CN115124408A - Co-crystallization resolution method of cresol isomer mixture - Google Patents

Abstract

The invention provides a method for co-crystallizing and resolving a cresol isomer mixture, and relates to the technical field of chemical engineering separation. The method fully utilizes the unique selective cocrystallization and dissolution performance characteristics between the cresol monomers and the cocrystallization ligands, and can realize the high-efficiency resolution of the m-cresol and the p-cresol only through three unit operations of cocrystallization, solid-liquid separation and decomplexation. The method provided by the invention is applicable to mixed phenol with wide purity range (the content of cresol in the middle of the mixed phenol is 0-100%), high separation efficiency, simple required equipment, high yield, large treatment scale and simple operation, can be used for industrial production, does not use water in the separation process, can recycle eutectic ligands, organic solvents and the like used in the separation process, saves resources, and has better technical economy and higher industrial application value.

Description

A kind of co-crystallization resolution method of cresol isomer mixture

technical field

The invention relates to the technical field of chemical engineering separation, in particular to a co-crystallization separation method of a cresol isomer mixture.

Background technique

Cresol contains three positional isomers of o-cresol, m-cresol and p-cresol, all of which are important fine organic chemical products. It is an important raw material for active agents, etc., and is widely used in various fields such as industry and national economy. m-cresol (melting point: 11.95°C; boiling point: 202.20°C) at room temperature is a colorless or pale yellow liquid, o-cresol (melting point: 30.94°C; boiling point: 190.95°C) and p-cresol (melting point: 34.78°C; boiling point : 201.90℃) is a colorless or slightly yellow crystal, the three isomers are slightly soluble in water, soluble in ethanol, ether, lye, etc. Its structural formula is as follows:

Cresol is mainly obtained by chemical synthesis or separation from coal tar, and is generally a mixture of three isomers. The added value of cresol mixture is low, but its various isomer monomers are important chemical raw materials, which have a wide range of uses and higher economic value, so the production and development prospects are very broad. In recent years, the demand for high-purity cresol monomer products at home and abroad has been increasing, but the production capacity is insufficient, resulting in a shortage of cresol monomer products. Since the physicochemical properties of the three cresol isomer mixtures are relatively similar, it is difficult to separate and purify them, which has always been a huge challenge in industry, especially the separation of the mixture containing both m-cresol and p-cresol. From the physical properties of cresol, it can be seen that the boiling points of o-cresol, m-cresol and p-cresol are quite different, and they can be efficiently separated from mixed phenol by rectification; while the boiling points of m-cresol and p-cresol are They are so close that it is difficult to effectively separate the two using traditional rectification. Although the melting points of m-cresol and p-cresol are quite different, their mixtures have the disadvantages of eutectic and high viscosity fluids at low temperatures.

The separation and purification of p-mixed phenol (mainly the mixture of m-cresol and p-cresol, the same below) has a long history. The traditional methods for producing high-purity m-cresol and p-cresol are mainly m-toluidine diazotization hydrolysis method and Sulfonation alkali fusion method, but these two methods are more complicated, and use a large amount of highly polluting compounds such as diazonium salt, sulfuric acid, sodium nitrite in the production process, the atom utilization rate is low, and the process route is seriously polluted, which is not in line with modern Concept of green chemistry. Although Chinese patents CN103333052A, CN104058936A, CN105061156A, CN107445806A, CN107840785A, CN109232192A, CN111909004A, etc. all adopt the method of complexation and crystallization separation to separate p-cresol and m-cresol, which can realize the separation of m-cresol and p-cresol, However, in the separation process, the types and amounts of complexing agent and solvent, complexation reaction and crystallization temperature, reaction and crystallization time, and complexing agent removal are all quite different, and the use of water as decomplexing agent is prone to cause harm to a higher degree. Large phenol-containing wastewater cannot fundamentally solve the problem of obtaining high-purity m-cresol and p-cresol monomers from mixed phenol.

In order to overcome the above defects, it is necessary to develop a simple, efficient and industrially applicable separation and purification process for high-purity m-cresol and high-purity p-cresol monomers, which will help to increase cresol production capacity and significantly improve economic benefits of the business.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for co-crystallization and resolution of a cresol isomer mixture. The present invention is applicable to a wide range of mixed phenol purity, high degree of separation, no water is used in the separation process, simple operation, and can be carried out Industrial production.

In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:

The invention provides a co-crystallization splitting method of cresol isomer mixture, comprising the following steps:

(1) mixing the cresol isomer mixture and the co-crystal ligand I, carrying out the first-stage co-crystallization, and carrying out solid-liquid separation after the first-stage co-crystallization finishes to obtain the co-crystal I; the cresol The isomer mixture includes m-cresol and p-cresol, and the content of the m-cresol is 0-100%; the co-crystal ligand I includes 2,5-dimethylpiperazine, 2-methyl One of piperazine, nicotinamide, fumaric acid, tetramethyl urea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; the co-crystal I is m-cresol Co-crystal or p-cresol co-crystal;

(2) mixing the filtrate obtained by the solid-liquid separation described in step (1) with the eutectic ligand II to carry out second-stage co-crystallization, and performing solid-liquid separation after the second-stage co-crystallization to obtain co-crystal II; the Co-crystal ligand II includes 2,5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; when the co-crystal I is a m-cresol co-crystal, the co-crystal II is a p-cresol co-crystal; when the co-crystal I is a p-cresol co-crystal, the Described co-crystal II is m-cresol co-crystal;

(3) first decomplexing the co-crystal I to obtain the isomer I; when the co-crystal I is a m-cresol co-crystal, the isomer I is m-cresol; when the co-crystal I is m-cresol I is a co-crystal of p-cresol, and the isomer I is p-cresol;

(4) Perform the second decomplexation of the co-crystal II to obtain the isomer II; when the co-crystal II is a m-cresol co-crystal, the isomer II is m-cresol; when the co-crystal II is m-cresol II is a co-crystal of p-cresol, and the isomer II is p-cresol;

The steps (3) and (4) have no sequence relationship.

