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(11) | EP 4 140 992 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
| published in accordance with Art. 153(4) EPC |
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| (54) | METHOD FOR PREPARING S-NICOTINE |
| (57) The present invention discloses a preparation method of S-nicotine, including: performing
condensation in the presence of a base catalyst, performing cyclization through a
reflux reaction with concentrated hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone,
reacting with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone,
inducing by (+)-B-diisopinocampheyl chloroborane to produce a chiral hydroxyl group
so as to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol, performing chlorination and
cyclization in the presence of a base to obtain S-demethylnicotine, and finally performing
amine methylation to obtain S-nicotine. The present application has mild reaction
conditions and is easy to operate, and S-nicotine in a single configuration is obtained
with high selectivity; the yield and the purity of S-nicotine are high, and the steps
are simple; and the present application uses cheap and readily available nicotinate
and γ-butyrolactone as starting materials, and the cost is low, which is particularly
suitable for industrial production of S-nicotine. |
TECHNICAL FIELD
[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of S-nicotine.
BACKGROUND ART
[0002] With the rapid development of e-cigarette industry, the demand of nicotine, which is one of the important active ingredients of e-cigarette, is increasing, among which nicotine in a single configuration with optical activity is widely concerned. S-Nicotine has a molecular formula of C10H14N2, a CAS number of 54-11-5, and a structural formula of
[0003] At present, there are few studies on the preparation methods of S-nicotine. S-nicotine is basically obtained by a chiral resolution method, but chiral resolution reagents are expensive, which is not conducive to industrial production.
[0004] A patent with a publication No. CN104341390A discloses a preparation method of S-nicotine. According to the method, cyclic imine is used as a starting material, an expensive chiral catalyst is required, high-pressure hydrogen equipment is required, and the production cost is relatively high, so that the method is not suitable for large-scale industrial production. A patent with a publication No. CN11233829A discloses a preparation method of nicotine with optical activity. According to the method, a chiral ligand containing nitrogen or phosphorus is used to prepare an organometallic catalyst, an imide derivative is used as a stating material to prepare S-nicotine, the preparation of the organometallic catalyst is relatively complicated, the production cost is relatively high, and the yield of S-nicotine is relatively low.
[0005] Therefore, the present application provides a preparation method of S-nicotine, cheaper and readily available raw materials are used, and the yield of prepared S-nicotine is higher.
SUMMARY
[0006] In order to increase the yield of S-nicotine, the present application provides a preparation method of S-nicotine.
[0007] In a first aspect, the present application provides a preparation method of S-nicotine, which is implemented by adopting the following technical solutions:
a preparation method of S-nicotine, including the following steps:
S1: adding nicotinate and γ-butyrolactone into an organic solvent I, performing condensation in the presence of a base catalyst to obtain a condensation product, and performing cyclization on the condensation product in the presence of hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone;
S2: reacting the 4-chloro-1-(3-pyridin)-1-butanone with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone;
S3: adding the 4-amino-1-(3-pyridin)-1-butanone and (+)-B-diisopinocampheyl chloroborane into an organic solvent II, and reacting at -30 to 10°C to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol;
S4: reacting the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine;
S5: performing cyclization on the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine in the presence of a base to obtain S-demethylnicotine; and
S6: reacting the S-demethylnicotine with an amine methylation reagent to obtain crude S-nicotine, and purifying to obtain S-nicotine.
[0008] By adopting the above technical solution, nicotinate and γ-butyrolactone are used as raw materials, nicotinate and γ-butyrolactone are both cheap and readily available raw materials, (+)-B-diisopinocampheyl chloroborane is used to reduce a carbonyl group of an intermediate and obtain a target chiral center; the (+)-B-diisopinocampheyl chloroborane induces the production of a chiral hydroxyl group, chlorination and cyclization are performed to form chiral S-demethylnicotine, and finally amine methylation is performed to obtain S-nicotine with photochemical activity. The preparation method of S-nicotine provided in the present application has the advantages of high purity, simple process, easy operation, high yield and mild reaction conditions, and S-nicotine in a single configuration is obtained with a high ee value, which is suitable for industrial production.
[0010] Preferably, at S1, a molar ratio of the nicotinate to the γ-butyrolactone to the base catalyst is 1: (1-2): (1.2-3); and more preferably, the molar ratio of the nicotinate to the γ-butyrolactone to the base catalyst is 1: 1: 2.
