712 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Hirokawa et al.
the solvent, saturated aqueous NaHCO3 was added to the
residue. The resultant solid was collected by filtration, washed
successively with water and hexane, and dried to give 4.38 g
dried over anhydrous MgSO4. The solvent was evaporated, and
the residue was chromatographed on silica gel with hexane/
AcOEt ) 10/1 to give 2.1 g (83%) of 21 as a solid, mp 50-52
1
1
(80%) of 13, mp 94-96 °C (EtOH/diisopropyl ether). H NMR
°C (AcOEt/hexane). H NMR δ: 3.05 (d, 3H, J ) 5.0), 3.81 (s,
δ: 1.34 (t, 3H, J ) 7.0), 1.41 (t, 3H, J ) 7.0), 2.95 (d, 3H, J )
5.0), 4.28 (q, 2H, J ) 7.0), 4.42 (q, 2H, J ) 7.0), 4.79 (br., 1H),
5.92 (d, 1H, J ) 8.5), 8.00 (d, 1H, J ) 8.5). MS m/z; 225 (MH+).
IR cm-1; 3350, 1690, 1601, 1259, 1155. Anal. (C11H16N2O3) C,
H, N.
3H), 3.94 (s, 3H), 5.92 (d, 1H, J ) 8.4), 7.97 (d, 1H, J ) 8.4),
8.00 (br., 1H). MS m/z; 197 (MH+). IR cm-1; 3377, 2947, 1686,
1593, 1251, 1232. Anal. (C9H12N2O3) C, H, N.
Meth yl 5-Ch lor o-6-m eth oxy-5-m eth yla m in op yr id in e-
3-ca r boxyla te (22). In a similar manner to that described
above, 22 was prepared from 21 and NCS in 85% yield, mp
120-122 °C (AcOEt/hexane). 1H NMR δ: 3.04 (d, 3H, J ) 5.0),
3.82 (s, 3H), 4.03 (s, 3H), 7.95 (br., 1H), 8.01 (s, 1H). MS m/z;
231 (MH+). IR cm-1; 3363, 1678, 1600, 1589, 1231. Anal.
(C9H11ClN2O3) C, H, N, Cl.
E t h yl 5-Ch lor o-2-et h oxy-6-m et h yla m in op yr id in e-3-
ca r boxyla te (14). In a similar manner to that described
above, 14 was prepared from 13 and NCS in 90% yield, mp
1
126-127 °C (EtOH). H NMR δ: 1.34 (t, 3H, J ) 7.0), 1.44 (t,
3H, J ) 7.0), 3.06 (d, 3H, J ) 5.0), 4.28 (q, 2H, J ) 7.0), 4.47
(q, 2H, J ) 7.0), 5.29 (br., 1H), 8.00 (s, 1H). MS m/z; 259 (MH+).
5-Ch lor o-6-m eth oxy-2-m eth yla m in op yr id in e-3-ca r box-
ylic Acid (23). In a similar manner to that described above,
alkaline hydrolysis of 22 gave 23 in 84% yield. Analysis sample
of 23 was obtained by recrystallization from EtOH. The solid
IR cm-1; 3389, 1709, 1593, 1570, 1227, 1080. Anal. (C11H15
ClN2O3) C, H, N, Cl.
-
E t h yl 5-Br om o-2-et h oxy-6-m et h yla m in op yr id in e-3-
ca r boxyla te (15). A solution of 13 (1.66 g, 7.41 mmol),
N-bromosuccinimide (NBS, 1.32 g, 7.41 mmol), and DMF (15
mL) was heated at 80 °C for 1 h. The reaction mixture was
poured into ice-water and the resulting precipitate was
collected by filtration, washed successively with water and
hexane, and dried to give 2.17 g (97%) of 15, mp 126-127 °C
(AcOEt/hexane). 1H NMR δ: 1.35 (t, 3H, J ) 7.0), 1.45 (t, 3H,
J ) 7.0), 3.06 (d, 3H, J ) 5.0), 4.28 (q, 2H, J ) 7.0), 4.48 (q,
2H, J ) 7.0), 5.32 (br., 1H), 8.15 (s, 1H). MS m/z; 303 (MH+).
IR cm-1; 3385, 1711, 1589, 1568, 1227. Anal. (C11H15BrN2O3)
C, H, N, Br.
