A variety of synthetic routes to   acid have been developed. The first reported chemical syntheses approached HMB by oxidation of alkene, vicinal diol, and alcohol precursors:
* in 1877, Russian chemists Michael and Alexander Zaytsev reported the preparation of HMB by oxidation of 2-methylpent-4-en-2-ol with chromic acid (HCrO);
* in 1880 and 1889, Schirokoff and Reformatsky (respectively) reported that the oxidative cleavage of the vicinal diol 4-methylpentane-1,2,4-triol with acidified potassium permanganate (KMnO) yields HMB – this result is closest related to the first synthesis as cold dilute KMnO oxidises alkenes to vicinal cis-diols which hot acid KMnO further oxidises to carbonyl-containing compounds, and the diol intermediate is not obtained when hot acidic conditions are used for alkene oxidation.  In other words, racemic 4-methylpentane-1,2,4-triol is a derivative of 2-methylpent-4-en-2-ol and β-hydroxy β-methylbutyric acid is a derivative of both; and,
* in 1892, Kondakow reported the preparation of HMB by permanganate oxidation of 3-methylbutane-1,3-diol.
Depending on the experimental conditions, cycloaddition of acetone and ketene produces either  or 4,4-dimethyloxetan-2-one, both of which hydrolyze under basic conditions to yield the conjugate base of HMB. The haloform reaction provides another pathway to HMB involving the exhaustive halogenation of the methyl-ketone region of diacetone alcohol with sodium hypobromite or sodium hypochlorite; Diacetone alcohol is readily available from the aldol condensation of acetone. An organometallic approach to HMB involves the carboxylation of tert-butyl alcohol with carbon monoxide and Fentons reagent (hydrogen peroxide and ferrous iron). Alternatively, HMB can be prepared through microbial oxidation of  acid by the fungus Galactomyces reessii'.