WO2019085876A1

WO2019085876A1 - Continuous-flow clean production process for pyrazolone series products

Info

Publication number: WO2019085876A1
Application number: PCT/CN2018/112589
Authority: WO
Inventors: 庆九; 俞新南; 薛金全; 刘芳; 朱小刚; 周新建; 朱爱华; 石春明
Original assignee: 南通醋酸化工股份有限公司; 南通立洋化学有限公司
Priority date: 2017-10-31
Filing date: 2018-10-30
Publication date: 2019-05-09
Also published as: CN107827821B; CN107827821A

Abstract

The present invention discloses a continuous-flow clean production process for pyrazolone series products, comprising reacting an aromatic amine with an aqueous sulfuric acid solution for 0.5-2 h to obtain an aromatic amine sulfate solution; simultaneously introducing the aromatic amine sulfate solution and a sodium nitrite into a pre-mixer solution for mixing, and then introducing the mixture into a continuous flow reactor for a diazotization reaction; adding the generated diazonium salt to an aqueous ammonium sulfite solution and an aqueous ammonium hydrogen sulfite solution in sequence for a reduction reaction; upon completion of the reduction reaction, adding a sulfuric acid solution for a hydrolyzation reaction at 70-120°C; carrying out neutralization after the hydrolyzation reaction, the pH being controlled between 2 and 5, and then carrying out a condensation reaction with diethylamine at 40-70°C for 1-3 h, cooling the solution to 10-40°C, followed by filtration and drying to give a pyrazolone product; and subjecting the mother liquor to extraction with a solvent or decolorization with activated carbon, followed by concentration by evaporation, gradient cooling at stages, and separation by crystallization, to give ammonium sulfate and sodium sulfate. The present invention has fewer side reactions, a high diazotization yield, and is capable of producing a series of products.

Description

Continuous flow cleaning production process of pyrazolone series products

Technical field

The invention relates to the field of chemical synthesis, in particular to a method for producing a pyrazolone series product.

Background technique

The pyrazolone series product is CnHmNpOqClrSt, n=10-11, m=9-12, p=2, q=1~4, r=0-2, t=0-1. Take C ₁₀ H ₁₀ N ₂ O (1-phenyl-3-methyl-5-pyrazolone) as an example:

Appearance properties: light yellow crystal or powder.

Solubility: soluble in water, slightly soluble in alcohol and benzene, insoluble in ether, petroleum ether and cold water.

Molecular weight: 174.20

Melting point: 127-131 ° C

Boiling point: 287 ° C 265 mmHg

Density: 1.26

Flash point: 191 ° C

Relative density: 1.17

Water solubility: 3g / L (20 ° C)

use:

This product is an important fine chemical intermediate, mainly used in the synthesis of pyrazolone antipyretic analgesics such as analgin, antipyrine, aminopyrine, pyrazolone acid dyes such as acid Medium Jujube BN, Permanent Yellow G and intermediates for color film dyes, pesticides and other fine chemicals.

Prior art synthesis process:

At present, the conventional production method in industrial production is: batch production method, 30-70 ° C, aniline, hydrochloric acid, sodium nitrite solution is simultaneously added to the diazotization reactor reaction (n (aniline): n (hydrochloric acid): n ( Sodium nitrite) = 1:1.5 to 3.0: 1.0 to 1.15), after the completion of the diazotization reaction, it is cooled to 0 to 80 ° C, and added to an ammonium hydrogen sulfite solution for reduction (n (aniline): n (sulfurous acid) Ammonium hydroxide) = 1:1.0 to 2.5), and then slowly adding sulfuric acid to the reduction reaction solution, and heating to 80 to 120 ° C for hydrolysis (n (aniline): n (sulfuric acid) = 1: 1.0 to 2.5), 0.5 to After 2h, cool to 30 ~ 70 ° C, neutralize liquid ammonia to pH = 2.0 ~ 3.5, add acetyl acetamide for condensation reaction, maintain the reaction temperature of 40 ~ 60 ° C, pH = 1.0 ~ 2.5, the reaction 0.5 ~ 2.0h Thereafter, the pH was adjusted to 3.0 to 5.0 to obtain a 1-phenyl-3-methyl-5-pyrazolone reaction solution, which was filtered, washed, and purified to give a product.

