A study concerning the synthesis, basicity and hydrolysis of 4-amino-2-(n,n-diethylamino)quinazoline derivatives

Article abstract of DOI:10.1002/jhet.5570390627

A group of 2-(N,N-diethylamino)-4-aminoquinazoline derivatives have been synthesized in the reaction of N¹,N¹-diethyl-N²-arylchlorocarboxyamidines with cyanamide in the presence of TiCl₄ as a catalyst. Such quin

Full text of DOI:10.1002/jhet.5570390627

Nov-Dec 2002
A Study Concerning the Synthesis, Basicity and Hydrolysis
of 4-Amino-2-(N,N-diethylamino)quinazoline Derivatives
Wojciech Zielin´ski* and Agnieszka Kudelko
1289
Institute of Organic Chemistry and Technology, Silesian University of Technology,
Ul. Krzywoustego 4, PL-44101 Gliwice, Poland
Received August 8, 2001
Received Revised June 26, 2002
A group of 2-(N,N-diethylamino)-4-aminoquinazoline derivatives have been synthesized in the reaction
of N1,N1-diethyl-N2-arylchlorocarboxyamidines with cyanamide in the presence of TiCl4 as a catalyst. Such
quinazolines decompose into the corresponding quinazolones in dilute aqueous HCl solutions at higher tem-
perature. Hydrolysis rates of 2-(N,N-diethylamino)-4-aminoquinazoline and 2-(N,N-diethylamino)-4-(N,N-
dimethylamino)-quinazoline have been determined to observe the influence of substituents at the 4-amino
group upon the hydrolysis. pKa values have been also determined for these compounds and analyzed in con-
junction with the Hammett constants.
J. Heterocyclic Chem., 39, 1289(2002).
The work described here forms a part of our general pro-
temperature in an anhydrous inert solvent in the presence
gram on the synthesis of the 4-aminoquinazolines due to
their pharmacologic activity. Some of these compounds
were found to be inhibitors of the tyrosine kinase [1,2] or
dihydrofolate reductase enzymes [3,4] so they work as
potent anticancer agents. The methods making use of N-
phenylbenzimidoyl chlorides or esters in the synthesis of
the arrangement of that type were initiated by Meerwein
and co-workers [5]. There are some references that
2-amino- and 2,4-diaminoquinazolines could be obtained
starting from chlorocarboxyamidine derivatives [6,7]. First
attempts involving the application of cyanamide in the
cyclization of chlorocarboxyamidines in the presence of
of TiCl as catalyst.
4
TiCl as a catalyst gave negative results [7]. We have
4
renewed our attempts encouraged by MNDO calculations
not excepting such reaction possibility. In the present
paper, we are reporting on the synthesis of 2-(N,N-diethy-
lamino)-4-aminoquinazoline derivatives substituted in the
position 6 or 7 with electron-donating and withdrawing
groups, the basicity and some kinetic aspects of the hydrol-
ysis of 2,4-diaminoquinazolines.
1
1
2
N ,N -Diethyl-N -arylchlorocarboxyamidine deriva-
tives (2) were obtained in the reaction of the previously
described [7] N-aryl-N',N'-diethylureas (1) with SOCl ,
2
POCl or PCl , but the best results were afforded with the
3
5
1
1
2
use of the last agent. The crude N ,N -diethyl-N -
arylchlorocarboxyamidines, which were obtained in near
quantitative yields, are usually yellowish oils having
unpleasant irritating odours. Similarly to the typical imi-
doyl chlorides [8], they are highly reactive substances and
must often be prepared as required, because they are very
sensitive to moisture, forming the starting ureas.
A great advantage of titanium tetrachloride in comparison
to other often used Lewis acid catalysts is the stabilisation of
the cis arrangement of the diene complex (3) of the cycliz-
ing linear product. Highly stable quinazoline-catalyst com-
plexes were broken with the use of concentrated inorganic
base solutions and the crude quinazolines were immediately
removed from the reaction medium via extraction.
According to the presented scheme, a new group of 2-(N,N-
diethylamino)-4-aminoquinazoline (4a-4g) and 3,4-dihy-
dro-2-(N,N-diethylamino)-4-quinazolone (5a) have been
synthesized. The reaction yields, with respect to the initial
ureas varied slightly, and are the lowest as expected for
quinazolines with electron-withdrawing groups (4f, 4g).
