C.J.A. Ribeiro et al.
EuropeanJournalofPharmaceuticalSciences118(2018)67–79
was stirred at 50 °C for 12–24 h. The solvent was removed in vacuo and
the crude was dissolved in CH2Cl2, washed with Na2CO3 solution and
brine, dried over Na2SO4 and evaporated in vacuo to produce the crude
product. Purification of the crude product using Combi flash with
0–40% hexane in ethyl acetate as eluent furnished the desired product
2.1.4. 2-((6-Methoxy-4-methylquinazolin-2-yl) amino) quinazolin-4(3H)-
A mixture of 11a (0.05 g, 0.22 mmol) and anthranilic acid (0.04 g,
0.26 mmol) in 1 mL of DMSO was heated at 170 °C until the starting
material disappeared. The reaction mixture was cooled, water was
added, and the resulting product was filtered and washed with excess
water. The crude mixture was recrystallized from chloroform to yield
the desired product as colorless crystals (0.046 g, 64%). 1H NMR
(600 MHz, DMSO‑d6) δ 13.60 (s, 1H), 11.11 (s, 1H), 8.04 (d, J = 7.7 Hz,
1H), 7.77–7.69 (m, 2H), 7.60 (dd, J = 9.1, 2.7 Hz, 1H), 7.47 (t,
J = 7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 3.92 (s, 3H), 2.89 (s, 3H).
HRMS-ESI (+) m/z calculated for C18H16N5O2, 334.1304 [M + H]+;
2.1.1.1. 6-Methoxy-2,2,4-trimethyl-1,2-dihydroquinoline
(10a). Yield:
40%; 1H NMR (600 MHz, DMSO‑d6) δ 6.59–6.52 (m, 2H), 6.41 (d,
J = 9.0 Hz, 1H), 5.38 (s, 1H), 5.31 (s, 1H), 3.64 (s, 3H), 1.88 (d,
J = 0.8 Hz, 3H), 1.16 (s, 6H).
2.1.1.2. 6-Chloro-2,2,4-trimethyl-1,2-dihydroquinoline (10c) (Li et al.,
2006). Yield: 65%; 1H NMR (600 MHz, CDCl3) δ 7.00 (s, 1H), 6.92
(d, J = 8.3 Hz, 1H), 6.36 (d, J = 7.7 Hz, 1H), 5.35 (s, 1H), 3.11 (s, 1H),
1.96 (s, 3H), 1.27 (s, 6H).
2.1.5. 1-(6-Methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)guanidine (15)
To a solution of anthranilic acid (0.1 g, 0.59 mmol) in 1 mL of 10%
H2SO4, was added cyanoguanidine (0.075 g, 0.89 mmol) and refluxed
for 60 min. The hot solid was precipitated and washed with excess
water to furnish the desired product as colorless solid (0.077 g, 55%).
1H NMR (600 MHz, DMSO‑d6) δ 11.12 (s, 1H), 7.48 (s, 2H), 7.35 (d,
J = 2.7 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 8.8, 2.7 Hz,
1H), 3.80 (s, 3H). HRMS-ESI (+) m/z calculated for C10H12N5O2,
234.0991 [M + H]+; found: 234.0994.
2.1.2. General procedural for synthesis of substituted quinazolines (11)
To a solution of 10 (2.46 mmol) in water (5 mL), was added cya-
noguanidine (2.46 mmol), concentrated HCl (1 mL) and the resulting
mixture was stirred under reflux for 4 h. The hot mixture was decanted
from oils, cooled and stirred continuously by treating with concentrated
KOH until a pH of 10–11 was obtained. The resulting precipitate was
filtered and washed several times with isopropanol followed by re-
crystallization from ethanol gave the desired product in 55–62% yield.
2.1.6. 4-Amino-5-(furan-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
To a solution of KOH (0.67 g, 11.89 mmol) in methanol (10 mL),
was added furoic hydrazide (1.0 g, 7.92 mmol), CS2 (0.72 mL,
11.89 mmol) and stirred at room temperature for 24 h and then ether
was added and stirred the reaction mixture for another 2 h. The re-
sulting solid was filtered, washed with cold methanol and ether and air
dried. The solid was refluxed in excess of hydrazine hydrate (10 eq) for
5 h, cooled and poured into the acidic water (pH = 2). The solid was
filtered and recrystallized from ethanol to produce the desired com-
pound as colorless crystals (1.01 g, 70% over two steps). 1H NMR
(600 MHz, DMSO‑d6) δ 13.92 (s, 1H), 7.94 (dd, J = 1.8, 0.6 Hz, 1H),
7.39 (dd, J = 3.5, 0.6 Hz, 1H), 6.73 (dd, J = 3.5, 1.8 Hz, 1H), 5.83 (s,
2.1.2.1. 1-(6-Methoxy-4-methylquinazolin-2-yl) guanidine (11a). Yield:
55%; 1H NMR (600 MHz, DMSO‑d6) δ 7.51 (d, J = 9.0 Hz, 1H), 7.37 (d,
J = 9.1 Hz, 1H), 7.28 (s, 1H), 7.07 (s, 2H), 3.87 (s, 3H), 2.71 (s, 3H).
