1,2-Benzisoxazole-3-carboxylic acid ethyl ester

Synthesis

At 0 °C and atmospheric pressure, 10% palladium-carbon catalyst (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were sequentially added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300 ml). Subsequently, the reaction system was subjected to nitrogen displacement treatment by removing the nitrogen by evacuation and replacing it with hydrogen, keeping the reaction mixture under hydrogen atmosphere for 1 hour. Upon completion of the reaction, hydrogen was again removed by evacuation and replaced with nitrogen, and the reaction mixture was filtered through diatomaceous earth to remove the palladium-carbon catalyst. The filter cake was washed with ethanol (3 x 50 mL), the filtrates were combined and concentrated. The concentrated residue was dissolved in dichloromethane (200 mL) and the resulting solution was washed sequentially with water (4 x 50 mL), dried over anhydrous sodium sulfate and the solvent was evaporated to give 13.0 g of the target product, ethyl 1,2-benzisoxazole-3-carboxylate, as a yellow solid in 96% yield. Subsequently, saponification of the ester group was carried out by aqueous sodium hydroxide to obtain the corresponding carboxylic acid product 1,2-benzisoxazole-3-carboxylic acid. Finally, the carboxylic acid was subjected to a coupling reaction with a bicyclic base according to Method A. Ref: Angell, R.M.; Baldwin, I.R.; Bamborough, P.; Deboeck, N.M.; Longstaff, T.; Swanson, S. W004010995A1.

References

[1] Patent: WO2005/63767, 2005, A2. Location in patent: Page/Page column 44-45
[2] Patent: WO2005/111038, 2005, A2. Location in patent: Page/Page column 66-67
[3] Patent: US2005/250808, 2005, A1. Location in patent: Page/Page column 40