S. Zhu et al. / Bioorg. Med. Chem. 17 (2009) 4496–4502
4501
311.1120) (100%). Anal. Calcd for C14H16N4O3ꢂHCl: C, 51.78; H,
5.28; Cl, 10.92; N, 17.25. Found: C, 51.83; H, 5.25; Cl, 10.81; N,
17.34.
1H), 4.39 (m, 1H), 4.24 (m, 1H), 3.47–3.41 (m, 2H), 2.85 (dd,
J = 15.7, 4.4 Hz, 1H), 2.77 (dd, J = 15.7, 5.9 Hz, 1H), 2.20 (m, 1H),
1.92 (m, 1H); 13C NMR (CD3OD): 203.3, 167.8, 162.6, 147.3, 137.1,
133.5, 129.8, 128.1, 127.4, 119.2, 76.9, 58.2, 57.1, 38.8, 33.1, 30.9.
HRESIMS m/z 378.1035 [M+Na]+ (calcd for C16H16F3N3NaO3
,
þ
4.1.10. (2R,3S)-5-Fluoro-3-[3-(3-hydroxy-pyrrolidin-2-yl)-2-
oxo-propyl]-3H-quinazolin-4-one (12)
378.1041) (100%). Anal. Calcd for C16H16F3N3O3ꢂHCl: C, 49.05; H,
4.37; Cl, 9.05; F, 14.55; N, 10.73. Found: C, 48.98; H, 4.41; Cl, 9.11;
F, 14.49; N, 10.67.
Pale-yellow crystals. Mp: 242 °C. ½a D25
ꢃ
ꢀ33.8 (c 0.5, EtOH). 1H
NMR (CD3OD): 8.32 (s, 1H), 8.20 (d, J = 7.1 Hz, 1H), 7.73 (d,
J = 7.2 Hz, 1H), 7.55 (t, J = 7.1 Hz, 1H), 5.10 (d, J = 17.4 Hz, 1H),
4.93 (d, J = 17.4 Hz, 1H), 4.43 (m, 1H), 4.10 (m, 1H), 3.48–3.40 (m,
2H), 2.82 (m, 1H), 2.77 (dd, J = 15.2 and 5.8 Hz, 1H), 2.28 (m, 1H),
1.93 (m, 1H); 13C NMR (CD3OD): 203.1, 164.1, 158.5, 152.7,
4.1.15. (2R,3S)-5-tert-Butyl-3-[3-(3-hydroxy-pyrrolidin-2-yl)-2-
oxo-propyl]-3H-quinazolin-4-one (17)
Off-white crystal. Mp: 193–194 °C. ½a D25
ꢃ
+12.4 (c 0.51, EtOH). 1H
NMR (CD3OD): 8.25 (d, J = 7.2 Hz, 1H), 8.17 (s, 1H), 7.74 (d,
J = 7.2 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 5.12 (d, J = 16.9 Hz, 1H),
5.00 (d, J = 16.9 Hz, 1H), 4.34 (m, 1H), 4.12 (m, 1H), 3.49–3.42 (m,
2H), 2.91 (dd, J = 15.5, 4.5 Hz, 1H), 2.82 (dd, J = 15.5, 5.8 Hz, 1H),
2.22 (m, 1H), 1.89 (m, 1H), 1.31 (s, 9H); 13C NMR (CD3OD): 202.3,
169.5, 165.1, 152.9, 147.2, 143.1, 133.9, 130.1, 129.9, 77.3, 58.6,
149.3, 147.5, 132.8, 132.2, 129.6, 80.2, 58.6, 53.2, 50.9, 43.8, 35.9.
HRESIMS m/z 328.1082 [M+Na]+ (calcd for C15H16FN3NaO3
,
þ
328.1073) (100%). Anal. Calcd for C15H16FN3O3ꢂHCl: C, 52.71; H,
5.01; Cl, 10.37; F, 5.56; N, 12.30. Found: C, 52.80; H, 5.00; Cl,
10.26; F, 5.51; N, 12.34.
56.4, 39.4, 35.6, 33.6, 31.9, 30.5. HRESIMS m/z 366.1782 [M+Na]+
, 366.1794) (100%). Anal. Calcd for
C19H25N3O3ꢂHCl: C, 60.07; H, 6.90; Cl, 9.33; N, 11.06. Found: C,
4.1.11. (2R,3S)-6-Fluoro-3-[3-(3-hydroxy-pyrrolidin-2-yl)-2-
oxo-propyl]-3H-quinazolin-4-one (13)
þ
(calcd for C19H25N3NaO3
Pale-yellow crystal. Mp: 196–197 °C. ½a D25
ꢃ
+26.3 (c 0.5, EtOH).
60.13; H, 6.87; Cl, 9.29; N, 11.12.
