According to one approach, therefore, the desired S-enantiomer of AV1013 is prepared by chiral resolution of the corresponding racemic mixture. As shown in FIG. 6, and described in the Example 1 below, synthesis of AV1013 involves several steps. The first step involves the synthesis of 2-chloro-nor-methylibudilast using either ibudilast (2-methyl-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one) or the corresponding 3-carboxylic acid (2-isopropyl-pyrazolo[1,5-a]pyridin-3-carboxylic acid, ibudilast acid) as the starting material. Thus, reacting ibudilast with an aqueous solution of a strong inorganic acid, for example, 50% aqueous sulfuric gave isopropylpyrazolo[1,5-a]pyridine (IPPP) following a loss of its 3-ring substituent (2-methyl-propan-1-one). Alternatively IPPP is obtained via the decarboxylation of 2-isopropyl-pyrazolo[1,5-a]pyridin-3-carboxylic acid under acidic conditions. See, Example 1, method 2, step 1.
