6-methylnicotine-tartrate, single crystal and preparation method of 6-methylnicotine-tartrate

Abstract

The invention belongs to the technical field of nicotine salt, and relates to 6-methylnicotine-tartrate, a single crystal and a preparation method of the 6-methylnicotine-tartrate. The preparation method of the 6-methylnicotine-tartrate comprises the following steps: S11, dissolving L-tartaric acid in ethanol to obtain an L-tartaric acid solution; s12, dropwise adding 6-methylnicotine into the L-tartaric acid solution to obtain a reaction solution, adding the reaction solution into ethyl acetate, stirring, filtering and washing to obtain a reaction product; and S13, drying the reaction product, so as to obtain the 6-methyl nicotine-tartrate. The technical scheme provided by the invention is simple and easy to operate, low in production cost and high in product purity, can reduce the probability of toxic solvent residues in 6-methylnicotine-tartrate, and is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nicotine salt, more particularly, to a 6-methyl nicotine-tartaric acid salt, a single crystal and a preparation method thereof. BACKGROUND

[0002] The affinity of nicotine analogues is determined by the lipophilicity of the 6-position substituent, and also related to the size of the substituent; among them, the 6-methyl nicotine has the smallest 6-position substituent volume and strong lipophilicity, and also has strong affinity with nAChR receptor, which has good medicinal prospects.

[0003] At present, patent CN115974836A discloses a S-(-)-6-methyl nicotine salicylate and a preparation method thereof, but the method uses methyl tert-butyl ether as a solvent in the preparation process, and methyl tert-butyl ether is a toxic compound, which increases the probability of toxic residual solvents in the product. SUMMARY

[0004] The present application provides a 6-methyl nicotine-tartaric acid salt, a single crystal and a preparation method thereof, which is used to solve the problem that the use of methyl tert-butyl ether as a solvent in the prior art increases the probability of toxic residual solvents in the product.

[0005] In order to solve the above technical problems, the present application provides a preparation method of 6-methyl nicotine-tartaric acid salt, which adopts the following technical scheme:

[0006] A preparation method of 6-methyl nicotine-tartaric acid salt, the method comprises:

[0007] S11, dissolving L-tartaric acid in ethanol to obtain an L-tartaric acid solution;

[0008] S12, adding 6-methyl nicotine dropwise to the L-tartaric acid solution to obtain a reaction liquid, adding the reaction liquid into ethyl acetate, and stirring, filtering, and washing to obtain a reaction product;

[0009] S13, drying the reaction product to obtain 6-methyl nicotine-tartaric acid salt.

[0010] Further, the step S12 specifically comprises: adding 6-methyl nicotine dropwise to the L-tartaric acid solution, stirring at room temperature for 2-3 hours to obtain a reaction liquid, slowly adding the reaction liquid into ethyl acetate, continuing to stir for 2-3 hours, and then placing in 0-4℃ for cold storage to precipitate a solid; filtering, washing the filter cake with ethanol for 2-3 times to remove residual ethyl acetate, and obtaining a reaction product.

[0011] Further, in the step S12, the molar ratio of 6-methylnicotyrine to L-tartaric acid is 1:(2-2.2); and the mass of the ethyl acetate used in the step S12 is 6-8 times of the mass of the ethanol used in the step S11.

[0012] Further, in the step S11, the concentration of the ethanol is 75%-95%; and the mass of the ethanol used in the step S11 is 2-6 times of the mass of the L-tartaric acid.

[0013] Further, in the step S12, the mass of the ethanol used in each washing of the filter cake is 2-6 times of the mass of the L-tartaric acid; and the concentration of the ethanol used in the step S12 is 75%-95%.

[0014] Further, the step S13 specifically includes: vacuum drying the reaction product to obtain 6-methylnicotyrine-tartaric acid salt; wherein the temperature of the vacuum drying is 45-70℃.

[0015] To solve the above technical problems, the embodiments of the present application further provide a 6-methylnicotyrine-tartaric acid salt, which adopts the technical scheme as follows:

[0016] A 6-methylnicotyrine-tartaric acid salt is prepared by using the above-mentioned method for preparing 6-methylnicotyrine-tartaric acid salt.

[0017] To solve the above technical problems, the embodiments of the present application further provide a method for preparing 6-methylnicotyrine-tartaric acid salt, which adopts the technical scheme as follows:

[0018] A method for preparing 6-methylnicotyrine-tartaric acid salt, which comprises:

[0019] S21, obtaining 6-methylnicotyrine-tartaric acid salt prepared by using the above-mentioned method for preparing 6-methylnicotyrine-tartaric acid salt;

[0020] S22, dissolving the 6-methylnicotyrine-tartaric acid salt in ultrapure water to obtain a 6-methylnicotyrine-tartaric acid salt aqueous solution; and volatilizing the ultrapure water under the condition of room temperature and light shielding to obtain 6-methylnicotyrine-tartaric acid salt single crystal.

