Preparation method of high-purity m-cresol

Abstract

The application discloses a preparation method of high-purity m-cresol and belongs to the technical field of compound refining and purification. The application comprises the following steps: (1) preparation of a stationary phase: urea and a carrier are loaded on the carrier by cooling crystallization in an alcohol solvent, and then alcohol solvent is removed by drying under reduced pressure to obtain a supported crystalline urea, which is the stationary phase filler; (2) column loading: the stationary phase filler is loaded into a chromatographic column; (3) column chromatography: m-cresol raw materials to be separated are loaded on the column, a mobile phase is injected into the chromatographic column for gradient elution, and elution fractions in different time periods are collected; (4) post-treatment: the collected elution fractions rich in m-cresol are concentrated and dried to obtain high-purity m-cresol. The carrier loaded with urea is used as the stationary phase of the chromatographic column, m-cresol with a purity higher than 99.0% and a p-cresol content lower than 0.01% is prepared through column chromatography separation, and the method has the characteristics of simple process, high purity, high yield, low energy consumption and cost, less pollution and easy industrialization.

Description

Technical Field

[0001] This invention relates to the field of compound purification technology, specifically to a method for preparing high-purity m-cresol. Background Technology

[0002] m-Cresol, also known as 3-methylphenol, is a colorless to pale yellow transparent liquid. In the chemical industry, it is mainly used as a pesticide intermediate, and can also be used as a disinfectant, fumigant, and photographic developer. In the pharmaceutical field, it is often used as an excipient in disinfectant and antiseptic drugs, such as an antibacterial preservative in intramuscular, subcutaneous, and intradermal injections.

[0003] The synthesis processes of industrial-grade m-cresol include toluene sulfonation, toluene chlorination and hydrolysis, toluene hydroxylation, phenol alkylation, and isopropyl toluene oxidation. However, existing methods produce industrial-grade m-cresol with low purity, failing to meet the requirements for injectable excipients. In the field of pharmaceutical excipients, to ensure their safety, consistency, and stability, pharmacopoeias of various countries have made clear requirements regarding impurities that may be introduced during the m-cresol production process, especially highly toxic m-cresol isomers (e.g., the Chinese Pharmacopoeia requires: o-cresol ≤ 0.5%, p-cresol ≤ 0.5%, m-cresol ≥ 98.0%). In the production of vitamin E, it is even required that the p-cresol content in the raw material drug-grade m-cresol is no more than 0.2%, and the m-cresol content is ≥ 99.8%.

[0004] The boiling points of o-cresol and m-cresol, two of the cresol isomers, differ significantly (≥10℃), allowing for efficient separation using traditional distillation processes. However, the boiling point difference between p-cresol and m-cresol is very small, only 0.6℃, making separation and purification more difficult. Currently disclosed methods for separating p-cresol and m-cresol include complexation crystallization, molecular sieve adsorption, and alkylation. CN103204766B uses urea complexation crystallization to separate m-cresol and p-cresol, obtaining m-cresol with a purity of 98.7%–99.4% and an extraction efficiency of 45%–65%. However, this process suffers from problems such as low crystallization temperature, large solvent consumption, difficulty in separating and purifying the complex, and high energy consumption. CN111689838A uses molecular sieve adsorption to obtain m-cresol with a purity >98.0%. However, this process suffers from disadvantages such as difficulty in preparing molecular sieves, limited adsorption capacity, and high actual operating costs. CN101863742B uses alkylation to separate a mixture of m- and p-cresol to obtain high-purity m-cresol. However, this method requires a large amount of alkylation and dealkylation catalysts, resulting in complex equipment and high investment costs. Summary of the Invention

[0005] The present invention aims to solve the technical problems of complex processes, high costs, heavy pollution, and difficulty in industrialization in the separation of m-cresol and p-cresol in the prior art. The purpose is to provide a method for preparing high-purity m-cresol, which has the characteristics of simple process, high purity, high yield, low energy consumption and cost, less pollution, and easy industrialization.

[0006] This invention is achieved through the following technical solution:

[0007] A method for preparing high-purity m-cresol includes the following steps:

[0008] (1) Preparation of stationary phase: Urea and support are crystallized in alcohol solvent by cooling to load urea onto the support, and then the alcohol solvent is removed by vacuum drying to obtain supported crystalline urea, which is the stationary phase filler.

[0009] (2) Column packing: The stationary phase packing is packed into the chromatography column;

[0010] (3) Column chromatography: The m-cresol raw material to be separated is loaded onto the column, and the mobile phase is injected into the chromatography column for gradient elution. The eluents at different time points are collected.

