Multistage Cross-Current and Countercurrent Flow Crystallization for

Article pubs.acs.org/IECR

Multistage Cross-Current and Countercurrent Flow Crystallization for Separation of Racemic 2‑Methylbutanoic Acid Maksymilian Olbrycht,† Maciej Balawejder,‡ Kinga Matuła,§ Wojciech Piatkowski,† and Dorota Antos*,† †

Department of Chemical and Process Engineering, Rzeszow University of Technology, 35-959 Rzeszow, Poland Chair of Chemistry and Food Toxicology, University of Rzeszow, 35-959 Rzeszow, Poland § Institute of Physical Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland ‡

ABSTRACT: Diastereomeric crystallization has been used to separate the racemic mixture of enantiomers of 2-methylbutanoic acid. The enantiomers have been converted into a pair of diastereomeric salts using optically pure (R)-(+)-α-methylbenzylamine as a resolving agent. The mixture obtained formed a solid solution in the crystalline phase. The solution was further processed by multistage fractional crystallization where diastereomeric excess of the target derivative of (S)-(+)-2-methylbutanoic acid was generated in the solid phase. The process was realized in cross-current and countercurrent flow systems consisting of batch crystallizers. In both flow modes all streams were properly synchronized to enable direct connection of inlets and outlets of subsequent stages, i.e., without intermediate adjusting of the composition and volume of the solid and liquid phases. The flow sheets for both operation modes were determined by use of an optimization routine accounting for yield and purity of the product as the performance indicators. Additionally, a procedure for recycling of the postreaction mother liquor has been proposed, which was based on the synthesis of diastereomeric salts with pure (S)-(−)-α-methylbenzylamine.

1. INTRODUCTION Diastereomeric crystallization, termed also as the classical resolution method, is one of the most widely used techniques in the resolution of racemic mixtures. Due to the low price and the simplicity of standard equipment required for accomplishing the process, this method is considered straightforward, economical, and easy to perform on a large scale.1−5 The principle of diastereomeric crystallization relies on the crystallization-induced transformation of a racemic mixture using an optically active compound (chiral resolving agent); i.e., an optically active base is used to react with a racemic acid or an optically active acid is used to reach with a racemic base. The reaction yields two diastereomeric salts characterized by different physical properties, which allows their separation by physical means. Typically, fractional crystallization is used for this purpose.6,7 The process consists of multistage operation in which the solid phase and mother liquor are enriched with the salt of the opposite diastereomer. The target enantiomer can be recovered by addition of a strong achiral acid or base to each of the two phases. The effectiveness of the separation depends on the difference in solubility of the formed diastereomeric salts in the solvent used as well as on other characteristics of the system such as polymorphism, the presence of solvate, or a double salt.8 In an ideal situation a simple eutectic is formed with a large difference between the solubilities of the diastereomers.7 A typical solubility phase diagram for such an ideal system is presented in Figure 1a. The racemic mixture at an initial composition contained between two bounds represented by points 1 and 2 can be successfully resolved by single-stage crystallization. Diastereomerically pure salt can be obtained in the solid phase which is leaving at equilibrium with the mother liquor saturated in both diastereomers with the composition characterized by the upper end of the corresponding tie line.7,9 © 2014 American Chemical Society

However, the separation of a diastereomeric mixture can be hindered by the formation of double salts or solid solutions exhibiting complete or partial miscibility in the crystalline phase. In the former case the resolution of the racemic mixture into pure diasteromeric salts is unfeasible, whereas in the latter one it can be accomplished by fractional crystallization. The solid solution forming systems are reported to frequently occur for a family of resolving agents used for diastereomeric salt formation in the crystallization based resolution of racemic mixtures by the Dutch resolution technique.7,10,11 However, such a crystallization system is difficult to detect and therefore it is often not recognized.12 Diastereomeric mixtures forming solid solutions can be enriched with the target compound; nevertheless, due to the miscibility of components in the solid phase, the tie lines no longer run across the pure salt vertex but connect the equilibrium phase compositions with an excess of the desired compound in either the solid or liquid phase depending on the solubility pattern of diastereomers (see Figure 1b).7,9 To achieve proper diastereomeric excess, multistage crystallization has to be employed. Several design procedures have already been proposed for multistage crystallization in solid solution forming systems.13−17 In our recent studies different flow sheet schemes for cross-current and countercurrent flow crystallization cascades consisting of batch crystallizers have been analyzed.14,15 The multistage process was used to separate enantiomeric and diastereomeric mixtures characterized by complete miscibility in the crystalline phase. Received: Revised: Accepted: Published: 15990

April 25, 2014 August 14, 2014 September 17, 2014 September 17, 2014 dx.doi.org/10.1021/ie501703w | Ind. Eng. Chem. Res. 2014, 53, 15990−15999

Industrial & Engineering Chemistry Research

Article

Figure 1. Ternary solubility phase diagrams of diastereomeric salts: (a) ideal solution; (b) complete solid solution. Dashed lines: tie lines.

Finally, a procedure for recycling postreaction mother liquor depleted in the target diastereomer has been suggested. The procedure exploited the synthesis reaction of the diastereomeric salt pair with the opposite enantiomer of the resolving agent, e.g., (S)-(−)-α-methylbenzylamine. The study was focused on the main and most important stage of the synthesis, i.e., on the crystallization process. Because of the industrial relevance of the subject of the study, both theoretical and practical aspects of the work can be considered as equally important.

