Water → Mglu1 C-11

Participants

Reaction Steps

To a solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (280 g, 1.00 equivalent) and pyridine (catalytic, 0.03 equivalent) in anhydrous THF (350 mL) is added the above acid chloride solution dropwise over 30 min at 6 to 13° C.; and the reaction mixture is stirred at room temperature 1 h. (The progress of the reaction may be followed by HPLC, and acid chloride addition terminated if monitoring indicates complete reaction of the amine.) Water (2.5 L) is added, the phases are separated and aqueous phase is re-extracted with dichloromethane. The combined organic phase is washed (aqueous NaOH (1 L), then water (1 L)). partially evaporated to about 1 kg, and then diluted with THF (2 L) to give an homogeneous solution, from which some water separates. The mixture is allowed to stand overnight at room temperature during which the two phases separate, with the aqueous phase above the organic phase. The phases are separated, THF is added to each phase, water is added to the upper (organic) phase, and each layer is reequilibrated, with very slow phase separation and the organic phase as the top layer. The combined organic phase is charged to a rotary evaporator (10-L flask) through a clarifying membrane (5 μm), toluene (4 L) is added, resulting in opacification of the mixture, and THF/water are evaporated (160 mbar, bath temp 45° C.). As the THF/water are evaporated, crystals begin to form. When 2 L has been distilled, toluene (2 L) is added and distillation continued (85 mbar, bath temp 45° C.). After distillation of a further 2 L of solvent, the system is set to atmospheric pressure, cooled to ambient temperature, and, after 1 h, the resulting suspension is filtered. The filter cake is resuspended in toluene (1 L), refiltered, and washed with toluene (1 L) before it is dried overnight to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 357 g, 92%.

Provenance & Evidence