[0011] (4) Post-processing: The collected eluent rich in m-cresol was concentrated and dried to obtain high-purity m-cresol.

[0012] The separation principle of this invention is as follows:

[0013] This invention uses m-cresol (containing 0.5% to 10% p-cresol) as raw material and a urea-loaded carrier as the stationary phase of a chromatography column to obtain a high-purity m-cresol product through column chromatography separation.

[0014] The polarity differences between m-cresol isomers are very small, and conventional column chromatography cannot effectively separate m-cresol and p-cresol. Since urea can complex and adsorb with m-cresol but not react with p-cresol, this invention prepares supported crystalline urea by loading urea onto a high specific surface area support. This supported crystalline urea is used as the stationary phase in the chromatography column. Utilizing the selectivity of the stationary phase for different isomers, and by selecting an appropriate mobile phase for gradient elution, the target analyte can be repeatedly balanced and distributed between the stationary and mobile phases, thus eluting all the target analyte sequentially. This method effectively separates m- and p-cresol and features a simple process, high purity, high yield, low energy consumption and cost, low pollution, and ease of industrialization.

[0015] Furthermore, in step (1), the carrier is any one of alumina, silica gel, and activated carbon, and the mass ratio of urea to carrier is 5 to 0.5:1. The specific surface area of ​​the carrier is 100 to 500 m². 2 / g.

[0016] Furthermore, in step (1), the alcohol solvent is one or more of methanol, ethanol, isopropanol and butanol, and the mass ratio of the alcohol solvent to urea is 3 to 10:1.

[0017] Furthermore, in step (1), the cooling crystallization conditions are: slowly cooling from 50 to 70°C to 1 to 10°C, with the cooling rate controlled at 5 to 10°C / h.

[0018] Furthermore, in step (1), the reduced pressure drying conditions are: temperature controlled at 0-20℃ and vacuum degree controlled at 0-10pa.

[0019] Furthermore, in step (2), a wet loading method is used for column loading.

[0020] Furthermore, in step (3), the mobile phase is a binary solvent system, comprising solvent A and solvent B; wherein solvent A is any one of petroleum ether-ethyl acetate or petroleum ether-methyl acetate system; and solvent B is any one of n-heptane-ethyl acetate or n-heptane-methyl acetate system.

[0021] In the mobile phase selected in this invention, solvent A can completely dissolve the m-cresol raw material to be separated, improve the adsorption and fixation effect of urea on m-cresol, and enable it to be better fixed by urea. Subsequently, mobile phase B is used to elute and separate m-cresol. By selecting a suitable mobile phase, it is ensured that m-cresol can be fully separated from p-cresol.

[0022] Furthermore, in step (3), the mobile phase is used for gradient elution at a flow rate of 0.5 to 5 mL / min; the mobile phase gradient elution program is as follows: solvent A is used as the mobile phase for 0 to 20 min, and solvent B is used as the mobile phase for 20 to 60 min.

[0023] Furthermore, in step (4), the concentration is carried out by vacuum distillation, with the vacuum degree controlled at 100-1000 Pa and the temperature controlled at 30-60 °C.

[0024] Furthermore, in step (4), the drying is carried out by vacuum distillation, with the vacuum degree controlled at 0 to 100 Pa and the temperature controlled at 0 to 30 °C.

[0025] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0026] 1. This invention prepares supported crystalline urea by loading urea onto a high specific surface area support, which is then used as the stationary phase of a chromatography column. By utilizing the selectivity of the stationary phase for different isomers and selecting an appropriate mobile phase for gradient elution, the target analytes can be repeatedly balanced and distributed between the stationary and mobile phases, thereby eluting all the target analytes sequentially. This method can effectively separate m-cresol and p-cresol, yielding m-cresol with a purity higher than 99.0% and p-cresol with a content lower than 0.01%. It features a simple process, high purity, high yield, low energy consumption and cost, low pollution, and ease of industrialization.

[0027] 2. In the mobile phase selected in this invention, solvent A can completely dissolve the m-cresol raw material to be separated, improve the adsorption and fixation effect of urea on m-cresol, and enable it to be better fixed by urea. Subsequently, mobile phase B is used to elute and separate m-cresol. By selecting a suitable mobile phase, it is ensured that m-cresol can be fully separated from p-cresol.

