3946
D. Kaushik et al. / European Journal of Medicinal Chemistry 45 (2010) 3943e3949
D
3.2-5.9 A
1.5-5.5A
H
H3C
C=O
Cl
H-D
R
N
2.4-2.6A
2.40-6.51A
219
N
220
H-A
Fig. 1. Distance range between the essential structure elements R, D & HBD.
191
spectra were recorded for the compounds on FT-IR Rez Bio Rad
Win-IR (KBr) and Brucker DRX-300 instruments, respectively.
Chemical shifts were expressed in parts per million (ppm) with
tetramethyl silane as an internal standard. The elemental analysis
(C, H, N) were performed on Vario EL III CHNS analyzer using sul-
phanilic acid as a standard, and all the values were with in ꢁ0.4% of
the theoretical compositions. The Fast atom bombardment (FAB)
spectra were recorded on Jeol SX 102/DA-600 mass spectra system
using Argon/Xenon (6 KV 10 mA) as the FAB gas. The homogeneity
of the compounds was monitored by ascending thin layer chro-
matography (TLC), visualized by iodine vapour.
Fig. 2. Prospective mass fragmentation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-
4-carboxaldehyde (2).
off the crystals of the acid hydrazide (4ael), and recrytallised from
ethanol. The physical data of the hydrazones are given in Table 6.
6.1.4. General procedure for the synthesis of acid hydrazide-
hydrazone derivative (5aeo)
An equimolar quantity of aldehyde and acid hydrazide in
absolute ethanol containing few drops of glacial acetic acid was
refluxed for 3e4 h. The excess of ethanol was distilled off and
cooled. The precipitate obtained was filtered off, washed with
water and recrystallized from the chloroform-methanol mixture.
The physical data of the acid hydrazide-hydrazone are given in
Table 1.
6.1.1. Synthesis of 3-methyl-1-phenyl-2-pyrazolin-5-one (1)
A mixture of ethyl acetoacetate (0.1 mol) and phenylhydrazine
(0.1 mol) was heated at 110e120 ꢀC (oil bath) for 4 h. The reaction
mixture was cooled and ether (20 ml) is added to it. The mixture
was stirred to give a solid product. It was filtered, washed with
ether and recrystallized from ethanol to give the desired product as
a pale yellow crystalline compound. Yield 75e80%, m.p.124e126 ꢀC,
IR: vmax (cm-1): 1680 (C¼O), 1593, 1453 and 1329 (pyrazole ring),
6.1.4.1. N’-[(1E)-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) meth-
ylene] benzohydrazide (5a). IR: vmax (cm-1): 3267 (NH),1658 (C¼O),
1H NMR(CDCl3) (
d, ppm): 7.81e7.78 (d, 2H, Ar-H), 7.59e7.54 (t, 2H,
1608 (C¼N), 1H NMR(CDCl3) (
d, ppm): 9.4 (s, 1H, NH, D2O
exchangeable), 8.37 (s, 1H, CH¼N), 7.82e7.43 (m, 10H, Ar-H), 2.39 (s,
Ar-H) 7.44e7.39 (t, 1H, Ar-H), 3.34 (s, 2H, CH2), 1.12 (s, 3H, CH3)
3H, CH3).
6.1.2. Synthesis of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carboxaldehyde (2)
6.1.4.2. N’-[(1E)-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)meth-
ylene]-4-methyl benzohydrazide (5b). IR: vmax (cm-1): 3270
The 3-methyl-1-phenyl-2-pyrazolin-5-one in dry dimethyl
formamide was cooled to 0 ꢀC and treated dropwise with phos-
phorous oxychloride, maintaining the temperature between
10e15 ꢀC. The reaction mixture was heated on a steam bath for 1 h,
cooled and poured into crushed ice with stirring. The separated
product was filtered and washed with water. It was recrystallized
from ethanol and occured as yellow needles. Yield 45e55%, m.p.
