Method for splitting racemic nicotine salt, levorotatory nicotine benzoate, cigarette oil and reactor

Abstract

The present invention relates to the technical field of racemic compound separation, and in particular to a separation method of racemic nicotine salt, L-nicotine benzoate, cigarette oil and a reactor. The separation method of racemic nicotine salt comprises the following steps: putting racemic nicotine and an organic acid into a reaction container, heating and stirring, so that the racemic nicotine and the organic acid react to obtain a liquid racemic nicotine organic acid salt; maintaining the temperature of the liquid racemic nicotine organic acid salt within a preset temperature range to obtain a solid-liquid mixed racemic nicotine organic acid salt; separating the solid-liquid mixed racemic nicotine organic acid salt to separate the L-nicotine salt and the D-nicotine salt. The present application realizes the separation of the L-nicotine salt and the D-nicotine salt by having the L-nicotine salt and the D-nicotine salt have different solid-liquid states within a preset temperature range. The method of the present application has the advantages of low cost, simple operation, low risk, and easy acquisition of raw materials.

Description

Technical Field

[0001] The invention relates to the technical field of racemic compound resolution, and in particular to a method for resolving a racemic nicotine salt, L-nicotine benzoate, cigarette oil and a reaction kettle. Background Art

[0002] When optically active compounds are prepared by conventional chemical synthesis methods, racemic mixtures are generally obtained.

[0003] Nicotine, 3-[1-methylpyrrolidin-2-yl]pyridine, contains what chemists call a chiral carbon. This molecule usually has two non-superimposable structures, called enantiomers. They have the same chemical formula, but the positions of their atoms may be different, making the two molecules non-superimposable, such as left and right hands; mirror images of each other, or enantiomers. In chemistry, these two enantiomers are S- and R-nicotine.

[0004] S-nicotine and R-nicotine can be distinguished optically because S-nicotine rotates plane polarized light to the left (levorotatory) and R-nicotine to the right (dextrorotatory). A recent basic concept in stereochemistry, a mixture in which two enantiomers coexist in a 1:1 ratio is called a racemic mixture (the deviation of plane polarized light is zero). In the case of nicotine, the racemic mixture is called RS-nicotine.

[0005] In e-liquid, compared with nicotine, replacing nicotine with nicotine salt does not affect the smoking effect, but has a certain improvement on the taste. By salting, nicotine is solidified, which can also improve the sustained release effect of nicotine and reduce the irritation to the digestive tract. Therefore, nicotine complexes show potential application value in the tobacco industry.

[0006] However, in general, industrially prepared nicotine salts are racemic nicotine salts, which contain L-nicotine salts and D-nicotine salts. Since D-nicotine has no psychoactive activity, D-nicotine salts will not have any effect when added to e-liquid. Therefore, it is necessary to provide a method for splitting racemic nicotine salts to improve the quality of nicotine salts used in e-liquids. Summary of the invention

[0007] The main purpose of the present invention is to provide a method for splitting racemic nicotine salt, aiming to split racemic nicotine salt by a method with simple operation and low cost, thereby improving industrial production.

[0008] To achieve the above object, the present invention provides a method for separating racemic nicotine salt, comprising the following steps:

[0009] Putting racemic nicotine and an organic acid into a reaction container, heating and stirring, so that the racemic nicotine and the organic acid react to obtain a liquid racemic nicotine organic acid salt;

[0010] Maintaining the temperature of the liquid racemic nicotine organic acid salt within a preset temperature range to obtain a solid-liquid mixed racemic nicotine organic acid salt;

[0011] The solid-liquid mixed racemic nicotine organic acid salt is separated to separate the left-rotational nicotine salt and the right-rotational nicotine salt.

[0012] Optionally, in the step of adding racemic nicotine and an organic acid into a reaction container, heating and stirring to react the racemic nicotine and the organic acid to obtain a liquid racemic nicotine organic acid salt, the organic acid is benzoic acid.

[0013] Optionally, the step of adding racemic nicotine and benzoic acid into a reaction container, heating and stirring, and reacting the racemic nicotine and the benzoic acid to obtain liquid racemic nicotine benzoate includes the following steps:

[0014] First, racemic nicotine is added into a reaction container, and then benzoic acid is added into the reaction container, and the mixture is heated and stirred to allow the racemic nicotine and the benzoic acid to react to obtain liquid racemic nicotine benzoate.

[0015] Optionally, the molar ratio of the racemic nicotine and the benzoic acid added into the reaction container is (1:1)-(1:1.2).

[0016] Optionally, in the step of pouring racemic nicotine and benzoic acid into a reaction container, heating and stirring, the heating temperature is 60°C ± 5°C.

