A very interesting reaction, shown in the diagram was reported in a patent issued today (26-Nov-2024). The reaction is a one-step process that uses ammonia to replace the hydroxy group in 4-hydroxy-5-methyl-1H-pyridin-2-one, DIRECTLY with an amino group.
The motivation for developing this reaction was to avoid a 2-step process that first reacts the hydroxy group with a large excess of benzylamine at 185 deg C for 36 hours followed by hydrogenation with a Pd/C catalyst at high catalyst loading.
The reaction uses ammonia as the solvent (~50 equiv) under high pressure (rise in pressure to 90 bar) at 170 deg C for 20 hours. The reaction uses stoichiometric tetrabutylammonium bromide. The excess ammonia is captured and recycled directly into an autoclave ready for the next reaction.
One may speculate that the purpose of the quat salt is to help bring the ammonia and the hydroxypyridine into contact by hydrogen bonding between the bromide of the quat salt and an N-H group. This may be similar to the use of quats salts for reactions with HCl or hydrogen peroxide in which the anion of the quat salt hydrogen bonds to the acid or hydrogen peroxide and transfers the hydrogen-containing molecule into the reaction phase.
PTC Organics has contemplated the use of ammonia with phase-transfer catalysts, but under much more favorable conditions that are much more likely to result in an economically feasible process for multiple reasons. We do not disclose these conditions without a business agreement.
About Marc Halpern
Dr. Halpern is founder and president of PTC Organics, Inc., the only company dedicated exclusively to developing low-cost high-performance green chemistry processes for the manufacture of organic chemicals using Phase Transfer Catalysis. Dr. Halpern has innovated PTC breakthroughs for pharmaceuticals, agrochemicals, petrochemicals, monomers, polymers, flavors & fragrances, dyes & pigments and solvents. Dr. Halpern has provided PTC services on-site at more than 260 industrial process R&D departments in 37 countries and has helped chemical companies save > $200 million. Dr. Halpern co-authored five books including the best-selling “Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives” and has presented the 2-day course “Practical Phase-Transfer Catalysis” at 50 locations in the US, Europe and Asia.
Dr. Halpern founded the journal “Industrial Phase-Transfer Catalysis” and “The PTC Tip of the Month” enjoyed by 2,100 qualified subscribers, now beyond 130 issues. In 2014, Dr. Halpern is celebrating his 30th year in the chemical industry, including serving as a process chemist at Dow Chemical, a supervisor of process chemistry at ICI, Director of R&D at Sybron Chemicals and founder and president of PTC Organics Inc. (15 years) and PTC Communications Inc. (20 years). Dr. Halpern also co-founded PTC Interface Inc. in 1989 and PTC Value Recovery Inc. in 1999. His academic breakthroughs include the PTC pKa Guidelines, the q-value for quat accessibility and he has achieved industrial PTC breakthroughs for a dozen strong base reactions as well as esterifications, transesterifications, epoxidations and chloromethylations plus contributed to more than 100 other industrial PTC process development projects.
Dr. Halpern has dedicated his adult life to his family and to phase-transfer catalysis (in that order!).
