https://onlinelibrary.wiley.com/doi/pdf/10.1002/bip.1976.360150922

A procedure for the facile synthesis of amino-acid N-carboxyanhydrides

Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.

Rapid and Mild Synthesis of Amino Acid N -Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor

The subject invention concerns a method for identifying complementary chemical functionalities to form a desired supramolecular synthon. The subject invention also pertains to multiple-component phase compositions comprising one or more pharmaceutical entities and methods for producing such compositions.

https://digitalcommons.usf.edu/cgi/viewcontent.cgi?article=2158&context=usf_patents

Multiple-component solid phases containing at least one active pharmaceutical ingredient

Exploring new activating groups for reactive cysteine NCAs

β-Amino acid N-carboxy anhydrides (β-NCAs) are rarely used in the synthesis of β-peptides, which is due mainly to the poor availability of these potentially useful substrates. Herein, we describe the heretofore challenging synthesis of β-NCAs via a single-step, rapid, and mild formation using pH flash switching and flash dilution, which are aspects of micro-flow technology. We synthesized 15 β-NCAs in good to excellent yields that included acid-labile β-NCAs that cannot be readily synthesized using the conventional Leuchs approach. Scaled-up synthesis using this process can be readily achieved via continuous operation.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/asia.201901586

Single-Step, Rapid, and Mild Synthesis of β-Amino Acid N-Carboxy Anhydrides Using Micro-Flow Technology.

Oligopeptides were synthesized in high yields by the controlled coupling reaction of N-carboxy α-amino acid anhydrides (NCA's) with amino acid and peptide sodium salts in the heterogeneous reaction medium of acetonitrile–water which contained sodium carbonate. In this solvent, it could be considered that the reaction could occur at the interface of acetonitrile and aqueous layers, and that NCA's could be protected by the organic layer from side reactions such as hydrolysis and polymerization. The careful control of reaction conditions such as pH of the solution was not necessary when the heterogeneous mixed solvent was used. Sodium carbonate which had not been used for a reaction of this kind could be satisfactorily used for stabilizing the carbamate intermediates in the aqueous layer of the heterogeneous reaction medium.

Oshio Iwakura

Papers

Stepwise synthesis of oligopeptides with N-carboxy alpha-amino acid anhydrides.