Phosgene → 2-Chloro-1-[2-(1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]-1-propanone

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Reaction Steps

The second step in the synthesis of AV1013 involves reacting the intermediate (IPPP), with 2-chloro-propan-1-one under Friedel-Craft conditions to synthesize the corresponding chloroketone. Thus, reaction of isopropylpyrazolo[1,5-a]pyridine (IPPP) with 2-chloropropionyl chloride in the presence of aluminum chloride (Example 1, Step 2), gave 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (i.e., 2-chloro-desmethylibudilast). In an alternate strategy as described in Example 8, IPPP is allowed to react with propanoyl chloride under Friedel-Crafts acylation conditions to give desmethylibudilast. It should be noted that the terms desmethylibudilast and Nor-methyl ibudilast are used interchangeably throughout the specification. The obtained Nor-methyl ibudilast is then converted to the corresponding alpha-chloroketone (2-chloro-desmethylibudilast), by techniques known in the chemical art, for example, via chlorination.

Provenance & Evidence