A method for preparing racemic nicotine based on electrochemical reduction method

Abstract

The invention discloses a method for preparing racemic nicotine based on an electrochemical reduction method, wherein a homogeneous solution formed by dissolving 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride and / or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine in a solvent is used as a cathode electrolyte; an acid solution is used as an anode electrolyte; and a current density during the electrolysis process is 100 to 500 mA / dm 2 , the electrolysis temperature is 25-80°C, and the electrolysis pressure is 0Mpa-0.5Mpa. The racemic nicotine synthesized by this synthesis method has a high yield, which can reach about 95%. The reaction conditions are mild and easy to operate. The raw materials are easy to obtain and the required types are small (no catalyst and external reducing agent are required). The price is cheap and the conversion rate is high, thus reducing the cost of synthesizing racemic nicotine. It is environmentally friendly and has little pollution, and is worthy of promotion and use.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparation of racemic nicotine, and more specifically, relates to a method for preparing racemic nicotine based on an electrochemical reduction method. Background Art

[0002] Nicotine, also known as nicotine, is an alkaloid found in Solanaceae plants and an important component of tobacco. Nicotine is a typical agonist of nicotinic acetylcholine receptors. Nicotinic acetylcholine receptors (nAChRs) have an important regulatory effect on the central nervous system (CNS), and nicotine is expected to become an effective drug for the treatment of Parkinson's disease, Alzheimer's disease, Tourette syndrome, schizophrenia, attention deficit disorder, smoking cessation, epilepsy and depression.

[0003] Nicotine is a colorless, transparent, oily liquid with high volatility. It is easily oxidized to dark gray in the air. It has a strong pungent taste and is soluble in water, ethanol, chloroform, ether, and oils. It is deliquescent and can be easily absorbed by the body through the mouth, nose, and bronchial mucosa. It can also penetrate the skin. Its molecular formula is: C 10 H 14 N 2 , structural formula:

[0004]

[0005] As an alkaloid, nicotine can combine with complex amino acids and has the effect of resisting plant pathogens. Nicotine has the characteristics of fumigation, contact killing, stomach poisoning and rapid degradation without residue, and is widely used as an insecticide for crops. At the same time, nicotine has high medicinal value. Some medically acceptable salts of nicotine have the effect of treating certain diseases: for example, local application of nicotine bitartrate can treat muscle spasms and joint pain that aspirin cannot treat. Oral administration of nicotine bitartrate can significantly reduce the systolic and diastolic blood pressure of patients with hypertension, and blood pressure can return to the level before taking the medicine after stopping the medicine for two weeks.

[0006] With the development of society, people attach importance to the medicinal value of nicotine and its similar compounds, and the synthesis of nicotine and its similar compounds has attracted more and more attention of researchers. Chavdarian (J.Org.Chem.1982) used the chiral carbon molecule in the tetrahydropyridine ring as the chiral source and completed the synthesis of optically active nicotine by constructing the pyridine ring.

[0007] Although this route provides a new method for synthesizing chiral compounds, using known chiral compounds as chiral sources to construct the chiral center of the target molecule, the target product obtained by this route has only 24% ee, and a large amount of organic solvent is used in the hydrogenation step, which pollutes the environment. The use of hydrogen also increases the risk of the experiment. Lebreton (J.Org.Chem.2000) synthesized nicotine using a shorter synthetic route.

[0008]

[0009] Although the total yield of this method reaches 60%, the target product obtained is (R)-nicotine. Helmchen (Org. Biomol. Chem. 2005) synthesized nicotine through iridium-catalyzed asymmetric propylene amination and metathesis ring-closure reaction.

[0010]

[0011] This method can avoid racemization during catalytic hydrogenation, but the reaction uses lithium aluminum hydride for reduction, which is also dangerous. At the same time, organic solvents such as tetrahydrofuran used in the reduction step are harmful to the environment and personnel to varying degrees. Patent CN110357853 uses palladium carbon for catalytic hydrogenation reduction. Under a pressure of 1.0 MPa, the target product nicotine is obtained by reacting at room temperature overnight. The purity of the product obtained by this method reaches 99.6% and the yield is 90%, but the method of catalytic hydrogenation reduction also has certain dangers.

