Chlorphenesin coupling crystallization-adsorption purification method based on eutectic solvent

Abstract

The invention discloses a chlorphenesin coupling crystallization-adsorption purification method based on a deep eutectic solvent, and belongs to the technical field of chemical purification. According to the technical scheme, the method comprises the following steps: S1, mixing crude chlorphenesin with supercritical CO2, and extracting to obtain pretreated chlorphenesin; s2, dissolving the pretreated chlorphenesin in a choline chloride-glycerol DES system, adding an adsorbent after sufficient dissolution, cooling, and separating out chlorphenesin. The technical problems that an organic solvent is used in an existing chlorphenesin purification method, and the solvent is inflammable, toxic, large in dosage, long in purification time and high in energy consumption are solved, and the chlorphenesin coupling crystallization-adsorption purification method based on the eutectic solvent is safe, environmentally friendly, capable of improving production efficiency and high in product purity and yield.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical purification, and particularly relates to a chlorphenesin coupling crystallization-adsorption purification method based on a eutectic solvent. BACKGROUND

[0002] Chlorphenesin is a good antifungal and antibacterial agent, and has good inhibitory effect on various bacteria, especially on fungal, bacterial, and trichomonas diseases. There are about nine process routes for the current synthesis method of chlorphenesin. Process raw materials mainly include p-chlorophenol and 3-chloro-1,2-propanediol or 3-chloro-epoxy propane. The preparation of chlorphenesin is a classical Williamson ether reaction of sodium p-chlorophenol and halogenated alcohol. The reaction is an SN2 bimolecular nucleophilic reaction, and a small amount of p-chlorophenol, 3-chloro-1,2-propanediol or 3-chloro-epoxy propane cannot react and enters the product post-processing link, which brings troubles to the purification of the product. Therefore, product separation and purification become an important part of the product preparation process.

[0003] At present, there are few reports on the purification process of chlorphenesin product. The literature mainly uses solvent system crystallization to realize the purification of the product. Solvents include chloroform, alcohol aqueous solution and the like. The process has the problems of long time, large amount of waste liquid and great environmental hazards. At present, the organic solvent crystallization process and multiple washing process are mainly used for the purification of chlorphenesin product at home and abroad, and these solvents mainly involve toxic, harmful, flammable and explosive solvents such as methanol and chloroform. Moreover, the production implementation time is long, the requirements are high, and the process has the disadvantages of high risk level. In addition, a large amount of eluent is often required in the elution link, and the elution is repeated multiple times, so that a large amount of waste liquid is generated. The above reflects that the chlorphenesin purification process has the problems of large amount of solvent, flammability, toxicity, long time, high energy consumption and great hazards, which seriously restrict the rapid development of the industry.

[0004] Therefore, it is urgent to develop a chlorphenesin product purification method with high efficiency and environmental protection, which can reduce energy consumption and material consumption and improve production efficiency. SUMMARY

[0005] In view of the problems in the prior art, the technical problem to be solved by the application is that the existing chlorphenesin purification method uses organic solvents, and the solvents are flammable, toxic, have a large amount, have a long purification time and high energy consumption. The application provides a chlorphenesin coupling crystallization-adsorption purification method based on a eutectic solvent, which is safe and environmentally friendly, improves production efficiency, has high product purity and high yield.

[0006] To solve the technical problem, the application adopts the technical scheme that: A chlorphenesin coupling crystallization-adsorption purification method based on a eutectic solvent, comprising the following steps: S1: mixing the crude chlorphenesin with supercritical CO2, extracting to obtain pretreated chlorphenesin; S2: dissolving the pretreated chlorphenesin in a choline chloride-glycerol DES system, after fully dissolving, adding an adsorbent, cooling, and precipitating chlorphenesin.

[0007] In some embodiments, the solid-liquid mass ratio of chlorphenesin to the choline chloride-glycerol DES system is 1:5-8.

