CN104513211A - Method for preparing linezolid - Google Patents
Method for preparing linezolid Download PDFInfo
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- CN104513211A CN104513211A CN201310453588.1A CN201310453588A CN104513211A CN 104513211 A CN104513211 A CN 104513211A CN 201310453588 A CN201310453588 A CN 201310453588A CN 104513211 A CN104513211 A CN 104513211A
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- linezolid
- inorganic base
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
Abstract
The invention discloses a method for preparing linezolid. The method comprises: dissolving (R)-{2(R)-2-[(3-fluoro-4-morpholin-4-ylphenyl)amino]-2-hydroxyethyl}acetamide and a carbonylation reagent in an orgnic solvent, adding an aluminium-oxide-supported inorganic base catalyst, controlling the pH value of the reaction system to be 8-10, and reacting at 20-60 DEG C; and cooling, and performing extraction, washing, drying, purification and recrystallization, so as to obtain a linezolid solid. Compared with the prior art, the method employs an aluminium-oxide-supported inorganic base as the catalyst replacing an organic catalyst, helps to improve the atom utilization rate of the reaction, also helps to improve the clean property and the safety of the industrial preparation reaction and reduce environmental pollution. The aluminium-oxide-supported inorganic base is employed as the catalyst, and is simple to prepare and reusable through regeneration. The method avoids high-toxicity and toxicity-easily-generating reagents used in a conventional synthetic method, and helps to improve the clean property of the industrial synthetic reaction and reduce environmental pollution.
Description
Technical field
The present invention relates to Yi Zhong oxazolidinone antibiotic preparation method, particularly a kind of synthetic method of linezolid, belong to medical chemistry synthesis field.
Background technology
In recent years, the resistant organism of all kinds of microbiotic and antimicrobial drug develops rapidly, such as, Methicillin resistant Staph. aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin resistance pneumococcus (PRSP), multi-drug resistant tubercule bacillus, especially resistance to ten thousand appearance accounting for mycin faecalis (VRE), difficulty is caused to clinical treatment, after bacterium contact antibacterials, morphed by plasmid or Chromosome-encoded, obtain resistance, existing medicine is still difficult effectively controls these drug-fast bacteria infections, Pharmaceutical Chemist is impelled to make great efforts development of new anti-drug resistance bacterial drug, planned well screening has new chemical structure, the novel antibacterials of novel mechanism or 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-(the fluoro-4-morpholino phenyl of 3-)-2-oxo-5-oxazolidinyl] methyl] ethanamide, has following formula (I) structure.Linezolid is synthetic oxazolidinone microbiotic, within 2000, obtains U.S. FDA approval, is used for the treatment of gram-positive (G+) coccigenic infection.
The synthetic method of current linezolid is roughly following three routes:
1., with 3,4 one difluoro nitrobenzenes are raw material, be substituted, reduce, acidylate, condensation, esterification, replacement, ammonia solution and acetylization reaction synthesis linezolid.
2. adopt the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-in tert-butyl lithium ,-78 DEG C and the shrink of R-Glycidyl Butyrate, obtain 5-Qiang base methyl oxazolidinone, then diazotization, then hydrogenation, acetylization reaction obtains linezolid.
3. by fluoro-for 3-4-morpholinyl phenylamine and N-2(R)-epoxy ethanamide is dissolved in organic solvent, 10-30 hour is reacted at 20-100 DEG C, obtain N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) are amino]-2-hydroxyethyl } ethanamide, again the compound obtained and carbonylation agent are dissolved in halohydrocarbon organic solvent, under alkaline catalysts catalysis, in 0-50 DEG C of reaction 0.5-5 hour, obtain linezolid.
Although the third technique processing step is simple, reaction conditions is gentle, owing to adopting organic bases or inorganic base catalyst, comparatively large on the yield impact of target product, makes the productive rate of whole technique not high.
Summary of the invention
The object of the invention is to overcome prior art Problems existing, a kind of method preparing linezolid is provided.
Technical scheme of the present invention 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 } ethanamide and carbonylation agent be dissolved in organic solvent, add the inorganic base catalyst of alumina load, control the pH value of reaction system in 8-10, react at 20-60 DEG C;
Second step, obtains linezolid solid after reaction terminates rear extraction, washing, drying, purifying, recrystallization.
Carbonylation agent described in the first step is methyl-chloroformate.
Organic solvent described in the first step is methylene dichloride.
In the inorganic base catalyst of the alumina load described in the first step, mineral alkali 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 } ethanamide mass ratio is 0.1-0.3.
Extraction described in second step adopts ethyl acetate, and described washing adopts saturated sodium bicarbonate solution, and described purifying adopts column chromatography; Described recrystallization adopts ethyl acetate-light petrol.
