Preparation method of 2,5-dihydropyrrolidine derivatives and racemic nicotine

Abstract

The present invention discloses a preparation method of 2,5-dihydropyrrolidine derivatives and racemic nicotine. The preparation of the 2,5-dihydropyrrolidine derivatives comprises the following steps: under an inert atmosphere and blue light irradiation, 1-R-1,3-butadiene and tert-butyl N-(trifluoromethylsulfonyloxy)carbamate are subjected to a cyclization reaction in the presence of a photocatalyst and a solvent to obtain the 2,5-dihydropyrrolidine derivatives. The reaction raw materials of the above cyclization reaction are readily available, the reaction conditions are mild, the catalyst dosage is small and the yield is high. In addition, when R is 3-pyridyl, the 2,5-dihydropyrrolidine derivative is N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine. This compound can be prepared into racemic nicotine through a deprotection reaction, a hydrogenation reduction reaction and a methylation reaction. The reaction conditions of the above synthesis route are mild, easy to operate and low in cost, and are suitable for the industrial mass production of nicotine.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of nitrogen-containing heterocyclic compounds, and particularly relates to a method for preparing 2,5-dihydropyrrolidine derivatives and racemic nicotine. Background Art

[0002] Nicotine is an important component of traditional tobacco and is an alkaloid present in solanaceous plants (Solanum). Traditional tobacco not only contains nicotine but also tar, and a large amount of harmful gases will be generated during the ignition process. Among them, nitrosamines and benzopyrene are the two substances with the strongest carcinogenicity in tar. In recent years, electronic cigarettes have gradually developed to replace traditional tobacco, and nicotine is the main active ingredient in e-cigarette oil. In addition, as a typical agonist of nicotinic acetylcholine receptors, nicotine has an important regulatory effect on the central nervous system. Clinical studies have shown that nicotine is expected to become a drug for the treatment of diseases such as depression and Alzheimer's disease.

[0003] At present, the main source of nicotine in the market is extracted from tobacco plants, and this approach has two defects. One is that the extraction of nicotine from tobacco is affected by raw materials, climate, growth cycle, etc.; the other is that according to the United States Pharmacopoeia, among the nicotine extracted from tobacco, there are seven impurities harmful to the human body, namely anabasine, nornicotine, cotinine, myosmine, nicotine-N-oxide, nor nicotine, and anhalinine. In order to overcome the above defects, synthetic nicotine has received extensive attention.

[0004] However, the existing methods for preparing racemic nicotine have problems such as difficult acquisition or high cost of starting materials, harsh reaction conditions, long reaction cycles, low conversion rates, and complex separation and purification operations. Therefore, they are not suitable for large-scale industrial production. Therefore, there is an urgent need for a method for preparing racemic nicotine with low cost and high efficiency to be suitable for large-scale industrial production of high-purity nicotine. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing 2,5-dihydropyrrolidine derivatives and racemic nicotine. The present invention uses 3-pyridinecarboxaldehyde or 3-(3-pyridyl)acrolein, which is low-cost and easily available, as raw materials, and racemic nicotine can be prepared through a Wittig reaction, a cyclization reaction, a deprotection reaction, a hydrogenation reduction reaction, and a methylation reaction in sequence. Each step of the reaction in this synthetic route can be carried out at room temperature, the reaction conditions are mild, and the products of each step of the reaction do not need to be purified and can be directly used in the next step of the reaction, with simple operation and high yield; among them, the cyclization reaction is carried out under photocatalysis, the reaction conditions are mild, the catalyst dosage is small, the time consumption is short, and while improving the reaction yield, the reaction cost is effectively reduced.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0007] In the first aspect of the present invention, a method for preparing a 2,5-dihydropyrrolidine derivative is provided. Under an inert atmosphere and blue light irradiation, 1-R-1,3-butadiene and tert-butyl (trifluoromethylsulfonyloxy)carbamate are subjected to a cyclization reaction in the presence of a photocatalyst and a solvent to obtain the 2,5-dihydropyrrolidine derivative; the 2,5-dihydropyrrolidine derivative has the following general structural formula:

[0008]

[0009] Among them, R is an aliphatic hydrocarbon group, an aryl group or a heteroaryl group.

[0010] The structure of the above 1-R-1,3-butadiene is The structure of tert-butyl (trifluoromethylsulfonyloxy)carbamate is

[0011] Furthermore, R is preferably an alkyl group having 1 to 10 carbon atoms, a phenyl group or a pyridyl group, such as 3-pyridyl.

