CN104513211B - A kind of method preparing linezolid - Google Patents

Abstract

The invention discloses a kind of method preparing linezolid.N { 2(R) 2 [(3 fluorine 4 morpholine 4 base phenyl) amino] 2 hydroxyethyls } acetamide and carbonylation agent are dissolved in organic solvent, add the inorganic base catalyst of alumina load, the pH value of control reaction system, in 8 10, reacts at 20 60 DEG C；Extract after cooling, wash, be dried, obtain linezolid solid after purification, recrystallization.Compared with prior art, the inorganic base that present invention employs alumina load is catalyst, replaces organic alkali catalyst, not only increases the atom utilization of reaction, and improve spatter property and the safety of industrially prepared reaction, reduce environmental pollution.Present invention employs the inorganic base of alumina load simple as catalyst preparation and can regenerate use and inventive process avoids and use high poison in prior synthesizing method, easily system poison reagent, improves the spatter property of commercial synthesis reaction, reduces environmental pollution.

Description

A kind of method preparing linezolid

Technical field

The present invention relates to the preparation method of a kind of (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic, the synthetic method of a kind of linezolid, belong to medical chemistry synthesis field.

Background technology

In recent years, all kinds of antibiotic quickly grow with the fastbacteria of antimicrobial drug, such as, Methicillin resistant Staph. aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin resistance pneumococcus (PRSP), multi-drug resistant tubercule bacillus, the most resistance to ten thousand appearance accounting for mycin enterococcus (VRE), difficulty is caused to clinical treatment, after antibacterial contact antibacterials, morphed by plasmid or Chromosome-encoded, obtain drug resistance, existing medicine is still difficult effectively controls these drug-fast bacteria infections, Pharmaceutical Chemist is promoted to make great efforts development of new anti-drug resistance bacterial drug, planned well screening has new chemical constitution, novel mechanism or the novel antibacterials of new role target position.

Linezolid, have another name called Linezolid, Lei Naizuoli, molecular formula is C16H20FN3O4, CAS:165800-03-3, chemical name: (S)-N-[[3-(3-fluoro-4-morpholino phenyl)-2-oxo-5-oxazolidinyl] methyl] acetamide, has lower formula (I) structure.Linezolid is the (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic of synthetic, within 2000, obtains U.S. FDA approval, is used for treating Grain-positive (G+) coccigenic infection.

Substantially following three routes of the synthetic method of linezolid at present:

1. with 3,4 one difluoro nitrobenzenes are raw material, are substituted, reduce, are acylated, are condensed, are esterified, replace, ammonolysis and acetylization reaction synthesis linezolid.

2. using N-benzyloxycarbonyl group-3-fluoro-4-morpholinyl phenylamine to shrink at tert-butyl lithium ,-78 DEG C and R-Glycidyl Butyrate, obtain 5-hydroxymethyl oxazolidone, then diazotising, then hydrogenate, acetylization reaction obtains linezolid.

3. by fluoro-for 3-4-morpholinyl phenylamine and N-2(R)-epoxy acetamide is dissolved in organic solvent, react 10-30 hour at 20-100 DEG C, obtain N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } acetamide, again the compound obtained and carbonylation agent are dissolved in halohydrocarbon organic solvent, under base catalyst is catalyzed, react 0.5-5 hour in 0-50 DEG C, obtain linezolid.

Although the third technique processing step is simple, reaction condition is gentle, but owing to using organic base or inorganic base catalyst, affects bigger on the yield of target product so that the productivity of whole technique is the highest.

Summary of the invention

The problem that it is an object of the invention to overcome prior art to exist, it is provided that a kind of method preparing linezolid.

Technical scheme is as follows: a kind of method preparing linezolid, comprises the steps:

The first step, by N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } acetamide and carbonylation agent be dissolved in organic solvent, adding the inorganic base catalyst of alumina load, the pH value of control reaction system, in 8-10, reacts at 20-60 DEG C；

Second step, reaction extracts, washs, is dried after terminating, acquisition linezolid solid after purification, recrystallization.

