CN115850123B

CN115850123B - Preparation method of 2, 4-dichloroaniline/hydrazine

Info

Publication number: CN115850123B
Application number: CN202211434242.2A
Authority: CN
Inventors: 李志清; 宫风华; 李伟; 魏成前; 赵广理; 康瑞雪
Original assignee: Shandong Weifang Rainbow Chemical Co Ltd
Current assignee: Shandong Weifang Rainbow Chemical Co Ltd
Priority date: 2022-11-16
Filing date: 2022-11-16
Publication date: 2024-04-19
Anticipated expiration: 2042-11-16
Also published as: CN115850123A

Abstract

The invention discloses a preparation method of 2, 4-dichloroaniline/hydrazine, which takes phenylurea as a raw material, obtains 2, 4-dichloroaniline or 2, 4-dichloroaniline hydrochloride with high yield through dichloro reaction and hydrolysis reaction, and is used for preparing 2, 4-dichloroaniline hydrochloride.

Description

Preparation method of 2, 4-dichloroaniline/hydrazine

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method of 2, 4-dichloroaniline and a preparation method of 2, 4-dichlorobenzene.

Background

2, 4-Dichloroaniline/hydrazine has wide industrial application as an important raw material and intermediate. For example in the pesticide sector for the production of the herbicides mesotrione, the plant growth regulator cyproconazole, 5, 7-dichloroindol-3-acetic acid, 2- (5, 7-dichloro-1H-indol-3-yl) -3, 3-trifluoropropionic acid, the bactericides amidazole, imibenconazole, the acaricide pyriminostrobin; in the aspect of medicine, the preparation is mainly used for synthesizing anti-inflammatory, antibacterial, weight-reducing medicines and the like, such as ciprofloxacin which is an anti-inflammatory medicine and rimonabant which is a weight-reducing medicine; in terms of dye, the method is used for synthesizing pigment yellow 15 and pigment red 148.

Taking 2, 4-dichlorobenzylamine as an example, two methods of using acetanilide and m-dinitrobenzene as raw materials are mainly used for preparation.

Using acetanilide as a starting material.

In patent application CN 110590564A, aniline is used as a raw material, acetic acid is used as a solvent, and the yield of 2, 4-dichloroaniline is up to 95% by using a continuous chlorination method. However, as described in the background art, when using chlorine as the chlorinating agent, there is a problem that the availability of chlorine is low, the reaction temperature is difficult to control, and a polychlorinated substitution product is easily produced. In this patent application, although the reaction rate and chlorine loss are improved by a method using a continuous flow of the tubular reactor, the requirements on the reaction temperature or the reaction equipment are high, resulting in unstable yields and poor reproducibility, which are difficult to be used for mass production.

In addition, according to the results reported by chemical engineers, month 6 of 2002, third stage, p 58-59) in the literature describing the synthesis method of 2, 4-dichloroaniline, the average yield of 2, 4-dichloroaniline prepared by dichloroaniline is 61.9%, the combination nature of hydrochloric acid and potassium hypochlorite is that chlorine is prepared in situ, and the chlorine is subjected to dichloroaniline again, and the fact that the dichloroaniline is not good in reaction selectivity as a raw material of dichloroaniline is also demonstrated.

Literature Chlorination Reaction of Aromatic Compounds and Unsaturated Carbon-Carbon Bonds with Chlorine on Demand,Organic Letters,2021,23(8),3015-3020 reports that 2, 4-dichloroacetanilide is prepared by an electrolysis method, the method has high power consumption and limited productivity, tetraethylammonium chloride and trichloroacetonitrile are used, the difficulty of three-waste treatment is increased, and the cost is high.

The m-dinitrobenzene is used as a raw material to prepare 2, 4-dichloroaniline.

Patent CN104086352 a reports a method for preparing m-dichlorobenzene by introducing chlorine into m-dinitrobenzene at high temperature, which requires special material equipment and is easy to cause explosion due to improper reaction treatment; patent CN113004142a reports a process for preparing m-dichlorobenzene from 2, 4-dichloronitrobenzene, which produces a large amount of waste acid and has a high environmental pressure; reduction of nitro groups is described in A metal-organic framework-templated synthesis ofγ-Fe₂O₃ nanoparticles encapsulated in porous carbon for efficient and chemoselective hydrogenation of nitro compounds,Chemical Communications,2016,52(22),4199-4202.

In addition, literature Anthranilic diamides derivatives as potential ryanodine receptor modulators:Synthesis,biological evaluation and structure activity relationship,Bioorganic and Medicinal Chemistry,2018,26(2),3541-3550 reports a synthetic method of 2, 4-dichlorobenzyl hydrazine hydrochloride, and the use of stannous chloride generates a large amount of waste; in patent WO2018019250A1, an integrated continuous flow reactor is adopted to prepare 2, 4-dichlorobenzyl hydrazine hydrochloride, and n-butyl nitrite is a strong carcinogen, so that the environment is polluted and the ecology is poisoned.

The production of 2, 4-dichloroaniline/hydrazine is divided into two types from the raw material, wherein one type is to take aniline as the raw material, and the main problem is that the dichloroselectivity is generally poor, a large number of dichloroisomer, trichloro and tetrachloro are generated, and the yield is low due to the loss of separation and purification; the other is that m-dinitrobenzene is used as a raw material, a large amount of dangerous chemical processes exist or dangerous raw materials are used, safety accidents are easy to cause, and equipment corrosion is serious; the cost of hydrazine preparation from 2, 4-dichlorophenylamine is generally high. In view of the above, there is currently no safe, efficient and inexpensive production technology for 2, 4-dichloroaniline/hydrazine.

Disclosure of Invention

Object of the Invention

In order to overcome the defects, the invention aims to provide a preparation method of 2, 4-dichloroaniline and 2, 4-dichlorobenzene which are easy to produce in a large scale and have low cost.

Solution scheme

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

In a first aspect, the invention provides a preparation method of 2, 4-dichloroaniline, which takes phenylurea (I) as a raw material, obtains 2, 4-dichloroaniline or 2, 4-dichloroaniline hydrochloride (III) through dichloro reaction and hydrolysis reaction, and prepares 2, 4-dichlorobenzene hydrazine hydrochloride (IV) through diazotization reduction.

The reaction route is as follows:

Further, in the dichloro reaction, phenylurea (I) is introduced with chlorine gas in an organic solvent to obtain 2, 4-dichlorobenzurea (II).

Further, in the dichloro reaction, the organic solvent is an aprotic solvent and/or a protic solvent; optionally, the aprotic solvent is selected from one or more of chloroalkanes (e.g., 1, 2-dichloroethane, DCE), N-Dimethylformamide (DMF), N-Dimethylacetamide (DME); alternatively, the aprotic solvent is N, N-dimethylformamide; optionally, the protic solvent is an organic acid, optionally, the organic acid is selected from the group consisting of C1-C4 organic acids; optionally, the protic solvent is selected from one or more of formic acid, acetic acid, propionic acid and butyric acid; optionally, the protic solvent is acetic acid, optionally, the organic solvent is acetic acid.

Further, in the dichloro reaction, the mass ratio of phenylurea to the organic solvent is 1:3-20, alternatively 1:3-10, alternatively 1:4-9.

Further, in the dichlorination reaction, the introducing speed of chlorine gas is 1 to 4 bubbles/second.

Further, in the dichloro reaction, for aprotic solvents, the 2-position substitution is very slow at too low a temperature and the selectivity is poor at too high a temperature, and the reaction temperature is generally controlled to be 40-60 ℃, optionally 45-55 ℃, optionally 50 ℃;

Further, in the dichloro reaction, the reaction temperature is 10 to 40 ℃, alternatively 15 to 35 ℃, alternatively 15 to 30 ℃ for the protic solvent.

Optionally, in the dichloro reaction, the reaction time is 4 to 30 hours, optionally 6 to 20 hours;

further, the reaction was terminated when phenylurea was less than 1% or less by liquid phase (LC) tracking.

Further, adding cold water to precipitate solid after the dichloro reaction, and purifying to obtain 2, 4-dichlorobenzurea; optionally, the purification method comprises suction filtration, water washing and drying.

Further, the impurities generated in the dichloro reaction include at least one of 4-chlorobenzourea, 2,4, 6-trichloro-phenylurea, tetrachlorophenylurea.

The inventor found that when chlorine is introduced into the phenylurea-DMF system, the 2, 4-dichlorobenzene urea can be prepared with high selectivity, more importantly, the chlorination reaction mainly stays in the dichloro stage, even if the increase of the introduced excessive chlorine and polychloride is not obvious, and further research shows that the dichloro selectivity is better under the condition of lower temperature of the phenylurea-acetic acid system.

In a second aspect, a method for preparing 2, 4-dichloroaniline is provided, wherein 2, 4-dichloroaniline or 2, 4-dichloroaniline hydrochloride is obtained by taking 2, 4-dichloroaniline as a raw material through hydrolysis reaction.

The inventors have studied the hydrolysis of phenylurea and found that phenylurea-hydrochloric acid does not produce the expected aniline even under the condition of heating reflux with the addition of a cosolvent acetic acid; the addition of hydrochloric acid in different proportions to 2, 4-dichlorobenzene cannot be hydrolyzed to 2, 4-dichloroaniline (example 9), i.e., the hydrolysis of 2, 4-dichlorobenzene in hydrochloric acid does not find the target product. The inventors have unexpectedly found that when a co-solvent is added to hydrochloric acid, 2, 4-dichlorobenzene can hydrolyze to 2, 4-dichloroaniline in the presence of the co-solvent (examples 10-20), and that studies on the co-solvent have found that different co-solvents have different effects on the hydrolysis efficiency, for example, hydrolysis is much slower when ethanol is used as the co-solvent in example 11, and a large amount of starting material remains. The inventors tried hydrolysis of 2, 4-dichlorobenzurea under alkaline conditions, although a small amount of product was found, the hydrolysis rate was very slow (see example 21).

Further, inorganic acid is added into the cosolvent for acidolysis reaction in the hydrolysis reaction to obtain 2, 4-dichloroaniline acid salt or 2, 4-dichloroaniline.

Further, in the hydrolysis reaction, the cosolvent is selected from one or more of alcohols, organic acids, 1, 4-dioxane and tetrahydrofuran; optionally, the co-solvent is selected from alcohols and/or organic acids; optionally, the organic acid is selected from the group consisting of C1-C4 organic acids; optionally, the cosolvent is selected from one or more of methanol, ethanol, propanol, formic acid, acetic acid, propionic acid and butyric acid; optionally, the cosolvent is selected from one or more of ethanol, formic acid and acetic acid; optionally, the cosolvent is acetic acid.

Further, in the hydrolysis reaction, the inorganic acid is selected from hydrochloric acid and/or dilute sulfuric acid; alternatively, the inorganic acid is hydrochloric acid to obtain 2, 4-dichloroaniline hydrochloride.

Further, the molar ratio of the inorganic acid to the cosolvent is 0.2-20:1, optionally 0.3-10:1; optionally 1-10:1; alternatively, 2 to 10:1, alternatively 2 to 8:1, alternatively 2 to 5:1, alternatively 2 to 3:1.

Further, in the hydrolysis reaction, the reaction temperature is 60 to 120 ℃, alternatively 70 to 110 ℃, alternatively 80 to 105 ℃, alternatively 90 to 105 ℃, alternatively 95 to 100 ℃, alternatively 100 ℃.

