SYNTHESIS OF SOME DERIVATIVES OF 8-AMINOMETHYL- AND 8-AZOLYLMETHYL-2-PHENYL-3H-QUINAZOLINE-4-THIONES

Full text of DOI:10.1135/cccc19950705

New Compounds
705
SYNTHESIS OF SOME DERIVATIVES OF 8-AMINOMETHYL- AND
8-AZOLYLMETHYL-2-PHENYL-3H-QUINAZOLINE-4-THIONES
Stefan STANKOVSKY and Katarina SPIRKOVA
Department of Organic Chemistry,
Slovak Technical University, 812 37 Bratislava, The Slovak Republic
Received December 20, 1994
Accepted February 14, 1995
Derivatives of folic acid, the quinazoline-based antifolates, and their 4-thiosubstituted
analogues are potent inhibitors of the enzyme thymidylate synthase and show promi-
sing antitumor activity1,2. This has motivated us to prepare a series of thio analogues of
mentioned antifolate.
The starting 8-chloromethyl-2-phenyl-3H-quinazoline-4-thione (I) was prepared by
intramolecular cyclization of N-(2-chloromethylphenyl)benzimidoyl isothiocyanate3.
The title compounds II were prepared by the reaction of the thione I with the corresponding
secondary amines and azoles.
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Stankovsky, Spirkova:
EXPERIMENTAL
The IR spectra (ν, cm−1) were measured with Philips PU 9800 FTIR spectrometer in KBr pellets.
1H NMR spectra (δ, ppm) of hexadeuteriodimethyl sulfoxide solutions were recorded on Tesla BS
487C (80 MHz) spectrometer using tetramethylsilane as an internal standard. Preparation of the start-
ing N-(2-chloromethylphenyl)benzimidoyl chloride was reported in the literature3.
TABLE I
Characteristic data of prepared compounds
Calculated/Found
Formula
(M.w.)
M.p., °C
Yield, %
Compound
% C
% H
% N
IIa
IIb
IIc
IId
IIe
IIf
C19H19N3OS
(337.4)
134 – 136
42
67.63
67.57
5.68
5.61
12.45
12.32
C20H21N3S
(335.5)
191– 193
50
71.61
71.39
6.31
6.18
12.53
12.67
C19H21N3S
(323.5)
121 – 123
46
70.55
70.43
6.54
6.50
12.99
12.92
C21H24N4OS
(380.5)
217 – 219
88
66.29
66.17
6.36
6.29
14.72
14.67
C17H13N5S
(319.4)
232 – 235
54
63.93
63.89
4.10
4.05
21.93
21.83
C18H14N4S
(318.4)
169 – 170
47
67.90
67.79
4.43
4.41
17.60
17.51
IIg
IIh
IIi
C21H15N5S
(369.4)
210 – 212
53
68.27
68.13
4.09
3.98
18.96
18.88
C22H16N4S
(368.5)
170 – 172
49
71.71
71.68
4.38
4.42
15.21
15.17
C19H15N3O2S
(349.4)
151 – 153
64
65.31
65.23
4.33
4.30
12.03
11.91
IIj
C23H15N3O2S
(397.5)
133 – 135
49
69.51
69.48
3.80
3.75
10.57
10.47
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

New Compounds
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8-Chloromethyl-2-phenyl-3H-quinazoline-4-thione (I)
To N-(2-chloromethylphenyl)benzimidoyl chloride (5.28 g, 0.02 mol) in dry acetone (40 ml) potas-
sium thiocyanate (1.94 g, 0.02 mol) dissolved in dry acetone (10 ml) was added dropwise under stir-
ring and cooling to −10 °C. The reaction mixture was stirred for 1 h, the separated potassium
chloride was filtered off and the solvent was evaporated almost to dryness. To the solid residue dry
toluene (50 ml) was added and the resulting solution was refluxed for 8 h. After cooling the precipi-
tate of the product I was collected by filtration and recrystallized from chloroform, yield 2.7 g, 48%,
m.p. 253 – 255 °C. For C15H11ClN2S (286.8) calculated: 12.36% Cl, 11.18% S; found: 12.26% Cl,
11.46% S. IR spectrum: 3 200 ν(NH), 2 910 ν(CH2), 1 608 ν(C=N), 1 568, 1 595 ν(C=Carom.). 1H NMR
spectrum: 10.88 s, 1 H (NH), 8.66 – 7.63 m, 8 H (H-arom), 5.18 s, 2 H (CH2). Mass spectrum (m/z):
286 (M+), 288.
8-R-Methyl-2-phenyl-3H-quinazoline-4-thiones IIa – IId
To 0.003 mol of 8-chloromethyl-2-phenyl-3H-quinazoline-4-thione (I), 0.03 mol of the corresponding
secondary amine was added. The reaction mixture was stirred for 24 h at room temperature. After
addition of cold water (20 ml), the mixture was extracted with ether, dried and evaporated to dryness.
The crude product was recrystallized from methanol. The yields and melting points are given in
1
Table I, the IR and H NMR spectral data in Table II.
TABLE II
Spectral data of compounds II
IR spectrum (ν, cm−1)
1H NMR spectrum (δ, ppm)
quinazoline azole resp. amine
Compound
ν(NH) ν(CH2) ν(C=N)
CH2
IIa
IIb
IIc
3 206 2 918 1 603
3 366 2 922 1 603
3 296 2 920 1 606
5.86 d, 2 H 7.58 – 7.38 m, 8 H
5.59 d, 2 H 8.75 – 7.59 m, 8 H
5.46 d, 2 H 8.69 – 7.50 m, 8 H
3.76 t, 4 H
2.74 t, 4 H
1.57 m, 6 H
2.9 – 2.57 m, 4 H
2.84 q, 4 H
1.23 t, 6 H
IId
IIe
IIf
3 331a 2 910 1 608
3 167 2 918 1 608
3 292 2 920 1 603
3 155 2 918 1 608
3 154 2 918 1 608
3 333 2 918 1 610
3 359 2 922 1 604
5.42 d, 2 H 8.50 – 7.44 m, 8 H
5.49 d, 2 H 8.59 – 7.61 m, 8 H
5.45 d, 2 H 8.64 – 7.47 m, 11 H
5.32 d, 2 H 7.68 – 7.33 m, 8 H
2.81 – 2.43 m, 12 H
8.70 s, 2 H
IIg
IIh
IIi
8.51 – 8.19 m, 4 H
5.40 d, 2 H 7.94 – 7.34 m, 12 H 8.06 s, 1 H
5.49 d, 2 H 8.75 – 7.50 m, 8 H
5.51 d, 2 H 8.27 – 7.81 m, 8 H
2.88 – 2.81 m, 4 H
7.47 m, 4 H
IIj
a ν(OH) and ν(NH).
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Stankovsky, Spirkova:
8-R-Methyl-2-phenyl-3H-quinazoline-4-thiones IIe – IIj
To 0.003 mol of 8-chloromethyl-2-phenyl-3H-quinazoline-4-thione (I) in acetonitrile (50 ml), 0.003 mol
sodium salt of corresponding azole was added. The reaction mixture was stirred under reflux for 4 h,
filtered and let to crystallize. The crude product was purified by recrystallization from ethanol. The
1
yields and melting points are given in Table I, the IR and H NMR spectral data in Table II.
REFERENCES
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J. Med. Chem. 34, 978 (1991).
2. Bisset G. M. F., Pawelczak P., Jackman A. L., Calvert A. H.: J. Med. Chem. 35, 859 (1992).
3. Bodajla M., Stankovsky S., Jantova S., Spirkova K.: Chem. Papers, in press.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)