Preparation of (R)-3-aminopiperidine by resolution with optically active cyclic phosphoric acids.

(R)-3-aminopiperidine ((R)-APD), a key intermediate for alogliptin, trelagliptin, and linagliptin, was successfully resolved from racemic 3-aminopiperidine with an enantiomerically pure resolving agent, namely, (R)-4-(2-chlohydroxy-1.3.2-dioxaphosphorinane 2-oxide ((R)-CPA), via diastereomeric salt formation. By this resolution approach, (R)-3-aminopiperidine was obtained in 99.5% yield with 99.6%e.e.

Selecting Resolving Agents with Respect to Their Eutectic Compositions.

In order to develop a resolution procedure for a given racemic compound, the first and the most important step is finding the most suitable resolving agent. We studied 18 individual resolutions that were carried out with resolving agents having high eutectic composition. We found that very high enantiomeric excess values were obtained in all cases. We assume that the eutectic composition of a given resolving agent is one of the most important properties that should always be considered during the search for the most efficient resolving agent.

Crystal structure of racemic cis-2-amino-1,2-di-phenyl-ethanol (ADE).

In the title racemic compound, C14H15NO, the hy-droxy and amino groups form a bent tweezer-like motif towards the phenyl groups. In the crystal, enanti-omers aggregate with each other and are linked by O-H⋯N hydrogen bonds, forming chiral 21-helical columnar structures from C(5) chains along the b-axis direction. Left- and right-handed 21 helices are formed from (1S,2R)-2-amino-1,2-di-phenyl-ethanol and (1R,2S)-2-amino-1,2-di-phenyl-ethanol, respectively.