Linezolid preparation method

Abstract

The invention discloses a linezolid preparation method. Dichloromethane is taken as a solvent, a potassium bromide solution is added, cooling is carried out, (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone is added, a catalyst of a tetramethyl piperidinyloxyl nitride oxide is added while stirring is carried out, a sodium hypochlorite solution is added dropwise, after adding is carried out dropwise, reaction is carried out for 1-3 hours at the temperature of 0-10 DEG C, dichloromethane is added for extraction, an organic phase is dried and filtered through anhydrous sodium sulfate, and (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-formaldehyde-2-oxazolidinone is obtained after the solvent is condensed. Methyl alcohol is taken as a solvent, the (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-formaldehyde-2-oxazolidinone is added and heated to 20-50 DEG C, acetamide is slowly added, liquid-phase chromatogram track reaction is conducted, a reduction agent is directly added after the reaction is completed, precipitation and filtering are carried out, and linezolid is obtained. The method is moderate in reaction condition and environmentally friendly, and can be used for industrial large-scale production.

Description

technical field [0001] The invention relates to a compound synthesis process, in particular to a preparation method of linezolid. Background technique [0002] Linezolid is a synthetic oxazolidinone antibiotic approved by the US FDA in 2000 for the treatment of infections caused by Gram-positive (G+) cocci, including suspected or confirmed hospital-acquired pneumonia (HAP) caused by MRSA, Community-acquired pneumonia (CAP), complicated skin or skin and soft tissue infection (SSTI), and vancomycin-resistant enterococci (VRE) infection. Linezolid is a bacterial protein synthesis inhibitor that acts on the bacterial 50S ribosomal subunit and is closest to the site of action. Unlike other drugs, linezolid does not affect the activity of peptidyl transferase, but only acts on the initial stage of the translation system, inhibits the connection between mRNA and ribosomes, prevents the formation of the 70S initiation complex, and thus inhibits bacterial protein synthesis. The sit...

AI Technical Summary

Problems solved by technology

: ① (S)-epichlorohydrin and benzaldehyde react in ammonia water, and the imine generated is hydrolyzed with hydrochloric acid to obtain (2S)-1-amino-3-chloro-2-propanol, and after diacetylation Condensation with N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline under the action of lithium tert-butoxide in water yielded linezolid with a total yield of about 50% (PerraultWR, PearlmanBA, GodrejDB, et al. The synthesis of N-aryl-5 -(S)-aminomethyl-2-oxazolidinoneantibacterialsandderivativesinonestepfromarylcarbamates[J].OrgProcessResDev,2003,7(4):533-546), the raw materials of this method are easy to get, and the operation steps are less, but it needs to use expensive and very easy to absorb moisture Lithium tert-butoxide anhydrous

② (S)-glycidyl butyrate reacted with n-butyllithium at -78°C to obtain (S)-3-(3-fluoro-4-morpholinephenyl)-5-hydroxymethyl-1,3 -Oxazolidinone-2-one, after mesylation and azidation, then reduction and acetylation to get linezolid (BricknerSJ, HutchinsonDK, BarbachynMR, et al. positivebacterial infections[J].JMedChem,1996,39(3):673-679.) This method has more steps, harsh reaction conditions, and needs to use explosive sodium azide

③Using 3-fluoro-4-morpholine phenyl isocyanate to condense with (S)-glycidyl butyrate under the action of lithium bromide and tri-n-butylphosphine oxide to construct (S)-oxazolidinone core, after further transformation Delinezolid, (Huang Qiang, Li Hua, Niu Bolin, etc. .2006-05-17) This method has many steps, expensive raw materials and low overall yield

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