Synthesis of several new quinazolin-4-amines containing p-toluenesulfonate moiety

Article abstract of DOI:10.3184/174751916X14725679922221

A series of novel quinazolin-4-amine derivatives containing p-toluenesulfonate moiety have been synthesised through the reaction of 4-chloro-7-methoxyquinazolin-6-yl acetate with substituted anilines in toluene solution at 90°C. Further treatment of the synthesised compound with ammonium hydroxide gave the corresponding substituted quinazoline derivatives which were subsequently processed through the sulfonyl reaction into quinazolin-4-amines containing p-toluenesulfonate moiety in DMF. Their structures were established by elemental analysis, IR and ¹H NMR spectra.

Full text of DOI:10.3184/174751916X14725679922221

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 SEPTEMBER, 573–575
RESEARCH PAPER 573
Synthesis of several new quinazolin-4-amines containing p-toluenesulfonate
moiety
Zhi-qiang Caia, Zheng-sheng Jina, De-qiang Zhengb*, Ling Houa, Guan-wang Huanga, Jun-qiang
Tiana and Guo-jiang Wanga
aSchool of Petrochemical Engineering, Shenyang University of Technology, 111003, Liaoyang, P.R. China
bInstitute of Pharmaceutical Sciences of Shandong Province, Key Laboratory for Chemical Drug Research of Shandong Province, 250101, Shandong, P.R. China
A series of novel quinazolin-4-amine derivatives containing p-toluenesulfonate moiety have been synthesised through the reaction of
4-chloro-7-methoxyquinazolin-6-yl acetate with substituted anilines in toluene solution at 90 °C. Further treatment of the synthesised
compound with ammonium hydroxide gave the corresponding substituted quinazoline derivatives which were subsequently processed
through the sulfonyl reaction into quinazolin-4-amines containing p-toluenesulfonate moiety in DMF. Their structures were established by
elemental analysis, IR and 1H NMR spectra.
Keywords: quinazolin-4-amine, p-toluenesulfonate, heterocycles, synthesis
Substituted quinazolines are important and useful skeletons
in organic synthesis and medicine chemistry.1 Quinazolines
and related fused heterocycles have been found to possess
significant pharmacological activities.2 Quinazoline derivatives
have been utilised extensively in medicinal chemistry due to
its privileged structure that shows various pharmacological
activities, such as antibacterial,3 antihypertensive,4 anti-
inflammatory,5 antifungal,6 anticonvulsant7 and anticancer
activities8–10 among others. This scaffold has been identified as
new class of cancer chemotherapeutic agents acting as potent
inhibitors for epidermal growth factor receptor (EGFR).11,12
Our interest in fused quinazoline heterocycles is due to their
known biological activity reported in the literature.11 In order
to find novel antitumor bioactive compounds, several new
kind of quinazoline derivatives have been synthesised in our
laboratory.13 We now report the synthesis a series of quinazolin-
4-amines by a four-step method.
in a molar ratio 1:1.1, in toluene under reflux gave the desired
compounds 3a–f at 90 °C. Compounds 3a–f were converted into
4a–f by reaction with ammonium hydroxide (28%) in methanol
solution at room temperature for 12 h with a high yield. Finally
5a–f were prepared by reaction with p-toluenesulfonyl chloride
in DMF at 90 °C for 12 h. Compounds 5a–f were appropriately
established by spectroscopic and analytical methods. IR shows
the peak at about 3500–3600 cm–1 results from the stretching
1
vibration of aromatic amino in all products. H NMR data
were consistent with structures 5a–f, for example, the 1H NMR
spectrum for compound 5f exhibits a sharp singlet at 2.43 and
another singlet at 3.57 ppm, corresponding to the methyl proton
at benzene ring and to the methoxy proton at quinazoline ring,
respectively. Aromatic protons resonate as multiples at δ 7.17–
8.46. The presence of these signals agrees with the proposed
structure reaction route.
Conclusion
Results and discussion
In summary, we have prepared several new quinazolin-4-
amines containing p-toluenesulfonate moiety 5a–f. The
structure elucidation of these compounds was achieved using
The synthetic methods for compounds 5a–f are outlined in
Scheme 1. The substituted quinazolin-4-amine derivatives
have been synthesised starting from compound 1. Upon
refluxing with freshly distilled phosphoryl chloride (POCl3)
in presence of triethylamine (Et3N), compound 1 yielded the
corresponding key 4-chloro intermediates 2, which were used
without purification. Reaction of 2 with the substituted anilines
1
IR, H NMR and elemental analyses. These new compounds
like all other biologically active heterocyclic compounds may
be good candidates for investigating their pharmaceutical
properties in biological systems. These studies are currently in
progress in our laboratory and will be published in due course.