[0028] 3. The process of this invention is simple and the production cost is low. Compared with the traditional urea freeze crystallization process, it solves the problems of large urea consumption, difficult separation and recovery, and complex post-processing. On the other hand, since the purification process does not require high temperature, low temperature or high pressure, the equipment cost is low and it is easy to carry out industrial production. Attached Figure Description

[0029] To more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of the present invention and should not be considered as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort. In the drawings:

[0030] Figure 1 This is a process flow diagram of the present invention;

[0031] Figure 2 Here is the gas chromatogram of Example 9;

[0032] Figure 3 This is the gas chromatogram of Example 10. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments and accompanying drawings. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.

[0034] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that these specific details are not necessary to practice the invention. In other embodiments, well-known materials or methods have not been specifically described in order to avoid obscuring the invention.

[0035] Throughout this specification, references to "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the invention. Therefore, the phrases "an embodiment," "an example," "an example," or "an example" appearing in various places throughout the specification do not necessarily refer to the same embodiment or example. Furthermore, specific features, structures, or characteristics can be combined in one or more embodiments or examples in any suitable combination and / or sub-combination. Moreover, those skilled in the art will understand that the illustrations provided herein are for illustrative purposes and are not necessarily drawn to scale. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0036] This invention is based on the fact that the boiling points of o-cresol and m-cresol, which are cresol isomers, differ significantly (≥10℃), and can be efficiently separated by traditional distillation processes; while the boiling point difference between p-cresol and m-cresol is very small, only 0.6℃, making separation and purification difficult. Furthermore, the polarity difference between the m-cresol isomers is very small, and ordinary column chromatography cannot effectively separate m-cresol and p-cresol.

[0037] Currently disclosed separation methods include complexation crystallization, molecular sieve adsorption, and alkylation. The urea complexation crystallization method for separating m-cresol and p-cresol suffers from problems such as low crystallization temperature, large solvent consumption, difficulty in separating and purifying the complex, and high energy consumption. The molecular sieve adsorption method has drawbacks such as difficulty in preparing molecular sieves, limited adsorption capacity, and high actual operating costs. The alkylation method for separating m-cresol and p-cresol mixtures requires large amounts of alkylation and dealkylation catalysts, resulting in complex equipment and high investment costs. Therefore, existing methods for separating m-cresol and p-cresol generally have various shortcomings. This invention aims to provide a new method for separating m-cresol and p-cresol, achieving the preparation of high-purity m-cresol, while overcoming the technical problems of complex processes, strict temperature requirements, large solvent consumption, difficult separation, high energy consumption, and high costs in existing technologies.

[0038] Example 1

[0039] Preparation of stationary phase

[0040] Weigh 200 mL of anhydrous methanol and 50 g of urea into a 1 L three-necked flask, place it in a heating mantle at 55 ± 5 °C, and stir for 0.5 h until completely dissolved. Add 50 g of silica gel and stir evenly. Begin cooling and crystallization (cooling rate controlled at 5 °C / h). After cooling to 5 °C, maintain the temperature for 2 h. Turn on the vacuum pump and adjust the vacuum to 0–10 Pa. Distill under reduced pressure at 10 °C for 2–3 h to obtain supported crystalline urea (99.7 g), which serves as the stationary phase packing. In this experiment, the mass ratio of urea to support was 1:1. Experiments have shown that the supported crystalline urea prepared at this ratio has the highest yield and the highest utilization rate of raw material urea and support.

[0041] Example 2

[0042] The difference between this embodiment and Embodiment 1 is that the mass ratio of urea to silica gel is 5:1.

[0043] Example 3

[0044] The difference between this embodiment and Embodiment 1 is that the mass ratio of urea to silica gel is 4:1.

[0045] Example 4

[0046] The difference between this embodiment and Embodiment 1 is that the mass ratio of urea to silica gel is 3:1.

[0047] Example 5

[0048] The difference between this embodiment and Embodiment 1 is that the mass ratio of urea to silica gel is 2:1.

[0049] Example 6

[0050] The difference between this embodiment and Embodiment 1 is that the mass ratio of urea to silica gel is 0.5:1.

[0051] Example 7

[0052] The difference between this embodiment and Embodiment 1 is that the carrier is replaced with aluminum oxide.

[0053] Example 8

[0054] The difference between this embodiment and Embodiment 1 is that the carrier is replaced with activated carbon.

[0055] Example 9

[0056] This embodiment provides a method for preparing high-purity m-cresol, including the following steps:

[0057] (1) The 40g stationary phase prepared in Example 1 was loaded into the chromatography column by a wet method.

[0058] (2) Slowly add 1.0g of industrial grade m-cresol (m-cresol content 97.0%, p-cresol 0.98%) sample into the chromatography column.

