The inventors at 2Y-Chem developed a “one pot” process for the synthesis of a xanthine derivative that uses three consecutive phase-transfer catalysis N-alkylations in high yield without the need to isolate intermediates. The three N-alkylations were screened with a variety of phase-transfer catalyst quats and PEG’s and co-catalysts such as iodide, though only one sequence is shown in the diagram. It is worthwhile to read this patent to learn of the smart approaches taken by the inventors.
The first alkylation was performed at N(7) which has a reported pKa of 11.6. This pKa is higher than that of N(1) reported to be 8.3 (see http://www.actabp.pl/pdf/2_2004/493.pdf). When PTC is used with K2CO3 for two alkylations on the same molecule, the first alkylation almost always occurs at the more acidic site which in this case is N(1). This may be the reason that an amine was used as the base for the first N-alkylation (this is just speculation and may not be correct).
Several solvents were screened for these reactions and were successful. We chose to highlight methyl-THF here to show the minimum number of solvent exchanges as well as using one phase-transfer catalyst for all three reactions.
If your company wants to streamline processes by performing consecutive PTC reactions, now contact Marc Halpern of PTC Organics to integrate the most highly specialized expertise in industrial phase-transfer catalysis to achieve low-cost high-performance green chemistry.
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!).
