CN115611857A - 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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Abstract
The invention discloses a preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine, which takes 6-methylnicotinate and 2-oxypyrrolidine-1-carboxylic acid tert-butyl ester as raw materials to prepare the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine through a series of reactions. The 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared by the preparation method disclosed by the invention is high in purity, the content of the levorotatory isomer is up to more than 70%, and when the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is used for electronic cigarette products, the usage amount is lower, the satisfaction and throat-hitting feeling are strong, and good sensory experience is achieved.
Description
Technical Field
The invention relates to the technical field of novel tobacco preparation, and particularly relates to a preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine.
Background
With the progress of the technology level, the electronic cigarette is taken as a novel tobacco and an important form thereof, and the demand of the flavor substances in the tobacco ingredients as the core functional ingredients of the whole electronic cigarette industry is increasing day by day.
At present, most of commercially available nicotine is mainly extracted from tobacco, but the yield is seriously influenced by external factors such as climate, the yield of tobacco raw materials, growth cycle and the like, and components such as macimine, neonicotinoid, dehydroneonicotinoid, nitrosamine and the like in the tobacco are extracted from the nicotine extracted from the tobacco inevitably, so that the removal difficulty is extremely high, and potential danger is caused to human health.
In the preparation method of the artificial synthetic nicotine, the racemic nicotine contains nicotine with R and S configurations, chiral separation is needed to achieve the use effect of extracting nicotine from natural tobacco, the psychoactive isomer S-nicotine is retained, and the R-nicotine of the non-psychoactive isomer cannot be applied, so that the yield is low and the cost is extremely high.
For example, patent CN114437025A proposes to synthesize 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine from 6-methylnicotinic acid methyl ester, but the final structure is racemate, and the content of active ingredients is low, which is not favorable for application.
Disclosure of Invention
The first purpose of the invention is to provide a preparation method of 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine, wherein the content of the levorotatory isomer in the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine prepared by the preparation method is more than 70%, and the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine has more excellent sensory experience.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the invention provides a preparation method of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine, which comprises the following steps:
(a) Respectively adding 6-methylnicotinate, organic base and 2-oxypyrrolidine-1-carboxylic acid tert-butyl ester into an organic solution for reaction to obtain a 3- (6-methylnicotinamido) -2-oxypyrrolidine-1-carboxylic acid tert-butyl ester solution;
(b) Adding an inorganic strong acid aqueous solution into a 3- (6-methylnicotinamido) -2-oxypyrrolidine-1-carboxylic acid tert-butyl ester solution, uniformly mixing, standing for layering, retaining an acidic aqueous solution phase, then reacting the acidic aqueous solution phase at 110-130 ℃, cooling to adjust the pH value to 10-12 after the reaction is finished, filtering to remove impurities, adding an organic solvent into the filtrate for extraction, standing for layering, retaining the organic phase, and distilling or distilling under reduced pressure to remove the organic solvent to obtain 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine;
(c) Dissolving 5- (4, 5-dihydro-1H-pyrrole-2-yl) -2-methylpyridine in an alcohol solvent, adding a catalyst for hydrogenation reduction reaction, and after the reaction is finished, performing nitrogen pressure filtration to obtain a 2-methyl-5- (pyrrolidine-2-yl) pyridine alcohol solution;
(d) Adjusting the pH value of the 2-methyl-5- (pyrrolidine-2-yl) pyridine alcoholic solution to 3-5, adding a methylating agent to carry out methylation reaction to obtain 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine acidic aqueous solution;
(e) Adjusting the pH value of the acidic aqueous solution of the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine to 10-12, filtering to remove impurities, adding an organic solvent for extraction, standing for layering, keeping an organic phase, distilling or distilling under reduced pressure to remove the organic solvent to obtain a crude product of the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine, and then distilling and purifying to obtain the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine.