Preferably, the co-crystal ligand I is also obtained after the first decomplexation, and the obtained co-crystal ligand I is returned to the first-stage co-crystallization.

Preferably, the co-crystal ligand II is also obtained after the second decomplexation, and the obtained co-crystal ligand II is returned to the second-stage co-crystallization.

Preferably, when the co-crystal ligand I is nicotinamide or metformin, the co-crystal I is a m-cresol co-crystal;

When the co-crystal ligand I is methylmalonic acid, adipic acid or glutaric acid, the co-crystal I is a p-cresol co-crystal.

Preferably, when the co-crystal ligand II is nicotinamide or metformin, the co-crystal II is a m-cresol co-crystal;

When the co-crystal ligand II is methylmalonic acid, adipic acid or glutaric acid, the co-crystal II is a p-cresol co-crystal.

Preferably, when the co-crystal ligand I is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the first stage is co-crystallized When the end point temperature is 68～80 ℃, described co-crystal I is p-cresol co-crystal;

When the co-crystal ligand I is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, cresol isomer mixture m-cresol The content of I is higher than that of p-cresol and the end temperature of the first-stage co-crystallization is room temperature, and the co-crystal I is a m-cresol co-crystal.

Preferably, when the co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the second stage is co-crystallized When the end point temperature is 68～80℃, the co-crystal II is a p-cresol co-crystal;

When the co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the end temperature of the second-stage co-crystallization At room temperature, the co-crystal II is a m-cresol co-crystal.

Preferably, when the co-crystal I is a m-cresol co-crystal, the molar ratio of the co-crystal ligand I to the cresol isomer mixture m-cresol is 1.1-2.5:1;

When the co-crystal I is a p-cresol co-crystal, the molar ratio of the co-crystal ligand I to the p-cresol in the cresol isomer mixture is 0.6-1.25:1.

Preferably, when the first decomplexing and the second decomplexing are performed, a decomplexing agent is added independently.

Preferably, when the first-stage co-crystallization and the second-stage co-crystallization are carried out, an organic solvent is added independently.

The invention provides a method for co-crystallization and separation of cresol isomer mixture. The invention uses co-crystallization technology to prepare m-cresol co-crystal and p-cresol co-crystal respectively, and uses solid-liquid separation to remove co-crystal ligands , using a simple decomplexing operation to obtain high-purity isomers, and finally obtain high-purity m-cresol and p-cresol products. The invention makes full use of the unique selective co-crystallization and solubility characteristics between the cresol monomer and the co-crystal ligand, and only through the three unit operations of co-crystallization, solid-liquid separation and decomplexation, the synthesis of m-cresol and p-cresol can be realized. Efficient splitting. The method provided by the invention is applicable to a wide range of purity of mixed phenols (the content of m-cresol in mixed phenols is 0% to 100%), has high separation efficiency, simple required equipment, high yield, large processing scale and simple operation, and can be industrialized Moreover, water is not used in the separation process, and the used co-crystal ligands, organic solvents, etc. can be recycled, which saves resources and has good technical economy and high industrial application value.

Description of drawings

Fig. 1 is the co-crystallization method resolution process schematic diagram of cresol isomer mixture;

Fig. 2 is a microscope photo of the co-crystal product prepared in Example 1 of the present invention; the left picture in Fig. 2 is the m-cresol eutectic product; the right picture is the p-cresol eutectic product;

Fig. 3 is a microscope photo of the co-crystal product prepared in Example 3 of the present invention; the left picture in Fig. 3 is the m-cresol eutectic product; the right picture is the p-cresol eutectic product;

Fig. 4 is a microscope photo of the co-crystal product prepared in Example 5 of the present invention; the left picture in Fig. 4 is the m-cresol eutectic product; the right picture is the p-cresol eutectic product;

Figure 5 is a microscope photo of the co-crystal product prepared in Example 6 of the present invention; the left figure in Figure 5 is the m-cresol co-crystal product; the right figure is the p-cresol co-crystal product.

Detailed ways

The invention provides a co-crystallization splitting method of cresol isomer mixture, comprising the following steps:

(1) mixing the cresol isomer mixture and the co-crystal ligand I, carrying out the first-stage co-crystallization, and carrying out solid-liquid separation after the first-stage co-crystallization finishes to obtain the co-crystal I; the cresol The isomer mixture includes m-cresol and p-cresol, and the content of the m-cresol is 0-100%; the co-crystal ligand I includes 2,5-dimethylpiperazine, 2-methyl One of piperazine, nicotinamide, fumaric acid, tetramethyl urea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; the co-crystal I is m-cresol Co-crystal or p-cresol co-crystal;

(2) mixing the filtrate obtained by the solid-liquid separation described in step (1) with the eutectic ligand II to carry out second-stage co-crystallization, and performing solid-liquid separation after the second-stage co-crystallization to obtain co-crystal II; the Co-crystal ligand II includes 2,5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; when the co-crystal I is a m-cresol co-crystal, the co-crystal II is a p-cresol co-crystal; when the co-crystal I is a p-cresol co-crystal, the Described co-crystal II is m-cresol co-crystal;

(3) first decomplexing the co-crystal I to obtain the isomer I; when the co-crystal I is a m-cresol co-crystal, the isomer I is m-cresol; when the co-crystal I is m-cresol I is a co-crystal of p-cresol, and the isomer I is p-cresol;

(4) Perform the second decomplexation of the co-crystal II to obtain the isomer II; when the co-crystal II is a m-cresol co-crystal, the isomer II is m-cresol; when the co-crystal II is m-cresol II is a co-crystal of p-cresol, and the isomer II is p-cresol;

The steps (3) and (4) have no sequence relationship.

