Preparation method of p-hydroxyphenyl hydantoin

Abstract

The invention discloses a preparation method of p-hydroxyphenyl hydantoin, which belongs to the technical field of preparation of medical intermediates, and particularly comprises the following steps: by taking glyoxylic acid, phenol and urea as raw materials, preparing p-hydroxyphenyl hydantoin through condensation according to a certain molar ratio under an acidic condition, and then carrying out simple post-treatment to obtain a pure product of p-hydroxyphenyl hydantoin. The p-hydroxyphenyl hydantoin prepared by the method is high in reaction selectivity, simple in feed liquid post-treatment, low in three-waste generation amount and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical intermediate preparation, and specifically relates to a preparation method of p-hydroxyphenylhydantoin. Background Art

[0002] p-Hydroxyphenylhydantoin is an intermediate for the production of β-lactam antibiotics such as ampicillin and cefalexin, and can only be obtained by artificial synthesis. At present, p-hydroxyphenylhydantoin is mainly prepared by the condensation of glyoxylic acid, phenol and urea under acidic conditions. The industrial production yield of p-hydroxyphenylhydantoin at home and abroad is 60% - 65%.

[0003] In recent years, there have been many reports on the improvement of p-hydroxyphenylhydantoin synthesis technology in China. The improvement work mainly focuses on the optimization of synthesis conditions such as the ratio of reaction raw materials and the control of reaction temperature. However, these changes are not sufficient to have sufficient advantages for industrial production. Patent CN106083629A reports the optimization of the p-hydroxyphenylhydantoin synthesis process by controlling the dropping time of glyoxylic acid and variable-temperature reaction, but does not solve the problem of large amounts of three wastes generated, which is not conducive to industrial production; Patent CN101973941 reports the inhibition of some side reactions by adding aminosulfonic acid to the reaction system, and the product separation yield is 62.7%, but more side reactions and waste salts are introduced after the additional addition of aminosulfonic acid; Patent CN110330460A reports a method using solid acid as a catalyst to prepare p-hydroxyphenylhydantoin from glyoxylic acid, phenol and urea, and the synthesis yield is basically between 60% and 70%, which improves the yield, but the solid acid used has a high synthesis cost and a short service life, which is not conducive to actual industrial production. The main problems existing in the current production of p-hydroxyphenylhydantoin are low yield, a large amount of waste water and solid waste, which increase the production waste treatment cost and environmental pollution pressure. Summary of the Invention

[0004] To solve the above problems, the purpose of the present invention is to provide a preparation method of p-hydroxyphenylhydantoin.

[0005] To achieve the above purpose, the present invention is realized through the following technical solutions: A preparation method of p-hydroxyphenylhydantoin, comprising the following steps: 1) Add phenol and urea to deionized water, heat to 60°C and stir to dissolve to obtain a mixed solution. Take 40% - 80% of the total mass of the mixed solution and add it to the reactor. Introduce hydrogen chloride into it, then add p-hydroxyphenylhydantoin crystals, stir and heat to 70°C, and then pump the 50% mass concentration aqueous glyoxylic acid solution into the reactor at a speed of 0.25 g / min; 2) After adding the glyoxylic acid aqueous solution to 20% - 60% of the total mass, the remaining part of the mixed solution in step 1) is added dropwise to the reactor. After the dropwise addition of the glyoxylic acid aqueous solution and the mixed solution is completed, it is aged at 70 °C for 1 h to obtain a reaction solution; 3) The reaction solution obtained in step 2) is heated to 90 °C, stirred for 1 h, then cooled to 60 - 80 °C, centrifuged while maintaining the temperature, and the obtained filter cake is rinsed 3 - 5 times with deionized water, and then dried by blowing air at 80 - 90 °C for 5 h to obtain 4 - Hydroxy - 5 - imidazolidinone.

[0006] In step 1), the molar ratio of phenol to urea is 1:0.5 - 2.0.

[0007] In step 1), the amount of deionized water added is 0.9 - 1 times the total mass of phenol and urea.

