L. Liang et al.
Bioorganic & Medicinal Chemistry 39 (2021) 116165
resulting solid was filtrated and dried to give compound 11 (2.9 g, 91%).
1H NMR (400 MHz, DMSO‑d6) δ 12.74 (brs, 1H), 8.30 (s, 1H), 8.09 (d, J
= 8.0 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 2.58 (d, J = 5.6 Hz, 2H), 2.40 (s,
2H), 1.79–1.64 (m, 4H). 13C NMR (101 MHz, DMSO‑d6) δ 175.16,
171.76, 165.55, 160.47, 159.90, 159.70, 157.13, 147.93, 134.70,
134.60, 132.64, 129.03, 128.99, 124.50, 124.37, 121.60, 119.66,
119.42, 72.83, 43.25, 40.57, 40.37, 40.16, 39.95, 39.74, 39.53, 39.32,
31.44, 22.49, 21.99, 21.61.
δ 7.98 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.01 (tt,
J = 2.0, 6.0 Hz, 1H), 5.42 (dd, J = 17.2, 1.2 Hz, 1H), 5.32 (d, J = 10.4
Hz, 1H), 4.83 (dd, J = 6.0, 1.2 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H), 2.57 (t, J
= 5.6 Hz, 2H), 1.89 1.74 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 163.01,
160.27, 159.98, 145.90, 132.58, 131.32, 126.76, 123.25, 120.27, 120
0.04, 119.48, 66.66, 31.42, 22.39, 21.91, 21.47. HRMS (ESI): calcd for
C
18H17ClFN2O3 [M+H]+ 363.0912, found: 363.0907.
4.1.21. Data for prop-2-yn-1-yl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
tetrahydroquinazolin-3(4H)-yl)benzoate (2g)
4.1.15. The general method to synthesize compounds 2b-p
A mixture of intermediate 11 (0.5 mmol), K2CO3 (0.083 g, 0.6
mmol), and N,N-dimethylformamide (20 mL) was stirred at 25 ◦C for 15
min. Then, R2I or R2Br (0.6 mmol) was added to the reaction mixture.
After stirring for 6 h, 60 mL of CH3CO2C2H5 and 60 mLof H2O were
added to the mixture. The CH3CO2C2H5 layer was separated and washed
with Na2CO3 (100 mL) and brine (50 mL), and concentrated using rotary
evaporation. The residue was purified by column chromatography to
provide compounds 2b-p.
White solid, m.p. 147–149 ◦C, yield 87%; 1H NMR (400 MHz, CDCl3)
δ 8.01 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 4.93 (d,
J = 2.4 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.63–2.52 (m, 3H), 1.98–1.69
(m, 4H); 13C NMR (101 MHz, CDCl3) δ 162.35, 160.45, 160.30, 160.00,
157.68, 145.82, 137.66, 137.56, 132.84, 125.84, 123.86, 123.73,
123.20, 120.39, 120.16, 76.85, 75.81, 53.24, 31.50, 22.39, 21.94,
21.50. HRMS (ESI): calcd for C18H15ClFN2O3 [M+H]+ 361.0755, found:
361.0751.
4.1.16. Data for ethyl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
4.1.22. Data for 2-ethoxy-2-oxoethyl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
tetrahydroquinazolin-3(4H)-yl)benzoate (2h)
tetrahydroquinazolin-3(4H)-yl)benzoate (2b)
White solid, m.p. 155–157 ◦C, yield 93%; 1H NMR (400 MHz, CDCl3)
δ 7.95 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.42 (d, J = 9.2 Hz, 1H), 4.39 (q,
J = 7.2 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 6.0 Hz, 2H),
1.88–1.75 (m, 4H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 163.38, 160.38, 160.02, 159.90, 157.29, 145.89, 137.04, 136.94,
132.45, 127.15, 123.73, 123.60, 123.16, 120.13, 119.90, 62.07, 31.49,
22.38, 21.95, 21.50, 14.15. HRMS (ESI): calcd for C17H17ClFN2O3
[M+H]+ 351.0912, found: 351.0911.
White solid, m.p. 102–104 ◦C, yield 83%; 1H NMR (400 MHz, CDCl3)
δ 8.07 (dd, J = 7.6, 2.0 Hz, 1H), 7.92 (s, 1H), 7.48–7.41 (m, 1H), 4.84 (t,
J = 2.0 Hz, 2H), 4.26 (dddd, J = 9.6, 7.2, 4.8, 2.4 Hz, 2H), 2.69 (s, 2H),
2.57 (s, 2H), 1.89–1.73 (m, 4H), 1.30 (tt, J = 7.2, 2.4 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 167.16, 162.55, 160.41, 159.97, 157.74, 145.84,
132.94, 125.80, 123.87, 123.17, 120.33, 120.10, 61.74, 61.58, 31.48,
22.38, 21.94, 21.50, 14.11. HRMS (ESI): calcd for C19H19ClFN2O5
[M+H]+ 409.0967, found: 409.0968.
4.1.17. Data for propyl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
4.1.23. Data for 1-ethoxy-1-oxopropan-2-yl 2-chloro-4-fluoro-5-(4-oxo-
5,6,7,8-tetrahydroqui-nazolin-3(4H)-yl)benzoate (2i)
tetrahydroquinazolin-3(4H)-yl)benzoate (2c)
White solid, m.p. 143–145 ◦C, yield 70%; 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 9.2 Hz, 1H), 4.30 (t, J = 6.8 Hz,
2H), 2.70 (t, J = 5.6 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.84 (d, J = 7.2 Hz,
2H), 1.79 (dd, J = 14.0, 7.2 Hz, 4H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 160.31, 145.91, 132.42, 123.23, 120.16, 119.93,
67.75, 31.47, 22.40, 21.94, 21.50, 10.56. HRMS (ESI): calcd for
C18H19ClFN2O3 [M+H]+ 365.1068, found: 365.1067.
