CN109232457A - A kind of preparation method of Linezolid - Google Patents
A kind of preparation method of Linezolid Download PDFInfo
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- CN109232457A CN109232457A CN201810249763.8A CN201810249763A CN109232457A CN 109232457 A CN109232457 A CN 109232457A CN 201810249763 A CN201810249763 A CN 201810249763A CN 109232457 A CN109232457 A CN 109232457A
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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
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Abstract
The present invention relates to a kind of preparation methods of Linezolid; using the fluoro- 4- morpholinyl phenylamine of 3- as starting material; first with (S)-(+)-N- (2; 3- ethoxycarbonyl propyl) phthalimide reaction generation intermediate 1; then intermediate 2 is generated with carbonylation reagent cyclization; using ammonolysis reaction and acetylization reaction, target compound is obtained.It is poor that the present invention solves Linezolid preparation method safety in the prior art, condition is harsh, impurity mostly the problem of of being not suitable for industrialized production such as low with yield, this route starting material is cheap and easily-available, easy to operate, avoids using hazardous agents, solvent for use is easy to recovery of applied, reaction yield is higher, and finished product purity is up to 99.9% or more, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of medical material medicine Linezolid.
Background technique
In recent years, the appearance of a large amount of drug-resistant bacterias annoyings global clinical and public health, and this kind of situation is more tight
Weight.Therefore, there are the antibacterials of novel mechanism of action, structure novel to become more and more important in the treatment of bacterium infection for exploitation.
The Linezolid developed by Pfizer Inc. is as artificial synthesized (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic, for treating
Remove from office positive (G+) the coccigenic infection of orchid property, including as caused by MRSA it is doubtful or make a definite diagnosis nosocomial pneumonia, community obtains
Obtain property pneumonia, complexity skin or skin soft-tissue infection and vancomycin enterococcal infection.
Linezolid contains a chiral centre, knot as a kind of (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic clinically used at present
Structure formula is
The preparation method of Linezolid is in US5688792, US5837870, WO2006004922, J.Med.Chem.39
(3), 673-679,1996, Tetrahedron Lett., 40 (26), 4855,199, US4150029, US4250318,
US4476136, US4340606, US4461773, J.Med.Chem.32,1673 (1989), J.Med.Chem. 2005,48
(19), 5900-5908, Tetrahedron Lett., 45,1323 (1989), WO9309103, US9512751 and
It is had been reported that in the documents such as US3654298.
But the synthetic method of document above report, always there is various problem, for example, WO9309103 and
Carbamate and n-BuLi are disclosed in US9512751, lithium diisopropylamine reacts to prepare 5S- acetyl ammonia
The oxazolidone that ylmethyl replaces, operational hazards, side reaction are more；J.Med.Chem. 2005, 48(19), 5900-5908
Identical with us synthetic route of document report, but its operation includes that column chromatographs, it is cumbersome, and higher cost；WO
95/07271 report document in used explosive reagents sodium azide, and it is subsequent also need catalytic hydrogenation step, there are safety
Hidden danger, while by-product is more.
Summary of the invention
To the deficiency of Linezolid preparation method in the prior art, the problem to be solved in the present invention is to provide a kind of improved
Linezolid preparation method is produced suitable for amplification.
The method of the present invention includes following steps in sequence.
(1) starting material 1 and starting material 2 being dissolved in polar solvent, is warming up to 50-90 DEG C, end of reaction cools down,
Filtering, it is dry, intermediate 1(is obtained without being further purified).
(2) obtained intermediate is dissolved in organic solvent, catalyst and carbonylation agent is added, heated up, end of reaction,
Filtering, it is dry, obtain intermediate 2.
(3) intermediate 2, aminolysis reagent are dissolved in alcohol water mixed solvent, are heated up, end of reaction removes under reduced pressure organic molten
Agent cools down, and extraction dries, filters, obtains the organic solution of intermediate 3, which is directly used in and is reacted in next step.
(4) solution of intermediate 3 is down to certain temperature, a certain amount of alkali is added, acetylation reagent is added dropwise, drop finishes, and rises
Temperature the reaction was continued certain time, end of reaction are successively washed with acidic aqueous solution, alkaline aqueous solution and sodium chloride saturated solution,
It is dry, it removes organic solvent under reduced pressure, a certain amount of acetone or ethyl acetate crystallization is added, filters, it is dry, obtain target product.
Polar solvent used in step (1) is selected from methanol, ethyl alcohol, isopropanol, n-butanol, N,N-dimethylformamide, four
Hydrogen furans, preferred alcohol；Reaction temperature is 50-90 DEG C, preferably 60-80 DEG C；Reaction time is 10-24 hours, and preferably 12-16 is small
When；The molar ratio of starting material 1 and starting material 2 is 1:1-1:1.5, preferably 1:1-1:1.2；Crystallization temperature is 10-50 DEG C,
It is preferred that 15-35 DEG C.
