Development of Chemoenzymatic Process for Preparing Optically Pure Intermediates for the Preparation of Antidepressant (1s,2r)-Tranylcypromine and the Alike

In the past years, the substrate engineering approach has been employed for developing lipase-catalyzed kinetic resolution processes, in which the enzyme activity and enantioselectivity is greatly improved by using (R,S)-azolides as the substrate. Many drugs and their intermediates may contain two chiral centers, and hence four diastereomers are obtained from the organic synthesis. This will certainly causes much difficulty in the diastereomer separation and purification (including using enzymatic kinetic resolution). In the two-year project, we will focus on the topic of “Development of optically pure diastereomers via chemoenzymatic method”, in which the optically pure azide intermediate for the synthesis of (1S,2R)-tranylcypromine antidepressant and the alike in one-pot. In the first year, trans-2-phenylcyclopropanecarboxylic acid (trans-2-PCPCA) containing equal amount of (1R,2R)- and (1S,2S)-2-PCPCA (as well as cis-2-phenylcyclopropanecarboxylic acid (cis-2-PCPCA) containing equal amount of (1S,2R)- and (1R,2S)-2-PCPCA) is employed for synthesizing the azolide substrate. The best reaction condition (i.e. temperature, organic solvent, hydrolysis or transesterification, leaving azole) based on CALB activity and stereoselectivity is firstly selected. The enzymatic kinetic and thermodynamic analysis at the best reaction condition will be studied in order to elucidate effects of different diastereomer on the lipase performance. In the second year, the feasibility of using one-pot method for synthesizing the azide intermediate from remained (1S,2S)-azolide, as well as using of substrate consisting of four diastereomeric azolides, will be investigated. Moreover, the synthesis strategy will be extended to the alike compounds, e.g. trans-2-(4-chlorophenyl)cyclopropanecarboxylic azolide.

Project ID:PB10608-3644
External Project ID:MOST106-2221-E182-049-MY2