WO2023284058A1 - 一种手性合成尼古丁的制备方法 - Google Patents

一种手性合成尼古丁的制备方法 Download PDF

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WO2023284058A1
WO2023284058A1 PCT/CN2021/112799 CN2021112799W WO2023284058A1 WO 2023284058 A1 WO2023284058 A1 WO 2023284058A1 CN 2021112799 W CN2021112799 W CN 2021112799W WO 2023284058 A1 WO2023284058 A1 WO 2023284058A1
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chiral
mixture
nicotine
acid
chloro
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PCT/CN2021/112799
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English (en)
French (fr)
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邹军
邹阳
刘梅森
罗维贤
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深圳市真味生物科技有限公司
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Priority to EP21810889.2A priority Critical patent/EP4144727A4/en
Priority to US17/547,251 priority patent/US20230025652A1/en
Publication of WO2023284058A1 publication Critical patent/WO2023284058A1/zh

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    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/12—Chemical features of tobacco products or tobacco substitutes of reconstituted tobacco
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/42—Treatment of tobacco products or tobacco substitutes by chemical substances by organic and inorganic substances
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to the technical field of chemical synthesis, in particular to a preparation method of chiral synthetic nicotine.
  • Nicotine is mainly derived from tobacco extracts and artificial chemical synthesis methods.
  • the nicotine extracted and purified from tobacco and other plants also contains other carcinogenic tobacco compound impurities, which are harmful to human health; and tobacco extracts are more affected by raw materials and climate, so it is difficult to carry out large-scale industrial production.
  • Artificial chemically synthesized nicotine has almost no other carcinogenic tobacco compound impurities, is suitable for large-scale industrial production, and has received widespread attention.
  • reaction formula 1 wherein, document Journal of Organic Chemistry, 1990,55 (6), 1736-44. reported a kind of with pyrrolidine as starting material, the preparation method of synthesizing racemic nicotine through four-step reaction, as shown in reaction formula 1:
  • reaction formula 1 has too harsh conditions, and the yield is not high, and its product is racemic nicotine.
  • Grignard reagent is needed in the middle, and the use of Grignard reagent is also to obtain racemized nicotine.
  • reaction formula 3 uses 3-bromopyridine as the starting material.
  • 3-bromopyridine is expensive and requires ultra-low temperature (-78°C) conditions.
  • the experimental conditions are harsh and not suitable for industrial production, and its product is also racemic body nicotine.
  • Chiral synthesis of nicotine is basically obtained by chiral resolution, but chiral resolution reagents are expensive, which is not conducive to industrial production. Therefore, it is important to study the preparation method of chiral synthetic nicotine.
  • the patent with the publication number CN104341390A discloses a preparation method of S-nicotine, which uses cyclic imine as the starting material, requires expensive chiral catalysts, and requires high-pressure hydrogen equipment. The production cost is relatively high, and it is not suitable for large-scale industrialization. Production.
  • the patent with the publication number CN11233829A discloses a preparation method of optically active nicotine, using nitrogen-containing or phosphorus-containing chiral ligands to prepare organometallic catalysts, and using imide salt derivatives as starting materials to prepare chiral synthetic nicotine , the preparation of organometallic catalysts is more complicated, the production cost is higher, and the yield and purity of chiral synthetic nicotine are lower.
  • the present application provides a novel preparation method of chiral synthetic nicotine, which adopts cheaper and easier-to-obtain raw materials and is easier to operate.
  • the application provides a preparation method of chiral synthetic nicotine.
  • the present application provides a preparation method for chiral synthesis of nicotine, which is realized by the following technical scheme:
  • a preparation method for chiral synthetic nicotine comprising the steps of:
  • step S2 adding an acidic substance to the first mixture described in step S1 to undergo a ring-opening reaction to obtain a second mixture;
  • step S3 separate 4-chloro-1-(3-pyridine)-1-butanone from the second mixture described in step S2, in organic solvent II and titanate, 4-chloro-1-(3-pyridine )-1-butanone reacts with chiral tert-butylsulfinamide to obtain chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-ylidene
  • the third mixture of sulfonamides was filtered, extracted, and solvent removed to obtain chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-sulfinamide;
  • step S5 Reacting the fourth mixture described in step S4 with an amine methylating reagent to obtain a fifth mixture, and purifying the fifth mixture to obtain chiral nicotine.
  • the present application uses nicotinic acid ester and ⁇ -butyrolactone as raw materials, both of which are cheap and easy-to-obtain raw materials, which significantly reduces the production cost of chiral nicotine.
  • This application uses the chiral steric hindrance of chiral tert-butyl sulfinamide to construct the target chiral center. Chiral tert-butyl sulfinamide induces chiral amine groups and then undergoes ring closure to construct chiral demethylnicotine. Finally Amine methylation yields a single configuration of nicotine.
  • the preparation method for chiral synthesis of nicotine provided by the present application has the advantages of simple steps, easy operation, high yield and mild reaction conditions, and obtains nicotine of a single configuration with high ee value, which is suitable for industrial production.
  • the molar ratio of the nicotinic acid ester, ⁇ -butyrolactone and the alkaline condensate is 1:(1 ⁇ 2):(1.2 ⁇ 3); more preferably, the nicotinic acid
  • the molar ratio of acid ester, ⁇ -butyrolactone and basic condensate is 1:1:3.
  • the nicotinic acid ester is methyl nicotinate or ethyl nicotinate.
  • the alkaline condensate is selected from alkali metal alkoxides, alkaline earth metal hydrides, alkaline earth metal oxides, amines, metal salts of amines, hydroxides, carbonates and bicarbonates One or more types of salt.
