3-Bromopropionitrile → Methyl 2-(6-chloro-2-methoxypyridin-3-yl)-4-cyano-2-methylbutanoate

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To a solution of methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (100 g, 435 mmol) in THF (1.5 L) was added LiHMDS (609 mL, 609 mmol) dropwise over a period of 60 min at −60° C. while maintaining reaction temperature below −50° C. After the addition, the reaction mixture was stirred below −50° C. for 30 min. Then a solution of 3-bromopropanenitrile (92 g, 697 mmol) in THF (0.4 L) was added dropwise to above solution below −50° C. over a period of 90 min. The resulting mixture was stirred at r.t. for 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (500 mL) below 25° C. The 22 batches were combined for workup together. The mixture was diluted with H2O (15 L), and extracted with EtOAc (15 L). The combined organic layers were washed with water (15 L) and brine (15 L), dried over Na2SO4 and concentrated to dryness. The crude residue was purified by column chromatography (petroleum ether/EtOAc=100:0˜80:20) to give methyl 2-(6-chloro-2-methoxypyridin-3-yl)-4-cyano-2-methylbutanoate (1100 g, 41%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.56 (s, 3H), 2.16-2.33 (m, 3H), 2.35-2.47 (m, 1H), 3.65 (s, 3H), 3.93 (s, 3H), 6.96 (d, 1H), 7.44 (d, 1H).

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