Preparation method and purification method of chiral 6-methyl nicotine

Abstract

The present invention relates to the field of chemical synthesis technology. Specifically, the present invention provides a method for preparing chiral 6-methyl-nicotine, by ingeniously selecting different protecting groups for two hydroxyl groups on the raw material chiral 1-(6-methylpyridine-3-yl)butyl-1,4-diol, and obtaining a better reaction result. The present invention also provides a method for purifying (S)-6-methyl-nicotine, which is simple in means and improves the chiral purity and chemical purity of (S)-6-methyl-nicotine.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and specifically relates to a preparation method and a purification method of chiral 6-methyl nicotine. Background Art

[0002] Nicotine, commonly known as nicotine, is an alkaloid present in solanaceous plants (Solanum) and is also an important component of tobacco. It is a foul-smelling, bitter-tasting, colorless and transparent oily liquid. In agricultural production, nicotine is a widely used insecticide; in the medical field, nicotine can be used as a smoking cessation drug to relieve withdrawal symptoms by providing a low-dose sustained-release nicotine. 6-Methyl nicotine is a compound in which the 6-position of nicotine pyridine is substituted by a methyl group. It is commonly used in medical and scientific research, can also be used to relieve the tobacco withdrawal syndrome of smokers, and can also be used in the research of nervous system and cardiovascular system diseases.

[0003] Many synthesis methods of nicotine have been disclosed in the prior art, and there is little research on 6-methyl nicotine. CN117164553A discloses a synthesis method of methyl nicotine, but this method cannot obtain chiral 6-methyl nicotine. The patent CN115611857A mentions that the content of levorotatory 6-methyl nicotine is as high as more than 70%. When used in e-cigarette products, the dosage is lower, and the satisfaction and throat hit are stronger, with a good sensory experience, but it cannot completely obtain a single chiral 6-methyl nicotine. Summary of the Invention

[0004] The present invention provides a preparation method of chiral 6-methyl nicotine. The present invention cleverly selects different protecting groups for the two hydroxyl groups on the raw material chiral 1-(6-methylpyridin-3-yl)butane-1,4-diol, making such reactions more smooth when synthesizing 6-methyl nicotine, with better reaction results, and obtaining good results in terms of product yield and chiral purity. The present invention also provides a purification method of (S)-6-methyl nicotine. By salifying the crude product of (S)-6-methyl nicotine with phthalic acid, the chiral purity of (S)-6-methyl nicotine is improved by a simple means.

[0005] Specifically, the present invention provides a preparation method of chiral 6-methyl nicotine, including:

[0006]

[0007] S1: Reacting chiral 1-(6-methylpyridin-3-yl)butane-1,4-diol with a first hydroxyl protecting reagent in a first organic solvent

[0008] S2: After post-treatment, it reacts with a second hydroxyl protecting reagent to obtain an intermediate in which both hydroxyl groups are protected by protecting groups; wherein, the first hydroxyl protecting reagent and the second hydroxyl protecting reagent are different;

[0009] S3: The intermediate reacts with methylamine gas in a second organic solvent to obtain chiral 6-methylnicotine.

[0010] In some embodiments,

[0011] The first hydroxyl protecting reagent is selected from one of methyl halide, ethyl halide, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methylsulfonyl chloride, ethylsulfonyl chloride, methanesulfonic acid, ethanesulfonic acid, acetic anhydride, trifluoromethanesulfonic anhydride, methyl acetate, ethyl acetate, benzyl halide, benzyloxycarbonyl halide, benzyloxycarbonyl alkane ester, benzoyl halide, benzoyl alkane ester, benzoyl halide, benzoyl alkane ester, benzenesulfonyl halide and benzenesulfonyl alkane ester;

[0012] The second hydroxyl protecting reagent is selected from one of methyl halide, ethyl halide, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methylsulfonyl chloride, ethylsulfonyl chloride, methanesulfonic acid, ethanesulfonic acid, acetic anhydride, trifluoromethanesulfonic anhydride, methyl acetate, ethyl acetate, benzyl halide, benzyloxycarbonyl halide, benzyloxycarbonyl alkane ester, benzoyl halide, benzoyl alkane ester, benzoyl halide, benzoyl alkane ester, benzenesulfonyl halide and benzenesulfonyl alkane ester.

