CN103709045A

Movatterモバイル変換

Info

Publication number: CN103709045A
Application number: CN201310680578.1A
Authority: CN
Inventors: 李可庆
Original assignee: Jiangsu Jixian Green Chemistry Science & Technology Research Institute Co Ltd
Current assignee: Jiangsu Jixian Green Chemistry Science & Technology Research Institute Co Ltd
Priority date: 2013-12-12
Filing date: 2013-12-12
Publication date: 2014-04-09

Abstract

The invention provides a preparation method of 4-chlorine-3-trifluoromethyl aniline hydrochloride. By taking 1-chlorine-2-trifluoromethylbenzene as a raw material, the 4-chlorine-3-trifluoromethyl aniline hydrochloride is obtained through three-step reaction, namely nitration, hydrogenation reduction and salification. According to the preparation method of 4-chlorine-3-trifluoromethyl aniline hydrochloride, a nitration reaction aftertreatment method is easy, the product purity is high, the reduction reaction only needs to be carried out at room temperature, has not high requirements for reaction equipment, and is suitable for industrial production, after salification, the product nature is stable, and excessive HCl gas is introduced into alkali liquor so as to avoid the environmental pollution.

Description

The preparation method of the chloro-3-trifluoromethylbenzene of a kind of 4-amine hydrochlorate

Technical field

The present invention relates to a kind of preparation method of medicine intermediate, be specifically related to the preparation method of the chloro-3-trifluoromethylbenzene of a kind of 4-amine hydrochlorate.

Background technology

The chloro-3-5-trifluoromethylaniline of 4-, molecular formula is C₇h₅clF₃n, structural formula is as follows:

Being a very important starting raw material in synthetic anticarcinogen Xarelto technique, is also the important intermediate of synthetic fluoro-containing pesticide.

The synthetic chloro-3-5-trifluoromethylaniline of 4-of bibliographical information comprises that phenyl ring is nitrated, nitroreduction two-step reaction, and reaction formula is as follows:

Extract nitration product usually by organic solvent extraction, and a small amount of isomers producing in nitration reaction can not be eliminated, and extracting operation is loaded down with trivial details, toxicity is large, and cost consumption is high; In industrial production, the reduction of nitro still be take iron powder reducing as main, aftertreatment trouble, and total recovery is lower, and raw material consumption is higher, and the trade effluent environmental pollution causing is serious; In addition, the amino of the chloro-3-5-trifluoromethylaniline of 4-is easily oxidized, unsuitable standing storage.

Summary of the invention

In order to overcome the above problems, the present invention has improved the post-treating method of nitration reaction, and by the chloro-3-5-trifluoromethylaniline of 4-salify, makes it more stable.

The preparation method who the invention provides the chloro-3-trifluoromethylbenzene of a kind of 4-amine hydrochlorate, comprises following reactions steps:

(1), nitration reaction: drip after the concentrated nitric acid of same volume to being equipped with in the reactor of the vitriol oil, add the chloro-2-trifluoromethylbenzene of 1-, reacting by heating 3.5 hours, the cooling frozen water that adds, has solid to separate out, suction filtration, washing leaching cake, recrystallization, suction filtration, is dried to obtain the chloro-4-nitro-2-of 1-trifluoromethylbenzene;

(2), the chloro-4-nitro-2-of hydrogenating reduction: 1-trifluoromethylbenzene, Pd-C, methyl alcohol hydrogenation room temperature reaction 8 hours, reclaim solvent and Pd-C, resistates recrystallization, suction filtration, the dry chloro-4-fluoroaniline of 3-that to obtain;

(3), salify: by the chloro-4-nitro-2-of 1-trifluoromethylbenzene dissolution with solvents, lead to wherein HCl gas, tail gas passes in alkali lye, suction filtration, the dry chloro-3-trifluoromethylbenzene of the 4-amine hydrochlorate that to obtain.

Preferably, in nitration reaction, the solvent of recrystallization is the mixed solution that second alcohol and water forms, and the volume ratio of second alcohol and water is 1:1～5:1.

Most preferably, the volume ratio of second alcohol and water is 5:1.

In hydrogenation reduction, preferred 10%Pd-C.

In hydrogenation reduction, the solvent of recrystallization is Virahol.

Preferably, in salt-forming reaction, described solvent is selected from methyl alcohol, ethanol or acetone.

Preferably, in salt-forming reaction, described solvent is methyl alcohol.

In salt-forming reaction, described alkali lye is 30%NaOH solution.

The preparation method of the chloro-3-trifluoromethylbenzene of a kind of 4-provided by the invention amine hydrochlorate, nitration reaction post-treating method is simple, product purity improves, and with the reaction of hydrogen and Pd-C reduction nitro, only need carry out at normal temperature, less demanding to conversion unit, be suitable for suitability for industrialized production, the equal recoverable of solvent and Pd-C, after salify, product characteristics is stable, excessive HCl gas passes in alkali lye, has avoided environmental pollution.