The reaction formula in step (a) is shown as formula I, the reaction formula in step (b) is shown as formula II, the reaction formula in step (c) is shown as formula III, and the reaction formula in step (d) is shown as formula IV;
in the formulae I and II, R 1 Is methyl, ethyl, propyl, tert-butyl, n-propyl or isopropyl;
M + is a metal ion, specifically Na + 、K + And Li + 。
Preferably, in the step (a), the 6-methylnicotinate is selected from at least one of methyl 6-methylnicotinate, ethyl 6-methylnicotinate, tert-butyl 6-methylnicotinate, n-propyl 6-methylnicotinate and isopropyl 6-methylnicotinate.
Preferably, in the step (a), the organic solvent is at least one selected from the group consisting of toluene, xylene, tetrahydrofuran, n-hexane and acetone.
Preferably, in the step (a), the organic base is at least one selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide and lithium tert-butoxide.
Preferably, in the step (a), the reaction temperature is 90-120 ℃; heating reflux is carried out in the reaction process.
Preferably, in the step (b), the aqueous solution of a strong inorganic acid is at least one selected from concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride and perchloric acid.
Preferably, in the step (b), the inorganic strong acid aqueous solution is added to the mixed solution with the pH value less than or equal to 1.
Preferably, in the step (b), heating reflux is performed during the reaction.
Preferably, in the step (b), the organic solvent is at least one selected from the group consisting of dichloromethane, ethyl acetate, n-hexane, petroleum ether and chloroform.
Preferably, in the step (b), the pH regulator is a 20-50% inorganic strong alkali solution, and the inorganic strong alkali solution is an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous sodium carbonate solution or an aqueous sodium bicarbonate solution.
Preferably, in the step (c), the temperature of the hydrogenation reduction reaction is 25-40 ℃ and the pressure is 10-30 psi.
Preferably, in the step (c), the amount of the catalyst added is 0.1-15% of the molar amount of 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine.
Preferably, in the step (c), the catalyst is selected from at least one of (1R) -1- [ bis (1, 1-dimethylethyl) phosphine ] -2- [ (1R) -1- [ bis (2-methylphenyl) phosphine ] ethyl ] ferrocene, bis (1, 5-cyclooctadiene) rhodium (l) tetrafluoroborate and triethylamine.
Preferably, in the step (c), the alcoholic solvent is at least one selected from methanol, ethanol, t-butanol and isopropanol.
Preferably, in the step (d), the methylation reaction temperature is 80-100 ℃.
Preferably, in step (d), the methylating agent is selected from paraformaldehyde and/or an aqueous alcohol solution of formaldehyde.
Preferably, in the step (d), the pH regulator is aqueous formic acid.
Preferably, in the step (e), the pH adjustor is at least one selected from the group consisting of a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate aqueous solution and a sodium bicarbonate aqueous solution.
Preferably, in the step (e), the organic solvent is at least one selected from the group consisting of dichloromethane, ethyl acetate, methanol, petroleum ether and n-hexane.
Preferably, in the step (e), the distillation and purification temperature is 150-200 ℃, and the vacuum degree is 0.095-0.1MPa.
Compared with the prior art, the invention has the beneficial effects that at least:
the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared by the preparation method has high purity, the content of the levorotatory isomer is up to more than 70%, and the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine has the advantages of lower usage amount, strong satisfaction and throat feeling and good sensory experience when being used for electronic cigarette products.
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In order to more clearly illustrate the detailed description of the invention or the technical solutions in the prior art, the drawings that are needed in the detailed description of the invention or the prior art will be briefly described below. Throughout the drawings, like elements or portions are generally identified by like reference numerals. In the drawings, elements or portions are not necessarily drawn to scale.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared by the embodiment of the invention;
FIG. 2 is a chiral HPLC test spectrum of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 1 of the present invention;
FIG. 3 is a chiral HPLC test pattern of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 2 of the present invention;
FIG. 4 is a chiral HPLC test pattern of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 3 of the present invention;
FIG. 5 is a chiral HPLC test pattern of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in comparative example 1 of the present invention.
Detailed Description
The following describes embodiments of the present invention in detail with reference to the following embodiments. The following examples are only for illustrating the technical solutions of the present invention more clearly, and therefore are only examples, and the protection scope of the present invention is not limited thereby.
