Molecules 2020, 25, 1423
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2.2 Hz, 1H), 7.56–7.49 (m, 2H), 7.28–7.26 (m, 2H), 6.58 (s, 2H), 6.48 (s, 2H), 5.49 (s, 1H), 5.38 (s, 1H),
5.21 (q, J = 4.6 Hz, 2H), 4.82–4.73 (m, 2H), 4.18 (s, 3H), 4.01–3.98 (m, 2H), 3.98 (s, 6H), 3.87 (s, 3H),
3.85 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.80 (s, 6H), 3.79 (s, 3H), 3.79–3.73 (m, 2H), 2.65–2.53 (m, 2H),
2.32–2.22 (m, 2H), 2.22 (s, 3H), 2.12 (s, 3H), 1.92–1.82 (m, 2H), 1.63–1.55 (m, 2H), 1.39 (t, J = 7.1 Hz,
3H), 1.23 (t, J = 7.1 Hz, 3H) (no OH, NH observed). Found: [M + H] = 687.2. HRMS: calculated for
C32H39BrN4O8: 686.1951; found: 686.1955.
4-(1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-2,6-
dimethoxypyridin-3-ol (5A). To a solution of 39 (0.70 g, 1.02 mmol) in dioxane (5 mL) was added
1 M HCl (5 mL). The reaction mixture was stirred for 24 h, poured onto sat. aq. NaHCO3 (10 mL),
extracted with EtOAc (3
×
10 mL). The combined organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure to obtain a yellowish residue. Column chromatography
with EtOAc:MeOH (9:1) gave fore fractions, followed by isomer A of 5A* (0.13 g, 20%). Elution with
EtOAc:MeOH (4:1) gave isomer B of 5A* (0.18 g, 27%). Isomer A: 1H NMR (CDCl3, 400 MHz)
δ 8.48
(s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.68–7.60 (m, 2H), 6.51 (s, 2H), 6.08 (s, 1H), 5.00 (s, 1H), 4.15 (s, 3H),
3.88 (s, 9H), 3.61 (s, 3H), 2.65–2.60 (m, 1H), 2.40–2.32 (m, 1H), 2.19 (s, 3H), 1.90–1.85 (m, 1H), 1.77–1.69
(m, 1H), (no OH, NH observed) Found: [M + H] = 629.2. HRMS: calculated for C29H33BrN4O7:
628.1533; found: 628.1543. Isomer B: 1H NMR (CDCl3, 400 MHz)
δ 8.28 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H),
7.58–7.51 (m, 2H), 6.32 (s, 2H), 6.18 (s, 1H), 5.04 (s, 1H), 4.01 (s, 3H), 3.83 (s, 6H), 3.81 (s, 3H), 3.77
(s, 3H), 2.95–2.90 (m, 1H), 2.74–2.68 (m, 1H), 2.51 (s, 3H), 2.20–2.02 (m, 2H) (no OH, NH observed)
Found: [M + H] = 629.2. HRMS: calculated for C29H33BrN4O7: 628.1533; found: 628.1543.
4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-5,6-dimethoxypyridin-2(1H)-one (41). To a solution of 7 (0.60 g,
1.44 mmol) in DMF (5 mL) was added lithium chloride (0.30 g, 7.18 mmol) and p-toluenesulfonic acid
(1.24 g, 7.18 mmol). The reaction mixture was heated at 120 ◦C for 1 h. Reaction mixture was washed
with water, extracted with EtOAc (3 × 20 mL). The organic fractions were collected and washed with
brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a
1
yellow residue. Column chromatography with EtOAc gave 41 (0.52 g, 90%). H NMR (DMSO)
δ 12.0
(s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.16
(s, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 3.76 (s, 2H), 3.64 (s, 3H). Found: [M + H] = 405.1. HRMS: calculated
for C18H17BrN2O4: 404.0372; found: 404.0374.
6-Bromo-3-((6-(ethoxymethoxy)-2,3-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (43). To a solution of
41 (0.52 g, 1.29 mmol) in DCM (25 mL) was added diisopropylethylamine (0.34 mL, 1.94 mmol) followed
by chloromethyl ethyl ether (0.24 mL, 2.58 mmol). The mixture was warmed to 50 ◦C and stirred for
18 h. The reaction was washed with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic
fractions were collected and washed with brine (100 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure to obtain a yellow residue. Column chromatography with hexanes:EtOAc (9:1)
1
gave 43 (0.30 g, 49%). H NMR (CDCl3)
δ 7.77 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.63–7.60
(m, 2H), 6.04 (s, 1H), 5.75 (s, 2H), 4.02 (s, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H), 3.70 (q, J = 7.1 Hz,
2H), 1.22 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3)
δ
159.7, 157.8, 155.7, 144.7, 144.2, 136.9, 135.8, 132.4,
129.3, 129.0, 127.0, 125.2, 117.7, 101.4, 91.2, 65.9, 60.7, 53.8, 53.7, 30.2, 15.4. Found: [M + H] = 463.1.
HRMS: calculated for C21H23BrN2O5: 462.0790; found: 462.0788.
1-(6-Bromo-2-methoxyquinolin-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1-
(6-(ethoxymethoxy)-2,3-dimethoxypyridin-4-yl)butan-2-ol (44). The product was prepared from 43 and 15
using the General Coupling Procedure above. Column chromatography with EtOAc:hexanes (1:1)
gave fore fractions, then 44 as a mixture of isomers (83%), as a yellow foam which were used crude for
the next step. LRMS: calculated for C41H49BrN4O10: 836.3; found: [M + H] = 837.2.
4-(1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-5,6-
dimethoxypyridin-2(1H)-one (5B). To a solution of 44 (0.44 g, 0.53 mmol) in DCM (50 mL) cooled to 0 ◦C,
was added triethylamine (0.16 mL, 1.16 mmol) and trifluoroacetic anhydride (0.15 mL, 1.06 mmol).