52
X. Zhang et al. / European Journal of Medicinal Chemistry 149 (2018) 45e55
NMR (101 MHz, DMSO-d6)
d
159.4, 134.5, 131.0, 129.9, 128.0, 123.5,
5.1.2.2. 12N-p-chlorobenzoyl aloperine (3b). Yield: 80%; white
solid; mp 62e64 ꢁC; 1H NMR (500 MHz, CDCl3)
116.7, 115.3, 64.8, 58.4, 55.6, 55.3, 53.9, 51.7, 45.1, 32.5, 30.3, 27.1,
23.0, 22.7, 22.0, 20.3, 17.8. HRMS: calcd for C23H33N2O$2HCl
[Me2HClþH]þ: 353.2587, found: 353.2584.
d
7.37 (d, J ¼ 8.4 Hz,
2H), 7.32 (d, J ¼ 8.3 Hz, 2H), 5.63 (d, J ¼ 3.9 Hz, 1H), 4.84 (s, 1H), 3.64
(s, 1H), 3.34 (s, 1H), 3.12e3.09 (m, 1H), 2.78e2.70 (m, 2H), 2.58 (d,
J ¼ 11.8 Hz, 2H), 2.48 (d, J ¼ 11.6 Hz, 1H), 2.28e2.18 (m, 2H), 1.97 (s,
1H), 1.87e1.78 (m, 4H), 1.73e1.62 (m, 3H), 1.48e1.38 (m, 1H),
5.1.1.7. 12N-benzyl aloperine dihydrochloride (2g). Yield: 83%; yel-
1.13e1.05 (m, 2H). 13C NMR (151 MHz, CDCl3)
d 169.9, 135.8, 135.7,
low solid; mp 113e115 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d 11.23 (br,
135.2,128.8 (2),128.2,128.1 (2), 59.5, 58.6, 54.5, 47.0, 43.7, 35.1, 31.2,
28.1, 26.3, 25.1, 25.0, 24.1, 19.3. HRMS: calcd for C22H28N2OCl
[MþH]þ: 371.1885, found: 371.1882.
1H), 8.08 (br, 1H), 7.66e7.63 (m, 2H), 7.46e7.45 (m, 3H), 5.85 (d,
J ¼ 5.8 Hz, 1H), 5.23 (s, 2H), 4.72 (d, J ¼ 12.6 Hz, 1H), 4.40e4.36 (m,
1H), 4.20e4.15 (m, 1H), 3.88e3.82 (m, 1H), 3.60 (d, J ¼ 13.2 Hz, 1H),
3.46 (d, J ¼ 13.1 Hz, 1H), 3.28e3.21 (m, 1H), 3.15e3.09 (m, 1H),
3.06e3.01 (m, 1H), 2.45e2.39 (m, 3H), 2.25e2.13 (m, 3H), 1.80e1.78
(m, 2H), 1.72e1.62 (m, 4H), 1.49e1.42 (m, 1H). 13C NMR (101 MHz,
5.1.2.3. 12N-30,40-dichlorobenzoyl aloperine (3c). Yield: 84%; white
solid; mp 66e68 ꢁC; 1H NMR (500 MHz, CDCl3)
d
7.47 (d, J ¼ 8.2 Hz,
2H), 7.24e7.20 (m, 1H), 5.64 (d, J ¼ 4.6 Hz, 1H), 4.82 (s, 1H), 3.67 (s,
1H), 3.31 (s, 1H), 3.13e3.10 (m, 1H), 2.78e2.70 (m, 2H), 2.59 (d,
J ¼ 11.7 Hz, 2H), 2.46 (d, J ¼ 11.5 Hz, 1H), 2.30e2.16 (m, 2H), 1.98 (s,
1H), 1.88e1.80 (m, 3H), 1.71e1.61 (m, 4H), 1.48e1.39 (m, 1H),
DMSO-d6)
d 134.5, 131.7 (2), 129.5 (2), 128.8 (2), 128.0, 64.6, 58.4,
55.5, 53.9, 51.6, 45.1, 32.5, 30.3, 27.1, 23.0, 22.8, 22.0, 20.3, 17.8.
HRMS: calcd for C22H31N2$2HCl [Me2HClþH]þ: 323.2482, found:
323.2481.
1.13e1.05 (m, 2H). 13C NMR (151 MHz, CDCl3)
d 168.6, 137.3, 135.5,
133.6, 133.0, 130.7, 128.9, 128.5, 126.0, 59.6, 58.7, 54.6, 47.0, 43.8,
35.1, 31.2, 28.1, 26.4, 25.2, 25.0, 24.2, 19.4. HRMS: calcd for
C
5.1.1.8. 12N-p-trifluoromethoxylbenzyl aloperine dihydrochloride
(2h). Yield: 81%; white solid; mp 138e140 ꢁC; 1H NMR (400 MHz,
22H27N2OCl2 [MþH]þ: 405.1495, found: 405.1492.