In the present invention, the cresol isomer mixture and the co-crystal ligand I are mixed to carry out the first-stage co-crystallization, and after the first-stage co-crystallization is completed, solid-liquid separation is performed to obtain the co-crystal I. In the present invention, the cresol isomer mixture includes m-cresol and p-cresol; the content of the m-cresol is 0-100%, preferably 20-100%. In the present invention, the cresol isomer mixture preferably further includes impurities, and the impurities preferably include one or more of naphthalene, 1-methylnaphthalene and cyanobenzene. In the present invention, the mass content of the impurities is preferably 0-20%. In the present invention, the impurities mainly originate from the upstream process.

In the present invention, the co-crystal ligand I includes 2,5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, One of adipic acid, glutaric acid and N-methylurea. In the present invention, the co-crystal I is m-cresol co-crystal or p-cresol co-crystal.

In the present invention, the temperature at which the cresol isomer mixture and the co-crystal ligand I are mixed is preferably 60-80°C, more preferably 68-78°C.

In the present invention, when the co-crystal ligand I is nicotinamide or metformin, the co-crystal I is a m-cresol co-crystal; when the co-crystal ligand I is methylmalonic acid, adipic acid or glutaric acid, the co-crystal I is a p-cresol co-crystal.

In the present invention, the first stage co-crystallization is preferably carried out in a crystallizer. In the present invention, the end temperature of the first-stage co-crystallization is preferably 25-80° C.; and the time is preferably 4-8 h.

In the present invention, when the co-crystal ligand I is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the first stage When the end point temperature of the co-crystallization is 68-80° C., the co-crystal I is a p-cresol co-crystal;

When the co-crystal ligand I is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, cresol isomer mixture m-cresol When the content of I is higher than that of p-cresol and the end temperature of the first-stage co-crystallization is room temperature, the co-crystal I is a m-cresol co-crystal. In the present invention, the temperature range of the room temperature is 18-30°C.

In the present invention, when the mass content of m-cresol in the cresol isomer mixture is 50-100%, it is preferable to prepare m-cresol co-crystal first. When the co-crystal I is a m-cresol co-crystal, the molar ratio of the co-crystal ligand I to the cresol isomer mixture m-cresol is preferably 1.1-2.5:1. In the present invention, when the mass content of p-cresol in the cresol isomer mixture is 50-100%, it is preferable to prepare the p-cresol co-crystal first. When the co-crystal I is a p-cresol co-crystal, the molar ratio of the co-crystal ligand I to the p-cresol in the cresol isomer mixture is preferably 0.6-1.25:1.

In the present invention, when the mass content of m-cresol in the cresol isomer mixture is 50-100%, and m-cresol co-crystals are prepared first, it is preferable to add organic compounds during the first-stage co-crystallization. solvent. In the present invention, the organic solvent preferably includes n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether one or both. In the present invention, when the m-cresol content of the cresol isomer mixture is 50-100%, the quality of the organic solvent is preferably 0.4-2.5 times the mass of the cresol isomer mixture, More preferably, it is 1.1 to 1.7 times.

In the present invention, when the mass content of m-cresol in the cresol isomer mixture is 50-100%, and the p-cresol co-crystal is prepared first, preferably no organic solvent is added. In this case, m-cresol is used as a solvent for the first-stage co-crystallization to obtain a co-crystal of p-cresol.

In the present invention, when the mass content of p-cresol in the cresol isomer mixture is 50-100%, and the p-cresol co-crystal is prepared first, it is preferable to add it during the first-stage co-crystallization. Organic solvents. In the present invention, the organic solvent preferably includes n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether one or both. In the present invention, when the content of p-cresol in the cresol isomer mixture is 50-100%, the mass of the organic solvent is preferably 0.4-2.5 times the mass of the cresol isomer mixture , more preferably 0.8 to 1.7 times.

In the present invention, when the mass content of p-cresol in the cresol isomer mixture is 50-100%, and the m-cresol co-crystal is prepared first, preferably no organic solvent is added. In this case, p-cresol is used as a solvent to perform the first-stage co-crystallization to obtain m-cresol co-crystals.

In the present invention, preferably, after the solid-liquid separation, drying is performed to obtain the co-crystal I. In the present invention, when the co-crystal I is a m-cresol co-crystal, the m-cresol co-crystal preferably includes m-cresol and a co-crystal ligand I; when the co-crystal I is a p-cresol co-crystal , the p-cresol co-crystal preferably includes p-cresol and co-crystal ligand I.

After the co-crystal I is obtained, the present invention mixes the filtrate obtained by the solid-liquid separation with the co-crystal ligand II to carry out the second-stage co-crystallization. After the second-stage co-crystallization is completed, solid-liquid separation is performed to obtain the co-crystal II. In the present invention, the co-crystal ligand II includes 2,5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, One of adipic acid, glutaric acid and N-methylurea. In the present invention, when the co-crystal I is a m-cresol co-crystal, the co-crystal II is a p-cresol co-crystal; when the co-crystal I is a p-cresol co-crystal, the co-crystal II is a meta-cresol co-crystal cresol co-crystal.

In the present invention, the temperature at which the filtrate obtained by the solid-liquid separation is mixed with the eutectic ligand II is preferably 10-60°C, more preferably 15-40°C.

In the present invention, when the co-crystal ligand II is nicotinamide or metformin, the co-crystal II is a m-cresol co-crystal; when the co-crystal ligand II is methylmalonic acid, adipic acid or glutaric acid, the co-crystal II is a p-cresol co-crystal.

In the present invention, the second stage co-crystallization is preferably carried out in a crystallizer. In the present invention, the end temperature of the second-stage co-crystallization is preferably 25-80° C.; and the time is preferably 4-8 h.

In the present invention, when the co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the second stage When the end point temperature of the co-crystallization is 68-80° C., the co-crystal II is a p-cresol co-crystal;

When the co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the end temperature of the second-stage co-crystallization At room temperature, the co-crystal II is a m-cresol co-crystal.

