Process Development and Scale-Up of a Novel Atypical DAT Inhibitor (S)-CE-123.

Area of Science:

• Medicinal Chemistry
• Process Chemistry
• Drug Development

Background:

• Large-scale synthesis and kilo-lab production are vital for advanced drug development.
• (S)-CE-123, an atypical dopamine transporter (DAT) inhibitor, is a promising candidate requiring preclinical evaluation.
• Process transfer and scale-up are critical for advancing drug candidates.

Purpose of the Study:

• To detail the successful scale-up and process optimization for the synthesis of 1 kg of (S)-CE-123.
• To adapt and implement the Kagan asymmetric oxidation protocol for large-scale production.
• To overcome challenges encountered during scale-up and improve product quality.

Main Methods:

• Application of the Kagan protocol for asymmetric sulfide to sulfoxide oxidation within a four-step synthesis.
• Iterative optimization of the final synthetic step, including workup and chromatographic purification.
• Introduction of additional washing steps to enhance yield and enantiomeric purity.

Main Results:

• Successful synthesis of a 1 kg preclinical batch of (S)-CE-123.
• Achieved high product purity exceeding 99%.
• Obtained an enantiomeric excess value of 95% for the final product.

Conclusions:

• The modified synthetic process enables efficient and scalable production of (S)-CE-123.
• Process optimization successfully addressed scale-up challenges, enhancing yield and enantiomeric excess.
• The 1 kg batch of (S)-CE-123 meets stringent purity requirements for preclinical drug development.