R1
O
H2N
R1
R3 R2
Cl
N
HN
N
R2
O
O
O
O
POCl3
NH
N
O
O
R3
N
O
O
N
O
1
2
a f
−
3
R1
R2
R1
R2
O
S
Cl
HN
O
HN
NH3•H2O
HO
R3
O
R3
S
O
O
O
N
N
O
N
−
N
a f
4
a f
5
−
Comp. a
b
c
d
e
f
R1
R2
R3
Cl Cl
H
OCH3 Cl
F
H
F
H
H
F
OCH3
H
H
H
Cl
F
H
Scheme 1
* Correspondent. E-mail: kahongzqc@163.com

574 JOURNAL OF CHEMICAL RESEARCH 2016
Experimental
Synthesis of 7-methoxy-4-(substituted anilines)quinazolin-6-ol
(4a–f); general procedure
Unless specified otherwise, all starting materials and reagents were
obtained from commercial supplies without further purification. All
melting points were taken on a Beijing Taike X-4 microscopy melting
point apparatus and were uncorrected. 1H NMR spectra were recorded
on a Bruker Biospin 400 MHz instrument using TMS as the internal
standard. All chemical shifts are reported in ppm. IR spectra were
recorded on a Bruker Platinum ART Tensor II FTIR spectrometer.
Elemental analysis of the newly synthesised compounds was carried
out on Carlo Erba 1108 analyser and are found within the range of
theoretical value. Compound 1 was synthesised according to reported
procedures.14
Synthesis of 4-chloro-7-methoxyquinazolin-6-yl acetate (2): A
mixture of 1 (1.0 g, 4.27 mmol), triethylamine (1.2 mL, 8.66 mmol) and
phosphorus oxychloride (1.2 mL, 13.11 mmol) in toluene (15 mL) was
heated to 80 °C for 4 h, which directly to the next step reaction without
purification.
7-methoxy-4-(substituted anilines)quinazolin-6-yl acetate (30 mmol)
(3a–f) was admixed with methanol (100 mL). The mixture was cooled
to 10 °C, added with an ammonia solution (45 g), and stirred for
5 hours at 20 °C. The solid thus obtained was filtered and washed with
a mixed solvent of methanol (20 mL) and water (20 mL). The resulting
solid was dried at 50 °C in an oven to afford 4a–f as white powder.
4-[(4-chlorophenyl)amino]-7-methoxyquinazolin-6-ol (4a): Yield
67.3%; m.p. 252–254 °C; IR (νmax, cm–1) KBr: 3378 (NH), 3356 (OH),
1455, 1274; 1H NMR (DMSO-d6, 400 MHz): δ 3.98 (s, 3H, OCH3), 7.21
(s, 1H, ArH), 7.38–7.42 (m, 2H, ArH), 7.84 (s, 1H, ArH), 7.92–7.96 (m,
2H, ArH), 8.47 (d, J = 4.8 Hz, 1H, ArH), 9.48 (s, 1H, NH); Anal. calcd
for C15H12ClN3O2: C, 59.71; H, 4.01; N, 13.93; found: C, 59.76; H, 4.03;
N, 13.98%.
4-[(4-chloro-3-fluorophenyl)amino]-7-methoxyquinazolin-6-ol
(4b): Yield 69.0%; m.p. > 260 °C; IR (νmax, cm–1) KBr: 3382 (OH),
1470, 1245; 1H NMR (DMSO-d6, 400 MHz): δ 3.98 (s, 3H, OCH3), 7.21
(d, J = 5.2 Hz, 1H, ArH), 7.41 (t, J = 9.2 Hz, 1H, ArH), 7.79 (s, 1H,
ArH), 8.22 (dd, J = 2.4 Hz, J = 6.8 Hz, 1H, ArH), 8.48 (s, 1H, ArH),
9.49 (s, 1H, NH); Anal. calcd for C15H11ClFN3O2: C, 56.35; H, 3.47; N,
13.14; found: C, 56.39; H, 3.48; N, 13.17%.
