Biocatalytic approaches to a key building block for the anti-thrombotic agent ticagrelor

Abstract

Three different enzymatic routes were employed to produce a precursor of the important antithrombotic agent Ticagrelor with high ee.

Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor

“…As reported previously, the lipase from Thermomyces lanuginosa was found to efficiently catalyse the kinetic resolution of substrate ester 2 with high enantioselectivity (E =100) 11 .…”

“…An increase of only 7% conversion was observed, perhaps due to the combined effects of by-product acid 4 enzyme inhibition, and the pH on enzyme activity; nevertheless the substrate e.e. reached a higher value than that obtained in previous trials 11 . The space time yield of the flow reactor equals 28.2 mmol L -1 h -1 , and is therefore 64 times more efficient than the batch reactor which yielded the desired product with 0.4 mmol L -1 h -1 .…”

“…Although the liquid preparation of the lipase was preferentially used on small scale, 11 and yielded better kinetic resolution of the target ester 3, we chose the immobilised version of the enzyme (covalently linked to immobead; Immobead 100, 9820 Units/g) throughout the study for all batch, recycling and flow reactions, in order to simplify the work-up procedure. As can be seen from Table 1 (Entry 1), the liquid preparation afforded a very good kinetic resolution of the target ester 3 on small scale (E > 200).…”

“…8 In this context, application of biocatalytic retrosynthesis 9 identified a synthetic strategy towards the cyclopropyl subunit (1R, 2S)-2 starting from the racemic cyclopropyl ester 3 (Scheme 2), a low value precursor easily prepared on large (kg) scale 10 . Recently we reported 11 the lipase mediated kinetic resolution of (±)-3, under biphasic conditions, wherein the substrate ester 3 was hydrolysed to yield the desired ester (1R, 2R)-3 and the by-product acid (1S, 2S)-4 (Scheme 2). Under these conditions the acid (1S, 2S)-4…”

Gram‐Scale Synthesis of Chiral Cyclopropane‐Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity

“…[15] Of note, this intermediate is currently accessible through synthetic routes involving no less than four to five steps. [15, 18] Conveniently, the key cyclopropane building block 26 could be obtained in a single step in high yield (94%) and selectivity (98% de , 58% ee ) via whole-cell cyclopropanation of commercially available 3,4-difluoro-styrene with cells expressing the ( 1R,2R )-selective Mb(L29T,H64V,V68L) variant. Taken together, these results demonstrate the promise and scalability of stereoselective myoglobin-catalyzed cyclopropanations in the context of relevant and challenging building blocks for drug synthesis.…”