A Facile Synthesis of 5-Halopyrimidine-4-Carboxylic Acid Esters via a Minisci Reaction

Abstract

This paper reports the synthesis of various 5-halopyrimidine-4-carboxylic acid esters via the Minisci homolytic alkoxycarbonylation of 5-halopyrimidines. The reaction was found to be highly regioselective, allowing the one-step synthesis of useful amounts (>10 g) of ethyl 5-bromopyrimidine-4-carboxylate where other methods proved difficult. Ethyl 5-bromopyrimidine-4-carboxylate was used for the preparation of potent CK2 inhibitors including CX-5011. This work represents an interesting application of radical chemistry for the preparation of pharmacologically active molecules.

Key words

Minisci reaction - alkoxycarbonylation - radicals - pyrimidine - antitumor agents

References and Notes

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24

Methyl pyruvate typically gave conversions and isolated yields that were inferior (ca. 10-20% lower) to ethyl pyruvate on a variety of tested substrates. This had no practical consequences on the preparation of the target molecule CX-5011, where no significant differences were observed when using the methyl or the ethyl ester as a starting material.

27

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.