CN103664813A - Preparation method of linezolid - Google Patents
Preparation method of linezolid Download PDFInfo
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- CN103664813A CN103664813A CN201310700336.4A CN201310700336A CN103664813A CN 103664813 A CN103664813 A CN 103664813A CN 201310700336 A CN201310700336 A CN 201310700336A CN 103664813 A CN103664813 A CN 103664813A
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- 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
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Abstract
The invention relates to a preparation method of linezolid. According to the method, 3-fluoro-4-morpholinyl aniline (1) is taken as an initiating material and reacts with chiral glycidyl phthalimide to obtain one adduct (III) under the action of a catalyst, a compound (IV) is obtained through cyclization of a carbonylation reagent, and aminolysis and acetylation are performed to obtain linezolid (VI). Compared with conventional methods, the method has the characteristics that the route is simple, some hazardous reagents are avoided, the operation is convenient, the reaction time is short, the used solvent is low in cost and easy to recycle, the reaction yield is higher, and industrial production is facilitated.
Description
Technical field:
The present invention relates to a kind of preparation method of medical material medicine Linezolid
Background technology:
Linezolid (linezolid) dehuaxue mingchen wei:(S)-N-((3-(the fluoro-4-(morpholinyl of 3-) phenyl)-2-oxo-5-oxazolidinyl) methyl) ethanamide, structural formula is as follows:
Linezolid is the (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides microbiotic of synthetic, by Pfizer Inc., developed, within 2000, obtain U.S. FDA approval, be used for the treatment of the coccigenic infection of gram-positive (G+), comprise caused by MRSA doubtful or make a definite diagnosis nosocomial pneumonia (HAP), community acquired pneumonia (CAP), complicacy skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infects.
Synthetic more representational document about Linezolid has: patent WO2002085849 and Org.Proce.Res.Dev2003; 7:533.Its common feature is, the fluoro-4-morpholinyl-aniline of the 3-of take is starting raw material, with (S)-N-[2-acetoxy-3-substituted propyl] ethanamide carries out the method that Linezolid is prepared in cyclization, the main drawback of these class methods is in preparation process, to have used condensing agent trimethyl carbinol lithium, and solvent for use is polar protic solvent, when operation, potassium tert.-butoxide is added in projection mixture punching material easily occurs, be unfavorable for suitability for industrialized production.
The method of the synthetic Linezolid that an other class is more representative is: Journal of heterocyclic chemistry, 49(5), 1143-1146; 2012 and Journal of chemical research (12), 739-740; 2009 and two pieces of Chinese patent CN102702125, CN101638392.The method of report, first after the synthetic fluoro-4-morpholinyl-phenylisocyanate of 3-with epoxy compounds generation addition reaction, wherein in the synthetic fluoro-4-morpholinyl-phenylisocyanate of 3-, to use hypertoxic phosgene, there is violent pungency, be unfavorable for industrial production, and will use sodiumazide while preparing epoxy nitrine propane, sodiumazide has severe toxicity, explosive decomposition under clashing into, operation inconvenience, is unfavorable for amplifying and produces.
Also have the more classical preparation method of a class, with magazine Bulletin of the Korean Chemical Society, 33(4) 1389-1392; 2012 and patent WO2011077310; WO2011114210; US5952324; CN102617500 is representative; bibliographical information with (R)-[the fluoro-4-4 morpholinyl of 3-(3-phenyl)-2-oxo-5-oxazolidinyl] methylol; Cheng oxazolidinone compounds with the phenyl SULPHURYL CHLORIDE generation sulfonylation Sheng of Methanesulfonyl chloride or replacement, through ammonia solution, and acetylize; obtain end product; also can pass through azido reaction, the reduction of hydrogen palladium carbon, acetylize obtains end product.The reaction conditions that wherein passes through aminolysis is harsher, need under high pressure react, and temperature of reaction is higher, is unfavorable for suitability for industrialized production.Through the reaction of azide, major defect is that route is longer, has used explosive sodiumazide in ammonifying process, is unfavorable for suitability for industrialized production.In reduction process, used 10% Pd/C, price is higher, has increased production cost.