[0013] In some embodiments,

[0014] The first hydroxyl protecting reagent is selected from one of methylsulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride;

[0015] The second hydroxyl protecting reagent is selected from one of methylsulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride.

[0016] In some embodiments, in step S1, after the reaction of chiral 1-(6-methylpyridin-3-yl)butane-1,4-diol with the first hydroxyl protecting reagent in the first organic solvent is completed, through a water quenching reaction, the first organic phase reacts with the second hydroxyl protecting reagent to obtain an intermediate with different first and second hydroxyl protecting groups.

[0017] In some embodiments, the first hydroxyl protecting reagent reacts with the 4-position hydroxyl group of 1-(6-methylpyridin-3-yl)butane-1,4-diol, and the second hydroxyl protecting reagent reacts with the 1-position hydroxyl group of 1-(6-methylpyridin-3-yl)butane-1,4-diol.

[0018] In some embodiments, the first hydroxyl protecting reagent is p-toluenesulfonyl chloride; the second hydroxyl protecting reagent is methylsulfonyl chloride or trifluoromethanesulfonic anhydride.

[0019] In some embodiments, methylsulfonyl chloride or trifluoromethanesulfonic anhydride as the second hydroxyl protecting reagent participates in the reaction under the action of N-methylmorpholine or N-methylpiperazine.

[0020] On the other hand, the present invention also provides a purification method for 6-methyl-(S)-nicotine, comprising:

[0021] 1) Salifying 6-methyl-(S)-nicotine crude product with phthalic acid in a third organic solvent to produce crude (S)-nicotine phthalate;

[0022] 2) Adding a fourth organic solvent to the third solvent in step 1) to precipitate (S)-nicotine phthalate, and filtering;

[0023] 3) Dissolving the (S)-nicotine phthalate obtained in step 3) in a fifth organic solvent, adjusting the pH to 9-10 with an aqueous alkali solution, and concentrating the fifth organic phase to obtain high-purity (S)-nicotine.

[0024] In some embodiments, the third organic solvent is one or more of alcohols or chloroalkane solvents; the fourth organic solvent is one or more of ether or alkane solvents; the fifth organic solvent is one or more of water-immiscible solvents.

[0025] In some embodiments,

[0026] the third organic solvent is one or more of methanol, ethanol, isopropanol, and dichloromethane;

[0027] the fourth organic solvent is one or more of methyl tert-butyl ether and n-heptane;

[0028] the fifth organic solvent is one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and n-heptane.

[0029] Term Explanation

[0030] Certain embodiments of the present invention are now described in detail, and their examples are illustrated by the accompanying structural formulas and chemical formulas. The present invention is intended to cover all alternative, modification, and equivalent technical solutions, which are all included within the scope of the present invention as defined by the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the case where one or more of the incorporated documents, patents, and similar materials are different from or contradictory to the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0031] It should be further recognized that certain features of the present invention, for clarity, are described in multiple independent embodiments, but can also be provided in combination in a single embodiment. Conversely, various features of the present invention, for brevity, are described in a single embodiment, but can also be provided individually or in any suitable sub-combination.

[0032] Unless otherwise stated, all scientific and technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. All patents and published publications referred to in the present invention are incorporated herein by reference in their entirety.

[0033] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials, or characteristics described in connection with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0034] In the following content, all the numbers disclosed herein are approximate values whether or not words such as "about" or "approximately" are used. There may be differences of 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20% etc. in the numerical value of each number. Whenever a number with an N value is disclosed, any number with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" means plus or minus. Description of the Drawings

[0035] Figure 1 1H NMR spectrum of (S)-6-Me-nicotine in Example 2.

[0036] Figure 2 (±)-6-Me-nicotine chiral HPLC chromatogram.

[0037] Figure 3 Chiral HPLC chromatogram of (S)-6-Me-nicotine in Example 4.

[0038] Figure 4 GC chromatogram of (S)-6-Me-nicotine in Example 4.

[0039] Figure 5 (±)-2-Me-Nicotine chiral HPLC chromatogram.

[0040] Figure 6 Chiral HPLC chromatogram of (S)-2-Me-nicotine in Example 5.

[0041] Figure 7 GC chromatogram of (S)-2-Me-nicotine in Example 5.

