Preparation method and detection method of nicotine salt, prepared nicotine salt and application

Abstract

The invention discloses a nicotine salt preparation method, which comprises: mixing dicarboxylic acid and nicotine, adding a strong acid to adjust the pH value, carrying out a heating reaction to obtain a light yellow liquid salt, and freezing to separate out the solid nicotine salt. According to the invention, azelaic acid and nicotine are adopted as raw materials, and formed azelaic acid nicotine salt can diffuse in water more quickly and penetrate through cell membranes, so that the membrane permeability of azelaic acid is greatly improved. The methanesulfonic acid is adopted to adjust the pH value, so that the residue is low, the reaction irritation is small, the pH value is easy to adjust, and the process difficulty is low. The prepared nicotine salt has the effects of resisting bacteria, diminishing inflammation and resisting oxidation, and when the nicotine salt is applied to buccal nicotine products and buccal betel nut products, oral irritation is reduced, and oral inflammation is avoided.

Description

Technical Field

[0001] This invention relates to the field of tobacco substitute preparation, specifically to a method for preparing nicotine salt, a method for detecting nicotine salt, the prepared nicotine salt, and its application. Background Technology

[0003] Chinese invention patent application CN111961032A discloses a method for preparing synthetic nicotine salts and its composition. The method involves mixing a nicotine mixture with benzoic acid, refluxing at high temperature, and then cooling to obtain nicotine salts. This method improves the yield of nicotine salts, is simple and easy to operate, highly practical, cost-effective, and suitable for large-scale industrial production. However, the product contains phenyl residues, posing certain safety concerns for ingestion. Chinese invention patent CN114343229B discloses a novel method for preparing nicotine salts. Using mixed acids as raw materials and employing a step-by-step feeding method, the resulting nicotine salts have a unique flavor, and the e-cigarette liquid is closer to the taste of traditional cigarettes. The addition of auxiliary acids allows the nicotine salts to form a gel structure, increasing stability and facilitating storage. However, this only improves the taste and does not have an anti-inflammatory effect. Summary of the Invention

[0004] To prepare a nicotine salt with high purity, high yield, and the ability to relieve oral inflammation, the first aspect of the present invention provides a method for preparing a nicotine salt, comprising the following steps:

[0005] Dicarboxylic acid and nicotine are mixed, a strong acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

[0006] In one embodiment, the dicarboxylic acid includes at least one of azelaic acid or citric acid.

[0007] In one embodiment, the dicarboxylic acid includes azelaic acid.

[0008] In this application, nicotine and azelaic acid are combined to prepare nicotine salts. The pyridine ring of nicotine is amphiphilic, and the resulting azelaic acid nicotine salt can diffuse more quickly in water and permeate through cell membranes, greatly improving the membrane permeability of azelaic acid.

[0009] In one embodiment, the molar ratio of the dicarboxylic acid to nicotine is 1:(1-5).

[0010] In one embodiment, the molar ratio of the dicarboxylic acid to nicotine is 1:(1-4).

[0011] In one embodiment, the molar ratio of the dicarboxylic acid to nicotine is 1:(1-3).

[0012] In one embodiment, the molar ratio of the dicarboxylic acid to nicotine is 1:(1.5-2.5).

[0013] In one embodiment, the molar ratio of the dicarboxylic acid to nicotine is 1:2.

[0014] In one embodiment, the strong acid includes inorganic strong acids and organic strong acids, wherein the organic strong acid includes at least one of methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or trichloroacetic acid.

[0015] In one embodiment, the strong acid includes an organic strong acid, which includes methanesulfonic acid.

[0016] In one embodiment, the amount of methanesulfonic acid added accounts for 1-3% of the total mass of the raw materials for preparing nicotine salt.

[0017] In one embodiment, the amount of methanesulfonic acid added accounts for 1-2% of the total mass of the raw materials for preparing nicotine salt.

[0018] In one embodiment, the amount of methanesulfonic acid added accounts for 1% of the total mass of the raw materials for preparing nicotine salt.

[0019] In one implementation, the strong acid is used to adjust the pH value to 1.5-3.5.

