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In a pre-dried flask, Dl (12.6 g; 82.9 mmol) was dissolved in Et2O (anhydrous) (200 ml) and under N2 (gas) protection, bro mo methyl magnesium (100 ml) was added slowly. The reaction mixture was stirred at room temperature overnight and then poured slowly into a mixture of ice-H2O (600 ml) and 37% aqueous HCl (100 ml). The reaction mixture was stirred and extracted with Et2O (200 ml x 4). The combined organic phases were then washed with brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo. Yield: 11.6 g of D2 (88 % pure product).
2-Chloro-3-methyl-4-pyridinecarboxylic acid (30 g; 174 mmol) was dissolved in pyri- dine (250 ml) and cooled to 0 0C. Methanesulfonyl chloride (13.6 ml) was then added dropwise and the reaction mixture was stirred at 0 0C for 1 hour. NH3 (gas) was added under pressure and the reaction mixture was stirred at room temperature for 1 h. After the reaction had reached completion, the excess NH3 was removed in vacuo. The reaction mixture was then cooled to 0 0C, methanesulfonyl chloride (140 ml) was added and the reaction mixture stirred at room temperature overnight. The mixture was then poured into 0.1 M HCl (200 ml ) at 0 0C (with care), and adjusted to pH =7 with 1 M NaOH. The reaction mixture was extracted with EtOAc (2 x 100 ml), washed with brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (Biotage flash purification system; gradient: EtO Ac/heptane from 15/85 to 30/70). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 12.6 g of Dl.
A stirring solution of Intermediate 121A (3.5 g, 26.1 mmol) in POCl3 (48.6 mL, 52 mmol) was heated at 100 C for 3 h. The reaction mixture was cooled to ambient temperature and poured into cold water (50 mL), basified with 10% NaHCO3 solution and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-80 g, 0-20% EtOAc/n- Hexane) to obtain Intermediate 121B (0.62 g, 15.57%) as a pale yellow solid.1H NMR (400 MHz, CDCl3) delta ppm 2.41 - 2.83 (m, 3 H), 7.44 (d, J = 5.00 Hz, 1 H), 8.39 (dd, J = 5.00, 0.75 Hz, 1 H). LCMS (Method-D): retention time 1.66 min, [M+H] 153.2
With trichlorophosphate; In dichloromethane; at 0 - 70℃; for 16.0h;
Cooled POCI3 (16 mL) was added dropwise to 4-cyano-3-methylpyridine 1 -oxide (1.6 g, 12 mmol) at 0 C and the resulting reaction mass was heated at 70 C for 16 hours. After completion of reaction, the reaction mixture was poured into ice water, neutralised with 10% NaHCO solution and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to give a mixture of title compound and 2-chloro-3-methylisonicotinonitrile (1.15 g). GC-MS m/z 1 52.0 ( X I I ) .
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