CN115124408B - Co-crystallization resolution method of cresol isomeride mixture - Google Patents
Co-crystallization resolution method of cresol isomeride mixture Download PDFInfo
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- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/685—Processes comprising at least two steps in series
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Abstract
The invention provides a co-crystallization resolution method of a cresol isomeride mixture, and relates to the technical field of chemical engineering separation. The invention fully utilizes the unique selective co-crystallization and solubility characteristics between the cresol monomer and the eutectic ligand, and can realize the high-efficiency resolution of m-cresol and p-cresol only through three unit operations of co-crystallization, solid-liquid separation and decomplexing. The method provided by the invention is applicable to mixed phenols with wide purity range (the cresol content in the mixed phenols is 0% -100%), has 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 the used eutectic ligand, organic solvent and the like, saves resources, and has better technical economy and higher industrial application value.
Description
Technical Field
The invention relates to the technical field of chemical engineering separation, in particular to a co-crystallization resolution method of a cresol isomeride mixture.
Background
The cresol contains three positional isomers of o-cresol, m-cresol and p-cresol, is an important fine organic chemical product, is an important raw material for producing antioxidants, plasticizers, inhibitors, pesticides, dyes, preservatives, surfactants and the like, and is widely applied to various fields of industry, national economy and the like. M-cresol (melting point: 11.95 ℃ C.; boiling point: 202.20 ℃ C.) is colorless or pale yellow liquid at room temperature, o-cresol (melting point: 30.94 ℃ C.; boiling point: 190.95 ℃ C.) and p-cresol (melting point: 34.78 ℃ C.; boiling point: 201.90 ℃ C.) are colorless or yellowish crystals, and all three isomers are slightly soluble in water, ethanol, diethyl ether, alkali solution, etc. The structural formula is as follows:
Cresols are mainly prepared by chemical synthesis or separation from coal tar, typically as a mixture of three isomers. The cresol mixture has lower added value, but each isomer monomer is an important chemical raw material, has wide application and higher economic value, and therefore has very broad production and development prospects. In recent years, the demands for high-purity cresol monomer products are increasing at home and abroad, but the productivity is insufficient, so that the supply of the cresol monomer products is insufficient. Because of the relatively similar physicochemical properties of the three cresol isomer mixtures, the separation and purification of the three cresol isomer mixtures is relatively difficult, and has been a great challenge in industry, especially for separating mixtures containing both m-cresol and p-cresol. As known from physical properties of cresol, the o-cresol has a large boiling point difference from m-cresol and p-cresol, and can be efficiently separated from mixed phenol by using a rectification means; and the boiling points of the m-cresol and the p-cresol are very close, so that the m-cresol and the p-cresol are difficult to be effectively separated by using the traditional rectification. Although m-cresol and p-cresol have widely different melting points, their mixtures suffer from the disadvantages of eutectic and high viscosity fluids at low temperatures.
The separation and purification of p-cresol (mainly a mixture of m-cresol and p-cresol, the same applies hereinafter) are long-lasting, and the traditional method for producing high-purity m-cresol and p-cresol mainly comprises a m-toluidine diazotization hydrolysis method and a sulfonated alkali fusion method, but the two methods have relatively complex processes, and a large amount of high-pollution compounds such as diazonium salt, sulfuric acid, sodium nitrite and the like are used in the production process, so that the atomic utilization rate is low, the pollution of the process route is serious, and the modern green chemistry concept is not met. Although the separation of m-cresol and p-cresol can be realized by adopting the methods of complexation and crystallization separation in Chinese patent CN103333052A, CN104058936A, CN105061156A, CN107445806A, CN107840785A, CN109232192A, CN111909004A and the like, the types and the amounts of complexing agents and solvents, the complexation reaction and crystallization temperature, the reaction and crystallization time, the complexing agent removal and the like are greatly different in the separation process, and water is used as a decomplexing agent, so that phenol-containing wastewater with larger hazard degree is easy to generate, and the problem of obtaining high-purity m-cresol and p-cresol monomers from mixed phenol cannot be fundamentally solved.
In order to overcome the defects, the separation and purification process of the high-purity m-cresol and the high-purity p-cresol monomers which are simple, efficient and applicable to industrial production is necessary, which is helpful for improving the cresol yield and remarkably improving the economic benefit of enterprises.
Disclosure of Invention
The invention aims to provide a co-crystallization resolution method of a cresol isomeride mixture, which is applicable to mixed phenol with wide purity range and high separation degree, does not use water in the separation process, is simple to operate and can be used for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a co-crystallization resolution method of a cresol isomeride mixture, which comprises the following steps:
(1) Mixing the cresol isomer mixture with the eutectic ligand I, performing first-stage co-crystallization, and performing solid-liquid separation after the first-stage co-crystallization is finished to obtain a eutectic I; the cresol isomer mixture comprises m-cresol and p-cresol, wherein the content of the m-cresol is 0-100%; the eutectic ligand I comprises one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; the eutectic I is m-cresol eutectic or p-cresol eutectic;
(2) Mixing the filtrate obtained in the step (1) with a eutectic ligand II, and performing second-stage co-crystallization, wherein after the second-stage co-crystallization is finished, solid-liquid separation is performed to obtain a eutectic II; the eutectic ligand II comprises one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; when the eutectic I is m-cresol eutectic, the eutectic II is p-cresol eutectic; when the eutectic I is a paracresol eutectic, the eutectic II is a metacresol eutectic;
(3) First decomplexing the eutectic I to obtain an isomer I; when the eutectic I is m-cresol eutectic, the isomer I is m-cresol; when the eutectic I is a paracresol eutectic, the isomer I is paracresol;
(4) Second decomplexing the eutectic II to obtain an isomer II; when the eutectic II is m-cresol eutectic, the isomer II is m-cresol; when the eutectic II is a paracresol eutectic, the isomer II is paracresol;
and (3) and (4) have no precedence relationship.