Temmel et al. performed separations of binary mixtures in different solid solution systems by a continuous countercurrent crystallization process.16,17 To ensure continuity of the operation, the concentration of inlet streams of each crystallization unit were adjusted, which involved a number of operating variables to be manipulated during the separation process. Despite obvious advantages of continuous processes over batchwise operations in terms of increasing yield and reducing solvent consumption, the former can be difficult to control, especially if crystallization kinetics is slow. In such cases batch crystallization can be a method of choice for efficient downstream processing. In this work we extended the studies on the design and experimental realization of the cross-current and countercurrent batchwise crystallization of solid solution forming systems. The design of processes was based on optimization of solid and liquid phase distributions in the crystallization cascade to achieve a maximum yield of the operation at a desired purity of the target compound. The streams of the cascade were synchronized in such a way that no composition adjustment, i.e., additional concentration or dilution, was necessary. This simplified markedly the procedure for the process realization. Moreover, to increase the yield of the operation, recycling of exhausted streams was considered. Multistage crystallization was used to produce industrially relevant compounds, i.e., enantiomers of 2-methylbutanoic acid (MBA). Among the enantiomers of that compound, the (S)-form can be used to synthesize methyl ester of 2-methylbutanoic acid (S-MBE), which is characterized by a specific fruit flavor18−21 and is used as a high value additive in the food industry and in perfumery. It is produced in limited supply because of the difficulty in isolation of the active form from the enantiomeric mixture.18,19 Typically, enzymatic methods are used to produce (S)-MBE from racemic MBA (rac-MBA) exploiting the enantioselectivity of esterifying enzymes such as esterases and lipases, which were found to be suitable for synthesizing the esters from fatty and other acids.18,19 In this study we suggested an attractive alternative to the enzymatic method which was based on multistage separation of diastereomeric salts of MBA with (R)-(+)-α-methylbenzylamine (R,S′-salt and R,R′-salt of MBA). Diastereomeric mixtures exhibited miscibility in the crystalline phase. Enantiomerically pure (S)-(+)-2-methylbutanoic acid, (S)MBA, was then liberated from diastereomeric salt by addition of an achiral acid. A standard synthesis routine can then be employed for subsequent esterification to produce ester (S)-MBE.

2. THEORY 2.1. Cross-Current Flow Crystallization. Multistage crystallization can be realized in cross-current or countercurrent flow mode. The former has an advantage of simplicity of the operation and easiness of adjusting the equilibrium composition in each stage since only one of the outlet streams is transported through the whole unit enriching diastereomeric purity. The scheme depicted in Figure 2 illustrates a cascade of

Figure 2. Flow sheet scheme of cross-current flow crystallization cascade.

crystallizers operating in cross-current flow mode modified in such a way that the product streams can be partly recycled into the same unit.14,15 The scheme corresponds to solid solution forming systems which can be enriched with the target product in the solid phase. This type of the solid solution is exhibited by the experimental system being analyzed, i.e., diastereomeric salts of MBA. The material balances for the kth stage of a cross-current flow crystallization unit for enrichment of solid solution in the solid phase can be presented as follows (see Figures 2 and 3):

15991

Sk′− 1 + Reck + Solk = Mk

(1)

Sk + Lk = Mk

(2)

Sk′− 1xiS, k − 1 + ReckxiS, k = MkxiM ,k

(3)

dx.doi.org/10.1021/ie501703w | Ind. Eng. Chem. Res. 2014, 53, 15990−15999


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de of the solid stream. If Rec = 0, pure solvent is delivered to the unit. To realize the process with Rec > 0, the proper amount of the recycled streams has to be invested or produced in a preceding run of multistage crystallization. If the de of the exhausted mother liquor of the first stage is set equal to zero, then, after liberation from the diasteromeric salt, the racemic mixture obtained can be directly recycled to the synthesis reaction with the resolving agent. If the purity of the product withdrawn from the last stage is also fixed, only the de of the mother liquors in the intermediate steps can be altered to optimize the yield of the whole operation. Additionally, to improve yield, the mother liquors, Lk, of all stages can be mixed at appropriate proportions and processed again as a fresh feed stream (see Figure 2, LRec). 2.2. Countercurrent Flow Crystallization. The material balances for the kth stage of the counterflow crystallization unit can be presented as follows (see Figure 4): Figure 3. Illustration of cross-current flow crystallization process in kth stage of the cascade. Solid line, solubility curve; dashed line, tie line; dashed−dotted lines, mixing lines; M, mixing point for Rec = 0 (mixing the inlet stream with pure solvent); MI, MII, mixing points for Rec > 0, with decreased amount of the solvent added to the stage, respectively.

SkxiS, k

+

Lk xiL, k

=

MkxiM ,k

Figure 4. Flow sheet scheme of countercurrent flow crystallization.

(4)

Sk − 1 + Lk′+ 1 = Mk

2

∑

xiS, k

=1

i=1

i = R , R′ or R , S′

Sk + Lk = Mk

(5)

Sk − 1xiS, k − 1

Equations 1−5 are coupled with the solid−liquid equilibrium (SLE) relationship relating the equilibrium composition of the solid phase (crystalline phase) and liquid phase (mother liquor):

xiL, k

=

f (xiS, k)

(7)

+

Lk′+ 1xiL, k + 1

SkxiS, k + Lk xiL, k = MkxiM ,k

(8)

=

MkxiM ,k

(9) (10)

where Lk − Lk′ = Wk is a mass excess of the liquid stream (Lk) at the outlet of the kth stage over that at the inlet of a subsequent one (L′k), where the composition of the streams is the same: L xi,k = xL′ i,k. Equations 7−10 are coupled with eq 5 and the SLE relationship (eq 6). The set of mass balance equations for each kth stage is described by nine equations. If Lk = L′k it contains 15 unknown variables, six of them result from values of the mass and compositions of the liquid and solid streams incoming from the preceding and subsequent stages, including the first stage, where the feed stream is delivered, S0 ≡ F, and the last stage, where pure solvent is added. Therefore, the system has no degrees of freedom and only one set of the operating variables fulfills the set of nonlinear algebraic equations resulting from the material balances expressed by eqs 5−10. However, that only one mathematical solution can output unfeasible process conditions yielding a negative value of mass streams. This can be illustrated on the ternary diagram by the case in which the mixing and tie-line lines have no common point below the solubility line for at least one of the stages. Therefore, to ensure the feasibility of the process, additional free variables can be involved in the process design, e.g., when Lk ≠ L′k. The mass excess, Wk = Lk − L′k, can be recycled or wasted. To proceed with the first run of the countercurrent operation, the proper amount of solid and liquid streams determined by the mass balance equations listed above has to be available. This amount can be produced by a preliminary process of cross-current flow crystallization with Rec = 0, which does not require any initial stream investment. Next, the countercurrent