[0011] Preferably, at S1, the base catalyst is selected from one or more of alkali metal alkoxide, alkaline earth metal hydride, alkaline earth metal oxide, amine, a metal salt of amine, hydroxide, carbonate, and bicarbonate.
[0012] In the present application, the alkali metal alkoxide includes, but is not limited to, any one of sodium tert-butoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
[0013] In the present application, the alkaline earth metal hydride includes, but is not limited to, one or more of NaH, LiH, and KH.
[0014] In the present application, the alkaline earth metal oxide includes, but is not limited to, one or more of Na2O, Li2O, and K2O.
[0015] In the present application, the amine includes, but is not limited to, triethylamine and/or diisopropylethyl amine.
[0016] In the present application, the metal salt of amine includes, but is not limited to, sodium bis(trimethylsilyl)amide and/or lithium diisopropylamide.
[0017] In the present application, the hydroxide includes, but is not limited to, one or more of sodium hydroxide, lithium hydroxide, and magnesium hydroxide.
[0018] In the present application, the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
[0019] In the present application, the bicarbonate includes, but is not limited to, sodium bicarbonate and/or potassium bicarbonate.
[0020] More preferably, the base catalyst is selected from any one of sodium tert-butoxide, NaH, and potassium tert-butoxide.
[0021] In the present application, at S1, the organic solvent I is selected from one or more of tetrahydrofuran, methyl tertiary butyl ether, dimethyl tetrahydrofuran, and 1,4-dioxane; and preferably, the organic solvent I is 1,4-dioxane.
[0022] In the present application, at S1, the reaction needs to be performed under an N2 atmosphere, and an adding order of the nicotinate, the γ-butyrolactone and the base catalyst is that: the γ-butyrolactone is added first, followed by the base catalyst and finally the nicotinate.
[0023] In the present application, the reaction temperature of the γ-butyrolactone and the base catalyst is 0°C, and the reaction time is 30 min; and the reaction temperature of the nicotinate, the γ-butyrolactone and the base catalyst is 25°C.
[0024] In the present application, at S1, the hydrochloric acid is concentrated hydrochloric acid, and the concentration of the concentrated hydrochloric acid is 12 mol/L.
[0025] In the present application, at S1, a molar ratio of the condensation product to HCl in the hydrochloric acid is 1: (1-6); and preferably, the molar ratio of the condensation product to the HCl in the hydrochloric acid is 1: 1.
[0026] In the present application, at S1, the reflux reaction time of the condensation product and the hydrochloric acid at 70 to 90°C is 0.5 to 1.5 h; and preferably, the reflux reaction time of the condensation product and the hydrochloric acid at 80°C is 1 h.
[0027] In the present application, at S1, after cyclization is performed on the condensation product in the presence of hydrochloric acid, post-processing is further required to obtain the 4-chloro-1-(3-pyridin)-1-butanone, wherein the post-processing includes: diluting with saline, neutralizing with a base substance, extracting, taking an organic phase, and performing rotary drying for removing the solvent to obtain the 4-chloro-1-(3-pyridin)-1-butanone.
[0028] In the present application, before the reaction of S2, the 4-chloro-1-(3-pyridin)-1-butanone obtained at S1 needs to be dissolved in a solvent. The solvent includes, but is not limited to, one or more of acetonitrile, 1,4-dioxane, dichloromethane, DMF, and tetrahydrofuran; and preferably, the solvent is acetonitrile.
[0029] In the present application, at S2, the reaction temperature of the 4-chloro-1-(3-pyridin)-1-butanone and the animation reagent under the alkaline conditions is 60 to 100°C, and the reaction time is 6 to 10 h; and preferably, the reaction temperature of the 4-chloro-1-(3-pyridin)-1-butanone and the animation reagent under the alkaline conditions is 80°C, and the reaction time is 8 h.
[0030] Preferably, at S2, a molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: (1-3); and more preferably, the molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: 2.
[0031] Preferably, at S2, the amination reagent is ammonium hydroxide or formamide; and more preferably, the amination reagent is formamide.
[0032] In the present application, at S2, the pH of an alkaline environment in the reaction of the 4-chloro-1-(3-pyridin)-1-butanone and the amination reagent under the alkaline conditions is 8 to 12; and preferably, the pH of the alkaline environment in the reaction of the 4-chloro-1-(3-pyridin)-1-butanone and the amination reagent under the alkaline conditions is 9. The alkaline environment can be adjusted with a 52 wt% NaOH aqueous solution.
