CN101659645B - Method for preparing 3-fluorine-4 morpholinyl phenylamine - Google Patents
Method for preparing 3-fluorine-4 morpholinyl phenylamine Download PDFInfo
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Abstract
The invention belongs to a method for preparing pharmaceutical intermediate, and discloses a method for preparing 3-fluorine-4 morpholinyl phenylamine, comprising the steps: (1) reducing o-fluoro-nitrobenzene to obtain o-fluoroaniline; (2) adding the o-fluoroaniline and deacidifying agent into organic solvent, and slowly adding disubstituted ethyl ether into a reaction system at the temperature of 100-150 DEG C and then stirring at the temperature of 100-200 DEG C to react for preparing o-fluoro-morpholinyl benzene; (3) taking nitric acid with the mass percent of 65-98% as nitrating agent and acetic acid as solvent, and leading the o-fluoro-morpholinyl benzene obtained in the step (2) to have nitration reaction to obtain 3-fluorine-4 morpholinyl nitrobenzene; (4) reducing the 3-fluorine-4 morpholinyl nitrobenzene obtained in the step (3) and obtaining the 3-fluorine-4 morpholinyl phenylamine. As the method takes the o-fluoro-nitrobenzene as initial reactant, the price of the raw materials is low, and the production cost can be reduced. Meanwhile, no waste water containing fluorine is generated in the preparation process of the method, so that the method has little environmental pollution and is environment-friendly.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, be specifically related to a kind of preparation method of key intermediate 3-fluoro-4 morpholinyl aniline of Zhi oxazolidinones antiseptic-germicide Linezolid
Background technology
Linezolid is a kind of novel oxazolidinone class antiseptic-germicide, though a lot of about the synthetic report route of Linezolid both at home and abroad, 3-fluoro-4 morpholinyl aniline are synthetic necessary intermediates.
The preparation method of 3-fluoro-4 morpholinyl aniline, be to adopt 3 in the prior art, the 4-difluoro nitrobenzene is a raw material, and replacement of process morpholine and nitroreduction (referring to: [1]: Steven JB, Douglas KH, Michael RB, et al.J Med Chem, 1996,39 (3): 673-679.[2]: Chinese pharmaceutical chemistry is assorted, in February, 2003, total 51 phases), the shortcoming of the method for described two step synthetic routes has two:
The price of (1) 3,4-difluoro nitrobenzene is more expensive, about 200,000 yuan/ton;
(2) reacting leavings group in the morpholine substitution reaction in this route is fluorion, the aftertreatment more complicated of fluoride waste.
Summary of the invention
The object of the invention provides a kind of preparation method of 3-fluoro-4 morpholinyl aniline.
For achieving the above object, the technical solution used in the present invention is: the preparation method of 3-fluoro-4 morpholinyl aniline may further comprise the steps:
(1) the reduction o-fluoronitrobenzene obtains adjacent fluoroaniline;
(2) adjacent fluoroaniline and de-acidying agent are added in the organic solvent, at 100～150 ℃ two replacement ether are slowly added reaction system then, behind reinforced the finishing, prepare adjacent fluoro-morpholinyl benzene at 100～200 ℃ of following stirring reactions;
(3) nitric acid with massfraction 65%～98% is nitrating agent, is solvent with acetate, the adjacent fluoro-morpholinyl of step (2) gained benzene is carried out nitration reaction obtain 3-fluoro-4-morpholinyl oil of mirbane;
(4) reduction step (3) gained 3-fluoro-4-morpholinyl oil of mirbane obtains 3-fluoro-4 morpholinyl aniline.
In the technique scheme, step (1) and the described reduction reaction of step (4) relate to that nitroreduction becomes amino on the phenyl ring, and method of reducing can be selected for use: catalytic hydrogenating reduction method or chemical reducing agent reduction method.Catalyzer in the catalytic hydrogenating reduction method is selected from: a kind of in Raney's nickel, palladium carbon or the platinum oxide, preferred Raney's nickel; Catalyst consumption is 1%～10% of a reactant quality.Reductive agent in the chemical reducing agent reduction method is selected from: a kind of in iron powder, zinc powder, sodium sulphite, S-WAT or the Sulfothiorine, preferred iron powder or sodium sulphite.Because can generate iron mud after the iron powder catalyzed reaction is finished, aftertreatment more complicated, Raney's nickel catalyst be recycle easily then, so most preferred method of reducing is the catalytic hydrogenating reduction method, and catalyzer is selected Raney's nickel for use, and catalyst consumption is 1%～5% of a reactant quality.
In the technique scheme, in the step (2), described two chemical structural formulas that replace ether are:
In the technique scheme, in the step (2), adjacent fluoroaniline with the ratio of the amount of substance of two replacement ether is: 1: 1～1: 2, and, be preferably 1: 1.5 smaller or equal to 1: 1.5; In the industrial production, can two replacement ether be added in the reaction system by header tank.
