A. Nakazato et al. / Bioorg. Med. Chem. 8 (2000) 1183±1193
1191
isoPr), 2.32 (3H, s, CH3 of pyrimidine), 2.58±2.73 (2H,
m,=CCH2C), 2.78±2.94 (1H, m, CH of isoPr), 3.91
(2H, t, J=5.7 Hz, NCH2), 4.21 (2H, d d, J=2.5, 5.6 Hz,
NCH2), 5.98 (1H, s, H of pyrimidine), 6.11±6.20 (1H, m,
C=CH), 7.11±7.49 (8H, m, ArH and NH), 8.45 (1H, d,
J=8.6 Hz, ArH); MS (CI) m/z 465 (M++3, 99%), 463
(M++1, 100%).
dropwise a saturated aqueous NH4Cl. After 10 min, the
mixture was extracted with AcOEt. The extract was
washed with saturated aqueous NaHCO3 and saturated
brine, dried (Na2SO4), ®ltered, and then concentrated in
vacuo. Chromatography of the residue on silica gel
using a mixture of AcOEt and hexanes (1:4) aorded
238 mg (59%) of 4-(4-(3-chlorophenyl)-4-hydroxy-
piperidino)-2-(N-ethyl-2-bromo-4-isopropylanilino)-6-
methylpyrimidine as a yellow amorphous solid: 1H
NMR (CDCl3) d 1.22 (3H, t, J=7.1 Hz, CH3 of Et),
1.24 (6H, d, J=7.0 Hz, CH3 of isoPr), 1.53±1.75 (2H, m,
H of CCH2C), 1.82±2.10 (2H, m, H of CCH2C), 2.23
(3H, s, CH3 of pyrimidine), 2.80±3.01 (1H, m, CH of
isoPr), 3.08±3.35 (2H, m, H of NCH2), 3.58±4.35 (4H,
m, H of NCH2 and CH2 of NEt), 5.86 (1H, s, H of
pyrimidine), 7.13±7.21 (2H, m, ArH), 7.21±7.35 (3H, m,
ArH), 7.43±7.53 (2H, m, ArH); MS (CI) m/z 545
(M++3, 100%), 543 (M++1, 82%).
Compound 30a (453 mg, 0.98 mmol) was treated with
ethyl iodide (214 mg, 1.37 mmol) and 60% NaH in oil
(51 mg, 1.27 mmol) in dry DMF (5 mL) using the same
procedure as in the third step of Method A to aord
325 mg (61%) of 11a as a light yellow crystal: mp 124±
127 ꢀC; H NMR (DMSO-d6) d 1.19 (3H, d, J=7.0 Hz,
1
CH3 of Et), 1.26 (6H, t, J=7.0 Hz, CH3 of isoPr), 2.28
(3H, br s, CH3 of pyrimidine), 2.55±2.80 (2H, m,
=CCH2C), 2.93±3.09 (1H, m, CH of isoPr), 3.30±4.68
(6H, m, NCH2 and CH2 of Et), 6.26 (1H, br s, H of
pyrimidine), 6.51±6.86 (1H, m, C=CH), 7.23±7.63 (7H,
m, ArH), 7.73 (1H, br s, ArH); MS (CI) m/z 493
A solution of 4-(4-(3-chlorophenyl)-4-hydroxypiperi-
dino)-2-(N-ethyl-2-bromo-4-isopropylanilino)-6-methyl-
pyrimidine (170 mg, 0.31 mmol) in tri¯uoroacetic acid
(1.25 mL) was stirred at room temperature for 2 days.
The solution was concentrated in vacuo and then parti-
tioned between AcOEt and saturated aqueous NaHCO3.
The separated organic phase was washed with saturated
aqueous NaHCO3 and saturated brine, dried (Na2SO4),
®ltered, and then concentrated in vacuo. Chromato-
graphy of the residue on silica gel using a mixture of
AcOEt and hexanes (1:7), treatment with 4 N HCl in
AcOEt in MeOH and recrystallization from a mixture
of isopropanol and diisopropyl ether aorded 131 mg
(75%) of 11h as a light yellow crystal: mp 183±185 ꢀC;
1H NMR (CDCl3) d 1.29 (6H, d, J=7.0 Hz, CH3 of
isoPr), 1.34 (3H, t, J=6.8 Hz, CH3 of Et), 2.20±2.88 (2H,
m, C=CCH2C), 2.80 (3H, br s, CH3 of pyrimidine),
2.88±3.05 (1H, m, CH of isoPr), 3.30±4.75 (6H, m, NCH2
and CH2 of Et), 5.88 (1H, br s, H of pyrimidine), 5.94±
6.08 (1H, m, C=CH), 7.00±7.61 (7H, m, ArH); MS (CI)
m/z 527 (M++3, 100%), 525 (M++1, 84%); IR (KBr)
3504, 2960, 1654, 1610, 1588, 1546, 1492 cm 1. Anal.