It is to be noted that, unless otherwise specified, technical or scientific terms used herein shall have the ordinary meaning as understood by those skilled in the art to which the invention pertains.
Example 1
In a 5L reaction bottle, at room temperature of 25 ℃, 200g of sodium tert-butoxide is taken, 500ml of toluene is used for fully stirring for 30min, then a constant pressure funnel is slowly added with mixed solution of 378g of 2-oxypyrrolidine-1-carboxylic acid tert-butyl ester and 400ml of toluene, the addition is completed within 20min, then a constant pressure funnel is slowly added with mixed solution of 300g of methyl 6 methylnicotinate and 300ml of toluene, the addition is completed within 40min, after nitrogen replacement, the temperature is raised to 120 ℃, the condensation reflux temperature is 15 ℃, after reaction is carried out for 3h, the reaction completion degree is reached through LCMS, and after the reaction is completed, the temperature is lowered to the room temperature;
adding 750mL of 36% concentrated hydrochloric acid aqueous solution into the reaction solution for 3 times, stirring for 40min, transferring to 5L extraction solution separation bottle, standing for layering, and keeping the lower layer of hydrochloric acid aqueous phase; transferring the hydrochloric acid water phase into a 5L reactor, heating to 130 ℃, condensing and refluxing at 15 ℃, connecting a tail end of a condensing tube with a tail gas receiver (20% sodium hydroxide aqueous solution), reacting for 8h, performing LCMS reaction to complete the reaction, and cooling to room temperature after the reaction is completed; under the condition of ice-water bath at 0 ℃, 250ml of 30% sodium hydroxide aqueous solution is slowly dripped through a constant-temperature funnel, the ph is adjusted to 11, after solid impurities are filtered, a water phase is retained, the water phase is transferred to a 5L reaction bottle, 4L dichloromethane is added to the reaction bottle, the mixture is fully stirred for 30min, then the mixture is transferred to a 5L extraction liquid separation bottle to be kept stand for layering, a lower dichloromethane layer is retained, the mixture is transferred to a 10L rotary evaporator, the temperature is raised to 45 ℃, the vacuum is carried out under 0.07MPa, and the solvent is evaporated to dryness, so that 294g of 5- (4, 5-dihydro-1H-pyrrole-2-yl) -2-methylpyridine is obtained;
dissolving 294g of 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine by using 3L of absolute ethanol, transferring the solution into a 10L hydrogenation kettle, adding 2.5g of (1R) -1- [ bis (1, 1-dimethylethyl) phosphine ] -2- [ (1R) -1- [ bis (2-methylphenyl) phosphine ] ethyl ] ferrocene, 1.5g of bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (L) and 18.5g of triethylamine through feed ports, introducing nitrogen for 5min after the feed ports are closed, introducing hydrogen pressure of 30psi, reacting at the hydrogenation temperature of 30 ℃ for 8H, and sampling to judge the reaction completeness by LCMS; carrying out pressure filtration on the reaction solution by nitrogen to obtain a 2-methyl-5- (pyrrolidine-2-yl) pyridine alcoholic solution, and recovering the catalyst solid for recycling;
transferring the hydrogenation reaction liquid to a 5L reaction bottle, adding 350g of 85% formic acid aqueous solution, adjusting ph =3.7, heating the reaction liquid to 60 ℃, slowly adding 150ml of 37% formaldehyde aqueous solution through a constant-pressure funnel, adding the solution within 30min, continuously heating to 90 ℃, after reacting for 3h, sampling, judging the reaction completion degree by LCMS, after the reaction is completed, cooling to 10 ℃, under the condition of 0 ℃ ice water bath, slowly adding 185g of 30% sodium hydroxide aqueous solution, adjusting ph =11, filtering out solid impurities by vacuum filtration, transferring the reaction liquid to a 10L reaction bottle, adding 7L methyl tert-butyl ether, fully stirring, transferring to an extraction solution splitting bottle, standing for layering, retaining an organic layer, transferring to a rotary evaporator, vacuumizing to 0.07Mpa, at the temperature of 45 ℃, and evaporating the solvent to dryness to obtain a crude product of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine; then, the vacuum degree is controlled to be 0.095Mpa, the temperature is 165 ℃, the distillation is continued to obtain 264g of pure 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine, the GC purity is 99.5 percent, and the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine levorotatory isomer: dextrorotatory isomer ratio = 96.
