Formamide, methanolysis

A second-generation process ronte was developed that improves upon the initial process route (Scheme 6). - - In this simplified process approach, the molecular symmetry of the starting caronic anhydride was maintained to the latest stage possible. Caronic anhydride (30) was initially converted directly to imide 40 by heating with either ammonium hydroxide or formamide with DMAP under Dean-Stark conditions. In an alternative two-step protocol, heating of 30 with benzyl amine produced an intermediate benzyl imide, which was deprotected to 40 under catalytic hydrogenation conditions. Reduction of imide 40 with lithium aluminum hydride afforded 41, which was desymmetrized under oxidative conditions to produce racemic imine 42. Diastereoselective cyanation favored trans-43, which underwent methanolysis under Pinner conditions. Finally, classical resolution by crystallization with D-DTTA afforded 24 as the D-DTTA salt with >95% ee. 

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