Further, in the hydrolysis reaction, the reaction time is 3 to 24 hours, alternatively 5 to 12 hours, alternatively 6 to 11.5 hours, alternatively 6 to 8 hours.

Further, after the hydrolysis reaction, concentrating the reaction solution, carrying out suction filtration or further pulping and purifying to obtain a2, 4-dichloroaniline acid salt product; optionally, the solvent added by beating is selected from one or more of ethanol, ethyl acetate, dichloromethane and petroleum ether. Beating is generally carried out under the condition of poor reaction selectivity.

In a third aspect, the invention provides a method for preparing 2, 4-dichlorophenylhydrazine, wherein 2, 4-dichlorophenylhydrazine hydrochloride or 2, 4-dichlorophenylhydrazine is prepared by diazotizing, reducing addition or direct addition or acidolysis by taking 2, 4-dichlorophenylhydrazine hydrochloride as a raw material.

Alternatively, the 2, 4-dichloroaniline salt is the 2, 4-dichloroaniline salt prepared by the preparation method according to the first or second aspect, and commercially available 2, 4-dichloroaniline salt can be used as a raw material.

Further, the diazotization reduction method includes:

1) Diazotizing 2, 4-dichloroaniline salt and nitrite to obtain diazonium salt reaction liquid; the reaction temperature is generally-5 to 5 ℃, alternatively 0 to 5 ℃. Optionally, the nitrite is sodium nitrite;

2) The diazonium salt reaction solution is subjected to reduction addition or direct addition reaction under the action of sulfite and bisulfite, so that a monosulfite addition product or a bisulfite addition product of diazonium salt can be obtained.

3) And (3) adding inorganic acid into the reaction liquid in the step (2) for hydrolysis to obtain 2, 4-dichlorophenylhydrazine acid salt or 2, 4-dichlorophenylhydrazine.

Further, in step 1), a solution of nitrite is added dropwise to a hydrochloric acid solution containing 2, 4-dichloroaniline salt to conduct diazotization. Alternatively, the nitrite is sodium nitrite.

Alternatively, the concentration of nitrite is 10-35%, alternatively 30-35%. Optionally, the molar ratio of the 2, 4-dichloroaniline acid salt to the nitrite is 1:1-2; optionally, 1:1-1.2; alternatively, 1:1.05-1.1.

Optionally, in step 1), the molar ratio of 2, 4-dichloroaniline to hydrochloric acid in the hydrochloric acid solution containing 2, 4-dichloroaniline salt is 1:3-5, optionally 1:4-5. Alternatively, the mass fraction of 2, 4-dichloroaniline salt in the hydrochloric acid solution of 2, 4-dichloroaniline salt is 10-20%, alternatively 14-18%.

And/or, in step 1), the reaction temperature is-5 to 5 ℃, optionally-5 to 0 ℃.

Further, in the step 2), the diazonium salt prepared in the step 1) is added dropwise into a solution containing sulfurous acid and hydrosulfite for reduction addition or direct addition reaction; optionally, the sulfite is selected from at least one of sodium sulfite and potassium sulfite; optionally, the sulfite is selected from at least one of sodium bisulfite and potassium bisulfite; alternatively, the solution containing sulfite and bisulfite has a pH of 6 to 8.

Alternatively, in step 2), the sulfite is combined with the bisulfite in different ratios, optionally the molar ratio of sulfite to bisulfite is 1-3:1, optionally the molar ratio is 1.5-2.7:1, optionally 2:1.

Optionally, in the step 2), the solution containing sulfite and bisulfite also contains sodium bicarbonate, and the solution is used for making the pH of the mixed solution 7-8; optionally, the molar ratio of sulfite, bisulfite and bicarbonate in the mixed solution is 1-3:1: 0.5 to 3, optionally 1 to 3:1:0.5 to 2, alternatively 2:1:1. Optionally, the bicarbonate is sodium bicarbonate and/or potassium bicarbonate. Alternatively, the bicarbonate may be replaced by carbonate as an alternative;

Further, in the step 2), the diazonium salt reaction solution is added to the solution containing sulfite and bisulfite in the form of a drop or syringe pump; optionally, the pH value of the reaction system is regulated to be 4-8 by using alkali liquor in the process of dropwise adding the diazonium salt, and optionally, the pH value of the reaction system is regulated to be 5-7 by using alkali liquor in the process of adding the diazonium salt; optionally, the alkaline solution for adjusting the pH in the process of dropwise adding the diazonium salt is added into the reaction solution in the form of dropwise adding or a syringe pump. It should be understood that the pH is adjusted to 5-7 by the alkali solution during the dropping process of diazonium salt because diazonium salt solution is strongly acidic and the pH is changed during the dropping process, so that the pH is adjusted by the alkali solution to maintain a relatively stable reaction environment having a pH of 5-7.

Further, in step 2), the base for adjusting the reaction pH is selected from a strong base and/or a weak base, optionally the strong base comprises an alkali metal hydroxide and/or an alkaline earth metal compound; optionally, the base for adjusting the pH value of the reaction during the dropwise addition of the diazonium salt is preferably a weak base, optionally selected from carbonates and/or bicarbonates; alternatively, the pH base for the reaction may be at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, optionally sodium carbonate and/or sodium bicarbonate, optionally sodium bicarbonate. The alkali for regulating the pH value in the dropping process of the diazonium salt is suitable for weak alkali, solution is suitable for dropping, the pH value in the whole dropping process needs to be kept between 5 and 7 uniformly so as not to generate azo byproducts, and the reaction system can generate azo byproducts even if the reaction system is partially alkaline. Optionally, the mass fraction of weak base (sodium carbonate and/or sodium bicarbonate) for regulating the pH value in the alkali liquor is 5-8.5%; alternatively 7 to 8.5%, alternatively 8.5% (saturated concentration of sodium bicarbonate).

Optionally, the amount of sodium bicarbonate to diazonium salt to adjust the pH is 0 to 3 equivalents, optionally 1 to 3 equivalents, optionally 2 to 3 equivalents;

further, in step 2), the molar ratio of sulfite to 2, 4-dichloroaniline salt is 2-4:1, alternatively 2-3:1, alternatively 2:1.

Further, in step 2), the reaction temperature is 0 to 100 ℃, alternatively 8 to 100 ℃, alternatively 10 to 80 ℃; optionally 25-80 ℃; optionally 30-60 ℃; optionally 40-60 ℃; alternatively 35 to 45 ℃.

Further, in step 3), the inorganic acid is hydrochloric acid or dilute sulfuric acid.

Further, in step 3), the acidolysis temperature is 80 to 100 ℃, optionally 90 to 100 ℃.

The preparation of 2, 4-dichlorobenzene hydrochloride from 2, 4-dichlorobenzidine hydrochloride undergoes three stages, namely the formation of diazonium salt, the reductive addition or direct addition of diazonium salt, the hydrolysis of the reductive addition (IX) or of the addition (X), respectively, wherein the reductive addition or direct addition stage of diazonium salt is the key step. 2, 4-Dichloroaniline was first formed into diazonium salt, and diazonium salt reaction solution was added dropwise to sodium sulfite and sodium bisulphite, and at higher temperatures (60-90 ℃) reference example 22, lcms detected a negative ion peak (ix) with a main product molecular weight of M-23=255, and no negative ion peak of M-1=335 (x appears as a monosulfite salt in the liquid rather than as a bissulfite salt), indicating that the diazonium salt addition product was not the product of sulfite bimolecular addition. See the following reactions:

In the process of reducing diazonium salts by sulfite to form hydrazono (v), the hydrazono instability is easily converted into a more stable intermediate viii (LCMS: M-1=209) by addition with hydrochloric acid on the one hand, which is further substituted by one molecule of sodium sulfite to obtain a monosulfite product (ix); on the other hand, hydrazine is unstable and easy to decompose, nitrogen is discharged to generate main byproducts of M-dichlorobenzene (VI, GCMS: M=146), diazonium salt is converted into M-dichlorobenzene, the hydrazine is decomposed faster at higher temperature, and the higher reaction is favorable for generating sodium sulfite salt substituent (IX), but is also favorable for generating M-dichlorobenzene by decomposing the hydrazine.

The diazonium salt undergoes a coupling reaction with M-dichlorobenzene in a weakly basic environment to yield a brown azo by-product (vii, LCMS: m+1=321). On the other hand, diazonium salts also decompose into M-dichlorobenzene radicals, which add to electron-rich M-dichlorobenzene to give a M-dichlorobenzene dimer (XI, LCMS: M+1=293). The following formula:

because of the relatively poor selectivity of free radical addition, there are actually three addition modes of m-dichlorobenzene free radicals to m-dichlorobenzene, and the formula XI is actually expressed as a collection of three isomers.

At a further study of the reaction at lower temperatures, such as 0-45 ℃, LCMS in examples 28-36 detected negative ion peaks of M-1=255 and M-1=335, and it was speculated that at low temperatures diazonium salts were reduced to hydrazono (v) and then added with hydrochloric acid to give intermediate viii, which was further substituted with sodium sulfite to give ix, while the addition of diazonium salts with sulfite gave the bis-sulfite adduct (x), but with the mono-sulfite adduct as the main (see example 32), as shown below:

the resulting brown oil was analyzed by GCMS, m=320, and experiments showed that the formation of the azo by-product (vii) was related to the weak basicity of the system and that the impurity was not formed when the system was maintained neutral and weakly acidic. One possible explanation is that the coupling reaction of the diazonium salt with m-dichlorobenzene (VI) occurs under alkaline or partially alkaline conditions (partial alkaline means that when the pH is adjusted, the system may sometimes be alkaline due to uneven addition of the pH adjusting base or the addition of a solid base may result in part of the reaction solution being alkaline) to give brown impurities (VII). When the reaction system ph=5 to 7 was precisely controlled, see examples 27, 28, 31, the pH was controlled by uniformly dropping the alkali solution, and the generation of brown oil was hardly observed; whereas the reactions which occur as brown oils during the dripping of diazonium salts are described in examples 25, 29, 30, which are associated with a locally higher pH adjustment by the addition of a base; other conditions in examples 30 and 31 were the same, except that there was a large difference in the different yields of the aggregate state of the base addition, and the solid addition was such that the local alkalinity was strong to produce azo byproducts; further comparing examples 27, 31, which did not produce brown oil, it was found that the reaction temperature had less effect on selectivity.

However, the process of decomposing diazonium salt to generate m-dichlorobenzene has a certain relation with temperature, and the higher the temperature is, the more the decomposition is. In this process, a suitable temperature or a high temperature is necessary, which is favorable for the addition reaction to obtain the adducts of mono-and di-sulphites, but also promotes the decomposition of diazonium salts into m-dichlorobenzene; the low temperature results in insufficient diazonium salt addition reaction or hydrazono addition, which also causes an increase in m-dichlorobenzene as a byproduct, so that control of the pH between 5 and 7 is necessary to reduce the production of byproducts, when sodium sulfite is used in molar ratio: sodium bisulfite: the solution prepared by sodium bicarbonate=2:1:1 forms a double buffer system in the process of dripping diazonium salt, namely a sodium sulfite-sodium bisulfite buffer system and a sodium bicarbonate-carbonic acid buffer system, so that the pH=5-7 of the system is maintained in the process of dripping diazonium salt and the fluctuation of the system is not larger. Therefore, the molar ratio of the materials with the pH value controlled in the diazonium salt dropwise adding step is sodium sulfite: sodium bisulfite: sodium bicarbonate=2:1:1 is preferred, and the pH can be adjusted by adding sodium bicarbonate solution during the dropping process.