Example 2
In a 5L reaction bottle, at room temperature of 25 ℃, 230g of potassium tert-butoxide is taken, 500ml of toluene is used for fully stirring for 30min, 378g of mixed solution of 2-oxypyrrolidine-1-carboxylic acid tert-butyl ester and 400ml of toluene is slowly added into a constant pressure funnel, the adding is finished after 20min, 300g of mixed solution of 6 methyl nicotinic acid methyl ester and 300ml of toluene is slowly added into the constant pressure funnel, the adding is finished after 40min, the temperature is raised to 120 ℃ after nitrogen replacement, the condensation reflux temperature is 15 ℃, the reaction is finished by LCMS after 3h of reaction, and the temperature is lowered to the room temperature after the reaction is finished;
adding 750mL of 36% concentrated hydrochloric acid aqueous solution into the reaction solution for 3 times, fully stirring for 40min, transferring to a 5L extraction solution separating bottle, standing for layering, and keeping a lower layer hydrochloric acid aqueous phase; transferring the hydrochloric acid water phase to a 5L reactor, heating to 110 ℃, condensing and refluxing at 15 ℃, connecting the tail end of a condensing tube with a tail gas receiver (20% sodium hydroxide aqueous solution), reacting for 12h, testing the reaction completeness by LCMS, and cooling to room temperature after the reaction is completed. Slowly dripping 250ml of 30% sodium hydroxide aqueous solution through a constant-temperature funnel under an ice-water bath at 0 ℃, adjusting the pH to 11, filtering solid impurities, retaining a water phase, transferring the water phase to a 5L reaction bottle, adding 4L petroleum ether, fully stirring for 30min, transferring to a 5L extraction liquid separation bottle, standing for layering, retaining an upper petroleum ether layer, transferring to a 10L rotary evaporator, heating to 45 ℃, and evaporating the solvent to dryness under the vacuum of 0.07MPa to obtain 278g of 5- (4, 5-dihydro-1H-pyrrole-2-yl) -2-methylpyridine;
dissolving 278g of 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine by using 2.5L of absolute ethyl alcohol, transferring the solution to a 10L hydrogenation kettle, adding 1.8g of (1R) -1- [ bis (1, 1-dimethylethyl) phosphine ] -2- [ (1R) -1- [ bis (2-methylphenyl) phosphine ] ethyl ] ferrocene, 1.2g of bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (L) and 15g of triethylamine through feed ports, introducing nitrogen after the feed ports are closed, introducing the hydrogen for 5min, introducing the hydrogen pressure of 30psi, reacting at the hydrogenation temperature of 30 ℃, reacting for 8H, and sampling to judge the reaction completeness by LCMS; carrying out nitrogen pressure filtration on the reaction solution to obtain a 2-methyl-5- (pyrrolidine-2-yl) pyridine alcoholic solution, and recovering the catalyst solid for recycling;
transferring the hydrogenation reaction liquid into a 5L reaction bottle, adding 360g of 85% formic acid aqueous solution, adjusting ph =3.4, heating the reaction liquid to 60 ℃, slowly adding 150ml of 37% formaldehyde aqueous solution through a constant-pressure funnel, adding the addition within 30min, continuously heating to 90 ℃, after reacting for 3h, sampling, judging the reaction completion degree by LCMS, after the reaction is completed, cooling to 10 ℃, slowly adding 210g of 30% sodium hydroxide aqueous solution under 0 ℃ ice water bath, adjusting ph =11, filtering out solid impurities by vacuum filtration, transferring the reaction liquid into a 10L reaction bottle, adding 7L methyl tert-butyl ether, fully stirring, transferring into an extraction liquid separating bottle, standing for layering, retaining an organic layer, transferring into a rotary evaporator, vacuum-drying at the temperature of 45 ℃, and evaporating the solvent to obtain a crude product of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine; controlling the vacuum degree to be 0.095Mpa and the temperature to be 165 ℃, continuously distilling to obtain 248g of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine pure product, having the GC purity of 99.3 percent and 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine levorotatory isomer: dextrorotatory isomer ratio = 85.