The existence of the process: the diazotization process usually adopts the batch method, and the continuous process is also relatively simple to directly enter the reactor reaction of hydrochloric acid, water, aniline and sodium nitrite solution, so that the reaction is not very uniform, the conversion rate of diazotization Both the selectivity and the selectivity are reduced, and the diazotization yield is generally below 95%. Therefore, the pyrazolone product obtained by the reaction is further reduced in yield, and the product contains a large amount of impurities. The mother liquor has high COD and mainly contains four kinds of salt components of sodium chloride, ammonium chloride, sodium sulfate and ammonium sulfate. It is difficult to separate and treat. After evaporation and concentration, 1 ton of product produces 4.5-7 tons of dangerous solid waste, hazardous waste. Large, low resource utilization.

Patent CN1365968A reports a method and apparatus for continuously preparing a primary aromatic amine diazonium salt. A mixed solution of a primary aromatic amine with sulfuric acid or hydrochloric acid is continuously fed into a tubular reactor together with a sodium nitrite solution.

Patent CN103664683A reports a continuous diazotization process for aromatic amines using a multi-stage tandem diazonium reactor.

Patent CN102078789 discloses a diazotized continuous tubular reactor in which a diazotization reaction raw material is separately stored in a plurality of liquid storage tanks, and then enters a mixer through a pipe and a flow controller, and each material is thoroughly mixed by a mixer and then introduced into a pipe. The reactor is fully reacted.

Patent CN1365968A mentions that the mixed solution of aromatic amine and sulfuric acid and the sodium nitrite solution enter the reactor at the same time, and the amount of sulfuric acid required for directly mixing the aniline with sulfuric acid to form a solution, and the mixed solution and sodium nitrite directly enter In the tubular reactor, according to the legend of the tubular reactor, the uniform mixing of the components is not enhanced, and the reaction may have unevenness, and the strong oxidizing property of sulfuric acid also increases the side reaction of diazotization.

The patent CN103664683A and the patent CN102078789 are three kinds of raw materials respectively added to the reactor for continuous reaction, and the three raw materials are difficult to be mixed uniformly. CN103664683A mentions that the solid raw material is added to the reactor, and the solid-liquid phase is continuously reacted, and the reaction effect is more difficult to ensure.

Summary of the invention

Therefore, the technical problem to be solved by the present invention is to develop a new continuous flow production process of pyrazolone with less side reactions and high yield of diazotization.

The technical proposal of the invention is a continuous flow cleaning production process of a pyrazolone series product,

(1) Aromatic amine and aqueous sulfuric acid are reacted for 0.5-2h to obtain an aromatic amine sulfate solution, the molar ratio of sulfuric acid to aromatic amine is 2.1-3; the aromatic amine sulfate solution and the sodium nitrite solution simultaneously enter the premixer, and are mixed. After entering the continuous flow reactor for diazotization, the diazonium salt is obtained; the molar ratio of sodium nitrite to aromatic amine is 1.01-1.5, the reaction temperature is 10-50 ° C, and the reaction residence time is 1-60 s;

(2) The produced diazonium salt is continuously added to the aqueous solution containing ammonium sulfite and the aqueous solution of ammonium hydrogen sulfite for reduction reaction, the reduction reaction temperature is 20-80 ° C, and the total reduction time is 1-4 hours;

(3) after the reduction reaction is completed, the sulfuric acid solution is added to carry out a hydrolysis reaction at 70-120 ° C, and the hydrolysis reaction time is 0.5-3 hours;

(4) After the hydrolysis reaction, the pH is controlled to between 2 and 5, and then condensation reaction is carried out with diethylamine at 40-70 ° C. After 1-3 hours, the reaction is cooled to 10-40 ° C, and dried by filtration to obtain pyrazolone. product;

(5) The filtrate obtained in the previous step is a mother liquor. After solvent extraction or decolorization of activated carbon, it is concentrated by evaporation, cooled in stages, and separated by crystallization to obtain ammonium sulfate and sodium sulfate.

