CN107987023A - A kind of method of solid acid catalysis synthesis 4-Hydroxyphenyl hydantoin - Google Patents

Abstract

The present invention relates to a kind of method of solid acid catalyzed synthesis p-hydroxyphenylhydantoin, characterized in that it is synthesized in the presence of composite solid superacid catalyst SO ₄ ^{2 -} /ZrO ₂ /TiO ₂ or SO ₄ ^{2 -} /ZrO ₂ /SiO ₂ p-Hydroxybenzone. The technical scheme adopted comprises three parts: the synthesis of p-hydroxymandelic acid, the synthesis of N-carbamoyl-4-hydroxyphenylglycine and the synthesis of p-hydroxyphenylhydantoin. The invention not only solves the pollution problem of high-concentration phenol-containing waste acid and the corrosion problem of production equipment, but also can effectively control the generation of by-products of o-hydroxyphenylhydantoin, thereby improving the synthesis yield of p-hydroxyphenylhydantoin.

Description

A kind of method for solid acid catalyzed synthesis of p-hydroxyphenylhydantoin

technical field

The invention relates to a method for synthesizing p-hydroxyphenylhydantoin by solid acid catalysis, in particular to synthesizing p-hydroxyphenylhydantoin in the presence of composite solid superacid catalyst SO ₄ ^2- /ZrO ₂ /TiO ₂ or SO ₄ ^2- /ZrO ₂ /SiO ₂ The method for hydroxyphenylhydantoin belongs to the field of medicine and chemical industry.

Background technique

p-Hydroxyphenylhydantoin (English name 4-Hydroxyphenyl hydantoin), molecular formula C ₉ H ₈ N ₂ O ₃ , molecular weight 192.2, melting point greater than 260°C, insoluble in water and alcohol solvents. P-Hydroxydiphenylhydantoin is an important raw material for the production of lactam antibiotics such as amoxicillin and amoxicillin cephalosporin. P-hydroxyphenylhydantoin is industrially produced by the condensation reaction of glyoxylic acid, phenol and urea under strongly acidic conditions. European Patent EP0001319 (1979-04-04) and U.S. Patent US4230869 (1980-10-28) disclosed its synthetic method in detail, and based on the main raw material glyoxylic acid, the synthetic yield of p-hydroxyphenylhydantoin can reach 65.5%. In the patent, the main reason for the low synthesis yield is attributed to the generation of a large amount of o-hydroxyphenylhydantoin. Chinese patent CN101591297 (2009-12-02) discloses a synthesis technology of p-hydroxyphenylhydantoin, the operation conditions are refined, and the synthesis yield is 65%. Add glyoxylic acid solution dropwise at -80°C. After the dropwise addition, keep it warm for a long time to react, then cool, separate and precipitate the formed p-hydroxyphenylhydantoin, wash with water, and wash with methanol to obtain the product.

China has built a p-hydroxyphenylhydantoin production plant with an annual output of 10,000 tons, with a production capacity of more than 20,000 tons. At present, the molar yield of p-hydroxyphenylhydantoin in industrial production is 60%-65% in terms of glyoxylic acid. In the past ten years, scientific and technical personnel have carried out a lot of technical development work, and the product quality of p-hydroxyphenylhydantoin has been continuously improved, but the synthesis yield has not been significantly improved. Only by screening out specific reaction catalysts can the production yield of p-hydroxyphenylhydantoin be further improved. With the increasingly stringent environmental protection regulations and strict environmental protection supervision, the waste residue and waste acid produced in the production process of p-hydroxyphenylhydantoin have a high cost of treatment, and there is a risk of secondary pollution. It is urgent to improve the production process to increase the synthesis yield, from Reduce the generation of waste acid and reduce the corrosion of production equipment at the source.

Korean patent KR930002277 (1993-03-27) discloses a method for synthesizing p-hydroxyphenylhydantoin by using strongly acidic ion-exchange resin instead of liquid inorganic acid, but there are problems that the ion-exchange resin is easily polluted and consumed too much. The solid acid catalyst can improve the superacid condition for the reaction surface, stabilize the carbonium ions adsorbed on the surface, and be easy to separate, remove and recycle after the catalytic reaction, and can greatly reduce the corrosion of production equipment. The research and development of solid acid catalysts has received extensive attention in recent years, but there has been no report on its application in the synthesis of p-hydroxyphenylhydantoin.

