A nicotine and derivatives thereof, method of preparation

Abstract

The application belongs to the technical field of nicotine preparation and relates to nicotine and a preparation method thereof. The method comprises the following steps: S1, starting material and N-methyl pyrrolidone dissolved in an organic solvent are subjected to ester condensation reaction under alkaline conditions, and then the organic solvent is removed by concentration under reduced pressure to obtain a first intermediate; wherein the starting material is selected from one of methyl nicotinate or a pyridine ring substituted derivative thereof, or ethyl nicotinate or a pyridine ring substituted derivative thereof; S2, the first intermediate is heated under acidic conditions to obtain a second intermediate through ring-opening reaction; and S3, the second intermediate is subjected to reductive amination ring-closing reaction, and then is purified by distillation to obtain nicotine and its derivatives. The final product obtained by the method has a determined substitution site, high yield, simple operation and suitability for industrial production.

Description

Technical Field

[0001] This application relates to the field of nicotine preparation technology, and more specifically, to a nicotine and its derivatives, and a preparation method thereof. Background Technology

[0002] Nicotine is widely found in plants of the Solanaceae family and is the main nitrogenous alkaloid component of tobacco, accounting for 3-4% of tobacco leaves. It can be used as a natural insecticide and also as a smoking cessation medication. In addition, clinical studies have shown that nicotine has the potential to become a drug for treating diseases such as Alzheimer's disease and depression.

[0003] Currently, nicotine is mainly extracted from waste tobacco. Nicotine extracted and purified from tobacco and other plants usually contains many other tobacco compounds that are unhealthy to the human body and have been proven to be carcinogenic. At the same time, the extraction and purification of nicotine from tobacco and other plants is also affected by many factors such as raw materials, climate, land resources, and cycle.

[0004] However, research on the synthesis of nicotine and its derivatives over the years has not yielded ideal results, and industrial production and application have not yet been achieved. For example, some related technologies use 3-bromopyridine as a raw material to prepare nicotine, and the synthetic route is shown below:

[0005]

[0006] However, the above technology uses 3-bromopyridine as a starting material, which is expensive and requires ultra-low temperature (-78°C) conditions, resulting in harsh experimental conditions that are not suitable for industrial production. Furthermore, its product is racemic nicotine.

[0007] In another technique (Journal of Organic Chemistry, Vol. 48, #25p. 4899-4904), 2-methylnicotine can be synthesized by reacting lithium methylate as a methyl source with nicotine. The synthetic route is shown below:

[0008]

[0009] However, the reaction conditions of the above technology are harsh, and the methyl substitution position of the synthesized product is not fixed, making it difficult to separate high-purity 2-methylnicotine, resulting in low actual production value.

[0010] Another study (Tetrahedron Letters, vol. 22, #33, pp. 3151-3154) used tert-butyl hydroperoxide as the methyl source to obtain methyl nicotine with different site substitutions. The synthetic route is shown below:

[0011]

[0012] However, the aforementioned technologies still have issues with separation and selectivity.

[0013] Therefore, in order to improve the yield and purity of synthetic nicotine and its derivatives, reduce costs, and enable industrial production, it is essential to develop a method for preparing nicotine and its derivatives. Summary of the Invention

[0014] Based on this, the present application provides a method for preparing nicotine and its derivatives.

[0015] To address the aforementioned technical problems, this application provides a method for preparing nicotine and its derivatives, employing the following technical solution:

[0016] A method for preparing nicotine and its derivatives, the method comprising:

[0017] Step S1: The starting material and N-methylpyrrolidone dissolved in an organic solvent undergo an ester condensation reaction under alkaline conditions, followed by concentration under reduced pressure to remove the organic solvent, yielding a first intermediate; wherein the starting material is selected from methyl nicotinic acid or its pyridine ring-substituted derivatives, or ethyl nicotinic acid or its pyridine ring-substituted derivatives.

[0018] Step S2: The first intermediate is heated under acidic conditions to undergo a ring-opening reaction, yielding the second intermediate;

[0019] Step S3: The second intermediate undergoes a reductive amination ring-closing reaction, followed by distillation purification to obtain nicotine and its derivatives.

[0020] To address the aforementioned technical problems, this application also provides nicotine and its derivatives, employing the technical solution described below:

[0021] A nicotine and its derivatives are prepared using the method described above.

