反应详情

温度

50 °C

To a solution of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in toluene (as obtained in example 7) was added 121.1 g CDI (724 mmol, purity 97 wt %) was added in six portions at 20-25° C. After the addition of each portion the reaction mixture was stirred for 20 min. The funnel was rinsed with 100 mL of toluene and the reaction mixture was stirred at 20-25° C. for 1 h. Then 112.5 g (648 mmol) of 4-fluoroisoindoline hydrochloride was added followed by 30.4 g (300 mmol) of TEA and 100 mL of toluene. The resulting suspension was heated to 48-52° C. temperature and stirred at this temperature for 5 h. After the conversion is completed the reaction mixture was heated to 57-62° C. and 546 g of aqueous HCl (2M) was added. The phases were separated and the organic layer was washed with 500 mL of water. The organic phase was then concentrated at a jacket temperature of 60° C. under reduced pressure to a residual volume of 600 mL. To the residue was added 1140 mL of EtOAc. The obtained solution 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 was used in the next step without further purification.

1. additionwas added in six portions at 20-25° C
2. additionAfter the addition of each portion the reaction mixture
3. washThe funnel was rinsed with 100 mL of toluene
4. stirringthe reaction mixture was stirred at 20-25° C. for 1 h
5. stirringstirred at this temperature for 5 h
6. temperaturewas heated to 57-62° C.
7. customThe phases were separated
8. washthe organic layer was washed with 500 mL of water
9. concentrationThe organic phase was then concentrated at a jacket temperature of 60° C. under reduced pressure to a residual volume of 600 mL
10. additionTo the residue was added 1140 mL of EtOAc
11. customThe obtained solution 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 was used in the next step without further purification