[0042] Figure 8 1H NMR spectrum of (S)-2-Me-nicotine in Example 5. Detailed implementation manners

[0043] To make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and do not constitute any limitation to the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessarily confusing the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0044] The reagents used in the present invention can all be purchased from the market or can be prepared by the methods described in the present invention.

[0045] CN 114874134 A discloses a method for synthesizing chiral nicotine, which uses compound (1) as the starting material and finally obtains chiral nicotine with a high ee value through steps such as asymmetric hydrogenation catalytic reduction. The ee value measured by HPLC is 99%, the purity analyzed by GC is 97%, 26.6 g of pure (S)-nicotine product is obtained after distillation with a yield of 82%, the ee value measured by HPLC is 99%, and the purity analyzed by GC is 99.7%.

[0046]

[0047] Method exploration research:

[0048] Research experiment 1: Synthesize (S)-6-methyl nicotine by the method disclosed in CN 114874134 A

[0049]

[0050] S1: The reaction process is the same as that in Example 2 of CN 114874134 A. The yield of compound c is 75.2%.

[0051] S2: The reaction process is the same as that in Example 19 of CN 114874134 A. The yield of compound d is 94.5%.

[0052] S3 and S4: The reaction process is the same as that in Example 20 of CN 114874134 A:

[0053] Weigh (R)-6-Me-NG-3 (20.0 g, 110.3 mmol), add 200 mL of dichloromethane and triethylamine (33.5 g, 3.0 eq.), control the temperature of the reaction system to -10°C, slowly dropwise add MsCl (31.6 g, 2.5 eq.) into the reaction system. After adding, control the temperature to 0°C - 5°C. After reacting for 1 h and monitoring by TLC to ensure no raw material of NG-3 remains, add 50 mL of water to quench the reaction. Extract the aqueous phase with DCM three times (50 mL * 3). Combine the organic phases and wash them once with 20 mL of saturated NaHCO3 solution. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to one-fourth of the volume. At -10°C, dropwise add 36 mL of methylamine in methanol solution (33 wt% in EtOH) to the above-obtained concentrated solution, stir at -10°C for 24 h. After the reaction is completed, directly rotary evaporate the excess methylamine. Dilute the residue with water, extract it with DCM three times. Dry and concentrate the organic phase to obtain 10.5 g of crude (S)-6-Me-nicotine. The chemical purity of the crude nicotine measured by HPLC is 83.1%, the yield is 54.0%, the chiral purity is 51.7% ee. After distillation, 7.6 g of pure (S)-6-Me-nicotine is obtained, the yield is 39.1%, the purity measured by HPLC is 96.2%, and the chiral purity is 51.7% ee.

[0054] Research Experiment 2: Synthesize chiral (S)-2-methyl-nicotine using the method disclosed in CN 114874134 A

[0055]

[0056] Weigh compound 3-1 (20.0 g, 110.3 mmol), add 200 mL of dichloromethane and triethylamine (33.5 g, 3.0 eq.), control the temperature of the reaction system to -10 °C, slowly dropwise add MsCl (31.6 g, 2.5 eq.) into the reaction system. After addition, control the temperature to 0 °C - 5 °C. After reacting for 1 h and monitoring by TLC that there is no raw material of NG-3, add 50 mL of water to quench the reaction. Extract the aqueous phase with DCM three times (50 mL * 3). Combine the organic phases and wash them once with 20 mL of saturated NaHCO₃ solution. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to one-fourth of the volume. Dropwise add 36 mL of methylamine in methanol solution (33 wt% in EtOH) to the above-obtained concentrated solution, stir at -10 °C for 24 h. After the reaction is completed, directly rotary evaporate the excess methylamine. Dilute the residue with water, extract it with DCM three times. Dry and concentrate the organic phase to obtain 9.4 g of crude 2-Me-(S)-nicotine. The chemical purity of the crude nicotine measured by HPLC is 81.6%, the yield is 48.3%, and the chiral purity is 45.3% ee. After distillation, 6.8 g of pure 2-Me-(S)-nicotine is obtained, the yield is 34.5%, the purity measured by HPLC is 98.5%, and the chiral purity is 45.3% ee.