[0008] In some embodiments, in the choline chloride-glycerol DES system, the molar ratio of choline chloride to glycerol is 1:1-5.

[0009] In some embodiments, in step S1, the mass ratio of chlorphenesin to supercritical CO2 is 1:2-6.

[0010] In some embodiments, in step S1, the extraction temperature is 40-50℃.

[0011] In some embodiments, the adsorbent is modified mesoporous silica, and the amount of the adsorbent added is 1-10wt% of the raw material.

[0012] In some embodiments, in step S2, the temperature at which the chlorphenesin is dissolved in the choline chloride-glycerol DES system is 40-60℃.

[0013] In some embodiments, in step S2, the temperature is cooled to 5-15℃.

[0014] In some embodiments, it further comprises: S3: using an ethanol-water gradient system to wash the precipitated chlorphenesin.

[0015] In some embodiments, the adsorbent is one of amino-modified mesoporous silica and carboxyl-modified silica.

[0016] Compared with the prior art, the beneficial effects of the present application are that: The low eutectic solvent-based chlorphenesin coupled crystallization-adsorption purification method provided by the present application first extracts the crude chlorphenesin with supercritical CO2 to remove weakly polar impurities (mainly phenol derivatives that do not participate in the reaction or liposoluble polymers, hydrocarbons, pigments, etc. generated by side reactions); then through the choline chloride-glycerol DES system, remove strongly polar impurities (mainly isomers, chlorinated by-products, etc.); In the raw material pretreatment stage, ScCO2 is used instead of traditional organic solvents to avoid solvent residues and can be recycled and reused; In the extraction stage, the DES system is used, which is non-toxic and biodegradable compared with traditional solvents; The method is safe and environmentally friendly, has high production efficiency, good purification effect, and high product yield. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1The liquid chromatogram of the product of Example 1 of the present application; Figure 2 The liquid chromatogram of the product of Example 2 of the present application; Figure 3 The liquid chromatogram of the product of Example 3 of the present application. DETAILED DESCRIPTION

[0018] The technical solutions in the specific embodiments of the present application will be described in detail and completely below. Obviously, the described embodiments are only part of the specific implementations of the general technical solution of the present application, rather than all the implementations. All other embodiments obtained by those skilled in the art based on the general concept of the present application fall within the scope of protection of the present application.

[0019] The present application provides a chlorphenesin coupling crystallization-adsorption purification method based on a deep eutectic solvent, comprising: S1: mixing crude chlorphenesin with supercritical CO2, extracting, to obtain pretreated chlorphenesin; S2: dissolving the pretreated chlorphenesin in a choline chloride-glycerol DES system, adding an adsorbent after sufficient dissolution, and precipitating chlorphenesin by cooling.

[0020] The chlorphenesin coupling crystallization-adsorption purification method based on a deep eutectic solvent provided by the present application first extracts the chlorphenesin crude product with supercritical CO2 to remove weakly polar impurities (mainly referring to phenol derivatives that do not participate in the reaction or liposoluble polymers, hydrocarbons, pigments, etc. generated by side reactions); then removes strongly polar impurities (mainly referring to isomers, chlorinated by-products, etc.) through a choline chloride-glycerol DES system; in the raw material pretreatment stage, ScCO2 is used to replace traditional organic solvents, avoiding solvent residues and enabling recycling and reuse; in the extraction stage, the DES system is used, which is non-toxic and biodegradable compared to traditional solvents; the method is safe and environmentally friendly, has high production efficiency, good purification effect, and high product yield.

[0021] Supercritical carbon dioxide is added first, and then a deep eutectic solvent (DES) is added. Supercritical CO2 (ScCO2) is used as a pre-execution "rough purification". ScCO2 has diffusion properties similar to a gas and dissolution capacity similar to a liquid, and can efficiently and selectively dissolve and remove non-polar or weakly polar impurities in the chlorphenesin crude product, such as unreacted raw materials (e.g., phenol derivatives), reaction by-products (e.g., some liposoluble polymers, hydrocarbons), pigments, etc. This step is equivalent to providing a "pretreated" raw material with simpler impurities for subsequent DES treatment, avoiding interference of these liposoluble impurities with the subsequent DES system.