Contents of the invention

The purpose of the present invention is to provide a method for the synthesis of p-hydroxyphenylhydantoin by solid acid catalysis, especially in the presence of composite solid superacid catalyst SO ₄ ^2- /ZrO ₂ /TiO ₂ or SO ₄ ^2- /ZrO ₂ /SiO ₂ The method for synthesizing p-hydroxyphenylhydantoin is to improve the synthesis yield of p-hydroxyphenylhydantoin, eliminate the environmental pollution caused by a large amount of waste acid and greatly reduce the corrosion of production equipment.

The reaction mechanism for the synthesis of p-hydroxyphenylhydantoin from glyoxylic acid, phenol and urea is relatively complicated. The inventor agrees with the point of view proposed in the British patent GB2012756 (1979-08-01), that is, the formation of p-hydroxyphenylhydantoin is divided into three parts. Firstly, glyoxylic acid and phenol react to generate p-hydroxymandelic acid, then an amino group in the urea molecule condenses with a hydroxyl group in the p-hydroxymandelic acid molecule to generate N-carbamoyl-4-hydroxyphenylglycine, and finally It is the ring formation of N-carbamoyl-4-hydroxyphenylglycine molecules to generate p-hydroxyphenylhydantoin.

According to the inventor's long-term experience in the development of downstream products of glyoxylic acid, the reaction of glyoxylic acid and phenol to generate p-hydroxymandelic acid can be carried out under alkaline and acidic conditions. The ratio rises rapidly; the reaction between p-hydroxymandelic acid and urea to generate N-carbamoyl-4-hydroxyphenylglycine needs to be carried out under strong acidic conditions or the presence of a catalyst, and the reaction speed is very slow when the reaction temperature is less than 70°C; N-amino The ring formation of formyl-4-hydroxyphenylglycine to generate p-hydroxyphenylhydantoin can be carried out under both alkaline and acidic conditions, and the reaction speed is very slow when the reaction temperature is lower than 70°C. The reaction of p-hydroxymandelic acid and urea to generate N-carbamoyl-4-hydroxyphenylglycine is the speed and yield control step of synthesizing p-hydroxyphenylhydantoin, which usually requires the reaction solution to have high acidity and high temperature reaction conditions, and adopts Solid acid catalysts do not require harsh reaction conditions of high acidity.

The method for the solid acid catalyzed synthesis of p-hydroxyphenylhydantoin of the present invention comprises three parts: the synthesis of p-hydroxymandelic acid, the synthesis of N-carbamoyl-4-hydroxyphenylglycine and the synthesis of p-hydroxyphenylhydantoin. The specific steps adopted are:

(1) Add deionized water, phenol, urea and composite solid superacid catalyst (calculated as ZrO ₂ ) sequentially into a glass reactor equipped with an electric stirring device, a thermometer, and a constant pressure feeder, and add Glyoxylic acid solution, control the molar ratio of raw materials: glyoxylic acid: phenol: urea: catalyst: water = 1: 1.0-1.5: 1.5-2: 0.01-0.1: 15-30;

(2) When the reaction solution is heated to 50-60°C, add the glyoxylic acid aqueous solution dropwise under stirring, and the dropwise addition is completed within 12-16 hours, and the heat preservation reaction is carried out for 1-2 hours to generate p-hydroxymandelic acid solution;

(3) Heat the reaction solution to 85-95°C within 1-2 hours, and keep it warm for 4-8 hours. When a white precipitate appears in the reaction solution, filter and separate the composite solid superacid catalyst to generate N-carbamoyl-4 - hydroxyphenylglycine solution;

(4) Use sodium hydroxide solution to adjust the pH of the reaction solution to be 7.5-8.5, and keep it warm at 85-95° C. for 2-4 hours, and white precipitates are continuously precipitated to generate a p-hydroxyphenylhydantoin solution;

(5) Cool the reaction solution to 20-30°C, a large amount of p-hydroxyphenylhydantoin crystals precipitate, vacuum filter the precipitated white crystals, wash with deionized water until the crystals are neutral and loose, and dry to obtain p-hydroxyphenylhydantoin products , the content is 98.5%-99.3%, based on the converted glyoxylic acid, the molar yield is 62.5%-64.3%.