Preferably, the first decomplexing is followed by obtaining a eutectic ligand I, and the obtained eutectic ligand I is returned to the first-stage co-crystallization.
Preferably, the second decomplexing is followed by obtaining a eutectic ligand II, and the obtained eutectic ligand II is returned to the second stage of co-crystallization.
Preferably, when the eutectic ligand I is nicotinamide or metformin, the eutectic I is a m-cresol eutectic;
when the eutectic ligand I is methylmalonic acid, adipic acid or glutaric acid, the eutectic I is a paracresol eutectic.
Preferably, when the eutectic ligand II is nicotinamide or metformin, the eutectic II is a m-cresol eutectic;
when the eutectic ligand II is methylmalonic acid, adipic acid or glutaric acid, the eutectic II is a paracresol eutectic.
Preferably, when the eutectic ligand I is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the first-stage co-crystallization is 68-80 ℃, the eutectic I is a paracresol eutectic;
when the eutectic ligand I is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, the cresol content in the intermediate cresol of the cresol isomer mixture is higher than that of the p-cresol, the end point temperature of the first-stage co-crystallization is room temperature, and the eutectic I is m-cresol eutectic.
Preferably, when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the second-stage co-crystallization is 68-80 ℃, the eutectic II is p-cresol eutectic;
when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the second-stage co-crystallization is room temperature, the eutectic II is m-cresol eutectic.
Preferably, when the eutectic I is a m-cresol eutectic, the molar ratio of the eutectic ligand I to the intermediate cresol of the cresol isomeric mixture is 1.1-2.5: 1, a step of;
when the eutectic I is a paracresol eutectic, the molar ratio of the eutectic ligand I to paracresol in the cresol isomer mixture is 0.6-1.25: 1.
preferably, the first decomplexing agent and the second decomplexing agent are independently added when the first decomplexing agent and the second decomplexing agent are performed.
Preferably, the first-stage co-crystallization and the second-stage co-crystallization are performed with the organic solvent added independently.
The invention provides a co-crystallization resolution method of a cresol isomeride mixture, which utilizes a co-crystallization technology to prepare m-cresol eutectic and p-cresol eutectic respectively, utilizes solid-liquid separation to remove eutectic ligand, utilizes simple decomplexing operation to obtain high-purity isomeride, and finally obtains high-purity m-cresol and p-cresol products. The invention fully utilizes the unique selective co-crystallization and solubility characteristics between the cresol monomer and the eutectic ligand, and can realize the high-efficiency resolution of m-cresol and p-cresol only through three unit operations of co-crystallization, solid-liquid separation and decomplexing. The method provided by the invention is applicable to mixed phenols with wide purity range (the cresol content in the mixed phenols is 0% -100%), has 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 the used eutectic ligand, organic solvent and the like, saves resources, and has better technical economy and higher industrial application value.
Drawings
FIG. 1 is a schematic diagram of a co-crystallization resolution process for a cresol isomeric mixture;
FIG. 2 is a photomicrograph of a co-crystal product prepared in example 1 of the present invention; the left panel in fig. 2 is the m-cresol eutectic product; the right figure shows the p-cresol eutectic product;
FIG. 3 is a photomicrograph of a co-crystal product prepared in example 3 of the present invention; the left panel in fig. 3 is the m-cresol eutectic product; the right figure shows the p-cresol eutectic product;
FIG. 4 is a photomicrograph of a co-crystal product prepared in example 5 of the present invention; the left panel in fig. 4 is the m-cresol eutectic product; the right figure shows the p-cresol eutectic product;
FIG. 5 is a photomicrograph of a co-crystal product prepared in example 6 of the present invention; the left panel in fig. 5 is the m-cresol eutectic product; the right panel shows the p-cresol eutectic product.
Detailed Description
The invention provides a co-crystallization resolution method of a cresol isomeride mixture, which comprises the following steps:
(1) Mixing the cresol isomer mixture with the eutectic ligand I, performing first-stage co-crystallization, and performing solid-liquid separation after the first-stage co-crystallization is finished to obtain a eutectic I; the cresol isomer mixture comprises m-cresol and p-cresol, wherein the content of the m-cresol is 0-100%; the eutectic ligand I comprises one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; the eutectic I is m-cresol eutectic or p-cresol eutectic;
(2) Mixing the filtrate obtained in the step (1) with a eutectic ligand II, and performing second-stage co-crystallization, wherein after the second-stage co-crystallization is finished, solid-liquid separation is performed to obtain a eutectic II; the eutectic ligand II comprises one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; when the eutectic I is m-cresol eutectic, the eutectic II is p-cresol eutectic; when the eutectic I is a paracresol eutectic, the eutectic II is a metacresol eutectic;
(3) First decomplexing the eutectic I to obtain an isomer I; when the eutectic I is m-cresol eutectic, the isomer I is m-cresol; when the eutectic I is a paracresol eutectic, the isomer I is paracresol;
(4) Second decomplexing the eutectic II to obtain an isomer II; when the eutectic II is m-cresol eutectic, the isomer II is m-cresol; when the eutectic II is a paracresol eutectic, the isomer II is paracresol;
and (3) and (4) have no precedence relationship.
