Novel waterꢀsoluble anticancer agents
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1107
(1 : 3) was used as an eluent. Yield 89 mg (74%), white crystals,
m.p. 147—149 C. 1H NMR (CDCl3), : 1.49 (s, 9 H); 3.85
(s, 3 H); 3.93 (s, 3 H); 6.19 (s, 1 H); 6.78 (dd, 1 H, J = 8.9 Hz,
J = 2.5 Hz); 6.84 (d, 1 H, J = 2.4 Hz); 6.94 (d, 1 H, J = 8.4 Hz);
7.03 (dd, 1 H, J = 8.3 Hz, J = 2.1 Hz); 7.16 (s, 1 H); 7.48 (d, 1 H,
J = 8.9 Hz); 8.23 (s, 1 H). 13C NMR (CDCl3), : 28.38, 55.83,
55.96, 80.85, 101.09, 110.04, 111.55, 112.28, 112.79, 118.13,
122.55, 128.28, 128.36, 128.60, 148.51, 152.64, 155.90, 156.02,
161.50, 162.70. Found (%): C, 66.37; H, 5.85; N, 3.60.
C22H23NO6. Calculated (%): C, 66.49; H, 5.83; N, 3.52.
sure. Compounds 4a—f were isolated by recrystallization from
EtOH—H2O—Et2O.
4ꢀ(3ꢀAminoꢀ4ꢀmethoxyphenyl)coumarin hydrochloride (4a)
was obtained from compound 3a (49 mg, 0.134 mmol). Yield
34 mg (73%), white crystals, m.p. 172—179 C (decomp.). 1H NMR
(CD3OD), : 4.09 (s, 3 H); 6.41 (s, 1 H); 7.35 (t, 1 H, J = 7.6 Hz);
7.43 (d, 1 H, J = 5.3 Hz); 7.45 (d, 1 H, J = 4.9 Hz); 7.57 (d, 1 H,
J = 8.1 Hz); 7.59 (d, 1 H, J = 1.9 Hz); 7.62—7.70 (m, 2 H). 13C NMR
(CD3OD), : 57.27, 113.93, 115.98, 118.33, 119.82, 121.71,
125.23, 125.83, 127.89, 129.19, 131.87, 133.64, 155.22,
155.69, 155.44, 162.38. Found (%): C, 63.16; H, 4.64; N, 4.69.
C16H14ClNO3. Calculated (%): C, 63.27; H, 4.65; N, 4.61.
4ꢀ(3ꢀAminoꢀ4ꢀmethoxyphenyl)ꢀ5ꢀmethoxycoumarin hydroꢀ
chloride (4b) was obtained from compound 3b (46 mg, 0.115 mmol).
Yield 29 mg (76%), white crystals, m.p. 219—227 C (decomp.).
1H NMR (CD3OD), : 3.55 (s, 3 H); 4.06 (s, 3 H); 6.16 (s, 1 H);
6.90 (d, 1 H, J = 8.4 Hz); 7.04 (d, 1 H, J = 8.4 Hz); 7.29 (d, 1 H,
J = 8.6 Hz); 7.37 (d, 1 H, J = 2.1 Hz); 7.46 (dd, 1 H, J = 8.5 Hz,
J = 2.1 Hz); 7.59 (t, 1 H, J = 8.4 Hz). 13C NMR (CD3OD),
: 56.31, 57.05, 108.43, 109.82, 110.74, 112.52, 116.82, 119.93,
124.36, 130.60, 133.95, 134.35, 154.06, 155.42, 156.63, 158.65,
162.05. Found (%): C, 61.11; H, 4.84; N, 4.25. C17H16ClNO4.
Calculated (%): C, 61.18; H, 4.83; N, 4.20.
4ꢀ(3ꢀAminoꢀ4ꢀmethoxyphenyl)ꢀ7ꢀmethoxycoumarin hydroꢀ
chloride (4c) was obtained from compound 3c (42 mg, 0.106 mmol).
Yield 25 mg (71%), white crystals, m.p. 215—219 C (decomp.).
1H NMR (CD3OD), : 3.91 (s, 3 H); 4.09 (s, 3 H); 6.22 (s, 1 H);
6.93 (dd, 1 H, J = 8.9 Hz, J = 2.5 Hz); 7.00 (d, 1 H, J = 2.5 Hz);
7.42 (d, 1 H, J = 8.6 Hz); 7.46 (d, 1 H, J = 8.9 Hz); 7.55 (d, 1 H,
J = 2.1 Hz); 7.64 (dd, 1 H, J = 8.6 Hz, J = 2.1 Hz). 13C NMR
(CD3OD), : 56.56, 57.25, 102.27, 112.43, 113.21, 113.85,
113.88, 121.67, 125.14, 128.95, 129.62, 131.81, 155.17, 155.99,
157.36, 162.97, 164.89. Found (%): C, 61.14; H, 4.82; N, 4.24.
