Synthesis of some new quinazoline derivatives analogues to MKC-442 and TNK 561

Article abstract of DOI:10.1080/10426500307910

A series of different acyclo quinazoline nucleosides 6, 7, 8, 10, 12, 13, and 14 have been synthesized. The site of glycosylation was confirmed by ¹H-NMR and ¹³C-NMR spectroscopy.

Full text of DOI:10.1080/10426500307910

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some New Quinazoline Derivatives
Analogues to MKC-442 and TNK 561
Abd El-Hamid a b , A. A. Ismail a & Adel M. E. Attia b
a Menoufia University , Shebin El-Koom, Egypt
b Tanta University (Kafr El-Sheikh Branch) , Egypt
Published online: 27 Oct 2010.
To cite this article: Abd El-Hamid , A. A. Ismail & Adel M. E. Attia (2003) Synthesis of Some New Quinazoline Derivatives
Analogues to MKC-442 and TNK 561, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:6, 1231-1240, DOI:
10.1080/10426500307910
To link to this article: http://dx.doi.org/10.1080/10426500307910
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Phosphorus, Sulfur, and Silicon, 178:1231–1240, 2003
C
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200503
SYNTHESIS OF SOME NEW QUINAZOLINE
DERIVATIVES ANALOGUES TO MKC-442
AND TNK 561
Abd El-Hamid, A. A. Ismail,a and Adel M. E. Attiab
Menoufia University, Shebin El-Koom, Egypt;a and Tanta
University (Kafr El-Sheikh Branch), Egyptb
(Received September 8, 2002; accepted November 10, 2002)
A series of different acyclo quinazoline nucleosides 6, 7, 8, 10, 12, 13,
and 14 have been synthesized. The site of glycosylation was confirmed
by 1H-NMR and 13C-NMR spectroscopy.
Keywords: Acyclo quinazoline nucleosides; MKC-442; TNK 561
A number of quinazolin-4-one derivatives have been found to ex-
hibit high activity against a variety of microbes parasitizing ani-
mals and plants.1–4 Some quinazoline and their condensed deriva-
tives show antiviral, CNS-depressant, anticonvulsant, antimalaric, and
anticancer.5–8 A major challenge facing medicinal chemistry over the
next few years will be the development of drugs with significantly im-
proved resistance profiles for chronic us as anti-HIV combination ther-
apy. An important component of such regimens will be nonnucleoside in-
hibitors of HIV-1 reverse transcriptase (NNRTI’s). NNRTs are a class of
structurally divers aromatic compounds such as HEPT, MKC-442, and
thiocarboxanilides,9,10 Structural studies have revealed that NNRTIs
˚
inihibit HIV-1 RT by binding to an allosteric site, approximately 10 A
from the polymerase active site,11–13 causing a distortion of the catalytic
aspartite triad.14 The high selectivity of NNRTIs for HIV-1 RT over
HIV-2 RT and cellular polymerases contributes to lower cellular toxicity
The authors would like to express their thanks to DANIDA establishment Denmark,
which supports the project “Development of New Drugs Against Hepatitis” at the Chem-
istry Department, Faculty of Science, Monoufia University for the laboratory facilities
and spectroscopic measurements.
Address correspondence to A. A. Ismail, Chemistry Department, Faculty of Science,
Menoufia University, Shebin El-Koom, Egypt. E-mail: abdelhamide2002@yahoo.com
1231

