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R. S. Upadhayaya et al. / Bioorg. Med. Chem. 17 (2009) 4681–4692
1H), 8.27 (br s, 1H, D2O-exchangeable), 9.95 (br s, 1H, D2O-
exchangeable). 13C NMR (100.6 MHz, DMSO-d6): d 29.4, 35.5,
45.1, 115.4, 115.6, 119.8, 119.9, 120.1, 125.48, 125.55, 125.9,
126.3, 126.8, 127.0, 128.4, 128.5, 128.78, 128.85, 129.0, 131.8,
133.5, 133.6, 135.9, 136.0, 138.7, 139.2, 141.5, 147.42, 147.44,
157.4, 159.3, 159.8, 181.3. [M+H]+ = m/e 570, 572.
1H), 7.06–7.13 (m, 1H), 7.21–7.38 (m, 6H), 7.49 (d, J = 8.9 Hz,
1H), 7.54–7.63 (m, 2H), 7.73 (dd, J = 8.0, 1.7 Hz, 1H), 7.83 (dd,
J = 8.0, 1.7 Hz,1H), 8.10 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 8.61 (t,
J = 2.1 Hz, 1H), 9.09 (s, 1H, D2O-exchangeable), 9.32 (s, 1H, D2O-
exchangeable). 13C NMR (100.6 MHz, DMSO-d6): d 24.6, 35.7,
62.8, 112.1, 112.3, 112.5, 113.7, 113.90, 113.94, 116.3, 122.5,
124.1, 124.2, 124.3, 125.2, 126.20, 126.22, 127.1, 128.4, 128.5,
130.0, 136.0, 138.5, 139.4, 140.5, 140.9, 142.1, 142.2, 145.2,
145.3, 148.1, 152.5, 158.1, 158.8, 160.5. [M+H]+ = m/e 553.
5.3.6. 1-[2-(2-Acetyl-4-fluoro-phenoxy)-3-benzyl-quinolin-6-
yl]-3-(2-methoxy-phenyl)-thiourea (19)
Yield 56%. Sticky solid. 1H NMR (400 MHz, DMSO-d6): d 2.20 (s,
3H), 3.83 (s, 3H), 4.22 (s, 2H), 6.93 (t, J = 7.3 Hz, 1H), 7.06 (d,
J = 7.4 Hz, 1H), 7.11–7.28 (m, 3H), 7.29–7.39 (m, 4H), 7.43–7.56
(m, 2H), 7.61 (dd, J = 9.0, 3.2 Hz, 1H), 7.67 (dd, J = 9.0, 2.2 Hz, 1H),
7.86 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 9.29
(s, 1H, D2O-exchangeable), 10.10 (s, 1H, D2O-exchangeable). 13C
NMR (100.6 MHz, DMSO-d6): d 29.4, 35.5, 55.6, 111.4, 115.3,
115.6, 119.7, 119.9, 120.0, 120.1, 125.5, 125.6, 125.8, 125.9,
126.2, 126.4, 127.0, 127.4, 128.4, 128.8, 133.5, 133.6, 136.2,
138.7, 139.2, 141.5, 147.4, 152.0, 157.4, 159.3, 159.8, 179.5,
197.0. [M+H]+ = m/e 552.
5.4.2. 1-{3-Benzyl-2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-
quinolin-6-yl}-3-(2-methoxy-phenyl)-urea (23)
Yield 99%. Yellow solid, mp 216–219 °C. 1H NMR (400 MHz,
DMSO-d6): d 1.04 (d, J = 6.3 Hz, 3H), 3.88 (s, 3H), 4.20 (s, 2H),
4.54–4.62 (m, 1H), 5.18 (d, J = 4.2 Hz, 1H, D2O-exchangeable),
6.88–7.11 (m, 5H), 7.21–7.36 (m, 6H), 7.45–7.55 (m, 2H), 8.08
(d, J = 2.1 Hz, 1H), 8.12–8.20 (m, 2H), 8.29 (s, 1H, D2O-exchange-
able), 9.52 (s, 1H, D2O-exchangeable). 13C NMR (100.6 MHz,
DMSO-d6): d 24.6, 35.7, 55.7, 62.7, 110.6, 112.2, 112.5, 112.9,
113.7, 113.9, 118.2, 120.5, 121.8, 122.0, 124.0, 124.1, 125.1,
126.1, 126.3, 127.1, 128.4, 128.5, 136.5, 138.4, 139.4, 140.2,
142.1, 142.2, 145.22, 145.24, 147.6, 152.3, 158.0, 158.6, 160.4.
