Journal of Medicinal Chemistry
Article
d6, 303 K): δ 14.0 (CH2CH3), 55.5 (OCH3), 62.7 (CH2CH3), 91.6
(C-5), 105.8 (C-7), 112.5 (C-3), 125.1 (C-4a), 139.8 (C-8 or C-8a),
140.2 (C-8 or C-8a), 151.3 (C-2), 157.7 (C-6), 160.2 (CO2Et), 177.5
(C-4). LC−MS (m/z): negative mode 262 [M − H]−, positive mode
264 [M + H]+. Purity by HPLC−UV (254 nm)−ESI-MS: 98.7%. Mp:
144−145 °C.
Ethyl 6-Bromo-8-(2,6-difluoro-4-methoxybenzamido)-4-
oxo-4H-chromene-2-carboxylate (77). The compound was
synthesized using 2,6-difluoro-4-methoxybenzoic acid (226 mg, 1.2
mmol) and 18 (281 mg, 0.9 mmol). The precipitate was filtered off,
washed three times with 1 mL of DCM each, and dried in vacuum at
50 °C. The filtrate was concentrated under reduced pressure and
separated by column chromatography on a column of silica gel (95:5
DCM/EtOAc), yielding further product. The amide was isolated as a
Ethyl 6-Chloro-8-(2-fluoro-4-methoxybenzamido)-4-oxo-
4H-chromene-2-carboxylate (74). The compound was synthesized
using 2-fluoro-4-methoxybenzoic acid (204 mg, 1.2 mmol) and ethyl
8-amino-6-chloro-4-oxo-4H-chromene-2-carboxylate (71; 241 mg, 0.9
mmol). The precipitate was filtered off, washed three times with 1 mL
of DCM each, and dried in vacuum at 50 °C. The filtrate was
concentrated under reduced pressure and separated by column
chromatography on a column of silica gel (95:5 DCM/EtOAc),
yielding further product. The amide was isolated as a white powder
(310 mg, 82% yield). 1H NMR (500 MHz, DMSO-d6, 343 K): δ 1.37
(t, J = 7.1 Hz, 3H, CH2CH3), 3.89 (s, 3H, OCH3), 4.43 (q, J = 7.1 Hz,
2H, CH2CH3), 6.97−7.02 (m, 3H, 3-H, 3′-H, 5′-H), 7.74 (d, J = 2.5
Hz, 1H, 5-H), 7.95 (dd, J = 9.1 Hz, 1H, 6′-H), 8.57 (d, J = 2.5 Hz, 1H,
7-H), 9.64 (d, J = 11.7 Hz, 1H, NH). 13C NMR (126 MHz, DMSO-d6,
343 K): δ 13.5 (CH2CH3), 56.1 (OCH3), 62.7 (CH2CH3), 101.9 (d, J
= 28.4 Hz, C-3′), 111.3 (C-5′), 113.0 (d, J = 11.9 Hz, C-1′), 113.6 (C-
3), 118.5 (C-7), 124.7 (C-4a), 125.6 (C-5), 129.8 (C-6 or C-8), 130.2
(C-6 or C-8), 132.3 (d, J = 3.7 Hz, C-6′), 145.4 (C-8a), 151.7 (C-2),
159.4 (CO2Et), 161.1 (d, J = 249.3 Hz, C-2′), 161.3 (d, J = 3.7 Hz, C-
4′), 164.1 (d, J = 12.8 Hz, CONH), 175.7 (C-4). LC−MS (m/z):
negative mode 418 [M − H]−, positive mode 420 [M + H]+. Purity by
HPLC−UV (254 nm)−ESI-MS: 100.0%. Mp: 212−213 °C.