Composite solid superacid catalyst preparation has adopted the method that dipping method and sol-gel method combine among the present invention, and the technical scheme that takes and concrete steps are:

(1) Add 2 mol/L ammonia water to 2 mol/L zirconyl sulfate aqueous solution to pH 8-9 of the solution, filter and separate the formed Zr(OH) ₄ precipitate, wash the precipitate with deionized water until the washing water no longer contains sulfate radicals ions; add the precipitate to 2mol/L oxalic acid aqueous solution, stir at 60-70°C until completely peptized; evaporate and concentrate the nano-Zr(OH) ₄ hydrosol at 90-100°C to form a xerogel, and then dry it at 105 Dry at ℃, and further burn at 500-600℃ for 0.5-2h, the oxalic acid peptizer is decomposed to form nano _ZrO2 particles;

(2) Stir and impregnate nano-ZrO ₂ particles in 2-4mol/L H ₂ SO ₄ solution for 8-12 hours, filter and separate the SO ₄ ^2- /ZrO ₂ precipitate, then dry at 105°C, and further dry at 500-600 Burn at ℃ for 0.5-2h to obtain SO ₄ ^2- /ZrO ₂ solid superacid catalyst;

(3) Add the SO ₄ ^2- /ZrO ₂ solid superacid catalyst into the absolute ethanol solution of tetrabutyl titanate or tetraethyl orthosilicate for immersion, and slowly add deionized water dropwise under stirring to make tetratitanate The nano-oxide sol formed by the hydrolysis of butyl ester or ethyl tetrasilicate is dispersed and coated with SO ₄ ^2- /ZrO ₂ , and the molar ratio of raw materials is controlled as follows: Zr:Ti(Si):ethanol:water=1:1.5-2 :20-40:6-10;

(4) After the sol continues to stir for 1-2h, SO ₄ ^2- /ZrO ₂ /TiO ₂ or SO ₄ ^2- /ZrO ₂ /SiO ₂ gel is formed, and the gel is aged in the air for 12-24h, organic solvent After volatilization, dry gel is formed, and the gel is dried at 105°C for 0.5-2h and crushed to obtain SO ₄ ^2- /ZrO ₂ /TiO ₂ or SO ₄ ^2- /ZrO ₂ /SiO ₂ composite solid superacid catalyst.

The zirconia solid superacid catalyst SO ₄ ^2- /ZrO ₂ treated with sulfuric acid has strong acidity, and its acidity is equivalent to that of concentrated sulfuric acid. SO ₄ ^2- /ZrO ₂ solid superacid catalyst has the advantages of high acid strength, easy separation from products, environmental friendliness, high reactivity and selectivity for acid-catalyzed reactions, etc., but its specific surface area is small and acidic is not easy Disadvantages such as regulation and easy inactivation limit their practical applications. Using nano-TiO ₂ or nano-SiO ₂ with high specific surface area to disperse and coat SO ₄ ^2- /ZrO ₂ solid superacid catalyst can obtain a large specific surface area and long-lasting composite solid superacid catalyst SO ₄ ^2- /ZrO ₂ /TiO ₂ or SO ₄ ²⁻ /ZrO ₂ /SiO ₂ .

