tert-Butyl N-[3-hy­droxy-1-phenyl-4-(pyrimidin-2-ylsulfan­yl)butan-2-yl]carbamate monohydrate

Claudia R B Gomes; Thatyana R A Vasconcelos; Walcimar T Vellasco, Jr; James L Wardell; Solange M S V Wardell; Edward R T Tiekink

doi:10.1107/S1600536811031850

. 2011 Aug 11;67(Pt 9):o2313–o2314. doi: 10.1107/S1600536811031850

tert-Butyl N-[3-hydroxy-1-phenyl-4-(pyrimidin-2-ylsulfanyl)butan-2-yl]carbamate monohydrate

Claudia R B Gomes ^a, Thatyana R A Vasconcelos ^b, Walcimar T Vellasco Jr ^a,^b, James L Wardell ^c,^‡, Solange M S V Wardell ^d, Edward R T Tiekink ^c,^*

PMCID: PMC3200972 PMID: 22064897

Abstract

In the title hydrate, C₁₉H₂₅N₃O₃S·H₂O, the configuration at each chiral centre in the organic molecule is S, with the hydroxy and carbamate substituents being anti [O—C—C—N torsion angle = −179.3 (3)°]. The thiopyrimidyl and carbamate residues lie to one side of the pseudo-mirror plane defined by the C₅S backbone of the molecule; this plane approximately bisects the benzene ring at the 1- and 4-C atoms. The dihedral angle formed between the terminal rings is 5.06 (18)°. In the crystal, supramolecular tubes aligned along the b axis are found: these are sustained by a combination of O—H⋯O, O—H⋯N and N—H⋯O hydrogen bonds.

Related literature

For background to the use of hydroxyethylamine derivatives in medicinal chemistry, see: Brik & Wong (2003 ▶); Ghosh et al. (2001 ▶); Marcin et al. (2011 ▶); Trudel et al. (2008 ▶); Cunico et al. (2009a ▶,b ▶,c ▶, 2011 ▶).

Experimental

Crystal data

C₁₉H₂₅N₃O₃S·H₂O
M _r = 393.50
Monoclinic,
a = 19.4238 (7) Å
b = 5.1275 (2) Å
c = 22.4815 (8) Å
β = 114.319 (2)°
V = 2040.38 (13) Å³
Z = 4
Mo Kα radiation
μ = 0.19 mm⁻¹
T = 120 K
0.30 × 0.02 × 0.02 mm

Data collection

Bruker–Nonius Roper CCD camera on κ-goniostat diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2007 ▶) T _min = 0.801, T _max = 1.000
11781 measured reflections
4032 independent reflections
3409 reflections with I > 2σ(I)
R _int = 0.048

Refinement

R[F ² > 2σ(F ²)] = 0.055
wR(F ²) = 0.112
S = 1.04
4032 reflections
259 parameters
6 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.26 e Å⁻³
Absolute structure: Flack (1983 ▶), 1442 Friedel pairs
Flack parameter: 0.11 (11)

Data collection: COLLECT (Hooft, 1998 ▶); cell refinement: DENZO (Otwinowski & Minor, 1997 ▶) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶) and DIAMOND (Brandenburg, 2006 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811031850/hb6348sup1.cif

e-67-o2313-sup1.cif^{(22.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811031850/hb6348Isup2.hkl

e-67-o2313-Isup2.hkl^{(193.6KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811031850/hb6348Isup3.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
O1—H1o⋯O1wⁱ	0.83 (2)	2.00 (2)	2.813 (4)	168 (4)
O1w—H1w⋯N1ⁱⁱ	0.85 (2)	2.12 (2)	2.958 (4)	174 (4)
O1w—H2w⋯O1	0.84 (3)	2.06 (3)	2.893 (4)	170 (4)
N3—H3n⋯O2ⁱ	0.86 (2)	2.13 (2)	2.910 (3)	152 (3)

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

Acknowledgments

The use of the EPSRC X-ray crystallographic service at the University of Southampton, England, and the valuable assistance of the staff there is gratefully acknowledged. JLW acknowledges support from CAPES (Brazil).