C17H16ClNO4. Calculated (%): C, 61.18; H, 4.83; N, 4.20.
4ꢀ(3ꢀAminoꢀ4ꢀmethoxyphenyl)ꢀ6ꢀmethoxycoumarin hydroꢀ
chloride (4d) was obtained from compound 3d (43 mg, 0.108 mmol).
Yield 22 mg (62%), white crystals, m.p. 226—231 C (decomp.).
1H NMR (CD3OD), : 3.77 (s, 3 H); 4.06 (s, 3 H); 6.38 (s, 1 H);
6.99 (d, 1 H, J = 2.9 Hz); 7.26 (dd, 1 H, J = 9.1 Hz, J = 2.9 Hz);
7.35 (d, 1 H, J = 8.5 Hz); 7.39 (d, 1 H, J = 9.1 Hz); 7.43 (d, 1 H,
J = 2.1 Hz); 7.50 (dd, 1 H, J = 8.5 Hz, J = 2.1 Hz). 13C NMR
(CD3OD), : 56.26, 57.02, 110.79, 113.46, 116.08, 119.35,
120.39, 120.54, 123.15, 125.32, 129.27, 131.07, 149.71, 154.21,
155.98, 157.73, 162.78. Found (%): C, 61.25; H, 4.81; N, 4.23.
C17H16ClNO4. Calculated (%): C, 61.18; H, 4.83; N, 4.20.
4ꢀ(3ꢀAminoꢀ4ꢀmethoxyphenyl)ꢀ5,7ꢀdimethoxycoumarin hydroꢀ
chloride (4e) was obtained from compound 3e (47 mg, 0.110 mmol).
Yield 22 mg (54%), beige crystals, m.p. 237—244 C (decomp.).
1H NMR (DMSO), : 3.51 (s, 3 H); 3.87 (s, 3 H); 3.93 (s, 3 H);
5.93 (s, 1 H); 6.49 (d, 1 H, J = 2.3 Hz); 6.69 (d, 1 H, J = 2.3 Hz);
7.18 (d, 1 H, J = 8.5 Hz); 7.29 (dd, 1 H, J = 8.5 Hz, J = 1.8 Hz);
7.37 (d, 1 H, J = 1.8 Hz). 13C NMR (DMSO), : 56.03, 56.04,
56.19, 93.99, 96.09, 102.30, 111.19, 112.00, 121.40, 122.45,
126.85, 131.56, 151.65, 153.76, 156.62, 157.98, 159.51, 163.33.
Found (%): C, 59.33; H, 4.98; N, 3.87. C18H18ClNO5. Calculatꢀ
ed (%): C, 59.43; H, 4.99; N, 3.85.
4ꢀ(3ꢀtertꢀButoxycarbonylaminoꢀ4ꢀmethoxyphenyl)ꢀ6ꢀmethꢀ
oxycoumarin (3d) was obtained from trifluoromethylsulfonate 2d
(200 mg, 0.617 mmol) and arylboronic acid diester (250 mg,
0.712 mmol) in the presence of Pd(PPh3)4 (37 mg, 0.032 mmol),
K2CO3 (270 mg, 1.94 mmol), and CuI (12 mg, 0.062 mmol). For
column chromatography, light petroleum—ethyl acetate (3 : 1)
was used as an eluent. Yield 202 mg (83%), white crystals, m.p.
1
176 C. H NMR (CDCl3), : 1.50 (s, 9 H); 3.76 (s, 3 H); 3.95
(s, 3 H); 6.37 (s, 1 H); 6.97 (d, 1 H, J = 8.4 Hz); 7.07—7.14
(m, 3 H); 7.15 (s, 1 H); 7.29 (d, 1 H, J = 8.7 Hz); 8.30 (s, 1 H).
13C NMR (CDCl3), : 28.37, 55.84, 55.98, 80.57, 109.61, 110.26,
115.06, 118.21, 118.48, 119.51, 119.65, 122.65, 127.99, 128.54,
148.70, 148.71, 152.70, 155.28, 155.96, 161.29. Found (%):
C, 66.45; H, 5.80; N, 3.58. C22H23NO6. Calculated (%):
C, 66.49; H, 5.83; N, 3.52.