[0022] Compared with the prior art, the embodiments of this application have the following advantages: using methyl nicotinic acid or its pyridine ring-substituted derivatives, or ethyl nicotinic acid or its pyridine ring-substituted derivatives as starting materials, the functional group structure at the 3-substitution position is changed through a series of reactions with N-methylpyrrolidone, and finally, high-purity nicotine and its derivatives can be obtained through purification. At the same time, the reaction process can be effectively monitored and controlled, improving production efficiency and reducing costs. Moreover, the substitution site of the final product in this application is determined, effectively avoiding the problems of difficult separation and poor selectivity. In addition, the synthetic route of this application has few by-products, high purity, high yield, controllable conditions, and simple operation, making it suitable for industrial scale-up production and having clinical application prospects. Attached Figure Description

[0023] To more clearly illustrate the solution of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 A flowchart of an embodiment of a method for preparing nicotine and its derivatives according to this application;

[0025] Figure 2 The 1H-NMR spectrum of 2-methylnicotine prepared in Example 1 of this invention;

[0026] Figure 3 The C-NMR spectrum of 2-methylnicotine prepared in Example 1 of this invention;

[0027] Figure 4 The carbon-hydrogen correlation two-dimensional spectrum of 2-methylnicotine prepared in Example 1 of this invention;

[0028] Figure 5 The 1H-NMR spectrum of 6-methylnicotine prepared in Example 2 of this invention;

[0029] Figure 6 The C-NMR spectrum of 6-methylnicotine prepared in Example 2 of this invention;

[0030] Figure 7 The carbon-hydrogen correlation two-dimensional spectrum of 6-methylnicotine prepared in Example 2 of this invention. Detailed Implementation

[0031] 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.

[0032] 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.

[0033] To enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings.

[0034] This application provides a method for preparing nicotine and its derivatives, such as... Figure 1 As shown, the method includes:

[0035] Step S1: The starting material and N-methylpyrrolidone dissolved in an organic solvent undergo an ester condensation reaction under alkaline conditions, followed by concentration under reduced pressure to remove the organic solvent, yielding a first intermediate; wherein the starting material is selected from methyl nicotinic acid or its pyridine ring-substituted derivatives, or ethyl nicotinic acid or its pyridine ring-substituted derivatives.

[0036] Step S2: The first intermediate is heated under acidic conditions to undergo a ring-opening reaction, yielding the second intermediate;

[0037] Step S3: The second intermediate undergoes a reductive amination ring-closing reaction, followed by distillation purification to obtain nicotine and its derivatives.

[0038] In this embodiment, when the starting material is selected from methyl nicotinic acid or its pyridine ring-substituted derivative, its structural formula is shown in Formula I:

[0039]

[0040] R1 is selected from hydrogen, methyl or ethyl, and R1 is located at the 2, 4, 5 or 6 position of pyridine.

[0041] In this embodiment, when the starting material is selected from methyl nicotinic acid or its pyridine ring-substituted derivatives, the synthetic route of the method is as follows:

[0042]

[0043] In this embodiment, when the starting material is selected from ethyl nicotinic acid or its pyridine ring-substituted derivative, its structural formula is shown in Formula II:

[0044]

[0045] R2 is selected from hydrogen, methyl or ethyl, and R2 is located at the 2, 4, 5 or 6 position of pyridine.

[0046] This application provides a method for preparing nicotine and its derivatives. Using methyl nicotinic acid or its pyridine-substituted derivatives, or ethyl nicotinic acid or its pyridine-substituted derivatives, as starting materials, the method alters the functional group structure at the 3-substitution position through a series of reactions with N-methylpyrrolidone. High-purity nicotine and its derivatives can be obtained through purification. The method also allows for effective monitoring and control of the reaction process, improving production efficiency and reducing costs. Furthermore, the substitution sites of the final product are precisely defined, effectively avoiding problems of difficult separation and poor selectivity. In addition, the synthetic route of this application has few byproducts, high purity, high yield, controllable conditions, and simple operation, making it suitable for industrial-scale production and possessing promising clinical application prospects.

[0047] Further, step S1 specifically includes: first dissolving the N-methylpyrrolidone in the organic solvent, cooling it to -10℃ to 5℃ under a nitrogen atmosphere, adding alkali and reacting for 15 min to 90 min; then adding the starting material, heating it to 100℃ to 120℃ and refluxing, reacting for 3 h to 6 h until the ester condensation reaction endpoint; and then concentrating under reduced pressure to remove the organic solvent to obtain the first intermediate.