(6)

xpi,k

where is the mass fraction of the component i in the solid phase S (p = S) or liquid phase L (p = L); R,R′, R,S′ are diastereomers, where R,S′ is attributed to the target diastereomer; Sk, Lk, and Solk are the masses of the solid, liquid, and solvent streams in the kth stage (k = 0 denotes feed, F), respectively; Mk is the mass at the mixing point; Reck = Sk − Sk′ S is the mass of the recycled solid stream at xi,k = xS′ i,k. After each kth stage, the process can be interrupted; then, S′N denotes the product stream. The material balance for each of stage is described by nine equations (for i = R,R′ and R,S′) and contains 14 unknown variables: mass and mass fractions of all streams. Three of themmass and composition of the inlet streamare set to be equal to those of the outlet streams of the (k − 1)th stage (Sk−1 ′ , xS′i,k−1, i = R,R′, R,S′), where k = 0 denotes the mass and composition of the feed stream which are known a priori. This indicates that each stage has two degrees of freedom. It is convenient to manipulate: (1) the de (diastereomeric enrichment) of the exhausted streams (mother liquor), e.g., by setting the value of the solvent free mass fraction, xLR,S′,k * (xLR,S′,k * = xLR,S,k/ 2 L ∑i xi,k), and (2) the recycling stream, Reck, defining the ratio Sk/Sk′. The choice of the former determines the equilibrium composition of the outlet solid stream through the equilibrium equation (eq 6), whereas the latter determines the initial supersaturation of the mixed stream (stream M), which is illustrated by the distance of the mixing point from the solubility curve (see Figure 3). However, it has no impact on the yield and the 15992



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operation can be realized step by step where the streams produced in a preceding run are used to perform a subsequent one.

Next, samples of both crystalline phase and precipitate were taken and analyzed using the GC procedure described in section 3.5. To determine SLE for mixtures enriched with the opposite diastereomer, i.e., for xSR,S < 0.5, the crystalline phase obtained in the synthesis reaction of R,rac-salt (see section 3.2.1) was dissolved and recrystallized in ACN. The mother liquor obtained was evaporated under vacuum up to ca. 70% [v/v] of the initial volume and left again for crystallization. Next, the mother liquor was separated out of the crystalline phase and processed stepwise to enrich the liquid phase with the opposite diastereomer, i.e., R,R′-salt of MBA. After each step the equilibrium composition of both phases was determined (see section 3.5). 3.4. Multistage Crystallization. The procedure for the multistage crystallization of the R,S′-salt of MBA consisted of several equilibration steps. The verification of the idea of cross-current and countercurrent flow crystallization (see Figures 2 and 3) was preceded by computer calculations aimed at the selection of process variables enabling successful realization of the process. The demand for the product purity was set at the level minimum 95% (de = 90%), which was achieved in four crystallization stages. In cross-current flow crystallization, the crystalline phase (S, see Figure 2) produced in the kth stage was separated out of the mother liquor, L, washed, dried, weighed (see section 3.3), and transported into the next (k + 1)th stage. The solid phase produced in the last stage was the final product. For the sake of simplicity pure solvent was added into each of the stages; i.e., Reck was set equal to zero. To mimic countercurrent crystallization, an artificial mixture of solid R,S′-salt and R,rac-salt was prepared according to the expected de in the last stage and mixed with the proper amount of pure solvent. Then, the mother liquor was transported into the (k − 1)th stage and equilibrated again with the crystalline phase with the proper (according to the predicted value) de until the first, feed stage was reached. Small samples of the crystalline phase and precipitate from the mother liquor were analyzed using the GC procedure described in section 3.5. The composition of the mother liquor was calculated based on the mass balance closure for the mass input and output and the determined de values for both phases. 3.5. Determination of Diastereomeric Excess. 3.5.1. One-Pot Hydrolysis and Esterification Procedure of α-Methylbenzylammonium Salt of MBA. α-Methylbenzylammonium salts of MBA were converted to the methyl ester of MBA, which could be detected in the GC−MS system. For this purpose 0.2 g samples of diastereomeric salts were suspended in a mixture of 4.75 mL of hexane, 0.25 mL of methanol, and 2.5 mL of sulfuric acid (93%). The reaction mixture was heated under reflux and stirred for 30 min. After cooling the organic phases were separated and washed with aqueous solution of sodium bicarbonate and brine until neutral pH was reached. The organic phase was dried utilizing anhydrous magnesium sulfate, and the structure of MBE was confirmed using GC−MS analysis. 3.5.2. Determination of de Using Chiral Gas Chromatography Analysis. MBE was analyzed by GC-FID (flame ionization detector) using an Rt-βDEXse column (i.d. 0.25 mm, column length 30 m, stationary phase film thickness 0.25 μm) under the following conditions: mobile phase flow rate 1 mL/min (helium), injector temperature 200 °C, split 1:5,