In the present invention, when the mass content of m-cresol in the cresol isomer mixture is 50-100%, it is preferable to prepare m-cresol co-crystal first. When the co-crystal II is a p-cresol co-crystal, the molar ratio of the co-crystal ligand II to the p-cresol in the cresol isomer mixture is preferably 0.6-1.25:1. In the present invention, when the mass content of p-cresol in the cresol isomer mixture is 50-100%, it is preferable to prepare the p-cresol co-crystal first. When the co-crystal II is a m-cresol co-crystal, the molar ratio of the co-crystal ligand II to the cresol isomer mixture m-cresol is preferably 1.1-2.5:1.

In the present invention, when the cresol isomer with a relatively high content is preferentially separated, preferably no organic solvent is added during the second-stage co-crystallization; when an organic solvent is added during the first-stage co-crystallization, the Preferably, no organic solvent is added during the second-stage co-crystallization.

In the present invention, when an organic solvent is added during the second-stage co-crystallization, the amount of the organic solvent to be added is to satisfy the total amount of the organic solvent added during the first-stage co-crystallization and the second-stage co-crystallization. The amount is preferably 0.4 to 2.5 times the mass of the cresol isomer mixture.

In the present invention, the organic solvent preferably includes n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether one or both.

In the present invention, preferably, after the solid-liquid separation, drying is performed to obtain co-crystal II. In the present invention, when the co-crystal II is a m-cresol co-crystal, the m-cresol co-crystal preferably includes m-cresol and a co-crystal ligand II; when the co-crystal II is a p-cresol co-crystal , the p-cresol co-crystal preferably includes p-cresol and co-crystal ligand II.

After the co-crystal I is obtained, the present invention performs the first decomplexation of the co-crystal I to obtain the isomer I. In the present invention, when the co-crystal I is a m-cresol co-crystal, the isomer I is m-cresol; when the co-crystal I is a p-cresol co-crystal, the isomer I is p-cresol cresol.

In the present invention, when performing the first decomplexing, preferably a decomplexing agent is added; the first decomplexing preferably comprises: dissolving the co-crystal I in the decomplexing agent to perform the first decomplexing, solid-liquid decomplexing After separation, the resulting filtrate was distilled to give Isomer I. In the present invention, the decomplexing agent is preferably an organic decomplexing agent, more preferably including n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, One or both of butyl ether, acetone, acetonitrile and diethyl ether. In the present invention, the mass of the decomplexing agent is preferably 0.8 to 1.9 times the mass of the cocrystal I, more preferably 1.0 to 1.5 times.

In the present invention, when the co-crystal ligand I is 2,5-dimethylpiperazine, 2-methylpiperazine or N-methylurea, preferably without adding a decomplexing agent, distillation is performed directly to obtain Isomer I.

In the present invention, the co-crystal ligand I is preferably obtained after the first decomplexation, and the obtained co-crystal ligand I is preferably returned to the first-stage co-crystallization. In the present invention, preferably, the filter cake obtained after the solid-liquid separation is dried to obtain the co-crystal ligand I.

In the present invention, the distillation is preferably distillation under reduced pressure.

In the present invention, the purity of the isomer I is preferably ≥99.5 wt%.

After the co-crystal II is obtained, the present invention performs the second decomplexation of the co-crystal II to obtain the isomer II. In the present invention, when the co-crystal II is a m-cresol co-crystal, the isomer II is m-cresol; when the co-crystal II is a p-cresol co-crystal, the isomer II is p-cresol cresol.

In the present invention, when performing the second decomplexing, preferably a decomplexing agent is added; the second decomplexing preferably comprises: dissolving the co-crystal II in the decomplexing agent to perform the second decomplexing, solid-liquid decomplexing After separation, the resulting filtrate was distilled to give Isomer II. In the present invention, the decomplexing agent is preferably an organic decomplexing agent, more preferably including n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, One or both of butyl ether, acetone, acetonitrile and diethyl ether. In the present invention, in the present invention, the mass of the decomplexing agent is preferably 0.8 to 1.9 times the mass of the cocrystal II, more preferably 1.0 to 1.5 times.

In the present invention, when the co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine or N-methylurea, preferably without adding a decomplexing agent, distillation is performed directly to obtain Isomer II.

In the present invention, the co-crystal ligand II is preferably obtained after the second decomplexation, and the obtained co-crystal ligand II is preferably returned to the second-stage co-crystallization. In the present invention, the filter cake obtained after the solid-liquid separation is preferably dried to obtain the co-crystal ligand II.

In the present invention, the distillation is preferably distillation under reduced pressure.

In the present invention, the purity of the isomer II is preferably ≥99.5 wt%.

In a specific embodiment of the present invention, a schematic diagram of the co-crystallization process for the separation of cresol isomer mixture is shown in FIG. 1 .

The present invention has the only selectivity to cresol, a wide range of applicable mixed phenol purity (the content of mid-cresol in mixed phenol is 0% to 100%), high separation degree, and high purity of cresol monomer product (≥99.5wt%) , the process yield is high (>76%); the operation is simple, and industrial production is possible; the process does not need to use water, and the organic solvent and eutectic ligand used can be recycled, green and pollution-free.

The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1

(1) get 30.00g mixed phenol, the content of described mixed phenol m-cresol is 6.00g, and the content of p-cresol is 24.00g;

(2.1) Select 5.14g of N-methylurea as a eutectic ligand, put it into the mixed phenol, and stir it at a constant temperature of 68°C for 0.5h to dissolve it;

(2.2) After dissolving, cool down to 43°C within 3h, and stir at constant temperature for 1h. After a new eutectic appears, cool the system to 25°C within 3h, and continue stirring at 25°C for 0.5-1h;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 9.30g of m-cresol co-crystal; the obtained solid only contained m-cresol and N-methylurea in the chromatographic detection, which contained 4.98g of m-cresol;

(4.2) The m-cresol co-crystal obtained above was heated and melted and then simply rectified to obtain 4.77g m-cresol with a purity of 99.5% and a total yield of 79.10%; 4.53g of N-methylurea was obtained, which was recycled.