[0048] Furthermore, the molar ratio of the N-methylpyrrolidone to the starting material is (1.2–3):1.

[0049] In some optional embodiments of this example, the molar ratio of the N-methylpyrrolidone to the starting material is any one or any two of the following: 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, etc.

[0050] Furthermore, the mass-to-volume ratio of the starting material to the organic solvent is 1 g:(5-10) ml.

[0051] In some optional embodiments of this example, the mass-volume ratio of the starting material to the organic solvent is any one or any two of the following: 1g:5ml, 1g:6ml, 1g:7ml, 1g:8ml, 1g:9ml, 1g:10ml, etc.

[0052] Furthermore, the molar ratio of the N-methylpyrrolidone to the base is 1:(1-2).

[0053] In some optional embodiments of this example, the molar ratio of the N-methylpyrrolidone to the base is any one or any two of the following: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0054] Furthermore, the organic solvent is selected from at least one of toluene, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane.

[0055] Furthermore, the alkali is selected from at least one of 60% sodium hydride, potassium tert-butoxide, or sodium tert-butoxide.

[0056] Further, step S2 specifically includes: adding dilute hydrochloric acid to the first intermediate until no bubbles are generated, then adding 5 to 10 times the volume of concentrated hydrochloric acid, heating to 80°C to 120°C under reflux, reacting for 4 to 6 hours until the first intermediate is completely reacted; then cooling to room temperature, adding water and ethyl acetate for the first extraction, collecting the aqueous phase, adding an alkaline solution to the aqueous phase under ice bath conditions to adjust the pH to 9 to 12; then performing a second extraction with ethyl acetate, collecting the organic phase, concentrating and drying it to obtain the second intermediate.

[0057] In this embodiment, the second extraction with ethyl acetate can be repeated twice to improve the extraction efficiency of the organic phase.

[0058] Furthermore, the concentration of the dilute hydrochloric acid is 1 mol / L.

[0059] Furthermore, the concentration of the concentrated hydrochloric acid is 12 mol / L.

[0060] Furthermore, the alkaline solution is selected from sodium hydride solution.

[0061] Furthermore, the concentration of the alkaline solution is 2 mol / L.

[0062] Further, step S3 specifically includes: dissolving the second intermediate in tetrahydrofuran, adding glacial acetic acid, reacting at 25℃~30℃ for 1h~1.5h to close the ring and generate an imine; then cooling to -5℃~0℃, adding a reducing agent in batches, reacting for 6h~8h to obtain a crude product; then distilling and purifying to obtain the nicotine and its derivatives.

[0063] Furthermore, the reducing agent is selected from sodium borohydride, sodium triacetylborohydride, or sodium cyanoborohydride.

[0064] Furthermore, the mass-to-volume ratio of the second intermediate and the tetrahydrofuran is 1 g:(5-10) ml.

[0065] In some optional embodiments of this example, the mass-to-volume ratio of the second intermediate and the tetrahydrofuran is any one or any two of the following: 1g:5ml, 1g:6ml, 1g:7ml, 1g:8ml, 1g:9ml, 1g:10ml, etc.

[0066] Furthermore, the molar ratio of the second intermediate to the glacial acetic acid is 1:(0.1 to 0.5).

[0067] In some optional embodiments of this example, the molar ratio of the second intermediate to the glacial acetic acid is any one or any two of the following: 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc.

[0068] Furthermore, the molar ratio of the second intermediate to the reducing agent is 1:(1.1 to 1.5).

[0069] In some optional embodiments of this example, the molar ratio of the second intermediate to the reducing agent is any one or any two of 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0070] The above solution will be further described below with reference to specific embodiments. The preferred embodiments of the present invention are described in detail below:

[0071] Example 1: Preparation method of nicotine derivative (2-methylnicotine) :

[0072]

[0073] S1. Dissolve N-methylpyrrolidone (11.88 g, 120.0 mmol) in toluene (120 mL); cool to -5°C to 5°C under a nitrogen atmosphere, add alkali (NaH, 7.2 g, 180.0 mmol) and react for 30 min; then add starting material (2-methylnicotinic acid methyl ester, 15.0 g, 100.0 mmol), heat to 110°C and react for 5 h. TLC confirms complete consumption of 2-methylnicotinic acid methyl ester, indicating the reaction is complete; cool to room temperature, remove organic solvent by vacuum concentration to obtain the first intermediate (24.6 g, calculated at 100% yield), which can be directly added to the next step without purification.