Ethyl 6-Bromo-8-(2-fluoro-4-methoxybenzamido)-4-oxo-
4H-chromene-2-carboxylate (75). The compound was synthesized
using 2-fluoro-4-methoxybenzoic acid (204 mg, 1.2 mmol) and ethyl
8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (18; 281 mg, 0.9
mmol). The precipitate was filtered off, washed three times with 1 mL
of DCM each, and dried in vacuum at 50 °C. The product was isolated
as a white solid (267 mg, 64% yield). 1H NMR (600 MHz, DMSO-d6,
303 K): δ 1.35 (t, J = 7.1 Hz, 3H, CH2CH3), 3.88 (s, 3H, OCH3), 4.41
(q, J = 7.1 Hz, 2H, CH2CH3), 7.00 (dd, J = 8.9 Hz, J = 2.4 Hz, 1H, 5′-
H), 7.04 (s, 1H, 3-H), 7.07 (dd, J = 13.8 Hz, J = 2.3 Hz, 1H, 3′-H),
7.89 (d, J = 2.4 Hz, 1H, 5-H), 7.94 (dd, J = 8.9 Hz, 1H, 6′-H), 8.68 (d,
J = 2.4 Hz, 1H, 7-H), 9.82 (s, 1H, NH). 13C NMR (151 MHz, DMSO-
d6, 303 K): δ 14.2 (CH2CH3), 56.7 (OCH3), 63.4 (CH2CH3), 102.5
(d, J = 28.6 Hz, C-3′), 111.9 (C-5′), 113.6 (d, J = 13.2 Hz, C-1′),
114.4 (C-3), 118.6 (C-6), 122.3 (C-5), 125.7 (C-4a), 129.3 (C-7),
130.5 (C-8), 133.0 (d, J = 3.3 Hz, C-6′), 146.6 (C-8a), 152.3 (C-2),
160.0 (CO2Et), 161.7 (d, J = 248.7 Hz, C-2′), 162.0 (C-4′), 164.1 (d, J
= 12.1 Hz, CONH), 176.4 (C4). LC−MS (m/z): negative mode 464
[M − H]−, positive mode 464 [M + H]+. Purity by HPLC−UV (254
nm)−ESI-MS: 100.0%. Mp: 216 °C.
Ethyl 6-Bromo-8-(3-fluoro-4-methoxybenzamido)-4-oxo-
4H-chromene-2-carboxylate (76). The compound was synthesized
using 3-fluoro-4-methoxybenzoic acid (204 mg, 1.2 mmol) and 18
(281 mg, 0.9 mmol). The precipitate was filtered off, washed three
times with 1 mL of DCM each, and dried in vacuum at 50 °C. The
filtrate was concentrated under reduced pressure and separated by
column chromatography on a column of silica gel (98:2 DCM/
EtOAc), yielding further product. The amide was isolated as a white
solid (309 mg, 74% yield). 1H NMR (500 MHz, DMSO-d6, 343 K): δ
1.29 (t, J = 7.1 Hz, 3H, CH2CH3), 3.96 (s, 3H, OCH3), 4.37 (q, J = 7.1
Hz, 2H, CH2CH3), 7.00 (s, 1H, 3-H), 7.34 (dd, J = 8.5 Hz, 1H, 5′-H),
7.83−7.89 (m, 2H, 2′-H, 6′-H), 7.97 (d, J = 2.4 Hz, 1H, 5-H), 8.32 (d,
J = 2.4 Hz, 1H, 7-H), 10.05 (s, 1H, NH). 13C NMR (126 MHz,
DMSO-d6, 343 K): δ 13.4 (CH2CH3), 56.4 (OCH3), 62.6 (CH2CH3),
113.6 (C-3 or C-6′), 113.7 (C-3 or C-6′), 115.1 (d, J = 19.2 Hz, C-2′),
117.6 (C-6), 123.0 (C-5), 124.8 (d, J = 2.7 Hz, C-5′), 125.3 (C-4a),
126.0 (d, J = 5.5 Hz, C-1′), 130.0 (C-8), 131.8 (C-7), 147.9 (C-8a),
150.5 (d, J = 10.1 Hz, C-4′), 151.0 (d, J = 245.6 Hz, C-3′), 151.8 (C-
2), 159.4 (CO2Et), 163.7 (CONH), 175.7 (C4). LC−MS (m/z):
negative mode 461 [M − H]−, positive mode 466 [M + H]+. Purity by
HPLC−UV (254 nm)−ESI-MS: 97.2%. Mp: 251 °C.
