3. Results and discussion 54
3.4. Discussion
3.4.5. Method development for antisolvent processes
Although, as discussed in the previous section, the behaviour of the antisolvent resolution methods differs significantly, their development and implementation com-prised largely similar steps. These have been generalized and compiled here into a generic template for screening and developing antisolvent resolution processes. For the purposes of this section, assume that a resolution system is proven to achieve chi-ral discrimination in supercritical carbon dioxide (e.g. using thein situ or in vacuo methods).
First, one or more suitable solvent or solvent combination (henceforth referred to as "solvent") must be selected, based on solvent power and compatibility with carbon dioxide. The solvent must be able to efficiently dissolve not only the racemate and the resolving agent, but the formed diastereomers as well. A large number of resolution systems are based on acid–base interaction, thus the diastereomers in these systems are salts, the ionic character of which requires solvents of appreciable polarity (ionic salts, however, are not a prerequisite of successful resolution using scCO2: racemic trans-1,2-cyclohexanediol could be resolved using L-tartaric acid via intermolecular complex formation [84, 85, 188]). However, even if the diastereomers are ionic, highly polar solvents are typically unsuitable for the antisolvent resolution due to their incompatibility (in this case, immiscibility) with carbon dioxide. Solvents must be stable under pressure and unreactive towards but miscible with carbon dioxide.
Solvent selection in terms of solvent power can be done in simple atmospheric
solu-bility tests, suitable candidates can be tested for compatisolu-bility with carbon dioxide in view cell experiments or based on literature data.
In addition to determining solvent suitability, view cell experiments (described in Section 2.2.3) are valuable in establishing the range of process parameters (pressure, temperature, racemate/resolving agent concentration in the solvent and CO2:solvent ratio) in which the resolution is possible. The ability to visually observe the reaction mixture, as well as the variable volume of the view cell (allowing the alteration of pressure without affecting the composition of the reaction mixture), allow the efficient screening of different parameter combinations. However, due to the design of the equipment, efficient separation of the precipitates from the unreacted components is not possible. Therefore whether chiral discrimination occurs can only be inferred from the appearance of a precipitate and by measuring the enantiomeric excess of CO2 phase by sampling. Despite this limitation, view cell experiments can identify suitable solvents and process parameter combinations that can be used as starting points for GAS experiments.
Suitable systems (in the sense of racemate–resolving agent–solvent groups) are transferred to the batch reactor. The main advantage of the GAS technique over the view cell is its ability to achieve separation of CO2-soluble compounds from precip-itates. Since separate extract and raffinate phases are produced, yields and enan-tiomeric excesses can be determined, allowing for precise characterization of a given experiment. Furthermore, the separated fractions can be studied via powder X-ray diffraction or scanning electron microscopy, though the latter is typically only used for the raffinate (since the extract is collected in a liquid trap and evaporated in vac-uum, rendering its microscopic structure unrepresentative). The GAS method can be used to carry out detailed studies into the effects of process parameters (chiefly, pres-sure, temperature, CO2:solvent ratio and reaction time) and their interactions upon yields, optical purities and diastereomer structure.
Once a combination or range of optimal process parameters have been identified, the resolution can be implemented using the SAS technique. Although the exper-iments presented in Sections 3.1.3 and 3.3.2 were only preliminary, they indicate that if the process parameters of a successful GAS experiment are applied to the SAS method (with R being a direct substitute for R), similar results (in terms of optical purities and raffinate structure) can be achieved. The SAS technique has the added benefits of larger capacity (approximately one order of magnitude with respect to the mass of racemate) and more tightly controlled experimental conditions: while the
racemate and resolving agent are exposed to CO2 in the entire range of pressures from atmospheric up to the desired process pressure (and view cell measurements suggest that precipitation may begin before the desired pressure is reached), the so-lution in the SAS technique comes into contact with a stream of scCO2maintained at the desired pressure (typically to within±5 bar).
C ONCLUSION
Three resolution systems have been investigated: the resolution of ibuprofen with resolving agent 1-phenylethanamine (using (R)-(+)-1-phenylethanamine in most ex-periments, (S)-(−)-1-phenylethanamine in some additional studies), and the resolu-tion ofcis-permethric acid with the resolving agents (R)-(+)-1-phenylethanamine and (S)-(+)-2-(N-benzylamino)butan-1-ol.
The novel, solvent-free resolution in a heterogeneous-phase reaction with super-critical CO2(thein situmethod) was demonstrated on the ibuprofen–(R)-(+ )-1-phen-ylethanamine system. At 200 bar and 40 ◦C, both the (R)-(−)-ibuprofen-enriched diastereomers and the (S)-(+)-ibuprofen-enriched unreacted enantiomers had enan-tiomeric excesses of approximately 0.6, with an overall recovery of 83% (with re-spect to the racemate and the resolving agent). By raising the temperature to 50◦C, unreacted enantiomeric mixtures of nearly ee =0.8 could be obtained (though the resolution was unsuccessful at higher temperatures). Although no organic solvent and virtually no downstream processing of products was required to obtain the afore-mentioned optical purities in a single step, it must be noted that the results required reaction times in excess of 80 h.
