Diisopropylethylamine → 4-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Steps

To a stirred solution of 4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (48, 3.4 g, 6.20 mmol) in dry DMF (50 mL) was added (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester tosylate (2.23 g, 6.82 mmol) and diisopropylethylamine (2.70 mL, 17.1 mmol). Then, HATU (2.59 g, 6.82 mmol) was added at 0° C. under nitrogen. After 30 min at 0° C., the reaction mixture was successively allowed to warm up to room temperature for 4 h, then diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layers were combined and washed with a saturated solution of NaHCO3, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography (gradient EtOAc/CH2Cl2, 0:1 to 2:8) afforded 3.0 g (70%) of the title product 49: m/z=685 (M+H)+.

Provenance & Evidence