A method of preparing nicotine

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of nicotine. The preparation method of the nicotine comprises the following steps: 3-bromopyridine and N-tert-butoxycarbonyl-proline are used as raw materials to photocatalytically synthesize an intermediate N-tert-butoxycarbonyl-nor-nicotine; then N-tert-butoxycarbonyl-nor-nicotine is reacted with trifluoroacetic acid to remove the tert-butoxycarbonyl group, and nor-nicotine is synthesized; finally, the nor-nicotine is subjected to a methylation reaction to synthesize nicotine. The preparation method of the nicotine has a short synthesis route, is simple to operate, has high yield, is low in cost, and is suitable for industrialized scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing nicotine. Background Technology

[0002] Nicotine, also known as tobacco alkaloid, is widely found in nightshade plants and is a major component of tobacco. Nicotine intake stimulates the sympathetic nervous system and promotes dopamine secretion, which is one of the important reasons why smokers develop physiological addiction. A single burning cigarette contains more than 4,000 compounds, including dozens of carcinogens such as tar and carbon monoxide. Therefore, in 1978, the World Health Organization promoted nicotine replacement therapy to alleviate withdrawal symptoms while protecting against other harmful substances.

[0003] In recent years, the e-cigarette market has been expanding, and the demand for nicotine, as the main component of e-liquid, has been increasing. Currently, nicotine is mainly obtained through tobacco plant extraction and organic synthesis. Plant extraction is heavily limited by raw material supply, and the resulting nicotine inevitably contains various harmful impurities, such as neonicotinoids, dienicotinic acid, and nornicotinic acid. Synthetic nicotine, on the other hand, is synthesized from raw materials in a targeted manner, thus avoiding these harmful impurities and achieving high purity. Therefore, the preparation of nicotine through organic synthesis has attracted widespread attention in recent years.

[0004] Currently, the main method for synthesizing nicotine is the synthesis of racemic nicotine.

[0005] The literature J. Org. Chem., 1990, 55(6), 1736-1744 reports a four-step method for synthesizing nicotine from pyrrolidine:

[0006]

[0007] This method requires the use of 3-pyridine lithium, whose synthesis requires a reaction with n-butyllithium at -78°C, making it unsuitable for large-scale industrial production.

[0008] The literature J. Heterocyclic Chem., 2009, 46(6), 1252-1258 reports a four-step route for the synthesis of nicotine from 3-bromopyridine:

[0009]

[0010] This method also requires reaction with n-butyllithium at -78°C, and methylsulfonyl chloride is a highly toxic substance, which is not conducive to industrial production.

[0011] The literature J. Chem. Soc., Perkin Trans. 1, 2002, 143-154 reports a four-step route for the synthesis of nicotine from nicotinic acid:

[0012]

[0013] The 3-bromopropanal dimethyl acetal required for this method is expensive and not suitable for industrial production. Summary of the Invention

[0014] The technical problem solved by this invention is that the existing methods for preparing nicotine involve long synthetic routes, and most of them use hazardous reagents or harsh reaction conditions, which pose certain safety hazards and are not suitable for industrial production.

[0015] To address these technical problems, the present invention aims to provide a method for preparing nicotine that has a shorter synthesis step, milder reaction conditions, and a higher product yield, making it suitable for industrial production.

[0016] Specifically, the present invention is achieved through the following technical solution:

[0017] In a first aspect, the present invention provides a method for preparing nicotine, comprising the following steps:

[0018] (1) The intermediate N-tert-butoxycarbonyl-nornicotinine was synthesized by photocatalysis using 3-bromopyridine and N-tert-butoxycarbonyl-proline as raw materials;

[0019] (2) Remove the tert-butoxycarbonyl group from N-tert-butoxycarbonyl-nornicotine to synthesize nornicotine;

[0020] (3) Nicotine is synthesized from nornicotine via methylation.