[0012] In summary, the current synthesis method of racemic nicotine basically adopts the catalytic hydrogenation process, and this step of the reaction currently has certain risks. Although hydrogenation reduction is a cleaner reduction method with less pollution to the environment, the hydrogenation reduction conditions are harsh and require high pressure conditions, and the storage and use of hydrogen are very dangerous. At present, there is an urgent need for a new production process for racemic nicotine that is safe, environmentally friendly, has mild reaction conditions, and has low production costs. Summary of the invention

[0013] In view of the fact that the synthesis method of racemic nicotine in the prior art basically adopts a catalytic hydrogenation process, which is dangerous. The hydrogenation reduction conditions are harsh, and high pressure conditions are required. The storage and use of hydrogen are very dangerous. The present invention provides a method for preparing racemic nicotine based on an electrochemical reduction method. The purpose is to break the fixed mode of the existing chemical reduction (adding a reducing agent or catalytic hydrogenation) preparation method and provide a method for synthesizing racemic nicotine with high safety, mild reaction conditions, no pollution and simple operation.

[0014] The technical scheme adopted by the present invention is as follows: a method for preparing racemic nicotine based on an electrochemical reduction method, wherein a homogeneous solution formed by dissolving 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride and / or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine in a solvent is used as a cathode electrolyte; an acid solution is used as an anode electrolyte; and a current density during the electrolysis process is 100 to 500 mA / dm 2 , the electrolysis temperature is 25~80℃, and the electrolysis pressure is 0Mpa~0.5Mp.

[0015] In the present invention, although the electrochemical reduction method has been widely used in the chemical synthesis process, the use of active hydrogen generated by electrolysis to reduce 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine to obtain racemic nicotine is a new method for synthesizing racemic nicotine developed by the applicant of the present invention. This electrochemical reduction method does not require the addition of additional reducing agents or the purchase of additional hydrogenation reaction equipment. The electrolysis reaction conditions are mild, the operation is simple, the environmental pollution is small, and the raw materials used are easily available and low in price. The amount of raw materials used is small, and the manufacturing cost can be reduced to a certain extent, and it is worthy of promotion and use.

[0016] In the present invention, the active hydrogen generated by electrolysis is dissolved in the electrolyte and is isolated from the reaction solution. Therefore, 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine can be reduced to racemic nicotine, effectively avoiding the addition of additional catalysts. At the same time, the electrode sheet used in the cathode not only has a conductive effect in this electrolysis reaction, but also has a certain catalytic effect, and the cathode electrode sheet is almost not consumed during the electrolysis process and can be recycled, further reducing environmental pollution. Provide high-purity racemic nicotine for the pharmaceutical industry, etc., and do not cause danger and environmental pollution during the production process.

[0017] The synthetic route of the present invention is as follows:

[0018]

[0019] It can be seen that the method disclosed in the present invention uses nicotinic acid as a raw material, and obtains racemic nicotine after esterification, addition, acid hydrolysis (alkaline hydrolysis), and reduction of each unit.

[0020] The mass ratio of pyridine hydrochloride or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine to the solvent is 1:10 to 1:50; suitably, 1:15 to 30, more suitably, 1:20.

[0021] In the present invention, the solvent is generally a clean solvent, such as water or a salt solution formed by dissolving clean salt in water. The clean salt here refers to a salt that is dissolved in water and only ionizes the corresponding ions to improve the conductivity of the electrolyte, and will not affect the environment. For example: (NH 4 ) 2 SO 4 、NaHSO 4 MgCl 2 、Na 2 SO 4 , K 2 SO 4 In the present invention, the solute (clean salt) in the salt solution includes but is not limited to (NH 4 ) 2 SO 4 、NaHSO 4 MgCl 2 、Na 2 SO 4 , K 2 SO 4 NH 4 ) 2 CO 3 NH 4 Cl, NaCl, HCl, and H 2 SO 4 At least one of .