[0022] DES as a strong polar solvent system, its advantage is to separate the components with similar polarity through hydrogen bonding and other interactions. If DES is added first, these large amounts of fat-soluble impurities will also be dispersed in the system, not only increasing the amount and viscosity of DES, but also possibly wrapping the target product, reducing the effective extraction efficiency of DES. First, use ScCO2 to "clear" these interference items, so that DES can focus more efficiently on the separation of chlorphenesin and its key polar impurities (such as isomers, chlorinated byproducts). ScCO2 will automatically gasify after depressurization, completely separated from the raw materials, leaving no residue. After ScCO2 pretreatment, a dry and clean solid intermediate is obtained, which is convenient for accurate weighing and entering the next DES process. If the order is reversed, first use DES, then it will be difficult to introduce ScCO2 for effective treatment, because the dissolution and mass transfer process of ScCO2 in DES will become complex, and the moisture in the DES system may also affect the process stability of ScCO2.

[0023] In some embodiments, the solid-liquid mass ratio of chlorphenesin to choline chloride-glycerol DES system is 1:5-8. It can be understood that the skilled in the art can adjust the mass fraction of each component within the above range according to the actual situation, for example, the solid-liquid mass ratio of chlorphenesin to choline chloride-glycerol DES system can also be 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5 or any point value within the above range.

[0024] In some preferred embodiments, the solid-liquid mass ratio of chlorphenesin to choline chloride-glycerol DES system is 1:5-6.

[0025] In some embodiments, in the choline chloride-glycerol DES system, the molar ratio of choline chloride to glycerol is 1:1-5. It can be understood that the skilled in the art can adjust the fraction of each component within the above range according to the actual situation, for example, the molar ratio of choline chloride to glycerol can also be 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or any point value within the above range.

[0026] In some preferred embodiments, the molar ratio of choline chloride to glycerol is 1:1-3.

[0027] In some embodiments, in step S1, the mass ratio of chlorphenesin to supercritical CO2 is 1:2-6. It can be understood that the skilled in the art can adjust the mass fraction of each component within the above range according to the actual situation, for example, the mass ratio of chlorphenesin to supercritical CO2 can also be 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or any point value within the above range.

[0028] In some preferred embodiments, in step S1, the mass ratio of chlorphenesin and supercritical CO2 is 1:2-4.

[0029] In some embodiments, in step S1, the extraction temperature is 40-50°C. It can be understood that the temperature parameter can be adjusted by those skilled in the art within the above range according to the actual situation, for example, the extraction temperature in step S1 can also be 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or any point value within the above range.

[0030] In some preferred embodiments, in step S1, the extraction temperature is 40-45°C.

[0031] In some embodiments, the adsorbent is modified mesoporous silica, and the adsorbent addition amount is 1-10wt% of the raw material. It can be understood that the weight fraction of each component can be adjusted by those skilled in the art within the above range according to the actual situation, for example, the adsorbent addition amount is 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, 5wt%, 5.5wt%, 6wt%, 6.5wt%, 7wt%, 7.5wt%, 8wt%, 8.5wt%, 9wt%, 9.5wt% or any point value within the above range of the raw material.

[0032] The modified mesoporous silica adsorbent can "point-clear" trace harmful impurities through specific chemical forces (acid-base, hydrogen bond).

[0033] In some preferred embodiments, the adsorbent addition amount is 1-5wt% of the raw material.

[0034] In some preferred embodiments, the adsorbent pore size is 2-5 nm.

[0035] On the one hand, this size range is much larger than the molecular size of chlorphenesin and its impurities (usually <1 nm), which ensures that impurity molecules can freely diffuse into the pore interior, providing a large specific surface area for adsorption; on the other hand, its uniform pore structure can block larger polymer impurities by steric hindrance effect, playing a preliminary screening role.

