A Scalable Synthesis of l-Leucine-N-carboxyanhydride

Abstract

Due to its relevance in the synthesis of well-defined oligopeptides, the L-leucine-N-carboxyanhydride (leucine-NCA) synthesis was selected for fine chemical scale-up with a scope on application on larger scales. The heterogeneous gas-solidliquid nature of the leucine-NCA synthesis implied a mass transfer limited reaction rate towards phosgenation and was investigated on bench scale. Upon scale increase, the liquidgas mass transport of HCl is drastically reduced, retarding the reaction and consequently rendering the process unsuitable for scale-up. Addition of an HCl scavenger such as (+)-limonene prevented side reactions thus allowing a cost reduction, a considerably faster reaction, and minimization of the amount of phosgene source used. The modified leucine-NCA synthesis has successfully been made scalable, maintaining high product purity on a 1.0 dm 3 scale.

Homo and Block Copolymers of Poly(β‐benzyl‐L‐aspartate)s and Poly(γ‐benzyl‐L‐glutamate)s of Different Architectures

“…NCA preparation is generally straightforward and involves the treatment of the appropriate α‐amino acid or its derivative with an acylating agent, such as triphosgene 44. However, some measures must be taken to avoid side reactions which can occur in NCA synthesis, the majority being the consequence of HCl released during the phosgenation 38…”

“…Since NCAs, when stored for prolonged periods of time, even at freezing temperatures, are very sensitive to traces of moisture 38. They can also polymerize in the solid state 39.…”

Introducing PeptoPlexes: Polylysine‐block‐Polysarcosine Based Polyplexes for Transfection of HEK 293T Cells

“…[52] In a three necked flask equipped with a reflux condenser and a septum, 15 g (53.5 mmol) of N-e-Z-protected lysine were suspended in 300 mL of absolute THF under dry nitrogen atmosphere. The condenser outlet was connected to two gas washing bottles filled with aqueous NaOH, removing excess HCl and phosgene.…”

Preparation and aggregation behavior of mannose-terminated poly(ethylene glycol)-b-poly(l-leucine) in water

“…␣,-Diazido poly(ethylene glycol) (N 3 -PEG-N 3 ) was prepared from PEG (MW 1000, Aldrich) by a literature method [39]. l-Leucine-N-carboxyanhydride (Leu-NCA) [40] and 2-propynyl ␣-d-mannopyranoside (A-Man) [41] were also synthesized according to literature procedures. The purity of Leu-NCA was confirmed by NMR and elemental analysis.…”