The high or low concentration of H ₂ SO ₄ impregnated with ZrO ₂ will reduce the catalytic activity. When the concentration of H ₂ SO ₄ is 2-4mol/L, the catalytic effect of solid superacid is the best. The reason is that when the concentration is high, H ₂ SO ₄ covers the acid center, which reduces the catalytic activity, and when the concentration of H ₂ SO ₄ is too low, the acid strength and acid density on the surface of SO ₄ ^2- /ZrO ₂ are not enough, which makes the catalytic activity Reduced activity. During the SO ₄ ^2- /ZrO ₂ burning process, a small amount of SO ₄ ^2- on the surface of the solid superacid will be lost in the form of SO ₂ or SO ₃ , which will reduce the number of acid sites of the solid superacid. The roasting condition is 500-600 It is better to burn at ℃ for 0.5-2h. The SO ₄ ^2- /ZrO ₂ solid superacid catalyst is dispersed and coated with nano-TiO ₂ or nano-SiO ₂ with a high specific surface area, so that the active component SO ₄ ^2- /ZrO ₂ is uniformly dispersed, and the SO ₄ ^2- /ZrO 2 is improved. ZrO ₂ catalytic performance and improved service life.

Among the present invention, the raw material glyoxylic acid is 40% or 50% industrial product, and the glyoxal impurity content therein should be controlled to be less than 1.0%; Butyl ester, zirconyl sulfate and absolute ethanol are all chemically pure reagents.

In the present invention, the determination of p-hydroxyphenylhydantoin content adopts liquid chromatography, and Shimadzu LC-10 liquid chromatograph is used.

Chromatographic column: Kromasil-C18 (5μm, 250 mm×4.6mm); mobile phase: acetonitrile: water: tetrahydrofuran: glacial acetic acid=70:30:0.5:0.5 (volume ratio); flow rate: 1mL/min; detection wavelength: 254nm ; Column temperature: 35°C.

Advantage of the present invention and beneficial effect are embodied in:

(1) Synthesis of p-hydroxyphenylhydantoin over the catalysis of composite solid superacid solves the pollution problem of high-concentration phenol-containing waste acid and the corrosion problem of production equipment;

(2) The step-by-step synthesis of p-hydroxyphenylhydantoin in the presence of a composite solid superacid catalyst can effectively control the formation of by-products of o-hydroxyphenylhydantoin and increase the synthesis yield of p-hydroxyphenylhydantoin.

Detailed ways

The present invention is realized in the following manner, which will be described in detail below in conjunction with the embodiments:

Example 1

Add about 100 mL of 2 mol/L ammonia water to 50 mL of 2 mol/L zirconyl sulfate aqueous solution to make the solution pH 8-9, filter and separate the formed Zr(OH) ₄ precipitate, and wash the precipitate with deionized water until the washing water no longer contains sulfate groups ions; add the precipitate to 30mL of 2mol/L oxalic acid aqueous solution, stir at 60-70°C until completely peptized; evaporate and concentrate the nano-Zr(OH) ₄ hydrosol at 90-100°C to form a xerogel, and then Drying at 105°C, further burning at 500-600°C for 0.5-2h, the oxalic acid peptizer is decomposed to form 12.3g of nano ZrO ₂ particles. Stir and impregnate the prepared nano ZrO ₂ particles in 30mL of 2mol/L H ₂ SO ₄ solution for 12h, filter and separate the SO ₄ ^2- /ZrO ₂ precipitate, then dry at 105°C, and further burn at 500-600°C After 0.5h, 13.8g of SO ₄ ^2- /ZrO ₂ solid superacid catalyst was obtained.

SO ₄ ^2- / _ZrO 6.9 g of solid superacid catalyst was added to a mixed solution of 34.0 g tetrabutyl titanate and 92 g of absolute ethanol for impregnation, and 18 g of deionized water was slowly added dropwise under stirring to make tetrabutyl titanate The nano-oxide sol formed by ester hydrolysis was dispersed and coated with SO ₄ ^2- /ZrO ₂ , and after stirring for 1 hour, SO ₄ ^2- /ZrO ₂ /TiO ₂ gel was formed. The gel was aged in air for 24 hours, and the organic After the solvent evaporated, a dry gel was formed. The gel was dried at 105° C. for 2 hours and crushed to obtain 14.8 g of SO ₄ ^{2 −} /ZrO ₂ /TiO ₂ composite solid superacid catalyst.

