T. Kumagai et al. / Bioorg. Med. Chem. 9 (2001) 1349±1355
1353
2652, 1646, 1608, 1586, 1552, 1496, 1446, 1356,
1258 cmÀ1. Anal. (C27H31BrN4 HCl 0.7H2O) C, H, N,
Br, Cl.
4-(5-(3-Chlorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-methylthio-4-isopropylanilino)-6-methylpyrimidine
hydrochloride 2g. H NMR (CDCl3) d 1.10±1.44 (9H, m),
.
.
1
1.92±2.58 (5H, m), 2.62±3.08 (4H, m), 3.26±3.76 (2H, m),
3.85±4.39 (3H, m), 4.43±4.82(1H, m), 5.82±6.03 (1H, m),
6.08±6.35 (1H, m), 6.76±7.41 (7H, m), 13.65 (1H, br s); MS
(ESI Pos) m/z 517 (M++2+Na, 43%), 515 (M++Na,
Using a corresponding procedure, the following com-
pounds 2b±2i were prepared.
4-(5-(3-Fluorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-bromo-4-isopropylanilino)-6-methylpyrimidine
100%); IR (KBr) 2963, 1653, 1609, 1547, 1484, 1258 cmÀ1
.
. .
Anal. (C28H33ClN4S HCl 0.5H2O) C, H, N, Cl, S.
1
hydrochloride 2b. H NMR (CDCl3) d 1.10±1.45 (9H,
m), 1.97±2.56 (2H, m), 2.64±3.04 (4H, m), 3.21±3.78
(2H, m), 3.90±4.38 (3H, m), 4.50±4.88 (1H, m), 5.89±
6.06 (1H, m), 6.10±6.32(1H, m), 6.67±7.46 (6H, m), 7.56
(1H, br s), 13.79 (1H, br s); MS (ESI Pos) m/z 533
(M++2+Na, 100%), 531 (M++Na, 95%); IR (KBr)
4-(5-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-bromo-4-isopropylanilino)-6-methylpyrimidine 2h.
1H NMR (CDCl3) d 1.21 (3H, t, J=7.1 Hz), 1.26 (6H,
d, J=6.9 Hz), 2.12±2.37 (5H, m), 2.91 (1H, sept, J=6.9
Hz), 3.40±4.29 (6H, m), 5.85 (1H, s), 6.08±6.20 (1H, m),
7.10±7.35 (6H, m), 7.48 (1H, d, J=0.9 Hz); IR (Neat)
2962, 2361, 1574, 1557, 1538, 1505, 1455, 1247,
1208 cmÀ1; FAB-HRMS m/z calcd for C27H30-BrClN4:
527.1401 (M++2+H) and 525.1421 (M++H), found:
527.1396 (M++2+H) and 525.1418 (M++H).
2964, 1655, 1613, 1591, 1549, 1492, 1443, 1257 cmÀ1
.
.
Anal. (C27H30BrFN4 HCl) C, H, N, Br, Cl, F.
4-(5-(3-Fluorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-methylthio-4-isopropylanilino)-6-methylpyrimidine
1
hydrochloride 2c. H NMR (CDCl3) d 1.10±1.42(9H,
m), 2.00±2.55 (5H, m), 2.80 (3H, br s), 2.96 (1H, sept,
J=6.9 Hz), 3.29±3.76 (2H, m), 3.83±4.38 (3H, m), 4.43±
4.80 (1H, m), 5.83±6.04 (1H, m), 6.09±6.32(1H, m),
6.64±7.42(7H, m), 13.63 (1H, br s); MS (ESI Pos) m/z
499 (M++Na, 100%); IR (KBr) 2963, 1655, 1610,
4-(5-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-methylthio-4-isopropylanilino)-6-methylpyrimidine
hydrochloride 2i. H NMR (CDCl3) d 1.14±1.42(9H,
m), 1.97±2.56 (5H, m), 2.80 (3H, br s), 2.96 (1H, sept,
J=6.9 Hz), 3.22±3.77 (2H, m), 3.84±4.38 (3H, m), 4.49±
4.86 (1H, m), 5.85±6.30 (2H, m), 6.83±7.47 (7H, m),
13.63 (1H, br s); MS (SIMS Pos) m/z 495 (M++2+H,
41%), 493 (M++H, 100%); IR (KBr) 2866, 2673, 1642,
1608, 1584, 1553, 1489, 1355, 1261 cmÀ1
. Anal.
.
(C28H33ClN4S HCl) C, H, N, Cl, S.
1
1548, 1486, 1443, 1257 cmÀ1. Anal. (C28H33FN4S HCl
.
.
0.5H2O) C, H, N, Cl, F, S.
