Preparation method and purification method of chiral 6-methyl nicotine

Abstract

The invention relates to the technical field of formation synthesis. Specifically, the invention provides a preparation method of chiral 6-methyl-nicotine, different protecting groups are ingeniously selected for two hydroxyl groups on a raw material chiral 1-(6-methylpyridine-3-yl) butane-1, 4-diol, and a better reaction result is obtained. The invention further provides a purification method of the (S)-6-methyl-nicotine, the means is simple, and the chiral purity and the chemical purity of the (S)-6-methyl-nicotine are improved.

Description

Technical Field

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

[0002] Nicotine, commonly known as nicotine, is an alkaloid found in Solanaceae plants (Solanum), and is also an important component of tobacco. It is an unpleasant, bitter, colorless, transparent, oily liquid substance. In agricultural production, nicotine is a widely used pesticide; in the medical field, nicotine can be used as a smoking cessation drug to relieve withdrawal symptoms by providing low-dose sustained-release nicotine. 6-Methylnicotine is a nicotine pyridine with a methyl group at the 6th position. It is commonly used in medical and scientific research, and can also be used to relieve tobacco withdrawal syndrome in smokers who quit smoking, and can also be used in the study of nervous system and cardiovascular system diseases.

[0003] Many methods for synthesizing nicotine are disclosed in the prior art, but little research has been done on 6-methyl nicotine. CN117164553A6 discloses a method for synthesizing methyl nicotine, but this method cannot obtain chiral 6-methyl nicotine. Patent CN115611857A mentions that the content of left-handed 6-methyl nicotine is as high as 70% or more. When used in electronic cigarette products, the usage amount is lower, the satisfaction and throat hit are strong, and it has a good sensory experience, but it cannot completely obtain single chiral 6-methyl nicotine. Summary of the invention

[0004] The present invention provides a method for preparing chiral 6-methylnicotine. 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, so that such reaction is smoother and has better reaction results when synthesizing 6-methylnicotine, and obtains better results in product yield and chiral purity. The present invention also provides a method for purifying (S)-6-methyl-nicotine, which improves the chiral purity of (S)-6-methyl-nicotine by salting crude (S)-6-methyl-nicotine with phthalic acid using simple means.

[0005] Specifically, the present invention provides a method for preparing chiral 6-methyl nicotine, comprising:

[0006]

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

[0008] S2: after post-treatment, reacting with a second hydroxyl protecting agent to obtain an intermediate in which both hydroxyl groups are protected by protecting groups; wherein the first hydroxyl protecting agent and the second hydroxyl protecting agent 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 agent is selected from the group consisting of: methyl halide, ethyl halide, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl sulfonic acid, ethyl sulfonic 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, benzyl halide, benzyl alkane ester, benzyl sulfonyl halide and benzyl sulfonyl alkane ester;

[0012] The second hydroxyl protecting agent is selected from the group consisting of: methyl halide, ethyl halide, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl sulfonic acid, ethyl sulfonic 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, benzyl halide and benzenesulfonyl alkane ester.

[0013] In some embodiments,

[0014] The first hydroxyl protecting agent is selected from the group consisting of: methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, and p-toluenesulfonyl chloride;

[0015] The second hydroxyl protecting agent is selected from: methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, and p-toluenesulfonyl chloride.

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

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

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

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

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

[0021] 1) salting crude 6-methyl-(S)-nicotine 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 alkaline aqueous 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 an alcohol or a chlorinated alkane solvent; the fourth organic solvent is one or more of an ether or an alkane solvent; and the fifth organic solvent is one or more of a water-immiscible solvent.

[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] Terminology

[0030] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art 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 event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0031] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0032] Unless otherwise specified, all 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 belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

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

[0034] In the following, all numbers disclosed herein are approximate, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% is explicitly disclosed, where "+ / -" means plus or minus. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0036] Figure 2 Chiral HPLC spectrum of (±)-6-Me-nicotine.

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

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

[0039] Figure 5 Chiral HPLC spectrum of (±)-2-Me-nicotine.