Summary of the invention:
Deficiency to Linezolid preparation in prior art, the problem to be solved in the present invention is to provide a kind of improved Linezolid preparation method, particularly intermediate (III), the synthetic method of intermediate (IV).The synthetic method of intermediate (III) has been used high-selectivity catalyst, improves reaction yield, Reaction time shorten, simple to operate and conform to quality requirements; In the preparation of intermediate (IV), carbonylation agent adopts methylcarbonate, and toxicity is little, and environmental pollution is little, cost is low, and the utmost point is beneficial to suitability for industrialized production.
Preparation of the present invention (S)-N-((3-(the fluoro-4-(morpholinyl of 3-) phenyl)-2-oxo-5-oxazolidinyl) methyl) method of ethanamide (structural formula is VI), step is:
1), by potassium phthalimide, epoxy chloropropane, joins in aprotic, polar or polar protic solvent and reacts, and add phase-transfer catalyst, reacts complete, steams solvent, then carries out underpressure distillation, solidify, suction filtration, intermediate (II).
2) by the fluoro-4-morpholinyl phenylamine of 3-, intermediate (II) is dissolved in the mixed solvent of polar protic solvent and water, adds high-selectivity catalyst, is warming up to 65 ℃ of-100 ℃ of reactions, react complete, steam solvent, obtain oily matter, add water, organic solvent extraction, dry, steaming desolventizes, and obtains intermediate (III).
3) intermediate (III) is dissolved in organic solvent, adds organic weak base, slowly drip carbonylation agent, drip and finish, back flow reaction, reacts complete, steams except organic solvent, adds water, separates out solid, and suction filtration, obtains intermediate (IV).
4) intermediate (IV) is dissolved in polar solvent, slowly drips aminolysis reagent under room temperature, 25 ℃-100 ℃ reaction 2-5h, react complete, steam except organic solvent, add water solvent, and with organic solvent extraction, evaporate to dryness, obtains intermediate (V).
5) intermediate (V) is dissolved in organic solvent, adds under the effect of organic bases or mineral alkali and drip acetylation reagent, react complete, add mixture of ice and water, separate out solid, suction filtration, dry, obtain crude product (VI).
6) crude product (VI) is joined to recrystallization in organic solvent, and decolouring, purity obtained and be 98% target product (VI)
Above-mentioned preparation (S)-N-((3-(the fluoro-4-(morpholinyl of 3-) phenyl)-2-oxo-5-oxazolidinyl) methyl) in the method for ethanamide (structural formula is VI),
Step (1) Semi-polarity non-protonic solvent or polar protic solvent be, DMF, and THF, methyl alcohol, the trimethyl carbinol, Virahol, phase-transfer catalyst is preferably TMBAC, Bu
4nBr.
In further step (1), solvent is preferably THF, and phase-transfer catalyst is preferably TMBAC.
Solvent in step (2) is the mixed solvent of polar solvent and water, is the mixed solvent of ethanol and water, the mixed solvent of methyl alcohol and water, the mixed solvent of Virahol and water, high selecting catalyst is cuprous iodide, salt of wormwood, magnesium perchlorate, temperature of reaction is 65 ℃-100 ℃.
In further step (2), preferred solvent is the mixed solvent of ethanol and water, and mixed volume ratio is 9:1, and preferred catalyzer is magnesium perchlorate, and temperature of reaction is preferably 90 ℃.
In step (3), selected carbonylation agent is carbonyl dimidazoles, methylcarbonate, and diethyl carbonate, organic bases is preferably triethylamine, pyridine, DMAP,
In further step (3) most preferred carbonylation agent for for methylcarbonate organic weak base be DMAP.