[0021] In some embodiments, in step (1), the molar ratio of 3-bromopyridine to N-tert-butoxycarbonyl-proline is 1:(1-4).

[0022] In some implementations, in step (1), the molar ratio of 3-bromopyridine to N-tert-butoxycarbonyl-proline is 1:(1.5-4).

[0023] In some embodiments, in step (1), the molar ratio of 3-bromopyridine to N-tert-butoxycarbonyl-proline is 1:(3-4).

[0024] In some implementations, a photocatalyst is also required in step (1).

[0025] In some embodiments, in step (1), the molar amount of the photocatalyst is 1% to 3% of the molar amount of 3-bromopyridine.

[0026] In some implementations, in step (1), the photocatalyst is selected from iridium complex photocatalysts.

[0027] In some implementations, in step (1), the photocatalyst is selected from one or more of Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6 and fac-Ir(ppy)3.

[0028] In some implementations, a metal catalyst is also required in step (1).

[0029] In some embodiments, in step (1), the molar amount of the metal catalyst is 5% to 10% of the molar amount of 3-bromopyridine.

[0030] In some embodiments, in step (1), the molar amount of the metal catalyst is 7% to 10% of the molar amount of 3-bromopyridine.

[0031] In some implementations, in step (1), the metal catalyst is a nickel halide or a nickel halide complex.

[0032] In some embodiments, in step (1), the metal catalyst is one or more selected from nickel(II) ethylene glycol dimethyl ether complex NiCl2·glyme, nickel(II) diethylene glycol dimethyl ether complex NiCl2·diglyme, nickel(II) ethylene glycol dimethyl ether complex NiBr2·glyme, nickel(II) diethylene glycol dimethyl ether complex NiBr2·diglyme, nickel chloride NiCl2, and nickel bromide NiBr2.

[0033] In some implementations, a ligand needs to be added in step (1).

[0034] In some embodiments, in step (1), the molar amount of the ligand is 5% to 15% of the molar amount of 3-bromopyridine.

[0035] In some embodiments, in step (1), the molar amount of the ligand is 9% to 15% of the molar amount of 3-bromopyridine.

[0036] In some implementations, in step (1), the ligand is a nitrogen-containing heterocyclic compound.

[0037] In some embodiments, in step (1), the ligand is selected from one or more of 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine and 1,10-o-phenanthroline.

[0038] In some implementations, alkali needs to be added in step (1).

[0039] In some implementations, in step (1), the molar amount of the base is 2 to 4 times the molar amount of 3-bromopyridine.

[0040] In some embodiments, in step (1), the molar amount of the base is 2 to 3.5 times the molar amount of 3-bromopyridine.

[0041] In some embodiments, in step (1), the molar amount of the base is 2 to 3.2 times the molar amount of 3-bromopyridine.

[0042] In some implementations, in step (1), the base is selected from one or more of potassium carbonate, cesium carbonate, potassium tert-butoxide, and tripotassium phosphate.

[0043] In some embodiments, in step (1), the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, or N,N-dimethylacetamide.

[0044] In some embodiments, in step (1), the molar concentration of 3-bromopyridine in the solvent is 0.02 to 1 mmol / mL.

[0045] In some embodiments, in step (1), the molar concentration of 3-bromopyridine in the solvent is 0.02 to 0.2 mmol / mL.

[0046] In some implementations, in step (1), the catalytic reaction is carried out under an inert gas.

[0047] In some implementations, in step (1), the inert gas is N2 or Ar.

[0048] In some implementations, in step (1), the wavelength of light in the photocatalytic reaction is 420 nm to 450 nm.

[0049] In some implementations, the reaction time in step (1) is 48–72 h.

[0050] In some implementations, the reaction temperature in step (1) is 40°C to 50°C.

[0051] In some embodiments, in step (2), N-tert-butoxycarbonyl-nornicotinic acid is reacted with trifluoroacetic acid under an inert gas to remove the tert-butoxycarbonyl group, thereby synthesizing nornicotinic acid.

