Diisopropylethylamine → 3-(4-{[2-(4-Chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

Dissolve 2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carboxylic acid (147 g, 448 mmol), 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (120 g, 402 mmol), and 1-hydroxybenzotriazole hydrate (75 g, 490 mmol) in THF (1.2 L) and cool to about 10° C. under a nitrogen atmosphere Treat the above solution with diisopropylethylamine (117 mL, 673 mmol) dropwise over 2 min while keeping the temperature between 10-15° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93 g, 489 mmol) to the solution and stir at room temperature for 19 h. Cool the solution to 0° C. and dilute with water (1.2 L). Collect the precipitate by filtration and triturate with water (5×700 mL). Dry the tan solid for 3 days at 50° C. under vacuum to obtain 219 g (90%) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 10.03 (s, 1H), 7.90 (m, 2H), 7.66 (d, 1H, J=2.4), 7.42 (m, 2H), 6.88 (dd, 1H, J=2.4, 8.6), 6.57 (d, 1H, J=8.6), 4.86 (m, 1H), 4.84 (t, 1H, J=5.7), 4.26 (dd, 2H, J=6.7, 10.6), 4.08 (dd, 2H, J=4.3, 10.6), 3.90 (s, 3H), 3.53 (s, 6H), 3.37 (d, 2H, J=5.5), 1.43 (s, 9H).

Provenance & Evidence