Crystallization-Based Resolution Process for the 2,3-Dibenzoyl-d

Article pubs.acs.org/crystal

Crystallization-Based Resolution Process for the 2,3-Dibenzoyl‑D/L‑tartrate Salts of D‑/L‑Serine Benzyl Ester V. S. Sistla,*,† H. Lorenz,† and A. Seidel-Morgenstern†,‡ †

Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany Otto von Guericke University Magdeburg, Chair of Chemical and Process Engineering, Magdeburg, Germany

‡

ABSTRACT: It is shown that the 2,3-dibenzoyl-D-/L-tartrate salts of D-/L-serine benzyl ester (salt pair 1, L-D,D-D; salt pair 2, D-L,L-L) behave like simple eutectic systems in their binary (melting) and ternary (solubility) systems. Due to this essential thermodynamic property, these salts are separable via crystallization. Metastable zone width data for primary nucleation of both salts were measured to support a rational process design. Resolution processes for both salt pairs were designed and executed successfully delivering diastereomeric salts in high purity. The presence of excesses of resolving agents, previously not considered, was systematically studied and found to possess the potential to further improve the performance of the selective crystallization processes.

1. INTRODUCTION The separation of enantiomers can be efficiently carried out after forming diastereomeric salts using a suitable enantiopure resolving agent (RA). Frequently maximum possible yields are not reached via this classical resolution due to the unavailability of basic thermodynamic data of the salts in binary (melting points) and in ternary (solubilities) systems.1−4 Measurement of such data is laborious but very important, because these salts might show diverse behavior in their binary and ternary systems. Diastereomeric salts are characterized by three types of behavior: (1) simple eutectic; (2) formation of mixed crystals (solid solutions); (3) formation of double salts. Among these three types, systems characterized by a simple eutectic are best suited for separation via crystallization. The occurrence of the other two types requires more complicated separation processes and leads to limited yields and purities.5,6 For salts that are characterized by simple eutectic behavior, a screening of different solvents is recommended, and the most suitable solvent should be selected prior to measuring thermodynamic data (ternary solubility phase diagrams at different temperatures) and kinetic properties (metastable zone widths for primary nucleation). This basic information is necessary for a rational quantitative design of a crystallization based separation of the two salts.7−10 Usually diastereomeric salts that show simple eutectic behavior possess differences in their solubility and have only one two-salt-saturation point (the highest solubility for mixtures of both salts). The salt composition at this point is called eutectic composition. Because the location of this eutectic point is not 0.5 but moves toward one of the two salts, the potential to enhance yields increases. Connected with their solubility difference, these salts might also have differences in their metastable zone widths for primary nucleation. Provided this information is quantitatively available, it can be used to © XXXX American Chemical Society

rationally design an effective crystallization based separation of both diastereomeric salts. Chemical stability of diastereomeric salts at higher temperature plays a vital role in selecting a suitable type of crystallization-based separation process. If the eutectic composition is far away from the 50:50 mixtures of both salts and the salts are stable at high temperatures, cooling or evaporation crystallization can be applied for resolution. If the salts are not stable, cooling crystallization coupled with the addition of an antisolvent can be a good option, provided that the antisolvent does not cause the formation of solvate complexes with the desired salts.11 In classical resolution, the application of stoichiometric amounts of the racemate and the resolving agent is common. However, there were also applications reported using amounts of the resolving agent below the stoichiometric requirements. These approaches were due to toxicities or costs of the selected resolving agents. Applying smaller amounts is also followed in the so-called Dutch resolution technique, where a family of resolving agents is used together to enhance the probability of process success and to increase yields.12 An excess of resolving agent available during the reaction step will enhance the rate of the salt formation reaction. In contrast, an unconverted excess will act as an impurity or additive in the solution during the subsequent salt separation via crystallization. The amount of resolving agent might have also an effect on the basic thermodynamic and kinetic data of diastereomeric salts and thus can influence the crystallization based resolution of the two salts.13 Based on the substances that are dealt with, an excess resolving agent might enhance or reduce the separability of the salts Received: February 22, 2013 Revised: May 13, 2013

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dx.doi.org/10.1021/cg400296b | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Schematic representation for synthesis of L-D, D-D, L-L, and D-L salts, respectively.

