# Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

## TL;DR

This paper identifies and addresses a hidden impurity formed during the synthesis of a drug used for targeted protein degradation.

## Contribution

The study reveals a previously overlooked byproduct in PROTAC synthesis and proposes a simple method to remove it.

## Key findings

- A nucleophilic acyl substitution byproduct co-elutes with the desired product during HPLC.
- Taurine scavenging effectively reduces contamination from the byproduct.
- The impurity is generated due to competing reactions during the synthesis process.

## Abstract

Chemically induced dimerization is a powerful tool for studying protein function, wherein the IMiD (the “immunomodulatory drug”) class of PROTAC molecules with a PEG linker is frequently used to promote targeted protein degradation. The standard protocol for their synthesis involves nucleophilic aromatic substitution of 4-fluorothalidomide with a PEG-amine. We report herein the identification of a commonly ignored impurity generated in this process. Nucleophilic acyl substitution competes with aromatic substitution to displace glutarimide and gives a byproduct that can co-elute with the desired product on HPLC throughout the remainder of the synthesis. Scavenging with taurine is a convenient way to minimize this contamination.