In step (1), the molar ratio range is guaranteed to be slightly excess. The molar ratio of sodium nitrite to aromatic amine refers to the ratio of sodium nitrite to the aromatic amine in the previous reaction (the aromatic amine and sulfuric acid react to form aromatic amine sulfate). In the step of reacting an aromatic amine with an aqueous solution of sulfuric acid, the aromatic amine is not excessive and is an excess of sulfuric acid.

In the step (2), the aqueous ammonium sulfite solution and the aqueous ammonium hydrogen sulfite solution refer to the same aqueous solution. During the continuous addition, the feed rate is controlled according to the reaction temperature and the total reduction time.

The operation of the step (1) greatly reduces the side reaction of diazotization, and the conversion rate and selectivity are remarkably improved, the conversion rate can reach 99.9% or more, and the yield of diazotization reaches 99% or more.

According to the present invention, a pyridone series product continuous flow cleaning production process, preferably, the aromatic amine in the step (1) is selected from the group consisting of aniline, 4-methylaniline, 3-hydroxyaniline, 2-chloroaniline, 3 One of -chloroaniline, 4-chloroaniline, 2,5-dichloroaniline, 3-aminobenzenesulfonic acid, 4-aminobenzenesulfonic acid, and 2,5-dichloro-4-sulfonic acid aniline. The common point of these aromatic amines is that they are aromatic amines, all of which are aniline.

According to the continuous stream cleaning production process of the pyrazolone series of the present invention, it is preferred that the concentration of the aqueous sulfuric acid solution in the step (1) is from 10 to 50%.

According to the continuous stream cleaning production process of the pyrazolone series product according to the present invention, it is preferred that the concentration of the aqueous sodium nitrite solution in the step (1) is 20-40%. The action of sodium nitrite is a diazotization reaction with an aromatic amine.

According to the continuous stream cleaning production process of the pyrazolone series product according to the present invention, it is preferred that the manner of entering the premixer simultaneously in the step (1) is pumping. Preferably, in step (1), the molar ratio of sodium nitrite to aromatic amine is from 1.01 to 1.1.

Preferably, the amount of sulfuric acid added in step (3) relative to the amount of the aromatic amine is 1-4; and the amount of the diethylamine added in step (4) relative to the amount of the aromatic amine is 1-3. The amount of the aromatic amine substance herein is the amount of the substance of the initial aromatic amine.

According to the continuous stream cleaning production process of the pyrazolone series according to the present invention, it is preferred that the concentration of the sulfuric acid in the step (3) is 50-100%. The concentration of the sulfuric acid solution in step (1) and step (3) is different, and the solubility is different because the reaction is different.

According to the continuous stream cleaning production process of the pyrazolone series product according to the present invention, it is preferred that the amount of the ammonium sulfite and ammonium hydrogen sulfite added in the step (2) relative to the amount of the aromatic amine is 1- 4; the concentration of the aqueous ammonium sulfite solution is 20-60%, and the concentration of the aqueous ammonium hydrogen sulfite solution is 10-40%.

The action of ammonium sulfite and ammonium hydrogen sulfite aqueous solution is a necessary reducing agent for the reduction reaction.

The above aqueous solution concentrations are all mass concentrations.

According to the present invention, a pyridone series product continuous flow cleaning production process, preferably, the stepwise gradient cooling in step (5) is divided into two coolings; the first cooling is 1-5 hours cooling to 40- At 80 ° C, the second cooling is 1-6 h cooling to 0-40 ° C. The fractional cooling is mainly to separate ammonium sulfate and sodium sulfate. There are only two substances that only need to be cooled in two stages.

More preferably, the staged cooling temperature range is cooled to 50-70 ° C for the first cooling 2-5 h and cooled to 10-35 ° C for the second cooling 2-5 h.

According to the continuous stream cleaning production process of the pyrazolone series of the present invention, it is preferred that the organic solvent in the step (5) is one selected from the group consisting of benzenes, ethers and esters.

More preferably, the organic solvent is an ester. The aromatic nitrogen diazo sulphate is easily hydrolyzed under acidic conditions to form a by-product containing -OH, and an ester organic solvent is used to extract the hydroxy compound in the wastewater and improve the purity of the by-produced salt.