[0021] Further, the step S22 specifically comprises: dissolving the 6-methylnicotelline-tartaric acid salt in ultrapure water, ultrasonic dissolving to obtain a 6-methylnicotelline-tartaric acid salt aqueous solution, containing the 6-methylnicotelline-tartaric acid salt aqueous solution in a culture tank container, placing the culture tank container in a beaker containing anhydrous ethanol after sealing, sealing the beaker, and precipitating crystals of the 6-methylnicotelline-tartaric acid salt from the 6-methylnicotelline-tartaric acid salt aqueous solution under the condition of room temperature and light shielding to obtain 6-methylnicotelline-tartaric acid salt single crystals; wherein the concentration of the 6-methylnicotelline-tartaric acid salt aqueous solution is 25% to 40%.

[0022] To solve the above technical problems, the embodiment of the present application also provides a 6-methylnicotelline-tartaric acid salt single crystal, which adopts the technical scheme as follows:

[0023] A 6-methylnicotelline-tartaric acid salt single crystal is prepared by using the preparation method of the 6-methylnicotelline-tartaric acid salt single crystal as described above.

[0024] Compared with the prior art, the embodiment of the present application has the following beneficial effects: the preparation method of the 6-methylnicotelline-tartaric acid salt provided by the present application is based on the reaction of L-tartaric acid and 6-methylnicotelline to obtain 6-methylnicotelline-tartaric acid salt, which is an important organic compound and is widely used in medicine, food and chemical industry. In the reaction process, low-toxicity ethanol and other low-boiling-point protic solvents are used as the reaction solvent for the synthesis of 6-methylnicotelline-tartaric acid salt, which reduces the probability of toxic residual in the final 6-methylnicotelline-tartaric acid salt and is suitable for industrial scale-up production; 6-methylnicotelline is added dropwise into the L-tartaric acid solution to obtain a reaction solution, and after the reaction is completed, it is added into ethyl acetate to promote the precipitation of the reaction product, and then the reaction product is obtained by beating, filtering and washing; the reaction product is dried to obtain white or white-like powder, i.e. 6-methylnicotelline-tartaric acid salt, which has good properties and is convenient to use. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to more clearly illustrate the scheme of the present application, the drawings required in the following embodiment description will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creating laborious work.

[0026] Figure 1 is a flow chart of the preparation method of the 6-methylnicotelline-tartaric acid salt provided by the embodiment of the present application;

[0027] Figure 2 is a flow chart of the preparation method of the 6-methylnicotelline-tartaric acid salt single crystal provided by the embodiment of the present application;

[0028] Figure 3 This is a diagram showing the product obtained in step S12 of Example 1-1;

[0029] Figure 4 This is a diagram showing the product obtained in step S12 of Comparative Examples 1-4;

[0030] Figure 5 This is a diagram showing a single columnar crystal obtained from Example 2-1;

[0031] Figure 6 This is a structural analysis diagram of the 6-methylnicotine-tartrate monomer in Example 2-1;

[0032] Figure 7 This is the X-ray diffraction pattern of the 6-methylnicotine-tartrate single crystal in Example 2-1;

[0033] Figure 8 This is a diagram showing the case where a qualified single crystal was not obtained in step S22 of Comparative Example 2-2;

[0034] Figure 9 This is a diagram showing the case where a qualified single crystal was not obtained in step S22 of Comparative Examples 2-3;

[0035] Figure 10 This is a diagram showing the case where a qualified single crystal was not obtained in step S22 of Comparative Examples 2-4. Detailed Implementation

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs; the terminology used herein in the specification of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application; the terms "comprising" and "having," and any variations thereof, in the specification, claims, and foregoing drawings of this application are intended to cover non-exclusive inclusion. The terms "first," "second," etc., in the specification, claims, or foregoing drawings of this application are used to distinguish different objects, not to describe a particular order.

[0037] In this document, the term "embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The appearance of this phrase in various places throughout the specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment mutually exclusive with other embodiments. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments.

[0038] In order for those skilled in the art to better understand the scheme of the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings.

[0039] The present application provides a preparation method of 6-methylnicotine-tartrate, as shown in the following formula: Figure 1 The method comprises the following steps:

[0040] S11, dissolving L-tartaric acid in ethanol to obtain an L-tartaric acid solution;

[0041] S12, adding 6-methylnicotine dropwise to the L-tartaric acid solution to obtain a reaction solution, adding the reaction solution into ethyl acetate, and stirring, filtering and washing to obtain a reaction product;

[0042] S13, drying the reaction product to obtain 6-methylnicotine-tartrate.

[0043] The present application provides a preparation method of 6-methylnicotine-tartrate based on the reaction of L-tartaric acid and 6-methylnicotine to prepare 6-methylnicotine-tartrate. 6-methylnicotine-tartrate is an important organic compound and is widely used in medicine, food and chemical industry.