Synthesis of 7-methoxy-4-(substituted anilines)quinazolin-6-yl
acetate (3a–f); general procedure
A mixture of substituted anilines (4.70 mmol) in toluene (25 mL) was
added to the above reaction solution, followed by stirring for 3 h. Upon
completion of the reaction, the resulting mixture was cooled to 20 °C.
The solid thus obtained was filtered under a reduced pressure and
washed with toluene (20 mL). Isopropanol (18 mL) was added to the
solid, which was then stirred for 5 h. The resulting solid was filtered
and washed with isopropanol (10 mL). The solid was dried at 50 °C in
the oven to afford 3a–f as white powder.
7-methoxy-4-[(3-methoxyphenyl)amino]quinazolin-6-ol (4c): Yield
97.0%; m.p. 246–248 °C; IR (νmax, cm–1) KBr: 3306 (OH), 1466,
1
1271; H NMR (DMSO-d6, 400 MHz): δ 3.77 (s, 3H, OCH3), 6.65 (s,
1H, ArH), 7.21 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.51 (s, 1H, ArH), 7.57
(s, 1H, ArH), 7.82 (s, 1H, ArH), 8.46 (s, 1H, ArH), 9.31 (s, 1H, OH),
9.647(s, 1H, NH); Anal. calcd for C16H15N3O3: C, 64.64; H, 5.09; N,
14.13; found: C, 64.67; H, 5.17; N, 14.19%.
4-[(4-chlorophenyl)amino]-7-methoxyquinazolin-6-yl acetate (3a)
Yield 92.0%; m.p. 201–203 °C; IR (νmax, cm–1) KBr: 3285 (NH),
1771 (C=O), 1460, 1266; H NMR (DMSO-d6, 400 MHz): δ 2.39 (s,
7-methoxy-4-[(4-methoxyphenyl)amino]quinazolin-6-ol
(4d):
1
Yield 76.5%; m.p. 261–263 °C; IR (νmax, cm–1) KBr: 3337 (OH), 1510,
3H, CH3), 4.01 (s, 3H, OCH3), 7.54–7.57 (m, 2H, ArH), 7.62 (s, 1H,
ArH), 7.78–7.81 (m, 2H, ArH), 8.94 (d, J = 2.8 Hz, 2H, ArH), 11.79 (d,
J = 2.0 Hz, 1H, NH); Anal. calcd for C17H14ClN3O3: C, 59.40; H, 4.10;
N, 12.22; found: C, 59.45; H, 4.18; N, 12.29%.
4-[(4-chloro-3-fluorophenyl)amino]-7-methoxyquinazolin-6-yl
acetate (3b): Yield 93.2%; m.p. 220–222 °C; IR (νmax, cm–1) KBr:
1776 (C=O), 1471, 1455, 1257; 1H NMR (DMSO-d6, 400 MHz):δ
2.38 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 7.52–7.77 (m, 1H, ArH), 7.78
(s, 1H, ArH), 7.79–7.81 (m, 1H, ArH), 8.08–8.10 (m, 1H, ArH), 8.93
(s, 1H, ArH), 8.97 (s, 1H, ArH), 11.75 (s, 1H, NH); Anal. calcd for
C17H13ClFN3O3: C, 56.44; H, 3.62; N, 11.62; found: C, 56.49; H, 3.68;
N, 11.69%.
1
1472, 1225; H NMR (DMSO-d6, 400 MHz): δ 3.97 (s, 3H, OCH3),
6.93–6.96 (m, 2H, ArH), 7.17 (s, 1H, ArH), 7.68 (d, J = 2.4 Hz, 1H,
ArH), 7.70–7.71 (m, 1H, ArH), 7.78 (s, 1H, ArH), 8.36 (s, 1H, ArH),
9.26 (s, 1H, NH); Anal. calcd for C16H15N3O3: C, 64.64; H, 5.09; N,
14.13; found: C, 64.71; H, 5.16; N, 14.19%.
4-[(3,4-dichloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-ol
(4e): Yield 88.4%; m.p. > 260 °C; IR (νmax, cm–1) KBr: 3460 (OH),
1495, 1207; 1H NMR (DMSO-d6, 400 MHz): δ 3.97 (s, 3H, OCH3), 7.21
(s, 1H, ArH), 7.52–7.62 (m, 2H, ArH), 7.68 (s, 1H, ArH), 8.35 (s, 1H,
ArH), 9.57 (br, 2H, NH and OH); Anal. calcd for C15H10Cl2FN3O2: C,
50.87; H, 2.85; N, 11.86; found: C, 50.94; H, 2.90; N, 11.91%.