[0052] In some implementations, in step (2), the inert gas is N2 or Ar.

[0053] In some embodiments, in step (2), N-tert-butoxycarbonyl-nornicotinamide is dissolved in an organic solvent and cooled to -5 to 5°C. After adding trifluoroacetic acid, the mixture is preferably stirred for 10 to 60 minutes, and / or heated to 15 to 30°C, preferably 20 to 25°C, to continue the reaction; and / or the reaction time is 3 to 6 hours.

[0054] In some implementations, in step (2), the molar ratio of N-tert-butoxycarbonyl-nornicotinic acid and trifluoroacetic acid is 1:(5-10).

[0055] In some implementations, in step (2), the solvent is selected from dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, or diethyl ether.

[0056] In some embodiments, in step (2), the concentration of N-tert-butoxycarbonyl-nornicotinic acid in the solvent is 0.1 to 1 mmol / mL.

[0057] In some embodiments, in step (2), the concentration of N-tert-butoxycarbonyl-nornicotinic acid in the solvent is 0.2 to 0.5 mmol / mL.

[0058] In some implementations, in step (3), the methylation reaction is to react nornicotine with formaldehyde and formic acid to synthesize nicotine.

[0059] In some implementations, in step (3), the molar ratio of formaldehyde to formic acid is (1-3):1.

[0060] In some implementations, in step (3), the molar ratio of nornicotine, formaldehyde and formic acid is (0.2-1):(1-3):1.

[0061] In some implementations, in step (3), the molar ratio of nornicotine, formaldehyde and formic acid is (0.2-0.7):(1-3):1.

[0062] In some implementations, the reaction temperature in step (3) is 80–100°C.

[0063] In some implementations, the reaction temperature in step (3) is 83–93 °C.

[0064] In some implementations, the reaction time in step (3) is 16 to 24 hours.

[0065] In some implementations, in step (3), the reaction solvent is selected from water, acetonitrile, or tetrahydrofuran.

[0066] In some implementations, in step (3), the molar concentration of nornicotine in the solvent is 0.4 to 1.3 mmol / mL.

[0067] Secondly, the present invention provides nicotine prepared by the above-described preparation method.

[0068] The beneficial effects achieved by this invention are as follows:

[0069] The method for preparing nicotine in this invention has a short procedure, is simple to operate, has mild reaction conditions, and yields a high rate of completion, making it suitable for industrial production. Attached Figure Description

[0070] Figure 1 The image shows the 1H NMR spectrum of N-tert-butoxycarbonyl-nornicotinamide prepared in Example 1 of this invention.

[0071] Figure 2 The image shows the 1H NMR spectrum of nicotine prepared in Example 7 of this invention. Detailed Implementation

[0072] As mentioned above, the existing methods for preparing nicotine are complex and difficult to scale up for industrial production. The purpose of this invention is to provide a method for preparing nicotine, the specific synthetic route of which is shown below:

[0073]

[0074] In one specific embodiment of the present invention, a method for preparing nicotine is provided, comprising the following steps:

[0075] (1) Using 3-bromopyridine and N-tert-butoxycarbonyl-DL-proline as raw materials, a photocatalyst, a metal catalyst, a ligand and a base were added, followed by the addition of N,N-dimethylformamide. The reaction was carried out under nitrogen purging and the intermediate N-tert-butoxycarbonyl-(R,S)-nornicotinine was generated. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate solution and extracted with an organic solvent. The organic layer was dried, distilled under reduced pressure, and the product was separated by column chromatography to obtain N-tert-butoxycarbonyl-(R,S)-nornicotinine.

