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Example 20i 3-Bromo-5-methylpicolinonitrile Potassium cyanide (5.76 g, 88.42 mmol) was added to a solution of 3-bromo-2-fluoro-5-methylpyridine (14 g, 73.68 mmol) in DMSO (75 mL) at rt. The resulting mixture was stirred at 110° C. for 1 h. More potassium cyanide (1.5 g, 23.03 mmol) was added and stirring continued for 20 min. Then the temperature was lowered to 80° C. and the mixture stirred over night. When cooled to rt, the mixture was poured into water (200 mL) and extracted with DCM (3*100 mL). The combined organics were washed with water (100 mL) then poured into a phase separator. The organic phase was collected, silica was added and the mixture was concentrated until a free flowing powder was obtained. The residue was purified on a silica gel column eluted with 0-50percent EtOAc in heptane to afford 6.92 g (48percent yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57-8.68 (m, 1H) 8.21-8.34 (m, 1H) 2.40 (s, 3 H); MS (CI) m/z 197, 199 [M+H]+.
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h;
To a solution of B9.1 (300 mg, 1.596 mmol) in THF(10 mL) at -78 oC was added LDA (2 M, 0.8 mL) and the mixture was stirred at -78 oC for 2 h. The mixture was quenched by10 mL H2O and extracted with EtOAc (10 mL x 3). The combined organic phase was concentrated to give the crude product, which was purified by flash chromatography (Normal phase, silica gel, PE:EtOAc=0-100percent, UV254 & UV280) to give the title compound (130 mg , 43percent) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 2.37 (s, 3H), 7.19 (d, 1H), 8.05 (s, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6691 - 6703
[2] Patent: WO2017/221092, 2017, A1, . Location in patent: Paragraph 00181
With lithium diisopropyl amide; In tetrahydrofuran; at -78.0℃; for 2.0h;
To a solution of B9.1 (300 mg, 1.596 mmol) in THF(10 mL) at -78 oC was added LDA (2 M, 0.8 mL) and the mixture was stirred at -78 oC for 2 h. The mixture was quenched by10 mL H2O and extracted with EtOAc (10 mL x 3). The combined organic phase was concentrated to give the crude product, which was purified by flash chromatography (Normal phase, silica gel, PE:EtOAc=0-100%, UV254 & UV280) to give the title compound (130 mg , 43%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) delta ppm 2.37 (s, 3H), 7.19 (d, 1H), 8.05 (s, 1H).
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