反应详情

1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide (120 g, 401 mmol) was dissolved in 400 mL of dry tetrahydrofuran. 55.8 g (420 mmol) of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic acid was added in a single portion and the mixture was stirred overnight at room temperature. The mixture was then filtered and the tetrahydrofuran was evaporated under reduced pressure. The residue was dissolved in 800 mL of ethyl acetate, a solution of 86.0 g of sodium bicarbonate in 870 mL of water was added and then solid sodium chloride was added to saturate the aqueous layer. The aqueous layer was separated, washed with 250 mL of ethyl acetate, and then with diethyl ether (twice with 250 mL). The aqueous layer was then added slowly to a stirred mixture of 120 mL of concentrated hydrochloric acid, 240 mL of water, and 800 mL of tetrahydrofuran. Solid sodium chloride was then added to saturate the aqueous layer, the layers were separated, and the aqueous layer was extracted with 100 mL of tetrahydrofuran. The tetrahydrofuran layers were combined, dried over magnesium sulfate, and evaporated under reduced pressure to afford 173.43 g of the title compound as a glassy solid, suitable for use in the next step. 1H NMR (DMSO-d6): δ 2.0-2.3 (m, 1H), 2.5-2.6 (m, 1H), 3.66 (m, 1H), 3.86 (m, 1H), 4.97 (s, 2H), 5.40 (d, J=54 Hz, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 8.48 (s, 1H), 10.10 (br s, 1H).

1. filtrationThe mixture was then filtered
2. customthe tetrahydrofuran was evaporated under reduced pressure
3. dissolutionThe residue was dissolved in 800 mL of ethyl acetate
4. additiona solution of 86.0 g of sodium bicarbonate in 870 mL of water was added
5. additionsolid sodium chloride was added
6. concentrationto saturate the aqueous layer
7. customThe aqueous layer was separated
8. washwashed with 250 mL of ethyl acetate
9. additionThe aqueous layer was then added slowly to a stirred mixture of 120 mL of concentrated hydrochloric acid, 240 mL of water, and 800 mL of tetrahydrofuran
10. additionSolid sodium chloride was then added
11. concentrationto saturate the aqueous layer
12. customthe layers were separated
13. extractionthe aqueous layer was extracted with 100 mL of tetrahydrofuran
14. dry with materialdried over magnesium sulfate
15. customevaporated under reduced pressure