Nafithromycin

Present study described the facile and efficient synthesis of R‐nosylate (chemical name: (R)‐1‐(5‐(pyridin‐2‐yl)‐1,3,4‐thiadiazol‐2‐yl)‐ethyl,4‐nitrobenzenesulfonate) as new key intermediate of nafithromycin. The R‐nosylate (3 b) was prepared in six steps, starting from readily available methyl‐D‐lactate. To produce a 3 b with a good yield and remarkable chiral high performance liquid chromatography (CHPLC) purity more than 99 %, a large‐scale practical and environmentally friendly process was generated and optimized. The developed method, which was successfully established at the pilot scale and then used as the base for industrial production, considerably decreased the use of harmful reagents.

In structure activity relationship-driven novel ketolide drug development program at Wockhardt, the reaction between racemic 2-[5-(1-bromoethyl)-1,3,4-thiadiazol-2-yl]pyridine and novel amidoxime ketolide core concluded the synthesis of WCK 4871 as a diastereomeric mixtureThis mixture of compounds, when subjected for initial microbiol. evaluation, exhibited desired activities against resistant Gram-pos. Streptococcus pneumoniae and Streptococcus pyogenes.In order to attain further improvements in microbiol. activities, diastereomeric separation of WCK 4871 was essential.Initially, development of chiral preparative HPLC method helped to achieve the separation of diastereomeric mixture by giving out two compounds, WCK 4872 and WCK 4873.Here, WCK 4873 (nafithromycin) was found potent in preclin. studies and chosen for advance clin. developments as suitable drug candidate.In order to accomplish the chiral synthesis of nafithromycin, in the first attempt, chiral auxiliary, (S)-mandelic acid gave us undesired isomer, (S)-1-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)ethanol, leading into the synthesis of WCK 4872.Upon altering the chiral auxiliary, (R)-mandelic acid furnished the synthesis of nafithromycin, although associated problems in the recrystallization through chiral auxiliary approach prompted us in finding the alternate routes.Finally, the chiral synthesis of nafithromycin was achieved through the chiral pool approach where the side chain, (R)-1-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)ethyl 4-nitrobenzenesulfonate, was prepared in 5 steps, starting from Me D-lactate.