Deracemization of NMPA via Temperature Cycles

Abstract

Recent studies have shown that total deracemization of a racemic suspension of a conglomerate forming compound can be attained in the presence of a racemizing agent through either attrition enhanced deracemization or temperature cycles. We experimentally investigate the deracemization of N-(2-methylbenzylidene)-phenylglycine amide, in the presence of DBU as racemizing agent in a mixture of isopropanol and acetonitrile (95/5 w/w), at several different operating conditions. Based on several experiments, we determine how the operating parameters influence the temperature cycles, by varying the initial enantiomeric excess, the cooling rate, the operating temperature range, and the system volume. We examine how each parameter affects the phenomena characterizing the temperature cycles, e.g., total process time or total number of cycles to attain deracemization. Finally, we discuss in general how to improve the performance of the process.

Practical Role of Racemization Rates in Deracemization Kinetics and Process Productivities

“…This behaviour qualitatively rationalizes other results obtained experimentally for deracemization; for example, Breveglieri et al recently reported the deracemization of N-(2-methylbenzylidene)phenylglycine amide (NMPA) with DBU through temperature cycling, and concluded that a high operating temperature leads to fast deracemization. 15 Racemization of NMPA with DBU can be considered to be a catalytic reaction; consequently, the racemization rate is higher at higher operating temperatures. The faster deracemization kinetics at higher temperature for NMPA with DBU is, according to our interpretation, mostly due to the high racemization rate of NMPA.…”

Resolution of an Atropisomeric Naphthamide by Second-Order Asymmetric Transformation: A Highly Productive Technique

“…14,15 In comparison, the productivity of TCID is as low as 0.1-5.0 g h -1 L -1 . 6,8 Thus, although TCID can double the theoretical yield, the productivity of the process is almost one order of magnitude lower than that of PC.…”

“…For example, temperature-cycle-induced deracemization (TCID) is a process that converts a racemic mixture of the substrate to a nearly pure enantiomer in the solid phase without any external chiral source through temperature cycling. 1,[6][7][8][9][10][11] Scheme 1. Schematic representations of PC, TCID, and SOAT process.…”

“…The productivity of a separation process is defined as the amount of enantiomer produced per unit time and unit volume of crystallizer or suspension. 8,12 Productivity =…”

Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

“…Viedma ripening (VR) and temperature cycle‐induced deracemization (TCID) are key approaches to deracemization and are being actively studied. We recently reported that second‐order asymmetric transformation (SOAT), a combination of preferential crystallization (PC) and racemization, could achieve relatively high process productivity compared with TCID due to the short processing time.…”