White solid, m.p. 138–140 ◦C, yield 81%; 1H NMR (400 MHz, CDCl3)
δ 8.03 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 5.32 (q,
J = 7.2 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 2.69 (d, J = 6.0 Hz, 2H), 2.58
(d, J = 6.0 Hz, 2H), 1.90–1.73 (m, 4H), 1.61 (d, J = 7.2 Hz, 3H), 1.29 (t,
J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.21, 162.61, 160.50,
160.05, 157.68, 145.87, 137.48, 132.73, 126.14, 123.85, 123.17,
120.28, 120.05, 70.01, 61.72, 31.52, 22.40, 21.95, 21.50, 16.92, 14.13.
HRMS (ESI): calcd for C20H21ClFN2O5 [M+H]+ 423.1123, found:
423.1122.
4.1.18. Data for butyl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
tetrahydroquinazolin-3(4H)-yl)benzoate (2d)
White solid, m.p. 109–111 ◦C, yield 84%; 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 9.2 Hz, 1H), 4.34 (t, J = 6.8 Hz,
2H), 2.69 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 6.0 Hz, 2H), 1.89–1.77 (m, 4H),
1.73 (dd, J = 14.8, 6.8 Hz, 2H), 1.45 (dd, J = 15.2, 7.6 Hz, 2H), 0.97 (t, J
= 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.58, 160.37, 160.03,
159.91, 157.31, 145.90, 137.04, 136.94, 132.40, 127.28, 127.24,
123.75, 123.61, 123.20, 120.16, 119.93, 66.01, 31.50, 30.56, 22.40,
21.95, 21.51, 19.22, 13.69. HRMS (ESI): calcd for C19H21ClFN2O3
[M+H]+ 379.1225, found: 379.1226.
4.1.24. Data for 2-(allyloxy)-2-oxoethyl 2-chloro-4-fluoro-5-(4-oxo-
5,6,7,8-tetrahydroquinazo-lin-3(4H)-yl)benzoate (2j)
White solid, m.p. 158–160 ◦C, yield 70%; 1H NMR (400 MHz, CDCl3)
δ 8.08 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.45 (d, J = 9.2 Hz, 1H), 5.91
(ddd, J = 16.4, 10.8, 5.6 Hz, 1H), 5.32 (dd, J = 28.4, 13.6 Hz, 2H), 4.88
(s, 2H), 4.69 (d, J = 5.6 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.57 (t, J = 5.6
Hz, 2H), 1.90–1.71 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 166.89,
162.53, 160.40, 159.97, 157.77, 145.82, 137.70, 137.60, 132.97,
131.19, 125.71, 123.88, 123.75, 123.18, 120.36, 120.13, 119.31, 77.37,
77.05, 76.73, 66.20, 61.48, 31.49, 22.39, 21.94, 21.50. HRMS (ESI):
calcd for C20H19ClFN2O5 [M+H]+ 421.0967, found: 421.0963.
4.1.19. Data for isopropyl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
tetrahydroquinazolin-3(4H)-yl)benzoate (2e)
White solid; m.p. 135–137 ◦C, yield 70%; 1H NMR (400 MHz, CDCl3)
δ 7.92 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H),
5.31–5.22 (m, 1H), 2.69 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 5.6 Hz, 2H),
1.89–1.74 (m, 4H), 1.37 (d, J = 6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 163.01, 160.37, 160.05, 159.82, 157.22, 145.91, 136.91, 136.81,
132.23, 127.73, 123.73, 123.59, 123.17, 120.04, 119.81, 70.09, 31.49,
22.39, 21.95, 21.80, 21.51. HRMS (ESI): calcd for C18H19ClFN2O3
[M+H]+ 365.1068, found: 365.1064.
4.1.25. Data for 1-(allyloxy)-1-oxopropan-2-yl 2-chloro-4-fluoro-5-(4-
oxo-5,6,7,8-tetrahydro-quinazolin-3(4H)-yl)benzoate (2k)
White solid, m.p. 188–190 ◦C, yield 75%; 1H NMR (400 MHz, CDCl3)
δ 8.08 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.45 (d, J = 9.2 Hz, 1H), 5.92
(ddd, J = 16.4, 11.2, 5.6 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 5.28 (d, J =
10.4 Hz, 1H), 4.88 (s, 2H), 4.69 (d, J = 5.6 Hz, 2H), 2.63 (dt, J = 11.2,
5.6 Hz, 5H), 1.93–1.69 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 166.89,
162.53, 160.40, 159.97, 157.77, 145.82, 137.70, 137.60, 132.97,
131.19, 125.71, 125.68, 123.88, 123.75, 123.18, 120.36, 120.13,
119.31, 100.00, 77.37, 77.05, 76.73, 66.20, 61.48, 31.49, 22.39, 21.94,
21.50. HRMS (ESI): calcd for C21H21ClFN2O5 [M+H]+ 435.1123, found:
435.1120.
4.1.20. Data for allyl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-
tetrahydroquinazolin-3(4H)-yl)benzoate (2f)
White solid, m.p. 176–178 ◦C, yield 88%; 1H NMR (400 MHz, CDCl3)
8