4-(5-(4-Fluorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-bromo-4-isopropylanilino)-6-methylpyrimidine
1
hydrochloride 2d. H NMR (CDCl3) d 1.16±1.42(9H,
m), 1.95±2.56 (2H, m), 2.80 (3H, br s), 2.74±3.06 (1H,
m), 3.50±3.75 (2H, m), 3.94±4.38 (3H, m), 4.47±4.76
(1H, m), 5.98±6.21 (2H, m), 6.90±7.40 (6H, m), 7.43±
7.59 (1H, m), 13.77 (1H, br s); MS (ESI Pos) m/z
533 (M++2+Na, 100%), 531 (M++Na, 98%); IR
(KBr) 2963, 1655, 1610, 1590, 1542, 1493, 1396,
Method B: 4-(5-(2-Methylphenyl)-1,2,3,6-tetrahydropyri-
dino)-2-(N-ethyl-2-methylthio-4-isopropylanilino)-6-methyl-
pyrimidine hydrochloride 2m. To a solution of 2-methyl-
phenyl magnesium bromide in tetrahydrofurane (THF)
prepared from 2-bromotoluene (40.06 g, 234 mmol) and
magnesium (5.43 g, 226 mmol) in THF (400 mL) was added
N-tert-butoxycarbonyl-3-piperidone (42.42 g, 213 mmol)
with ice cooling. After stirring for 1.5 h with ice cooling,
satd aqueous NH4Cl was added to the reaction mixture
and extraction was performed with AcOEt three times. The
combined extract was washed with satd brine, dried
(Na2SO4), and concentrated under reduced pressure.
Chromatography of the residue on silica gel using a mixture
of AcOEt:hexanes (1:5) aorded 16.37 g (26%) of N-tert-
butoxycarbonyl-3-hydroxy-3-(2-methyl-phenyl)piperidine
1231 cmÀ1. Anal. (C27H30BrFN4 HCl 1.5H2O) C, H,
N, Br, Cl, F.
.
.
4-(5-(4-Fluorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-methylthio-4-isopropylanilino)-6-methylpyrimidine
1
hydrochloride 2e. H NMR (CDCl3) d 1.18±1.44 (9H,
m), 1.95±2.56 (5H, m), 2.80 (3H, br s), 2.96 (1H, sept,
J=6.9 Hz), 3.29±3.78 (2H, m), 3.90±4.38 (3H, m), 4.48±
4.82 (1H, m), 5.85±6.26 (2H, m), 6.86±7.40 (7H, m),
13.61 (1H, br s); MS (ESI Pos) m/z 499 (M++Na,
100%); IR (KBr) 2963, 1655, 1608, 1544, 1507, 1394,
1
4b as a light yellow oil: H NMR (CDCl3) d 1.49 (9H, s),
1.54±1.75 (1H, m), 1.88±2.28 (4H, m), 2.66 (3H, s), 2.75±
2.98 (1H, m), 3.20 (1H, d, J=13.7 Hz), 4.00±4.22 (1H, m),
4.27 (1H, d, J=13.7 Hz), 7.13±7.43 (5H, m, ArH); MS
(ESI, Pos) m/z 314 (M++Na).
1254 cmÀ1. Anal. (C28H33FN4S HCl 0.5H2O) C, H, N,
Cl, F, S.
.
.
4-(5-(3-Chlorophenyl)-1,2,3,6-tetrahydropyridino)-2-(N-
ethyl-2-bromo-4-isopropylanilino)-6-methylpyrimidine
hydrochloride 2f. H NMR (CDCl3) d 1.00±1.46 (9H,
To a solution of 4b (16.37 g, 56.2mmol) in dioxane
(23 mL) was added concentrated HCl (234 mL), and the
resulting mixture was stirred at room temperature for
30 min followed by heating at re¯ux for 3 h. The mixture
was concentrated and the resulting crystal was dried
under reduced pressure.
1
m), 2.00±2.54 (2H, m), 2.81 (3H, br s), 2.91 (1H, sept,
J=6.8 Hz), 3.21±3.78 (2H, m), 3.87±4.01 (3H, m), 4.46±
4.77 (1H, m), 5.90±6.05 (1H, m), 6.08±6.35 (1H, m),
6.80±7.45 (6H, m), 7.50±7.63 (1H, m), 13.81 (1H, br s);
MS (ESI Pos) m/z 551 (M++4+Na, 27%), 549
(M++2+Na, 100%), 547 (M++Na, 77%); IR (KBr)
2966, 1650, 1612, 1592, 1547, 1493, 1270 cmÀ1. Anal.
A mixture of the above crystal, 2,4-dichloro-6-methylpyr-
imidine 6 (9.16 g, 56.2mmol) and diisopropylethylamine
(18.15 g, 140.5 mmol) in EtOH (30 mL) was stirred at
.
(C27H30BrClN4 HCl) C, H, N, Br, Cl.