[0017] Optionally, in the step of maintaining the temperature of the liquid racemic nicotine benzoate within a preset temperature range to obtain a solid-liquid mixed racemic nicotine benzoate, the preset temperature range is 40°C-45°C.

[0018] Optionally, before the step of separating the solid-liquid mixed racemic nicotine benzoate to separate the levorotatory nicotine benzoate and the dextrorotatory nicotine benzoate, the method further comprises the following steps:

[0019] The solid-liquid mixed racemic nicotine benzoate salt is allowed to stand for more than 2 hours.

[0020] The present application also provides a L-nicotine benzoate, which is prepared by the separation method of the racemic nicotine salt.

[0021] The present application also provides a cigarette oil, wherein the cigarette oil comprises the levorotatory nicotine benzoate.

[0022] The present application also provides a reactor, which is used in the steps of the method for separating racemic nicotine salt, and comprises:

[0023] A reactor body, the reactor body comprising an inner liner and an outer shell, a heating medium is provided between the inner liner and the outer shell, and the inner liner is used to load the racemic nicotine and the organic acid;

[0024] A stirrer, wherein the upper end of the stirrer is arranged on the reactor body, and the lower end of the stirrer is located in the inner container, and is used for stirring the racemic nicotine and the organic acid.

[0025] The present application provides a method for separating racemic nicotine salts, comprising the following steps: putting racemic nicotine and an organic acid into a reaction vessel, heating and stirring, so that the racemic nicotine and the organic acid react to obtain a liquid racemic nicotine organic acid salt; maintaining the temperature of the liquid racemic nicotine organic acid salt within a preset temperature range to obtain a solid-liquid mixed racemic nicotine organic acid salt; separating the solid-liquid mixed racemic nicotine organic acid salt to separate the left-handed nicotine salt and the right-handed nicotine salt. The present application achieves the separation of the left-handed nicotine salt and the right-handed nicotine salt by having the left-handed nicotine salt and the right-handed nicotine salt have different solid and liquid states within a preset temperature range. The method of the present application has the advantages of low cost, simple operation, low risk, and easy acquisition of raw materials. The separated left-handed nicotine salt can be directly used as a component of the e-liquid, and the left-handed nicotine salt has psychoactive activity, which improves the quality of the nicotine salt used in the e-liquid. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

[0027] Figure 1 Schematic diagram of the process for separating racemic nicotine salt of the present invention;

[0028] Figure 2 The figure is a schematic diagram of the structure of a reaction kettle of the present invention.

[0029] Description of Figure Numbers:

[0030] Label name Label name 10 Reactor body 15 drain port 11 Mixer 16 Filter 12 Feed port 17 Switching valve 13 Heating medium 18 Material output pipeline 14 Air outlet

[0031] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0032] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] It should be noted that all directional indications in the embodiments of the present invention (such as up, down, left, right, front, back, etc.) are only used to explain the relative position relationship, movement status, etc. between the components under a certain specific posture (as shown in the accompanying drawings). If the specific posture changes, the directional indication will also change accordingly.

[0034] In the present invention, unless otherwise clearly specified and limited, the terms "connection", "fixation", etc. should be understood in a broad sense. For example, "fixation" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements, unless otherwise clearly defined. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0035] In addition, in the present invention, descriptions such as "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the meaning of "and / or" appearing in the full text is to include three parallel solutions. Taking "A and / or B as an example", it includes solution A, or solution B, or solutions that satisfy both A and B. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of ordinary technicians in this field to implement. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0036] Racemization is to change the molecular structure so that the optical activity of the molecule changes. Many molecules have optical activity. Racemization includes racemic and meso. Racemic is two molecules with the same molecular formula but mirror-image structures, with opposite optical activities, so the optical activity is eliminated. Meso is a molecule without optical activity. Meso: A compound that contains asymmetric atoms in the molecule but is not optically active due to symmetry factors. For example, although the meso tartaric acid molecule contains two asymmetric carbon atoms C, due to their symmetry factors, the right-handed action of half of the molecule is offset by the left-handed action of the other half of the molecule, so it is an optically inactive compound.

[0037] Racemate resolution refers to the separation of racemates into single enantiomers by physical, chemical or biological methods.

[0038] Nicotine is the main chemical component of natural alkaloids in tobacco leaves. Its molecular structure is composed of two nitrogen heterocyclic rings, with the pyrrole ring pKa = 7.87 and the pyridine ring pKa = 3.15. The nitrogen atom in the pyridine ring has a very weak alkalinity due to the influence of aromatization, which is similar to the alkalinity of aromatic amines. The nitrogen atom in the pyrrolidine ring belongs to a tertiary amine. Since this ring is not aromatic, its alkalinity is similar to that of aliphatic tertiary amines. Therefore, nicotine easily reacts chemically with acids.