Example 3
In a 5L reaction bottle, at room temperature of 25 ℃, 167g of lithium tert-butoxide is taken, 500ml of toluene is used for fully stirring for 30min, then 378g of mixed solution of 2-oxypyrrolidine-1-carboxylic acid tert-butyl ester and 400ml of toluene is slowly added into a constant pressure funnel, 20min is added, then 300g of mixed solution of 6 methyl nicotinic acid methyl ester and 300ml of toluene is slowly added into the constant pressure funnel, 40min is added, after nitrogen replacement, the temperature is raised to 120 ℃, the condensation reflux temperature is 15 ℃, after 3h of reaction, the reaction is completed through LCMS, and the temperature is lowered to room temperature after the reaction is completed.
Adding 750mL of 36% concentrated hydrochloric acid aqueous solution into the reaction solution for 3 times, stirring for 40min, transferring to 5L extraction solution separation bottle, standing for layering, and keeping the lower layer of hydrochloric acid aqueous phase; transferring the hydrochloric acid water phase to a 5L reactor, heating to 130 ℃, condensing and refluxing at 15 ℃, connecting the tail end of a condensing tube with a tail gas receiver (20% sodium hydroxide aqueous solution), reacting for 8h, performing LCMS reaction to complete the reaction, and cooling to room temperature after the reaction is completed. Under the condition of ice-water bath at 0 ℃, 250ml of 30% sodium hydroxide aqueous solution is slowly dripped through a constant-temperature funnel, the ph is adjusted to 11, after solid impurities are filtered, a water phase is reserved, the water phase is transferred to a 5L reaction bottle, 4L dichloromethane is added, the mixture is fully stirred for 30min, then the mixture is transferred to a 5L extraction separation bottle to be kept stand for layering, a lower dichloromethane layer is reserved, the mixture is transferred to a 10L rotary evaporator, the temperature is raised to 45 ℃, the vacuum is carried out under 0.07MPa, the solvent is evaporated to dryness, and 276g of 5- (4, 5-dihydro-1H-pyrrole-2-yl) -2-methylpyridine is obtained.
Dissolving 276g of 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine with 3L of absolute ethanol, transferring the solution to a 10L hydrogenation kettle, adding 2.5g of (1R) -1- [ bis (1, 1-dimethylethyl) phosphine ] -2- [ (1R) -1- [ bis (2-methylphenyl) phosphine ] ethyl ] ferrocene, 1.5g of bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (L) and 9g of triethylamine through feed inlets, sealing the feed inlets, introducing nitrogen for 5min, introducing hydrogen pressure of 30psi, reacting at the hydrogenation temperature of 30 ℃ for 8H, and sampling to judge the reaction completeness through LCMS; and (3) carrying out nitrogen pressure filtration on the reaction solution to obtain a 2-methyl-5- (pyrrolidine-2-yl) pyridine alcoholic solution, and recovering the catalyst solid for recycling.
Transferring the hydrogenation reaction liquid into a 5L reaction bottle, adding 350g of 85% formic acid aqueous solution, adjusting ph =3.7, heating the reaction liquid to 60 ℃, slowly adding 150ml of 37% formaldehyde aqueous solution through a constant-pressure funnel, adding the mixture within 30min, continuously heating to 90 ℃, after reacting for 3h, sampling, judging the reaction completion degree by LCMS, after the reaction is completed, cooling to 10 ℃, slowly adding 185g of 30% sodium hydroxide aqueous solution under 0 ℃ ice water bath, adjusting ph =11, filtering out solid impurities by vacuum filtration, transferring the reaction liquid into a 10L reaction bottle, adding 7L of methyl tert-butyl ether, fully stirring, transferring into an extraction liquid separating bottle, standing for layering, retaining an organic layer, transferring into a rotary evaporator, vacuumizing to 0.07Mpa, at the temperature of 45 ℃, and evaporating the solvent to dryness to obtain a crude product of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine; controlling the vacuum degree to be 0.095Mpa and the temperature to be 165 ℃, continuously distilling to obtain 254g of pure 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine, the GC purity to be 99.3 percent, and the levorotatory isomer of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine: dextrorotatory isomer ratio = 70.