[0033] In the present application, S2 further includes a post-processing step, wherein the post-processing step includes: adjusting the pH to 6 to 7 by adding an acid, extracting, performing rotary drying on an organic phase for removing the solvent to obtain the 4-amino-1-(3 -pyridin)-1 -butanone.
[0034] In the present application, at S3, the 4-amino-1-(3-pyridin)-1-butanone prepared at S2 needs to be dissolved in the organic solvent II.
[0035] Preferably, at S3, the organic solvent II is selected from one or more of tetrahydrofuran, dimethylte trahydrofuran, and 1,4-dioxane; and more preferably, the organic solvent II is tetrahydrofuran.
[0036] Preferably, at S3, a molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1-3); and more preferably, the molar ratio of the 4-amino-1-(3-pyridin)-1-butanone to the (+)-B-diisopinocampheyl chloroborane is 1: (1.5-2).
[0037] Preferably, at S3, the reaction temperature of the 4-amino-1-(3-pyridin)-1-butanone and the (+)-B-diisopinocampheyl chloroborane is 0°C, and the reaction time is 2 h.
[0038] In the present application, S3 further includes an extraction step, wherein an extraction agent is methylene chloride, after the extraction, rotary drying for removing the solvent is performed to obtain the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol.
[0039] In the present application, at S4, the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol prepared at S3 needs to be dissolved in a solvent and then react with the chlorination reagent. The solvent includes, but is not limited to, 1,4-dioxane.
[0040] Preferably, the reaction temperature of S4 is -10 to 10°C; and more preferably, the reaction temperature of S4 is 0°C.
[0041] In the present application, the reaction time of S4 is 20 to 40 min; and preferably, the reaction time of S4 is 30 min.
[0042] Preferably, at S4, the chlorination reagent is selected from oxalyl chloride, thionyl chloride, PCl3, and PCl5; and more preferably, the chlorination reagent is oxalyl chloride.
[0043] Preferably, at S4, a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: (1-2); and more preferably, the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: 1.5.
[0044] In the present application, at S4, after the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol reacts with the oxalyl chloride, quenching is required to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine, wherein a quenching reagent may be water.
[0045] In the present application, at S5, cyclization is performed on the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 in the presence of a base to form the S-demethylnicotine.
[0047] In the present application, the hydroxide includes, but is not limited to, one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, and magnesium hydroxide.
[0048] In the present application, the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
[0050] In the present application, at S5, a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine and the sodium hydroxide is 1: (1.5-2.5); and preferably, the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine and the sodium hydroxide is 1: 2.
[0051] In the present application, at S5, the reaction temperature of the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and the base is 55 to 65°C, and the reaction time is 2 to 3 h; and preferably, the reaction temperature of the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and the base is 60°C, and the reaction time is 2 h.
[0054] In the present application, at S6, a molar ratio of S-demethylnicotine in the mixture containing S-demethylnicotine to the methyl iodide is 1: (1.1-1.4); and preferably, the molar ratio of the S-demethylnicotine in the mixture containing S-demethylnicotine to the methyl iodide is 1: 1.2.
[0055] In the present application, at S6, the reaction temperature of the mixture containing S-demethylnicotine and the amine methylation reagent is 20 to 30°C, and the reaction time is 2 to 4 h; and preferably, the reaction temperature of the mixture containing S-demethylnicotine and the amine methylation reagent is 25°C, and the reaction time is 3 h.
[0056] In the present application, at S6, after the mixture containing S-demethylnicotine reacts with the amine methylation reagent, the pH needs to be adjusted to 6 by using an acid, extraction is performed, an organic phase is dried over Na2SO4 and concentrated under reduced pressure to obtain the crude S-nicotine.
[0057] In the present application, at S6, the purification is distillation purification, and specifically includes: performing atmospheric distillation extraction two times to obtain a levorotatory sample with high purity.
[0058] In summary, the present application has the following beneficial effects:
The present application provides a novel route for synthesizing S-nicotine by using cheap and readily available nicotinate and γ-butyrolactone as starting materials, and the cost is low. Condensation is performed in the presence of a base catalyst, cyclization is performed through a reflux reaction with concentrated hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone, a reaction is performed with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone, the production of a chiral hydroxyl group is induced by (+)-B-diisopinocampheyl chloroborane to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol, chlorination and cyclization in the presence of a base are performed to obtain S-demethylnicotine, and finally amine methylation is performed to obtain S-nicotine. The reaction route is simple, the reaction conditions are mild and easy to operate, S-nicotine in a single configuration is obtained with high selectivity, the yield and the purity of S-nicotine are high, and the steps are simple, so that the method is particularly suitable for industrial production of S-nicotine.