(5.1) mother liquor after the solid-liquid separation of the suspension in step (3) (containing 1.02g m-cresol, 24.00g p-cresol in the mother liquor at this time) and 27.78g 2-methylpiperazine were added to 30.00g cyclohexane In alkane, and constant temperature stirring at 80 ℃ for 0.2h to make it evenly suspended in the crystallizer;

(5.2) constant temperature stirring for 1h;

(5.3) Cool down to 35°C for 8h, and continue to stir at constant temperature for 1h at 35°C;

(6) above-mentioned suspension is carried out solid separation;

(7.1) the obtained solid was dried by blowing at room temperature for 6h to obtain 50.56g of p-cresol co-crystal; the obtained solid was detected by chromatography only containing p-cresol and 2-methylpiperazine, which contained 22.80g of p-cresol;

(7.2) Dissolve the above obtained p-cresol co-crystal in 50.56g ether at 15°C, stir at constant temperature for 2h, and then carry out solid-liquid separation; the obtained filter cake is dried by blast to obtain 27.78g 2-methylpiperazine, which can be recycled use; the obtained filtrate is simply rectified to obtain 21.66 g of p-cresol with a purity of 99.8% and a total yield of 90.07%. The microscopic photo of the product is shown in Figure 2. The left picture in Figure 2 is the m-cresol co-crystal product, and the right picture is the p-cresol co-crystal product. It can be seen from FIG. 2 that the present invention prepares a eutectic product.

Example 2

(1) get 30.00g mixed phenol, the content of described mixed phenol m-cresol is 6.00g, and the content of p-cresol is 24.00g;

(2.1) Select 15.73 g of methylmalonic acid as the eutectic ligand, put it into 30.00 g of toluene, and stir at a constant temperature of 80 °C for 0.5 h;

(2.2) adding the mixed phenol flow to the toluene solution of methylmalonic acid, the flow rate is 1.5mL/min, after adding, constant temperature stirring for 1h;

(2.3) Cool down to 40°C within 3 to 6 hours, and continue stirring at 40°C for 1 hour;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 34.26g of p-cresol co-crystal; the solid obtained by chromatography only contained p-cresol and methylmalonic acid, and contained 18.53g of p-cresol;

(4.2) The above obtained p-cresol co-crystal was dissolved in a mixed solution of 34.26g toluene-acetone at 25°C (wherein the mass ratio of toluene and acetone was 9.5:0.5), and the solid-liquid separation was carried out after stirring at a constant temperature for 1h; After the cake was dried by blasting, 15.73 g of methylmalonic acid was obtained, which could be recycled; the obtained filtrate was simply rectified to obtain 18.47 g, with a purity of 99.9% and a total yield of p-cresol of 76.88%.

(5.1) Add 7.52g nicotinamide to the mother liquor after the solid-liquid separation of the suspension in step (3) (the mother liquor contains 6.00g m-cresol, 5.47g p-cresol, 30.00g toluene at this time), and keep the temperature at 68°C Stir for 0.5h to dissolve;

(5.2) After dissolving, cool down to 47°C within 1h, and stir at constant temperature for 1.2h. After a new eutectic appears, cool the system to 25°C within 4h, and continue stirring at 25°C for 0.5-1h;

(6) above-mentioned suspension is carried out solid separation;

(7.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 12.47g of m-cresol co-crystal; the obtained solid only contained m-cresol and nicotinamide in chromatographic detection, and contained 4.95g of m-cresol;

(7.2) The above-mentioned m-cresol co-crystal obtained was dissolved in a mixed solution of 12.47g toluene-acetone at 25°C (wherein the mass ratio of toluene and acetone was 9.5:0.5), and the solid-liquid separation was carried out after stirring at a constant temperature for 1h; The cake was dried by blast to obtain 7.52 g of nicotinamide, which could be recycled; the obtained filtrate was simply rectified to obtain 4.92 g of m-cresol with a purity of 99.5% and a total yield of 82.00%.

Example 3

(1) get 30.00g mixed phenol, the content of described mixed phenol m-cresol is 6.00g, and the content of p-cresol is 24.00g;

(2.1) Select 17.62g of glutaric acid as the co-crystal ligand, put it into 30.00g of cyclohexane, and stir at a constant temperature of 80°C for 0.5h;

(2.2) adding the mixed phenol flow into the cyclohexane solution of glutaric acid, the flow rate is 2.5mL/min, after the addition is completed, constant temperature stirring for 1h;

(2.3) Cool down to 25°C for 8h, and continue stirring at 25°C for 1h;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 37.41g of p-cresol co-crystal; the obtained solid was detected by chromatography only containing p-cresol and glutaric acid, and contained 19.79g of p-cresol;

(4.2) Dissolve the above obtained p-cresol co-crystal in 37.41g n-butanol at 25°C, stir at constant temperature for 1.5h, and carry out solid-liquid separation; 19.61g of p-cresol was obtained after simple rectification of the obtained filtrate, the purity was 99.8%, and the total yield was 81.71%.

(5.1) adding 16.12g fumaric acid to the mother liquor after the solid-liquid separation of the suspension in the above step (3) (the mother liquor now contains 6.00g m-cresol, 4.21g p-cresol, 30.00g cyclohexane), Stir at constant temperature for 0.5h at 80°C to dissolve;

(5.2) After dissolving, cool down to 62°C within 1h, stir at constant temperature for 1.2h, after new eutectic appears, cool down the system from 8h to 25°C, and continue stirring at 25°C for 1h;

(6) above-mentioned suspension is carried out solid separation;

(7.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 19.32g of m-cresol co-crystal; the obtained solid only contained m-cresol and fumaric acid by chromatography, and contained 4.89g of m-cresol;

(7.2) Dissolve the above-mentioned m-cresol co-crystal in 19.32g isopropanol at 25°C, and perform solid-liquid separation after stirring at a constant temperature for 1 hour; the obtained filter cake is dried by blast to obtain 14.43g fumaric acid, which can be recycled The obtained filtrate was simply rectified to obtain 4.65g m-cresol with a purity of 99.7% and a total yield of 77.27%. The microscopic photo of the product is shown in Figure 3. The left picture in Figure 3 is the m-cresol co-crystal product, and the right picture is the p-cresol co-crystal product. It can be seen from FIG. 3 that the present invention prepares a eutectic product.