Comparative example 1
In a 5L reaction bottle, at room temperature of 25 ℃, 200g of sodium tert-butoxide is taken, 500ml of toluene is used for fully stirring for 30min, then 378g of mixed solution of tert-butyl 2-oxypyrrolidine-1-carboxylate and 400ml of toluene is slowly added into a constant pressure funnel, 20min is finished, then 300g of mixed solution of methyl 6 methylnicotinate and 300ml of toluene is slowly added into the constant pressure funnel, 40min is finished, after nitrogen replacement, the temperature is raised to 120 ℃, the condensation reflux temperature is 15 ℃, after 3h of reaction, the reaction completion degree is reduced to room temperature through LCMS after complete reaction;
adding 750mL of 36% concentrated hydrochloric acid aqueous solution into the reaction solution for 3 times, stirring for 40min, transferring to 5L extraction solution separation bottle, standing for layering, and keeping the lower layer of hydrochloric acid aqueous phase; transferring the hydrochloric acid water phase into a 5L reactor, heating to 130 ℃, condensing and refluxing at 15 ℃, connecting a tail end of a condensing tube with a tail gas receiver (20% sodium hydroxide aqueous solution), reacting for 8h, performing LCMS reaction to complete the reaction, and cooling to room temperature after the reaction is completed; under the condition of ice-water bath at 0 ℃, 140ml of 30% sodium hydroxide aqueous solution is slowly dripped through a constant temperature funnel, the pH is adjusted to 7.5, 200ml of methanol is added, 75g of sodium borohydride solid is added in batches, the reaction temperature is set to be 30 ℃, after 5 hours of reaction, sampling is carried out, the reaction completion degree is tested through LCMS, and after the reaction is completed, the temperature is reduced to 10 ℃;
adding 300g of 85% formic acid aqueous solution into a reduction reaction solution under the condition of ice-water bath at 0 ℃, adjusting pH =3.5, heating the reaction solution to 60 ℃, slowly adding 150ml of 37% formaldehyde aqueous solution through a constant-pressure funnel, adding the aqueous solution within 30min, continuously heating to 90 ℃, after reacting for 3h, sampling, introducing LCMS to judge the reaction completion degree, after the reaction is completed, cooling to 10 ℃, slowly adding 200g of 30% sodium hydroxide aqueous solution under the condition of ice-water bath at 0 ℃, adjusting pH =11, filtering out solid impurities through vacuum filtration, transferring the reaction solution into a 10L reaction bottle, adding 7L methyl tert-butyl ether, fully stirring, transferring into an extraction liquid separating bottle, standing for layering, retaining an organic layer, transferring into a rotary evaporator, vacuumizing to 0.07Mpa at the temperature of 45 ℃, and evaporating the solvent to dryness to obtain a 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine crude product; the vacuum degree is controlled to be 0.095Mpa, the temperature is 165 ℃, the distillation is continued to obtain 264g of pure 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine, the GC purity is 99.5 percent, and the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine levorotatory isomer: dextrorotatory isomer ratio = 1.
Examples of the experiments
1. The hydrogen nuclear magnetic resonance spectroscopy analysis of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine obtained in example 1 was carried out, and the analysis results are shown in FIG. 1:
as can be seen from fig. 1, δ:8.35 (d, j =2.0 HZ), 7.60 (dd, j =6.4, 2.0hz), 7.20 (d, j =6.4 HZ), 3.16-1.12 (m, 1H), 3.06-3.02 (m, 1H), 2.43 (s, 3H), 2.35-2.2.9 (m, 1H), 2.24-2.20 (m, 1H), 2.15-2.09 (m, 1H), 2.05 (s, 3H), 1.87-1.82 (m, 1H), 1.76-1.73 (m, 1H).