[0074] S2. Add a small amount of dilute hydrochloric acid (1 mol / L) to the first intermediate until no bubbles are generated, then add 150 mL of concentrated hydrochloric acid (12 mol / L) and heat to 120 °C under reflux for 5 h. The reaction is confirmed by TLC to ensure that the first intermediate has completely reacted. Then cool to room temperature, add water and ethyl acetate for the first extraction, and collect the aqueous phase. Add an alkaline solution (NaOH solution, 2 mol / L) to the aqueous phase under ice bath conditions to adjust the pH to 9-12. Then perform a second extraction with ethyl acetate, collect the organic phase, concentrate and dry it to obtain the second intermediate (16.8 g, yield 87.5%, purity 98.75%).

[0075] S3. Dissolve the second intermediate (16.8 g, 87.5 mmol) in tetrahydrofuran (150 mL), then add glacial acetic acid (0.95 g, 15.8 mmol), and react at 25℃~30℃ for 1~1.5 h to form an imine through ring closure. Then cool to -5℃~0℃, add reducing agent (sodium borohydride, 3.52 g, 92.5 mmol) in batches, and react at room temperature for 6~8 h. Confirm the complete reaction of the second intermediate by TLC. Add a small amount of 95% ethanol until no bubbles are generated, quenching the reaction. Concentrate under reduced pressure to remove tetrahydrofuran, add 200 mL of water and 200 mL of ethyl acetate, extract and separate the layers. Wash the organic phase once with water (100 mL), then wash with 100 mL of acetic acid. Wash once with saturated sodium chloride aqueous solution, dry with sodium sulfate, and concentrate to obtain crude product; further distillation and purification yields the target product: pale yellow transparent liquid 2-methylnicotine (12.9 g, total yield 73.3%, purity 99.79%).

[0076] Figure 2 The H-NMR spectrum of 2-methylnicotine prepared in Example 1 of this invention.

[0077] Figure 3 The C-NMR spectrum of 2-methylnicotine prepared in Example 1 of this invention.

[0078] Figure 4 The carbon-hydrogen correlation two-dimensional spectrum of 2-methylnicotine prepared in Example 1 of this invention.

[0079] The NMR 1H spectral data of 2-methylnicotine are as follows: 1 H-NMR (400MHz, CDC l3) δ8.33 (d, J = 4.0 Hz, 1H), δ 7.55 (d, J = 4.0 Hz, 1H), δ 7.06 (d, J = 8.0 Hz, 1H), δ 3.21-3.16 (m, 1H), δ 3.02-2.98 (m, 1H), δ

[0080] 2.63-2.58(m,1H),δ2.47(s,3H),δ2.27-2.21(m,1H),δ2.10(s,3H),δ

[0081] 1.95-1.84(m,1H), δ1.80-1.62(m,2H).

[0082] Example 2: Preparation method of nicotine derivative (6-methylnicotine) :

[0083]

[0084] S1. Dissolve N-methylpyrrolidone (11.88 g, 120.0 mmol) in toluene (100 mL); cool to -5°C to 5°C under a nitrogen atmosphere, add alkali (potassium tert-butoxide, 24.2 g, 216.0 mmol) and react for 30 min; then add starting material (methyl 6-methylnicotinic acid, 15.0 g, 100.0 mmol), heat to 120°C and react for 5 h. TLC confirms complete consumption of methyl 6-methylnicotinic acid, indicating the reaction is complete; cool to room temperature, remove organic solvent by vacuum concentration to obtain the first intermediate (30.6 g, calculated at 100% yield), which can be directly added to the next step without purification.

[0085] S2. Add a small amount of dilute hydrochloric acid (1 mol / L) to the first intermediate until no bubbles are generated, then add 200 mL of concentrated hydrochloric acid (12 mol / L) and heat to 120 °C under reflux for 5 h. The reaction is confirmed by TLC to ensure that the first intermediate has completely reacted. Then cool to room temperature, add water and ethyl acetate for the first extraction, and collect the aqueous phase. Add an alkaline solution (NaOH solution, 2 mol / L) to the aqueous phase under ice bath conditions to adjust the pH to 9-12. Then perform a second extraction with ethyl acetate, collect the organic phase, concentrate and dry to obtain the second intermediate (17.5 g, yield 91.1%, purity 97.55%).