  • the alkali metal alkoxide includes but not limited to any one of sodium tert-butoxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide.
  • the alkaline earth metal hydride includes but not limited to one or more of NaH, LiH and KH.
  • the amines include but not limited to triethylamine and/or diisopropylethylamine.
  • the metal salt of the amine includes but not limited to sodium bis(trimethylsilyl)amide and/or lithium diisopropylamide.
  • the hydroxide includes but not limited to one or more of sodium hydroxide, lithium hydroxide and magnesium hydroxide.
  • the carbonate includes but not limited to one or more of sodium carbonate, potassium carbonate and cesium carbonate.
  • the bicarbonate includes but not limited to sodium bicarbonate and/or potassium bicarbonate.
  • the alkaline condensate is selected from any one of sodium tert-butoxide, NaH and potassium tert-butoxide; most preferably, the alkaline condensate is NaH.
  • the reaction needs to be carried out under N2 atmosphere, and the order of adding the nicotinic acid ester, ⁇ -butyrolactone and alkaline condensate is to add ⁇ -butyrolactone first, and then add the alkali Condensate, finally add nicotinic acid ester.
  • the reaction temperature of the ⁇ -butyrolactone and the basic condensate is 0° C., and the reaction time is 30 minutes; 25°C, the reaction time is 1h.
  • the organic solvent I is anhydrous tetrahydrofuran.
  • the first mixture contains the condensation product after the condensation reaction between nicotinic acid ester and ⁇ -butyrolactone.
  • the specific operation of the step S2 is as follows: acidify the first mixture described in the step S1 until the pH of the system is 6-7, then add an acidic substance and reflux at 75-85°C for 6-10 hours, and obtain the second mixture after ring opening.
  • Two mixtures; preferably, the specific operation of the step S2 is: acidify the first mixture described in the step S1 until the pH of the system is 6, then add an acidic substance and reflux at 80° C. for 8 hours, and obtain the second mixture after ring opening.
  • the acidic substance is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, lemon One or more of acid, tartaric acid and maleic acid; more preferably, the acidic substance is hydrochloric acid.
  • the concentration of the acidic substance is 12mol/L.
  • the molar ratio of the acidic substance to the condensation product in the first mixture is (1-100):1; preferably, the molar ratio of the acidic substance to the condensation product in the first mixture
  • the molar ratio is (1-5):1; more preferably, the molar ratio of the acidic substance to the condensation product in the first mixture is 1:1.
  • the specific operation of the step of isolating 4-chloro-1-(3-pyridine)-1-butanone from the second mixture in the S2 step is: adjust the second mixture The pH is 6-7, extract, combine the organic phase, remove the water in the organic phase, and spin the solvent to obtain 4-chloro-1-(3-pyridine)-1-butanone; preferably, the step from S2
  • the specific operation of the step of isolating 4-chloro-1-(3-pyridine)-1-butanone in the second mixture is: adding alkali to adjust the pH of the second mixture to be 7, and using ethyl acetate-water (acetic acid The volume ratio of ethyl ester and water is 1:2), extract 3 times, combine organic phase, organic phase is dried through anhydrous MgSO , spin-dry solvent, obtain 4 -chloro-1-(3-pyridine)-1-butanone .
  • the molar ratio of the 4-chloro-1-(3-pyridine)-1-butanone to the chiral tert-butylsulfinamide is 1:(1 ⁇ 2.5); more preferably Yes, the molar ratio of 4-chloro-1-(3-pyridine)-1-butanone to chiral tert-butylsulfinamide is 1:2.
  • the chiral tert-butylsulfinamide in the step S3 is S-tert-butylsulfinamide
  • the chiral nicotine in the step S5 is S-nicotine.
  • the chiral tert-butylsulfinamide in the step S3 is R-tert-butylsulfinamide
  • the chiral nicotine in the step S5 is R-nicotine.
  • the organic solvent II is selected from one or more of anhydrous tetrahydrofuran, dimethyltetrahydrofuran and 1,4-dioxane; more preferably, the organic solvent II For anhydrous tetrahydrofuran.
  • anhydrous tetrahydrofuran, dimethyltetrahydrofuran and 1,4-dioxane are all solvents with a boiling point higher than 75°C, which can increase the concentration of 4-chloro-1-(3-pyridine)-1-butane Reaction yields of ketones and chiral tert-butylsulfinamides.
  • the reaction temperature of the 4-chloro-1-(3-pyridine)-1-butanone and chiral tert-butylsulfinamide is 70-90°C, and the reaction time is 5- 8h; more preferably, the reaction temperature of the 4-chloro-1-(3-pyridine)-1-butanone and chiral tert-butylsulfinamide is 70°C, and the reaction time is 6h.
  • the titanate is selected from any one of tetraethyl titanate, tetrabutyl titanate and tetraisopropyl titanate; preferably, the titanate is Tetraethyl titanate.
  • step S3 the reaction between the 4-chloro-1-(3-pyridine)-1-butanone and the chiral tert-butylsulfinamide needs to be quenched with saturated saline.
  • a post-processing step is required after the quenching reaction, and the specific operation of the post-processing step is: filter the filtrate, wash the filter cake with ethyl acetate and collect the filtrate, combine the filtrate, Extract with saturated brine, extract the aqueous layer with ethyl acetate, collect the organic phase and dry over anhydrous MgSO 4 , and concentrate in vacuo to give chiral N-(4-chloro-1-(pyridin-3-yl)butene)- 2-Methylpropane-2-sulfinamide.
  • the chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-sulfinamide and the reducing agent in the S3 step It needs to be dissolved in a solvent before the reaction, and the solvent includes but not limited to absolute ethanol.
