E. Roussel et al. / European Journal of Medicinal Chemistry 202 (2020) 112503
7
1H), 7.79 (t, J ¼ 8.4 Hz, 1H), 7.69e7.52 (m, 5H), 7.35 (d, J ¼ 8.1 Hz,
4.1.14. Methyl (5-((2-bromobenzyl)oxy)-4-oxo-4H-chromene-2-
carbonyl)-L-valinate (9c)
1H), 7.29 (d, J ¼ 8.1 Hz,1H), 7.25 (d, J ¼ 2.2 Hz,1H), 7.12 (d, J ¼ 8.3 Hz,
1H), 7.10e7.03 (m, 1H), 7.02e6.94 (m, 1H), 6.63 (s, 1H), 5.25 (s, 2H),
The crude was synthetized according to the General procedure
D starting from 7 (0,200 g, 0,53 mmol) and valine methyl ester
hydrochloride (0.179 g, 1.07 mmol). It was purified recrystallisation
in methanol and then washed with diethyl ether to afford 9c, a pale
yellow solid (0.126 g, 48%). C23H22BrNO6.
4.80e4.69 (m, 1H), 3.68 (s, 3H). Two signals under water peak. 13
C
NMR (101 MHz, DMSO‑d6)
d 176.34, 171.50, 159.19, 157.67, 156.92,
152.76, 136.25, 136.10, 135.04, 131.20, 128.92, 127.03, 123.78, 121.02,
120.59, 118.44, 118.04, 114.48, 112.54, 111.48, 110.61, 109.47, 109.06,
69.23, 53.79, 52.18, 26.39. m.p. 235.3e236.2 ꢁC. HRMS (ESI/QTOF)
calcd for C29H24BrN2O6 (M þ Hþ) 575.0818, found 575.0807.
1H NMR (400 MHz, DMSO‑d6)
d
9.20 (d, J ¼ 7.8 Hz, 1H), 8.12 (d,
J ¼ 7.4 Hz,1H), 7.82 (m,1H), 7.69 (d, J ¼ 7.8 Hz,1H), 7.51 (m,1H), 7.39
(d, J ¼ 8.4 Hz, 1H), 7.33 (m, 1H), 7.16 (d, J ¼ 8.3 Hz, 1H), 6.74 (s, 1H),
5.24 (s, 2H), 4.33 (m, 1H), 3.70 (s, 3H), 2.32e2.19 (m, 1H), 1.06e0.92
4.1.11. Methyl (5-((4-bromobenzyl)oxy)-4-oxo-4H-chromene-2-
carbonyl)-D-tryptophanate (8d)
(m, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 176.42, 171.34, 159.69,
157.41, 157.07, 153.03, 135.76, 135.09, 132.17, 129.57, 129.18, 127.84,
121.07, 114.53, 112.74, 111.10, 108.88, 69.76, 58.56, 51.90, 29.46,
19.04, 18.95. m.p. 127.0e128.2 ꢁC. HRMS (ESI/QTOF) calcd for
The crude was synthetized according to the General procedure
D starting from 6 (0,300 g, 0,80 mmol) and D-tryptophan methyl
ester hydrochloride (0.408 g, 1.60 mmol). It was purified by pre-
cipitation into ethyl acetate/cyclohexane (2:1) and then washed
with diethyl ether to afford 8d, a pale yellow solid (0.375 g, 81%).
C
23H23BrNO6 (M þ Hþ) 488.0709, found 488.0719.
4.1.15. Methyl (5-((2-bromobenzyl)oxy)-4-oxo-4H-chromene-2-
carbonyl)-L-phenylalaninate (9d)
The crude was synthetized according to the General procedure
D starting from 7 (0,194 g, 0,52 mmol) and L-phenylalanine methyl
ester hydrochloride (0.223 g, 1.03 mmol). It was purified by pre-
cipitation into ethyl acetate/cyclohexane (2:1) and then washed
with diethyl ether to afford 9d, a pale yellow solid (0.187 g, 70%).
C
29H23BrN2O6.