4-((2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-ol
(4f):
7-methoxy-4-[(3-methoxyphenyl)amino]quinazolin-6-yl
acetate
Yield 90.0%; m.p. 260–262 °C; IR (νmax, cm–1) KBr: 3225 (OH),
(3c): Yield 91.1%; m.p. 227–229 °C; IR (νmax, cm–1) KBr: 1771 (C=O),
1456, 1218, 1204; 1H NMR (DMSO-d6, 400 MHz): δ 2.39 (s, 3H, CH3),
3.79 (s, 3H, OCH3), 4.01 (d, J = 5.2 Hz, 3H, OCH3), 6.90–6.95 (m, 1H,
ArH), 7.32–7.38 (m, 2H, ArH), 7.39–7.42 (m, 1H, ArH), 7.58 (s, 1H,
ArH), 8.83 (s, 1H, ArH), 8.923 (s, 1H, ArH), 11.49 (s, 1H, NH); Anal.
calcd for C18H17N3O4: C, 63.71; H, 5.05; N, 12.38; found: C, 63.77; H,
5.09; N, 12.45%.
1
1510, 1137; H NMR (DMSO-d6, 400 MHz): δ 4.03 (s, 3H, OCH3),
7.10–7.12 (d, J = 8.0 Hz, 1H, ArH), 7.31 (s, 1H, ArH), 7.49–7.51 (d,
J = 8.0 Hz, 2H, ArH), 7.90 (s, 1H, ArH), 8.80 (s, 1H, ArH); Anal. calcd
for C15H11F2N3O2: C, 59.41; H, 3.66; N, 13.86; found: C, 59.48; H, 3.69;
N, 13.93%.
Synthesis of 7-methoxy-4-(substituted anilines)quinazolin-6-
toluenesulfonate (5a–f); general procedure
7-methoxy-4-[(4-methoxyphenyl)amino]quinazolin-6-yl
acetate
(3d): Yield 96.6%; m.p. 253–255 °C; IR (νmax, cm–1) KBr: 3381 (NH),
1771 (C=O), 1508, 1469, 1282; 1H NMR (DMSO-d6, 400 MHz): δ 2.39
(d, J = 4.0 Hz, 3H, CH3), 3.80 (d, J = 0.8 Hz, 3H, OCH3), 3.99 (s, 3H,
OCH3), 3.01–3.04 (m, 2H, ArH), 7. 90 (d, J = 4.0 Hz, 2H, ArH), 7.61 (d,
J = 2, 1H, ArH), 8.86 (s, 2H, ArH), 11.61 (s, 1H, NH); Anal. calcd for
C18H17N3O4: C, 63.71; H, 5.05; N, 12.38; found: C, 63.73; H, 5.08; N,
12.44%.
4-[(3,4-dichloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl
acetate (3e): Yield 94.0%; m.p. 211–213 °C; 1H NMR (DMSO-d6, 400
MHz): δ 2.38 (s, 3H, CH3), 4.01 (s, 3H, OCH3), 7.57–7.69 (m, 3H, ArH),
8.76 (s, 1H, ArH), 8.92 (s, 1H, ArH); Anal. calcd for C17H12Cl2FN3O3: C,
51.54; H, 3.05; N, 10.61; found: C, 51.59; H, 3.09; N, 10.68%.
A mixture of the appropriate 7-methoxy-4-(substituted aniline)
quinazolin-6-ol (3.0 mmol) 4a–f, K2CO3 (3.0 mmol) and
4-toluenesulfonyl chloride (3.0 mmol) in 50 mL dry N,N-
Dimethylformamide (DMF) was stirred at 90 °C for 5 h. The reaction
mixture was diluted with water (100 mL), extracted by ethyl acetate
(100 mL × 3), and dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to give crude product, which was purified by
column chromatography to afford 5a–f as white powder.
4- [(4-chlorophenyl) amino] -7-methoxyquinazolin- 6 -yl
4-methylbenzenesulfonate (5a): Yield 60.9%; m.p. 251–252 °C; IR
1
(νmax, cm–1) KBr: 3425 (NH), 1419, 1391, 1237, 1213, 762; H NMR
(DMSO-d6, 400 MHz): δ 2.43 (s, 3H, CH3), 3.55 (s, 3H, OCH3),
7.210(s, 1H, ArH), 7.44–7.48 (m, 4H, ArH), 7.74 (d, J = 7.6 Hz, 2H,
ArH), 7.89 (d, J = 8.8 Hz, 2H, ArH), 8.57 (s, 2H, ArH), 9.89 (s, 1H,
NH); Anal. calcd for C22H18ClN3O4S: C, 57.96; H, 3.98; N, 9.22; found:
C, 58.01; H, 4.07; N, 9.28.
