Org. Process Res. Dev. 2024, 28, 273−280. DOI: 10.1021/acs.oprd.3c00353 ◆MMV693183 is a promising antimalarial drug
candidate that works for uncomplicated malaria treatment and resistance
management. ◆The new approach is based on the
hypothesis that the steric differences of both primary amines in
(S)-1,2-diaminopropane dihydrochloride (10) would alone be sufficient to direct
acylation to the desired less hindered amine (in blue) in a regioselective fashion. ◆With conditions to provide predominately
the desired amide product 11, the separation of the mixture to exclude the undesired
secondary amide 12 was studied. ◆To complete the synthesis of MMV693183,
L-(+)-tartrate salt 18 was reacted with 2,4,5-trifluorobenzoyl chloride (19) in
the presence of 1.5 equiv of Na2CO3, providing the final API in 72% yield in
>99 area % (210 nm) purity as determined by HPLC. ◆To further showcase the synthetic utility
of our three-step protocol for preparation of MMV693183, two multigram batches
were carried out. |
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