Purification method of guaiacol glycerol ether

Abstract

The invention discloses a purification method of guaiacol glyceryl ether, and belongs to the technical field of pharmaceutical chemicals. The method aims at solving the problem that specific pharmacopoeia impurities in guaiacol glyceryl ether are difficult to effectively remove in the prior art. The method comprises the following steps: dissolving a guaiacol glyceryl ether crude product in a mixed solvent composed of ethyl acetate, alicyclic alcohol and C2-C4 low-carbon alcohol, heating to form a homogeneous solution, adding water to induce crystallization, carrying out programmed cooling crystallization, and finally filtering, washing and drying to obtain a high-purity product. Through a specific mixed solvent system and crystallization kinetics control, directional removal of key impurities is realized, and the obtained product is high in purity, high in yield, simple in process, low in cost and very suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, specifically to a purification method for guaiacol glycerol ether, and particularly to a method for selectively removing key pharmacopoeia impurities such as impurities B and C through a specific mixed solvent system and programmed cooling crystallization technology to obtain high chemical purity guaiacol glycerol ether. Background Technology

[0002] Guaifenesin, chemically named 3-(2-methoxyphenoxy)-1,2-propanediol, is a widely used expectorant. Currently, its industrial production mainly employs a process involving the condensation of epichlorohydrin or chloroglycerol with guaiacol under alkaline conditions. However, this synthetic reaction inevitably produces a series of byproducts and isomers with structures similar to the target product, such as 3-(2-methoxyphenoxy)-1,3-propanediol (impurity C) and 1-(2-methoxyphenoxy)-3-hydroxypropane-2-one (impurity B), which are under key control in pharmacopoeias.

[0003] The physicochemical properties (such as polarity and solubility) of these impurities are very similar to those of guaiacol glycerol ether, making their separation and removal extremely difficult. Existing purification techniques have significant limitations: Distillation: For example, Chinese patent CN119019230A uses vacuum distillation for purification. This method is energy-intensive, and because some impurities have boiling points close to the target product, the separation efficiency is limited. High temperatures may also promote material decomposition or generate new degradation impurities.

[0004] Conventional recrystallization method: For example, Chinese patent CN118084633A uses ethyl acetate as the extraction and recrystallization solvent. Although the operation is improved, the selective removal ability of key isomers such as impurities C and B is insufficient, and the product purity is usually difficult to consistently reach above 99.8%, especially the content of impurity C is not ideally controlled.

[0005] Therefore, there is an urgent need in this field to develop a new purification process that can remove these specific stubborn impurities in a targeted, efficient, and gentle manner, so as to improve product quality, meet the increasingly stringent quality standards of domestic and foreign pharmacopoeias, and adapt to the development trend of green and low-carbon industries. Summary of the Invention

[0006] The present invention aims to overcome the shortcomings of the prior art and provide a purification method that is simple to operate, low in cost, easy to industrialize, and can efficiently and selectively remove specific pharmacopoeia impurities from guaiacol glycerol ether.

[0007] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: A method for preparing guaiacol glycerol ether includes the following steps: (a) Dissolve crude guaiacol glycerol ether in a mixed solvent consisting of ethyl acetate, alicyclic alcohol, and C2-C4 low carbon alcohol, and heat to form a homogeneous hot solution; (b) Add water to the hot solution obtained in step (a) to induce crystallization; (c) The system obtained in step (b) is subjected to programmed cooling crystallization; (d) Filter, wash and dry to obtain high-purity guaiacol glycerol ether.

[0008] This invention discovers and utilizes a specific ternary solvent system of ethyl acetate / a specific alcohol / water to achieve an unexpected "synergistic dissolution effect" on impurities C and B. In this system, the impurities are more soluble in the mother liquor than the target product, thus being efficiently "excluded" from the crystal lattice during crystallization. The addition of water rapidly initiates the crystallization process, and combined with programmed cooling, efficient and controllable crystallization is maintained and completed. This method can stably reduce the content of impurity C to below 0.1%, achieving a product HPLC purity exceeding 99.5% and a purification yield consistently above 80%, solving a long-standing problem in the industry.

[0009] In some embodiments, the volume ratio of ethyl acetate, alicyclic alcohol, and C2-C4 lower alcohol is 3-5:0.4-0.6:1.

[0010] The volume ratio of ethyl acetate, alicyclic alcohol, and C2-C4 lower alcohol is crucial to the crystallization result. Guaifenesin glycerol ether has a molecular structure containing hydroxyl groups, ether bonds, hydrocarbon chains, and benzene rings, and is a moderately polar compound. By adjusting the polar volume ratio of ethyl acetate, alicyclic alcohol, and C2-C4 lower alcohol, the solvent system has good solubility for the crude product. At the same time, it can effectively and selectively dissolve during cooling, and impurities do not precipitate with the crystallization behavior, which greatly improves the purity. In addition, this system is conducive to promoting the crystallization behavior of guaiacol glycerol ether. Combined with programmed cooling, it can achieve efficient precipitation of guaiacol glycerol ether crystals, which effectively improves the yield.

