Journal of Medicinal Chemistry
Article
fluorobenzyl bromide (1.63 mmol), and NaI (0.55 mmol) using a
procedure similar to that for 8a. IR (neat) νmax 3433, 2991, 1614, 1503,
ArH), 7.92 (d, J = 9.0 Hz, 1H, ArH), 10.07 (s, 1H, ArH); 13C NMR
(100 MHz, DMSO-d6) δ: 27.2, 35.1, 55.1, 56.8, 102.0, 104.7, 108.1,
108.4, 111.3, 114.4, 114.4, 119.9, 120.0, 120.2, 129.0, 129.0, 130.7,
131.0, 131.9, 133.9, 136.6, 144.5, 144.9, 146.3, 147.0, 149.1,157.9; ESI-
MS (m/z): 440.1 [M − Cl]+.
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1158, 1041, 887, 776 cm−1; H NMR (300 MHz, DMSO-d6) δ: 3.15
(m, 2H, NCH2CH2), 4.75 (s, 2H, ArCH2Ar), 4.80 (m, 2H,
NCH2CH2), 6.08 (s, 2H, OCH2O), 6.55 (s, 2H, OCH2O), 6.92 (s,
1H, ArH), 7.00−7.16 (m, 3H, ArH), 7.16 (s, 1H, ArH), 7.36−7.43 (m,
1H, ArH), 7.59 (d, J = 8.7 Hz, 1H, ArH), 7.92 (d, J = 8.7 Hz, 1H,
ArH), 10.10 (s, 1H, ArH); 13C NMR (100 MHz, DMSO-d6) δ: 27.2,
35.5, 56.8, 102.0, 104.8, 108.1, 108.4, 111.3, 113.6 (d, J = 20.0 Hz, 1C),
114.9 (d, J = 21.0 Hz, 1C), 119.8, 119.9, 120.3, 124.1, 130.0, 130.9 (d,
J = 9.0 Hz, 1C), 131.8, 134.0, 136.8, 141.9 (d, J = 9.0 Hz, 1C), 144.7,
145.0, 146.3, 147.0, 149.2, 162.5 (d, J = 243.0 Hz, 1C); ESI-MS (m/z):
428.2 [M − Cl]+.
Procedure for the Synthesis of 13-(3-Trifluoromethylbenzyl)-
coptisine Chloride (8h). Target compound 8h was obtained (186 mg,
62.8% yield) as a yellow foamy solid from ( )-5a (0.53 mmol), 3-
trifluoromethylbenzyl bromide (1.64 mmol), and NaI (0.53 mmol)
using a procedure similar to that for 8a. IR (neat) νmax 3387, 2971,
1
2903, 1605, 1507, 1153, 1042, 898, 710 cm−1; H NMR (300 MHz,
CDCl3) δ: 3.24 (t, J = 5.7 Hz, 2H, NCH2CH2), 4.73 (s, 2H,
ArCH2Ar), 5.33 (m, 2H, NCH2CH2), 6.01 (s, 2H, OCH2O), 6.47 (s,
2H, OCH2O), 6.80 (s, 1H, ArH), 6.89 (s, 1H, ArH), 7.36 (d, J = 8.7
Hz, 1H, ArH), 7.44−7.61 (m, 5H, ArH), 11.00 (s, 1H, ArH); 13C
NMR (100 MHz, DMSO-d6) δ: 27.2, 35.6, 56.8, 102.1, 104.8, 108.1,
108.5, 111.3, 119.7, 120.0, 120.3, 123.6 (q, J = 3.6 Hz, 1C), 124.1 (q, J
= 270.9 Hz, 1C), 124.7 (q, J = 3.7 Hz, 1C), 129.6 (q, J = 31.4 Hz, 1C),
129.9, 130.0, 131.7, 132.0, 134.1, 137.0, 140.5, 144.8, 145.1, 146.4,
147.1, 149.2; ESI-MS (m/z): 478.1 [M − Cl]+.