Embodiment

The following examples can make the present invention of those skilled in the art comprehend, but do not limit the present invention in any way.

Embodiment 1

In reactor, drop into concentrated nitric acid 10L, open and stir, cooling reaction solution, to T=0～10 ℃, slowly drips vitriol oil 10L in salpeter solution, maintains temperature T=10～20 ℃ of reaction solution.Drip and finish, in reactor, slowly add the chloro-2-trifluoromethylbenzene of 1-9kg in batches, maintain reacting liquid temperature T≤25 ℃, finish, stirring at room 0.5 hour, then be warming up to T=60 ℃, stirring reaction 3 hours.Cooling reaction solution, to T=0～10 ℃, slowly drips 200kg frozen water in reactor, controls temperature of reaction and is no more than 15 ℃, separates out a large amount of solids.Filter, filter cake washes with water.Filter cake is transferred in reactor, adds 100L ethanol, 20L water and gac 0.5kg, reflux 30 minutes, filtered while hot, filtrate is cooled to T=0～5 ℃, stirring and crystallizing 8 hours.Filter, filtrate is reclaimed, filter cake water rinse, and 45 ℃ of reduced vacuum obtain yellow crystal solid 8.1kg, yield 72% for dry 6 hours.

Embodiment 2

In reactor, add the chloro-4-nitro-2-of 4kg1-trifluoromethylbenzene, 0.2kg10%Pd-C and 40L methyl alcohol, with after twice of hydrogen exchange air, logical hydrogen, stirring at room, reacts 8 hours, through TLC, follows the tracks of and reacts complete to raw material disappearance.Emptying remaining hydrogen, filters, and by reaction solution elimination catalyzer, reclaims after solvent, and underpressure distillation obtains solid residue.In this resistates, add Virahol 25L, reflux, filtered while hot, filtrate is cooled to T=0～5 ℃, stirring and crystallizing 8 hours.Filter, filter cake, through 30 ℃ of drying under reduced pressure 6 hours, obtains white solid 2.98kg, yield 86%, and HPLC purity is 98.8%.

Embodiment 3

In reactor, add the chloro-3-5-trifluoromethylaniline of 2kg4-and 20L methyl alcohol, stirring at room 1 hour, solid is entirely molten, in this clear liquor, passes into anhydrous HCl gas, regulates pH to 0.5, separates out a large amount of solids, and unnecessary tail gas passes in 30% NaOH solution.Filter, filter cake 2L methanol rinse, solid is dried 6 hours through 40 ℃ of reduced vacuum, obtains white solid 2.14kg, yield 90%, HPLC purity is 99.6%.

Embodiment 4

In reactor, add the chloro-3-5-trifluoromethylaniline of 2kg4-and 20L ethanol, stirring at room 1 hour, solid is entirely molten, in this clear liquor, passes into anhydrous HCl gas, regulates pH to 0.5, separates out a large amount of solids, and unnecessary tail gas passes in 30% NaOH solution.Filter, 2L ethanol rinsing for filter cake, solid is dried 6 hours through 40 ℃ of reduced vacuum, obtains white solid 1.82kg, yield 76.5%, HPLC purity is 99.9%.

Embodiment 5

In reactor, add the chloro-3-5-trifluoromethylaniline of 2kg4-and 20L acetone, stirring at room 1 hour, solid is entirely molten, in this clear liquor, passes into anhydrous HCl gas, regulates pH to 0.5, separates out a large amount of solids, and unnecessary tail gas passes in 30% NaOH solution.Filter, 2L acetone rinsing for filter cake, solid is dried 6 hours through 40 ℃ of reduced vacuum, obtains white solid 1.63kg, yield 68.6%, HPLC purity is 99.0%.

Claims

1. a preparation method for the chloro-3-trifluoromethylbenzene of 4-amine hydrochlorate, is characterized in that, comprises following reactions steps:

2. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 1 amine hydrochlorate, is characterized in that, in nitration reaction, the solvent of recrystallization is the mixed solution that second alcohol and water forms, and the volume ratio of second alcohol and water is 1:1 ~ 5:1.

3. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 2 amine hydrochlorate, is characterized in that, the volume ratio of second alcohol and water is 5:1.

4. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 1 amine hydrochlorate, is characterized in that, in hydrogenation reduction, Pd-C is 10%Pd-C.

5. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 1 amine hydrochlorate, is characterized in that, in hydrogenation reduction, the solvent of recrystallization is Virahol.

6. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 1 amine hydrochlorate, is characterized in that, in salt-forming reaction, described solvent is selected from methyl alcohol, ethanol or acetone.

7. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 6 amine hydrochlorate, is characterized in that, in salt-forming reaction, described solvent is methyl alcohol.

8. the preparation method of the chloro-3-trifluoromethylbenzene of 4-according to claim 1 amine hydrochlorate, is characterized in that, in salt-forming reaction, described alkali lye is 30%NaOH solution.