  • the reducing agent is selected from one or more of metal borohydride, iron, zinc, hydrogen, ferrous chloride, zincous chloride, stannous chloride and lithium aluminum tetrahydrogen Various.
  • the metal borohydride includes but not limited to one or more of sodium borohydride, potassium borohydride and sodium cyanoborohydride borane.
  • the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, iron powder, zinc powder and stannous chloride.
  • the reducing agent is sodium borohydride.
  • the organic solvent III includes but not limited to 1,4-dioxane.
  • the moles of the chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-sulfinamide and the reducing agent The ratio is 1:(1.1-1.5); more preferably, the chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-sulfinamide and The molar ratio of reducing agent is 1:1.2.
  • the reaction of the chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-sulfinamide with a reducing agent The temperature is -30 ⁇ 10°C, and the reaction time is 2 ⁇ 4h; preferably, the chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-
  • the reaction temperature of sulfinamide and reducing agent is 0°C, and the reaction time is 3h.
  • the dilute acid includes but not limited to dilute hydrochloric acid, and the concentration of the dilute hydrochloric acid can be 0.1 mol/L.
  • the hydrogen halide and chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-sulfinamide The molar ratio is (1.5 ⁇ 2.5):1; preferably, the halogenated hydrogen and chiral N-(4-chloro-1-(pyridin-3-yl)butene)-2-methylpropane-2-
  • the molar ratio of sulfenamide is 2:1.
  • the condition for the cyclization reaction under the action of hydrogen halide is reflux reaction for 6 to 10 hours; preferably, the condition for the cyclization reaction under the action of hydrogen halide is reflux Reaction 8h.
  • the reflux reaction temperature is 70-90°C; more preferably, the reflux reaction temperature is 80°C.
  • the alkali includes but not limited to 52wt% NaOH aqueous solution.
  • the fourth mixture obtained in the step S4 contains chiral demethylnicotine.
  • the reaction temperature between the fourth mixture and the amine methylation reagent is 70-90°C, and the reaction time is 6-10 hours; preferably, the fourth mixture reacts with the amine methylation reagent
  • the reaction temperature of the reagents is 80°C, and the reaction time is 8h.
  • the amine methylating reagent is formic acid and formaldehyde.
  • the specific operation for purifying the fifth mixture is as follows: cooling the fifth mixture to 20-30°C, adding water and aqueous hydrochloric acid, and then extracting with dichloromethane. Adjust the pH value to 11 with alkali and extract three times with dichloromethane, combine the organic phases extracted four times, dry the organic phase over Na 2 SO 4 , concentrate under reduced pressure to obtain chiral nicotine crude product, and then purify chiral nicotine through distillation.
  • This application uses nicotinic acid ester and ⁇ -butyrolactone as starting materials, which are cheap and easy to obtain, and overcome the problem of high cost of chiral synthesis of nicotine; chiral tert-butylsulfinamide induces chiral amine groups and then Cyclization to construct the target chiral center is a new preparation method for chiral synthesis of nicotine, which can obtain chiral synthesis of nicotine in a single configuration with high yield and high ee value.
  • the preparation process of the present application is simple, the reaction conditions are mild, easy to operate, the source of raw materials is wide, the cost is low, and the purity of the chiral synthetic nicotine obtained is high, and there are no other harmful tobacco compounds, which is especially suitable for industrial scale chiral nicotine Synthetic nicotine production.
  • the raw materials used in this application can be obtained from the market. Unless otherwise specified, the raw materials not mentioned in the examples and comparative examples of this application were all purchased from Sinopharm Chemical Reagent Co., Ltd.
  • Examples 1-16 provide a preparation method for chiral synthesis of nicotine, which will be described below by taking Example 1 as an example.
  • step S2 Use 12mol/L hydrochloric acid to adjust the pH of the system to 6 with the first mixture prepared in step S1, then add 0.083L 12mol/L hydrochloric acid (1mol, 1eq), and reflux at 80°C for 8h to open the condensation product in the first mixture. , to get the second mixture;
  • step S5 take 33g (1.1mol, 1.1eq) formaldehyde and make 37wt% formaldehyde aqueous solution; Add 82.7g (1.8mol, 1.8eq) formic acid to the fourth mixture prepared in step S4, after mixing evenly, heat up to 80 °C, in React at 80°C for 8 hours, then cool to 25°C and add 0.083L 12mol/L hydrochloric acid aqueous solution, then extract with dichloromethane, adjust the pH of the aqueous phase to 11 with 52wt% NaOH aqueous solution, and extract the adjusted aqueous phase three times with dichloromethane , combined the organic phases, added Na2SO4 to the organic phases for drying, concentrated under reduced pressure and evaporated the solvent to obtain crude S - nicotine, which was then subjected to atmospheric distillation to obtain S-nicotine with a yield of 74%.
  • the ee value is 99%, and the purity is 98%.
  • Example 2-3 The difference between Example 2-3 and Example 1 is that in the S1 step reaction, the type of the basic condensate is adjusted, as shown in Table 1.
  • Examples 4-5 differ from Example 1 only in that: in the S1 step reaction, the amounts of methyl nicotinate, ⁇ -butyrolactone and NaH are shown in Table 2.
  • Example 6-8 The difference between Examples 6-8 and Example 1 is that in the reaction of step S3, the organic solvent II is adjusted, as shown in Table 3.
  • Example 1 Anhydrous THF 74
  • Example 6 MTBE 0
  • Example 7 1,4-dioxane 52
  • Example 8 Dimethyltetrahydrofuran 70
  • Examples 9-11 differ from Example 1 only in that: in the S3 step reaction, the amount of S-tert-butylsulfinamide is adjusted, as shown in Table 4 for details.
