Research Article
MedChemComm
(d, J = 9.0 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 8.35 (s, 1H), 8.72
(s, 1H), 9.75 (s, 1H); 13C-NMR (CDCl3–CD3OD, 75 MHz) δ:
27.9, 41.3, 44.0, 47.5, 57.0, 57.8, 103.3, 106.3, 109.2, 111.5,
112.4, 121.0, 121.8, 123.3, 126.6, 127.5, 131.2, 134.5, 135.9,
139.6, 144.8, 149.7, 152.1, 152.3, 153.5, 158.8, 158.8, 162.2.
9-O-(4-Benzylpiperidine-1-carbonyl)berberrubine (3g). Yel-
low solid; yield: 56.3%. MS(ESI): m/z 524.5 [M–Cl]+, 1H-NMR
(CDCl3–CD3OD, 300 MHz) δ: 2.62 (br, 2H), 2.84–2.93 (m, 2H),
3.24 (t, J = 6.3 Hz, 2H), 3.34–3.38 (m, 2H), 3.72 (br, 2H), 3.84–
4.03 (m, 2H), 4.06 (s, 3H), 5.04 (t, J = 6.3 Hz, 2H), 6.11 (s,
2H), 6.88 (s, 1H), 7.27–7.40 (m, 5H), 7.53 (s, 1H), 8.15 (d, J =
9.3 Hz, 1H), 8.02 (d, J = 9.3 Hz, 1H), 8.60 (s, 1H), 9.88 (s, 1H);
13C-NMR (CDCl3–CD3OD, 75 MHz) δ: 27.2, 51.7, 52.1, 56.0,
57.0, 102.4, 105.4, 108.5, 120.0, 120.7, 122.5, 125.7, 126.5,
128.2, 128.5, 128.6, 129.9, 129.9, 130.0, 130.1, 130.2, 133.5,
135.0, 137.9, 138.6, 144.1, 148.8, 151.2, 151.4.
9-O-(4-(Ethoxycarbonyl)piperazine-1-carbonyl)berberrubine
(3h). Yellow solid; yield: 51.6%. MS(ESI): m/z 506.1 [M–Cl]+,
1H-NMR (CDCl3–CD3OD, 300 MHz) δ: 1.31 (t, J = 3.3 Hz, 3H),
3.24 (t, J = 6.3 Hz, 2H), 3.63 (s, 4H), 3.25 (dt, J = 13.5 Hz, 4H),
4.07 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 4.99 (t, J = 6.3 Hz, 3H),
6.09 (s, 2H), 6.89 (s, 1H), 7.57 (s, 1H), 8.08 (m, 2H), 8.68 (s,
1H), 9.80 (s, 1H); 13C-NMR (CDCl3–CD3OD, 75 MHz) δ: 14.5,
27.5, 43.6, 44.5, 45.3, 56.5, 57.4, 62.4, 102.8, 105.9, 108.8,
120.5, 121.3, 122.8, 126.1, 127.1, 130.7, 134.0, 135.3, 139.1,
144.4, 149.2, 151.6, 151.8, 152.9, 156.2.
126.6, 127.5, 131.2, 134.5, 136.0, 144.8, 149.7, 152.1, 152.2,
153.4.
9-O-(2-(Methoxycarbonyl)pyrrolidine-1-carbonyl)-
berberrubine (3l). Yellow solid; yield: 44.6%. MS (ESI): m/z
477.2 [M–Cl]+, 1H-NMR (CDCl3–CD3OD, 300 MHz) δ: 2.06–
2.16 (m, 4H), 2.30–2.50 (m, 1H), 3.23–3.27 (m, 2H), 3.62–3.64
(m, 2H), 3.67, 3.68 (s, 3H), 3.95, 3.97 (s, 3H), 4.87–4.97 (m,
2H), 6.07 (s, 1H), 6.93 (s, 1H), 7.57 (s, 1H), 8.03–8.10 (m, 2H),
8.67 (s, 1H), 9.58, 9.69 (s, 1H); 13C-NMR (CDCl3–CD3OD, 75
MHz) δ: 24.5, 25.5, 28.1, 31.1, 32.1, 53.2, 53.5, 57.5, 57.7,
57.9, 58.0, 61.0, 61.3, 103.8, 106.7, 109.5, 121.6, 121.9, 123.4,
123.6, 127.0, 127.1, 128.1, 132.0, 134.9, 135.4, 135.9, 140.0,
145.4, 149.9, 152.3, 152.8, 152.9, 153.2.
9-O-(Dipropylcarbamoyl)berberrubine (3m). Yellow solid;
yield: 92.8%. MS(ESI): m/z 449.2 [M–Cl]+, 1H-NMR
(CDCl3–CD3OD, 300 MHz) δ: 1.69–1.74 (m, 6H), 1.74–1.90 (m,
2H), 2.91 (t, J = 8.1 Hz, 2H), 3.25 (t, J = 6.2 Hz, 3H), 3.56(t, J =
7.8 Hz, 2H), 4.06 (s, 3H), 4.95 (t, J = 6.2 Hz, 2H), 6.09 (s, 1H),
6.91 (s, 1H), 7.60 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.08 (d, J =
9.0 Hz, 1H), 8.73 (s, 1H), 9.60 (s, 1H); 13C-NMR (CDCl3-
CD3OD, 75 MHz) δ: 11.3, 11.5, 20.3, 21.9, 22.7, 28.0, 50.9,
51.1, 57.7, 103.3, 106.4, 109.3, 121.1, 121.9, 123.4, 126.7,
127.3, 131.3, 134.6, 136.3, 139.6, 144.7, 149.7, 152.0, 152.4,
154.7.
