One-pot synthesis of zinc acetylsalicylate

Abstract

The application belongs to the technical field of zinc acetylsalicylate preparation, and discloses a one-pot synthesis method of zinc acetylsalicylate. (1) A mixed solvent is prepared by taking 55-65 parts of ethanol, 5-9 parts of acetic acid and the rest of water, with the total volume being 100 parts; (2) under the condition of condensation reflux, the mixed solvent is stirred and heated to 45-60 DEG C, acetylsalicylic acid is added, and then zinc hydroxide is added after the acetylsalicylic acid is completely dissolved, and the stirring and heating is continued to 75-90 DEG C for 0.2-2 h; wherein, the molar ratio of zinc hydroxide to acetylsalicylic acid is 1: (2-2.2) ; 80-100 mL of the mixed solvent is added for every 0.0555 mol of acetylsalicylic acid; (3) after the reaction is completed, the reaction liquid is concentrated to 1 / 4-1 / 3 of the original volume, naturally cooled to room temperature, then stored at 2-4 DEG C for 12-24 h, evaporated at 45-60 DEG C, and then vacuum dried, and the zinc acetylsalicylate is obtained. The synthesis method is a one-pot method, the process is simple, the reaction time is short, and the method is suitable for industrial production, and the obtained product has high yield and high purity.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of zinc acetylsalicylate preparation, and particularly relates to a one-pot synthesis method of zinc acetylsalicylate. BACKGROUND

[0002] Acetylsalicylic acid (ASP) is also known as aspirin, which is an organic compound with a chemical formula of C9H8O4. It is a white crystalline powder, soluble in ethanol and diethyl ether, and slightly soluble in water. It is mainly used as an antipyretic analgesic, a non-steroidal anti-inflammatory drug, and an anti-platelet aggregation drug. After nearly a hundred years of clinical application, it has been proved to be effective in relieving mild or moderate pain, such as toothache, headache, neuralgia, muscle soreness, and menstrual pain. It is also used for fever reduction in diseases such as colds and influenza, and for the treatment of rheumatic pain. It can prevent thrombosis and is clinically used to prevent transient ischemic attacks, myocardial infarction, artificial heart valve and venous fistula or other postoperative thrombosis. Zinc acetylsalicylate (ASZ) has the dual pharmacological effects of acetylsalicylic acid and zinc. Compared with the original acetylsalicylic acid, zinc acetylsalicylate has the advantages of increased water solubility, reduced acidity, enhanced anti-inflammatory activity, and earlier peak blood concentration in the body. Therefore, zinc acetylsalicylate has more research value and application prospects.

[0003] Some studies have used acetylsalicylic acid to react with sodium bicarbonate to obtain sodium acetylsalicylate, which is then reacted with a certain concentration of zinc sulfate to obtain ASZ (Gao G, Wang F H, Suo H X, et al. Preparation of zinc aspirin (I) [J]. Chinese Modern Applied Pharmacy, 2000, 17(1): 31-32, 12; Zeng R J, Liu M R, Sun W Z. Zinc acetylsalicylate: China, 1102179A [P]. 1995-05-03). Lambi et al. used ASP to react with potassium hydroxide to form potassium acetylsalicylate, and then added a certain concentration of zinc nitrate solution to obtain ASZ (Lambi J N, Nsehyuka A T, Egbewatt N, et al. Synthesis, spectral properties and thermal behaviour of zinc(II) acetylsalicylate [J]. Thermochimica Acta, 2003, 398: 145-151). The above reports all use a two-step method to obtain ASZ, which is relatively complicated and not suitable for industrial production. SUMMARY

[0004] In order to overcome the complicated process of the existing preparation method of zinc acetylsalicylate, the purpose of the present application is to provide a one-pot synthesis method of zinc acetylsalicylate.

[0005] To achieve the above-mentioned purpose, the technical solution adopted by the present application is as follows:

[0006] A one-pot synthesis method for zinc acetylsalicylate, characterized by the following steps:

[0007] (1) Based on a total volume of 100 parts, take 55-65 parts of ethanol, 5-9 parts of acetic acid, and the remainder of water to prepare a mixed solvent containing ethanol, acetic acid, and water for later use; the volume concentration of the ethanol is above 95%.