Experiments show that the reaction temperature is between 0 and 100 ℃, the influence on the reaction is not very obvious, the diazonium salt addition reaction speed is moderate relative to 35 to 45 ℃, but the diazonium salt decomposition speed is not too high, so that the diazonium salt addition reaction speed becomes the preferable interval temperature.

In the step 3), the acidolysis temperature is 80-100 ℃, and the hydrolysis speed is high when the temperature is high, otherwise, the hydrolysis speed is low.

Advantageous effects

(1) The invention takes phenylurea as a raw material, and can obtain 2, 4-dichloroaniline with high yield by introducing chlorine to perform dichloro reaction and then performing hydrolysis reaction.

(2) The phenylurea is used as a raw material, so that the dichloro reaction can be carried out at normal temperature, the selectivity is high, and a high-purity product is easy to obtain; moreover, no obvious dangerous reaction exists, the high-temperature explosive dangerous reaction existing in the prior art is avoided, and the safe production is facilitated; the invention has low requirements on equipment, is easy to amplify, and is suitable for industrialized large-scale production; the raw material cost and the three-waste treatment cost are low, and the method has higher application and popularization values.

(3) The inventors of the present invention have found that, when the hydrolysis of phenylurea is studied, the mixture of hydrochloric acid in different proportions (concentrations) in 2, 4-dichlorobenzurea cannot be hydrolyzed back to 2, 4-dichloroaniline (as in example 9), i.e., the hydrolysis of 2, 4-dichlorobenzurea in hydrochloric acid does not find the target product. The inventors have unexpectedly found that when a co-solvent is added to hydrochloric acid, 2, 4-dichlorobenzidine can be hydrolyzed to 2, 4-dichloroaniline by hydrochloric acid in the presence of the co-solvent (examples 10-20), but that different co-solvents have different effects on the hydrolysis efficiency, e.g., hydrolysis is much slower when ethanol is used as the co-solvent in example 11, and a large amount of starting material remains. The invention solves the problem of preparing 2, 4-dichloroaniline from phenylurea or 2, 4-dichlorophenylurea.

(4) The invention provides a method for preparing 2, 4-dichlorobenzene hydrazine with high yield by reducing addition or direct addition of 2, 4-dichlorobenzene hydrochloride with low-cost sodium sulfite and sodium bisulphite through diazonium salt and conveniently controlling the pH value of the reaction with sodium bicarbonate, which solves the problem of high production cost of 2, 4-dichlorobenzene hydrazine.

Drawings

One or more embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

FIG. 1 is a nuclear magnetic H-spectrum of an analytical sample (2, 4-dichlorobenzurea) of example 1 of the present invention.

FIG. 2 is a nuclear magnetic C-spectrum of an analysis sample (2, 4-dichlorobenzurea) of example 1 of the present invention.

FIG. 3 is a nuclear magnetic H-spectrum of an analytical sample (2, 4-dichloroaniline hydrochloride) according to example 13 of the present invention.

FIG. 4 is a nuclear magnetic C-spectrum of an analytical sample (2, 4-dichloroaniline hydrochloride) according to example 13 of the present invention.

FIG. 5 is a nuclear magnetic H-spectrum of an impurity (2, 4-dichloroacetanilide) of example 13 of the invention.

FIG. 6 is a graph showing the content of 2, 4-dichloroaniline and 2, 4-dichloroacetanilide in example 13 as a function of the molar ratio of hydrochloric acid to acetic acid.

Detailed Description

For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

In addition, numerous specific details are set forth in the following description in order to provide a better illustration of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, materials, protocols, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.

Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.

The product content in the following examples was confirmed by liquid or gas chromatography, and the tracking during the reaction was carried out by calculating the yield by area normalization method instead of external standard method, and the yield was slightly different from the actual yield (the difference from the actual yield was small).

LCMS: liquid chromatograpHy mass spectrometry, liquid quality.

GCMS Gas chromatograpHy mass spectrometry, gas mass.

HPLC: high Performance Liquid ChromatograpHy, high pressure liquid chromatography.

GC: gas chromatograpHy, gas chromatography.

And (3) NMR: nuclear magnetic resonance spectrometry nuclear magnetic resonance spectroscopy.

Phenylurea and 2, 4-dichloroaniline hydrochloride in the following examples are commercially available; if not specified, the reaction process and results were detected by high pressure liquid chromatography, and the purity and selectivity were normalized.

Examples 1 to 8 are a process for the preparation of 2, 4-dichlorobenzurea

Example 1

Phenylurea (5.0 g,36.3mmol, 98.9%) was dissolved in 1, 2-dichloroethane (35 g) and N, N-dimethylformamide (5 g), and the system was warmed to 60℃and purged with 1 to 2 bubbles per second. Monitoring liquid phase in real time, and reacting for 13 hours at a temperature of less than or equal to 0.5% of phenylurea as a raw material. The reaction solution was cooled to room temperature gradually, 1, 2-dichloroethane was removed by rotary evaporation, cold water (10 g) was added under stirring, a large amount of white solid was precipitated, crystallization was carried out at 5℃for 0.5 hour, suction filtration, water washing, and wet product drying to obtain 6.5g of white powder, purity 95.3%, yield of 2, 4-dichlorobenzurea was 83.2%. The analysis sample was subjected to nuclear magnetic H, C spectrum analysis, and the results are shown in fig. 1 and 2.

The nuclear magnetic data of 2, 4-dichlorobenzurea are as follows:

¹H NMR(500MHz,MeOD),δ(ppm)8.02(d,J＝9.0Hz,1H),7.41(d,J＝2.5Hz,1H),7.24(dd,J1＝2.0Hz,J2＝8.5Hz,1H)

¹³C NMR(126MHz,MeOD),δ(ppm)157.33,135.06,128.34,127.56,127.07,123.86,122.90

LCMS：M+1＝205。

Example 2

Phenylurea (15.0 g,0.11mol, 98.9%) is dissolved in N, N-dimethylformamide (150 g), the reaction system is heated to 50 ℃ and is filled with chlorine gas, 2 bubbles are filled in per second, the liquid phase is monitored in real time, the heat preservation reaction is carried out for 8 hours, and the raw material phenylurea is less than or equal to 0.5%. The reaction solution was cooled to room temperature, cold water (300 g) was added under stirring to precipitate a large amount of white solid, crystallization was performed at 0℃for 0.5 hours, suction filtration, water washing, and wet product drying to obtain 19.1g of white powder, purity of 98.3%, yield of 2, 4-dichlorobenzene urea of 84.0%.

Example 3

Phenylurea (38.5 g,0.28mol, 98.9%) was dissolved in acetic acid (154 g, 99.5%), the reaction system was purged with chlorine gas at 30℃for about 3 to 4 bubbles per second, the liquid phase was monitored in real time, and the reaction was continued for 6 hours and 40 minutes until the starting phenylurea disappeared, wherein the selectivity (2, 4-dichlorobenzene urea) was 97.4%, 4-chlorobenzoic urea was 0.3%, 2-chlorobenzoic urea was 1.0%, and 2,4, 6-trichlorobenzene urea was 0.5%. Cooling the reaction liquid to room temperature, adding cold water (300 g) under stirring, precipitating a large amount of white solid, crystallizing at 0 ℃ for 0.5 hour, carrying out suction filtration, washing with water, and drying the product to obtain 57.3g of white powder with the purity of 96.6%; the yield of 2, 4-dichlorobenzurea was 96.4%.

Example 4

Phenylurea (10 g, 99%) was dissolved in acetic acid (83.7 g, 99.5%) and chlorine gas was introduced at a temperature of 50 ℃. 1-2 bubbles per second, monitoring the disappearance of the raw materials in real time by the liquid phase, and carrying out heat preservation reaction for 7 hours. Cooling the reaction liquid to room temperature, adding cold water (200 g) under stirring, precipitating a large amount of white solid, crystallizing at 0 ℃ for 0.5 hour, carrying out suction filtration, washing with water, and drying the product to obtain 14.1g of white powder with the purity of 92.5%; the yield of 2, 4-dichlorobenzurea was 87.5%. The period was monitored in real time by liquid phase and the data as the reaction proceeded are shown in table 1: (liquid phase area normalization method)

TABLE 1 raw material and product data for the dichlorohydrin at 50℃for different reaction times

As is clear from Table 1, in this example, the phenylurea reacted relatively slowly in the initial stage at a reaction temperature of 50℃and, after the chlorine gas was introduced to reach a saturated state, the reaction was accelerated to shift to the direction of the product. After 6.5 hours of reaction, the phenylurea as a raw material is completely reacted, the selectivity of the target product 2, 4-dichlorobenzene is only 83%, the generation of the impurities of the trichlorophenylurea is obviously accelerated within the last 0.5 hour along with the gradual disappearance of the raw material, and the impurities of the tetrachlorophenylurea are generated, so that the high temperature has poor control tolerance to the reaction end point and is easy to overreact.

Example 5

Phenylurea (10 g,99%,72.7 mmol) was dissolved in acetic acid (50 g, 99.5%) and the temperature was raised to 35℃and chlorine gas was introduced. 1-2 bubbles per second, monitoring liquid phase in real time, and reacting for 7 hours at a constant temperature. During the process, the liquid phase is monitored in real time, and the raw material phenylurea is less than or equal to 0.3 percent. Cooling the reaction liquid to room temperature, adding 100mL of cold water, cooling to 5 ℃ and preserving heat for 1 hour, and drying the product after suction filtration and water washing to obtain 14.2g of white solid with the purity of 97.8 percent and the yield of 2, 4-dichlorobenzene of 93.1 percent.

Example 6

Phenylurea (38.0 g,0.28mol, 98.5%) is dissolved in acetic acid (300.0 g, 99.5%), chlorine is introduced at room temperature (25 ℃) for about 3-4 bubbles per second, liquid phase is monitored in real time, the reaction is kept for 6.5 hours, and the raw material phenylurea is less than or equal to 0.5%. Filtering the reaction solution, washing a filter cake with water, and drying the product to obtain 50.0g of white powder with the purity of 96.7%; cooling the mother solution to 5 ℃ and preserving heat for 1 hour, and drying the product after suction filtration and water washing to obtain 2.9g of white granular product with the purity of 95.1%; the total yield of 2, 4-dichlorobenzurea was 90.7%.

Example 7

Phenylurea (50.0 g,0.36mol, 99%) is dissolved in acetic acid (400 g, 99.5%), chlorine is introduced at room temperature (20 ℃) for about 1-2 bubbles per second, liquid phase is monitored in real time, and the temperature is kept for 15 hours for reaction, wherein the raw material phenylurea is less than or equal to 0.5%. The reaction solution was poured into water, a large amount of white solid was precipitated, the solution was cooled to 5℃and kept at the temperature for 1 hour, and the solution was filtered and the cake was dried to obtain 71.8g of a white powder, 98.3% purity and 94.7% yield.

Example 8

Phenylurea (50.0 g,0.36mol, 99%) is dissolved in acetic acid (250 g, 99.5%), chlorine is introduced under cold water bath (8-10 ℃) and 1-2 bubbles per second, liquid phase is monitored in real time, the reaction is carried out for 17 hours with heat preservation, and the raw material phenylurea is less than or equal to 0.5%. The reaction solution was poured into water, a large amount of white solid was precipitated, the solution was cooled to 5℃and kept at the temperature for 1 hour, and the solution was filtered and the cake was dried to obtain 71.2g of a white powder, 98.7% purity and 94.3% yield.

