Journal of Medicinal Chemistry
Article
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light yellow solid. mp 199−200 °C; purity 98% (HPLC); H NMR
(400 MHz, CDCl3): δ 8.14 (s, 1H), 7.84−7.82 (m, 2H), 7.26−7.25
(m, 1H), 7.24 (s, 1H), 4.49 (d, J = 15.7 Hz, 1H), 4.10 (s, 3H), 4.06 (s,
3H), 3.71 (d, J = 14.6 Hz, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.13 (d, J =
16.0 Hz, 1H), 3.00−2.94 (m, 1H), 2.70−2.62 (m, 1H), 2.49 (s, 1H),
2.40−2.34 (m, 1H), 2.18 (s, 1H), 2.15 (s, 1H), 1.92−1.86 (m, 6H),
1.75−1.60 (m, 4H), 1.52−1.31 (m, 4H); 13C NMR (400 MHz,
CDCl3): δ 174.9, 149.6, 148.7, 148.6, 129.8, 126.6, 126.4, 126.1, 123.8,
123.6, 120.1, 114.3, 103.8, 103.7, 57.5, 56.0, 55.9, 55.8, 43.4, 34.3, 33.3,
29.08, 29.06, 25.8, 25.6, 25.5, 24.0; HRMS (ESI) calcd for C30H36NO4
[M + H]+, 474.2644; found, 474.2625.
Hz, 1H), 1.80−1.75 (m, 2H), 1.55−1.42 (m, 2H); 13C NMR (400
MHz, CDCl3): δ 164.2, 158.7, 149.4, 148.3, 148.0, 140.7, 131.1, 129.7,
129.1, 127.2, 127.1, 126.9, 126.1, 125.2, 124.1, 123.3, 122.3, 119.2,
114.6, 103.7, 103.5, 57.3, 56.3, 55.9, 53.5, 34.9, 33.8, 26.0, 24.4; HRMS
(ESI) calcd for C30H28N3O4S [M + H]+, 526.1801; found, 526.1788.
Synthesis of 2-((2,3-Dimethoxy-11,12,13,14,14a,15-hexahydro-
9H-dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl)oxy)acetamide (19).
To a solution of 2-rac (0.5 g, 1.38 mmol) in DMF (9 mL) was
added cesium carbonate (0.54 g, 1.66 mmol). After stirring at room
temperature for 0.5 h, a solution of ethyl α-bromoacetamide (0.23 g,
1.65 mmol) in DMF (6 mL) was added dropwise under an ice bath.
The reaction mixture was then stirred at room temperature and
monitored by TLC. After the reaction was complete, ethyl acetate and
water were added. The organic layler was separated, and the water
layer was extracted with ethyl acetate three times. The combined
organic layer was washed with brine, dried with anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (ethyl acetate as eluent) to
give 19 as a brown solid (0.40 g, 69%). mp 205−207 °C; purity 96%
Synthesis of 2,3-Dimethoxy-11,12,13,14,14a,15-hexahydro-9H-
dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl Furan-2-carboxylate (15).
Synthesis was performed according to the procedure for 13 using 2-
furoic acid. Yield, 82%. mp 239−242 °C; purity 97% (HPLC); H
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NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H),
7.79 (s, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.17
(s, 1H), 6.61 (s, 1H), 4.38 (d, J = 15.2 Hz, 1H), 4.06 (s, 3H), 4.04 (s,
3H), 3.55 (d, J = 15.2 Hz, 1H), 3.24 (d, J = 12.0 Hz, 1H), 2.99 (d, J =
15.7 Hz, 1H), 2.85−2.79 (m, 1H), 2.28−2.23 (m, 1H), 1.99 (d, J =
10.6 Hz, 1H), 1.87 (d, J = 11.0 Hz, 1H), 1.79 (s, 2H), 1.54−1.40 (m,
2H); 13C NMR (400 MHz, CDCl3): δ 156.3, 148.4, 147.4, 146.8,
146.2, 143.1, 128.7, 125.9, 125.8, 125.2, 124.3, 123.0, 122.4, 118.7,
118.5, 113.5, 111.2, 102.7, 102.6, 56.3, 55.2, 55.0, 54.9, 54.0, 33.8, 32.7,
24.9, 23.3; HRMS (ESI) calcd for C28H28NO5 [M + H]+, 458.1967;
found, 458.1963.