1232
A. El-Hamid et al.
level than nucleoside analogues (NRTIs) such as AZT, ddI or ddC. As a
part of our program of research on the synthesis of new glycosides15–20
with considerable biological activity, we report in this paper the syn-
thesis of a new class of non-nucleosides analogues to MKC-442 and
TNK-561.
RESULTS AND DISCUSSION
3-Aryl-2-thio-quinazolin-4-ones 3 were prepared in high yields in two
steps from the reaction of anthranilic acid 1 with aryl isothiocyanates
2 according to reported procedures.21 Compounds 3 or 4 can be coupled
with different compounds 5, 9 and 11 to give a new series of quinazo-
line acyclonucleosides. For example 3 or 4 reacted with chloromethyl
ethyl ether or chloromethyl benzyl ether 5 in the presence of sodium
hydride in dry dimethylformamide at room temperature to furnish the
corresponding S2-acyclonucleosides 6a–f or N1-derivatives 8a–c in high
yields (Scheme 1). Only the S2-nucleoside 6c and N1-nucleoside 7 were
obtained in the reaction of 3c with chloromethyl ethyl ether 5 as the ma-
jor and minor products, respectively. The products 6c and 7 were easily
separated by silica gel column chromatography and fully characterized
by elemental and spectral analysis.
The site of glycosylation of compound 3 was confirmed from their
13C-NMR spectral. Thus, the observed shifts of C-2 (160.48 ppm) in
6c and C-2 (176.38 ppm) in 7 clearly show glycosidation on a sulfur
atom S2 in quinazoline derivative 6c and on a nitrogen atom N1 in
another derivative 7, respectively (see Experimental part). Similarly,
compounds 3 reacted with bromoethylacetate 9 or isopropylidenedioxy
propyl chloride 11 in the presence of NaH and DMF to give the cor-
responding acyclo quinazoline S-nucleosides 10 and 12, respectively
(Scheme 2).
TLC of the acyclonucleosides 10 and 12 showed that single com-
pounds were produced and their structures were further confirmed by
elemental analysis and spectral data (see Experimental part).
Finally, removal of the protecting groups from the glycon moieties of
10 and 12 were achieved by treatment of 10 with methanolic ammonia
and 12 with acetic acid to afforded the free acylcic nucleosides 13 and
14 receptively as the only isolated product (as tested by TLC analysis)
1
in good yields. The structure of 13a has been proved by H-NMR and
13C-NMR spectrometry in DMSO solution. A strong downfield shift of
C-2 signal (160.69 ppm) is an unequivocal indication of the position
of alkylation as well as of the disappearance of acetoxy protons in its
1H-NMR (see Experimental part).

Synthesis of Some New Quinazoline
1233
SCHEME 1
In conclusion, we have achieved a regiospecific synthesis of inter-
esting quinazoline acylconucleosides by the reaction of substituted
quinazoline-2-(1H)-thiones and their corresponding ketoneses with
compounds 5, 9, 11. The obtained quinazoline acycloncleosides are now
under biological evalution.
EXPERIMENTAL
NMR spectra were recorded on a Brucker 250 FT NMR spectrometer
TMS as internal standard. MS were recorded on a variant mat 311