The reaction parameters and reaction products of the above examples 1 to 8 are summarized in Table 1. The content of the reaction product is detected by a liquid phase normalization method.

TABLE 2 dichloro-reaction of phenylurea in different solvents and temperatures

As can be seen from Table 1, the dichlorohydrin reaction does not produce dichloroisomer, and generally, high temperature is beneficial to accelerating the reaction speed, but also reduces the selectivity of the reaction, and DMF has better temperature tolerance than acetic acid.

In the above reaction, the rate of introducing chlorine gas is generally about 1 to 4 bubbles per second, and the early stage of the reaction can be suitably accelerated to reduce the reaction time, but attention is paid to intense heat release, and the rate of introducing chlorine gas can be suitably reduced to the late stage of the reaction, and the slower the reaction, the better the selectivity, and the main components of impurities mainly include: 4-chlorobenzoic acid urea, 2,4, 6-trichloro-benzoic acid urea, tetrachloro-phenylurea and unreacted raw materials.

The reaction rate is related to the polarity of the solvent, and generally the greater the polarity, the faster the rate of reaction. For the alternative solvents, the smaller the polarity, the less favorable the chlorination reaction, which is related to the polarizability of chlorine after being dissolved in the solvent, the polar solvent is favorable for the polarization of chlorine to form positive and negative ion pairs and also favorable for the substitution reaction of chlorine, so that the rate of chlorination in different solvents is acetic acid > N, N-dimethylformamide > 1, 2-dichloroethane. As solvents for the reaction there may be mentioned DCE (1, 2-dichloroethane), DMF (N, N-dimethylformamide), DME (N, N-dimethylacetamide), organic acids or any combination of the above, wherein the organic acids may be C1-C4 organic acids, optionally formic acid, acetic acid, propionic acid, butyric acid, preferably DMF, acetic acid. The reaction time of the organic acid can be effectively shortened.

Further the selectivity of the reaction depends mainly on the temperature of the reaction, the lower the temperature the better the selectivity. For aprotic solvents such as DMF, the reaction temperature is low, chlorination reaction at the 2-position is difficult to occur, and the selectivity is reduced when the temperature is increased, so that the reaction temperature should be controlled between 40 and 60 ℃, optionally 45 to 55 ℃ and preferably 50 ℃; for a protonic solvent such as acetic acid, the reaction end point is difficult to control when the temperature is high, the reaction end point is easy to control when the temperature is low, but the temperature cannot be too low, otherwise, the acetic acid is easy to freeze, the reaction cannot be stirred, and the homogeneous reaction cannot be carried out. When acetic acid is used as a solvent, under the condition of lower temperature, even if the reaction time is prolonged, the system does not generate tetrachloro products, meanwhile, the byproduct of trichloro is obviously reduced, the control operability of the reaction end point is strong, and the acetic acid is used as a solvent and has obvious advantages compared with N, N-dimethylformamide, as shown in examples 6-8. The reaction temperature of acetic acid as solvent is 8-35 ℃, alternatively 15-30 ℃.

Examples 9 to 20 are methods for preparing 2, 4-dichloroaniline hydrochloride from 2, 4-dichloroaniline

Examples 9 to 16 starting materials 2, 4-dichlorobenzurea was derived from example 6; examples 17 to 21 starting materials 2, 4-dichlorobenzurea was derived from example 7

Example 9

2, 4-Dichlorobenzurea (1.05 g,4.95mmol, 96.7%) was suspended in a solution of hydrochloric acid (4.5 g,45mmol, 36.5%), warmed to 80℃and incubated for 6 hours, the liquid phase monitored the progress of the reaction, and no product was seen.

Example 10

2, 4-Dichlorobenzene urea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of formic acid (2.3 g,50mmol, 98%) and hydrochloric acid (1.5 g,15mmol, 36.5%), the reaction solution was clarified by heating to 100℃and keeping the temperature for 6 hours, the reaction progress was monitored by liquid phase, the raw material remained 4%,2, 4-dichlorobenzidine contained 24.9%, the other chloro by-product accounted for 3.5%, and the product (2, 4-dichlorobenzidine hydrochloride) accounted for 67.6%. The reaction is poor, and no subsequent treatment is carried out.

Example 11

2, 4-Dichlorophenylurea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of ethanol (2.3 g,50mmol, 99.5%) and hydrochloric acid (1.5 g,15mmol, 36.5%), the temperature was raised to 80℃and the reaction solution became clear, the reaction was kept at the temperature for 10 hours, the progress of the reaction was monitored by liquid phase, 36.6% of the raw material remained, 3.4% of the polychlorinated material and 60% of the product. The reaction mixture was cooled to room temperature, concentrated, and slurried with methylene chloride (3 g), followed by suction filtration to give 0.47g of a white powder having a purity of 97.0% and a yield of 2, 4-dichloroaniline hydrochloride of 46.4%.

Example 12

2, 4-Dichlorobenzurea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of acetic acid (7.6 g,125mmol, 99.5%) and hydrochloric acid (1.5 g,15mmol, 36.5%), the temperature was raised to 100℃and the reaction solution was kept clear, the reaction was kept at the temperature for 6 hours, the progress of the reaction was monitored by liquid phase, the raw material remained 7.3%,2, 4-dichloroacetanilide 13.7% and the product 75.9%. The reaction solution was cooled to room temperature and concentrated, and was slurried with ethanol (3 g), and suction filtered to give 0.65g of a white powder having a purity of 98.0% and a yield of 2, 4-dichloroaniline hydrochloride of 64.8%.

Example 13

2, 4-Dichlorobenzene urea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of acetic acid (2.4 g,40mmol, 99.5%) and hydrochloric acid (1.0 g,10mmol, 36.5%), the temperature was raised to 100℃and the reaction solution was kept clear, the progress of the reaction was monitored by liquid phase, the reaction was kept for 6 hours, the raw materials remained 3.1%,2, 4-dichloroacetanilide 26.3% and the product 67.8%. The reaction mixture was cooled to room temperature and concentrated, and then was slurried with methylene chloride (3 g), followed by suction filtration, to give 0.64g of a white powder having a purity of 98.2% and a yield of 2, 4-dichloroaniline hydrochloride of 63.9%.

Concentrating the dichloromethane mother liquor to obtain a crude product (2, 4-dichloroacetanilide: 2, 4-dichloroaniline hydrochloride=1:3), and performing silica gel column chromatography (eluent: V _{Petroleum ether}/V_{Acetic acid ethyl ester} =10:1) to obtain the target impurity 2, 4-dichloroacetanilide.

The analysis sample was subjected to nuclear magnetism H, C spectrum analysis, the results of 2, 4-dichloroaniline hydrochloride are shown in fig. 3 and 4, and the hydrogen spectrum of impurity 2, 4-dichloroacetanilide is shown in fig. 5.

The structural identification data of 2, 4-dichloroaniline hydrochloride are as follows:

¹H NMR(500MHz,MeOD),δ(ppm)7.68(s,1H),7.52(d,J＝9.0Hz,1H),7.48(dd,J1＝1.5Hz,J2＝8.5H,1H)

¹³C NMR(126MHz,MeOD),δ(ppm)133.76,129.96,129.34,128.48,127.86,124.79

LCMS：M+1＝162。

The structure identification data of 2, 4-dichloroacetanilide are as follows:

¹H NMR(500MHz,DMSO),δ(ppm)9.58(s,1H),7.75(dd,J1＝2.5Hz,J2＝11.0Hz,1H),7.64(d,J＝2.0Hz,1H),7.40(dd,J 1＝2.5Hz,J2＝8.5Hz,1H),2.10(s,3H).

LCMS：M+1＝204。

Example 14

2, 4-Dichlorophenylurea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of acetic acid (3.0 g,50mmol, 99.5%) and hydrochloric acid (1.5 g,15mmol, 36.5%), the temperature was raised to 100℃and the reaction was continued for 6 hours, the reaction solution became clear, the progress of the reaction was monitored by liquid phase, and the product was 90.9%. The reaction mixture was cooled to room temperature and concentrated, and was slurried with methylene chloride (3 g), followed by suction filtration to give 0.87g of a white powder having a purity of 99.0% and a yield of 2, 4-dichloroaniline hydrochloride of 87.6%.

Example 15

2, 4-Dichlorobenzene urea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of acetic acid (1.8 g,30mmol, 99.5%) and hydrochloric acid (1.5 g,15mmol, 36.5%), the temperature was raised to 100℃and the reaction solution was kept clear, the progress of the reaction was monitored by liquid phase, the reaction was kept for 6 hours, the starting material remained 1.4%, 2.2% of 2, 4-dichloroacetanilide and 93.1% of the product. The reaction mixture was cooled to room temperature and concentrated, and then was slurried with methylene chloride (3 g), followed by suction filtration to give 0.91g of a white powder having a purity of 97.9% and a yield of 2, 4-dichloroaniline hydrochloride of 90.6%.

Example 16

2, 4-Dichlorobenzurea (1.05 g,4.95mmol, 96.7%) was dissolved in a mixed solution of acetic acid (0.9 g,15mmol, 99.5%) and hydrochloric acid (1.5 g,15mmol, 36.5%), the temperature was raised to 100℃and the reaction solution was kept clear, the progress of the reaction was monitored by liquid phase, the reaction was kept for 6 hours, the raw materials remained 0.3%,2, 4-dichloroacetanilide 1.5% and the product 94.7%. The reaction mixture was cooled to room temperature and concentrated, and then was slurried with methylene chloride (3 g), followed by suction filtration to give 0.94g of a white powder having a purity of 98.0% and a yield of 2, 4-dichloroaniline hydrochloride of 93.7%.

Example 17

2, 4-Dichlorobenzene urea (2.09 g,10mmol, 98.3%) was dissolved in a mixed solution of acetic acid (0.96 g,16mmol, 99.5%) and hydrochloric acid (3.2 g,32mmol, 36.5%), the temperature was raised to 100 ℃, the reaction was kept at 100℃for 6.5 hours, the reaction solution became clear, the progress of the reaction was monitored by liquid phase, the raw material remained 0.6%,2, 4-dichloroacetanilide 0.7%, and the product 97.2%. The reaction solution was cooled to room temperature and concentrated, and then was slurried with petroleum ether (10 g), and suction-filtered to give 1.93g of a white powder having a purity of 98.2% and a yield of 2, 4-dichloroaniline hydrochloride of 95.3%.

Example 18

2, 4-Dichlorophenylurea (10.0 g,47.9mmol, 98.3%) was dissolved in a mixed solution of acetic acid (8.7 g,143mmol, 99.5%) and hydrochloric acid (42.8 g, 719 mmol, 36.5%), the temperature was raised to 100℃and kept, the reaction was continued for 2 hours, the reaction solution became clear, then solid was gradually precipitated and suspended above the solution, the reaction was continued for 7 hours, the progress of the reaction was monitored by liquid phase, and the raw material remained 0.7% and the product 97.5%. Cooling the reaction liquid to room temperature to precipitate a large amount of white solid, filtering to obtain a wet product, and drying to obtain 8.6g of white powder product with the purity of 99.6%; concentrating the mother solution after suction filtration to remove acetic acid, cooling to room temperature, standing to precipitate pale yellow solid, and suction filtering to obtain 0.7g of white powder with the purity of 92.0%. The total yield of the 2, 4-dichloroaniline hydrochloride is 96.8%.

