4000 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Palanki et al.
triethyl orthoformate (74 g, 0.50 mol), and Ac2O (77 g, 0.75
mol) was heated under N2 at 120 °C for 2 h and 140 °C for 5
h. The solution was concentrated to an oil and distilled to
obtain the title compound (58.6 g, 98%; bulb-to-bulb distilla-
tion, 80-90 °C, 1.5 mm/Hg): 1H NMR (CDCl3) δ 7.80 (d, 1H),
4.3 (m, 4H), 1.3 (m, 6H); IR (neat) 2992, 1741, 1623, 1590,
1202, 1019 cm-1; EIMS m/z 240 (M+).
1711, 1583, 1470, 1375, 1277, 1215, 1107, 1022 cm-1; EIMS
m/z 182 (M+).
E t h yl
4-et h yl-2-h yd r oxyp yr im id in e-5-ca r b oxyla t e
1
(24): yield 81%; mp 215-217 °C; H NMR (DMSO-d6) δ 8.47
(s, 1H), 8.30 (s, 1H), 4.09 (q, J ) 7.2 Hz, 2H), 2.69 (q, J ) 7.2
Hz, 2H), 1.22 (t, J ) 7.2 Hz, 3H), 1.04 (t, J ) 7.2 Hz, 3H); IR
2981, 1716, 1579, 1497, 1367, 1275, 1205, 800 cm-1; EIMS m/z
196 (M+).
Eth yl Ur eid om eth ylen ep en ta flu or op r op ion yla ceta te
(13). A solution of ethyl pentafluoropropionylacetate (5 g, 21
mmol), urea (1.3 g, 21 mmol), and triethyl orthoformate (3.2
g, 21 mmol) was heated at reflux for 3 h. The reaction mixture
was cooled, and the solid was collected by filteration. The solid
was washed with water, ether, and dried to give the title
E t h yl 2-h yd r oxy-4-p r op ylp yr im id in e-5-ca r b oxyla t e
1
(25): yield 72%; mp 185-186 °C; H NMR (DMSO-d6) δ 8.75
(bs, 1H), 8.04 (s, 1H), 4.21 (q, J ) 6.8 Hz, 2H), 2.85 (t, J ) 8.0
Hz, 2H), 1.59 (m, 2H), 1.26 (t, J ) 6.8 Hz, 3H), 0.90 (t, J ) 8.0
Hz, 3H); IR (neat) 2962, 1747, 1687, 1475, 1275 cm-1; EIMS
m/z 209 (M - H+).
1
compound (4.4 g, 68%) as a white solid: mp 160-162 °C; H
NMR (DMSO-d6) δ 9.90 (s, 1H), 8.4 (s, 1H), 7.5 (d, 2H), 4.1 (q,
J ) 7.2 & 6.9, 2H), 1.19 (t, J ) 7.2 Hz, 3H); IR (KBr) 3088,
2910, 1749, 1670, 1402, 1173, 1099 cm-1; EIMS m/z 258 ((M
- EtOH)+).
E t h yl 2-h yd r oxy-4-p h en ylp yr im id in e-5-ca r b oxyla t e
(26): yield 65%; mp >260 °C dec; 1H NMR (DMSO-d6) δ 1.00
(t, 3H, J ) 7.2 Hz), 4.02 (q, 2H, J ) 6.9 Hz), 7.46 (m, 5H),
8.05 (s, 1H), 10.30 (s, 1H); IR (KBr) 2981, 1713, 1587, 1547,
1261, 1105 cm-1; EIMS m/z 243 (M - H+).
Eth yl Ur eid om eth ylen ea cetoa ceta te (14). A mixture of
ethyl acetoacetate (200 g, 1.54 mmol), urea (105 g, 1.54 mmol),
and triethyl orthoformate (228 g, 1.54 mmol) was heated at
140 °C under N2 for 22 h. The reaction mixture was cooled,
and filtered. The solid was washed with Et2O (3 × 100 mL),
water (3 × 150 mL), and dried under vacuum to provide 156
g (51%) of the title compound: mp 173-174 °C; 1H NMR
(DMSO-d6) δ 11.42 (d, J ) 12.9 Hz, 1H), 8.46 (d, J ) 12.6 Hz,
1H), 7.72 (s, 1H), 7.26 (s, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 2.42
(s, 3H), 1.27 (t, 3H); IR (KBr) 3418, 2995, 1709, 1655, 1558,
1466, 1391, 1234, 1062 cm-1; EIMS m/z 200 (M+).