[0008] In step 1), the molar ratio of hydrogen chloride to phenol is 0.6 - 1.2:1.

[0009] In step 1), the addition amount of 4 - Hydroxy - 5 - imidazolidinone crystals is 2% - 8% of the total mass of phenol, urea, deionized water and 50% glyoxylic acid aqueous solution.

[0010] In step 1), the molar ratio of glyoxylic acid to phenol in the 50% glyoxylic acid aqueous solution is 1:1 - 1.5.

[0011] Preferably, in step 1), the molar ratio of phenol to urea is 1:1.

[0012] Preferably, in step 1), the molar ratio of hydrogen chloride to phenol is 0.83:1.

[0013] Preferably, in step 1), the molar ratio of glyoxylic acid to phenol in the 50% glyoxylic acid aqueous solution is 1:1.2.

[0014] Preferably, in step 1), the addition amount of 4 - Hydroxy - 5 - imidazolidinone crystals is 3% - 6% of the total mass of phenol, urea, deionized water and 50% glyoxylic acid aqueous solution.

[0015] Preferably, in step 1), 50% - 70% of the total mass of the mixed solution is taken, and hydrogen chloride is introduced into it.

[0016] Preferably, in step 3), the temperature is cooled to 70 - 75 °C.

[0017] The synthesis route of 4 - Hydroxy - 5 - imidazolidinone is , where the main impurities in the synthesis of 4 - Hydroxy - 5 - imidazolidinone and their corresponding structures are shown in Table 1.

[0018] Table 1 Main impurities and corresponding structures in the synthesis of 4 - Hydroxy - 5 - imidazolidinone

[0019] In the preparation process of p-hydroxyhydantoin, when glyoxylic acid is added dropwise to the mixed solution of phenol and urea, glyoxylic acid first reacts with urea to form an intermediate, and then the intermediate attacks the p-position of phenol to obtain N-formyl-p-hydroxyphenylglycine. N-formyl-p-hydroxyphenylglycine undergoes cyclization at high temperature to form p-hydroxyhydantoin. The relative concentrations of phenol and urea will affect the generation of impurities. If the concentration of phenol in the reaction solution is too high, phenol polymerization impurities are likely to be generated, and the phenol polymerization impurities will continue to polymerize with glyoxylic acid to form long-chain polymers. If the concentration of urea in the reaction solution is too high, since the primary amine nucleophilic ability of urea is stronger, it is more likely to continue to react with the intermediate under acidic conditions, consuming glyoxylic acid and reducing the reaction selectivity. Research shows that o-hydroxyhydantoin is the largest impurity affecting the reaction selectivity. Under traditional reaction conditions, o-hydroxyhydantoin accounts for about 10% of the selectivity of glyoxylic acid. To inhibit this impurity, the present invention precisely controls the concentration of phenol in the reaction solution. According to the dissolution differences between o-hydroxyhydantoin and p-hydroxyhydantoin, o-hydroxyhydantoin can be removed through simple post-treatment, greatly simplifying the product purification process.

[0020] The product backmixing impurities are generated by the reaction of the intermediate with p-hydroxyhydantoin. The present invention is a homogeneous reaction, but the product will continuously precipitate in the reaction solution. Due to the relatively complex reaction system and the presence of various intermediates in the reaction solution, the product p-hydroxyhydantoin is in a supersaturated state for a long time in the initial stage of formation. At this time, due to the accumulation of the concentration of p-hydroxyhydantoin, the product backmixing impurities also appear. The present invention promotes the precipitation of p-hydroxyhydantoin by adding crystal seeds, reduces the backmixing impurities, and at the same time continuously shifts the reaction equilibrium to the right to achieve the purpose of improving the reaction selectivity.

