3
40
Huang et al.
2
-Amino-6-fluoro-N-phenylbenzamide (10)
To a solution of 2-fiuoro-6-nitro-N-phenylbenzamide (1, 137 g, 0.53 mol) in MeOH
1000 ml) was added 10% Pd /C (13.7 g). The mixture was placed under hydrogen atmo-
(
sphere (5.0 bar) in a high pressure apparatus. After shaking overnight at room tempera-
ture, the resulting mixture was filtered through Celite and the filtrate was concentrated in
ꢀ
vacuo to give 10 (119.0 g, 98%) as a white solid, mp. 114–115 C. ESI-MS (m/z): 231
1
C
(
[MCH] ); H-NMR: d 8.27 (s, 1H), 7.59 (d, J D 8 Hz, 2H), 7.35 (t, J D 8 Hz, 2H),
7
.16–7.09 (m, 2H), 6.46 (d, J D 8.4 Hz, 1H), 6.40 (dd, J D 8.4, 13.2 Hz, 1H).
Anal. Calcdfor C H FN O: C, 67.82; H, 4.82; N, 12.17. Found: C, 67.68; H, 4.82; N, 12.13.
11
13
2
tert-Butyl [(1S)-1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)propyl]
carbamate (11)
ꢀ
To a solution of the acid 3 (256.8 g, 1.26 mol) in dry THF (1600 ml) at ¡15 C was
slowly added N-methylmorpholine (165 ml, 1.48 mol) dropwise followed by isobutyl
chloroformate (165 ml, 1.26 mol). The reaction mixture was stirred at ¡10 C for 2 h. A
ꢀ
solution of 10 (121 g, 0.53 mol) was added to the above reaction mixture over 0.5 h.
ꢀ
ꢀ
After stirring overnight at 60 C, the mixture was cooled to 25 C and then the solvent was
ꢀ
removed in vacuo at 30 C. The resulting residue was triturated with water (2000 ml), and
the suspension was filtered. The filter cake was washed with water (200 ml £ 3) and dried
under vacuum. The resulting solid was triturated with isopropyl ether to afford 11
C
ꢀ
(
214.3 g, 98.0%) as a white powder. mp. 179–180 C. ESI-MS (m/z): 438 ([MCNa] );
1
H-NMR: d 8.52 (d, J D 8.4 Hz, 1H), 8.38 (d, J D 14.4 Hz, 1H), 7.63 (d, J D 8 Hz, 2H),
7
.46-7.37 (m, 4H), 7.21 (t, J D 7.6 Hz, 1H), 6.90 (dd, J D 12, 8.4 Hz, 1H), 5.11 (s, 1H),
.26 (s, 1H), 1.80-1.73 (m, 2H), 1.44(s, 9H), 1.03 (t, J D 7.6 Hz, 3H).
4
Anal.CalcdforC H FN O :C,63.60;H,6.31;N,10.11.Found:C,63.45;H,6.40;N,10.12.
26
2
2
3 4
(S)-2-(1-Aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (7)
To a suspension of 11 (100 g, 0.24 mol) and iodine (183.7 g, 0.72 mol) in DCM (800 ml)
at room temperature was slowly added hexamethyldisilazane (301.7 ml, 1.45 mol) over
1
h. The reaction mixture was stirred at room temperature for 9 h, diluted with DCM
ꢀ
(500 ml), quenched with 5% Na SO (1200 ml) at 0 C and stirred for a further 50 min at
2
3
ꢀ
2
5 C. The organic layer was separated and washed with 5% Na SO (1000 ml £ 3),
2
3
water (1000 ml £ 2) and brine (1000 ml). The organic phase was dried over anhydrous
Na SO , filtered and the filtrate was concentrated under reduced pressure. The resulting
2
4
light green solid was triturated with isopropyl acetate to give 7 (51.5 g, 72.0%) as a white
C
ꢀ
1
powder, mp. 166–167 C. ESI-MS (m/z): 298 ([MCH] ); H-NMR: d 7.69–7.64 (m, 1H),
7
1
.56-7.48 (m, 4H), 7.29–7.24 (m, 2H), 7.19–7.06 (m, 1H), 3.45 (dd, J D 7.5, 5.2 Hz, 1H),
.82–1.76 (m, 1H), 1.55–1.45 (m, 1H), 0.79 (t, J D 7.5 Hz, 3H).
Anal. Calcd for C H FN O: C, 68.67; H, 5.42; N, 14.13. Found: C, 68.45; H, 5.46;
1
7
16
3
N, 14.04.
5-Fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl) amino)
propyl) quinazolin-4(3H)-one (13)
N,N-Diisopropylethylamine (36 ml, 0.22 mol) was added dropwise to a solution of 7
(32.4 g, 0.11 mol) and 6-chloro-9-(tetrahydro-2-pyranyl)purine (12, 31.1 g, 0.13 mol) in