Procedure for the Synthesis of 13-(4-Fluorobenzyl)coptisine
Chloride (8d). Target compound 8d was obtained (163 mg, 59.4%
yield) as a yellow foamy solid from ( )-5a (0.54 mmol), 4-
fluorobenzyl bromide (1.45 mmol), and NaI (0.53 mmol) using a
procedure similar to that for 8a. IR (neat) νmax 3425, 2997, 1605, 1507,
1
1160, 1033, 831, 744 cm−1; H NMR (400 MHz, DMSO-d6) δ: 3.15
(t, J = 5.6 Hz, 2H, NCH2CH2), 4.71 (s, 2H, ArCH2Ar), 4.81 (m, 2H,
NCH2CH2), 6.08 (s, 2H, OCH2O), 6.55 (s, 2H, OCH2O), 6.93 (s,
1H, ArH), 7.16 (s, 1H, ArH), 7.18−7.20 (m, 4H, ArH), 7.58 (d, J =
8.0 Hz, 1H, ArH), 7.92 (d, J = 8.0 Hz, 1H, ArH), 10.10 (s, 1H, ArH);
13C NMR (100 MHz, DMSO-d6) δ: 27.2, 35.1, 56.8, 102.1, 104.8,
108.1, 108.5, 111.3, 115.8 (d, J = 21.2 Hz, 2C), 119.9, 120.0, 120.3,
129.9 (d, J = 7.9 Hz, 2C), 130.6, 131.8, 134.0, 135.1 (d, J = 2.9 Hz,
1C), 136.7, 144.6, 145.0, 146.4, 147.0, 149.2, 160.9 (d, J = 241.7 Hz,
1C); ESI-MS (m/z): 428.1 [M − Cl]+.
Procedure for the Synthesis of 13-(2,4-Difluorobenzyl)-
dihydrocoptisine (9a). To a stirred methanol solution (4 mL)
containing 8a (0.09 mmol) and K2CO3 (0.27 mmol) was added a
solution of 5% NaOH in water (0.5 mL) containing NaBH4 (0.13
mmol) dropwise. The reaction mixture was stirred at room
temperature for 3 h and then filtered to obtain the precipitated
product. This product was washed sequentially with 30% ethanol (20
mL) and 80% ethanol (10 mL) and dried under high vacuum to give
pure 9a (27 mg, 63.5% yield) as a yellow powder. IR (neat) νmax 2900,
1603, 1557, 1499, 1041, 805 cm−1; 1H NMR (400 MHz, DMSO-d6) δ:
2.75 (m, 2H, NCH2CH2), 3.09 (m, 2H, NCH2CH2), 3.93 (s, 2H,
ArCH2Ar), 4.30 (s, 2H, NCH2Ar), 5.96 (s, 2H, OCH2O), 6.01 (s, 2H,
OCH2O), 6.36 (d, J = 8.4 Hz, 1H, ArH), 6.58 (s, 1H, ArH), 6.65 (d, J
= 8.4 Hz, 1H, ArH), 6.88 (s, 1H, ArH), 6.98−7.02 (m, 1H, ArH),
7.19−7.27 (m, 2H, ArH); 13C NMR (100 MHz, pyridine-d5) δ: 28.5
(d, J = 2.8 Hz, 1C), 31.1, 47.9, 50.1, 101.7, 101.7, 104.0, 104.0 (t, J =
2.3 Hz, 1C), 107.2, 108.1, 108.4, 111.6 (dd, J1 = 20.6 Hz, J2 = 3.5 Hz,
1C), 112.7, 115.2, 124.7 (dd, J1 = 15.8 Hz, J2 = 3.5 Hz, 1C), 125.3,
130.2, 131.0 (dd, J1 = 9.1 Hz, J2 = 6.2 Hz, 1C), 133.7, 141.8, 143.0,
146.0, 146.1, 147.6, 161.4 (dd, J1 = 245.7 Hz, J2 = 12.4 Hz, 1C), 161.9
(dd, J1 = 243.7 Hz, J2 = 11.4 Hz, 1C); ESI-MS (m/z): 448.1 [M + H]+.
