Development of Efficient Processes for the Preparation of Di-tert-butyl Potassium Phosphate and Di-tert-butyl (Chloromethyl) Phosphate

作者：Zheng Bin^*; Fox Richard J; Sugiyama Masano; Fritz Alan; Eastgate Martin D

来源：Organic Process Research & Development, 2014, 18(5): 636-642.

DOI：10.1021/op500066f

A new and efficient process to prepare di-tert-butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di-tert-butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficiency, an improved synthesis of DTBPP was required. The two-step process to DTBPP starts from PCl3 and leverages a H2O2/catalytic KI mediated oxidation of di-tert-butyl phosphite to provide DTBPP in 81% yield and high purity. In the development of the new process to di-tert-butyl (chloromethyl) phosphate, a comparison to the corresponding tosylate derivative was made. A rational selection of base, phase-transfer catalyst (PTC), and stabilizing additive minimized CMCS decomposition and led to an optimized yield (90% solution yield), improved product purity, and identification of a technique to enable the long-term storage of di-tert-butyl (chloromethyl) phosphate.

• 出版日期2014-5