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

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

[0042] Figure 8 H NMR spectrum of (S)-2-Me-nicotine in Example 5. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of 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 be purchased from the market or prepared by the method described in the present invention.

[0045] CN 114874134 A discloses a method for synthesizing chiral nicotine, which uses compound (1) as a 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%, and the purity of GC analysis is 97%. After distillation, 26.6g of pure (S)-nicotine is obtained, with a yield of 82%, and the ee value measured by HPLC is 99%, and the purity of GC analysis is 99.7%.

[0046]

[0047] Method Exploration Research:

[0048] Research experiment 1: Synthesis of (S)-6-methylnicotine using the method disclosed in CN 114874134 A

[0049]

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

[0051] S2: The reaction process is the same as 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 of 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 add MsCl (31.6 g, 2.5 eq.) to the reaction system, and control the temperature to 0 ° C ~ 5 ° C after the addition. After reacting for 1 hour, TLC monitors the absence of NG-3 raw materials, add 50 mL of water to quench, and the aqueous phase is extracted with DCM 3 times (50 mL * 3). The organic phases are combined and washed once with 20 mL of NaHCO3 saturated solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to one-quarter of the volume. -10°C, 36 mL of methylamine alcohol solution (33 wt% in EtOH) was added dropwise to the concentrated solution obtained above, and the mixture was stirred at -10°C for 24 h. After the reaction was completed, the excess methylamine was directly spun off, the residue was diluted with water, and extracted with DCM for 3 times. The organic phase was dried and concentrated to obtain 10.5 g of crude (S)-6-Me-nicotine. The chemical purity of the crude nicotine was 83.1% by HPLC, the yield was 54.0%, and the chiral purity was 51.7% ee. After distillation, 7.6 g of pure (S)-6-Me-nicotine was obtained, with a yield of 39.1%. The purity was 96.2% by HPLC, and the chiral purity was 51.7% ee.

[0054] Research experiment 2: Synthesis of 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 add MsCl (31.6 g, 2.5 eq.) to the reaction system, and control the temperature to 0 ° C ~ 5 ° C after the addition. After reacting for 1 hour, TLC monitors the absence of NG-3 raw materials, add 50 mL of water to quench, and extract the aqueous phase with DCM 3 times (50 mL * 3). The organic phases are combined and washed once with 20 mL of NaHCO3 saturated solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to one-quarter volume. 36 mL of methylamine alcohol solution (33 wt% in EtOH) was added dropwise to the concentrated solution obtained above, and the mixture was stirred at -10°C for 24 h. After the reaction was completed, the excess methylamine was directly spun off, and the residue was diluted with water and extracted three times with DCM. The organic phase was dried and concentrated to obtain 9.4 g of crude 2-Me-(S)-nicotine. The chemical purity of the crude nicotine was 81.6% by HPLC, the yield was 48.3%, and the chiral purity was 45.3% ee. After distillation, 6.8 g of pure 2-Me-(S)-nicotine was obtained, with a yield of 34.5%. The purity was 98.5% by HPLC, and the chiral purity was 45.3% ee.

[0057] Research experiment 3: Synthesis of 6-chloronicotine using the method disclosed in CN 114874134 A

[0058]

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

[0060] In summary, CN 114874134 A obtained good experimental results for synthesizing nicotine, but the preparation of nicotine with substituents on pyridine using the CN114874134 A method for synthesizing nicotine did not achieve the expected effect similar to that of synthesizing nicotine in CN 114874134 A. This may be because the electronic effect or steric hindrance affects the activity and alkalinity of pyridine, causing the two Ms substituents of the chiral 1,4-diol compounds substituted with pyridine to decompose or become unstable at high temperatures when encountering weak nucleophiles such as water, especially the OMs group connected to the chiral carbon is easily nucleophilically substituted by the chloride ion in the reaction system to undergo an SN2 reaction, resulting in a configuration flip, thereby reducing the chiral purity and yield of the substituted nicotine product.

