CN114195759B - Preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine - Google Patents
Preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/10—Chemical features of tobacco products or tobacco substitutes
- A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
- A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
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Abstract
The invention relates to a preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine, which is prepared by taking 6-methylnicotinate as a raw material, and the preparation route is as follows: wherein R is 1 Alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl; r is R 2 Hydrogen, methyl or ethyl; m is Na, K or Li. The preparation method has the advantages that raw materials are easy to obtain, the purity and the yield can meet the requirements of industrial production, and compared with nicotine racemate, the obtained product 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine has better sensory test data, and when the electronic cigarette atomized liquid is prepared, the effect of natural nicotine of 3mg/mL can be achieved by using 1.5mg/mL, and the sensory experience is good.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine.
The background technology is as follows:
in recent years, with the progress of the technology level, domestic tobacco companies continue to advance the development of new tobacco products, wherein electronic cigarettes are used as a form of new tobacco and important forms thereof, and are explosive growth, and nicotine (commonly called nicotine) is used as an effective component of the core of the whole electronic cigarette industry, so that the demand is increased.
The nicotine sold in the market at present is mainly extracted from tobacco, but the yield is seriously influenced by external factors such as climate, tobacco raw material yield, growth cycle and the like, and components such as the maisi, the neonicotinoid, the dehydroneonicotinoid and the nitrosamine in the tobacco are inevitably extracted from the nicotine extracted from the tobacco at the same time, so that the removal difficulty is extremely high, and the potential danger to human health is provided.
In the preparation method of the artificial synthetic nicotine, the racemic nicotine contains nicotine with two configurations of R and S, chiral resolution is needed to achieve the use effect of extracting the nicotine from natural tobacco, and the psychoactive isomer S-nicotine is reserved, so that the yield is low and the cost is extremely high.
For this reason, researchers have introduced alkaloids from other plant sources such as arecoline for application attempts, but the ideal sensory experience is not always achieved.
Disclosure of Invention
Based on this, it is necessary to provide a process for the preparation of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine which can be industrially produced.
The preparation method of the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is prepared by taking 6-methylnicotinate as a raw material, and the preparation route is as follows:
wherein R is 1 Alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl; r is R 2 Hydrogen, methyl or ethyl; m is Na, K or Li.
The organic base is at least one of sodium tert-butoxide, potassium tert-butoxide and lithium tert-butoxide, and the strong acid is at least one of concentrated hydrochloric acid, concentrated sulfuric acid, sulfoxide chloride and perchloric acid; the strong alkali is at least one selected from potassium hydroxide and sodium hydroxide; the reducing agent is at least one selected from sodium hydrosulfite, sodium borohydride, lithium aluminum hydride, lithium triethylborohydride and sodium triacetylborohydride.
Preferably, the reducing agent is used in an amount of 1.2 to 1.5 times the amount of 6-methylnicotinate material.
Preferably, the reducing agent is a mixed reducing agent of sodium dithionite and lithium triethylborohydride according to a molar ratio of 3-5:1. The sodium dithionite has optimal reduction effect under alkaline condition, simple subsequent impurity removal process, no toxic and harmful byproducts, high reduction effect of the triethyllithium borohydride and good selectivity. After the two components are compounded in a synergistic way, the product yield can be increased.
