1-Eth­oxy­methyl-5-methyl-9-phenyl-6,7,8,9-tetra­hydro-1H-pyrimido[4,5-b][1,4]diazepine-2,4(3H,5H)-dione

Gong Li; Xiaowei Wang; Zhili Zhang; Junyi Liu

doi:10.1107/S1600536812014985

. 2012 Apr 18;68(Pt 5):o1396. doi: 10.1107/S1600536812014985

1-Ethoxymethyl-5-methyl-9-phenyl-6,7,8,9-tetrahydro-1H-pyrimido[4,5-b][1,4]diazepine-2,4(3H,5H)-dione

Gong Li ^a, Xiaowei Wang ^a, Zhili Zhang ^a, Junyi Liu ^a,^*

PMCID: PMC3344522 PMID: 22590284

Abstract

The title compound, C₁₇H₂₂N₄O₃, comprises a 1,4-diazepine ring in a twist-boat conformation fused to a pyrimidine ring. The dihedral angle between the pyrimidine and phenyl rings is 80.8 (1)°. The crystal packing features N—H⋯O and C—H⋯O hydrogen bonds.

Related literature

For the preparation of 2,4-dimethoxy-5-methyl-9-phenyl-8,9-dihydro-5H- pyrimido[4,5-b][1,4]diazepin-6(7H), see: Li et al. (2012 ▶). For the biological activity of compounds with a pyrimidodiazepine scaffold, see: Ferreira et al. (2009 ▶); Gracias et al. (2008 ▶); Insuasty et al. (2008 ▶); Chen et al. (2012 ▶). The title compound was obtained during work on the structural modification of our previously reported HIV-1 reverse transcriptase inhibitor, see: Wang et al. (2006 ▶).

Experimental

Crystal data

C₁₇H₂₂N₄O₃
M _r = 330.39
Monoclinic,
a = 13.831 (3) Å
b = 8.9904 (18) Å
c = 14.978 (3) Å
β = 112.79 (3)°
V = 1717.1 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 298 K
0.40 × 0.30 × 0.30 mm

Data collection

Rigaku R-AXIS RAPID IPdiffractometer
Absorption correction: multi-scan (ABSCOR; Higashi, 1995 ▶) T _min = 0.965, T _max = 0.974
7151 measured reflections
3921 independent reflections
1601 reflections with I > 2σ(I)
R _int = 0.041

Refinement

R[F ² > 2σ(F ²)] = 0.079
wR(F ²) = 0.250
S = 0.86
3921 reflections
218 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.70 e Å⁻³
Δρ_min = −0.59 e Å⁻³

Data collection: RAPID-AUTO (Rigaku, 2000 ▶); cell refinement: RAPID-AUTO; data reduction: CrystalStructure (Rigaku/MSC, 2000 ▶); 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: SHELXL97.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812014985/kp2397sup1.cif

e-68-o1396-sup1.cif^{(20.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812014985/kp2397Isup2.hkl

e-68-o1396-Isup2.hkl^{(192.2KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812014985/kp2397Isup3.cdx

Supplementary material file. DOI: 10.1107/S1600536812014985/kp2397Isup4.cdx

Supplementary material file. DOI: 10.1107/S1600536812014985/kp2397Isup5.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
N1—H1A⋯O2ⁱ	0.95 (4)	1.91 (4)	2.862 (4)	175 (3)
C13—H13⋯O1ⁱⁱ	0.93	2.49	3.397 (5)	164

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

Acknowledgments

We acknowledge financial support from the National Natural Science Foundation of China. We also express our appreciation to Mr Wenxiong Zhang and Nengdong Wang for helping in the resolution of the title compound.

supplementary crystallographic information

Comment

The title compound (Fig. 1) belongs to a class having pyrimidodiazepine scaffold which in recent years has exhibited a range of biological activities such as antitumor agents (Insuasty et al., 2008; Chen et al., 2012), HIV-integrase inhibitors (Ferreira et al., 2009) and receptor tyrosine kinase inhibitors (Gracias et al., 2008). The title compound is gained during the structural modification work of our previously reported HIV-1 reverse transcriptase inhibitor (Wang et al., 2006). The main goal of this modification is to enhance the physicochemical properties and the flexibility of the seven-membered ring fused to the pyrimidine ring.

In the title compound, the dihedral angle between the phenyl ring and the pyrimidine ring is 80.8 (1)°. The diazepine ring exhibits a twist-boat conformation. To make a clear description of this boat conformation, the C4, C6, N3 and N4 atoms are regarded as coplanar, so that the C2, C7 and C5 atoms lie at the same side of the plane.

In the crystal structure, the molecules are linked by an intermolecular hydrogen bond [N1-H···O 2.862 (4) and C13-H···O1 3.397 (5)Å] (Table 1, Fig. 2).

Experimental

The important intermediate 2,4-dimethoxy-5-methyl-9-phenyl-8,9-dihydro-5H- pyrimido[4,5-b][1,4]diazepin-6(7H)-one was prepared according to our procedure (Li et al., 2012). To a suspension of LiAlH₄ (13 mg, 0.34 mmol, 2 equiv) in dry Et₂O (15 mL) the above-mentioned intermediate lactam (0.17 mmol) was slowly added. Then the mixture was refluxed for 15 min, monitored by TLC. The mixture was cooled to rt, and quenched with a minimum amount of saturated aqueous sodium sulfate solution. Then the mixture was diluted with EtOAc, washed with brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a yellow oil. This was purified by column chromatograpy on silica gel. Elution with solvent mixture petroleum ether: EtOAc = 7: 1 gave the 2,4-dimethoxy-5-methyl-9-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine in 76% yield. The reduction product (70 mg, 0.23 mmol) was dissolved in THF (25 mL) at room temperature and then concentrated hydrochloric acid (0.5 mL) was added. The mixture was refluxed for 8 h and monitored by TLC. Then the mixture was neutralised by saturated sodium bicarbonate solution and extracted twice with EtOAc (20 mL). The combined organic fractions were washed with brine, dried over anhydrous Na₂SO4 and concentrated. Then recrystallization from MeOH/EtOAc/petroleum ether gave the colourless crystal product 43 mg, in 73% yield. To a suspension of the corresponding uracil (0.1 mmol) in chloroform (2 mL) N,O-bis(trimethylsilyl)acetamide (BSA) (0.25 mmol, 2.5equiv) was added and the stirring was continued until a clear solution was observed. Then chloromethyl ethyl ether (0.13 mmol) was added and the reaction mixture was stirred until no change in amount of the starting material. The reaction was quenched with a saturated solution of NaHCO₃ and extracted twice with CHCl₃ (10 mL). The combined organic fractions were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a yellow oil. This was purified by a thin layer chromatograpy on silica gel. Developing with dichloromethane: MeOH = 50: 1 gave the pure title compound in 69% yield. Then recrystallization from EtOAc/petroleum ether gave the colourless crystal. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 7.31 (t, J = 7.6 Hz,2H), 6.96 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 2H), 4.93 (s, 2H),3.77 (br s, 2H), 3.47 (q, J = 7.2 Hz, 2H), 3.01 (t, J = 5.6 Hz, 2H), 2.81(s, 3H), 1.89 (t, J = 5.6 Hz, 2H),1.11 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.14, 151.14, 145.05, 129.81, 121.32, 116.09, 72.96, 64.80, 51.25, 48.93,39.79, 23.01, 15.03. Anal. Calcd. for C₁₇H₂₂N₄O₃: C, 61.80; H, 6.71; N, 16. 96. Found: C, 61.71; H, 6.616; N, 17.00.