Separation of Stereoisomeric Mixtures of Nafronyl as a Representative of Compounds Possessing Two Stereogenic Centers By Coupling Crystallization, Diastereoisomeric Conversion and Chromatography

Abstract

ABSTRACT:A procedure for the isolation of the most biologically active component of a stereoisomeric mixture of nafronyl -2-(diethylamino)ethyl 3-(naphthalen-1-yl)-2-((tetrahydrofuran-2-yl)methyl)propanoate, has been proposed. The molecule of nafronyl is a representative of compounds possessing two stereogenic centers, which may be produced in the form of a quaternary mixture that contains two pairs of racemates being diastereoisomers of one another. The components of such stereoisomeric mixtures usually differ in pharmacological activity, therefore, there is an interest in developing efficient methods for their resolution. The method suggested in this study comprised two sequential separation processes, including multistage cross-current crystallization and chiral chromatography.Crystallization was employed to enrich the raw material mixture with the target racemate, which contained the stereoisomer exhibiting the highest biological activity. To intensify the process, the mother liquors depleted with the target racemate were subjected to fast basecatalyzed diastereoisomeric conversion in melt, which provided equimolar mixtures of all four stereoisomers. The coupling of cross-current crystallization and diastereoisomeric conversion could improve yield of crystallization from 29% up to 84%. The purified racemate was further processed by chromatography to isolate finally the most active stereoisomer with 99% purity and total yield of 84%, at a relatively high throughput.

Genome mining and characterisation of a novel transaminase with remote stereoselectivity

“…The Active Pharmaceutical Ingredient (API), or target molecule, often contains at least one other stereocentre, and controlling the overall stereochemistry is challenging. Despite numerous advances in organic synthesis over the last number of decades, classical resolution remains a reliable and prominent technique in pharmaceutical manufacture 8,9 . Due to their prevalence in pharmaceuticals and fine chemicals, chiral amine subunits are high value synthetic targets and biocatalysis represents a highly enantioselective and sustainable route to them.…”

Development of a Route to the Most Active Nafronyl Stereoisomer by Coupling Asymmetric Synthesis and Chiral Chromatography Separation

“…Moreover, since crystallization involves losses of the target compound in the mother liquor, the total yield of the operation is very low. The yield can be improved by use of BCDC, but it can only be implemented into the first resolution stage, in which the unwanted racemate (2 R ,2′ R ):(2 S ,2′ S ) is converted to a quaternary mixture of four stereoisomers and recycled to crystallization 6.…”

“…In the former case, a quaternary mixture of stereoisomers is resolved into two pairs of racemates under an achiral environment, e.g., by conventional crystallization, and then the racemate (2 R ,2′ S ):(2 S ,2′ R ) containing the target product is separated under a chiral environment, e.g., by diastereoisomeric crystallization or chiral chromatography 5, 6. In that approach, as much as three less active stereoisomers, i.e., (2 R ,2′ R ), (2 S ,2′ S ), and (2 R ,2′ S ), are wasted.…”

“…The BCDC route was similar to that used in our previous work 6, in which the unwanted racemate (2 R ,2′ R ):(2 S ,2′ S ) was converted to a quaternary mixture of all stereoisomers. The reaction route was based on isomerization of the α ‐proton on the position C 2 in the nafronyl molecule (see Figs.…”

“…Two main approaches have been used to prepare the stereoisomer with the desired configuration: (i) non‐selective synthesis of a quaternary mixture of the stereoisomers followed by their resolution to isolate the most active stereoisomer (2 S ,2′ R ), or (ii) selective synthesis of a pair of two diastereoisomers (2 R ,2′ R ) and (2 S ,2′ R ), which were subsequently resolved to obtain the target compound. The former involved complex multistep separation procedures, which exploited fractional crystallization or coupling of crystallization and chromatography 5–7. The latter was based on stereoselective synthesis of nafronyl oxalate from ( R )‐tetrahydrofurfuryl alcohol, which provided the compound molecules with defined configuration on the stereogenic center C 2′ (Fig.…”