In a preferred embodiment of the present invention, the process for preparing 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine comprises the following steps:
(1) Uniformly mixing 6-methylnicotinate, alkenyl pyrrolidone, organic base and organic solvent, reacting at 90-120 ℃ for 5-8 hours, and carrying out solid-liquid separation to keep solid, wherein the solid is 1-methyl-3- (6-methyl-nicotinyl) -2-alkenyl pyrrolidone salt;
(2) Uniformly mixing the 1-methyl-3- (6-methyl-nicotinoyl) -2-alkenyl pyrrolidone salt obtained in the step (1) under the condition of strong acid solution, and reacting for 30-48h at 70-100 ℃;
(3) Cooling the system in the step (2) to the temperature of between 20 ℃ below zero and 0 ℃, adding strong base to adjust the pH value to 9 to 12, adding a reducing agent, uniformly mixing, heating to 60 to 80 ℃, reacting for 4 to 6 hours, carrying out solid-liquid separation, retaining liquid, extracting, and recovering the solvent under reduced pressure to obtain 2-methyl-5- (pyrrolidin-2-yl) pyridine;
(4) Uniformly mixing the 2-methyl-5- (pyrrolidin-2-yl) pyridine obtained in the step (3) with a methylating agent in an alcohol reagent, reacting for 5-10h at 50-70 ℃, distilling under reduced pressure, adjusting the pH value to 9-12, extracting, and distilling to obtain the product 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine.
The preparation process of the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine in the technical scheme is simple, byproducts are easy to remove, chiral resolution is not needed, and the cost is low. Sensory tests prove that the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine prepared by the preparation method is used for electronic cigarette products, and has good throat feeling and satisfaction and good sensory experience.
Further, in the step (1), the 6-methylnicotinic acid ester is at least one of 6-methylnicotinic acid methyl ester, 6-methylnicotinic acid ethyl ester, 6-methylnicotinic acid tert-butyl ester, 6-methylnicotinic acid n-propanol ester and 6-methylnicotinic acid isopropyl ester; the alkenyl pyrrolidone is at least one of vinyl pyrrolidone, propenyl pyrrolidone and n-butenyl pyrrolidone; the organic solvent is at least one of aprotic solvents such as toluene, xylene and tetrahydrofuran, and the selected solvent has a high boiling point and does not dissolve the generated product, so that the subsequent filtering and separating operation is facilitated.
Further, in the step (1), the molar ratio of the 6-methylnicotinate, the alkenyl pyrrolidone and the organic base is 1:1-1.1:1-1.3.
Further, in the step (2), the strongly acidic solution is at least one selected from the group consisting of concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride and perchloric acid, and the amount of the acid to be added is not particularly limited, and the reaction system may be maintained strongly acidic, and in one embodiment of the present invention, the amount of the strongly acidic solution is 50 to 100wt% of the 1-methyl-3- (6-methyl-nicotinyl) -2-vinylpyrrolidone salt. The acidic solution can be used as a reaction raw material and a solvent of 1-methyl-3- (6-methyl-nicotinoyl) -2-alkenyl pyrrolidone salt, and carbon dioxide gas and acidic gas generated in the reaction process can be absorbed, so that the influence on the environment is avoided.
Further, in the step (3), the reducing agent is at least one selected from sodium hydrosulfite, sodium borohydride, lithium aluminum hydride, lithium triethylborohydride and sodium triacetylborohydride; the extractant is selected from at least one of dichloromethane, ethyl acetate, n-hexane, petroleum ether, methyl tert-butyl ether and methanol during extraction.
Further, in the step (4), 2-methyl-5- (pyrrolidin-2-yl) pyridine is reacted in an alcohol solvent through a methylating agent, and after the reaction is finished, the product is obtained after extraction by an organic solvent. The methylating agent is at least one of paraformaldehyde and formaldehyde aqueous solution, the alcohol solvent is at least one of methanol, ethanol and n-butanol, and the extractant is at least one of dichloromethane, ethyl acetate, methanol, petroleum ether and n-hexane.
A second object of the present invention is to provide the use of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine for electronic smoking articles. Experiments prove that when the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine prepared by the method is used for electronic cigarette products, the satisfaction and throat feeling are strong, the good sensory experience is realized, and the application is utilized.
Preferably, when 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is formulated as an e-aerosolized liquid, its concentration is 1.5-4mg/mL, preferably 1.5-3mg/mL.
Other advantages of the present invention will be set forth in the description of specific technical features and solutions, by which those skilled in the art should understand the advantages that the technical features and solutions bring.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the product 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine.
FIG. 2 is chiral analysis data for the product 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine.
