Diastereomeric crystals

Figure 13.2 Some examples of chiral amine-containing pharmaceuticals manufactured using diastereomeric crystallization processes, and approximate product volumes.

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

The enantiomers are obtained by diastereomeric crystallization of the demethylated methoxyazepine derivative i with (D)-(+)-tartaric acid followed by methylation with HCHO, H2 and Pd/C in ethanol. 

Reactive crystallization, or precipitation, has been investigated by numerous research groups. Processes of industrial relevance include liquid-phase oxidation of para-xylene to terephthalic acid, the acidic hydrolysis of sodium salicylate to salicylic acid, and the absorption of ammonia in aqueous sulfuric acid to form ammonium sulfate (60). A very special type of reactive crystallization is diastereomeric crystallization, widely applied in the pharmaceutical industry for the resolution of enantiomers (61). Another fine example of reactive precipitation is the earlier-described production of nano-size particles of CaC03 in high-gravity fields (46). 

Diastereomeric crystallization is commonly used in the production of a number of pharmaceuticals, such as ampicillin, ethambutol, chloramphenicol, diltiazem, fosfomycin, and naproxen (136). 

In this chapter, we deal with resolutions involving crystallization techniques, i.e. preferential crystallization and diastereomeric crystallization. 

Diastereomeric crystallization. In this approach an optically pure auxiliary compound is added to the mixed optical isomers of the product to form the corresponding diastereomers which are then separated via crystallization. For example, S-naproxen is produced by reacting a chiral amine with the racemic mixture of 2-(6 -methoxy-2 -naphthyl)propionic acid to form the corresponding organoammonium salts of the S- and R- isomers followed by crystallization and reacidification (2). 

The major industrial route to calcium pantothenate starts from isobutyralde-hyde, which is condensed with formaldehyde. Hydrocyanation and hydrolysis affords the racemic pantolactone (Fig. 8.20). The resolution of pantolactone is carried out by diastereomeric crystallization with a chiral amine, such as (+)-2-aminopinane (BASF), 2-benzylamino-l-phenylethanol (Fuji) or (lR)-3-endo-ami-nonorbomeol (Roche). The undesired enantiomer is racemized and recycled. 

The diastereomeric crystallization of pantolactone is laborious due to the need to recycle the resolving agent. Various schemes to replace this latter step with the chemical or microbial oxidation of pantolactone, followed by microbial reduction to the (R)-enantiomer, were unsuccessful because the productivity of the microbial step remained too low [110 a]. 

Although the basic principle and procedure of diastereomeric resolution are not difficult to understand, the chiral discrimination mechanism involved in the selective crystallization of one diastereomer from the mixture is very complicated. The chiral discrimination mechanism for diastereomeric resolution changes in accord with the resolving system, since not only the properties of diastereomeric crystals but also the conditions for crystallization strongly influence the chiral discrimination mechanism. In particular, the polymorphism of crystal, the severe solvent effect on solubility, and the kinetic factor for crystal growth are still not perfectly understood regarding this chiral discrimination phenomenon. The study is therefore limited in its investigation of the chiral discrimination mechanism for the diastereomeric resolution, as the mechanism involves both the crystal and solution properties of diastereomers.7... 

For convenience, a phase diagram of a pair of diastereomeric crystals is ordinarily studied in detail, and the mechanism of the diastereomeric resolution is interpreted in terms of the thermodynamic and physical properties of the bulk of the diastereomeric crystals.4,7-10 Such studies reveal the importance for diastereomeric resolution of the type of mixture of diastereomers in a target system. There are three types of diastereomer mixtures an eutectic mixture, a 1 1 addition compound, and a solid solution. To achieve successful resolution, it is essential that the mixture of the diastereomeric crystals of a target racemate with a resolving agent be an eutectic mixture. The classic studies are thoroughly reviewed by Collet and co-workers.4,12... 

When a diastereomeric mixture is an eutectic mixture, the difference in solubility between the diastereomers can be roughly correlated to the difference in thermodynamic stability between them if the conditions for crystallization, such as temperature and solvent, are unchanged. Then it becomes meaningful to estimate the stabilities of a pair of diastereomeric crystals and to observe the correlation between the difference of the stability of the pair of diastereomeric crystals and the efficiency of the chiral discrimination. 

