10.1002/cmdc.202100282
ChemMedChem
FULL PAPER
3.97 (t, J = 6.5 Hz, 2H, OCH2CH2CH3), 3.84, (s, 3H, CH3), 1.72-1.67 (m,
2H, OCH2CH2CH3), 0.95 ppm (t, J = 7.4 Hz, 3H, OCH2CH2CH3).
compound 7b was obtained as a brown solid in 41% yield (0.08 g); mp =
142.0-142.5 °C. H NMR (400 MHz, CDCl3): δH 9.00 (dd, J = 1.9 and 7.2
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Hz, 1H, H7), 8.46 (dd, J = 1.9 and 8.1 Hz, 1H, H5), 8.19 (d, J = 8.7 Hz,2H,
H2’ and H6’), 7.35-7.32 (m, 1H, H6), 7.22 (s, 1H, H3), 6.98 (d, J = 8.7 Hz,
2H, H3’ and H5’), 4.39 (t, J = 5.9 Hz, 2H, OCH2CH2N), 3.97 (t, J = 6.5 Hz,
2H, OCH2CH2CH3), 2.94 (t, J = 5.9 Hz, 2H, OCH2CH2N), 2.59-2.51 (m, 4H,
piperidine NCH2 x2), 1.88-1.77 (m, 2H, OCH2CH2CH3), 1.64-1.58 (m, 4H,
piperidine CH2 x2), 1.47-1.43 (m, 2H, piperidine CH2) 1.03 ppm (t, J = 7.4
Hz, 3H, OCH2CH2CH3). 13C NMR (101 MHz, CDCl3): δC 162.30, 160.93,
160.87, 157.22, 153.63, 131.53, 131.40, 129.22, 120.28, 114.91, 114.50,
98.38, 69.57, 67.17, 57.49, 55.17, 25.99, 24.05, 22.57, 10.53 ppm. HPLC:
70% CH3CN, 30% H2O/0.1 Et2NH, rt = 4.18 min.
2-(5-Chloro-2-thienyl)-6-methoxyquinazolin-4-ol
(27).
General
procedure B (time = 3h, room temperature): starting from derivative 22
(0.60 g, 1.93 mmol) and using tBuOK (0.86 g, 7.72 mmol), compound 27
was obtained, after filtration, as a white solid in 75% yield (0.40 g). 1H NMR
(400 MHz, DMSO-d6): δH 12.67 (s, 1H, OH), 8.02 (d, J = 3.9 Hz, 1H, H4’),
7.61 (d, J = 8.9 Hz, 1H, H8), 7.57 (d, J = 2.5 Hz, 1H, H5), 7.39 (dd, J = 2.7
and 7.6 Hz, 1H, H7), 7.24 (d, J = 3.9 Hz, 1H, H3’), 3.88 ppm (s, 3H, OCH3).
4-Chloro-2-(4-propoxyphenyl)-1,8-naphthyridine (28). At 0 °C, POCl3
(1.5 mL) was added to 2-(4-propoxyphenyl)-1,8-naphthyridin-4-ol 24 (0.10
g, 0.36 mmol) and then the mixture was stirred at 100 °C for 3h. Then, the
excess of POCl3 was evaporated and the sat. sol. of NaHCO3 was added
to the reaction mixture at 0 °C. After stirring overnight, the obtained yellow
precipitate was filtered to give compound 28 in 80% yield (0.08 g). 1H NMR
(400 MHz, DMSO-d6): δH 9.14 (dd, J = 1.8 and 8.4 Hz, 1H, H7), 8.66 (dd,
J = 1.7 and 8.3 Hz, 1H, H5), 8.51 (s,1H, H3), 8.31 (d, J = 8.9 Hz, 2H, H2’
and H6’), 7.75-7.72 (m,1H, H6), 7.09 (d, J = 8.9 Hz, 2H, H3’ and H5’), 4.01
(t, J = 6.6 Hz, 2H, OCH2CH2CH3), 1.78-1.69 (m, 2H, OCH2CH2CH3), 0.97
ppm (t, J = 7.4 Hz, 3H, OCH2CH2CH3).
