No abstract

Polycysteine and other polyamino acid functionalized microfiltration membrane sorbents work exceptionally well for the removal and recovery of toxic heavy metals from aqueous streams. These are high capacity sorbents (0.3-3.7 mg/cm2) with excellent accessibility and selectivity for heavy metals, such as Hg(II), Pb(II), and Cd(II) over nontoxic components such as calcium. Polycysteine functionalized membranes work particularly well for metals such as Hg(II) and Cd(II), even in high total dissolved solids containing streams. Parameters such as permeate flow rate,feed metal concentration, and counterion (for Hg(II)) have also been found to influence sorbent behavior. For multicomponent systems, polyglutamic acid functionalized membranes have been found to selectively sorb Pb(II) versus Cd(II). Selective sorption of Cr(III) has also been observed with actual waste streams containing several heavy metals, hardness, and high sodium (2,000 mg/L). The high capacity, site accessibility, and ease of regeneration of these membrane-based sorbents make them ideal for environmental separations when volume reduction or selective recovery is required.

A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.

Three synthetic approaches, suitable for the large scale manufacture of the α2δ-ligand, (3S,5R)-3-(aminomethyl)-5methyloctanoic acid 3, have been evaluated. The selected seven step manufacturing process has then been optimized and used to deliver over 20 kg of API; salient features of the synthesis include the use of 4,4,4-trimethoxybutyronitrile as an efficient four carbon amino acid equivalent. Highly selective kinetic resolution of the C3 stereocentre was accomplished via diastereoselective hydrolysis of a cyanoester intermediate using Amano Lipase PS-SD. Extensive process optimisation of the route starting from (R)-2-methylpentanol, led to significant improvements through telescoping, with less than 62 kg of solvent being needed to produce 1 kg of API.