Techniques using supercritical CO2as an antisolvent were also successfully applied to the ibuprofen–(R)-(+)-1-phenylethanamine system. The effect of process param-eters was investigated in detail. At 100 bar, 45 ◦C, with half-equivalent amounts of resolving agent, using methanol with an antisolvent:solvent mass ratio of 11.3:1 g/g and a volumetric IBU concentration of 4.17 g/dm3 CO2, the optical purity in the diastereomeric salts and unreacted enantiomers was 0.747 and 0.589, respectively, with an overall recovery of 65%. Increasing the antisolvent:solvent ratio increased diastereomer yields according to a saturation curve while having negligible effect on their optical purities, only marginally influenced by the choice of solvent. Although the antisolvent:solvent ratio did not influence the crystalline structure (as determined by powder X-ray diffraction), scanning electron microscopy revealed significant dif-ferences between crystal habits of diastereomers obtained at different ratios. The resolution could be carried out at or above equimolar quantities of resolving agent, attributed to the decomposition of the diastereomers. This enabled a two-step resolu-tion, in which diastereomers formed in an antisolvent experiment were subjected to a second resolution step with no further resolving agent added. The second step yielded practically racemic unreacted enantiomers and diastereomers with an enantiomeric
excess of 0.9 (R)-(−)-ibuprofen, which exceeds the optical purity at the eutectic point of ibuprofen enantiomers. While the solvent consumption of this facile two-step pro-cess is remarkably low compared to traditional crystallizations from organic solvents, yields were significantly lower due to losses resulting from the laboratory-scale im-plementation.
A published resolution method[107]for ibuprofen, based on crystallization from organic solvent using (S)-(−)-phenylglycinol as a resolving agent, yielded a de of 53%
with yields around 50%. Thein situ method produced diastereomers with slightly higher yields and optical purity ( ˆY =0.56, ee(R)= 0.58 at 200 bar and 40◦C), al-though only after 73.5 h. The GAS method (at 150 bar, 45◦C,R=29.5) produced slightly lower yield with higher optical purity in the raffinate (Y =0.43, ee(R)=0.78), however, the required operation time was around 3 h. The two-step purification at 130 bar, 45◦C, using an initial SAS resolution with mr=1 and subjecting the raffi-nate to a GAS resolution with no additional resolving agent, diastereomers with an overallY =0.08 (albeit using only 22.5% of the raffinate) and ee(R)=0.90 could be obtained. In conclusion, thein situmethod yielded results comparable to published methods without the use of organic solvents, after much longer reaction times. The antisolvent methods produced higher purity diastereomers with operation times on the order of a few hours, albeit in lower yields.
The in situ method was successfully applied to the resolution of cis-permethric acid using (S)-(+)-2-(N-benzylamino)butan-1-ol. The effects of process parameters were investigated in detail. In contrast with the resolution of ibuprofen, the reaction time was found to have a minor effect, as good results could be obtained even af-ter 1 h. At 200 bar and 45◦C, diastereomers with an enantiomeric excess of 0.781 (1S,3S)-(−)-cis-permethric acid could be obtained at 60% theoretical yield (based on the total amount of diastereomer assuming a complete, irreversible diastereomer crystallization). A study of temperature effects suggests that these results could be further improved by lowering the temperature to 35◦C. Although the yields and opti-cal purities are inferior to those obtained in published resolution methods, they were achieved in a single step without the use of organic solvents and with virtually no downstream processing required (compared to the multiple recrystallizations from organic solvents in published methods).
The resolution ofcis-permethric acid with (S)-(+)-2-(N-benzylamino)butan-1-ol from organic solutions using pH-driven crystallizations[142]reported the obtained diastereomeric salts as "optically pure", however, 50% of the initialcis-permethric acid
remains at the end of the resolution. At 200 bar and 45◦C, recovery (with respect to the complete amount of material measured in) for thein situsystem is 0.77, however, the fractions are not optically pure (extract ee(+)=0.28, raffinate ee(−)=0.51).
Using (R)-(+)-1-phenylethanamine, the antisolvent resolution of cis-permethric acid was successful. The effect of pressure on optical purities showed unusual, sharp transitions, initially attributed solely to diastereomer decomposition. Further inves-tigation revealed that between 100–120 bar, a stable racemic salt forms, while be-tween 130–200 bar, the optical purity of the crystalline phase is influenced by the relative stability of the individual diastereomers. Between 130–170 bar, where only the (1S,3S)-(−)-cis-permethric acid salt is stable, diastereomers with ≥ 0.8 (up to 0.94) ee (1S,3S)-(−)-cis-permethric acid could be obtained. An apparatus for semi-continuous antisolvent resolution was developed and successfully tested. Although the diastereomer optical purities exceed previously published results, yields are di-minished due to diastereomer decomposition.
A crystallization-based resolution of cis-permethric acid, using amines derived from natural carenes [143], produced both enantiomers of cis-permethric acid in 82–86% yield with optical purities reported as 95% for (1R,3R)-(+)-cis-permethric acid and ≥ 98% for (1S,3S)-(−)-cis-permethric acid. However, these results were obtained using several recrystallizations (twice and three times for the (−) and (+) enantiomers, respectively), with one recrystallization for (1R,3R)-(+)-cis-permethric acid involving benzene. In contrast, the GAS method at 150 bar and 45◦C yielded the (1S,3S)-(−)-cis-permethric acid–(R)-(+)-1-phenylethanamine salt in 94% purity in a single step using methanol. Due to diastereomer dissociation, however, the ex-tract optical purity was low. The SAS method produced diastereomer salts with 0.93 ee and Y = 0.15, extract optical purity was 0.32 withY =0.09. In conclusion, the antisolvent methods yielded optical purities comparable to traditional methods with reduced solvent use and operation times, albeit with lower yields.
Based on the investigations carried out, some general guidelines for developing antisolvent resolution techniques have been presented.
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