[0044] In the reaction process, low-toxicity ethanol and other low-boiling point protic solvents are used as the reaction solvent for the synthesis of 6-methylnicotine-tartrate, which reduces the probability of toxic residual solvents in the final 6-methylnicotine-tartrate and is suitable for industrial scale-up production. 6-methylnicotine is added dropwise to the L-tartaric acid solution to obtain a reaction solution. After the reaction is completed, it is added to ethyl acetate to promote the precipitation of the reaction product. Then, the reaction product is purified by beating, filtering and washing to obtain the reaction product. The reaction product is dried to obtain white or white-like powder, i.e. 6-methylnicotine-tartrate, which has good properties and is easy to use.

[0045] In this embodiment, the reaction product obtained after drying in step S13 is white or white-like powder. The theoretical value detected needs to meet the chemical formula of 6-methylnicotine-tartrate: 2(C 11 H 18 N2)·4(C4H5O6)·H2O, containing 36.29% of 6-methylnicotine and 1.85% of water. It should be noted that the error caused by the residual water during drying is allowed.

[0046] Of course, in step S11, when the L-tartaric acid solution is added to ethanol, other low-boiling point protic solvents such as methanol and isopropyl alcohol can be used. However, these solvents have greater toxicity, which can lead to a high probability of toxic residual solvents in the prepared 6-methylnicotine-tartrate.

[0047] Of course, in step S12, when adding ethyl acetate into the reaction solution, other low-boiling aprotic solvents can be used to replace ethyl acetate, such as diethyl ether, methyl tert-butyl ether, dichloromethane, etc., but these solvents have greater toxicity, which can cause the 6-methylnicotinic acid-tartaric acid salt prepared to have a toxic solvent residue.

[0048] Further, the step S12 specifically comprises: adding 6-methylnicotinic acid into the L-tartaric acid solution dropwise, stirring at room temperature for 2-3 hours to obtain a reaction solution, slowly adding the reaction solution into ethyl acetate, continuing to stir for 2-3 hours, and then placing in 0-4℃ for refrigeration to precipitate a solid; filtering, washing the filter cake with ethanol for 2-3 times to remove the residual ethyl acetate, and obtaining a reaction product.

[0049] In the embodiment, when 6-methylnicotinic acid is added into the L-tartaric acid solution dropwise, and the reaction solution is stirred at room temperature for 2-3 hours, the solid begins to precipitate; after the reaction solution is slowly added into ethyl acetate, and continues to stir for 2-3 hours, the precipitation of the solid is promoted, and the beating and purification are realized; the solid is fully precipitated by placing in 0-4℃ for refrigeration; the filter cake is washed with ethanol for 2-3 times to remove the residual ethyl acetate, and the purity of the reaction product is improved.

[0050] Further, in the step S12, the molar ratio of 6-methylnicotinic acid to L-tartaric acid is 1:(2-2.2).

[0051] In the embodiment, in the step S12, the molar ratio of 6-methylnicotinic acid to L-tartaric acid is 1:(2-2.2), so that the 6-methylnicotinic acid can fully react with the L-tartaric acid to promote the generation of 6-methylnicotinic acid-tartaric acid salt.

[0052] Preferably, in the step S12, the molar ratio of 6-methylnicotinic acid to L-tartaric acid is 1:(2.05-2.1).

[0053] In some optional embodiments of the embodiment, in the step S12, the molar ratio of 6-methylnicotinic acid to L-tartaric acid can be any one of 1:2, 1:2.01, 1:2.03, 1:2.05, 1:2.08, 1:2.1, 1:2.13, 1:2.15, 1:2.18, 1:2.2, or a range between any two of them.

[0054] Further, in the step S12, the mass of the ethyl acetate is 6-8 times of the mass of the ethanol in the step S11.

[0055] In the embodiment, in the step S12, the mass of the ethyl acetate is 6-8 times of the mass of the ethanol in the step S11, which can promote the precipitation of the solid, thereby promoting the generation of 6-methylnicotinic acid-tartaric acid salt.

[0056] Further, in the step S11, the molar ratio of the L-tartaric acid to the ethanol is 1 : (2-2.2).

[0057] In the embodiment, in the step S11, the molar ratio of the L-tartaric acid to the ethanol is 1 : (2-2.2), which can fully dissolve the L-tartaric acid in the ethanol.

[0058] Preferably, in the step S11, the molar ratio of the L-tartaric acid to the ethanol is 1 : (2.05-2.1).

[0059] In some alternative embodiments of the embodiment, in the step S11, the molar ratio of the L-tartaric acid to the ethanol can be any one of 1 : 2, 1 : 2.01, 1 : 2.03, 1 : 2.05, 1 : 2.08, 1 : 2.1, 1 : 2.13, 1 : 2.15, 1 : 2.18, 1 : 2.2, or a range between any two of them.

[0060] Further, in the step S11, the concentration of the ethanol is 75%-95%.

[0061] In the embodiment, in the step S11, the concentration of the ethanol is 75%-95%, which can improve the solubility of the L-tartaric acid.

[0062] Preferably, in the step S11, the concentration of the ethanol is 90%-95%.