1
1
2
N ,N -Diethyl-N -arylchlorocarboxyamidine derivatives
(2, Scheme 1) react with cyanamide at room temperature
to give a linear product, a derivative of 4-amino-1-aryl-4-
chloro-2-(N,N-diethylamino)-2,4-diaza-1,3-butadiene (3).
Such compounds cyclize at the next step to corresponding
2-(N,N-diethylamino)-4-aminoquinazolines (4) at higher

1290
W. Zielin´ski and A.Kudelko
Vol. 39
The difficulties with the separation of the quinazolines from
post-reaction mixtures and the consecutive hydrolysis of
4-aminoquinazolines (4) to the corresponding 3,4-dihydro-
4-quinazolones (5) adversely affect the product yield. It was
particularly interesting at this stage to determine the hydrol-
ysis rates of 2-(N,N-diethylamino)-4-aminoquinazoline (4a)
and 2-(N,N-diethylamino)-4-(N,N-dimethylamino)-quina-
zoline (6a) because there are some contradictory references
on the hydrolysis of several 4-aminoquinazolines [9,10,11].
The kinetic study shows that quinazoline (4a) converts to
the corresponding quinazolone (5a) in the dilute aqueous
quinolines [16], investigations on electron interactions in
monosubstituted alternating systems [17] and our earlier
research on the basicity of 4-amino-2-phenylquinazolines
[18]. It should be mentioned here that a different correla-
tion was applied in the case of 4-(N,N-dimethylamino)-
quinazoline derivatives [19]. The bulky group in this posi-
tion causes a decrease of the electron density of the C-4-
C-4a bond and that is why the electron transfer occurs in
such systems in the way as in the substituted aniline.
Generally, 4-amino-2-(N,N-diethylamino)quinazolines
(4a-g) (pK values of the examined series: 5.99 – 8.31) are
a
HCl solution at the temperature of 80 °C about 10 times
stronger bases than the corresponding 4-amino-2-
-5 -1
faster (Scheme 2, k =6.12(±0.84)*10 s ) than the substi-
phenylquinazolines (pK values of the examined series:
I
a
-6 -1
tuted compound (6a) (k =6.52(±0.34)*10 s ). It should
5.33 - 6.40) [18]. Such a difference in basicity is caused by
electronic effects of the substituent in the position 2, that is
closest to the protonated ring nitrogen atoms.
II
be mentioned that 2,4-diaminoquinazolines have two poten-
tial sites of hydrolysis [12,13] and it was particularly inter-
esting to determine which site is more susceptible to hydrol-
ysis. The quinazoline 6a, while heating in a boiling 5%
aqueous HCl solution for a few days, afforded only one
product - 3,4-dihydro-2-(N,N-diethylamino)-4-quinazolone
(5a). The N,N-diethylamino group at the position 2 of such
the quinazolone remained unconverted.
EXPERIMENTAL
UV spectra were recorded by Shimadzu UV-2102 spectropho-
tometer; basic medium: 0.05 M NaOH in 50% aqueous methanol
solution, acidic medium: 0.05 M HCl in 50% aqueous methanol
solution. Elemental analyses were carried out by means of Perkin
Elmer 240c analyser. 1H and 13C nmr spectra were recorded on a
Varian Inova 300 spectrometer in DMSO solution using TMS as
internal standard. MS spectra were made by Shimadzu QP-200
mass spectrometer. Thin layer chromatography was carried out
on silica gel 60 F254 (Merck) thin layer chromatography plates
using a benzene-ethyl acetate-diethylamine mixture (6:2:1 v/v/v)
as the mobile phase.
Procedure for the Preparation of 4-Amino-1-aryl-4-chloro-2-(N,N-
diethylamino)-2,4-diaza-1,3-butadiene (3a).