[0008] (2) Under reflux conditions, when the mixed solvent is stirred and heated to 45-60 °C, acetylsalicylic acid is added. After the acetylsalicylic acid is completely dissolved, zinc hydroxide is added, and the mixture is stirred and heated to 75-90 °C for 0.2-2 h. The molar ratio of zinc hydroxide to acetylsalicylic acid is 1:(2-2.2). 80-100 mL of mixed solvent is added for every 0.0555 mol of acetylsalicylic acid.

[0009] (3) After the reaction is completed, concentrate the reaction solution to 1 / 4-1 / 3 of the original volume, cool it naturally to room temperature, then refrigerate it at 2-4℃ for 12-24 h, evaporate it at a constant temperature of 45-60℃, and then dry it under vacuum to obtain zinc acetylsalicylate.

[0010] Preferably, the water is distilled water.

[0011] Ideally, a rotary evaporator should be used to evaporate the reaction liquid, concentrating it to 1 / 4 to 1 / 3 of its original volume.

[0012] Ideally, the temperature for vacuum drying is 40-60 ℃.

[0013] Compared with the prior art, the present invention has the following beneficial effects: the synthesis method of the present invention is a one-pot cooking method, which is simple, has a short reaction time, and is suitable for industrial production. At the same time, the product obtained is not only highly yielded, but also highly pure. Attached Figure Description

[0014] Figure 1 Infrared spectrum of raw material acetylsalicylic acid.

[0015] Figure 2 Infrared spectrum of the product of Example 1. Detailed Implementation

[0016] To make the present invention clearer and more explicit, the present invention will be further described in detail below. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0017] Example 1

[0018] A one-pot cooking synthesis method for zinc acetylsalicylate, comprising the following steps:

[0019] (1) Prepare a mixed solvent containing anhydrous ethanol, acetic acid and distilled water by volume ratio of anhydrous ethanol: acetic acid: distilled water = 60: 5: 35, and set it aside.

[0020] (2) Take 100 mL of mixed solvent and put it into a 250 mL Erlenmeyer flask. Connect the Erlenmeyer flask to a reflux condenser. Place the Erlenmeyer flask on a heating electromagnetic stirrer and stir and heat it. When the temperature of the mixed solvent reaches 45 °C, add 0.0555 mol (10.00 g) of acetylsalicylic acid. After the acetylsalicylic acid is completely dissolved, add 0.0278 mol of zinc hydroxide (2.61 g), stir and heat to 80 °C and react for 0.2 h.

[0021] (3) After the reaction was completed, the reaction solution was evaporated to 30 mL using a rotary evaporator, cooled naturally to room temperature, and then placed in a 4 ℃ refrigerator for 24 h. It was then evaporated at a constant temperature of 45 ℃ to obtain white needle-like crystals. After vacuum drying at 50 ℃ for 10 h, 9.43 g of white crystals were obtained, with a yield of 94.3% (calculated based on acetylsalicylic acid) and a purity of 97.8%.

[0022] Product properties

[0023] The product of Example 1, after grinding, is a white crystalline powder with an acetic acid odor. It is slightly soluble in water and soluble in a 60 wt% ethanol solution. A 0.1 wt% aqueous solution has a pH of approximately 4.9. The Zn content in the product sample was determined by EDTA titration. 2+ The mass fraction was 14.52%, compared with zinc acetylsalicylate (C 18 H 14 The theoretical mass fraction of zinc in O8Zn·2H2O (14.22%) is basically consistent.

[0024] Infrared spectroscopy analysis

[0025] The infrared spectra of the raw material acetylsalicylic acid and the product of Example 1 are as follows: Figure 1 and Figure 2 As shown. By Figure 1 and Figure 2 It can be seen that acetylsalicylic acid is at 1681 cm⁻¹ -1 The disappearance of the C=O vibration peak in the carboxylic acid indicates that the carboxyl group in acetylsalicylic acid has coordinated with Zn(II); because the contribution of the shared electrons of the oxygen atom to the zinc atom leads to an increase in the C—O dipole, the C—O peak position shifts and appears at 1030 cm⁻¹. -1 At 463cm -1 A new absorption peak appeared at 3233 cm⁻¹, which should be the absorption peak of Zn-O. -1 It appeared at the same location, and was 657cm tall. -1 566cm-1 The occurrence of the wagging vibration absorption peak of water molecules indicates that water molecules in the product molecules participate in coordination; compared with the infrared spectrum of the raw material acetylsalicylic acid, the number of peaks in the infrared spectrum of the product is reduced, indicating that the spatial structure of the product molecules is more regular than that of the raw material acetylsalicylic acid.