[0076] (2) Under nitrogen protection, the dichloromethane solution of N-tert-butoxycarbonyl-(R,S)-nornicotine was cooled to -5 to 5°C, and trifluoroacetic acid was added dropwise to the system. The mixture was stirred for 10 to 60 min and then moved to 20 to 25°C to react. After the reaction was completed, the solvent was removed by vacuum distillation, and organic solvent and sodium hydroxide solution were added to the residue for extraction. The organic layer was dried and vacuum distilled to obtain DL-nornicotine.

[0077] (3) Under nitrogen protection, formaldehyde, formic acid and water were added to DL-nornicotine and the reaction was heated to 83-93°C. After the reaction was completed, sodium hydroxide solution and organic solvent were slowly added to the reaction system at zero degrees Celsius for extraction. The organic layer was dried and distilled under reduced pressure to obtain nicotine.

[0078] In this invention, N-tert-butoxycarbonyl-DL-proline and N-tert-butoxycarbonyl-proline represent the same product, namely, containing both N-tert-butoxycarbonyl-D-proline and N-tert-butoxycarbonyl-L-proline. Similarly, N-tert-butoxycarbonyl-(R,S)-nornicotinine and N-tert-butoxycarbonyl-nornicotinine represent the same product, meaning they simultaneously contain both N-tert-butoxycarbonyl-R-nornicotinine and N-tert-butoxycarbonyl-S-nornicotinine. Finally, DL-nornicotinine and nornicotinine represent the same product, meaning they simultaneously contain both D-nornicotinine and L-nornicotinine.

[0079] The experimental materials and instruments used in the embodiments of this invention are shown in Table 1:

[0080] Table 1 Experimental Materials / Equipment and Manufacturers

[0081]

[0082] To make the content of this invention easier to understand, the technical solutions of this invention will be further explained below with reference to specific embodiments.

[0083] Example 1: Preparation of N-tert-butoxycarbonyl-(R,S)-nornicotine

[0084] Add N-tert-butoxycarbonyl-DL-proline (57.0 g, 264.8 mmol), 3-bromopyridine (27.6 g, 174.7 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (Ir[dF(CF3)ppy]2(dtbbpy)PF6) (2.0 g, 1.8 mmol) to a dry double-necked flask. The reaction mixture consisted of nickel(II) glycol dimethyl ether complex NiCl2·glyme (3.9 g, 17.8 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (7.1 g, 26.5 mmol), and cesium carbonate (172 g, 527.6 mmol), followed by the addition of N,N-dimethylformamide (880 mL), nitrogen purging, and reaction under 450 nm blue light irradiation and 40 °C for 72 h.

[0085] After the reaction was completed, saturated sodium bicarbonate solution (2.0 L) was added to the reaction system, and the mixture was extracted with ethyl acetate (800 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (1.0 L * 2). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, silica gel column chromatography was performed using a petroleum ether-ethyl acetate system as the eluent to separate the intermediate N-tert-butoxycarbonyl-(R,S)-nornicotinine (30.0 g, 120.8 mmol), with a yield of 69%, as a colorless oil.

[0086] The characterization data for N-tert-butoxycarbonyl-(R,S)-nornicotine are as follows: 1H NMR (400MHz, CDCl3) δ 8.40 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.17 (dd, J = 7.5, 4.9 Hz, 1H), 4.80 (m, 1H), 3.65–3.37 (m, 2H), 2.29 (s, 1H), 1.89–1.67 (m, 2H), 1.38 (s, 1H), 1.12 (s, 3H).

[0087] Example 2: Preparation of N-tert-butoxycarbonyl-(R,S)-nornicotine

[0088] Add N-tert-butoxycarbonyl-DL-proline (112.7 g, 524 mmol), 3-bromopyridine (27.6 g, 174.7 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (Ir[dF(CF3)ppy]2(dtbbpy)PF6) (2.0 g, 1.8 mmol) to a dry double-necked flask. The following were prepared: nickel(II) glycol dimethyl ether complex NiCl2·glyme (3.9 g, 17.8 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (7.1 g, 26.5 mmol), cesium carbonate (172 g, 527.6 mmol), followed by the addition of N,N-dimethylformamide (8000 mL), nitrogen purging, and reaction at 450 nm blue light and 40 °C for 72 h.

