672
T. P. Tran, E. L. Ellsworth, B. M. Watson, J. P. Sanchez, H. D. H. Showalter,
J. R. Rubin, M. A. Stier, J. Yip, D. Q. Nguyen, P. Bird, and R. Singh
Vol. 42
2,4,5-Trifluoro-3-methoxy-benzamide (6c).
This compound was obtained in 100% yield; H NMR
hydroxylamine [15], to afford the target 3-amino-1H-
quinazoline-2,4-dione 11 in straightforward fashion. The
synthesis of compounds 11b and 11d has been disclosed
using alternative aminating reagents [16].
In conclusion, we have developed a highly efficient syn-
thesis for the 3-amino-1H-quinazoline-2,4-dione ring.
From any starting 2-fluorobenzoic acid, a corresponding 3-
aminoquinazolinedione can be synthesized in four steps.
The approach described allows much flexibility for substi-
tutions, especially at the 1- and 8-positions of the 3-amino-
quinazolinedione core.
1
(CDCl ): δ 4.06 (apparent t, J = 0.9 Hz, 3H), 5.92 (br s, 1H), 6.54
3
19
(br s, 1H), 7.58-7.65 (m, 1H); F NMR: δ -133 (m, 1F), -138 (m,
1F), -144 (m, 1F); MS (APCI+): m/z 206 (M+H) .
+
General Procedure for the Preparation of the 1-Substituted-3-
(2,4,5-trifluoro-benzoyl)-urea 7.
To a solution of trifluoro-benzamide 6a-c in 1,2-dichloro-
ethane at room temperature was added oxalyl chloride (1.5 eq).
The reaction mixture was heated at reflux for 4 h, and then con-
centrated. The resulting benzoyl isocyanate was dissolved in p-
dioxane, the resultant solution cooled to 0 °C and then treated
with a primary amine (1.2 eq). The reaction mixture was allowed
to gradually warm to room temperature over a 4 h period. The
mixture was concentrated to a residue, was dissolved in
dichloromethane, and the solution was washed successively with
saturated aqueous sodium bicarbonate, water, and brine, and then
dried. Concentration of the organic phase provided a residue that
was triturated in diethyl ether - hexanes to afford urea 7a-e as a
solid. The filtrate was processed as above to afford a second
crop.
EXPERIMENTAL
1
19
All H and F NMR were recorded at 400 MHz using a Varian
Inova spectrometer equipped with an ATB probe and two RF
channels. Positive and negative ion atmospheric pressure chemi-
cal ionization (APCI) mass spectra were obtained on a
Micromass Platform LC mass spectrometer operating in Open
Access mode. Samples were introduced by loop injection using a
Gilson 215 autosampler into a mobile phase of 80:20 acetoni-
trile:water flowing at 200 µL/min delivered by a Hewlett-
Packard HP1100 HPLC. The mass spectrometer source and
probe temperatures were 150 °C and 450 °C, respectively. The
cone voltage was 15 V while the corona pin was held at 3.5 kV in
positive ion and 3.0 kV in negative ion mode. Elemental analy-
ses were performed by Quantitative Technologies, Inc. Unless
stated otherwise, concentration of solvents utilized in reactions
and workups was conducted under reduced pressure. Anhydrous
magnesium sulfate was used to dry the organic phase during
workup.
1-Cyclopropyl-3-(2,4,5-trifluoro-benzoyl)-urea (7a).
1
This compound was obtained in 87% yield; H NMR (CDCl ):
3
δ 0.55-0.65 (m, 2H), 0.76-0.82 (m, 2H), 2.71-2.78 (m, 1H), 7.00-
7.07 (m, 1H), 7.82-7.89 (m, 1H), 8.40 (br s, 1H), 8.44 (br s, 1H);
19
F NMR: δ -112 (m, 1F), -123 (m, 1F), -139 (m, 1F); MS
+
(APCI+): m/z 259 (M+H) .
1-Cyclopropyl-3-(2,4,5-trifluoro-3-methyl-benzoyl)-urea (7b).
1
This compound was obtained in 93% yield; H NMR (CDCl ):
3
δ 0.61-0.65 (m, 2H), 0.80-0.85 (m, 2H), 2.29 (apparent t, J = 2.2,
3H), 2.75-2.81 (m, 1H), 7.66-7.73 (m, 1H), 8.49 (br s, 1H), 8.53
General Procedure for the Preparation of Substituted Trifluoro-
benzamide 6.