1
white powder (221 mg, 51% yield). H NMR (500 MHz, DMSO-d6,
343 K): δ 1.34 (t, J = 7.1 Hz, 3H, CH2CH3), 3.87 (s, 3H, OCH3), 4.39
(q, J = 7.1 Hz, 2H, CH2CH3), 6.85 (d, J = 10.0 Hz, 2H, 3′-H, 5′-H),
7.00 (s, 1H, 3-H), 7.97 (d, J = 2.4 Hz, 1H, 5-H), 8.33 (d, J = 2.4 Hz,
1H, 7-H), 10.27 (s, 1H, NH). 13C NMR (151 MHz, DMSO-d6, 303
K): δ 14.2 (CH2CH3), 57.0 (OCH3), 63.3 (CH2CH3), 99.1 (d, J =
28.6 Hz, C-3′, C-5′), 106.8−107.1 (m, C-1′), 114.4 (C-3), 118.3 (C-
6), 124.0 (C-5), 126.1 (C-4a), 129.7 (C-8), 132.1 (C-7), 148.1 (C-8a),
152.6 (C-2), 159.3 (C-4′), 160.1 (CO2Et), 160.0−161.7 (m, C-2′, C-
6′), 162.6 (t, J = 14.3 Hz, CONH), 176.4 (C4). LC−MS (m/z):
negative mode 482 [M − H]−, positive mode 484 [M + H]+. Purity by
HPLC−UV (254 nm)−ESI-MS: 98.6%. Mp: 263 °C.
Ethyl 8-(4-Methoxybenzamido)-6-methyl-4-oxo-4H-chro-
mene-2-carboxylate (78). The compound was synthesized using
ethyl 8-amino-6-methyl-4-oxo-4H-chromene-2-carboxylate (72; 226
mg, 0.9 mmol). The product was isolated as a white powder (278 mg,
81% yield). 1H NMR (500 MHz, DMSO-d6, 343 K): δ 1.27 (t, J = 7.1
Hz, 3H, CH2CH3), 2.46 (s, 3H, ArCH3), 3.87 (s, 3H, OCH3), 4.35 (q,
J = 7.1 Hz, 2H, CH2CH3), 6.93 (s, 1H, 3-H), 7.07−7.10 (m, 2H, 3′-H,
5′-H), 7.68−7.69 (m, 1H, 5-H), 7.98 (d, J = 2.1 Hz, 1H, 7-H), 8.00−
8.03 (m, 2H, 2′-H, 6′-H), 9.85 (s, 1H, NH). 13C NMR (126 MHz,
DMSO-d6, 343 K): δ 13.5 (CH2CH3), 20.5 (ArCH3), 55.4 (OCH3),
62.4 (CH2CH3), 113.3 (C-3), 113.7 (C-3′, C-5′), 120.2 (C-5), 123.9
(C-4a), 126.1 (C-1′), 128.2 (C-8), 129.4 (C-2′, C-6′), 130.9 (C-7),
135.3 (C-6), 147.2 (C-8a), 151.5 (C-2), 159.7 (CO2Et), 162.1 (C-4′),
164.7 (CONH), 176.9 (C4). LC−MS (m/z): negative mode 380 [M
− H]−, positive mode 382 [M + H]+. Purity by HPLC−UV (254
nm)−ESI-MS: 98.2%. Mp: 219 °C.