The benzene solvent is selected from the group consisting of benzene, toluene, ethylbenzene and the like. The ether solvent may be diethyl ether or the like, and the lipid solvent may be an ester such as methyl acetate or ethyl acetate.

The invention develops a new continuous flow production process of pyrazolone. The invention replaces hydrochloric acid with sulfuric acid as a diazotizing acid medium, and combines water and sulfuric acid into a certain concentration of dilute sulfuric acid, reacts with an aromatic amine to form an aromatic amine sulfate to form a uniform aqueous solution, and then mixes with a sodium nitrite solution through a premixer. After homogenization, it enters the continuous flow reactor for diazotization. Although a certain amount of water is added, the amount of sulfuric acid is greatly reduced, so that the amount of sulfuric acid is only slightly higher than the theoretical amount of the reaction. At the same time, the continuous flow reaction system is applied to the diazotization reaction of pyrazolone synthesis, and the problem of uniformity of reaction in the continuous flow reaction is enhanced, and the continuous, safe, efficient and stable production of the product is realized, and the purity and quality of the product are obtained. Significantly improved, compared with traditional batch processes and ordinary continuous reactions, it has reliable guarantees in terms of reaction uniformity, mass transfer, heat transfer enhancement, environmental protection and safety. The diazotization reaction by this process does not substantially produce nitrogen oxides, which greatly reduces the generation of side reactions, and the yield of the diazotization reaction is remarkably improved. The obtained diazonium salt is further reduced, hydrolyzed, neutralized, and condensed to obtain a pyrazolone product. Product quality and yield have improved. At the same time, in the production process of the product, a mother liquor containing only ammonium sulfate and sodium sulfate is obtained. The mother liquor can be treated to obtain two by-products of ammonium sulfate and sodium sulfate. The condensed water evaporated during the mother liquor treatment is returned to the previous reaction, so that no waste water and solid waste are produced in the production process, and clean production is realized.

The beneficial effects of the invention are:

The prior art adopts hydrochloric acid as a process for diazotizing a strong acid medium. The wastewater contains sodium chloride, ammonium chloride, sodium sulfate and ammonium sulfate. After treatment, 1 ton of product produces 4.5-7 tons of salt-containing solid waste. Waste is not convenient. The invention adopts sulfuric acid instead of the traditional hydrochloric acid to carry out the continuous flow diazotization reaction of the aromatic amine, and the dilute sulfuric acid solution is firstly reacted with the aromatic amine to form an aromatic amine sulfate solution, and then mixed with the sodium nitrite solution to uniformly enter the continuous flow reactor reaction. The whole process is continuous, safe and stable, and the product quality and yield are improved. The wastewater contains sodium sulfate and ammonium sulfate, which are treated to obtain by-products that meet the standards. No salt solid waste is produced, and the resources are rationally utilized.

Detailed ways

Example 1:

The clean production process of the pyrazolone series includes the following steps:

