PAPER
A Quinoline Building Block for Simeprevir Synthesis
905
IR: 3364 [(N-H)+(O-H)], 2961 (C-H), 1676 (C=O), 1613
13C NMR (62.9 MHz, CDCl3): δ = 169.70, 164.54, 162.76, 157.65,
151.65, 148.10, 121.55, 119.65, 116.10, 113.76, 111.86, 94.00,
55.84, 55.56, 30.73, 22.10, 9.51.
HRMS: m/z [M + H]+ for C18H21N2O2S: 329.1324; found:
329.1319.
[(C=C)Ar+(C=N)Ar], 1507 δ(N-H), 1252 (C-O) cm–1.
1H NMR (250 MHz, CDCl3): δ = 8.65 (br d, 1 H, NH), 8.07 (d, J =
5.0 Hz, 1 H, H-5), 7.61 (s, 1 H, H-3), 7.42 (d, J = 5.0 Hz, 2 H, H-2′,
6′), 7.25 (d, J = 5.0 Hz, 1 H, H-6), 6.94 (d, J = 5.0 Hz, 2 H, H-3′,5′),
5.23 (q, J = 5.0 Hz, 2 H, CH2O), 3.97 (s, 3 H, MeO), 3.94 (m, 1 H,
NCH), 3.85 (m, 2 H, CH2O), 3.81 (s, 3 H, MeO), 2.63 (s, 3 H, Me),
2.12 (m, 1 H, CH), 1.09 (s, 3 H, i-Pr), 1.07 (s, 3 H, i-Pr).
13C NMR (62.9 MHz, CDCl3): δ = 166.13, 163.01, 159.70, 158.05,
150.26, 147.28, 129.43, 127.79, 121.61, 120.43, 116.94, 114.06,
113.22, 96.50, 70.33, 64.66, 57.92, 56.21, 55.28, 29.34, 19.76,
18.30, 9.89.
UV: λmax (log ε) = 223 (4.51), 237 (4.51), 331 (4.26) nm.
Anal. Calcd for C18H20N2O2S: C, 65.83; H, 6.14; N, 8.53. Found: C,
65.66; H, 6.21; N, 8.71.
4,7-Dimethoxy-8-methylquinoline-2-carboxamide (13a)
A mixture of 9a (2.6 g, 10 mmol) and sat. ammonia in MeOH (25
mL) was stirred at r.t. in a pressure flask for 24 h (when commercial
7 M solution was used, prolonged time of about 3–4 days was nec-
essary for full conversion). The flask was placed in a refrigerator
overnight, then the insoluble portion was filtered off and dried to
give 13a.
HRMS: [M + H]+ calcd for C25H31N2O5: 439.2233; found:
439.2239.
UV: λmax (log ε) = 238 (4.82), 246 (4.84), 295 (3.98), 305 (3.93),
346 (3.72) nm.
Yield: 2.25 g (91%); white crystals; HPLC purity 99.7%; mp 187–
191 °C.
Anal. Calcd for C25H30N2O5: C, 68.47; H, 6.90; N, 6.39. Found: C,
68.44; H, 6.78; N, 6.51.
IR: 3427 (N-H), 3191, 2934 (C-H), 2836, 1694 (C=O), 1611
[(C=C)Ar+(C=N)Ar], 1257 (C-O), 1138 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 8.21 (br s, 1 H, NH2), 8.05 (d,
J = 7.5 Hz, 1 H, H-5), 7.73 (br s, 1 H, NH2), 7.50 (d, J = 7.5 Hz, 1 H,
H-6), 7.46 (s, 1 H, H-3), 4.08 (s, 3 H, MeO), 3.95 (s, 3 H, MeO),
2.61 (s, 3 H, Me).
13C NMR (62.9 MHz, CDCl3): δ = 166.52, 163.26, 157.83, 151.44,
146.90, 121.04, 119.90, 115.96, 113.77, 95.65, 56.18, 56.77, 10.12.
HRMS: m/z [M + H]+ for C13H15N2O3: 247.1083; found: 247.1080.
2-(4,7-Dimethoxy-8-methylquinoline-2-yl)-4-isopropyl-4,5-di-
hydrothiazole (11a)
A mixture of 10a (6.7 g, 20 mmol), P2S5 (6.7 g) and pyridine (100
mL) was stirred at 110 °C under nitrogen for 10 h. The residue after
evaporation was triturated with CH2Cl2 (250 mL) and the insoluble
portion was filtered off and washed with hot CH2Cl2 (4 × 50 mL).
The combined extracts were evaporated (6.9 g) and purified by flash
chromatography (silica; hexane–acetone, 9:1). Evaporation of the
combined fractions provided 11a. A sample crystallized from
MeOH provided yellow crystals.
UV: λmax (log ε) = 214 (4.43), 246 (4.70), 292 (3.85), 303 (3.82),
346 (3.55) nm.
Yield: 3.7 g (56%); yellowish solid; HPLC purity 99.0%; mp 89–
94 °C.
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.52; H, 5.55; N, 11.52.