  • Example 12-14 The difference between Examples 12-14 and Example 1 is that in the reaction of step S3, the reaction temperature and time are adjusted, as shown in Table 5.
  • Example 1 Numbering Reaction temperature (°C) Reaction time (h) S-nicotine yield (%) Example 1 70 6 74 Example 12 90 5 66 Example 13 70 8 72 Example 14 60 8 70
  • Example 15 differs from Example 1 only in that: in the S1 step, the equimolar replacement of methyl nicotinate with ethyl nicotinate (CAS No. 614-18-6), the yield of the obtained S-nicotine The yield is 73%, the ee value is 99%, and the purity is 98%.
  • Example 16 the only difference from Example 1 is that the equimolar replacement of the S-tert-butylsulfinamide with R-tert-butylsulfinamide yields 72% of the obtained R-nicotine, ee Value 99%, purity 98%.

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Abstract

一种手性合成尼古丁的制备方法，包括如下步骤：S1、烟酸酯和γ-丁内酯在碱性缩合物作用下发生缩合反应，得第一混合物；S2、向第一混合物中加入酸性物质发生开环反应，得第二混合物；S3、从第二混合物中分离出4-氯-1-(3-吡啶)-1-丁酮，并与手性叔丁基亚磺酰胺反应，得手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺；S4、手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺先与还原剂反应，后在酸性条件下环合，得手性去甲基尼古丁；S5、将手性去甲基尼古丁甲胺化，得手性尼古丁。该方法简单、易操作，成本低，产率高、ee值高，适合工业化生产。

Description

一种手性合成尼古丁的制备方法 技术领域
本发明涉及化学合成技术领域，具体涉及一种手性合成尼古丁的制备方法。
背景技术
近年来，随着电子烟行业的迅猛发展，尼古丁作为电子烟的重要活性成分之一，需求日益增大。尼古丁主要来源于烟草提取物和人工化学合成方法。其中，从烟草等植物中提取纯化的尼古丁还含有其他致癌的烟草化合物类杂质，损害人体健康；且烟草提取物受原材料和气候等影响较多，很难进行大规模工业化生产。人工化学合成尼古丁几乎无他致癌的烟草化合物类杂质，适合大规模工业化生产，受到广泛的关注。
其中，文献Journal of Organic Chemistry,1990,55(6),1736-44.报道了一种以吡咯烷为起始原料，经四步反应合成消旋尼古丁的制备方法，如反应式1所示：
Figure PCTCN2021112799-appb-000001
反应式1的制备方法，条件过于苛刻，而且产率不高，且其产物是消旋体尼古丁。
文献Journal of the Chemical Society,Perkin Transactions 1(2002),(2),143-154.报道了一种以烟酸为起始原料合成消旋尼古丁的制备方法，如反应式2所示：
Figure PCTCN2021112799-appb-000002
反应式2的制备方法，中间需要使用格氏试剂，格氏试剂的使用得到的也是消旋化尼古丁。
文献Journal of Heterocyclic Chemistry,2009,46(6),1252-1258.报道了一种以3-溴吡啶为原料制备尼古丁的方法，如反应式3所示：
Figure PCTCN2021112799-appb-000003
反应式3的制备方法以3-溴吡啶为起始原料，3-溴吡啶的价格昂贵，且需要超低温(-78℃)的条件，实验条件苛刻，不适合工业化生产，且其产物也是消旋体尼古丁。
目前手性合成尼古丁的制备方法研究较少。手性合成尼古丁基本是通过手性拆分的方法获得的，但手性拆分试剂昂贵，不利于工业化生产。因此，研究手性合成尼古丁的制备方法具有重要作用。
公开号为CN104341390A的专利公开了一种S-尼古丁的制备方法，以环状亚胺为起始原料，需要昂贵的手性催化剂，且需要高压氢气设备，生产成本较高，不适合大规模工业化生产。公开号为CN11233829A的专利公开了一种光学活性的尼古丁的制备方法，采用含氮或含磷的手性配体制备有机金属催化剂，以亚胺盐衍生物为起始原料制备了手性合成尼古丁，有机金属催化剂的制备较复杂，生产成本较高，手性合成尼古丁的产率和纯度较低。
因此，本申请提供一种新型手性合成尼古丁的制备方法，采用更廉价易得的原料，操作更简单。
发明内容
为了提高手性合成尼古丁的产率和纯度，并降低成本，本申请提供一种手性合成尼古丁的制备方法。
第一方面，本申请提供一种手性合成尼古丁的制备方法，采用如下技术方案实现：
一种手性合成尼古丁的制备方法，包括如下步骤：
S1、在有机溶剂I中，烟酸酯和γ-丁内酯在碱性缩合物作用下发生缩合反应，得第一混合物；
S2、向S1步骤所述第一混合物中加入酸性物质发生开环反应，得第二混合物；
S3、从S2步骤所述第二混合物中分离出4-氯-1-(3-吡啶)-1-丁酮，在有机溶剂II和钛酸酯中，4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺反应，得含手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺的第三混合物，过滤，萃取，除去溶剂，得手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺；
