CN102093229A - Preparation method of 4-nitro-3-trifluoromethylaniline - Google Patents
Preparation method of 4-nitro-3-trifluoromethylaniline Download PDFInfo
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- CN102093229A CN102093229A CN2010106088516A CN201010608851A CN102093229A CN 102093229 A CN102093229 A CN 102093229A CN 2010106088516 A CN2010106088516 A CN 2010106088516A CN 201010608851 A CN201010608851 A CN 201010608851A CN 102093229 A CN102093229 A CN 102093229A
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- trifluoromethylaniline
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Abstract
The invention provides a preparation method of 4-nitro-3-trifluoromethylaniline. The preparation method comprises the following steps: nitrifying m-trifluoromethyl)phenyl]acetamide obtained by reacting m-(trifluoromethyl)aniline with acetylchloride in a non-protic solvent so as to obtain 4-nitro-3-trifluoromethylacetanilide; and removing acetyl protection in ethanol solution by potassium carbonate so as to obtain the 4-nitro-3-trifluoromethylaniline. The preparation method has the advantages that reaction yield is high, generated three wastes are less, reaction is easy to control, impurities in product position positional isomers are less, yield is high, rectification is simple and the like.
Description
Technical field
The invention belongs to the flutamide intermediate, the preparation method of particularly a kind of 4-nitro-3-5-trifluoromethylaniline.
Background technology
Flutamide is a kind of on-steroidal male hormone antagonist; synthetic by the design of U.S. Schering-Plough company at first; at first went on the market in the U.S. as treatment prostate cancer medicine in 1989; its chemistry 2-methyl by name-N-[4-nitro-3-(trifluoromethyl) phenyl] propionic acid amide, belong to the anilid medicine.Because flutamide self is without any hormonal activity, the treatment prostatosis are effective, and to cardiovascular nothing influence, and can keep patient's sexual function, progressively become the common drug of treatment prostate cancer and hyperplasia of prostate at present in American-European countries, also can be used for the non-prostatosis relevant simultaneously, and the adverse reaction rate of flutamide is low with male sex hormone, patient can tolerate well when low dosage was repeatedly oral, so it is able to widespread use.
The preparation method of 4-nitro-3-5-trifluoromethylaniline is at present: (1) 1989 year patent EP0345688 report is a raw material with 4-nitro-3-trifluoromethyl chlorobenzene, reacts under high pressure-temperature with ammoniacal liquor, obtains through refining.Temperature of reaction is more than 170 degree, and pressure makes production safety can not get effective guarantee more than 3MPa.(2) mamino-trifluoromethyl benzene carries out acidylate protection, carries out nitratedly with nitric acid/sulfuric acid (nitration mixture) through diacetyl oxide, and it is synthetic to remove acetyl protection at last in strong alkali solution.But having diacetyl oxide is the easy malicious reagent of system, and nitrated employing nitration mixture carries out, reaction product location isomer, and have refining difficulty, problem (seeing J.Am.Chem.Soc.1951,73,3579) such as yield is low.
Summary of the invention
The present invention is raw material with the mamino-trifluoromethyl benzene; at first in aprotic solvent, obtain the m-trifluoromethyl Acetanilide with excess acetyl chloride; it is nitrated with the concentrated nitric acid to be that nitrating agent carries out; obtain 4-nitro-3-trifluoromethyl Acetanilide, obtain 4-nitro-3-5-trifluoromethylaniline after salt of wormwood removes the ethanoyl protection in ethanolic soln.
Specifically:
The preparation method of a kind of 4-nitro-3-5-trifluoromethylaniline is characterized in that, under heating condition, 4-nitro-3-trifluoromethyl Acetanilide removes ethanoyl and obtains in the alcoholic acid solution of potassium carbonate, and Heating temperature is 30 ℃-90 ℃.Described optimum heating temperature is 60 ℃-80 ℃.
The preparation of described 4-nitro-3-trifluoromethyl Acetanilide is a nitrating agent with the concentrated nitric acid, and the m-trifluoromethyl Acetanilide is carried out nitration reaction under heating condition, and its range of reaction temperature is 35 ℃-80 ℃.Described optimal reaction temperature scope is 60 ℃-65 ℃.
The preparation method of described wherein m-trifluoromethyl Acetanilide; with the Acetyl Chloride 98Min. is acylating reagent; m-trifluoromethyl aniline is raw material; in aprotic solvent, carry out acetylization reaction under the heating condition, wherein aprotic solvent is a toluene; hexanaphthene; chlorobenzene, dimethylbenzene a kind of, its range of reaction temperature is 35 ℃-60 ℃.Described optimum response temperature is 50 ℃-55 ℃;
Characteristics of the present invention
Adopt the inventive method, have the reaction yield height, the three wastes produce less, and reaction is control easily, and product positional isomers impurity is less, and the yield height is made with extra care advantages such as simple.
