J. Krzywik, M. Aminpour, J. Janczak et al.
European Journal of Medicinal Chemistry 215 (2021) 113282
4.3.3.4. Compound 11. Yellow solid, yield 69%.
ESI-MS for C23H25Cl3N2O6 (m/z): [MþH]þ 531/533, [2 M þ H]þ
1061/1063, [M ꢁ H]- 529/531.
1H), 6.53e6.50 (m, 2H), 5.62 (d, J ¼ 7.6 Hz, 1H), 4.49e4.43 (m, 1H),
3.97e3.84 (m, 8H), 3.63e3.51 (m, 3H), 3.06 (d, J ¼ 5.4 Hz, 3H),
2.52e2.43 (m, 1H), 2.40e2.21 (m, 2H), 1.82e1.78 (m, 1H), 1.55e1.45
(m, 2H), 1.27e1.20 (m, 10H), 0.84 (t, J ¼ 6.9 Hz, 3H).
1H NMR (500 MHz, CDCl3)
d 7.78e7.76 (m, 2H), 7.43 (d,
J ¼ 11.1 Hz, 1H), 7.34 (q, J ¼ 5.1 Hz, 1H), 6.63e6.47 (m, 2H), 4.76 (d,
J ¼ 12.1 Hz, 1H), 4.60e4.46 (m, 1H), 4.08 (d, J ¼ 12.1 Hz, 1H), 3.93 (s,
3H), 3.90 (s, 3H), 3.57 (s, 3H), 3.07 (d, J ¼ 5.4 Hz, 3H), 2.52e2.47 (m,
1H), 2.46e2.31 (m, 2H), 2.23e2.02 (m, 1H).
13C NMR (126 MHz, CDCl3)
d 175.5, 155.8, 155.2, 152.8, 151.1,
150.3, 141.5, 138.9, 134.5, 129.4, 126.9, 123.4, 107.6, 107.2, 65.2, 61.4,
61.2, 56.1, 53.8, 38.1, 31.8, 30.1, 29.5, 29.2, 29.2, 28.9, 25.8, 22.7, 14.1.
13C NMR (126 MHz, CDCl3)
d
175.4, 155.6, 154.2, 153.0, 151.0,
4.3.5.2. Compound 9. Yellow solid, yield 68%.
ESI-MS for C23H27ClN2O6 (m/z): [MþH]þ 463/465, [2 M þ H]þ
925/927, [M þ HCOOꢁ]- 507/509.
150.4, 141.6, 139.3, 134.6, 129.8, 126.9, 123.9, 108.1, 107.3, 95.6, 74.1,
61.5, 61.2, 56.1, 54.4, 37.8, 30.2, 29.5.
1H NMR (500 MHz, CDCl3)
d
7.63 (s, 1H), 7.44 (d, J ¼ 11.1 Hz, 1H),
4.3.3.5. Compound 13. Yellow solid, yield 68%.
ESI-MS for C27H28N2O6 (m/z): [MþH]þ 477, [MþNa]þ 499,
[2 M þ H]þ 953, [M ꢁ H]- 475.
7.32e7.29 (m, 1H), 7.02 (d, J ¼ 7.5 Hz, 1H), 6.56 (d, J ¼ 11.3 Hz, 1H),
6.54 (s, 1H), 4.54e4.39 (m, 1H), 4.09e3.97 (m, 2H), 3.92 (s, 3H), 3.88
(s, 3H), 3.58 (s, 3H), 3.40e3.36 (m, 1H), 3.30e3.22 (m, 1H), 3.06 (d,
J ¼ 5.4 Hz, 3H), 2.53e2.43 (m,1H), 2.42e2.30 (m, 2H), 2.04e1.93 (m,
1H).
1H NMR (500 MHz, CDCl3)
d 7.66 (s, 1H), 7.45e7.35 (m, 2H), 7.22
(t, J ¼ 7.9 Hz, 2H), 7.09 (t, J ¼ 7.4 Hz, 1H), 7.01 (d, J ¼ 7.6 Hz, 2H),
6.60e6.51 (m, 3H), 4.58e4.52 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.51
(s, 3H), 3.07 (d, J ¼ 5.3 Hz, 3H), 2.49e2.36 (m, 1H), 2.42e2.31 (m,
2H), 1.99e1.87 (m, 1H).
