3-Propylglutaric acid

The synthesis of a-alkylglutaric acids (e.g. 2-propylglutaric acid, Expt 5.136), is conveniently achieved by allowing an alkylmalonic ester to react with the a, / -unsaturated nitrile, acrylonitrile, in thfe Michael manner and then subjecting the product to vigorous acidic hydrolysis. 

Add 8.0g (10.0ml, 0.15 mol) of redistilled acrylonitrile (Expt 5.161, Note (1)) to a stirred solution of diethyl propylmalonate (30.2 g, 0.15 mol) (Expt 5.132) and of 30 per cent methanolic potassium hydroxide (4.0 g) in t-butyl alcohol (100 g). Keep the reaction mixture at 30-35 °C during the addition and stir for a further 3 hours. Neutralise the solution with 2 M-hydrochloric acid, dilute with water and extract with ether. Dry the ethereal extract with anhydrous sojdium sulphate and distil off the ether the residue [diethyl (2-cyanoethyl)-propylmalonate 11 g] solidifies on cooling in ice, and melts at 31—32 °C after recrystallisation from ice-cold ethanol. Boil the cyanoethyl ester (10 g) under reflux with 40 ml of 48 per cent hydrobromic acid solution for 8 hours, and evaporate the solution almost to dryness under reduced pressure. Add sufficient water to dissolve the ammonium bromide, extract several times with ether, dry the ethereal extract and distil off the solvent. The residual oil (4.5 g, 66%) soon solidifies upon recrystallisation from water, pure 2-propylglutaric acid, m.p. 70 °C, is obtained. 

Aliphatic to and to - I hydroxylations commonly take place in drug molecules with straight or branched alkyl chains. Thus, the antiepileptic agent valproic acid (Depakene) undergoes both tuand to- I oxidation to the S-hydroxy and 4-hydroxy metabolites, respectively.Further oxidation of the S-hydroxy metabolite yields 2-/i-propylglutaric acid. 

Dimethylbenzoic acid 3>lsopropylglutnric acid 3 /i-Propylglutaric acid Pbenylacetic acid... 

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