Thus we suggest that there are two factors for the stabilization of the diastereomeric crystals of the present system, hydrogen-bonding and van der Waals interactions. The difference in crystal stability between the less and more soluble diastereomeric salts, which are successfully separated upon crystallization, arises from the difference in magnitude of the interactions between them (Figure 4.5). Namely the crystals of the less soluble diastereomeric salts are stabilized by the two factors, while the crystals of the more soluble diastereomeric salts are stabilized by only one of the two factors. 

The authors group also determined the crystal structures of a pair of diastereomeric salts of 1 with 1-p-tolylethylamine (2), which could not be efficiently resolved by 1. We found that both diastereomeric crystals ((R)-b(R)-2 and (i )-l (5 )-2) do not satisfy the two factors that are found in the... 

Thus there are plenty of reports on the resolutions of a wide variety of racemates with conventional resolving agents and on the crystal structures of the diastereomeric crystals of some combinations. These studies are rarely concerned with the correlation between the difference in stability of a pair of diastereomeric crystals and the efficiency of resolutions. However, the information about supramolecular hydrogen-bond systems obtained from these studies is very valuable for understanding such relationship in the resolutions of systematically selected racemates with a resolving agent. 

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

In this section, diastereomeric crystallization is presented as a driving force -or internal selection pressure - to resolve dynamic diastereomeric systems. The dynamic diastereomeric systems are generated from reversible covalent bond formation, leading to compounds carrying chiral carbon centers under thermodynamic control. The dynamic systems can represent more variety of the possible diastereomer adducts. The selective diastereomers, A —B, , are subsequently chosen from the dynamic system by self-transformation and/or self-preferential crystallization. When the selective product C , is formed, the ratio of its corresponding diastereomer adducts A -Bm in the dynamic system will be decreased. The equilibrium in the dynamic system will force the reproduction of the intermediate until the resolution has reached completion. In the end, only one diastereomeric product Cnm is selectively crystallized and easily purified from the solution. 

Moreover, the cell dimensions gradually changed when the crystal was exposed to a xenon lamp. The optical rotation of the chloroform solution in which the irradiated crystals were dissolved increased significantly. This may indicate that the racemic-to-chiral transformation would also occur in a diastereomeric crystal. 

Although considered to be too empirical and based on a trial-and-error approach, diastereomeric crystallizations remain a method of choice for obtaining enantiomerically pure synthetic drugs in relatively small amounts. 

The diastereomeric crystallization relies on a different solubility of diastereomeric salts. The first enantioseparation based on a diastereomeric salt formation was performed by Pasteur in 1853 [2,10]. In this example, racemic tartaric acid was resolved as diastereomeric salts with (-t-)-cinchotoxine or (+)-quinotoxine. Diastereomeric complexes may also be of charge-transfer or inclusion type. 

Thus, in contrary to spontaneous crystallization, a resolving agent is required in diastereomeric crystallizations. The resolving agent should meet certain requirements ... 

Some commonly used resolving agents are summarized in Table 1 [15-48]. The formation of non-covalent diastereomeric salts is driven by ionic interactions. Therefore, suitable functional groups (acidic or basic) are required to be present in both counterparts. This makes impossible a direct application of the diastereomeric crystallization technique to several classes of chiral compounds such as alcohols, aldehydes, ketones, diols, thiols, dithiols, and phenols. This is a critical disadvantage of this technique. The compounds of the above-mentioned groups may be transformed to their more polar derivatives and resolved as such. However, this requires an additional reaction step, and reagents, and the recovery of the starting material after the resolution may not always be easy. 

Diastereomeric crystallization is intensively used for the preparation of enantiomerically pure chiral drugs on a relatively small scale. However, applications of this technique on the production scale are also described (Table 3) [5],... 

Table 3. Examples of pharmaceuticals resolved using diastereomeric crystallization in the process [5]...

As mentioned above, the different solubility of diastereomers offers a challenge for their separation by diastereomeric crystallization. The indirect HPLC separation of enantiomers relies on their different interaction with a (achiral) stationary phase. The interaction of the enantiomeric pair (R, S) with one (let us assume it to have S configuration) enantiomer of a chiral derivatizing reagent may be expressed as follows ... 

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