The paper will finally provide a comparison of the results obtained using the different operating concepts.

by influencing the specific solubilities and nucleation rates of both salts.14 If this influence would be known a priori, a decision can be taken regarding the amount of resolving agent to be used in the salt formation reaction and during the subsequent crystallization based resolution. The aim of the present work is the separation of DL-serine via classical resolution using as resolving agents 2,3-dibenzoyl-Dtartaric acid and 2,3-dibenzoyl-L-tartaric acid to generate both D- and L-serine in pure form. The 2,3-dibenzoyl-D-tartrate salts of D-/L-serine benzyl ester are abbreviated as L-D, D-D salts (pair 1) and the 2,3-dibenzoyl-L-tartrate salts of D-/L-serine benzyl ester are abbreviated as D-L, L-L salts (pair 2). The chemical structures and synthesis pathways of these salts are illustrated schematically in Figure 1. As mentioned above, knowledge regarding both thermodynamic and kinetic data is necessary for designing an effective crystallization-based separation process. Solubility data in methanol and water and metastable zone widths for primary nucleation in methanol were measured for all salts. The effect of water on the solubility of all salts in methanol was measured for different solvent compositions. Systematic experiments were performed to evaluate the effect of an excess of the resolving agent (2,3-dibenzoyl-D-tartaric acid) on the solubility of the L-D, D-D, and 50:50 mixture of the L-D and D-D salts in methanol. Based on the attained results, a resolution process that consists of cooling the solution to lower temperature and addition of antisolvent was designed and executed, first for stoichiometric amounts of racemate and resolving agent. Based on the observed influence of an excess of the resolving agent on the solubility of the diastereomeric salts in methanol, a suitable excess amount of resolving agent was estimated. Using this amount, the resolution procedure was repeated for both salt pairs.

2. EXPERIMENTAL SECTION 2.1. Materials Used and Analytical Methods. 2,3-Dibenzoylsalts of D-/L-serine benzyl ester (L-D, D-D, D-L, L-L) were synthesized in-house using conventional standard methods.15 Methanol was purchased from Merck GmbH (Darmstadt, Germany), Millipore purified water, as well as 2,3-dibenzoyl-D-tartaric acid and 2,3-dibenzoyl-L-tartaric acid were supplied from Sigma-Aldrich (Steinheim, Germany) with purities of ≥99%. 2.1.1. HPLC Method. A Crownpak CR 150 mm × 4.6 mm column and a mobile phase of 1.63 g of perchloric acid in 1 L of water at pH = 2 were applied in an HP Agilent 1100 HPLC machine. The temperature was 25 °C. The flow rate was 0.3 mL/min causing a pressure drop of 46 bar. 2.1.2. Solid Phase Analysis. The solid phases of all samples were studied by X-ray powder diffraction (XRPD), using an X̀ Pert Pro diffractometer (PANalytical GmbH, Germany) with Cu Kα radiation. Small amounts of samples were prepared on Si (background-free) sample holders and scanned between 3° and 40° 2θ with a step size of 0.017°. The measurements were used to identify the type of species present and also for investigation of different solvates or polymorphs. 2.2. Experimental Setup. 2.2.1. Solubility Measurements. An isothermal method was used to measure the solubility phase diagrams for L-D, D-D salt pair, and D-L, L-L salt pair in methanol and water at different temperatures.16 Certain amounts of pure or mixtures of diastereomeric salts were taken into glass vials and filled with pure methanol or water as solvents. They were stirred in a jacketed vessel at a given temperature constantly for 48 h to attain equilibrium. Subsequently, the liquid phases and solid phase were separated via filtration. The liquid phases were weighed and evaporated prior to measuring the solute masses. The compositions of the liquid phases were determined using HPLC. The effect of the antisolvent, water, on D-/L-tartrate

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the solubility of both salts in methanol was also measured using the same isothermal method. Solubility was determined according to eq 1.

w(solute) =

m(solute) m(solvent) + m(solute)

experiments 1 and 2 as the feed for the separation experiments. Introduced masses for experiments without excess resolving agent were 2.5 g of L-D or D-L salt and 2.5 g of D-D or L-L salt in 45 g of methanol. In experiment 3, an excess of resolving agent was used in the feed (details are given later). The experimental procedure followed for resolution of diastereomeric salt pairs was as follows: Initially the feed solution containing the two diastereomeric salts in methanol was taken into the crystallizer at 35 °C and cooled to 15 °C for experiment 1 and cooled to 0 °C for experiment 2. The experiments were conducted at atmospheric pressure. During the cooling process 0.1 g of seeds of the less soluble salt (L-D salt in the case of L-D, D-D salt pair and D-L salt in the case of D-L, L-L salt pair) was introduced at a temperature of 25 °C. When the temperature reached 15 or 0 °C, the antisolvent, water, was added immediately to the solution in two steps. Initially 45 g of water was added. Within the next 45 min the crystallization of the less soluble salt was enhanced. Further addition of 60 g of water was then done to adjust the solvent composition to 70:30 = water/methanol. Samples for liquid phase analysis were taken throughout the courses of the experiments. The samples were diluted with methanol, and the salt compositions were analyzed with HPLC. The salts crystallized were filtered, dried, and analyzed with HPLC and XRPD for purity determination and phase analysis.