Procedure for the Synthesis of 13-(4-Cyanobenzyl)-
dihydrocoptisine (9b). Target compound 9b was obtained (39 mg,
72.0% yield) as a yellow powder from 8b (0.12 mmol), K2CO3 (0.36
mmol), 5% NaOH (0.6 mL), and NaBH4 (0.16 mmol) using a
procedure similar to that for 9a. IR (neat) νmax 2914, 2894, 2229, 1607,
1502, 1479, 1038, 820 cm−1; 1H NMR (300 MHz, DMSO-d6) δ: 2.75
(m, 2H, NCH2CH2), 3.09 (m, 2H, NCH2CH2), 4.12 (s, 2H,
ArCH2Ar), 4.30 (s, 2H, NCH2Ar), 5.95 (s, 2H, OCH2O), 6.00 (s,
2H, OCH2O), 6.35 (d, J = 8.4 Hz, 1H, ArH), 6.58 (s, 1H, ArH), 6.62
(d, J = 8.4 Hz, 1H, ArH), 6.88 (s, 1H, ArH), 7.47 (d, J = 8.1 Hz, 2H,
ArH), 7.77 (d, J = 8.1 Hz, 2H, ArH); 13C NMR (100 MHz, DMSO-
d6) δ: 30.1, 35.0, 47.0, 49.2, 101.1, 101.1, 103.8, 106.6, 107.1, 108.0,
108.8, 111.7, 114.6, 118.9, 124.2, 128.9, 128.9, 129.1, 132.5, 132.5,
133.3, 140.9, 142.0, 144.9, 145.1, 146.7, 147.7; ESI-MS (m/z): 437.1
[M + H]+.
Procedure for the Synthesis of 13-(2-Fluorobenzyl)coptisine
Chloride (8e). Target compound 8e was obtained (110 mg, 40.1%
yield) as a yellow foamy solid from ( )-5a (0.54 mmol), 2-
fluorobenzyl bromide (1.66 mmol), and NaI (0.55 mmol) using a
procedure similar to that for 8a. IR (neat) νmax 3425, 2993, 2924, 1615,
1503, 1156, 1042, 725 cm−1; 1H NMR (300 MHz, DMSO-d6) δ: 3.14
(m, 2H, NCH2CH2), 4.65 (s, 2H, ArCH2Ar), 4.80 (m, 2H,
NCH2CH2), 6.08 (s, 2H, OCH2O), 6.56 (s, 2H, OCH2O), 6.82−
6.84 (m, 1H, ArH), 6.86 (s, 1H, ArH), 7.05−7.10 (m, 1H, ArH), 7.16
(s, 1H, ArH), 7.33−7.37 (m, 2H, ArH), 7.61 (d, J = 8.7 Hz, 1H, ArH),
7.93 (d, J = 8.7 Hz, 1H, ArH), 10.11 (s, 1H, ArH); 13C NMR (100
MHz, DMSO-d6) δ: 27.2, 29.8 (d, J = 3.1 Hz, 1C), 56.8, 102.1, 104.8,
107.9, 108.5, 111.2, 115.7 (d, J = 21.1 Hz, 1C), 119.6, 119.9, 120.4,
124.9 (d, J = 3.3 Hz, 1C), 125.8 (d, J = 15.2 Hz, 1C), 129.2 (d, J = 8.0
Hz, 1C), 129.5, 129.6 (d, J = 3.6 Hz, 1C), 131.8, 134.1, 136.9, 144.8,
145.1, 146.4, 147.1, 149.2, 159.8 (d, J = 243.7 Hz, 1C); ESI-MS (m/z):
428.1 [M − Cl]+.