Example 4

(1) get 30.00g mixed phenol, the content of described mixed phenol m-cresol is 15.00g, and the content of p-cresol is 15.00g;

(2.1) 19.71 g of metformin was selected as the eutectic ligand, put into the mixed phenol solution, and stirred at a constant temperature of 68 °C for 0.5 h to completely dissolve it;

(2.2) The temperature of the system was lowered to 57°C within 1h, and the constant temperature was stirred for 0.5h, and a new eutectic appeared in the system;

(2.3) Cool down to 25°C in 5.3h, when the system becomes thick, add 10.00g n-butanol, and the flow rate is 1.0mL/min;

(2.4) Continue constant temperature stirring for 1h after cooling to 25°C;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 33.25g of m-cresol co-crystal; the obtained solid only contained m-cresol and metformin in chromatographic detection, and contained 13.56g of m-cresol;

(4.2) The above obtained m-cresol co-crystal was dissolved in 33.25g of n-hexane at 25°C, and the solid-liquid separation was carried out after stirring at a constant temperature for 2.0h; the obtained filter cake was dried by blast to obtain 19.69g of metformin, which can be recycled; the obtained The filtrate was simply rectified to obtain 11.82 g of m-cresol with a purity of 99.9% and a total yield of 78.72%.

(5.1) 15.63g of adipic acid was added to 20.00g of n-butanol, and stirred at a constant temperature of 75°C for 0.2h to make it evenly suspended in the crystallizer;

(5.2) the mother liquor (containing 1.44g m-cresol, 15.00g p-cresol, 10.00g n-butanol in the mother liquor at this time) after the solid-liquid separation of the suspension in the above-mentioned step (3) stream was added to the n-butyl alcohol of adipic acid. In the alcoholic solution, the flow rate was 1.0 mL/min, and after the addition, the mixture was stirred at a constant temperature for 1 h;

(5.3) Cool down to 40°C for 3h, and continue stirring at 40°C for 1h;

(6) above-mentioned suspension is carried out solid separation;

(7.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 28.46g of p-cresol co-crystal; the obtained solid only contained p-cresol and adipic acid by chromatography, and contained 12.83g of p-cresol;

(7.2) The above obtained co-crystal was dissolved in 28.46g of acetonitrile solvent at 40°C, and the solid-liquid separation was carried out after stirring at a constant temperature for 1 h; the obtained filter cake was dried by blast to obtain 15.63g of adipic acid, which can be recycled; the obtained filtrate was simply After rectification, 12.11 g of p-cresol was obtained with a purity of 99.5% and a total yield of 80.33%.

Example 5

(1) get 30.00g mixed phenol, described mixed phenolic cresol content 15.00g, p-cresol content 15.00g;

(2.1) 14.5g of tetramethyl urea was added to 30.00g of toluene-n-heptane, and stirred at a constant temperature of 80°C for 0.5h to make it evenly suspended in the crystallizer;

(2.2) adding the mixed phenol flow to the n-heptane solution of tetramethyl urea, the flow rate was 1.0 mL/min, and after the addition was completed, constant temperature stirring was performed for 1 h;

(2.3) Cool down to 70°C for 3h, and continue stirring at 70°C for 1h;

(3) above-mentioned suspension is carried out solid separation;

(4.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 25.64g co-crystal; the obtained solid was detected by chromatography only containing p-cresol and tetramethyl urea, which contained p-cresol 12.28g;

(4.2) above-mentioned obtained co-crystal was dissolved in 25.64g n-heptane-diethyl ether mixed solvent (wherein the mass ratio of n-heptane and diethyl ether was 8:2) at 25°C, and solid-liquid separation was carried out after constant temperature stirring for 1h; After the cake is dried by blasting, 13.36 g of tetramethyl urea is obtained, which can be recycled; the obtained filtrate is simply rectified to obtain 11.99 g of p-cresol with a purity of 99.9% and a total yield of 79.85%.

(5.1) 24.16g of fumaric acid was used as a eutectic ligand, and put into the mother liquor after the above solid-liquid separation (the mother liquor at this time contained 15g of m-cresol, 2.72g of p-cresol, and 30.00g of n-heptane), at 78° C. Stir at constant temperature for 0.5h to make it completely dissolved;

(5.2) Reduce the temperature of the system to 53°C within 3h, stir at a constant temperature for 0.5h, and wait for a new eutectic to appear in the system;

(5.3) Cool down to 25°C in 4.6h;

(5.4) Continue constant temperature stirring for 1h after cooling to 25°C;

(6) above-mentioned suspension is carried out solid-liquid separation;

(7.1) The obtained solid was dried by blowing at room temperature for 4～8h to obtain 34.93g of co-crystal; the obtained solid only contained m-cresol and fumaric acid in the chromatographic detection, and contained 12.56g of m-cresol;

(7.2) the above-mentioned obtained co-crystal is dissolved in a mixed solvent of 34.93g n-heptane and diethyl ether (wherein the mass ratio of n-heptane and diethyl ether is 8:2) at 15°C, and solid-liquid separation is carried out after constant temperature stirring for 2.0h; The obtained filter cake was dried by blast to obtain 22.37 g of fumaric acid, which could be recycled; the obtained filtrate was simply rectified to obtain 11.88 g of m-cresol with a purity of 99.6% and a total yield of 78.88%. The product performance results are shown in Figure 4. The left picture in Figure 4 is the m-cresol co-crystal product, and the right picture is the p-cresol co-crystal product. It can be seen from FIG. 4 that the present invention prepares a eutectic product.