3. EXPERIMENTAL SECTION 3.1. Chemicals and Equipment. The following chemicals were used: (R,S)-2-methylbutanoic acid (rac-MBA) with purity Pu ≥ 98% (SAFC, Germany), (S)-(+)-2-methylbutanoic acid (S-MBA) with Pu ≥99% (Hangzhou DayangChem Co., Ltd.), (R)-(+)-α-methylbenzylamine (R)-A with Pu ≥ 99% and enantiomeric enrichment (ee) ≥ 98% (Sigma-Aldrich, Germany), (S)-(−)-α-methylbenzylamine (S)-A with Pu ≥ 98% and ee = 98% (Sigma-Aldrich, Germany), acetonitrile (ACN) for HPLC (POCH, Poland), hexane for HPLC (SigmaAldrich, Spain), methanol for HPLC (Chempur, Poland), sulfuric acid p.a. (POCH, Poland), and sodium bicarbonate p.a. (Chempur, Poland). The laboratory equipment used in this work included the following: a gas chromatograph (GC; Varian 450-GC) coupled with a mass spectrometer (MS; Varian 240-MS), a diffractometer PANalytical X’Pert Pro (PANalytical GmbH, Germany), a thermostat (Lauda Ecoline RE-104), and a balance (Mettler Toledo). 3.2. Synthesis Routes. 3.2.1. Synthesis of (R)-A Salt of rac-MBA (R,rac-Salt). A solution of 22.8 g (0.181 mol) of (R)-A in 105 mL of ACN was mixed with 19.2 g (0.181 mol) of rac-MBA dissolved in 105 mL of ACN. The reaction mixture was stirred at ambient temperature until crystallization was initiated. Next, the mixture was thermostated at 5 °C for 48 h to establish solid−liquid equilibrium. Subsequently, the solid phase and liquid phase were separated using vacuum filtration. The solid phase was washed with a small amount of cold ACN (t ≅ 5 °C) and dried first under ambient conditions and next under vacuum (t = 30 °C, p = 0.2 atm) to obtain ca. 35.0 g (0.157 mol) of white crystalline product with yield Y ≅ 83%. Reaction yield was defined by the mass ratio of the product obtained to that predicted based on the reaction stoichiometry. Samples of the crystalline product and mother liquor were analyzed using the GC procedure described in section 3.5. 3.2.2. Synthesis of (R)-A Salt of (S)-MBA (R,S′-Salt). The experimental procedure was similar to that described in section 3.2.1, but (S)-MBA was used instead of rac-MBA. The reaction yield obtained was Y ≅ 90%. 3.2.3. Synthesis of (S)-A Salt of rac-MBA (S,rac-Salt). The experimental procedure was similar to that described in section 3.2.1, but (S)-(−)-α-methylbenzylamine (S)-A was used instead of (R)-(+)-α-methylbenzylamine (R)-A. The reaction yield obtained was Y ≅ 88%. 3.3. Determination of SLE for Diastereomeric Salts of MBA with (R)-A. To determine the SLE for the solid mixtures enriched with the target diastereomer (xSR,S′ > 0.5), samples of crystalline phase were prepared by mixing R,rac-salt with R,S′salt with different proportions (the salts were synthesized as described in sections 3.2.1 and 3.2.2) to obtain 1.2 g of crystalline phase. The samples were suspended in 30 mL of ACN, and the mixture was stirred for 48 h at 22 °C to establish SLE. The solid phase obtained was separated using vacuum filtration. The mother liquid solution was evaporated in a vacuum evaporator to obtain the precipitate, which was dried under vacuum (t = 30 °C, p = 0.2 atm). 15993



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Table 1. Efficiency of the Synthesis Reaction of rac-MBA or (S)-MBA with the Resolving Agents (R)-A or (S)-A outlet inlet

liquid a

L x*R,S′

salt

MBA [g]

(R)-A [g]

SC [mL/g]

L [g]

(R)-A + rac-MBA

19.21 10.01 7.69

22.80 11.87 9.13

5.02 5.48 5.41

7.07 5.47 −

0.320 0.224 −

(R)-A + (S′)-MBA

inlet

a

[g/g]

solid deLR,S′b

[%]

S [g]

xSR,S′

[g/g]

−36.09 −55.14 −

34.93 16.41 15.21 outlet

0.5366 0.5637 0.9811

liquid

deSR,S′ [%]

Y [%]

7.31 12.74 96.22

83 75 90

solid

salt

MBA [g]

(R)-A [g]

SCa [mL/g]

L [g]

x*S,S′L [g/g]

deLS,S′ [%]

S [g]

xSS,S′ [g/g]

deSS,S′ [%]

Y [%]

(S)-A + rac-MBA

27.49

32.62

4.99

7.29

0.5460

9.24

52.82

0.4928

−1.45

88

SC denotes solvent consumption used per 1 g of synthesized salt. de = [(xR,S′ − xR,R′)/(xR,S′ + xR,R′)]·100%. b

and injection volume 5 μL. The peaks were registered using FID (t = 210 °C). The peak area method was used to calculate the de values of postcrystallization samples. 3.6. X-ray Powder Diffraction (XRPD) Measurements for Diastereomeric Salts of MBA with (R)-A. XRPD measurements were performed for samples of the crystalline phase composed of diastereomeric salts with different de values. The samples were prepared using the appropriate amount of diastereomeric salts (R,rac) and (R,S′) and dissolved in methanol. Then, crystallization was induced by spontaneous evaporation of the solvent. Subsequently, the solid phases were dried under vacuum (t = 30 °C, p = 0.2 atm) and analyzed by XRPD using a PANalytical X’Pert Pro diffractometer (PANalytical GmbH, Germany). The radiation source was Cu Kα. Samples were measured on Si holders and recorded in a 2θ range of 3−40° with a step size of 0.017 and counting time of 50 s for each step.

xiL = ai(xRS , S ′)3 + bi(xRS , S ′)2 + ci(xRS , S ′) + di

(11)