[0057] Research Experiment 3: Synthesize 6-chloronicotine using the method disclosed in CN 114874134 A

[0058]

[0059] S1: The reaction process is the same as that in Example 2 of CN 114874134 A. The chlorine atom on compound c participates in the reaction and is replaced by a tert-butoxy group, and the target product cannot be obtained.

[0060] In summary, CN 114874134 A has obtained good experimental results in synthesizing nicotine. However, when using the method of synthesizing nicotine in CN114874134 A to prepare nicotine with substituents on the pyridine, the expected effects similar to those of synthesizing nicotine in CN 114874134 A have not been obtained. This may be because the electronic effect or steric hindrance affects the activity and basicity of the pyridine, resulting in the decomposition of the chiral 1,4-diol compounds substituted on the pyridine with two Ms substituents in the presence of weak nucleophiles such as water or instability at high temperature. In particular, the OMs group connected to the chiral carbon is easily nucleophilically substituted by chloride ions in the reaction system to undergo an SN2 reaction, resulting in configuration inversion, thereby reducing both the chiral purity and the yield of the substituted nicotine product.

[0061] In view of this, in order to further obtain a legal method for nicotine with substituents on the pyridine, the present invention conducts research on the synthesis of 6-methyl-nicotine.

[0062] Example 1: Synthesis of chiral (S)-6-methyl-nicotine

[0063]

[0064] Weigh compound 1-1 (30.0 g, 165.5 mmol), DMAP (0.20 g, 1.65 mmol), and 150 mL of dichloromethane into a 250 mL three-necked flask. After replacing nitrogen three times, place the reaction bottle in a low temperature trough. After the internal temperature drops to -5°C to -10°C, add pyridine (17.0 g, 1.3 eq.), and then add TsCl (41.0 g, 1.3 eq.) in three batches. After adding, control the temperature to 0°C to 5°C. After reacting for 2 hours, TLC monitoring shows that there is no compound 1-1 raw material. Add saturated Na2CO3 solution (50 mL) to stir and quench the reaction, and adjust the pH to 7 to 8. The organic phase is extracted with DCM (30 mL*2). Twice, the combined organic phase was dried over anhydrous sodium sulfate and transferred to a dry 250mL three-necked flask, cooled to -5℃~-10℃, triethylamine (36.8g, 2.2eq.) and MsCl (28.4g, 1.5eq.) were added dropwise, and the temperature was controlled to 0℃~5℃ after the addition was completed. After the reaction was completed for 2h, TLC monitoring showed that there was no intermediate, and the organic phase was washed with 50mL saturated brine, dried and cooled to -10℃, methylamine gas was introduced for 2h, and the temperature was controlled to 0℃ and stirred for 24h. After the reaction was completed by TLC detection, the excess methylamine gas was pumped away with a water pump, the residue was dissolved and stirred with 30mL ethyl acetate, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 25.8g of crude (S)-6-Me-nicotine. HPLC measured the chemical purity of crude nicotine to be 93.9%, 88.4% yield, and chiral purity to be 91.8% ee.

[0065] Example 2: Synthesis of Chiral (S)-6-Methyl-Nicotine

[0066]

[0067] Weigh compound 1-1 (30.0 g, 165.5 mmol), DMAP (0.20 g, 1.65 mmol), and 150 mL of dichloromethane into a 250 mL three-necked flask. After replacing nitrogen three times, place the reaction bottle in a low temperature trough. After the internal temperature drops to -5°C to -10°C, add pyridine (17.0 g, 1.3 eq.), then add TsCl (41.0 g, 1.3 eq.) in three batches. After the addition is complete, control the temperature to 0°C to 5°C. After reacting for 2 hours, TLC monitoring shows that there is no raw material of compound 1-1. Add saturated Na2CO3 solution (50 mL) to stir and quench the reaction and adjust the pH to 7 to 8. The organic phase is extracted twice with DCM (30 mL*2). The organic phase was dried over anhydrous sodium sulfate and transferred to a dry 250mL three-necked flask, cooled to -5°C to -10°C, N-methylmorpholine (36.8g, 2.2eq.) and MsCl (28.4g, 1.5eq.) were added dropwise, and the temperature was controlled to 0°C to 5°C after the addition was complete. After reacting for 2h, morpholine hydrochloride was precipitated. After TLC monitoring of no intermediates, the organic phase was filtered under reduced pressure, the filtrate was dried and cooled to -10°C, methylamine gas was introduced for 2h, and the temperature was controlled to 0°C and stirred for 24h. After the reaction was completed by TLC detection, the excess methylamine gas was pumped away with a water pump, the residue was dissolved and stirred with 30mL ethyl acetate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 27.4g of crude (S)-6-Me-nicotine. HPLC measured the chemical purity of the crude nicotine to be 95.6%, 94.0% yield, and 97.5% ee. (S)-6-Me-Nicotine H NMR analysis is as follows: 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=2.0Hz,1H),7.58(dd,J=8.0,2.4Hz,1H),7.18(d,J=8.0Hz,1H),3.18–3.09(m,1H),3.03(t,J=8. 4Hz,1H),2.43(s,3H),2.25–2.16(m,1H),2.16–2.08(m,1H),2.04(s,3H)1.90–1.78(m,1H),1.77–1.69(m,1H),1.62–1.49(m,1H).