In step (4), aminolysis reagent dosage is that 3-8 doubly measures, 25 ℃ of-100 ℃ of reactions, and the reaction times is 2-5h.
In further step (4), the consumption of aminolysis reagent is 6 times of amounts, and temperature of reaction is 40 ℃, and the reaction times is 4h.
In step (5), organic bases used or mineral alkali are triethylamine, DIPEA, sodium hydroxide, salt of wormwood.
In further step (5), alkali used most preferably is triethylamine.
Step (6) recrystallization solvent can be methyl alcohol, ethanol, Virahol, acetone, acetonitrile.
Further step (6) recrystallization solvent most preferably is acetone.
Present method compares with other existing methods that to have route simple, easy to operate, avoid having used the hazardous agents such as sodiumazide, used high-selectivity catalyst magnesium perchlorate to shorten the reaction times, solvent for use is cheap easily to be reclaimed, and reaction yield is higher, and each intermediate purity of using the method to prepare is all higher, finished product purity reaches more than 98%, and this method is beneficial to suitability for industrialized production.
Embodiment:
By the embodiment of following examples form, foregoing of the present invention is described in further detail.For a person skilled in the art, this should be interpreted as to the scope of aforementioned body of the present invention only limits to following example: all technology realizing based on foregoing of the present invention all belong to scope of the present invention.
1, in 250ml eggplant-shape bottle, add 150mlTHF, take potassium phthalimide 15g(81.09mmol), epoxy chloropropane 22.38g (243.26mmol), in eggplant-shape bottle, adds TMBAC0.37g (1.62mmol), be warming up to 30 ℃, reaction 6h.React complete, first steam except reaction solvent, then remove epoxy chloropropane under reduced pressure, obtain water white transparency oily thing, at-10 ℃, add 120ml normal hexane, under stirring, separate out white solid, suction filtration, filter cake normal hexane drip washing, obtains white solid 14.42g, and yield is 87.56%
2, take the fluoro-4-morpholinyl phenylamine of 3-10g (50.99mmol), intermediate (II) 10.35g (50.99mmol) magnesium perchlorate 0.23g (1.02mmol) is in the eggplant-shape bottle of 250ml, aqueous ethanolic solution (the ethanol: water=9:1) dissolve, be warming up to 90 ℃ of back flow reaction 20h that adds 155.25ml.Steam except ethanol, obtain oily matter, with DCM extraction (3 * 100ml), merge organic phase, organic phase washing (2 * 200ml), saturated common salt washing (2 * 200ml) for organic phase, collects organic phase, anhydrous magnesium sulfate drying, suction filtration, steam except filtrate, obtain yellow solid 17.78g, yield is 87.34%.
3, the THF that adds 120ml in the three-necked bottle of 250ml, add intermediate (III) 8g (20.04mmol), DMAP0.05g (4.01mmol), slowly drips methylcarbonate 3.61g (40.08mmol) under room temperature, drip to finish to be warming up to back flow reaction 5h.Remove THF under reduced pressure, obtain oily matter, under stirring, add a large amount of water, separate out solid, suction filtration, yellow solid, 6.99g, yield is 82%.
4, in 100ml eggplant-shape bottle, add 75ml methyl alcohol, add intermediate (IV) 5g (11.76mmol), under room temperature, slowly drip hydrazine hydrate 3.53g (70.56mmol), drip and finish, rise to 40 ℃, reaction 3h.React complete steaming and desolventize, separate out white solid, add water, white solid dissolves, with dichloromethane extraction (3 * 50ml), merge organic phase, saturated common salt washing (2 * 50ml), anhydrous sodium sulfate drying, suction filtration, solvent evaporated obtains faint yellow solid 3.23g, and yield is 93.12%.