1
was sublimated at 136 °C. H NMR δ: 3.06 (d, 3H, J ) 4.8),
4.05 (s, 3H), 7.86 (br., 1H), 8.05 (s, 1H). MS m/z; 217 (MH+).
IR cm-1; 3389, 1670, 1582, 1259, 1238. Anal. (C8H9ClN2O3) C,
H, N, Cl.
Meth yl 6-Eth yla m in o-2-flu or op yr id in e-3-ca r boxyla te
(25). Et3N (10.5 g, 104 mmol) was added to a solution of methyl
2,6-difluoropyridine-3-carboxylate (24, 9.0 g, 52 mmol) and
EtNH2‚HCl (4.24 g, 52 mmol) in DMF (50 mL) under ice-
cooling. The mixture was stirred at the same temperature for
1 h. The solvent was evaporated, and the residue was dissolved
in AcOEt. The solution was washed successively with water
and brine and dried over anhydrous MgSO4. The solvent was
evaporated, and the residue was chromatographed on silica
gel with CHCl3/hexane ) 1/1 to CHCl3 to give first 3.2 g (31%)
of methyl 2-ethylamino-6-fluoropyridine-3-carboxylate (26) and
then 6.3 g (61%) of 25 both as solids. 25; mp 116-117 °C
(AcOEt/hexane). 1H NMR δ: 1.27 (t, 3H, J ) 7.5), 3.3-3.47
(m, 2H), 3.87 (s, 3H), 5.12 (br., 1H), 6.22 (dd, 1H, J ) 2.0, 8.5),
8.07 (dd, 1H, J ) 8.5, 10.0). MS m/z; 199 (MH+). IR cm-1; 3267,
3132, 1701, 1626, 1437, 1298, 1151. Anal. (C9H11FN2O2) C, H,
N, F.
5-Ch lor o-2-et h oxy-6-m et h yla m in op yr id in e-3-ca r b ox-
ylic Acid (16). In a similar manner to that described above,
alkaline hydrolysis of 14 gave 16 in 81% yield, mp 161-162
1
°C (EtOH). H NMR (dimethyl sulfoxide-d6) δ: 1.32 (t, 3H, J
) 7.0), 2.90 (d, 3H, J ) 5.0), 4.38 (q, 2H, J ) 7.0), 7.23 (br. q,
1H, J ) 5.0), 7.85 (s, 1H), 12.00 (s, 1H). MS m/z; 231 (MH+).
IR cm-1; 3348, 3323, 1713, 1603, 1450, 1385, 1331. Anal.
(C9H11ClN2O3) C, H, N, Cl.
5-Br om o-2-et h oxy-6-m et h yla m in op yr id in e-3-ca r b ox-
ylic Acid (17). In a similar manner to that described above,
alkaline hydrolysis of 15 gave 17 in 96% yield, mp 169-170
26; mp 127-128 °C (hexane/AcOEt). 1H NMR δ: 1.26 (t,
3H, J ) 7.5), 3.42-3.6 (m, 2H), 3.86 (s, 3H), 6.05 (dd, 1H, J )
3.0, 8.0), 8.17 (dd, 1H, J ) 8.0, 8.0). MS m/z; 199 (MH+). IR
cm-1; 3350, 1701, 1612, 1583, 1516, 1437, 1294, 1259, 1130.
Anal. (C9H11FN2O2) C, H, N, F.
1
°C (EtOH). H NMR δ: 1.50 (t, 3H, J ) 7.5), 3.08 (d, 3H, J )
5.0), 4.62 (q, 2H, J ) 7.5), 5.56 (br., 1H), 8.30 (s, 1H), 10.33
(br. s, 1H). MS m/z; 275 (MH+). IR cm-1; 3348, 3321, 1707,
1599, 1450, 1381, 1329. Anal. (C9H11BrN2O3) C, H, N, Br.
Meth yl 6-Dim eth yla m in o-2-flu or op yr id in e-3-ca r boxy-
la te (27) a n d Meth yl 2-Dim eth yla m in o-6-flu or op yr id in e-
3-ca r boxyla te (28). A mixture of 24 (10.0 g, 58 mmol), Me2NH
(11.4 g, 127 mmol), and EtOH (50 mL) was stirred at -20 °C
for 4 h. The reaction mixture was then diluted with water,
extracted with AcOEt/hexane ) 1/1, and washed with brine.
