Isobutyric acid crystallization

The solution of N-acetyl-N-(3-aminophenyl)-p-amino-isobutyric acid was filtered after standing overnight, mixed with an equal volume of acetic acid, and there after with a solution of 275.0 g iodine monochloride and 200.0 g sodium chloride in 1 L water. The mixture was kept at 50°C with stirring for 48 h. Light brown crystals of crude N-acetyl-N-(2,4,6-triiodo-3-aminophenyl)-p-amino-isobutyric acid precipitated, were filtered off, washed with water, and dried. They weighed 195.0 g (84.5% yield based on N-acetyl-N 3-nitrophenyl-p-amino-isobutyric acid). 

A few comments concerning the crystallization of carbanions are in order. These comments are based upon the personal experience developed in our own laboratory and also upon observations noted in the literature in the course of crystallizing enolate anions. Although alkali metal enolate anions are relatively unstable compounds, they have been prepared in the solid state, isolated, and characterized by IR and UV spectroscopy in the 1970s. Thus the ot-lithiated esters of a number of simple esters of isobutyric acid are prepared by metallation of the esters with lithium diisopropylamide in benzene or toluene solution. The soluble lithiated esters are quite stable at room temperature in aliphatic or aromatic hydrocarbon solvents and are crystallized out of solution at low temperature (e.g. -70 °C.). Alternatively the less soluble enolates tend to precipitate out of solution and are isolated by centrifugation and subsequent removal of the solvent. Recrystallization from a suitable solvent can then be attempted. The thermal stability of the lithiated ester enolates is dramatically decreased in the presence of a solvent with a donor atom such as tetrahydrofuran. 

Fig. 2 Crystal structure of 4 bound to HPV-11 E2. Primary ligand is in magenta. Secondary hot spots are at positions of isobutyric acid and chlorophenyl group of second inhibitor molecule. Conformationally mobile binding pocket residues are highlighted (pdb lr6n)...

To a 10-mL Et20 solution containing 610 mg benzoic acid (5 mmol) were added 360 mg isobutyric aldehyde (5 mmol) and 586 mg benzyl isocyanide (5 mmol). The resulting mixture was stirred overnight at room temperature. The crystallized product was filtered off, washed with cold Et20, and dried under high vacuum to give 1.30 g l-benzylcarbamoyl-2-methyl propyl benzoate as a solid, in a yield of 84%. 

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