Example 19

2, 4-Dichlorophenylurea (3.1 g,14.9mmol, 98.3%) was dissolved in a mixed solution of acetic acid (1.8 g,30mmol, 99.5%) and hydrochloric acid (15 g,150mmol, 36.5%), the temperature was raised to 100℃and kept for 7 hours, the central control starting material remained 1.8%, the reaction was kept for 11.5 hours until the reaction solution was clear, then a solid was gradually precipitated and suspended above the solution, the progress of the reaction was monitored by the liquid phase, the starting material remained 0.3%, and the product was 97.6%. The acetic acid was recovered under reduced pressure, and the resultant was filtered to obtain 2.86g of a white solid, with a purity of 99.2%, and a yield of 2, 4-dichloroaniline hydrochloride of 96.2%.

Example 20

2, 4-Dichlorobenzurea (2.1 g,10mmol, 98.3%) was suspended in a mixed solution of acetic acid (0.6 g,10mmol, 99.5%) and hydrochloric acid (10 g,100mmol, 36.5%), the reaction was continued at 100℃for 6 hours with a liquid phase monitoring of the progress of the reaction, 3.6% of the starting material remained, 94.4% of the product continued to be reacted at 11 hours with a heat preservation until the reaction solution became clear, then a solid was gradually precipitated and suspended above the solution, the progress of the reaction was monitored with a liquid phase monitoring of the progress of the reaction, 1.4% of the starting material remained, 96.9% of the product. The acetic acid was recovered under reduced pressure, and the resultant was filtered to obtain 1.95g of a white solid, with a purity of 98.4%, and a yield of 2, 4-dichloroaniline hydrochloride of 96.0%.

The reaction parameters of examples 9 to 20 are summarized in Table 3.

TABLE 3.2,4 hydrolysis product analysis of dichlorobenzurea under different acid systems

In Table 3, 2, 4-dichlorobenzurea was used as a raw material.

In Table 3, note 1 represents 2, 4-dichlorobenzidine, i.e., 24.9% of 2, 4-dichlorobenzidine was produced in example 10.

In table 3, note 2: other impurities include monochloroaniline, trichloroaniline, tetrachloroaniline, and the like.

In order to optimize the hydrolysis condition of 2, 4-dichlorobenzene urea, a cosolvent is selected as an organic acid, and researches show that when acetic acid in mixed acid is relatively high, a certain amount of byproducts are always produced, the extension time is slightly increased, and the more the proportion of acetic acid is high, the more 2, 4-dichloroacetanilide is produced as a byproduct, which is shown in examples 12 and 13; similar situation exists with formic acid, with the formation of by-product 2, 4-dichloro-formamide, see example 10.

Further examining the temperature of the reaction, we found that at lower temperatures, the hydrolysis reaction readily produced more byproduct 2, 4-dichloroacetanilide. Therefore, the reaction temperature is 100 ℃ which is taken as the fixed temperature of the reaction and is used for optimizing the proportion of the mixed acid.

To reduce the production of by-product 2, 4-dichloroacetanilide, we reduce the ratio of acetic acid-hydrochloric acid, and as a result, found that when acetic acid: at a molar ratio of 1:2, a small amount of 2, 4-dichloroacetanilide was formed, see example 17; when the ratio is less than 1: no formation of by-product 2, 4-dichloroacetanilide was found at3, see examples 18, 19, but when hydrochloric acid: at 5:1 acetic acid, the reduction of the co-solvent significantly slows the hydrolysis rate, see example 19; when further scaled up to hydrochloric acid: at 10:1 acetic acid, 1.4% of the starting material was unconverted, indicating that too little co-solvent is detrimental to the complete hydrolysis reaction, see example 20.

The following trends are evident from table 3: 1) When hydrochloric acid: when the acetic acid proportion is gradually increased, the hydrolysis byproduct 2, 4-dichloroacetanilide is gradually reduced, the selectivity is increased, but as the hydrochloric acid: the reaction rate is obviously slowed down after the acetic acid reaches 5:1 and 10:1; 2) When hydrochloric acid: when the acetic acid reaches 2:1, the impurity 2, 4-dichloroacetanilide is obviously reduced, and along with the increase of the hydrochloric acid ratio, the hydrochloric acid: when acetic acid reaches 10:1, the inclusion of the formed product into the feedstock increases the non-conversion due to poor feedstock and product solubility, but other impurity levels do not change significantly, which is related to the impurity transfer of the starting feedstock; 3) When the duty ratio of hydrochloric acid is reduced, such as hydrochloric acid: when the molar ratio of acetic acid is lower than 1:2, the conversion rate can be improved by prolonging the reaction time, but the byproduct 2, 4-dichloroacetanilide is not reduced, and even slightly increased; 4) When hydrochloric acid: when the molar ratio of acetic acid is 0.3-10:1, the hydrolysis reaction can be smoothly carried out; 5) When hydrochloric acid: at acetic acid molar ratios of 2-5:1, the by-product 2, 4-dichloroacetanilide is significantly reduced toward 0, while the yield tends to be maximized, as shown in FIG. 6.

From the above analysis, it is readily apparent that the hydrolyzed co-solvent may be selected from: alcohols, organic acids, 1, 4-dioxane, tetrahydrofuran, etc.; optionally the organic acid is C1-C4 organic acid or C1-C4 alcohol, and optionally the organic acid is formic acid or acetic acid.

In general, the selectivity of the target product can be improved with a reduced proportion of co-solvent (e.g., organic acid such as acetic acid), generally with better yields and selectivities at 1 to 10:1, optionally 2 to 8:1, optionally 2 to 5:1, of hydrochloric acid and co-solvent (preferably organic acid), while also shortening the hydrolysis time.

Example 21

2, 4-Dichlorophenylurea (2.1 g,10mmol, 98.3%) was suspended in a mixed solution of ethanol (10 g) and water (1 ml), sodium hydroxide (1.0 g,25 mmol) was added and the temperature was raised to about 80℃for reflux reaction for 6 hours, the progress of the reaction was monitored by a liquid phase, about 8.1% of the objective product, the raw material remained 90.0%, continued to be kept at a temperature for 14 hours, the raw material remained 77.8% and the product 19.5%. The alkaline hydrolysis effect is poor and the reaction is stopped.

Example 21 demonstrated far less effective acid than hydrolysis of 2, 4-dichlorobenzurea with base.

Examples 22 to 37 are methods for preparing 2, 4-dichlorobenzene hydrochloride from 2, 4-dichlorobenzamide hydrochloride

In examples 22 to 33, selectivity is the sum of the yield and the product-reduced yield of the mother liquor, as determined by the normalization method. The raw material 2, 4-dichloroaniline hydrochloride can be prepared from the raw materials, or can be purchased from outsources.

EXAMPLE A preparation of diazonium salts

2, 4-Dichloroaniline hydrochloride (3.8 g,18.8mmol, 98%) is dissolved in 18% aqueous solution prepared by hydrochloric acid (6.0 g,60mmol, 36.5%) and 6g water, stirred at room temperature for 0.5 hours, cooled to-5 ℃, 33% aqueous solution of sodium nitrite (1.5 g sodium sulfite (21.7 mol) and 33% aqueous solution prepared by water (3.0 g)) are slowly added dropwise, the reaction temperature is controlled to be not more than-2 ℃, the reaction progress is monitored by liquid phase, the reaction is kept for 1 hour, insoluble particles are observed in the system, and the raw material conversion is complete.

EXAMPLE B preparation of diazonium salts

2, 4-Dichloroaniline (4.9 g,30mmol, 99%) was suspended in an 18% aqueous solution of hydrochloric acid (17.6 g,150mmol,5eq, 31%) and 12.7g water, heated to 80℃and stirred for 1 hour before slowly cooling to 0℃as a white particle slurry. 30% aqueous sodium nitrite (2.2 g of sodium sulfite (31.5 mol,1.05 eq) and 30% aqueous solution of 5.1g of water) were slowly added dropwise with stirring, the temperature slightly increasing during the dropwise addition and the temperature being controlled at 0-5 ℃. After the completion of the dropwise addition, the reaction liquid changed from white slurry to pale yellow green clear liquid. The liquid phase monitors the reaction progress, the reaction is kept for 0.5 hour, the raw material is completely converted, and the normalized value of the diazonium liquid is 99.6 percent.

EXAMPLE C preparation of diazonium salts

2, 4-Dichloroaniline (4.9 g,30mmol, 99%) was suspended in a 16.3% aqueous solution of hydrochloric acid (14.1 g,120mmol,4eq, 31%) and 12.7g water, heated to 80℃and stirred for 1 hour before slowly cooling to below 5℃as a white particle slurry. 30% aqueous sodium nitrite (2.2 g of sodium sulfite (31.5 mol,1.05 eq) and 30% aqueous solution of 5.1g of water) were slowly added dropwise with stirring, the temperature slightly increasing during the dropwise addition and the temperature being controlled at 0-5 ℃. After the completion of the dropwise addition, the reaction liquid changed from white slurry to light yellow-green slightly turbid solution, and less insoluble particles were observed in the system. The liquid phase monitors the reaction progress, the reaction is kept at the temperature for 0.5 hour, and the raw materials are completely converted.

EXAMPLE D preparation of diazonium salts

2, 4-Dichloroaniline (4.9 g,30mmol, 99%) was suspended in a 14.1% aqueous solution of hydrochloric acid (10.6 g,90mmol,3eq, 31%) and 12.7g water, heated to 80℃and stirred for 1 hour before slowly cooling to below 5℃as a white particle slurry. 30% aqueous sodium nitrite (2.2 g of sodium sulfite (31.5 mol,1.05 eq) and 30% aqueous solution of 5.1g of water) were slowly added dropwise with stirring, the temperature slightly increased during the dropwise addition, and the temperature was controlled at 0-5 ℃. After the completion of the dropwise addition, the reaction liquid changed from white slurry to light yellowish green turbid liquid, and insoluble particles were observed in the system. The liquid phase monitors the reaction progress, the reaction is kept at the temperature for 0.5 hour, and the raw materials are completely converted.

Comparing the four above schemes for diazonium salts, it can be seen that example A, D has insoluble particle generation, only example B diazonium liquid was prepared with 2, 4-dichloroaniline: hydrochloric acid molar ratio = 1:5 conversion was most complete, with minimal by-products, example C times.

By comparing the four methods, when the diazonium salt is prepared, the molar ratio of the 2, 4-dichloroaniline to the hydrochloric acid is 1: 3-5, and the conversion is more complete when the molar ratio is 1:4-5.

The reaction temperature is controlled between-5 ℃ and the quality of diazonium salt is basically not different.

Example 22

Sodium sulfite (6.4 g,50 mmol) was mixed with water (19.2 g) to prepare a 25% aqueous solution, and the solution was heated to 80℃to dissolve completely. The diazonium salt solution prepared as in example a was added dropwise to the system, after incubation at 80 ℃ for 1 hour, the negative ion peak containing M-23=255 (47.6%), the negative ion peak of M-1=209 (17.7% in ratio), three M-dichlorobenzene dimers m+1=293 (5.2%), the impurity m+1=321 (8.9% in ratio), the small polar impurity (17.7% in ratio) were detected by LCMS, and the small polar impurity m=146 was detected by GCMS. After 2 hours incubation, the liquid monitor material was completely converted, ph=7, and the system had a small amount of brown oil. Hydrochloric acid (12 g, 36.5%) is added for heat preservation for 1 hour, the system has solid precipitation, the reaction liquid is cooled to room temperature, light yellow flaky solid is obtained by filtering, 2.6g of the light yellow flaky solid is obtained by drying, the purity is 97.7%, the yield is 63.4%, the folding content in the mother liquid is 2.1%, and the selectivity is 65.5%.