1234
A. El-Hamid et al.
SCHEME 2

Synthesis of Some New Quinazoline
1235
A spectrometer. MS were recorded on a kratos MS-50 spectrometer.
Results of elemental analysis were in acceptable range.
General Procedure for Compound 5, 6, 7, 8, 10, and 12
Quinazoline derivatives 3 or 4 (5 mmol) and sodium hydride (6 mmol)
in 20 mL dry DMF, stirring at room temperature 1 h. Compound 5,
9, or 11 (5.5 mmol) was added and the reaction mixture was stirred
24 h untill TLC shows no starting material left. Evaporated the solvent
under vacuum, the residue was dissolved in 30 mL ethylacetate and
20 mL of H2O. The extracted organic layer was dried over Na2SO4 and
the solvent evaporated under vacuum, the residue was purified by silica
gel column chromatography (cyclohoxane/ethylacetate, 90/10, v/v).
2-Ethoxymethylthio-3-phenyl-quinazolin-(3H)-4-one (6a)
Yield 80%; m.p. 142–144 C as a white powder; 1H-NMR (DMSO-d 6),
8.11-7.43 (m, 8H, Ar-H), 5.41 (s, 2H, H-10), 3.57 (m, 2H, OCH2 CH3),
1.13 (t, J = 14.04 Hz, OCH2CH3); 13C-NMR (DMSO-d 6), 135.99,
134.85, 129.68, 129.34, 129.29, 126.49, 126.02, 119.64 (Ar-C), 72.25
(C-10), 64.59 (OCH2CH3), 14.56 (OCH2CH3); Anal. cald for
C17H16N2O2S (312.31) C, 65.37; H, 5.16; N, 8.97 found C, 65.19;
H, 5.00; N, 9.13%.
2-Ethoxymethylthio-3-tolyl-quinazolin-(3H)-4-one (6b)
Yield 75%; m.p. 140–141 C as a white powder; 1H-NMR (DMSO-d
)
6
8.25-7.43 (m, 8H, Ar-H), 5.87 (s, 2H, H-10), 3.69 (m, 2H, OCH2 CH3),
3.18 (s, 3H, CH3-tolyl), 1.27 (t, 3H, J = 9.13 Hz, CH2CH3); 13C-
NMR (DMSO-d
)
160.78 (C-2), 155.92 (C-4), 146.90, 139.63, 134.44,
6
131.33, 128.81, 128.14, 126.49, 126.06, 119.63 (Ar-C), 72.34 (C-10),
64.46 (OCH2CH3), 14.77 (CH3-tolyl), 14.56 (OCH2CH3); Anal. cald for
C18H18N2O2S (326.33) C, 66.25; H, 5.56; N, 8.58. found C, 66.49; H, 5.33;
N, 8.66%.
2-Ethoxymethylthio-3-(4-methoxyphenyl)-quizazolin-(3H)
-4-one (6c)
Seperated by silica gel column chromatography (cyclohexane/ethyl-
acetate 90/10, v/v) as fraction (1); Yield 72%; m.p. 133–134 C as a white
1
powder; H-NMR (DMSO-d
)
8.31-6.95 (m, 8H, Ar-H), 5.70 (s, 2H,
6
H-10), 3.75 (m, 2H, OCH2CH3), 3.60 (s, 3H, OCH3), 1.25 (t, J = 6.13 Hz,
3H, OCH2CH3); 13C-NMR (DMSO-d
)
160.84, (C-2), 159.40 (C-4),
6
147.53, 134.51, 130.14, 129.07, 127.44, 127.17, 126.32, 125.91, 125.25,
124.39, 114.41 (Ar-C), 72.96 (C-10), 64.39 (OCH2CH3), 55.38 (OCH3),

1236
A. El-Hamid et al.
14.02 (OCH2CH3); Anal cald for C18 H18 N2O3S (342.33) C, 63.15; H,
5.30; H, 8.18; found C, 62.96; H, 5.55; N, 7.00.
2-Benzyloxymethylthio-3-phenyl-quinazolin-(3H)-4-
one (6d)
Yield 67%; m.p. 100–102 C as a white powder; 1H-NMR (DMSO-d
)
6
7.96-7.15 (m, 14H, Ar-H), 5.33 (s, 2H, H-10), 4.35 (s, 2H, OCH2Ph); 13C-
NMR (DMSO-d 160.80 (C-2), 155.77 (C-4), 146.92 137.32, 135.98,
)
6
134.84, 129.78, 129.70, 129.30, 128.21, 127.74, 127.55 (Ar-C), 87.89 (C-
10), 70.82 (OCH2Ph); MS: m/z 374 (M+); Anal. cald for C22H18N2O2S
(374.41) C, 70.57; H, 4.85; N, 7.48 found C, 70.70; H, 4.75; N, 7.76%.
2-Benzyloxymethylthio-3-tolyl-quinazolin-(3H)-4-one (6e)
1
Yield 78%; m.p. 120–121 C as a white powder; H-NMR (DMSO-
d
)
7.89-7.05 (m, 13H, Ar-H), 5.26 (s, 2H, H-10), 4.29 (s, 2H,
6
OCH2Ph), 3.13 (s, 3H, CH3-tolyl); 13C-NMR (DMSO-d
)
161.50
6
(C-2), 156.67 (C-4), 1473.56, 139.99, 137.97, 135.43, 133.97, 129.62,
128.55, 128.25, 127.11, 126.64 (Ar-C), 72.67 (C-10), 71.45 (OCH2Ph),
21.40 (CH3-tolyl); MS: m/z 388 (M+); Anal. cald for C23H20N2O2S
(388.48) C, 71.10; H, 5.19; N, 7.21; found C, 71.20; H, 5.59; N,
7.25%.
3-Benzyloxymethylthio-3-(4-methoxyphenyl)-quinazolin-
(3H)-4-one (6f)
Yield 82%; m.p 105–107 C as a white powder; 1H-NMR (DMSO-d
)
6
8.28-7.45 (m, 13H, Ar-H), 5.48 (s, 2H, H-10), 4.68 (s, 2H, OCH2Ph),
3.66 (s, 3H, OCH3); 13C-NMR (DMSO-d 6) 160.49 (C-2), 156.21 (C-4),
147.45 138.99, 134.52, 130.13, 128.35, 127.94, 127.85, 127.16, 126.33,
125.96 (Ar-C); MS: m/z 404 (M+); Anal. cald for C23H20N2O3S (404.48)
C, 68.30; H, 4.98; N, 6.93 found C, 68.09; H, 5.18; N, 6.86%.
1-Ethoxymethyl-3-(4-methoxyphenyl)-2-thio-1,2,3,4-
tetrahydroquinazolin-4-one (7)
Seperated by silica gel column chromatography (cyclohexaane/ethyl-
acetate 90/10, v/v) as fraction (2); Yield 20%; m.p. 138–139% as a white
powder; 1H-NMR (DMSO-d
) 8.15-7.00 (m, 8H, Ar-H), 5.55 (s, 2H, H-
6
10) 3.86 (m, 2H, OCH2CH3), 3.60 (s, 3H, OCH3), 1.18 (t, J = 8.61 Hz, 3H
OCH2CH3); 13C-NMR (DMSO-d
) 176.36 (C s), 158.68 (C-4), 139.56,
6
135.48, 131.83, 129.96, 128.49, 127.82, 127.35, 124.21, 123.17 (Ar-C),
72.96 (C-10), 63.49 (OCH2CH3), 55.93 (OCH3), 14.96 (OCH2CH3); Anal.
cald for C18H18N2O3S (342.33). C, 63.15; H, 5.30; N, 8.18 found C, 62.91;
H, 4.07; N, 8.40%.