S4、S3步骤所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺用有机溶剂III溶解，先与还原剂反应，后在卤代氢作用下发生环合反应，得第四混合物；
S5、将S4步骤所述第四混合物与胺甲基化试剂反应，得第五混合物，对第五混合物进行提纯，得手性尼古丁。
通过采取上述技术方案，本申请采用烟酸酯和γ-丁内酯为原材料，烟酸酯和γ-丁内酯均是廉价易得的原料，显著降低了手性尼古丁的生产成本。本申请利用手性叔丁基亚磺酰胺的手性位阻构建了目标手性中心，手性叔丁基亚磺酰胺诱导产生手性胺基再经过环合构建手性去甲基尼古丁，最后胺甲基化得到单一构型的的尼古丁。本申请提供的手性合成尼古丁的制备方法，具有步骤简单、易操作、高产率和反应条件温和的优点，且得到了单一构型的尼古丁，ee值高，适用于工业化生产。
优选的，所述S1步骤中，所述烟酸酯、γ-丁内酯和碱性缩合物的摩尔比为1:(1～2):(1.2～3)；更优选的，所述烟酸酯、γ-丁内酯和碱性缩合物的摩尔比为1:1:3。
本申请中，所述烟酸酯为烟酸甲酯或烟酸乙酯。
优选的，所述S1步骤中，所述碱性缩合物选自碱金属烷氧化物、碱土金属氢化物、碱土金属氧化物、胺、胺的金属盐、氢氧化物、碳酸盐和碳酸氢盐中的一种或几种。
本申请中，所述碱金属烷氧化物包括但不限于叔丁醇钠、甲醇钠、乙醇钠和叔丁醇钾中任一种。
本申请中，所述碱土金属氢化物包括但不限于NaH、LiH和KH中的一种或多种。
本申请中，所述碱土金属氧化物包括但不限于Na 2O、Li 2O和K 2O中的一种或多种。
本申请中，所述胺包括但不限于三乙胺和/或二异丙基乙基胺。
本申请中，所述胺的金属盐包括但不限于二(三甲基硅基)氨基钠和/或二异丙基氨基锂。
本申请中，所述氢氧化物包括但不限于氢氧化钠、氢氧化锂和氢氧化镁中的一种或多种。
本申请中，所述碳酸盐包括但不限于碳酸钠、碳酸钾和碳酸铯中的一种或多种。
本申请中，所述碳酸氢盐包括但不限于碳酸氢钠和/或碳酸氢钾。
更优选的，所述碱性缩合物选自叔丁醇钠、NaH和叔丁醇钾中的任一种；最优选的，所述碱性缩合物为NaH。
本申请中，所述S1步骤中，反应需要在N 2氛围下进行，所述烟酸酯、γ-丁内酯和碱性缩合物的加料顺序是先加入γ-丁内酯，再加碱性缩合物，最后加烟酸酯。
本申请中，所述γ-丁内酯和碱性缩合物的反应温度为0℃，反应时间为30min；所述烟酸酯加入后与γ-丁内酯和碱性缩合物的反应温度为25℃，反应时间为1h。
本申请中，所述S1步骤中，所述有机溶剂I为无水四氢呋喃。
本申请中，所述S1步骤中，所述第一混合物中含有烟酸酯与γ-丁内酯缩合反应后的缩合产物。
本申请中，所述S2步骤的具体操作为：将S1步骤所述第一混合物酸化至体系的pH为6～7，再加入酸性物质在75～85℃回流6～10h，开环后得第二混合物；优选的，所述S2步骤的具体操作为：将S1步骤所述第一混合物酸化至体系的pH为6，再加入酸性物质在80℃回流8h，开环后得第二混合物。
优选的，所述S2步骤中，所述酸性物质选自盐酸、硫酸、磷酸、硝酸、氢溴酸、氢碘酸、高氯酸、三氟甲磺酸、三氟乙酸、三氯乙酸、柠檬酸、酒石酸和马来酸中的一种或几种；更优选的，所述酸性物质为盐酸。
本申请中，所述酸性物质的浓度为12mol/L。
本申请中，所述S2步骤中，所述酸性物质与第一混合物中的缩合产物的摩尔比为(1～100):1；优选的，所述酸性物质与第一混合物中的缩合产物的摩尔比为(1～5):1；更优选的，所述酸性物质与第一混合物中的缩合产物的摩尔比为1:1。
本申请中，所述S2步骤中，所述回流的温度为50～300℃；优选的，所述回流的温度为80℃。
本申请中，所述S3步骤中，所述从S2步骤所述第二混合物中分离出4-氯-1-(3-吡啶)-1-丁酮的步骤的具体操作为：调节第二混合物的pH为6～7，萃取，合并有机相，除有机相中的水，旋干溶剂，得4-氯-1-(3-吡啶)-1-丁酮；优选的，所述从S2步骤所述第二混合物中分离出4-氯-1-(3-吡啶)-1-丁酮的步骤的具体操作为：加碱调节第二混合物的pH为7，用乙酸乙酯-水(乙酸乙酯和水的体积比为1:2)萃取3次，合并有机相，有机相经无水MgSO 4干燥，旋干溶剂，得4-氯-1-(3-吡啶)-1-丁酮。
优选的，所述S3步骤中，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的摩尔比为1:(1～2.5)；更优选的，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的摩尔比为1:2。
优选的，所述S3步骤中所述手性叔丁基亚磺酰胺为S-叔丁基亚磺酰胺，所述S5步骤中所述手性尼古丁为S-尼古丁。
优选的，所述S3步骤中所述手性叔丁基亚磺酰胺为R-叔丁基亚磺酰胺，所述S5步骤中所述手性尼古丁为R-尼古丁。
优选的，所述S3步骤中，所述有机溶剂II选自无水四氢呋喃、二甲基四氢呋喃和 1,4-二氧六环中的一种或多种；更优选的，所述有机溶剂II为无水四氢呋喃。
本申请中，所述无水四氢呋喃、二甲基四氢呋喃和1,4-二氧六环均是沸点高于75℃的溶剂，可以提高4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的反应产率。
优选的，所述S3步骤中，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的反应温度为70～90℃，反应时间为5～8h；更优选的，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的反应温度为70℃，反应时间为6h。
本申请中，所述S3步骤中，所述钛酸酯选自钛酸四乙酯、钛酸四丁酯和钛酸四异丙酯中的任一种；优选的，所述钛酸酯为钛酸四乙酯。
本申请中，所述S3步骤中，所述钛酸酯与手性叔丁基亚磺酰胺的摩尔比为(2～3):1；优选的，所述钛酸酯与手性叔丁基亚磺酰胺的摩尔比为2:1。
本申请中，所述S3步骤中，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺反应的反应温度为65～75℃，反应时间为4-8h；优选的，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的反应温度为70℃，反应时间为6h。