[0036] In some embodiments, after adding the adsorbent, stirring for 2h.

[0037] In some embodiments, in step S2, the temperature for dissolving the chlorphenesin in the choline chloride-glycerol DES system is 40-60°C. It can be understood that the temperature parameter can be adjusted by those skilled in the art within the above range according to the actual situation, for example, the temperature for dissolving the chlorphenesin in the choline chloride-glycerol DES system in step S2 can also be 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or any point value within the above range.

[0038] In some preferred embodiments, in step S2, the temperature for dissolving the chlorphenesin in the choline chloride-glycerol DES system is 50-60°C.

[0039] In some embodiments, in step S2, the temperature is lowered to 5-15°C. It can be understood that the temperature parameter can be adjusted by those skilled in the art within the above range according to the actual situation, for example, the final temperature for lowering the temperature in step S2 can also be 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C or any point value within the above range.

[0040] In some preferred embodiments, in step S2, the temperature is lowered to 8-12°C.

[0041] In some embodiments, it further comprises: S3: washing the precipitated chlorphenesin using an ethanol-water gradient system.

[0042] In some preferred embodiments, the washing process using the ethanol-water gradient system is that the precipitated chlorphenesin is washed ≥3 times using ethanol aqueous solutions with a gradient decrease in concentration.

[0043] In some embodiments, the concentration of the ethanol aqueous solution is 5-20%.

[0044] In some preferred embodiments, the concentration of the ethanol aqueous solution is 10-20%.

[0045] In some embodiments, the adsorbent is one or both of an amino-modified mesoporous silica and a carboxyl-modified mesoporous silica. The target of the amino-modified mesoporous silica is acidic impurities, especially p-chlorophenol. The amino group on the amino-modified mesoporous silica is a basic group, which can strongly bind with the phenolic hydroxyl group through acid-base interaction or hydrogen bonding, thereby selectively "grabbing" and fixing trace amounts of p-chlorophenol from the solution onto the adsorbent. The target of the carboxyl-modified mesoporous silica is basic impurities or impurities that can form strong hydrogen bonds with the carboxyl group, such as 3-chloro-1,2-propanediol. The carboxyl group on the carboxyl-modified mesoporous silica is an acidic group, which can form strong hydrogen bonds with the hydroxyl group in the impurity molecule. At the same time, the chlorine atom in 3-chloro-1,2-propanediol also has a certain polarity, which can interact with the surface of the silica through dipole-dipole interaction, further enhancing adsorption. By selecting different surface modifications, targeted removal of impurities of different properties can be achieved. For example, when there are many acidic impurities in the crude product, amino modification is preferred; when it is necessary to remove neutral but hydroxyl-rich impurities such as chloropropanediol, carboxyl modification can be more effective.