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(HPLC); H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 8.04 (s,
1H), 7.80 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.28−7.24
(m, 2H), 4.68 (s, 2H), 4.31 (d, J = 16.0 Hz, 1H), 4.02 (s, 3H), 3.93 (s,
3H), 3.40 (d, J = 16.0 Hz, 1H), 3.19−3.05 (m, 2H), 2.73−2.66 (m,
1H), 2.21−2.10 (m, 2H), 1.93 (d, J = 9.2 Hz, 1H), 1.78 (d, J = 8.8 Hz,
1H), 1.71 (d, J = 11.6 Hz, 1H), 1.63−1.54 (m, 1H), 1.39−1.32 (m,
2H); 13C NMR (400 MHz, DMSO-d6): δ 170.2, 155.6, 149.3, 148.2,
129.5, 125.7, 125.3, 124.7, 124.1, 123.2, 122.8, 115.8, 105.9, 104.4,
103.9, 67.1, 57.3, 55.7, 55.5, 55.4, 55.3, 33.9, 33.1, 25.5, 24.0; HRMS
(ESI) calcd for C25H29N2O4 [M + H]+, 421.2083; found, 421.2127.
Synthesis of 2,3-Dimethoxy-6-(prop-2-yn-1-yloxy)-
11,12,13,14,14a,15-hexahydro-9H-dibenzo[f,h]pyrido[1,2-b]-
isoquinoline. (20). Synthesis was performed according to the
procedure for 19 using propargyl bromide instead of α-bromoaceta-
mide. Obtained 0.47 g (yield 85%) as a brown solid. mp 202−204 °C;
purity 96% (HPLC); 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 2.5
Hz, 1H), 7.90 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.26−7.22 (m, 2H),
4.89 (s, 2H), 4.42 (d, J = 15.5 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 3.62
(d, J = 15.4 Hz, 1H), 3.26 (d, J = 11.3 Hz, 1H), 3.09 (dd, J = 16.3, J =
3.1 Hz, 1H), 2.90−2.86 (m, 1H), 2.60 (s, 1H), 2.40−2.34 (m, 1H),
2.29 (td, J = 11.2, J = 3.9 Hz, 1H), 2.03 (d, J = 13.1 Hz, 1H), 1.89 (d, J
= 12.4 Hz, 1H), 1.79−1.72 (m, 2H), 1.57−1.42 (m, 2H); 13C NMR
(400 MHz, DMSO-d6): δ 155.2, 149.3, 148.3, 129.6, 125.8, 125.4,
124.8, 124.1, 123.3, 122.8, 115.6, 106.5, 104.6, 104.0, 79.4, 78.2, 57.2,
55.9, 55.5, 55.4, 35.8, 34.0, 33.2, 30.7, 25.5, 24.0; HRMS (ESI) calcd
for C26H28NO3 [M + H]+, 402.2024; found, 402.2604.
Synthesis of 2-((2,3-Dimethoxy-11,12,13,14,14a,15-hexahydro-
9H-dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl)oxy)acetonitrile (21-
rac). Synthesis was performed according to the procedure for 19
using α-bromoacetonitrile instead of α-bromoacetamide. Obtained
0.45 g (yield 87%) as a brown solid. mp 199−201 °C; purity 95%
(HPLC); 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.79−7.75 (m,
2H), 7.20−7.16 (m, 2H), 4.92 (s, 2H), 4.39 (d, J = 16.0 Hz, 1H), 4.08
(s, 3H), 4.04 (s, 3H), 3.57 (d, J = 16.0 Hz, 1H), 3.27 (d, J = 8.0 Hz,
1H), 3.00 (d, J = 16.0 Hz, 1H), 2.87−2.81 (m, 1H), 2.35−2.26 (m,
2H), 2.04−1.99 (m, 1H), 1.88 (d, J = 16.0 Hz, 1H), 1.80−1.75 (m,
2H), 1.58−1.52 (m, 1H), 1.44−1.41 (m, 1H); 13C NMR (400 MHz,
DMSO-d6): δ 162.3, 154.2, 149.4, 148.4, 129.5, 125.8, 125.3, 124.4,
123.9, 122.8, 116.8, 115.3, 106.7, 104.7, 103.9, 57.0, 55.9, 55.4, 53.9,
35.7, 33.8, 33.0, 30.7, 25.4, 23.9; HRMS (ESI) calcd for C25H27N2O3
[M + H]+, 403.1977; found, 403.2016.