Embodiment
Therefore; in order to improve reaction yield; reducing production danger has carried out conscientiously inquiring into and designing; the result is that mamino-trifluoromethyl benzene and Acetyl Chloride 98Min. are at aprotic solvent (toluene; hexanaphthene, chlorobenzene) obtains the m-trifluoromethyl Acetanilide through acylation reaction in, in the presence of concentrated nitric acid; the m-trifluoromethyl Acetanilide obtains 4-nitro-3-5-trifluoromethylaniline after salt of wormwood removes the ethanoyl protection in ethanolic soln through nitrated and obtain 4-nitro-3-trifluoromethyl Acetanilide.On the basis of improving reaction yield, improve production process.
That is, the present invention relates to the preparation method of 4-nitro-3-5-trifluoromethylaniline, the method is characterized in that,
(1) in aprotic solvent (toluene, hexanaphthene, chlorobenzene), mamino-trifluoromethyl benzene and Acetyl Chloride 98Min. react under heating condition, obtain the m-trifluoromethyl Acetanilide, here the preferred hexanaphthene of aprotic solvent.35 ℃-60 ℃ of temperature of reaction, preferred 50 ℃-55 ℃;
(2) in the presence of concentrated nitric acid, the m-trifluoromethyl Acetanilide by nitrated, obtains 4-nitro-3-trifluoromethyl Acetanilide through heating.35 ℃-80 ℃ of range of reaction temperature, preferred 60 ℃-65 ℃.
(3) after salt of wormwood removes the ethanoyl protection and obtains 4-nitro-3-5-trifluoromethylaniline in ethanolic soln, Heating temperature is 30 ℃-90 ℃ here, preferred 60 ℃-80 ℃.
In the industrial circle, mamino-trifluoromethyl benzene can preferably utilize mamino-trifluoromethyl benzene at aprotic solvent-toluene according to the method for present inventor's exploitation, in hexanaphthene or the chlorobenzene, reacts acquisition at low temperatures with excess acetyl chloride.This method is described in detail, preferably use cyclohexane give to be solvent, in addition, 35 ℃-60 ℃ of temperature of reaction, preferred 50 ℃-55 ℃.
In addition, the nitration reaction that the present invention relates to, in concentrated nitric acid, the m-trifluoromethyl Acetanilide the heating under through nitrated acquisition 4-nitro-3-trifluoromethyl Acetanilide.Here, temperature of reaction can be selected 35 ℃-80 ℃ scope, and preferably temperature of reaction is controlled at 60 ℃-65 ℃.
In addition, the present invention relates to remove the reaction of ethanoyl, in the ethanolic soln of salt of wormwood, 4-nitro-3-trifluoromethyl Acetanilide obtains 4-nitro-3-5-trifluoromethylaniline through the heating deacetylation.Here, 30 ℃-90 ℃ of Heating temperatures, preferred 60 ℃-80 ℃.
Embodiment
Below, the present invention will be described in more detail by embodiment.Yield is represented with molecular fraction.
First part: the preparation of m-trifluoromethyl Acetanilide
(embodiment 1)
M-trifluoromethyl aniline is dissolved in the 10L toluene for 1.0 kilograms, and controlled temperature is at 50 ℃, and 0.55 kilogram of dripping acetyl chloride after dropwising, is warmed up to 55 ℃ of reactions 5 hours.White solid is separated out in cooling, filters, and obtains 0.98 kilogram of m-trifluoromethyl Acetanilide, yield 78%.
(embodiment 2)
M-trifluoromethyl aniline is dissolved in the 20L hexanaphthene for 1.0 kilograms, and controlled temperature is at 50 ℃, and 0.55 kilogram of dripping acetyl chloride after dropwising, is warmed up to 55 ℃ of reactions 5 hours.White solid is separated out in cooling, filters, and obtains 1.1 kilograms of m-trifluoromethyl Acetanilides, yield 91%.
(embodiment 3)
M-trifluoromethyl aniline is dissolved in the 20L chlorobenzene for 1.0 kilograms, and controlled temperature is at 50 ℃, and 0.55 kilogram of dripping acetyl chloride after dropwising, is warmed up to 55 ℃ of reactions 5 hours.White solid is separated out in cooling, filters, and obtains 0.87 kilogram of m-trifluoromethyl Acetanilide, yield 69%.