5, the dry DMF that adds 48ml in the three-necked bottle of 100ml, add intermediate (V) 3g (10.16mmol), add triethylamine 4.25ml (30.50mmol), under room temperature, slowly drip diacetyl oxide 1.44ml (15.25mmol), drip Bi Jixu room temperature reaction 1h.React complete, to the mixture of ice and water that slowly adds 30ml in reaction solution, stir and have solid to separate out, suction filtration, filtration cakes torrefaction, obtains pale solid 3.23g, and yield is 94.21%.
6, by prepared compound (VI) crude product 10g, be dissolved in the acetone of 80ml, reflux is to all dissolving, slowly be down to, add 3% gac, decolour, backflow 2h, carry out while hot suction filtration, filtrate Slow cooling crystallization, suction filtration, dry, obtain white powder solid 7.10g, yield is 88.75%.
Claims (12)
1. a method of preparing Linezolid (VI), is characterized in that, step is as follows:
Take epoxy chloropropane and potassium phthalimide as starting raw material is in aprotic, polar or polar protic solvent, under the condition existing at phase-transfer catalyst, prepare epoxypropyl phthalic imidine (II);
With the fluoro-4-morpholinyl phenylamine of 3-(I) and epoxypropyl phthalic imidine (II), in the mixed solvent of polar protic solvent and water, under high-selectivity catalyst existence, carry out nucleophilic reaction and make intermediate (III);
Intermediate (III) is having cyclization under the weak base of adding condition to obtain intermediate (IV) with carbonylation agent;
Intermediate (IV) carries out ammonia solution and obtains intermediate (V) in polar solvent;
Intermediate (V) carries out acetylization reaction by diacetyl oxide and obtains target compound (VI) under organic weak base exists,
2. method according to claim 1, is characterized in that, prepares intermediate (II) solvent used and is selected from DMF, THF, methyl alcohol, the trimethyl carbinol, Virahol, phase-transfer catalyst is selected from: TMBAC(benzyl trimethyl ammonium chloride), Bu4NBr(tetra-n-butyl ammonium bromide).
3. method according to claim 1, it is characterized in that, preparing intermediate (III) solvent used is selected from: the mixed solvent of ethanol and water, the mixed solvent of methyl alcohol and water, the mixed solvent of Virahol and water, phase-transfer catalyst used is selected from: cuprous iodide, salt of wormwood, magnesium perchlorate, temperature of reaction is 65 ℃-100 ℃.
4. method according to claim 1, is characterized in that, prepares intermediate (IV); Organic bases used is selected from: triethylamine, pyridine, DMAP(4-Dimethylamino pyridine), carbonylation agent used is selected from: carbonyl dimidazoles, methylcarbonate, diethyl carbonate.
5. method according to claim 1, is characterized in that, prepares intermediate (V) aminolysis reagent used and is selected from: hydrazine hydrate, and aminolysis is temperature required is 25 ℃-100 ℃, and the reaction times is 2-5h, and reaction mol ratio is 1:3-8.
6. method according to claim 1, is characterized in that, prepares target product (VI) alkali used and is selected from: triethylamine, DIPEA(N, N-diisopropylethylamine), sodium hydroxide, salt of wormwood.
7. method according to claim 2, is characterized in that, solvent for use is THF, and phase-transfer catalyst is TMBAC.
8. method according to claim 3, is characterized in that, preparing intermediate (III) solvent used is the mixed solvent of ethanol and water, and ratio is that 1:9. phase-transfer catalyst used is magnesium perchlorate, and temperature of reaction is 90 ℃.
9. method according to claim 4, is characterized in that, wherein carbonylation agent is methylcarbonate.Organic bases is DMAP.
10. method according to claim 5, is characterized in that, the preparation of intermediate (V), and temperature is 40 ℃, and the reaction times is 3h, and the mol ratio of intermediate (4) and hydrazine hydrate is 1:6.
11. methods according to claim 6, is characterized in that, the compound of preparation (VI) alkali used is triethylamine, and prepared compound (VI) can be prepared highly purified Linezolid via recrystallization, and wherein recrystallization solvent is acetone.
