Application of cyclic quaternary ammonium bases in the preparation of racemic nicotine

Abstract

This invention relates to the application of cyclic quaternary ammonium bases in the preparation of racemic nicotine. The structure of the cyclic quaternary ammonium base is shown in Formula I or Formula II, where n is an integer from 1 to 7; t and m are independently integers from 1 to 4. When the cyclic quaternary ammonium base of this invention is used as a catalyst in the preparation of racemic nicotine, racemic nicotine can be synthesized in one step. This method uses S-nicotine as a raw material and has the advantages of readily available raw materials, fewer reaction steps, fewer reaction byproducts, less likelihood of introducing other impurities, no introduction of other carbon sources during preparation, and ease of large-scale preparation.

Description

Technical Field

[0001] This invention belongs to the field of racemic nicotine preparation technology, specifically relating to the application of a cyclic quaternary ammonium base in the preparation of racemic nicotine. Background Technology

[0002] Nicotine is a crucial quality element in tobacco products and the most important alkaloid in tobacco. Studies have shown that it possesses strong physiological activity, regulating the central nervous system, peripheral nervous system, and adrenal medulla. Beyond this, nicotine has wide applications in medicine and pesticides. In medicine, isoniazid, nicotinamide, and nicotinic acid are all synthesized from nicotine, exhibiting good efficacy in anti-tuberculosis, antidepressant, antibacterial, Parkinson's disease treatment, antioxidant, memory enhancement, and learning disability treatment. In pesticides, nicotine can be used for disinfection of poultry living environments and is also used as a plant growth regulator and insecticide.

[0003] Nicotine molecules contain a chiral center, resulting in two enantiomers: (R)-(+)-nicotine (R-nicotine) and (S)-(-)-nicotine (S-nicotine), as shown below. In nature, the nicotine contained in tobacco and tobacco products is primarily S-nicotine.

[0004]

[0005] Chirality is universal and important in nature. A pair of enantiomers share many of the same physicochemical properties in an achiral environment, such as the same melting point and solubility. However, in a chiral environment, because the enantiomers act differently, their properties often differ or are even opposite. For example, L-dopa, used to treat Parkinson's disease, can be readily decarboxylated by enzymes in the body to form a pharmacologically active species. If D-dopa is taken, it cannot be decarboxylated, thus affecting health. The S-configuration of ibuprofen is a nonsteroidal antipyretic and highly effective analgesic, while the R-configuration of ibuprofen is completely inactive and only increases the metabolic burden in the body.

[0006] Racemic nicotine can sometimes differ significantly from S-nicotine (natural) or R-nicotine in physiological activity, such as toxicity and sensory properties. Therefore, the preparation of racemic nicotine is attracting increasing attention.

[0007] Currently, racemic nicotine is mainly obtained through artificial synthesis. It can be synthesized via various routes using different raw materials.

[0008] In patent application CN112876454A, racemic nicotine was synthesized from 4-methylamino-1-(3-pyridine)butanone hydrochloride as the starting material through neutralization, cyclization under alkaline conditions, dehydration, and hydrogenation.

[0009]

[0010] In the Journal of Organic Chemistry, 1990, 55, 1736, racemic nicotine was synthesized from pyrrolidine via a four-step reaction involving oxidation, coupling, hydrogenation, and formylation. The reaction involved harsh experimental conditions such as anhydrous and oxygen-free environments and low temperatures.

[0011]

[0012] In the Journal of the Chemical Society, Perkin Transactions 2002, pp. 143-154, a three-step reaction was described, starting with nicotinic acid, followed by condensation, coupling with a brominated Grignard reagent, and finally cyclization with methylamine hydrochloride under resin catalyst conditions. The second step of the reaction also required anhydrous and oxygen-free operation.

[0013]

[0014] In US patent application US2014031554A1, nicotinic acid is also used as the starting material, and the first two steps of the reaction are the same. The difference is that the aldehyde is prepared by reacting with acetone first, and then reacted with methylamine to obtain nicotine.

[0015]

[0016] In patent applications US2010209006A1, US20160326134, WO2012100722, and CN102617547, N-methyl-3-benzoyl-1-pyrrolidone was prepared by condensation reaction of methyl nicotinate and N-methylpyrrolidone under sodium hydride conditions, followed by hydrolysis and reduction under palladium carbon conditions to synthesize racemic nicotine.

