阅读说明：本技术 一种2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸钠及其制备方法 (2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate and preparation method thereof ) 是由 张国庆 梁陈静 张朝霞 于 2021-08-09 设计创作，主要内容包括：本发明公开了一种2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸钠及其制备方法,将2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸溶解在纯水中,加入钠基碱搅拌反应后生成2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸钠溶液。上述盐溶液经过冷冻干燥得到2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸钠。成盐后的产品相比2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸具有更好的水溶性和稳定性。有利于制剂,同时提高了成品药物的溶出性能和生物利用度。该工艺流程简单,易于操作,具有潜在的利用价值。(The invention discloses 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate and a preparation method thereof, wherein 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate is dissolved in pure water, sodium base is added, and sodium base is stirred for reaction to generate a 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate solution. The salt solution is frozen and dried to obtain the sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate. Compared with 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid, the salified product has better water solubility and stability. Is beneficial to the preparation, and simultaneously improves the dissolution performance and bioavailability of the finished product medicine. The process flow is simple, the operation is easy, and the potential utilization value is realized.)

1. A preparation method of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate is characterized by comprising the following steps:

(1) adding a solvent into a reaction vessel, adding 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid into the reaction vessel, heating and stirring until the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid is completely dissolved to obtain a 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid solution;

(2) adding a certain amount of alkali into the reaction vessel, and stirring for 4-10 hours to ensure that the alkali and the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid fully react;

(3) and (3) carrying out post-treatment on the product obtained in the step (2) to obtain 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate crystal powder.

2. The process for preparing sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate according to claim 1, wherein: in the step (1), the used solvent is pure water, and the feed liquid mass ratio of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid to the solvent pure water is 1: 2, the temperature of the reaction solution is 60-80 ℃.

3. The process for preparing sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate according to claim 1, wherein: the alkali in the step (2) is sodium-based alkali selected from one of sodium hydroxide, sodium bicarbonate and sodium carbonate.

4. The process for preparing sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate according to claim 1, wherein: the post-treatment step in the step (3) is as follows: freezing the product at low temperature to solidify, and freeze drying.

5. A sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate characterized by: crystalline powder of sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate obtained by the production method according to claim 1.

6. A sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate according to claim 5, wherein: the melting point of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate crystal powder is 153 ℃.

7. A sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate according to claim 5, wherein: the sodium-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate crystal powder is off-white crystal powder, and the main characteristic diffraction peak positions of the powder are 6.0 degrees, 12.5 degrees, 18.1 degrees, 19.5 degrees, 26.7 degrees, 30.4 degrees, 34.5 degrees +/-0.2 degrees at 2 theta.

Technical Field

The invention belongs to the field of preparation of pharmaceutical compounds, and particularly relates to 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate and a preparation method thereof.

Background

Senile dementia, Alzheimer Disease (AD), is a degenerative disease of the central nervous system that is mainly characterized by progressive cognitive impairment and memory impairment, and dementia is the most prominent mental symptom thereof. As the etiology and pathogenesis of the senile dementia are not known, a specific etiology treatment method is still lacked at present, but according to research findings of medical scientists for many years, a plurality of medicines have good effects on improving the memory capacity and cognitive function of senile dementia patients, delaying senility and the like. The research and development of the medicine for treating the senile dementia arouses high importance of the medicine world in various countries, and with the continuous and deep research on the aspects of neurophysiology, biochemistry, pharmacology and the like of the elderly, the development and research of related medicines are continuously advanced.

Korean reuuter corporation developed a compound having a superior therapeutic effect for treating neurological diseases such as alzheimer's disease and parkinson's disease, which is referred to as 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid;

the English name 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethyl) ] benzoic acid, and the structural formula is shown as follows.

Chinese patent CN101874016A discloses the compound and its preparation technology, and clinical tests show that the compound has better inhibitory effect on Alzheimer's disease. However, the solubility of the medicine in water at normal temperature and pressure is low, so that the dissolution rate of the prepared tablet is low, and the bioavailability is low.

Disclosure of Invention

The invention aims to provide 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate and a preparation method thereof, wherein the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid is salified to improve the solubility aiming at poor water solubility of the existing 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid, and the salified 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid is formed by reacting with an alkaline substance under certain conditions, so that the solubility and the bioavailability of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid are improved.

In order to solve the technical problems, the following technical scheme is adopted:

a preparation method of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate is characterized by comprising the following steps:

(1) adding a solvent into a reaction vessel, adding 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid into the reaction vessel, heating and stirring until the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid is completely dissolved to obtain a 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid solution;

(2) adding a certain amount of alkali into the reaction vessel, and stirring for 4-10 hours to ensure that the alkali and the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid fully react;

(3) and (3) carrying out post-treatment on the product obtained in the step (2) to obtain 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate crystal powder.

Preferably, in the step (1), the solvent is pure water, and the feed liquid mass ratio of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid to the solvent pure water is 1: 2, the temperature of the reaction solution is 60-80 ℃.

Preferably, the alkali in the step (2) is a sodium-based alkali selected from one of sodium hydroxide, sodium bicarbonate and sodium carbonate.

Preferably, the post-treatment step in the step (3) is: freezing the product at low temperature to solidify, and freeze drying.

2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate, and 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate crystal powder prepared by the preparation method.

Preferably, said crystalline powder of sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate has a melting point of 153 ℃.