[0020] As one implementation method, the strong acid is used to adjust the pH value to 2-3.

[0021] As one implementation method, the strong acid is used to adjust the pH value to 2.5.

[0022] In this application, methanesulfonic acid is used to adjust the pH to 2.5, which yields high-purity azelaic acid nicotine salt. This is likely because azelaic acid, being a dicarboxylic acid, would exhibit a product competition effect if an optimal pH is not used, leading to the formation of azelaic acid dinic acid salt as a byproduct, thus affecting the purity of the azelaic acid nicotine salt. The applicant further discovered that using methanesulfonic acid to adjust the pH not only results in low residue but also minimizes reaction irritation and facilitates pH adjustment, reducing process difficulty. This is likely because using a weak acid to adjust to strong acid reaction conditions would be more difficult; using strong inorganic acids such as hydrochloric acid or sulfuric acid would be highly irritating and pose a hazardous production process; and using benzene-based organic acids would leave residues, posing a potential hazard in the subsequent preparation of oral products.

[0023] In one implementation, the heating temperature is 30-50°C.

[0024] In one implementation, the heating temperature is 35-45°C.

[0025] In one implementation, the heating temperature is 40°C.

[0026] In one implementation method, the reaction time is 1-2 hours.

[0027] In one implementation, the reaction time is 1.5 hours.

[0028] In one embodiment, the precipitation temperature is -4 to -10°C.

[0029] In one implementation, the precipitation temperature is -4°C.

[0030] A second aspect of the present invention provides a method for detecting nicotine salts, comprising the following steps: performing LC-MS analysis on the prepared nicotine salts using a positive nonpolar solvent, and then observing the morphology of the nicotine salts using an electron microscope.

[0031] In one embodiment, in the positive ion mode of the LC-MS analysis, the solvent is acetonitrile + 0.1 wt% fatty acid aqueous solution, and the volume ratio of acetonitrile to 0.1 wt% fatty acid aqueous solution is 6:4; the solvent flow rate is 0.4 mL / min.

[0032] In one embodiment, in the negative ion mode of the LC-MS analysis, the solvent is acetonitrile + 0.05wt% ammonia solution, with a volume ratio of acetonitrile to 0.05wt% ammonia solution of 6:4; the solvent flow rate is 0.4mL / min.

[0033] If the azelaic nicotine salt of this application is analyzed by LC-MS using a reverse polar solvent, the weak acid-weak base bond will be broken, which is not conducive to morphological observation. However, if a normal non-polar solvent is used for LC-MS analysis, the morphology after the reaction can be seen by electron microscopy.

[0034] A third aspect of the present invention provides a nicotine salt prepared using the aforementioned method for preparing nicotine salt.

[0035] In one embodiment, the nicotine salt is azelaic acid nicotine salt.

[0036] A fourth aspect of the present invention provides an application of the nicotine salt in nicotine lozenges and areca nut lozenges.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] (1) The method for preparing nicotine salt according to the present invention uses azelaic acid and nicotine as raw materials. The resulting azelaic acid nicotine salt can diffuse in water and permeate the cell membrane more quickly, which greatly improves the membrane permeability of azelaic acid.

[0039] (2) The method for preparing nicotine salt described in this invention uses methanesulfonic acid to adjust the pH, which not only results in low residue and low irritation, but also makes the pH easy to adjust and the process is easy.

[0040] (3) The method for preparing nicotine salt described in this invention, by adjusting the pH to 2.5, can obtain high-purity azelaic acid nicotine salt without byproducts.

[0041] (4) The nicotine salt prepared by this invention has antibacterial, anti-inflammatory and antioxidant effects. When applied to nicotine oral products and areca nut oral products, it reduces oral irritation and avoids oral inflammation.