The polynomial parameters are presented in Table 2. Additionally, the equilibrium distribution diagram was constructed and is plotted in Figure 5c. Here the solvent free * , in the mother liquor versus mass fraction of the R,S′-salt, xLR,S′ its fraction in the crystalline phase is shown. The plot also contains the results of replicate measurements. Discrepancies between replicates can be observed, yet within a range allowing feasibility and predictability of the process. The presented plots indicate that the de of the target diastereomer can be upgraded in the solid phase. The enrichment of the mother liquor with the opposite diastereomer was limited by the position of a lyotropic point at which the composition of the liquid phase and that of the solid phase were the same (xSR,S′ ≅ 0.18, see Figure 5c). Moreover, it is evident that partial miscibility occurs in a wide range of diastereomeric salt compositions. This was confirmed by XRPD measurements presented in Figure 6. It can be observed that characteristic reflexes shift gradually with increasing de of the R,S′-diastereomer over the range of crystallization experiments (xR,S′ = 0.56−0.98), indicating the formation of solid solution of two diastereomers which exhibited two distinct XRPD patterns in the crystalline phase. 4.3. Cross-Current Flow Crystallization. The experiments of cross-current flow crystallization were preceded by the model predictions using the set of equations, eqs 1−5 and 11, along with the SLE parameters summarized in Table 2. Because of the model simplicity, simple software could be used; namely, Microsoft Excel Solver was employed to solve the model for a four-stage crystallization cascade as well as to optimize the yield of the operation. The feed composition was determined by the de of the target diastereomer in the crystalline phase obtained in the synthesis reaction (see section 4.1). The desired purity of the R,S′ diastereomer in the product was 95% (de = 90%). The experimental results and predictions are compared in Table 3. The model predictions and the experimental data were found to be in acceptable agreement, which confirmed the feasibility and quantifiability of the separation process. The model was then used to maximize the yield of the operation defined as the mass ratio of the target diastereomer contained in the product withdrawn from the last stage and in the feed stream:

4. RESULTS AND DISCUSSION 4.1. Synthesis of Diastereomeric Salts of MBA. The first stage of the separation of racemic MBA consisted of the synthesis reaction with the resolving agent, i.e., (R)-A, according to the procedure described in section 3.1. The composition of the crystalline phase and the mother liquor and the yield of the synthesis reaction are summarized in Table 1. Depending on the mass ratio of the crystalline phase and solvent, different yields and de values could be achieved according to the established SLE. An increase of yield was counterbalanced by reduction of de and vice versa. In any case, the mother liquor was enriched with the opposite diastereomer, i.e., R,R′-salt, and could not be reused in multistage crystallization, which was aimed at isolating R,S′-salt. Therefore, only the crystalline phase enriched with the target diastereomer was further processed, as described in sections 4.3 and 4.4. To investigate the possibility of recycling of the exhausted mother liquor, the synthesis reaction of MBA with the opposite resolving agent, i.e., (S)-A, was conducted according to the procedure described in section 3.2. The reaction input and output are presented in Table 1. It can be seen that the pattern of the phase enrichment was reversed; now, the solid phase depleted in S,S′-salt was leaving at equilibrium with the mother liquor enriched with the target salt. 4.2. SLE of Diastereomeric Salts of MBA with (R)-A. SLE was determined according to the procedure described in section 3.3. The results obtained are depicted on the ternary phase diagram (Figure 5a) and in the Cartesian coordinate system (Figure 5b). The latter system was used to quantify the SLE relationship expressed by a third degree polynomial equation:

Y= 15994

Sk′= 4xRS , S ′ , k = 4 FxRS , S ′ , F

(12)



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Table 2. Parameters of the Equilibrium Equation (eq 11) S (Used for Calculation within the Range 0.5 ≤ xR,S′ ≤ 0.95) param

i = R,S′

i = R,R′

a b c d

0.0119 0.0478 −0.0625 0.0241

0.226 −0.679 0.782 −0.330

Figure 6. XRPD patterns of diastereomeric salts of MBA with (R)-A with different de values.

liquor of the first stage was set equal to zero; i.e., de1 = 0. In such a case the racemic mixture obtained after liberation of the resolving agent could be recycled to the synthesis reaction. Moreover, the de of the product was set the same as above: de4 = 90% to obtain 95% purity of the R,S′ diastereomer in the product received at the outlet of the last stage. The composition of the mother liquor withdrawn from the last stage (i.e., values of xLR,S′,4 * and xLR,R′,4 * ) resulted from the SLE relationship. Therefore, only the composition of the mother liquors of the intermediate stages, i.e., xLR,S′,2 * and xLR,S′,3 * , could be used as the decision variables in the optimization procedure. Eventually, the following optimization problem was solved: Y (xRL,*S ′ ,2 , xRL,*S ′ ,3) ⇒ max

(13)

xSR,S′,4

subject to the purity constraint: = 0.95. The optimization results are depicted in Figure 7, where changes of the objective function versus the decision variables are shown. The optimum, i.e., the total yield of the whole cascade, was Y = 11%, which corresponded to xLR,S′,2 * = 0.590 and xLR,S′,3 * = 0.698. To increase the yield, the total amount of mother liquors, Lk, obtained in all stages for k > 1 can be mixed with the appropriate proportion with the mother liquor of the first stage, L1, to get the de of the solution corresponding to the fresh feed stream. Then, after adjustment of the concentration according to that required at the mixing point in the first stage (i.e., by partial evaporation), the recycled solution LRec can be processed again (see Figure 2). Threefold recycling of LRec produced under conditions corresponding to the optimum depicted in Figure 4 resulted in an increase of the yield up to 29% (see Table 4). For further improvement of the yield, the wasted mother liquor of the first stage, W1, with de = 0 (here 62% of total mass L1),

Figure 5. (a) Ternary phase diagram for diastereomeric salts of MBA with (R)-A with different de in ACN at 22 °C. Solid line, solubility curve; dashed lines, tie lines. For the sake of clarity only selected SLE measurements are depicted. (b) SLE relationship for diastereomeric salts of MBA with (R)-A at 22 °C. Points, measured data; line, polynomial approximation. (c) Distribution diagram of diastereo* , concentration of the target meric salts of MBA with (R)-A. xLR,S′ diastereomer in solvent free fraction; points, measured SLE data; solid line, trend line.