Synthesis of Some New Quinazoline
1237
1-Ethoxymethyl-3-phenyl-1,2,3,4-tetrahydroquinazolin-
2,4-dione (8a)
Yield 71%; m.p 138–140 C as a white powder; 1H-NMR (DMSO-
d
)
8.09-7.23 (m, 9H, Ar-H); 5.58 (s, 2H, H-10), 3.67 (m, 2H,
6
OCH2CH3), 1.16 (t, J = 5.00 Hz, 3H, OCH2CH3); 13C-NMR (DMSO-
d
)
161.26 (C-2), 150.82 (C-4), 139.73, 139.62, 136.01, 135.26,
6
128.82, 128.75, 128.13, 127.81, 123.22, 115.32 (Ar-C), 72.96 (C-10),
63.54 (O-CH2CH3), 14.78 (OCH2CH3); MS: m/z 296 (M+); Anal. cald for
C17H16N2O3 (296.29) C, 68.91, H, 5.44, N, 9.45, found C, 69.08, H, 5.51,
N, 9.33%.
1-Ethoxymethyl-3-tolyl-1,2,3,4-tetrahydroquinazolin-
2,4-dione (8b)
Yield 75%; m.p. 143–145 C as a white powder; 1H-NMR (DMSO-d
)
6
8.26-7.14 (m, 8H, Ar-H), 5.64 (s, 2H, H-10), 3.74 (m, 2H, OCH2CH3),
2.41 (s, 3H, CH3-tolyl), 1.26 (t, J= 10.04 Hz, 3H, OCH2CH3); 13C-
NMR (DMSO-d
)
161.99 (C-2), 151.83 (C-4), 139.77, 135.29, 132.64,
6
130.06, 128.03, 128.95, 127.92, 123.57, 115.99, 115.03 (Ar-C), 73.83 (C-
10), 64.72 (OCH2CH3), 21.86 (CH3-tolyl), 14.92 (OCH2CH3); Anal. cald
for C18H18N2O3 (310.35) C, 69.86; H, 5.85; N, 9.03 found C, 69.88; H,
5.90; N, 9.29%.
1-Benzyloxymethyl-3-tolyl-1,2,3,4-tetrahydro-quinazolin-
2,4-dione (8c)
Yield 74%; m.p. 145–146 C as a white powder; 1H-NMR (DMSO-d
)
6
8.90-7.17 (m, 13H, Ar-H), 5.67 (s, 2H, H-10), 4.84 (s, 2H, OCH2Ph), 2.36
(S, 3H, CH3-tolyl); 13C-NMR (DMSO-d
)
161.27 (C-2), 150.86 (C-4),
6
139.55, 137.66, 137.49, 135.21, 133.36, 129.26, 128.49, 128.07, 127.49,
123.24 (Ar-C), 73.07 (C-10), 69.96 (OCH2Ph), 20.69 (CH3-tolyl); Anal.
cald for C23H20N2O3 (372.42), C, 74.18; H, 5.41; N, 7.52 found C, 74.05;
H, 2.63; N, 7.31%.
2-(Acetoxyethylthio)-3-phenyl-quinazolin-(3H)-4-one (10a)
Yield 77%; m.p. 130–132 C; 1H-NMR (DMSO-d
)
8.10-8. 45
6
(m, 9H, Ar-H), 4.30 (t, J = 12.91 Hz, 2H, H-10), 3.40 (t, J =
21.19 Hz, 2H, H-20), 1.98 (s, 3H, COCH3); 13C-NMR (DMSO-d
)
6
170.02 ( COCH3), 160.64 (C-2); 158.49 (C-4), 147.05, 135.78, 134.81,
129.77, 129.38, 129.32, 126.46, 125.91, 119.49 (Ar-C); 61.72 (C-
10), 30.00 (C-2), 20.53 (COCH3); MS: m/z 340 (M+). Anal. cald for
C18H16N2O3S (340.30) C, 63.51; H, 4.79; N, 8.23 found C, 63.78; H, 5.00;
N, 8.10%.