13C NMR (126 MHz, CDCl3)
d 175.4, 155.4, 155.2, 152.9, 151.0,
150.6, 141.5, 139.2, 134.7, 129.7, 126.8, 123.7, 108.0, 107.3, 64.5, 61.4,
61.0, 56.1, 54.1, 41.9, 37.9, 30.2, 29.5.
13C NMR (126 MHz, CDCl3)
d 175.2, 155.3, 153.9, 152.9, 151.1,
150.9, 150.1, 141.6, 139.2, 134.5, 129.7, 129.3, 126.7, 125.4, 123.1, 121.7,
108.0, 107.3, 61.5, 61.3, 56.1, 54.3, 38.1, 30.1, 29.6.
4.3.5.3. Compound 10. Yellow solid, yield 27%.
ESI-MS for C23H26Cl2N2O6 (m/z): [MþH]þ 498, [MþNa]þ 519,
[2 M þ H]þ 993, [M ꢁ H]- 495.
4.3.4. Synthesis of 7
1H NMR (500 MHz, CDCl3)
d
7.63 (s, 1H), 7.47 (d, J ¼ 11.1 Hz, 1H),
To a solution of compound 3 (1.0 equiv.) in DCM, Et3N (3.0
equiv.) and Boc2O (1.1 equiv.) were added. Reaction progress was
monitored by LC-MS. Then the reaction mixture was diluted with
EtOAc, washed with H2O, 5% NaHCO3, brine and dried over Na2SO4.
The residue was purified using column flash chromatography (silica
gel; DCM/MeOH) and next lyophilized from dioxane to give the
pure product 7 as a yellow solid with a yield of 95%.
ESI-MS for C25H32N2O6 (m/z): [MþH]þ 457, [MþNa]þ 479,
[2 M þ H]þ 913, [M ꢁ H]- 455.
7.33e7.29 (m, 2H), 6.58 (d, J ¼ 11.3 Hz, 1H), 6.55 (s, 1H), 5.43 (dd,
J ¼ 6.9, 5.2 Hz, 1H), 4.50e4.44 (m, 1H), 4.17 (dd, J ¼ 11.7, 7.0 Hz, 1H),
4.09 (dd, J ¼ 11.7, 5.2 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.61 (s, 3H),
3.08 (d, J ¼ 5.4 Hz, 3H), 2.51e2.49 (m, 1H), 2.43e2.32 (m, 2H),
2.05e2.01 (m, 1H).
13C NMR (126 MHz, CDCl3)
d 175.3, 155.5, 154.5, 153.0, 151.0,
150.3, 141.6, 139.4, 134.6, 129.7, 126.7, 123.5, 108.2, 107.3, 68.9, 68.8,
61.5, 61.1, 56.2, 54.3, 37.8, 30.2, 29.5.
1H NMR (500 MHz, CDCl3)
d
7.42e7.32 (m, 2H), 7.25e7.23 (m,1H),
4.3.5.4. Compound 12. Yellow solid, yield 19%.
6.53e6.45 (m, 2H), 5.25 (d, J ¼ 8.4 Hz,1H), 4.46e4.34 (m,1H), 3.89 (s,
3H), 3.85 (s, 3H) 3.57 (s, 3H), 3.03 (d, J ¼ 5.3 Hz, 3H), 2.43e2.35 (m,
1H), 2.36e2.17 (m, 2H), 1.73e1.68 (m, 1H), 1.31 (s, 9H).
ESI-MS for C27H35ClN2O6 (m/z): [MþH]þ 519/521, [MþNa]þ 541/
543, [2 M þ H]þ 1037/1039, [M ꢁ H]- 517, [M þ HCOOꢁ]- 563.
