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Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐ 2H ‐1,4‐benzoxazine‐2‐carboxylate
Author(s) -
Pham HongNgoc,
Arrault Axelle,
Vanthuyne Nicolas,
Acherar Samir
Publication year - 2021
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.23313
Subject(s) - racemization , enantiopure drug , chemistry , enantioselective synthesis , enantiomer , enantiomeric excess , chiral column chromatography , organic chemistry , stereochemistry , catalysis
Abstract Racemic ethyl 3,4‐dihydro‐ 2H ‐1,4‐benzoxazine‐2‐carboxylate is a key synthon for the design of promising therapeutic drugs. It is mainly synthesized from racemic ethyl 2,3‐dibromopropionate and 2‐aminophenol in presence of K 2 CO 3 in refluxed acetone. Unfortunately, synthesis of ( R )‐ and ( S )‐enantiomers using the enantioselective version of this reaction, which should normally be performed with a double S N 2 mechanism, is unsuitable due to a racemization process involving the dehydrobromination of enantiopure ethyl 2,3‐dibromopropionate into ethyl 2‐bromoacrylate. For the first time, the enantioselective version is studied (ee ≈ 55–66%), and the percentage of racemization process has estimated to around 34–46% after determination of the optimal experimental conditions for analytical HPLC enantioseparation of racemate. The influence of the experimental and purification conditions on the racemization rate is also studied. The results indicate that racemization occurs faster at the beginning of the reaction but the initiation of the double S N 2 process takes place more faster to limit the racemization rate. The study of the influence of experimental conditions (reaction times, temperature, solvent or type of base, etc.) on the degree of racemization of the ( R )‐ enantiomer is performed and shows that despite changes in the experimental conditions, the synthesis of the ( R )‐ enantiomer is always accompanied by a racemization rate which is difficult in reducing. In parallel, ( R )‐ and ( S )‐enantiomers are obtained in high enantiopurity (ee > 99.5%) by preparative HPLC enantioseparation of racemate on multigram scale and characterized by optical rotation measurements, ECD and UV spectra.