Arch. Pharm. Chem. Life Sci. 2012, 345, 185–194
Synthesis and Pharmacology of Pyrrolidone Derivatives
191
compounds was checked by thin layer chromatography (TLC)
on silica gel G (Merck) coated plates by using toluene/ethyl
acetate/formic acid (5:4:1) as solvent system. Iodine chamber
and UV lamp were used for the visualization of TLC spots.
The calculated log P values were taken from the ACD Labs
Software 2.0. and the results are shown in Table 1.
(d, 2H, COCH2), 6.86–7.91 (m, 9H, ArH), 11.14 (s, 1H, OH,
D2O exchangeable).
1-[6-(4-Chlorophenyl)-3-cyano-4-(4-methylphenyl)-
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acid (3e)
Yield 64%; mp 2328C; IR (KBr) cmꢀ1: 3219 (COO–H), 3056
–
(Ar-CHstr), 2917 (C-Haliph), 2219 (C N), 1714 (C O), 1702
–
–
(C OOH), 759 (C–Cl); 1H NMR (CDCl3): d 2.26 (s, 3H, CH3), 3.15
(d, 2H, NCH2), 3.53 (m, 1H, CHpyrr), 4.42 (d, 2H, COCH2), 6.89–7.94
(m, 9H, ArH), 10.86 (s, 1H, OH, D2O exchangeable).
General procedure for the synthesis of 2-amino-6-
(4-substituted phenyl)-4-(substituted phenyl)
nicotinonitriles (2a–t)
–
A mixture of various substituted acetophenones (1a–d, 0.01 mole)
and the appropriate aromatic aldehydes (0.01 mole) in
ethanol (40 mL) was treated with malonotrile (0.01 mole) and
ammonium acetate (2g). The reaction mixture was refluxed for
10 h, where a crystalline precipitate separated. The formed pre-
cipitate was filtered, washed with ethanol, dried and recrystal-
lized from acetic acid and ethanol.
1-[6-(4-Bromophenyl)-3-cyano-4-phenyl-pyridin-2-yl]-
5-oxopyrrolidine-3-carboxylic acid (3f)
Yield 68%; mp 2788C; IR (KBr) cmꢀ1: 3312 (COO–H), 3016
–
–
(Ar-CHstr), 2298 (C N), 1743 (C O), 1714 (C OOH), 645 (C–Br);
–
–
1H NMR (CDCl3): d 3.16 (d, 2H, NCH2), 3.53 (m, 1H, CHpyrr), 4.42
(d, 2H, COCH2), 6.92–7.86 (m, 10H, ArH), 10.79 (s, 1H, OH,
D2O exchangeable).
General procedure for the synthesis of 1-
[6-(4-substituted phenyl)-3-cyano-4-(substituted phenyl)-
1-[6-(4-Bromophenyl)-3-cyano-4-(2-hydroxyphenyl)-
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acid (3g)
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acids (3a–t)
A mixture of substituted nicotinonitriles (2a–t, 0.5 mol) and
itaconic acid (0.6 mol) in 150 mL of water was heated at reflux
for 15 h, and then treated with 280 mL 10% NaOH. After cooling
to 208C the reaction mixture was filtered and the filtrate was
acidified with aq HCl to pH 1. Resulting precipitate formed was
filtered, washed with water, dried and recrystallized with etha-
nol to the get the final compounds (3a–t).
Yield 54%; mp 2498C; IR (KBr) cmꢀ1: 3457 (O–H), 3345 (COO–H),
–
3045 (Ar-CHstr), 2249 (C–N), 1734 (C–O), 1709 (C OOH), 657
–
(C–Br); 1H NMR (CDCl3): d 3.13 (d, 2H, NCH2), 3.57 (m, 1H,
CHpyrr), 4.40 (d, 2H, COCH2), 6.87–7.91 (m, 9H, ArH), 8.13 (s,
1H, OH, D2O exchangeable), 11.19 (s, 1H, OH, D2O exchangeable).
1-[6-(4-Bromophenyl)-3-cyano-4-(4-hydroxyphenyl)-
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acid (3h)
Yield 71%; mp 2588C; IR (KBr) cmꢀ1: 3416 (O–H), 3347 (COO–H),
1-[6-(4-Chlorophenyl)-3-cyano-4-phenyl-pyridin-2-yl]-
5-oxopyrrolidine-3-carboxylic acid (3a)
–
3016 (Ar-CHstr), 2214 (C N), 1748 (C–O), 1721 (C OOH),
–
629 (C–Br); 1H NMR (CDCl3): d 3.15 (d, 2H, NCH2), 3.59 (m, 1H,
CHpyrr), 4.43 (d, 2H, COCH2), 6.91–7.96 (m, 9H, ArH),
8.17 (s, 1H, OH, D2O exchangeable), 11.21 (s, 1H, OH,
D2O exchangeable).
