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Diastereomeric Crystallisation

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Diastereomeric Crystallisation CHEMICAL TECHNOLOGY Diastereomeric crystallisation - the “classical” chiral technology Even today, diastereomeric crystallisation still represents a key process in making optically active compounds in bulk quantities. Dr Niteen A Vaidya, Ychem International In principle, it hiral technology has wide application in (asymmetric the field of specialty chemicals such as pharmaceuticals, herbicides, pheromones, synthesis) C liquid crystals, non-linear optical materials and should be the polymers, aromas and flavours, vitamins, sweeteners, most cost- dyes and pigments, and so on. The worldwide market for chiral products is over $200 billion; in effective pharmaceuticals alone, the market for single method for enantiomer drugs is $115 billion (1). It has been producing recognised for a long time that the shape of a molecule has a considerable influence on its single-enan- physiological properties. Differentiation within tiomer products, enantiomeric pairs are numerous and can often be Figure 1. Melting point diagrams of racemates. because all the dramatic; a few examples are given in Table 1. This emphasises the reasons for the level of com- precursors are require auxiliary chiral synthesis or asymmetric mercial interest in chirality and the incentive to catalysis. In principle, it should be the most cost- converted to produce optically pure materials by methods effective method for producing single-enantiomer the desired applicable to at least multigram amounts, and in products, because all the precursors are converted many cases to hundreds or thousands of tonnes. enantiomer to the desired enantiomer. However, in an industrial There are two basic approaches to obtaining setting, the decision to implement an asymmetric chiral compounds: resolution and asymmetric synthesis approach is typically based on an synthesis. The resolution of racemic mixtures assessment of efficiency and cost. Among the involves separation methods such as chromatography, factors to be considered are: 1) the efficiency of the polymer-supported liquid membrane and preferential catalyst (that is, the number of product molecules or diastereomeric crystallisation. Chiral chro- produced per molecule of the catalyst); 2) the matography is a particularly useful technique for availability of the metal, the ligand and the starting the small-scale resolution of racemic mixtures (less materials (especially critical for low-value products); than one kilogram of material). and 3) the reaction conditions, such as a Asymmetric synthesis (the introduction of very low temperature or high pressure, and chirality during the synthetic sequence) may reaction kinetics. 82 Innovations in Pharmaceutical Technology CHEMICAL TECHNOLOGY Diastereomeric crystallisation Despite its image as a “low-tech” method, diastere- omeric crystallisation is widely used today in the separation of racemic mixtures, even though the theoretical yield is only 50%. But if the unwanted isomer could be racemised back to the mixture, this would set up a recycle process to yield the desired isomer - which would have an unprecedented economic advantage over other methods (2). The utilisation of phase diagrams generally speeds up the selection of a good resolving agent and determination of the best crystallisation conditions - although the selection process is still very empirical, and trial-and-error can sometimes be the best solution. An alternative to diastereomeric salt formation is direct, preferential crystallisation of the desired enantiomer, usually initiated by seeding with a pure enantiomer. If applicable, preferential crystallisation of enantiomers is a highly economic approach; in fact, Merck has used it with the great s success in the manufacture of α-methyl DOPA. However, in practice, the method has Diastereomeric crystallisation has the advantage of relative simplicity and requires only standard production equipment limited application because it can only be applied to a conglomerate - that is, a mechanical mixture of crystals of the two enantiomers. By contrast, a true racemic compound - where both enantiomers exist in a unit cell - cannot be resolved by preferential crystallisation. Unfortunately, less than 20% of all known racemates are conglomerates - the remainder are true racemic compounds and thus cannot be separated by preferential crystallisation. The question of to which of the two classes a racemate belongs is readily ascertained by reference to its melting point diagram, which is determined using differential scanning calorimetry (3) (see Figure 1). A list of optically active pharmaceuticals produced wholly or partially using crystallisation Innovations in Pharmaceutical Technology 83 CHEMICAL TECHNOLOGY the