Methylenedioxyl derivatives

Various substituted and unsubstituted methylenedioxyl derivatives of apomorphine and V-n-propyl-norapomorphine have been studied by Baldessarini et and one of... 

Various substituted and unsubstituted methylenedioxyl derivatives of apomorphine and V-n-propy 1-norapomorphine have been studied by Baldessarini et and one of these, 10,11-methylenedioxy-V-n-propyl-norapomorphine, was found to be both a long-acting and an orally efficient prodrug (Figure 36.29a). The oral activity of the compound can be ascribed to the protection of the catechol system from first-pass effects by the methylenedioxyl group. The conversion to the free catechol is possible, thanks to the hepatic microsomal enzymes (see Chapters 33 and 34 on drug metabohsm). 

As mentioned before structure of 2-2 was proposed by spectral analyses, the position of methylenedioxyl group in isoquinoline of 2-2 is in position C-5—C-6, but it did not exclude its possibility in position C-7—C-8. A total synthesis was accomplished in order to confirm the structure and to derive more samples for pharmacological tests. Piperonal 2-4 was used as starting material. It was oxidized by silver oxide in basic condition to get 2-5, then amidized with dimethyl amine to 2-6 and directed ortho-lithiation with n-butyl-lithium in THF (tetrahydrofuran) to get homogeneous yellow solution, which upon treatment with methyl iodide afforded toluamide 2-7, the yield was 85%. The model synthesis study showed that lithiated toluamide 2-7 could condense with compound 2-14 to achieve the final product 2-2 through several steps (see below). The intermediate compound 2-14 could be synthesized starting from the same piperonal 2-4. It was reacted with cyclohexylamine to get Shiff base 2-8, the latter was reacted with 1.13 equiv. of n-butyllithium at -78°C, the metalated intermediate was carbethoxylated in situ by addition of excess ethyl chloroformate and the aldehyde 2-9 was obtained by extraction with dilute acid. Combination of 2-9 with equimolar of propane-1,3-dithiol a compound 2-10 was obtained, then 2-10 was reduced by lithium aluminum hydride and benzylated with benzyl bromide to 2-12. After treatment with bis(trifluoroacetoxy) iodobenzene, the obtained compound 2-13 was reacted with benzylamine to get the key compound 2-14. 

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