Yield 62%; mp 2748C; IR (KBr) cmꢀ1: 3412 (COO–H), 3045
–
–
(Ar-CHstr), 2236 (C N), 1734 (C O), 1712 (C OOH), 816 (C–Cl);
–
–
1H NMR (CDCl3): d 3.12 (d, 2H, NCH2), 3.48 (m, 1H, CHpyrr), 4.42
(d, 2H, COCH2), 6.87–7.83 (m, 10H, ArH), 10.28 (s, 1H, OH,
D2O exchangeable).
1-[6-(4-Bromophenyl)-4-(4-chlorophenyl)-3-cyano-pyridin-
2-yl]-5-oxopyrrolidine-3-carboxylic acid (3i)
1-[6-(4-Chlorophenyl)-3-cyano-4-(2-hydroxyphenyl)-
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acid (3b)
Yield 73%; mp 2678C; IR (KBr) cmꢀ1: 3289 (COO–H), 3014 (ArHstr),
2267 (C N), 1745 (C–O), 1724 (C–OOH), 867 (C–Cl), 649 (C–Br);
1H NMR (CDCl3): d 3.17 (d, 2H, NCH2), 3.52 (m, 1H, CHpyrr),
4.43 (d, 2H, COCH2), 6.91–7.99 (m, 9H, ArH), 10.86 (s, 1H, OH,
D2O exchangeable).
Yield 54%; mp 2458C; IR (KBr) cmꢀ1: 3534 (O–H), 3143 (COO–H),
–
–
3013 (Ar-CHstr), 2247 (C N), 1741 (C O), 1687 (C OOH), 798
–
–
(C–Cl); 1H NMR (CDCl3): d 3.15 (d, 2H, NCH2), 3.51 (m, 1H,
CHpyrr), 4.40 (d, 2H, COCH2), 6.84–7.94 (m, 9H, ArH), 8.12 (s,
1H, OH, D2O exchangeable), 11.12 (s, 1H, OH, D2O exchangeable).
1-[6-(4-Bromophenyl)-3-cyano-4-(4-methylphenyl)-
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acid (3j)
Yield 47%; mp 2378C; IR (KBr) cmꢀ1: 3324 (COO–H), 3045
(Ar-CHstr), 2897 (C-Haliph), 2237 (C N), 1729 (C–O), 1717
(C–OOH), 678 (C–Br); 1H NMR (CDCl3): d 2.37 (s, 3H, CH3), 3.20
(d, 2H, NCH2), 3.49 (m, 1H, CHpyrr), 4.38 (d, 2H, COCH2), 6.87–7.94
(m, 9H, ArH), 10.91 (s, 1H, OH, D2O exchangeable).
1-[6-(4-Chlorophenyl)-3-cyano-4-(4-hydroxyphenyl)-
pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acid (3c)
Yield 61%; mp 2578C; IR (KBr) cmꢀ1: 3516 (O–H), 3267 (COO–H),
–
–
3048 (Ar-CHstr), 2229 (C N), 1728 (C O), 1694 (C OOH), 757
–
–
(C–Cl); 1H NMR (CDCl3): d 3.16 (d, 2H, NCH2), 3.48 (m, 1H,
CHpyrr), 4.43 (d, 2H, COCH2), 6.96–7.98 (m, 9H, ArH), 8.09 (s,
1H, OH, D2O exchangeable), 11.16 (s, 1H, OH, D2O exchangeable).
1-[3-Cyano-6-(4-nitrophenyl)-4-phenyl-pyridin-2-yl]-
5-oxopyrrolidine-3-carboxylic acid (3k)
Yield 69%; mp 2478C; IR (KBr) cmꢀ1: 3349 (COO–H), 3037
1-[4,6-Bis-(4-chlorophenyl)-3-cyano-pyridin-2-yl]-
5-oxopyrrolidine-3-carboxylic acid (3d)
–
–
(Ar-CHstr), 2279 (C N), 1737 (C O), 1710 (C OOH), 1538
–
–
–
Yield 51%; mp 2168C; IR (KBr) cmꢀ1: 3248 (COO–H), 2979
(N O); 1H NMR (CDCl3): d 3.24 (d, 2H, NCH2), 3.46 (m, 1H,
CHpyrr), 4.41 (d, 2H, COCH2), 6.86–7.87 (m, 10H, ArH), 10.84
(s, 1H, OH, D2O exchangeable).
–
–
–
(Ar-CHstr), 2216 (C N), 1726 (C O), 1698 (C OOH), 749 (C–Cl);
–
–
1H NMR (CDCl3): d 3.11 (d, 2H, NCH2), 3.56 (m, 1H, CHpyrr), 4.47
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com