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N. S. M. Ismail, M. Hattori / Bioorg. Med. Chem. 19 (2011) 374–383
113.85, 118.49, 118.81, 119.59, 121.96, 122.03, 122.10, 122.14,
123.06, 126.99, 127.57, 128.61, 131.76, 136.06, 153.77, 157.37,
170.87, 173.41, 183.68. MS (EI+): m/z: 508 [MꢂH]+; HRMS (EI+)
508.1872 [MꢂH]+, found 508.1876. Anal. Calcd for C30H25N3O5: C,
70.99; H, 4.96; N, 8.28. Found: C, 71.02; H, 4.71; N, 7.99.
(40 mL) was added then, the reaction mixture was heated under
reflux for 18 h. The reaction mixture was poured into water
(100 mL), the aqueous layer was extracted with ethyl acetate
(3 ꢃ 100 mL) and the combined organic extracts were washed with
brine (50 mL) and with sodium sulfate anhydrous. The ethyl ace-
tate solution was concentrated in vacuo, to give bright yellow solid
crystallized from ethyl acetate/n-hexane mixture as 4:6 v/v. Yield
4.3.4. (S,E)-2-[2-[4-(3-(1H-Indol-3-yl)-3-oxoprop-1-enyl)-
80%, mp 163–164 °C. IR:
m
max/cmꢁ1 3339, 3050, 3000, 2934,
phenoxy]acetamido]-3-(1H-imidazol-4-yl)propanoic acid (10d)
Yield 81%, mp 147–148 °C; ½a D26
¼ þ17:18 (c 0.81%, methanol).
ꢄ
2833, 1713, 1678, 1609, 1509, 1484, 1455, 1247, 1218, 1031,
772. 1H NMR (400 MHz, DMSO-d6): d 4.76 (s, 2H), 6.99 (d,
J = 8.74 Hz, 2H), 7.24–7.29 (m, 2H), 7.49 (d, J = 7.16 Hz, 2H), 7.58
(d, J = 15.64 Hz, 1H), 7.72 (d, J = 15.60 Hz, 2H), 7.80 (d, J = 8.74 Hz,
2H), 8.33 (d, J = 6.66 Hz, 1H), 8.57 (s, 1H), 8.64 (s, 1H), 8.71 (d,
J = 3.04 Hz, 1H), 12.10 (br s, 1H). 13C NMR (125 MHz, DMSO-d6):
d 64.50, 109.75, 109.82, 111.26, 111.82, 112.09, 113.86, 118.49,
118.81, 119.59, 121.96, 122.03, 122.10, 122.14, 123.06, 126.99,
127.57, 128.61, 131.76, 136.06, 153.77, 158.01, 171.51, 172.31,
183.66. MS (EI+): m/z: 443 [MꢂH]+; HRMS (EI+) 443.1355 [MꢂH]+,
found 443.1362. Anal. Calcd for C24H18N4O5: C, 65.15; H, 4.10; N,
12.66, Found: C, 65.49; H, 4.28; N, 12.92.
IR: m
max/cmꢁ1 3257, 3141, 3034, 2936, 2840, 1715, 1673, 1655,
1619, 1543, 1485, 1416, 1325, 1218, 1165, 1120, 1067. 1H NMR
(400 MHz, DMSO-d6): d 3.29–3.32 (m, 2H), 4.39–4.43 (m, IH),
4.76 (s, 2H), 6.99 (d, J = 8.74 Hz, 2H), 7.22–7.30 (m, 2H), 7.49 (d,
J = 7.26 Hz, 2H), 7.52 (s, 1H), 7.59 (d, J = 15.62 Hz, 1H), 7.71 (d,
J = 15.60 Hz, 1H), 7.80 (d, J = 8.74 Hz, 2H), 8.32 (d, J = 6.95 Hz,
1H), 8.71 (d, J = 2.72 Hz, 1H), 9.08 (s, 1H), 12.16 (br s, 1H). 13C
NMR (125 MHz, DMSO-d6): d 27.59, 48.55, 64.52, 111.05, 113.44,
114.75, 116.77, 120.65, 122.52, 123.24, 123.57, 123.81, 125.03,
125.06, 125.40, 126.47, 126.72, 127.95,128.36, 130.03, 134.97,
149.78, 155.64, 170.90, 173.44, 183.67. MS (EI+): m/z: 459
[MꢂH]+; HRMS (EI+) 459.1668 [MꢂH]+, found 459.1678. Anal. Calcd
for C25H22N4O5: C, 65.49; H, 4.84; N, 12.22. Found: C, 65.36; H,
4.60; N, 12.43.
