Fast Scale-Up Using Solid-Phase Chemistry

Abstract

A novel approach using solid-phase chemistry for scale-up was developed. The method makes use of commercially available high-load Merrifield resin. Three representative solid-phase chemistries leading to a diketopiperazine, a tetramic acid, and a β-lactam were scaled-up effectively and resulted in products with good yields and high crude purities. Affording close to 1 g of product per 1 g of Merrifield resin, the high-load resins showed high-volume productivity. The advantages of the work-ups, consisting simply of resin washes, are discussed. The need for low reactant and reagent equivalents results from higher reactant concentration, and it is shown that these stoichiometries can be reduced to affordable amounts.

Post‐Condensation Modifications of the Passerini and Ugi Reactions

“…The Raillard group at Affymax developed a multigram synthesis of a 2,5diketopiperazine and other heterocyclic systems by employing a high-load Merrifield resin transformed into polymer-supported valine, which was used as the amino component in an Ugi-4CR to gave the target diketopiperazine 137 after cleavage of 136 from the resin [77] (Scheme 2.49).…”

Ketenes in Polymer‐Assisted Synthesis

“…Polymer-bound amines 45 generated from polymer-bound amino acids 43 by reductive amination were also treated with acyl Meldrum's acid derivatives 34, to give b-ketoamides 46 (Scheme 11) [21,22] that undergo an intramolecular cyclization, accompanied by cleavage from the resin, to give 3-acyltetramic acids 47 (tetramic acid = 2,4-pyrrolidinedione) in mediocre yields (11-61 %), but with excellent purity (80-100 %).…”

Ketene in der Polymer‐unterstützten Synthese

“…Die polymergebundenen Amine 45 , die durch reduktive Aminierung aus den polymergebundenen Aminosäuren 43 gewonnen wurden, reagierten ebenfalls mit den acylierten Meldrumsäure‐Derivaten 34 ; es entstanden die β‐Ketoamide 46 (Schema ),21, 22 die unter Abspaltung vom Harz intramolekular cyclisierten und 3‐Acyltetramsäuren 47 (Tetramsäure=2,4‐Pyrrolidindion) in mäßigen Ausbeuten (11–61 %), aber ausgezeichneter Reinheit (80–100 %) ergaben.…”