1H NMR (400 MHz, DMSO‑d6)
d
10.90 (s, 1H), 9.34 (d, J ¼ 7.8 Hz,
1H), 7.79 (t, J ¼ 8.4 Hz, 1H), 7.66e7.57 (m, 5H), 7.35 (d, J ¼ 8.1 Hz,
1H), 7.29 (d, J ¼ 8.3 Hz,1H), 7.25 (d, J ¼ 2.1 Hz,1H), 7.12 (d, J ¼ 8.3 Hz,
1H), 7.07 (t, J ¼ 7.2 Hz, 1H), 6.98 (t, J ¼ 7.4 Hz, 1H), 6.63 (s, 1H), 5.25
(s, 2H), 4.79e4.70 (m, 1H), 3.69 (s, 3H), 3.43e3.38 (m, 1H),
3.33e3.27 (m, 1H). 13C NMR (101 MHz, DMSO‑d6)
d 176.33, 171.51,
C
27H22BrNO6.
159.18, 157.67, 156.93, 152.75, 136.26, 136.10, 135.04, 131.20, 128.91,
127.03, 123.78, 121.01, 120.59, 118.43, 118.04, 114.48, 112.54, 111.48,
110.60, 109.47, 109.04, 69.21, 53.79, 52.18, 26.38. m.p.
236.2e237.9 ꢁC. HRMS (ESI/QTOF) calcd for C29H24BrN2O6 (M þ Hþ)
575.0818, found 575.0822.
1H NMR (400 MHz, DMSO‑d6)
d
9.47 (s, 1H), 8.13 (dd, J ¼ 7.7,
1.5 Hz, 1H), 7.82 (m, 1H), 7.68 (dd, J ¼ 8.0, 1.1 Hz, 1H), 7.51 (m, 1H),
7.35e7.27 (m, 6H), 7.25e7.19 (m, 1H), 7.16 (d, J ¼ 8.0 Hz, 1H), 6.64 (s,
1H), 5.24 (s, 2H), 4.77e4.71 (m, 1H), 3.69 (s, 3H), 3.26 (dd, J ¼ 13.8,
5.4 Hz, 1H), 3.21e3.13 (m, 1H). 13C NMR (101 MHz, DMSO‑d6)
d
176.33,171.26,159.21, 157.42,156.95, 152.77,137.22,135.74,135.24,
4.1.12. Methyl (5-((2-bromobenzyl)oxy)-4-oxo-4H-chromene-2-
carbonyl)-L-alloisoleucinate (9a)
The crude was synthetized according to the General procedure
D starting from 7 (0,511 g, 1.36 mmol) and L-isoleucine methyl ester
132.15, 129.54, 129.11, 129.06, 128.31, 127.84, 126.62, 121.01, 114.43,
112.57, 110.82, 108.85, 69.69, 54.13, 52.20, 30.67. m.p.
145.5e147.5 ꢁC. HRMS (ESI/QTOF) calcd for C27H23BrNO6 (M þ Hþ)
536.0709, found 536.0711.
hydrochloride (0.495 g, 2.72 mmol). It was purified by recrystalli-
sation in methanol and then washed with diethyl ether to afford 9a,
crystal, (0.352 g, 51%). C24H24BrNO6.
4.1.16. Methyl (5-((2-bromobenzyl)oxy)-4-oxo-4H-chromene-2-
carbonyl)-L-tryptophanate (9e)
1H NMR (400 MHz, DMSO‑d6)
d
9.23 (d, J ¼ 7.7 Hz, 1H), 8.14 (d,
The crude was synthetized according to the General procedure
D starting from 7 (0,100 g, 0,27 mmol) and L-tryptophan methyl
ester hydrochloride (0.137 g, 0.54 mmol). It was purified by pre-
cipitation into methanol and then washed with diethyl ether to
afford 9e, a white solid (0.043 g, 28%). C29H23BrN2O6.
J ¼ 7.4 Hz,1H), 7.82 (m,1H), 7.69 (d, J ¼ 7.9 Hz,1H), 7.52 (m,1H), 7.40
(d, J ¼ 8.4 Hz, 1H), 7.33 (m, 1H), 7.17 (d, J ¼ 8.3 Hz, 1H), 6.74 (s, 1H),
5.25 (s, 2H), 4.39 (t, J ¼ 7.7 Hz, 1H), 3.70 (s, 3H), 2.10e1.99 (m, 1H),
1.60e1.48 (m, 1H), 1.33e1.23 (m, 1H), 0.97e0.86 (m, 6H). 13C NMR
1H NMR (400 MHz, DMSO‑d6)
d
10.89 (s, 1H), 9.36 (d, J ¼ 7.8 Hz,
(101 MHz, DMSO‑d6)
d 176.44, 171.41, 159.61, 157.38, 157.05, 152.97,
135.76, 135.11, 132.17, 129.56, 129.14, 127.85, 121.04, 114.49, 112.75,
111.09, 108.81, 69.70, 57.26, 51.90, 35.48, 25.09, 15.37, 10.77. m.p.
