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V. Pittala et al. / Bioorg. Med. Chem. Lett. 16 (2006) 150–153
153
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3. Patane, E.; Pittala, V.; Guerrera, F.; Salerno, L.; Romeo,
G.; Siracusa, M.; Russo, F.; Manetti, F.; Botta, M.;
Mereghetti, I.; Cagnotto, A.; Mennini, T. J. Med. Chem.
2005, 48, 2420.
(3.44 mmol, 0.840 g) and 2-chloroethyl isocyanate
(5.16 mmol, 0.438 mL) in 8 mL of toluene was stirred for
6 h at reflux. The reaction mixture was then filtered, and the
obtained solid was washed several times with EtOH to give
the title compound as a pure solid (0.811 g, 67%): mp 112-
114 ꢁC; IR (KBr, selected lines) cmÀ1 3332, 2919, 2865,
1673, 1606, 1549, 1359, 1263, 1097, 778, 655. 1H NMR
(DMSO-d6) d 11.26 (br s, 1H, NH which exchanges with
D2O), 9.24 (br s, 1H, NHCONHCH2 which exchanges with
D2O), 7.99 (t, J = 5.8 Hz, 1H, NHCONHCH2 which
exchanges with D2O), 7.47–7.40 (m, 2H, aromatic), 7.20–
4. Meyer, M. D.; Carrol, W. A. U.S. 6,153,614; 2000.
5. (a) Toja, E.; DePaoli, A.; Tuan, G.; Kettenring, J. Synthesis
1987, 3, 272; (b) Cocco, M. T.; Congiu, C.; Maccioni, A.;
Plumitallo, A.; Schivo, M. L.; Palmieri, G. Farmaco 1988,
43, 103.
6. Experimental procedure for the synthesis of compounds 7,
14, and 26. 2-Amino-5-(4-methylphenyl)-1H-pyrrole-3-car-
boxylic acid ethyl ester (7). Ammonium chloride
(15.3 mmol, 0.820 g) was added to a suspension of 3-
ethoxy-3-iminopropanoic acid ethyl ester hydrochloride
(10.2 mmol, 2.00 g) and K2CO3 (17.9 mmol, 2.47 g) in
10 mL of anhydrous ethanol. The reaction mixture was
then stirred at 22 ꢁC for 24 h. The obtained suspension of 3-
amino-3-iminopropanoic acid ethyl ester was used for the
subsequent step without isolating it from the reaction
4
7.13 (m, 2H, aromatic), 6.61 (d, J = 2.8 Hz, 1H, pyrrole),
4.31 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.69 (t, J = 6.0 Hz, 2H,
CH2Cl), 3.52–3.46 (m, 2H, NHCH2), 2.29 (s, 3 H, CH3),
1.34 (t, J = 7.0 Hz, 3H, OCH2CH3). Anal. (C17H20ClN3O3)
C, H, N. 3-[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl]-6-(4-
methylphenyl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(26) A suspension of 2-[[[(2-chloroethyl)amino]carbon-
yl]amino]-5-(4-methyl)phenyl-1H-pyrrole-3-carboxylic acid
ethyl ester (14) (1.06 mmol, 0.370 g), 1-(2-chlorophenyl)pi-
perazine hydrochloride (1.27 mmol, 0.296 g), NaHCO3
(4.23 mmol, 0.356 g), and a catalytic amount of NaI in
2 mL of anhydrous THF was refluxed for 24 h. After this
period the obtained mixture was concentrated, and the
residue was diluted with water (50 mL) and extracted with
CH2Cl2 (3 · 50 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and evaporated.
The obtained crude material was dissolved in EtOAc,
filtered through a pad of silica gel, and concentrated. The
obtained urea was refluxed in methanolic KOH (1 N, 4 mL)
for 3 h. The reaction mixture was then allowed to cool at
22 ꢁC, acidified (pH 4) with glacial AcOH, and neutralized
with saturated NaHCO3. A white precipitate was isolated,
washed with water, and triturated in EtOAc to afford the
desired product 26 as a white solid (0.285 g, 58%): mp 254–
256 ꢁC; IR (KBr, selected lines) cmÀ1 2973, 2828, 1699,
1636, 1574, 1480, 1444, 1231, 1041, 932, 764, 708. 1H NMR
(DMSO-d6) d 7.60–7.52 (m, 2H, aromatic), 7.42–6.95 (m,
6H, aromatic), 6.58 (s, 1H, pyrrole), 4.06 (t, J = 6.6 Hz, 2H,
CONCH2CH2N), 2.99–2.94 (m, 4H, NCH2), 2.69–2.49 (m,
4H + 2H, NCH2 + CONCH2CH2N), 2.27 (s, 3H, CH3).
Anal. (C25H24ClN5O2) C, H, N.
environment.
2-Bromo-1-(4-methylphenyl)ethanone
(10.2 mmol, 2.18 g) and K2CO3 (5.11 mmol, 0.706 g) were
added to the previously obtained suspension of 3-amino-3-
iminopropanoic acid ethyl ester and the reaction mixture
was refluxed for 2 h. After this period the solvent was
evaporated at reduced pressure, and the residue was diluted
with NaOH 1 N (100 mL) and extracted with EtOAc (3·
100 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and evapo-
rated in vacuo. The obtained crude material was purified by
column chromatography (silica gel, 60,230–400 mesh,
Merck) using cyclohexane/EtOAc (6:4) as eluant, to afford
the title compound (7) as a white powder (1.03 g, 55%): mp
140–142 ꢁC; IR (KBr, selected lines) cmÀ1 3484, 3361, 1666,
1641, 1508, 1369, 1237, 1190, 1071, 799, 765. The 1H NMR
spectrum was recorded at 200 MHz on a Varian Inova
Unity 200 spectrometer in DMSO-d6. 1H NMR (DMSO-d6)
d 10.68 (br s, 1H, NH which exchanges with D2O), 7.41–
7.34 (m, 2H, aromatic), 7.14–7.07 (m, 2H, aromatic), 6.39
(d, 4J = 2.8 Hz, 1H, pyrrole), 5.63 (br s, 2H, NH2 which
exchanges with D2O), 4.13 (q, J = 7.0 Hz, 2H, OCH2CH3),
2.28 (s, 3H, CH3), 1.24 (t, J = 7.0 Hz, 3H, OCH2CH3).
Anal. (C14H16N2O2) C, H, N. 2-[[[(2-Chloroethyl)ami-
no]carbonyl]amino]-5-(4-methylphenyl)-1H-pyrrole-3-car-
boxylic acid ethyl ester (14). A suspension of 2-amino-5-(4-
methylphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (7)
7. van Rossum, J. M. Arch. Int. Pharmacodyn. 1963, 143, 299.
8. Arunlakshana, O.; Schild, H. O. Br. J. Pharmacol. Chemo-
ther. 1959, 14, 48.