Miles Goodman Siegel

Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries

Abstract Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly advantageous for the construction of non-peptide libraries in a parallel array format.

Rapid purification of small molecule libraries by ion exchange chromatography

Abstract Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.

Combinatorial chemistry using polymer-supported reagents

During the past several years, the field of combinatorial chemistry has expanded to include not only solid- and solution-phase methods for expedited compound synthesis, but also hybrid approaches that span these two extremes. In particular, polymer-supported reagents have emerged as useful combinatorial chemistry tools for the discovery and optimization of new pharmaceutical leads.

The Application of High-Throughput Synthesis And Purification To The Preparation Of Ethanolamines

Abstract A 48 compound library of structurally diverse ethanolamines was prepared using a parallel synthesis approach. The synthetic paradigm employed a solution phase epoxide-opening reaction followed by rapid purification by ion exchange chromatography to yield products with near-analytical purity. An array of epoxides and primary amines, arranged in an 8×6 matrix, were reacted in the presence of an in situ silylating agent to form 48 individual compounds with an average yield of 75% and an average purity of 92.3%.

The use of high-throughput synthesis and purification in the preparation of a directed library of adrenergic agents

A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 × 12 matrix, were combined to form 96 individual compounds.

Rapid parallel synthesis applied to the optimization of a series of potent nonpeptide neuropeptide Y-1 receptor antagonists

Abstract This study describes the integrated application of parallel synthesis and computational chemistry to the design of potent nonpeptide antagonists for the neuropeptide Y-1 (NPY1) receptor. A lead molecule was modeled in the active site of the NPY1 receptor, and a potentially fruitful region for analog construction was identified. Synthesis of suitable scaffolds followed by solution phase generation of a small library of analogs produced a compound with 5-fold improvement in binding over the already potent lead. This new compound was shown to be an unanticipated side product of the parallel synthesis reaction.

The synthesis of ethanolamine libraries from olefin scaffolds

Abstract A solution-phase, multi-reaction sequence has been developed for the parallel synthesis of ethanolamine libraries. This approach uses 2,3-dibromopropene as a template for the synthesis of a small olefin sub-library, which is then further functionalized to form the final ethanolamine library. The methodology is demonstrated by the synthesis of a 5×4 array of ethanolamines.