[0012] Furthermore, the wavelength of the blue light is 450 to 480 nm; in some preferred embodiments, the power of the blue light irradiation is 22 W.

[0013] Furthermore, the photocatalyst is preferably fac[Ir(ppy)3], Ir(ppy)2dtbbpy]PF6, 4CZIPN, Ir[(dF(CF3)ppy)]2(dtbbpy)PF6 or [Ir(dFCF3ppy)2(dCF3bpy)]PF6, and more preferably fac[Ir(ppy)3].

[0014] Furthermore, the molar ratio of the feed of 1-R-1,3-butadiene to tert-butyl (trifluoromethylsulfonyloxy)carbamate is preferably 1:1 to 1.5, such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, including but not limited to the ratios listed above.

[0015] In some preferred embodiments, the molar ratio of the feed of 1-R-1,3-butadiene to the photocatalyst is 1:0.018.

[0016] Furthermore, the cyclization reaction is preferably carried out in the presence of a copper catalyst and a base reagent.

[0017] In some preferred embodiments, the copper catalyst is copper acetate, the base reagent is sodium methoxide, and the molar ratio of the feed of 1-R-1,3-butadiene to the copper catalyst and the base reagent is 1:0.045:0.9.

[0018] Further, the reaction temperature of the cyclization reaction is 20 to 40 °C, more preferably 30 to 35 °C, such as 35 °C; the reaction time of the cyclization reaction is 12 to 24 h, more preferably 24 h.

[0019] In some preferred embodiments, under an inert atmosphere, tert-butyl N-(trifluoromethylsulfonyloxy)carbamate, 1-R-1,3-butadiene, a photocatalyst, a copper catalyst, a base reagent, and a solvent are mixed at 20 to 25 °C, and after mixing, the mixture is irradiated under a blue LED lamp. After the reaction is completed, N-tert-butoxycarbonyl-2-R-2,5-dihydropyrrolidine is obtained through extraction, washing, and drying.

[0020] The second aspect of the present invention provides a method for synthesizing racemic nicotine. Using 3-pyridinecarboxaldehyde or 3-(3-pyridyl)acrolein as raw materials, through a Wittig reaction, a cyclization reaction, a deprotection reaction, a hydrogenation reduction reaction, and a methylation reaction in sequence, the racemic nicotine is obtained.

[0021] Further, the synthesis method includes the following steps:

[0022] (1) Under an inert atmosphere, 3-pyridinecarboxaldehyde or 3-(3-pyridyl)acrolein is reacted with the corresponding phosphonium ylide reagent in the presence of a base reagent and a solvent to obtain 1-(3-pyridyl)-1,3-butadiene; the phosphonium ylide reagent corresponding to 3-pyridinecarboxaldehyde is allyltriphenylphosphonium bromide, and the phosphonium ylide reagent corresponding to 3-(3-pyridyl)acrolein is methylphenylphosphonium bromide;

[0023] (2) The 1-(3-pyridyl)-1,3-butadiene prepared in step (1) and tert-butyl N-(trifluoromethylsulfonyloxy)carbamate are used to prepare N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine through the preparation method described in the first aspect;

[0024] (3) The N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine prepared in step (2) is subjected to a deprotection reaction in the presence of an acidic reagent and a solvent to obtain 2-(3-pyridyl)-2,5-dihydropyrrolidine;

[0025] (4) The 2-(3-pyridyl)-2,5-dihydropyrrolidine prepared in step (3) is subjected to a hydrogenation reduction reaction in the presence of palladium on carbon, hydrogen, and a solvent to obtain 2-(3-pyridyl)pyrrolidine;

[0026] (5) The 2-(3-pyridyl)pyrrolidine prepared in step (4) and paraformaldehyde are subjected to a methylation reaction in the presence of a reducing agent organic acid and a solvent to obtain the racemic nicotine.

[0027] The synthesis route of the above synthesis method is as follows:

[0028]

[0029] Further, in step (1), the base reagent includes one or two of potassium tert-butoxide and n-butyllithium, and more preferably n-butyllithium with stronger alkalinity.

[0030] Further, in step (1), the solvent is preferably anhydrous tetrahydrofuran.

[0031] Further, in step (1), the temperature of the reaction is 0 - 25°C, and the time is 4 - 8 h.