123.1e125.7 ꢁC. HRMS (ESI/QTOF) calcd for C24H25BrNO6 (M þ Hþ)
502.0865, found 502.0860.
1H), 8.12 (d, J ¼ 7.7 Hz, 1H), 7.83 (m, 1H), 7.69 (dd, J ¼ 8.0, 0.9 Hz,
1H), 7.62 (d, J ¼ 7.8 Hz, 1H), 7.51 (m, 1H), 7.39e7.28 (m, 3H), 7.25 (d,
J ¼ 2.2 Hz, 1H), 7.17 (d, J ¼ 8.3 Hz, 1H), 7.07 (m, 1H), 6.98 (m, 1H),
6.65 (s, 1H), 5.24 (s, 2H), 4.80e4.70 (m, 1H), 3.69 (s, 3H). Two proton
signals under water peak 13C NMR (101 MHz, DMSO‑d6)
d 176.36,
4.1.13. Methyl (5-((2-bromobenzyl)oxy)-4-oxo-4H-chromene-2-
carbonyl)-L-leucinate (9b)
The crude was synthetized according to the General procedure
D starting from 7 (0,500 g, 1,33 mmol) and L-leucine methyl ester
171.52, 159.18, 157.43, 156.95, 152.81, 136.09, 135.74, 135.21, 132.17,
129.57, 129.15, 127.85, 127.03, 123.79, 121.05, 121.02, 118.44, 118.04,
114.43, 112.55, 111.48, 110.83, 109.47, 108.89, 69.73, 53.80, 52.19,
26.38. m.p. 250e252.8 ꢁC. HRMS (ESI/QTOF) calcd for C29H24BrN2O6
(M þ Hþ) 575.0818, found 575.0821.
hydrochloride (0.483 g, 2.66 mmol). It was purified recrystallisation
in methanol and then washed with diethyl ether to afford 9b, a pale
yellow solid (0.234 g, 35%). C24H24BrNO6.
4.1.17. (5-((4-bromobenzyl)oxy)-4-oxo-4H-chromene-2-carbonyl)-
1H NMR (400 MHz, CDCl3)
7.48 (d, J ¼ 7.9 Hz, 1H), 7.38 (m, 1H), 7.18e7.05 (m, 3H), 6.98 (s, 1H),
6.90 (d, J ¼ 8.3 Hz, 1H), 5.18 (s, 2H), 4.82e4.73 (m, 1H), 3.74 (s, 3H),
1.80e1.60 (m, 3H), 0.99e0.87 (m, 6H). 13C NMR (101 MHz, CDCl3)
d
8.13 (d, J ¼ 7.4 Hz, 1H), 7.57 (m, 1H),
L
-alloisoleucine (10)
The crude was synthetized according to the General procedure E
starting from 8a (0,671 g, 0.51 mmol). It was purified by recrys-
tallisation in methanol and then washed with diethyl ether to
afford 10, white crystals, (0.419 g, 51%). C23H22BrNO6.
d
177.52, 172.93, 159.05, 158.46, 157.33, 152.34, 135.55, 134.74,
132.10, 129.07, 128.79, 128.12, 120.82, 115.42, 114.21, 110.63, 108.66,
70.38, 52.73, 51.14, 41.81, 25.02, 22.82, 22.05. m.p. 115.1e116.7 ꢁC.
HRMS (ESI/QTOF) calcd for C24H25BrNO6 (M þ Hþ) 502.0865, found
502.0865.
1H NMR (400 MHz, DMSO)
7.78 (m, 1H), 7.67e7.57 (m, 4H), 7.37 (dd, J ¼ 8.5, 0.6 Hz, 1H), 7.13 (d,
J ¼ 8.2 Hz, 1H), 6.72 (s, 1H), 5.26 (s, 2H), 4.40e4.29 (m, 1H),
2.07e1.96 (m, 1H), 1.61e1.45 (m, 1H), 1.38e1.20 (m, 1H), 0.96 (d,
d
12.91 (s, 1H), 8.98 (d, J ¼ 8.1 Hz,1H),