DETAILED DESCRIPTION
[0060] The raw materials used in the present application can be obtained commercially, and if there is no special description, the raw materials not mentioned in the present application are purchased from Sinopharm Chemical Reagent Co., Ltd.
[0061] Embodiments 1 to 20 provide a preparation method of S-nicotine, which will be described below by taking Embodiment 1 as an example.
[0062] Embodiment 1 provides a preparation method of S-nicotine, wherein nicotinate is methyl nicotinate, and a synthetic route is shown as Reaction Formula 1:
[0063] Specific preparation steps were as follows:
S1: 86.1 g (1 mol, 1 eq) of γ-butyrolactone (with a CAS No. of 96-48-0) was added into 1 L of 1,4-dioxane at 0°C and mixed, 48 g (2 mol, 2 eq) of sodium hydride was added, a reaction was performed at 0°C for 0.5 h, 137.1 g (1 mol) of methyl nicotinate (with a CAS No. of 93-60-7) was added, a condensation reaction was performed at 25°C and monitored by TLC until the end of the reaction to obtain a condensation product, 0.083 L of 12 mol/L (1 mol, 1 eq) hydrochloric acid was added into the condensation product, a reflux reaction was performed at 80°C for 1 h, a saturated salt solution was added for extraction, sodium bicarbonate was added to adjust the pH of the system to 7, extraction was performed three times by using dichloromethane, and organic phases were combined and subjected to rotary drying for removing the solvent to obtain 4-chloro-1-(pyridin-3-yl)-1-butanone.
S2: the 4-chloro-1-(pyridin-3-yl)-1-butanone obtained at S1 was dissolved in 1 L of acetonitrile, a 52 wt% NaOH aqueous solution was used to adjust pH of the system to 9, 90.1 g (2 mol, 2 eq) of formamide was added, a reaction was performed at 80°C for 8 h, after the reaction, 4 mol/L hydrochloric acid was used to adjust the pH to 6, extraction was performed by using ethyl acetate, an organic phase was taken and subjected to rotary evaporation for removing the solvent to obtain 4-amino-1-(pyridin-3-yl)-1-butanone.
S3: the 4-amino-1-(pyridin-3-yl)-1-butanone obtained at S2 was dissolved in 5 L of tetrahydrofuran, after the dissolution, 641.5 g (2 mol, 2 eq) of (+)-B-diisopinocampheyl chloroborane was added at 0°C, a reaction was performed at 0°C for 2 h, extraction was performed three times by using dichloromethane, and rotary drying for removing the solvent was performed to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol.
S4: 2 L of 1,4-dioxane was added into the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol obtained at S3 and mixed, 190.4 g (1.5 mol, 1.5 eq) of oxalyl chloride was added at 0°C, a reaction was performed at 0°C for 30 min, and quenching was performed by adding 10 mL of water to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine.
S5: 80 g (2 mol, 2 eq) of NaOH was added into the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine prepared at S4 and dissolved under stirring, and at the same time, a reaction was performed at 60°C for 2 h to obtain a mixture containing S-demethylnicotine; and
S6: 170.3 g (1.2 mol, 1.2 eq) of methyl iodide was added into the mixture containing S-demethylnicotine prepared at S5, a reaction was performed at 25°C for 3 h, the pH of the system was adjusted to 6 by using 12 mol/L hydrochloric acid, extraction was performed by using dichloromethane, an organic phase was taken, dried over Na2SO4, and concentrated under reduced pressure for removing the solvent to obtain crude S-nicotine, and the crude S-nicotine was further purified once by atmospheric distillation to obtain S-nicotine with a yield of 52%, an ee value of 98%, and a purity o 99%.
[0064] It is worthwhile to note that each mass and specific molar weight in the embodiments of the present application can be selected according to the size of an industrially produced vessel as long as the equivalence ratio of each reaction raw material is consistent.