[0089] After the reaction was completed, saturated sodium bicarbonate solution (10.0 L) was added to the reaction system, and the mixture was extracted with ethyl acetate (1000 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (5.0 L * 2). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, silica gel column chromatography was performed using a petroleum ether-ethyl acetate system as the eluent to separate the intermediate N-tert-butoxycarbonyl-(R,S)-nornicotinine (34.7 g, 139.8 mmol), with a yield of 80%, as a colorless oil.

[0090] Example 3: Preparation of N-tert-butoxycarbonyl-(R,S)-nornicotine

[0091] N-tert-butyloxycarbonyl-DL-proline (94.0 g, 436.8 mmol), 3-bromopyridine (27.6 g, 174.7 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (Ir(ppy)2(dtbbpy)PF6) (3.3 g, 3.6 mmol), nickel(II) diethylene glycol dimethyl ether complex NiBr2·diglyme (3.1 g, 8.7 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.3 g, 8.7 mmol), and potassium carbonate (84.0 g, 609 mmol) were added to a dry double-necked flask. Then, N,N-dimethylformamide (3500 mL) was added, and the mixture was purged with argon. The reaction was carried out under blue light at 420 nm and at 50 °C for 48 h.

[0092] After the reaction was completed, saturated sodium bicarbonate solution (10.0 L) was added to the reaction system, and the mixture was extracted with ethyl acetate (800 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (5.0 L * 2). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, silica gel column chromatography was performed using a dichloromethane-methanol system as the eluent to separate the intermediate N-tert-butoxycarbonyl-(R,S)-nornicotinine (26.0 g, 104.8 mmol), with a yield of 60%, as a colorless oil.

[0093] Example 4: Preparation of N-tert-butoxycarbonyl-(R,S)-nornicotine

[0094] Add N-tert-butoxycarbonyl-DL-proline (112.7 g, 524 mmol), 3-bromopyridine (27.6 g, 174.7 mmol), and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (Ir[dF(CF3)ppy]2(dtbbpy)PF6) (5.8 g, 5.2 mmol) to a dry double-necked flask. The reaction mixture consisted of nickel(II) ethylene glycol dimethyl ether complex NiBr2·glyme (4.0 g, 13.1 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (4.2 g, 15.7 mmol), and cesium carbonate (172 g, 527.6 mmol), followed by the addition of N,N-dimethylformamide (8000 mL), argon purging, and reaction under 450 nm blue light irradiation and 40 °C for 56 h.

[0095] After the reaction was completed, saturated sodium bicarbonate solution (10.0 L) was added to the reaction system, and the mixture was extracted with ethyl acetate (1000 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (5.0 L * 2). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, silica gel column chromatography was performed with dichloromethane-methanol as the eluent to separate the intermediate N-tert-butoxycarbonyl-(R,S)-nornicotinine (32.5 g, 131.0 mmol), with a yield of 75%, as a colorless oil.

[0096] Example 5: Preparation of DL-nornicotine

[0097] N-tert-butoxycarbonyl-nornicotine (34.7 g, 139.8 mmol) and dichloromethane (480 mL) prepared in Experimental Example 2 were added to a 1000 mL dry double-necked flask. Nitrogen gas was purged, and trifluoroacetic acid (90.0 mL, 1211.6 mmol) was added dropwise at 0 °C. After reacting for 30 min, the mixture was moved to 20 °C and reacted for 6 h.

[0098] After the reaction was completed, sodium hydroxide solution (5.0 M, 300 mL) was slowly added to the reaction system at 0 °C and stirred for 10 min. Then, dichloromethane (300 mL * 3) was added for extraction. The organic layer was then washed with saturated ammonium chloride solution (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain DL-nornicotine (18.2 g, 123 mmol), with a yield of 88%, in a colorless oil.