[0042] (5) The method for detecting nicotine salt described in this invention uses a positive nonpolar solvent for LC-MS analysis, and then the new morphology of nicotine salt can be observed by electron microscopy. Attached Figure Description

[0043] Figure 1 Electron micrographs of nicotine prepared in Example 1 at different resolutions, with scale bars from left to right and from top to bottom of 5 μm, 10 μm, 30 μm, 50 μm, and 500 μm, respectively;

[0044] Figure 2 Electron micrographs of azelaic acid prepared in Example 1 at different resolutions, with scale bars from left to right and top to bottom of 5 μm, 10 μm, 30 μm, 50 μm, and 500 μm, respectively;

[0045] Figure 3 Electron micrographs of the azelaic acid nicotine salt prepared in Example 1 at different resolutions, with scale bars from left to right and from top to bottom being 5 μm, 10 μm, 30 μm, 50 μm, and 500 μm, respectively;

[0046] Figure 4 NMR of the azelaic acid nicotine salt prepared in Example 1 1 H-NMR spectrum;

[0047] Figure 5 NMR of the azelaic acid nicotine salt prepared in Example 1 13 C-NMR spectrum;

[0048] Figure 6 The high-resolution mass spectrum of the azelaic acid nicotine salt prepared in Example 1 in the range of m / z = 0-1400;

[0049] Figure 7 The high-resolution mass spectrum of the azelaic acid nicotine salt prepared in Example 1 in the range of m / z = 50-500;

[0050] Figure 8The high-resolution mass spectrum of the azelaic acid nicotine salt prepared in Example 1 in the range of m / z = 0-500;

[0051] Figure 9 The high-resolution mass spectrum of the azelaic acid nicotine salt prepared in Example 1 is shown in the range of m / z = 500-1500.

[0052] Figure 6-9 From top to bottom, the peak values ​​are: azelaic acid nicotine salt in positive ion mode, blank sample (methanol) in positive ion mode, azelaic acid nicotine salt in negative ion mode, and blank sample (methanol) in negative ion mode. Detailed Implementation

[0053] Example 1

[0054] A method for preparing nicotine salt, comprising the following steps:

[0055] Dicarboxylic acid and nicotine are mixed, a strong acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

[0056] The dicarboxylic acid is azelaic acid; the molar ratio of the dicarboxylic acid to nicotine is 1:2.

[0057] The strong acid is methanesulfonic acid;

[0058] The amount of methanesulfonic acid added accounts for 1% of the total mass of the raw materials used in the preparation of nicotine salt.

[0059] The strong acid is used to adjust the pH value to 2.5.

[0060] The heating temperature is 40°C.

[0061] The reaction time is 1.5 hours.

[0062] The temperature at which the solid nicotine salt precipitates is -4°C.

[0063] The method for detecting nicotine salts includes the following steps: the prepared nicotine salts are analyzed by LC-MS using a positive nonpolar solvent, and then the morphology of the nicotine salts is observed by electron microscopy.

[0064] In the positive ion mode of the LC-MS analysis, the solvent was acetonitrile + 0.1 wt% fatty acid aqueous solution, with a volume ratio of acetonitrile to 0.1 wt% fatty acid aqueous solution of 6:4; the solvent flow rate was 0.4 mL / min.

[0065] In the negative ion mode of the LC-MS analysis, the solvent was acetonitrile + 0.05 wt% ammonia solution, with a volume ratio of acetonitrile to 0.05 wt% ammonia solution of 6:4; the solvent flow rate was 0.4 mL / min.

[0066] The electron micrograph of the azelaic acid nicotine salt prepared in Example 1 is shown below. Figure 3 ,Depend on Figure 1-3 As can be seen, the morphology of the product changed significantly, indicating that the synthesis of azelaic acid nicotine salt was successful. The yield of azelaic acid nicotine salt was 90%.

[0067] The NMR spectrum of the prepared azelaic acid nicotine salt is shown in the figure. Figure 4-5 Mass spectrum (see) Figure 6-9 .

[0068] Comparative Example 1

[0069] A method for preparing nicotine salt, comprising the following steps:

[0070] Dicarboxylic acid and nicotine are mixed, a strong acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

[0071] The dicarboxylic acid is azelaic acid; the molar ratio of the dicarboxylic acid to nicotine is 1:2.

[0072] The strong acid is sulfuric acid;

[0073] The amount of sulfuric acid added accounts for 1% of the total mass of the raw materials used in the preparation of nicotine salt.