[0059] (3) Prepare the mobile phase and perform gradient elution in the following order:

[0060] Elution was performed from 0 to 20 min using petroleum ether to ethyl acetate at a ratio of 10:1.

[0061] Elution was performed for 20–60 min using a heptane:ethyl acetate ratio of 7:1.

[0062] The mobile phase flow rate was controlled at 2.0 mL / min, and one elution fraction was collected every 20 mL.

[0063] (4) After removing and recovering most of the solvent by rotary evaporation for 30 min using a rotary evaporator (temperature 50℃, vacuum degree 700Pa), dry under reduced pressure for 2 h (adjust vacuum degree to 0-20Pa, temperature 15℃).

[0064] (5) The m-cresol content of each component was determined by gas chromatography according to the method for testing m-cresol content in the 2020 edition of the Chinese Pharmacopoeia, Part IV. Components with a content ≥98.0% were collected, and finally 0.94 g of m-cresol was obtained (m-cresol purity reached 99.5%, p-cresol ≤0.01%), that is, the m-cresol recovery rate was as high as 96.9%. The gas chromatogram is shown below. Figure 2 As shown in Table 1, the quantitative results are as follows.

[0065] Table 1. Quantitative results of gas chromatography in this embodiment

[0066] Serial Number Compound Name Retention time area high concentration 1 phenol 8.634 253165 74841 0.000 2 m-cresol 11.055 249201 54397 99.477 total 502366 129238

[0067] Example 10

[0068] This embodiment provides a method for preparing high-purity m-cresol, including the following steps:

[0069] (1) The 50g stationary phase prepared in Example 1 was loaded into the chromatography column by a wet method.

[0070] (2) Slowly add 1.2g of industrial grade m-cresol (m-cresol content 97.0%, p-cresol 0.98%) sample into the chromatography column.

[0071] (3) Prepare the mobile phase and perform gradient elution in the following order:

[0072] Elution was performed from 0 to 20 minutes with petroleum ether and methyl acetate in a ratio of 9:1.

[0073] Elution was performed for 20–60 minutes with a heptane:methyl acetate ratio of 8:1.

[0074] The mobile phase flow rate was controlled at 2.0 mL / min, and one elution fraction was collected every 20 mL.

[0075] (4) After removing and recovering most of the solvent by rotary evaporation for 30 min using a rotary evaporator (temperature 45℃, vacuum degree 400Pa), dry under reduced pressure for 2 h (adjust vacuum degree to 0-20Pa, temperature 10℃).

[0076] (5) The m-cresol content of each component was determined by gas chromatography according to the method for testing m-cresol content in the 2020 edition of the Chinese Pharmacopoeia, Part IV. Components with a content ≥98.0% were collected, and a total of 1.09 g of m-cresol was finally obtained (m-cresol purity reached 99.1%, p-cresol ≤0.01%), that is, the m-cresol recovery rate was as high as 93.6%. The gas chromatogram is shown below. Figure 3 As shown in Table 2, the quantitative results are as follows.

[0077] Table 2. Quantitative results of gas chromatography in this embodiment

[0078] Serial Number Compound Name Retention time area high concentration 1 phenol 8.577 242134 72164 0.000 2 m-cresol 10.965 246202 53102 99.113 total 488336 125267

[0079] Example 11

[0080] The difference between this example and Example 9 is that the mobile phase flow rate was controlled at 4.0 mL / min, and one eluent was collected every 20 mL. Finally, 0.93 g of m-cresol was obtained (m-cresol purity reached 99.3%, p-cresol ≤0.01%), meaning the m-cresol recovery rate was as high as 95.9%.

[0081] Example 12

[0082] The difference between this example and Example 9 is that the mobile phase flow rate was controlled at 0.5 mL / min, and one eluent was collected every 20 mL. Finally, 0.95 g of m-cresol was obtained (m-cresol purity reached 99.4%, p-cresol ≤0.01%), meaning the m-cresol recovery rate was as high as 97.9%.

[0083] Example 13

[0084] The difference between this embodiment and embodiment 9 is as follows:

[0085] In step (4), the rotary evaporator was operated at a temperature of 30°C and a vacuum of 1000 Pa. During vacuum drying, the vacuum was controlled at 0-20 Pa and the temperature at 30°C. Finally, 0.94 g of m-cresol was obtained (m-cresol purity reached 99.2%, p-cresol ≤0.01%), meaning the m-cresol recovery rate was as high as 96.9%.

