DBTA salt formation

As indicated by the above enantiomeric purity assay, the quality of the DBTA salt prepared according to Scheme 8 was often borderline (ca. 97%). A process was registered (as an IND update) for occasional use in which the salt was split back to the base (in -butanol) and the DBTA salt formation step repeated. As time passed, it became apparent that it would be better, from an operations and economics standpoint, to seek a higher first crop yield (by cooling to ca. 0°C) and to recrystallize the wet first crop routinely. This position became the subject of criticism during the FDA s pre-approval inspection (q.v.). 

The use of a wet //-butanol recrystallization for reprocessing out-of-specification DBTA salt to replace the original split back to the base and repeating the DBTA salt formation. The recrystallization process gave a product with higher enantiomeric purity. 

Biased classification of DBTA into the group of agents for diastereoisomeric salt formation was breaken through when Hatano and his co-workers recognized that trans-bicyclo[2.2. l]heptane-2,3-diamine (1, Scheme 2) form diastereoisomeric complexes with DBTA instead of regular salts [15]. Our laboratory has also reported such complex formations of eight N-alkylpipecolic acid-anilide derivatives (2, Scheme 2) with DBTA. [22]... 

Transformation of the a- or P-hydroxycarboxylic acids into esters eliminates the acidic character of the racemate, thus one can avoid formation of the above mentioned unsoluble calcium salts. In the same time formation of a mixed calcium salt of DBTA and the racemic acid is impossible therefore coordination bonds should entirely replace it. 

Series of racemic a- and p-hydroxycarboxylic acid esters (4 and 5, Scheme 4) could be separated into their enantiomers via coordination complex formation but in these cases the acidic salt, (DBTA)2Ca had to be used as resolving agent. [23, 24]... 

Coordination complex formation of alkoxyalcohols (8, 9, 10, 14), 2-butanol (15) and 1,3-butanediol (16, Scheme 7) with the zinc salt of DBTA was investigated, too. [25] The resolving agent (DBTAZn) was prepared again from DBTA monohydrate and zinc oxide or zinc acetate in aqueous ethyl alcohol solution. 

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