2-(1-Adamant­yl)-1-{4-[(2-chloro-9-isopropyl-9H-purin-6-yl)amino­meth­yl]phen­yl}ethanone

Michal Rouchal; Marek Nečas; Fabiana Pires de Carvalho; Robert Vícha

doi:10.1107/S160053680900052X

. 2009 Jan 14;65(Pt 2):o298–o299. doi: 10.1107/S160053680900052X

2-(1-Adamantyl)-1-{4-[(2-chloro-9-isopropyl-9H-purin-6-yl)aminomethyl]phenyl}ethanone

Michal Rouchal ^a, Marek Nečas ^b, Fabiana Pires de Carvalho ^a, Robert Vícha ^a,^*

PMCID: PMC2968337 PMID: 21581908

Abstract

The structure of the title compound, C₂₇H₃₂ClN₅O, consists of two crystallographically independent conformers differing slightly in all geometric parameters. Both contain nearly planar purine and benzene ring systems [maximum deviations of 0.046 (3) and 0.005 (2) Å, respectively], the dihedral angles between them being 76.44 (6) and 82.39 (6)°, and an adamantane cage consisting of three fused cyclohexane rings in almost ideal chair conformations, with C—C—C angles in the range 108.7 (2)–110.6 (2)°. The carbonyl plane and the benzene ring are almost coplanar [dihedral angles of 6.43 (9) and 0.64 (8)° in the two conformers]. The crystal structure is stabilized by intermolecular N—H⋯N interactions that link adjacent molecules into dimers and by some non-bonding contacts of the C—H⋯Cl type.

Related literature

The title compound was prepared according to a modified procedure published by Fiorini & Abel (1989 ▶). For the synthesis and/or biological activity of related compounds, see: Veselý et al. (1994 ▶); Havlíček et al. (1997 ▶); de Azevedo et al. (1997 ▶); Kryštof et al. (2002 ▶); Kryštof et al. (2005 ▶); Legraverend & Grierson (2006 ▶). For some important properties of adamantane-bearing compounds, see: van Bommel et al. (2001 ▶); Cromwell et al. (1985 ▶). For related structures, see: Wang et al. (2001 ▶); Trávníček & Zatloukal (2004 ▶); Trávníček & Popa (2007a ▶,b ▶).

Experimental

Crystal data

C₂₇H₃₂ClN₅O
M _r = 478.03
Monoclinic,
a = 15.8778 (5) Å
b = 20.2779 (5) Å
c = 15.2225 (5) Å
β = 104.233 (3)°
V = 4750.7 (3) Å³
Z = 8
Mo Kα radiation
μ = 0.19 mm⁻¹
T = 120 (2) K
0.50 × 0.40 × 0.30 mm

Data collection

Kuma KM-4 CCD diffractometer
Absorption correction: multi-scan (Xcalibur; Oxford Diffraction, 2006 ▶) T _min = 0.872, T _max = 0.944
47831 measured reflections
8353 independent reflections
5567 reflections with I > 2σ(I)
R _int = 0.026

Refinement

R[F ² > 2σ(F ²)] = 0.042
wR(F ²) = 0.150
S = 1.09
8353 reflections
617 parameters
H-atom parameters constrained
Δρ_max = 0.35 e Å⁻³
Δρ_min = −0.29 e Å⁻³

Data collection: Xcalibur (Oxford Diffraction, 2006 ▶); cell refinement: Xcalibur; data reduction: Xcalibur; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680900052X/pk2141sup1.cif

e-65-0o298-sup1.cif^{(41.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680900052X/pk2141Isup2.hkl

e-65-0o298-Isup2.hkl^{(408.6KB, 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
N5—H5A⋯N53ⁱ	0.88	2.20	2.997 (3)	150
N55—H55A⋯N3ⁱⁱ	0.88	2.18	2.946 (3)	145
C27—H27A⋯Cl1ⁱⁱⁱ	0.98	2.86	3.732 (3)	149
C54—H54B⋯Cl51^iv	0.99	2.76	3.698 (3)	158

Open in a new tab

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

Table 2. Comparative torsion angles (°) for selected 2,6,9-trisubstituted purines containing the 2-chloro 6-benzylamino and 9-isopropyl unit.

