Morpholine → 3-Fluoro-4-morpholinobenzoic acid

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Reaction Steps

A 2 L 3-neck round bottom flask fitted with mechanical stirrer and reflux condenser was charged with morpholine (700 g, 700 ml, 8 mol) and to the stirring solution was added 3,4-difluorobenzoic acid (158 g, 1 mol) (AmplaChem, Inc). The clear solution was heated at reflux and after 29 hours a ca. 0.5 ml aliquot was removed from the light yellow reaction solution, acidified with 6 N HCl and the precipitate was analyzed by 1H NMR (DMSO-d6) showing that the reaction was complete by the absence of the aromatic peaks at δ7.78-7.92 present in the starting material. The reaction was allowed to cool to below 100° C. and was carefully acidified (pH 1 to 2) with 6 N hydrochloric acid with rapid stirring (initial addition of 6N HCl was dropwise but then as a slow stream with cooling). The product starts to precipitate as the pH falls below 6. The precipitate was collected by filtration and washed thoroughly with hot (80° C.) water (2 L) to ensure the removal of morpholine hydrochloride (that appears as two triplets just above the morpholine peaks for (14) in the NMR) The white precipitate was dried at 110° C. under house vacuum and recrystallized by dissolving in ethanol (4.5 L) and concentration to 1.5 L with stirring. Crystals started to form in the refluxing solution when the volume had been reduced to ca. 3.5 L. The crystals were cooled to room temp with stirring, cooled in an ice bath for 1 hour with stirring, collected by filtration and dried in vacuo at 80° C. (172.5 g, 77%). 1H NMR spectrum identical with that for the product described in the previous paragraph.

Provenance & Evidence