Detailed Description
In order that the above objects, features and advantages of the invention will be readily understood, a more particular description of the invention will be rendered by reference to the appended drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The present invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit of the invention, whereby the invention is not limited to the specific embodiments disclosed below.
Example 1
(1) 400g of methyl 6-methylnicotinate, 300g of vinyl pyrrolidone and 255g of sodium tert-butoxide are taken, 2L of toluene is added under the protection of nitrogen, after being uniformly mixed, the mixture is heated to 110 ℃ for reflux, the product is separated out in a solid form, the completion degree of the reaction is monitored by LC-MS, after 8 hours of reaction, toluene solvent is filtered, and then the mixture is washed three times with 300g of petroleum ether and dried for 2 hours at 30 ℃ to obtain 583g of 1-methyl-3- (6-methyl-nicotinyl) -2-vinyl pyrrolidone salt.
(2) 583g of 1-methyl-3- (6-methyl-nicotinoyl) -2-vinyl pyrrolidone salt was obtained in the step (1), 1.25kg of 36% concentrated hydrochloric acid was added, the mixture was heated to 88℃and the reaction completion was monitored by LC-MS to conduct a reaction for 44 hours.
(3) Cooling to-20 ℃, adding 40% potassium hydroxide aqueous solution to adjust the pH to 11, adding 570g sodium dithionite solid, stirring at 75 ℃ for reaction, monitoring the reaction completion degree through LC-MS, cooling to 25 ℃ after 6 hours, filtering solid impurities, reserving filtrate, extracting with 3L ethyl acetate, 2L ethyl acetate and 1L ethyl acetate respectively, merging organic phases, washing twice with saturated 3L sodium chloride aqueous solution, drying the organic phases through anhydrous sodium sulfate, and distilling at 40 ℃ under reduced pressure to recover ethyl acetate to obtain 295g of 2-methyl-5- (pyrrolidin-2-yl) pyridine.
(4) 295g of 2-methyl-5- (pyrrolidin-2-yl) pyridine obtained in the step (3) is dissolved by 600ml of methanol, 127g of paraformaldehyde is added, the temperature is raised to 50 ℃, the completion of the reaction is monitored by LC-MS, after 7 hours, methanol and paraformaldehyde are removed by reduced pressure distillation at 50 ℃, 500ml of 40% sodium hydroxide aqueous solution is added to adjust the pH to 11, extraction is performed three times by 1.5L of ethyl acetate, recovery of ethyl acetate is performed by reduced pressure distillation at 40 ℃, 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is obtained, 500ml of 18% aqueous solution is added, extraction is performed 2 times by 600ml of petroleum ether, water phase is reserved, cooling is performed to-15 ℃, sodium hydroxide solid is added to adjust the pH to 12, extraction is performed three times by 1L of ethyl acetate, saturated 1L of aqueous solution of sodium chloride is used for two times, after the organic phase is dried by anhydrous sodium sulfate, ethyl acetate is recovered by reduced pressure distillation at 40 ℃, and then 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is obtained by reduced pressure distillation at 0.95140 ℃, and the purity of methyl nicotinate is taken as a standard product with purity of 6.56% and total purity of methyl nicotinate is obtained by taking 6.95% as a standard.
FIG. 1 is a schematic illustration of the resulting product 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine 1 HNMR profile.
FIG. 2 is chiral analysis data for the resulting product, 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine, with the results shown in Table 1 and FIG. 2 below:
TABLE 1
| Retention time | Peak height | Peak area% | |
| Peak 1 | 5.523 | 1884283 | 49.956 |
| Peak 2 | 5.912 | 1566750 | 50.044 |
From the results of chiral detection, it can be seen that the ratio of the two configurations of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine R and S is close to 1:1, and the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is a racemate.
Example 2
Other conditions and operations were the same as in example 1 except that 343g of lithium triethylborohydride was used as the reducing agent in step 3, and 263g of 2-methyl-5- (pyrrolidin-2-yl) pyridine was obtained in step 3. Finally, 235g of pure 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is obtained, the GC purity is 99.2%, and the total yield is 50.00% based on 6-methylnicotinic acid methyl ester.