This example follows the diazotisation reduction process and makes preliminary assumptions about the possible formation of reactive intermediates and mechanisms. Wherein: the structures m=146, M-1=209, M-23=255, m+1=321, m+1=293 are presumed as follows:

example 23

Sodium sulfite (6.4 g,50 mmol) and water (19.2 g) were prepared as 25% aqueous solutions, and the temperature was raised to 80 ℃ (ph=9 to 10). Sodium bisulphite (2.6 g,25 mmol) was combined with water (3.9 g) to give a 40% aqueous solution (ph=4 to 5). Adding sodium bisulphite aqueous solution into sodium sulfite aqueous solution, stirring and mixing (pH=6-7) to prepare sodium bisulphite-sodium sulfite mixed solution, heating to 80 ℃, dropwise adding diazonium solution prepared according to the embodiment A into the sodium bisulphite-sodium sulfite mixed solution, and after 2 hours, monitoring the conversion of diazonium salt completely, wherein pH=2-3. Hydrochloric acid (12 g, 36.5%) is added for heat preservation for 1 hour, the system has solid precipitation, the reaction liquid is cooled to room temperature, light yellow flaky solid 3.1g is obtained by filtering, the purity is 86.0%, the yield is 66.6%, the folding content in the mother liquid is 3.1%, and the selectivity is 69.7%.

Example 24

Sodium sulfite (9.52 g,76.6mmol,2.5 eq), sodium bisulphite (6.29 g,60.5mmol,2.0 eq) was mixed with 89.63g of water to prepare a 15% aqueous solution (ph=7) to prepare a sodium bisulphite-sodium sulfite mixed solution.

Dropwise adding diazonium salt prefabricated according to example C into the sodium bisulfite-sodium sulfite mixed solution heated to 80 ℃, keeping the pH at 6 for 1 hour after adding, completely converting the liquid monitoring raw material, adding hydrochloric acid (10 g,31.0%,3.0 eq) and stirring at 100 ℃ for 2 hours, wherein the system has solid precipitation, TLC detection raw material is about 70% remained, stirring at 100 ℃ for 3 hours, TLC detection raw material is not remained, the reaction liquid is cooled to 30 ℃ and has solid precipitation, the reaction liquid is cooled to 0 ℃, light yellow flaky solid is obtained by filtering, the normalized purity is 99.2%, the yield is 55.8%, the folding content in the mother liquid is 2.6%, and the selectivity is 58.4%.

Example 25

Sodium sulfite (7.6 g,60mmol,2 eq) was mixed with 82g of water to prepare an 8.5% aqueous solution (ph=9 to 10). Sodium bisulphite (3.2 g,30mmol,1 eq) was mixed with 12.8g water to give a 20% aqueous solution (ph=4-5). The sodium bisulphite aqueous solution is added to the sodium sulfite aqueous solution and stirred and mixed (ph=6 to 7) to prepare a sodium bisulphite-sodium sulfite mixed solution.

To the above mixed solution of sodium bisulphite-sodium sulfite heated to 80 ℃ was added dropwise a diazonium solution prepared as in example B (20% sodium hydroxide lye was used to adjust pH to 5-7 during diazonium dropwise addition, 1eq sodium hydroxide was consumed), and reddish brown tar was generated (wall built) in the reaction solution during the addition, and ph=7 was completed by the addition. After 1 hour of incubation, the liquid monitoring material was completely converted and the addition product of dichlorophenyl diazonium salt with sodium sulfite was detected, LCMS: M-1 = 255. Hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 90 ℃ and the temperature is kept for hydrolysis for 2 hours, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 4.5g of the pale yellow flaky solid is obtained by drying, the normalized purity is 99.5%, the yield is 70.0%, the product folding content in the mother liquor is 4.3%, and the selectivity is 74.3%.

Example 26

To the above mixed solution of sodium bisulphite-sodium sulfite heated to 80 ℃ was added dropwise a diazonium solution prepared as in example D, and a reddish brown tar was generated in the reaction solution during the addition, and the addition was completed at ph=3. The temperature is kept for 1 hour, the liquid quality monitoring raw materials are completely converted, hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 90 ℃ and the temperature is kept for 2 hours, the system is kept for solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 4.3g of normalized purity is obtained by drying, the yield is 66.6%, the product folding content in the mother liquor is 3.0%, and the selectivity is 69.6%.

Table 4.80 ℃ examine sodium sulfite: molar ratio of sodium bisulfite (based on 2, 4-dichloroaniline)

Sodium sulfite in examples 23, 25, 26: the pH at the end of the addition was relatively high in yield despite the large difference at a molar ratio of sodium bisulfite of 2:1. It is presumed that the pH of example 23 was maintained at 5 to 7 for a long period of time during the entire diazo dropwise addition process, except that the pH reaction end was rapidly lowered to 2 to 3 with the dropwise addition of the diazonium salt; example 25 consistently uses sodium hydroxide to adjust ph=5-7 during the dropwise addition of diazonium salt, thus higher yields; for examples 22 and 24, the pH value of sodium sulfite should be kept between 8 and 10 basically during the process of dropping diazonium salt, but the end point pH value is reduced along with the dropping of diazonium salt, and the slightly strong alkalinity is the reason for low yield. Therefore, maintaining the pH between 5 and 7 during the dropwise addition of diazonium salts is critical to improving the yield of the reaction.

Example 27

To the above mixed solution of sodium bisulphite-sodium sulfite heated to 60 ℃ was added dropwise a diazonium solution prepared as in example B (8.5% aqueous sodium bicarbonate solution was used in the form of a syringe pump to adjust pH to 5-7 during the diazonium dropwise addition, 3eq of sodium bicarbonate was consumed) without the formation of reddish brown tar in the reaction solution during the dropwise addition, and the addition was completed at ph=7. The temperature is kept for 1 hour, the liquid quality monitoring raw materials are completely converted, hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 90 ℃ and the temperature is kept for hydrolysis for 2 hours, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 4.8g of normalized purity is obtained by drying, the yield is 75.5%, the product folding content in the mother liquor is 3.5%, and the selectivity is 79.0%.

Example 28

To the above mixed solution of sodium bisulphite and sodium sulfite heated to 40 ℃, a diazonium solution prepared in accordance with example C (8.5% aqueous sodium bicarbonate solution was used to adjust pH to 5 to 7 during the diazonium solution addition, 2eq sodium bicarbonate was consumed altogether) was added in the form of a syringe pump, the dropwise addition was completed at ph=7, the reaction solution was pale yellow clear solution, and no brown tar was produced. The temperature is kept for 1 hour, the liquid quality monitoring raw materials are completely converted, hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 90 ℃ and the temperature is kept for hydrolysis for 2 hours, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 5.2g of normalized purity is obtained by drying, the yield is 80.5%, the product folding content in the mother liquor is 4.5%, and the selectivity is 85.0%.

Example 29

Sodium sulfite (7.6 g,60mmol,2 eq) was mixed with 82g of water to prepare a 10% aqueous solution (ph=9 to 10). Sodium bisulphite (3.2 g,30mmol,1 eq) was mixed with 12.8g water to give a 20% aqueous solution (ph=4-5). Sodium bicarbonate (2.5 g,30mmol,1 eq) was mixed with 27g of water to give an 8.5% aqueous solution (ph=8 to 9). The aqueous sodium bisulfite solution, aqueous sodium sulfite solution and aqueous sodium bicarbonate solution were stirred and mixed (ph=7 to 8) to prepare a mixed solution.

To the above mixed solution of sodium bisulphite, sodium sulfite and sodium bicarbonate at 25 ℃ was added dropwise a diazonium solution prepared as in example B (1 eq of sodium carbonate was consumed by adjusting pH to 5 to 7 with solid sodium carbonate during diazonium dropwise addition), brown tar was present during the dropwise addition, and ph=5 to 7 was completed. The temperature is kept for 2 hours, the liquid quality monitoring raw materials are completely converted, hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 100 ℃, the temperature is kept for hydrolysis for 1 hour, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 4.2g of normalized purity is obtained by drying, the yield is 65.4%, the product folding content in the mother liquor is 3.0%, and the selectivity is 68.4%.

Example 30

To the above mixed solution of sodium bisulphite, sodium sulfite and sodium bicarbonate at 0 ℃ was added dropwise a diazonium solution prepared as in example B (sodium bicarbonate was consumed 3eq in total by adjusting pH to 5 to 7 using solid sodium bicarbonate during diazonium dropwise addition), brown tar was present during the dropwise addition, and ph=7 was completed. The temperature is kept for 2 hours, the liquid quality monitoring raw materials are completely converted, hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 90 ℃ and kept for 1 hour, the temperature is kept for hydrolysis, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 4.2g is obtained by drying, the content is 99.6%, the normalized purity is 99.6%, the yield is 65.4%, the product folding content in the mother liquor is 2.9%, and the selectivity is 68.3%.

Example 31

Sodium sulfite (7.6 g,60mmol,2 eq) was prepared as an 8.6% aqueous solution (ph=8 to 9) with 80g of water, sodium bisulphite (3.2 g,30mmol,1 eq) was prepared as a 20% aqueous solution (ph=4 to 5) with 12.8g of water, and then the aqueous sodium bisulphite solution and the aqueous sodium sulfite solution were mixed with stirring (ph=7 to 8) to prepare a mixed solution.

The diazonium solution prepared in example B was added dropwise to a mixture of sodium bisulphite and sodium sulfite at 0 ℃ as described above, and the pH was adjusted to 5 to 7 (3 eq sodium bicarbonate was consumed) by using an aqueous sodium bicarbonate solution (sodium bicarbonate (7.5 g,90mmol,3 eq) and 81g water to prepare an 8.5% aqueous solution (ph=8 to 9)) during the addition, and the reaction solution was a pale yellow clear solution, and no brown tar was produced. The reaction solution was incubated for 0.5 hour, and the liquid quality was monitored for complete conversion of the starting material. The system was warmed to 90℃and incubated with hydrochloric acid (25 g, 31.0%) for 1 hour, and solids precipitated. The reaction solution is slowly cooled to 0 ℃, a large amount of pale yellow flaky solids are separated out, the white solids are obtained by filtering and drying, the normalized purity is 99.5%, the yield is 76.3%, the product folding content in the mother solution is 2.8%, and the selectivity is 79.1%.

Table 5 sodium sulfite: when the molar ratio of sodium bisulphite is 2:1, alkali is used for adjusting pH=5-7 in the dripping process to examine different reaction temperatures

In table 5, L represents a formulation solution, and S represents a solid.