N-Phenyl-N',N'-diethylurea (1a) (9.6 g, 0.05 mole), anhydrous
toluene (70 ml) and PCl5 (11.5 g, 0.055 mole) were gently heated
at about 50 °C until the disappearance of the urea (TLC) was com-
pleted. Then the toluene and POCl3 were removed using a rotary
evaporator. The crude N1,N1-diethyl-N2-chlorocarboxyamidine
(2a) was dissolved in a new portion of anhydrous toluene (70 ml)
and cyanamide (2.1 g, 0.05 mole) in anhydrous diethyl ether (5
ml) was added. The mixture was left for about 24 hours at room
temperature. Then the toluene was removed in the rotary evapora-
tor. The resulted oil was washed with anhydrous diethyl ether (50
ml) and neutralized with methanolic NaOH solution. A precipitate
(inorganic salt) was filtered off, and the methanolic solution was
evaporated. The oily product 3a (10.6 g, 84%) was chromato-
The determination of the dissociation constants pK of
a
4-amino-2-(N,N-diethylamino)quinazolines (4a-4g) was
performed according to the spectrophotometric method of
Albert and Serjeant [14] in 50% aqueous methanol solu-
-5
tion (10 M, room temperature). The results show that the
donosicity of the substituent in the 6 or 7 position of the
quinazoline ring in 4-amino-2-(N,N-diethylamino)quina-
1
graphically pure: Rf: 0.68; H nmr: d 1.06 (t, 6H, N(CH2CH3)2),
zolines greatly affects pK values. Donor substituents
3.35 (q, 4H, N(CH2CH3)2), 6.80-7.48 (m, 2H (NH2), 5Harom); uv:
l max (e*10-3) (methanol): 209.4 (30.12), 240.2 (16.62).
Anal. Calcd. for C12H17N4Cl: C, 57.02; H, 6.79; N, 22.15.
Found: C, 57.60; H, 6.84; N, 22.40.
a
cause an increase in basicity (higher pK values) compared
a
with pK of the original arrangement (R=H) and withdraw-
a
ing substituents cause a decrease (lower pK values). The
a
determined dissociation constants pK correlated well with
General Procedure for the Preparation of 4-Amino-2-(N,N-
diethylamino)-(6,7)-R-substituted quinazolines (4a-4g).
a
appropriate Hammett s constants [15] for 6-R substituted
m
compounds and s constants for 7-R substituted com-
The crude N1,N1-diethyl-N2-chlorocarboxyamidine (2) (0.05
mole), prepared from the appropriate N-(3(4)-R-phenyl)-N',N'-
diethylurea (1) according to the procedure described in the syn-
thesis of 3a was dissolved in a portion of anhydrous toluene (70
ml). Then cyanamide (2.1 g, 0.05 mole) in anhydrous diethyl
p
pounds (Equation: pK : -2.335* + 7.794; the Number of
a
data points used: N: 7; Residual sum of squares: S: 0.170;
Coefficient of determination: r: 0.985). This correlation is
consistent with Charton's results on 6- and 7-substituted

Nov-Dec 2002
4-Amino-2-(N,N-diethylamino)quinazoline Derivatives
1291
ether (5 ml) was added there. The mixture was left for 1 hour, and
then, TiCl4 (5 ml, 0.05 mole) in anhydrous toluene (20 ml) was
gradually added. The agitation was continued at 50 °C for 3 h.
Solvents were removed using a rotary evaporator and the
resulting gluey solid was washed with toluene and 20% aqueous
NaOH (100 ml) was added. After a rapid decomposition the mix-
ture was immediately extracted with toluene in order to avoid a
hydrolysis to 3,4-dihydro-2-(N,N-diethylamino)-4-quinazolones.
Purified and dried (calcium chloride) compounds (4) were crys-
tallized from ethanol or acetone. In the case of difficulties in
crystallization the compounds were chromatographed on silica
gel (benzene-ethyl acetate mixture 3:1 v/v).
247.4 (13.79), 216.3 (14.05) nm; ms: m/z (%) 28 (21), 29 (61), 42
(18), 44 (56), 51 (15), 72 (100), 77 (12), 152 (14), 178 (65), 180
(32), 221 (15), 250 (M+, 23); pKa = 6.98 ± 0.17 (l anal = 271 nm).
Anal. Calcd. for C12H15N4Cl: C, 57.48; H, 6.04; N, 22.33.
Found: C, 56.98; H, 6.17; N, 22.20.
4-Amino-7-chloro-2-(N,N-diethylamino)quinazoline (4e).
This compound was obtained in 65% yield; mp: 120-122 °C;
Rf: 0.58; 1H nmr d 1.10 (t, 6H, N(CH2CH3)2), 3.35 (q, 4H,
N(CH2CH3)2), 6.80-7.60 (m, 4H, H-5,6,8, NH), 8.32 (s, 1H, NH)
ppm; uv: l max (e*10-3) acidic: 237.4 (12.67), 208.1 (21.34),
basic: 261.0 (12.54), 215.4 (17.72) nm; ms: m/z (%) 29 (56), 32
(42), 42 (15), 44 (59), 51 (17), 64 (14), 72 (100), 74 (10), 77 (15),
100 (17), 152 (13), 178 (80), 180 (26), 210 (11), 221 (13), 234
(12), 250 (M+, 30), 252 (10);pKa = 7.09 ± 0.12 (l anal = 261 nm).