1H NMR (500 MHz, CDCl3)
d 7.43e7.39 (m, 2H), 7.26e7.24 (m,
13C NMR (126 MHz, CDCl3)
d
175.5, 155.1, 154.5, 152.8, 151.0,
1H), 6.54e6.50 (m, 2H), 5.42 (d, J ¼ 7.6 Hz, 1H), 4.54e4.39 (m, 1H),
3.97e3.88 (m, 8H), 3.58 (s, 3H), 3.50 (t, J ¼ 6.7 Hz, 2H), 3.07 (d,
J ¼ 5.4 Hz, 3H), 2.50e2.44 (m, 1H), 2.41e2.33 (m, 1H), 2.31e2.28 (m,
1H), 1.83e1.77 (m, 1H), 1.76e1.71 (m, 2H), 1.58e1.52 (m, 2H),
1.41e1.39 (m, 2H), 1.33e1.31 (m, 2H).
150.6, 141.5, 138.9, 134.6, 129.5, 126.9, 123.3, 107.6, 107.1, 79.4, 61.3,
61.3, 56.1, 53.2, 38.4, 30.2, 29.5, 28.3.
4.3.5. General procedure for the synthesis of colchicine derivatives
6, 9e10 and 12
13C NMR (126 MHz, CDCl3)
d 175.6, 155.7, 155.3, 153.0, 151.2,
Compounds 6, 9e10 and 12 were obtained in a two-step pro-
cedure. The first step involved the synthesis of chloroformate and
the second - the reaction of the obtained chloroformate with the
starting compound 3.
150.3, 141.6, 139.0, 134.6, 129.5, 127.0, 123.3, 107.7, 107.3, 65.1, 61.5,
61.3, 56.2, 53.9, 45.1, 38.2, 32.6, 30.2, 29.6, 28.8, 26.6, 25.3.
4.3.6. General procedure for the synthesis of colchicine derivatives
14 and 15
Compounds 14 and 15 were obtained in a two-step procedure.
The first step involved the synthesis of chloroformate and the
second the reaction of the obtained chloroformate with the starting
compound 3.
The solution of an appropriate benzyl alcohol (3.0 eqiuv.) in THF
was cooled in an ice bath and next to the mixture, phosgene (so-
lution 20% in PhCH3, 5.0 equiv.) was added dropwise. Then the ice
bath was removed and the reaction mixture was stirred at RT for
24 h. After this time the mixture was concentrated under reduced
pressures and then solved in THF and added dropwise to the so-
lution of compound 3 (1.0 equiv.) and Py (5.0 equiv.) in THF. Reac-
tion progress was monitored by LC-MS. Then the reaction mixture
was diluted with EtOAc, washed with H2O, 5% NaHCO3, brine and
dried over Na2SO4. The residue was purified using column flash
chromatography (silica gel; EtOAc/MeOH) and next lyophilized
from dioxane to give a desired compound.
To a solution of an appropriate alcohol (2.0 eqiuv.) in THF, Py (6.0
equiv.) was added and then the mixture was cooled in an ice bath.
To the mixture, phosgene (solution 20% in PhCH3, 2.6 equiv.) was
added dropwise. Then the ice bath was removed and the reaction
mixture was stirred at RT for additional 20 min. After this time, a
solution of the obtained chloroformate was added dropwise to the
solution of compound 3 (1.0 equiv.) in THF. Reaction progress was
monitored by LC-MS. Then the reaction mixture was diluted with
EtOAc, washed with H2O, 5% NaHCO3, brine and dried over Na2SO4.
The residue was purified using column flash chromatography (silica
gel; EtOAc/MeOH) and next lyophilized from dioxane to give a
desired compound.
4.3.5.1. Compound 6. Yellow solid, yield 29%.
ESI-MS for C29H40N2O6 (m/z): [MþH]þ 513, [MþNa]þ 535,
[2 M þ H]þ 1025, [M ꢁ H]- 511, [M þ HCOOꢁ]- 557.
1H NMR (500 MHz, CDCl3)
d 7.46e7.36 (m, 2H), 7.26e7.24 (m,
19