production process and plant utilisation. Futhermore, recovery of the resolving agent is usually necessary for environmental and economic reasons, but the cost of recovery - particularly for α1=+4.0 inexpensive resolving agents - can be quite high. The feasibility of racemisation of the “unwanted” enantiomer has a major effect on the production economics. While the occurrence of desirable crystal behaviour and solubilities are largely unpredictable, a systematic search for exploitable properties at all relevant points in a sequence will certainly reward the effort, and should form part of the modus operandi of the process development chemist. For example, if a substance is readily racemised and a crystallisation-induced asymmetric transformation (de-racemisation) is possible, it offers an extremely attractive industrial option. There are two types of diastereomer: ionic/salt ... if the techniques is shown in Table 2. Examination of a and covalent/neutral. Covalent diastereomers unwanted representative group of such drugs shows that are easier to separate by HPLC than are ionic roughly 65% owe there optical activity to classical diastereomers. Even so, covalent diastereomers are isomer could be resolution. There are clearly many instances where not preferred because their formation is not as easy racemised back resolution is both economically viable and the as that of the salt - and neither is their decomposition. preferred method. Moreover, the forward and reverse reactions are to the mixture, Diastereomeric crystallisation has the advantage more subject to racemisation of chiral centres than this would set of relative simplicity and requires only standard is salt formation. up a recycle process to yield the desired isomer - which 1-Butanol would have an unprecedented economic advantage over other methods production equipment. From a practical point of Optimisation of the resolution view, the method is flexible and suited to intermittent batch production, which is often the The initial problem associated with diastereomeric case in pharmaceutical manufacture. However, in crystallisation is to choose the right resolving agent, spite of its simplicity, the procedure has disadvantages and the nature and composition of the solvent. when employed at a large scale, including the need This can be time-consuming, tedious and labour- for space-consuming process equipment, reactors, intensive. Some of the important points which holding tanks and so on. The storage of the various must be taken into consideration are: mother liquors, as well as second and third crops • The diastereomeric salt must crystallise well, held pending future re-work, takes up considerable and there must be an appreciable difference in space in the plant and can create a bottleneck in solubility between the two salts. 84 Innovations in Pharmaceutical Technology CHEMICAL TECHNOLOGY • The compound between the resolving agent developing a resolution package. In a process The initial and the substance to be resolved should be known as the “Dutch resolution”, a family of easily formed, and the resolving agent should resolving agents is used instead of a single agent - problem be easily recoverable in a pure state from the for example, the tartaric acid family composed of associated with salt following the crystallisation step. dibenzoyltartaric acid, ditolyltartaric acid and diastereomeric tartaric acid. According to the authors of the study, • In general, a resolving agent should be when such a mixture is added to a solution of crystallisation is available in an optically pure form, because a racemic substrate, a crystalline salt usually to choose the the substance to be resolved cannot be precipitates immediately. In most cases, the substrate right resolving obtained in a higher state of optical purity than contained in the precipitated salt is resolved to the resolving agent by mere crystallisation of about 90-98% enantiomeric excess (ee) (6). agent, and the diastereoisomers. nature and References composition of • The chiral centre should be as close as possible to the functional group responsible for salt 1. Technology Catalyst International, Falls the solvent formation. Church, VA. • An agent must be chemically stable and must 2. Bayley CR and Vaidya NA (1992). Chirality not racemise under the conditions of the in Industry, P69. resolution processes. 3. Sheldon Roger A (1993). Chirotechnology, • The resolving agent should be available as P173. both enantiomers, so that both forms of the substrate can be prepared. 4. Collet Andrew (2000). Encyclopedia of Separation, Vol 5, 2326. • For industrial purposes, a resolving agent should be relatively inexpensive and readily 5. Dyer UC, Henderson DA, Mitchell MB recoverable in high yield after completion of (1999). Org Proc R&D, 3, 161-165. the resolution. There is no
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