Development of a Process for the Preparation of Chloromethyl Chlorosulfate

Abstract

A new and efficient synthesis of chloromethyl chlorosulfate (CMCS) from chloroiodomethane and chlorosulfonic acid is described. This process leverages a chlorosulfonic acid-mediated iodide oxidation to drive the equilibrating displacement process to full conversion. The resulting iodine byproduct is further oxidized and removed as iodate, to prevent iodide-induced decomposition of CMCS. This new process provides an efficient and scalable protocol for the preparation of CMCS in 92% solution yield and high purity (>99 GC area %).

Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8. Installation of the Phosphonoxymethyl Prodrug Moiety

“…In the first paper in this series, 1 we described the initial route to prepare 3, the final intermediate in the preparation of the highly potent HIV-attachment inhibitor BMS-663068, 2 from di-tertbutyl (chloromethyl) phosphate (2) and the parent BMS-626529 freebase (5). However, this route suffered from an extremely slow filtration of 5, low-yielding formation of 2, and challenges in suspending Cs 2 CO 3 in the NMP reaction mixture.…”

“…3 While this modified endgame enabled the production of >1000 kg of API, we more recently reported a proposed commercial route to BMS-663068 which led to a dramatic improvement in overall efficiency and a significant reduction in cost. 4 Two of the key features in this new route were the return to the use of alkylation agent 2 as the electrophile for installation of the phosphonoxymethyl prodrug moiety, 5 and modification of the parent BMS-626529 freebase starting material 5 to the corresponding BMS-626529-Li salt (1).…”

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 …”

“…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, 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).…”

Preparation of the HIV Attachment Inhibitor BMS-663068. Part 1. Evolution of Enabling Strategies

“…Due to success in delivering >100 kg API, coupled with the aggressive timelines for the project, it was decided for the second scale-up campaign to continue to utilize the existing chemistry to convert 2-amino-4-picoline 17 to 14 , but focus optimization efforts on identifying alternative C(3) side-chain and pro-drug installation strategies. The goals of a revised endgame sequence were: (1) to eliminate the use of 16 , due both to the low yield of its synthesis and the challenges associated with sourcing the chloromethyl chlorosulfate starting material, (2) to avoid the isolation of 2 due mainly to its poor filtration properties, and (3) to maintain the isolation of 37 as our quality gate intermediate. Toward this end, we envisioned a strategy from 14 that would entail: (1) N(1) alkylation, (2) benzoyl piperazine side-chain installation, (3) conversion of the N(1) substituent to a halomethylderivative, and (4) reaction with di- t -butyl potassium phosphate to afford 37 (Scheme ).…”