(M++3, 99%), 491 (M++1, 100%); IR (KBr) 3505,
1
2960, 1652, 1609, 1588, 1546, 1493, 1379, 1255 cm
.
.
Anal. (C27H31BrN4 HCl H2O) C, H, N, Br, Cl.
.
Method G. 4-(4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyri-
dino)-2-(N-ethyl-2,4-dimethoxyanilino)-6-methylpyrimidine
11ag. A mixture of 4-(4-(4-chlorophenyl)-1,2,3,6-tetra-
hydropyridino)-2-chloro-6-methylpyrimidine (500 mg,
1.55 mmol), which was prepared by treatment of 2,4-
dichloro-6-methylpyrimidine 14 with 4-(4-chloro-
phenyl)-1,2,3,6-tetrahydropyridine HCl using the same
procedure as in Method E, and N-ethyl-2,4-dimethoxy-
aniline (281 mg, 1.55 mmol) in ethylene glycol (2 mL)
was heated at re¯ux for 1.5 h. The mixture was parti-
tioned between AcOEt and saturated aqueous NaHCO3.
The separated organic phase was washed with saturated
brine, dried (Na2SO4), ®ltered, and then concentrated in
vacuo. Chromatography of the residue on silica gel using
a mixture of AcOEt and hexanes (1:4) and recrystalliza-
tion from Et2O aorded 360 mg (50%) of 11ag as a light
yellow crystal: mp 159±160 ꢀC; 1H NMR (CDCl3) d 1.19
(6H, d, J=7.0 Hz, CH3 of isoPr), 1.15 (3H, t, J=7.0 Hz,
CH3 of Et), 2.20 (3H, br s, CH3 of pyrimidine), 2.41±2.57
(2H, m,=CCH2C), 3.61±4.12 (6H, m, NCH2 and CH2 of
Et), 3.73 (3H, s, CH3O), 3.84 (3H, s, CH3O), 5.77 (1H, s,
H of pyrimidine), 6.02±6.12 (1H, m, C=CH), 6.45±6.58
(2H, m, ArH), 7.10 (1H, d, J=8.4 Hz, ArH), 7.26±7.35
(4H, m, ArH), 7.73 (1H, br s, ArH); MS (EI) m/z 466
.
(C27H30BrClN4 HCl) C, H, N, Br, Cl.
Method I. 4-(4-Furan-2-yl-1,2,3,6-tetrahydropyridino)-2-
(N-ethyl-2-bromo-4-isopropylanilino)-6-methylpyrimidine
11d. To a stirred solution of furan (136 mg, 2.00 mmol)
in dry THF (1 mL), cooled to 15 ꢀC, was added drop-
wise 1.63M solution of n-butyllithium in hexane
(0.9 mL, 1.47 mmol) over 10 min. After 20 min at 5 ꢀC,
to the stirred mixture, cooled to 15 ꢀC, was added
dropwise a solution of 26 (432 mg, 1.00 mmol) in dry
THF over 10 min. After 30 min at 15 ꢀC to 0 ꢀC and
then 1 h at room temperature, to the stirred mixture,
cooled in an ice-bath, was added dropwise a saturated
aqueous NH4Cl. After 10 min, the mixture was extrac-
ted with AcOEt. The extract was washed with saturated
aqueous NaHCO3 and saturated brine, dried (Na2SO4),
®ltered, and then concentrated in vacuo. Chromato-
graphy of the residue on silica gel using a mixture of
AcOEt and hexanes (1:3) aorded 279 mg (56%) of 4-
(4-furan-2-yl-4-hydroxypiperidino)-2-(N-ethyl-2-bromo-
4-isopropylanilino)-6-methylpyrimidine as a yellow oil:
1H NMR (CDCl3) d 1.20 (3H, t, J=7.0 Hz, CH3 of Et),
(M++2, 3%), 464 (M+, 8%), 433 (M+-CH3O, 100%);
1
IR (KBr) 2954, 2836, 1586, 1438, 1412, 1160 cm
Anal. (C26H29ClN4O2) C, H, N, Cl.
.
Method H. 4-(4-(3-Chlorophenyl)-1,2,3,6-tetrahydropyri-
dino)-2-(N-ethyl-2-bromo-4-isopropylanilino)-6-methyl-
pyrimidine hydrochloride 11h. A stirred suspension of 3-
bromochlorobenzene (427 mg, 2.23 mmol), magnesium
(27 mg, 1.12 atoms) and trace iodine in dry THF (5 mL)
was heated at re¯ux under a nitrogen atmosphere, and
then cooled in an ice-bath. To the stirred solution was
added dropwise a solution of compound 26a (321 mg,
0.74 mmol). After 1 h, the mixture was warmed to room
temperature and stirred for 1 h. The mixture was re-
cooled in an ice-bath, and to the mixture was added