Example 3
Other conditions and operations were the same as in example 1 except that 443g of sodium dithionite and 77g of lithium triethylborohydride were used as the reducing agent in step 3, and 307g of 2-methyl-5- (pyrrolidin-2-yl) pyridine was obtained in step 3. Finally, 276g of pure 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is obtained, the GC purity is 99.3%, and the total yield is 58.78% based on 6-methylnicotinic acid methyl ester.
Example 4
Other conditions and operations were the same as in example 1 except that 374g of sodium dithionite and 115g of lithium triethylborohydride were used as the reducing agent in step 3, and 311g of 2-methyl-5- (pyrrolidin-2-yl) pyridine was obtained in step 3. Finally, 279g of pure 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is obtained, the GC purity is 98.8%, and the total yield is 59.12% based on 6-methylnicotinic acid methyl ester.
Effect example:
sensory evaluation methods in reference to standards GB5606.4-2005, GB/T22366-2008, GB/T12312-2012 and YCT/138-1998, in combination with the current application state of novel tobacco products, sensory evaluation of the application of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine in novel tobacco products is carried out.
Natural nicotine and synthetic (R, S) nicotine are purchased from products sold in the market, propylene glycol is used for preparing 3mg/mL of electronic cigarette atomized liquid, propylene glycol is used for preparing 1.5mg/mL of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine obtained in the example, 3mg/mL,4mg/mL and 5mg/mL are respectively marked as effect examples 1, 2 and 3,4, and three indexes including aroma, throat feeling and head feeling are subjected to sensory evaluation by using an electronic cigarette appliance: and respectively taking 1.5mL of electronic cigarette atomized liquid, adding the electronic cigarette atomized liquid into electronic cigarette equipment, and sequentially evaluating the electronic cigarette by 10 professional evaluation staff to evaluate the fragrance, throat feeling and head feeling respectively. Each index 10 was divided into full scores, with higher scores indicating a better sensory experience. Wherein, the sensory evaluation conditions are as follows: room temperature 25 ℃ and air humidity 50%; and 3 times of repeatedly rinsing with saline water and distilled water each time when the test sample is replaced, so that objectivity and accuracy of sensory testing are ensured. The results are shown in Table 2 below:
TABLE 2
| Fragrance of fragrance | Throat feeling | Feeling of getting on the head | Total score | |
| Natural nicotine | 7.5 | 7.4 | 6.3 | 22.0 |
| Synthesis of (R, S) nicotine | 7.2 | 4.7 | 3.8 | 15.7 |
| Effect example 1 | 7.7 | 7.8 | 8.4 | 23.3 |
| Effect example 2 | 8.4 | 8.2 | 8.6 | 25.2 |
| Effect example 3 | 9.1 | 9.0 | 8.9 | 26.5 |
| Effect example 4 | 9.4 | 9.2 | 9.1 | 27.0 |
The sensory evaluation data show that when the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine prepared by the method is applied to electronic cigarette products, the dosage of 1.5mg/mL can reach the effect of 3mg/mL of natural nicotine, and the application potential is proved to be good. When the content of the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine in the electronic cigarette atomized liquid is increased, the sensory index of the electronic cigarette atomized liquid is stronger, and the electronic cigarette atomized liquid is more suitable for audience groups sucking traditional cigarettes and has better sensory experience. However, when the concentration of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine exceeds the concentration of 6mg/mL, although the evaluation of aroma, throat-hitting feeling and head feeling is highest, obvious discomfort is caused, and choking throat phenomenon can be caused at a high concentration, so that the concentration of the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared by the invention is preferably 1.5-3mg/mL when the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is used for an electronic cigarette atomized liquid.
It will be understood that the above-described embodiments are merely illustrative and not restrictive, and that all obvious or equivalent modifications and substitutions to the details given above may be made by those skilled in the art without departing from the underlying principles of the invention, are intended to be included within the scope of the appended claims.
