Journal of Medicinal Chemistry
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added. The mixture was stirred at room temperature for 30 min. The
reaction was diluted with dichloromethane. The organic layer was
washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered,
and evaporated to dryness.
cyanoacetamide (326 mg, 3.88 mmol) in anhydrous DMF (5.9 mL)
was added at 0 °C. After 1 h, a solution of 1228 (624 mg, 3.52 mmol)
in anhydrous DMF (5.9 mL) was slowly added and stirring was
continued at room temperature for 1 h. Volatiles were removed. The
residue obtained was purified by flash column chromatography
(dichloromethane/methanol, 20:1) to yield 641 mg (70%) of 13 as
a yellowish solid.
General Procedure for the Synthesis of [1,2,3]Triazolo[4,5-
d]pyrimidin-7(6H)-ones (15a−g) from the 5-Amino-1H-1,2,3-
triazole-4-carboxamide 13. To a solution of Na (5.00 mmol) in
ethanol (10 mL/mmol), the carboxamide 13 (1.00 mmol) and the
appropriate ester (4.00 mmol) were added. The reaction mixture was
heated at reflux for 1−8 h. After cooling, the reaction was concentrated
to dryness. The residue was dissolved in water and acidified by
addition of acetic acid, and the precipitate thus formed was isolated by
filtration and purified as specified.
5-Ethyl-3-(3′-isopropoxyphenyl)-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7(6H)-one (15b). Following the general procedure, to a
solution of Na (44 mg, 1.90 mmol) in ethanol (3.8 mL), 13 (100 mg,
0.38 mmol) and ethyl propionate (176 μL, 1.52 mmol) were added.
The reaction mixture was refluxed for 8 h. After work-up, a precipitate
was obtained that was purified by CCTLC (dichloromethane/
methanol, 20:1) to yield 15b (60 mg, 53%) as a white solid. mp:
242−244 °C. MS (ES, positive mode): m/z 300 (M + H)+. 1H NMR
(400 MHz, DMSO-d6): δ 1.23 (t, J = 7.5 Hz, 3H, CH3), 1.31 (d, J =
6.0 Hz, 6H, CH(CH3)2), 2.71 (q, J = 7.5 Hz, 2H, CH2), 4.69 (hept, J =
6.0 Hz, 1H, CH), 7.06 (d, J = 8.0, 1H, H-4′), 7.51 (pt, J = 8.1 Hz, 1H,
H-5′), 7.58 (d, J = 8.0 Hz, 1H, H-6′), 7.63 (s, 1H, H-2′), 12.70 (s 1H,
NH). 13C NMR (100 MHz, DMSO-d6): δ 11.5 (CH3), 22.1
(CH(CH3)2), 28.1 (CH2), 70.3 (CH), 109.2, 114.0, 116.6 (Ar),
129.4 (C-7a), 131.1, 136.9 (Ar), 149.1 (C-3a), 156.3 (C-7), 158.5
(Ar), 165.0 (C-5). Anal. (C15H17N5O2): C, H, N.
7-Chloro-3-(2′-methoxyphenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-
d]pyrimidine (10a). Following the general procedure, to a suspension
of 9a (296 mg, 1.12 mmol) in dichloromethane (3.9 mL), NaNO2 (81
mg, 1.17 mmol) and 1 N HCl (3.9 mL) were added. After work-up,
233 mg (75%) of 10a were obtained as a pale brown solid. mp: 156−
1
158 °C. MS (ES, positive mode): m/z 276 (M + H)+ ; H NMR
(DMSO-d6, 300 MHz): δ 2.34 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 7.15
(ddd, J = 7.6, 1.7, 1.1 Hz, 1H, H-5′), 7.32 (dd, J = 8.5, 1.1 Hz, 1H, H-
3′), 7.47 (dd, J = 7.8, 1.7 Hz, 1H, H-6′), 7.62 (ddd, J = 8.4, 7.5, 1.7 Hz,
1H, H-4′).
The synthesis of compounds 10b−m was performed following a
similar procedure, and all details and analytical and spectroscopic data
are included in the Supporting Information.