Procedure for the Synthesis of 13-(4-Methylbenzyl)coptisine
Chloride (8f). Target compound 8f was obtained (222 mg, 80.0%
yield) as a yellow foamy solid from ( )-5a (0.55 mmol), 4-
methylbenzyl bromide (1.66 mmol), and NaI (0.55 mmol) using a
procedure similar to that for 8a. IR (neat) νmax 3442, 3000, 2902, 1616,
1504, 1366, 1155, 1037, 929 cm−1; 1H NMR (300 MHz, DMSO-d6) δ:
2.29 (s, 3H, ArCH3), 3.15 (m, 2H, NCH2CH2), 4.67 (s, 2H,
ArCH2Ar), 4.82 (m, 2H, NCH2CH2), 6.08 (s, 2H, OCH2O), 6.56 (s,
2H, OCH2O), 6.97 (s, 1H, ArH), 7.06 (d, J = 7.5 Hz, 2H, ArH), 7.16
(s, 1H, ArH), 7.17 (d, J = 7.5 Hz, 2H, ArH), 7.57 (d, J = 9.0 Hz, 1H,
ArH), 7.92 (d, J = 9.0 Hz, 1H, ArH), 10.09 (s, 1H, ArH); 13C NMR
(100 MHz, DMSO-d6) δ: 20.6, 27.2, 35.5, 56.8, 102.0, 104.7, 108.1,
108.4, 111.3, 119.9, 120.0, 120.2, 127.8 (2C), 129.6 (2C), 130.8, 131.9,
134.0, 135.9, 135.9, 136.6, 144.5, 144.9, 146.3, 147.0, 149.1; ESI-MS
(m/z): 424.1 [M − Cl]+.
Procedure for the Synthesis of 13-(3-Fluorobenzyl)-
dihydrocoptisine (9c). Target compound 9c was obtained (24 mg,
63.2% yield) as a yellow powder from 8c (0.09 mmol), K2CO3 (0.27
mmol), 5% NaOH (0.5 mL), and NaBH4 (0.13 mmol) using a
procedure similar to that for 9a. IR (neat) νmax 2935, 2889, 1586, 1502,
Procedure for the Synthesis of 13-(4-Methoxybenzyl)coptisine
Chloride (8g). Target compound 8g was obtained (248 mg, 86.7%
yield) as a yellow foamy solid from ( )-5a (0.55 mmol), 4-
methoxylbenzyl bromide (1.71 mmol), and NaI (0.55 mmol) using
a procedure similar to that for 8a. IR (neat) νmax 3393, 2960, 1612,
1507, 1365, 1153, 1037, 831 cm−1; 1H NMR (300 MHz, DMSO-d6) δ:
3.14 (m, 2H, NCH2CH2), 3.73 (s, 3H, OCH3), 4.63 (s, 2H,
ArCH2Ar), 4.81 (m, 2H, NCH2CH2), 6.07 (s, 2H, OCH2O), 6.54 (s,
2H, OCH2O), 6.91 (d, J = 8.4 Hz, 2H, ArH), 6.99 (s, 1H, ArH), 7.07
(d, J = 8.4 Hz, 2H, ArH), 7.15 (s, 1H, ArH), 7.59 (d, J = 9.0 Hz, 1H,
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1042, 889, 783 cm−1; H NMR (300 MHz, DMSO-d6) δ: 2.75 (t, J =
4.8 Hz, 2H, NCH2CH2), 3.09 (t, J = 4.8 Hz, 2H, NCH2CH2), 4.05 (s,
2H, ArCH2Ar), 4.29 (s, 2H, NCH2Ar), 5.95 (s, 2H, OCH2O), 6.00 (s,
2H, OCH2O), 6.40 (d, J = 8.4 Hz, 1H, ArH), 6.64 (d, J = 8.4 Hz, 1H,
ArH), 6.67 (s, 1H, ArH), 6.88 (s, 1H, ArH), 6.99−7.14 (m, 3H, ArH),
7.32−7.40 (m, 1H, ArH); 13C NMR (100 MHz, pyridine-d5) δ: 31.1,
35.5, 48.0, 50.1, 101.7, 101.7, 105.6, 107.1, 108.3, 108.4, 112.7, 113.2
(d, J = 21.0 Hz, 1C), 115.3 (d, J = 21.2 Hz, 1C), 115.6, 124.4 (d, J =
2.6 Hz, 1C), 125.5, 130.4, 130.6 (d, J = 8.2 Hz, 1C), 133.6, 141.5,
L
J. Med. Chem. XXXX, XXX, XXX−XXX