Ethyl 6-Methoxy-8-(4-methoxybenzamido)-4-oxo-4H-chro-
mene-2-carboxylate (79). The compound was synthesized using
73 (237 mg, 0.9 mmol). The product was isolated as a white solid
(304 mg, 85% yield). 1H NMR (500 MHz, DMSO-d6, 343 K): δ 1.30
(t, J = 7.1 Hz, 3H, CH2CH3), 3.87 (s, 3H, 6-OCH3 or 4′-OCH3), 3.90
(s, 3H, 6-OCH3 or 4′-OCH3), 4.36 (q, J = 7.1 Hz, 2H, CH2CH3), 6.93
(s, 1H, 3-H), 7.09 (d, J = 8.8 Hz, 2H, 3′-H, 5′-H), 7.27 (d, J = 3.1 Hz,
1H, 5-H), 7.85 (d, J = 3.0 Hz, 1H, 7-H), 8.00 (d, J = 9.1 Hz, 2H, 2′-H,
6′-H), 9.76 (s, 1H, NH). 13C NMR (126 MHz, DMSO-d6, 343 K): δ
13.5 (CH2CH3), 55.4 (6-OCH3 or 4′-OCH3), 55.8 (6-OCH3 or 4′-
OCH3), 62.4 (CH2CH3), 101.1 (C-5), 112.5 (C-3), 113.8 (C-3′, C-
5′), 118.0 (C-7), 124.7 (C-4a), 126.0 (C-1′), 129.3 (C-2′, C-6′), 129.7
(C-8), 143.5 (C-8a), 151.3 (C-2), 156.6 (C-6), 159.7 (CO2Et), 162.3
(C-4′), 164.6 (CONH), 176.5 (C4). LC−MS (m/z): negative mode
396 [M − H]−, positive mode 398 [M + H]+. Purity by HPLC−UV
(254 nm)−ESI-MS: 98.9%. Mp: 217−218 °C.
6-Chloro-8-(2-fluoro-4-methoxybenzamido)-4-oxo-4H-chro-
mene-2-carboxylic Acid (80). The compound was synthesized
using 74 (168 mg, 0.40 mmol). Recrystallization from 1:1 acetone/
ethanol afforded the product as a white powder (126 mg, 80% yield).
1H NMR (500 MHz, DMSO-d6, 303 K): δ 3.87 (s, 3H, OCH3), 6.96−
7.03 (m, 3H, 3-H, 3′-H, 5′-H), 7.72 (d, J = 2.5 Hz, 1H, 5-H), 7.92 (dd,
J = 9.0 Hz, 1H, 6′-H), 8.56 (d, J = 2.5 Hz, 1H, 7-H), 9.77 (d, J = 11.7
Hz, 1H, NH). 13C NMR (126 MHz, DMSO-d6, 303 K): δ 56.3
(OCH3), 102.1 (d, J = 27.5 Hz, C-3′), 111.6 (C-5′), 113.3 (d, J = 11.9
Hz, C-1′), 113.6 (C-3), 118.7 (C-7), 124.9 (C-4a), 125.8 (C-5), 130.0
(C-6 or C-8), 130.2 (C-6 or C-8), 132.6 (d, J = 3.7 Hz, C-6′), 145.7
(C-8a), 153.1 (C-2), 160.3 (CO2H), 161.3 (d, J = 249.3 Hz, C-2′),
161.7 (d, J = 3.7 Hz, C-4′), 164.2 (d, J = 11.9 Hz, CONH), 176.4 (C-
4). LC−MS (m/z): negative mode 346 [M − CO2H]−, 390 [M −
H]−, positive mode 392 [M + H]+. Purity by HPLC−UV (254 nm)−
ESI-MS: 99.3%. Mp: 279−280 °C dec.
6-Bromo-8-(2-fluoro-4-methoxybenzamido)-4-oxo-4H-chro-
mene-2-carboxylic Acid (81). The compound was synthesized
L
dx.doi.org/10.1021/jm4009373 | J. Med. Chem. XXXX, XXX, XXX−XXX