By comparing the data in Table 5, it was found that the selectivity of the reaction was lower for the brown oil during the drop of diazonium salt, resulting in the formation of azo by-products (VII), see examples 25, 29, 30; in contrast, the reaction which did not produce brown oil produced no azo by-product, and the reaction selectivity was high, see examples 27, 28, 31, and it was found that the reaction temperature was not a factor affecting the formation of azo by-products, and comparative examples 27 and 31 showed that the effect of the reaction temperature on the selectivity was almost negligible. The reason for the higher selectivity of example 28 than example 27 may be that the higher temperature of example 27 more readily results in the decomposition of the diazonium salt to produce more m-dichlorobenzene. Example 28 is more selective than example 30 probably because: example 30 is that the low temperature, slow down of the rate of addition of sulfite to hydrazono (v) results in incomplete decomposition of the subsequent step addition to more m-dichlorobenzene upon subsequent heating. A large part of the reason for the oil generation is due to the local basicity of the system during the dripping of diazonium salts, such as example 25; further, in comparative examples 30 and 31, the other conditions were the same, except that there was a large difference in the yields of the different aggregate states of the base addition, and the solid addition was performed in such a way that the local alkalinity was strong to produce azo byproducts. Therefore, the alkali for adjusting the pH value is suitable for weaker alkali, weak alkali is suitable for dropwise adding in a solution form after adding the diazonium solution, the pH value needs to be kept at 5-7 uniformly in the whole dropwise adding process so as not to generate azo byproducts, and the azo byproducts can be generated even if the reaction system is partially alkaline.

Example 32

Sodium sulfite (7.6 g,60mmol,2 eq) was mixed with 82g of water to prepare an 8.5% aqueous solution (ph=9 to 10). Sodium bisulphite (3.2 g,30mmol,1 eq) was mixed with 12.8g water to give a 20% aqueous solution (ph=4-5). Sodium bicarbonate (2.5 g,30mmol,1 eq) was mixed with 27g of water to give an 8.5% aqueous solution (ph=8 to 9). The aqueous sodium bisulfite, aqueous sodium sulfite, and aqueous sodium bicarbonate were mixed with stirring (ph=7-8) to prepare a mixed solution.

To the above mixed solution of sodium bisulphite, sodium sulfite and sodium bicarbonate heated to 40 ℃ was added dropwise a diazonium solution prepared as in example B (pH was adjusted to 5 to 7 using 8.5% aqueous sodium bicarbonate solution during diazonium dropwise addition, and 3eq total sodium bicarbonate was consumed), no brown tar was generated during the dropwise addition, and the ph=7 was completed. After 2 hours of incubation, the liquid monitoring of the complete conversion of the starting material, the detection of the addition product of dichlorophenyl diazonium salt with sodium sulfite, LCMS followed the intermediate formed in the reaction, ion peak M-23=255 (as sodium monosulfite, 65% in ratio) and ion peak M-1=335 (or M-23=335, as sodium bissulfite, 32% in ratio). Hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 100 ℃, the temperature is kept for hydrolysis and heat preservation for 1 hour, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 5.5g is obtained by drying, the normalized purity is 96.0%, the yield is 82.6%, the product folding content in the mother liquor is 9.2%, and the selectivity is 91.8%.

At lower temperature, the diazonium salt reacts with sulfite to generate intermediate structure shown as IX and X, and sodium monosulfite (IX) is used as the main material, and the ratio of the two is about 2:1. Note that the sodium disulfite salt (x) shows the structure (xi) of disulfonic acid in LCMS.

Example 33

Sodium sulfite (7.6 g,60mmol,2 eq) was mixed with 82g of water to prepare a 10% aqueous solution (ph=9 to 10). Sodium bisulphite (3.2 g,30mmol,1 eq) was mixed with 12.8g water to give a 20% aqueous solution (ph=4-5). Sodium bicarbonate (7.6 g,90mmol,3 eq) was mixed with 82g of water to give an 8.5% aqueous solution (ph=8 to 9). The aqueous sodium bisulfite solution, aqueous sodium sulfite solution and aqueous sodium bicarbonate solution were stirred and mixed (ph=7 to 8) to prepare a mixed solution.

To the above mixed solution of sodium bisulphite, sodium sulfite and sodium bicarbonate heated to 40 ℃ was added dropwise a diazonium solution prepared as in example B (pH was maintained at 6 to 8 using 8.5% aqueous sodium bicarbonate solution during diazonium dropwise addition), brown tar was present during dropwise addition, and ph=8 was achieved by dropwise addition. The temperature is kept for 1 hour, the liquid quality monitoring raw materials are completely converted, hydrochloric acid (15 g, 31.0%) is added, the temperature is raised to 90 ℃ and the temperature is kept for hydrolysis for 2 hours, the system has solid precipitation, the reaction liquid is gradually cooled to 0 ℃, the pale yellow flaky solid is obtained by filtering, 4.0g of normalized purity is obtained by drying, the yield is 64.5%, the product folding content in the mother liquor is 4.5%, and the total yield is 69.0%.

Table 6. Sodium sulfite at 40 ℃ under investigation: when the molar ratio of sodium bisulphite is 2:1, different feeding modes of sodium bicarbonate are examined

Examples 28, 32, 33 were essentially the same except for the manner of addition, wherein example 33 was consistently more basic, the reaction endpoint was at a minimum ph=8, and selectivity was low in anticipation, notably example 32 was at a pH of 7 to 8 before the addition of the diazonium salt, and at a ph=5 to 7 after the addition, indicating that maintaining a pH of 5 to 7 during the addition reaction was advantageous, although the initial pH was slightly higher.

Examples 34 to 37 were conducted under the same conditions as in example 32, except that the reaction temperature was different when the diazonium salt was added dropwise.

Example 34

The reaction temperature of the diazonium salt was 25℃in drops. 5.2g of the product is obtained, the purity is 97.8%, the yield is 79.5%, the product folding content in the mother liquor is 7.3%, and the selectivity is 86.8%.

Example 35

The reaction temperature of the diazonium salt was 35℃in drops. 5.6g of the product is obtained, the purity is 96.7%, the yield is 84.7%, the product folding content in the mother liquor is 8.5%, and the selectivity is 93.2%.

Example 36

The reaction temperature of the diazonium salt was 45℃with drops. 5.5g of the product is obtained, the purity is 95.8%, the yield is 82.4%, the product folding content in the mother liquor is 9.1%, and the selectivity is 91.5%.

Example 37

The reaction temperature of the diazonium salt was 60℃dropwise. 5.1g of the product is obtained, the purity is 99.1%, the yield is 79.0%, the product folding content in the mother liquor is 7.1%, and the selectivity is 86.3%.

Table 7. Investigate sodium sulfite: sodium bisulfite: the effect of different reaction temperatures on selectivity when ph=5 to 7 was adjusted with 2eq sodium bicarbonate at a sodium bicarbonate (molar ratio) of 2:1:1

Examples	Reaction temperature (DEG C) in the reduction step	Yield after hydrolysis (%)	Selectivity after hydrolysis (%)
				32	40	82.6	91.8
34	25	79.5	86.8
				35	35	84.7	93.2
36	45	82.4	91.5
				37	60	79.0	86.3

As can be seen from Table 7, the yields and selectivities of examples 32 and 34 to 37 are not greatly different, and the production of azo byproducts is not found in the above examples, indicating that the reaction is not particularly sensitive to the influence of temperature. However, the partial diazonium salt reaction is incomplete due to the too low temperature, and more m-dichlorobenzene is easily produced due to the higher temperature.

Comparative example 1

Acetylaniline (4.9 g,36.3 mmol) was suspended in acetic acid (20 g), dissolved by stirring (colorless clear liquid), and was supplied with chlorine gas at 25℃for 2 to 3 bubbles per second. After 30 minutes, solid particles are precipitated in the system, the reaction process is tracked by HPLC, the system is dissolved again after 2 hours, the system is precipitated again (the system becomes sticky) after stirring for 20 minutes, the reaction solution is pasty (the system has larger viscosity) all the time, and after 20g of acetic acid is added for 2.5 hours, chlorine is continuously introduced. The monochloroacetanilide is difficult to convert (react for 4 hours) in the later stage of the chlorination reaction, and the reaction liquid turns yellow green. The prior conversion of the acetanilide is normal, the reaction is difficult to continue when the monochloro product is remained for 6.7% after 4 hours, and the trichloro product is gradually increased. When the monochloro product remained at 6.7%, the 2, 4-dichloroacetanilide content was 90.2%, after which the dichloroacetanilide content was reduced and the trichloro product increased, the reaction was stopped by 4 hours and 40 minutes. The reaction temperature is 25-28 deg.c, and the data of the material and product are shown in table 8.

TABLE 8 raw material and product data for comparative example 1 over reaction time

Reaction time (h)	Acetanilide (%)	Monochloroacetanilide (%)	Dichloroacetanilide (%)	Trichloroacetanilide (%)
					1h30min	10.7	71.3	16.5	0.3
2h	0.1	58.0	39.7	0.5
					2h20min	0	48.6	50.0	0.7
2h30min	0	42.4	55.1	1.0
					3h10min	0	12.8	85.3	1.1
3h40min	0	9.8	85.4	2.4
					4h	0	6.7	90.2	2.6
4h10min	0	6.4	89.3	3.7
					4h20min	0	4.8	86.3	8.0
4h40min	0	3.8	84.7	9.1

Compared with example 6, the selectivity of the phenylurea used as a substrate for dichloro in example 6 can reach 97.9% (see table 2), the yield is 90.7%, but the selectivity of the acetanilide in comparative example 1 in dichloro is only 90.2% at the highest, which shows that the selectivity of phenylurea in dichloro is better and the yield is higher than that of the acetanilide in normal temperature reaction conditions.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A preparation method of 2, 4-dichloroaniline or 2, 4-dichloroaniline acid salt is characterized in that phenylurea is used as a raw material to obtain 2, 4-dichloroaniline or 2, 4-dichloroaniline acid salt through dichloro reaction and hydrolysis reaction; wherein,

In the dichloro reaction, introducing chlorine into phenylurea in an organic solvent to obtain 2, 4-dichlorobenzene urea;

in the dichloro reaction, the organic solvent is a protic solvent and/or an aprotic solvent; the proton solvent is organic acid selected from one or more of formic acid, acetic acid, propionic acid and butyric acid; the aprotic solvent is selected from one or more of chloralkane, N-dimethylformamide and N, N-dimethylacetamide;

carrying out acidolysis reaction on the hydrolysis reaction in a cosolvent through inorganic acid to obtain 2, 4-dichloroaniline acid salt or 2, 4-dichloroaniline; the mol ratio of the inorganic acid to the cosolvent is 0.3-20:1; the inorganic acid is selected from hydrochloric acid and/or dilute sulfuric acid;

In the hydrolysis reaction, the cosolvent is selected from one or more of alcohols, organic acid, 1, 4-dioxane and tetrahydrofuran; the organic acid is selected from one or more of formic acid, acetic acid, propionic acid and butyric acid, and the alcohol is C1-C4 alcohol.

2. The method according to claim 1, wherein the aprotic solvent is N, N-dimethylformamide.

3. The preparation method according to claim 1, wherein in the dichloro reaction, the mass ratio of phenylurea to the organic solvent is 1:3-20.

4. The process according to claim 1, wherein the 2, 4-dichlorobenzurea is obtained by adding cold water to precipitate a solid after the dichloro reaction and purifying the solid.

5. The preparation method according to claim 1, wherein in the dichloro reaction, the mass ratio of phenylurea to the organic solvent is 1:3-10.

6. The preparation method according to claim 1, wherein in the dichloro reaction, the mass ratio of phenylurea to the organic solvent is 1:4-8.

7. The method according to claim 1, wherein the chlorine gas is introduced at a rate of 1 to 4 bubbles/sec in the dichloro reaction.

8. The method according to claim 1, wherein the reaction temperature is 40 to 60 ℃ when the organic solvent is an aprotic solvent in the dichloro reaction.

