With lithium aluminium tetrahydride In tetrahydrofuran at -10 - 20℃;
Preparation of S-bromo^-chloronicotinaldehyde (D-2-3).To a stirred solution of compound D-2-2 (25 g, 89.4 mmol) in dry THF (200 mL) was added LiAIH4 (1.7 g, 27 mmol) at -10 0C under N2 atmosphere. After the addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. TLC (petroleum ether/EtOAc 5:1 ) indicated complete consumption of starting material. To the reaction mixture was added 1 N KHSO4 (200 mL) and extracted with EtOAc (300 mL><3). The combined organic layers were washed with saturated aqueous NaCI (200 mL), dried over Na2SO4 and concentrated in vacuo to yield crude compound D-2-3, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 30:1 ) to yield pure compound D-2-3 (8.0 g, 45percent) as a white solid.
In tetrahydrofuran; at 0 - 20℃; for 0.5h;Inert atmosphere;
To a solution of compound4(2.0 g, 7.15 mmol) in anhydrous THF (15mL) was addedmethylmagnesium bromide(1M in THF, 8 mL, 8 mmol) dropwise at 0Cunderargon atmosphere. The resulting mixture was stirred at room temperaturefor 30 min. The reaction was quenched with sat. NH4Cl solution,diluted withwater(50 mL) and extracted with ethyl acetate (50 mL×3).The combined organic layers werewashed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1, v/v) to give the title compound5as a yellow solid(1.5 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.71 (d,J= 2.5 Hz, 1H), 8.46 (d,J= 2.5 Hz, 1H), 2.62 (s, 3H).
54.3%
In tetrahydrofuran; at -78℃; for 3h;
Starting material 5-bromo-2- chloro-N-methoxy-N-methylnicotinamide (5.0 g, 17.89 mmol) was charged into a 250 ml round bottom flask and the flask was chilled to -78 0C. Methyl magnesium bromide 96.5 ml, 19.68 mmol) in 5 ml THF was added dropwise via addition funnel. The resulting mixture was allowed to stir for 3 hours at -78 0C. After removing the THF solvent via rotatory evaporation under reduced pressure, the reaction mixture was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. After removing the ethylacetate, the resulting crude product was subject to a silica gel column with 20% ethylacetate in hexane. The resulting product (2.28 g, y=54.3%) was used for the following step.
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