[0021] In the traditional process for the synthesis of p-hydroxyhydantoin, the urea equivalent in the substrate is relatively high. Hydrochloric acid is added to generate urea hydrochloride. In addition, a high urea equivalent will decompose to generate ammonium chloride and carbon dioxide during the reaction process, consuming urea and hydrogen chloride. Therefore, the amount of urea used is not less than 1.5 equivalents, and the amount of hydrochloric acid used is usually not less than 2.0 equivalents. The present invention greatly reduces the feeding amount of hydrochloric acid by controlling the concentrations of phenol and urea in the reaction solution, thereby reducing the generation of reaction waste acid. In addition, to promote the precipitation of the product, the amount of water is also reduced compared with the traditional process, thereby reducing the generation of waste solids and waste water in the post-treatment process.

[0022] The present invention has the following advantages compared with the prior art: The preparation method of p-hydroxyhydantoin of the present invention improves the selectivity of the p-hydroxyhydantoin reaction by inhibiting the generation of impurities, and high-purity p-hydroxyhydantoin can be obtained through simple post-treatment. The acid- and phenol-containing wastewater generated by the reaction is recycled, solving the problem of high production cost of p-hydroxyhydantoin.

[0023] The present invention has high reaction selectivity, with the formation of o-hydroxyhydantoin reduced by 40%, the formation of backmixing impurities in the product reduced by 20%, the formation of phenol polymerization impurities reduced by 30%, the separation yield of the product being 85% - 88%, and the raw material cost being low.

[0024] The preparation method of p-hydroxyhydantoin of the present invention has a short reaction cycle, simple process operation, low generation of three wastes, effectively reduces the environmental protection pressure, and is convenient for large-scale production. Specific embodiments

[0025] To better understand the technical solution of the present invention, the following provides a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0026] Example 1: 114.10 g of phenol, 72.01 g of urea, and 168.24 g of deionized water were heated to 60 °C and stirred until dissolved to obtain a mixed solution. 173.32 g of the mixed solution was taken in a three-necked round-bottom flask, 36.70 g of hydrogen chloride gas was introduced into it, and then 38.29 g of p-hydroxyhydantoin crystals were added. After stirring and heating to 70 °C, 150.14 g of an aqueous glyoxylic acid solution with a mass concentration of 50% was pumped into the round-bottom flask at a rate of 0.25 g / min. After adding 20% of the total mass of the aqueous glyoxylic acid solution, the remaining mixed solution was started to be added dropwise. After the addition of the aqueous glyoxylic acid solution and the mixed solution was completed, it was aged at 70 °C for 1.0 h, heated to 90 °C, stirred for 1.0 h, cooled to 60 °C, centrifuged while maintaining the temperature, the filter cake was washed 3 times with deionized water, and the filter cake was placed in a blast dryer at 80 °C for 5.0 h to obtain 204.28 g of p-hydroxyhydantoin with a purity of 99.21% and a product separation yield of 85.19%.

[0027] Example 2: 113.950 g of phenol, 72.17 g of urea, and 168.10 g of deionized water were heated to 60 °C and stirred until dissolved to obtain a mixed solution. 172.88 g of the mixed solution was taken in a three-necked round-bottom flask, 36.85 g of hydrogen chloride gas was introduced into it, and then 16.37 g of p-hydroxyhydantoin crystals were added. After stirring and heating to 70 °C, 149.62 g of an aqueous glyoxylic acid solution with a mass concentration of 50% was pumped into the round-bottom flask at a rate of 0.25 g / min. After adding 40% of the total mass of the aqueous glyoxylic acid solution, the remaining mixed solution was started to be added dropwise. After the addition of the aqueous glyoxylic acid solution and the mixed solution was completed, it was aged at 70 °C for 1.0 h, heated to 90 °C, stirred for 1.0 h, cooled to 75 °C, centrifuged while maintaining the temperature, the filter cake was washed 4 times with deionized water, and the filter cake was placed in a blast dryer at 80 °C for 5.0 h to obtain 181.86 g of p-hydroxyhydantoin with a purity of 98.89% and a product separation yield of 85.23%.