(1)

In this equation w is the weight fraction of a solute in the solution, and the m stand for masses. The solid phases were analyzed with X-ray powder diffraction to check for the possible formation of solvates, double salts, mixed crystals, or polymorphs. The influence of an excess of resolving agent on the solubility of pure L-D, pure D-D, and 50:50 mixture of L-D and D-D salts was quantified using a polythermal method. A “Crystal 16”-device was used during these measurements. (Aventium, Netherlands). The device determines clear and cloud points in solutions. It offers the option to handle simultaneously 16 samples in four rows. Each row can be operated at different conditions. One milliliter of a solution of 6 wt % L-D salt in methanol (λr, stoichimetric feed ratio = 1 (explained in section 3.1.4)) was prepared and inserted in the first slot of the first row. The other three slots of the first row were filled with 1 mL samples of 6 wt % of L-D salt in methanol with increased amounts of resolving agent (λr = 1.37, 1.7, and 2.05). In the same manner four samples were prepared for 14 wt % D-D salts in methanol with different excess amounts of resolving agent (λr = 1, 1.24, 1.54, and 1.7) and inserted in row 2. In row 3, the four samples contained 10 wt % of the 50:50 mixture of L-D/D-D salts, and an excess amounts of resolving agent of λr = 1, 1.24, 1.42, and 1.65 in methanol was prepared and inserted. The λr values were selected randomly for all the samples. A heating rate of 0.0075 K/min was applied in the temperature range from 10 to 55 °C, and turbidity changes were detected using laser light. Sets of clear point temperatures could be determined from these measurements. 2.2.2. Metastable Zone Width for Primary Nucleation. The metastable zone widths for primary nucleation for all four salts in methanol were measured applying a polythermal method using again the Crystal16-device. Samples of 1 mL of solution with different concentrations of solute in methanol were taken into glass vials and used for measurements. Different cooling programs for a temperature range between 55 and 0 °C with cooling rates of 0.04, 0.05, 0.06, and 0.07 K/min were applied to determine the cloud points, which provide the metastable zone widths.17 These metastable zone widths were identified by extrapolating the cooling rate down to a zero. A magnetic stirrer was inserted in all samples and operated at 700 rpm to homogenize the solution inside the vial. The same process was applied for all four salts in methanol. 2.2.3. Resolution of Salt Pairs by Cooling and Antisolvent Crystallization. Resolution experiments were initially designed for salt pair 1 (see for more details section 3.3) and executed in the equipment shown in Figure 2. The same resolution procedure was used for salt pair 2 as well.

3. RESULTS AND DISCUSSION 3.1. Solubilities and Effect of Excess of Resolving Agent. 3.1.1. Solubility in Methanol. The measured solubilities of L-D, D-D salts in methanol are plotted in a ternary phase diagram shown in Figure 3a. Similarly, the solubility results for D-L, L-L salts are shown in Figure 3b. At all three different temperatures studied, the L-D and D-L salts have a very low solubility compared with their counter diastereomeric salts D-D and L-L, respectively. Each diastereomeric salt increases the solubility of the counter diastereomeric salt and both pairs of diastereomeric salts investigated show simple eutectic behavior in methanol. At 25 °C, both salt pairs possess a maximum solubility at a eutectic composition of 20:80 of L-D/D-D or D-L/L-L. At 15 and 35 °C, the same simple eutectic behavior is again present for both salt pairs, but slight changes are observed in the eutectic composition. At 15 °C, the eutectic composition moved to 15:85 of L-D/D-D or D-L/L-L, while at 35 °C, it is at around 22:78 of L-D/D-D or D-L/L-L. These eutectic compositions were confirmed based on at least three repetitions of the same experiment. Thus, the results reveal a gradual change in the eutectic composition with temperature. For increased temperature, the eutectic position moves gradually toward a 50:50 composition of the diastereomeric salts. Such a change in eutectic composition can be helpful to identify suitable temperature ranges for resolution experiments via cooling crystallization. It allows increasing yields compared with cases of constant eutectic composition.18 The phase diagrams shown in the Figure 3a,b are similar. This is because the L-D salt is a mirror image of the D-L salt, and the D-D salt is a mirror image of the L-L salt. The observed solubility of L-L salt is slightly higher compared with the solubility of D-D salt, which is probably due to some undetected impurities present in the solutions. 3.1.2. Solubility in Water. The solubilities of both salt pairs measured in water are shown in Figure 4. The simple eutectic behavior that was observed for both salt pairs in methanol was also found with the solvent water. The solubility of L-D, D-L salts is much lower than for the corresponding diastereomeric salts D-D, L-L. Each diastereomeric salt pair is characterized by the same eutectic composition of 20:80 L-D/D-D or D-L/L-L at the two