[0039] Using the unique chemical properties of nicotine, we rationally select small organic or inorganic acid molecules and synthesize nicotine salt complexes through acid-base reactions. Although nicotine exists in another chemical form, it does not affect the smoking effect of nicotine. On the contrary, it has a certain improvement on the taste. By salting, nicotine is solidified, which can also improve the sustained release effect of nicotine and reduce the irritation to the digestive tract. Therefore, nicotine complexes show potential application value in the tobacco industry.

[0040] Generally, industrially prepared nicotine salts are racemic nicotine salts, which contain L-nicotine salts and D-nicotine salts. Since D-nicotine has no psychoactive activity, D-nicotine salts will not have any effect when added to e-liquid. Therefore, it is necessary to provide a method for splitting racemic nicotine salts to improve the quality of nicotine salts used in e-liquids.

[0041] In order to provide a method for splitting racemic nicotine salt, the invention aims to split racemic nicotine salt by a method with simple operation and low cost, thereby improving industrial production.

[0042] like Figure 1As shown, the present application provides a method for splitting racemic nicotine salts, and the method for splitting racemic nicotine salts comprises the following steps: putting racemic nicotine and an organic acid into a reaction vessel, heating and stirring, so that the racemic nicotine and the organic acid react to obtain a liquid racemic nicotine organic acid salt; maintaining the temperature of the liquid racemic nicotine organic acid salt within a preset temperature range to obtain a solid-liquid mixed racemic nicotine organic acid salt; separating the solid-liquid mixed racemic nicotine organic acid salt to separate the left-handed nicotine salt and the right-handed nicotine salt. The present application achieves the separation of the left-handed nicotine salt and the right-handed nicotine salt by having the left-handed nicotine salt and the right-handed nicotine salt have different solid-liquid states within the preset temperature range. The method of the present application has the advantages of low cost, simple operation, low risk, and easy acquisition of raw materials. The separated left-handed nicotine salt can be directly used as a component of the e-liquid, and the left-handed nicotine salt has psychoactive activity, which improves the quality of the nicotine salt used in the e-liquid.

[0043] It is understandable that racemic nicotine refers to a 50% content of L-nicotine and D-nicotine. Under ideal conditions, the content of L-nicotine salt and D-nicotine salt generated by the reaction is also 50% each.

[0044] It is understandable that the organic acid includes at least one of lactic acid, benzoic acid, salicylic acid, fruit acid, tartaric acid, citric acid, levulinic acid, etc. The organic acid can be selected according to specific needs. It should be noted that the racemic nicotine salts generated by different organic acids have different specific preset temperature ranges during the separation process. As mentioned above, the present application realizes the separation of left-handed nicotine salt and right-handed nicotine salt by having different solid-liquid states of left-handed nicotine salt and right-handed nicotine salt in the preset temperature range. Because different substances have different temperatures that cause solid-liquid state changes, they need to be selected specifically according to the characteristics of the substances.

[0045] Furthermore, in the step of adding racemic nicotine and an organic acid into a reaction container, heating and stirring to react the racemic nicotine and the organic acid to obtain a liquid racemic nicotine organic acid salt, the organic acid is benzoic acid.

[0046] That is, benzoic acid is reacted with nicotine, the reaction products are L-nicotine benzoate and D-nicotine benzoate, and the solid-liquid mixed racemic nicotine organic acid salt is separated to separate the L-nicotine salt and the D-nicotine salt, wherein the L-nicotine benzoate is liquid and the D-nicotine salt is solid, and after the solid-liquid separation, the mixture is cooled at room temperature, and the liquid portion can obtain L-nicotine benzoate, which can be directly used as the nicotine salt of the atomizer.

[0047] Furthermore, the step of adding racemic nicotine and an organic acid into a reaction container, heating and stirring, allowing the racemic nicotine and the organic acid to react, and obtaining a liquid racemic nicotine organic acid salt comprises the following steps: firstly adding racemic nicotine into a reaction container, and then adding an organic acid into the reaction container, heating and stirring, allowing the racemic nicotine and the organic acid to react, and obtaining a liquid racemic nicotine organic acid salt.

[0048] That is, the step of adding racemic nicotine and benzoic acid into a reaction container, heating and stirring, allowing the racemic nicotine and benzoic acid to react, and obtaining liquid racemic nicotine benzoate includes the following steps: firstly adding racemic nicotine into the reaction container, then adding benzoic acid into the reaction container, heating and stirring, allowing the racemic nicotine and benzoic acid to react, and obtaining liquid racemic nicotine benzoate.