The invention mixes the cresol isomeride mixture and the eutectic ligand I, carries out the first-stage co-crystallization, and carries out solid-liquid separation after the first-stage co-crystallization is finished to obtain the eutectic I. In the present invention, the cresol isomeric mixture includes m-cresol and p-cresol; the content of m-cresol is 0 to 100%, preferably 20 to 100%. In the present invention, the cresol isomer mixture preferably further includes an impurity, and the impurity preferably includes one or more of naphthalene, 1-methylnaphthalene and cyanobenzene. In the present invention, the impurity content is preferably 0 to 20% by mass. In the present invention, the impurities originate mainly from the upstream process.
In the present invention, the eutectic ligand I includes one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea. In the present invention, the co-crystal I is a m-cresol co-crystal or a p-cresol co-crystal.
In the present invention, the temperature at which the cresol isomeric mixture and the eutectic ligand I are mixed is preferably 60 to 80 ℃, more preferably 68 to 78 ℃.
In the present invention, when the eutectic ligand I is nicotinamide or metformin, the eutectic I is m-cresol eutectic; when the eutectic ligand I is methylmalonic acid, adipic acid or glutaric acid, the eutectic I is a paracresol eutectic.
In the present invention, the first-stage co-crystallization is preferably performed in a crystallizer. In the present invention, the end point temperature of the first-stage co-crystallization is preferably 25 to 80 ℃; the time is preferably 4 to 8 hours.
In the invention, when the eutectic ligand I is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the first-stage co-crystallization is 68-80 ℃, the eutectic I is p-cresol eutectic;
When the eutectic ligand I is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea, the cresol content in the intermediate of the cresol isomer mixture is higher than the p-cresol content, and the end point temperature of the first-stage co-crystallization is room temperature, the eutectic I is a m-cresol co-crystal. In the present invention, the room temperature is in the range of 18 to 30 ℃.
In the present invention, when the mass content of cresol in the mixture of cresol isomers is 50 to 100%, it is preferable to prepare the m-cresol eutectic first. When the eutectic I is a m-cresol eutectic, the molar ratio of the eutectic ligand I to the intermediate cresol of the cresol isomeric mixture is preferably 1.1 to 2.5:1. in the present invention, when the mass content of p-cresol in the mixture of cresol isomers is 50 to 100%, it is preferable to prepare p-cresol eutectic first. When the eutectic I is a paracresol eutectic, the molar ratio of the eutectic ligand I to paracresol in the cresol isomer mixture is preferably 0.6 to 1.25:1.
in the present invention, when the mass content of cresol in the intermediate cresol isomer mixture is 50 to 100% and the m-cresol eutectic is prepared first, it is preferable to add an organic solvent at the time of performing the first-stage co-crystallization. In the present invention, the organic solvent preferably includes one or two of n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether. In the present invention, when the intermediate cresol content of the cresol isomer mixture is 50 to 100%, the mass of the organic solvent is preferably 0.4 to 2.5 times, more preferably 1.1 to 1.7 times the mass of the cresol isomer mixture.
In the present invention, when the mass content of cresol in the intermediate cresol isomer mixture is 50 to 100% and the p-cresol eutectic is prepared first, it is preferable that no organic solvent is added. In this case, the m-cresol is subjected to first-stage co-crystallization as a solvent to obtain a p-cresol co-crystal.
In the present invention, when the mass content of p-cresol in the mixture of cresol isomers is 50 to 100% and the p-cresol eutectic is prepared first, it is preferable to add an organic solvent at the time of performing the first-stage co-crystallization. In the present invention, the organic solvent preferably includes one or two of n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether. In the present invention, when the content of p-cresol in the cresol isomer mixture is 50 to 100%, the mass of the organic solvent is preferably 0.4 to 2.5 times, more preferably 0.8 to 1.7 times the mass of the cresol isomer mixture.
In the present invention, when the mass content of p-cresol in the cresol isomer mixture is 50 to 100% and the m-cresol eutectic is prepared first, it is preferable that no organic solvent is added. In this case, the first-stage co-crystallization of p-cresol as a solvent gives a m-cresol co-crystal.
In the present invention, the co-crystal I is preferably obtained by drying after the solid-liquid separation. In the present invention, when the eutectic I is a m-cresol eutectic, the m-cresol eutectic preferably includes m-cresol and a eutectic ligand I; when the co-crystal I is a p-cresol co-crystal, the p-cresol co-crystal preferably includes p-cresol and a co-crystal ligand I.
After the eutectic I is obtained, the filtrate obtained by solid-liquid separation is mixed with the eutectic ligand II to carry out second-stage co-crystallization, and after the second-stage co-crystallization is finished, the solid-liquid separation is carried out to obtain the eutectic II. In the present invention, the co-crystal ligand II includes one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea. In the present invention, when the eutectic I is a m-cresol eutectic, the eutectic II is a p-cresol eutectic; when the eutectic I is a paracresol eutectic, the eutectic II is a metacresol eutectic.
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 to 60 ℃, more preferably 15 to 40 ℃.
In the present invention, when the eutectic ligand II is nicotinamide or metformin, the eutectic II is m-cresol eutectic; when the eutectic ligand II is methylmalonic acid, adipic acid or glutaric acid, the eutectic II is a paracresol eutectic.
In the present invention, the second stage co-crystallization is preferably performed in a crystallizer. In the present invention, the end point temperature of the second-stage co-crystallization is preferably 25 to 80 ℃; the time is preferably 4 to 8 hours.
In the invention, when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the second-stage co-crystallization is 68-80 ℃, the eutectic II is p-cresol eutectic;
when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the second-stage co-crystallization is room temperature, the eutectic II is m-cresol eutectic.