[0086] S3. Dissolve the second intermediate (17.5 g, 91.1 mmol) in tetrahydrofuran (150 ml), then add glacial acetic acid (0.95 g, 15.8 mmol), and react at 25℃~30℃ for 1~1.5 h to form an imine through ring closure; then cool to -5℃~0℃, add reducing agent (sodium borohydride, 3.52 g, 92.5 mmol) in batches, and react at room temperature for 6~8 h. Confirm the complete reaction of the second intermediate by TLC. Add a small amount of 95% ethanol until no bubbles are generated, quenching the reaction. Concentrate under reduced pressure to remove tetrahydrofuran, add 200 ml of water and 200 ml of ethyl acetate, extract and separate the layers. Wash the organic phase once with water (100 ml), then with 100 ml of acetic acid. Wash once with saturated sodium chloride aqueous solution, dry with sodium sulfate, and concentrate to obtain crude product; further distillation and purification yield the target product: 6-methylnicotine (14.1 g, total yield 80.1%, purity 98.67%).

[0087] Figure 5 The H-NMR spectrum of 6-methylnicotine prepared in Example 2 of this invention.

[0088] Figure 6 The C-NMR spectrum of 6-methylnicotine prepared in Example 2 of this invention.

[0089] Figure 7 The carbon-hydrogen correlation two-dimensional spectrum of 6-methylnicotine prepared in Example 2 of this invention.

[0090] The NMR 1H spectral data of 6-methylnicotine are as follows: 1 HNMR(400MHz,CDC l3) δ8.40(d,1H), δ7.60(dd,1H), δ7.13(d,1H), δ3.23(ddd,1H), δ3.05(dd,1H), δ2.5 4(s,3H), δ2.29(td,1H), δ2.23–2.10(m,4H), δ1.96(ddddd,1H), δ1.87–1.66(m,2H).

[0091] Example 3: Method for preparing nicotine :

[0092]

[0093] S1. Dissolve (N-methylpyrrolidone, 11.88 g, 120.0 mmol) in DMF (100 mL); after cooling to -5℃ to 5℃ under a nitrogen atmosphere, add alkali (NaH, 7.2 g, 180.0 mmol) and react for 30 min; then add the starting material (methyl nicotinic acid, 13.6 g, 100.0 mmol), heat to 110℃, and react for 5 h. The reaction ends when the methyl nicotinic acid is completely consumed by TLC. Cool to room temperature and remove the organic solvent by vacuum concentration to obtain the first intermediate (20.4 g, calculated at 100% yield), which can be directly added to the next step without purification.

[0094] S2. Add a small amount of dilute hydrochloric acid (1 mol / L) to the first intermediate until no bubbles are generated, then add 150 mL of concentrated hydrochloric acid (12 mol / L) and heat to 120 °C under reflux for 5 h. The reaction is confirmed by TLC to ensure that the first intermediate has completely reacted. Then cool to room temperature, add water and ethyl acetate for the first extraction, and collect the aqueous phase. Add an alkaline solution (NaOH solution, 2 mol / L) to the aqueous phase under ice bath conditions to adjust the pH to 9-12. Then perform a second extraction with ethyl acetate, collect the organic phase, concentrate and dry it to obtain the second intermediate (14.7 g, yield 76.6%, purity 97.74%).

[0095] S3. Dissolve the second intermediate (14.7 g, 76.6 mmol) in tetrahydrofuran (120 mL), then add glacial acetic acid (0.95 g, 15.8 mmol), and react at 25℃~30℃ for 1~1.5 h to form an imine through ring closure. Then cool to -5℃~0℃, add reducing agent (sodium borohydride, 3.52 g, 92.5 mmol) in batches, and react at room temperature for 6~8 h. Confirm the complete reaction of the second intermediate by TLC. Add a small amount of 95% ethanol until no bubbles are generated, quenching the reaction. Concentrate under reduced pressure to remove tetrahydrofuran, add 200 mL of water and 200 mL of ethyl acetate, extract and separate the layers. Wash the organic phase once with water (100 mL), then wash with 100 mL of acetic acid. Wash once with saturated sodium chloride aqueous solution, dry with sodium sulfate, and concentrate to obtain crude product; then further distill and purify to obtain the target product: nicotine (10.9 g, total yield 67.2%, purity 98.39%).