Eth yl 4-Hyd r oxy-2-tr iflu or om eth ylp yr im id in e-5-ca r -
boxyla te (27). A solution of diethyl ethoxymethylenemalonate
(35.0 g, 162 mmol), trifluoroacetamidine (18 g, 162 mmol) and
NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at
reflux under N2 for 6 h. The reaction mixture was concentrated
under reduced pressure and treated with H2O (48 mL). The
solid was filtered and washed with Et2O (300 mL) and H2O
(200 mL), and dried under vacuum to give the title compound
1
(21 g, 50%): mp > 220 °C (turned brown); H NMR (DMSO-
d6) δ 8.38 (s, 1H), 4.16 (q, J ) 7.2 & 6.9 Hz, 2H), 1.25 (q, J )
7.2 Hz, 3H); IR (KBr) 3230, 2932, 1689, 1657, 1471, 1376, 1280,
1206,1062 cm-1; EIMS m/z 236 (M+).
Eth yl u r eid om eth ylen ep r op ion oyla ceta te (15): yield
1
37%; mp 148-150 °C; H NMR (CDCl3) δ 10.2 (dd, J ) 12.6
Hz, 1H), 8.39 (d, J ) 12.6 Hz, 1H), 7.67 (bs, 1H), 7.29 (s, 1H),
4.17 (m, 2H), 2.80 (q, J ) 7.2 Hz, 2H), 1.25 (t, J ) 7.2 Hz,
3H), 0.96 (t, J ) 6.0 Hz, 3H); IR (KBr) 3386, 2995, 1713, 1643,
1552, 1230 cm-1; EIMS m/z 214 (M+).
Eth yl u r eidom eth ylen ebu ton oylacetate (16): yield 42%;
mp 153-154 °C; 1H NMR (CDCl3) δ 10.45 (d, J ) 12 Hz, 1H),
8.56 (dd, J ) 12 Hz, 1H), 4.27 (m, 2H), 2.96 (t, J ) 7.2 Hz,
2H), 2.78 (t, J ) 7.2 Hz, 2H0, 2.55 (s, 2H), 1.35 (m, 3H), 0.94
(q, J ) 7.2 Hz, 3H); IR (neat) 3396, 3209, 2950, 1703, 1643,
1552, 1221, 1147, 766 cm-1; EIMS m/z 228 (M+).
Eth yl 4-m eth yl-2-tr iflu or om eth ylp yr im id in e-5-ca r box-
yla te (28): yield 55%; H NMR (CDCl3) δ 9.26 (s, 1H), 4.51
1
(q, J ) 6.9 Hz, 2H), 2.82 (s, 3H), 1.46 (t, J ) 7.2 Hz, 3H); IR
(KBr) 2863, 1748, 1652, 1593, 1487, 1238 cm-1; EIMS m/z 234
(M+).
Eth yl 2-m eth yl-4-tr iflu or om eth ylp yr im id in e-5-ca r box-
yla te (29): yield 58%; 1H NMR (CDCl3) δ 9.13 (s, 1H), 4.46 (q,
J ) 7.2 Hz, 2H), 2.90 (s, 3H), 1.38 (t, J ) 7.1 Hz, 3H); IR (KBr)
2932, 1758, 1668, 1620, 1418, 1381, 1275, 1179 cm-1; EIMS
m/z 234 (M+).
Eth yl u r eid om eth ylen eben zoyla ceta te (17): yield 55%;
mp 124-126 °C; 1H NMR (CDCl3) δ 11.43 (d, J ) 12.9 Hz,
1H), 8.44 (d, J ) 12.7 Hz, 1H) 7.72 (s, 1H), 7.3 (m, 6H), 4.17
(q, J ) 7.2 Hz, 2H), 1.27 (t, J ) 7.1 Hz, 3H); IR (KBr) 3411,
2994, 1711, 1644, 1551, 1472 cm-1; EIMS m/z 246 (M+).
Eth yl Ur eid om eth ylen eth ien oyla ceta te (18) a n d Di-
eth yl Tr iflu or oa ceta m id om eth ylen em a lon a te (19). These
compound were ring-closed to 20 and 27, respectively, under
the reaction conditions.
Eth yl 2-h yd r oxy-4-(2′-th ien yl)p yr im id in e-5-ca r boxy-
la te (20): yield 51%; mp >220 °C; 1H NMR (CDCl3) δ 8.55 (s,
1H), 7.82 (dd, J ) 1.2, 3.9 Hz, 1H), 7.59 (dd, 1H, 0.9, 5.1 Hz,
1H), 7.11 (m, 1H), 5.25 (bs, 1H), 4.31 (q, J ) 7.2 Hz, 2H), 1.33
(t, J ) 6.9 Hz, 3H), IR (neat) 2995, 1714, 1647, 1605, 1409,
1290 cm-1; ESMS m/z 251 (M + H+).