61.3 g of sulfuric acid was slowly added to a solution of 20% sulfuric acid under stirring and cooling in 245.2 g of water, and 23.3 g of aniline was further added dropwise, and stirred for 1 hour. The prepared aniline sulphate and 91.4 g of 20% sodium nitrite solution were respectively pumped into the premixer at a flow rate of 3.61:1 by mass, and then entered into the continuous flow reactor for diazotization reaction (n aniline: n sub- Sodium nitrate: n sulfuric acid = 1: 1.06: 2.5). The reaction temperature was controlled to 20 ° C by a reactor cooling system, and the reaction residence time was 50 s, and the mixture was continuously discharged to a reduction reactor. 200 g of an aqueous solution containing 49.5 g of ammonium hydrogen sulfite and 58 g of ammonium sulfite was added in advance to the reduction kettle. After the addition, the temperature was raised to 80 ° C, and the temperature was kept for 2 hours. 100 g of 60% sulfuric acid was added dropwise, and the temperature was raised to 90 ° C, and the temperature was kept for 2 hours. To 60 ° C, 164 g of 20% diethylamine was slowly added dropwise. After the completion of the dropwise addition, the mixture was further stirred for 2 hours, cooled to 25 ° C for filtration, and washed to obtain 40.2 g of a pale yellow pyrazolone product. The yield was 92.4% and the content was 99.8%. About 600 g of the mother liquid was added to 1.2 g of activated carbon, and the temperature was raised to 80 ° C, and the mixture was kept for 30 minutes, and then filtered to obtain 586.4 g of a mother liquid. The mother liquid was heated to 100 ° C, 300.6 g of water was distilled off, cooled to 80 ° C, crystallized and separated, and dried to obtain 70.5 g of ammonium sulfate. The appearance was white, and the amount of N was 20.7%, which was in line with agricultural grade standards. Sodium hydroxide was added to the separated filtrate to adjust the pH to 7.2, the negative pressure was raised to 60 ° C, 45.6 g of distilled water and NH 317.3 g were distilled off, and the kettle liquid was cooled to 15 ° C, separated by crystallization, and dried to obtain 64.1 g of sodium sulfate, the content was 97.2%. . After heating to 110 ° C steamed water, steaming out about 300 g of water, cooled to 50 ° C filtered, dried to obtain ammonium sulfate, the appearance of white, content 21.7% (based on nitrogen content). The filtrate was added with 8 g of sodium hydroxide to adjust the pH, and at the same time, vacuum distillation, evaporation and condensation to obtain an ammonia water recovery jacket obtained by water absorption with the tail gas was used in the reaction of synthesizing pyrazolone in the previous stage, and the kettle liquid was cooled to 0 ° C, and filtered to obtain sodium sulfate.

Example 2:

73.5 g of sulfuric acid was slowly added to a 30% sulfuric acid solution under stirring and cooling in 171.5 g of water, and 23.3 g of aniline was further added dropwise, and stirred for 1 hour. The prepared aniline sulphate and 94.9 g of 20% sodium nitrite solution were respectively pumped into the premixer at a flow rate of 2.83:1 by mass ratio, and then entered into the continuous flow reactor for diazotization reaction (n aniline: n sub- Sodium nitrate: n sulfuric acid = 1:1.1:3). The reaction temperature was controlled to 20 ° C by a reactor cooling system, and the reaction residence time was 50 s, and the mixture was continuously discharged to a reduction reactor. The following procedure was the same as in Example 1 to obtain 40.1 g of the pyrazolone product, the yield was 92.2%, and the content was 99.8%.

Example 3:

Under stirring and cooling in 206.0 g of water, 51.5 g of sulfuric acid was slowly added to prepare a 20% sulfuric acid solution, and then 23.3 g of aniline was added dropwise, and stirred for 1 hour. The prepared aniline sulphate and 87.1 g of 20% sodium nitrite solution were separately pumped into the premixer at a flow rate of 3.22:1 by mass, and then entered into the continuous flow reactor for diazotization (n aniline: n sub- Sodium nitrate: n sulfuric acid = 1: 1.01: 2.1). The reaction temperature was controlled to 20 ° C by a reactor cooling system, and the reaction residence time was 50 s, and the mixture was continuously discharged to a reduction reactor. The following procedure was the same as in Example 1 to obtain 40.1 g of the pyrazolone product, the yield was 92.2%, and the content was 99.8%.

Example 4:

61.3 g of sulfuric acid was slowly added to a solution of 20% sulfuric acid under stirring and cooling in 245.2 g of water, and 23.3 g of aniline was further added dropwise, and stirred for 1 hour. The prepared aniline sulphate and 91.4 g of 20% sodium nitrite solution were respectively pumped into the premixer at a flow rate of 3.61:1 by mass, and then entered into the continuous flow reactor for diazotization reaction (n aniline: n sub- Sodium nitrate: n sulfuric acid = 1: 1.06: 2.5). The reaction temperature was controlled to 40 ° C by a reactor cooling system, and the reaction residence time was 20 s, and the mixture was continuously discharged to a reduction reactor. The following operation was the same as in Example 1 to obtain 39.9 g of a pyrazolone product, the yield was 91.7%, and the content was 99.8%.

