part of the National Science and Technology Major Project "The synthesis and anticancer activity screening of novel chalcone derivatives". The authors thank the State Key Laboratory of Elemento-organic Chemistry Nankai University, for the X-ray data collection.

supplementary crystallographic information

Comment

Vandetanib is a small molecule tyrosine kinase inhibitor, which can act on the tumor cells epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and the RET tyrosine kinase (Heymach, 2005; Morabito et al., 2009). Vandetanib has a good therapeutic effect for Medullary thyroid cancer and Non-small cell lung cancer (Wells et al., 2010; Natale et al., 2009).

(3R,4S,5R)-Methyl 3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methoxycyclohex-1-enecarboxylate (Fig. 1) is an intermediate to synthetize Vandetanib derivatives. Here, the synthesis and crystallographic characterization of the compound are reported.

The crystal structure of the compound has monoclinic (P2₁) symmetry at 113 K. No hydrogen-bonding or π–π interactions are observed in the crystal structure. Despite the relatively large steric size of substituent groups, the cyclohexene still has a nearly ideal half-chair form with carbon atoms C3, C4,C5 and C2 lying in one plane.

Experimental

Solid sodium hydroxide (2.8 g, 0.07 mol) was added to a stirred solution of (3R,4S,5R)-methyl 3,5-bis((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohex-1-εnecarboxylate (5.6 g, 0.134 mol) in acetonitrile (60 ml) at room temperature.The reaction mixture was added dropwise to a solution of dimethyl sulfate (4.2 ml, 0.044 mol) in acetonitrile (60 ml). After the dropwise addition, the temperature was raised to 40 °C. The reaction was completed within 15 hrs at 40 °C stirring. The solvent was removed under reduced pressure, and ethyl acetate (300 ml) and H₂O (100 ml) were added three times to extract the solid. The ethyl acetate layer was dried with anhydrous magnesium sulfate and a white solid was obtained after removal of the solvent. The yield was 4.8 g (82.7%). About 0.5g of the product was put in an ampoule bottle and 10 ml absolute methanol was added. The white single crystals suitable for X-ray diffraction analysis were obtained by slow evaporation of the solvent at room temperature after 1 week.