1238
A. El-Hamid et al.
2-(2-Acetoxyethylthio)-3-tolyl-quinazolin-(3H)-4-one (10b)
1
Yield 86%; m.p. 125–126 C; H-NMR (DMSO-d
)
8.11-7.32 (m,
6
8H, Ar-H); 4.30 (t, J = 13.40 Hz, 2H, H10), 3.41 (t, J = 22.87, 2H, H-
20) 2.43 (s, 3H, CH3-tolyl), 2.00 (s, 3H, COCH3); 13C-NMR (DMSO-d
)
6
189.98 (COCH3), 180.04 (C-2), 156.74 (C-4), 147.01, 139.40, 134.73,
133.10, 129.84, 128.98, 126.42, 125.23, 125.08, 119.44, (Ar-C), 63.53
(C-10), 61.68 (C-20), 30.36 (CH3-tolyl), 20.99 (COCH3); MS: m/z 354 (M+);
Anal. cald for C19H18N2O3S (354.42) C, 64.31; H, 5.12; N, 7.90 found C,
54.01; H, 5.03, N, 7.96%.
2-(Isopropylidenedioxypropylthio)-3-tolyl-quinazolin-
(3H)-4-one (12a)
1
Yield 66%; m.p. 126–128 C; H-NMR (DMSO-d
)
7.93-7.13 (m,
6
8H, Ar-H), 4.17 (m, 1H, H-20), 3.90 (m, 2H, H-10), 3.19 (m, 3H, H-3),
2.25 (s, 3H, CH3-tolyl), 1.22 (s, 3H, CH3-isopropyl), 1.08 (s, 3H, CH3
isopropyl); 13C-NMR (DMSO-d
)
160.66 (C-2), 157.00 (C-4), 139.38,
6
134.69, 133.17, 129.86, 128.99, 126.44, 125.78, 119.44; (A-C) 108.00
(C-isopropyl) 73.62 (C-20), 67.00 (C-10), 34.79 (C-30), 29.50 (CH3-tolyl);
26.58, 26.20 (2CH3-isopropyl); Anal. cald for C21H22N2O3S (382.38)
C, 65.96; 5.80; N, 7.32 found C, 66.07; H, 8.63; N, 7.09%.
2-(Isopropylidenedioxypropylthio)-3-(4-methoxyphenyl)-
quinazolin-(3H)-4-one (12b)
Yield 63%; m.p. 131–133 C; 1H-NMR (DMSO-d 6), 8.26-7.25 (m,
8H, Ar-H), 4.14 (m, 1H, H-20), 3.91 (m, 1H, H-10), 3.65 (s, 3H,
OCH3), 3.36 (m, 1H, H-30), 1.40 (s, 3H, CH3-isopropyl), 1.43 (s,
3H, CH3 isopropyl) 13C-NMR (DMSO-d 6), 160.51 (C-2), 147.52 (C-
4), 134.56, 130.21, 130.12, 127.20, 126.14, 125.85, 119.76, 114.89,
114.85, (Ar-C), 109.59 (C-isopropyl); 74.32 (C-20), 68.57 (C-10), 55.33
(OCH3), 35.33 (C-30), 26.83, 26.87, (2CH3-isopropyl); Anal. cald for
C21H22N2O45 (398.37) C, 63.22; H, 5.57; N, 7.03 found C, 63.40; H, 5.39;
N, 7.29%.
General Procedure for Compound 13a,b
Saturated ammonia in methanol (20 mL) was added with stirring to a
solutions of 10a or 10b in methanol (10 mL) at 0 C. The reaction mix-
ture was stirred at room temperature 24 h (monitored by TLC anal-
ysis). The solvent was evaporated under vacuum and the residue pu-
rified by silica gel column chromatography (cyclohexane/ethylacetate,
50/50, v/v).