[0068] In this experiment, the inventors surprisingly found that in a reaction involving a second protecting agent, such as a reaction involving MsCl, using N-methylmorpholine instead of TEA can achieve better results, which is completely unexpected.

[0069] Example 3: Synthesis of chiral 6-methyl-nicotine

[0070]

[0071] Weigh compound 1-1 (30.0 g, 165.5 mmol), DMAP (0.20 g, 1.65 mmol), and 150 mL of dichloromethane into a 250 mL three-necked flask. After replacing nitrogen three times, place the reaction bottle in a low-temperature trough. After the internal temperature drops to -5°C to -10°C, add pyridine (17.0 g, 1.3 eq.), and then add TsCl (41.0 g, 1.3 eq.) in three batches. After the addition is complete, control the temperature to 0°C to 5°C. After reacting for 2 hours, TLC monitoring shows that there is no raw material of compound 1-1. Then add saturated Na2CO3 solution (50 mL) to stir and quench the reaction and adjust the pH to 7 to 8. The organic phase is extracted twice with DCM (30 mL*2). The combined organic phases were dried over anhydrous sodium sulfate and transferred to a dry 250 mL three-necked flask, cooled to -5°C to -10°C, N-methylmorpholine (50.2 g, 3.0 eq.) and Tf2O (60.7 g, 1.3 eq.) were added in batches, and the temperature was controlled to 0°C to 5°C after the addition was completed. After the reaction was completed for 2 hours, TLC monitoring showed that there was no intermediate. The organic phase was washed with 50 mL of saturated brine, dried, cooled to -10°C, methylamine gas was introduced for 2 hours, and the temperature was controlled to 0°C and stirred for 24 hours. After the reaction was completed by TLC detection, the excess methylamine gas was pumped away with a water pump, the residue was dissolved and stirred with 30 mL of ethyl acetate, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 26.3 g of crude (S)-6-Me-nicotine. HPLC measured the chemical purity of the crude nicotine to be 95.0%, the yield was 90.1%, and the chiral purity was 96.0% ee.

[0072] In this embodiment, compared with embodiment 2, the second protective agent was changed, and excellent results were also obtained under the action of N-methylmorpholine.

[0073] In addition, the present invention studied the synthesis of (R)-6-Me-NG by selecting S-configuration raw materials, with similar results.

[0074] Through research, it was found that for the synthesis of 6-methyl-nicotine, when different protecting groups are used for the two hydroxyl groups during the synthesis process, the entire reaction and operation can be smoother and ultimately achieve better results. Based on the experimental results, it is reasonable to speculate that the two hydroxyl groups on the substrate have different activities. TsCl reacts preferentially with primary alcohols, while MsCl is too active to effectively distinguish the two hydroxyl groups, which makes the intermediates of the two Ms groups unstable. After the primary alcohol is protected by the Ts group, it is stable after washing with water, and its activity is relatively low. At the same time, it can also remove chloride ions in the reaction system. In addition, by replacing triethylamine with N-methylmorpholine, the reaction byproduct morpholine hydrochloride can be precipitated from the reaction system and recovered, reducing the interference of chloride ions caused by this step, indirectly improving the purity of the reaction solution, and no water washing is required, avoiding the problem of the intermediate decomposing in water.