Claims (8)
1. Use of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine in the preparation of an electronic cigarette nebulization liquid, characterized in that the concentration of the compound 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is 1.5-4mg/mL.
2. Use according to claim 1, characterized in that the concentration of the compound 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is 1.5-3mg/mL.
3. The use according to claim 1, wherein the compound 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is prepared from 6-methylnicotinate as a starting material, which is prepared according to the following route:
wherein R is 1 Methyl, ethyl, propyl or butyl; r is R 2 Hydrogen, methyl or ethyl; m is Na, K or Li.
4. Use according to claim 3, characterized in that the process for the preparation of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine comprises the following steps:
(1) Uniformly mixing 6-methylnicotinate, alkenyl pyrrolidone, organic base and organic solvent, reacting at 90-120 ℃ for 5-8 hours, and carrying out solid-liquid separation to keep solid, wherein the solid is 1-methyl-3- (6-methyl-nicotinyl) -2-alkenyl pyrrolidone salt;
(2) Uniformly mixing the 1-methyl-3- (6-methyl-nicotinoyl) -2-alkenyl pyrrolidone salt obtained in the step (1) under the condition of strong acid solution, and reacting for 30-48h at 70-100 ℃;
(3) Cooling the system in the step (2) to the temperature of between 20 ℃ below zero and 0 ℃, adding strong base to adjust the pH value to 9 to 12, adding a reducing agent, uniformly mixing, heating to 60 to 80 ℃, reacting for 4 to 6 hours, carrying out solid-liquid separation, retaining liquid, extracting, and recovering the solvent under reduced pressure to obtain 2-methyl-5- (pyrrolidin-2-yl) pyridine;
(4) Uniformly mixing the 2-methyl-5- (pyrrolidin-2-yl) pyridine obtained in the step (3) with a methylating agent in an alcohol reagent, reacting for 5-10h at 50-70 ℃, distilling under reduced pressure, adjusting the pH value to 9-12, extracting, and distilling to obtain a product 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine;
the organic base is at least one of sodium tert-butoxide, potassium tert-butoxide and lithium tert-butoxide; the strong acid is at least one selected from concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride and perchloric acid; the strong alkali is at least one selected from potassium hydroxide and sodium hydroxide;
the reducing agent is a mixed reducing agent of sodium dithionite and lithium triethylborohydride according to a molar ratio of 3-5:1; the amount of the reducing agent is 1.2-1.5 times the amount of the 6-methylnicotinate material.
5. The use according to claim 4, wherein the 6-methylnicotinate is at least one of methyl 6-methylnicotinate, ethyl 6-methylnicotinate, t-butyl 6-methylnicotinate, n-propanol 6-methylnicotinate and isopropyl 6-methylnicotinate; the alkenyl pyrrolidone is at least one of vinyl pyrrolidone, propenyl pyrrolidone and n-butenyl pyrrolidone.
6. The use according to claim 4, wherein in step (1), the molar ratio of 6-methylnicotinate, alkenylpyrrolidone and organic base is from 1:1 to 1.1:1-1.3; and/or
In the step (2), the strong acid solution is at least one selected from concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride and perchloric acid.
7. The use according to claim 4, wherein in step (3), the extractant is selected from at least one of dichloromethane, ethyl acetate, n-hexane, petroleum ether, methyl tert-butyl ether and methanol; and/or
In the step (4), the methylating agent is at least one of paraformaldehyde and formaldehyde aqueous solution, the alcohol solvent is at least one of methanol, ethanol and n-butanol, and the extracting agent is at least one of dichloromethane, ethyl acetate, methanol, petroleum ether and n-hexane.
8. The electronic cigarette atomized liquid is characterized by comprising a compound of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine and propylene glycol, wherein the concentration of the compound of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is 1.5mg/mL,3mg/mL,4mg/mL or 5mg/mL.
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