本申请中，所述S3步骤中，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺反应需要用饱和食盐水淬灭反应。
本申请中，所述S3步骤中，所述淬灭反应后还需要后处理步骤，所述后处理步骤的具体操作为：过滤取滤液，并用乙酸乙酯洗涤滤饼并收集滤液，合并滤液，用饱和食盐水萃取，用乙酸乙酯萃取水层，收集有机相并经无水MgSO 4干燥，真空浓缩，得手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺。
本申请中，所述S4步骤中，S3步骤所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺与还原剂反应前需要用溶剂溶解，所述溶剂包括但不限于无水乙醇。
优选的，所述S4步骤中，所述还原剂选自金属硼氢化物、铁、锌、氢气、氯化亚铁、氯化亚锌、氯化亚锡和四氢锂铝中的一种或多种。
本申请中，所述金属硼氢化物包括但不限于硼氢化钠、硼氢化钾和氰基硼氢化钠硼烷中的一种或多种。
更优选的，所述还原剂选自硼氢化钠、硼氢化钾、四氢锂铝、铁粉、锌粉和氯化亚锡中的一种或多种。
最优选的，所述还原剂为硼氢化钠。
本申请中，所述S4步骤中，所述有机溶剂III包括但不限于1,4-二氧六环。
本申请中，所述S4步骤中，所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷- 2-亚磺酰胺与还原剂的摩尔比为1:(1.1-1.5)；更优选的，所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺与还原剂的摩尔比为1:1.2。
本申请中，所述S4步骤中，所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺与还原剂的反应温度为-30～10℃，反应时间为2～4h；优选的，所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺与还原剂的反应温度为0℃，反应时间为3h。
本申请中，所述S4步骤中，所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺与还原剂反应后需要用稀酸调节体系至无起泡产生，所述稀酸包括但不限于稀盐酸，所述稀盐酸的浓度可以为0.1mol/L。
本申请中，所述S4步骤中，所述卤代氢与手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺的摩尔比为(1.5～2.5):1；优选的，所述卤代氢与手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺的摩尔比为2:1。
本申请中，所述S4步骤中，所述卤代氢选自HCl、HBr、HF和HI中的任一种；优选的，所述卤代氢为HBr。
本申请中，所述S4步骤中，所述在卤代氢作用下发生环合反应的条件为回流反应6～10h；优选的，所述在卤代氢作用下发生环合反应的条件为回流反应8h。
本申请中，所述S4步骤中，所述回流反应温度为70-90℃；更优选的，所述回流反应温度为80℃。
本申请中，所述S4步骤中，所述回流反应后还需要用碱调节体系的pH为7，再用乙酸乙酯-水(乙酸乙酯和水的体积比为1:2)萃取，得第四混合物。其中，所述碱包括但不限于52wt％NaOH水溶液。
本申请中，所述S4步骤中得到的第四混合物中含有手性去甲基尼古丁。
本申请中，所述S5步骤中，所述第四混合物与胺甲基化试剂的反应温度为70～90℃，反应时间为6～10h；优选的，所述第四混合物与胺甲基化试剂的反应温度为80℃，反应时间为8h。
本申请中，所述S5步骤中，所述胺甲基化试剂为甲酸和甲醛。
本申请中，所述S5步骤中，所述甲酸、甲醛和S4步骤所述第四混合物中手性去甲基尼古丁的摩尔比为(1.6-2):(1.05-1.2):1；优选的，所述甲酸、甲醛和S4步骤所述第四混合物中手性去甲基尼古丁的摩尔比为1.8:1.1:1。
本申请中，所述S5步骤中，所述对第五混合物进行提纯的具体操作为：将第五混合物冷却至20～30℃，并加水和盐酸水溶液，再用二氯甲烷萃取，水相用碱调节其pH值为11 并用二氯甲烷萃取3次，合并四次萃取的有机相，有机相经Na 2SO 4干燥，减压浓缩得手性尼古丁粗品，再经过蒸馏纯化得手性尼古丁。
综上所述，本申请具有以下有益效果：
1、本申请采用烟酸酯和γ-丁内酯为起始原料，廉价易得，克服了手性合成尼古丁成本昂贵的问题；手性叔丁基亚磺酰胺诱导产生手性胺基再经过环合构建目标手性中心，是一种手性合成尼古丁的全新制备方法，可以获得单一构型的手性合成尼古丁，产率高、ee值高。
2、本申请的制备工艺简单、反应条件温和，易操作，原料来源广，成本低廉，且制得的手性合成尼古丁的纯度高，无其他有害的烟草化合物，特别适用于工业规模化手性合成尼古丁生产。
具体实施方式
以下结合实施例对本申请作进一步详细说明。
本申请使用的原料均可通过市售获得，若无特殊说明，本申请各实施例、对比例中未提及的原料均购买自国药集团化学试剂有限公司。
实施例
实施例1-16提供了一种手性合成尼古丁的制备方法，以下以实施例1为例进行说明。
实施例1提供的手性合成尼古丁(S-尼古丁)的制备方法，其中，烟酸酯为烟酸甲酯，其合成路线如反应式4所示：
Figure PCTCN2021112799-appb-000004
具体的制备步骤为：
S1、在0℃，N 2保护下，将86.1g(1mol，1eq)γ-丁内酯(CAS号96-48-0)加至2L无水四氢呋喃，以600rpm的搅拌速度，溶解后加入72g(3mol，3eq)NaH，在0℃反应0.5h，反应后加入137.1g(1mol)烟酸甲酯(CAS号93-60-7)，在25℃反应1h，完成缩合反应，得第一混合物；
S2、将S1步骤制备的第一混合物用12mol/L盐酸调节体系pH为6，再加入0.083L 12mol/L 盐酸(1mol，1eq)，80℃回流反应8h使第一混合物中的缩合产物开环，得第二混合物；