Synthesis of Some New Quinazoline
1239
2-(2-Hydroxyethylthio)-3-phenyl-quinazolin-
(3H)-4-one (13a)
Yield 68%; m.p. 136–137 C; 1H-NMR (DMSO-d 6) 8.09-7.09 (m, 9H,
Ar-H), 4.89 (br, 1H, OH), 3.66 (t, J = 12.05 Hz, 2H, H-10), 3.27 (t, J =
12.68 Hz, 2H, H-20), 13C-NMR (DMSO-d
) 160.89 (C-2), 157.38 (C-4),
6
147.19, 135.97, 134.79, 129.67, 129.35, 129.00, 126.47, 122.40, 119.44,
115.15 (Ar-C), 59.12 (C-10), 34.81 (C-2); MS: m/z 298 (M+); Anal. cald
for C16H14N2O2S (298.36) C, 64.41; H, 4.73; N, 9.39 found C, 64.34; H,
4.82; N, 9.35%.
2-(2-Hydroxyethylthio)-3-tolyl-quinazolin-(3H)-4-one (13b)
1
Yield 64%; m.p. 142–144 C; H-NMR (DMSO-d
)
8.09-7.30 (m,
6
8H, Ar-H), 4.99 (m, 1H, OH), 3.66 (t, J = 11.82 Hz, 2H, H-10),
3.24 (t, J = 12.71 Hz, 2H, H-20), 2-38 (s, 3H, CH3-tolyl); 13C-NMR
(DMSO-d ) 161.34 (C-2), 158.27 (C-4), 147.80, 139.95, 135.36, 133.95,
130.47, 129.67, 127.09, 126.52, 126.33, 120.04 (Ar-C), 59.43 (C-10),
35.42 (C-20), 21.39 (CH3-tolyl); MS: m/z 312 (M+); Anal. cald for
C17H16N2O2S (312.78) C, 65.36; H, 5.16; N, 8.97 found C, 65.64; H, 5.28;
N, 8.75%.
General Procedure for Compounds 14a,b
Compounds 12a or 12b (1 mmol) was dissolved in 10 mL 90%
CH3COOH and the reaction mixture was stirred at room temperature
24 h, untill the TLC shows no starting material left. The solvent was
evaporated under vacuum and the residue purified by silica gel column
chromatography (cyclohexane/ethylacetate, 50/50, v/v).
2-(2,3-Dihydroxypropylthio)-3-tolyl-quinazolin-
(3H)-4-one (14a)
Yield 80%; m.p. 108–109 C; Anal. cald for C18H18N2O3S (342.31) C,
63.16; H, 5.30; N, 8.18 found C, 63.43; H, 5.51; N, 8.39%.
2-(2,3-Dihydroxypropylthio)-3-(4-methoxyphenyl)-
quinazolin-(3H)-4-one (15b)22
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