Wherein the characteristic peaks are indicated by conventional abbreviations: s, single peak; d. double peaks; t, triplet; q, quartet; m, multiplet; dd. A doublet of two peaks; j. a coupling constant.
From the nuclear magnetic spectrum and the hydrogen nuclear magnetic data of the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine, the actual spectrum of the final product is consistent with the presumed structure.
2. Chiral analysis, chiral HPLC test method for 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in examples 1 to 3 and comparative example 1:
a chromatographic column: uniChiral CMZ-5h.4.6 x 250mm; the mobile phase is 90% of n-hexane/10% of methanol/0.1% of diethanolamine; the flow rate is 1ml/min; the sample injection amount is 5 mu L; detector UV 254nm; the temperature is 30 ℃.
Chiral HPLC test spectra of the products of examples 1-3 and comparative example 1 are shown in FIGS. 2-5 in sequence;
as can be seen from fig. 2 to 5: levorotatory isomer of pyridine in 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 1: dextrorotatory isomer ratio = 96;
levorotatory isomer of pyridine in 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 1: dextrorotatory isomer ratio = 96;
levorotatory pyridine isomer in 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 2: dextrorotatory isomer ratio = 85;
levorotatory isomer of pyridine in 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in example 3: dextrorotatory isomer ratio = 70;
levorotatory isomer of pyridine in 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared in comparative example 1: dextrorotatory isomer ratio = 1.
3. Sensory evaluation of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine obtained in example 1
The sensory evaluation method in the standard GB5606.4, GB/T22366 2008, GB/T12312-2012 and YCT/1381998 is combined with the current application state of the novel tobacco product, and the application of the 2-methyl-5 (1-methylpyrrolidine-2-yl) pyridine in the novel tobacco product is evaluated.
The natural nicotine is purchased from a product sold on the market, is prepared into 3mg/mL electronic cigarette atomized liquid by propylene glycol, the 2 methyl 5 (1 methyl pyrrolidine 2 base) pyridine obtained in the example is respectively prepared into 0.5mg/mL,1mg/mL and 1.5mg/mL by propylene glycol and respectively marked as effect examples 1, 2 and 3, the 2 methyl 5 (1 methyl pyrrolidine 2 base) pyridine prepared in the comparative example is prepared into 2mg/mL by propylene glycol, and three indexes of aroma, throat hitting feeling and head feeling are subjected to sensory evaluation by an electronic cigarette appliance: 1.5mL of the electronic cigarette atomized liquid is respectively added into electronic cigarette equipment, and 10 professional smokers smoke in sequence to respectively evaluate the fragrance, the throat hitting feeling and the head feeling. Each index is divided into 100 points, and the higher the point is, the better the sensory experience is. Wherein the sensory evaluation conditions are as follows: room temperature 25 deg.C, air humidity 50%; when the test sample is replaced each time, the mouth is repeatedly rinsed for 3 times by using the salt solution and the distilled water, so that the objectivity and the accuracy of the sensory test are ensured. The results are shown in table 1 below:
TABLE 1
| Group of | Fragrance | Feeling of hitting throat | Feeling of putting head |
| Natural nicotine | 79 | 81 | 78 |
| Effect example 1 | 82 | 83 | 84 |
| Effect example 2 | 83 | 85 | 86 |
| Effect example 3 | 80 | 82 | 81 |
| Comparative example 1 | 78 | 81 | 78 |
As can be seen from Table 1, when the 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine prepared by the method is applied to an electronic cigarette product, the effect of natural nicotine can be achieved by using the dosage of 0.5mg/ml, and the effect has a better sensory effect compared with the natural nicotine and the comparative example 1, and the good application potential is proved.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; such modifications and substitutions do not depart from the spirit and scope of the present invention, and they should be construed as being included in the following claims and description.