Figure 2. Illustration of the equipment used for resolution experiments. A saturated solution of 10 wt % solute in methanol at 35 °C with a solute composition of 50:50 of salt pair 1 or salt pair 2 was used as in C



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Figure 3. Solubility phase diagrams: (a) L-D, D-D salt pair 1 and (b) D-L, L-L salt pair 2 for the solvent methanol (only upper 50% of phase diagram given).

Figure 4. Solubility phase diagrams: (a) L-D, D-D salt pair 1 and (b) D-L, L-L salt pair 2 for the solvent water (only upper 10% of the phase diagrams are given).

diastereomeric salt pairs 1 and 2. To avoid this problem, processing at lower temperatures is mandatory. Supersaturation in solution can be attained either by cooling, by addition of an antisolvent, or by using both concepts. As reported above water was identified as a suitable antisolvent. It has nonazeotropic behavior with methanol. In Figure 5a is shown the effect of water on the solubility of L-D and D-D salts in methanol at 25 and 5 °C. At these two temperatures, solubility of pure L-D and D-D salts are very different in methanol and water. If the content of methanol in the solvent mixture is reduced by water addition, there is a drastic decrease in the solubility of both pure salts with a minimum solubility found in pure water. In the same manner, a strong solubility change with the addition of the antisolvent water to methanol was observed for D-L and L-L salts (salt pair 2) at 15 °C. The results are presented

temperatures for which solubility isotherms were measured. Thus, in contrast to the observation made for methanol, there is no measurable change in the eutectic composition of solubility isotherms for different temperatures. From the solubility phase diagrams of the two L-D, D-D and D-L, L-L salt pairs measured in methanol and water can be concluded that the eutectic composition of diastereomeric salts might change with temperature in specific solvents or might remain constant. As mentioned above, a change in eutectic composition could be exploited to increase crystallization yields. Since the solubility in water is very small, it is an attractive candidate to be used as an antisolvent. 3.1.3. Effect of Water as an Antisolvent on the Solubility of Pure Diastereomeric Salts in Methanol. Usually diastereomeric salts are unstable and might also undergo chemical degradation when the temperature is elevated. This is also true for the D



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Figure 5. Solubility changes for all four diastereomeric salts as a function of solvent composition.

Figure 6 show the changes in the corresponding saturation temperatures for increasing amounts of the resolving agent

in Figure 5b. Similar effects were observed also regarding the solubility of salt pair 1 (Figure 5a). It can be seen from the figure that the solubility of both salts decreases significantly with increasing water amounts. At all temperatures investigated for all four salts, there was no further reduction of solubilities found beyond a composition of 70:30, which implies that adding more water offers no advantage in potentially increasing the yield. For the runs applying antisolvent, a final solvent composition of 70:30 water/methanol was selected and utilized in the three resolution experiments carried out. Because the use of antisolvent in crystallization is known to be more prone to the formation of polymorphs and solvates,19 the solid samples of excess solute obtained at the end of the solubility measurements were analyzed by XRPD to check for the appearance of any new phases. Hereby the XRPD patterns of all four salts were found to be identical to those of the reference patterns. This confirms the absence of polymorphs or solvates within the covered ranges of temperatures and solvent compositions. 3.1.4. Effect of an excess of resolving agent on solubility. For a chemical reaction between a racemate (Rac) and a resolving agent (RA) νRac·Rac + νRA ·RA → Products

Figure 6. Variation of the saturation temperature in methanol with respect to excess amounts of the resolving agent RA expressed by λr (eq 3) for L-D (◆), D-D (■), and 50:50 mixture of L-D: D-D salts (▲).

(2)

2,3-dibenzoyl-D-tartaric acid (excesses, λr > 1). The saturation temperature of L-D increases above 50 °C with increasing λr indicating a decrease in the solubility of pure L-D salt due to the presence of an excess of the resolving agent. Above a particular value of approximately λr = 1.6, the saturation temperature starts to decrease and approaches again to the initial saturation temperature of pure L-D salt as λr reaches 2, which means the solubility of the L-D salt starts to increase again. An excess of the RA has also considerable effect on the solubility of D-D salt (Figure 6, squares). There is again a slight reduction in the solubility of the D-D salt initially, followed by a drastic increase in solubility (reduction in saturation temperature to 8 °C when λr =1.53), which occurs at lower λr-values than for the L-D salt. The effect of changing the amount of the resolving agent on the solubility of a 50:50 mixture of both salts is similar to the effect for the L-D salt. In this case (Figure 6, triangles), the saturation temperatures are located between the corresponding values for the two pure salts. The observed effect of the relative amount of RA on the solubility (Figure 6) clearly indicates that improved separation

with the stoichiometric coefficients νRac and νRA, a dimensionless ratio λr, can be used to describe the feed composition: ⎛ n Feed ⎞ ( −ν ) Rac ⎟ λr = ⎜⎜ RA Feed ⎟ ( − ν n ⎝ Rac ⎠ RA )