In the technique scheme, in the step (2), described organic solvent is selected from: ethylene glycol, propylene glycol, Diethylene Glycol, ethylene glycol monomethyl ether, glycol dimethyl ether, ethylene glycol ethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol ether, diethylene glycol diethyl ether, dimethyl formamide (DMF), tetrahydrofuran (THF) (THF) or dimethyl sulfoxide (DMSO) (DMSO); Preferred ethylene glycol; The requirement of described organic solvent is for can dissolving adjacent fluoroaniline and two replace ether, but the insoluble de-acidying agent of separating, and in the reaction process, is reflected at organic solution and carries out in mutually, and deacidification is to occur in organic solution mutually and between the de-acidying agent solid phase; The consumption of described solvent is generally conventional amount used according to well known to a person skilled in the art: according to mass ratio, and adjacent fluoroaniline: organic solvent=1: 4～1: 6.
In the technique scheme, in the step (2), described de-acidying agent is selected from: a kind of in yellow soda ash, salt of wormwood, sodium bicarbonate or the saleratus; Because sodium bicarbonate or saleratus can produce water in deacidification, can influence the productive rate of reaction, so described de-acidying agent is preferred: a kind of in yellow soda ash or the salt of wormwood; The consumption of de-acidying agent should guarantee to remove the hydrogen ion that produces in the reaction process.
In the technique scheme, in the step (2), preferred 130～160 ℃ of temperature of reaction; Can use phase-transfer catalyst, also can not use phase-transfer catalyst, described phase-transfer catalyst is selected from: a kind of in quaternary ammonium salt phase transfer catalyst or the alkylsulphonic acid salt catalyst.
In the technique scheme, in the step (3), described nitration reaction, if the method (being solvent with halohydrocarbon, is nitrating agent with nitric acid or nitration mixture) of using those skilled in the art to use always can't obtain target product, therefore, inventor group creatively is solvent with acetate, is that 65%～98% nitric acid is nitrating agent with massfraction, just makes nitration reaction be able to smooth generation; In the prior art, it is excessive in a large number that the consumption of nitrating agent generally all needs, and among the present invention, and the ratio of adjacent fluoro-morpholinyl benzene and the amount of substance of nitric acid was preferably 1: 1 more than or equal to 1: 0.8.
Because nitration reaction is thermopositive reaction, in order better to control nitration reaction, prevent that by product from generating in a large number, so preferred temperature of reaction is 0～25 ℃.
The reaction process of above-mentioned entire method is as follows:
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. the present invention is initial reactant with the o-fluoronitrobenzene, and this cost of material cheap (4～4.5 ten thousand yuan/ton) therefore, can reduce production costs.
2. do not produce fluoride waste in the preparation process of the present invention, environmental pollution is little, and is environmentally friendly.
Embodiment
Below in conjunction with embodiment the present invention is further described, these embodiment are used to illustrate the present invention, rather than limitation of the scope of the invention:
Embodiment one:
(1) in the 250ml reaction flask that dropping and reflux are housed, adds 100ml water, massfraction 36% hydrochloric acid 1.44g (0.04mol), iron powder 22.3g (0.4mol), under refluxing, slowly drip o-fluoronitrobenzene 14.1g (0.1mol), finish and refluxed 2 hours, cool off in 50 ℃, add 100ml toluene, filter, filter cake with the 20ml toluene wash is once abandoned iron mud.Layering, water layer extracts once with 50ml toluene, the combining methylbenzene layer, concentrating under reduced pressure, rectifying get adjacent fluoroaniline 10g, yield 90%.
(2) with the adjacent fluoroaniline 66g (0.6mol) of step (1) gained, be dissolved in the 300ml ethylene glycol, add 99g (0.92mol) anhydrous sodium carbonate then, drip 127.5g (0.9mol) dichloroethyl ether at 140 ℃, drip and finish, made in 5 hours 150 ℃ of stirrings to react completely, cool off in 50 ℃, with 2 * 100ml toluene extraction, toluene layer obtains the toluene solution of adjacent fluoro-morpholinyl benzene with 3 * 100ml water washing.Concentrating under reduced pressure, rectifying obtain the adjacent fluoro-morpholinyl of 81g benzene, yield 75%.
(3) with the adjacent fluoro-morpholinyl benzene 54.3g (0.3mol) of step (2) gained, be dissolved in the 150ml Glacial acetic acid, under the ice bath cooling, drip massfraction 68% concentrated nitric acid 28g (0.3mol), drip and finish, made in 2 hours in stirring at room to react completely.Add 700ml water, stirred 1 hour, suction filtration, washing obtains solid 48.5g, yield 71.5%.
