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

Abstract

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.

Synthesis and Evaluation of Marine-Inspired Compounds Result in Hybrids with Antitrypanosomal and Antileishmanial Activities

“…Our attempts to convert these benzoxazinones directly into the respective quinazolinones by reaction with ammonia did not result in success, contrary to what was reported in another work [24]. In this case, instead of quinazolinones, 2-acylamino-benzamides 8a-8d were obtained as described by Kelleher and coworkers [18], who used this ammonia-based method for the synthesis of this type of benzamide. Intermediates 6a and 7a were easy to handle and could be purified and properly characterized.…”

“…Compounds 8a-8d were prepared in three steps from the respective anthranilic acids, following the classical methods reported before [18,23]. As the intermediates 6b-6d, 7b-7d and 8a-8d were quite unstable, they were readily used in the subsequent reactions without purification.…”

“…Chemical modifications of the eugenol structure or integration of this unit into a given privileged structure is an approach often taken by medicinal chemists to obtain derivatives with improved biological profiles. Therefore, keeping in mind the diversity and potential of marine compounds, particularly of the marine quinazolinones, a series of derivatives of novel quinazolinones associated with the eugenol moiety was designed via a well-known click chemistry reaction [18]. We hypothesized that this new structure scaffold could be promising against parasitic diseases since it brings together essential moieties from bioactive compounds.…”

Novel 1,3-Benzodioxole From Marine-Derived Actinomycete in East Vietnam Sea

“…The calculated carbon chemical shifts of compound 1a (supplemental Table 5S) were in good agreement with those reported in the literature. 8 Other known compounds, 2-[(5-methyl-1,4-dioxan-2-yl) methoxy]ethanol (2), 11 1H-pyrrole-2-carboxylic acid (3), 12 norharman (4), 13 3-hydroxy-adenosine (5), 14 2-acetamidobenzamide (6), 15 cyclo-[Pro-Gly] (7), 16 cyclo-[Pro-Ala] (8), 17 cylo-[Pro-Leu] (9), 18 cyclo-trans-4-OH-[Pro-Phe] (10), 18 and cyclo-[Leu-Tyr] (11) 19 were also isolated and characterized from the culture broth of G261 strain. Their structures were determined by spectral data analysis and comparison with those reported in the literature.…”

Peggy Etter and Polymorphism: Highlights of an Enduring Scientific Legacy

“…It is this difference between the polymorphs in intramolecular vs intermolecular hydrogen-bonding that has since made o -acetamidobenzamide the subject of extensive computational studies relevant to crystal structure prediction . Its structure has been determined by neutron diffraction, and its crystallization in the presence of additives and in a variety of solvated forms has been examined. A direct application of Peggy’s graph set methodology in examining hydrogen-bonding patterns is presented in her study of two polymorphs of 4′-nitrosalicylanilide (Figure ).…”