Diastereomeric crystallization, production

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

In a probe for the presence of stereoelectronic effects in nucleophilic addition to 12 sterically unbiased ketones, calculations have identified subtle bond length differences in the C-Nu bond of the diastereomeric alcohol products, where Nu- = H-or Me-.304 The calculated differences are weak (<1%) but consistent the bond is longer in the major product, acting as a fossil record of the TS. Using microscopic reversibility, the easier bond to cleave (the longer one) is the easier to form. The effect bears comparison with the kinetic anomeric effect in sugars, where such bond length differences in calculation are borne out in X-ray crystal structures. 

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). 

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 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]. 

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. 

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],... 

At present moment, no generally feasible method exists for the large-scale production of optically pure products. Although for the separation of virtually every racemic mixture an analytical method is available (gas chromatography, liquid chromatography or capillary electrophoresis), this is not the case for the separation of racemic mixtures on an industrial scale. The most widely applied method for the separation of racemic mixtures is diastereomeric salt crystallization [1]. However, this usually requires many steps, making the process complicated and inducing considerable losses of valuable product. In order to avoid the problems associated with diastereomeric salt crystallization, membrane-based processes may be considered as a viable alternative. 

A solution of 0.11 mol of 1.5M butyllithium in hexane is added to 30 mL of THF under a layer of argon or nitrogen at —78 C, followed by 0.10 mol of (4S,5/ )-1-allyl-3,4-dimcthyl-5-phenyl-2-imidazolidinone in 75 mL of THF. After 25 min, a solution of 0.11 mol of chlorotris(diethylamino)titanium in 30 mL of THF is introduced. The mixture is stirred at — 20 °C for 45 min, then 0.11 mol of the aldehyde or ketone in 10 mL of THF is added. After 2 h. 20 mL of water and 200 mL of diethyl ether are added. The ethereal solution is separated, washed with 20 mL of 10% aq NaHS03 followed by 20 mL of water, dried over Na2S04 and concentrated, whereupon the product crystallizes. Diastereomerically pure samples are prepared by recrystallization from hexane or hexane/ethyl acetate. 

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

---