Formation of Diastereomeric Salts

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). 

Resolution of chiral acids through the formation of diastereomeric salts requires adequate supplies of suitable chiral bases. Brucine, strychnine, and quinine frequently are used for this purpose because they are readily available, naturally occurring chiral bases. Simpler amines of synthetic origin, such as 2-amino-1-butanol, amphetamine, and 1-phenylethanamine, also can be used, but first they must be resolved themselves. 

The old school method for resolving a racemic mixture is through formation of diastereomeric salts. Salts form through reaction of a racemic drug with an enantiomeri-cally pure acid or base (Scheme 13.2). Of course, the drug must contain a basic or acidic functional group, normally an amine or carboxylic acid, respectively. The salt product is... 

Amines react with strong acids to form amine salts. The pKas of amine salts are related to the base strength of the corresponding amines. Alkylammonium salts have pKas of 9-10 while arylammonium salts have pKas of 4-5. The fact that these salts are usually water-soluble can be exploited in separating amines from neutral or acidic contaminants. Chiral amines can be used to resolve enantiomeric acids, through the formation of diastereomeric salts. 

The R and S enantiomers of ammonium salt A can interconvert only by processes that involve breaking a carbon-nitrogen bond. This does not occur easily, and thus, the enantiomers can be separated by formation of diastereomeric salts. 

An overwhelming majority of classic resolutions still involve the formation of diastereomeric salts of the racemate with a chiral acid or base (Table 6.1). These chiral-resolving agents are relatively inexpensive and readily available in large quantities (Table 6.2). They also tend to form salts with good crystalline properties.8... 

Chemical Resolution of Compounds Containing Basic Groups. 3-Bromocamphor-8-sulfonic acid has been widely used as a resolving agent for compounds containing basic groups. A number of primary (1), secondary (2), and tertiary (3) amines as well as oxazolines (4) have been resolved by the formation of diastereomeric salts derived from 3-bromo-8-camphorsulfonic acid. 

Another further way of purification is the formation of diastereomeric salts. However, partial solid solution are often observed and it is difficult to achieve high... 

Resolution of a carboxylic acid can be achieved directly by formation of diastereomeric salts with an amine. Naturally occurring bases such as brucine (34) or ephedrine (35) are often used, though it should be mentioned that choice of a suitable amine is usually a matter of trial and... 

This is a step carried out to improve the purity or form of an intermediate or final product, and includes distillations, recrystallisations, chromatography and resolutions (by chromatography or formation of diastereomeric salts, isolation and neutralisation). 

As an example, consider the case where a racemic acid is to be resolved through the use of a basic resolving agent. The first step of the resolution procedure involves formation of diastereomeric salts as in the table. 

Enantiomerically pure amines are often used to resolve racemic forms of acidic compounds by the formation of diastereomeric salts. 

As there was an amine handle for the formation of diastereomeric salts, classical resolution of to obtain CP-465,022 was also an option (Scheme 23). With the ability to thermally racemize the wrong antipode, one could envision a dynamic resolution (or, asymmetric transformation). In the presence of the appropriate chiral acid, there would be an equilibrium of the enantiomers of CP-392,110 in solution, with only the desired antipode CP-465,022 crystallizing out as the insoluble diastereomeric salt. Pfizer has developed a number of other atropisomers, and this sort of dynamic resolution has been worked out for one of those candidates. 

Figure 11.2 Enantiomeric f CJintermediates separated through formation of diastereomeric salts...

In another approach, optically pure (—)-brucine was mixed with ( )-ibuprofen while preparing the solution prior to its application onto TLC plates [16]. The premixing resulted in the formation of diastereomeric salts of the type (-1-)-ibuprofen-(—)-brucine and (—)-ibuprofen-(—)-brucine without resorting to any covalent linkage. It was the movement of these ionic diastereomers on TLC plates that resulted in separation. Chromatograms were developed at 28 2°C for 20 min in acetonitrile/methanol (5 1, v/v), and the spots were located with iodine vapors. 

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