Step (2) prepares intermediate 2: intermediate therefor 1 is without purifying；Used catalyst is 4-dimethylaminopyridine
(DMAP), triethylamine and pyridine；It is preferred that DMAP；Catalyst amount is 1-100%(mole, in terms of intermediate 1), preferably 1-
20%；Carbonylation agent used is selected from: carbonyl dimidazoles, dimethyl carbonate, diethyl carbonate, phosgene and solid phosgene, preferably carbonyl
Base diimidazole and solid phosgene；The molar ratio of carbonylation agent and intermediate 1 is 1-2:1, preferably 1-1.5:1；Reaction dissolvent choosing
N,N-Dimethylformamide, tetrahydrofuran, acetonitrile isopolarity aprotic solvent, preferably acetonitrile；Reaction temperature is 20-90 DEG C, excellent
Select 40-80 DEG C；The crystallization time is 0.5-10 hours, preferably 0.5-2 hours；Crystallization temperature is 10-50 DEG C, preferably 20-45 DEG C.
It is the mixed of methanol, ethyl alcohol, isopropanol, n-butanol or the above alcohol and water that step (3), which prepares reaction dissolvent in intermediate 3,
The mixed solvent of bonding solvent, preferred alcohol and water；Ethyl alcohol is 1-100%, preferably 40-100% in the ratio of mixed solvent；Deprotection
Reagent be selected from hydrazine hydrate, methylamine solution etc., preferably hydrazine hydrate；Deprotection reaction temperature is 40-90 DEG C, preferably 50-80 DEG C；Instead
It is 0.5-5 hours, preferably 1-3 hours between seasonable；Reaction molar ratio is 1:3-15；It is preferred that 1:6-12.
Alkali used in step (4) is selected from: triethylamine, pyridine, n,N-diisopropylethylamine, potassium carbonate, sodium hydroxide etc.,
It is preferred that triethylamine；Reaction dissolvent is THF, DMF, methylene chloride, acetonitrile etc., preferably methylene chloride；Acetylation reagent be chloroacetic chloride,
Acetic anhydride, preferably acetic anhydride；Reaction temperature is 0-40 DEG C, preferably 0-30 DEG C；Recrystallisation solvent is selected as ethyl acetate, acetone.
Compared with other methods reported in the literature, starting material has been commercialized this method, cheap to be easy to get, operation letter
It is single, it is only necessary to which that target product can be obtained in conventional filtering, extraction etc., while avoiding that sodium azide, butyl lithium etc. has been used to endanger
Dangerous reagent, solvent for use is easy to be recycled, and reaction yield is higher, and finished product purity is up to 99.9% or more, is suitable for industry metaplasia
It produces.
Specific embodiment
The synthesis of N- (3- phthalimide group -2- (S)-hydroxypropyl) -3- fluoro- 4- (morpholinyl) aniline (intermediate 1):
1) the fluoro- 4- of 3- (4- morpholinyl)-aniline (starting material 1) 1000g, (S)-N- glycidol phthalimide is taken
(starting material 2) 1243g is put into reaction kettle, and 15L ethyl alcohol, the lower 60 DEG C of back flow reaction 16h of nitrogen protection is added；End of reaction
Afterwards, reaction solution is cooled to 45 DEG C, filtered, filter cake ethyl alcohol is washed, and 40 DEG C of dryings obtain yellow solid (intermediate 1) 1834.05g, is received
Rate 90.09%；
2) the fluoro- 4- of 3- (4- morpholinyl)-aniline (starting material 1) 1000g, (S)-N- glycidol phthalimide is taken
(starting material 2) 1036g is put into reaction kettle, and 20L ethyl alcohol, the lower 80 DEG C of back flow reaction 12h of nitrogen protection is added；End of reaction
Afterwards, reaction solution is cooled to 10 DEG C, filtered, filter cake ethyl alcohol is washed, and 40 DEG C of dryings obtain yellow solid (intermediate 1) 1732.11g, is received
Rate 85%.