[0017]

[0018] It can be seen that the reported methods have the following main drawbacks: long routes, harsh conditions, low yields, and difficulty in obtaining starting materials, making it difficult to achieve large-scale industrial production. Summary of the Invention

[0019] To overcome the shortcomings of the prior art, this application provides an application of a cyclic quaternary ammonium base in the preparation of racemic nicotine. This cyclic quaternary ammonium base is novel. Under the catalysis of this cyclic quaternary ammonium base, racemic nicotine can be synthesized in one step. The reaction raw materials are readily available, the reaction steps are few, the reaction byproducts are few, and it is easy to prepare racemic nicotine in large quantities.

[0020] One object of the present invention is to provide the application of cyclic quaternary ammonium bases in the preparation of racemic nicotine.

[0021] Another object of the present invention is to provide a cyclic quaternary ammonium base.

[0022] Another object of the present invention is to provide a method for preparing a cyclic quaternary ammonium base.

[0023] Another object of the present invention is to provide a method for preparing racemic nicotine using the above-mentioned cyclic quaternary ammonium base.

[0024] The objective of this invention is achieved through the following technical solution.

[0025] On the one hand, the present invention provides an application of a cyclic quaternary ammonium base in the preparation of racemic nicotine.

[0026] Preferably, the structure of the cyclic quaternary ammonium base is as shown in Formula I or Formula II:

[0027]

[0028] Where n is an integer from 1 to 7; t and m are independent integers from 1 to 4.

[0029] Preferably, n is an integer from 1 to 4;

[0030] Preferably, t and m are independent integers from 1 to 2.

[0031] Most preferably, the cyclic quaternary ammonium base is selected from:

[0032]

[0033] On the other hand, the present invention provides a cyclic quaternary ammonium base, the structure of which is shown in Formula I or Formula II:

[0034]

[0035] Where n is an integer from 1 to 7; t and m are independent integers from 1 to 4.

[0036] Preferably, n is an integer from 1 to 4;

[0037] Preferably, t and m are independent integers from 1 to 2.

[0038] Most preferably, the cyclic quaternary ammonium base is selected from:

[0039]

[0040] The cyclic quaternary ammonium base of the present invention has the characteristics of strong basicity, large steric hindrance, and strong skeletal rigidity, and exhibits high catalytic activity in the preparation of racemic nicotine.

[0041] Furthermore, this invention provides a method for preparing the above-mentioned cyclic quaternary ammonium base, the method comprising: using quaternary ammonium iodide as a raw material, reacting it with Ag₂O in a redox reaction to obtain the cyclic quaternary ammonium base; the synthetic route is as follows:

[0042] or

[0043]

[0044] In another aspect, the present invention provides a method for preparing racemic nicotine using the above-mentioned cyclic quaternary ammonium base, wherein the above-mentioned cyclic quaternary ammonium base is a catalyst.

[0045] Preferably, the method includes using S-nicotine as a raw material, and obtaining racemic nicotine through a one-step reaction under the catalysis of the cyclic quaternary ammonium base. The synthetic route is as follows:

[0046]

[0047] Preferably, the method includes reacting S-nicotine and the above-mentioned cyclic quaternary ammonium base in a solvent-free or organic solvent in a one-pot manner under inert gas protection, cooling after the reaction is complete, and purifying to obtain the product.

[0048] Preferably, the inert gas is selected from nitrogen, argon, or helium.

[0049] Preferably, the organic solvent is selected from one or more of toluene, xylene, chlorobenzene, methanol, ethanol, ethyl acetate, chloroform, acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and dimethyl sulfoxide, and more preferably from one or more of xylene, tetrahydrofuran, or dimethyl sulfoxide.

[0050] Preferably, the reaction temperature is 80-200℃, and more preferably 100-150℃.

[0051] Preferably, the reaction time is 1-24 hours, more preferably 2-10 hours.

[0052] Preferably, the molar ratio of S-nicotine to the cyclic quaternary ammonium base is 100:1-100:20.

[0053] The method for preparing racemic nicotine according to the present invention has few reaction steps, readily available raw materials, and is suitable for large-scale production.

[0054] Compared with existing technologies, this invention provides a novel cyclic quaternary ammonium base. When using the cyclic quaternary ammonium base as a catalyst to prepare racemic nicotine, racemic nicotine can be synthesized in one step. Moreover, this method uses S-nicotine as raw material and has the advantages of readily available raw materials, fewer reaction steps, fewer reaction byproducts, less likelihood of introducing other impurities, no introduction of other carbon sources in the preparation process, and ease of large-scale preparation.