Example 6

(1) get 30.00g mixed phenol, the content of described mixed phenol m-cresol is 24.00g, and the content of p-cresol is 6.00g;

(2.1) Select 32.97g of metformin as the eutectic ligand, put it into the mixed phenol solution, and stir at a constant temperature of 78°C for 1.0h to completely dissolve it;

(2.2) Reduce the temperature of the system to 55°C within 1h, stir at a constant temperature for 0.5h, and a new eutectic appears in the system;

(2.3) Cool down to 25°C in 4.5h, when the system becomes viscous, add 45.00g of n-hexane to the flow, and the flow rate is 2.0mL/min;

(2.4) After cooling to 25°C, continue stirring at constant temperature for 1.5h;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) The obtained solid was dried by blasting at room temperature for 6h to obtain 51.97g of m-cresol co-crystal; the obtained solid only contained m-cresol and metformin in the chromatographic detection, and contained 20.19g of m-cresol;

(4.2) The above-mentioned m-cresol co-crystal obtained was dissolved in 77.96g isopropanol at 15°C, and the solid-liquid separation was carried out after stirring at a constant temperature for 2.0h; the obtained filter cake was dried by blast to obtain 31.79g of metformin, which can be recycled; The obtained filtrate was simply rectified to obtain 19.38 g of m-cresol with a purity of 99.8% and a total yield of 80.59%.

(5.1) 9.17g of glutaric acid was added to the mother liquor after the solid-liquid separation of the suspension in the above step (3) (the mother liquor at this time contained 3.81g of m-cresol, 6.00g of p-cresol, and 45.00g of n-hexane), and Stir at a constant temperature of 75°C for 0.2h to make it evenly suspended in the crystallizer;

(5.2) Cool down to 25°C in 6.3h, and continue stirring at 25°C for 1h;

(6) above-mentioned suspension is carried out solid separation;

(7.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 11.43g of p-cresol co-crystal; the obtained solid was detected by chromatography only containing p-cresol and glutaric acid, which contained p-cresol 4.83g;

(7.2) The above obtained p-cresol co-crystal was dissolved in 11.43g isopropanol at 40°C, and the solid-liquid separation was carried out after stirring at a constant temperature for 0.5h; the obtained filter cake was dried by blast to obtain 6.60g glutaric acid, which can be recycled use; the obtained filtrate is simply rectified to obtain 4.52 g of p-cresol with a purity of 99.6% and a total yield of 75.03%. The microscopic photo of the product is shown in Figure 5. The left picture in Figure 5 is the m-cresol co-crystal product, and the right picture is the p-cresol co-crystal product. It can be seen from FIG. 5 that the present invention prepares a eutectic product.

Example 7

(1) get 30.00g mixed phenol, the content of described mixed phenol m-cresol is 24.00g, and the content of p-cresol is 6.00g;

(2.1) Select 38.66g of fumaric acid as the eutectic ligand, put it into the mixed phenol solution, and stir at a constant temperature of 80°C for 1.0h to completely dissolve it;

(2.2) Reduce the temperature of the system to 68°C within 1h, stir at a constant temperature for 1.5h, and a new eutectic appears in the system;

(2.3) Cool down to 38°C for 5h, when the system becomes viscous, add 45.00g n-butyl ether, and the flow rate is 2.5mL/min;

(2.4) After cooling to 35°C, continue stirring at constant temperature for 1.5h;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 54.00g of m-cresol co-crystal; the obtained solid only contained m-cresol and fumaric acid by chromatography, and contained 19.16g of m-cresol;

(4.2) The above-mentioned m-cresol co-crystal obtained was dissolved in a mixed solution of 81.00g toluene-diethyl ether (wherein the mass ratio of toluene and diethyl ether was 9:1) at 15°C, and the solid-liquid separation was carried out after stirring at a constant temperature for 2.0h; the obtained After the filter cake was dried by blasting, 34.84 g of fumaric acid was obtained, which could be recycled; the obtained filtrate was simply rectified to obtain 18.66 g of m-cresol with a purity of 99.6% and a total yield of 77.45%.

(5.1) 9.53g 2-methylpiperazine is added to the mother liquor after the above-mentioned step (3) suspension solid-liquid separation (at this moment, the mother liquor contains 4.84g m-cresol, 6.00g p-cresol, 45.00g n-butyl ether ), and stirred at 78°C for 1 h to dissolve it;

(5.2) Cool down to 75°C for 1 hour, and continue stirring at 75°C for 1-3 hours to make it crystallize;

(5.3) Cool down to 68°C for 4h, and continue stirring at 68°C for 1h;

(6) above-mentioned suspension is carried out solid separation;

(7.1) the obtained solid was dried by blasting at room temperature for 6h to obtain 14.54g of p-cresol co-crystal; the obtained solid was detected by chromatography only containing p-cresol and 2-methylpiperazine, and contained 5.37g of p-cresol;

(7.2) above-mentioned obtained p-cresol co-crystal was dissolved in 21.81g ether-isopropanol mixed solvent (wherein the mass ratio of ether and ethanol was 9.5:0.5) at 15°C, and solid-liquid separation was carried out after constant temperature stirring for 2.5h; The obtained filter cake is blown and dried to obtain 9.17 g of 2-methylpiperazine, which can be recycled; the obtained filtrate is simply rectified to obtain 5.12 g of p-cresol with a purity of 99.8% and a total yield of 85.16%.

Example 8

(1) get 30.00g mixed phenol, described mixed phenolic cresol content 24.00g, p-cresol content 6.00g;

(2.1) Select 8.06g of tetramethylurea as the eutectic ligand, put it into 45.00g of n-propanol, and stir at a constant temperature of 68°C for 0.5h to make it suspended in the crystal;

(2.2) adding the mixed phenol flow into the n-propanol solution of tetramethylurea, the flow rate is 1.2mL/min, after adding, stirring at constant temperature for 8h;

(3) above-mentioned suspension is carried out solid-liquid separation;

(4.1) The obtained solid was dried by blasting at room temperature for 4～8h to obtain 12.36g of p-cresol co-crystal; the obtained solid was detected by chromatography only containing p-cresol and tetramethylurea, and 5.53g of p-cresol was contained therein;

(4.2) Dissolve the obtained p-cresol co-crystal in 18.54g acetone at 15°C, stir at constant temperature for 2.5h, and then carry out solid-liquid separation; the obtained filter cake is dried by blast to obtain 6.83g of tetramethylurea, which can be recycled ; The obtained filtrate obtained 5.37g after simple rectification, the purity was 99.5%, and the total yield of p-cresol was 89.05%.