148 ꢀC, IR: vmax (cm-1): 1705 (C¼O), 1600, 1550, 1470 and 1320
(pyrazole ring), 740 (C-Cl) and 700, 760 cm-1(monosubstituted
(NH),1645 (C¼O), 1619 (C¼N), 1H NMR(CDCl3) (
d, ppm): 9.26 (s, 1H,
NH), 8.38 (s, 1H, CH¼N), 7.78e7.24 (m, 9H, Ar-H), 2.60 (s, 3H, Ar-
CH3), 2.41 (s, 3H, CH3), Mass spectra: Mþ (353), M-1 (352), Mþ2
(355). See Fig. 3.
6.1.4.3. N’-[(1E)-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)meth-
ylene]-4-nitro benzohydrazide (5c). IR: vmax (cm-1): 3259 (NH), 1647
(C¼O), 1605 (C¼N), 1H NMR(CDCl3) (
d, ppm): 9.41 (s, 1H, NH), 8.43
benzene), 1H NMR(CDCl3) (
d, ppm): 9.90 (s, 1H, CHO), 7.78e7.75 (d,
(s, 1H, CH¼N), 8.34 (d, 2H, 30,50 Ar-H), 8.21 (d, 2H, 20,60Ar-H),
7.78e7.75 (d, 2H, Ar-H), 7.58e7.53 (t, 2H, Ar-H), 7.42e7.37 (t, 1H, Ar-
H), 2.39 (s, 3H, CH3).
2H, Ar-H), 7.58e7.53 (t, 2H, Ar-H), 7.42e7.37 (t, 1H, Ar-H), 2.44 (s,
3H, CH3), CHN Anal. Calcd.: C, 59.88; H, 4.11; N, 12.70. Found: C,
59.48; H, 4.06; N, 12.43, Mass spectra: Mþ (220), M-1 (219), M-29
(191), & Characteristic Mþ 2 (222). See Fig. 2.
6.1.4.4. N’-[(1E)-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)meth-
ylene]isonicotinohydrazide (5d). IR: vmax (cm-1): 3261 (NH), 1666
6.1.3. General procedure for the synthesis of acid hydrazide (4aeo)
Aromatic acids were first converted to its ester (3ael) by
esterification procedure using conc. sulphuric acid as a catalyst in
absolute ethanol. The mixture of acid, absolute ethanol and conc.
sulphuric acid were refluxed for 10e12 h, Distilled off about half of
the alcohol on a water bath after this, diluted the residue with
sufficient quantity of water and removed the upper layer of the
crude ester and extracted the aqueous layer with ether. Later on,
combined ethereal extract and crude ester were washed with
water, then with saturated sodium hydrogen carbonate solution
until effervescence ceased, and finally with water. Dried with
anhydrous sodium sulphate & removed the ether on a water bath.
To an alcoholic solution of aromatic ester (3ael), hydrazine hydrate
was added. The resulting reaction mixture was refluxed for
10e12 h. The excess of alcohol was distilled off and cooled. Filtered
(C¼O), 1602 (C¼N), 1H NMR(CDCl3) (
d, ppm): 9.31 (s, 1H, NH), 8.96
(d, 2H, 20,60INH), 8.43 (s, 1H, CH¼N), 8.01 (d, 2H, 30,50INH), 7.78e7.75
(d, 2H, Ar-H), 7.58e7.53 (t, 2H, Ar-H), 7.42e7.37 (t, 1H, Ar-H), 2.41 (s,
3H, CH3).
6.1.4.5. N’-[(1E)-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)meth-
ylene]-2-(4-chlorophenyl)acetohydrazide (5e). IR: vmax (cm-1): 3273
(NH),1665 (C¼O), 1611 (C¼N), 1H NMR(CDCl3) (
d, ppm): 9.40 (s, 1H,
NH), 8.66 (s, 1H, CH¼N), 7.56e7.34 (m, 5H, Ar-H), 7.22e7.14 (m, 4H,
Ar-H), 3.44 (s, 2H, CH2), 2.53 (s, 3H, CH3).
6.1.4.6. N’-[(1E)-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)meth-
ylene]-2-(1-naphthyl)acetohydrazide (5f). IR: vmax (cm-1): 3201 (NH),
1659 (C¼O), 1613 (C¼N), 1H NMR(CDCl3) (
d, ppm): 9.28 (s, 1H, NH),