Pivaloyl chloride → 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropyl-carbamoyl)-pyrrolidin-3-yl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 57.7 g (128 mmol) (S)-2-tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt (commercially available from Synthetech Oregon, USA) in 350 mL of THF was added dropwise to a solution of 15.1 g (125 mmol) pivaloyl chloride in 200 mL of THF while maintaining the temperature at 0-5° C. The dosing funnel was rinsed with 50 mL of THF and the suspension was stirred for 90 min at 5° C. jacket temperature. The temperature was decreased to −5° C. and 50.0 g (116 mmol) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester was added in five portions within 30 min to the mixed anhydride at −5° C. to 0° C. The funnel was rinsed with 25 mL of THF. The suspension was first stirred for 30 min at 0° C., then for 6 h at 23° C. After complete conversion 150 mL of water was added. The reaction mixture was concentrated at 50° C. jacket temperature under reduced pressure to a residual volume of 300 mL. After cooling to 23° C. 500 mL of toluene and 58 mL of aqueous HCl (1M) were added. The suspension was filtered and the reaction vessel and filter cake were washed with 220 mL of toluene. The phases of the filtrate were separated and the aqueous layer was extracted with 150 mL of toluene. The organic layers were washed separately with 200 mL of aqueous Na2CO3 (10 wt %) and 58 mL of aqueous HCl (1M). The combined organic layers were concentrated at 50° C. under reduced pressure using a rotary evaporator to afford 143.3 g of crude (54.5 wt %) 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropyl-carbamoyl)-pyrrolidin-3-yl ester in a yield of 98.4%.

Provenance & Evidence