[0011] In some embodiments, the C2-C4 lower alcohol is a mixture of ethanol, tert-butanol and n-butanol in a volume ratio of 5:2-4:1-3.

[0012] In some embodiments, the volume ratio of ethanol, tert-butanol, and n-butanol is 5:3:2.

[0013] The inventors discovered that selecting C2-C4 low-carbon alcohols such as ethanol, tert-butanol, and n-butanol, and controlling them within the above-mentioned ratios, can effectively optimize the purity and yield of guaiacol glycerol ether. This may be due to the fact that ethanol molecules are small, moderately polar, and have high hydroxyl activity. The ethanol hydroxyl group can form stable hydrogen bonds with the phenolic and alcoholic hydroxyl groups of guaiacol glycerol ether. At the same time, the weak hydrophobicity of the ethyl group is compatible with the aliphatic chain segment of guaiacol glycerol ether, and can be miscible with guaiacol glycerol ether in any proportion, thus improving solubility. n-Butanol contains a longer hydrophobic chain and has lower polarity, which reduces the matching degree with the moderate polarity of guaiacol glycerol ether. However, its heating promotes its kinetics and improves solubility. Tert-butanol has relatively poor solubility. The steric hindrance effect of its branched structure weakens the hydrogen bonding efficiency between the hydroxyl group and guaiacol glycerol ether. By mixing three low-carbon alcohols with different polarities and steric hindrance structures, the branched chain of tert-butanol and the long-chain hydrophobic structure of n-butanol weaken the hydrogen bond network and improve the solubility of crude guaiacol glycerol ether. During programmed cooling, the selective combination of the above alcohols with ethyl acetate can selectively dissolve impurities and improve the crystallization selectivity of guaiacol glycerol ether. Therefore, by adjusting the solvents with ethanol, tert-butanol, and n-butanol, guaiacol glycerol ether and impurities can be dissolved well at the heating temperature. As the temperature decreases, the solvents further promote the weakening of the dissolution of guaiacol glycerol ether and its precipitation, while maintaining the solubility of impurities, thus achieving efficient selective crystallization. Within the scope of the present application, this dissolution characteristic is more obvious, which can achieve both selective crystallization and impurity dissolution, thereby achieving a high yield and high purity of guaiacol glycerol ether.

[0014] In some embodiments, the alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxycyclohexanol in a volume ratio of 1:0.8-1.2.

[0015] In some embodiments, the volume ratio of 3-methylcyclohexanol to 3-hydroxycyclohexanol is 1:1.

[0016] The inventors discovered that adding a certain volume of alicyclic alcohol to a mixed solvent can further improve the purity and yield of guaiacol glycerol ether. In particular, the addition of 3-methylcyclohexanol and 3-hydroxycyclohexylethanol at a volume ratio of 1:1 significantly improved the purity and yield of guaiacol glycerol ether. Analysis suggests this may be because 3-methylcyclohexanol is a monohydroxy alicyclic alcohol; its alicyclic structure provides a weakly polar backbone, and the hydroxyl group provides hydrogen bonding sites, resulting in overall moderate polarity. This polarity highly matches that of guaiacol glycerol ether. Furthermore, its alicyclic ring and the methyl group on the alicyclic ring provide some hydrophobicity, making it compatible with guaiacol glycerol ether and impurities. In contrast, 3-hydroxycyclohexylethanol has higher polarity, which does not match the moderate polarity of guaiacol glycerol ether. Heating to high temperatures helps weaken intermolecular hydrogen bonding, thereby improving the solubility of guaiacol glycerol ether molecules and impurities. During the gradient cooling process while maintaining a certain temperature, the aliphatic hydroxyl groups of 3-hydroxy-cyclohexanol and the hydroxyl groups of 3-methylcyclohexanol can gradually achieve weak bonding at a certain temperature, forming a molecule containing two aliphatic rings and alicyclic hydroxyl groups. This molecule has high steric hindrance, and the hydrogen bonding weakens the effect on guaiacol glycerol ether. Based on the above-mentioned dual effects of steric hindrance and weakened hydrogen bonding, guaiacol glycerol ether tends to aggregate and precipitate, while retaining impurities in the system. The above-mentioned range of this application can achieve the best synergistic effect, thereby improving purity and yield.