(3)

Feed where nFeed RA and nRac are the initial numbers of moles of resolving agent and racemate. If the ratio λr is 1, the feed is stoichiometrically composed. If λr < 1, less resolving agent is supplied than stoichiometrically required, and unconverted racemate will remain in the solution. If λr > 1, an excess amount of unconverted resolving agent will remain. The influence of an excess of the resolving agent on the solubility of pure L-D and D-D salts and of a 50:50 mixture of L-D, D-D salts in methanol is shown in Figure 6. For stoichiometric composition of the resolving agent (λr = 1), the following saturation temperatures were found for the pure salts: 46 °C for 6 wt % L-D salt, 25 °C for 14 wt % D-D salt, and 40 °C for 10 wt % of 50:50 L-D, D-D salts in methanol. The other points given in

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Figure 7. Solubilities and metastable zone widths for primary nucleation curves in methanol for (a) L-D salt, (b) D-D salt, (c) D-L salt, and (d) L-L salt.

For example, when a saturated solution for a 50:50 mixture of both diastereomeric salts (either L-D, D-D salt pair or D-L, L-L salt pair) is taken as the feed with a concentration of 10 wt % at 35 °C, undercooling of 10−15 °C is feasible prior to seeding for selectively crystallizing the less soluble L-D or D-L salts. The crystallization of the counter-diastereomeric salts should be strongly retarded. 3.3. Design of Resolution Experiments for Salt Pair 1 (L-D, D-D). The schematic phase diagram given in Figure 8 is used to explain in more detail the trajectories and the design of the specific resolution process realized experimentally. The initial composition prior to the separation process is indicated by point 1, characterizing a saturated equimolar solution of both L-D and D-D salts in pure methanol at 35 °C. To exploit the observed eutectic composition change with temperature toward the pure D-D salt (see section 3.1.1), the solution is cooled from 35 °C (eutectic 56% de of D-D salt) to 15 °C (eutectic 70% de of D-D salt, experiment 1) and in another experiment further down to 0 °C (extrapolation result for eutectic ∼74% de of D-D salt, experiment 3), being the limit since water was used subsequently as the antisolvent. In the step described, liquid phase composition moves in Figure 8 to point 2. During cooling, seeds of the less soluble L-D salt have to be provided to initiate a selective crystallization of the desired L-D salt. Metastable zone width results (explained in section 3.2) were used to specify a suitable temperature at which seeds were introduced (here at 25 °C). When the liquid phase reaches point 2 (Figure 8), there is still further possibility to increase yield by increasing supersaturation via addition of the antisolvent water. With regard to the solubility results given above,

and higher yields should be in principle possible if an excess of RA is used, compared with using λr = 1. Values around λr = 1.6 appear to be in particular attractive for the system under consideration. In the resolution experiments described below, a λr value of 1.58 was practically realized. 3.2. Metastable Zone Width for Primary Nucleation. The estimated widths of the metastable zones for primary nucleation of the pure L-D, D-D and D-L, L-L salt pairs in methanol are presented in Figure 7. In Figure 7a can be seen that there is a well-defined metastable zone width for the L-D salt. At higher temperatures, the maximum possible undercooling for nucleation is around 11.5 K. As the saturation temperature is decreased the gap between the solubility line and the nucleation line increases. On the other hand, the other diastereomeric D-D salt (Figure 7b) does not nucleate at all within the temperature range covered (the lowest temperature realized was 0 °C because water was used as antisolvent). This is due to the high solubility of the D-D salt in methanol and its limited tendency to crystallize. Because the D-L salt is an enantiomer of the L-D salt, it shows the same behavior in methanol and a defined metastable zone width is observed (Figure 7c). In contrast for its diastereomeric salt pair L-L salt (enantiomer of D-D salt), no nucleation is observed (Figure 7d). From the results obtained for the two salt pairs (Figure 7), suitable temperature ranges to introduce seeds can be specified for separation experiments devoted to isolate selectively the less soluble L-D/D-L diastereomeric salts from mixtures with the corresponding other diastereomeric species. F



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3.4. Resolution Results for Salt Pair-1 (L-D, D-D). The three resolution experiments described were executed for salt pair 1 (L-D, D-D) to obtain the less soluble L-D salt. A first two experiments, Exp-1 and Exp-2, were carried out to study under identical conditions the effect of an excess of the resolving agent. In both experiments, the final cooling temperature was 15 °C. Exp-1 was conducted with a stoichiometric amount of resolving agent. In Exp-2, in the initial solution was an excess of resolving agent of (λr = 1.58). The observed trajectories of these two experiments are illustrated in Figure 9 based on the

Figure 8. Schematic illustration of the phase diagram and the resolution experiments carried out.

