P. J. Gilligan et al. / Bioorg. Med. Chem. 7 (1999) 2321±2328
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DMF (50 mL) was added. A solution of N-(2-bromo-4-
isopropylphenyl)-4-carbomethoxy-6-methylpyrimidin-2-
amine (22.4 g, 61.5 mmol) in DMF (100 mL) was added
and the resulting mixture was stirred for 30 min.
Iodoethane (11.5 g, 73.8 mmol) was added and stirring
was continued for 5 h. The reaction was quenched with
water (850 mL) and extracted three times with chloro-
form (200 mL). The combined organic layers were
washed with water (200 mL) twice, then dried. Filtra-
tion and removal of solvent in vacuo provided a brown
oil. Column chromatography (EtOAc/hexanes, 1/7)
gave the title compound, a pale-yellow solid (13.3 g,
55% yield): mp 85±86 C; H NMR (CDCl3) d 7.3±7.1
(m, 2H), 7.1 (s, 1H), 4.30±4.15 (m, 1H), 4.05±3.70 (m,
4H), 2.9 (quintet, 1H, J=7 Hz), 2.5±2.2 (m, 3H), 1.4±
1.2 (m, 9H). Anal. calcd for C18H22BrN3O2: C,55.11, H,
5.65, N, 10.71, Br, 20.37; found: C, 54.88, H, 5.64, N,
10.62, Br, 20.67.
1H), 4.30±4.10 (m, 1H), 3.80±3.60 (m, 8H), 3.50±3.30
(m, 2H), 2.9 (septet, 1H, J=8 Hz), 2.55±2.45 (m, 3H),
1.30 (d, 6H, J=8 Hz), 1.20 (t, 3H, J=7 Hz); CI-HRMS
m/z calcd: 433.1603, Found: 433.1586 (M++H).
2-(N-(2-Bromo-4-isopropylphenyl)-N-ethyl-6-methyl-4-
(imidazol-1-yl)methyl)pyrimidin-2-amine (3-5) (Steps C,
A). A solution of 2 (4 g, 10.2 mmol) in dry THF (20
mL) was cooled to 0ꢀC with stirring. A solution of
lithium borohydride in THF (2 M, 10 mL, 20 mmol)
was added dropwise. The mixture was gradually
warmed to room temperature over 19 h and then it was
poured onto water (50 mL). The aqueous mix was
extracted three times with EtOAc (20 mL). The com-
bined organic layers were dried, ®ltered and con-
centrated in vacuo to give 2-(N-(2-bromo-4-iso-
propylphenyl)-N-ethyl-6-methyl-4-(hydroxymethyl)pyr-
ꢀ
1
1
imidin-2-amine, a clear, colorless oil (3.64 g): H NMR
(CDCl3) d 7.55 (d, 1H, J=1 Hz), 7.20 (dd, 1H, J=7, 1
Hz), 7.15 (d, 1H, J=7 Hz), 6.30 (s, 1H), 4.60±4.30 (m,
2H), 4.30±4.10 (m, 1H), 3.85±3.50 (br s, 2H), 3.00±2.85
(m, 1H), 2.50±2.20 (br s, 3H), 1.27 (d, 6H, J=7 Hz),
1.22 (t, 3H, J=7 Hz); CI-MS m/z 366, 364 (M++H).
2-(N-(2-Bromo-4-isopropylphenyl)-N-ethyl)amino-6-methyl-
pyrimidine-4-carboxylic acid, morpholine amide (Step
A). Sodium hydride (60% in oil, 240 mg, 6 mmol) was
washed with hexanes and decanted twice. Anhydrous
THF (5 mL) was added. A solution of morpholine
(0.52 g, 6 mmol) in THF (5 mL) was added with stir-
ring. The reaction mixture was heated to re¯ux tem-
perature and stirred at that temperature for 45 min. A
solution of 2 (2 g, 5.1 mmol) in THF (10 mL) was added
and the resulting mixture was stirred for 17 h at re¯ux
temperature. After being cooled to room temperature,
water (50 mL) was added carefully and the resulting mix
was extracted twice with EtOAc. The combined organic
layers were dried and ®ltered. Column chromatography
(ether) gave the title product (900 mg, 39% yield): mp
145ꢀC; 1H NMR (CDCl3, 300 MHz) d 7.50 (d, 1H, J=1
Hz), 7.20 (dd, 1H, J=7, 1 Hz), 7.10 (d, 1H, J=7 Hz),
6.80 (br s, 1H), 4.30±4.15 (m, 1H), 3.90±3.32 (m, 11H),
3.10±3.00 (m, 1H), 2.90 (septet, 1H, J=7 Hz), 1.30 (d,
6H, J=7 Hz), 1.25 (t, 3H, J=7 Hz). Anal. calcd for
C21H27BrN4O2: C, 56.38, H, 6.08, N, 12.52, Br, 17.86;
C, 56.07, H, 6.05, N, 12.29, Br, 18.08.