General Procedure for the Synthesis of [1,2,3]Triazolo[4,5-
d]pyrimidin-7(6H)-ones (11a−m). To a solution of the correspond-
ing 7-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (10) (1.00 mmol) in
anhydrous DMF (4.5 mL/mmol), sodium acetate (3.00 mmol) was
added. The reaction was microwave-irradiated at 120 °C for 1 h. The
mixture was dissolved in dichloromethane and washed with brine. The
organic layer was dried over Na2SO4, filtered, and evaporated to
dryness. The residue was purified as indicated in each case.
3-(2′-Methoxyphenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7(6H)-one (11a). Following the general procedure, to a
solution of 10a (170 mg, 0.62 mmol) in anhydrous DMF (2.8 mL),
sodium acetate (154 mg, 1.85 mmol) was added. After work-up, the
residue was purified by precipitation with dichloromethane/hexane to
yield 79 mg (50%) of 11a as a beige solid. mp: 235−237 °C. MS (ES,
positive mode): m/z 258 (M + H)+. 1H NMR (DMSO-d6, 400 MHz):
δ 2.34 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 7.16 (m, 1H, H-5′), 7.33 (d,
J = 8.5, 1H, H-3′), 7.48 (dd, J = 7.8, 1.3 Hz, 1H, H-4′), 7.63 (m, 1H,
H-6′), 12.63 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz): δ 21.8
(CH3), 56.5 (OCH3), 113.5, 121.1, 123.3, 127.9 (Ar), 129.2 (C-7a),
132.7 (Ar), 150.8 (C-3a), 154.9 (Ar), 156.3 (C-5), 160.7 (C-7). Anal.
(C12H11N5O2): C, H, N.
The synthesis of compounds 15a, c−g was performed following a
similar procedure, and all details and analytical and spectroscopic data
are included in the Supporting Information.
3-(3′-Isopropoxyphenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7-
(6H,4H)-dione (16). To a solution of 13 (120 mg, 0.50 mmol) in DMF
(2.5 mL), 1,1′-carbonyldiimidazole (89 mg, 0.55 mmol) was added.
The mixture was stirred at 90 °C overnight. Then, it was concentrated
to dryness, and the residue was suspended in acetone. The precipitate
thus formed was filtered to yield 81 mg (56%) of 16 as a white solid.
The synthesis of compounds 11b−m was performed following a
similar procedure, and all details and analytical and spectroscopic data
are included in the Supporting Information.
1
mp: 286−288 °C. MS (ES, positive mode): m/z 288 (M + H)+. H
5-Amino-1-(3-isopropoxyphenyl)-1H-1,2,3-triazole-4-carboxa-
mide (13). Procedure A. To a solution of Na (71 mg, 3.08 mmol) in
ethanol (3 mL), cyanoacetamide (130 mg, 1.54 mmol) was slowly
added for 30 min. This was followed by the addition of the azide 1228
(273 mg, 1.54 mmol) and reflux for 2 h. The mixture was concentrated
to dryness. The crude obtained was dissolved in water (10 mL),
acidified by addition of acetic acid, and extracted with ethyl acetate (2
× 10 mL). The combined organic phases were washed with a solution
of NaHCO3 and brine, dried on Na2SO4, filtered, and evaporated. The
residue was purified by flash chromatography (hexane/ethyl acetate,
1:1). The fastest moving fractions afforded 274 mg (68%) of 14 as a
yellow solid while the slowest fractions afforded 60 mg (15%) of 13.
Data for ((3′-isopropoxyphenyl)amino)-1H-1,2,3-triazole-4-carboxa-
mide (14): mp: 212−213 °C. MS (ES, positive mode): m/z 262 (M +
NMR (400 MHz, DMSO-d6): δ 1.25 (d, J = 6.0 Hz, 6H, CH(CH3)2),
4.63 (hept, J = 6.1 Hz, 1H, CH), 6.97 (m, 1H, H-4′), 7.31 (s, 1H, H-
2′), 7.40 (m, 2H, H-5′, H-6′), 8.34 (s, 1H, N4H),10.63 (s, 1H, N6H).
