WO2023004919A1 - 一种消旋尼古丁的制备方法 - Google Patents

一种消旋尼古丁的制备方法 Download PDF

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WO2023004919A1
WO2023004919A1 PCT/CN2021/115397 CN2021115397W WO2023004919A1 WO 2023004919 A1 WO2023004919 A1 WO 2023004919A1 CN 2021115397 W CN2021115397 W CN 2021115397W WO 2023004919 A1 WO2023004919 A1 WO 2023004919A1
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Prior art keywords
racemic nicotine
methyl
methylamine
preparation
reaction
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PCT/CN2021/115397
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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 EP21810890.0A priority Critical patent/EP4151629B1/en
Priority to US17/547,254 priority patent/US20230075688A1/en
Publication of WO2023004919A1 publication Critical patent/WO2023004919A1/zh

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    • 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

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a preparation method of racemic nicotine.
  • nicotine is mainly derived from tobacco extracts and artificial chemical synthesis. Nicotine extracted and purified from tobacco and other plants is more affected by raw materials and climate, and it is difficult to carry out large-scale industrial production. It also contains other carcinogenic tobacco compound impurities other than nicotine, which affects the health of e-cigarette smokers.
  • the artificial chemical method to synthesize nicotine can effectively avoid the above-mentioned problems of extracting nicotine from plants such as tobacco.
  • the preparation method of Reaction Formula 1 uses 3-bromopyridine as the starting material.
  • 3-bromopyridine is expensive and requires ultra-low temperature (-78°C).
  • the experimental conditions are harsh and are not suitable for industrial production.
  • reaction formula 2 requires the use of Grignard reagent in the middle, and the operating conditions are relatively harsh, which is not suitable for industrial production, and the yield and purity are low.
  • the application provides a method for preparing racemic nicotine.
  • the present application provides a method for preparing racemic nicotine, which is realized by the following technical scheme:
  • a preparation method of racemic nicotine comprising the steps of:
  • nicotinyl chloride and methylamine are cheap and easy-to-obtain raw materials, and nicotinyl chloride and methylamine are obtained under alkaline conditions to obtain methylnicotinamide, which is then condensed with monochloroacetone to obtain N-methyl-N-(2 -Oxypropyl)nicotinamide, and then carry out its own aldol condensation reaction to obtain 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one, and finally reduce it to obtain Racemic nicotine.
  • This application uses nicotinyl chloride and methylamine as starting raw materials, the cost is relatively low, and it is a new route to synthesize racemic nicotine. The yield is high, and it is suitable for industrialized large-scale production.
  • the molar ratio of the niacinyl chloride, methylamine and the base is 1:(1.5 ⁇ 2.5):(3 ⁇ 5); more preferably, the molar ratio of the niacinyl chloride, methylamine and the base is The molar ratio is 1:2:4.
  • the methylamine is selected from any one of monomethylamine, methylamine hydrochloride, methylamine hydrobromide and methylamine hydroiodide; preferably, the methylamine The amine is methylamine hydrochloride.
  • the alkali is selected from alkali metal alkoxides, alkaline earth metal hydrides, alkaline earth metal oxides, amines, metal salts of amines, hydroxides, carbonates and bicarbonates any kind.
  • 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 alkaline earth metal oxide includes but not limited to one or more of Na 2 O, Li 2 O and K 2 O.
  • the amine is selected from any one of N,N-diisopropylethylamine, triethylamine, and N,N-diethylethylamine; preferably, the amine is N,N- Diisopropylethylamine or triethylamine.
  • 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 base is amine or carbonate; further preferably, the base is any one of N,N-diisopropylethylamine, triethylamine and potassium carbonate.
  • the solvent used in the S1 step includes but not limited to tetrahydrofuran.
