CN-121990885-A - Guaiacol method for purifying glyceryl ether

Abstract

The invention discloses a purification method of guaifenesin, and belongs to the technical field of pharmaceutical chemicals. The method aims to solve the problem that the specific pharmacopoeia impurities in guaifenesin are difficult to effectively remove in the prior art. The invention dissolves guaifenesin crude product in mixed solvent composed of ethyl acetate, alicyclic alcohol and C2-C4 low carbon alcohol, heats to form homogeneous phase solution, then adds water to induce crystallization, then reduces temperature to crystallize through program, finally filters, washes and dries to obtain high purity product. The invention realizes the directional removal of key impurities through the control of a specific mixed solvent system and crystallization dynamics, and the obtained product has high purity, high yield, simple process and low cost, and is very suitable for industrial production.

Inventors

• GONG LIFENG
• Shao Zhongkun
• YANG WENCHANG
• QIAN DONG
• YIN YIFENG

Assignees

• 江苏同禾药业有限公司

Dates

Publication Date

20260508

Application Date

20260115

Claims (9)

1. 1. The preparation method of guaifenesin is characterized by comprising the following steps: (a) Dissolving guaifenesin crude product in a mixed solvent composed of ethyl acetate, alicyclic alcohol and C2-C4 low-carbon alcohol, and heating to form a homogeneous phase hot solution; (b) Adding water to the hot solution obtained in the step (a) to induce crystallization; (c) Performing program cooling crystallization on the system obtained in the step (b); (d) Filtering, washing and drying to obtain the high-purity guaifenesin.
2. 2. The method for preparing guaifenesin in accordance with claim 1, wherein the volume ratio of ethyl acetate, alicyclic alcohol and C2-C4 lower alcohol is 3-5:0.4-0.6:1.
3. 3. The method for preparing guaifenesin in accordance with claim 1, wherein the C2-C4 lower alcohol is a mixture of ethanol, t-butanol and n-butanol in a volume ratio of 5:2-4:1-3.
4. 4. The method for preparing guaifenesin in accordance with claim 3, wherein the volume ratio of ethanol, t-butanol and n-butanol is 5:3:2.
5. 5. The method for preparing guaifenesin in accordance with claim 1, wherein the alicyclic alcohol is a mixture of 3-methylcyclohexanol and 3-hydroxy-cyclohexylethanol in a volume ratio of 1:0.8-1.2.
6. 6. The method for preparing guaifenesin in accordance with claim 5, wherein the volume ratio of 3-methylcyclohexanol to 3-hydroxy-cyclohexylethanol is 1:1.
7. 7. The method for preparing guaifenesin in accordance with claim 1, wherein the water is added in an amount of 10-30% of the total volume of the mixed solvent.
8. 8. The method of preparing guaifenesin in accordance with claim 1 wherein the programmed cooling rate is from 0.1 ℃ per minute to 0.5 ℃ per minute.
9. 9. The method of preparing guaifenesin in accordance with claim 1 wherein the heating in step (a) is at a temperature of from 50 ℃ to 65 ℃.

Description

Guaiacol method for purifying glyceryl ether Technical Field The invention relates to the technical field of pharmaceutical chemicals, in particular to a purification method of guaifenesin, and especially relates to a method for selectively removing key pharmacopoeia impurities such as impurities B and C and the like through a specific mixed solvent system and a programmed cooling crystallization technology to obtain high-chemical-purity guaifenesin. Background Guaifenesin (Guaifenesin), known as 3- (2-methoxyphenoxy) -1, 2-propanediol, is a widely used expectorant. At present, the industrialized production mainly adopts a process route of condensing epichlorohydrin or chloroglycerol with guaiacol under alkaline condition. However, a series of by-products and isomers having a structure similar to that of the target product are inevitably produced during the synthesis reaction, for example, 3- (2-methoxyphenoxy) -1, 3-propanediol (impurity C) and 1- (2-methoxyphenoxy) -3-hydroxypropan-2-one (impurity B) which are controlled with emphasis in pharmacopoeia. The physicochemical properties (e.g., polarity, solubility) of these impurities are very close to those of guaifenesin, resulting in very difficult separation and removal. The prior purification technology has obvious limitations: The rectification method is, for example, that Chinese patent CN119019230A adopts vacuum rectification to purify. The method has high energy consumption, and because part of impurities have close boiling points to the target product, the separation efficiency is limited, and the high temperature can promote the decomposition of materials or generate new degradation impurities. For example, the conventional recrystallization method adopts ethyl acetate as extraction and recrystallization solvent in Chinese patent CN118084633A, and the operation is improved, but the selectivity removal capability of key isomers such as impurity C, B is insufficient, the purity of the product is usually difficult to reach more than 99.8%, and the content control of impurity C is especially unsatisfactory. Therefore, the field is urgent to develop a new purification process capable of directionally, efficiently and mildly removing the specific intractable impurities so as to improve the product quality, meet the increasingly strict quality standards of domestic and foreign pharmacopoeias, and adapt to the development trend of green and low-carbon industries. Disclosure of Invention The invention aims to overcome the defects of the prior art and provides a purification method which is simple and convenient to operate, low in cost, easy to industrialize and capable of efficiently and selectively removing specific pharmacopoeia impurities in guaifenesin. In order to solve the technical problems, the invention adopts the following technical scheme: A method for preparing guaifenesin, comprising the following steps: (a) Dissolving guaifenesin crude product in a mixed solvent composed of ethyl acetate, alicyclic alcohol and C2-C4 low-carbon alcohol, and heating to form a homogeneous phase hot solution; (b) Adding water to the hot solution obtained in the step (a) to induce crystallization; (c) Performing program cooling crystallization on the system obtained in the step (b); (d) Filtering, washing and drying to obtain the high-purity guaifenesin. The present invention finds and exploits the unexpected "synergistic dissolution effect" of the specific ternary solvent system ethyl acetate/specific alcohol/water on impurities C and B. In this system, impurities are more soluble in the mother liquor than the desired product and are therefore effectively "rejected" from the crystal lattice during crystallization. The crystallization process is started rapidly by adding water, and the high-efficiency and controllable crystallization maintenance and completion are realized by combining program cooling, so that the content of impurity C can be reduced to below 0.1%, the purity of the product HPLC exceeds 99.5%, and the purification yield is stabilized to above 80%, thereby solving the problem which puzzles the industry for a long time. In some embodiments, the volume ratio of ethyl acetate, cycloaliphatic alcohol, C2-C4 lower alcohols is 3-5:0.4-0.6:1. The volume ratio of ethyl acetate, alicyclic alcohol and C2-C4 low-carbon alcohol is critical to the crystallization result, the molecular structure of guaifenesin contains hydroxyl, ether bond, hydrocarbon chain and benzene ring structure, and belongs to a medium-polarity compound, the solvent system has better solubility to crude products through the mixing of the polar volume ratio of ethyl acetate, alicyclic alcohol and C2-C4 low-carbon alcohol, and meanwhile, the solvent system can be effectively and selectively dissolved when the temperature is reduced, impurities are not separated out along with crystallization behavior, so that the purity is greatly improved, in addition, the system is favorable for promoting