Example 2

SO ₄ prepared in Example 1 ^2- / _ZrO Solid superacid catalyst 6.9g is added to the mixed solution of 20.8g orthosilicate and 92g dehydrated alcohol for impregnation, slowly dripping deionized water 18g under stirring , to disperse and coat SO ₄ ^2- /ZrO ₂ with the nano-oxide sol formed by hydrolysis of tetraethyl orthosilicate, continue to stir for 2 hours and place it to form SO ₄ ^2- /ZrO ₂ /SiO ₂ gel. After medium aging for 24 hours, the organic solvent volatilized to form a dry gel, which was dried at 105°C for 2 hours and pulverized to obtain 12.8 g of SO ₄ ^2- /ZrO ₂ /SiO ₂ composite solid superacid catalyst.

Example 3

270mL of deionized water, 47g of phenol, 60g of urea and 14.8g of SO ₄ ^2- /ZrO ₂ /TiO ₂ composite solid superacid catalyst were successively added into a glass reactor equipped with an electric stirring device, a thermometer, and a constant pressure feeder. When the reaction solution was heated to 50-60°C, 92.5 g of glyoxylic acid aqueous solution with a concentration of 40% by mass was added dropwise under stirring, and the addition was completed within 12 hours, and the reaction was kept for 2 hours to generate p-hydroxymandelic acid solution. The temperature of the reaction solution is raised to 85-95°C within 2 hours, and the temperature is maintained for 4 hours. When white precipitate appears in the reaction solution, the solid superacid catalyst is separated by filtration to generate N-carbamoyl-4-hydroxyphenylglycine solution. Adjust the pH of the reaction solution to 7.5-8.5 with 20% sodium hydroxide solution by mass percent, and keep the reaction at 85-95°C for 2 hours. White precipitates are continuously precipitated to form p-hydroxyphenylhydantoin solution. Cool the reaction solution to 20-30°C, a large amount of p-hydroxyphenylhydantoin crystals precipitated, vacuum filtered the precipitated white crystals, washed with deionized water until the crystals were neutral and loose, dried to obtain 61.7g of p-hydroxyphenylhydantoin product, The content is 99.3%, and the molar yield in terms of purified glyoxylic acid is 64.3%.

Example 4

270mL of deionized water, 47g of phenol, 60g of urea and 12.8g of SO ₄ ^2- /ZrO ₂ /SiO ₂ composite solid superacid catalyst were sequentially added into a glass reactor equipped with an electric stirring device, a thermometer, and a constant pressure feeder. When the reaction solution was heated to 60°C, 92.5 g of glyoxylic acid aqueous solution with a mass percent concentration of 40% was added dropwise under stirring, and the addition was completed within 16 hours, and the reaction was kept for 4 hours to generate p-hydroxymandelic acid solution. The temperature of the reaction solution is raised to 85-95°C within 2 hours, and the temperature is maintained for 4 hours. When white precipitate appears in the reaction solution, the solid superacid catalyst is separated by filtration to generate N-carbamoyl-4-hydroxyphenylglycine solution. Adjust the pH of the reaction solution to 7.5-8.5 with 20% sodium hydroxide solution by mass percent, and keep the reaction at 85-95°C for 2 hours. White precipitates are continuously precipitated to form p-hydroxyphenylhydantoin solution. The reaction solution was cooled to 20-30°C, a large amount of p-hydroxyphenylhydantoin crystals precipitated, and the precipitated white crystals were vacuum filtered, washed with deionized water until the crystals were neutral and loose, and dried to obtain 59.9 g of p-hydroxyphenylhydantoin product. The content is 99.1%, and the molar yield in terms of purified glyoxylic acid is 62.5%.

