反应详情

温度

60 °C

A solution of 64.4 g (630 mmol) of H2SO4 in 120 mL of EtOAc was added to a suspension of 1.7 L 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 (theoretical amount: 600 mmol; as obtained from example 8) in EtOAc at 50-60° C. The dropping funnel was rinsed with 80 mL of EtOAc and the reaction mixture was stirred for 3 h at 60° C. To the reaction mixture 800 mL of an aqueous solution of Na2CO3 (10 wt %) was added. The phases were separated and the organic layer was washed with 400 mL of water. The organic layer was concentrated at a jacket temperature of 105° C. to a residual volume of 450 mL. To the residue 1000 mL of toluene was added. To initiate crystallization the temperature was decreased to 60° C. and maintained for 30 min at this value. The suspension is cooled to −2° C. and stirred for 1 h at this temperature. The crystals were collected on a suction filter and washed three times with a total of 400 mL of toluene. After drying at 53° C. under reduced pressure there was obtained 198.2 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as colorless crystals in a purity of 98.0 wt % and a yield of 75% over 4 steps.

1. washThe dropping funnel was rinsed with 80 mL of EtOAc
2. additionTo the reaction mixture 800 mL of an aqueous solution of Na2CO3 (10 wt %) was added
3. customThe phases were separated
4. washthe organic layer was washed with 400 mL of water
5. concentrationThe organic layer was concentrated at a jacket temperature of 105° C. to a residual volume of 450 mL
6. additionTo the residue 1000 mL of toluene was added
7. customcrystallization the temperature
8. customwas decreased to 60° C.
9. temperaturemaintained for 30 min at this value
10. temperatureThe suspension is cooled to −2° C.
11. stirringstirred for 1 h at this temperature
12. customThe crystals were collected on a suction
13. filtrationfilter
14. washwashed three times with a total of 400 mL of toluene
15. customAfter drying at 53° C. under reduced pressure