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

Abstract

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 PCl 3 and leverages a H 2 O 2 /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, phasetransfer 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.

Evolving Green Chemistry Metrics into Predictive Tools for Decision Making and Benchmarking Analytics

“…In all the strategies, prodrug installation would require an excess (more than 1.2 equiv) of reagents such as di- tert -butyl potassium phosphate 10 and di- tert -butyl (chloromethyl) phosphate 11 . BMS developed technology to prepare these reagents in high quality (Scheme ); thus, we calculated the impact of these reagents along with the 4-chlorophenylchloromethyl sulfide reagent toward the global cumulative PMI. Taking into account the existing cumulative PMI and overall yields from phosphorus chloride to both 10 and 11 , we are able to update the cumulative PMI predictive distributions as shown in Figure .…”

Five‐Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade

“…Electrophilic halogenation of electron‐rich ketones ( 5 ), [12] or a Wittig olefination of electron‐deficient aldehydes ( 6 ) using a commercially available ylide [13] provided the α‐chloroketones that were readily converted to the α‐phosphates ( 4 ) by an S N 2 reaction (Scheme 2). [14] …”

Preparation of the HIV Attachment Inhibitor BMS-663068. Part 2. Strategic Selections in the Transition from an Enabling Route to a Commercial Synthesis

“…Several issues for the long-term supply and availability of chloromethyl chlorosulfate (CMCS) were evident and caused by reagent limitations. Hence, new protocols for the preparation of CMCS, potassium di- tert -butyl phosphate, and chloromethyl-di- tert -butyl phosphate were discovered, developed, and reported …”

“…Hence, new protocols for the preparation of CMCS, 16 potassium di-tert-butyl phosphate, and chloromethyl-di-tert-butyl phosphate were discovered, developed, and reported. 17 To complete the synthesis, the starting amide 75 was prepared from bromide 73 by Friedel−Crafts acylation, saponification, and amide bond formation (Scheme 10). Screening the Ullmann−Goldberg−Buchwald coupling of indole 75 with triazole 12 leveraged the insight gathered during the initial work on the simpler azaindole 11 (Scheme 11).…”