H
J. L. Holmes et al.
Paper
Synthesis
HRMS: m/z [M
366.18127.
+
H]+ calcd for C21H24N3O3: 366.18122; found
Further experimental details and compound data are available in the
Supporting Information.
Quinazolin-4(3H)-ones 18a–k; General Procedure
Acknowledgments
DIPEA (0.30 mL, 1.70 mmol) was added in one portion to (2-chloro-4-
oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (16; 101 mg, 0.40
mmol) and amine HNR2 (0.40 mmol) in DMF (3 mL). The resulting
solution was stirred at 100 °C for 30–60 minutes. K2CO3 (273 mg, 1.98
mmol) and MeOH (5 mL) were added and the mixture was stirred
overnight at 50 °C. The crude product was purified by preparative
HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diame-
ter, 100 mm length) using decreasingly polar mixtures of H2O (con-
taining 1% NH3) and MeCN as eluents. Fractions containing the de-
sired compound were evaporated to dryness to afford the desired
products.
We would like to thank Rebecca Burton, Gemma Mayers, Caroline Mc-
Millan, Nia Lock, Howard Beeley and Paul Davey for purification, NMR
and mass spectrometry assistance.
Supporting Information
Supporting information for this article is available online at
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References
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893.
The above method was used to provide the target 18a as a colourless
solid; yield: 75 mg (37%).
(2) Johannes, J. W.; Almeida, L.; Barlaam, B.; Boriack-Sjodin, P. A.;
Casela, R.; Croft, R. A.; Dishington, A. P.; Gingipalli, L.; Gu, C.;
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(3) (a) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
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Chang, R. S. L.; Lotti, V. J.; Chen, T. B.; Scheck, S. A.; Faust, K. A.
J. Med. Chem. 1993, 36, 3207.
1H NMR (500 MHz, DMSO-d6): δ = 3.75 (s, 3 H), 3.81–3.95 (m, 1 H),
4.03 (dd, J = 6.4, 8.6 Hz, 2 H), 4.48 (t, J = 8.6, 2 H), 4.78 (s, 2 H), 6.87–
6.98 (m, 2 H), 7.07–7.19 (m, 1 H), 7.27–7.38 (m, 2 H), 7.58–7.73 (m, 1
H), 7.83 (dd, J = 1.7, 7.9 Hz, 1 H).
13C NMR (176 MHz, DMSO): δ = 32.80, 55.06, 57.83, 59.33, 114.00,
116.61, 121.34, 123.98, 127.98, 130.79, 133.95, 136.06, 147.46,
151.53, 158.14, 162.76.
HRMS: m/z [M
+
H]+ calcd for C19H20N3O3: 338.14992; found
338.14972.
Quinazolin-4(3H)-ones 20a,b; General Procedure
DIPEA (0.15 mL, 0.88 mmol) was added to the imidazole (0.29 mmol,
1 equiv) in DMA (6 mL) and the mixture was stirred for 10 minutes.
(2-Chloro-4-oxo-3-tosyl-3,4-dihydroquinazolin-8-yl)methyl acetate
(19; 118 mg, 0.29 mmol) and sodium methanesulfinate (30 mg, 0.29
mmol) were added and the mixture stirred for 72 hours at 80 °C. The
temperature was reduced to 50 °C and K2CO3 (100 mg, 0.72 mmol) in
MeOH (3 mL) was added. The mixture was stirred overnight. The re-
action mixture was filtered and concentrated in vacuo. The crude
product was purified by preparative HPLC (Waters XBridge Prep C18
OBD column, 5μ silica, 19 mm diameter, 100 mm length) using de-
creasingly polar mixtures of H2O (containing 1% NH3) and MeCN as
eluents. Fractions containing the desired compound were evaporated
to dryness to afford the desired compounds.
(5) (a) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.;
Duch, D. S.; Ferone, R.; Hall, W. R.; Humphreys, J.; Kelly, J. M.;
Wilson, D. C. J. Med. Chem. 1993, 36, 2279. (b) Kung, P. P.;
Casper, M. D.; Cook, K. L.; Wilson-Lingardo, L.; Risen, L. M.;
Vickers, T. A.; Rankin, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D.
J. Med. Chem. 1999, 42, 4705.
(6) (a) Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S. W.;
Yen, M. H.; Chien, S. L.; Rong, J. K. J. Med. Chem. 1998, 41, 3128.
(b) Hirai, S.; Kikuchi, H.; Kim, H.-S.; Begum, K.; Watay, Y.;
Tasaka, H.; Miyazawa, Y.; Yamamoto, K.; Oshima, Y. J. Med.
Chem. 2003, 46, 4351. (c) Kikuchi, H.; Tasaka, H.; Hirai, S.;
Takaya, Y.; Iwabuchi, Y.; Ooi, H.; Hatakeyama, S.; Kim, H.-S.;
Wataya, Y.; Oshima, Y. J. Med. Chem. 2002, 45, 2563.
(7) Ravn, C.; Rasmussen, S. R. PCT Int. Appl. WO2006002255, 2006;
Chem. Abstr. 2006, 144, 94418.
8-(Hydroxymethyl)-2-(4-phenyl-1H-imidazol-1-yl)quinazolin-
4(3H)-one (20b)
(8) (a) Segarra, V.; Crespo, M. I.; Pujol, F.; Beleta, J.; Domenech, T.;
Miralpeix, M.; Palacios, J. M.; Castro, A.; Martinez, A. Bioorg.
Med. Chem. Lett. 1998, 8, 505. (b) Connelly, D. J.; Guiry, P. J.
Synlett 2001, 1707. (c) Liu, J. F.; Ye, P.; Zhang, B.; Bi, G.; Sargent,
K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70,
6339. (d) Kshirshagar, U. A.; Agarde, N. P. Org. Lett. 2010, 12,
3716.
The above method was used to provide the target 20b as a colourless
solid; yield: 12 mg (13%).
1H NMR (400 MHz, DMSO-d6): δ = 4.98 (s, 2 H), 7.23–7.31 (m, 1 H),
7.34 (t, J = 7.5 Hz, 1 H), 7.38–7.47 (m, 2 H), 7.77 (d, J = 6.9 Hz, 1 H),
7.89 (dd, J = 1.3, 8.2 Hz, 2 H), 7.94–8.00 (m, 1 H), 8.42 (d, J = 1.2 Hz, 1
H), 8.63 (d, J = 1.2 Hz, 1 H).
(9) (a) Xu, L.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 1150. (b) Zhou, J.;
Fu, L.; Lv, M.; Liu, J.; Pei, D. Ding K. 2008, 15, 3974. (c) Liu, X.; Fu,
H.; Jiang, Y.; Xhao, Y. Angew. Chem. Int. Ed. 2009, 48, 348; Angew.
Chem. 2009, 121, 354.
(10) (a) Cox, C. D.; Raheem, I. T.; Flores, B. A.; Whitman, D. B. US Pat.
Appl. Publ. US20110319409, 2011; Chem. Abstr. 2011, 156,
92460. (b) Dumaître, B.; Dodic, N. J. Med. Chem. 1996, 39, 1635.
13C NMR (100 MHz, DMSO-d6): δ = 59.21, 112.56, 120.54, 123.45,
124.20, 124.59, 126.82, 128.57, 129.85, 133.72, 136.12, 137.66,
141.06, 146.82, 147.59, 167.62.
HRMS: m/z [M
+
H]+ calcd for C18H15N4O2: 319.11895; found
319.11893.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I