[0022] In the present invention, in order to make the cathode electrolyte have good conductivity, generally, the concentration of the salt solution is 1-10%, preferably 5-10%, more preferably 8-10%.

[0023] In the present invention, generally, the concentration of the acid solution is 0.1 to 2 mol / L, more preferably, 1 to 2 mol / L. In the present invention, the acid solution can be a strong acid solution (such as hydrochloric acid) or a weak acid solution (acetic acid); generally, the acid solution can be selected from but not limited to H 2 SO 4 , HCl, CH 3 COOH or H 3 PO 4 .

[0024] In the present invention, the temperature during the electrochemical reduction reaction is generally 25 to 80°C, suitably 40 to 80°C, more suitably 60 to 80°C.

[0025] In the present invention, the current density during the electrochemical reduction reaction is generally 100 to 500 mA / dm 2 , suitably 100~300mA / dm 2, more preferably, 150~200mA / dm 2 .

[0026] As a possible design, the present invention can also design a reference electrode, which can be but is not limited to a saturated calomel electrode.

[0027] In the present invention, the cathode electrode not only plays the role of conducting electrolysis, but also serves as a catalyst for the reaction, but is not consumed in the reaction. Therefore, the cathode electrode can be but is not limited to foamed nickel.

[0028] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0029] 1. The method for preparing racemic nicotine based on electrochemical reduction is simple, the reaction conditions are mild and easy to operate, the raw materials are easily available and the required types are few (no catalyst and external reducing agent are required), the price is cheap and the conversion rate is high, thus reducing the cost of synthesizing racemic nicotine.

[0030] 2. Environmentally friendly and less polluting.

[0031] 3. The yield of racemic nicotine is high, reaching more than 92%, and is worthy of promotion and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The present invention will now be described by way of example with reference to the accompanying drawings, in which:

[0033] Figure 1 It is a device for synthesizing racemic nicotine by electrochemical reduction;

[0034] Figure 2 is the hydrogen spectrum of the product obtained after synthesis and purification in Example 1;

[0035] Figure 3 is the carbon spectrum of the product obtained after synthesis and purification in Example 1;

[0036] Figure 4 It is the LC-MS chart of the product obtained after synthesis and purification in Example 1.

[0037] Among them, 1-power supply; 2-electrolytic cell; 3-cathode; 4-anode; 5-reference electrode; 6-proton exchange membrane. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application are clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present application.

[0039] The present invention is described in detail below.

[0040] The invention discloses a method for preparing racemic nicotine based on an electrochemical reduction method, wherein a homogeneous solution formed by dissolving 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride and / or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine in a solvent is used as a cathode electrolyte; an acid solution is used as an anode electrolyte; and a current density during the electrolysis process is 100 to 500 mA / dm 2 , the electrolysis temperature is 25-80°C, and the electrolysis pressure is 0Mpa-0.5Mpa.

[0041] The present invention also discloses a device for implementing the above method, such as Figure 1 As shown. A device for synthesizing racemic nicotine by electrochemical reduction method comprises a power supply 1 and a reaction system electrically connected to each other, wherein the reaction system comprises an electrolytic cell 2, wherein a proton exchange membrane 6 is arranged in the electrolytic cell 2, and the proton exchange membrane 6 is used to divide the electrolytic cell 2 into an anode cell and a cathode cell which are not connected to each other; an anode 4 is arranged in the anode cell, and a cathode 3 and a reference electrode 5 are arranged in the cathode cell, wherein the anode 4, the cathode 3 and the reference electrode 5 are all electrically connected to the power supply 1. In the present invention, the anode 4 can be made of a material that does not react with the electrolyte, hydrogen and oxygen, such as graphite. In the present invention, the cathode 3 can be made of a material that does not react with the electrolyte, hydrogen, oxygen and the reaction products, such as nickel foam, iron, copper, etc. In the present invention, the reference electrode 5 can be, but is not limited to, a saturated calomel electrode.

