Process Development For Menthyl Carbonyl Esters And Their Applications Of In Synthesis Of Emtricitabine And Maytansinoid

The thesis dealt with process development of menthyl carbonyl esters via ester-exchange reaction and applications in synthesis of intermediates of emtricitabine and maytansinoid.p-Toluenesulfonic acid (p-TsOH) was founded to be the optimal catalyst for the ester-exchange reaction of (3-carbonyl esters with menthol while pyridinium p-toluenesulfonate (PPTS) showed the best catalytic activity in reaction of ethyl glyoxalate and menthol. The scope of reaction of β-carbonyl esters with menthol was explored, showing that steric hinerance affected the reaction significantly.The key emtricitabine intermediate,1,3-oxathiolane-2-carboxylic acid,5-hydroxy-methyl-2-(1-methylethyl) cyclohexyl ester, was synthesized from L-(-) menthyl glyoxylate hydrate in46%total yield. Dimenthyl1,3-acetonedicarboxylate was obtained by p-TsOH-catalyzed ester exchange of diethyl1,3-acetonedicarboxylate with L-(-)-menthol in78%yield, from which pentanedioic acid-2,4-bimethyl-2,3-pentene-1,5-bis [5-methyl-2-(1-methylethyl)cyclohexyl] ester, a key intermediate for maytansine was synthesized through methylaltion, reduction, hydroxyl elimination in25%total yield. Another aromatic intermediate for maytasine,3-methoyl-4-chloro-5-methyl acetamido methyl benzoate, was also synthesied in30%total yield from vanillate through nitration, chloration, reduction, and methylation. Alternative route to the aromatic intermedaite via C-N and C-O cross-coupling of3,5-bibromo-4-chlorobenzaldehyde/propiophenone starting from p-aminotoluene and bromobenzene was also explored.