12. methods according to claim 1, is characterized in that, step is as follows:
In 250ml eggplant-shape bottle, add 150mlTHF, take potassium phthalimide 15g(81.09mmol), epoxy chloropropane 22.38g (243.26mmol), in eggplant-shape bottle, adds TMBAC0.37g (1.62mmol), be warming up to 30 ℃, reaction 6h.React complete, first steam except reaction solvent, then remove epoxy chloropropane under reduced pressure, obtain water white transparency oily thing, at-10 ℃, add 120ml normal hexane, under stirring, separate out white solid, suction filtration, filter cake normal hexane drip washing, obtains intermediate (II).
Take the fluoro-4-morpholinyl phenylamine of 3-10g (50.99mmol), intermediate (II) 10.35g (50.99mmol) magnesium perchlorate 0.23g (1.02mmol) is in the eggplant-shape bottle of 250ml, aqueous ethanolic solution (the ethanol: water=9:1) dissolve, be warming up to 90 ℃ of back flow reaction 20h that adds 155.25ml.Steam except ethanol, obtain oily matter, with DCM extraction (3 * 100ml), merge organic phase; organic phase washing (2 * 200ml), saturated common salt washing (2 * 200ml) for organic phase, collects organic phase, anhydrous magnesium sulfate drying; suction filtration, steams except filtrate, obtains intermediate (III);
The THF that adds 120ml in the three-necked bottle of 250ml, add intermediate (III) 8g (20.04mmol), DMAP0.05g (4.01mmol), slowly drips methylcarbonate 3.61g (40.08mmol) under room temperature, drip to finish to be warming up to back flow reaction 5h.Remove THF under reduced pressure, obtain oily matter, add a large amount of water under stirring, separate out solid, suction filtration, obtains intermediate (IV); In 100ml eggplant-shape bottle, add 75ml methyl alcohol, add intermediate (IV) 5g (11.76mmol), under room temperature, slowly drip hydrazine hydrate 3.53g (70.56mmol), drip and finish, rise to 40 ℃, reaction 3h.React complete steaming and desolventize, separate out white solid, add water, white solid dissolves, and with dichloromethane extraction (3 * 50ml), merges organic phase, saturated common salt washing (2 * 50ml), and anhydrous sodium sulfate drying, suction filtration, solvent evaporated obtains intermediate (V);
The dry DMF that adds 48ml in the three-necked bottle of 100ml, add intermediate (V) 3g (10.16mmol), add triethylamine 4.25ml (30.50mmol), under room temperature, slowly drip diacetyl oxide 1.44ml (15.25mmol), drip Bi Jixu room temperature reaction 1h.React complete, to the mixture of ice and water that slowly adds 30ml in reaction solution, stir and have solid to separate out, suction filtration, filtration cakes torrefaction, obtains compound (VI) crude product, get compound (VI) crude product 10g, be dissolved in the acetone of 80ml, reflux is to all dissolving, slowly be down to, add 3% gac, decolour, backflow 2h, carries out suction filtration while hot, filtrate Slow cooling crystallization, suction filtration, dry, obtain Linezolid.
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| CN201310700336.4A CN103664813A (en) | 2013-12-18 | 2013-12-18 | Preparation method of linezolid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN109232457A (en) * | 2018-03-26 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Linezolid |
| CN111606870A (en) * | 2020-05-31 | 2020-09-01 | 湖北扬信医药科技有限公司 | Linezolid-related substance and preparation method and application thereof |
-
2013
- 2013-12-18 CN CN201310700336.4A patent/CN103664813A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN109232457A (en) * | 2018-03-26 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Linezolid |
| CN111606870A (en) * | 2020-05-31 | 2020-09-01 | 湖北扬信医药科技有限公司 | Linezolid-related substance and preparation method and application thereof |
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