The solvent was evaporated, and the residue was chromato-
graphed on silica gel with CHCl3/hexane ) 10/1 to give 7.9 g
(69%) of a mixture of 27 and 28 as a solid. 1H NMR δ: 3.02 (s,
1.2H, Me2M of 28), 3.15 (s, 6H, Me2M of 27), 3.87 (s, 3H, CO2-
Me of 27), 3.99 (s, 0.6H, CO2Me of 28), 6.18 (dd, 0.2H, J ) 3.5,
8.5, pyridine-5H of 28), 6.31 (dd, 1H, J ) 2.5, 8.8, pyridine-
5H of 27), 8.02 (dd, 0.2H, J ) 8.5, 8.5, pyridine-4H of 28), 8.08
(dd, 1H, J ) 8.8, 10.0, pyridine-4H of 27). MS m/z; 199 (MH+).
The mixture (1.35 g) was recrystallized from AcOEt/hexane
to afford 0.3 g of 27, mp 69-70 °C. IR cm-1; 1728, 1622, 1537,
1290. Anal. (C9H11FN2O2) C, H, N, F.
Meth yl 2-Ch lor o-6-m eth oxypyr idin e-3-car boxylate (20).
A mixture of 2,6-dichloropyridine-3-carboxylic acid (18, 90%,
6.5 g, 30 mmol), potassium tert-butoxide (11.4 g, 0.10 mol),
and MeOH (300 mL) was heated to reflux for 4 days and cooled
to room temperature. After evaporation of the solvent, the
residue was diluted with water and acidified with 35% aqueous
HCl. The resulting solid was collected by filtration, washed
with water, and dried to give 4.8 g (84%) of 2-chloro-6-
methoxypyridine-3-carboxylic acid (19). A mixture of 19 (4.8
g, 25.6 mmol) and SOCl2 (20 mL, 0.27 mol) was heated to reflux
for 5 h and cooled to room temperature. Excess SOCl2 was
evaporated, and the residue was dissolved in toluene. After
the volatiles were evaporated, the residue was redissolved in
toluene. Again, the solution was concentrated to dryness, and
the residue was dissolved in MeOH. The solution was heated
to reflux for 1 h and cooled to room temperature. The solvent
was evaporated, and the residue was diluted with water and
extracted with CHCl3. The solvent was evaporated and the
residual solid was recrystallized from EtOH to afford 4.0 g
(78%) of 20, mp 71-72 °C. 1H NMR δ: 3.92 (s, 3H), 4.00 (s,
3H), 6.70 (d, 1H, J ) 8.8), 8.12 (d, 1H, J ) 8.8). 13C NMR δ:
52.40, 54.59, 109.22, 118.42, 142.96, 149.28, 164.75, 164.86.
MS m/z; 202 (MH+). IR cm-1; 1736, 1597, 1491, 1321, 1246.
Anal. (C8H8ClNO3) C, H, N, Cl.
Meth yl 6-Eth yla m in o-2-m eth oxyp yr id in e-3-ca r boxy-
la te (29). In a similar manner to that described above, 29 was
prepared from 25 in 82% yield, mp 113-115 °C (AcOEt/
1
hexane). H NMR (dimethyl sulfoxide-d6) δ: 1.15 (t, 3H, J )
7.0), 3.23-3.42 (m, 2H), 3.67 (s, 3H), 3.84 (s, 3H), 6.04 (d, 1H,
J ) 9.0), 7.39 (br., 1H), 7.79 (d, 1H, J ) 9.0). MS m/z; 211
(MH+). IR cm-1; 3366, 1693, 1596, 1578, 1258. Anal. (C10H14
N2O3) C, H, N.
-
Meth yl 6-Meth oxy-2-m eth yla m in op yr id in e-3-ca r boxy-
la te (21). A solution of 20 (2.6 g, 12.9 mmol) and 30% MeNH2
in EtOH (5.5 g, 53.2 mmol) in EtOH (20 mL) was heated to
reflux for 12 h and cooled to room temperature. After evapora-
tion of the volatiles, the residue was dissolved in CHCl3. The
solution was washed successively with water and brine and
Met h yl 6-Dim et h yla m in o-2-m et h oxyp yr id in e-3-ca r -
boxyla te (30). A mixture of nonseparated 27 and 28 (6.55 g,
35 mmol), potassium tert-butoxide (9.26 g, 83 mmol), and
MeOH (150 mL) was heated to reflux for 2 h and cooled to
room temperature. After evaporation of the solvent, saturated