反应详情

8.19 g of crude (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 60 mL of toluene and 4.25 g carbonyldiimidazole (26.2 mmol) was added in portions at a temperature of 22° C. to 25° C. The reaction mixture was stirred for 1.5 h at ambient temperature. Then 3.66 g (21.0 mmol) of 4-fluoroisoindoline hydrochloride was added in portions followed by 3.1 mL of triethylamine. The resulting suspension was heated to 52° C. bath temperature. After stirring for 3 h at this temperature the reaction mixture was cooled with an ice bath and 70 mL of aqueous HCl (1M) were added. The mixture was extracted with 50 mL of toluene. The separated aqueous layer was extracted twice with 50 mL toluene. The combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of sodium carbonate (5% w/w). The toluene extract was dried with sodium sulfate, filtered, and the solvent was completely removed to afford 9.21 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as a grey solid, which was used in the next step without further purification.

1. temperatureThe resulting suspension was heated to 52° C. bath temperature
2. stirringAfter stirring for 3 h at this temperature the reaction mixture
3. temperaturewas cooled with an ice bath
4. extractionThe mixture was extracted with 50 mL of toluene
5. extractionThe separated aqueous layer was extracted twice with 50 mL toluene
6. washThe combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of sodium carbonate (5% w/w)
7. extractionThe toluene extract
8. dry with materialwas dried with sodium sulfate
9. filtrationfiltered
10. customthe solvent was completely removed