S3、用52wt％NaOH水溶液调节S2步骤制备的第二混合物的pH为7，加入乙酸乙酯-水(乙酸乙酯和水的体积为1:2)萃取三次，合并有机相，有机相中加入无水MgSO 4干燥，旋干溶剂，得4-氯-1-(3-吡啶)-1-丁酮；接着，将4-氯-1-(3-吡啶)-1-丁酮和242.4g(2mol，2eq)S-叔丁基亚磺酰胺加入到7L无水四氢呋喃中，以600rpm的搅拌速度溶解，并加入456.3g(2mol，2eq)钛酸四乙酯，在70℃搅拌反应6h，加入50mL饱和食盐水淬灭反应，得第三混合物；对第三混合物过滤，取滤液，并用乙酸乙酯洗涤滤饼并收集滤液，合并滤液，用饱和食盐水萃取，用乙酸乙酯萃取水层，有机相经无水MgSO 4干燥，过滤除去无水MgSO 4，取滤液，真空浓缩除去溶剂，得(S,Z)-N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺。
S4、取步骤S3制备的(S,Z)-N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺溶于2L 1,4-二氧六环中，0℃下加入45.4g(1.2mol，1.2eq)硼氢化钠，并在0℃下以600rpm的速度搅拌反应3h，得含(S)-N-((S)-4-氯-1-(吡啶-3-基)丁基)-2-甲基丙烷-2-亚硫酰胺的混合物；再向含(S)-N-((S)-4-氯-1-(吡啶-3-基)丁基)-2-甲基丙烷-2-亚硫酰胺的混合物中加入12mol/L盐酸调节反应体系至无起泡产生，加入161.8g(2mol，2eq)HBr，在80℃回流反应8h，回流结束后用52wt％NaOH水溶液调节体系的pH为7，再用乙酸乙酯-水(乙酸乙酯和水的体积比为1:2)萃取，得第四混合物；
S5、取33g(1.1mol，1.1eq)甲醛配成37wt％甲醛水溶液；向S4步骤制备的第四混合物中加入82.7g(1.8mol，1.8eq)甲酸，混合均匀后，升温至80℃，在80℃反应8h，后冷却至25℃加入0.083L 12mol/L盐酸水溶液，再用二氯甲烷萃取，水相用52wt％NaOH水溶液调节pH为11，并用二氯甲烷对调节后的水相萃取三次，合并有机相，有机相中加入Na 2SO 4干燥，减压浓缩蒸干溶剂，得S-尼古丁粗品，S-尼古丁粗品再经过一次常压蒸馏，纯化得S-尼古丁，收率74％，ee值99％，纯度98％。
值得注意的是，本申请中实施例中各质量和具体的摩尔量可以根据工业化生产的容器的大小进行选择，只需要保持各反应原料之间的当量比一致即可。
实施例2-3，与实施例1不同之处仅在于：所述S1步骤反应中，对碱性缩合物的种类进行调整，具体如表1所示。
表1 S1步骤反应中碱性缩合物选择对反应的影响
编号 碱性缩合物选择 S-尼古丁的收率(％)
实施例1 NaH 74
实施例2 叔丁醇钠 68
实施例3 叔丁醇钾 65
实施例4-5，与实施例1不同之处仅在于：所述S1步骤反应中，烟酸甲酯、γ-丁内酯和NaH的用量如表2所示。
表2 S1步骤反应中各物质用量对反应的影响
Figure PCTCN2021112799-appb-000005
实施例6-8，与实施例1不同之处仅在于：所述S3步骤反应中，对有机溶剂II进行调整，具体如表3所示。
表3 S3步骤反应中有机溶剂II选择对反应的影响
编号 有机溶剂II选择 S-尼古丁的收率(％)
实施例1 无水四氢呋喃 74
实施例6 甲基叔丁基醚 0
实施例7 1,4-二氧六环 52
实施例8 二甲基四氢呋喃 70
实施例9-11，与实施例1不同之处仅在于：所述S3步骤反应中，对S-叔丁基亚磺酰胺的用量进行调整，具体如表4所示。
表4 S3步骤反应中S-叔丁基亚磺酰胺的用量对反应的影响
编号 S-叔丁基亚磺酰胺的当量数(eq) S-尼古丁的收率(％)
实施例1 2 74
实施例9 1.5 70
实施例10 1 63
实施例11 2.5 72
实施例12-14，与实施例1不同之处仅在于：所述S3步骤反应中，对反应温度和时间进行调整，具体如表5所示。
表5 S3步骤反应中反应温度和时间对反应的影响
编号 反应温度(℃) 反应时间(h) S-尼古丁的收率(％)
实施例1 70 6 74
实施例12 90 5 66
实施例13 70 8 72
实施例14 60 8 70
实施例15，与实施例1不同之处仅在于：所述S1步骤中，烟酸甲酯等摩尔替换为烟酸乙酯(CAS号614-18-6)，制得的S-尼古丁的收率73％，ee值99％，纯度98％。
实施例16，与实施例1不同之处仅在于：所述S-叔丁基亚磺酰胺等摩尔替换为R-叔丁基亚磺酰胺，制得的R-尼古丁的收率72％，ee值99％，纯度98％。
本具体实施例仅仅是对本申请的解释，其并不是对本申请的限制，本领域技术人员 在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本申请的权利要求范围内都受到专利法的保护。

Claims (10)

  1. 一种手性合成尼古丁的制备方法，其特征在于，包括如下步骤：
    S1、在有机溶剂I中，烟酸酯和γ-丁内酯在碱性缩合物作用下发生缩合反应，得第一混合物；
    S2、向S1步骤所述第一混合物中加入酸性物质发生开环反应，得第二混合物；
    S3、从S2步骤所述第二混合物中分离出4-氯-1-(3-吡啶)-1-丁酮，在有机溶剂II和钛酸酯中，4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺反应，得含手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺的第三混合物，过滤，萃取，除去溶剂，得手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺；
    S4、S3步骤所述手性N-(4-氯-1-(吡啶-3-基)丁烯)-2-甲基丙烷-2-亚磺酰胺用有机溶剂III溶解，先与还原剂反应，后在卤代氢作用下发生环合反应，得第四混合物；
    S5、将S4步骤所述第四混合物与胺甲基化试剂反应，得第五混合物，对第五混合物进行提纯，得手性尼古丁。
  2. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S3步骤中所述手性叔丁基亚磺酰胺为S-叔丁基亚磺酰胺，所述S5步骤中所述手性尼古丁为S-尼古丁。