[0063] In some alternative embodiments of the embodiment, in the step S11, the concentration of the ethanol can be any one of 75%, 78%, 80%, 83%, 85%, 88%, 90%, 93%, 95%, or a range between any two of them.

[0064] Further, in the step S11, the mass of the ethanol is 2-6 times the mass of the L-tartaric acid.

[0065] In the embodiment, in the step S11, the mass of the ethanol is 2-6 times the mass of the L-tartaric acid, which can fully dissolve the L-tartaric acid in the ethanol.

[0066] Preferably, in the step S11, the mass of the ethanol is 3-5 times the mass of the L-tartaric acid.

[0067] In some alternative embodiments of the embodiment, in the step S11, the mass of the ethanol in the step S11 can be any one of 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, or a range between any two of them.

[0068] Further, in the step S12, the ethanol used for washing the filter cake each time is 2-6 times the mass of the L-tartaric acid.

[0069] In the embodiment, in the step S12, the ethanol used for washing the filter cake each time is 2-6 times the mass of the L-tartaric acid, so as to sufficiently wash the filter cake.

[0070] Preferably, in the step S12, the ethanol used for washing the filter cake each time is 3-5 times the mass of the L-tartaric acid.

[0071] In some optional embodiments of the embodiment, in the step S12, the ethanol used for washing the filter cake each time can be any one of 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, or a range between any two of them.

[0072] Further, in the step S12, the concentration of the ethanol is 75%-95%.

[0073] In the embodiment, in the step S12, the concentration of the ethanol is 75%-95%, which can improve the probability of removing the ethyl acetate residue.

[0074] Preferably, in the step S12, the concentration of the ethanol is 90%-95%.

[0075] In some optional embodiments of the embodiment, in the step S12, the concentration of the ethanol can be any one of 75%, 78%, 80%, 83%, 85%, 88%, 90%, 93%, 95%, or a range between any two of them.

[0076] Further, the step S13 specifically includes vacuum drying the reaction product to obtain 6-methylnicotine-tartaric acid salt; wherein the temperature of vacuum drying is 45-70°C.

[0077] In the embodiment, vacuum drying the reaction product can obtain 6-methylnicotine-tartaric acid salt in white or white-like powder, which has good properties and is convenient to use; and without freeze-drying, the method is simple and easy to operate, and has low production cost.

[0078] Preferably, the temperature of vacuum drying is 55-60°C.

[0079] In some optional embodiments of the embodiment, the temperature of vacuum drying can be any one of 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or a range between any two of them.

[0080] To solve the above technical problems, the embodiment of the present application further provides a 6-methylnicotine-tartrate salt prepared by the preparation method of the 6-methylnicotine-tartrate salt.

[0081] The 6-methylnicotine-tartrate salt prepared by the present application is an important organic compound, which is widely used in medicine, food and chemical industry, and the probability of toxic residue in the 6-methylnicotine-tartrate salt is reduced, the property is good, and the use is convenient.

[0082] To solve the above technical problems, the embodiment of the present application further provides a preparation method of a 6-methylnicotine-tartrate salt single crystal, as shown in the following formula (I): Figure 2 The method comprises the following steps:

[0083] S21, obtaining the 6-methylnicotine-tartrate salt prepared by the preparation method;

[0084] S22, dissolving the 6-methylnicotine-tartrate salt in ultrapure water to obtain a 6-methylnicotine-tartrate salt aqueous solution, and volatilizing the ultrapure water under room temperature and light-proof conditions to obtain a 6-methylnicotine-tartrate salt single crystal.

[0085] The preparation method of the 6-methylnicotine-tartrate salt single crystal provided by the embodiment of the present application dissolves the 6-methylnicotine-tartrate salt in ultrapure water and uses the diffusion method for culture, the preparation method is simple, the crystallization is simple, and the environment is not polluted; meanwhile, the impurities can be removed by crystallization to obtain a 6-methylnicotine-tartrate salt single crystal with high purity, and the industrial application is better realized.

[0086] In the embodiment, the structural formula of the 6-methylnicotine-tartrate salt single crystal is shown in the following figure:

[0087]

[0088] Further, the step S22 specifically comprises: dissolving the 6-methylnicotine-tartrate salt in ultrapure water and ultrasonic dissolving to obtain a 6-methylnicotine-tartrate salt aqueous solution, and pouring the 6-methylnicotine-tartrate salt aqueous solution into a culture jar container, placing the culture jar container in a beaker containing anhydrous ethanol after sealing, sealing the beaker, and precipitating crystals from the 6-methylnicotine-tartrate salt aqueous solution under room temperature and light-proof conditions to obtain a 6-methylnicotine-tartrate salt single crystal; wherein the concentration of the 6-methylnicotine-tartrate salt aqueous solution is 25% to 40%.

[0089] In the embodiment, the ultrapure water and the anhydrous ethanol are diffused by using the vapor pressure, and the 6-methylnicotine-tartrate salt aqueous solution is precipitated.