Claims (10)
1. A preparation method of 2-methyl-5- (1-methylpyrrolidin-2-yl) pyridine is characterized by comprising the following steps:
(a) Respectively adding 6-methylnicotinate, organic base and 2-oxypyrrolidine-1-carboxylic acid tert-butyl ester into an organic solution for reaction to obtain a 3- (6-methylnicotinamido) -2-oxypyrrolidine-1-carboxylic acid tert-butyl ester solution;
(b) Adding an inorganic strong acid aqueous solution into a 3- (6-methylnicotinamido) -2-oxypyrrolidine-1-carboxylic acid tert-butyl ester solution, uniformly mixing, standing for layering, retaining an acidic aqueous solution phase, then reacting the acidic aqueous solution phase at 110-130 ℃, cooling to adjust the pH value to 10-12 after the reaction is finished, filtering to remove impurities, adding an organic solvent into the filtrate for extraction, standing for layering, retaining the organic phase, and distilling or distilling under reduced pressure to remove the organic solvent to obtain 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine;
(c) Dissolving 5- (4, 5-dihydro-1H-pyrrole-2-yl) -2-methylpyridine in an alcohol solvent, adding a catalyst for hydrogenation reduction reaction, and filtering after the reaction is finished to obtain a 2-methyl-5- (pyrrolidine-2-yl) pyridine alcohol solution;
(d) Adjusting the pH value of the 2-methyl-5- (pyrrolidine-2-yl) pyridine alcoholic solution to 3-5, adding a methylating agent to carry out methylation reaction to obtain 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine acidic aqueous solution;
(e) Adjusting the pH value of the acidic aqueous solution of the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine to 10-12, filtering to remove impurities, adding an organic solvent for extraction, standing for layering, retaining an organic phase, distilling or distilling under reduced pressure to remove the organic solvent to obtain a crude product of the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine, and distilling and purifying to obtain the 2-methyl-5- (1-methylpyrrolidine-2-yl) pyridine.
2. The method according to claim 1, wherein the step (a) is performed by heating under reflux during the reaction, and the reaction temperature is 90 to 120 ℃.
3. The method according to claim 1, wherein in the step (a), the 6-methylnicotinate is at least one selected from the group consisting of methyl 6-methylnicotinate, ethyl 6-methylnicotinate, tert-butyl 6-methylnicotinate, n-propyl 6-methylnicotinate and isopropyl 6-methylnicotinate;
the organic base is at least one selected from sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide and lithium tert-butoxide.
4. The method according to claim 1, wherein in the step (b), the aqueous solution of the strong inorganic acid is added to the mixed solution at a pH of 1 or less.
5. The method according to claim 1, wherein in the step (b), the aqueous solution of a strong inorganic acid is at least one selected from the group consisting of an aqueous solution of concentrated hydrochloric acid, concentrated sulfuric acid, sulfoxide chloride and perchloric acid;
the pH regulator is 20-50% inorganic strong alkali solution.
6. The method according to claim 1, wherein the temperature of the hydrogenation reduction reaction in the step (c) is 25 to 40 ℃ and the pressure is 10 to 30psi.
7. The method according to claim 1, wherein the catalyst is added in an amount of 0.1 to 15% by mole based on the amount of 5- (4, 5-dihydro-1H-pyrrol-2-yl) -2-methylpyridine in the step (c).
8. The production method according to claim 1, wherein in the step (c), the catalyst is at least one selected from the group consisting of (1R) -1- [ bis (1, 1-dimethylethyl) phosphine ] -2- [ (1R) -1- [ bis (2-methylphenyl) phosphine ] ethyl ] ferrocene, bis (1, 5-cyclooctadiene) rhodium (l) tetrafluoroborate and triethylamine.
9. The method according to claim 1, wherein the methylation reaction temperature in the step (d) is 80 to 100 ℃.
10. The method according to claim 1, wherein the distillation purification temperature is 150 to 200 ℃ and the degree of vacuum is 0.095 to 0.1MPa in the step (e).
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