Compared with prior art, the mineral alkali that present invention employs alumina load is catalyzer, replaces organic alkali catalyst, not only increases the atom utilization of reaction, and improve spatter property and the security of industrial preparation feedback, reduce environmental pollution.The mineral alkali that present invention employs alumina load is simple and can regenerate use and inventive process avoids in prior synthesizing method and use high poison as catalyst preparing, and easily the malicious reagent of system, improves the spatter property of commercial synthesis reaction, reduce environmental pollution.
Embodiment
Embodiment 1
By 50gN-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } sodium hydroxide catalyst of ethanamide and 5g alumina load joins in 250ml methylene dichloride, after 20-30 DEG C of lower magnetic force stirs 0.5h, add 24g methyl-chloroformate, regulation system pH value be weakly alkaline (8-10) and continue magnetic agitation reaction 2h after, mixture glass funnel filters, elimination catalyzer.Filtrate adopts extraction into ethyl acetate, and with water and saturated sodium bicarbonate washing, obtain target product linezolid 42.6g after anhydrous magnesium sulfate drying, rotary evaporation of solvent, purification by column chromatography, ethyl acetate-light petrol recrystallization, productive rate 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 ethanamide and 15g alumina load joins in 250ml methylene dichloride, after 30-40 DEG C of lower magnetic force stirs 0.5h, add 24g methyl-chloroformate, regulation system pH value be weakly alkaline (8-10) and continue magnetic agitation reaction 2h after, mixture glass funnel filters, elimination catalyzer.Filtrate adopts extraction into ethyl acetate, and with water and saturated sodium bicarbonate washing, obtain target product linezolid 43.2g after anhydrous magnesium sulfate drying, rotary evaporation of solvent, purification by column chromatography, ethyl acetate-light petrol recrystallization, productive rate 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 ethanamide and 10g alumina load joins in 250ml methylene dichloride, after 50-60 DEG C of lower magnetic force stirs 0.5h, add 24g methyl-chloroformate, regulation system pH value be weakly alkaline (8-10) and continue magnetic agitation reaction 2h after, mixture glass funnel filters, elimination catalyzer.Filtrate adopts extraction into ethyl acetate, and with water and saturated sodium bicarbonate washing, obtain target product linezolid 45.3g after anhydrous magnesium sulfate drying, rotary evaporation of solvent, purification by column chromatography, ethyl acetate-light petrol recrystallization, productive rate is 86.1.
Claims (5)
1. prepare a method for linezolid, it is characterized in that comprising the steps:
The first step, by N-{2(R)-2-[(the fluoro-4 morpholine-4-base phenyl of 3-) amino]-2-hydroxyethyl } ethanamide and carbonylation agent be dissolved in organic solvent, add the inorganic base catalyst of alumina load, control the pH value of reaction system in 8-10, react at 20-60 DEG C;
Second step, obtains linezolid solid after reaction terminates rear extraction, washing, drying, purifying, recrystallization.
2. the method preparing linezolid according to claim 1, is characterized in that the carbonylation agent described in the first step is methyl-chloroformate.
3. the method preparing linezolid according to claim 1, is characterized in that the organic solvent described in the first step is methylene dichloride.
4. the method preparing linezolid according to claim 1, is characterized in that in the inorganic base catalyst of the alumina load described in the first step, mineral alkali 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 } ethanamide mass ratio is 0.1-0.3.
5. the method preparing linezolid according to claim 1, it is characterized in that the extraction described in second step adopts ethyl acetate, described washing adopts saturated sodium bicarbonate solution, and described purifying adopts column chromatography; Described recrystallization adopts ethyl acetate-light petrol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310453588.1A CN104513211B (en) | 2013-09-29 | 2013-09-29 | A kind of method preparing linezolid |
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| CN201310453588.1A CN104513211B (en) | 2013-09-29 | 2013-09-29 | A kind of method preparing linezolid |
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| CN104513211A true CN104513211A (en) | 2015-04-15 |
| CN104513211B CN104513211B (en) | 2017-01-04 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220001A (en) * | 2008-01-25 | 2008-07-16 | 浙江博泰化工有限公司 | Synthesis of linezolid |
| CN102516191A (en) * | 2011-12-21 | 2012-06-27 | 吉林省博大伟业制药有限公司 | Method for preparing Linezolid |
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2013
- 2013-09-29 CN CN201310453588.1A patent/CN104513211B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220001A (en) * | 2008-01-25 | 2008-07-16 | 浙江博泰化工有限公司 | Synthesis of linezolid |
| CN102516191A (en) * | 2011-12-21 | 2012-06-27 | 吉林省博大伟业制药有限公司 | Method for preparing Linezolid |
Non-Patent Citations (1)
| Title |
|---|
| K.CHANDRA BABU 等: "A new and alternate synthesis of Linezolid: An antibacterial agent", 《DER PHARMA CHEMICA》, vol. 3, no. 4, 31 December 2011 (2011-12-31) * |
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| CN104513211B (en) | 2017-01-04 |
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