Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core

Abstract

The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic understanding of the cyclization step in the presence of guanidine was established by performing isotopic labeling experiments and identification of impurities. Guided by the mechanistic understanding, further attempts to modify the cyclization reaction by employing additives to reduce the triazine (9) formation and guanidine loading will also be presented. This newly developed method delivered compound 1 in 88−94% yield on a commercial scale and addressed the shortcomings of the early synthetic route including high PMI, low atom economy, long cycle-time, and multiple purifications to achieve the desired quality.

Synthetic Approaches to the New Drugs Approved During 2022

“…247 Alkylation of phenol 34.3 with chloroacetonitrile in the presence of aqueous sodium hydroxide provided cyanomethyl intermediate 34.4. 248 The diaminopyrimidine heterocycle was formed by formylation using ethyl formate and KOtBu followed by reaction with guanidine HCl to complete the cyclization and obtain 34.5 in 81% yield. 249 This was performed in a hybrid flow-batch telescoped process.…”

“…This enabled the Cu-catalyzed methoxylation to proceed without the need for phenol protection as well as the suppression of undesired dimerization products . Alkylation of phenol 34.3 with chloroacetonitrile in the presence of aqueous sodium hydroxide provided cyanomethyl intermediate 34.4 . The diaminopyrimidine heterocycle was formed by formylation using ethyl formate and KOtBu followed by reaction with guanidine HCl to complete the cyclization and obtain 34.…”

DELTA50: A Highly Accurate Database of Experimental 1H and 13C NMR Chemical Shifts Applied to DFT Benchmarking

“…Such calculations can aid in NMR peak assignments [ 9 , 10 ], as highlighted in our recent example of misassigned beta-lactam carbonyl chemical shifts [ 11 ]. They have been used to confirm organic [ 12 , 13 , 14 , 15 ], inorganic [ 16 , 17 ], and organometallic [ 18 , 19 ] reaction products, particularly those with unexpected or unusual molecular structures [ 20 , 21 , 22 ], and they have been applied in complex speciation studies [ 23 , 24 , 25 ]. Perhaps most notably, chemical shift calculations were used to revise incorrectly reported natural product structures: aquatolide [ 26 ], vannusal B [ 27 ], glabramycin C [ 28 ], and hexacyclinol [ 29 ].…”

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 5: Completion of the API Free Base via a Direct Chlorosulfonylation Process

“…After successfully developing a streamlined synthesis of the diaminopyrimidine 1 , , we turned our attention to completing the synthesis of gefapixant through the installation of the sulfonamide functionality to give the API free base 3 . Unfortunately, the first-generation supply route protocol for this transformation suffered from several deficiencies that would preclude its use in a commercial route (Scheme A): (1) the synthetic sequence required three distinct chemical steps to install the sulfonamide; (2) the use of sulfolane, a Class 2 solvent with strict residual limits (<160 ppm), was undesirable in the final steps of the synthesis; (3) the use of two highly toxic and hazardous chemicals, chlorosulfonic acid (HSO 3 Cl) and POCl 3 , was likewise unattractive; (4) issues with process robustness were observed on scale-up; and (5) multiple recrystallizations of the free base product were required to reach the purity specifications with respect to impurities 4 , 5 , and unidentified phosphate oligomers.…”

“…470 g, 1.19 mol) aged for 2 h, acidified to pH 10.5−11.3 with a 2 M aqueous solution of citric acid over 5−10 h, and then aged for 2 h. The slurry was filtered, the resulting cake was washed with 9:1 water:acetonitrile (2 × 118 L) and water (2 × 235 L) and dried at 55 °C under vacuum to provide gefapixant free base 3 (50.9 kg, 91%) as a solid 1. H NMR (500 MHz, DMSO-d 6 ) δ 7.36 (s, 1H), 7.07 (s, 1H), 7.05−6.89 (m, 3H), 6.37 (s, 2H), 5.85 (s, 2H), 3.89 (s, 3H), 3.41 (hept, J = 6.6 Hz, 1H), 1.27 (d, J = 6.8 Hz, 6H).…”