Uses
It finds its application as a useful synthetic intermediate and in the straightforward and efficient synthesis of 3-benzyloxy-4-bromopicolinate ester and 3-benzyloxy-5-bromopicolinate ester, common building blocks for pharmaceuticals and agrochemicals. It is used in the synthesis of biaryl mannoside FimH inhibitors for use in urinary infection treatment.
Synthesis
Methyl 4-bromopyridine-2-carboxylate (147) was synthesized as follows: first, 4-bromopyridine hydrochloride (595 mg, 3.06 mmol) was dissolved in dichloromethane (DCM, 20 mL), washed with saturated aqueous sodium bicarbonate (NaHCO3) (2 × 20 mL), followed by drying and filtration with anhydrous magnesium sulfate (MgSO4). The filtrate was adjusted to 45 mL by the addition of additional DCM, followed by the addition of water (3 mL), iron(II) sulfate heptahydrate (8.51 g, 30.6 mmol) and concentrated sulfuric acid (H2SO4, 0.95 mL, 9.18 mmol). In another flask, methyl pyruvate (4.15 mL, 46 mmol) was treated with hydrogen peroxide (3.5 mL, 30.6 mmol, 30% aqueous solution) in a mixture at -10 °C, which was subsequently added to the above DCM/water mixture under vigorous stirring, keeping the temperature at -10 °C. After 15 min of reaction, the reaction mixture was diluted with ice water (100 mL) and extracted with DCM (4 x 20 mL). The DCM phases were combined and dried with anhydrous magnesium sulfate (MgSO4) and subsequently concentrated under reduced pressure. Purification by column chromatography (gradient elution conditions: first using 10-40% ethyl acetate (EtOAc) in heptane solution containing 0.5% triethylamine, followed by 0-20% EtOAc/heptane containing 0.5% triethylamine) gave the target compound. Yield: 211 mg (32%). lC/MS retention time (tv) 0.98 min. mass spectra (ES+) m/z 218, 216 ([M+H]+).
References
[1] Patent: WO2007/89669, 2007, A2. Location in patent: Page/Page column 199-200
[2] Patent: WO2008/57469, 2008, A1. Location in patent: Page/Page column 288-289
[3] Patent: WO2008/57468, 2008, A1. Location in patent: Page/Page column 288-289