[0042] When using the above device, pour the anolyte that meets the temperature and pressure conditions into the anode cell and pour the catholyte that meets the temperature and pressure conditions into the cathode cell, and then turn on the power.

[0043] It should be noted that in the present invention, the 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride can be purchased on the market or synthesized by the following method.

[0044] 100g of 1-methyl-3-nicotinoyl-2-pyrrolidone was added with 500ml of concentrated hydrochloric acid, and the temperature was raised to reflux; after 56h, the raw material disappeared completely during liquid phase detection; an aqueous solution of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride was obtained, and the reaction solution was concentrated under reduced pressure at 60°C and evaporated to dryness to obtain 97.08g of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride; the total yield was 85.01%.

[0045] In the present invention, the 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine can be purchased on the market or synthesized by the following method.

[0046] 69.97 g of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride was dissolved in 100 ml of water, and the pH value was adjusted to 11 by adding 30% aqueous sodium hydroxide solution. 100 ml of ethyl acetate was added for extraction three times, and the organic layers were combined; anhydrous sodium sulfate was added for drying; 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine was obtained by filtration and evaporation, with a yield of 96.23%.

[0047] Example

[0048] The following embodiments are based on Figure 1 The device shown for synthesizing racemic nicotine by electrochemical reduction is completed.

[0049] The 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride used in the following examples were synthesized by the above method.

[0050] Example 1

[0051] Preparation of racemic nicotine:

[0052] 10g of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride was added to 75ml of 1.0% NaCl solution, stirred to form a homogeneous solution, added to 100mL of cathode tank, added 75ml of 0.1mol / L acid solution to the anode tank, started stirring, and then turned on the power supply for powering on. Under the conditions of current density of 100mA / dm2, temperature of 25°C and normal pressure, the reaction was kept warm and powered on for 10h. Stop the power supply, cool down, extract with toluene at room temperature for 15min, separate the liquids, and desolventize the toluene phase by rotary evaporation to obtain 6.45g of 3-(1-methylpyrrolidin-2-yl)pyridine, with a content of 98.7% and a yield of 92.66%.

[0053] The obtained product NMR: 1H NMR (400MHz, Methanol-d4) δ8.52–8.39 (m, 2H), 7.85 (dt, J=8.0, 2.0 Hz, 1H), 7.42 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 3.27–3.15 (m, 2H), 2.42–2.21 (m, 2H), 2.17 (s, 3H), 2.04–1.83 (m, 2H), 1.77 (dddd, J=12.7, 11.0, 9.2, 5.7 Hz, 1H).

[0054] 13C NMR (101MHz, Methanol-d4) δ149.53 (dd, J = 66.4, 4.7Hz), 140.12, 137.46, 125. 47(d,J=2.1Hz),70.16,57.98,40.62(d,J=5.8Hz),35.76(d,J=2.9Hz),23.31.

[0055] LC-MS: m / z+1=163.4

[0056] Example 2

[0057] Preparation of racemic nicotine:

[0058] 10g of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine was added to 85ml of 1.0% HCl and 1.0% NaCl solution, and stirred until 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine, HCl and NaCl solution were completely dissolved, and then added to 100mL of cathode pool, 85ml of 0.1mol / L acid solution was added to the anode pool, stirring was started, and then the power supply was turned on, and the current density was 200mA / dm2, the temperature was 40℃, and the reaction was kept warm for 10h. Stop the power supply, cool down, extract with toluene at room temperature for 15min, separate the liquid, and desolventize the toluene phase by rotary evaporation to obtain 9.75g of 3-(1-methylpyrrolidin-2-yl)pyridine, with a content of 99.0% and a yield of 95.47%.