[0090] In the embodiment, the concentration of the 6-methylnicotyrine-tartaric acid salt aqueous solution is 25% to 40% to facilitate crystallization, avoid the crystallization failure due to the too low concentration of the 6-methylnicotyrine-tartaric acid salt aqueous solution, and avoid the direct powder form precipitation due to the too high concentration of the 6-methylnicotyrine-tartaric acid salt aqueous solution, and the regular crystals cannot be formed.

[0091] In some optional embodiments of the embodiment, the concentration of the 6-methylnicotyrine-tartaric acid salt aqueous solution can be any one of 25%, 28%, 30%, 33%, 35%, 38%, 40%, or a range between any two of them.

[0092] Further, the volume of the anhydrous ethanol is 20 to 50 times of the 6-methylnicotyrine-tartaric acid salt aqueous solution.

[0093] In the embodiment, the volume of the anhydrous ethanol is 20 to 50 times of the 6-methylnicotyrine-tartaric acid salt aqueous solution, which avoids the waste caused by the excessive use of anhydrous ethanol, and avoids the insufficient diffusion of the anhydrous ethanol in the bitartrate-nicotine dihydrate aqueous solution, thereby avoiding the situation that the crystals cannot be precipitated.

[0094] Preferably, the volume of the anhydrous ethanol is 30 to 40 times of the 6-methylnicotyrine-tartaric acid salt aqueous solution.

[0095] In some optional embodiments of the embodiment, the volume of the anhydrous ethanol can be any one of 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, or a range between any two of them of the 6-methylnicotyrine-tartaric acid salt aqueous solution.

[0096] To solve the above technical problems, the embodiment of the present application also provides a 6-methylnicotyrine-tartaric acid salt single crystal, which is prepared by the preparation method of the 6-methylnicotyrine-tartaric acid salt single crystal as described above.

[0097] The 6-methylnicotyrine-tartaric acid salt single crystal prepared by the present application has high purity, and better realizes the industrial application.

[0098] The present application will be specifically described below through specific embodiments, and the following embodiments are only part of the embodiments of the present application, and are not a limitation on the present application.

[0099] A preparation method of 6-methylnicotyrine-tartaric acid salt

[0100] Example 1-1

[0101] Step Sll, 30.75 g of L-tartaric acid was dissolved in 100 mL of ethanol (90%), stirred until completely dissolved to obtain a L-tartaric acid solution;

[0102] Step S12, 17.6 g of 6-methylnicotine was added dropwise to the L-tartaric acid solution obtained in step Sll, stirred at room temperature for 2-3 hours to obtain a reaction solution, the reaction solution was slowly added to 800 mL of ethyl acetate, and stirred for 2-3 hours, then placed in a refrigerator at 0-4°C for 16 hours, and a solid was precipitated; filtered, the filter cake was washed with 100 mL of ethanol (90%), and the washing was repeated once to remove the residual ethyl acetate, to obtain a reaction product;

[0103] Step S13, the reaction product obtained in step S12 was vacuum dried at 55°C to obtain a white solid powder: 6-methylnicotine-tartaric acid salt 48.2 g, as shown in Figure 3 The detection showed that the content of 6-methylnicotine was 36.81%, and the moisture was 1.79%, which met the theoretical value range.

[0104] Example 1-2

[0105] The difference from Example 1-1 is that in step Sll, the amount of L-tartaric acid is 31.5 g; in step S12, the molar ratio of 6-methylnicotine to L-tartaric acid is 1:2.1.

[0106] Example 1-3

[0107] The difference from Example 1-1 is that in step Sll, the concentration of ethanol used is 95%.

[0108] Example 1-4

[0109] The difference from Example 1-1 is that in step Sll, the volume of ethanol used is 150 mL.

[0110] Example 1-5

[0111] The difference from Example 1-1 is that in step S12, the volume of ethyl acetate used is 600 mL.

[0112] Example 1-5

[0113] The difference from Example 1-1 is that in step S13, the drying temperature is 60°C.

[0114] Comparative analysis: the product obtained in step S13 in examples 1-2 to 1-5 is a white solid powder, the appearance of the white solid powder is the same as that of example 1-1, and the yield is greater than 95%. The detection shows that the 6-methylnicotine content is 36.29±1%, and the moisture content is 1.85±0.5%, both of which are within the theoretical value range, and it is determined to be 6-methylnicotine-tartrate.

[0115] Comparative Example 1-1

[0116] Step S11, solution preparation: 28.5 g of L-tartaric acid was dissolved in 100 mL of ethanol (90%), and stirred until completely dissolved to obtain an L-tartaric acid solution;

[0117] Step S12, reaction process: 17.6 g of 6-methylnicotine was added dropwise to the L-tartaric acid solution obtained in step S11, and stirred at room temperature for 2-3 hours to obtain a reaction solution. The reaction solution was slowly added to 800 mL of ethyl acetate, and stirred for another 2-3 hours. Then, it was placed in a refrigerator at 0-4℃ for 16 hours to precipitate solids. The solids were filtered, the filter cake was washed with 100 mL of ethanol (90%), and the washing was repeated once to remove the residual ethyl acetate, and the reaction product was obtained;

[0118] Step S13, drying: the reaction product obtained in step S12 was dried at 55℃ under vacuum to obtain 45.9 g of white solid powder. The detection shows that the 6-methylnicotine content is 38.2%, which does not meet the theoretical value range, and part of it is a product generated by the reaction of one tartaric acid and 6-methylnicotine.