[M+H]+ = m/e 538.
5.3.7. 1-[2-(2-Acetyl-4-fluoro-phenoxy)-3-benzyl-quinolin-6-
yl]-3-(3-methoxy-phenyl)-thiourea (20)
Yield 56%. Off white solid. Mp 111–112 °C. 1H NMR (400 MHz,
DMSO-d6): d 2.19 (s, 3H), 3.73 (s, 3H), 4.21 (s, 2H), 6.71 (dd,
J = 8.2, 2.1 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 8.9,
4.7 Hz, 1H), 7.17 (t, J = 1.9 Hz, 1H), 7.19–7.27 (m, 2H), 7.28–7.38
(m, 4H), 7.44–7.54 (m, 2H), 7.56–7.68 (m, 2H), 7.97 (d, J = 2.1 Hz,
1H), 8.21 (s, 1H), 9.90 (s, 1H, D2O-exchangeable), 10.00 (s, 1H,
D2O-exchangeable). 13C NMR (100.6 MHz, DMSO-d6): d 29.4, 35.5,
55.0, 109.2, 109.8, 111.1, 114.4, 115.3, 115.60, 115.65, 118.1,
119.9, 120.1, 120.2, 125.5, 125.8, 126.2, 126.4, 127.1, 128.4,
128.8, 129.2, 133.5, 133.6, 136.2, 138.7, 139.2, 140.4, 141.5,
147.4, 157.4, 159.2, 159.3, 159.8, 179.5, 196.9. [M+H]+ = m/e 552.
5.4.3. 1-{3-Benzyl-2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-
quinolin-6-yl}-3-(3-methoxy-phenyl)-urea (24)
Yield 96%. White solid, mp 217–218 °C. 1H NMR (400 MHz,
DMSO-d6): d 1.04 (d, J = 6.0 Hz, 3H), 3.73 (s, 3H), 4.20 (s, 2H),
4.52–4.65 (m, 1H), 5.19 (d, J = 3.9 Hz, 1H, D2O-exchangeable),
6.55 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.98–7.13 (m, 2H),
7.14–7.39 (m, 8H), 7.47 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H),
8.06 (s, 1H), 8.17 (s, 1H), 8.81 (s, 1H, D2O-exchangeable), 8.92 (s,
1H, D2O-exchangeable). 13C NMR (100.6 MHz, DMSO-d6): d 24.6,
35.7, 54.9, 62.8, 103.9, 107.3, 110.5, 112.3, 112.5, 113.3, 113.7,
113.9, 122.3, 124.1, 124.2, 125.2, 126.2, 126.3, 127.1, 128.4,
128.5, 129.5, 136.4, 138.4, 139.5, 140.3, 140.8, 142.1, 142.2,
145.3, 152.5, 158.1, 158.7, 159.6, 160.5. [M+H]+ = m/e 538.
5.3.8. 1-[2-(2-Acetyl-4-fluoro-phenoxy)-3-benzyl-quinolin-6-
yl]-3-(4-methoxy-phenyl)-thiourea (21)
Yield 47%. Light brown solid, mp 63–64 °C. 1H NMR
(400 MHz, DMSO-d6): d 2.19 (s, 3H), 3.74 (s, 3H), 4.21 (s, 2H),
6.90 (d, J = 8.9 Hz, 2H), 7.13 (dd, J = 8.9, 4.7 Hz, 1H), 7.19–7.39
(m, 7H), 7.42–7.54 (m, 2H), 7.59–7.69 (m, 2H), 7.97 (d,
J = 1.9 Hz, 1H), 8.20 (s, 1H), 9.72 (s, 1H, D2O-exchangeable),
9.84 (s, 1H, D2O-exchangeable). 13C NMR (100.6 MHz, DMSO-
d6): d 29.9, 36.0, 55.6, 114.1, 115.5. 115.8, 116.0, 120.4, 120.6,
122.6, 125.9, 126.0, 126.3, 126.5, 126.7, 126.9, 127.6, 127.8,
128.9, 129.3, 132.5, 134.0, 134.1, 136.8, 139.2, 139.7, 142.0,
147.91, 147.93, 157.0, 157.9, 159.0, 159.7, 160.3, 180.5, 197.4.
