Triphenylphosphine Oxide Removal from Reactions: The Role of Solvent and Temperature

A reliable and scalable purification procedure for the easy removal of triphenylphosphine oxide by complexation with CaBr 2 in ethereal solvents or toluene was developed. The resulting insoluble precipitated complex was easily eliminated from crude reaction mixtures in high yields by filtration without the need of purification by column chromatography. The compatibility of this procedure with different organic solvents, salts, filtration aids, packing materials, and several molecules containing most common organic functional groups was examined to explore the scope and limitations of this method. Additionally, precipitation of TPPO by complexation with other halide salts was also explored.

Section: Introductionmentioning

confidence: 99%

Easy Removal of Triphenylphosphine Oxide from Reaction Mixtures by Precipitation with CaBr₂

Hergueta¹

2022

“…Various aspects of the physicochemical properties of reaction components must be explored for developing processes. − Our first objective was to choose an appropriate reaction solvent. Water is the most economical solvent; it is abundant in nature, readily recyclable, environmentally benign, less harmful, safe to transport, nonflammable, easy to handle, and has a higher heat capacity. , The use of water as a solvent instead of toxic and hazardous solvents considerably reduces waste generation. , Using EDC.HCl/1-hydroxybenzotriazole (HOBt) has multiple advantages over other coupling agents.…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Amide Coupling in Aqueous Media: Process for the Production of Diazabicyclooctane β-Lactamase Inhibitors

Tamboli

Kilbile

Merwade

2023

Self Cite

Herein, the amide coupling of six primary amines with the sodium salt of diazabicyclooctane acid in an aqueous medium without an additional base/surfactant or organic solvent is described. The product was efficiently isolated from the reaction through simple filtration and recrystallized using hot water treatment as a swift and cost-effective process. The methodology was implemented on a kilogram scale to produce penultimate intermediates for synthesizing β-lactamase inhibitors such as zidebactam, relebactam, and nacubactam. The comparison of green metrics for several previously reported amide coupling methods was discussed. The developed procedure avoids using hazardous organic solvents and provides a simple isolation method at the operational level with high purity and efficiency.

“…Ultimately, pyrophoric lithium aluminum hydride (LAH) has been avoided. Alcohol 4 was transformed to 5 via the Mitsunobu reaction in toluene to purge the majority of TPPO-H 2 DIAD, followed by kilogram-scale recrystallization of solid 5 with IPA to achieve an excellent purity (>99%) by HPLC with the single largest impurity less than 0.1%, as shown in Scheme …”

Section: Resultsmentioning

confidence: 99%

Process Development and Scale-Up of the Novel β-Lactamase Inhibitor WCK 6395

Tamboli

Kilbile

Deshmukh

et al. 2023

Self Cite

The initial process development of the novel β-lactamase inhibitor WCK 6395 is described. All key intermediates were readily isolated by either crystallization or precipitation to eliminate related impurities. Seven possible process-related impurities were hypothesized, and initial control strategies were implemented. Additionally, process parameters were identified and improved to decrease or circumvent these impurities. The parameters of each step were optimized through prior knowledge and experimentation to improve yield and desired quality of WCK 6395 to support toxicological studies. The improved process effectively reduced the use of hazardous reagents, was robust on the kilogram scale, demonstrated at the pilot scale, and subsequently served as the basis for commercial route development.