[0046] The technical solution of the present application has a good synergistic removal effect on a small amount of p-chlorophenol, 3-chloro-1,2-propanediol or 3-chloropropylene oxide impurities which are difficult to remove in p-chlorophenyl ether. The following is illustrated by examples: (1) the removal process of p-chlorophenol: the first link (ScCO2 pretreatment): p-chlorophenol has a certain polarity and has limited solubility in ScCO2, and this step can partially remove it; the second link (DES extraction selectivity): in the DES (such as choline chloride-glycerol) system, chlorophenyl ether is preferentially dissolved because its molecular structure matches the hydrogen bond network of DES, while the solubility of p-chlorophenol in DES is relatively low, and part of it is left in the residue or the phase interface; the third link (core link: adsorption): as described above, the amino-modified mesoporous silica strongly and specifically adsorbs the residual trace amount of p-chlorophenol in the solution through acid-base interaction, which is a very critical step; the fourth link (gradient washing): even if there is a trace amount of adsorbed phenolic impurities, they will also be eluted in the gradient washing. (2) the removal process of 3-chloro-1,2-propanediol: the first link (ScCO2 pretreatment): this substance has strong polarity and very low solubility in ScCO2, and most of it remains in the solid; the second link (distribution in DES): although 3-chloro-1,2-propanediol also contains a hydroxyl group, its overall molecular structure is less compatible with DES than chlorophenyl ether, so it tends to remain in the mother liquor during the distribution process between the DES phase and the crystalline phase; the third link (core link: adsorption and spatial exclusion): carboxyl-modified silica can adsorb it through strong hydrogen bonds; more importantly, this type of small molecular impurity will be excluded by the growing chlorophenyl ether crystals during crystallization (because the size, shape and polarity of the molecules do not match, they cannot enter the crystal lattice); the adsorbent added synchronously acts like a "cleaner" and captures these impurities excluded around the crystals in time, preventing them from adhering again; the fourth link (gradient washing): due to its good water solubility, it is effectively washed out in the ethanol-water gradient washing; (3) the removal process of 3-chloropropylene oxide: this substance usually has a very low boiling point and is a volatile impurity; the first link (ScCO2 pretreatment): ScCO2 has good solubility for it, which can effectively extract it in the first step and remove it with CO2; the final link: even if there is a trace amount of residual, it will be evaporated and removed in the final drying step due to its high volatility, thereby ensuring that the final product does not contain this impurity.

[0047] In order to more clearly and specifically introduce the low-eutectic solvent-based chlorophenyl ether coupled crystallization-adsorption purification method provided by the embodiments of the present application, the following will be described in combination with specific examples.

[0048] Example 1 Take 10 g of chlorphenesin crude product (purity 85%), add 30 g of supercritical CO2, extract at 40°C for 30 min; prepare choline chloride: glycerol DES system in advance, molar ratio of 1:2, dissolve the pretreated chlorphenesin at 50°C, solid-liquid mass ratio of chlorphenesin to DES system is 1:5; the dissolved system is cooled to 10°C at a cooling rate of 0.5°C / min, and 0.5 g of amino-modified mesoporous silica with a pore size of 3 nm is added synchronously, stirring for 2 h; finally, the crystals are washed with 20%, 15%, and 10% ethanol aqueous solution in turn, each time with 10 mL, and the obtained crystals are sent into a 50°C oven for drying for 15 h to obtain the chlorphenesin finished product with a purity of 99.6% and a yield of 93%. As shown in Figure 1 .

[0049] Example 2 Take 10 g of chlorphenesin crude product (purity 85%), add 20 g of supercritical CO2, extract at 45°C for 30 min; prepare choline chloride: glycerol DES system in advance, molar ratio of 1:1, dissolve the pretreated chlorphenesin at 55°C, solid-liquid mass ratio of chlorphenesin to DES system is 1:6; the dissolved system is cooled to 8°C at a cooling rate of 0.5°C / min, and 0.1 g of amino-modified mesoporous silica with a pore size of 3 nm is added synchronously, stirring for 2 h; finally, the crystals are washed with 20%, 15%, and 10% ethanol aqueous solution in turn, each time with 10 mL, and the obtained crystals are sent into a 50°C oven for drying for 15 h to obtain the chlorphenesin finished product with a purity of 99.6% and a yield of 94%. As shown in Figure 2 .

[0050] Example 3 Take 10 g of chlorphenesin crude product (purity 85%), add 40 g of supercritical CO2, extract at 40°C for 30 min; prepare choline chloride: glycerol DES system in advance, molar ratio of 1:3, dissolve the pretreated chlorphenesin at 60°C, solid-liquid mass ratio of chlorphenesin to DES system is 1:5; the dissolved system is cooled to 12°C at a cooling rate of 0.5°C / min, and 0.5 g of carboxyl-modified mesoporous silica with a pore size of 3 nm is added synchronously, stirring for 2 h; finally, the crystals are washed with 20%, 15%, and 10% ethanol aqueous solution in turn, each time with 10 mL, and the obtained crystals are sent into a 50°C oven for drying for 15 h to obtain the chlorphenesin finished product with a purity of 99.5% and a yield of 92%. As shown in Figure 3 .