Anal. Calcd. for C12H15N4Cl: C, 57.48; H, 6.04; N, 22.33.
Found: C, 57.05; H, 5.94; N, 22.90.
4-Amino-2-(N,N-diethylamino)quinazoline (4a).
This compound was obtained in 71% yield; mp: 73-74 °C; Rf:
0.50; 1H nmr: d 1.08 (t, 6H, N(CH2CH3)2), 3.34 (q, 4H,
N(CH2CH3)2), 6.91 (s, 1H, NH), 7.22 (dd, J = 7.5 Hz, 2H, H-6, 7),
7.47 (d, J = 7.5 Hz, 2H, H-5, 8), 8.12 (s, 1H, NH) ppm; 13C nmr: d
9.44 (CH3), 37.14 (CH2), 115.28 (C-4a), 118.30 (C-5), 124.31 (C-
6), 125.27 (C-8), 135.12 (C-7), 142.44 (C-8a), 150.20 (C-2),
162.26 (C-4) ppm; uv: l max (e*10-3) acidic: 289.2 (1.40), 238.9
(16.61); basic: 275.0 (3.27), 238.4 (15.41), 212.1 (20.65) nm; ms:
m/z (%) 27 (28), 28 (26), 29 (69), 30 (51), 39 (12), 42 (17), 44 (65),
51 (17), 56 (14), 65 (16), 72 (100), 91 (13), 92 (12), 93 (17), 100
(73), 118 (24), 174 (31), 187 (13), 216 (M+, 40);pKa = 7.79± 0.15
(l anal = 236 nm);kI = 6.12 (±0.84)*10-5 s-1 (l anal = 238 nm).
Anal. Calcd. for C12H16N4: C, 66.64; H, 7.47; N, 25.89.
Found: C, 66.80; H, 7.41; N, 25.67.
4-Amino-6-nitro-2-(N,N-diethylamino)quinazoline (4f).
This compound was obtained in 26% yield; mp: 148-150 °C;
Rf: 0.38; 1H nmr: d 1.07 (t, 6H, N(CH2CH3)2), 3.37 (q, 4H,
N(CH2CH3)2), 6.62 (s, 1H, NH), 6.99 (s, 1H, H-5), 7.13 (d, J =
9.0 Hz, 1H, H-7), 7.23 (d, J = 9.0 Hz, 2H, H-8), 8.90 (s, 1H, NH)
ppm; uv:l max (e*10-3) acidic: 290.5 (15.44), 216.9 (13.79), basic:
322.0 (12.58), 216.5 (13.63) nm; ms: m/z (%) 46 (27), 51 (13), 65
(11), 72 (100), 163 (17), 189 (55), 190 (27), 219 (20), 232 (64),
246 (30), 261 (M+, 51); pKa = 6.05 ± 0.08 (l anal = 270 nm).
Anal. Calcd. for C12H15N5O2: C, 55.16; H, 5.80; N, 26.79.
Found: C, 55.30; H, 5.70; N, 26.43.
4-Amino-6-methoxy-2-(N,N-diethylamino)quinazoline (4b).
4-Amino-7-nitro-2-(N,N-diethylamino)quinazoline (4g).
This compound was obtained in 45% yield; mp: 218-220 °C;
Rf: 0.70. 1H nmr: d 1.16 (t, 6H, N(CH2CH3)2), 3.54 (q, 4H,
N(CH2CH3)2), 3.73 (s, 3H, OCH3), 6.62 (s, 1H, NH), 6.99 (s, 1H,
H-5), 7.13 (d, J = 9.0 Hz, 1H, H-7), 7.23 (d, J = 9.0 Hz, 2H, H-8),
8.38 (s, 1H, NH) ppm; uv: l max (e*10-3) acidic: 255.3 (26.00),
201.0 (36.51), basic: 254.9 (26.00), 213.0 (14.80), 206.9 (11.00)
nm; ms: m/z (%) 28 (17), 29 (20), 40 (11), 42 (16), 51 (14), 72
(100), 174 (36), 175 (66), 204 (27), 217 (54), 230 (12), 246 (M+,
25); pKa = 7.82 ± 0.09 (l anal = 251 nm).
