(3 ¥ 30 mL). The combined organic layers were washed with water
(2 ¥ 30 mL) and dried (Na2SO4), and the solvent was removed in
vacuo. The compounds were purified as specified.
rac-4-(4-Amino-6-sec-butoxy-5-formylpyrimidin-2-
ylamino)benzenesulfonamide (22h)
General procedure F. 4-(4-amino-6-chloro-5-formylpyrimidin-
2-ylamino)benzenesulfonamide (21a) (0.40 g, 1.22 mmol), sec-
butanol (2.3 mL, 24.5 mmol). Chromatography (silica; 2–15%
MeOH, DCM) and HPLC, Phenomenex Synergi (35–100%
MeCN, water) gave 22h as a white solid (97 mg, 11%), m.p. 265–
267 ◦C. UV lmax (EtOH): 325 nm; IR nmax 3278, 3215, 2923, 2852,
1645, 1564, 1321, 1149 cm-1; dH (300 MHz, d4-MeOD) 1.00 (3H,
t, J = 7.5 Hz, CH3CHORCH2CH3), 1.38 (3H, d, J = 6.2 Hz,
CH3CHORCH2CH3), 1.65–1.86 (2H, m, CH3CHORCH2CH3),
5.30–5.41 (1H, m, CH3CHORCH2CH3), 7.82 (2H, d, J = 8.9 Hz,
ArH(2,6)), 7.95 (2H, d, J = 8.9 Hz, ArH(3,5)), 9.97 (1H, s, CHO);
dC (75 MHz, d4-MeOD): 10.1, 19.8, 30.6, 75.9, 96.1, 120.6, 128.0,
138.1, 144.7, 156.7, 162.1, 170.4, 188.0. MS (ESI+) m/z 366.31
[M+H]+; HRMS (ESI+) m/z: Calc. for C15H19N5O4S: 366.1231
[M+H]+. Found 366.1237 [M+H]+.
4-(4-Amino-6-chloro-5-formylpyrimidin-2-
ylamino)benzenesulfonamide (21a)
General
procedure
E. 4-amino-2,6-dichloro-5-formyl-
pyrimidine (20) (0.5 g, 2.62 mmol), sulfanilamide (0.54 g,
3.13 mmol), trifluoroacetic acid (1.0 mL, 13.1 mmol) and
trifluoroethanol (10 mL). Recrystallisation (methanol) gave 21a
as a yellow solid (0.63 g, 74%) m.p.: 244 –246 ◦C. UV lmax (EtOH):
332 and 262 nm. IR nmax/cm-1: 3325, 3194, 3155, 2852, 1713,
1574, 1503, 1342, 1163, 1061; dH (300 MHz, d6-DMSO): 7.28
(2H, s, NH2 exchangeable with D2O), 7.74 (2H, d, J = 8.2 Hz,
ArH(2,6)), 8.01 (2H, d, J = 8.2 Hz, ArH(3,5)), 8.51 (1H, br,
NH exchangeable with D2O), 8.64 (1H, br, NH exchangeable
with D2O), 10.04 (1H, s, CHO), 10.58 (1H, br, NH exchangeable
with D2O). dC (75 MHz, d6-DMSO): 102.8, 120.2, 126.7, 138.6,
142.4, 159.0, 163.7, 165.0, 188.3. MS (ESI+) m/z 328.10 [M+H]+.
HRMS (ESI+) m/z: Calc for C11H10ClN5O3S: 328.0266 [M+H]+.
Found 328.0264 [M+H]+. C11H10ClN5O3S·0.1CH2Cl2: requires C,
39.65; H, 3.06; N, 20.83%. Found C, 39.58; H, 2.98; N, 20.95%.
(S)-4-(4-Amino-6-sec-butoxy-5-formylpyrimidin-2-
ylamino)benzenesulfonamide (22j)
General procedure F. 4-(4-amino-6-chloro-5-formylpyrimidin-
2-ylamino)benzenesulfonamide (21a) (0.40 g, 1.22 mmol), (S)-
sec-butanol (1.1 mL, 12.2 mmol). Chromatography (silica; 2–
15% MeOH–DCM) and HPLC, Phenomenex Synergi (35–100%
MeCN, water), gave 22j as a white solid (31 mg, 7%), m.p.: 269–
270 ◦C. UV lmax (EtOH): 319 nm; IR nmax 3275, 3230, 2959, 2924,
2861, 1650, 1558, 1377, 1156 cm-1; dH (300 MHz, d3-MeCN) 0.74
(3H, t, J = 7.4 Hz, CH3CHORCH2CH3), 1.13 (3H, d, J = 6.2 Hz,
CH3CHORCH2CH3), 1.39–1.61 (2H, m, CH3CHORCH2CH3),
5.01–5.09 (1H, m, CH3CHORCH2CH3), 5.36 (2H, s, NH2), 6.06
(1H, br, NH), 7.56 (2H, d, J = 8.9 Hz, ArH(2,6)), 7.68 (2H, d,
J = 8.9 Hz, ArH(3,5)), 7.97 (1H, br, NH), 8.34 (1H, s, NH), 9.80
(1H, s, CHO); dC (75 MHz, d4-MeOD) 10.2, 20.0, 30.4, 76.4, 90.4,
121.3, 128.3, 137.0, 144.7, 155.9, 162.5, 173.2, 188.4. MS (ESI+)
m/z 366.24 [M+H]+. HRMS (ESI+) m/z: Calc. for C15H19N5O4S:
366.1231 [M+H]+. Found 366.1236 [M+H]+.