The variable set was the mass of the feed stream, F, and its composition resulting from the output of the synthesis reaction with the resolving agent. Additionally, the de of the mother 15995



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Table 3. Experimental Results and Predictions of Four-Stage Cross-Current Flow Crystallization inlets

outlets

solid stage k 1 2 3 4

Sk−1 [g]

S XR,S′,k−1

[g/g]

solvent added S deR,S′,k−1

[%]

Sk [g]

Solk [g]

23.00

0.616

23.22

249

12.72

0.701

40.18

175

4.90

0.824

64.88

32

3.30

0.874

74.86

74

solid 11.64 13.23 6.00 5.65 3.83 3.63 1.32 1.26

XSR,S′,k

[g/g]

0.704 0.701 0.805 0.824 0.866 0.874 0.947 0.950

liquid deSR,S′,k

[%]

Lk [g]

40.86 40.18 60.92 64.88 73.18 74.86 89.48 90.02

XLR,S′,k

260 258 182 182 32.7 32.9 75.7 75.7

[g/g]

0.0230 0.0190 0.0225 0.0233 0.0221 0.0262 0.0216 0.0223

deLR,S′,k [%]

Y [%]

5.26 0.26 21.68 20.45 35.08 36.18 65.12 65.52

57.84 65.43 54.13 52.23 82.14 78.69 43.35 41.43

theor expt theor expt theor expt theor expt

optimization were masses of the side streams: W2 and W3. The optimization problem was defined as follows: Y (de1, W2 , W3) ⇒ max

Maximization of yield involved simultaneous minimization of W2 and W3. However, to account for the mass loss of the liquid stream accompanying the experimental realization of the process in a small laboratory scale, a lower limit for W2 and W3 was set to cover the mass deficit (i.e., 15 g for both side streams). The product purity was set at the level of minimum 95%, similarly to the cross-flow operation. To initiate the experiment, pure solvent was added to the crystalline phase with the amount and composition corresponding to the predictions of the fourth process stage. The crystalline phase used was a mixture of products of the preceding cross-flow process combined at suitable proportions. The mother liquor obtained after equilibration of the system was used as the input liquid stream for the third crystallization stage, which was performed in a manner analogous to the previous one. The operation was repeated until the first stage was realized. For each stage the equilibrium concentration was measured in both solid and liquid phases. After the initiation the process is ready to be continued in subsequent runs using for the inputs the intermediate products withdrawn from preceding ones. The predictions and the experimental data are shown in Table 5. As can be observed, the agreement between the experimental data and simulations is very good in terms of the composition of outlet and inlet streams and worse if the mass of the streams is considered. That difference was caused by a ca. 10% decrease in the solubility of the solution. The reason for that was a low level presence of products of salt decomposition which were transferred into the liquid phase. To improve the quality of the prediction, the SLE relationship might be properly adjusted. Additionally, the optimization procedure was used to generate the Pareto plot, where the course of the two conflicting objective functions, yield (Y) versus product purity (Pu), could be observed. In this case the optimization problem was defined as follows:

Figure 7. Results of optimization of yield in four-stage cross-current flow crystallization.

Table 4. Input and Output of the Cascade for Threefold Recycling cascade inlet run 1c 2 3 4 total

deF [%]

23

cascade outlet a

S1 [g]

Sol1 [mL]

SC [mL/g]

100 − − −

843 615 476 392

30.0 21.6 21.6 21.6 94.8

deS4 [%]

S4 [g]

Lrecb [g]

Y [%]

90

7.09 5.18 3.78 2.76

2008 1465 1069 760

11 11 11 11 29

(14)

a

SC, total solvent volume used in the cascade per gram of the solid salts delivered into the first stage. bRecycled stream before evaporation: Lrec = 0.38L1 + L2 + L3 + L4. cRun 1: fresh feed is processed.

could be converted into free rac-MBA and reused in the reaction synthesis with the resolving agent. 4.4. Countercurrent Flow Crystallization. The countercurrent flow operation was performed according to the concept presented in section 2 and the experimental procedure described in section 3. The design of the experimental realization of four-stage crystallization was preceded by the optimization of the yield. The product purity was set at the level of 95%; i.e., xSR,S′,4 = 0.95; values of xLR,S′,4 * and xLR,R′,4 * resulted from the SLE relationship, accordingly. To avoid further reduction of the number of degrees of freedom, i.e., the number of decision variables, the constraint of de1 = 0 for the mother liquor in the first stage was relieved. Two decision variables selected for the

(Pu, Y ) ⇒ max

(15)

The decision variables were de1, W2, and W3. The optimization was performed with the same numerical tool as before, i.e., Microsoft Excel Solver. To perform multiobjective optimization, a simplified method was used; i.e., yield 15996



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Table 5. Experimental Results and Predictions of Four-Stage Counterflow Crystallization inlets

outlets

solid stage k 1 2 3 4 a

Sk−1 [g]

S xR,S′,k−1

[g/g]

liquid S deR,S′,k−1

[%]

Lk+1 ′ [g]

5.69

0.600

20.00

101.0

6.58

0.650

29.95

111.0

5.43

0.730

46.01

120.2

5.11

0.842

68.44

127.5a

solid Sk [g]

xSR,S′,k

4.23 5.01 5.31 6.20 4.10 4.54 1.57 2.02

[g/g]

0.650 0.652 0.730 0.735 0.842 0.836 0.937 0.955

liquid deSR,S′,k

[%]

29.95 30.39 46.01 46.97 68.44 67.11 87.46 90.96

Lk [g] 103 102 112 111 122 121 131 131

xLR,S′,k

[g/g]

0.0232 0.0183 0.0229 0.0169 0.0222 0.0195 0.0216 0.0182

deLR,S′,k [%]

Y [%]

−3.28 −10.14 9.13 1.01 29.34 26.33 60.03 53.80

53.59 63.77 60.16 70.75 56.15 61.68 34.14 44.69

theor expt theor expt theor expt theor expt

Pure solvent.

