Process for preparation of Linezolid and its novel intermediates

Inventors

Alla, Raghu Mitra • Dubey, Ajay Kumar • SIRIGIRI, Aruna Kumari • Mareedu, Naga Kama Kumar

Assignees

Lee Pharma Ltd

Abstract

A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.

Core Innovation

The problem addressed by the patent is that prior syntheses of Linezolid require hazardous n-BuLi at very low temperature or generate difficult-to-remove impurities, which limits the overall practicality of those routes. The document seeks a cost-reducing synthetic route to Linezolid and stereochemically defined key oxazolidinone intermediates.

The invention provides a defined, multi-step process in which R-epichlorohydrin is used to form stereochemically defined oxazolidinone intermediates. In one process, a compound of formula IX is reacted with R-epichlorohydrin to produce a compound of formula VIII, which is further converted to a chloromethyl oxazolidinone compound of formula VII and crystallized, followed by sodium acetate conversion to an acetyl derivative and hydrolysis to the corresponding hydroxy methyl oxazolidinone of formula V.

In a process for preparation of Linezolid, 3-fluoro-4-morpholinyl aniline is reacted with R-epichlorohydrin to give N-[3-chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline, followed by carbonylation to produce (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl)-oxazolidin-2-one. The route continues through acetylation with sodium acetate, base hydrolysis to the corresponding methanol, mesylation, substitution with potassium phthalimide, deprotection with hydrazine hydrate to the methyl amine, and final acetylation with acetic anhydride, to provide Linezolid in high yield and high enantiomeric purity.

Claims Coverage

The partial content provides two independent claims covering (i) a process for preparing the R stereochemically defined hydroxy methyl oxazolidinone of formula V and (ii) a process for preparing Linezolid. Across these claims, the document recites multiple inventive features comprising defined stereochemical transformations and sequence-specific intermediate conversions.

The claim coverage centers on (1) forming and crystallizing a chloromethyl oxazolidinone intermediate from R-epichlorohydrin followed by sodium acetate conversion and hydrolysis to the (R) hydroxy methyl oxazolidinone, and (2) an end-to-end Linezolid synthesis that carries stereochemical definitions through carbonylation, sodium acetate acetylation, base hydrolysis, mesylation, potassium phthalimide substitution, hydrazine deprotection, and final acetylation.

Stated Advantages

Documented Applications

No documented applications found