Eth yl 2-h yd r oxy-4-tr iflu or om eth ylp yr im id in e-5-ca r -
boxyla te (21): yield 45%; 1H NMR (DMSO-d6) δ 9.89 (s, 1H),
8.41 (bs, 1H), 4.0 (q, J ) 7.2 Hz, 2H), 1.2 (t, J ) 7.1 Hz, 3H);
EIMS m/z 236 (M+).
Eth yl 2,4-Bis(tr iflu or om eth yl)p yr im id in e-5-ca r boxy-
la te (30). A solution of ethyl ethoxymethylene-4,4,4-trifluo-
roacetoacetate (15 g, 62.5 mmol), and trifluoroacetamidine
(12.6 g, 112.5 mmol) in EtOH (50 mL) was heated at reflux
for 24 h under N2. The reaction mixture was cooled to room
temperature and concentrated to an oil under reduced pres-
sure. Flash chromatography (SiO2, 20% ethyl acetate in
hexane) afforded the title compound as an oil (7.0 g, 39%): 1H
NMR (CDCl3) δ 9.37 (s, 1H), 3.70 (q, J ) 7.2 & 6.9 Hz, 2H),
1.27 (t, J ) 7.2 Hz, 3H); IR (neat) 2978, 2864, 1732, 1216, 1159
cm-1; EIMS m/z 287 (M+).
2-Hyd r oxy-4-(2′-th ien yl)p yr im id in e-5-ca r boxylic a cid
1
(31): yield 89%; mp > 200 °C; H NMR (DMSO-d6) 8.37 (s,
1H), 7.81 (m. 2H), 7.15 (m, 1H); IR (KBr) 2994, 1630, 1605,
1420, 1400, 1215 cm-1; ESMS m/z 221 (M - H+). Anal.
(C9H6N2O3S) C, H, N.
2-Ch lor o-4-tr iflu or om eth ylpyr im idin e-5-car boxylic acid
(32): mp 158 °C; 1H NMR (DMSO-d6) δ 12.4 (bs, 1H), 9.36 (s,
1H); ESMS m/z 225 (M - H+).
Eth yl 2-h yd r oxy-4-p en ta flu or oeth ylp yr im id in e-5-ca r -
boxyla te (22): yield 66%; mp 171 °C; 1H NMR (DMSO-d6) δ
8.56 (s, 1H), 4.15 (q, 2H), 1.23 (t, 3H); IR 2968, 1730, 1653,
1420, 1179, 1221 cm-1; EIMS m/z 258 (M+).
E t h yl 2-H yd r oxy-4-m et h ylp yr im id in e-5-ca r b oxyla t e
(23). A solution of ethyl ureidomethylene acetoacetate (50 g,
250 mmol), NaOEt (22.1 g, 325 mmol) in EtOH (500 mL) was
stirred at room temperature under N2 for 3 days. The white
precipitate was collected by filtration and washed with EtOH
and dried under reduced pressure to yield 45 g (88%) of the
title compound as the sodium salt: mp >220 °C dec; 1H NMR
(DMSO-d6) δ 12.22 (bs, 1H), 8.75 (s, 1H), 4.25 (q, J ) 7.2 &
6.7 Hz, 2H), 1.31 (t, J ) 7.2 Hz, 3H); IR (KBr) 2646, 1755,
2-H yd r oxy-4-p en t a flu or oet h ylp yr im id in e-5-ca r b oxy-
lic a cid (33): yield 98%; mp >210 °C dec; H NMR (DMSO-
d6) δ 9.9 (bs, 1H), 8.43 (s, 1H); IR (KBr) 3232; 2964, 1732, 1657,
1427, 1223, 1176 cm-1; ESMS m/z 257 (M - H+). Anal.
(C7H3F5N2O3‚1.25H2O) C, H, N.
2-Ch lor o-4-m eth ylp yr im id in e-5-ca r boxylic Acid (34).
A solution of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate
(1.0 g, 5 mmol), NaOH (0.24 g, 6 mmol), and H2O (30 mL) was
stirred at room temperature for 3 h. The solution was acidified
to below pH ) 1 with 6 N HCl and cooled to 0 °C. The white
solid was filtered, and dried to give 0.67 g (78%) of the title
compound: 1H NMR (DMSO-d6) δ 9.01 (s, 1H), 2.75 (s, 3H);
13C NMR (DMSO-d6) δ 171.95, 165.33, 161.59, 161.47, 123.33,
1