[0055] The cyclic quaternary ammonium base of the present invention has the characteristics of strong basicity, large steric hindrance, and strong framework rigidity, and exhibits high catalytic activity in this reaction. Attached Figure Description

[0056] Figure 1 The liquid chromatogram of racemic nicotine prepared in this invention (test method refers to YC / T561-2018). Detailed Implementation

[0057] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0058] Catalyst preparation

[0059] Example 1: Preparation of cat-1

[0060]

[0061] Add raw material 1 (10 mmol) to a 50 mL round-bottom flask, add 25 mL of water to the flask, stir evenly with a magnetic stir bar, place the system in an ice-water bath, add Ag2O (30 mmol) to the system in batches, and then slowly restore the reaction system to room temperature. After reacting for about 10 hours, the corresponding cat-1 is obtained through post-processing.

[0062] The NMR data for cat-1 are as follows: 1 H NMR (DMSO-d6, 400MHz); δ: 3.68 (s, 8H).

[0063] Example 2: Preparation of cat-2

[0064] The preparation method of cat-2 is the same as that of cat-1.

[0065] The NMR data for cat-2 are as follows: 1 H NMR (DMSO-d6, 400MHz); δ: 2.17 (m, 4H), 3.22 (t, 8H).

[0066] Example 3: Preparation of cat-3

[0067] The preparation method of cat-3 is the same as that of cat-1.

[0068] The MRI data for cat-3 are as follows: 1 H NMR (DMSO-d6, 400MHz); δ: 1.65-1.75 (m, 8H), 3.18-3.35 (m, 8H).

[0069] Example 4: Preparation of cat-4

[0070] The preparation method of cat-4 is the same as that of cat-1.

[0071] The NMR data for cat-4 are as follows: 1 H NMR (DMSO-d6, 400MHz); δ: 1.52-1.83 (m, 12H), 3.16-3.34 (m, 8H).

[0072] Example 5: Preparation of cat-5

[0073] The preparation method of cat-5 is the same as that of cat-1.

[0074] The MRI data for cat-5 are as follows: 1 H NMR (DMSO-d6, 400MHz); δ: 1.42-1.56 (m, 2H), 1.68-1.99 (m, 3H), 2.99-3.28 (m, 6H), 3.30 (s, 3H).

[0075] Example 6: Preparation and confirmation of cat-6

[0076] The preparation method of cat-6 is the same as that of cat-1.

[0077] The MRI data for cat-6 are as follows: 1 H NMR (DMSO-d6, 400MHz) δ: 1.22-1.36 (m, 3H), 1.43-1.99 (m, 4H), 3.12-3.38 (m, 6H), 3.31 (s, 3H).

[0078] Example 7: Preparation and Validation of cat-7

[0079] The preparation method of cat-7 is the same as that of cat-1.

[0080] The MRI data for cat-7 are as follows: 1H NMR (DMSO-d6, 400MHz) δ: 1.42-1.56 (m, 2H), 2.51-2.65 (m, 1H), 2.92-3.43 (m, 6H), 3.35 (s, 3H).

[0081] Preparation of racemic nicotine

[0082] The cat-1 to cat-7 used in the following examples were prepared from Examples 1-7.

[0083] Example 8

[0084] Under anaerobic conditions, anhydrous toluene, cat-1 (molar ratio 1%), S-nicotine, and a magnetic induction device were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the mixture was heated to 110°C. The reaction was completed after 1 hour. Afterward, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with toluene, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. After concentration, the organic phase was distilled under reduced pressure to obtain a colorless liquid. The liquid chromatogram of the prepared racemic nicotine is shown below. Figure 1 As shown, the yield is 96%.

[0085] Example 9

[0086] Under anaerobic conditions, anhydrous xylene, cat-2 (molar ratio 5%), S-nicotine, and a magnetic flux were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the mixture was heated to 120°C. The reaction was completed after 5 hours. Afterward, the reaction system was cooled to room temperature, and a suitable amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with xylene, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 96%.

[0087] Example 10

[0088] Under anaerobic conditions, anhydrous ethanol, cat-3 (molar ratio 15%), S-nicotine, and a magnetic induction device were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the mixture was heated to 90°C. The reaction was completed after 2 hours. Afterward, the reaction system was cooled to room temperature, and a suitable amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with dichloromethane, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 93%.