In the present invention, when the mass content of cresol in the mixture of cresol isomers is 50 to 100%, it is preferable to prepare the m-cresol eutectic first. When the eutectic II is a paracresol eutectic, the molar ratio of the eutectic ligand II to paracresol in the cresol isomer mixture is preferably 0.6 to 1.25:1. in the present invention, when the mass content of p-cresol in the mixture of cresol isomers is 50 to 100%, it is preferable to prepare p-cresol eutectic first. When the eutectic II is a m-cresol eutectic, the molar ratio of the eutectic ligand II to the intermediate cresol of the cresol isomeric mixture is preferably 1.1 to 2.5:1.
In the present invention, when the cresol isomer having a relatively high content is preferentially separated, it is preferable that no organic solvent is added at the time of the second-stage co-crystallization; when the organic solvent is added during the first-stage co-crystallization, the organic solvent is preferably not added during the second-stage co-crystallization.
In the present invention, in the case where the organic solvent is added at the time of performing the second-stage co-crystallization, the addition amount of the organic solvent is preferably such that the total amount of the organic solvent added during the first-stage co-crystallization and the second-stage co-crystallization is 0.4 to 2.5 times the mass of the cresol isomer mixture.
In the present invention, the organic solvent preferably includes one or two of n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether.
In the present invention, the solid-liquid separation is preferably followed by drying to obtain the co-crystal II. In the present invention, when the eutectic II is a m-cresol eutectic, the m-cresol eutectic preferably includes m-cresol and a eutectic ligand II; when the co-crystal II is a p-cresol co-crystal, the p-cresol co-crystal preferably includes p-cresol and a co-crystal ligand II.
After the eutectic I is obtained, the invention carries out first decomplexing on the eutectic I to obtain an 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.
In the present invention, when the first decomplexing is performed, a decomplexing agent is preferably added; the first decomplexing preferably includes: and dissolving the eutectic I in a decomplexing agent for first decomplexing, and distilling the obtained filtrate after solid-liquid separation to obtain an isomer I. In the present invention, the decomplexer is preferably an organic decomplexer, and more preferably includes one or two of n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether. In the present invention, the decomplexer is preferably 0.8 to 1.9 times, more preferably 1.0 to 1.5 times the mass of the co-crystal I.
In the present invention, when the eutectic ligand I is 2, 5-dimethylpiperazine, 2-methylpiperazine or N-methylurea, it is preferable to directly perform distillation without adding a decomplexer to obtain isomer I.
In the present invention, the first decomplexing is preferably followed by obtaining a eutectic ligand I, and the obtained eutectic ligand I is preferably returned to the first-stage co-crystallization. In the invention, the filter cake obtained after the solid-liquid separation is preferably dried to obtain the eutectic ligand I.
In the present invention, the distillation is preferably reduced pressure distillation.
In the present invention, the purity of the isomer I is preferably not less than 99.5% by weight.
After the eutectic II is obtained, the invention carries out second decomplexing on the eutectic II to obtain an 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 paracresol co-crystal, the isomer II is paracresol.
In the present invention, when the second decomplexing is performed, a decomplexing agent is preferably added; the second decomplexing preferably includes: and dissolving the eutectic II in a decomplexing agent for second decomplexing, and distilling the obtained filtrate after solid-liquid separation to obtain isomer II. In the present invention, the decomplexer is preferably an organic decomplexer, and more preferably includes one or two of n-hexane, cyclohexane, n-heptane, toluene, n-propanol, isopropanol, n-butanol, isobutanol, n-butyl ether, acetone, acetonitrile and diethyl ether. In the present invention, the decomplexer is preferably 0.8 to 1.9 times, more preferably 1.0 to 1.5 times the mass of the co-crystal II.
In the present invention, when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine or N-methylurea, it is preferable to directly perform distillation without adding a decomplexer to obtain isomer II.
In the present invention, the second decomplexing is preferably followed by obtaining a eutectic ligand II, and the obtained eutectic ligand II is preferably returned to the second stage for co-crystallization. In the invention, the filter cake obtained after the solid-liquid separation is preferably dried to obtain the eutectic ligand II.
In the present invention, the distillation is preferably reduced pressure distillation.
In the present invention, the purity of the isomer II is preferably not less than 99.5% by weight.
In a specific embodiment of the present invention, a schematic diagram of the co-crystallization resolution process of the cresol isomer mixture is shown in fig. 1.
The p-cresol has unique selectivity, the applicable mixed phenol has wide purity range (the content of the mixed phenol intermediate cresol is 0-100%), the separation degree is high, the purity of the cresol monomer product is high (more than or equal to 99.5 wt%), and the process yield is high (more than 76 percent); the operation is simple, and industrial production can be performed; the process does not need water, and the used organic solvent and eutectic ligand can be recycled, so that the method is green and pollution-free.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
(1) Taking 30.00g of mixed phenol, wherein the content of cresol in the mixed phenol is 6.00g, and the content of cresol in the mixed phenol is 24.00g;
(2.1) selecting 5.14-g N-methyl urea as a eutectic ligand, adding the eutectic ligand into the mixed phenol, and stirring at a constant temperature of 68 ℃ for 0.5h to dissolve the eutectic ligand;
(2.2) cooling to 43 ℃ within 3h after dissolution, stirring at constant temperature for 1h, cooling the system to 25 ℃ from 3h after new eutectic appears, and continuing stirring at constant temperature for 0.5-1 h at 25 ℃;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) air-drying the obtained solid at room temperature for 6 hours to obtain 9.30g of m-cresol eutectic; the solid obtained by chromatographic detection only contains m-cresol and N-methyl urea, wherein 4.98g of m-cresol is contained;
(4.2) heating and melting the obtained m-cresol eutectic, and then carrying out simple rectification to obtain 4.77g of m-cresol, wherein the purity is 99.5%, and the total yield is 79.10%; 4.53g of N-methylurea is obtained and recycled.