4.5. Synthesis of 2-(4-acetamidobenzoyl)benzoic acid (3)
To a solution of phthalic anhydride (10 mmol) in dichloroeth-
ane (50 mL) was added acetylaniline (15 mmol). The solution
was cooled in an ice bath; aluminum chloride (100 mmol) was
added portionwise. The ice bath was removed after 10 min and
warmed to room temperature over 1 h. The reaction mixture was
refluxed for 16 h, cooled to room temperature and poured carefully
into a stirred solution of ice/1 N HCl (100 mL). The organic layer
was separated, and the aqueous layer was extracted with dichloro-
ethane (3 ꢃ 50 mL). The combined organic layer was extracted
with cold aqueous 1 N NaOH (100 mL). The aqueous layer was ex-
tracted with dichloroethane (1 ꢃ 50 mL). The organic layers were
discarded and the cold aqueous basic layer was acidified with con-
centrated HCl (12 mL) resulting in a milky white suspension which
was extracted with dichloroethane (3 ꢃ 50 mL), dried over anhy-
drous Na2SO4 and concentrated affording 3. Yield 72%, mp 170–
171 °C. 1H NMR (400 MHz, DMSO-d6): d 3.25 (s, 3H), 6.36–6.39
(m, 1H), 6.79–6.81 (m, 1H), 6.86–6.88 (m, 1H), 7.19–7.24
(m, 1H), 7.27 (br s, 1H), 7.30–7.32 (m, 1H), 7.56–7.60 (m, 1H),
7.65–7.69 (m, 1H), 7.94–7.96 (m, 1H); MS (EI+): m/z: 284 [MꢂH]+.
4.3.5. (E)-2-[4-[2-[4-(3-(1H-Indol-3-yl)-3-oxoprop-1-enyl)-
phenoxy]acetamido]benzoyl]-benzoic acid (10e)
Yield 80%, mp 181–182 °C. IR:
m
max/cmꢁ1 3282, 3224, 3141,
3005, 2936, 2840, 1720, 1670, 1655, 1619, 1530, 1485, 1436,
1416, 1325, 1218, 1165, 1120, 1067. 1H NMR (400 MHz, DMSO-
d6): d 4.76 (s, 2H), 6.38 (t, J = 7.58 Hz, 1H), 6.82 (d, J = 8.36 Hz,
1H), 6.88 (d, J = 8.14 Hz, 1H), 6.99 (d, J = 8.69 Hz, 2H), 7.24–7.31
(m, 4H), 7.39 (d, J = 7.47 Hz, 1H), 7.49 (d, J = 7.88 Hz, 1H), 7.59 (d,
J = 15.60 Hz, 1H), 7.63 (d, J = 7.62 Hz, 1H), 7.73–7.79 (m, 2H), 7.83
(d, J = 8.71 Hz, 2H), 7.96 (d, J = 7.67 Hz, 1H), 8.33 (d, J = 7.18 Hz,
1H), 8.70 (d, J = 3.01 Hz, 1H), 12.11 (br s, 1H). 13C NMR (125 MHz,
DMSO-d6):
d 64.50, 100.61, 109.40, 110.92, 111.38, 112.00,
116.67, 117.93, 118.35, 120.90, 122.66, 123.27, 123.63, 124.90,
124.93,125.44, 126.32, 126.41, 126.56, 127.05, 128.38, 128.95,
131.47, 136.03, 136.51, 137.44, 137.59, 150.01, 152.88, 158.95,
171.27, 171.29, 172.37, 183.71. MS (EI+): m/z: 545 [MꢂH]+; HRMS
(EI+) 545.1712 [MꢂH]+, found 545.1726. Anal. Calcd for
C31H32N2O6.5H2O: C, 72.78; H, 4.44; N, 5.14. Found: C, 72.56; H,
4.71; N, 5.23.