IR: 2960 (C-H), 2917, 2849, 1613 [(C=C)Ar+(C=N)Ar], 1260 (C-
O) cm–1.
1H NMR (250 MHz, CDCl3): δ = 8.04 (d, J = 7.5 Hz, 1 H, H-5), 7.42
(s, 1 H, H-3), 7.27 (d, J = 7.5 Hz, 1 H, H-6), 4.58 (m, 1 H, =NCH),
4.09 (s, 3 H, MeO), 3.98 (s, 3 H, MeO), 3.36 (m, 1 H, CH2S), 3.10
(m, 1 H, CH2S), 2.69 (s, 3 H, Me), 2.18 (m, 1 H, CH), 1.16 (s, 3 H,
i-Pr), 1.06 (s, 3 H, i-Pr).
7-Methoxy-4-(methoxymethoxy)-8-methylquinoline-2-carbox-
amide (13b)
Prepared from 1.45 g (5 mmol) of 9b.
Yield: 1.2 g (88%); white crystals; HPLC purity 99.1%; mp 192–
197 °C.
13C NMR (62.9 MHz, CDCl3): δ = 170.90, 162.76, 157.96, 151.76,
148.16, 122.57, 119.92, 116.70, 112.94, 95.23, 84.81, 56.22, 55.88,
33.67, 33.42, 19.84, 18.84, 9.94.
HRMS: m/z [M + H]+ for C18H23N2O2S: 331.1480; found:
331.1477.
IR: 3403 (N-H), 3150, 2921 (C-H), 2835, 1685 (C=O), 1611
[(C=C)Ar+(C=N)Ar], 1254 (C-O), 1140 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 8.19 (br s, 1 H, NH2), 8.08 (d,
J = 7.5 Hz, 1 H, H-5), 7.73 (br s, 1 H, NH2), 7.60 (s, 1 H, H-3), 7.51
(d, J = 7.5 Hz, 1 H, H-6), 5.56 (s, 2 H, CH2), 3.98 (s, 3 H, MeO),
3.49 (s, 3 H, MeO), 2.63 (s, 3 H, Me).
13C NMR (62.9 MHz, DMSO-d6): δ = 166.35, 160.58, 157.74,
151.00, 147.04, 121.03, 119.86, 116.13, 113.82, 98.00, 94.18,
56.28, 56.06, 9.94.
UV: λmax (log ε) = 253 (4.61), 305 (3.90), 292 (3.98) nm.
Anal. Calcd for C18H22N2O2S: C, 65.42; H, 6.71; N, 8.48. Found: C,
65.38; H, 6.65; N, 8.62.
HRMS: m/z [M + H]+ calcd for C14H17N2O4: 277.1188; found:
277.1196.
2-(4,7-Dimethoxy-8-methylquinoline-2-yl)-4-isopropylthiazole
(12a); Method A
A mixture of 11a (1 g, 3 mmol), trifluoromethylbenzene (10 mL)
and activated MnO2 (Alfa Aesar, Lot USLF005538; 2.5 g) was heat-
ed at reflux for 24 h. The mixture was filtered through Celite, the
cake was washed with hot trifluoromethylbenzene (4 × 5 mL), the
combined filtrates were evaporated and the residue was crystallized
from MeOH to give 12a.
UV: λmax (log ε) = 225 (4.46), 246 (4.72), 292 (3.82), 303 (3.78),
347 (3.60) nm.
Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
61.03; H, 5.77; N, 10.21.
7-Methoxy-4-(4-methoxybenzyloxy)-8-methylquinoline-2-car-
boxamide (13c)
Prepared from 1.8 g (5 mmol) of 9c.
Yield: 0.5 g (50%); white crystals; HPLC purity 95.7%; mp 104–
106 °C.
IR: 2959 (C-H), 2931, 2868, 1608 [(C=C)Ar+(C=N)Ar], 1265 (C-
O) cm–1.
1H NMR (250 MHz, CDCl3): δ = 8.03 (d, J = 7.5 Hz, 1 H, H-5), 7.56
(s, 1 H, H-3), 7.22 (d, J = 7.5 Hz, 1 H, H-6), 7.02 (s, 1 H, H-5′), 4.14
(s, 3 H, MeO), 3.98 (s, 3 H, MeO), 3.20 (m, 1 H, CH), 2.70 (s, 3 H,
Me), 1.40 (s, 3 H, i-Pr), 1.38 (s, 3 H, i-Pr).
Yield: 1.5 g (85%); white crystals; HPLC purity 99.8%; mp 178–
180 °C.
IR: 3422 (N-H), 3138, 2994 (C-H), 2918, 1704 (C=O), 1611
[(C=C)Ar+(C=N)Ar], 1255 (C-O), 1175 cm–1.
1H NMR (250 MHz, CDCl3): δ = 8.23 (br s, 1 H, NH2), 8.03 (d, J =
10 Hz, 1 H, H-5), 7.73 (br s, 1 H, NH2), 7.58 (s, 1 H, H-3), 7.47–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 899–908