[0075] Example 4: Purification of Chiral (S)-6-Methyl-Nicotine

[0076] According to the method of Example 2, (R)-1-(6-Methylpyridin-3-yl)butane-1,4-diol was used as the raw material to synthesize (S)-6-methyl-nicotine. 27.4 g of the crude product was obtained and added with 28.0 g of phthalic acid and 28 mL of methanol. After heating to 60 °C and reacting for 1 h, the temperature was lowered to 40 °C, and 140 mL of MTBE was slowly added dropwise. After addition, the mixture was restored to room temperature and stirred for 16 h. The solid was filtered under reduced pressure, and dried in vacuo at 40 °C to obtain 52.7 g of (S)-6-methyl-nicotine phthalate. It was dissolved in 50 mL of DCM, adjusted to pH 9-10 with sodium hydroxide solution, and the aqueous phase was extracted twice with DCM (30 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 25.9 g of pure (S)-6-methyl-nicotine with a yield of 94.5%. The purity measured by GC was 99.92%, and the chiral HPLC purity was 99.5% ee.

[0077] The present invention also provides a method for further purifying (S)-6-methyl-nicotine by forming a salt with phthalic acid to obtain a product with higher chiral purity.

[0078] Example 5: Synthesis of Chiral (S)-2-Methyl-Nicotine

[0079]

[0080] Weigh compound 2-1 (30.0 g, 165.5 mmol), DMAP (0.20 g, 1.65 mmol), and 150 mL of dichloromethane into a 250 mL three-necked flask. After replacing nitrogen three times, place the reaction bottle in a low-temperature trough. After the internal temperature drops to -5°C to -10°C, add pyridine (17.0 g, 1.3 eq.), and then add TsCl (41.0 g, 1.3 eq.) in three batches. After the addition is complete, control the temperature to 0°C to 5°C. After reacting for 2 hours, TLC monitoring shows that there is no compound 2-1 raw material. Add saturated Na2CO3 solution (50 mL) to stir and quench the reaction, and adjust the pH to 7 to 8. The organic phase is extracted twice with DCM (30 mL*2). The combined organic phases were dried over anhydrous sodium sulfate and transferred to a dry 250 mL three-necked flask, cooled to -5°C to -10°C, N-methylmorpholine (36.8 g, 2.2 eq.) and MsCl (28.4 g, 1.5 eq.) were added dropwise, and the temperature was controlled to 0°C to 5°C after the addition. After reacting for 2 hours, TLC monitored the absence of intermediates, and the organic phase was washed with 50 mL of saturated brine, dried, cooled to -10°C, methylamine gas was introduced for 2 hours, and the temperature was controlled to 0°C and stirred for 24 hours. After the reaction was completed by TLC detection, the excess methylamine gas was pumped away with a water pump, the residue was dissolved and stirred with 30 mL of ethyl acetate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 25.7 g of crude (S)-2-Me-nicotine. The chemical purity of the crude nicotine was 94.2% and the yield was 88.1% by HPLC. After distillation, the HPLC purity of (S)-2-Me-nicotine was 98.37% and the chiral purity was 94.9% ee. The hydrogen spectrum nuclear magnetic analysis of (S)-2-Me-nicotine is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.34(dd,J=4.8,1.6Hz,1H),7.81(dd,J=8.0,2.0Hz,1H),7.12(dd,J=8.0,4.8Hz,1H),3. 34–3.18(m,2H),2.55(s,3H),2.36–2.21(m,2H),2.17(s,3H),1.97–1.85(m,1H),1.86–1.73(m,1H),1.60–1.47(m,1H).

[0081] Example 6: Synthesis of Chiral (S)-2-Methyl-Nicotine

[0082]