(S)-N- [[3- (the fluoro- 4'- morpholino phenyl of 3'-) -2- oxo -5- oxazolidinyl] methyl] phthalimide
The synthesis of (intermediate 2):
1) by 1800g intermediate 1,876.7g N, N'- carbonyl dimidazoles, 28.1gDMAP is added into reaction kettle, and 9L second is added
Nitrile, nitrogen protection, 80 DEG C of reaction 1.5h；After completion of the reaction, reaction system is cooled to 25 DEG C；It filters, 50 DEG C of dryings obtain white
Solid (intermediate 2) 1351.86g, yield 70.51%；
2) by 1800g intermediate 1,1461g N, N'- carbonyl dimidazoles, 7g 4- dimethylamino pyridine is added into reaction kettle, adds
Enter 20L acetonitrile, nitrogen protection, 40 DEG C of reaction 6h；After completion of the reaction, reaction system is cooled to rapidly 45 DEG C；It filters, 50 DEG C dry
It is dry, obtain white solid (intermediate 2) 1158g, yield 60%；
3) by 1800g intermediate 1,2669g solid phosgene, 14g 4- dimethylamino pyridine is added into reaction kettle, and 20L second is added
Nitrile, nitrogen protection, 40 DEG C of reaction 6h；After completion of the reaction, reaction system is cooled to rapidly 45 DEG C；It filters, 50 DEG C of dryings obtain white
Solid (intermediate 2) 1158g, yield 60%.
(S) synthesis of -5- (amino methyl) -3- (the fluoro- 4- morpholino phenyl of 3-) -2- oxazolidone (intermediate 3):
1) 1200g intermediate 2 is added into reaction kettle, 50% ethanol water of 12L and 80% hydrazine hydrate of 2160g is added, is warming up to
70 DEG C are stirred to react 0.5h；After completion of the reaction, decompression steams ethyl alcohol, and methylene chloride extraction merges organic phase, and anhydrous sodium sulfate is dry
It is dry, filter compound (intermediate 3) dichloromethane solution；
2) 1200g(2.82mol) intermediate 2 is added into reaction kettle, sequentially adds 66% ethanol water of 6L, 80% water of 1800g
Hydrazine is closed, 50 DEG C is warming up to and is stirred to react 1.5h；After completion of the reaction, decompression steams ethyl alcohol, and methylene chloride extraction merges organic phase,
Anhydrous sodium sulfate is dry, obtains the dichloromethane solution of compound (intermediate 3)；
3) 1200g(2.82mol) intermediate 2 is added into reaction kettle, sequentially adds 20% ethanol water of 24L, 80% water of 1080g
Hydrazine is closed, 90 DEG C is warming up to and is stirred to react 5h；After completion of the reaction, decompression steams ethyl alcohol, and methylene chloride extraction merges organic phase, nothing
Aqueous sodium persulfate is dry, obtains the dichloromethane solution of compound (intermediate 3).
The synthesis of Linezolid:
1) dichloromethane solution of compound (intermediate 3) is added into reaction kettle, 285g triethylamine is added, at room temperature slowly
345g acetic anhydride is added dropwise；After being added dropwise, the reaction was continued 2h is successively washed with water 3 times, merges organic phase, and anhydrous sodium sulfate is dry
It is dry, it filters, decompression steams solvent, and 20L acetone or 12L ethyl acetate, rising temperature for dissolving is added, is then down to room temperature, filters, and does
It is dry, obtain white solid (Linezolid) 664.81g, yield 69.87%；
2) the dichloromethane solution suction filtration of compound (intermediate 3) is taken into filtrate, addition is cooled to 0 DEG C into reaction kettle, is added
345g acetic anhydride is slowly added dropwise in 570g triethylamine；After being added dropwise, system is warming up to 25 DEG C of reaction 0.5h, rear that 2.4L salt is added
Aqueous acid stirs 10min；It is washed with water again 3 times, merges organic phase, anhydrous sodium sulfate is dry, filters, and decompression steams molten
Agent is added 9.6L acetone recrystallization, is cooled to 10 DEG C of suction filtrations, 40 DEG C of dryings obtain white solid 758.85g, yield 80%.
Claims (5)
1. a kind of preparation method of Linezolid comprising following steps:
1) sub- with the fluoro- 4- morpholinyl phenylamine (starting material 1) of 3- and (S)-(+)-N- (2,3- ethoxycarbonyl propyl) phthalyl
Amine (starting material 2) is starting material, in polar protic solvent or polar aprotic solvent, is carried out during necleophilic reaction is made
Mesosome 1；
2) intermediate 1 and carbonylation agent appropriate cyclization under weak base and catalyst action obtain intermediate 2；
3) intermediate 2 is deprotected to obtain intermediate 3 in polar solvent；
4) intermediate 3 is reacted to obtain target compound Linezolid with acetylation reagent in the presence of weak base.
2. according to the method described in claim 1, it is characterized in that preparing solvent used in intermediate is selected from methanol, ethyl alcohol, different
Propyl alcohol, n-butanol, n,N-Dimethylformamide, tetrahydrofuran, preferred alcohol；Reaction temperature is 50-90 DEG C, preferably 60-80 DEG C；
Reaction time is 10-24 hours, preferably 12-16 hours；The molar ratio of starting material 1 and starting material 2 is 1:1-1:1.5,
It is preferred that 1:1-1:1.2；Crystallization temperature is 10-50 DEG C, preferably 15-35 DEG C.