[0032] Further, in step (1), when 3-pyridinecarboxaldehyde reacts with allyltriphenylphosphonium bromide, the reaction product is a mixture of cis- and trans-1-(3-pyridyl)-1,3-butadiene; when 3-(3-pyridyl)acrolein reacts with methyltriphenylphosphonium bromide, the obtained reaction product is trans-1-(3-pyridyl)-1,3-butadiene; whether the 1-(3-pyridyl)-1,3-butadiene in the reaction product is in cis- or trans-structure has no influence on the reaction in step (2).

[0033] Further, in step (3), the acidic reagent includes one or two of trifluoroacetic acid and hydrochloric acid; more preferably hydrochloric acid with a concentration of 2M - 3M.

[0034] Further, in step (3), the solvent is preferably dichloromethane and / or 1,4-dioxane.

[0035] Further, in step (3), the temperature of the deprotection reaction is 20 - 25°C, and the time is 4 - 8 h.

[0036] Further, in step (4), the solvent is preferably methanol and / or ethanol.

[0037] Further, in step (4), palladium-carbon is used as a reducing agent, hydrogen is used as a reducing agent, the temperature of the hydrogenation reduction reaction is 20 - 25°C, and the time is 2 - 8 h.

[0038] Further, in step (5), the solvent is preferably methanol and / or ethanol.

[0039] Further, in step (5), paraformaldehyde provides a carbon source, the reducing agent includes one or two of sodium borohydride and sodium cyanoborohydride, and the organic acid is preferably acetic acid.

[0040] Compared with the prior art, the beneficial effects of the present invention are:

[0041] 1. The present invention uses 1-R-1,3-butadiene to prepare 2,5-dihydropyrrolidine derivatives through a photocatalytic cyclization reaction. The reaction conditions of this reaction are mild, the catalyst dosage is small, the whole reaction takes a short time, and the reaction efficiency can be improved while effectively reducing the reaction cost.

[0042] 2. In addition, the present invention provides a new synthetic route for racemic nicotine. Using low-cost and easily available 3-pyridinecarboxaldehyde or 3-(3-pyridyl)acrolein as raw materials, racemic nicotine can be prepared through a Wittig reaction, a cyclization reaction, a deprotection reaction, a hydrogenation reduction reaction, and a methylation reaction in sequence. Each step of the reaction in this synthetic route can be carried out at room temperature, the reaction conditions are mild, and the products of each step of the reaction do not need to be purified and can be directly used in the next step of the reaction. The operation is simple and the yield is high, which is suitable for the industrial mass production of nicotine. Detailed implementation manners

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this invention belongs. The terms used in the specification of this invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items. The "including" or "comprising" described in this invention means that in addition to the components described, other components may also be included or comprised. The "including" or "comprising" described in this invention can also be replaced by the closed "is" or "consists of".

[0044] The present invention will be further described below in conjunction with specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the exemplified embodiments are not intended to limit the present invention.

[0045] Example 1

[0046] This example relates to the preparation of N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine. Using 1-(3-pyridyl)-1,3-butadiene as a raw material, the target product is prepared through a one-step photocatalytic cyclization reaction. The specific operation is as follows:

[0047] tert-Butyl (trifluoromethyl)phenylsulfonyloxycarbamate (28.8 g, 120 mmol), fac[Ir(ppy)3] (1.6 g, 1.6 mmol), Cu(OAc)2 (0.8 g, 4 mmol), CH3ONa (4.3 g, 80 mmol) and 1-(3-pyridyl)-1,3-butadiene (11.6 g, 89 mmol) were added to a dry 500 mL two-necked flask. Under a nitrogen atmosphere, 1,2-dichloroethane (150 mL) was added. The reaction was irradiated under a 22 W blue LED lamp for 12 h. The reaction temperature was maintained at 35 °C when the LED lamp was on. The mixture was extracted with dichloromethane (150 mL × 3), the organic phases were combined and washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, and the excess solvent was evaporated to obtain N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine (17.9 g, 82%), which was a pale yellow oily liquid. 1 1H NMR (400 MHz, CDCl3) δ: 8.73–8.11 (m, 2H), 7.49 (s, 1H), 7.15 (s.1H), 6.14–5.78 (m, 2H), 5.44 (s, 1H), 4.29–3.68 (m, 2H), 1.36 (s, 9H).