[0061] In this regard, in order to further obtain a legal method for nicotine with substituents on pyridine, the present invention studies 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, (S)-6-methyl-nicotine was synthesized using (R)-1-(6-methylpyridin-3-yl)butane-1,4-diol as a raw material. 27.4 g of the crude product was added with 28.0 g of phthalic acid and 28 mL of methanol, heated to 60° C. for reaction for 1 h, then 140 mL of MTBE was slowly added dropwise when the temperature was lowered to 40° C., and the mixture was returned to room temperature and stirred for 16 h. The solid was filtered out under reduced pressure and dried in vacuo at 40° C. to obtain 52.7 g of (S)-6-methyl-nicotine phthalate, which was dissolved in 50 mL of DCM and adjusted to pH 9-10 with sodium hydroxide solution. The aqueous phase was extracted twice with DCM (30 mL*2), and the organic phases were combined, 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 purity by chiral HPLC was 99.5% ee.

[0077] The present invention also provides a method for further purifying (S)-6-methyl-nicotine by using phthalic acid to form salts, thereby obtaining 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 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 adding, 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 (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, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 24.5 g of crude (S)-2-Me-nicotine. The chemical purity of the crude nicotine was 93.8%, the yield was 84.0%, and the chiral purity was 94.5% ee as measured by HPLC.

[0084] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine 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 refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they 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: chiral 1-(6-methylpyridin-3-yl)butane-1,4-diol reacts with a first hydroxyl protecting agent in a first organic solvent; S2: after post-treatment, reacting with a second hydroxyl protecting agent to obtain an intermediate in which both hydroxyl groups are protected by protecting groups; wherein the first hydroxyl protecting agent and the second hydroxyl protecting agent are different; S3: The intermediate reacts with methylamine gas in a second organic solvent to obtain chiral 6-methylnicotine.

2. The preparation method according to claim 1, characterized in that: The first hydroxyl protecting agent is selected from the group consisting of: methyl halide, ethyl halide, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl sulfonic acid, ethyl sulfonic 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, benzyl halide, benzyl alkane ester, benzyl sulfonyl halide and benzyl sulfonyl alkane ester; The second hydroxyl protecting agent is selected from the group consisting of: methyl halide, ethyl halide, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl sulfonic acid, ethyl sulfonic 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, benzyl halide and benzenesulfonyl alkane ester.

3. The preparation method according to claim 1, characterized in that: The first hydroxyl protecting agent is selected from the group consisting of: methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, and p-toluenesulfonyl chloride; The second hydroxyl protecting agent is selected from: methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, and p-toluenesulfonyl chloride.

4. The preparation method according to any one of claims 1 to 3, characterized in that In step S1, after the chiral 1-(6-methylpyridin-3-yl)butane-1,4-diol reacts with the first hydroxyl protecting agent in the first organic solvent, the reaction is quenched with water, and the first organic phase reacts with the second hydroxyl protecting agent to obtain an intermediate having different first hydroxyl protecting groups and second hydroxyl protecting groups.

5. The preparation method according to claim 4, characterized in that: The first hydroxyl protecting agent reacts with the 4-hydroxyl group of 1-(6-methylpyridin-3-yl)butane-1,4-diol, and the second hydroxyl protecting agent reacts with the 1-hydroxyl group of 1-(6-methylpyridin-3-yl)butane-1,4-diol.

6. The preparation method according to claim 5, characterized in that: The first hydroxyl protecting agent is p-toluenesulfonyl chloride; the second hydroxyl protecting agent is methanesulfonyl chloride or trifluoromethanesulfonic anhydride.

7. The preparation method according to claim 6, 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.

8. A method for purifying 6-methyl-(S)-nicotine, characterized in that: include: 1) salting crude 6-methyl-(S)-nicotine with phthalic acid in a third organic solvent to produce crude (S)-nicotine phthalate; 2) adding a fourth organic solvent to the third solvent in step 1) to precipitate (S)-nicotine phthalate, and filtering; 3) dissolving the (S)-nicotine phthalate obtained in step 3) 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 (S)-nicotine.

9. The purification method according to claim 8, 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.

10. The purification method according to claim 8, 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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