Synthesis of 2,3-Dimethoxy-11,12,13,14,14a,15-hexahydro-9H-
dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl Thiophene-2-carboxylate
(16). Synthesis was performed according to the procedure for 13
using thiophene-2-carboxylic acid. Obtained 0.45 g (yield 87%) as a
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light yellow solid. mp 247−249 °C; purity 98% (HPLC); H NMR
(400 MHz, CDCl3): δ 8.28 (s, 1H), 8.04 (s, 1H), 7.86−7.81 (m, 2H),
7.69 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 (s, 2H), 4.41 (d, J = 15.2
Hz, 1H), 4.07 (s, 3H), 4.05 (s, 3H), 3.58 (d, J = 15.1 Hz, 1H), 3.25 (d,
J = 15.1 Hz, 1H), 3.03 (d, J = 15.8 Hz, 1H), 2.88−2.81 (s, 1H), 2.32−
2.25 (s, 2H), 2.01 (d, J = 9.8 Hz, 1H), 1.87 (d, J = 11.8 Hz, 1H), 1.80
(s, 2H), 1.56−1.41 (m, 2H); 13C NMR (400 MHz, CDCl3): δ 161.0,
149.6, 148.6, 148.3, 134.8, 133.6, 133.0, 129.8, 128.1, 127.0, 126.9,
126.3, 125.5, 124.0, 123.6, 120.0, 114.6, 103.9, 103.8, 57.5, 56.3, 56.1,
56.02, 55.97, 34.9, 33.8, 25.9, 24.8, 24.3; HRMS (ESI) calcd for
C28H28NO4S [M + H]+, 474.1739; found, 474.1732.
Synthesis of 2,3-Dimethoxy-11,12,13,14,14a,15-hexahydro-9H-
dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl Nicotinate (17). Synthesis
was performed according to the procedure for 13 using nicotinic acid.
Obtained 0.51 g (yield 80%) as a light yellow solid. mp 183 °C (dec.);
purity 96% (HPLC); H NMR (400 MHz, CDCl3): δ 1H NMR (400
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MHz, CDCl3): δ 9.49 (s, 1H), 8.89 (dd, J = 4.8 Hz, J = 1.4 Hz, 1H),
8.55−8.52 (m, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H),
7.86 (s, 1H), 7.52−7.49 (m, 1H), 7.41 (dd, J = 8.0 Hz, J = 2.0 Hz,
1H), 4.48 (d, J = 15.4 Hz, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 3.68 (d, J =
15.4 Hz, 1H), 3.31 (d, J = 11.1 Hz, 1H), 3.14 (dd, J = 16.8 Hz, J = 3.2
Hz, 1H), 3.10−2.90 (m, 1H), 2.44 (t, J = 10.6 Hz, 1H), 2.34 (td, J =
10.8 Hz, J = 3.9 Hz, 1H), 2.10−2.06 (m, 1H), 1.91 (d, J = 12.8 Hz,
1H), 1.84−1.79 (m, 2H), 1.62−1.53 (m, 1H), 1.51−1.42 (m, 1H); 13C
NMR (400 MHz, CDCl3): δ 164.3, 154.1, 151.5, 149.7, 148.7, 148.3,
137.7, 129.9, 127.0, 126.9, 126.3, 125.7, 125.0, 124.1, 123.5, 119.8,
114.5, 106.5, 103.8, 103.8, 57.5, 56.1, 56.0, 56.0, 55.9, 34.6, 33.5, 25.7,
24.2; HRMS (ESI) calcd for C29H29N2O4 [M + H]+, 469.2127; found,
469.2120.
Synthesis of 2,3-Dimethoxy-11,12,13,14,14a,15-hexahydro-9H-
dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl Benzo[d][1,2,3]-
thiadiazole-7-carboxylate (18). Synthesis was performed according
to the procedure for 13 using benzo[d][1,2,3]thiadiazole-7-carboxylic
acid. Obtained 0.48 g (yield 83%) as a yellow-green solid. mp 159−
161 °C; purity 98% (HPLC); 1H NMR (400 MHz, CDCl3): δ 8.77 (d,
J = 8.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.29 (s, 1H), 7.80 (d, J = 9.2
Hz, 1H), 7.67 (s, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 4.31 (d, J
= 15.6 Hz, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.48 (d, J = 15.6 Hz, 1H),
3.24 (d, J = 10.8 Hz, 1H), 2.96 (d, J = 16.0 Hz, 1H), 2.83−2.75 (m,
1H), 2.29−2.23 (m, 2H), 2.01 (d, J = 11.6 Hz, 1H), 1.90 (d, J = 11.6
Synthesis of 21-(S). Synthesis was performed according to the
procedure for 21-rac using 2-S instead of 2-rac. Purity 95% (HPLC).
Synthesis of 21-(R). Synthesis was performed according to the
procedure for 21-rac using 2-R instead of 2-rac. Purity 95% (HPLC).
Syntheisis of Ethyl 2-((2,3-Dimethoxy-11,12,13,14,14a,15-hexa-
hydro-9H-dibenzo[f,h]pyrido[1,2-b]isoquinolin-6-yl)oxy)acetate
(22). Synthesis was performed according to the procedure for 19 using
ethyl α-bromoacetate instead of α-bromoacetamide. Obtained 0.50 g
(yield 81%) as a brown solid. mp 84−86 °C; purity 96% (HPLC); 1H
NMR (400 MHz, CDCl3): δ 7.96 (d, J = 2.5 Hz, 1H), 7.87 (s, 1H),
M
J. Med. Chem. XXXX, XXX, XXX−XXX