[0048] Example 2

[0049] This example relates to the preparation of racemic nicotine. Using 3-pyridinecarboxaldehyde as a raw material, racemic nicotine was prepared through Wittig reaction, cyclization reaction, deprotection reaction, hydrogenation reduction reaction and methylation reaction in sequence. The specific operations are as follows:

[0050] (1) Preparation of 1-(3-pyridyl)-1,3-butadiene by Wittig reaction of 3-pyridinecarboxaldehyde with a phosphonium ylide reagent

[0051] Allyltriphenylphosphonium bromide (58.0 g, 150 mmol) was weighed and placed in a dry 500 mL two-necked flask. Anhydrous tetrahydrofuran (150 mL) was added. Under a nitrogen atmosphere, 2.5 M n-butyllithium (60 mL) was added. After stirring for 20 min, 3-pyridinecarboxaldehyde (10.7 g, 100 mmol) was added, and stirring was continued at room temperature for 4 h. After the reaction was completed, it was poured into ice water, quenched with saturated ammonium chloride solution (50 mL), extracted with dichloromethane (150 mL × 3), the organic phases were combined and washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, and the excess solvent was evaporated to obtain 1-(3-pyridyl)-1,3-butadiene (11.6 g, 89%), which was a yellow oily liquid. 11H NMR (400 MHz, CDCl3) δ: 8.55 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 7.73 - 7.57 (m, 1H), 7.19 (m, 1H), 6.77 (dd, J = 16.4, 10.7, 1H), 6.54 - 6.36 (m, 2H), 5.33 (d, J = 16.4 Hz, 1H), 5.19 (d, J = 10.1 Hz, 1H).

[0052] (2) The cyclization reaction of 1-(3-pyridyl)-1,3-butadiene was carried out in the same manner as in Example 1 to prepare N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine.

[0053] (3) The deprotection reaction of N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine was carried out to prepare 2-(3-pyridyl)-2,5-dihydropyrrolidine.

[0054] N-tert-Butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine (17.9 g, 73.0 mmol) was placed in a dry 250 mL flask, dissolved in 1,4-dioxane (80 mL), and 2 M hydrochloric acid-1,4-dioxane solution (80 mL) was added under a nitrogen atmosphere, followed by stirring at room temperature for 4 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the hydrochloride salt of 2-(3-pyridyl)-2,5-dihydropyrrolidine (9.6 g, 90%), which was a white solid and could be directly used in the next step without further purification.

[0055] (4) The hydrogenation reduction reaction of 2-(3-pyridyl)-2,5-dihydropyrrolidine was carried out to prepare 2-(3-pyridyl)-pyrrolidine.

[0056] The hydrochloride salt of 2-(3-pyridyl)-2,5-dihydropyrrolidine (9.6 g, 65.7 mmol) and palladium on carbon (2.3 g) were weighed and placed in a dry 250 mL two-necked flask. After evacuation with an oil pump, the flask was purged with a hydrogen balloon three times, and methanol (80 mL) was added, followed by stirring at room temperature for 8 h. After the reaction was completed, the solid residue was removed by suction filtration, and the filtrate was concentrated to obtain 2-(3-pyridyl)-pyrrolidine (7.2 g, 74%), which was a yellow oily liquid and could be directly used in the next step without purification.

[0057] (5) The racemic nicotine was prepared by the methylation reaction of the nitrogen atom in pyrrolidine of 2-(3-pyridyl)-pyrrolidine.

[0058] Weigh paraformaldehyde (5 g) and place it in a dry 250 mL two-necked flask. Add methanol (50 mL) and stir to dissolve. Then add 2-(3-pyridyl)-pyrrolidine (5.7 g, 40 mmol) and acetic acid (4.8 g, 80 mmol). After stirring for 1 h, add sodium cyanoborohydride (7.4 g, 120 mmol) and stir at room temperature for 1 h. After the reaction is completed, perform suction filtration, concentrate the filtrate, and obtain racemic nicotine (5.9 g, 75%), which is a yellow oily liquid. 1 1H NMR (300 MHz, CDCl3) δ: 8.55–8.19 (m, 2H), 7.50 (s, 1H), 7.09 (s, 1H), 3.07 (s, 1H), 2.94 (d, J = 6.9 Hz, 1H), 2.25–2.10 (m, 1H), 2.00 (s, 3H), 1.75 (d, J = 22.9 Hz, 2H), 1.68–1.41 (m, 2H).

