When using phase-transfer catalysis to make a phosphate ester, usually the reaction is between an alcohol (alkoxide) or phenol (phenoxide) and a phosphoryl chloride. US Patent 9,242,941 describes the formation of a phosphate ester from an alkyl bromide and the tetrabutylammonium salt of a dialkylphosphate in the presence of DMF. This procedure is not phase-transfer catalyzed and could be improved if performed using true PTC conditions. If this reaction needed to be optimized for cost on a commercial scale, costs could be reduced by using catalytic phase-transfer catalyst and making workup much easier by replacing DMF with an easily recoverable solvent that forms two phases with water.
Specifically, we would recommend using actual PTC conditions with potassium di-t-butylphosphate (or the sodium salt if available or the free acid with a base), a catalytic quantity of tetrabutylammonium bromide and an easily recoverable solvent such as toluene. Additional cost reduction may be able to be achieved if one uses the benzyl chloride derivative instead of the benzyl bromide derivative shown in the diagram.
Before locking in a process for a nucleophilic substitution, contact Marc Halpern of PTC Organics to avoid missing an opportunity to reduce the cost of manufacture that phase-transfer catalysis can help you achieve.
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!).