[0049] The order of adding racemic nicotine and the organic acid will not affect the reaction product. However, considering the convenience of operation, liquid nicotine is added first, and then solid benzoic acid is added, which is more convenient for stirring.

[0050] Furthermore, the molar ratio of racemic nicotine and benzoic acid added to the reaction container is (1:1)-(1:1.2).

[0051] That is, raw materials in equimolar ratios can be used, and benzoic acid can be slightly excessive, for example, 1:1, 1:11, 1:1.2. Because benzoic acid is solid at a certain temperature, in the final product separation process, the liquid part is separated, and excessive benzoic acid does not exist in the liquid product as an impurity, and excessive benzoic acid can also accelerate the reaction and improve the reaction speed. Moreover, it is not necessary to add other solvents in the reaction process, which is easy to operate on the one hand, and also saves costs on the other hand, and avoids the need to process the solvent.

[0052] Furthermore, in the step of pouring racemic nicotine and benzoic acid into a reaction container, heating and stirring, the heating temperature is 60°C ± 5°C.

[0053] The heating process helps to speed up the reaction. At the same time, within the temperature range of 60°C±5°C, both L-nicotine benzoate and D-nicotine benzoate are in liquid form, which facilitates the separation of L-nicotine benzoate and D-nicotine benzoate after subsequent cooling treatment.

[0054] Furthermore, in the step of maintaining the temperature of the liquid racemic nicotine organic acid salt within a preset temperature range to obtain a solid-liquid mixed racemic nicotine organic acid salt, the preset temperature range is 40°C-45°C.

[0055] In the preset temperature range of 40°C-45°C, the right-handed nicotine benzoate is solid, while the left-handed nicotine salt is liquid, and it is convenient to separate the two. Specifically, the preset temperature can be 40°C, 41°C, 42°C, 43°C, 44°C, and 45°C.

[0056] Furthermore, before the step of separating the solid-liquid mixed racemic nicotine organic acid salt to separate the L-nicotine salt and the D-nicotine salt, the method further comprises the following steps: allowing the solid-liquid mixed racemic nicotine organic acid salt to stand for more than 2 hours.

[0057] In order to make the dextrorotatory nicotine benzoate become a solid as much as possible, it is left to stand for a period of time. For example, the solid-liquid mixed racemic nicotine organic acid salt is left to stand for more than 2 hours. In this way, there is enough time for the dextrorotatory nicotine benzoate to become a solid.

[0058] The present application also provides a L-nicotine benzoate, which is prepared by the aforementioned method for splitting a racemic nicotine salt. Since the method for splitting a racemic nicotine salt adopts all the technical solutions of all the above embodiments, it at least has all the beneficial effects brought by the technical solutions of the above embodiments, which will not be described one by one here.

[0059] The present application also provides a cigarette oil, which includes the aforementioned L-nicotine benzoate. Since L-nicotine benzoate adopts all the technical solutions of all the above embodiments, it at least has all the beneficial effects brought by the technical solutions of the above embodiments, which will not be described one by one here.

[0060] The application also provides a reactor, which is used in the steps of the aforementioned method for splitting racemic nicotine salt. The reactor includes a reactor body 10 and a stirrer 11. The reactor body includes an inner liner and an outer shell. A heating medium is provided between the inner liner and the outer shell. The inner liner is used to load racemic nicotine and an organic acid. The upper end of the stirrer is provided on the reactor body, and the lower end of the stirrer is located in the inner liner to stir the racemic nicotine and the organic acid.

[0061] It is understandable that a heating medium is provided between the inner tank and the outer shell. The heating medium may be a heat-conducting metal in the form of electric heating, an oil medium in the form of oil bath heating, or a water medium in the form of water bath heating. There is no specific limitation as long as it can be used to heat the inner tank.

[0062] The reactor body 10 is provided with an air outlet 14 and a feed port 12 at the top, and a liquid discharge port 15 at the bottom. The reactor body includes an outer shell and an inner shell. A gap is formed between the outer shell and the inner shell for filling a heating medium 13. The material in the inner shell is heated by heating the heating medium 13 to form a certain temperature condition to facilitate the reaction and the separation of the reaction products. The agitator 11 includes a stirring shaft and a driving motor fixed to the top of the stirring shaft. The lower end of the stirring shaft is located in the reactor body 10, and the upper end of the stirring shaft passes through the reactor body and is connected to the output end of the driving motor. A stirring blade is provided on the outer surface of the stirring shaft. The liquid discharge port 15 is connected to a material output pipe 18, and a switch valve 17 and a filter screen 16 are provided on the material output pipe 18 to facilitate the separation of solid and liquid materials in the reactor from the filter screen 16.