4-[(2,4-difluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate
(3f): Yield 94.3%; m.p. 216–218 °C; IR (νmax, cm–1) KBr: 2978, 2945,
(CH3), 1766 (C=O), 1474, 1396, 1035; Anal. calcd for C17H13F2N3O3: C,
59.13; H, 3.79; N, 12.17; found: C, 59.19; H, 3.84; N, 12.25%.

JOURNAL OF CHEMICAL RESEARCH 2016 575
4-[(4-chloro-3-fluorophenyl)amino]-7-methoxyquinazolin-6-yl
This work was supported financially by the Scientific Research
Foundation of the Education Department of Liaoning Province
(L2015383) and the Doctoral Start-Up Fund of Shenyang
University of Technology (No. 521422).
4-methylbenzenesulfonate (5b): Yield 54.6%; m.p. 228–229 °C; IR
1
(νmax, cm–1) KBr: 3599 (NH), 1496, 1447, 1365; H NMR (DMSO-d6,
400 MHz): δ 2.43 (s, 3H, CH3), 3.55 (s, 3H, OCH3), 7.21 (s, 1H, ArH),
7.42–7.48 (m, 3H, ArH), 7.73–7.78 (m, 2H, ArH), 7.79–7.83 (m, 1H,
ArH), 8.15–8.17 (m, 1H, ArH), 8.54 (s, 1H, ArH), 8.59 (s, 1H, ArH),
9.90 (s, 1H, NH); Anal. calcd for C22H17ClFN3O4S: C, 55.76; H, 3.62;
N, 8.87; found: C, 55.80; H, 3.69; N, 8.95%.
Electronic Supplementary Information
The ESI {IR and 1H NMR} is available through:
7-methoxy- 4- [(3-methoxyphenyl) amino]quinazolin- 6-yl
4-methylbenzenesulfonate (5c): Yield 46.1%; m.p. 113–115 °C;
IR (νmax, cm–1) KBr: 3421 (NH), 1532, 1484, 1191, 820; 1H NMR
(DMSO-d6, 400 MHz): δ 2.43 (s, 3H, CH3), 3.55 (s, 3H, OCH3), 3.79
(s, 3H, OCH3), 6.72–6.74 (m, 1H, ArH), 7.21 (s, 1H, ArH), 7.31 (s, 1H,
ArH), 7.46–7.512 (m, 4H, ArH), 7.74 (d, J = 8.4 Hz, 2H, ArH), 8.58 (d,
J = 8.0 Hz, 2H, ArH), 9.77 (s, 1H, NH); Anal. calcd for C23H21N3O5S:
C, 61.18; H, 4.69; N, 9.31; found: C, 61.24; H, 4.77; N, 9.41%.
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 8 July 2016; accepted 19 July 2016
Paper 1604181 doi: 10.3184/174751916X14725679922221
Published online: 6 September 2016
References
1
2
J.A. Palop, D. Plano, E. Moreno and C. Sanmartín, Arkivoc, 2014, 2, 187.
S.I. Salah, M.A. Ali, G. Yassien, E. Soummaia and M.A. Reda, J. Chem.
Res. (S), 1997, 5, 154.
7-methoxy- 4- [(4-methoxyphenyl) amino]quinazolin- 6-yl
4-methylbenzenesulfonate (5d): Yield 52.0%; m.p. 219–221 °C; IR
1
(νmax, cm–1) KBr: 3556 (NH), 1507，1471，1456，1276，826; H NMR
3
4
5
6
R.P. Modh, A.C. Patel, D.H. Mahajan, C. Pannecouque, E.D. Clercq and
K.H. Chikhalia, Arch. Pharm., 2012, 345, 964.
O.I. El-Sabbagh, M.A. Shabaan, H.H. Kadry and E.S. Al-Din, Eur. J. Med.
Chem., 2010, 45, 5390.
N. Chatterjee, S. Das, D. Bose, S. Banerjee, D. Chattopadhyay and K.D.
Saha, Toxicol. Appl. Pharmacol., 2012, 264, 182.