(5.1) adding the mother liquor after the solid-liquid separation of the suspension in the step (3) (at the moment, the mother liquor contains 1.02g of m-cresol, 24.00g of p-cresol) and 27.78g of 2-methylpiperazine into 30.00g of cyclohexane, and stirring at a constant temperature of 80 ℃ for 0.2h to uniformly suspend the mother liquor in a crystallizer;
(5.2) stirring at constant temperature for 1h;
(5.3) cooling to 35 ℃ for 8 hours, and continuously stirring at the constant temperature of 35 ℃ for 1 hour;
(6) Separating solids from the suspension;
(7.1) drying the obtained solid by air blast at room temperature for 6 hours to obtain 50.56g of paracresol eutectic; the solid obtained by chromatographic detection only contains p-cresol and 2-methylpiperazine, wherein 22.80g of p-cresol is contained;
(7.2) dissolving the obtained paracresol eutectic in 50.56g of diethyl ether at 15 ℃, stirring at constant temperature for 2 hours, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 27.78g of 2-methylpiperazine which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 21.66g of p-cresol with a purity of 99.8% and a total yield of 90.07%. The microscopic photograph of the product is shown in fig. 2, wherein the left graph in fig. 2 is a m-cresol eutectic product, and the right graph is a p-cresol eutectic product. As can be seen from fig. 2, the present invention produces a eutectic product.
Example 2
(1) Taking 30.00g of mixed phenol, wherein the content of cresol in the mixed phenol is 6.00g, and the content of cresol in the mixed phenol is 24.00g;
(2.1) selecting 15.73g of methylmalonic acid as a eutectic ligand, putting the eutectic ligand into 30.00g of toluene, and stirring the mixture at a constant temperature of 80 ℃ for 0.5h;
(2.2) adding the mixed phenol flow into toluene solution of methyl malonic acid, wherein the flow rate is 1.5mL/min, and stirring for 1h at constant temperature after the addition is finished;
(2.3) cooling to 40 ℃ within 3-6 h, and continuously stirring at the constant temperature of 40 ℃ for 1h;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) drying the obtained solid by air blast at room temperature for 6 hours to obtain 34.26g of paracresol eutectic; the solid obtained by chromatographic detection only contains p-cresol and methylmalonic acid, wherein 18.53g of p-cresol is contained;
(4.2) dissolving the obtained paracresol eutectic in 34.26g of mixed solution of toluene and acetone (wherein the mass ratio of toluene to acetone is 9.5:0.5) at 25 ℃, stirring at constant temperature for 1h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 15.73g of methylmalonic acid which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 18.47g, the purity was 99.9%, and the total yield of p-cresol was 76.88%.
(5.1) adding 7.52g of nicotinamide into the mother solution (at the moment, the mother solution contains 6.00g of m-cresol, 5.47g of p-cresol and 30.00g of toluene) after the suspension in the step (3) is subjected to solid-liquid separation, and stirring at a constant temperature of 68 ℃ for 0.5h to dissolve the nicotinamide;
(5.2) cooling to 47 ℃ in 1h after dissolution, stirring at constant temperature for 1.2h, cooling the system to 25 ℃ from 4h after new eutectic appears, and continuing stirring at constant temperature for 0.5-1 h at 25 ℃;
(6) Separating solids from the suspension;
(7.1) drying the obtained solid by air-drying at room temperature for 6 hours to obtain 12.47g of m-cresol eutectic; the solid obtained by chromatographic detection only contains m-cresol and nicotinamide, wherein 4.95g of m-cresol is contained;
(7.2) dissolving the obtained m-cresol eutectic in a mixed solution of 12.47g of toluene-acetone (the mass ratio of toluene to acetone is 9.5:0.5) at 25 ℃, stirring at constant temperature for 1h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 7.52g of nicotinamide which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 4.92g of m-cresol with a purity of 99.5% and a total yield of 82.00%.
Example 3
(1) Taking 30.00g of mixed phenol, wherein the content of cresol in the mixed phenol is 6.00g, and the content of cresol in the mixed phenol is 24.00g;
(2.1) selecting 17.62g of glutaric acid as a eutectic ligand, putting into 30.00g of cyclohexane, and stirring at a constant temperature of 80 ℃ for 0.5h;
(2.2) adding the mixed phenol stream into a cyclohexane solution of glutaric acid, wherein the adding speed is 2.5mL/min, and stirring for 1h at a constant temperature after adding;
(2.3) cooling to 25 ℃ for 8 hours, and continuously stirring at the constant temperature of 25 ℃ for 1 hour;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) drying the obtained solid by air blast at room temperature for 6 hours to obtain 37.41g of paracresol eutectic; the solid obtained by chromatographic detection only contains p-cresol and glutaric acid, wherein 19.79g of p-cresol is contained;
(4.2) dissolving the obtained paracresol eutectic in 37.41g of n-butanol at 25 ℃, stirring at constant temperature for 1.5h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 17.62g of glutaric acid, which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 19.61g of p-cresol with a purity of 99.8% and a total yield of 81.71%.
(5.1) adding 16.12g of fumaric acid into the mother solution (6.00 g of m-cresol, 4.21g of p-cresol and 30.00g of cyclohexane) obtained by solid-liquid separation of the suspension in the step (3), and stirring at a constant temperature of 80 ℃ for 0.5h to dissolve the fumaric acid;
(5.2) cooling to 62 ℃ within 1h after dissolution, stirring at constant temperature for 1.2h, cooling the system to 25 ℃ within 8h after new eutectic appears, and continuing stirring at constant temperature for 1h at 25 ℃;
(6) Separating solids from the suspension;
(7.1) air-drying the obtained solid at room temperature for 6 hours to obtain 19.32g of m-cresol eutectic; the solid obtained by chromatography detection only contains m-cresol and fumaric acid, wherein 4.89g of m-cresol is contained;
(7.2) dissolving the m-cresol eutectic in 19.32g of isopropanol at 25 ℃, stirring at constant temperature for 1h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 14.43g of fumaric acid which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 4.65g of m-cresol with a purity of 99.7% and a total yield of 77.27%. The microscopic photograph of the product is shown in fig. 3, the left graph in fig. 3 is a m-cresol eutectic product, and the right graph is a p-cresol eutectic product. As can be seen from fig. 3, the present invention produces a eutectic product.