70 wt % of the antisolvent amount in the final solvent is the limit that can be used. The corresponding solvent composition of 70:30 (water/methanol) can be approached in either one step or several steps by adding gradually smaller quantities of water to the solution. After completion, the liquid phase reaches point 3 in Figure 8. The difference between points 3 and 4 denotes the amount of pure L-D salt crystallized during the resolution. The movement from point 1 to point 4 describes the overall composition change occurring in the vessel. The resolution procedure described for experiment 1 was also followed in an additional experiment 2 devoted to studying the effect of an introduced excess of the resolving agent on the process of separating the two diastereomeric salts. Based on the above discussion, a value of λr = 1.58 was chosen for this second experiment. The following feed amounts were used in the three mentioned experiments carried out to resolve salt pair 1: Exp-1 and Exp-3 with λr = 1, 0.01332 mol of DL-SBE + 0.0067 mol of RA (→ 0.00334 mol of D-D + 0.00334 mol of L-D) with the molecular weights MWDL‑SBE = 195.18g/mol, MWRA = 358.30g/mol, and MWL‑D/D‑D = 748.6 g/mol, corresponding to 2.6 g of DL-SBE + 2.4 g of RA → 2.5 g of D-D + 2.5 g of L-D (later in Table 1); hence 2.5 g of L-D and 2.5 g of D-D salt were taken for crystallization-based separation; Exp-2 with λr = 1.58, appling this normalized excess amount of the resolving agent required for the otherwise identical conditions of Exp-1 and Exp-3, here 0.01059 mol of RA corresponding to 3.8 g; hence the excess RA introduced in the crystallizer was 3.8 − 2.4 = 1.4 g (later in Table 1).

Figure 9. Liquid phase composition (HPLC) during resolution experiments Exp-1, Exp-2, and Exp-3 to resolve the L-D and D-D (salt pair 1) as function of time.

HPLC liquid phase analysis of various samples collected at different times. In the figure are also indicated the times at which the antisolvent water was added. In both resolution experiments, similar trends of the liquid phase composition were observed. The diastereomeric excesses were unstable for a while after seeding. As the crystallization of L-D salt proceeded, there was a steady increase in the diastereomeric excess (de) of the D-D salt in the liquid phase. In Exp-1 without an excess of resolving agent, a final de of 38% was measured (i.e., a final liquid phase composition of 31:69 L-D/D-D). A higher maximum de of 48% was observed at the end of the Exp-2 using an excess of the resolving agent (i.e., a final liquid phase composition of 26:74 L-D/D-D). Thus, there is an increase of 10% in the final diastereomeric excess of the D-D salt in the case of applying the excess of resolving agent. This can be explained by the fact that the excess of resolving agent enhanced the solubility of the D-D salt and reduced the solubility of the L-D salt. This increased the supersaturation of L-D salt and allowed more to crystallize. Additionally, in the third experiment, Exp-3, just the final equilibrium state was altered implementing a more severe cooling to the lowest accessible temperature of T = 0 °C using

Table 1. Conditions and Results of Three Experiments To Resolve L-D and D-D Salts (Salt Pair 1) initial amounts of L-D, D-D, and RA for crystallization based separation (g) L-D salt

D-D

experiment

salt

RA

λr

final solution temp (°C)

1 2 3

2.5 2.5 2.5

2.5 2.5 2.5

0 1.4 0

1 1.58 1

15 15 0

final de in mother liquor

purity (HPLC)

38% d.e of D-D salt 97.6% L-D salt 48% d.e of D-D salt 99.1% L-D salt 62% d.e. of D-D salt 98.1% L-D salt G

solid phase (XRPD) L-D

salt salt L-D salt L-D

amount of L-D salt crystallized (g)

yield based on L-D salt as basis (%)