[0099] Example 6: Preparation of DL-nornicotine

[0100] Add N-tert-butoxycarbonyl-nornicotine (34.7 g, 139.8 mmol) prepared in Experimental Example 2 and dichloromethane (300 mL) to a 1000 mL dry double-necked flask, purge with nitrogen, and add trifluoroacetic acid (54.0 mL, 727.1 mmol) dropwise at 5 °C. After reacting for 30 min, move the flask to 25 °C and react for 3 h.

[0101] After the reaction was completed, sodium hydroxide solution (5.0 M, 300 mL) was slowly added to the reaction system at 0 °C and stirred for 10 min. Then, dichloromethane (300 mL * 3) was added for extraction. The organic layer was then washed with saturated ammonium chloride solution (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain DL-nornicotine (18.5 g, 125 mmol), with a yield of 89%, in a colorless oil.

[0102] Example 7: Preparation of Nicotine

[0103] Add DL-nornicotine (18.5 g, 125 mmol) prepared in Example 6, 37% formaldehyde solution (44.0 mL, 542.3 mmol), formic acid (8.2 mL, 217 mmol), and deionized water (220 mL) to a 250 mL dry double-necked flask, and react at 85 °C for 20 h.

[0104] After the reaction was completed, sodium hydroxide solution (5.0 mol / L, 60 mL) was slowly added at 0°C, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain DL-nicotine (16.9 g, 104.3 mmol), with a yield of 83%, in a colorless oil.

[0105] The characterization data for nicotine are as follows: 1H NMR (300MHz, cdcl3) δ 8.43 (s, 1H), 8.38 (d, J = 3.6Hz, 1H), 7.59 (d, J = 7.8Hz, 1H), 7.14 (dd, J = 7.6, 4.8Hz, 1H), 3.13 (t, J = 8.4Hz, 1H), 2.97 (t, J = 8.2Hz, 1H), 2.20 (m, 1H), 2.14–2.00 (m, 4H), 1.94–1.79 (m, 1H), 1.77–1.53 (m, 2H).

[0106] Example 8: Preparation of Nicotine

[0107] Add DL-nornicotine (18.5 g, 125 mmol) prepared in Example 6, 37% formaldehyde solution (35.5 mL, 437.5 mmol), formic acid (12.3 mL, 326 mmol), and deionized water (110 mL) to a 250 mL dry double-necked flask, and react at 90 °C for 24 h.

[0108] After the reaction was completed, sodium hydroxide solution (5.0 mol / L, 80 mL) was slowly added at 0°C, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain DL-nicotine (17.1 g, 105.5 mmol), with a yield of 84%, in a colorless oil.

[0109] Example 9: Preparation of Nicotine

[0110] Add DL-nornicotine (18.5 g, 125 mmol) prepared in Example 6, 37% formaldehyde solution (40.5 mL, 500 mmol), formic acid (9.4 mL, 250 mmol), and deionized water (220 mL) to a 250 mL dry double-necked flask, and react at 93 °C for 18 h.

[0111] After the reaction was completed, sodium hydroxide solution (5.0 mol / L, 60 mL) was slowly added at 0°C, and the mixture was extracted with ethyl acetate (200 mL * 3). The organic layer was then washed with saturated ammonium chloride solution (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain DL-nicotine (17.4 g, 107.4 mmol), with a yield of 86%, in a colorless oil.

