Improved Manufacturing Process for Pyronaridine Tetraphosphate

Abstract

Pyronaridine tetraphosphate (1) is a well-known antimalarial drug. However, it required a carefully optimized production process for the manufacture of pyronaridine tetraphosphate. Each step of its manufacturing process was reinvestigated. For the cyclization of 4-chloro-2-(6-methoxy-pyridin-3-yl-amino)-benzoic acid 6 to 7,10-dichloro-2-methoxybenzo[b]-1,5-naphthyridine 5, an improved process was developed to eliminated critical process impurity (BIA). By the redesign of the formation of triphosphate salt, the purity as API grade was increased. Thus, a robust manufacturing process with an acceptable process performance has been developed to produce high quality pyronaridine tetraphosphate.

Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine

“…Cyclization and concomitant deoxychlorination of compound 3 to form heteroaromatic 4 was achieved using POCl 3 . Et 3 N was included to prevent evolved HCl from demethylating the methoxy group and leading to impurity I (Figure ) following subsequent deoxychlorination . Although water could not be used in this step due to the water-sensitive nature of POCl 3 , toluene served nicely and could be recovered following isolation of product 4 , thereby limiting organic waste generation.…”

“…The overall linear sequence, therefore, is performed in four individual steps in three pots. The overall efficiency has been increased from 43% to 87% using this process.…”

Fused 1,5-Naphthyridines: Synthetic Tools and Applications

“…The process has been applied to the industrial preparation of pyronaridine tetraphosphate 21 ( Scheme 6 ), a well-known antimalarial drug, by introducing several modifications [ 17 ]. The cyclization of compound 19 to derivative 20 is the most important stage in the synthesis of pyronaridine tetraphosphate 21 .…”

“…The same reaction was used in the industrial preparation of pyronaridine tetraphosphate 21 ( Scheme 6 , vide supra) a well-known antimalarial drug. Thus, the halogen atom at position 10 of the benzo[ b ][1,5]naphthyridine ring in 20 was replaced (S N Ar) by an aminophenol group to give compound 162g ( Scheme 39 ) used later in the preparation of pyronaridine tetraphosphate [ 17 ].…”

“…In the industrial preparation of antimalarial drug pyronaridine tetraphosphate 21 , the compound 162g previously described ( Scheme 39 , vide supra) underwent a Mannich reaction with pyrrolidine in the presence of formaldehyde to give pyronaridine 184 ( Scheme 50 ) and the yield increased about 20% [ 17 ]. Finally, 184 was treated with phosphoric acid to yield pyronaridine tetraphosphate 21 .…”