[M+H]+ = m/e 552.
5.4.4. 1-{3-Benzyl-2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-
quinolin-6-yl}-3-(4-methoxy-phenyl)-urea (25)
Yield 40%. White solid, mp 200–201 °C. 1H NMR (400 MHz,
DMSO-d6): d 1.04 (d, J = 6.3 Hz, 3H), 3.72 (s, 3H), 4.20 (s, 2H),
4.52–4.62 (m, 1H), 5.20 (d, J = 4.3 Hz, 1H, D2O-exchangeable),
6.88 (d, J = 8.9 Hz, 2H), 6.97–7.14 (m, 2H), 7.19–7.42 (m, 8H),
7.46 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 9.1, 2.0 Hz, 1H), 8.05 (s, 1H),
8.15 (s, 1H), 8.56 (s, 1H, D2O-exchangeable), 8.82 (s, 1H, D2O-
exchangeable). 13C NMR (100.6 MHz, DMSO-d6): d 25.1, 36.2,
55.6, 63.2, 112.7, 112.9, 113.5, 114.2, 114.4, 120.5, 122.7, 124.5,
124.6, 125.6, 126.6, 126.7, 127.5, 128.9, 129.0, 133.0, 137.1,
138.8, 139.9, 140.6, 142.6, 142.7, 145.73, 145.75, 153.2, 154.9,
158.5, 159.1, 160.9. [M+H]+ = m/e 538.
5.4. General procedure for the synthesis of compound 22–29
(procedure C)
To a solution of compounds 14–21 (1 equiv) in ethanol–tetrahy-
drofuran mixture (1:1, 4 mL), sodium borohydride (2.5 eq) was
added at 0 °C and stirred at room temperature for 2 h. Reaction
mixture was concentrated under reduced pressure, poured into
ice water and extracted with ethyl acetate (50 mL ꢂ 2). The organic
layer was dried over anhydrous sodium sulfate, filtered and con-
centrated under vacuum. The sticky compounds were triturated
with n-pentane to furnish pure compounds 22–29.
5.4.5. 1-{3-Benzyl-2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-
quinolin-6-yl}-3-(4-chloro-benzyl)-thiourea (26)
Yield 80%. White Solid, mp 183–184 °C. 1H NMR (400 MHz,
DMSO-d6): d 1.02 (d, J = 6.3 Hz, 3H), 4.21 (s, 2H), 4.51–4.63 (m,
1H), 4.80 (d, J = 5.1 Hz, 2H), 5.18 (d, J = 4.3 Hz, 1H, D2O-exchange-
able), 7.00 (dd, J = 8.8, 5.0 Hz, 1H), 7.04–7.13 (m, 1H), 7.20–7.41
(m, 9H), 7.45 (d, J = 7.4 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.59 (dd,
J = 8.9, 2.1 Hz, 1H), 8.02 (s, 1H), 8.21 (s, 1H), 8.30 (br s, 1H, D2O-
exchangeable), 10.00 (s, 1H, D2O-exchangeable). 13C NMR
(100.6 MHz, DMSO-d6): d 24.6, 35.6, 45.0, 62.7, 112.3, 112.6,
113.8, 114.0, 119.7, 124.1, 124.2, 125.2, 125.8, 126.2, 126.6,
126.8, 127.0, 128.4, 128.5, 128.8, 129.0, 131.8, 135.8, 136.0,
138.7, 139.4, 141.7, 142.1, 142.2, 145.1, 145.2, 158.1, 159.4,
160.5, 181.3. [M+H]+ = m/e 572, 574.
5.4.1. 1-{3-Benzyl-2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-
quinolin-6-yl}-3-(3-nitro-phenyl)-urea (22)
Yield 94%. White solid, mp 217–219 °C. 1H NMR (400 MHz,
DMSO-d6): d 1.04 (d, J = 6.3 Hz, 3H), 4.20 (s, 2H), 4.52–4.62 (m,
1H), 5.19 (d, J = 4.4 Hz, 1H, D2O-exchangeable), 6.80–7.05 (m,