4.3.6. (E)-2-[2-[2-[4-(3-(1H-indol-3-yl)-3-oxoprop-1-enyl)-
4.6. Synthesis of 2-(4-aminoobenzoyl)benzoic acid (4)
phenoxy]acetamido]benzoyl]-benzoic acid (10f)
Yield 80%, mp 181–182 °C. IR:
m
max/cmꢁ1 3282, 3224, 3141,
To 2-(4-acetamidobenzoyl) benzoic acid (3) (2.83 g, 10 mmol)
was added hydrochloric acid 37% (50 mL) and the reaction mixture
was heated under reflux for 6 h then, the reaction mixture was
poured into water (100 mL). The aqueous layer was extracted with
ethyl acetate (3 ꢃ 100 mL) and the combined organic extracts were
washed with brine (50 mL) and dried over sodium sulfate anhy-
drous. The ethyl acetate solution was concentrated in vacuo, to
give yellow solid recrystallized from hot concentrated hydrochloric
acid affording 4. Yield 72%, mp 203–204 °C. 1H NMR (400 MHz,
DMSO-d6): d 6.36–6.40 (t, J = 7.20 Hz, 1H), 6.82 (d, J = 8.26 Hz,
1H), 6.88–6.91(m, 1H), 7.21–7.25 (m, 1H), 7.32 (br s,1H), 7.39 (d,
J = 7.07 Hz, 1H), 7.60–7.64 (m, 1H), 7.71–7.73 (m, 1H), 7.96 (d,
J = 7.75 Hz, 1H). MS (EI+): m/z: 242 [MꢂH]+.
3005, 2936, 2840, 1720, 1670, 1655, 1619, 1530, 1485, 1436,
1416, 1325, 1218, 1165, 1120, 1067. 1H NMR (400 MHz, DMSO-
d6): d 4.76 (s, 2H), 6.38 (t, J = 7.58 Hz, 1H), 6.82 (d, J = 8.36 Hz,
1H), 6.88 (d, J = 8.14 Hz, 1H), 6.99 (d, J = 8.69 Hz, 2H), 7.24–7.30
(m, 4H), 7.39 (d, J = 7.47 Hz, 1H), 7.49 (d, J = 7.88 Hz, 1H), 7.59 (d,
J = 15.60 Hz, 1H), 7.63 (d, J = 7.62 Hz, 1H), 7.73–7.80 (m, 2H), 7.83
(d, J = 8.71 Hz, 2H), 7.96 (d, J = 7.67 Hz, 1H), 8.33 (d, J = 7.18 Hz,
1H), 8.70 (d, J = 3.01 Hz, 1H), 12.11 (br s, 1H). 13C NMR (125 MHz,
DMSO-d6):
d 64.50, 100.61, 109.40, 110.92, 111.38, 112.00,
116.67, 117.93, 118.35, 120.90, 122.66, 123.27, 123.63, 124.90,
124.93,125.44, 126.32, 126.41, 126.56, 127.05, 128.38, 128.95,
131.47, 136.03, 136.51, 137.44, 137.59, 150.01, 152.88, 158.95,
171.27, 171.29, 172.37, 183.71. MS (EI+): m/z: 545 [MꢂH]+; HRMS
(EI+) 545.1712 [MꢂH]+, found 545.1726.
4.7. Synthesis of ethyl 2-(4-aminobenzoyl)benzoate (5)
4.4. Synthesis of (E)-4-[2-[4-(3-(1H-Indol-3-yl)-3-oxoprop-1-
enyl)phenoxy]acetamido]-pyrimidine-5-carboxylic acid (10g)
To
a solution of 2-(4-aminobenzoyl) benzoic acid (4)
(15.5 mmol) in absolute ethanol (150 mL) concd H2SO4 (2 mL)
was added and the mixture was refluxed for 6 h. The reaction
mixture was cooled to room temperature and concentrated. The
To cyanopyrimidine derivative (9g) (2.00 g, 10.35 mmol), glacial
acetic acid (20 mL), concd sulfuric acid (98%, 20 mL) and water