2262 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Widler et al.
lin-2-one (prepared analogously to compound 10a) and 10 g
(180 mmol) of iron powder in 180 mL of glacial acetic acid was
stirred at 45 °C for 30 h. After 6 and 15 h, additional batches of
10 g of iron powder were added. The mixture was filtered
through Hyflo and distributed between water and dichloro-
methane. The crude product was obtained as a yellow foam,
which was purified by chromatography (ethyl acetate/petro-
leum ether) to yield 5.05 g (61%) of 1-(3-amino-benzyl)-4-(4-
isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one.
1H NMR (300 MHz, CDCl3): δ 7.75 (d, 2H), 7.48 (s, 1H), 7.39
(d, 2H), 7.30 (s, 2H), 7.11 (t, 1H), 6.73 (d, 1H), 6.62 (s, 1H), 6.57
(d, 1H), 5.46 (broad s, 2H), 4.64 (d, 2H), 3.65 (broad s, NH2),
3.02 (hept, 1H), 2.54 (t, 1H), 1.32 (d, 6H).
The aniline (13.60 g; 32.0 mmol) obtained above was dis-
solved in 200 mL of dichloromethane and 5.4 mL (38.5 mmol) of
triethylamine and was treated at -5 °C dropwise with 2.74 mL
(35.2 mmol) of chloroacetyl chloride. After completed addition,
the cooling bath was removed and the suspension allowed to
come to rt. Workup was done after stirring for 2 h at rt by the
addition of water and additional dichloromethane. A quantita-
tive crude yield (16.0 g) of 2-chloro-N-{3-[4-(4-isopropyl-
phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phe-
nyl}-acetamide was obtained in the form of dark-green crystals
which were used without purification for the next step. 1H NMR
(300 MHz, CDCl3): δ 8.34 (broad, NH), 7.72 (d, 2H), 7.60 (d,
1H), 7.49 (d, 1H), 7.46 (s, 1H), 7.37 (d, 2H), 7.27-7.35 (m, 3H),
7.12 (d, 1H), 5.53 (broad, 2H), 4.64 (d, 2H), 4.16 (s, 2H), 3.01
(hept, 1H), 2.55 (t, 1H), 1.32 (d, 6H).
A DMEU solution (25 mL) of 11.0 g (33.3 mmol) of the
chloroacetyl derivative obtained above was treated with potas-
sium carbonate (6.1 g; 44 mmol) and 1-(2-methoxyethyl)-piper-
azine (4.75 g; 33.0 mmol). The mixture was heated to 65 °C for
2 h. The yellow product was filtered off from the resulting
suspension and washed with water. Furthermore, the filtrate
was extracted with ethyl acetate, and the organic layers were
concentrated in vacuo to give additional material. The com-
bined crude material was purified by chromatography
(dichloromethane/methanol). Yield: 14.0 g (98%) 21b; mp
199-200 °C. 1H NMR (300 MHz, CDCl3): δ 9.05 (broad,
NH), 7.75 (d, 2H), 7.58 (s, 1H), 7.53 (d, 1H), 7.49 (d, 1H), 7.39
(d, 2H), 7.27-7.35 (m, 3H), 7.05 (d, 1H), 5.53 (broad s, 2H), 4.64
(s, 2H), 3.55 (broad t, 2H), 3.35 (s, 3H), 3.13 (s, 2H), 3.02 (hept,
1H), 2.75-2.56 (broad, 10H), 2.54 (t, 1H), 1.32 (d, 6H). MS: 608
(M þ 1)þ.
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Acknowledgment. We thank Prof. Gerda Breitwieser
(Syracuse University, NY) for providing us with point muta-
tions of CaSR to investigate the binding mode of our com-
pounds. Expert technical assistance of the following
colleagues is gratefully acknowledged. Chemistry: Sandra
Ammon Vetter, Nadine Braendlin, Pascale Fille, Bernard
Flueckiger, Hansjoerg Haas, Doris Huerzeler, Sabine Kim-
ꢀ
mel, Michael Kindler, Remy Klein, Patrick Lerch, Uzel
Nilufer, Esther Roehn-Carnemolla, Karin Ryffel, Gerard
Schreiber, Ivan Trkulja. Prep lab: Dominik Wiss, Thomas
Ruppen, Martin Roggwiller. HTS: Laurent Tenaillon, Jochen
Wyss. Biology: Heinz Anklin, Margot Bruederlin, Reto Cor-
tesi, Lilian Hartmann, Marcel Merdes, Roger Vuille, Barbara
ꢀ
Wilmering-Wetter. PK/PD: Valerie Cordier, Lothar Dillo,
Paul Hernandez, Laura Pedrini, Jean-Louis Runser, Esther
Scheidegger, Hans Zihlmann. We thank Angela Mackay for
proofreading and correcting the manuscript.
Supporting Information Available: Experimental information
on synthetic preparation and analytical data of compounds
2b-2e, 2g-2j, 7b-7e, 7g-7i, 8, 10b-10l, 16a-16d, 16f, 16g,
16i, 21a, and 21c. This material is available free of charge via the
(7) Marquis, R. W.; Ramanjulu, J. M.; Casillas, L. N. Preparation of
acyloxy-amino-functionalized-aromatic carboxy compounds as