13C NMR (100 MHz, DMSO-d6): δ 22.2 (CH3), 70.1 (CH), 110.0,
115.3, 116.2 (Ar), 121.0 (C-7a), 130.8 (Ar), 135.2 (C-3a), 136.5 (Ar),
154.3 (C-5), 157.5 (C-7), 158.3 (Ar). Anal. (C13H13N5O3): C, H, N.
1-(Azidomethyl)-3-isopropoxybenzene (18). To a solution of 17
(185 mg, 1.11 mmol) in anhydrous DMF (1.4 mL), DMAP (163 mg,
1.34 mmol) and CH3SO2Cl (104 μL, 1.34 mmol) were added. The
reaction mixture was stirred at room temperature for 5 h. Then, NaN3
was added and stirring was continued at room temperature for 4 h. It
was diluted with water (20 mL) and extracted with diethyl ether (4 ×
10 mL). The organic layer was dried over Na2SO4, filtered, and
evaporated to dryness to yield 226 mg (89%) of 18 as an oil. 1H NMR
(300 MHz, DMSO-d6): δ 1.25 (d, J = 6.1 Hz, 6H, CH(CH3)2), 4.38
(s, 2H, CH2), 4.61 (hept, J = 6.0 Hz, 1H, CH), 6.89 (m, 3H, H-2′, H-
4′, H-6′), 7.28 (pt, J = 7.7 Hz, 1H, H-5′).
1
H)+. H NMR (400 MHz, DMSO-d6): δ 1.25 (d, J = 6.0 Hz, 6H,
CH(CH3)2), 4.56 (sept, J = 6.0 Hz, 1H, CH), 6.42 (d, J = 7.7 Hz, 1H,
H-4′), 6.96 (d, J = 7.7 Hz, 1H, H-6′), 7.13 (t, J = 8.1 Hz, 1H, H-5′),
7.21 (s 1H, H-2′), 7.53 (s, 1H, NH-amide), 7.86 (s, 1H, NH-amide),
8.53 (s, 1H, NH-amine), 14.67 (s, 1H, NH-triazol). Anal. Calcd. for
(C12H15N5O2): C, H, N. Data for 13: mp: 123−125 °C. MS (ES,
positive mode): m/z 262 (M + H)+. 1H NMR (400 MHz, DMSO-d6):
δ 1.29 (d, J = 6.0 Hz, 6H, CH(CH3)2), 4.70 (hept, J = 5.7 Hz, 1H,
CH), 6.37 (s, 2H, NH2), 7.08 (m, 3H, H-2′, H-4′, H-6′), 7.26 (s, 1H,
5-Amino-1-(3′-isopropoxybenzyl)-1H-1,2,3-triazole-4-carboxa-
mide (19). To a suspension of NaH (60% in mineral oil, 37 mg, 1.55
mmol) in anhydrous DMF (1.4 mL) at 0 °C, a solution of
cyanoacetamide (79 mg, 0.94 mmol) in anhydrous DMF (1.4 mL)
was added. After 1 h, a solution of 18 (196 mg, 0.86 mmol) in
anhydrous DMF (1.4 mL) was slowly added and stirring was
continued at room temperature for 1 h. Volatiles were removed. The
residue obtained was purified by flash column chromatography
(dichloromethane/methanol, 20:1) to yield 183 mg (77%) of 19 as
a white solid. mp: 171−173 °C. MS (ES, positive mode): m/z 276 (M
CONH2), 7.47 (pt, J = 7.9 Hz, 1H, H-5′), 7.62 (s, 1H, CONH2). 13
C
NMR (100 MHz, DMSO-d6): δ 22.4 (CH3), 70.4 (CH), 111.6, 116.5,
116.9 (Ar), 122.3 (C-4), 131.3, 136.6 (Ar), 145.3 (C-5), 158.9 (Ar),
165.0 (CO). Anal. (C12H15N5O2): C, H, N.
Procedure B. To a suspension of NaH (60% in mineral oil, 152 mg,
6.24 mmol) in anhydrous DMF (5.9 mL), a solution of
1
+ H)+. H NMR (300 MHz, DMSO-d6): δ 1.23 (d, J = 6.0 Hz, 6H,
G
dx.doi.org/10.1021/jm401844c | J. Med. Chem. XXXX, XXX, XXX−XXX