19
(br s, 1H); F NMR: δ -116 (m, 1F), -127 (m, 1F), -140 (m, 1F);
+
MS (APCI+): m/z 273 (M+H) .
To a stirred solution of commercially available trifluoroben-
zoic acid 5a-c in dichloromethane at room temperature was
added oxalyl chloride (1.2 eq) followed by N,N-dimethylfor-
mamide (0.1 eq). After 90 min, the reaction mixture was concen-
trated. The resulting acid chloride was taken up in
dichloromethane, cooled to 0 °C, then ammonia gas was added
via a dispersion tube until the solution was saturated. The solu-
tion was stirred for 2 h, and then concentrated to a residue that
was triturated in diethyl ether to afford amide 6a-c as a solid.
1-Phenyl-3-(2,4,5-trifluoro-3-methyl-benzoyl)-urea (7c).
1
This compound was obtained in 96% yield; H NMR (d -
6
DMSO): δ 2.19 (s, 3H), 7.08 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6
Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.65 (apparent q, J = 6.6 Hz,
19
1H), 10.28 (br s, 1H), 11.04 (br s, 1H); F NMR: δ -118 (m, 1F),
+
-132 (m, 1F), -142 (m, 1F); MS (APCI+): m/z 309 (M+H) .
Anal. Calcd. for C H F N O : C, 58.45; H, 3.60; N, 9.09, F,
15 11
3 2 2
18.49. Found: C, 58.30; H, 3.31; N, 8.97; F, 18.40.
1-Cyclopropyl-3-(2,4,5-trifluoro-3-methoxy-benzoyl)-urea (7d).
2,4,5-Trifluoro-benzamide (6a).
1
1
This compound was obtained in 90% yield; H NMR (CDCl ):
This compound was obtained in 75% yield; H NMR (CDCl ):
3
3
δ 0.57-0.62 (m, 2H), 0.76-0.81 (m, 2H), 2.71-2.77 (m, 1H), 4.03
(s, 3H), 7.46-7.53 (m, 1H), 8.35 (br s, 1H), 8.38 (br s, 1H);
NMR: δ -132 (m, 1F), -137 (m, 1F), -141 (m, 1F); MS (APCI+):
δ 5.88 (br s, 1H), 6.58 (br s, 1H), 6.95-7.02 (m, 1H), 7.91-7.98
(m, 1H); F NMR: δ -114 (m, 1F), -126 (m, 1F), -140 (m, 1F);
19
19
F
+
MS (APCI+): m/z 176 (M+H) .
+
m/z 289 (M+H) .
Anal. Calcd. for C H F N O : C, 48.01; H, 2.30; N, 8.00, F,
32.55. Found: C, 48.05; H, 2.09; N, 7.71; F, 32.60.
7
4 3 1 1
Anal. Calcd. for C H F N O : C, 50.01; H, 3.85; N, 9.72, F,
19.77. Found: C, 49.94; H, 3.65; N, 9.91; F, 19.45.
12 11
3 2 3
2,4,5-Trifluoro-3-methyl-benzamide (6b).
1-Isopropyl-3-(2,4,5-trifluoro-3-methoxy-benzoyl)-urea (7e).
1
This compound was obtained in 100% yield; H NMR
1
(CDCl ): δ 2.28 (apparent t, J = 2.2 Hz, 3H), 5.99 (br s, 1H), 6.65
(br s, 1H), 7.77-7.84 (m, 1H); F NMR: δ -118 (m, 1F), -130 (m,
This compound was obtained in 75% yield; H NMR (CDCl ):
3
3
19
δ 1.21 (d, J = 6.6 Hz, 6H), 3.98-4.03 (m, 1H), 4.03 (apparent t, J
= 1.1 Hz, 3H), 7.47-7.54 (m, 1H), 8.20 (br d, J = 5.4 Hz, 1H),
+
1F), -141 (m, 1F); MS (APCI+): m/z 190 (M+H) .
19
Anal. Calcd. for C H F N O : C, 50.80; H, 3.20; N, 7.41, F,
8.39 (br d, J = 11.8, 1H); F NMR δ -132 (m, 1F), -137 (m, 1F),
8
6 3 1 1
+
30.13. Found: C, 50.76; H, 2.94; N, 7.31; F, 30.14.
-142 (m, 1F); MS (APCI+): m/z 291 (M+H) .