Temperature Cycle-Induced Deracemization of Cl-TAK Using Amberlyst A26: A Heterogeneous Catalyst Approach for Efficient and Reusable Racemization ^†

Abstract

This study investigates the feasibility of employing Amberlyst A26 as a racemizing agent for the temperature cycle-induced deracemization (TCID) of the model compound Cl-TAK (1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl) pentan-3-one). We assessed Amberlyst A26 for its potential as a reusable heterogeneous catalyst, compatible with various solvents and easily separable from the solution. Racemization rates at 20 °C and 25 °C confirmed its suitability, with experiments showing that Cl-TAK undergoes racemization only in the presence of the catalyst. TCID experiments with Amberlyst A26 yielded successful deracemization, achieving an 88% enantiomeric excess from an initial 30%. These findings highlight Amberlyst A26’s viability for industrial-scale TCID applications, emphasizing reusability and cost efficiency.

1. Introduction

Obtaining optically pure compounds is crucial across various industries, particularly in pharmaceuticals, agrochemicals, and materials science, due to the distinct properties exhibited by enantiomers [1]. These mirror-image forms of a molecule can have vastly different effects, with one enantiomer potentially being therapeutic and the other ineffective or harmful. Achieving high enantiopurity is thus essential to ensure both efficacy and safety in chiral compounds.

Several methods exist to synthesize and separate enantiopure compounds, including chromatography [2,3,4,5,6,7,8,9,10], asymmetric synthesis [11,12,13,14,15], and crystallization-based techniques. Crystallization-based deracemization has emerged as a particularly attractive approach, as it enables the selective rejection of one enantiomer from the crystal lattice, increasing efficiency and productivity while reducing costs compared to chromatography. Additionally, it provides superior selectivity over certain synthetic methods.

Prominent crystallization-based techniques such as temperature cycle-induced deracemization (TCID) [16,17,18,19,20,21,22], attrition-enhanced deracemization (Viedma Ripening) [23,24,25,26,27], and second-order asymmetric transformation (SOAT) [28,29,30] have proven effective in generating enantiopure crystals. These solid-state deracemization methods exploit crystallization to amplify the desired enantiomer while eliminating the unwanted form from the solid phase.

Solid-state deracemization typically involves the following three components: the target compound, a suitable solvent, and a racemizing agent. While some compounds do not require a racemizing agent due to their achirality in solution, most systems do. Therefore, choosing a racemizing agent compatible with the solvent and ensuring an appropriate racemization rate are critical for successful deracemization. Racemization permits a continuous interconversion between enantiomers in the solution phase, which is necessary for driving the crystallization of the desired pure enantiomer, and the rate of racemization has been previously reported to directly affect the overall rate of deracemization [31].

In this study, we focus on determining whether TCID is feasible using Amberlyst A26, a heterogeneous catalyst chosen for several reasons. Amberlyst A26 is easily removed from the system due to its solid form, and it is also reusable—an attractive feature for large-scale applications. It is compatible with many commonly used solvents, adding flexibility to the process. The possibility to easily separate the racemizing agent from the system should permit easier processing of the final product without the risk of racemizing the enantiopure mixture. Amberlyst A26 has also been shown to successfully racemize an ibuprofen ester at a faster rate than NaOH [32]. One study demonstrated the use of immobilized amino acid racemase to deracemize asparagine monohydrate; however, this heterogeneous catalyst lacked reusability and broader applicability to other systems [18]. In contrast, reusable heterogeneous catalysts like Amberlyst A26 have not yet been explored in TCID experiments. Investigating Amberlyst A26 presents an exciting opportunity to enhance the cost efficiency and reusability of racemizing agents in TCID processes.

The compound 1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pentan-3-one (Cl-TAK) was selected as the model compound for this investigation. Cl-TAK is an ideal model for TCID studies, as it has been shown to undergo TCID under various conditions without signs of degradation [22,33,34,35,36]. The first step in this study is to determine whether Amberlyst A26 can racemize Cl-TAK, a compound known to racemize rapidly with NaOH. Following this, the racemization rates at two temperatures (20 °C and 25 °C) were evaluated to confirm their suitability for the process. Additionally, it was essential to confirm that racemization does not occur when removed from the system to ensure that racemization only occurs when Amberlyst A26 is physically present in the solution. After confirming these conditions, full TCID experiments using only Amberlyst A26 as the racemization agent were conducted.

The success of this study could open doors to using Amberlyst A26 and other heterogeneous catalysts in TCID for a variety of species. These catalysts offer key advantages such as reusability, easy removal, and compatibility with commonly used solvents, reducing the need for solvent-specific racemizing agents, making them environmentally friendly, and cutting costs associated with wasted agents after each experiment. This would make TCID a more efficient and cost-effective option for large-scale applications.

2. Materials and Methods

2.1. Racemization Rates

In a 10 mL flask, 5 g of 60 wt% methanol–water solution and 0.05 g of enantiomerically pure Cl-TAK were added. A water bath was set to either 20 or 25 °C, and the flask was placed in the water bath for 15 min. After all the Cl-TAK had dissolved, 0.05 g of Amberlyst A26 was added into the flask. Then, 100 μL of the solution was extracted periodically from 5 min to 2 h and analyzed via cHPLC to determine the change in the enantiomeric excess (e.e.) in the liquid over time.

