Step b) Synthesis of ethyl 3-(4-fluorophenyl)-5-methylisoxazole-4-carboxylate: To a suspension of 4-fluorobenzaldehyde oxime (1.39 g, 10.0 mmol) in DMF (10 mL) was added N-chlorosuccinimidyl chloride (1.36 g, 10.0 mmol) in batches over a period of 5 min at 15 to 20 °C. The resulting mixture was stirred at room temperature for 90 min to produce a yellow solution containing N-hydroxy-4-fluorobenzimidoyl chloride. Subsequently, a solution of ethyl 3-(1-pyrrolidinyl)crotonate (1.89 g, 10.0 mmol) in DMF (5 mL) was added dropwise to this solution over 2 min at room temperature. The reaction mixture was continued to be stirred at room temperature for 28 hours. After completion of the reaction, the mixture was diluted with water (25 mL) and extracted with ethyl acetate (4 x 25 mL). The organic layers were combined, washed sequentially with 1 M HCl (2 × 25 mL) and water (2 × 25 mL), dried over anhydrous Na2SO4, and subsequently concentrated to dryness at 45 °C/25 mbar to yield 2.37 g (95% yield) of ethyl 3-(4-fluorophenyl)-5-methylisoxazole-4-carboxylate as a brown solid, with purity of 100% by GC and HPLC analysis The purity was 97% by GC and 97% by HPLC.