[0017] In some embodiments, the amount of water added is 10-30% of the total volume of the mixed solvent.

[0018] In some implementations, the rate of temperature reduction is from 0.1°C / min to 0.5°C / min.

[0019] In some embodiments, the heating temperature in step (a) is 50°C to 65°C.

[0020] Based on the thermodynamic properties of the mixed solvents in this application, efficient crystallization of guaiacol glycerol ether is achieved by gradient cooling and controlling the cooling rate, thereby improving the purity and yield of the product.

[0021] Compared with the prior art, the present invention has the following significant advantages and unexpected technical effects: 1) This invention is the first to discover and utilize the unexpected "synergistic dissolution effect" of a specific ternary solvent system of ethyl acetate / a specific alcohol / water on impurities C and B. In this system, the impurities are more soluble in the mother liquor than the target product, thus being efficiently "excluded" from the crystal lattice during crystallization. Using the method of this invention, the content of impurity C can be stably reduced to below 0.1%, solving a long-standing problem in the industry.

[0022] 2) This invention further optimizes the solvent system by selecting specific combinations of C2-C4 low-carbon alcohols and specific combinations of alicyclic alcohols in the mixed solvent, thereby stabilizing the purification yield at over 80% and the product HPLC purity at over 99.5%, which is far superior to existing recrystallization and distillation processes, achieving the best balance between product quality and economic benefits.

[0023] 3) All operation units in this method (dissolving, mixing, programmed cooling, and filtration) are routine chemical operations with low equipment requirements, clear and controllable process parameters, making it very suitable for large-scale production in workshops and with low technology transfer risks. Example

[0024] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. In the following embodiments, unless otherwise specified, the reagents used are conventional commercially available products.

[0025] Example 1: Purification method of the present invention Take 100g of crude guaiacol glycerol ether synthesized via the epichlorohydrin route (HPLC purity: 94.2%), place it in a 1000mL three-necked flask, add 250mL of mixed solvent, and heat to 60℃ with stirring until the solid is completely dissolved to obtain a clear solution.

[0026] The mixed solvent contains ethyl acetate, alicyclic alcohol, and C2-C4 lower alcohol in a volume ratio of 4:0.5:1; the C2-C4 lower alcohol is a mixture of ethanol, tert-butanol, and n-butanol in a volume ratio of 5:3:2; and the alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxy-cyclohexanol in a volume ratio of 1:1. Maintain the temperature and slowly add 50 mL of purified water dropwise to the clear, hot solution. After the addition is complete, the solution will exhibit a slight opalescence.

[0027] Subsequently, the program cooling controller was activated to slowly cool down to 5°C at a rate of 0.2°C / minute, and then matured at 5°C for 2 hours.

[0028] Vacuum filtration was performed, and the filter cake was washed with 20 mL of mixed solvent. The wet solids were then vacuum dried at 50 °C and -0.095 MPa for 6 hours.

[0029] Example 2 The only difference between Example 2 and Example 1 is that the C2-C4 lower alcohols are a mixture of ethanol and tert-butanol in a volume ratio of 1:1; Example 3

[0030] The only difference between Example 3 and Example 1 is that the C2-C4 lower alcohols are a mixture of ethanol and n-butanol in a volume ratio of 1:1; Example 4

[0031] The only difference between Example 4 and Example 1 is that the alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxy-cyclohexanol in a volume ratio of 1:0.3; Example 5

[0032] The only difference between Example 5 and Example 1 is that the alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxy-cyclohexanol in a volume ratio of 1:1.6; Example 6

[0033] The only difference between Example 6 and Example 1 is that the alicyclic alcohol is 3-methylcyclohexanol; Example 7

[0034] The only difference between Example 7 and Example 1 is that the alicyclic alcohol is 3-hydroxy-cyclohexaneethanol; Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the mixed solvent is replaced by an equal volume of ethyl acetate, that is, only ethyl acetate is used as the solvent.

[0035] Take 100g of crude guaiacol glycerol ether synthesized via the epichlorohydrin route (HPLC purity: 94.2%), place it in a 1000mL three-necked flask, add 250mL of ethyl acetate, and heat to 60℃ with stirring until the solid is completely dissolved to obtain a clear solution.

[0036] Maintain the temperature and slowly add 50 mL of purified water dropwise to the clear, hot solution. After the addition is complete, the solution will exhibit a slight opalescence.

[0037] Subsequently, the program cooling controller was activated to slowly cool down to 5°C at a rate of 0.2°C / minute, and then matured at 5°C for 2 hours.

[0038] The filter cake was washed with 20 mL of ethyl acetate under vacuum. The wet solid was then dried under vacuum at 50 °C and -0.095 MPa for 6 hours.