[0096] Example 4: Preparation method of nicotine derivative (2-ethylnicotine) :

[0097]

[0098] S1. Dissolve N-methylpyrrolidone (11.88 g, 120.0 mmol) in toluene (100 mL); cool to -5°C to 5°C under a nitrogen atmosphere, add alkali (potassium tert-butoxide, 20.2 g, 180.0 mmol) and react for 30 min; then add the second raw material (methyl 2-ethylnicotinate, 16.4 g, 100.0 mmol), heat to 120°C and react for 5 h. TLC confirms complete consumption of methyl 2-ethylnicotinate, indicating the reaction is complete; cool to room temperature, remove organic solvent by vacuum concentration to obtain the first intermediate (28.6 g, calculated at 100% yield), which can be directly added to the next step without purification.

[0099] S2. Add a small amount of dilute hydrochloric acid (1 mol / L) to the first intermediate until no bubbles are generated, then add 200 mL of concentrated hydrochloric acid (12 mol / L) and heat to 120 °C under reflux for 5 h. The reaction is confirmed by TLC to ensure that the first intermediate has completely reacted. Then cool to room temperature, add water and ethyl acetate for the first extraction, and collect the aqueous phase. Add an alkaline solution (NaOH solution, 2 mol / L) to the aqueous phase under ice bath conditions to adjust the pH to 9-12. Then perform a second extraction with ethyl acetate, collect the organic phase, concentrate and dry to obtain the second intermediate (16.6 g, yield 86.5%, purity 98.57%).

[0100] S3. Dissolve the second intermediate (16.6 g, 86.5 mmol) in tetrahydrofuran (150 mL), then add glacial acetic acid (0.95 g, 15.8 mmol), and react at 25℃~30℃ for 1~1.5 h to form an imine through ring closure; then cool to -5℃~0℃, add reducing agent (sodium triacetylborohydride, 19.6 g, 92.5 mmol) in batches, and react at room temperature for 6~8 h. Confirm the complete reaction of the second intermediate by TLC. Add a small amount of 95% ethanol until no bubbles are generated, quenching the reaction. Concentrate under reduced pressure to remove tetrahydrofuran, add 200 mL of water and 200 mL of ethyl acetate, extract and separate the layers. Wash the organic phase once with water (100 mL), then with 100 mL of acetic acid. Wash once with saturated sodium chloride aqueous solution, dry with sodium sulfate, and concentrate to obtain crude product; then further distill and purify to obtain the target product: 2-ethylnicotine (12.6 g, total yield 66.2%, purity 99.17%).

[0101] As can be seen from the above embodiments, the method for preparing nicotine and its derivatives provided in this application uses methyl nicotinic acid or its pyridine ring-substituted derivatives, or ethyl nicotinic acid or its pyridine ring-substituted derivatives, as starting materials. Through a series of reactions with N-methylpyrrolidone, the functional group structure at the 3-substitution position is changed. Finally, high-purity nicotine and its derivatives can be obtained through purification. At the same time, the reaction process can be effectively monitored and controlled, improving production efficiency and reducing costs. Moreover, the substitution site of the final product in this application is determined, effectively avoiding the problems of difficult separation and poor selectivity. In addition, the synthetic route of this application has few by-products, high purity, high yield, controllable conditions, and simple operation, making it suitable for industrial scale-up production and having clinical application prospects.

[0102] This application also provides a nicotine and its derivatives, prepared using the method described above.

[0103] The nicotine and its derivatives provided in this application are prepared using a method for preparing nicotine and its derivatives. Specifically, methyl nicotinic acid or its pyridine ring-substituted derivatives, or ethyl nicotinic acid or its pyridine ring-substituted derivatives, are used as starting materials. Through a series of reactions with N-methylpyrrolidone, the functional group structure at the 3-substitution position is changed. Finally, high-purity nicotine and its derivatives can be obtained through purification. At the same time, the reaction process can be effectively monitored and controlled, improving production efficiency and reducing costs. Moreover, the substitution site of the final product in this application is determined, effectively avoiding the problems of difficult separation and poor selectivity. In addition, the synthetic route of this application has few by-products, high purity, high yield, controllable conditions, and simple operation, making it suitable for industrial scale-up production and having clinical application prospects.