[0119] Comparative analysis: in step S11 of comparative example 1-1, the amount of L-tartaric acid used is less than that used in example 1-1, which is not enough to fully react with 6-methylnicotine to form a double tartrate salt, resulting in the formation of a single tartrate salt. The single tartrate salt is insoluble in ethanol, so it is not washed by ethanol, and the product is not pure 6-methylnicotine-tartrate.

[0120] Comparative Example 1-2

[0121] Step S11, 38.4 g of L-tartaric acid was dissolved in 100 mL of ethanol (90%), and stirred until completely dissolved to obtain an L-tartaric acid solution;

[0122] Step S12, 17.6 g of 6-methylnicotine was added dropwise to the L-tartaric acid solution obtained in step S11, and stirred at room temperature for 2-3 hours to obtain a reaction solution. The reaction solution was slowly added to 800 mL of ethyl acetate, and stirred for another 2-3 hours. Then, it was placed in a refrigerator at 0-4℃ for 16 hours to precipitate solids. The solids were filtered, the filter cake was washed with 100 mL of ethanol (90%), and the washing was repeated once to remove the residual ethyl acetate, and the reaction product was obtained;

[0123] Step S13, the reaction product obtained in step S12 was vacuum dried at 55°C to obtain 28.5 g of white solid powder; the content of 6-methylnicotine was 35.9%, which was in the range of the theoretical value.

[0124] Control analysis: in the example 1-2, L-tartaric acid was in excess and could react with 6-methylnicotine to form a double tartaric acid salt. The excess tartaric acid could be dissolved in ethanol and washed by ethanol. The product was pure 6-methylnicotine-tartaric acid salt. However, the excess tartaric acid could not improve the yield and caused waste of raw materials.

[0125] Comparative Example 1-3

[0126] Step S11, 30.75 g of L-tartaric acid was dissolved in 100 mL of ethanol (75%) to obtain an L-tartaric acid solution;

[0127] Step S12, 17.6 g of 6-methylnicotine was added dropwise to the L-tartaric acid solution obtained in step S11, and stirred at room temperature for 2-3 hours to obtain a reaction solution. The reaction solution was slowly added to 800 mL of ethyl acetate, and stirred for another 2-3 hours. Then, it was placed in a refrigerator at 0-4°C for 16 hours to precipitate solids. The solids were filtered, and the filter cake was washed with 100 mL of ethanol (75%) and repeated once to remove residual ethyl acetate, thereby obtaining a reaction product;

[0128] Step S13, the reaction product obtained in step S12 was vacuum dried at 55°C to obtain 28.5 g of white solid powder; the content of 6-methylnicotine was 35.9%, which was in the range of the theoretical value.

[0129] Control analysis: in the example 1-3, the concentration of ethanol used in step S11 and step S12 was 75%. The L-tartaric acid could be dissolved in 75% ethanol, but the yield of the reaction product was reduced.

[0130] Comparative Example 1-4

[0131] Step S11, 30.75 g of L-tartaric acid was dissolved in 100 mL of ethanol (75%) to obtain an L-tartaric acid solution;

[0132] Step S12, 17.6 g of 6-methylnicotine was added dropwise to the L-tartaric acid solution obtained in step S11, and stirred at room temperature for 2-3 hours to obtain a reaction solution. The reaction solution was slowly added to 800 mL of ethyl acetate, and stirred for another 2-3 hours. Then, it was placed in a refrigerator at 0-4°C for 16 hours to precipitate solids. The solids were filtered, and the filter cake was washed with 100 mL of ethanol (75%) and repeated once to remove residual ethyl acetate, thereby obtaining a reaction product;

[0133] Comparative analysis: in the step S12 of Comparative Example 1-4, the amount of ethyl acetate used is less than 6 times the amount of ethanol, which is not enough to make 6-methylnicotine-tartaric acid salt crystallize out, and the solid cannot be well formed; the product obtained in the step S12 is shown in Figure 4 .

[0134] Comparative Example 1-5

[0135] Step S11, 30.75 g of L-tartaric acid was dissolved in 100 mL of ethanol (90%), and stirred until completely dissolved to obtain an L-tartaric acid solution;

[0136] Step S12, 17.6 g of 6-methylnicotine was added dropwise to the L-tartaric acid solution obtained in the step S11, and stirred at room temperature for 2-3 hours to obtain a reaction solution; the reaction solution was slowly added to 1000 mL of ethyl acetate, and stirred for another 2-3 hours, and then placed in a refrigerator at 0-4°C for 16 hours to precipitate a solid; the solid was filtered, and the filter cake was washed with 100 mL of ethanol (90%) and repeated once to remove the residual ethyl acetate, and the reaction product was obtained;

[0137] Step S13, the reaction product obtained in the step S12 was vacuum dried at 55°C to obtain 48.5 g of white solid powder; the content of 6-methylnicotine was detected to be 36.81%, which was within the range of the theoretical value.