13C NMR (150 MHz, DMSO‑d6) δ 167.4, 159.3, 155.1, 145.9, 127.7,
125.2, 119.7, 104.3, 55.8, 22.0. HRMS-ESI (+) m/z calculated for
C
11H14N5O, 232.1198 [M + H]+; found: 232.1196.
2.1.2.2. 1-(6-Ethoxy-4-methylquinazolin-2-yl) guanidine (11b) (Brown,
1965). Yield: 62%; 1H NMR (600 MHz, DMSO‑d6)
7.50 (d,
δ
J = 9.1 Hz, 1H), 7.35 (dd, J = 9.1, 2.6 Hz, 1H), 7.27 (d, J = 2.6 Hz,
1H), 6.98 (s, 2H), 4.13 (q, J = 6.9 Hz, 2H), 2.69 (s, 3H), 1.38 (t,
J = 6.9 Hz, 3H). 13C NMR (100 MHz, DMSO‑d6) δ 167.0, 159.0, 154.0,
145.5, 127.3, 125.1, 119.4, 104.8, 63.6, 21.7, 14.7. HRMS-ESI (+) m/z
calculated for C12H16N5O, 246.1349 [M + H]+; found: 246.1340.
2.1.7. General procedure for the synthesis of 3-(furan-2-yl)-6-phenyl-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (19)
To a mixture of 18 (1.0 mmol) in POCl3 (5 mL), was added sub-
stituted benzoic acid (1.1 mmol) and refluxed for 6 h. The reaction
mixture was cooled and slowly poured into crushed ice with stirring
and neutralized with sodium bicarbonate. The precipitated solid was
filtered, washed with cold water, dried, and recrystallized from ethanol
to afford the desired compounds (19) as colorless crystals in 53–70%
2.1.2.3. 1-(6-Chloro-4-methylquinazolin-2-yl) guanidine hydrochloride
DMSO‑d6) δ 11.39 (s, 1H), 10.91 (s, 1H), 8.19 (s, 3H), 8.12 (d,
J = 9.0 Hz, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 9.0, 2.3 Hz,
1H), 2.67 (s, 3H). 13C NMR (150 MHz, DMSO‑d6) δ 201.8, 155.6, 151.7,
136.8, 133.9, 131.2, 127.7, 126.9, 123.5, 29.2. HRMS-ESI (+) m/z
calculated for C10H11ClN5, 236.0697 [M + H]+; found: 236.0696.
2.1.7.1. 6-(3,4-Dimethylphenyl)-3-(furan-2-yl)-[1,2,4]triazolo[3,4-b]
[1,3,4] thiadiazole (19a). Yield: 53%; 1H NMR (600 MHz, DMSO‑d6) δ
8.04 (s, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 6.4 Hz,
2H), 6.82 (s, 1H), 2.35 (s, 3H), 2.33 (s, 3H). 13C NMR (150 MHz,
DMSO‑d6) δ 167.5, 145.4, 142.5, 140.1, 139.3, 138.1, 130.6, 127.8,
126.5, 124.8, 112.2, 111.8, 19.60, 19.18. HRMS-ESI (+) m/z calculated
for C15H13N4OS, 297.0810 [M + H]+; found: 297.0813.
2.1.3. 2-((6-Methoxy-4-methylquinazolin-2-yl) amino)-5, 6-dimethylpyrimidin-
4(3H)-one (12a)
To a solution of 11a (0.10 g, 0.43 mmol) in minimal hot DMSO, was
added ethyl 2-methylacetoacetate (0.07 mL, 0.52 mmol) and NaHCO3
(0.044 g, 0.52 mmol). The reaction mixture was heated at 170 °C until
the disappearance of starting material. The solution was cooled, and
water was added to precipitate the product which was collected by
filtration, washed with acetone and water and dried to afford 12a
(0.04 g, 30%) as a tan solid. 1H NMR (600 MHz, DMSO‑d6) δ 13.28 (s,
1H), 11.00 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 9.1, 2.7 Hz,
1H), 7.48 (d, J = 2.5 Hz, 1H), 3.93 (s, 3H), 2.87 (s, 3H), 2.18 (s, 3H),
1.90 (s, 3H). HRMS-ESI (+) m/z calculated for C16H18N5O2, 312.1460
2.1.7.2. 3-(Furan-2-yl)-6-(2-methoxyphenyl)-[1,2,4]triazolo[3,4-b]
(600 MHz, DMSO‑d6) δ 8.32 (dd, J = 7.9, 1.5 Hz, 1H), 8.02 (dd,
J = 1.6, 0.5 Hz, 1H), 7.74–7.56 (m, 1H), 7.41 (d, J = 3.5 Hz, 1H),
7.35 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.81 (dd, J = 3.4,
1.8 Hz, 1H), 4.06 (s, 3H). 13C NMR (150 MHz, DMSO‑d6) δ 162.5,
157.1, 154.8, 145.2, 140.2, 138.6, 134.4, 127.9, 121.7, 116.8, 113.1,
112.2, 111.3, 56.5. HRMS-ESI (+) m/z calculated for C14H11N4O2S,
299.0603 [M + H]+; found: 299.0606.
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