N,N-diethyl-2-{[2-(4-propoxyphenyl)quinazolin-4-yl]oxy}ethanamine
hydrochloride (8a). General procedure D (time = 1h): starting from
derivative 25 (0.40 g, 1.30 mmol) and using K2CO3 (0.72 g, 5.20 mmol)
and (2-chloroethyl)diethylamine hydrochloride (0.45 g, 2.60 mmol), the
free base of compound 8a was obtained, after extraction with EtOAc and
purification by flash chromatography column (EtOAc/MeOH 95/5), as a
yellow oil in 11% yield (0.05 g). HClgas was bubbled into a solution of the
oil in Et2O until obtaining a precipitate that was recovered by filtration to
give compound 8a as a yellow solid; mp = 183.5-184.0 °C. 1H NMR (400
MHz, DMSO-d6): δH 10.85 (s,1H, HCl), 8.49 (d, J = 8.8 Hz, 2H, H2’ and
H6’), 8.25 (d, J = 8.1 Hz, 1H, H5), 8.02 (d, J = 8.3 Hz, 1H, H8), 7.95 (t, J =
7.2 Hz, 1H, H6), 7.64 (t, J = 7.3 Hz, 1H, H7), 7.09 (d, J = 8.9 Hz, 2H, H3’
and H5’), 5.05 (t, J = 4.1 Hz, 2H, OCH2CH2N), 3.97 (t, J = 6.5 Hz, 2H,
OCH2CH2CH3), 3.59 (d, J = 5.9 Hz, 2H, OCH2CH2N), 3.30-3.20 (m, 4H,
NCH2CH3 x2), 1.78-1.69 (m, 2H, CH2CH2CH3), 1.27 (t, J =7.2 Hz, 6H,
NCH2CH3 x2), 0.97 ppm (t, J = 7.4 Hz, 3H, OCH2CH2CH3). 13C NMR (101
MHz, DMSO-d6): δC 166.30, 161.99, 158.97, 150.46, 135.30, 130.70,
128.80, 127.56, 126.76, 124.26, 114.92, 114.51, 69.66, 62.04, 49.68,
47.37, 22.46, 10.86, 8.98 ppm. HPLC: 90% CH3CN 10%, H2O/0.1 Et2NH,
rt = 4.61 min.
N,N-diethyl-2-{[2-(4-propoxyphenyl)-1,7-naphthyridin-4-
yl]oxy}ethanamine (6a). General procedure C (time 20 min. 100 °C):
starting from derivative 23 (0.20 g, 0.71 mmol) and using (2-
chloroethyl)diethylamine hydrochloride (0.24 g, 1.42 mmol) and K2CO3
(0.39 g, 2.84 mmol), compound 6a was obtained, after purification via flash
chromatography column (CH2Cl2/MeOH 95:5), as a pink solid in 15% yield
(0.04 g); mp = 69.0-69.5 °C 1H NMR (400 MHz, CDCl3): δH 9.41 (s,1H, H8),
8.49 (d, J = 5.6 Hz, 1H, H6), 8.05 (d, J = 8.4 Hz, 2H, H2’ and H6’), 7.87 (d,
J = 5.3 Hz, 1H, H5), 7.26 (s, 1H, H3), 7.00 (d, J = 8.4 Hz, 2H, H3’ and H5’),
4.31 (t, J = 5.8 Hz, 2H, OCH2CH2N), 3.97 (t, J = 6.5 Hz, 2H, OCH2CH2CH3),
3.04 (t, J = 5.7 Hz, 2H, OCH2CH2N), 2.68 (q, J = 7.0 Hz, 4H, NCH2CH3 x2),
1.85-1.80 (m, 2H, OCH2CH2CH3), 1.10 (t, J = 7.0 Hz, 6H, NCH2CH3 x2),
1.04 ppm (t, J = 7.3 Hz, 3H, OCH2CH2CH3).13C NMR (101 MHz, CDCl3):
δC 161.01, 160.76, 159.82, 153.37, 144.16, 142.56, 131.65, 128.85,
123.89, 114.75, 114.38, 100.99, 69.62, 67.79, 51.26, 48.10, 22.54, 12.10,
10.52 ppm. HPLC: 70% CH3CN, 30% H2O/0.1 Et2NH, rt = 6.03 min.
4-(2-Piperidin-1-ylethoxy)-2-(4-propoxyphenyl)quinazoline
(8b).
General procedure D (time = 1h): starting from derivative 25 (0.50 g, 1.62
mmol) and using K2CO3 (0.89 g, 6.48 mmol) and 1-(2-
chloroethyl)piperidine hydrochloride (0.59 g, 3.24 mmol), compound 8b
was obtained, after extraction with EtOAc and purification by flash
chromatography column (EtOAc/MeOH 95/5), as yellow solid in 17% yield
(0.10 g); mp = 84.0-84.5 °C . 1H NMR (400 MHz, CDCl3): δH 8.49 (d, J =
9.0 Hz, 2H, H2’ and H6’), 8.09 (dd, J = 1.8 and 8.2 Hz, 1H, H5), 7.91 (d, J
= 8.3 Hz, 1H, H8), 7.76 (dt, J = 1.5 and 8.4 Hz, 1H, H7), 7.44 (dt, J = 1.7
and 8.1 Hz, 1H, H6), 6.98 (d, J = 9.0 Hz, 2H, H3’ and H5’), 4.87 (t, J = 5.9
Hz, 2H, OCH2CH2N), 3.99 (t, J = 6.6 Hz, 2H, OCH2CH2CH3), 2.99 (t, J =
5.8 Hz, 2H, OCH2CH2N), 2.69-2.60 (m, 4H, piperidine NCH2 x2), 1.87-1.79
(m, 2H, OCH2CH2CH3), 1.67-1.64 (m, 4H, piperidine CH2 x2), 1.47-1.46 (m,
2H, piperidine CH2), 1.05 ppm (t, J = 7.4 Hz, 3H, OCH2CH2CH3).13C NMR
(CDCl3, 101 MHz): δC 166.19, 161.23, 159.78, 151.97, 133.35, 130.42,
129.97, 127.63, 125.84, 123.36, 114.90, 114.19, 69.50, 64.23, 57.26,
54.85, 25.62, 23.86, 22.51, 10.46 ppm. HPLC: 80% CH3CN, 20% H2O/0.1
Et2NH, rt = 12.02 min.