Example 4
(1) Taking 30.00g of mixed phenol, wherein the content of cresol in the mixed phenol is 15.00g, and the content of cresol in the mixed phenol is 15.00g;
(2.1) selecting 19.71g of metformin as a eutectic ligand, putting the eutectic ligand into a mixed phenol solution, and stirring the mixed phenol solution at a constant temperature of 68 ℃ for 0.5h to completely dissolve the metformin;
(2.2) reducing the temperature of the system to 57 ℃ within 1h, and stirring at constant temperature for 0.5h, wherein new eutectic is formed in the system;
(2.3) cooling to 25 ℃ for 5.3 hours, and when the system becomes viscous, adding 10.00g of n-butanol into the flow, wherein the flow rate is 1.0mL/min;
(2.4) cooling to 25 ℃, and continuing constant-temperature stirring for 1h;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) air-drying the obtained solid at room temperature for 6 hours to obtain 33.25g of m-cresol eutectic; the solid obtained by chromatographic detection only contains m-cresol and metformin, wherein 13.56g of m-cresol is contained;
(4.2) dissolving the m-cresol eutectic in 33.25g of n-hexane at 25 ℃, stirring at constant temperature for 2.0h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 19.69g of metformin which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 11.82g 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℃for 0.2h to be uniformly suspended in the crystallizer;
(5.2) adding a mother solution (at this time, the mother solution contains 1.44g of m-cresol, 15.00g of p-cresol and 10.00g of n-butanol) after the solid-liquid separation of the suspension in the step (3) into an n-butanol solution of adipic acid at a flow rate of 1.0mL/min, and stirring at a constant temperature for 1h after the addition;
(5.3) cooling to 40 ℃ for 3 hours, and continuously stirring at the constant temperature of 40 ℃ for 1 hour;
(6) Separating solids from the suspension;
(7.1) drying the obtained solid by air-drying at room temperature for 6 hours to obtain 28.46g of paracresol eutectic; the solid obtained by chromatography detection only contains p-cresol and adipic acid, wherein the solid contains 12.83g of p-cresol;
(7.2) dissolving the obtained eutectic in 28.46g of acetonitrile solvent at 40 ℃, stirring at constant temperature for 1h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 15.63g of adipic acid which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 12.11g of p-cresol with a purity of 99.5% and a total yield of 80.33%.
Example 5
(1) Taking 30.00g of mixed phenol, wherein the mixed phenol has an intermediate cresol content of 15.00g and a p-cresol content of 15.00g;
(2.1) 14.5g of tetramethylurea was added to 30.00g of toluene n-heptane and stirred at a constant temperature of 80℃for 0.5h to be uniformly suspended in the crystallizer;
(2.2) adding the mixed phenol flow into an n-heptane solution of tetramethyl urea, wherein the flow rate is 1.0mL/min, and stirring at constant temperature for 1h after the addition;
(2.3) cooling to 70 ℃ for 3 hours, and continuously stirring at the constant temperature of 70 ℃ for 1 hour;
(3) Separating solids from the suspension;
(4.1) air-drying the obtained solid at room temperature for 6 hours to obtain 25.64g of a co-crystal; the solid obtained by chromatographic detection only contains p-cresol and tetramethyl urea, wherein the solid contains 12.28g of p-cresol;
(4.2) dissolving the obtained eutectic in 25.64g of n-heptane-diethyl ether mixed solvent (wherein the mass ratio of n-heptane to diethyl ether is 8:2) at 25 ℃, stirring at constant temperature for 1h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 13.36g of tetramethyl urea which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 11.99g 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 the mother liquor after the solid-liquid separation (in this case, the mother liquor contains 15g of m-cresol, 2.72g of p-cresol, 30.00g of n-heptane) was stirred at a constant temperature of 78 ℃ for 0.5h to be completely dissolved;
(5.2) reducing the temperature of the system to 53 ℃ within 3 hours, and stirring at constant temperature for 0.5 hour until new eutectic is generated in the system;
(5.3) cooling to 25 ℃ for 4.6 hours;
(5.4) cooling to 25 ℃, and continuing constant-temperature stirring for 1h;
(6) Carrying out solid-liquid separation on the suspension;
(7.1) drying the obtained solid by blowing at room temperature for 4-8 hours to obtain 34.93g of eutectic; the solid obtained by chromatographic detection only contains m-cresol and fumaric acid, wherein 12.56g of m-cresol is contained;
(7.2) dissolving the obtained eutectic in a mixed solvent of 34.93g of n-heptane and diethyl ether (wherein the mass ratio of the n-heptane to the diethyl ether is 8:2) at 15 ℃, stirring at constant temperature for 2.0h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 22.37g of fumaric acid which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 11.88g of m-cresol with a purity of 99.6% and a total yield of 78.88%. The product performance results are shown in fig. 4, wherein the left graph in fig. 4 is a m-cresol eutectic product, and the right graph is a p-cresol eutectic product. As can be seen from fig. 4, the present invention produces a eutectic product.
