Studies on the preparation and crystal polymorphism of 2-acetamidobenzamide and related compounds

2-Acetamidobenzamide 1 exists in two crystal polymorphic forms: α and β. The α form features an approximately planar molecular conformation and an intramolecular N-H...O hydrogen bond. In the β form, the amido groups are out of the plane of the benzene ring and no intramolecular hydrogen bonds are present. In our study, the α form was found to be the more readily obtainable initially, usually as well-formed needles. 2-Acetamido-4-chlorobenzamide 8 and 2-acetamido-5-chlorobenzamide 9 were prepared and assessed as additives in recrystallizations of 2- acetamidobenzamide. In the presence of compound 8, attempted recrystallization of 2-acetamidobenzamide gave crystals of the anhydrous form of 2-methylquinazol-4-one 4. Addition of compound 9 had no effect on the crystal form obtained. 10,11-Dihydro-5-acetyldibenzo[b,e][1,4]diazepin-11-one 14 was prepared as a conformational mimic of the molecular conformation of the β form of 2-acetamidobenzamide. Compound 14 had no effect on the recrystallization of 2-acetamidobenzamide from acetone when added in 10% w/w or from water when added in 1% w/w. When 14 was added in 10% w/w quantities to crystallizations of 2-acetamidobenzamide from water, fine crystallites were obtained which gave infra-red spectra consistent with the α form, but gave PXRD patterns suggesting the presence of another form or compound. Disruption of the intramolecular hydrogen bonds in the α form of 2-acetamidobenzamide 1 by direct trimethylsilylation gave mixtures of 1 and 2-methylquinazol-4-one 4. Indirect trimethylsilylation by reaction of 2-methyl-4H-benzo[d][1,3]oxazin-4- one 3 with tris(trimethylsilyl)amine gave crystals of the anhydrous form of 2-methylquinazol-4-one 4. 2-Phthalimidobenzoic acid 18 and 2- phthalimidobenzamide 19 were prepared as structural analogues of compound 1 which are incapable of possessing an intramolecular hydrogen bond. Addition of compound 18 to recrystallizations of 2-acetamidobenzamide 1 had no effect on the outcome. However addition of compound 19 resulted in needle-like crystals of the α form of considerably reduced dimensions.