9-O-(Diallylcarbamoyl)berberrubine (3n). Yellow solid;
1
yield: 74.9%. MS(ESI): m/z 445.3 [M–Cl]+, H-NMR (DMSO-d6,
9-O-(CyclohexylIJmethyl)carbamoyl)berberrubine (3i). Yel-
low solid; yield: 66.1%. MS(ESI): m/z 461.2 [M–Cl]+, HRMS
(ESI) calcd for C27H29N2O5 [M–Cl]+ 461.2071, found m/z
300 MHz) δ: 3.22 (m 2H), 3.95 (d, J = 5.2 Hz, 2H), 4.03 (s,
3H), 4.17 (d, J = 4.5 Hz, 2H), 4.96 (t, J = 6.1 Hz, 2H), 5.28–5.39
(m, 4H), 5.88 (ddd, J = 22.3, 10.3, 5.3 Hz, 1H), 6.07 (ddd, J =
15.9, 10.5, 5.4 Hz, 1H), 6.18 (s, 2H), 7.10 (s, 2H), 7.81 (s, 1H),
8.26 (d, J = 9.3 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 9.03 (s, 1H),
9.78 (s, 1H); 13C-NMR (DMSO-d6, 75 MHz) δ: 26.2, 49.5, 49.7,
55.5, 57.3, 102.1, 105.6, 108.5, 117.2, 117.3, 120.4, 120.6,
121.6, 126.1, 126.2, 130.9, 132.8, 132.9, 133.6, 134.7, 144.4,
147.7, 150.0, 150.8, 152.3.
1
461.2100. H-NMR (CDCl3–CD3OD, 300 MHz) δ: 1.22 (m, 2H),
1.43 (m, 2H), 1.65 (m, 3H), 1.89 (m, 3H), 2.02 (s, 1H), 2.99,
3.18,(s, 3H), 3.26 (t, J = 6.3 Hz, 2H), 3.88–4.04, 4.20–4.34 (m,
1H), 4.09 (s, 3H), 4.96 (t, J = 6.3 Hz, 2H), 6.12 (s, 1H), 7.63 (s,
1H), 8.10 (m, 2H), 8.75 (s, 1H), 9.61, 9.70 (s, 1H); 13C-NMR
(CDCl3–CD3OD, 75 MHz) δ: 25.1, 25.5, 25.5, 27.0, 28.7, 29.0,
29.6, 30.2, 56.0, 56.1, 56.5, 56.7, 56.8, 102.3, 105.4, 108.2,
120.1, 120.8, 122.4, 122.5, 125.6, 125.8, 126.2, 126.4, 130.2,
133.6, 135.5, 138.6, 143.8, 148.7, 151.1, 151.4, 153.6.
General procedure for the synthesis of 9-O-(ω-
bromoalkyl)berberrubine 4a–4b
9-O-(Morpholine-4-carbonyl)berberrubine
(3j).
Yellow
Alkyl bromides (1,2-dibromoethane or 1,3-dibromopropane;
15 mmol) and K2CO3 (15 mmol) were added to a stirred solu-
tion of berberrubine (3.1 mmol) in MeCN (30 ml) at 60 °C.
When the reaction (monitored by TLC) was complete, the
suspension was filtered. The residue obtained by evaporation
from the filtrate was then purified by flash column chroma-
tography (SiO2, CHCl3 : MeOH = 12 : 1) to give corresponding
bromide 4a–4b.
solid; yield: 56.7%. MS(ESI): m/z 435.6 [M–Cl]+, 1H-NMR
(CDCl3–CD3OD, 300 MHz) δ: 3.26 (t, J = 6.2 Hz, 2H), 3.59–3.68
(m, 2H), 3.82–3.85 (m, 2H), 3.86–3.95 (m, 4H), 4.11 (s, 1H),
4.99 (t, J = 6.2 Hz, 2H), 6.12 (s, 2H), 6.90 (s, 1H), 7.57 (s, 1H),
8.18 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 8.66 (s, 1H),
9.78 (s, 1H); 13C-NMR (CDCl3–CD3OD, 75 MHz) δ: 27.1, 44.6,
45.5, 56.1, 56.9, 66.3, 77.7, 102.4, 105.4, 108.4, 120.0, 120.8,
122.4, 125.7, 126.6, 130.2, 133.6, 134.9, 138.7, 143.9, 148.8,
151.1, 151.4, 152.5.
General procedure for the synthesis of berberine derivatives
5a–5e
9-O-(Thiomorpholine-4-carbonyl)berberrubine (3k). Yellow
solid; yield: 64.6%. MS(ESI): m/z 451.3 [M–Cl]+, 1H-NMR
(CDCl3–CD3OD, 300 MHz) δ: 2.76 (m, 2H), 2.85 (m, 2H), 3.24
(t, J = 6.2 Hz, 2H), 3.88 (m, 2H), 4.09 (s, 3H), 4.15 (m, 2H),
4.95 (t, J = 6.2 Hz, 2H), 6.10 (s, 1H), 6.91 (s, 1H), 7.63 (s, 1H),
8.18 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 8.71 (s, 1H),
9.69 (s, 1H); 13C-NMR (CDCl3–CD3OD, 75 MHz) δ: 27.7, 27.9,
28.0, 57.0, 57.8, 103.3, 106.3, 109.2, 121.0, 121.8, 123.3,
K2CO3 (3 mmol) and corresponding amines (1 mmol) were
added to 9-O-(ω-bromoalkyl)berberrubine (4a–4b) (1 mmol) in
MeCN (20 ml) at 80 °C. After stirring for 12–24 h, the solution
was filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography (SiO2, CHCl3 : MeOH = 12 : 1) to give 5a–5e.
Med. Chem. Commun.
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