Example 6
(1) Taking 30.00g of mixed phenol, wherein the content of cresol in the mixed phenol is 24.00g, and the content of cresol in the mixed phenol is 6.00g;
(2.1) selecting 32.97g of metformin as a eutectic ligand, putting the eutectic ligand into a mixed phenol solution, and stirring the mixed phenol solution at a constant temperature of 78 ℃ for 1.0h to completely dissolve the mixed phenol solution;
(2.2) reducing the temperature of the system to 55 ℃ within 1h, and stirring at constant temperature for 0.5h, wherein new eutectic is formed in the system;
(2.3) cooling to 25 ℃ for 4.5 hours, and when the system becomes viscous, adding 45.00g of n-hexane into the flow, wherein the flow rate is 2.0mL/min;
(2.4) cooling to 25 ℃, and continuing constant-temperature stirring for 1.5h;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) drying the obtained solid by air blast at room temperature for 6 hours to obtain 51.97g of m-cresol eutectic; the solid obtained by chromatographic detection only contains m-cresol and metformin, wherein the solid contains 20.19g of cresol;
(4.2) dissolving the obtained m-cresol eutectic in 77.96g of isopropanol at 15 ℃, stirring at constant temperature for 2.0h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 31.79g of metformin which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 19.38g 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 solid-liquid separation of the suspension in the step (3) (in this case, the mother liquor contains 3.81g of m-cresol, 6.00g of p-cresol, 45.00g of n-hexane), and the mixture was stirred at a constant temperature of 75 ℃ for 0.2h to be uniformly suspended in the crystallizer;
(5.2) cooling to 25 ℃ for 6.3h, and continuously stirring at the constant temperature of 25 ℃ for 1h;
(6) Separating solids from the suspension;
(7.1) drying the obtained solid by air-drying at room temperature for 6 hours to obtain 11.43g of a paracresol eutectic; the solid obtained by chromatographic detection only contains p-cresol and glutaric acid, wherein 4.83g of p-cresol is contained;
(7.2) dissolving the obtained paracresol eutectic in 11.43g of isopropanol at 40 ℃, stirring at constant temperature for 0.5h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 6.60g of glutaric acid, which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 4.52g of p-cresol with a purity of 99.6% and a total yield of 75.03%. The microscopic photograph of the product is shown in fig. 5, the left graph in fig. 5 is a m-cresol eutectic product, and the right graph is a p-cresol eutectic product. As can be seen from fig. 5, the present invention produces a eutectic product.
Example 7
(1) Taking 30.00g of mixed phenol, wherein the content of cresol in the mixed phenol is 24.00g, and the content of cresol in the mixed phenol is 6.00g;
(2.1) selecting 38.66g of fumaric acid as a eutectic ligand, putting the eutectic ligand into a mixed phenol solution, and stirring the mixed phenol solution at a constant temperature of 80 ℃ for 1.0h to completely dissolve the fumaric acid;
(2.2) reducing the temperature of the system to 68 ℃ within 1h, and stirring at constant temperature for 1.5h, wherein new eutectic is formed in the system;
(2.3) cooling to 38 ℃ for 5 hours, and adding 45.00g of n-butyl ether into the flow when the system becomes viscous, wherein the flow rate is 2.5mL/min;
(2.4) cooling to 35 ℃ and then continuously stirring at constant temperature for 1.5h;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) air-drying the obtained solid at room temperature for 6 hours to obtain 54.00g of m-cresol eutectic; the solid obtained by chromatography detection only contains m-cresol and fumaric acid, wherein 19.16g of m-cresol is contained;
(4.2) dissolving the obtained m-cresol eutectic in a mixed solution of 81.00g of toluene-diethyl ether (wherein the mass ratio of toluene to diethyl ether is 9:1) at 15 ℃, stirring at constant temperature for 2.0h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 34.84g of fumaric acid which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 18.66g of m-cresol with a purity of 99.6% and a total yield of 77.45%.
(5.1) adding 9.53g of 2-methylpiperazine into the mother liquor after the solid-liquid separation of the suspension in the step (3) (at the moment, the mother liquor contains 4.84g of m-cresol, 6.00g of p-cresol and 45.00g of n-butyl ether), and stirring at a constant temperature of 78 ℃ for 1h to dissolve the 2-methylpiperazine;
(5.2) cooling to 75 ℃ for 1h, and continuously stirring at the constant temperature of 75 ℃ for 1-3 h to enable the crystals to be crystallized;
(5.3) cooling to 68 ℃ for 4 hours, and continuously stirring at the constant temperature of 68 ℃ for 1 hour;
(6) Separating solids from the suspension;
(7.1) drying the obtained solid by air blast at room temperature for 6 hours to obtain 14.54g of paracresol eutectic; the solid obtained by chromatographic detection only contains p-cresol and 2-methylpiperazine, wherein 5.37g of p-cresol is contained;
(7.2) dissolving the obtained paracresol eutectic in 21.81g of diethyl ether-isopropanol mixed solvent (the mass ratio of diethyl ether to ethanol is 9.5:0.5) at 15 ℃, stirring at constant temperature for 2.5 hours, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 9.17g of 2-methylpiperazine which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 5.12g of p-cresol with a purity of 99.8% and a total yield of 85.16%.
