Biomimetic synthesis of the metabolites of trequinsin

摘要

Six metabolites of Trequinsin [9,10-dimethoxy-3-methyl-2-(2,4,6-trimethylphenylimino-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-4-one. hydrochloride] are identified which have been synthesised from the parent molecule trequinsin 1. A base-promoted selective demethylation of 1 at position 9 gives the metaboline 4. An acid aided demeethylation at position 10 furnishes the metabolite 7. Treatment of compounds 1 and 4 with DDQ gives the 4'-DDQ complexes 10 and 14 respectively. These complexes on treatment with ZnCl_2-MeOH afford the 4'-methoxymethyl derivatives 11 and 15 respectively, which on subsequent demethylation with dil. HCI give the corresponding hydroxy derivatives 2 and 5. When treated with two equivalents of DDQ, 1 gives the DDQ complex 12, which on subsequent treatment with Zn(OAc)_2 yields the 4'-formyl derivative 13. Oxidation of 13 with AgNO_3-NaOH gives the 4'-carboxy derivative 3, which was subsequently selectively demethylated to give the metabolite 6. Treatment of 13 with NH_2OH.HCI produces the oxime 17, which is then dehydrated to the nitrile 18 using (Ac)_2O. Alkaline hydrolysis of 18 gives 3.