DMSO-d6)
d
11.37 (br, 1H), 7.97 (br, 1H), 7.80 (d, J ¼ 8.1 Hz, 2H), 7.47
(d, J ¼ 7.8 Hz, 2H), 5.86 (d, J ¼ 5.2 Hz, 1H), 4.75 (d, J ¼ 11.9 Hz, 1H),
4.34 (s, 1H), 4.26e4.21 (m, 1H), 3.86e3.79 (m, 1H), 3.64e3.57 (m,
2H), 3.47 (d, J ¼ 13.0 Hz, 1H), 3.28e3.22 (m, 1H), 3.15e3.00 (m, 3H),
2.46e2.40 (m, 3H), 2.18e2.13 (m, 3H), 1.81e1.63 (m, 6H), 1.49e1.43
5.1.2.4. 12N-30,40-dichlorobenzenesulfonyl aloperine (4a). Yield:
82%; yellow solid; mp 177e179 ꢁC; 1H NMR (500 MHz, CDCl3)
7.98
d
(d, J ¼ 2.1 Hz, 1H), 7.72e7.70 (m, 1H), 7.58 (d, J ¼ 8.4 Hz, 1H), 5.55 (d,
J ¼ 4.8 Hz, 1H), 4.24 (d, J ¼ 5.5 Hz, 1H), 3.69e3.65 (m, 1H), 3.62e3.56
(m, 1H), 3.08e3.05 (m, 1H), 2.78 (d, J ¼ 13.4 Hz, 1H), 2.70e2.64 (m,
2H), 2.49 (d, J ¼ 12.0 Hz, 1H), 2.22 (s, 1H), 2.04e2.00 (m, 1H), 1.93 (s,
1H), 1.88e1.79 (m, 3H), 1.69e1.61 (m, 3H), 1.53e1.44 (m, 1H),
1.43e1.35 (m, 2H), 1.03e1.03 (m, 2H). 13C NMR (126 MHz, CDCl3)
(m, 1H). 13C NMR (101 MHz, DMSO-d6)
d 149.0, 134.3, 134.0 (2),
128.9, 128.2, 121.3, 121.1 (2), 64.6, 58.3, 54.4, 53.8, 51.6, 45.1, 32.5,
30.2, 27.2, 22.9, 22.7, 22.0, 20.3, 17.7. HRMS: calcd for
C
23H30N2OF3$2HCl [Me2HClþH]þ: 407.2305, found: 407.2302.
d
141.2, 137.0, 134.5, 133.6, 131.2, 129.1, 128.8, 126.2, 61.0, 59.4, 54.3,
5.1.1.9. 12N-p-fluorobenzyl
Yield: 80%; yellow solid; mp 198e200 ꢁC; 1H NMR (400 MHz,
DMSO-d6) 11.30 (br, 1H), 8.00 (br, 1H), 7.72e7.69 (m, 2H),
aloperine
dihydrochloride
(2i).
46.6, 42.0, 35.2, 35.0, 27.9, 26.2, 25.0, 24.2, 24.0, 19.4. HRMS: calcd
for C21H27N2O2Cl2S [MþH]þ: 441.1165, found: 441.1176.
d
7.33e7.27 (m, 2H), 5.86 (d, J ¼ 5.9 Hz, 1H), 4.71 (d, J ¼ 12.8 Hz, 1H),
4.36e4.32 (m, 1H), 4.23e4.18 (m, 1H), 3.86e3.81 (m, 1H), 3.61 (t,
J ¼ 13.3 Hz, 2H), 3.47 (d, J ¼ 13.0 Hz, 1H), 3.28e3.21 (m, 1H),
3.15e3.00 (m, 3H), 2.46e2.36 (m, 3H), 2.42e2.12 (m, 3H), 1.81e1.62
5.1.2.5. 12N-30,50-dichlorobenzenesulfonyl aloperine (4b). Yield:
83%; yellow solid; mp 171e173 ꢁC; 1H NMR (500 MHz, CDCl3)
d 7.77
(d, J ¼ 1.9 Hz, 2H), 7.53 (t, J ¼ 1.8 Hz, 1H), 5.60e5.52 (m, 1H), 4.24 (d,
J ¼ 5.8 Hz,1H), 3.70e3.57 (m, 2H), 3.09e3.06 (m,1H), 2.80e2.77 (m,
1H), 2.70e2.65 (m, 2H), 2.51e2.49 (m, 1H), 2.24e2.21 (m, 1H),
2.06e2.02 (m, 1H), 1.93 (d, J ¼ 1.1 Hz, 1H), 1.89e1.77 (m, 3H),
1.72e1.59 (m, 3H), 1.55e1.35 (m, 3H), 1.13e1.03 (m, 2H). 13C NMR
(m, 6H), 1.48e1.39 (m, 1H). 13C NMR (101 MHz, DMSO-d6)
d 162.7,
134.4, 134.1 (2), 128.1, 125.8, 115.7 (2), 64.5, 58.3, 54.5, 53.9, 51.4,
45.1, 32.5, 30.3, 27.1, 22.9, 22.7, 22.0, 20.3, 17.7. HRMS: calcd for
C
22H30N2F$2HCl [Me2HClþH]þ: 341.2388, found: 341.2388.