(5.1) adding 27.86g 2,5-27.86g 2,5- Dimethylpiperazine was dissolved under constant temperature stirring at 80°C for 0.5h;

(5.2) After dissolving, cool down to 68°C within 1h, stir at constant temperature for 1.5h, and wait for a new eutectic to appear in the crystallizer;

(5.3) Cool the system to 25°C within 4h, and finally continue stirring at a constant temperature of 25°C for 0.5-1h;

(6) above-mentioned suspension is carried out solid separation;

(7.1) The obtained solid was dried by blasting at room temperature for 6h to obtain 49.06g of m-cresol co-crystal; the obtained solid only contained m-cresol and 2,5-dimethylpiperazine, and 22.31g of m-cresol was detected in the obtained solid. ;

(7.2) The above obtained m-cresol co-crystal was dissolved in 73.59g isobutanol at 25°C, and the solid-liquid separation was carried out after stirring at a constant temperature for 1 h; Piperazine can be recycled; the obtained filtrate is simply rectified to obtain 21.91 g of m-cresol with a purity of 99.8% and a total yield of 91.11%.

The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.

Claims (10)

1. a co-crystallization resolution method of cresol isomer mixture, comprises the following steps: (1) mixing the cresol isomer mixture and the co-crystal ligand I, carrying out the first-stage co-crystallization, and carrying out solid-liquid separation after the first-stage co-crystallization finishes to obtain the co-crystal I; the cresol The isomer mixture includes m-cresol and p-cresol, and the content of the m-cresol is 0-100%; the co-crystal ligand I includes 2,5-dimethylpiperazine, 2-methyl One of piperazine, nicotinamide, fumaric acid, tetramethyl urea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; the co-crystal I is m-cresol Co-crystal or p-cresol co-crystal; (2) mixing the filtrate obtained by the solid-liquid separation described in step (1) with the eutectic ligand II to carry out second-stage co-crystallization, and performing solid-liquid separation after the second-stage co-crystallization to obtain co-crystal II; the Co-crystal ligand II includes 2,5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; when the co-crystal I is a m-cresol co-crystal, the co-crystal II is a p-cresol co-crystal; when the co-crystal I is a p-cresol co-crystal, the Described co-crystal II is m-cresol co-crystal; (3) first decomplexing the co-crystal I to obtain the isomer I; when the co-crystal I is a m-cresol co-crystal, the isomer I is m-cresol; when the co-crystal I is m-cresol I is a co-crystal of p-cresol, and the isomer I is p-cresol; (4) Perform the second decomplexation of the co-crystal II to obtain the isomer II; when the co-crystal II is a m-cresol co-crystal, the isomer II is m-cresol; when the co-crystal II is m-cresol II is a co-crystal of p-cresol, and the isomer II is p-cresol; The steps (3) and (4) have no sequence relationship. 2. The co-crystal splitting method according to claim 1, wherein the co-crystal ligand I is also obtained after the first decomplexation, and the obtained co-crystal ligand I is returned to carry out the first-stage co-crystallization. 3 . The co-crystal splitting method according to claim 1 , wherein the co-crystal ligand II is also obtained after the second decomplexation, and the obtained co-crystal ligand II is returned to carry out the second-stage co-crystallization. 4 . 4. co-crystal splitting method according to claim 1, is characterized in that, when described co-crystal ligand I is nicotinamide or metformin, described co-crystal I is m-cresol co-crystal; When the co-crystal ligand I is methylmalonic acid, adipic acid or glutaric acid, the co-crystal I is a p-cresol co-crystal. 5. co-crystal splitting method according to claim 1, is characterized in that, when described co-crystal ligand II is nicotinamide or metformin, described co-crystal II is m-cresol co-crystal; When the co-crystal ligand II is methylmalonic acid, adipic acid or glutaric acid, the co-crystal II is a p-cresol co-crystal. 6. co-crystal splitting method according to claim 1, is characterized in that, when described co-crystal part I is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetrakis Methyl urea or N-methyl urea, and when the end temperature of the first-stage co-crystallization is 68 to 80° C., the co-crystal I is a p-cresol co-crystal; When the co-crystal ligand I is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, cresol isomer mixture m-cresol The content of I is higher than that of p-cresol and the end temperature of the first-stage co-crystallization is room temperature, and the co-crystal I is a m-cresol co-crystal. 7. co-crystal splitting method according to claim 1, is characterized in that, when described co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetrakis Methyl urea or N-methyl urea, and when the end point temperature of the second-stage co-crystallization is 68 to 80° C., the co-crystal II is a p-cresol co-crystal; When the co-crystal ligand II is 2,5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, and the end temperature of the second-stage co-crystallization At room temperature, the co-crystal II is a m-cresol co-crystal. 8. co-crystal splitting method according to claim 1, is characterized in that, when described co-crystal I is m-cresol co-crystal, described co-crystal ligand I and cresol isomer mixture intermediate The molar ratio of cresol is 1.1～2.5:1; When the co-crystal I is a p-cresol co-crystal, the molar ratio of the co-crystal ligand I to the p-cresol in the cresol isomer mixture is 0.6-1.25:1. 9 . The co-crystal splitting method according to claim 1 , wherein a decomplexing agent is added independently when the first decomplexing and the second decomplexing are performed. 10 . 10 . The method for splitting co-crystallization according to claim 1 , wherein, when carrying out the first-stage co-crystallization and the second-stage co-crystallization, an organic solvent is added independently. 11 .

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