The reaction of pyrazine-2,3-dicarboxylic acid anhydride (I) with 2-amino-5-chloropyridine (II) in refluxing acetonitrile gives 3-(5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid (III), which is cyclized by treatment with refluxing SOCl2 affording 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (IV). The partial reduction of (IV) with KBH4 in dioxane-water yields 6-(5-chloro-2-pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one (V), which is finally esterified with 4-methylpiperazine-1-carbonyl chloride (VI) by means of NaH in DMF.
The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with vinyl chloroformate (II) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (95% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.
The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with chloromethyl chloroformate (V) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (96% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.