0.95 1.2 1.9

38 48 76



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in solution). In the case of stoichiometric amounts of resolving agent (Exp-1), only 0.95 g of L-D salt crystallized, which leads to 38% yield. An even higher yield was obtained in Exp-3 with 76% due to the further reduced final temperature. Probably this value could have been further increased in the presence of an excess of the resolving agent. However, such an experiment was not done. The yields given were calculated excluding the experimental losses during filtration and solution transport. 3.5. Resolution Experiments and Results for Salt Pair-2 (D-L, L-L). In order to perform the separation also for D-L and L-L salts (salt pair 2), the two experiments, Exp-4 and Exp-5, were carried out. The amounts of substances applied correspond to the already described Exp-1 and Exp-2 made with salt pair 1. Goals of these two additional experiments were to evaluate the general transferability of the results made for salt pair 1 to another salt pair and to check again the observed positive effect of an excess of resolving agent. The composition trajectories observed during Exp-4 and Exp-5 are shown in Figure 11. Main features of these two experiments are summarized in Table 2. The trends are similar as for salt pair 1. The diastereomeric excess of L-L salt in the liquid phase at the end is again higher for the experiment with an excess of resolving agent (Exp-5, 10% more de than for Exp-4 using stoichiometric amounts). Main reason is again the fact that the excess of resolving agent reduced the solubility of the D-L salt and increased the solubility of the L-L salt. The results of the solid phase analysis of the filtered and dried product of both experiments are shown in Figure 12.

again the stoichiometric amount of the resolving agent (λr = 1). In this experiment, the final liquid composition (also marked in Figure 9) was found to be just below the eutectic composition (estimated to be at 0 °C at 16:84 L-D/D-D, compare Figure 3a). The solid phases obtained from the experiments were collected, dried, and weighed directly without any further purification. A purity analysis (based on HPLC) and a yield comparison for all three experiments are given in Table 1. The purity is in all cases high (>97%). The XRPD patterns of all solid products shown in Figure 10 resemble exactly the L-D salt pattern. There is no

Figure 10. XRPD solid phase analysis for resolution experiments for LD, D-D salts (pair 1).

specific extra peak from either D-D salt or excess resolving agent. All solid phases reveal the absence of polymorph or solvate formation. There is a considerable difference in the yields achieved in the three experiments. Exp-2 with excess resolving agent gave a yield of 48% (1.2 g of L-D salt crystallized out of 2.5 g initially

Figure 12. XRPD solid phase analysis for the two resolution experiments Exp-4 and Exp-5 for D-L, L-L salts (pair 2).

The XRPD of both products resemble exactly the D-L salt XRPD patterns. No signals from either the other diastereomeric salt L-L salt or the excess resolving agent were found. The corresponding satisfying results of the purity analysis using HPLC are also shown in Table 2.

Figure 11. Liquid phase analysis (HPLC) of resolution experiments EXP-4 and Exp-5 for D-L, L-L salts (pair 2) as a function of time.

Table 2. Conditions and Results of the Two Experiments To Resolve D-L and L-L Salts (Salt Pair 2) initial amounts of and RA for crystallization based separation (g)

D-L, L-L,

experiment

D- L

L -L

RA

λr

final solution temperature (°C)

4 5

2.5 2.5

2.5 2.5

0 1.4

l 1.58

15 15

final de in mother liquor

purity (HPLC)

42% d.e of L-L salt 98.6% D-L salt 52% d.e of L-L salt 99% D-L salt H

solid phase (XRPD) D- L D- L

salt salt

amount of D-L salt crystallized (g)

yield based on D-L salt as basis (%)