9. The process according to claim 1, wherein in the dichloro reaction, the reaction temperature is 45 to 55℃when the organic solvent is an aprotic solvent.

10. The process according to claim 1, wherein in the dichloro reaction, the reaction temperature is 50℃when the organic solvent is an aprotic solvent.

11. The method according to claim 1, wherein the reaction temperature is 10 to 40 ℃ when the organic solvent is a protic solvent in the dichloro reaction.

12. The method according to claim 1, wherein the reaction temperature is 15 to 35 ℃ when the organic solvent is a protic solvent in the dichloro reaction.

13. The method according to claim 1, wherein the reaction temperature is 15 to 30 ℃ when the organic solvent is a protic solvent in the dichloro reaction.

14. The method according to claim 1, wherein the reaction time is 4 to 30 hours in the dichloro reaction.

15. The preparation method according to claim 1, wherein in the dichloro reaction, the reaction time is 6 to 20 hours.

16. The preparation method according to claim 1, wherein in the dichloro reaction, the reaction is terminated when phenylurea is less than 1% by liquid phase normalization tracking.

17. The method of claim 16, wherein in the dichloro reaction, the purification method comprises suction filtration, water washing and drying.

18. The method according to claim 1, wherein the impurities produced in the dichloro reaction include at least one of 4-chlorobenzourea, 2,4, 6-trichloro-phenylurea and tetrachlorophenylurea.

19. A preparation method of 2, 4-dichloroaniline or 2, 4-dichloroaniline acid salt is characterized in that 2, 4-dichloroaniline or 2, 4-dichloroaniline acid salt is obtained by taking 2, 4-dichloroaniline as a raw material through hydrolysis reaction; wherein,

Carrying out acidolysis reaction on the hydrolysis reaction in a cosolvent through inorganic acid to obtain 2, 4-dichloroaniline acid salt or 2, 4-dichloroaniline; the mol ratio of the inorganic acid to the cosolvent is 0.2-20:1; the inorganic acid is selected from hydrochloric acid and/or dilute sulfuric acid;

In the hydrolysis reaction, the cosolvent is selected from one or more of alcohols and organic acids; the organic acid is selected from one or more of formic acid, acetic acid, propionic acid and butyric acid, and the alcohol is C1-C4 alcohol.

20. The method according to any one of claims 1 to 19, wherein the cosolvent is one or more selected from methanol, ethanol, propanol, formic acid, acetic acid, propionic acid, and butyric acid.

21. The process according to any one of claims 1 to 19, wherein the inorganic acid is hydrochloric acid to obtain 2, 4-dichloroaniline hydrochloride.

22. The method of any one of claims 1 to 19, wherein the molar ratio of inorganic acid to co-solvent is 0.3 to 10:1.

23. The method of any one of claims 1 to 19, wherein the molar ratio of the inorganic acid to the co-solvent is 1-10:1.

24. The method of any one of claims 1 to 19, wherein the molar ratio of inorganic acid to co-solvent is 2-10:1.

25. The method of any one of claims 1 to 19, wherein the molar ratio of inorganic acid to co-solvent is 2-8:1.

26. The method of any one of claims 1 to 19, wherein the molar ratio of inorganic acid to co-solvent is 2-5:1.

27. The method of any one of claims 1 to 19, wherein the molar ratio of inorganic acid to co-solvent is 2-3:1.

28. The process according to any one of claims 1 to 19, wherein the reaction temperature in the hydrolysis reaction is 60 to 120 ℃.

29. The process according to any one of claims 1 to 19, wherein the reaction temperature in the hydrolysis reaction is 70 to 110 ℃.

30. The process according to any one of claims 1 to 19, wherein the reaction temperature in the hydrolysis reaction is 80 to 105 ℃.

31. The process according to any one of claims 1 to 19, wherein the reaction temperature in the hydrolysis reaction is 80 to 100 ℃.

32. The process according to any one of claims 1 to 19, wherein the reaction temperature in the hydrolysis reaction is 95 to 100 ℃.

33. The process according to any one of claims 1 to 19, wherein the reaction temperature in the hydrolysis reaction is 100 ℃.

34. The method according to any one of claims 1 to 19, wherein the reaction time in the hydrolysis reaction is 3 to 24 hours.

35. The method according to any one of claims 1 to 19, wherein the reaction time in the hydrolysis reaction is 5 to 12 hours.

36. The method according to any one of claims 1 to 19, wherein the reaction time in the hydrolysis reaction is 6 to 12 hours.

37. The method according to any one of claims 1 to 19, wherein the reaction time in the hydrolysis reaction is 6 to 11.5 hours.

38. The method according to any one of claims 1 to 19, wherein the reaction time in the hydrolysis reaction is 6 to 8 hours.

39. The process according to any one of claims 1 to 19, wherein after the hydrolysis reaction, the reaction solution is concentrated and suction filtered to obtain a 2, 4-dichloroaniline acid salt product.

40. The process of claim 39, wherein the concentrated and filtered mixture is further pulped and filtered.

41. The process of claim 40 wherein the solvent added by beating is an organic solvent which is poorly soluble in 2, 4-dichlorobenzoate and is selected from one or more of ethanol, methylene chloride and petroleum ether.

42. A process for preparing 2, 4-dichlorobenzoate or 2, 4-dichlorobenzazide, characterized in that 2, 4-dichlorobenzoate is prepared from the process according to any one of claims 1 to 41 by diazotizing, reducing addition or direct addition, acidolysis.

43. The method of claim 42, comprising the steps of:

1) Diazotizing 2, 4-dichloroaniline salt and nitrite to obtain diazonium salt reaction liquid;

2) The diazonium salt reaction liquid is subjected to reduction addition or direct addition reaction under the action of sulfite and bisulfite;

3) And (2) adding inorganic acid into the reaction liquid in the step (2) to hydrolyze to obtain 2, 4-dichlorobenzoic acid salt or 2, 4-dichlorobenzene hydrazine.

44. The process according to claim 43, wherein in step 1), the solution of 2, 4-dichloroaniline in hydrochloric acid is added dropwise to the nitrite solution to effect diazotization.

45. The method of claim 44, wherein the nitrite is sodium nitrite.

46. The method according to claim 44, wherein in the step 1), the molar ratio of 2, 4-dichloroaniline to hydrochloric acid in the hydrochloric acid solution containing 2, 4-dichloroaniline salt is 1:3-5.

47. The process according to claim 44, wherein in step 1), the molar ratio of 2, 4-dichloroaniline to hydrochloric acid in the hydrochloric acid solution containing 2, 4-dichloroaniline salt is 1:4 to 5.

48. The method according to claim 44, wherein the mass fraction of 2, 4-dichloroaniline salt in the hydrochloric acid solution of 2, 4-dichloroaniline salt is 10-20%.

49. The method according to claim 44, wherein the mass fraction of 2, 4-dichloroaniline salt in the hydrochloric acid solution of 2, 4-dichloroaniline salt is 14-20%.

50. The method according to claim 44, wherein the mass fraction of 2, 4-dichloroaniline salt in the hydrochloric acid solution of 2, 4-dichloroaniline salt is 14-18%.

51. The method of claim 44, wherein in step 1), the reaction temperature is-5 to 5 ℃.

52. The process of claim 44 wherein in step 1) the reaction temperature is-5~0 ℃.

53. The process according to claim 43, wherein in step 2), the diazonium salt prepared in step 1) is added dropwise to a solution containing sulfite and bisulfite to carry out a reductive addition or direct addition reaction.

54. The process according to claim 53, wherein the sulfite is at least one selected from sodium sulfite and potassium sulfite.

55. The process according to claim 53, wherein the bisulphite is at least one selected from the group consisting of sodium bisulphite and potassium bisulphite.

56. The method of claim 53, wherein the pH of the solution containing sulfite and bisulfite is 6 to 8.

57. The process according to claim 53, wherein in step 2), the molar ratio of sulfite to bisulfite is 1 to 3:1.

58. The process according to claim 53, wherein in step 2), the molar ratio of sulfite to bisulfite is 1.5 to 2.7:1.

59. The process according to claim 53, wherein in step 2), the molar ratio of sulfite to bisulfite is 2:1.

60. The process according to claim 53, wherein in step 2), the solution containing sulfite and bisulfite further contains bicarbonate, and the pH of the mixed solution is 7 to 8.

61. The method of claim 60, wherein the molar ratio of sulfite, bisulfite, and bicarbonate in the mixed solution is 1-3: 1:0.5 to 3.

62. The method of claim 60, wherein the molar ratio of sulfite, bisulfite, and bicarbonate in the mixed solution is 1-3: 1: 0.5-2.

63. The process of claim 60 wherein the molar ratio of sulfite, bisulfite, and bicarbonate in the mixed solution is 2:1:1.

64. The process according to claim 60, wherein the bicarbonate is sodium bicarbonate and/or potassium bicarbonate.

65. The process according to claim 60, wherein the bicarbonate is replaced with carbonate.

66. The process according to claim 60, wherein in step 2), the diazonium salt reaction solution is added in the form of a drop or syringe pump to the solution containing sulfite and bisulfite.

67. The process of claim 66, wherein the diazonium salt is added by adjusting the pH of the reaction system to 4-8 with an alkaline solution.

68. The process of claim 66, wherein the diazonium salt is added by adjusting the pH of the reaction system to 5-7 with an alkaline solution.

69. The process of claim 66 wherein the pH adjusting lye is added to the reaction solution in the form of a drop or syringe pump during the dropping of diazonium salt.

70. The process of claim 67 wherein in step 2) the pH base used to adjust the reaction is selected from the group consisting of a strong base and a weak base.

71. The process according to claim 70, wherein the strong base comprises an alkali metal hydroxide and/or an alkaline earth metal compound.

72. The process of claim 67 wherein the pH base of the reaction is a weak base during the diazonium salt addition.

73. The process according to claim 72, wherein the weak base is selected from carbonates and/or bicarbonates.

74. The process according to claim 67, wherein the pH adjusting base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate.

75. The process according to claim 67, wherein the pH base of the reaction is sodium carbonate and/or sodium bicarbonate.

76. The process of claim 67, wherein in step 2), the molar ratio of sulfite to 2, 4-dichloroaniline salt is 2-4:1.

77. The process of claim 67, wherein in step 2), the molar ratio of sulfite to 2, 4-dichloroaniline salt is 2.5-4:1.

78. The process of claim 67, wherein in step 2), the molar ratio of sulfite to 2, 4-dichloroaniline salt is 2.5-3:1.

79. The process according to claim 43, wherein in step 2), the reaction temperature is 0 to 100 ℃.

80. The process according to claim 43, wherein in step 2), the reaction temperature is 8 to 100 ℃.

81. The process according to claim 43, wherein in step 2), the reaction temperature is 10 to 80 ℃.

82. The process according to claim 43, wherein in step 2), the reaction temperature is 25 to 80 ℃.

83. The process according to claim 43, wherein in step 2), the reaction temperature is 30 to 60 ℃.

84. The process according to claim 43, wherein in step 2), the reaction temperature is 40 to 60 ℃.

85. The process according to claim 43, wherein in step 2), the reaction temperature is 35 to 45 ℃.

86. The process according to claim 43, wherein in step 3), the mineral acid is hydrochloric acid or dilute sulfuric acid.

87. The process according to claim 43, wherein in step 3), the hydrolysis temperature is 80 to 100 ℃.

88. The process according to claim 43, wherein in step 3), the hydrolysis temperature is 90 to 100 ℃.