C.K. Ryu, Y.H. Kim, H.A. Im, J.Y. Kim, J.H. Yoon and A. Kim, Bioorg.
Med. Chem. Lett., 2012, 22, 500.
(DMSO-d6, 400 MHz): δ 2.43 (s, 3H, CH3), 3.54 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 6.98 (d, J = 8.8 Hz, 2H, ArH), 7.17 (s, 1H, ArH), 7.47 (d,
J = 8.0 Hz, 2H, ArH), 7.66 (d, J = 8.8 Hz, 2H, ArH), 7.74 (d, J = 8.0 Hz,
2H, ArH), 8.48 (s, 1H, ArH), 8.54 (s, 1H, ArH), 9.75 (s, 1H, NH); Anal.
calcd for C23H21N3O5S: C, 61.18; H, 4.69; N, 9.31; found: C, 61.24; H,
4.79; N, 9.38%.
4-[(3,4-dichloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-
yl 4-methylbenzenesulfonate (5e): Yield 48.8%; m.p. 230–231 °C;
IR (νmax, cm–1) KBr: 3622 (NH), 1524, 1466, 1389, 810; 1H NMR
(DMSO-d6, 400 MHz): δ 2.44 (s, 3H, CH3), 3.59 (s, 3H, OCH3), 7.25
(s, 1H, ArH), 7.48 (d, J = 8.0 Hz, 2H, ArH), 7.59 (s, 2H, ArH), 7.76 (d,
J = 8.0 Hz, 2H, ArH), 8.46 (s, 1H, ArH), 8.50 (s, 1H, ArH), 10.08 (s,
1H, NH); Anal. calcd for C22H16Cl2FN3O4S: C, 51.98; H, 3.17; N, 8.27;
found: C, 52.09; H, 3.26; N, 8.34%.
7
8
A.S. El-Azab and K.E. Eltahir, Bioorg. Med. Chem. Lett., 2012, 22, 327.
H.K. Rhee, J.H. Yoo, E. Lee, Y.J. Kwon, H.R. Seo, Y.S. Lee and H.Y. Choo,
Eur. J. Med. Chem., 2011, 46, 3900.
9
N. Jiang, X. Zhai, Y. Zhao, Y. Liu, B. Qi, H. Tao and P. Gong, Eur. J. Med.
Chem., 2012, 54, 534.
10 S. Das, N. Chatterjee, D. Bose, S.K. Dey, R.N. Munda, A. Nandy, S. Bera,
S.K. Biswas and K.S. Das, Cell. Physiol. Biochem., 2012, 29, 251.
11 D.D. Li, F. Fang, J.R. Li, Q.R. Du, J. Sun, H.B. Gong and H.L. Zhu, Bioorg.
Med. Chem. Lett., 2012, 22, 5870.
12 X. Cai, H.X. Zhai, J. Wang, J. Forrester, H. Qu, L. Yin, C.J. Lai, R. Bao and
C. Qian, J. Med. Chem., 2010, 53, 2000.
13 Z.Q. Cai, W.Y. Ma, J.Y. Wang, Z.Y. Li, H.B. Guo, A.F. Cai and B. Xue,
Chin. J. Synth. Chem., 2015, 23, 194.
14 T. Furuta, T. Sakai, T. Senga, T. Osawa, K. Kubo, T. Shimizu, R. Suzuki, T.
Yoshino, M. Endo and A. Miwa, J. Med. Chem., 2006, 49, 2186.
4-[(2,4-difluorophenyl)amino]-7-methoxyquinazolin-6-yl
4-methylbenzenesulfonate (5f): Yield 43.8%; m.p. 196–197 °C; IR
1
(νmax, cm–1) KBr: 3569 (NH), 3476 (NH), 1507，1294，807; H NMR
(DMSO-d6, 400 MHz): δ 2.43 (s, 3H, CH3), 3.57 (s, 3H, OCH3), 7.17
(s, 1H, ArH), 7.22 (s, 1H, ArH), 7.34–7.56 (m, 4H, ArH), 7.75 (d,
J = 8.0 Hz, 2H, ArH), 8.44–8.46 (d, J = 8.0 Hz, 2H, ArH), 9.87 (s, 1H,
NH); Anal. calcd for C22H17F2N3O4S: C, 57.76; H, 3.75; N, 9.19; found:
C, 57.88; H, 3.78; N, 9.25%.