supplementary crystallographic information

Comment

Compounds having a hydroxyethylamine core play important roles in the medicinal chemistry field. They inhibit aspartyl protease enzymes and are widely used as anti-HIV agents (Brik & Wong, 2003; Ghosh et al., 2001), as inhibitors of BACE-1 to combat Alzheimer's disease (Marcin, et al., 2011) and have also been considered in the treatment of leishmania/HIV-1 co-infections (Trudel et al., 2008). Cunico and co-workers have reported on the in vitro activity of hydroxyethylamine derivatives as anti-malarial agents (Cunico et al., 2009a, 2009b, 2009c, 2011) and in this article we report the structure of the title molecule, isolated from ethanol solution as a monohydrate, (I).

The structure analysis of (I) confirms the stereochemistry at each of the C1 and C7 atoms to be S, Fig. 1, as anticipated from the synthesis. The O1 and N3 substituents on C1 and C7, respectively, have an anti disposition [the O1—C1—C7—N3 torsion angle = -179.3 (3) °]. With reference to the C₅S backbone of the molecule, i.e. comprising the C1/C2/C7/C13/C14/S1 atoms, the benzene ring occupies a position that is approximately bisected by the pseudo mirror plane through these atoms [the C7—C13—C14···C17 torsion angle = -17.1 (5) °] whereas the thiopyrimidyl group lies to one side of the plane [the C3—S1—C2—C1 torsion angle = 89.9 (2) °]. The terminal rings of the C₅S backbone are almost parallel forming a dihedral angle of 5.06 (18) °. The carbamate residue lies to the same side of the C₅S plane as does the thiopyrimidyl group with the t-BuO atoms being directed away from the rest of the molecule.

In the crystal, the water molecules serve to link translationally related hydroxy groups by forming both donor and acceptor interactions, and at the same time the water molecule forms a donor interaction to one of the pyrimidyl-N atoms, Table 1. The resultant supramolecular assembly, a tube, is further stabilized by amine-H···O(carbonyl) interactions. Side-on and end-on views of the supramolecular tube are shown in Figs 2 and 3, respectively. The tubes are aligned along the b direction as seen in Fig. 4.

Experimental

A solution of (2S,3S)-boc-phenylalanine epoxide (1.6 mmol) (Cunico et al., 2009a), mercaptopyrimidine (1.5 mmol) and triethylamine (1.6 mmol) in methanol (10 ml) was stirred at room temperature for 2 h, rotary evaporated and HCl (5%) added to the residue. The mixture was extracted with CH₂Cl₂ and the combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄ and evaporated, giving the title molecule in 95% yield. The crude product was purified by crystallization in methanol/water (7:3) to yield colourless needles of (I); M.pt.: 371–373 K.. EI—MS (m/z) (%): 398.2 (M++Na, 52%). ¹H NMR [400.00 MHz, DMSO-d6] δ: 8.59 (d, 2H, J = 4.8 Hz, H3' and H5'); 7.18 (t, 1H, J = 4.7 Hz, H4'); 7.19–7.13 (m, 5H, Ph); 6.70 (d, 1H, J = 8.7 Hz, NH); 5.33 (d, 1H, J = 6.0 Hz, OH); 3.66–3.58 (m, 2H, H3 and H2); 3.52 (dd, 1H, ¹J = 13.6 Hz, ²J = 3.2 Hz, H1b); 3.08 (dd, 1H, ¹J = 13.6, ²J = 8.0 Hz, H1a); 3.03 (dd, 1H, ¹J = 13.5, ²J = 2.6 Hz, H4b); 2.56 (dd, 1H, ¹J = 13.7, 2 J = 10.0 Hz, H4a); 1.26 (s, 9H, Boc) p.p.m.. ¹³C NMR [100.0 MHz, DMSO-d6] δ: 171.4; 157.6; 155.3; 139.5; 129.1; 127.9; 125.7; 117.0; 77.5; 72.1; 56.3; 35.8; 35.0; 28.2 p.p.m.. IR (cm^-1; KBr): ν_max: 3358 (OH); 3030 (NH); 1686 (C═O); 640 (C—S). The crystals used in the structure determination were grown from moist EtOH solution explaining the presence of water in the title structure, (I).