[0112] The applicant declares that this invention illustrates the nicotine preparation method of this invention through the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials of this invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

Claims

1. A method for preparing nicotine, characterized in that, Includes the following steps: (1) with 3-bromopyridine and N Photocatalytic synthesis intermediates using tert-butyloxycarbonyl-proline as a starting material N -tert-butyloxycarbonyl-nornicotine; a photocatalyst, a metal catalyst, a ligand, and a base also need to be added; The base is cesium carbonate, and its molar amount is 2 to 4 times that of 3-bromopyridine; 3-Bromopyridine and N The molar ratio of -tert-butyloxycarbonyl-proline is 1:3~4; The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6; the molar amount of the photocatalyst is 1% to 3% of the molar amount of 3-bromopyridine. The metal catalyst is selected from nickel halides or nickel halide complexes, and the molar amount of the metal catalyst is 5% to 10% of the molar amount of 3-bromopyridine; In photocatalytic reactions, the wavelength of light is 420–450 nm; the reaction time is 48–72 h; and the reaction temperature is 40–50 °C. o C; (2) will N -tert-butyloxycarbonyl-nornicotine is dissolved in an organic solvent and cooled to -5~5°C. o After adding trifluoroacetic acid (C), the temperature is raised to 15-30℃ and the reaction continues for 3-6 hours. N The tert-butyloxycarbonyl group in -tert-butyloxycarbonyl-nornicotine is removed to synthesize nornicotine; the aforementioned N The molar ratio of -tert-butyloxycarbonyl-nornicotinic acid to trifluoroacetic acid is 1:5~10; (3) Nicotine is synthesized by methylation reaction of nornicotine. The methylation reaction is to react nornicotine with formaldehyde and formic acid to synthesize nicotine. The reaction temperature is 80~100℃ and the reaction time is 16~24 h.

2. The method for preparing nicotine according to claim 1, wherein, In step (1), the metal catalyst is selected from one or more of the following: nickel(II) ethylene glycol dimethyl ether complex NiCl2·glyme, nickel(II) diethylene glycol dimethyl ether complex NiCl2·diglyme, nickel(II) ethylene glycol dimethyl ether complex NiBr2·glyme, nickel(II) diethylene glycol dimethyl ether complex NiBr2·diglyme, nickel chloride NiCl2, and nickel bromide NiBr2.

3. The method for preparing nicotine according to claim 1, wherein, In step (1), the molar amount of the ligand is 5% to 15% of the molar amount of 3-bromopyridine.

4. The method for preparing nicotine according to claim 2, wherein, In step (1), the molar amount of the ligand is 5% to 15% of the molar amount of 3-bromopyridine.

5. The method for preparing nicotine according to claim 1, wherein, In step (1), the ligand is a nitrogen-containing heterocyclic compound.

6. The method for preparing nicotine according to claim 2, wherein, In step (1), the ligand is a nitrogen-containing heterocyclic compound.

7. The method for preparing nicotine according to claim 3, wherein, In step (1), the ligand is a nitrogen-containing heterocyclic compound.

8. The method for preparing nicotine according to claim 1, wherein, In step (1), the ligand is selected from one or more of 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine and 1,10-o-phenanthroline.

9. The method for preparing nicotine according to claim 2, wherein, In step (1), the ligand is selected from one or more of 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine and 1,10-o-phenanthroline.

10. The method for preparing nicotine according to claim 3, wherein, In step (1), the ligand is selected from one or more of 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine and 1,10-o-phenanthroline.

11. The method for preparing nicotine according to claim 1, wherein, In step (1), the solvent is selected from N , N - Dimethylformamide, dimethyl sulfoxide or N , N -Dimethylacetamide.

12. The method for preparing nicotine according to claim 2, wherein, In step (1), the solvent is selected from N , N - Dimethylformamide, dimethyl sulfoxide or N , N -Dimethylacetamide.

13. The method for preparing nicotine according to claim 3, wherein, In step (1), the solvent is selected from N , N - Dimethylformamide, dimethyl sulfoxide or N , N -Dimethylacetamide.

14. The method for preparing nicotine according to claim 5, wherein, In step (1), the solvent is selected from N , N - Dimethylformamide, dimethyl sulfoxide or N , N -Dimethylacetamide.