A solution of 2-(N-(2-bromo-4-isopropylphenyl)-N-ethyl-
6-methyl-4-(hydroxymethyl)pyrimidin-2-amine (1.57 g,
4.3 mmol) and triethylamine (2.5 mL, 17 mmol) in
dichloromethane (15 mL) was cooled to 0±5ꢀC with
stirring. Methanesulfonyl chloride (0.54 g, 4.73 mmol)
was added dropwise. Stirring at 0±5ꢀC was continued
for 1.5 h. The reaction mixture was transferred to a
separatory funnel, washed once with an ice-cold 1 N
HCl solution (17 mL), washed twice with a saturated
NaHCO3 solution and once with brine. Drying, ®ltra-
tion and removal of solvent in vacuo aorded 2-(N-(2-
bromo-4-isopropylphenyl)-N-ethyl-6-methyl-4-(methane-
sulfonyloxy-methyl)pyrimidin-2-amine, a clear colorless
1
oil (1.6 g): H NMR (CDCl3) d 7.50 (d, 1H, J=1 Hz),
7.25±7.10 (m, 2H), 6.50 (s, 1H), 5.05±4.90 (br s, 2H),
4.30±4.10 (m, 1H), 3.80±3.60 (m, 1H), 3.00±2.85 (m,1H),
2.70 (br s, 3H), 2.35 (br s, 3H), 1.30 (d, 6H, J=8 Hz),
1.20 (t, 3H, J=8 Hz); CI-MS m/z 444, 442 (M++H).
2-(N-(2-Bromo-4-isopropylphenyl)-N-ethyl-6-methyl-4-
(morpholinylmethyl)pyrimidin-2-amine (3-4) (Step B). A
solution of borane in THF (1 M, 3.6 mL, 3.6 mmol) was
added dropwise via syringe to a stirred solution of the
above intermediate (800 mg, 1.79 mmol) in anhydrous
THF (3 mL). The reaction mixture was heated to re¯ux
temperature and stirred for 19 h. After being cooled to
ambient temperature, the reaction was quenched by
addition of glacial HOAc (1 mL) and subsequent heat-
ing at re¯ux temperature for 30 min. The reaction mix-
ture was cooled to room temperature. Solvent was
removed in vacuo. The residue was treated with a 1 N
NaOH solution (10 mL) (pH 12) and the resulting aqu-
eous mix was extracted three times with EtOAc (20
mL). The combined organic layers were washed twice
with water (10 mL), dried and ®ltered. Solvent was
removed in vacuo to give an oil. Column chromato-
graphy (EtOAc) gave the title product (Rf 0.3). Removal
of solvent in vacuo aorded a pale-yellow oil (300 mg,
Sodium hydride (60% in oil, 0.1 g, 2.4 mmol) was
washed with hexanes and decanted twice. Dry THF (10
mL) was added, followed by imidazole (146 mg, 2.14
mmol). The reaction mix was heated to re¯ux tempera-
ture, stirred for 2 h, then cooled to ambient tempera-
ture. A solution of 2-(N-(2-bromo-4-isopropylphenyl)-
N-ethyl-6-methyl-4-(methanesulfonyloxy-methyl)pyr-
imidin-2-amine (900 mg, 2 mmol) in dry THF (10 mL)
was added. The reaction mixture was stirred at room
temperature for 68h, then it was poured onto water (50
mL). Three extractions with EtOAc (20 mL), drying the
combined organic layers, ®ltration, and removal of sol-
vent in vacuo gave a brown oil. Column chromato-
graphy (EtOAc) gave two fractions after removal of
solvent in vacuo: (1) 2-(N-(2-bromo-4-isopropylphenyl)-
N-ethyl-6-methyl-4-(methanesulfonyloxy-methyl)pyr-
imidin-2-amine (Rf 0.7, 130 mg) and (2) the title product,
1
a yellow oil (500 mg, 59% yield): H NMR (CDCl3) d
7.60±7.40 (m, 2H), 7.20 (dd, 1H, J=7, 1 Hz), 7.15 (d,
1H, J=8 Hz), 7.05 (s, 1H), 7.00±6.80 (m, 1H), 6.05 (s,
1
39% yield): H NMR (CDCl3) d 7.50 (d, 1H, J=1 Hz),
7.2 (dd, 1H, J=7, 1 Hz), 7.10 (d, 1H, J=7), 6.50 (s,