[0104] Obviously, the embodiments described above are only some embodiments of this application, not all embodiments. The accompanying drawings show preferred embodiments of this application, but do not limit the patent scope of this application. This application can be implemented in many different forms; rather, the purpose of providing these embodiments is to provide a more thorough and comprehensive understanding of the disclosure of this application. Although this 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 substitutions for some of the technical features. Any equivalent structures made using the content of this application's specification and drawings, directly or indirectly applied to other related technical fields, are similarly within the scope of patent protection of this application.

Claims

1. A method for preparing nicotine and its derivatives, characterized in that, The method includes: Step S1: The starting material and N-methylpyrrolidone dissolved in an organic solvent undergo an ester condensation reaction under alkaline conditions, followed by concentration under reduced pressure to remove the organic solvent, yielding a first intermediate; wherein the starting material is selected from methyl nicotinic acid or its pyridine ring-substituted derivatives, or ethyl nicotinic acid or its pyridine ring-substituted derivatives. Step S2: The first intermediate is heated under acidic conditions, undergoing a ring-opening reaction to obtain the second intermediate; Step S2 specifically includes: The first intermediate was added to dilute hydrochloric acid until no bubbles were generated, then 5 to 10 times the volume of concentrated hydrochloric acid was added, and the mixture was heated to 80°C to 120°C under reflux for 4 to 6 hours until the first intermediate was completely reacted. Then the mixture was cooled to room temperature, and water and ethyl acetate were added for the first extraction. The aqueous phase was collected, and the pH of the aqueous phase was adjusted to 9 to 12 by adding an alkaline solution under ice bath conditions. The second extraction was performed with ethyl acetate, and the organic phase was collected, concentrated, and dried to obtain the second intermediate. Step S3: The second intermediate undergoes a reductive amination ring-closure reaction, followed by distillation purification to obtain nicotine and its derivatives; Step S3 specifically includes: The second intermediate was dissolved in tetrahydrofuran, and then glacial acetic acid was added. The mixture was reacted at 25℃~30℃ for 1h~1.5h to form an imine by ring closure. The temperature was then lowered to -5℃~0℃, and a reducing agent was added in batches. The mixture was reacted for 6h~8h to obtain the crude product. The product was then purified by distillation to obtain the nicotine and its derivatives.

2. The method for preparing nicotine and its derivatives according to claim 1, characterized in that, Step S1 specifically includes: First, N-methylpyrrolidone is dissolved in the organic solvent, and the mixture is cooled to -10°C to 5°C under a nitrogen atmosphere. A base is added and the mixture is reacted for 15 min to 90 min. Then, the starting material is added, and the mixture is heated to 100°C to 120°C and refluxed for 3 h to 6 h until the ester condensation reaction ends. The organic solvent is removed by vacuum concentration to obtain the first intermediate.

3. The method for preparing nicotine and its derivatives according to claim 1, characterized in that, The molar ratio of the N-methylpyrrolidone to the starting material is (1.2–3):1; and / or The mass of the starting material and the organic solvent The volume ratio is 1g:(5~10)ml.

4. The method for preparing nicotine and its derivatives according to claim 2, characterized in that, The molar ratio of the N-methylpyrrolidone to the base is 1:(1-2); and / or The organic solvent is selected from at least one of toluene, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane.

5. The method for preparing nicotine and its derivatives according to claim 1, characterized in that, The concentration of the dilute hydrochloric acid is 1 mol / L; and / or The concentration of the concentrated hydrochloric acid is 12 mol / L; and / or The alkaline solution is selected from sodium hydride solution; and / or The concentration of the alkaline solution is 2 mol / L.

6. The method for preparing nicotine and its derivatives according to claim 1, characterized in that, The reducing agent is selected from sodium borohydride, sodium triacetylborohydride, or sodium cyanoborohydride.

7. The method for preparing nicotine and its derivatives according to claim 1, characterized in that, The mass-to-volume ratio of the second intermediate to the tetrahydrofuran is 1 g:(5-10) ml; and / or The molar ratio of the second intermediate to the glacial acetic acid is 1:(0.1–0.5); and / or The molar ratio of the second intermediate to the reducing agent is 1:(1.1 to 1.5).

8. A nicotine and its derivatives, characterized in that, It is prepared by the preparation method of nicotine and its derivatives as described in any one of claims 1 to 7.

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