Comparative example 1:

49 g of sulfuric acid was slowly added to a 20% sulfuric acid solution under stirring and cooling in 196 g of water, and then 23.3 g of aniline was added dropwise, and stirred for 1 hour. The prepared aniline sulphate and 86.2 g of 20% sodium nitrite solution were respectively pumped into the premixer at a flow rate of 3.11:1 mass ratio, and then entered into the continuous flow reactor for diazotization reaction (n aniline: n sub- Sodium nitrate: n sulfuric acid = 1:1.0:2.0). The reaction temperature was controlled to 40 ° C by a reactor cooling system, and the reaction residence time was 20 s, and the mixture was continuously discharged to a reduction reactor. The following operation was the same as in Example 1 to obtain 35.6 g of the pyrazolone product, the yield was 81.8%, and the content was 99.6%.

The invention has been disclosed in the above preferred embodiments, and is not intended to limit the invention, and the technical solutions obtained by equivalent substitution or equivalent transformation are all within the scope of the invention.

Claims

A continuous flow cleaning production process of pyrazolone series products, characterized in that:

(1) Aromatic amine and aqueous sulfuric acid are reacted for 0.5-2h to obtain an aromatic amine sulfate solution, the molar ratio of sulfuric acid to aromatic amine is 2.1-3; the aromatic amine sulfate solution and the sodium nitrite solution simultaneously enter the premixer, and are mixed. After entering the continuous flow reactor for diazotization, the diazonium salt is obtained; the molar ratio of sodium nitrite to aromatic amine is 1.01-1.5, the reaction temperature is 10-50 ° C, and the reaction residence time is 1-60 s;

(2) The produced diazonium salt is continuously added to the aqueous solution containing ammonium sulfite and the aqueous solution of ammonium hydrogen sulfite for reduction reaction, the reduction reaction temperature is 20-80 ° C, and the total reduction time is 1-4 hours;

(3) after the reduction reaction is completed, the sulfuric acid solution is added to carry out a hydrolysis reaction at 70-120 ° C, and the hydrolysis reaction time is 0.5-3 hours;

(4) After the hydrolysis reaction, the pH is controlled to between 2 and 5, and then condensation reaction is carried out with diethylamine at 40-70 ° C. After 1-3 hours, the reaction is cooled to 10-40 ° C, and dried by filtration to obtain pyrazolone. product;

(5) The filtrate obtained in the previous step is a mother liquor. After solvent extraction or decolorization of activated carbon, it is concentrated by evaporation, cooled in stages, and separated by crystallization to obtain ammonium sulfate and sodium sulfate.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the aromatic amine in the step (1) is selected from the group consisting of aniline, 4-methylaniline, 3-hydroxyaniline and 2-chloro One of aniline, 3-chloroaniline, 4-chloroaniline, 2,5-dichloroaniline, 3-aminobenzenesulfonic acid, 4-aminobenzenesulfonic acid, and 2,5-dichloro-4-sulfonic acid aniline .
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the concentration of the aqueous sulfuric acid solution in the step (1) is 10-50%; and the sodium nitrite in the step (1) The concentration of the aqueous solution is 20-40%.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the step of entering the premixer at the same time as the step (1) is pumping; in the step (1), sodium nitrite The molar ratio to the aromatic amine is from 1.01 to 1.1.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein in the step (2), the amount of ammonium sulfite and ammonium hydrogen sulfite added is relative to the amount of the aromatic amine. It is 1-4; the concentration of the aqueous ammonium sulfite solution is 20-60%, and the concentration of the aqueous ammonium hydrogen sulfite solution is 10-40%.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the amount of sulfuric acid added in step (3) is 1-4 relative to the amount of aromatic amine; step (4) double B The amount of amine added is 1-3 relative to the amount of the aromatic amine.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the concentration of the sulfuric acid solution in the step (3) is 50-100% concentration.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the stepwise gradient cooling in the step (5) is performed in two stages; the first cooling is 1-5 hours cooling. At 40-80 ° C, the second cooling is 1-6 h cooling to 0-40 ° C.
The continuous stream cleaning production process of a pyrazolone series product according to claim 1, wherein the organic solvent in the step (5) is one selected from the group consisting of benzenes, ethers and esters.
The continuous stream cleaning production process of a pyrazolone series product according to claim 9, wherein the organic solvent in the step (5) is selected from the group consisting of ester solvents.