[0039] Comparative Example 2: The difference between Comparative Example 2 and Example 1 is that conventional rapid cooling is used; that is, instead of programmed cooling, the hot solution is directly placed in an ice-water bath for rapid cooling to 5°C. Take 100g of crude guaiacol glycerol ether synthesized via the epichlorohydrin route (HPLC purity: 94.2%), place it in a 1000mL three-necked flask, add 250mL of mixed solvent, and heat to 60℃ with stirring until the solid is completely dissolved to obtain a clear solution.

[0040] The mixed solvent contains ethyl acetate, alicyclic alcohol, and C2-C4 lower alcohol in a volume ratio of 4:0.5:1; the C2-C4 lower alcohol is a mixture of ethanol, tert-butanol, and n-butanol in a volume ratio of 5:3:2; and the alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxy-cyclohexanol in a volume ratio of 1:1. Maintain the temperature and slowly add 50 mL of purified water dropwise to the clear, hot solution. After the addition is complete, the solution will exhibit a slight opalescence.

[0041] Then, it is placed in an ice water bath to cool rapidly to 5°C, and then aged at 5°C for 2 hours.

[0042] Vacuum filtration was performed, and the filter cake was washed with 20 mL of mixed solvent. The wet solids were then vacuum dried at 50 °C and -0.095 MPa for 6 hours.

[0043] The yields and HPLC purities of the crystallized products from the examples and comparative examples are shown in Table 1: Crystalline product yield HPLC purity Example 1 84.50% 99.93% Example 2 82.37% 99.71% Example 3 81.84% 99.68% Example 4 82.56% 99.85% Example 5 83.04% 99.90% Example 6 80.17% 99.51% Example 7 80.45% 99.59% Comparative Example 1 76.0% 99.20% Comparative Example 2 78.5% 99.45% Examples 1-7 and Comparative Examples 1-2 demonstrate that the synergistic effect of the specific mixed solvent system combined with programmed cooling crystallization yields high-purity, low-impurity, and high-yield guaiacol glycerol ether, with a yield as high as 84.5% and a purity of 99.93%. Examples 1-3 show that the selection of C2-C4 lower alcohols affects the yield and purity. Experiments in this application have shown that a volume ratio of ethanol, tert-butanol, and n-butanol of 5:3:2 for 2-C4 lower alcohols optimizes the yield and purity. Examples 1 and 4-7 show that, compared to using them alone, adding 3-methylcyclohexanol and 3-hydroxycyclohexanol together as an alicyclic alcohol as a solvent significantly improves the yield and purity, indicating that 3-methylcyclohexanol and 3-hydroxycyclohexanol can synergistically improve the product yield and purity. Furthermore, setting their volume ratio to 1:1 yields the optimal product yield and purity.

[0044] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing guaiacol glycerol ether, characterized in that, Includes the following steps: (a) Dissolve crude guaiacol glycerol ether in a mixed solvent consisting of ethyl acetate, alicyclic alcohol, and C2-C4 low carbon alcohol, and heat to form a homogeneous hot solution; (b) Add water to the hot solution obtained in step (a) to induce crystallization; (c) The system obtained in step (b) is subjected to programmed cooling crystallization; (d) Filter, wash and dry to obtain high-purity guaiacol glycerol ether.

2. The method for preparing guaiacol glycerol ether as described in claim 1, characterized in that, The volume ratio of ethyl acetate, alicyclic alcohol, and C2-C4 lower alcohol is 3-5:0.4-0.6:

1.

3. The method for preparing guaiacol glycerol ether as described in claim 1, characterized in that, The C2-C4 low-carbon alcohols are mixtures of ethanol, tert-butanol, and n-butanol in a volume ratio of 5:2-4:1-3.

4. The method for preparing guaiacol glycerol ether as described in claim 3, characterized in that, The volume ratio of ethanol, tert-butanol, and n-butanol is 5:3:

2.

5. The method for preparing guaiacol glycerol ether as described in claim 1, characterized in that, The alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxycyclohexanol in a volume ratio of 1:0.8-1.

2.

6. The method for preparing guaiacol glycerol ether as described in claim 5, characterized in that, The volume ratio of 3-methylcyclohexanol to 3-hydroxycyclohexanol is 1:

1.

7. The method for preparing guaiacol glycerol ether according to claim 1, characterized in that, The amount of water added is 10-30% of the total volume of the mixed solvent.

8. The method for preparing guaiacol glycerol ether as described in claim 1, characterized in that, The cooling rate of the program is from 0.1°C / minute to 0.5°C / minute.

9. The method for preparing guaiacol glycerol ether as described in claim 1, characterized in that, The heating temperature described in step (a) is 50°C to 65°C.