[0074] The strong acid is used to adjust the pH value to 2.5.

[0075] The heating temperature is 40°C.

[0076] The reaction time is 1.5 hours.

[0077] The precipitation temperature is -4℃.

[0078] The prepared experimental product, azelaic acid nicotine salt, is highly irritating.

[0079] Comparative Example 2

[0080] A method for preparing nicotine salt, comprising the following steps:

[0081] Dicarboxylic acid and nicotine are mixed, a strong acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

[0082] The dicarboxylic acid is azelaic acid; the molar ratio of the dicarboxylic acid to nicotine is 1:2.

[0083] The strong acid is hydrochloric acid;

[0084] The amount of hydrochloric acid added accounts for 1% of the total mass of the raw materials used in the preparation of nicotine salt.

[0085] The strong acid is used to adjust the pH value to 2.5.

[0086] The heating temperature is 40°C.

[0087] The reaction time is 1.5 hours.

[0088] The precipitation temperature is -4℃.

[0089] The prepared experimental product, azelaic acid nicotine salt, is highly irritating.

[0090] Comparative Example 3

[0091] A method for preparing nicotine salt, comprising the following steps:

[0092] Dicarboxylic acid and nicotine are mixed, a strong acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

[0093] The dicarboxylic acid is azelaic acid; the molar ratio of the dicarboxylic acid to nicotine is 1:2.

[0094] The strong acid is benzoic acid;

[0095] The amount of benzoic acid added accounts for 1% of the total mass of the raw materials used in the preparation of nicotine salt.

[0096] The strong acid is used to adjust the pH value to 2.5.

[0097] The heating temperature is 40°C.

[0098] The reaction time is 1.5 hours.

[0099] The precipitation temperature is -4℃.

[0100] The prepared experimental product, azelaic acid nicotine salt, contained phenyl residue.

[0101] Comparative Example 4

[0102] A method for preparing nicotine salt, comprising the following steps:

[0103] Dicarboxylic acid and nicotine are mixed, acetic acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

[0104] The dicarboxylic acid is azelaic acid; the molar ratio of the dicarboxylic acid to nicotine is 1:2.

[0105] The amount of acetic acid added accounts for 1% of the total mass of the raw materials for preparing nicotine salt.

[0106] The acetic acid is used to adjust the pH to 4.

[0107] The heating temperature is 40°C.

[0108] The reaction time is 1.5 hours.

[0109] The precipitation temperature is -4℃.

[0110] The prepared experimental product, azelaic acid nicotine salt, had low purity and contained the byproduct, diazelaic acid nicotine salt.

Claims

1. A method for preparing nicotine salt, characterized in that, Includes the following steps: Dicarboxylic acid and nicotine are mixed, a strong acid is added to adjust the pH, and the reaction is heated to obtain a light yellow liquid salt. The solid nicotine salt is then precipitated by freezing.

2. The method for preparing nicotine salt according to claim 1, characterized in that, The dicarboxylic acid includes at least one of azelaic acid or citric acid.

3. The method for preparing nicotine salt according to claim 1, characterized in that, The molar ratio of the dicarboxylic acid to nicotine is 1:(1-5).

4. The method for preparing nicotine salt according to claim 1, characterized in that, The strong acid includes inorganic strong acids and organic strong acids, and the organic strong acid includes at least one of methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or trichloroacetic acid.

5. The method for preparing nicotine salt according to claim 4, characterized in that, The strong acid is used to adjust the pH value to 1.5-3.

5.

6. The method for preparing nicotine salt according to claim 1, characterized in that, The heating temperature is 30-50℃.

7. The method for preparing nicotine salt according to claim 1, characterized in that, The precipitation temperature is -4 to -10℃.

8. A method for detecting nicotine salts, characterized in that, Includes the following steps: The prepared nicotine salts were analyzed by LC-MS using a positive nonpolar solvent, and their morphology was observed by electron microscopy.

9. A nicotine salt, characterized in that, The nicotine salt was prepared using the method described in claim 1.

10. An application of the nicotine salt according to claim 9, characterized in that, It is used in nicotine lozenges and areca nut lozenges.

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