15. The method for preparing nicotine according to claim 8, wherein, In step (1), the solvent is selected from N , N - Dimethylformamide, dimethyl sulfoxide or N , N -Dimethylacetamide.

16. The method for preparing nicotine according to claim 11, wherein, In step (1), the molar concentration of 3-bromopyridine in the solvent is 0.02~1 mmol / mL.

17. The method for preparing nicotine according to claim 11, wherein, In step (1), the molar concentration of 3-bromopyridine in the solvent is 0.02~0.2 mmol / mL.

18. The preparation method according to any one of claims 1-17, wherein, The catalytic reaction in step (1) is carried out under an inert gas.

19. The preparation method according to claim 18, wherein, The inert gas is N2 or Ar.

20. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (2), N -tert-butyloxycarbonyl-nornicotinamide reacts with trifluoroacetic acid to remove the tert-butyloxycarbonyl group under an inert gas to synthesize nornicotinamide.

21. The method for preparing nicotine according to claim 18, wherein, In step (2), N -tert-butyloxycarbonyl-nornicotinamide reacts with trifluoroacetic acid to remove the tert-butyloxycarbonyl group under an inert gas to synthesize nornicotinamide.

22. The method for preparing nicotine according to claim 20, wherein, In step (2), the inert gas is N2 or Ar.

23. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (2), the temperature is raised to 20~25℃ to continue the reaction.

24. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (2), the solvent is selected from dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane or diethyl ether.

25. The method for preparing nicotine according to claim 18, wherein, In step (2), the solvent is selected from dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane or diethyl ether.

26. The method for preparing nicotine according to claim 20, wherein, In step (2), the solvent is selected from dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane or diethyl ether.

27. The method for preparing nicotine according to claim 24, wherein, In step (2), the solvent contains N The concentration of -tert-butyloxycarbonyl-nornicotinamide is 0.1~1 mmol / mL.

28. The method for preparing nicotine according to claim 24, wherein, In step (2), the solvent contains N The concentration of -tert-butyloxycarbonyl-nornicotinic acid is 0.2~0.5 mmol / mL.

29. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (3), the molar ratio of formaldehyde to formic acid is (1~3):

1.

30. The method for preparing nicotine according to claim 18, wherein, In step (3), the molar ratio of formaldehyde to formic acid is (1~3):

1.

31. The method for preparing nicotine according to claim 20, wherein, In step (3), the molar ratio of formaldehyde to formic acid is (1~3):

1.

32. The method for preparing nicotine according to claim 24, wherein, In step (3), the molar ratio of formaldehyde to formic acid is (1~3):

1.

33. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (3), the molar ratio of nornicotine, formaldehyde and formic acid is (0.2~1): (1~3):

1.

34. The method for preparing nicotine according to claim 18, wherein, In step (3), the molar ratio of nornicotine, formaldehyde and formic acid is (0.2~1): (1~3):

1.

35. The method for preparing nicotine according to claim 20, wherein, In step (3), the molar ratio of nornicotine, formaldehyde and formic acid is (0.2~1): (1~3):

1.

36. The method for preparing nicotine according to claim 24, wherein, In step (3), the molar ratio of nornicotine, formaldehyde and formic acid is (0.2~1): (1~3):

1.

37. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (3), the reaction temperature is 83~93℃.

38. The method for preparing nicotine according to any one of claims 1-17, wherein, In step (3), the reaction solvent is selected from water, acetonitrile or tetrahydrofuran.

39. The method for preparing nicotine according to claim 29, wherein, In step (3), the reaction solvent is selected from water, acetonitrile or tetrahydrofuran.

40. The method for preparing nicotine according to claim 33, wherein, In step (3), the reaction solvent is selected from water, acetonitrile or tetrahydrofuran.

41. The method for preparing nicotine according to claim 38, wherein, In step (3), the molar concentration of nornicotine in the solvent is 0.4~1.3 mmol / mL.

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