Abstract
A new chemoenzymatic method has been developed for the synthesis of (S)- and (R)-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl) acetamide, two key synthons for the preparation of (S)-pramipexole, an anti-Parkinson drug, and its enantiomer dexpramipexole, which is currently under investigation for the treatment of eosinophil-associated disorders. These two building blocks have been obtained in good yields and high enantiomeric excess (30% and >98% ee for the R-enantiomer, and 31% and >99% ee for the S- one) through a careful optimization of the reaction conditions, starting from the corresponding racemic mixture and using two consecutive irreversible transesterifications, catalyzed by Candida antarctica lipase type A. Single crystal X-ray analysis has been carried out to unambiguously define the stereochemistry of the two enantiomers, and to explore in depth their three-dimensional features.
Highlights
Pramipexole is a dopamine agonist approved for the treatment of Parkinson’s disease and for restless legs syndrome; it is marketed as dihydrochloride salt under the brand name Mirapex [1,2,3].Pramipexole or 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole 1, has a stereogenic center on C6 (Figure 1), and only the isomer (S)-1 exhibits anti-Parkinson properties
Taking into account the promising results of our previous experiments [15], in which a Saccharomyces cerevisiae-catalyzed reduction of ketone 3 (Figure 2) afforded the optically pure (R)-4 (Figure 2), and considering the few chemoenzymatic approaches [16,17] available for the synthesis of pramipexole, we studied the resolution of the alcohol rac-4 by means of an enzymatic transformation
The enantiopure alcohol (R)-4 proved to be a useful synthon for the synthesis of (S)-1 dihydrochloride monohydrate, thepurity commercial form of thisisactive ingredient, in five steps and 21%process, overall due yieldto[15]
Summary
Pramipexole or 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole 1, has a stereogenic center on C6 (Figure 1), and only the isomer (S)-1 exhibits anti-Parkinson properties. The isomer (R)-1, known as dexpramipexole, was studied some years ago for the treatment of ALS (amyotrophic lateral sclerosis) [4,5,6]; despite the promising results in early clinical studies, its development was discontinued in 2013, due to a lack of efficacy observed in a Phase 3 study [7,8]. A reduction in the absolute eosinophil count (AEC), coincidentally detected during the ALS-related clinical development, suggested a possible application of dexpramipexole for the treatment of eosinophil-associated disorders [9,10]. The optical purity this compound Catalysts 10, x FOR. The rac-1 or its precursor, the amine rac-2 (Figure 2), are resolved by fractional crystallization of a diastereomeric salt [11,12] or by preparative chiral high-performance liquid chromatography (HPLC) [13,14]
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