Claims (2)

1. the present invention relates to a kind of method of solid acid catalysis synthesis 4-Hydroxyphenyl hydantoin, it is characterized in that in complex solid superacid Catalyst SO₄ ^2-/ZrO₂/TiO₂Or SO₄ ^2-/ZrO₂/SiO₂In the presence of synthesize 4-Hydroxyphenyl hydantoin, the technical solution of use includes The synthesis of parahydroxymandelic acid, the synthesis of N- carbamyl -4- hydroxyphenylglycines, 4-Hydroxyphenyl hydantoin synthesis three parts, specifically Step is：

(1) sequentially added in the glass reactor for being configured with electric mixing device, thermometer, constant pressure addition device deionized water, Phenol, urea and composite solid catalyst for production of superstrong（With ZrO₂Meter）, glyoxylic acid solution is added in constant pressure addition device, control is former Expect that molar ratio is：Glyoxalic acid：Phenol：Urea：Catalyst：Water=1：1.0-1.5：1.5-2：0.01-0.1：15-30；

(2) when reaction solution being heated to 50-60 DEG C, glyoxalic acid solution is added dropwise under agitation, is added dropwise in 12-16h, protects Temperature reaction 1-2h, generates parahydroxymandelic acid solution；

(3) reaction solution is warming up to 85-95 DEG C, insulation reaction 4-8h in 1-2 h, when occurring white precipitate in reaction solution, Composite solid catalyst for production of superstrong is separated by filtration, generates N- carbamyl -4- hydroxyphenylglycine solution；

(4) it is 7.5-8.5 with the pH of sodium hydroxide solution adjustment reaction solution, the insulation reaction 2-4h at 85-95 DEG C, constantly has white Color Precipitation, generates 4-Hydroxyphenyl hydantoin solution；

(5) reaction solution is cooled to 20-30 DEG C, there are a large amount of 4-Hydroxyphenyl hydantoin crystallizations to separate out, the white knot that vacuum filter separates out Crystalline substance, is washed with deionized neutral and loose to crystallization, is dried to obtain 4-Hydroxyphenyl hydantoin product, content 98.5%-99.3%, In terms of glyoxalic acid after pure, molar yield 62.5%-64.3%.

2. the method for solid acid catalysis synthesis 4-Hydroxyphenyl hydantoin according to claim 1, it is characterized in that complex solid surpasses Strong acid catalyst prepares and employs the method that infusion process and sol-gel process are combined, the technical solution and specific steps taken For：

(1) ammonium hydroxide of 2mol/L is added into the zirconium oxysulfate aqueous solution of 2mol/L to pH value of solution 8-9, is separated by filtration the Zr to be formed (OH)₄Precipitation, is cleaned to be precipitated in wash water with deionized water and no longer contains sulfate ion；The oxalic acid for adding 2mol/L will be precipitated In aqueous solution, stirred at 60-70 DEG C to complete peptization；By nanometer Zr (OH)₄The hydrosol is concentrated by evaporation shape at 90-100 DEG C Into xerogel, then dried at 105 DEG C, further the calcination 0.5-2h at 500-600 DEG C, oxalic acid peptizing agent is formed after decomposing Nanometer ZrO₂Particle；

(2) by nanometer ZrO₂H of the particle in 2-4mol/L₂SO₄Stirring dipping 8-12h, is separated by filtration SO in solution₄ ^2-/ZrO₂It is heavy Form sediment, then dry at 105 DEG C, further the calcination 0.5-2h at 500-600 DEG C, obtains SO₄ ^2-/ZrO₂Solid super-strong acid is urged Agent；

(3) by SO₄ ^2-/ZrO₂Solid super acid catalyst is added to the ethanol solution of butyl titanate or ethyl orthosilicate Middle dipping, is slowly added dropwise deionized water under agitation, the nano-oxide for forming butyl titanate or teos hydrolysis Colloidal dispersion and cladding SO₄ ^2-/ZrO₂, control the raw material molar ratio to be：Zr：Ti(Si)：Ethanol：Water=1：1.5-2：20-40： 6-10；

(4) colloidal sol continues to form SO after stirring 1-2h₄ ^2-/ZrO₂/TiO₂Or SO₄ ^2-/ZrO₂/SiO₂Gel, by gel in atmosphere 12-24h is placed in ageing, and xerogel is formed after organic solvent volatilization, by gel at 105 DEG C dry 0.5-2h, crush, obtain SO₄ ^2-/ZrO₂/TiO₂Or SO₄ ^2-/ZrO₂/SiO₂Composite solid catalyst for production of superstrong.