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

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Reaction Conditions

Reaction Steps

Mix 1-propanephosphonic acid cyclic anhydride (50% in EtOAc) (528.7 g, 831.3 mmol) and THF (1110 mL) and chill to 5° C. Add 2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carboxylic acid (185.0 g, 593.43 mmol) followed by 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (192.2 g, 914.4 mmol). Charge N-methylmorpholine (99 mL, 1247 mmol) dropwise over 15 min and remove the ice bath immediately after the addition. Heat the reaction to 65° C. for 16 h and quench with water (555 mL). Dilute with EtOAc (1110 mL) and partition the layers. Wash with saturated sodium bicarbonate (555 mL) and with brine (555 mL). Distill the organic solvent until <5% THF remains and then back-add with ethyl acetate as needed to a total of 740 mL solvent at the end of the distillation. Add heptane (230 mL) at 75° C. and seed with authentic product at 55° C. Allow to cool to room temperature, filter, and rinse twice with heptane-EtOAc (2×100 mL, 1:1). Dry in a vacuum oven at 40° C. to obtain 313.5 g (90%) of the title compound as an orange-brown solid. ES/MS m/z (35Cl) 586 [M−1]−.

Provenance & Evidence