General procedure F. The chosen alcohol (10 eq.) was added
dropwise to a suspension of sodium hydride (5 eq.) in THF (anh;
5 mL), and the mixture was stirred at rt under N2 for 30 min.
The chosen 4-amino-6-chloro-2-(arylamino)-5-formylpyrimidine
(1 eq.) was added slowly, in small portions and the reaction mixture
was heated at reflux 16 h, then allowed to cool to rt, quenched
with water (10 mL), and acidified (2 M HCl) to pH < 2, then THF
(10 mL) was added, the resulting mixture was stirred overnight,
neutralised (saturated aq. sodium bicarbonate), and concentrated
in vacuo. The residue was extracted with EtOAc (4 ¥ 30 mL) and the
combined organic layers were dried (Na2SO4), and concentrated
in vacuo to give a yellow–orange oil. Chromatography (silica; 40–
100% EtOAc, petrol, or 10% MeOH, DCM) and recrystallisation
(methanol) or HPLC purification, gave the product as a white
solid.
General procedure G. The appropriate O4-substituted pyrim-
idine (1 eq.) was dissolved in 30% aq. acetic acid (1 ml–4 ml) at
rt. The temperature was increased to 80 ◦C and sodium nitrite
(1.3 eq.) in water (1 ml–3 ml) was added dropwise to give a
purple precipitate. The reaction was maintained at 80 ◦C for
40 min, allowed to cool to rt and the precipitate was collected
by filtration. The crude product was purified by recrystallisation
from the appropriate solvent.
4-Amino-6-cyclohexylmethoxy-2-(4-methoxyphenylamino)-5-
formylpyrimidine (22a)
General
procedure
F. 4-amino-6-chloro-2-(4-methoxy-
phenylamino)-5-formylpyrimidine (21b) (0.20 g, 0.72 mmol),
cyclohexylmethanol (0.88 mL, 7.2 mmol). Chromatography
(silica; 40–100% EtOAc, Petrol) and recrystallisation (methanol)
gave 22a as an off-white solid (0.159 g, 62%) m.p. 94–97 ◦C.
UV lmax (EtOH): 325 nm. IR nmax/cm-1: 3311, 3070, 2920, 1663,
1550, 1491, 1236. dH (300 MHz, d4-MeOD): 0.81–1.32 (5H, m,
C6H11), 1.64–1.78 (6H, m, C6H11), 3.72 (3H, s, OCH3), 4.15 (2H,
d, J = 6.0 Hz, OCH2), 6.81 (2H, d, J = 8.9 Hz, ArH(3,5)), 7.48
(2H, d, J = 8.9 Hz, ArH(2,6)), 9.83 (1H, s, CHO); dC (75 MHz,
d4-MeOD): 26.8, 27.6, 30.9, 38.8, 56.1, 72.9, 94.3, 115.1, 124.3,
133.6, 157.8, 162.7, 166.3, 173.6, 187.3. MS (ESI+) m/z 357.33
[M+H]+. HRMS (ESI+) m/z: Calc. for C19H24N4O3: 357.1921
[M+H]+. Found 357.1922 [M+H]+. C19H24N4O3.0.4 M MeOH
requires C, 63.02; H, 6.96; N, 15.23%; found C, 63.49; H, 6.46, N,
14.78%.
6-Methoxy-5-nitrosopyrimidine-2,4-diamine (4a)
General procedure G. 6-methoxypyrimidine-2,6-diamine
(3a)(0.25 g, 1.78 mmol), 30% aq. acetic acid (5 mL), sodium
nitrite (160 mg, 2.32 mmol) in water (2 mL). The purple precipitate
was filtered off and dried (P2O5) giving 4a. (246 mg, 82%). m.p.
249.2–251.8 ◦C; UV (EtOH): lmax1 = 330 nm; IR nmax 3508, 3282,
1566, 1492, 1441, 1372, 1311 cm-1; dH (300 MHz, d6-DMSO) d
4.05 (3H, s, CH3), 7.81 (1H, br s, NH2), 7.87 (1H, br s, NH2), 8.03
(1H, br s, NH2), 10.07 (1H, br s, NH2); HRMS (ESI+) m/z: Calc.
for C5H7N5O2: 141.0771 [M+H]+. Found 141.0770 [M+H]+.
2406 | Org. Biomol. Chem., 2010, 8, 2397–2407
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The Royal Society of Chemistry 2010
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