This compound was obtained in 12% yield; mp: 164-166 °C;
Rf: 0.27; 1H nmr: d 1.05 (t, 6H, N(CH2CH3)2), 3.76 (q, 4H,
N(CH2CH3)2), 7.20-8.40 (m, 4H, H-5,6,8, NH), 10.01 (s, 1H,
NH) ppm; uv: l max (e*10-3) acidic: 243.0 (17.79), basic: 254.0
(16.19), 214.7 (13.84) nm; ms: m/z (%)51 (12), 72 (100), 100
(14), 118 (11), 163 (15), 189 (64), 219 (21), 232 (48), 245 (17),
261 (M+, 25); pKa = 5.99 ± 0.21 (l anal = 269 nm).
Anal. Calcd. for C12H15N5O2: C, 55.16; H, 5.80; N, 26.79.
Found: C, 54.96; H, 5.97; N, 26.49.
Anal. Calcd. for C13H18N4O: C, 63.38; H, 7.38; N, 22.73.
Found: C, 64.03; H, 7.21; N, 22.96.
2-(N,N-Diethylamino)-4-(N,N-dimethylamino)quinazoline (6a).
4-Amino-7-methoxy-2-(N,N-diethylamino)quinazoline (4c).
This compound was synthesized according to the procedure
given in [7]. Yield: 79%; mp: 125-127 °C; Rf: 0.64; pKa = 8.88 ±
0.09 (l anal = 279 nm); kII =6.52(±0.34)*10-6s-1 (l anal=289 nm).
This compound was obtained in 39% yield; mp: 216-217 °C;
Rf: 0.64; 1H nmr: d 1.17 (t, 6H, N(CH2CH3)2), 3.51 (q, 4H,
N(CH2CH3)2), 3.78 (s, 3H, OCH3), 6.82 (s, 1H, NH), 6.90-7.60
(m, 3H, H-5,6,8), 8.32 (s, 1H, NH) ppm; uv: l max (e*10-3) acidic:
278.8 (7.00), 243.6 (23.39), 204.0 (24.92), basic: 273.9 (5.64),
255.2 (16.03), 214.3 (13.44) nm; ms:m/z (%) 29 (18), 33 (80), 38
(86), 40 (31), 46 (64), 51 (17), 72 (100), 77 (12), 78 (11), 148
(14), 174 (27), 175 (23), 202 (19), 217 (76), 218 (20), 231 (18),
246 (M+, 35), 247 (11); pKa = 8.31 ± 0.05 (l anal = 255 nm).
Anal. Calcd. for C13H18N4O: C, 63.38; H, 7.38; N, 22.73.
Found: C, 62.96; H, 7.32; N, 22.60.
Procedures for the Preparation of 3,4-Dihydro-2-(N,N-diethyl-
amino)-4-quinazolone (5a).
Procedure A.
The sediment resulted from the reaction of the crude N1,N1-
diethyl-N2-chlorocarboxyamidine (2) with cyanamide, and TiCl4
was treated with 20% HCl (100 ml) and left for 24 hours at room
temperature. The suspension was filtered off and the solution was
alkalized with 20% NaOH. The precipitate was extracted with
toluene (100 ml). The combined extracts were dried over CaCl2
and concentrated. The product (5a) was crystallized from acetone.
4-Amino-6-chloro-2-(N,N-diethylamino)quinazoline (4d).
This compound was obtained in 79% yield; mp; 126-128 °C; Rf:
0.65; 1H nmr: d 1.09 (t, 6H, N(CH2CH3)2), 3.33 (q, 4H,
N(CH2CH3)2), 6.70 (s, 1H, NH), 6.99 (s, 1H, H-5), 7.25 (d, J = 8.7
Hz, 1H, H-7), 7.40 (s, 1H, H-5), 7.53 (d, J = 8.7 Hz, 1H, H-8), 8.25
(s, 1H, NH) ppm; uv: l max (e*10-3) acidic: 243.8 (15.34), basic:
Procedure B.
2-(N,N-Diethylamino)-4-(N,N-dimethylamino)quinazoline (6a)
(0.3 g, 1.25 mmole) was dissolved in 5% aqueous HCl (30 ml).