[0138] Comparative analysis: in Comparative Example 1-5, the amount of ethyl acetate used is more than 8 times the amount of ethanol, but the solid of 6-methylnicotine-tartaric acid salt precipitated is not significantly increased, that is, the yield is not increased, and the large amount of ethyl acetate used also leads to an increase in production cost.

[0139] A method for preparing a 6-methylnicotine-tartaric acid salt single crystal

[0140] Example 2-1

[0141] Step S21, the 6-methylnicotine-tartaric acid salt prepared in Example 1-1 was obtained;

[0142] Step S22, the 6-methylnicotine-tartaric acid salt was dissolved in ultrapure water, and ultrasonic dissolution was performed to prepare a 6-methylnicotine-tartaric acid salt aqueous solution with a concentration of 35%; 10 mL of the 6-methylnicotine-tartaric acid salt aqueous solution was placed in a 20 mL culture cylinder container, sealed with filter paper, and placed in another beaker containing 300 mL of anhydrous ethanol; the beaker was tightly sealed, and the slow crystallization of 6-methylnicotine-tartaric acid salt was allowed to occur under room temperature and light-free conditions.

[0143] A single columnar crystal was obtained from Example 2-1, as shown in Figure 5 ; and the crystal structure was tested, and the results are as follows:

[0144] Single crystal determination condition: Mo-Ka ray (λ=0.736 nm) was used, the temperature was 100 K, and the crystal structure analysis and refinement were completed by using Mercury software. The single crystal data was the result of single crystal X-ray diffraction method.

[0145] The cell parameters are as follows: α=90°, β=110.402° (1), γ=90.00°, Z=1.

[0146] The chemical formula is: 2(C 11 H 18 N2)·4(C4H5O6)·H2O.

[0147] The single crystal structure analysis diagram of 6-methylnicotine-tartaric acid salt is shown in Figure 6 The single crystal X-ray diffraction diagram (XRD diagram) of 6-methylnicotine-tartaric acid salt is shown in Figure 7 .

[0148] Through the above verification analysis, it is shown that the 6-methylnicotine-tartaric acid salt single crystal is successfully prepared in Example 2-1.

[0149] Example 2-2

[0150] The difference from Example 2-1 is that in step S22, the concentration of the 6-methylnicotine-tartaric acid salt aqueous solution is 40%.

[0151] Example 2-3

[0152] The difference from Example 2-1 is that in step S22, the 6-methylnicotine-tartaric acid salt aqueous solution is 10 mL, and the anhydrous ethanol in the beaker is 400 mL.

[0153] Control analysis: the crystals prepared in Examples 2-2 and 2-3 are detected, and the detection results are the same as those of Example 2-1, which are determined as 6-methylnicotine-tartaric acid salt single crystals.

[0154] Comparative Example 2-1

[0155] The difference from Example 2-1 is that in step S22, 600 mL of anhydrous ethanol is added into the beaker; and qualified single crystals are obtained, which are the same as those of Example 2-1.

[0156] Control analysis: in the process of culturing single crystals, the excessive anhydrous ethanol is used in Comparative Example 2-1, the vapor pressure of the anhydrous ethanol in the system meets the requirements, but the excessive anhydrous ethanol does not produce better benefits, and causes excessive anhydrous ethanol consumption.

[0157] Comparative Example 2-2

[0158] The difference from Example 2-1 is that in step S22, 50 mL of anhydrous ethanol is added to the beaker; no qualified single crystal is obtained, as shown in Figure 8 .

[0159] Comparative analysis: In the process of culturing single crystals, the amount of anhydrous ethanol used in Comparative Example 2-2 is too small, and the vapor pressure of ethanol in the system is too low, which is not enough to diffuse into the 6-methyl nicotine-tartrate aqueous solution, resulting in the failure of the crystal to precipitate.

[0160] Comparative Example 2-3

[0161] The difference from Example 2-1 is that in step S22, the concentration of the 6-methyl nicotine-tartrate aqueous solution is 15%. No qualified single crystal is obtained, as shown in Figure 9 .

[0162] Comparative analysis: In the process of culturing single crystals, the 6-methyl nicotine-tartrate aqueous solution in Comparative Example 2-3 is too low to form a qualified single crystal.

[0163] Comparative Example 2-4

[0164] The difference from Example 2-1 is that in step S22, the concentration of the 6-methyl nicotine-tartrate aqueous solution is 60%. The 6-methyl nicotine-tartrate is completely precipitated, and no qualified single crystal is obtained, as shown in Figure 10 .

[0165] Comparative analysis: In the process of culturing single crystals, the concentration of the 6-methyl nicotine-tartrate aqueous solution in Comparative Example 2-4 is too high, resulting in too fast precipitation of the crystal, and no qualified single crystal is obtained.