[0051] Comparative Example 1 Unlike Example 1, the choline chloride-urea system is used to dissolve the pretreated crude product at 60°C to obtain the chlorphenesin finished product with a purity of 99.4% and a yield of 88%.

[0052] Comparative Example 2 Different from Example 1, the raw material pretreatment stage was omitted, and DES extraction was directly used to obtain the chlorophenyl glycol ether product with a purity of 99.1% and a yield of 90%.

[0053] Comparative Example 3 Different from Example 1, supercritical methane was used as the extractant, and other conditions were the same, and the chlorophenyl glycol ether product obtained had a purity of 98.5% and a yield of 89%.

[0054] Comparative Example 4 Different from Example 1, no mesoporous silica adsorbent was added, and the final chlorophenyl glycol ether product obtained had a purity of 88.7% and a yield of 92%.

[0055] Comparative Example 5 Different from Example 1, methyl-modified silica was used, and the final chlorophenyl glycol ether product obtained had a purity of 89.4% and a yield of 88%.

[0056] Comparative Example 6 Different from Example 1, the crystals were washed with 20%, 15%, and 10% methanol aqueous solution, each time with a dosage of 10 mL, and the obtained crystals were sent to a 50°C oven for drying for 15h, to obtain the chlorophenyl glycol ether product with a purity of 98.7% and a yield of 84%.

[0057] Comparative Example 7 10g of the crude product was dissolved in 50g of an ethanol water system with a ratio of 1:5, heated to 60°C for dissolution, cooled to 0°C for crystallization, and the crystals were washed with the same proportion of ethanol water 30mL, and dried at 50°C for 15h, to obtain the chlorophenyl glycol ether product with a purity of 98.1% and a yield of 74%.

[0058]

Claims

1. A low eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process characterized in that, The application relates to a method for purifying crude chlorphenesin, comprising the following steps: S1: mixing crude chlorphenesin with supercritical CO2, extracting, and obtaining pretreated chlorphenesin; S2: dissolving the pretreated chlorphenesin in a choline chloride-glycerol DES system, adding an adsorbent after sufficient dissolution, and precipitating chlorphenesin by cooling.

2. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 1, characterized in that, The solid-liquid mass ratio of the chlorphenesin to the choline chloride-glycerol DES system is 1:5-8.

3. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 1, characterized in that, In the choline chloride-glycerol DES system, the molar ratio of choline chloride to glycerol is 1:1-5.

4. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 1, characterized in that, In step S1, the mass ratio of the chlorphenesin to the supercritical CO2 is 1:2-6.

5. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 1, wherein, In step S1, the extraction temperature is 40-50 DEG C.

6. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 1, wherein, The adsorbent is modified silicon dioxide, and the adsorbent addition amount is 1-10 wt% of the raw material.

7. The deep eutectic solvent-based chlorphenesin coupled crystallization-adsorption purification method according to claim 1, characterized by, In step S2, the temperature for dissolving the chlorphenesin in the choline chloride-glycerol DES system is 40-60 DEG C.

8. The deep eutectic solvent-based chlorphenesin coupled crystallization-adsorption purification method according to claim 1, characterized by, In step S2, the temperature is cooled to 5-15 DEG C.

9. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 1, wherein, The application further relates to a method for purifying crude chlorphenesin, comprising the following steps: S3: using an ethanol-water gradient system to wash the precipitated chlorphenesin.

10. The deep eutectic solvent based chlorphenesin coupled crystallization-adsorption purification process according to claim 6, characterized in that, The adsorbent is one of mesoporous silicon dioxide, amino-modified mesoporous silicon dioxide and carboxyl-modified silicon dioxide.

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