[0065] A difference between Embodiments 2 to 3 and Embodiment 1 is that: in the reaction of S1, the kind of the base catalyst was adjusted as specifically shown in Table 1.
| Serial number | Selection of base catalyst | Yield of S-nicotine (%) |
| Embodiment 1 | Sodium hydride | 52 |
| Embodiment 2 | Sodium tert-butoxide | 42 |
| Embodiment 3 | Potassium tert-butoxide | 43 |
[0066] A difference between Embodiment 4 and Embodiment 1 is that: in the reaction of S2, the kind of the amination reagent was adjusted as specifically shown in Table 2.
| Serial number | Selection of amination reagent | Yield of S-nicotine (%) |
| Embodiment 1 | Formamide | 52 |
| Embodiment 4 | Ammonium hydroxide | 48 |
[0067] A difference between Embodiments 5 to 6 and Embodiment 1 is that: in the reaction of S2, the usage amount of the amination reagent was adjusted as specifically shown in Table 3.
| Serial number | Equivalent quantity (eq) of amination reagent | Yield of S-nicotine (%) |
| Embodiment 1 | 2 | 52 |
| Embodiment 5 | 3 | 48 |
| Embodiment 6 | 1 | 45 |
[0068] A difference between Embodiments 7 to 9 and Embodiment 1 is that: in the reaction of S3, the usage amount of the (+)-B-diisopinocampheyl chloroborane was adjusted as specifically shown in Table 4.
| Serial number | Equivalent quantity (eq) of (+)-B-diisopinocampheyl chloroborane | Yield of S-nicotine (%) |
| Embodiment 1 | 2 | 52 |
| Embodiment 7 | 1 | 42 |
| Embodiment 8 | 3 | 46 |
| Embodiment 9 | 1.5 | 48 |
[0069] A difference between Embodiments 10 to 12 and Embodiment 1 is that: in the reaction of S3, the kind of the organic solvent II was adjusted as specifically shown in Table 5.
| Serial number | Selection of organic solvent II | Yield of S-nicotine (%) |
| Embodiment 1 | Tetrahydrofuran | 52 |
| Embodiment 10 | 1,4-dioxane | 50 |
| Embodiment 11 | Methyl tertiary butyl ether | 25 |
| Embodiment 12 | Absolute ether | 48 |
[0070] A difference between Embodiments 13 to 15 and Embodiment 1 is that: in the reaction of S3, the reaction temperature was adjusted as specifically shown in Table 6.
| Serial number | Reaction temperature (°C) | Yield of S-nicotine (%) |
| Embodiment 1 | 0 | 52 |
| Embodiment 13 | -30 | 50 |
| Embodiment 14 | 10 | 45 |
| Embodiment 15 | 5 | 48 |
[0071] A difference between Embodiments 16 to 17 and Embodiment 1 is that: in the reaction of S4, the reaction temperature was adjusted as specifically shown in Table 7.
| Serial number | Reaction temperature (°C) | Yield of S-nicotine (%) |
| Embodiment 1 | 0 | 52 |
| Embodiment 16 | 10 | 43 |
| Embodiment 17 | -10 | 48 |
[0072] A difference between Embodiments 18 to 19 and Embodiment 1 is that: in the reaction of S4, the usage amount of the oxalyl chloride was adjusted as specifically shown in Table 8.
| Serial number | Equivalent quantity (eq) of oxalyl chloride | Yield of S-nicotine (%) |
| Embodiment 1 | 1.5 | 52 |
| Embodiment 18 | 1 | 48 |
| Embodiment 19 | 2 | 35 |
[0073] A difference between Embodiment 20 and Embodiment 1 is that: at S1, the methyl nicotinate was replaced with equimolar ethyl nicotinate (with a CAS No. of 614-18-6), and produced S-nicotine had a yield of 52%, an ee value of 98%, and a purity of 99%.
[0074] The specific embodiments are merely an explanation of the present application and are not intended to limit the present application. After reading the present description, those skilled in the art can make modifications to the present embodiments as required without any inventive contribution, and these modifications shall fall within the scope of protection of the present application.
S1: adding nicotinate and γ-butyrolactone into an organic solvent I, performing condensation in the presence of a base catalyst to obtain a condensation product, and performing cyclization on the condensation product in the presence of hydrochloric acid to obtain 4-chloro-1-(3-pyridin)-1-butanone;
S2: reacting the 4-chloro-1-(3-pyridin)-1-butanone with an amination reagent under alkaline conditions to obtain 4-amino-1-(3-pyridin)-1-butanone;
S3: adding the 4-amino-1-(3-pyridin)-1-butanone and (+)-B-diisopinocampheyl chloroborane into an organic solvent II, and reacting at -30 to 10°C to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol;
S4: reacting the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine;
S5: performing cyclization on the (S)-4-amino-1-(pyridin-3-yl)butyl-1-chlorine in the presence of a base to obtain S-demethylnicotine; and
S6: reacting the S-demethylnicotine with an amine methylation reagent to obtain crude S-nicotine, and purifying to obtain S-nicotine.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description