[0166] In comparison of Examples 1-1 to 1-5 and Comparative Examples 1-1 to 1-5, the preparation method of 6-methyl nicotine-tartrate provided by the present application can prepare 6-methyl nicotine-tartrate with good properties, convenient to use, and stable 6-methyl nicotine content, which is suitable for industrial production; in comparison of Examples 2-1 to 2-3 and Comparative Examples 2-1 to 2-4, the preparation method of 6-methyl nicotine-tartrate single crystal provided by the present application can obtain high-purity crystals in the process of culturing single crystals.

[0167] Obviously, the above-described embodiments are only some embodiments but not all the embodiments of the present application, the preferred embodiments of the present application are shown in the drawings, but do not limit the patent scope of the present application. The present application can be implemented in many different forms, and conversely, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive. Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing specific embodiments, or make equivalent replacements to some technical features therein. Any equivalent structure made by using the content of the specification and drawings, directly or indirectly applied to other related technical fields, is also within the patent protection scope of the present application.

Claims

1. A process for the preparation of 6-methylnicotyne-tartrate salt, characterized by, The method comprises: S11, dissolving L-tartaric acid in ethanol to obtain an L-tartaric acid solution; S12, adding 6-methyl nicotine dropwise to the L-tartaric acid solution to obtain a reaction liquid, adding the reaction liquid into ethyl acetate, and stirring, filtering and washing to obtain a reaction product; S13, drying the reaction product to obtain 6-methyl nicotine-tartaric acid salt.

2. The process for the preparation of 6-methylnicotyrine-tartrate salt according to claim 1, characterized in that, The step S12 specifically comprises: adding 6-methyl nicotine dropwise to the L-tartaric acid solution, stirring at room temperature for 2-3 hours to obtain a reaction liquid, slowly adding the reaction liquid into ethyl acetate, continuing to stir for 2-3 hours, and then placing in 0-4°C for cold storage to precipitate a solid; filtering, washing the filter cake with ethanol for 2-3 times to remove residual ethyl acetate, and obtaining a reaction product.

3. The process for the preparation of 6-methylnicotyrine-tartrate salt according to claim 1 or 2, characterized in that, In the step S12, the molar ratio of 6-methyl nicotine to L-tartaric acid is 1:(2-2.2); In the step S12, the mass of the ethyl acetate is 6-8 times of the mass of the ethanol in the step S11.

4. The method of preparing 6-methylnicotyrine-tartrate salt according to claim 1 or 2, characterized by, In the step S11, the concentration of the ethanol is 75%-95%; In the step S11, the mass of the ethanol is 2-6 times of the mass of the L-tartaric acid.

5. The method of claim 2, wherein the 6-methylnicotyrine-tartrate salt is prepared by, In the step S12, when washing the filter cake, the ethanol used each time is 2-6 times of the mass of the L-tartaric acid; In the step S12, the concentration of the ethanol is 75%-95%.

6. The method of preparing 6-methylnicotyrine-tartrate salt according to claim 1 or 2, characterized by, The step S13 specifically comprises: vacuum drying the reaction product to obtain 6-methyl nicotine-tartaric acid salt; wherein the temperature of vacuum drying is 45°C-70°C.

7. A 6-methylnicotyne-tartrate salt characterized in that, Prepared by using the preparation method of 6-methyl nicotine-tartaric acid salt according to any one of claims 1-6.

8. A method for producing a 6-methylnicotyrine-tartrate salt single crystal, characterized by, The method comprises: S21, obtaining 6-methyl nicotine-tartaric acid salt prepared by using the preparation method according to any one of claims 1-5; S22, dissolving the 6-methyl nicotine-tartaric acid salt in ultrapure water to obtain a 6-methyl nicotine-tartaric acid salt aqueous solution, and volatilizing the ultrapure water under room temperature and light-proof conditions to obtain 6-methyl nicotine-tartaric acid salt single crystals.

9. The method for preparing 6-methylnicotine-tartrate single crystals according to claim 8, characterized in that, The step S22 specifically comprises: dissolving the 6-methyl nicotine-tartaric acid salt in ultrapure water and ultrasonically dissolving to obtain a 6-methyl nicotine-tartaric acid salt aqueous solution, pouring the 6-methyl nicotine-tartaric acid salt aqueous solution into a culture jar container, sealing the culture jar container, placing it in a beaker containing anhydrous ethanol, sealing the beaker, and precipitating crystals from the 6-methyl nicotine-tartaric acid salt aqueous solution under room temperature and light-proof conditions to obtain 6-methyl nicotine-tartaric acid salt single crystals; The concentration of the 6-methyl nicotine-tartaric acid salt aqueous solution is 25%-40%.

10. A 6-methylnicotyne-tartrate monocrystal characterized in that, Prepared by using the preparation method of 6-methyl nicotine-tartaric acid salt single crystals according to any one of claims 8-9.

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