An efficient and high-yielding protocol for the production…
7
.40 (d,J = 2.4 Hz,1H), 7.13 (dd,J = 2.8, 5.6 Hz, 1H), 7.08 (dd, J = 2.4, 12 Hz,
H), 6.98 (t, J = 8.8 Hz, 1H), 6.85 (dd, J = 2.8, 8.4 Hz, 1H), 5.50 (brs, 2H), 2.80
d, J = 4.8 Hz, 3H).
1
(
Synthesis of 4-Chloro-3-trifluoromethylphenylisocyanate (8) To a stirred, cooled
solution of triphosgene (120 g, 0.4 mol) in EA (1.2 L), 4-chloro-3-(trifluo-
romethyl)aniline (9) (200 g, 1 mol) was added in batches, and the reaction mixture
was heated at 80 °C for 1 h. The desired product 8 was collected at 120 °C
(
0.1 MPa) by distillation under reduced pressure as a white crystal (224 g, 99.2 %)
?
with 99.7 % HPLC purity. Mp: 37–38 °C. MS m/z: 254.0 [M ? H] .
Synthesis of 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-
N-methylpicolinamide (1) To a stirred solution of 7 (131 g, 0.5 mol) in EA
(
900 mL), 8 (153 g, 0.7 mol) was added in batches. The mixture was stirred at room
temperature for 1.5 h, and filtered to afford the crude title product. Next, the
precipitate was suspended in diethyl ether (2 L), and stirred for 2 h. Then, the
mixture was filtered and dried to give the target compound 1 as a white crystal
(
229 g, 94.5 %) with 99.8 % HPLC purity. Mp: 206–207 °C. MS m/z: 480.9, 481.7,
- ? 1
4
82.9 [M-H] , 504.9, 505.8, 506.9 [M ? Na] . H-NMR (400 MHz, DMSO-d ) d:
6
9
.55 (s, 1H), 8.79 (q, J = 4.8 Hz, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.53 (d,
J = 5.6 Hz, 1H), 8.16 (t, J = 9.0 Hz, 1H), 8.13 (t, J = 1.5 Hz, 1H), 7.63 (d,
J = 1.5 Hz, 2H), 7.43 (d, J = 2.6 Hz, 1H), 7.34 (dd, J = 11.6, 2.7 Hz, 1H),
7
.21–7.17 (m, 1H), 7.08 (ddd, J = 8.9, 2.8, 1.3 Hz, 1H), 2.80 (d, J = 4.8 Hz, 3H).
Acknowledgments The project was supported by Program for Liaoning Excellent Talents in University
(
(
Grant No. LR2014030) and the Special Research Foundation of Shenyang Pharmaceutical University
Grant No. ZCJJ2014401).
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