(4) in being housed, the 250ml reaction flask of reflux condensing tube adds 50ml water and 34.5g (0.44mol) industrial sodium sulfide (62～68%), the stirring heating dissolving, slowly add step (3) gained 3-fluoro-4-morpholinyl oil of mirbane 50g (0.22mol) at 90 ℃, finish, reheat refluxes to make in 2.5 hours and reacts completely.Cool off in 30 ℃ of filtrations, get crude product.Crude product is dissolved in recrystallization in 20% the aqueous ethanolic solution, obtaining purity is 99.5% (HPLC) 3-fluoro-4-morpholinyl aniline 36.8g, yield 85%.
Embodiment two
(1) add 20g (0.142mol) o-fluoronitrobenzene, 130ml methyl alcohol, 1g Raney's nickel in the autoclave of 200ml, regulating hydrogen pressure is 20 normal atmosphere, at room temperature stirs 10 hours, makes to react completely.Filtration obtains reaction solution, and filtrate decompression concentrates, rectifying obtains oily matter 14.2g.Yield is 90%.
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, ethylene glycol is replaced with the diethylene glycol dimethyl ether solvent, obtain the adjacent fluoro-morpholinyl of 86g benzene, yield 80%.
(3) according to the method for the adjacent fluoro-morpholinyl oil of mirbane of embodiment one step (3) preparation, massfraction 68% concentrated nitric acid is replaced with massfraction 98% nitrosonitric acid, obtain solid 57.7g, yield 85%.
(4) with step (3) gained 3-fluoro-4-(1-morpholinyl)-oil of mirbane 50g (0.22mol), 500ml methyl alcohol, 2g Raney Ni are added in the autoclave of 1000ml, regulate hydrogen pressure to 20 normal atmosphere, at room temperature stir 8 hours, make to react completely.Filtration obtains reaction solution, and filtrate decompression concentrates, and obtains 3-fluoro-4-morpholinyl aniline 39g, yield 90%.
Embodiment three
(1) according to the catalytic hydrogenating reduction method of embodiment two steps (1), Raney's nickel is replaced with palladium carbon.
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, anhydrous sodium carbonate is replaced with Anhydrous potassium carbonate, obtain the adjacent fluoro-morpholinyl of 80g benzene, yield 74.3%.
(3) with embodiment one step (3).
(4) with embodiment two steps (4).
Embodiment four
(1) according to the chemical reducing agent reduction method of embodiment one step (1),
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, dichloroethyl ether is replaced with the diethylene glycol bis-p-toluenesulfonic esters, obtain the adjacent fluoro-morpholinyl of 85.9g benzene, yield 79.8%.
(3) with embodiment two steps (3).
(4) with embodiment one step (4).
Embodiment five
(1) according to the catalytic hydrogenating reduction method of embodiment two steps (1), Raney's nickel is replaced with platinum oxide, catalyst levels is 2g.
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, dichloroethyl ether is replaced with the Diethylene Glycol double A sulphonate, obtain the adjacent fluoro-morpholinyl of 88.3g benzene, yield 82%.
(3) with embodiment one step (3).
(4) with embodiment one step (4).
Embodiment six
(1) with embodiment one step (1).
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, anhydrous sodium carbonate is replaced with sodium bicarbonate, obtain the adjacent fluoro-morpholinyl of 43g benzene, yield 40%.(reason that yield is low: can decompose under the sodium bicarbonate high temperature, produce equimolar water) to reacting influential
(3) with embodiment two steps (3).
(4) with embodiment one step (4).
Embodiment seven
(1) with embodiment two step (1).
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, ethylene glycol is replaced with DMF, obtain the adjacent fluoro-morpholinyl of 84g benzene, yield 78.1%.
(3) with embodiment two steps (3).
(4) with embodiment two steps (4).
Embodiment eight
(1) with embodiment one step (1).
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, ethylene glycol is replaced with THF, dichloroethyl ether is replaced with the Diethylene Glycol double A sulphonate, obtain the adjacent fluoro-morpholinyl of 80g benzene, yield 74.3%.
(3) with embodiment one step (3).
(4) with embodiment one step (4).
Embodiment nine
(1) with embodiment two step (1).
(2) according to the method for the adjacent fluoro-morpholinyl benzene of embodiment one step (2) preparation, dropping temperature is remained on 100 ℃, insulation reaction also remains on 100 ℃, obtains the adjacent fluoro-morpholinyl of 37.7g benzene, yield 35%.(reason that yield is low: raw material reaction is not intact, does not have enough heat energy.)