The mixture was kept at the temperature of 80 °C for 5 days untill

1292
W. Zielin´ski and A.Kudelko
Vol. 39
265, 1093 (1994).
the disappearance of starting quinazoline was completed. Then it
was cooled down and 5% aqueous NaOH solution (30 ml) was
added yielding a precipitate that was extracted with toluene (100
ml). Extracts were dried over CaCl2, concentrated and the product
(5a) was crystallized from acetone as white crystalls. Yield (A):
76%; (B) 95%; mp: 164-165 °C; Rf: 0.13. 1H nmr: d 1.13 (t, 6H,
N(CH2CH3)2), 3.56 (q, 4H, N(CH2CH3)2), 7.07 (dd, J = 7.5, 6.9
Hz, 1H, H-6), 7.22 (d, J = 7.5 Hz, 1H, H-5), 7.55 (dd, J = 7.5, 6.9
Hz, 1H, H-7), 7.88 (d, J = 7.5 Hz, H-8), 11.06 (s, 1H, NH) ppm;
uv: l max (e*10-3) acidic: 308.9 (3.08), 233.7 (41.65), 207.7
(18.83), basic: 341.1 (3.89), 275.9 (19.25), 252.8 (25.22), 235.1
(31.29), 212.0 (33.64) nm; ms: m/z (%) 63 (14), 64 (11), 72 (50),
90 (43), 91 (10), 92 (10), 117 (14), 119 (17), 132 (11), 145 (43),
146 (18), 171 (13), 174 (41), 188 (100), 189 (15), 217 (M+, 46).
Anal. Calcd. for C12H15N3O: C, 66.33; H, 6.97; N, 19.33.
Found: C, 66.05; H, 7.09; N, 19.23.
[2] T. M. Traxler, P. Furet, H. Melt, E. Buchdunger, T. Meyer
and N. Lydon, J. Med. Chem., 39, 2289 (1996).
[3] J. B. Hynes, A. Tomazic´, A. Kumar, V. Kumar and J. H.
Freisheim, J. Heterocyclic Chem., 28, 1981 (1991).
[4] N. V. Harris, C. Smith and K. Bowden, J. Med. Chem., 27,
7 (1992).
[5] H. Meerwein, P. Laasch, R. Mersch and J. Nentwig, Chem.
Ber., 89, 224 (1956).
[6] V. Gomez Parra, R. Madronero and S. Vega, Synthesis,
1977, 345.
[7] W. Zielin´ski, A. Kudelko and E. M. Holt, Heterocycles,
48, 319 (1998).
[8] A. Hantzsch, Ber. Dtsch. Chem. Ges., 64, 667 (1931).
[9] W. Zielin´ski and M. Mazik, Polish J. Chem., 68, 489
(1994).
[10] J. R. Keneford, J. S. Morley, J. C. Simpson and P. H.
Wright, J. Chem. Soc., 1950, 1104.
[11] B. E. Christensen and A. J. Tomisek, J. Am. Chem. Soc.,
68, 1306 (1946).
Determination of the Hydrolysis Rates of (4a) and (6a) quinazo-
lines.
[12] W. Dymek and D. Sybistowicz, Monatsh. Chem., 96, 542
(1965).
[13] E. C. Taylor and R. V. Ravindranathan, J. Org. Chem., 27,
2622 (1962).
[14] A. Albert and E. P. Serjeant, Ionization Constants of Acids
and Bases, London: Methuen & Co Ltd, New York: J. Wiley&Sons,
1962, p 69.
[15] J. Shorter, Correlation Analysis in Organic Chemistry,
Clarendon Press, Oxford, 1973.
[16] M. Charton, J. Org. Chem., 30, 3341 (1965).
[17] M. Dewar and R. Dougherty, The PMO Theory of Organic
Chemistry, New York 1975, pp 99-110.
[18] W. Zielin´ski and A. Kudelko, Monatsh.Chem., 131, 895
(2000).
The appropriate quinazoline (0.53mmole) was dissolved in 50
ml of methanol. Then 2 ml of the standard solution was dilluted
with 5% HCl in 50 ml measuring flask. Such solution was kept at
the temperature of 80 °C for 3 h. Samples taken in regular inter-
vals were analyzed by the spectrophotometric method.
Acknowledgements.
This work was supported by the State Committee of Scientific
Research, Grant. No T09B08317.
REFERENCES AND NOTES
[1] D. W. Fry, A. J. Kraker, A. McMichael, L. A. Ambroso, J.
M. Nelson, W. R. Leopold, R. W. Connors and A. J. Bridges, Science,
[19] W. Zielin´ski and A. Kudelko, Monatsh.Chem., 131, 733
(2000).