Crystallization chiral amine resolution

Three methods for chiral amine resolution are used in the manufacture of pharmaceuticals crystallization used most commonly enzymic resolution used occasionally chromatography used frequently during early phase and increasingly in commercial production. In each of these an isomer waste stream of at least 50% of the starting material is produced. 

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. 

Structure of the complex was fiirther confirmed by X-ray crystal structure analysis. We have also observed an interesting solvent effect on this reaction. Whereas the borate complex prepared fi om R-a-methylbenzylamine and S-bi-2-naphthol is insoluble in CH3CN, the complex obtained using the same amine and R-bi-2-naphthol is insoluble in THF. This interesting solubility difference has been exploited in resolving ( )-bi-2-naphthol to obtain the enantiomers in >99% ee as shown in Scheme 6. The chiral amine can be recovered in 90% yield after the resolution. 

In synthetic operations, when a symmetrical (achiral) substrate is used, the product is racemic. Diastereomers are separated by physical methods, and the enantiomers of racemic amines are frequently obtained by fractional crystallization of diastereomeric salts formed with chiral acids. Although resolution of racemic amines by fractional crystallization of enantiomeric salts is still an important technique and the laboratory scale resolutions of many racemic amines have been reported , the separation of the enantiomers of chiral amines by chromatography " and their preparation by asymmetric synthesis using enzymes and other asymmetric catalysts have had extensive development during the... 

A wide range of bidentates containing one or more asymmetric phosphorus or arsenic donor atoms is now available due to the exploitation of a resolution technique involving the fractional crystallization of pairs of diastereomeric complexes formed by the chiral bidentates with pal-ladium(II) complexes containing optically active dimethyl(a-methylbenzyl)amine or dimethyl(l-ethyl-a-naphthyl)amine. Indeed, in recent work the two enantiomer pairs of l-(methylphenyl-arsino)-2-(methylphenylphosphino)benzene, (29a) and (29b), have been separated and isolated as optically pure air-stable crystalline solids with [a]o values of 79° (R, R ) and 15.5° (R, S ). 95... 

In principle, any of the photoproducts shown in Table 4 could have been prepared in enantiomerically pure form by irradiating their achiral precursors in solution to form a racemate and then separating the enantiomers by means of the classical Pasteur resolution procedure [36]. This sequence is shown in the lower half of Fig. 3. The top half of Fig. 3 depicts the steps involved in the solid-state ionic chiral auxiliary method of asymmetric synthesis. The difference between this approach and the Pasteur method is one of timing. In the ionic chiral auxiliary method, salt formation between the achiral reactant and an optically pure amine precedes the photochemical step, whereas in the Pasteur procedure, the photochemical step comes first and is followed by treatment of the racemate with an optically pure amine to form a pair of diastereomeric salts. The two methods are similar in that the crystalline state is crucial to their success. The Pasteur resolution procedure relies on fractional crystallization for the separation of the diastereomeric salts, and the ionic chiral auxiliary approach only gives good ees when the photochemistry is carried out in the crystalline state. 

---