1H NMR (CD3OD): 8.24 (s, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.53 (s,
1H), 7.46 (d, J = 7.1 Hz, 1H), 5.08 (d, J = 17.3 Hz, 1H), 4.95 (d,
J = 17.3 Hz, 1H), 4.48 (m, 1H), 4.15 (m, 1H), 3.47–3.39 (m, 2H),
2.86 (m, 1H), 2.79 (dd, J = 15.1 and 5.6 Hz, 1H), 2.32 (m, 1H), 1.89
(m, 1H); 13C NMR (CD3OD): 202.9, 167.9, 163.6, 147.1, 133.2,
4.1.16. (2R,3S)-6-tert-Butyl-3-[3-(3-hydroxy-pyrrolidin-2-yl)-2-
oxo-propyl]-3H-quinazolin-4-one (18)
Off-white crystal. Mp: 190–191 °C. ½a D25
ꢃ
ꢀ10.3 (c 0.45, EtOH). 1H
NMR (CD3OD): 8.20 (s, 1H), 7.94 (d, J = 7.1 Hz, 1H), 7.69 (d,
J = 7.1 Hz, 1H), 7.56 (s, 1H), 5.09 (d, J = 17.1 Hz, 1H), 4.97 (d,
J = 17.1 Hz, 1H), 4.30 (m, 1H), 4.18 (m, 1H), 3.48–3.40 (m, 2H),
2.93 (dd, J = 15.9, 4.6 Hz, 1H), 2.84 (dd, J = 15.9, 5.9 Hz, 1H), 2.29
(m, 1H), 1.92 (m, 1H), 1.34 (s, 9H); 13C NMR (CD3OD): 202.9,
167.9, 164.6, 154.1, 143.2, 134.7, 129.9, 128.8, 128.4, 79.2, 59.1,
129.7, 128.9, 128.0, 127.7, 78.4, 60.4, 54.0, 51.1, 42.5, 34.5. HRE-
SIMS m/z 328.1066 [M+Na]+ (calcd for C15H16FN3NaO3
,
þ
328.1073) (100%). Anal. Calcd for C15H16FN3O3ꢂHCl: C, 52.71; H,
5.01; Cl, 10.37; F, 5.56; N, 12.30. Found: C, 52.64; H, 5.05; Cl,
10.42; F, 5.52; N, 12.24.
56.9, 38.8, 36.2, 34.2, 31.7, 30.2. HRESIMS m/z 366.1803 [M+Na]+
, 366.1794) (100%). Anal. Calcd for
C19H25N3O3ꢂHCl: C, 60.07; H, 6.90; Cl, 9.33; N, 11.06. Found: C,
4.1.12. (2R,3S)-5,6-Difluoro-3-[3-(3-hydroxy-pyrrolidin-2-yl)-2-
oxo-propyl]-3H-quinazolin-4-one (14)
þ
(calcd for C19H25N3NaO3
Pale-yellow crystal. Mp: 241 °C. ½a D25
ꢃ
ꢀ11.8 (c 0.5, EtOH). 1H
60.01; H, 6.93; Cl, 9.37; N, 10.98.
NMR (CD3OD): 8.31 (s, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.74 (d,
J = 6.9 Hz, 1H), 5.06 (d, J = 17.4 Hz, 1H), 4.92 (d, J = 17.4 Hz, 1H),
4.39 (m, 1H), 4.12 (m, 1H), 3.48–3.40 (m, 2H), 2.92 (m, 1H), 2.78
(dd, J = 14.9 and 5.8 Hz, 1H), 2.28 (m, 1H), 1.87 (m, 1H); 13C NMR
(CD3OD): 202.8, 162.8, 161.6, 158.5, 152.1, 149.4, 147.2, 132.4,
130.5, 80.7, 58.5, 53.8, 51.4, 43.6, 37.2. HRESIMS m/z 346.0984
[M+Na]+ (calcd for C15H15F2N3NaO3þ, 346.0979) (100%). Anal. Calcd
for C15H15F2N3O3ꢂHCl: C, 50.08; H, 4.48; Cl, 9.85; F, 10.56; N, 11.68.
Found: C, 50.14; H, 4.44; Cl, 9.91; F, 10.49; N, 11.75.