  3. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S3步骤中所述手性叔丁基亚磺酰胺为R-叔丁基亚磺酰胺，所述S5步骤中所述手性尼古丁为R-尼古丁。
  4. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S3步骤中，所述有机溶剂II选自无水四氢呋喃、二甲基四氢呋喃和1,4-二氧六环中的一种或多种。
  5. 根据权利要求4所述的一种手性合成尼古丁的制备方法，其特征在于，所述S3步骤中，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的反应温度为70～90℃，反应时间为5～8h。
  6. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S3步骤中，所述4-氯-1-(3-吡啶)-1-丁酮和手性叔丁基亚磺酰胺的摩尔比为1:(1～2.5)。
  7. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S1步骤中，所述烟酸酯、γ-丁内酯和碱性缩合物的摩尔比为1:(1～2):(1.2～3)。
  8. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S1步骤中，所述碱性缩合物选自碱金属烷氧化物、碱土金属氢化物、碱土金属氧化物、胺、胺的金属盐、氢氧化物、碳酸盐和碳酸氢盐中的一种或几种。
  9. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S2步骤中，所述酸性物质选自盐酸、硫酸、磷酸、硝酸、氢溴酸、氢碘酸、高氯酸、三氟甲磺酸、三氟乙酸、三氯乙酸、柠檬酸、酒石酸和马来酸中的一种或几种。
  10. 根据权利要求1所述的一种手性合成尼古丁的制备方法，其特征在于，所述S4步骤中，所述还原剂选自金属硼氢化物、铁、锌、氢气、氯化亚铁、氯化亚锌、氯化亚锡和四氢锂铝中的一种或多种。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1233829A (zh) 1998-04-28 1999-11-03 索尼株式会社 盘片装载装置
CN104341390A (zh) 2014-11-04 2015-02-11 南开大学 一种植物源农药烟碱和毒藜碱的不对称合成方法
WO2019037761A1 (zh) * 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途
CN110256403A (zh) * 2019-07-02 2019-09-20 深圳市馨艺坊生物科技有限公司 一种人工合成尼古丁的制备方法
CN111875620A (zh) * 2020-09-28 2020-11-03 上海美迪西生物医药股份有限公司 吡唑并嘧啶类大环衍生物及其应用
CN112876461A (zh) * 2021-01-20 2021-06-01 上海零诺生物科技有限公司 尼古丁及其中间体的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA88792C2 (ru) * 2004-11-10 2009-11-25 Таргасепт, Інк. Гидроксибензоатные соли метаникотиновых соединений
RU2753548C1 (ru) * 2017-12-22 2021-08-17 Зигфрид АГ Способ производства никотина
CN112409329A (zh) * 2020-12-11 2021-02-26 山东金城医药化工有限公司 S-尼古丁的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1233829A (zh) 1998-04-28 1999-11-03 索尼株式会社 盘片装载装置
CN104341390A (zh) 2014-11-04 2015-02-11 南开大学 一种植物源农药烟碱和毒藜碱的不对称合成方法
WO2019037761A1 (zh) * 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途
CN110256403A (zh) * 2019-07-02 2019-09-20 深圳市馨艺坊生物科技有限公司 一种人工合成尼古丁的制备方法
CN111875620A (zh) * 2020-09-28 2020-11-03 上海美迪西生物医药股份有限公司 吡唑并嘧啶类大环衍生物及其应用
CN112876461A (zh) * 2021-01-20 2021-06-01 上海零诺生物科技有限公司 尼古丁及其中间体的制备方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 46, no. 6, 2009, pages 1252 - 1258
JOURNAL OF THE CHEMICAL SOCIETY, vol. 1, no. 2, 2002, pages 143 - 154
SATO, M. ET AL.: "Psychotropic Agents. I. Synthesis of 1-Pyridinyl-1-butanones, 1-Indolyl-1- butanones and the Related Compounds", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 26, no. 11, 31 December 1978 (1978-12-31), pages 3296 - 3305, XP001149137 *
See also references of EP4144727A4
THE JOURNAL OF ORGANIC CHEMISTRY, vol. 55, no. 6, 1990, pages 1736 - 44

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