[0028] Example 3: 113.99 g of phenol, 72.52 g of urea and 168.37 g of deionized water were heated to 60 °C and stirred until dissolved to obtain a mixed solution. 141.95 g of the mixed solution was taken in a three-necked round-bottom flask, 36.79 g of hydrogen chloride gas was introduced into it, and then 32.84 g of p-hydroxyphenylhydantoin crystals were added. The mixture was stirred and heated to 70 °C, and then 149.81 g of a 50% aqueous glyoxylic acid solution was pumped into the round-bottom flask at a rate of 0.25 g / min. After 30% of the total mass of the aqueous glyoxylic acid solution was added dropwise, the remaining mixed solution was started to be added dropwise. After the addition of the aqueous glyoxylic acid solution and the mixed solution was completed, it was aged at 70 °C for 1.0 h, heated to 90 °C, stirred for 1.0 h, cooled to 73 °C, centrifuged while maintaining the temperature, the filter cake was washed 5 times with deionized water, and the filter cake was placed in a blast dryer at 85 °C for 5.0 h to obtain 203.15 g of p-hydroxyphenylhydantoin, with a purity of 99.04% and a product separation yield of 87.60%.

[0029] Example 4: 227.86 g of phenol, 145.71 g of urea and 336.45 g of deionized water were heated to 60 °C and stirred until dissolved to obtain a mixed solution. 300.4 g of the mixed solution was taken in a three-necked round-bottom flask, 73.65 g of hydrogen chloride gas was introduced into it, and then 45.28 g of p-hydroxyphenylhydantoin crystals were added. The mixture was stirred and heated to 70 °C, and then 300.68 g of a 50% aqueous glyoxylic acid solution was pumped into the round-bottom flask at a rate of 0.25 g / min. After 50% of the total mass of the aqueous glyoxylic acid solution was added dropwise, the remaining mixed solution was started to be added dropwise. After the addition of the aqueous glyoxylic acid solution and the mixed solution was completed, it was aged at 70 °C for 1.0 h, heated to 90 °C, stirred for 1.0 h, cooled to 75 °C, centrifuged while maintaining the temperature, the filter cake was washed 5 times with deionized water, and the filter cake was placed in a blast dryer at 85 °C for 5.0 h to obtain 383.28 g of p-hydroxyphenylhydantoin, with a purity of 99.22% and a product separation yield of 86.62%.

[0030] Example 5: 456.8 g of phenol, 289.36 g of urea and 672.6 g of deionized water were heated to 60 °C and stirred until dissolved to obtain a mixed solution. 650.63 g of the mixed solution was taken in a three-necked round-bottom flask, 145.52 g of hydrogen chloride gas was introduced therein, and then 66.87 g of p-hydroxyhydantoin crystals were added. The mixture was stirred and heated to 70 °C, and then 596.38 g of an aqueous glyoxylic acid solution with a mass concentration of 50% was pumped into the round-bottom flask at a rate of 0.25 g / min. After 60% of the total mass of the aqueous glyoxylic acid solution was added dropwise, the remaining mixed solution was started to be added dropwise. After the addition of the aqueous glyoxylic acid solution and the mixed solution was completed, it was aged at 70 °C for 1.0 h, heated to 90 °C, stirred for 1.0 h, cooled to 80 °C, kept warm and centrifuged. The filter cake was washed 5 times with deionized water, and the filter cake was placed in a blast dryer at 90 °C for 5.0 h to obtain 731.46 g of p-hydroxyhydantoin with a purity of 98.96% and a product separation yield of 85.87%.

