AZD-4407

The development of two efficient strategies for the synthesis of AZD4407 (I) is reported, both of which are considered suitable for large-scale manufactureIn the first approach, 3-bromothiophene is coupled with (2S)-2-methyltetrahydropyran-4-one using Grignard chem.Following hydroxyl protection and lithiation at thiophene C-2, reaction with a protected 5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing a leaving group on sulfur provides AZD4407 after acid-catalyzed deprotection and epimerization.The second approach starts from 2,4-dibromothiophene, which undergoes a selective Grignard exchange reaction at C-2 followed by reaction with similar protected mercapto-oxindole derivativesReprotection of the oxindole ring, followed by a second Grignard exchange, and reaction with (2S)-2-methyltetrahydropyran-4-one provides AZD4407 after acid-catalyzed deprotection and epimerization.

Process development has been conducted to identify a synthetic route to the 5-lipoxygenase inhibitor ZD4407 that could be used for pilot plant manufactureEfficient and environmentally acceptable carbon functionalization of the 3-position of thiophene using readily available 3-bromothiophene has been achieved using a titanium carbanionic intermediate.An efficient functionalization of the 5-position with a thiol group has also been realized using di-Me disulfide, where the side product of the functionalization reaction is used in situ as the reagent for the subsequent deprotections, thereby considerably reducing the impact on the environment.