反应详情

A slurry of 1-isopropylpiperidine-4-carboxylic acid (501.0 mg, 2.92 mmol) and 50% DMF/THF (6.3 mL) was cooled in an ice bath, and a solution of iso-butyl chloroformate (0.34 mL, 2.63 mmol) and 50% DMF/THF (0.7 mL) was added over 10 min via syringe. The ice bath was removed at addition's end, and the mixture was allowed to warm to ambient temperature. After 1 h, 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (414.8 mg, 1.47 mmol) was added in one portion, and the slurry was heated to 70° C. in an oil bath. Analysis by HPLC after 17 h showed only 2.5% of unacylated amine remained, so the volatiles were removed under reduced pressure, and EtOAc (25 mL) and water (20 mL) were added. The organic layer was extracted with saturated NaHCO3 (2×20 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to 0.97 g of yellow solid which was found to be contaminated with 45 wt % DMF. Corrected yield was 0.53 g (83% yield), and no further purification was performed:

1. customThe ice bath was removed at addition's end
2. temperaturethe slurry was heated to 70° C. in an oil bath
3. waitAnalysis by HPLC after 17 h showed only
4. customwere removed under reduced pressure, and EtOAc (25 mL) and water (20 mL)
5. additionwere added
6. extractionThe organic layer was extracted with saturated NaHCO3 (2×20 mL)
7. extractionthe combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL)
8. dry with materialThe combined organic layers were dried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated to 0.97 g of yellow solid which
11. customCorrected yield was 0.53 g (83% yield), and no further purification