[0031] Comparative Example: 114.02 g of phenol, 91.33 g of urea, 184.57 g of deionized water and 199.45 g of 36.54% concentrated hydrochloric acid were successively added to a three-necked round-bottom flask, and the mixture was placed in a 60 °C water bath and stirred to raise the temperature. After the temperature of the liquid in the round-bottom flask rose to 58 °C, 148.12 g of a 50% aqueous glyoxylic acid solution was started to be added dropwise at a rate of 0.25 g / min. The total addition time of the aqueous glyoxylic acid solution was 10 h. After the addition of the glyoxylic acid was completed, the temperature was raised to 105 °C and reacted for 2.0 h, and the reaction ended; after the reaction solution was cooled to 30 °C, it was centrifuged, and the filter cake was washed 3 times with deionized water. The filter cake was placed in a blast dryer at 80 °C for 5.0 h to obtain 142.69 g of pure p-hydroxyhydantoin with a purity of 98.23% and a product separation yield of 74.23%.

[0032] Although the specific embodiments of the present invention have been described above, it is not a limitation to the protection scope of the present invention. Based on the technical solutions of the present invention, various modifications or deformations that can be made by those skilled in the art without creative labor are still within the protection scope of the present invention.

Claims

1. A preparation method of p-hydroxyhydantoin, characterized in that: It includes the following steps: 1) Add phenol and urea into deionized water, heat to 60 °C and stir to dissolve to obtain a mixed solution. Take 40 - 80% of the total mass of the mixed solution and add it into a reactor. Introduce hydrogen chloride into it, then add p - hydroxyphenylhydantoin crystals, stir and heat to 70 °C, and then pump the 50% aqueous glyoxylic acid solution into the reactor at a rate of 0.25 g / min; 2) After 20% - 60% of the total mass of the aqueous glyoxylic acid solution is added dropwise, add the remaining part of the mixed solution in step 1) dropwise into the reactor. After the addition of the aqueous glyoxylic acid solution and the mixed solution is completed, keep it warm and cure at 70 °C for 1 h to obtain a reaction solution; 3) Heat the reaction solution obtained in step 2) to 90 °C, stir and react for 1 h, then cool down to 60 - 80 °C, keep warm and centrifuge. The obtained filter cake is rinsed with deionized water 3 - 5 times, and then dried in a blast dryer at 80 - 90 °C for 5 h to obtain p - hydroxyphenylhydantoin.

2. The preparation method of p-hydroxyphenylhydantoin according to claim 1, characterized in that: In step 1), the molar ratio of the phenol and urea is 1:0.5 - 2.

0.

3. The preparation method of p-hydroxyhydantoin according to claim 1, characterized in that: In step 1), the addition amount of the deionized water is 0.9 - 1 times the total mass of the phenol and urea; in step 1), the molar ratio of the hydrogen chloride and phenol is 0.6 - 1.2:

1.

4. The preparation method of p-hydroxyhydantoin according to claim 1, characterized in that: In step 1), the addition amount of the p - hydroxyphenylhydantoin crystals is 2 - 8% of the total mass of the phenol, urea, deionized water and 50% aqueous glyoxylic acid solution.

5. The preparation method of p-hydroxyhydantoin according to claim 1, characterized in that: In step 1), the molar ratio of the glyoxylic acid and phenol in the 50% aqueous glyoxylic acid solution is 1:1 - 1.

5.

6. The preparation method of p-hydroxyhydantoin according to claim 1, characterized in that: In step 1), the molar ratio of the phenol and urea is 1:1; in step 1), the molar ratio of the hydrogen chloride and phenol is 0.83:

1.

7. The preparation method of p-hydroxyphenylhydantoin according to claim 1, characterized in that: In step 1), the molar ratio of the glyoxylic acid and phenol in the 50% aqueous glyoxylic acid solution is 1:1.

2.

8. The preparation method of p-hydroxyhydantoin according to claim 1, characterized in that: In step 1), the addition amount of the p - hydroxyphenylhydantoin crystals is 3 - 6% of the total mass of the phenol, urea, deionized water and 50% aqueous glyoxylic acid solution.

9. The preparation method of p-hydroxyphenylhydantoin according to claim 1, characterized in that: In step 1), take 50 - 70% of the total mass of the mixed solution and introduce hydrogen chloride into it.

10. The preparation method of p-hydroxyphenylhydantoin according to claim 1, characterized in that: In step 3), cool down to 70 - 75 °C.

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