Methyl 2-(2-{[(benz­yloxy)carbon­yl]amino}­propan-2-yl)-5-hy­droxy-6-oxo-1,6-dihydro­pyrimidine-4-carboxyl­ate

Zhenhua Shang; Jing Ha; Yifeng Yu; Xiaodan Zhao

doi:10.1107/S1600536811016278

. 2011 May 7;67(Pt 6):o1336. doi: 10.1107/S1600536811016278

Methyl 2-(2-{[(benzyloxy)carbonyl]amino}propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Zhenhua Shang ^a,^*, Jing Ha ^a, Yifeng Yu ^a, Xiaodan Zhao ^a

PMCID: PMC3120555 PMID: 21754732

Abstract

In the title compound, C₁₇H₁₉N₃O₆, the dihedral angle between the two aromatic rings is 45.9 (1)°. The crystal structure is stabilized through intermolecular N—H⋯O hydrogen bonds and intramolecular O—H⋯O hydrogen bonds are also present.

Related literature

For related structures, see: Fun et al. (2009 ▶); Shang & Shang (2007 ▶). The title compound is an intermediate in the preparation of the antiretroviral drug raltegravir [systematic name N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide. For therapeutic details of raltegravir, see Steigbigel et al. (2008 ▶). For synthetic details, see: Culbertson (1979 ▶).

Experimental

Crystal data

C₁₇H₁₉N₃O₆
M _r = 361.35
Monoclinic,
a = 12.122 (2) Å
b = 16.300 (3) Å
c = 9.1766 (18) Å
β = 106.29 (3)°
V = 1740.4 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 113 K
0.24 × 0.20 × 0.16 mm

Data collection

Bruker SMART diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 1997 ▶) T _min = 0.975, T _max = 0.983
15564 measured reflections
4142 independent reflections
3386 reflections with I > 2σ(I)
R _int = 0.035

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.103
S = 1.09
4142 reflections
250 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.24 e Å⁻³

Data collection: SMART (Bruker, 1997 ▶); cell refinement: SAINT (Bruker, 1997 ▶); 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/S1600536811016278/wn2426sup1.cif

e-67-o1336-sup1.cif^{(20.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811016278/wn2426Isup2.hkl

e-67-o1336-Isup2.hkl^{(203KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811016278/wn2426Isup3.cml

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—H3⋯O5ⁱ	0.882 (15)	2.133 (15)	2.8911 (14)	143.7 (12)
N2—H2⋯O2ⁱⁱ	0.938 (16)	1.886 (16)	2.8135 (16)	169.3 (13)
O1—H1⋯O3	0.918 (17)	1.788 (17)	2.6163 (14)	148.7 (16)

Open in a new tab

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

Acknowledgments

The authors thank the funds of Hebei Province Science and Technology Research and Development Projects (No. 08276409D) and Hebei University of Science and Technology.

supplementary crystallographic information

Comment

Raltegravir (MK-0518, brand name Isentress), an antiretroviral drug produced by Merck & Co, is used to treat HIV infection (Steigbigel et al., 2008). It received FDA approval in October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval. The title compound is a key intermediate in the preparation of Raltegravir.

The pyrimidinone ring is planar, as it is in a related compound (Fun et al., 2009). This is in contrast with another related compound (Shang et al., 2007), where the heterocyclic ring is twisted. In the title compound the dihedral angle between the two aromatic rings is 45.9 (1)°. The crystal structure is stabilized through intermolecular N—H···O hydrogen bonds; intramolecular O—H···O hydrogen bonds are also present.

Experimental

The title compound was prepared by a published method (Culbertson, 1979). To a slurry of benzyl 1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate (2.9 g) in methanol (12 ml) was added dimethyl acetylenedicarboxylate (1.77 g) slowly at room temperature. After 1.5 h, the mixture was added to xylene (20 ml). The reaction mixture was then heated to reflux for 2 h and cooled to 60 °C. Methyl tert-butyl ether (9 ml) was added slowly to build a seed bed. The batch was then cooled to 0 °C for 14 h, and then further cooled to -5 °C and allowed to stand for 1 h before filtration. The solid was washed with methyl tert-butyl ether (4 ml) and dried. 50 mg of the title compound was dissolved in 30 ml methanol and the solution was kept at room temperature for 10 d. Natural evaporation gave colorless single crystals of the title compound which were suitable for X-ray analysis.