Figure 8. Changes of total yield Y and SC versus the purity demand. SC, solvent consumption per 1 g of feed.

was maximized subject to the product purity, where the latter was stepwise changed over the range ca. 88−99%. Moreover, the eluent consumption versus the product purity was calculated. The results of calculations are depicted in Figure 8. It is evident that yield of the operation was upgraded markedly compared to that achieved in the cross-current flow crystallization (compare Tables 3 and 5). Moreover, since the solvent was added only to the last stage, significant reduction in the solvent consumption was achieved. Because no constraint on the composition of the mother liquor of the first stage was set, that value varied depending on the purity constraint; e.g., xLR,S′,1 * = 0.47 corresponded to the purity demand of 88% and xLR,S′,1 * = 0.59 to 99%. The mother liquors with the excess of the target diastereomer (i.e., xLR,S′,1 * ≥ 0.5) can be directly recycled into the process, whereas the depleted ones might be reused after additional treatment, i.e., after reaction with the opposite resolving agent as described in section 4.5. 4.5. Recovery of Exhausted Mother Liquor. As mentioned above, the mother liquor obtained in the synthesis of R,S′-MBA salts was depleted with the target diastereomer and could not be reused in the multistage crystallization. To investigate the possibility of recycling of the postreaction mother liquor, i.e., recovering the excess of the target diastereomer, several SLE measurements were performed for S,S′-MBA salt obtained after synthesis of rac-MBA with the opposite resolving agent, i.e., (S)-A. As can be observed in Figure 9, the solutions depleted with the target diastereomer (now the crystalline phase) are at equilibrium with enriched mother liquors. This indicates that the diastereomeric salts contained in the exhausted mother liquor with deficiency of the

Figure 9. Typical course of the tie lines in the ternary phase diagram for diastereomeric salts of MBA with (S)-A in ACN.

target diastereomer can be liberated and subjected to the reaction synthesis with (S)-A to recover the de of the target stereomer in the liquid phase. Next, the salts contained in the enriched solutions can be converted again to the R,S′-MBA salt and reused in the multistage crystallization to recover pure (S)-MBA. Because a few operations are involved in the recycling procedure, including two reaction synthesis with the resolving agents, economic evaluation should be performed prior to its implementation into the downstream processing.

5. SUMMARY The multistage crystallization was used to isolate the industrially relevant compound, the S-enantiomer of 2-methylbutanoic acid, (S)-MBA, from racemic mixtures exploiting the synthesis reaction of diastereomeric salts of MBA with (R)-(+)-αmethylbenzylamine (R,S′-salt and R,R′-salt of MBA). Diastereomeric mixtures processed exhibited miscibility in the crystalline phase. The enantiomerically pure acid, (S)-MBA, was then liberated from the diastereomeric salt by the addition of an achiral acid. In this work we extended our previous study on the design and optimization of the cross-current and countercurrent batchwise crystallization of solid solution forming systems. The optimization procedure has been suggested, in which distributions of solid and liquid phases in the crystallization cascade were synchronized to eliminate the necessity of the composition 15997



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Subscripts

adjustment between the inlets and outlets of subsequent stages. The procedure allowed reduction of the number of process variables to be controlled, which streamlined the process realization. The cross-current flow procedure was simple for the realization since only one stream, i.e., the solid stream, was transported from stage to stage along the cascade. However, the operation yield was relatively low and to upgrade its value recycling of the mother liquor of each stage was suggested. This procedure markedly improved yield but appeared to be laborious. The countercurrent flow operation was much more efficient in terms of yield and eluent consumption but also more difficult to predict since both solid and liquid streams were transported through the crystallization cascade. Finally, a procedure for the recycling postreaction mother liquor depleted in the target diastereomer has been suggested. The procedure exploited the synthesis reaction of the diastereomeric salt pair with the opposite enantiomer of the resolving agent, i.e., (S)-(−)-α-methylbenzylamine. The results of SLE measurements in that system indicted the possibility of restoring positive values of the de of the target stereomer in the exhausted postreaction solutions.

■

i = R,S′ or R,R′ salt k = stage number N = number of stages R,R′ = salt of (R)-(−)-2-methylbutanoic acid with (R)(+)-α-methylbenzylamine R,S′ = salt of (S)-(+)-2-methylbutanoic acid with (R)-(+)-αmethylbenzylamine Rec = recycled stream S,R′ = salt of (R)-(−)-2-methylbutanoic acid with (S)-(−)-αmethylbenzylamine S,S′ = salt of (S)-(+)-2-methylbutanoic acid with (S)-(−)-αmethylbenzylamine Superscripts