[0026] In combination with the product properties and the infrared spectrum results described above, it can be seen that the product prepared in this embodiment 1 is indeed zinc acetylsalicylate, which confirms that the one-pot synthesis method of the present application successfully prepares zinc acetylsalicylate.

[0027] Comparative example 1

[0028] The difference from embodiment 1 is that step (1) is omitted, and 100 mL of distilled water is used instead of 100 mL of mixed solvent in step (2); the others are the same as embodiment 1.

[0029] When the reaction time is 1 h, 5 h, 10 h, and 12 h, respectively, we observe the reaction in the triangular flask, and we find that zinc hydroxide and acetylsalicylic acid cannot react. The reason is that zinc hydroxide is insoluble in water, and acetylsalicylic acid is also slightly soluble in water, so the insoluble zinc hydroxide and the slightly soluble acetylsalicylic acid cannot react in aqueous solution.

[0030] Comparative example 2

[0031] The difference from embodiment 1 is that in step (1), the mixed solvent containing anhydrous ethanol and distilled water is prepared in a volume ratio of anhydrous ethanol: distilled water = 65:35; in step (2), the reaction time is set to 2 h, 10 h, and 20 h, respectively; the others are the same as embodiment 1.

[0032] The product yield (calculated based on acetylsalicylic acid) of this comparative example when the reaction time is 2 h, 10 h, and 20 h is 4.3%, 5.1%, and 7.9%, respectively, which is significantly lower than the product yield of embodiment 1. The reason is that acetic acid acts as a catalyst in the present application, which not only greatly shortens the reaction time, but also greatly improves the product yield.

[0033] Comparative example 3

[0034] The difference from embodiment 1 is that in step (3), the refrigeration process is omitted, that is, after natural cooling to room temperature, direct 45 ℃ constant temperature evaporation and 50 ℃ vacuum drying are carried out; the others are the same as embodiment 1.

[0035] The purity of the product obtained in this comparative example is 78.2%, which is significantly lower than the purity of the product of embodiment 1, indicating that refrigeration helps to improve the purity of the product.

Claims

1. A one-pot synthesis of zinc acetylsalicylate, characterized by, The steps are as follows: (1) taking ethanol 55-65 parts, acetic acid 5-9 parts and the rest of water, with the sum of total volume parts being 100 parts, to prepare a mixed solvent containing ethanol, acetic acid and water for standby use; the volume concentration of the ethanol is above 95%; (2) under the condition of condensation reflux, the mixed solvent is stirred and heated to 45-60 ℃, acetylsalicylic acid is added, after the acetylsalicylic acid is completely dissolved, zinc hydroxide is added, and stirring and heating is carried out to 75-90 ℃ for 0.2-2 h; wherein, in terms of molar ratio, zinc hydroxide: acetylsalicylic acid = 1: (2-2.2); 80-100 mL of mixed solvent is added per 0.0555 mol of acetylsalicylic acid; (3) after the reaction is completed, the reaction liquid is concentrated to 1 / 4-1 / 3 of the original volume, naturally cooled to room temperature, then 2-4 ℃ cold storage for 12-24 h, 45-60 ℃ constant temperature evaporation, and then vacuum drying, to obtain zinc acetylsalicylate.

2. The one pot synthesis of zinc acetylsalicylate as claimed in claim 1 wherein: In step (1), the water is distilled water.

3. The one pot synthesis of zinc acetylsalicylate as claimed in claim 1 wherein: In step (3), the reaction liquid is evaporated by using a rotary evaporator, so as to be concentrated to 1 / 4-1 / 3 of the original volume.

4. The one pot synthesis of zinc acetylsalicylate as claimed in claim 1 wherein: In step (3), the temperature for vacuum drying is 40-60 ℃.

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