[0086] Example 14

[0087] The difference between this embodiment and embodiment 9 is as follows:

[0088] In step (4), the rotary evaporator was operated at a temperature of 60°C and a vacuum of 300 Pa. During vacuum drying, the vacuum was controlled at 30-50 Pa and the temperature at 10°C. Finally, 0.93 g of m-cresol was obtained (m-cresol purity reached 99.3%, p-cresol ≤0.01%), meaning the m-cresol recovery rate was as high as 95.9%.

[0089] Comparative Example 1

[0090] Elution was performed using only one solvent as the mobile phase, and the separation purity and yield were compared. The specific steps are as follows:

[0091] (1) The 50g stationary phase prepared in Example 1 was loaded into the chromatography column by a wet method.

[0092] (2) Slowly add 1.2g of industrial grade m-cresol (m-cresol content 97.0%, p-cresol 0.98%) sample into the chromatography column.

[0093] (3) Prepare the mobile phase and perform gradient elution in the following order: elute with petroleum ether from 0 to 60 min; control the flow rate of the mobile phase to 2.0 mL / min and collect one eluent fraction every 20 mL.

[0094] (4) After removing and recovering most of the solvent by rotary evaporation for 30 min in a rotary evaporator (temperature 45℃, vacuum 400Pa), dry under reduced pressure for 2 h (adjust vacuum to 0-20Pa and temperature to 10℃).

[0095] (5) The m-cresol content of each component was determined by gas chromatography according to the m-cresol content test in the 2020 edition of the Chinese Pharmacopoeia, Volume IV. Components with a content ≥98.0% were collected, and finally 0.23g of m-cresol was obtained (m-cresol purity reached 98.1%, p-cresol 0.77%), that is, the m-cresol recovery rate was only 19.2% and the purity was low.

[0096] Comparative Example 2

[0097] The difference between this comparative example and Comparative Example 1 is that ethyl acetate was used instead of petroleum ether as the mobile phase for elution, and 0.81 g of m-cresol was finally obtained (m-cresol purity was 98.2%, p-cresol was 0.65%), that is, the m-cresol recovery rate was 69.6%, but its purity was low.

[0098] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing high-purity m-cresol, characterized in that, Includes the following steps: (1) Preparation of stationary phase: Urea and support are crystallized in alcohol solvent by cooling, and then the alcohol solvent is removed by vacuum drying to obtain supported crystalline urea, which is the stationary phase filler; the support is any one of alumina, silica gel and activated carbon, and the mass ratio of urea to support is 5~0.5:1; the cooling crystallization conditions are: slowly cooling from 50~70℃ to 1~10℃, and the cooling rate is controlled at 5~10℃ / h; the vacuum drying conditions are: temperature controlled at 0~20℃, and vacuum degree controlled at 0~10pa; (2) Column packing: The stationary phase packing material is packed into the chromatography column; (3) Column chromatography: The m-cresol raw material to be separated is loaded onto the column, and the mobile phase is injected into the chromatography column for gradient elution. The eluents at different time points are collected. (4) Post-processing: The collected eluent rich in m-cresol was concentrated and dried to obtain high-purity m-cresol.

2. The method for preparing high-purity m-cresol according to claim 1, characterized in that, In step (1), the alcohol solvent is one or more of methanol, ethanol, isopropanol and butanol, and the mass ratio of the alcohol solvent to urea is 3~10:

1.

3. The method for preparing high-purity m-cresol according to claim 1, characterized in that, In step (2), wet loading is used.

4. The method for preparing high-purity m-cresol according to claim 1, characterized in that, In step (3), the mobile phase is a binary solvent system, comprising solvent A and solvent B; wherein solvent A is any one of petroleum ether-ethyl acetate or petroleum ether-methyl acetate system; and solvent B is any one of n-heptane-ethyl acetate or n-heptane-methyl acetate system.

5. The method for preparing high-purity m-cresol according to claim 1, characterized in that, In step (3), the mobile phase is used for gradient elution at a flow rate of 0.5~5 mL / min; the mobile phase gradient elution program is as follows: solvent A is used as the mobile phase for 0~20 min, and solvent B is used as the mobile phase for 20~60 min.

6. The method for preparing high-purity m-cresol according to claim 1, characterized in that, In step (4), the concentration is carried out by vacuum distillation, with the vacuum degree controlled at 100~1000pa and the temperature controlled at 30~60℃.

7. A method for preparing high-purity m-cresol according to claim 1, characterized in that, In step (4), the drying is carried out by vacuum distillation, with the vacuum degree controlled at 0~100pa and the temperature controlled at 0~30℃.

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