Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis

Amara, Zacharias; Poliakoff, Martyn; Duque, Rub�n; Geier, Daniel; Franci�, Giancarlo; Gordon, Charles M.; Meadows, Rebecca E.; Woodward, Robert; Leitner, Walter

Abstract

© 2016 American Chemical Society. The development of a continuous flow process for asymmetric hydrogenation with a heterogenized molecular catalyst in a real industrial context is reported. The key asymmetric step in the synthesis of an API (active pharmaceutical ingredient) has been developed on a kilogram scale with constant high single-pass conversion (>95.0%) and enantioselectivity (>98.6% ee) through the asymmetric hydrogenation of the corresponding enamide. This performance was achieved using a commercially available chiral catalyst (Rh/(S,S)-EthylDuphos) immobilized on a solid support via strong interaction resulting from the requirement of electroneutrality. The factors affecting the long-term catalyst stability and enantioselectivity were identified using small-scale continuous flow setups. A dedicated automated software-controlled high-pressure pilot system with a small footprint was then built and the asymmetric hydrogenation on kilogram-scale was realized with a space time yield (STY) of up to 400 g L-1 h-1 at predefined conversion and enantiopurity levels. No catalyst leaching was detected in the virtually metal-free product stream, thereby eliminating costly and time-consuming downstream purification procedures. This straightforward approach permitted an easy and robust scale-up from gram to kilogram scale fully matching the pharmaceutical quality criteria for enantiopurity and low metal content, thus demonstrating the high versatility of fully integrated continuous flow molecular catalysis.

Citation

Amara, Z., Poliakoff, M., Duque, R., Geier, D., Franciò, G., Gordon, C. M., Meadows, R. E., Woodward, R., & Leitner, W. (2016). Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis. Organic Process Research and Development, 20(7), 1321-1327. https://doi.org/10.1021/acs.oprd.6b00143

• Journal Article Type: Article
• Acceptance Date: May 19, 2016
• Online Publication Date: Jun 10, 2016
• Publication Date: Jul 15, 2016
• Deposit Date: Sep 12, 2017
• Publicly Available Date: Aug 19, 2020
• Journal: Organic Process Research & Development
• Print ISSN: 1083-6160
• Electronic ISSN: 1520-586X
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Issue: 7
• Pages: 1321-1327
• DOI: https://doi.org/10.1021/acs.oprd.6b00143
• Keywords: Physical and Theoretical Chemistry; Organic Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/1113065
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.oprd.6b00143