Compound	angle	value	angle	value
NG38^a	C6—N6—C9—C10	115.22 (13)	H17—C17—N9—C4	−13.38 (18)
CIBAP1^b	C6—N6—C9—C10	178.97 (15)	H16—C16—N9—C4	−63.03 (2)
CIBAP2^c	C6—N6—C9—C10	−117.35 (2)	H16—C16—N9—C4	30.35 (3)
CIABAP^d	C20—N5—C19—C16	100.28 (3)	H25—C25—N4—C22	45.01 (3)
CIABAP^d	C70—N55—C69—C66	−99.62 (3)	H75—C75—N54—C72	−40.79 (3)

Open in a new tab

Notes: (a) Trávníček & Zatloukal (2004 ▶), where NG38 is N-[(2-azepan-1-yl)-9-isopropyl-9H-purin-6-yl]-4-methoxybenzylamine; (b) Trávníček & Popa (2007a ▶), where CIBAP1 is 2-chloro-6-[(2,6-dimethoxybenzyl)amino]-9-isopropylpurine; (c) Trávníček & Popa (2007b ▶), where CIBAP2 is 2-chloro-6-[(4-hydroxy-3,5-dimethoxybenzyl)amino]-9-isopropylpurine; (d) this work, where CIABAP is the title compound (the structure consists of two crystallographically independent molecules).

Acknowledgments

The financial support of this work by the Science Foundation of the Czech Republic (grant No. 203/06/P362) and by the Czech Ministry of Education (project No. MSM 7088352101) is gratefully acknowledged.

supplementary crystallographic information

Comment

The title molecule is related to the family of 2,6,9-trisubstituted purines that behave as potent inhibitors of cyclin-dependent kinases and show anticancer activity. The antiproliferative and proapoptotic effects of these drugs have been studied extensively with both an important and a promising result (Veselý et al., 1994; Havlíček et al., 1997; de Azevedo et al., 1997; Kryštof et al., 2002; Kryštof et al., 2005; Legraverend & Grierson, 2006). The adamantane group is frequently used to improve the pharmacological properties of potential drugs. Whereas the lipophilic adamantane cage itself may increase solubility in non-polar systems (e.g. cell membranes), the non-covalent complex of adamantane with cyclodextrins can enhance solubility in water based media (Cromwell et al., 1985; van Bommel et al., 2001). Both these facilities have considerable importance in drug design and formulation. To the best of our knowledge, the title compound is the first described derivative of a 2,6,9-trisubstituted purine with an adamantyl group linked to 6-benzylamino substituent.

The structure consists of two crystallographically independent molecules slightly variant in geometry. Each ring is essentially planar, the maximum deviations from the best planes being 0.026 (2) Å for atom C23 (pyrimidine rings), 0.0050 (10) Å for atoms C72 and C73 (imidazole rings) and 0.005 (2) Å for atoms C13, C16 and C68 (benzene rings). The dihedral angles between purine and benzene rings are 76.44 (6)° and 82.39 (6)° respectively. The torsion angles C19–N5–C20–C23, C20–N5–C19–C16, N5–C19–C16–C17, C18–C13–C12–C11 and C13–C12–C11–C1 are 172.35 (2), 100.28 (3), 146.27 (2), -6.92 (4) and -100.18 (3)° respectively. The corresponding values of torsion angles for the second distinct conformer are -176.98 (2), -99.62 (3), -168.68 (2), 0.16 (4) and 95.57 (3) respectively. Comparative torsion angles for selected related molecules are shown in Table 2. The crystal structure is stabilized by intermolecular N–H···N interactions that link the molecules into pairs (Fig. 2 and Table 1), the N···N distances being 2.997 (3) and 2.946 (3) Å. respectively. There are also some additional intermolecular non-bonding contacts of the type C–H···Cl (Table 1). One from the two conformers is linked by C27–H27A···Cl1 interaction into pairs and the second conformer is linked by C54–H54B···Cl51 into linear chains. No other short intermolecular interactions were found.

Experimental

The title compound was prepared according to a slightly modified literature procedure (Fiorini & Abel, 1989). 2,6-Dichloro-9-(propan-2-yl)-9H-purine (0.65 mmol, 150 mg) and 1-[4-(aminoethyl)phenyl)]-2-(1-adamantyl)ethanone hydrochloride (0.68 mmol, 218 mg) were dissolved in the mixture of DMF (2 cm³) and triethylamine (1.30 mmol, 0.18 cm³). The resulting solution was stirred and refluxed for 2.5 h. After the starting material had all reacted (according to TLC), the mixture was diluted with water and extracted five times with 15 cm³ of diethyl ether. The combined organic layers were washed twice with brine, dried over sodium sulfate and evaporated in vacuum. The crude product was purified by column chromatography (silica gel; petroleum ether/ethyl acetate, v/v, 1/1). The desired product was obtained as pale yellow crystalline powder (228 mg, 74%, mp 146–150°C). The crystal used for data collection was grown by liquid diffusion (acetone/hexane, v/v, 1/3) at -18°C within 48 h.