Carbonylation agent described in the first step is methylchloroformate.

Organic solvent described in the first step is dichloromethane.

In the inorganic base catalyst of the alumina load described in the first step, inorganic base is sodium hydroxide or potassium hydroxide；The inorganic base catalyst of described alumina load and described N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } acetamide mass ratio is 0.1-0.3.

Extraction described in second step uses ethyl acetate, described washing to use saturated sodium bicarbonate solution, described purification to use column chromatography；Described recrystallization uses ethyl acetate-light petrol.

Compared with prior art, the inorganic base that present invention employs alumina load is catalyst, replaces organic alkali catalyst, not only increases the atom utilization of reaction, and improve spatter property and the safety of industrially prepared reaction, reduce environmental pollution.Present invention employs the inorganic base of alumina load simple as catalyst preparation and can regenerate use and inventive process avoids and use high poison in prior synthesizing method, easily system poison reagent, improves the spatter property of commercial synthesis reaction, reduces environmental pollution.

Detailed description of the invention

Embodiment 1

By 50gN-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } sodium hydroxide catalyst of acetamide and 5g alumina load joins in 250ml dichloromethane, at 20-30 DEG C after magnetic agitation 0.5h, add 24g methylchloroformate, regulation system pH value be alkalescence (8-10) and continue magnetic agitation reaction 2h after, mixture glass funnel filters, and filters off catalyst.Filtrate is adopted and is extracted with ethyl acetate, and washs with water and saturated sodium bicarbonate, and anhydrous magnesium sulfate is dried, obtain target product linezolid 42.6g after rotary evaporation of solvent, column chromatography purification, ethyl acetate-light petrol recrystallization, and productivity is 84.7.

Embodiment 2

By 50gN-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } potassium hydroxide catalyst of acetamide and 15g alumina load joins in 250ml dichloromethane, at 30-40 DEG C after magnetic agitation 0.5h, add 24g methylchloroformate, regulation system pH value be alkalescence (8-10) and continue magnetic agitation reaction 2h after, mixture glass funnel filters, and filters off catalyst.Filtrate is adopted and is extracted with ethyl acetate, and washs with water and saturated sodium bicarbonate, and anhydrous magnesium sulfate is dried, obtain target product linezolid 43.2g after rotary evaporation of solvent, column chromatography purification, ethyl acetate-light petrol recrystallization, and productivity is 84.9.

Embodiment 3

By 50gN-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } sodium hydroxide catalyst of acetamide and 10g alumina load joins in 250ml dichloromethane, at 50-60 DEG C after magnetic agitation 0.5h, add 24g methylchloroformate, regulation system pH value be alkalescence (8-10) and continue magnetic agitation reaction 2h after, mixture glass funnel filters, and filters off catalyst.Filtrate is adopted and is extracted with ethyl acetate, and washs with water and saturated sodium bicarbonate, and anhydrous magnesium sulfate is dried, obtain target product linezolid 45.3g after rotary evaporation of solvent, column chromatography purification, ethyl acetate-light petrol recrystallization, and productivity is 86.1.

Claims (1)

1. the method preparing linezolid, it is characterised in that comprise the steps:

The first step, by N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } acetamide and carbonylation agent be dissolved in organic solvent, adding the inorganic base catalyst of alumina load, the pH value of control reaction system, in 8-10, reacts at 20-60 DEG C；

Second step, reaction extracts, washs, is dried after terminating, acquisition linezolid solid after purification, recrystallization；

Wherein: the carbonylation agent described in the first step is methylchloroformate；

Organic solvent described in the first step is dichloromethane；

In the inorganic base catalyst of the alumina load described in the first step, inorganic base is sodium hydroxide or potassium hydroxide；The inorganic base catalyst of described alumina load and described N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } acetamide mass ratio is 0.1-0.3；

Extraction described in second step uses ethyl acetate, described washing to use saturated sodium bicarbonate solution, described purification to use column chromatography；Described recrystallization uses ethyl acetate-light petrol.