Process Development of a Novel Azetidinyl Ketolide Antibiotic

Abstract

Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.

Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260

“…Compound 15 was synthesized in two steps from commercially available 6-methylpyridazin-3-amine 16 by treatment with DMF–DMA followed by cyclization of the intermediate amidine 19 with bromoacetonitrile (Scheme ). Treatment of 15 with DMF–DMA provided enamine 14 , which was oxidatively cleaved with sodium periodate to furnish aldehyde 6 . − We were able to rapidly achieve proof-of-concept on this route, which enabled our route-selection efforts. The next section describes the development of this synthetic route into a scalable process.…”

“…While the conversions were low to modest in most of the solvents screened (Table 1, entries 3−7), 38 it was gratifying to note that methanol provided ∼83 area % product at ambient temperature (Table 1, entry 8). 28 Interestingly, the addition of 10% v/v water to the methanol reaction pushed the reaction to 96 area % product (Table 1, entry 9). The addition of water facilitated the reaction presumably by increasing the solubility of NaIO 4 in the reaction medium.…”

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

“…Additionally, the 3-bromo-1,5-naphthyridine 2b [ 9 ], was reached through a modified Skraup reaction using m -NO 2 PhSO 3 Na [ 10 ]. 2-Methyl- [ 11 ] and 3-methoxy-4-methyl-1,5-naphthyridines 2c – 2e [ 12 , 13 , 14 ] ( Scheme 1 ) were also reported.…”

“…The substituents on the 1-5-naphthyridine ring have been subjected to a wide range of chemical transformations. Researchers at Pfizer modified the 2-methyl-3-methoxy-1,5-naphthyridine 2d (previously prepared, vide supra, Scheme 1 ) to give, after three steps, the 3-hydroxy-1,5-naphthyridine-4-carbaldehyde 191 necessary for the preparation of a novel azetidinyl tethered ketolide series ( Scheme 78 ) [ 13 , 14 ]. Before, the same group prepared the same carbaldehyde derivative 191 by synthesizing the hydroxyl derivative 188 followed by the proteccion of naphthyridine 190 [ 12 ].…”

“…The scale-up synthesis of the antibacterial azetidinyl ketolide 219 was achieved by a reductive amination between the 1,5-naphthyridine aldehyde 191 (previously prepared, vide supra, Scheme 78 ) and some clarithromycin derivatives 218 ( Scheme 89 ) [ 13 ].…”