[0059] In addition, using 1-ethyl-1,3-butadiene and 1-phenyl-1,3-butadiene as reaction raw materials respectively, N-tert-butoxycarbonyl-2-ethyl-2,5-dihydropyrrolidine and N-tert-butoxycarbonyl-2-phenyl-2,5-dihydropyrrolidine are prepared by the photocatalytic cyclization reaction described in Example 1, which further verifies that the above photocatalytic cyclization reaction has a wide range of applicable substrates.

[0060] The above-described embodiments are merely preferred embodiments given to fully illustrate the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are all within the protection scope of the present invention. The protection scope of the present invention is subject to the claims.

Claims

1. A method for preparing 2,5-dihydropyrrolidine derivatives, characterized in that, Under an inert atmosphere and blue light irradiation, 1-R-1,3-butadiene and tert-butyl N-(trifluoromethylsulfonyloxy)carbamate are subjected to a cyclization reaction in the presence of a photocatalyst fac[Ir(ppy)3], a copper catalyst copper acetate, a base reagent sodium methoxide, and a solvent to obtain the 2,5-dihydropyrrolidine derivatives; The solvent is 1,2-dichloroethane or tetrahydrofuran; The 2,5-dihydropyrrolidine derivatives have the following general structural formula: Wherein, R is an alkyl group with 1 to 10 carbon atoms, a phenyl group or a pyridyl group.

2. The preparation method according to claim 1, characterized in that, The wavelength of the blue light is 450 to 480 nm.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the feed of 1-R-1,3-butadiene to tert-butyl N-(trifluoromethylsulfonyloxy)carbamate is 1:1 to 1.

5.

4. The preparation method according to claim 1, characterized in that, The reaction temperature of the cyclization reaction is 20 to 40 °C, and the reaction time is 12 to 24 h.

5. A method for synthesizing racemic nicotine, characterized in that, It includes the following steps: (1) Under an inert atmosphere, 3-pyridinecarboxaldehyde or 3-(3-pyridyl)acrolein reacts with the corresponding phosphonium ylide reagent in the presence of a base reagent n-butyllithium and a solvent tetrahydrofuran to obtain 1-(3-pyridyl)-1,3-butadiene; wherein the phosphonium ylide reagent corresponding to 3-pyridinecarboxaldehyde is allyltriphenylphosphonium bromide, and the phosphonium ylide reagent corresponding to 3-(3-pyridyl)acrolein is methylphenylphosphonium bromide; (2) The 1-(3-pyridyl)-1,3-butadiene prepared in step (1) and tert-butyl N-(trifluoromethylsulfonyloxy)carbamate are prepared into N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine by the preparation method described in any one of claims 1 to 4; (3) The N-tert-butoxycarbonyl-2-(3-pyridyl)-2,5-dihydropyrrolidine prepared in step (2) is subjected to a deprotection reaction in the presence of an acidic reagent and a solvent to obtain 2-(3-pyridyl)-2,5-dihydropyrrolidine; (4) The 2-(3-pyridyl)-2,5-dihydropyrrolidine prepared in step (3) is subjected to a hydrogenation reduction reaction in the presence of palladium on carbon, hydrogen, and a solvent to obtain 2-(3-pyridyl)-pyrrolidine; (5) The 2-(3-pyridyl)-pyrrolidine prepared in step (4) and paraformaldehyde are subjected to a methylation reaction in the presence of a reducing agent, an organic acid, and a solvent to obtain the racemic nicotine.

6. The synthesis method according to claim 5, characterized in that, In step (1), the reaction temperature is 0 to 25 °C, and the time is 4 to 8 h.

7. The synthesis method according to claim 5, characterized in that, In step (3), the acidic reagent includes one or two of trifluoroacetic acid and hydrochloric acid; the temperature of the deprotection reaction is 20 to 25 °C, and the time is 4 to 8 h.

8. The synthesis method according to claim 5, characterized in that, In step (4), the temperature of the hydrogenation reduction reaction is 20 to 25 °C, and the time is 2 to 8 h.

9. The synthesis method according to claim 5, characterized in that, In step (5), the reducing agent includes one or two of sodium borohydride and sodium cyanoborohydride; the organic acid is acetic acid; the temperature of the methylation reaction is 20 to 25 °C, and the time is 1 to 4 h.

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