Efficient Preparation of a Key Intermediate in the Synthesis of Roxifiban by Enzymatic Dynamic Kinetic Resolution on Large Scale

Abstract

Additional information is presented for the transformation of a kinetic resolution into a dynamic kinetic resolution of the isobutyl ester 5b to form the acid 2 in high yield and ee via the intermediacy of a thioester 6c, (

Novel Chiral Auxiliary for Attempted Resolution of Key Roxifiban Intermediate: A Simple Diastereoselective Coupling Approach for the Synthesis of Roxifiban

“…While this study was under investigation, Pesti et al [12] reported the synthesis of the R-acid 2 with 80.4% yield and .99.9% ee after crystallization by following enzymatic hydrolysis. This attracted our attention to the use of thioethyl ester of (+) acid 2.…”

“…1) Hydrolysis by amano lipase P30; [4] 2) EtSH, DCC, DMAP, EtOAc; 3) amano lipase P30, NaH 2 PO 4 buffer, Me 3 N, triton X; [12] de. If we compare this value (58% de) with the starting acid (28% ee), it is clear that significant diastereomeric enrichment (30%) had occurred.…”

“…[3-(4-Cyano-phenyl)-4,5-dihydro-isoxazol-5-yl]-acetic acid (2) [12] Finely powdered 7 (27.4 g; 100 mmol) was suspended in 0.65 N NaH 2 PO 4 (406 mL), trimethyl amine (25 g in 100 mL water), Triton X 100 (2.3 g), and amino lipase PS 30 (2.3 g), and the mixture was stirred at 408C. A solution of 6N NaOH (200 mL) was added at intervals such that the pH of the mixture was maintained at 8.9 to 9.5.…”

A Powerful Hydrogen‐Bond‐Donating Organocatalyst for the Enantioselective Intramolecular Oxa‐Michael Reaction of α,β‐Unsaturated Amides and Esters

“…Chiral oxygen‐containing heterocycles, such as isoxazolines, isoxazolidines,1 chromans,2 and dihydrobenzofurans,3 can be found in numerous natural products and biologically active compounds, and significant efforts have been directed towards the development of synthetic methods that are capable of providing facile access to these materials. In particular, O‐heterocycles bearing an amide moiety,4 such as roxifiban1c and erythrococcamide,2c,e exhibit pharmaceutically important activities (Figure 1). Related carboxylic acids, such as acivicin1d and raxofelast,3b,c have been used as biological tools for drug discovery and as key synthetic intermediates for the construction of more complex derivatives.…”

Enzyme Catalysis in the Synthesis of Active Pharmaceutical Ingredients

“…An ingenious combination of enzymatic hydrolysis of thioester coupled with a retro-Michael/Michael equilibrium with a mild base (trimethylamine) for racemization was employed to effect dynamic resolution for the synthesis of a key chiral pharmaceutical intermediate for the synthesis of a platelet glycoprotein receptor antagonist [50]. Hydrolysis of the racemic thioester 97 catalyzed by the lipase from Pseudomonas cepacia led to the R-acid 98.…”