Example 8
(1) Taking 30.00g of mixed phenol, wherein the mixed phenol has an intermediate cresol content of 24.00g and a p-cresol content of 6.00g;
(2.1) 8.06g of tetramethylurea is selected as a eutectic ligand, and is put into 45.00g of n-propanol, and is stirred for 0.5h at a constant temperature of 68 ℃ to suspend in the crystal;
(2.2) adding the mixed phenol stream into an n-propanol solution of tetramethylurea at a flow rate of 1.2mL/min, and stirring at a constant temperature for 8 hours after the addition;
(3) Carrying out solid-liquid separation on the suspension;
(4.1) drying the obtained solid by blowing at room temperature for 4-8 hours to obtain 12.36g of paracresol eutectic; the solid obtained by chromatographic detection only contains p-cresol and tetramethylurea, wherein 5.53g of p-cresol is contained;
(4.2) dissolving the obtained paracresol eutectic in 18.54g of acetone at 15 ℃, stirring at constant temperature for 2.5 hours, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 6.83g of tetramethyl urea which can be recycled; the obtained filtrate was subjected to simple rectification to obtain 5.37g, the purity was 99.5%, and the total yield of p-cresol was 89.05%.
(5.1) adding 27.86g of 2, 5-dimethylpiperazine into the mother liquor (24.00 g of m-cresol, 0.47g of p-cresol and 45.00g of n-propanol) after the suspension in the step (3) is subjected to solid-liquid separation, and stirring at a constant temperature of 80 ℃ for 0.5h to dissolve the 2, 5-dimethylpiperazine;
(5.2) cooling to 68 ℃ within 1h after dissolution, stirring at constant temperature for 1.5h, and waiting for new eutectic to appear in the crystallizer;
(5.3) cooling the system to 25 ℃ from 4 hours, and finally continuing to stir at the constant temperature of 25 ℃ for 0.5-1 hour;
(6) Separating solids from the suspension;
(7.1) air-drying the obtained solid at room temperature for 6 hours to obtain 49.06g of m-cresol eutectic; the solid obtained by chromatographic detection only contains m-cresol and 2, 5-dimethylpiperazine, wherein 22.31g of m-cresol is contained;
(7.2) dissolving the obtained m-cresol eutectic in 73.59g of isobutanol at 25 ℃, stirring at constant temperature for 1h, and then carrying out solid-liquid separation; the obtained filter cake is dried by blowing to obtain 26.75g of 2, 5-dimethylpiperazine which can be recycled; the filtrate obtained was subjected to simple rectification to obtain 21.91g of m-cresol with a purity of 99.8% and a total yield of 91.11%.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. A process for the co-crystallization resolution of a mixture of cresol isomers comprising the steps of:
(1) Mixing the cresol isomer mixture with the eutectic ligand I, performing first-stage co-crystallization, and performing solid-liquid separation after the first-stage co-crystallization is finished to obtain a eutectic I; the cresol isomer mixture comprises m-cresol and p-cresol, wherein the content of the m-cresol is 20-80%; the eutectic ligand I is one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; the eutectic I is m-cresol eutectic or p-cresol eutectic;
(2) Mixing the filtrate obtained in the step (1) with a eutectic ligand II, and performing second-stage co-crystallization, wherein after the second-stage co-crystallization is finished, solid-liquid separation is performed to obtain a eutectic II; the eutectic ligand II is one of 2, 5-dimethylpiperazine, 2-methylpiperazine, nicotinamide, fumaric acid, tetramethylurea, metformin, methylmalonic acid, adipic acid, glutaric acid and N-methylurea; when the eutectic I is m-cresol eutectic, the eutectic II is p-cresol eutectic; when the eutectic I is a paracresol eutectic, the eutectic II is a metacresol eutectic;
(3) First decomplexing the eutectic I to obtain an isomer I; when the eutectic I is m-cresol eutectic, the isomer I is m-cresol; when the eutectic I is a paracresol eutectic, the isomer I is paracresol;
(4) Second decomplexing the eutectic II to obtain an isomer II; when the eutectic II is m-cresol eutectic, the isomer II is m-cresol; when the eutectic II is a paracresol eutectic, the isomer II is paracresol;
and (3) and (4) have no precedence relationship.
2. The method of claim 1, wherein the first decomplexing is followed by obtaining a eutectic ligand I, and the obtained eutectic ligand I is returned to the first stage of co-crystallization.
3. The method of claim 1, wherein the second decomplexing is followed by obtaining eutectic ligand II, and the obtained eutectic ligand II is returned to the second stage of co-crystallization.
4. The co-crystallization resolution method according to claim 1, wherein when the co-crystal ligand I is nicotinamide or metformin, the co-crystal I is a m-cresol co-crystal;
when the eutectic ligand I is methylmalonic acid, adipic acid or glutaric acid, the eutectic I is a paracresol eutectic.
5. The co-crystallization resolution method according to claim 1, wherein when the co-crystal ligand II is nicotinamide or metformin, the co-crystal II is a m-cresol co-crystal;
when the eutectic ligand II is methylmalonic acid, adipic acid or glutaric acid, the eutectic II is a paracresol eutectic.
6. The method according to claim 1, wherein when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the second-stage co-crystallization is 68 to 80 ℃, the eutectic II is p-cresol eutectic;
when the eutectic ligand II is 2, 5-dimethylpiperazine, 2-methylpiperazine, fumaric acid, tetramethylurea or N-methylurea and the end point temperature of the second-stage co-crystallization is room temperature, the eutectic II is m-cresol eutectic.
7. The method of claim 1, wherein when the eutectic I is a m-cresol eutectic, the molar ratio of the eutectic ligand I to the cresol in the cresol isomer mixture is 1.1-2.5: 1, a step of;
when the eutectic I is a paracresol eutectic, the molar ratio of the eutectic ligand I to paracresol in the cresol isomer mixture is 0.6-1.25: 1.
8. The co-crystallization resolution method according to claim 1, wherein a decomplexing agent is independently added when the first decomplexing and the second decomplexing are performed.
9. The method according to claim 1, wherein the first-stage co-crystallization and the second-stage co-crystallization are performed by adding an organic solvent independently.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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