(126 MHz, CDCl3)
d 144.2, 136.0, 134.5, 132.3, 129.0, 125.5 (3), 61.1,
59.3, 54.3, 46.6, 42.1, 35.3, 35.0, 27.8, 26.2, 25.0, 24.2, 23.9, 19.4.
21H27N2O2Cl2S [MþH]þ: 441.1165, found:
5.1.2. General procedures for the synthesis of 12N-acyl/sulfonyl
aloperine
HRMS: calcd for
441.1163.
C
To
a stirred solution of aloperine (2.0 mmol) and K2CO3
(6.0 mmol) in dichloromethane (20 mL), and the substituted ben-
zoyl chloride or sulfonyl chloride (2.0 mmol) was added. The re-
action mixture was stirred at 0 ꢁC for 1e2 h until TLC analysis
showed completion of the reaction. Then the solvent was washed
successively with water (20 mL), brine (20 mL). The organic layer
was concentrated and purified by flash column chromatography on
silica gel with CH2Cl2/CH3OH as the eluent to get target compounds
3aeb or 4aee.
5.1.2.6. 12N-o-thiophenesulfonyl aloperine (4c). Yield: 80%; light
red solid; mp 133e135 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d
7.98e7.97 (m, 1H), 7.77e7.76 (m, 1H), 7.23e7.21 (m, 1H), 5.55 (d,
J ¼ 5.1 Hz, 1H), 4.24 (d, J ¼ 5.7 Hz, 1H), 3.64e3.59 (m, 1H), 3.49e3.41
(m, 1H), 3.06e3.03 (m, 1H), 2.73 (d, J ¼ 12.8 Hz, 1H), 2.66e2.56 (m,
2H), 2.46 (d, J ¼ 11.6 Hz, 1H), 2.11 (s, 1H), 2.02e1.92 (m, 2H),
1.85e1.74 (m, 3H), 1.66e1.56 (m, 3H), 1.42e1.26 (m, 3H), 1.09e1.01
(m, 2H). 13C NMR (101 MHz, DMSO-d6)
d 140.7, 134.3, 132.8, 132.1,
128.1 (2), 60.0, 58.7, 53.8, 46.2, 41.6, 34.7, 34.2, 27.1, 25.6, 24.4, 23.6,
23.1, 18.9. HRMS: calcd for C19H27N2O2S2 [MþH]þ: 379.1509,
found:379.1540.
5.1.2.1. 12N-30,50-dichlorobenzoyl aloperine (3a). Yield: 85%; white
solid; mp 63e65 ꢁC; 1H NMR (500 MHz, DMSO-d6)
d 7.69 (s, 1H),
7.45 (d, J ¼ 1.9 Hz, 2H), 5.62 (d, J ¼ 3.6 Hz, 1H), 4.64 (s, 1H),
3.54e3.50 (m, 1H), 3.16e3.14 (m, 1H), 3.06e3.03 (m, 1H), 2.80 (d,
J ¼ 13.0 Hz, 1H), 2.67e2.62 (m, 1H), 2.54e2.52 (m, 2H), 2.40 (s, 1H),
2.19 (d, J ¼ 6.8 Hz, 2H), 1.95 (s, 1H), 1.86e1.80 (m, 4H), 1.66e1.53 (m,
3H), 1.40e1.35 (m, 1H), 1.07e1.02 (m, 2H). 13C NMR (126 MHz,
5.1.2.7. 12N-m-cyanobenzenesulfonyl aloperine (4d). Yield: 82%;
white solid; mp 177e179 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d
8.44e8.43 (m, 1H), 8.26e8.24 (m, 1H), 8.18e8.15 (m, 1H),
7.83e7.92 (m, 1H), 5.53 (d, J ¼ 5.3 Hz, 1H), 4.34 (d, J ¼ 5.4 Hz, 1H),
3.69e3.64 (m, 1H), 3.48e3.40 (m, 1H), 3.05e3.02 (m, 1H), 2.72 (d,
J ¼ 12.4 Hz, 1H), 2.66e2.63 (m, 1H), 2.54 (d, J ¼ 11.4 Hz, 1H), 2.46 (d,
J ¼ 11.8 Hz, 1H), 2.08 (s, 1H), 1.97e1.91 (m, 2H), 1.84e1.73 (m, 3H),
DMSO-d6)
d 166.8, 140.5, 135.3, 134.4, 128.7, 127.7, 125.0 (3), 58.7,
58.1, 53.6, 46.0, 43.0, 34.3, 30.8, 27.2, 25.7, 24.4, 24.1, 23.3, 18.7.
HRMS: calcd for C22H27N2OCl2 [MþH]þ: 405.1495, found: 405.1494.