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Typical Procedure
for the Synthesis of Ethyl 5-bromo-pyrimidine-4-carboxylate
In
a 250 mL round-bottom flask, ethyl pyruvate (4.5 equiv, 50 mL, 450
mmol) was cooled to -10 ˚C. AcOH (70
mL) was added while maintaining the internal temperature below -5 ˚C.
A 30% aq H2O2 solution (3 equiv,
34 g, 300 mmol) was added dropwise while maintaining the internal temperature
below -2 ˚C. In a separate two-neck 2
L round-bottom flask fitted with a mechanical stirrer was charged
5-bromopyrimidine (1.0 equiv, 15.90 g, 100 mmol), toluene (300 mL),
and H2O (70 mL). This solution was cooled to
-10 ˚C,
and concentrated H2SO4 (3 equiv, 16 mL, 300 mmol)
was added followed by FeSO4˙7H2O
(3.05 equiv, 84.79 g, 305 mmol). To this reaction mixture under
vigorous stirring was added the peroxide solution over 1 h, while keeping
the internal temperature below 0 ˚C. Once the addition
was complete, the reaction mixture was stirred for 30 min and then
decanted onto ice water (200 mL). The pH was adjusted to 7 by the
addition of 1 N NaOH, and the solution was filtered over a pad of
Celite and washed with CH2Cl2 (1 L). The aqueous
layer was extracted with CH2Cl2 (2 × 800
mL). The organics were washed with 5% NaHSO3 (2 × 500
mL), brine (1.5 L), and then dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified via flash column
chromatography (10% EtOAc-hexanes) to give a slightly
yellow oil (12.49 g, 54%, >90% pure). Vacuum
distillation (bp, 75-76 ˚C, ca. 1 mm
Hg) provided analytically pure ethyl 5-bromopyrimidine-4-carboxylate
as a clear, colorless oil (11.18 g, 48%). ¹H
NMR (400 MHz, CDCl3): δ = 9.20 (s,
1 H), 9.00 (s, 1 H), 4.51 (q, J = 7.2
Hz, 2 H), 1.46 (t, J = 7.2
Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 163.2,
161.0, 156.5, 155.8, 117.7, 62.9, 14.0 ppm. LC-MS (ES): >95% pure, m/z 185 [M - OEt]+.
GC-MS (EI): >99% pure, m/z = 230.
The structure of the material was confirmed by its successful use
in the next chemical step on route to CX-5011. All other examples
described in this paper were prepared with a similar procedure,
typically
on a 2-mmol scale. In cases involving poorly
soluble pyrimidines, H2SO4 was added without
external cooling, with the resulting exotherm dissolving the organic
substrate. The solution was then cooled to -10 ˚C
prior to carrying on the rest of the reaction. Compounds were purified
by flash chromatography on silica gel (eluting with 10% EtOAc
in hexanes or 2.5% MeOH in CH2Cl2)
and found to be 95% pure by GC-MS.
All compounds isolated were characterized by ¹H
NMR, ¹³C NMR, and GC-MS.