4ꢀ(3ꢀtertꢀButoxycarbonylaminoꢀ4ꢀmethoxyphenyl)ꢀ5,7ꢀdiꢀ
methoxycoumarin (3e) was obtained from trifluoromethylsulꢀ
fonate 2e (50 mg, 0.141 mmol) and arylboronic acid diester
(54 mg, 0.155 mmol) in the presence of Pd(PPh3)4 (8.2 mg,
0.008 mmol), K2CO3 (58 mg, 0.424 mmol), and CuI (2.7 mg,
0.014 mmol). For column chromatography, light petroleum—
ethyl acetate (3 : 1) was used as an eluent. Yield 50 mg (84%),
light yellow crystals, m.p. 178 C. 1H NMR (CDCl3), : 1.49
(s, 9 H); 3.48 (s, 3 H); 3.86 (s, 3 H); 3.92 (s, 3 H); 6.01 (s, 1 H);
6.24 (d, 1 H, J = 2.4 Hz); 6.50 (d, 1 H, J = 2.4 Hz); 6.84 (d, 1 H,
J = 8.4 Hz); 6.90 (dd, 1 H, J = 8.3 Hz, J = 2.1 Hz); 7.10 (s, 1 H);
8.06 (s, 1 H). 13C NMR (CDCl3), : 28.46, 55.73, 55.85, 55.90,
80.54, 93.69, 96.10, 103.90, 108.88, 112.79, 117.67, 121.25,
127.24, 132.75, 147.46, 152.66, 155.73, 157.29, 158.51, 161.12,
163.31. Found (%): C, 64.74; H, 5.88; N, 3.32. C23H25NO7.
Calculated (%): C, 64.63; H, 5.90; N, 3.28.
4ꢀ(3ꢀtertꢀButoxycarbonylaminoꢀ4ꢀmethoxyphenyl)ꢀ5,6,7ꢀtriꢀ
methoxycoumarin (3f) was obtained from trifluoromethylsulꢀ
fonate 2f (142 mg, 0.360 mmol) and arylboronic acid diester
(138 mg, 0.396 mmol) in the presence of Pd(PPh3)4 (21 mg,
0.018 mmol), K2CO3 (149 mg, 1.080 mmol), and CuI (7 mg,
0.036 mmol). For column chromatography, light petroleum—
ethyl acetate (3 : 1) was used as an eluent. Yield 155 mg (94%),
yellow crystals, m.p. 168 C. 1H NMR (CDCl3), : 1.47 (s, 9 H);
3.34 (s, 3 H); 3.76 (s, 3 H); 3.90 (s, 3 H); 3.91 (s, 3 H); 6.05
(s, 1 H); 6.70 (s, 1 H); 6.88 (d, 1 H, J = 8.4 Hz); 6.92 (dd, 1 H,
J = 8.3 Hz, J = 2.1 Hz); 7.13 (s, 1 H); 8.10 (s, 1 H). 13C NMR
(CDCl3), : 28.40, 55.87, 56.32, 61.14, 61.35, 80.62, 96.26,
107.54, 109.04, 114.13, 117.21, 121.18, 127.36, 131.96, 139.52,
147.36, 151.30, 151.77, 152.62, 155.50, 156.82, 160.92. Found (%):
C, 64.81; H, 5.87; N, 3.29. C24H27NO8. Calculated (%): C, 64.63;
H, 5.90; N, 3.28.
4ꢀ(3ꢀAminoꢀ4ꢀmethoxyphenyl)ꢀ5,6,7ꢀtrimethoxycoumarin
hydrochloride (4f) was obtained from compound 3f (100 mg,
0.219 mmol). Yield 63 mg (73%), white crystals, m.p.
245—253 C (decomp.). 1H NMR (CD3OD), : 3.31 (s, 3 H);
3.78 (s, 3 H); 3.96 (s, 3 H); 4.06 (s, 3 H); 6.04 (s, 1 H); 6.90
(s, 1 H); 7.29 (d, 1 H, J = 8.5 Hz); 7.40 (d, 1 H, J = 2.1 Hz);
Synthesis of compounds 4a—f (general procedure). 4ꢀArylꢀ
coumarin 3a—f was dissolved in EtOAc, and an equal volume of
3 M HCl in EtOH was added. The reaction mixture was stirred
at 50 C for 1—5 h. The course of the reaction was moniꢀ
tored by TLC. The solvent was removed under reduced presꢀ