1.05 1.31

42 52



Article

(2) Attwood, B. C.; Hall, C. K. AIChE J. 2008, 54, 1886−1894. (3) Schroer, J. W.; Wibowo, C.; Ng, K. M. Synthesis of chiral crystallization processes. AIChE J. 2001, 47, 369−387. (4) Takano, K.; Gani, R.; Ishikawa, T.; Kolar, P. Conceptual design and analysis methodology for crystallization processes with electrolyte systems. Fluid Phase Equilib. 2002, 194−197, 783−803. (5) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; Krieger Publishing, Malabar, FL, 1994. (6) Shimura, Y.; Tsutsui, K. Optical Resolution and Ternary Solubility Isotherms of Cobalt(III) Complex Salts. Bull. Chem. Soc. Jpn. 1977, 50, 145−149. (7) McCabe, W. L.; Smith, J. C.; Harriot, P. Unit Operations of Chemical Engineering; The Mc Graw Hill Companies, Inc.: New York, 2005. (8) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann: Oxford, 1997. (9) Jones, A. G. Crystallization Process Systems; ButterworthHeinemann: Oxford, 2002. (10) Mersmann, A. Crystallization Technology; Marcel Dekker Inc.: New York, 2001. (11) Korovessi, E.; Linninger, A. A. Batch Processes; CRC Taylor & Francis Group.: New York, 2006. (12) Vries, T.; Wynberg, H.; van Echten, E.; Koek, J.; ten Hoeve, W.; Kellogg, R. M.; Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; van der Sluis, S.; Hulshof, L.; Kooistra, J. The Family Approach to the Resolution of Racemates. Angew. Chem., Int. Ed. 1998, 37, 2349−2354. (13) Kozma, D. Optical Resolutions via Diastereomeric Salt Formation; CRC Press LLC: London, 2002. (14) Sangwal, K. Additives and Crystallization Processes; John Wiley & Sons, Ltd: West Sussex, U.K., 2007. (15) Sistla, V. S.; von Langermann, J.; Lorenz, H.; SeidelMorgenstern, A. Analysis and Comparison of Commonly Used Acidic Resolving Agents in Diastereomeric Salt Resolution − Examples for DL-Serine. Cryst. Growth Des. 2011, 11 (9), 3761−3768. (16) Hefter. G. T.; Tomkins, R. P. T. The Experimental Determination of Solubilities; J. Wiley & Sons. Ltd: New York, 2003. (17) Nyvlt, J. The Kinetics of Industrial Crystallisation; Elsevier: Amsterdam, 1985. (18) Kaemmerer, H.; Jones, M. J.; Lorenz, H.; Seidel-Morgenstern, A. Selective crystallisation of a chiral compound-forming system − Solvent screening, SLE determination and process design. Fluid Phase Equilib. 2010, 296, 192−205. (19) Takuma, M.; Hiroshi, T. Control of polymorphism in the antisolvent crystallization with a particular temperature profile. J. Cryst. Growth 2013, 361, 135−139.

In the experiment without excess resolving agent (Exp-4), 1.05 g of dry cake was isolated after all losses during the filtration process. This leads for the 2.5 g of D-L salt present in the feed to a yield of 42%. On the other hand, 1.31 g of dry cake, leading to 52% yield, was found for the experiment with excess of resolving agent. Due to more careful handling and reduced losses during the postcrystallization processes (filtration and drying), slightly higher yields were observed in Exp-4 and Exp-5 compared with Exp-1 and Exp-2, respectively.

4. CONCLUSIONS The crystallization separation process of two diastereomeric salt pairs of D-/L-serine benzyl ester-2,3-dibenzoyl-L/D-tartrate (pair 1 L-D, D-D; pair 2 D-L, L-L) was studied. Prior to carrying out resolution experiments, solubility phase diagrams, effects of an antisolvent on the solubility of pure salts, widths of metastable zones, and the influence of an excess of resolving agent on the solubilities were investigated. Based on a rational resolution design, separation processes to obtain the less soluble salts of each salt pair were planned and successfully carried out. Without performing a process optimization in the case of salt pair 1, a maximum possible yield of 76% was achieved for the L-D salt. During the resolution of both salt pairs, an excess of the resolving agent present in the solution (λr approximately 1.6) allowed more L-D salt (Exp-2) or D-L salt (Exp-5) to crystallize than in case of applying a stoichiometric ratio using otherwise the same driving forces. Regarding salt pair 1, the main reason was the solubility decrease of the L-D salt due to the remaining excess of resolving agent and the parallel increase of the D-D salt solubility in the used methanol−water mixtures. From the results of this study, it can be concluded that it is useful to evaluate a possible influence of an excess of resolving agents on the basic thermodynamic and kinetic properties of diastereomeric salts before applying classical resolution. A nonstoichiometric amount of resolving agent possesses the attractive potential to enhance yields of selectively crystallizing diastereomeric salts.

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AUTHOR INFORMATION

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors cordially acknowledge the help of Dr. Jan von Langermann, Luise Borchert, and Jacqueline Kaufmann during experimentation.

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LIST OF ABBREVIATIONS AND SYMBOLS L-D salt: L-serine benzyl ester−D-dibenzoyl tartrate salt D-D salt: D-serine benzyl ester−D-dibenzoyl tartrate salt D-L salt: D-serine benzyl ester−L-dibenzoyl tartrate salt L-L salt: L-serine benzyl ester−L-dibenzoyl tartrate salt de: diastereomeric excess RA: resolving agent MW: molecular weight DL-SBE: DL-serine benzyl ester λr: stoichiometric feed ratio of reactants ν: stoichiometric coefficient

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REFERENCES

(1) Sistla, V. S.; Langermann, v. L.; Lorenz, H.; Seidel-Morgenstern, A. Chem. Eng. Technol. 2010, 33, 780−786. I


Crystallization-Based Resolution Process for the 2,3-Dibenzoyl-d

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