Second section: the preparation of 4-nitro-3-trifluoromethyl Acetanilide
(embodiment 4)
The m-trifluoromethyl Acetanilide is dissolved in 2 kilograms of concentrated nitric acids for 1.3 kilograms, slowly is heated to 60 ℃ and reacts.After reaction finishes, in 5 kilograms of frozen water of reaction solution impouring, filter washing.Drying obtains 2.1 kilograms of solids, yield 83%, fusing point 108-109 ℃.
(embodiment 5)
The m-trifluoromethyl Acetanilide is dissolved in 2 kilograms of concentrated nitric acids for 1.3 kilograms, slowly is heated to 45 ℃ and reacts.After reaction finishes, in 5 kilograms of frozen water of reaction solution impouring, filter washing.Drying obtains 1.5 kilograms of solids, yield 61%, fusing point 108-109 ℃.
Third part: the preparation of 4-nitro-3-5-trifluoromethylaniline
(embodiment 6)
4-nitro-3-trifluoromethyl Acetanilide joins in the 5L ethanol for 1.2 kilograms, adds 0.8 kilogram in salt of wormwood, and 70 ℃ were heated 10 hours.Decompression recycling ethanol 50%, cooling is filtered and is obtained 0.8 kilogram of product, yield 81%.
(embodiment 7)
4-nitro-3-trifluoromethyl Acetanilide joins in the 5L ethanol for 1.2 kilograms, adds 0.8 kilogram in salt of wormwood, and 50 ℃ were heated 10 hours.Decompression recycling ethanol 50%, cooling is filtered and is obtained 0.62 kilogram of product, yield 62%.
Claims (6)
1. the preparation method of 4-nitro-3-5-trifluoromethylaniline is characterized in that, under heating condition, 4-nitro-3-trifluoromethyl Acetanilide removes ethanoyl and obtains in the alcoholic acid solution of potassium carbonate, and Heating temperature is 30 ℃-90 ℃.
2. the preparation method of 4-nitro according to claim 1-3-5-trifluoromethylaniline is characterized in that, described Heating temperature is 60 ℃-80 ℃.
3. the preparation method of 4-nitro according to claim 1-3-5-trifluoromethylaniline, it is characterized in that, the preparation of 4-nitro-3-trifluoromethyl Acetanilide, with the concentrated nitric acid is nitrating agent, the m-trifluoromethyl Acetanilide is carried out nitration reaction under heating condition, its range of reaction temperature is 35 ℃-80 ℃.
4. the preparation method of 4-nitro according to claim 3-3-5-trifluoromethylaniline is characterized in that, the described m-trifluoromethyl Acetanilide is carried out nitration reaction under heating condition range of reaction temperature is 60 ℃-65 ℃.
5. the preparation method of 4-nitro according to claim 3-3-5-trifluoromethylaniline; it is characterized in that the preparation method of described wherein m-trifluoromethyl Acetanilide is an acylating reagent with the Acetyl Chloride 98Min.; m-trifluoromethyl aniline is raw material; in aprotic solvent, carry out acetylization reaction under the heating condition, wherein aprotic solvent is a toluene; hexanaphthene; chlorobenzene, dimethylbenzene a kind of, its range of reaction temperature is 35 ℃-60 ℃.
6. the preparation method of 4-nitro according to claim 5-3-5-trifluoromethylaniline is characterized in that, described is acylating reagent with the Acetyl Chloride 98Min.; m-trifluoromethyl aniline is raw material; in aprotic solvent, carry out acetylization reaction under the heating condition, reaction temperature be 50 ℃-55 ℃.
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| CN2010106088516A CN102093229A (en) | 2010-12-28 | 2010-12-28 | Preparation method of 4-nitro-3-trifluoromethylaniline |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408447A (en) * | 2013-07-01 | 2013-11-27 | 昆山三友医药原料有限公司 | Process for synthesizing flutamide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0345688A1 (en) * | 1988-06-09 | 1989-12-13 | Hoechst Aktiengesellschaft | Process for preparing 4-nitro-3-trifluoromethyl aniline |
-
2010
- 2010-12-28 CN CN2010106088516A patent/CN102093229A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0345688A1 (en) * | 1988-06-09 | 1989-12-13 | Hoechst Aktiengesellschaft | Process for preparing 4-nitro-3-trifluoromethyl aniline |
Non-Patent Citations (2)
| Title |
|---|
| 夏鹏等: "非甾体抗雄激素药物Flutamide的合成", 《中国医药工业杂志》 * |
| 陈冠凡等: "4-三氟甲基苯胺的合成方法", 《农药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408447A (en) * | 2013-07-01 | 2013-11-27 | 昆山三友医药原料有限公司 | Process for synthesizing flutamide |
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Application publication date: 20110615 |