(3) prepare the method for 3-fluoro-4-morpholinyl oil of mirbane according to embodiment one step (3), nitrated temperature is brought up to 60 ℃, obtain solid 28.5g, yield 42%.(reason that yield is low: the polynitration product is many under the high temperature.And high temperature is nitrated certain danger).
(4) with embodiment two steps (4).
Embodiment ten
(1) with embodiment one step (1).
(2) with embodiment five steps (2).
(3) with embodiment two steps (3).
(4) with embodiment two steps (4).
Claims (7)
1. the preparation method of a 3-fluoro-4-morpholinyl aniline is characterized in that, may further comprise the steps:
(1) the reduction o-fluoronitrobenzene obtains adjacent fluoroaniline;
(2) adjacent fluoroaniline and de-acidying agent are added in the organic solvent, at 100～150 ℃ two replacement ether are slowly added reaction system then, behind reinforced the finishing, prepare adjacent fluoro-morpholinyl benzene at 100～200 ℃ of following stirring reactions;
(3) nitric acid with massfraction 65%～98% is nitrating agent, is solvent with acetate, the adjacent fluoro-morpholinyl of step (2) gained benzene is carried out nitration reaction obtain 3-fluoro-4-morpholinyl oil of mirbane;
(4) reduction step (3) gained 3-fluoro-4-morpholinyl oil of mirbane obtains 3-fluoro-4-morpholinyl aniline;
In the step (2), described two chemical structural formulas that replace ether are:
Wherein X is selected from: chlorine, bromine, iodine, OSO
2CH
3, OSO
2C
6H
5Or OSO
2C
6H
4CH
3A kind of among the-p.
2. according to the preparation method of the described 3-fluoro-of claim 1 4-morpholinyl aniline, it is characterized in that in the step (2), adjacent fluoroaniline with the ratio of the amount of substance of two replacement ether is: 1: 1～1: 2.
3. according to the preparation method of the described 3-fluoro-of claim 1 4-morpholinyl aniline, it is characterized in that, in the step (2), described organic solvent is selected from: ethylene glycol, propylene glycol, Diethylene Glycol, ethylene glycol monomethyl ether, glycol dimethyl ether, ethylene glycol ethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol ether, diethylene glycol diethyl ether, dimethyl formamide, tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO).
4. according to the preparation method of the described 3-fluoro-of claim 3 4-morpholinyl aniline, it is characterized in that in the step (2), described solvent is an ethylene glycol.
5. according to the preparation method of the described 3-fluoro-of claim 1 4-morpholinyl aniline, it is characterized in that in the step (2), described de-acidying agent is selected from: a kind of in yellow soda ash, salt of wormwood, sodium bicarbonate or the saleratus.
6. according to the preparation method of the described 3-fluoro-of claim 1 4-morpholinyl aniline, it is characterized in that in the step (2), temperature of reaction is 130～160 ℃.
7. according to the preparation method of the described 3-fluoro-of claim 1 4-morpholinyl aniline, it is characterized in that in the step (3), adjacent fluoro-morpholinyl benzene is 1: 1 with the ratio of the amount of substance of nitric acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355165A (en) * | 2001-12-19 | 2002-06-26 | 中国医学科学院医药生物技术研究所 | 3,5-substituted oxazolidinone derivative and its preparing process and application |
| CN1673224A (en) * | 2004-03-23 | 2005-09-28 | 中国科学院上海药物研究所 | N-[4(R)-(1,3-dioxane)methyl] aniline and its prepn and use |
| CN1772750A (en) * | 2005-11-15 | 2006-05-17 | 郑州大学 | Prepn process of (R)-N-(3-fluoro-4-morpholinyl phenyl)-oxazolone-5-methyl alcohol |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355165A (en) * | 2001-12-19 | 2002-06-26 | 中国医学科学院医药生物技术研究所 | 3,5-substituted oxazolidinone derivative and its preparing process and application |
| CN1673224A (en) * | 2004-03-23 | 2005-09-28 | 中国科学院上海药物研究所 | N-[4(R)-(1,3-dioxane)methyl] aniline and its prepn and use |
| CN1772750A (en) * | 2005-11-15 | 2006-05-17 | 郑州大学 | Prepn process of (R)-N-(3-fluoro-4-morpholinyl phenyl)-oxazolone-5-methyl alcohol |
Non-Patent Citations (2)
| Title |
|---|
| Steven J. Brickner, et al.Synthesis and Antibacterial Activity of U-100592 and U-100766, Two Oxazolidinone Antibacterial Agents for the Potential Treatment of Multidrug-Resistant Gram-Positive Bacterial Infections.《J. Med. Chem.》.1996,第39卷(第3期),673-679. * |
| 孟庆国等.利奈唑酮的合成工艺改进.《中国药物化学杂志》.2003,第13卷(第1期),28-30. * |
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