4-(2-Piperidin-1-ylethoxy)-2-(4-propoxyphenyl)-1,7-naphthyridine
(6b). General procedure C (time 10 min. 100 °C): starting from derivative
23 (0.20 g, 0.71 mmol) and using 1-(2-chloroethyl)piperidine hydrochloride
(0.26 g, 1.42 mmol) and K2CO3 (0.39 g, 2.84 mmol), compound 6b was
obtained, after purification via flash chromatography column
(CH2Cl2/MeOH 95:5), as a pink solid in 14% yield (0.04 g); mp = 92.5-
94.0 °C. 1H NMR (400 MHz, CDCl3,): δH 9.41 (s, 1H, H8), 8.49 (d, J = 5.5
Hz, 1H, H6), 8.05 (d, J = 8.6 Hz, 2H, H2’ and H6’), 7.86 (d, J = 5.5 Hz, 1H,
H5), 7.25 (s, 1H, H3), 7.00 (d, J = 8.6 Hz, 2H, H3’ and H5’), 4.38 (t, J = 5.9
Hz, 2H, OCH2CH2N), 3.97 (t, J = 6.5 Hz, 2H, OCH2CH2CH3), 2.94 (t, J =
5.8 Hz, 2H, OCH2CH2N), 2.61-2.52 (m, 4H, piperidine NCH2 x2), 1.87-1.78
(m, 2H, OCH2CH2CH3), 1.63-1.58 (m, 4H, piperidine CH2 x2), 1.45-1.44
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(m, 2H, piperidine CH2), 1.04 ppm (t, J = 7.4 Hz, 3H, OCH2CH2CH3). C
4-(2-Azepan-1-ylethoxy)-2-(4-propoxyphenyl)quinazoline
(8c).
NMR (101 MHz, CDCl3): δC 160.90, 160.78, 159.82, 153.37, 144.17,
142.58, 131.66, 128.85, 123.89, 114.77, 114.36, 101.01, 69.63, 67.11,
57.43, 55.18, 26.00, 24.04, 22.54, 10.50 ppm. HPLC: 80% CH3CN, 20%
H2O/0.1 Et2NH, rt = 4.67 min.
General procedure C (time 15 min. 90 °C): starting from derivative 25 (0.10
g, 0.32 mmol) and using 1-(2-chloroethyl)azepane hydrochloride (0.13 g,
0.64 mmol) and K2CO3 (0.22 g, 1.60 mmol), compound 8c was obtained,
after purification via flash chromatography column (EtOAc/MeOH 97/3), as
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a white solid in 84% yield (0.10 g); mp =112.5-113.0 °C . H NMR (400
4-(2-Piperidin-1-ylethoxy)-2-(4-propoxyphenyl)-1,8-naphthyridine
(7b). Under N2 atmosphere, to a suspension of 60% NaH (0.04g, 0.66
mmol) in dry DMF (5 mL), 1-(2-hydroxyethyl)piperidine (0.06 mL, 0.66
mmol) was added. After stirring for 10 min at room temperature, 4-chloro-
2-(4-propoxyphenyl)-1,8-naphthyridine 28 (0.05 g, 0.16 mmol) was added
and the reaction mixture was stirred at room temperature for 3h. Then, the
excess of NaH was quenched with EtOAc and the mixture was poured in
ice/water and extracted with EtOAc (x3). The organic layer was washed
with brine, dried over Na2SO4 and evaporated to dryness to give a yellow
oil. After purification by flash chromatography column (CH2Cl2/MeOH 97/3),
MHz, CDCl3): δH 8.50 (d, J = 8.9 Hz, 2H, H2’ and H6’), 8.10 (d, J = 8.5 Hz,
1H, H5), 7.91 (d, J = 8.5 Hz, 1H, H8), 7.78-7.74 (m, 1H, H7), 7.46-7.43 (m,
1H, H6), 6.99 (d, J = 8.9 Hz, 2H, H3’ and H5’), 4.79 (t, J = 5.0 Hz, 2H,
OCH2CH2N), 3.99 (t, J = 6.5 Hz, 2H, OCH2CH2CH3), 3.11 (t, J = 6.3 Hz,
2H, OCH2CH2N), 2.89-2.80 (m, 4H, azepane NCH2 x2), 1.88-1.79 (m, 2H,
OCH2CH2CH3), 1.67-1.59 (m, 8H, azepane CH2 x4), 1.05 ppm (t, J = 7.4
Hz, 3H, OCH2CH2CH3). 13C NMR (101 MHz, CDCl3): δC 166.42. 161.24,
159.84, 151.96, 133.27, 130.54, 129.96, 127.60, 125.76, 123.43, 115.01,
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