3. according to the method described in claim 1, it is characterized in that preparing intermediate 2: intermediate therefor 1 is without purifying；It is used
Catalyst is 4-dimethylaminopyridine (DMAP), triethylamine and pyridine；It is preferred that DMAP；Catalyst amount is 1-100%(mole,
In terms of intermediate 1), preferably 1-20%；Carbonylation agent used is selected from: carbonyl dimidazoles, dimethyl carbonate, diethyl carbonate, light
Gas and solid phosgene, preferably carbonyl dimidazoles and solid phosgene；The molar ratio of carbonylation agent and intermediate 1 is 1-2:1, preferably
1-1.5:1；Reaction dissolvent is n,N-Dimethylformamide, tetrahydrofuran, acetonitrile isopolarity aprotic solvent, preferably acetonitrile；Instead
Answering temperature is 20-90 DEG C, preferably 40-80 DEG C；The crystallization time is 0.5-10 hours, preferably 0.5-2 hours；Crystallization temperature is 10-
50 DEG C, preferably 20-45 DEG C.
4. according to the method described in claim 1, it is characterized in that preparing intermediate 3: reaction dissolvent is methanol, ethyl alcohol, isopropyl
The mixed solvent of the mixed solvent of alcohol, n-butanol or the above alcohol and water, preferred alcohol and water；Alcohols is in the ratio of mixed solvent
1-100%, preferably 40-100%；The reagent of deprotection is selected from hydrazine hydrate, methylamine solution etc., preferably hydrazine hydrate；Deprotection reaction temperature
Degree is 40-90 DEG C, preferably 50-80 DEG C；Reaction time is 0.5-5 hours, preferably 1-3 hours；Reaction molar ratio is 1:3-15；It is excellent
Select 1:6-12.
5. according to the method described in claim 1, it is characterized in that preparing Linezolid: alkali used is selected from: triethylamine, pyrrole
Pyridine, n,N-diisopropylethylamine, potassium carbonate, sodium hydroxide etc., preferably triethylamine；Reaction dissolvent be THF, DMF, methylene chloride,
Acetonitrile etc., preferably methylene chloride；Acetylation reagent is chloroacetic chloride, acetic anhydride, preferably acetic anhydride；Reaction temperature is 0-40 DEG C, excellent
Select 0-30 DEG C；Recrystallisation solvent is ethyl acetate, acetone.
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| CN201810249763.8A CN109232457A (en) | 2018-03-26 | 2018-03-26 | A kind of preparation method of Linezolid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113880784A (en) * | 2021-11-08 | 2022-01-04 | 湖南增达生物科技有限公司 | Linezolid impurity 1 and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060247435A1 (en) * | 2004-07-20 | 2006-11-02 | Dodda Mohan Rao | Novel intermediates for linezolid and related compounds |
| US20090093422A1 (en) * | 2006-10-23 | 2009-04-09 | Roger Tung | Oxazolidinone derivatives and methods of use |
| CN102311400A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone |
| CN103626749A (en) * | 2012-08-21 | 2014-03-12 | 苏州泽璟生物制药有限公司 | Substituted oxazolidinone compound, and pharmaceutical composition containing compound and application thereof |
| CN103664813A (en) * | 2013-12-18 | 2014-03-26 | 沈阳中海药业有限公司 | Preparation method of linezolid |
-
2018
- 2018-03-26 CN CN201810249763.8A patent/CN109232457A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060247435A1 (en) * | 2004-07-20 | 2006-11-02 | Dodda Mohan Rao | Novel intermediates for linezolid and related compounds |
| EP1768967B1 (en) * | 2004-07-20 | 2009-04-22 | Symed Labs Limited | Novel intermediates for linezolid and related compounds |
| US20090093422A1 (en) * | 2006-10-23 | 2009-04-09 | Roger Tung | Oxazolidinone derivatives and methods of use |
| CN102311400A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone |
| CN103626749A (en) * | 2012-08-21 | 2014-03-12 | 苏州泽璟生物制药有限公司 | Substituted oxazolidinone compound, and pharmaceutical composition containing compound and application thereof |
| CN103664813A (en) * | 2013-12-18 | 2014-03-26 | 沈阳中海药业有限公司 | Preparation method of linezolid |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113880784A (en) * | 2021-11-08 | 2022-01-04 | 湖南增达生物科技有限公司 | Linezolid impurity 1 and preparation method thereof |
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