Preferably, the crystalline powder of sodium-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate is off-white crystalline powder, and the main characteristic diffraction peak positions are 6.0 °, 12.5 °, 18.1 °, 19.5 °, 26.7 °, 30.4 °, 34.5 ° +/-0.2 ° in 2 θ.

Due to the adoption of the technical scheme, the method has the following beneficial effects:

according to the salification method of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid, the water solubility and stability of the salified product are better than those of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid. Because the water solubility of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid is poor, the solubility of the benzoic acid in water solution can be increased after salification, the absorption in vivo after preparation is facilitated, and the treatment effect of the finished product medicament is improved; the process flow is simple, the operation is easy, and the cost is low.

Drawings

The invention is further described with reference to the accompanying drawings in which:

FIG. 1 is an X-ray diffraction pattern (XRD) of an inorganic salt of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid according to the present invention;

FIG. 2 is a differential scanning spectrum (DSC) of inorganic salt of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid in accordance with the present invention;

FIG. 3 is an infrared spectrum (FTIR) of the inorganic salt of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid of the present invention;

FIG. 4 is a Scanning Electron Micrograph (SEM) of the inorganic salt of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid according to the present invention.

FIG. 5 is a photograph of nuclear magnetic resonance (1HNMR) of an inorganic salt of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid according to the present invention.

Detailed Description

The invention aims to provide 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate with simple process flow and low cost and a preparation method thereof.

The drug 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino)]Sodium benzoate is an off-white powder crystal with molecular formula C₁₆H₁₆NO₃And (4) Na. The structural formula is as follows:

the corresponding main characteristic X-ray diffraction peaks are at 6.0 °, 12.5 °, 18.1 °, 19.5 °, 26.7 °, 30.4 °, 34.5 ° +/-0.2 °.

The characteristic diffraction peaks of the rays corresponding to the sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate are shown in the following table, and correspond to the attached figure 1:

the melting point of the sodium 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoate is 153 ℃ by thermal analysis (as shown in figure 2) and calculation; the enthalpy value is 122.4J/g.

The FTIR characteristic absorption peaks (shown in figure 3) of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate are 3422cm-1, 1916cm-1, 1581cm-1, 1501cm-1, 1330cm-1, 1167cm-1, 1128cm-1, 1070cm-1, 833cm-1,817cm-1, 703cm-1 and the like.

The 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino)]Sodium benzoate nuclear magnetic resonance chemical shift (as shown in figure 5)¹HNMR(300MHz,D₂O)δ7.67(dd,J＝16.3,8.3Hz),7.35(t,J＝10.1 Hz),7.27–7.02(m),7.00(d,J＝6.2Hz),6.89,6.68(dd,J＝6.5,1.8Hz),6.64–6.49 (m),6.43,2.92,2.50(d,J＝11.2Hz)。

The invention selects a proper amount of samples to test the dissolving capacity of the samples in water. The test shows that the solubility of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] sodium benzoate in water at 25 ℃ is improved by about 5-8 times compared with the solubility of the 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid, and the sodium benzoate has better solubility and better bioavailability.

The invention is further illustrated by the following specific examples:

example 1

60 g of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid as a raw material was weighed into a flask, and pure water was added dropwise to the flask while stirring, and the mixture was dissolved in a 60 ℃ constant temperature water bath. And dropwise adding a certain amount of sodium hydroxide solution into the clear solution, keeping the temperature at 60 ℃ unchanged, fully reacting for 6 hours, taking out the reactant, placing the reactant into a beaker, and carrying out freeze drying treatment. The target product was obtained after 72 hours and the calculated yield after weighing the product was about 83%.

Example 2

30 g of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid as a starting material was weighed into a flask, and pure water was added dropwise to the flask while stirring, followed by dissolving in a 70 ℃ constant temperature water bath. And (3) dropwise adding a certain amount of sodium carbonate aqueous solution into the clear solution, keeping the temperature at 70 ℃ unchanged, fully reacting for 5 hours, taking out the reactant, placing the reactant into a beaker, and carrying out freeze drying treatment. The target product was obtained after 60 hours and the calculated yield after weighing of the product was about 87%.

Example 3

50 g of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid as a starting material was weighed into a flask, and pure water was added dropwise to the flask while stirring, followed by dissolving in a water bath at a constant temperature of 80 ℃. Dropping a certain amount of sodium bicarbonate water solution into the clear solution, keeping the temperature at 80 ℃, fully reacting for 9 hours, taking out the reactant, placing the reactant in a beaker, and carrying out freeze drying treatment. The target product was obtained after 72 hours and the calculated yield after weighing of the product was about 86%.

Example 4

40 g of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid as a starting material was weighed into a flask, and pure water was added dropwise to the flask while stirring, followed by dissolving in a water bath at a constant temperature of 80 ℃. And dropwise adding a certain amount of sodium carbonate aqueous solution into the clear solution, keeping the temperature at 75 ℃ unchanged, fully reacting for 6 hours, taking out the reactant, and placing the reactant in a rotary evaporator to remove the solvent. The solvent was evaporated until the solvent was completely removed to obtain an oily substance, and the sodium salt of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid could not be obtained.

The above is only a specific embodiment of the present invention, but the technical features of the present invention are not limited thereto. Any simple changes, equivalent substitutions or modifications made on the basis of the present invention to solve the same technical problems and achieve the same technical effects are all covered in the protection scope of the present invention.