[0059] Example 3

[0060] Preparation of racemic nicotine:

[0061] 10g of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride was added to 75ml of 1.0% NaCl solution, stirred until the mixture was uniform and homogeneous, then added to 100mL of cathode tank, 75ml of 0.1mol / L acid solution was added to the anode tank, stirred, and then the power supply was turned on, and the current density was 400mA / dm2, the temperature was 60℃, and the reaction was carried out for 8h. The power supply was stopped, the temperature was lowered, and the mixture was extracted with toluene at room temperature for 15min, separated, and the toluene phase was desolvated by rotary evaporation to obtain 6.54g of 3-(1-methylpyrrolidin-2-yl)pyridine, with a content of 98.8% and a yield of 94.05%.

[0062] Example 4

[0063] Preparation of racemic nicotine:

[0064] 10g of 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine was added to 85ml of 1.0% HCl and 1.0% NaCl solution, and stirred until 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine, HCl and NaCl solution were completely dissolved, and then added to 100mL of cathode pool, 85ml of 0.1mol / L acid solution was added to the anode pool, stirring was started, and then the power supply was turned on, and the current density was 500mA / dm2, the temperature was 80℃, and the reaction was kept warm for 10h. Stop the power supply, cool down, extract with toluene at room temperature for 15min, separate the liquids, and desolventize the toluene phase by rotary evaporation to obtain 9.78g of 3-(1-methylpyrrolidin-2-yl)pyridine, with a content of 99.1% and a yield of 95.86%.

[0065] The product obtained after synthesis and purification in the embodiment is now identified by NMR and LC-MS. The identification results are as follows: Figure 2-4 As shown, Figure 2 is the hydrogen spectrum of the product, Figure 3 is the carbon spectrum of the product, Figure 4 The LC-MS diagram of the product is shown in Figure 2. Figure 2-4 It can be seen that Example 1 successfully synthesized racemic nicotine by electrochemical reduction. It is deduced that the method for preparing racemic nicotine based on electrochemical reduction method disclosed in the present invention can successfully synthesize racemic nicotine with a high yield of about 95%, mild and easy reaction conditions, easy to obtain raw materials and few types required (no catalyst and external reducing agent are required), cheap and high conversion rate, thus reducing the cost of synthesizing racemic nicotine. It is environmentally friendly, less polluting, and worthy of promotion and use.

[0066] The above-mentioned embodiments only express the specific implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the protection scope of the present application. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the technical solution concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A method for preparing racemic nicotine based on an electrochemical reduction method, characterized in that: A homogeneous solution formed by dissolving 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride and / or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine in a solvent is used as a cathode electrolyte; an acid solution is used as an anode electrolyte; and a current density during the electrolysis process is 100-500 mA / dm 2 , the electrolysis temperature is 25~80℃, and the electrolysis pressure is 0Mpa~0.5Mpa; The cathode uses nickel foam as the electrode sheet.

2. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1, characterized in that: The mass ratio of the 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine hydrochloride or 3-(1-methyl-4,5-dihydro-1H-pyrrol-3-yl)pyridine to the solvent is 1:10 to 1:

50.

3. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1 or 2, characterized in that: The solvent is a water / saline solution.

4. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 3, characterized in that: The concentration of the salt solution is 1-10 wt %.

5. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 3, characterized in that: The solute in the salt solution is at least one of (NH4)2SO4, NaHSO4, MgCl2, Na2SO4, K2SO4, (NH4)2CO3, NH4Cl, NaCl, HCl and H2SO4.

6. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1, characterized in that: The concentration of the acid solution is 0.1-2 mol / L.

7. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1 or 6, characterized in that: The solute in the acid solution is H2SO4, HCl, CH3COOH or H3PO4.

8. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1, characterized in that: The electrolysis temperature is 40-80°C.

9. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1, characterized in that: The current density is 150-200 mA / dm 2 .

10. The method for preparing racemic nicotine based on electrochemical reduction method according to claim 1, characterized in that: A saturated calomel electrode was used as the reference electrode.

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