■

L = liquid phase S = solid phase

REFERENCES

(1) Collet, A. Separation and purification of enantiomers by crystallization methods. Enantiomer 1999, 4, 157−172. (2) Müller, S.; Afraz, M. C.; Gelder, R.; Ariaans, G. J. A.; Kaptein, B.; Broxterman, Q. B.; Bruggink, A. Phase diagrams of diastereomeric pairs in inclusion resolution. Eur. J. Org. Chem. 2005, 6, 1082−1096. (3) Ferreira, F. C.; Ghazali, N. F.; Cocchini, U.; Livingston, A. G. Rational approach to the selection of conditions for diastereomeric resolution of chiral amines by diacid resolving agents. Tetrahedron 2006, 17, 1337−1348. (4) Lorenz, H.; Seidel-Morgenstern, A. Process to separate enantiomers. Angew. Chem., Int. Ed. 2014, 53, 1218−1250. (5) Sistla, V. S.; von Langermann, J.; Lorenz, H.; Seidel-Morgenstern, A. Analysis and comparison of commonly used acidic resolving agents in diastereomeric salt resolutionexamples for DL-serine. Cryst. Growth Des. 2011, 11, 3761−3768. (6) Ahuja, S. Chiral Separations Applications and Technology; American Chemical Society: Washington, DC, 1997. (7) Kaptein, B.; Vries, T. R.; Nieuwenhuijzen, J. W.; Kellogg, R. M.; Grimbergen, R. F. P.; Broxterman, Q. B. New Developments in Crystallization-Induced Resolution. In Handbook of Chiral Chemicals; Ager, D., Ed.; CRC Press: Boca Raton, FL, USA, 2005. (8) Marchand, P.; Lefèbvre, L.; Querniard, F.; Cardinaël, P.; Perez, G.; Counioux, J.-J.; Coquerel, G. Diastereomeric resolution rationalized by phase diagrams under the actual conditions of the experimental process. Tetrahedron: Asymmetry 2004, 15, 2455−2465. (9) Mullin, J. W. Crystallization, 4th ed.; Butterworth-Heinemann: Boston, 2001. (10) Kellog, R. M.; Kaptein, B.; Vries, T. R. Dutch Resolution of Racemates and the Roles of Solid Solution Formation and Nucleation Inhibition; Springer-Verlag: Berlin, 2007. (11) Kellogg, R.; Nieuwenhuijzen, J. W.; Pouwer, K.; Vries, T. R.; Broxterman, Q. B.; Grimbergen, R. F.; Kaptein, B.; La Crois, R. M.; de Wever, E.; Zwaagstra, K.; van der Laan, A. C. Dutch Resolution: Separation of Enantiomers with Families of Resolving Agents. A Status Report. Synthesis 2003, 10, 1626−1638. (12) Crystallization: Basic Concepts and Industrial Applications; Lorenz, H., Beckmann, W., Eds.; Wiley-VCH: Weinheim, Germany, 2013. (13) Lin, S. W.; Ng, K. M.; Wibowo, C. Synthesis of crystallization processes for systems involving solid solutions. Comput. Chem. Eng. 2008, 32, 956−970. (14) Balawejder, M.; Kiwala, D.; Lorenz, H.; Seidel-Morgenstern, A.; Piatkowski, W.; Antos, D. Resolution of a Diasteromeric Salt of Citalopram by Multistage Crystallization. Cryst. Growth Des. 2012, 12 (5), 2557−2566. (15) Balawejder, M.; Galan, K.; Elsner, M. P.; Seidel-Morgenstern, A.; Piatkowski, W.; Antos, D. Multi-stage crystallization for resolution of enantiomeric mixtures in a solid solution forming system. Chem. Eng. Sci. 2011, 66, 5638−5647.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +48 178651853. Fax: +48 178543655. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The XRPD measurements were performed at the Max-Planck Institute in Magdeburg, Germany, by courtesy of Prof. Heike Lorenz.

■

SYMBOLS de = diastereomeric excess [%] F = mass of feed stream [g] L = mass of liquid phase stream [g] M = mass of mixed stream [g] MBA = 2-methylbutanoic acid Pu = purity [%] R,S′-salt = salt of (S)-(+)-2-methylbutanoic acid with (R)-(+)-α-methylbenzylamine R,R′-salt = salt of (R)-(−)-2-methylbutanoic acid with (R)-(+)-α-methylbenzylamine rac-MBA = (R,S)-(±)-2-methylbutanoic acid Rec = mass of solid phase recycle stream [g] S = mass of solid phase stream [g] SC = solvent consumption [mL g−1] Sol = mass of solvent stream [g] W = mass of waste stream x = mass fraction [g g−1] Y = yield [%] (R)-A = (R)-(+)-α-methylbenzylamine R,rac-salt = (R)-A salt of rac-MBA = salt of (R,S)-(±)-2methylbutanoic acid with (R)-(+)-α-methylbenzylamine (S)-A = (S)-(−)-α-methylbenzylamine S,rac-salt = (S)-A salt of rac-MBA = salt of (R,S)-(±)-2methylbutanoic acid with (S)-(−)-α-methylbenzylamine (S)-MBA = (S)-(+)-2-methylbutanoic acid (S)-MBE = methyl ester of (S)-2-methylbutanoic acid 15998



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(16) Temmel, E.; Wloch, S.; Müller, U.; Grawec, D.; Eilers, R.; Lorenz, H.; Seidel-Morgenstern, A. Separation of systems forming solid solutions using counter-current crystallization. Chem. Eng. Sci. 2013, 104, 662−673. (17) Temmel, E.; Müller, U.; Grawe, D.; Eilers, R.; Lorenz, H.; Seidel-Morgenstern, A. Equilibrium model of a continuous crystallization process for separation of substances exhibiting solid solutions. Chem. Eng. Technol. 2012, 35, 980−985. (18) Kwon, D. Y.; Hong, Y.-J.; Yoon, S. H. Enantiomeric Synthesis of (S)-2-Methylbutanoic Acid Methyl Ester, Apple Flavor, Using Lipases in Organic Solvent. J. Agric. Food Chem. 2000, 48, 524−530. (19) Chang, Ch.-Sh.; Ho, S.-Ch. Enantioselective esterification of (R,S)-2-methylalkanoic acid with Carica papaya lipase in organic solvents. Biotechnol. Lett. 2011, 33, 2247−2253. (20) Kazuhiko, T.; Uchiumi, K. Method for improving flavor of food or drink. U.S. Patent 5,496,580, March 5, 1996. (21) Rettinger, K.; Burschka, Ch.; Scheeben, P.; Fuchs, H.; Mosandl, A. Chiral 2-alkylbranched acids, esters and alcohols. Preparation and stereospecific flavour evaluation. Tetrahedron: Asymmetry 1991, 2 (10), 965−968.

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Multistage Cross-Current and Countercurrent Flow Crystallization for

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