4.1.17. (2R,3S)-3-[3-(3-Benzyloxy-pyrrolidin-2-yl)-2-oxo-
propyl]-3H-pyrido[3,2-d]pyrimidin-4-one (19)
Yellow crystal. Mp: 232–233 °C. ½a D25
ꢃ
+25.7 (c 0.5, EtOH). 1H NMR
(CD3OD): 9.61 (d, J = 7.2 Hz, 1H), 9.19 (d, J = 7.2 Hz, 1H), 8.76 (s, 1H),
8.31 (t, J = 7.2 Hz, 1H), 7.22–7.18 (m, 5H), 5.08 (d, J = 17.2 Hz, 1H),
4.89 (d, J = 17.2 Hz, 1H), 4.69 (m, 2H), 4.40 (m, 1H), 4.12 (m, 1H),
3.48–3.42 (m, 2H), 2.88 (m, 1H), 2.78 (dd, J = 15.1 and 6.0 Hz, 1H),
2.26 (m, 1H), 1.92 (m, 1H); 13C NMR (CD3OD): 204.3, 163.2, 159.9,
151.1, 149.3, 146.1, 137.9, 133.8, 131.6, 128.9, 127.8, 127.5, 81.1,
75.1, 573, 54.8, 51.3, 44.2, 36.2. HRESIMS m/z 401.1586 [M+Na]+
4.1.13. (2R,3S)-3-[3-(3-Hydroxy-pyrrolidin-2-yl)-2-oxo-propyl]-
5-trifluoromethyl-3H-quinazolin-4-one (15)
þ
(calcd for C21H22N4NaO3
, 401.1590) (100%). Anal. Calcd for
Off-white crystals. Mp: 262 °C. ½a D25
ꢃ
+27.5 (c 0.5, EtOH). 1H NMR
C21H22N4O3ꢂHCl: C, 60.79; H, 5.59; Cl, 8.55; N, 13.50. Found: C,
(CD3OD): 8.28 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.2 Hz,
1H), 7.50 (t, J = 7.2 Hz, 1H), 5.05 (d, J = 16.8 Hz, 1H), 4.84 (d,
J = 16.8 Hz, 1H), 4.40 (m, 1H), 4.19 (m, 1H), 3.47–3.41 (m, 2H),
2.85 (m, 1H), 2.78 (dd, J = 15.3 and 6.2 Hz, 1H), 2.27 (m, 1H), 1.93
(m, 1H); 13C NMR (CD3OD): 202.8, 162.7, 158.2, 150.5, 148.3,
60.83; H, 5.55; Cl, 8.62; N, 13.44.
4.1.18. (2R,3S)-3-[3-(3-Benzyloxy-pyrrolidin-2-yl)-2-oxo-
propyl]-5-trifluoromethyl-3H-quinazolin-4-one (20)
Pale yellow crystals. Mp: 229–230 °C. ½a D25
ꢀ17.9 (c 0.5, EtOH).
ꢃ
1H NMR (CD3OD): 8.22 (s, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.62 (d,
J = 7.1 Hz, 1H), 7.55 (t, J = 7.1 Hz, 1H), 7.23–7.19 (m, 5H), 5.09 (d,
J = 16.9 Hz, 1H), 4.82 (d, J = 16.9 Hz, 1H), 4.71 (m, 2H), 4.39 (m,
1H), 4.13 (m, 1H), 3.46–3.40 (m, 2H), 2.89 (m, 1H), 2.79 (dd,
J = 15.4 and 6.0 Hz, 1H), 2.29 (m, 1H), 1.91 (m, 1H); 13C NMR
(CD3OD): 203.7, 162.1, 158.9, 151.2, 149.1, 140.7, 139.2, 133.5,
132.4, 131.9, 128.9, 127.8, 127.7, 116.8, 80.1, 76.2, 57.9, 52.9,
141.4, 133.3, 132.7, 131.7, 116.8, 80.5, 57.6, 53.6, 50.5, 42.4, 36.5.
HRESIMS m/z 378.1050 [M+Na]+ (calcd for C16H16F3N3NaO3
,
þ
378.1041) (100%). Anal. Calcd for C16H16F3N3O3ꢂHCl: C, 49.05; H,
4.37; Cl, 9.05; F, 14.55; N, 10.73. Found: C, 49.12; H, 4.33; Cl,
9.01; F, 14.62; N, 10.82.
4.1.14. (2R,3S)-3-[3-(3-Hydroxy-pyrrolidin-2-yl)-2-oxo-propyl]-
6-trifluoromethyl-3H-quinazolin-4-one (16)
51.5, 42.1, 33.8. HRESIMS m/z 468.1519 [M+Na]+ (calcd for
Off-white crystal. Mp: 206–207 °C. ½a D25
ꢃ
+16.7 (c 0.5, EtOH). 1H
NMR (CD3OD): 8.26 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H),
7.58 (d, J = 7.2 Hz, 1H), 5.09 (d, J = 17.4 Hz, 1H), 4.98 (d, J = 17.4 Hz,
þ
C23H22F3N3NaO3
,
468.1511)
(100%).
Anal.
Calcd
for
C23H22F3N3O3ꢂHCl: C, 57.32; H, 4.81; Cl, 7.36; F, 11.83; N, 8.72.
Found: C, 57.39; H, 4.76; Cl, 7.42; F, 11.74; N, 8.80.