[0089] Example 11

[0090] Under anaerobic conditions, cat-4 (20% molar ratio), S-nicotine, and a magnetic induction device were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the reactor was heated to 130°C. The reaction was completed after 3 hours. Afterward, the reaction system was cooled to room temperature, and a suitable amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with chloroform, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 75%.

[0091] Example 12

[0092] Under anaerobic conditions, anhydrous 1,4-dioxane, CAT-5 (molar ratio 2%), S-nicotine, and a magnetic induction device were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the reactor was heated to 120°C. The reaction was completed after 10 hours. Afterward, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with dichloromethane, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 88%.

[0093] Example 13

[0094] Under anaerobic conditions, anhydrous chloroform, CAT-6 (molar ratio 4%), S-nicotine, and a magnetic flux were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the mixture was heated to 100°C. The reaction was completed after 12 hours. Afterward, the reaction system was cooled to room temperature, and a suitable amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with chloroform, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 87%.

[0095] Example 14

[0096] Under anaerobic conditions, anhydrous methanol, CAT-7 (6% molar ratio), S-nicotine, and a magnetic induction device were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the reactor was heated to 80°C. The reaction was completed after 14 hours. Afterward, the reaction system was cooled to room temperature, and a suitable amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with dichloromethane, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 92%.

[0097] Example 15

[0098] Under anaerobic conditions, CAT-5 (8% molar ratio), S-nicotine, and a magnetic flux were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the reactor was heated to 160°C. The reaction was completed after 20 hours. Afterward, the reaction system was cooled to room temperature, and a suitable amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with ethyl acetate, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 90%.

[0099] Example 16

[0100] Under anaerobic conditions, anhydrous acetonitrile, cat-3 (molar ratio 3%), S-nicotine, and a magnetic flux were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the reactor was heated to 95°C. The reaction was completed after 10 hours. Afterward, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with diethyl ether, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 86%.

[0101] Example 17

[0102] Under anaerobic conditions, ethylene glycol dimethyl ether, cat-1 (molar ratio 7%), S-nicotine, and a magnetic induction device were added to the reactor. A reflux condenser and a nitrogen balloon were then installed, and the reactor was heated to 100°C. The reaction was completed after 20 hours. Afterward, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added. The organic phase was extracted with dichloromethane, and the organic phases were combined and dried over magnesium sulfate for 30 minutes, then filtered through diatomaceous earth. The concentrated organic phase was then distilled under reduced pressure to obtain a colorless liquid with a yield of 90%.

Claims

1. Use of a cyclic quaternary ammonium base as a catalyst in the preparation of racemic nicotine from S-nicotine as a raw material. wherein The cyclic quaternary ammonium base has a structure as shown in Formula I or Formula II: wherein n is an integer of 1-7; t, m are independently integers of 1-4.

2. The use according to claim 1, wherein, n is an integer of 1-4.

3. The use according to claim 1, wherein, t, m are independently integers of 1-2.

4. The use according to claim 1, wherein, The cyclic quaternary ammonium base is selected from: 。 5. A method for preparing racemic nicotine, the method comprising using S-nicotine as a raw material, under the catalysis of a cyclic quaternary ammonium base, under the protection of a gas, in a one-pot reaction of adding S-nicotine and the cyclic quaternary ammonium base in a solvent or an organic solvent, cooling after the reaction is completed, purifying, and obtaining racemic nicotine, and the synthetic route is as follows: ； wherein, The cyclic quaternary ammonium base has a structure as shown in Formula I or Formula II: wherein n is an integer of 1-7; t, m are independently integers of 1-4. The gas is selected from nitrogen, argon or helium.

6. The method of claim 5, wherein, The organic solvent is selected from one or more of toluene, xylene, chlorobenzene, methanol, ethanol, ethyl acetate, chloroform, acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and dimethyl sulfoxide.

7. The method of claim 5, wherein, The organic solvent is selected from one or more of xylene, tetrahydrofuran or dimethyl sulfoxide.

8. The method of claim 5, wherein, The temperature of the reaction is 80-200°C.

9. The method of claim 5, wherein, The temperature of the reaction is 100-150°C.

10. The method of claim 5, wherein, The time of the reaction is 1-24 hours.

11. The method of claim 5, wherein, The time of the reaction is 2-10 hours.

12. The method of claim 5, wherein, The molar ratio of the S-nicotine to the cyclic quaternary ammonium base is 100:1-100:

20.

13. The method of claim 5, wherein, The molar ratio of the S-nicotine to the cyclic quaternary ammonium base is 100:5-100:15.

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