2.2. Testing for Residual Catalytic Activity After the Removal of Amberlyst A26

In a 10 mL flask, 5 g of 60 wt% methanol–water solution and 0.05 g of Amberlyst A26 were added and placed in a water bath set at 25 °C for 18 h. The Amberlyst A26 was filtered and removed from the solution, and 0.05 g of enantiomerically pure Cl-TAK was added into the solution and stirred in the water bath. Finally, 100 μL of the solution was extracted periodically from 5 min to 2 h and analyzed via cHPLC.

2.3. TCID Experiments

Into a 50 mL jacketed round-bottom flask with an oval-shaped magnetic stirrer set to 500 rpm, 25 mL of 60 wt% methanol–water solution and 1.5 g of Cl-TAK were added to the system with an initial enantiomeric excess in the crystal phase (c.e.e.) of 30% and stirred at 20 °C for 1 h. Then, 0.7 g of Amberlyst A26 was added into the system, and the temperature cycle was started. The mass ratios between Amberlyst A26 and Cl-TAK were adjusted to be equal to the mass of Cl-TAK dissolved in solution at 20 °C.

2.3.1. Temperature Cycle

A LAUDA ECO RE 630 S (Königshofen, Germany) thermostat was programmed as follows: Heating from 20 °C to 25 °C in 5 min (1 °C/min); a 5 min isothermal hold at 25 °C; cooling back to 20 °C in 45 min (0.11 °C/min); and a final isothermal hold for 5 min for a total cycle duration of 60 min.

2.3.2. Sampling

Before starting the temperature program, and 5 min after starting the final isothermal hold at 20 °C, samples were taken by pipetting a small amount of suspension using a plastic pipette (approximately 0.3 mL of suspension with 7 mg of solids) which were then vacuum filtered on a fritted glass funnel. The solids were then dissolved in methanol and analyzed by cHPLC. As the c.e.e. was determined by cHPLC, which determines the relative concentrations of the two enantiomers, the precise masses and volumes of each sample were not recorded.

2.4. Analysis Techniques

Chiral HPLC analyses were carried out using an Ultimate 3000 system equipped with a Chiralcel OD-H column (4.6 mm × 250 mm, 5 μm particle size) from Daicel, with UV detection at 220 nm. The mobile phase consisted of an 80:20 v/v mixture of n-heptane and isopropanol, delivered at a flow rate of 1 mL/min at room temperature. The retention times for the R- and S-enantiomers were approximately 7 min and 9 min, respectively.

3. Results

3.1. Racemization Rates

Notably, 0.05 g of Amberlyst A26 in 5 mL of methanol–water solution was able to racemize Cl-TAK with a half-life of approximately 9.6 min and 6.5 min at 20 and 25 °C, respectively (Figure 1). As the half-life is within the order of magnitude of the chosen temperature cycle at 60 min, these rates were deemed to be fast enough, and further studies used the same ratio of Amberlyst A26 to dissolve Cl-TAK.

3.2. Testing for Residual Catalytic Activity After the Removal of Amberlyst A26

After the Amberlyst A26 was left to stir overnight in a solution of 60 wt% methanol–water and filtered, the remaining solution did not contain base ions sufficient to racemize Cl-TAK. The enantiomerically pure Cl-TAK retained its composition, with no degradation to the enantiomeric excess over 24 h of stirring at 25 °C. This suggests that the racemization of Cl-TAK only occurs when Amberlyst A26 is physically present in the solution. In addition, this shows that the basic polymer is stable under these conditions and does not release any monomer which could cause significant racemization to occur.

3.3. TCID Experiments with Amberlyst A26

Starting from 30% c.e.e., after six temperature cycles, the c.e.e. reached 88% (Figure 2). Successful deracemization could be performed using Amberlyst A26 as the sole racemizing agent.

4. Discussion

Amberlyst A26 proved to be an effective racemizing agent for the deracemization of Cl-TAK, successfully replacing NaOH. The deracemization of Cl-TAK performed with Amberlyst A26 proceeded similarly to the previous experiments reported using NaOH [22,34,36,37]. Racemization rates at 20 and 25 °C were appropriate for deracemization, as shown in Figure 2. The advantages of using Amberlyst A26 include compatibility with various solvents, lower costs compared to organic bases, and its reusability and thus environmentally friendly racemizing agent, which can significantly reduce production costs.

Additionally, the base leaching investigation confirmed that racemization ceased when Amberlyst A26 was physically removed from the system. This feature makes Amberlyst A26 a valuable tool for future studies on the role of racemization during the different phases of TCID, enabling the controlled removal and reintroduction of the catalyst.

5. Conclusions

Herein, we demonstrated the use of Amberlyst A26 as a racemizing agent for TCID. The use of such a heterogeneous catalyst as the racemization agent could open doors for various target compounds, as it alleviates the need to search for a compatible solvent system, and it could further reduce the production cost as the catalyst would be reusable and easily separated from the system. The evidence of racemization occurring only when the catalyst is present in the solution could lead to investigations into the importance of racemization in the individual stages throughout the process of TCID.