[0083] Weigh compound 2-1 (30.0 g, 165.5 mmol), DMAP (0.20 g, 1.65 mmol), and add 150 mL of dichloromethane to a 250 mL three-necked flask. After displacing nitrogen three times, place the reaction flask in a low-temperature bath. When the internal temperature drops to -5°C to -10°C, add pyridine (17.0 g, 1.3 eq.), and then add TsCl (41.0 g, 1.3 eq.) in three portions. After adding, control the temperature at 0°C to 5°C. After reacting for 2 h and monitoring by TLC to ensure no raw material of compound 2-1 remains, add saturated Na2CO3 solution (50 mL), stir to quench the reaction and adjust the pH to 7 - 8. Extract the organic phase twice with DCM (30 mL * 2). Combine the organic phases, dry over anhydrous sodium sulfate, and transfer to a dry 250 mL three-necked flask. Cool to -5°C to -10°C, add N-methylmorpholine (50.2 g, 3.0 eq.) and add Tf2O (60.7 g, 1.3 eq.) in portions. After adding, control the temperature at 0°C to 5°C. After reacting for 2 h and monitoring by TLC to ensure no intermediate remains, wash the organic phase with 50 mL of saturated brine, dry, and cool to -10°C. Pass methylamine gas for 2 h and then control the temperature at 0°C and stir for 24 h. After detecting the end of the reaction by TLC, use a water pump to evacuate the excess methylamine gas. Dissolve the residue in 30 mL of ethyl acetate, stir, filter under reduced pressure. Concentrate the filtrate under reduced pressure to obtain 24.5 g of crude (S)-2-Me-nicotine. The chemical purity of the crude nicotine measured by HPLC is 93.8%, the yield is 84.0%, and the enantiomeric purity is 94.5% ee.

[0084] The method of the present invention has been described through preferred embodiments. It is obvious that relevant personnel can make changes or appropriate modifications and combinations to the methods and applications described herein within the content, spirit, and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can draw on the content of this article and appropriately modify the process parameters to achieve it. It should be particularly noted that all such similar substitutions and modifications are obvious to those skilled in the art and are all considered to be included in the present invention.

Claims

1. A method for preparing chiral 6-methyl nicotine, characterized in that: include: ； S1: After the chiral 1-(6-methylpyridin-3-yl)butane-1,4-diol and the first hydroxyl protecting agent react in the first organic solvent, the reaction is quenched with water, and the first hydroxyl protecting agent reacts with the 4-hydroxyl group of the 1-(6-methylpyridin-3-yl)butane-1,4-diol; S2: after post-treatment, the first organic phase reacts with a second hydroxyl protecting agent to obtain an intermediate having different first and second hydroxyl protecting agents; the second hydroxyl protecting agent reacts with the 1-hydroxyl group of 1-(6-methylpyridin-3-yl)butane-1,4-diol; S3: the intermediate reacts with methylamine gas in a second organic solvent to obtain chiral 6-methylnicotine; The first hydroxyl protecting reagent is p-toluenesulfonyl chloride; The second hydroxyl protecting agent is selected from: methanesulfonyl chloride, ethylsulfonyl chloride, and trifluoromethanesulfonic anhydride.

2. The preparation method according to claim 1, characterized in that: The first hydroxyl protecting agent is p-toluenesulfonyl chloride; the second hydroxyl protecting agent is methanesulfonyl chloride or trifluoromethanesulfonic anhydride.

3. The preparation method according to claim 2, characterized in that: Methanesulfonyl chloride or trifluoromethanesulfonic anhydride as the second hydroxyl protecting agent participates in the reaction under the action of N-methylmorpholine or N-methylpiperazine.

4. A method for purifying 6-methyl-(S)-nicotine, characterized in that: include: 1) Preparing crude 6-methyl-(S)-nicotine according to any one of claims 1 to 3; salting the crude 6-methyl-(S)-nicotine with phthalic acid in a third organic solvent to produce a crude 6-methyl-(S)-nicotine phthalate; 2) adding a fourth organic solvent to the third solvent in step 1) to precipitate 6-methyl-(S)-nicotine phthalate, and filtering; 3) dissolving the 6-methyl-(S)-nicotine phthalate obtained in step 2) in a fifth organic solvent, adjusting the pH to 9-10 with an alkaline aqueous solution, and concentrating the fifth organic phase to obtain high-purity 6-methyl-(S)-nicotine.

5. The purification method according to claim 4, characterized in that The third organic solvent is one or more of alcohol or chlorinated alkane solvents; the fourth organic solvent is one or more of ether or alkane solvents; and the fifth organic solvent is one or more of water-immiscible solvents.

6. The purification method according to claim 4, characterized in that The third organic solvent is one or more of methanol, ethanol, isopropanol, and dichloromethane; The fourth organic solvent is one or more of methyl tert-butyl ether and n-heptane; The fifth organic solvent is one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and n-heptane.

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