[0063] Example 1

[0064] Resolution of racemic nicotine benzoate

[0065] First, pour racemic nicotine (50% left-handed and 50% right-handed) into the reactor, then pour in benzoic acid in a 1:1 molar ratio, heat to 60 degrees, and stir thoroughly to obtain liquid racemic nicotine benzoate. Subsequently, maintain the temperature of the device in the range of 40-45 degrees, and right-handed nicotine benzoate begins to crystallize. After two hours, a lower layer of solid and an upper layer of liquid will be obtained in the reactor. After solid-liquid separation, cool to room temperature, and the liquid part can obtain a 1:1 molar ratio of left-handed nicotine benzoate. Left-handed nicotine benzoate can be directly used as e-cigarette oil.

[0066] Example 2

[0067] Analysis and testing of L-nicotine benzoate

[0068] The separation and analysis methods of nicotine optical isomers mainly include gas chromatography (GC), gas chromatography-mass spectrometry (GC-MS), high performance liquid chromatography-diode array detector (HPLC-DAD), capillary electrophoresis, nuclear magnetic resonance (NMR), electronic circular dichroism, super convergence chromatography, etc. Similarly, nicotine benzoate optical isomers can also be separated and analyzed by high performance liquid chromatography-diode array detector method. The key to the separation of nicotine benzoate optical isomers lies in the chromatographic column. In this embodiment, CHIRALPAK-IC chromatographic column is used for analysis, and the instrument adopts Agilent 1290 high performance liquid chromatograph, and Agilent 1290 high performance liquid chromatograph-diode array detector (HPLC-DAD) is used to analyze the sample. Under the conditions of suitable detection wavelength, the appropriate chromatographic column, mobile phase and mobile phase additive are selected by experiment, the flow rate is 1.0mL / min, isocratic elution, and the injection volume is 10μL. The preparation method of the mobile phase is as follows: prepare 1L of mobile phase mixed solution, add 1mL of mobile phase additive, and mix well.

[0069] Accurately weigh a fixed mass of nicotine benzoate racemate, dissolve it in n-hexane, and prepare a standard stock solution. Dilute the standard stock solution to solutions with different concentration gradients, prepare a standard solution series, and use it to fit the standard curve. The standard solution of nicotine benzoate optical isomers is stored at -20°C in the dark. The HPLC-DAD method is used to determine the standard series of solutions of nicotine benzoate optical isomers to obtain the peak areas of left-handed and right-handed. The standard curve is established by the mass concentration and area of ​​each compound, and the retention time of the left-handed and right-handed optical isomers of nicotine benzoate is obtained at the same time.

[0070] The L-nicotine benzoate obtained in Example 1 was prepared into a target solution, and the L-nicotine benzoate in the target solution was determined by the same method to obtain the retention time of the target. By comparing the retention times obtained in the standard solution and the target solution, the retention time in the target solution was consistent with the retention time of the L-nicotine benzoate in the standard solution, indicating that the L-nicotine benzoate was separated in Example 1.

[0071] The above are only preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent structural changes made using the contents of the present invention's specification and drawings, or directly / indirectly applied in other related technical fields, are included in the patent protection scope of the present invention.

Claims

1. A method for resolving racemic nicotine salt, characterized in that: The following steps are involved: putting racemic nicotine and benzoic acid into a reaction vessel, heating and stirring, so that the racemic nicotine and the benzoic acid react to obtain liquid racemic nicotine benzoate; maintaining the temperature of the liquid racemic nicotine benzoate at 40° C. to 45° C. to obtain a solid-liquid mixture of racemic nicotine benzoate; The solid-liquid mixture of racemic nicotine benzoate is allowed to stand for more than 2 hours; separating the racemic nicotine benzoate in the solid-liquid mixture to separate levorotatory nicotine benzoate and dextrorotatory nicotine benzoate; wherein the molar ratio of the racemic nicotine to the benzoic acid is (1:1)-(1:1.2); The heating temperature is 60°C±5°C.

2. The method for resolving racemic nicotine salt according to claim 1, wherein: The step of adding racemic nicotine and benzoic acid into a reaction vessel, heating and stirring, and reacting the racemic nicotine and benzoic acid to obtain liquid racemic nicotine benzoate includes the following steps: First, racemic nicotine is added into a reaction container, and then benzoic acid is added into the reaction container. The mixture is heated and stirred to allow the racemic nicotine and the benzoic acid to react to obtain liquid racemic nicotine benzoate.

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