Development of Scaled-Up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals

Abstract

Small-molecular drugs, which are generally inexpensive compared with biopharmaceuticals and can often be taken orally, may contribute to the Sustainable Development Goals (SDGs) adopted by the United Nations. We previously reported the retinoid X receptor (RXR) agonist 4-(ethyl(3-isobutoxy-4-isopropylphenyl)amino)benzoic acid (NEt-3IB, 1) as a small-molecular drug candidate to replace biopharmaceuticals for the treatment of inflammatory bowel disease. The previous synthetic method to 1 required a large amount of organic solvent and extensive purification. In line with the SDGs, we aimed to develop an environmentally friendly, inexpensive method for the large-scale synthesis of 1. The developed method requires only a hydrophobic ether and EtOH as reaction and extraction solvents. The product was purified by recrystallization twice to afford 99% pure 1 at 100 mmol scale in about 30% yield. The optimized process showed a 35-fold improvement of the E-factor (an index of environmental impact) compared to the original method. This work, which changes the solvent used to environmentally preferable ones based on the existing synthetic method for 1, illustrates how synthetic methods for small-molecular drugs can be adapted and improved to contribute to the SDGs.

Characterization and Interconversion of Two Crystal Forms of NEt-3IB, a Retinoid X Receptor Agonist

“…Preparation of RXR Agonist NEt-3IB (1) NEt-3IB (1) was synthesized according to the previous report. 16) Weight Change Tracking of NEt-3IB (1) Dried NEt-3IB (1, 3.56 g, 1.0 mmol) was accurately weighed into a glass bottle, sealed with filter paper, and stored in a desiccator. The weight of the container was measured at 10 a.m., and the weight change of NEt-3IB (1) was measured by subtracting the tare weight.…”

“…As a first step, we have established a process method to synthesize 1 in large amounts. 16) This method employs only lipophilic ether and EtOH as organic solvents, which can be recovered and reused, and affords 1 with at least 99% purity in 7 steps in a yield of 30% or more.…”

Ligand Screening System for the RXRα Heterodimer Using the Fluorescence RXR Agonist CU-6PMN

“…For example, the RXR agonist bexarotene ( 1 ) has been used for the treatment of cutaneous T-cell lymphoma and NEt-3IB ( 2 ) has the potential to be a therapy for inflammatory bowel disease (Figure ). Thus, RXRα has potential as a drug discovery target.…”