  • the reaction temperature of the S1 step is 20-30°C; preferably, the reaction temperature of the S1 step is 25°C.
  • reaction time of the S1 step is 2.5-3.5 hours; preferably, the reaction time of the S1 step is 3 hours.
  • the system in the S1 step, after the reaction of nicotinyl chloride, methylamine and alkali, the system needs to be adjusted to slightly acidic with acid, then extracted, and the solvent is removed by rotary evaporation to obtain the crude methyl nicotinamide, which can be carried out to the next step without purification reaction.
  • the pH of the system can be adjusted to 6 with 0.1 mol/L hydrochloric acid; ethyl acetate can be used for extraction.
  • the molar ratio of the methylnicotinamide, monochloroacetone and organic base is 1:(1.1 ⁇ 2):(1.1 ⁇ 1.5); more preferably, the methylnicotinamide , the mol ratio of monochloroacetone and organic base is 1:(1.1 ⁇ 1.3):(1.05 ⁇ 1.15); most preferably, the mol ratio of described methyl nicotinamide, monochloroacetone and organic base is 1:1.2: 1.1.
  • the organic base is an amine or an alkali metal alkoxide; more preferably, the organic base is an amine.
  • the amine is N,N-diisopropylethylamine.
  • the solvent used in the S2 step includes but not limited to dichloroethane.
  • the reaction temperature of the S2 step is 20-30°C; preferably, the reaction temperature of the S2 step is 25°C.
  • reaction time of the S2 step is 4-6 hours; preferably, the reaction time of the S2 step is 5 hours.
  • the solvent used in the step S3 includes but not limited to tetrahydrofuran.
  • the aldol condensation reaction of the N-methyl-N-(2-oxypropyl)nicotinamide itself needs to be carried out under alkaline conditions; the base used in the alkaline conditions Including but not limited to any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, cesium hydroxide and barium hydroxide; preferably, the N-methyl-N-(2-oxopropane Base)
  • the aldol condensation reaction of nicotinamide needs the catalysis of sodium hydroxide.
  • the molar ratio of N-methyl-N-(2-oxypropyl)nicotinamide and sodium hydroxide is 1:(1.2 ⁇ 1.7); preferably, the N - The molar ratio of methyl-N-(2-oxypropyl)nicotinamide and sodium hydroxide is 1:1.5.
  • the reaction temperature of the S3 step is 20-30°C; preferably, the reaction temperature of the S3 step is 25°C.
  • the reaction time of the step S3 is 5-8 hours; preferably, the reaction time of the step S3 is 6 hours.
  • N-methyl-N-(2-oxypropyl)nicotinamide needs to add acid to adjust the pH of the system to be neutral after its own aldol condensation reaction, and then extract and spin dry solvent to obtain crude 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one, which can be used for the next reaction without purification.
  • the molar ratio of the 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one to the reducing agent is 1: (1 ⁇ 2);
  • the molar ratio of the 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one and the reducing agent is 1:1.5 .
  • 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 metal borohydride; more preferably, the reducing agent is sodium borohydride.
  • the solvent used in the step S4 includes but not limited to tetrahydrofuran.
  • the reaction temperature of the step S4 is -5-5°C; preferably, the reaction temperature of the step S4 is 0°C.
  • the reaction time of the step S4 is 1-3 hours; preferably, the reaction time of the step S4 is 2 hours.
  • 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one can be extracted with ethyl acetate after being reduced with a reducing agent , spin to dry the solvent to obtain crude racemic nicotine, and then carry out refining and purification to obtain racemic nicotine.
  • This application adopts cheap and easy-to-obtain nicotinyl chloride and methylamine as starting raw materials, and the cost of raw materials is low, and provides a new route for synthesizing racemic nicotine.
  • Nicotinyl chloride and methylamine are obtained under alkaline conditions to obtain methylnicotinamide, Then condense with monochloroacetone to get N-methyl-N-(2-oxypropyl)nicotinamide, and then carry out its own aldol condensation reaction to get 1-methyl-5-(pyridin-3-yl)-1, 2-dihydro-3H-pyrrol-3-one, and finally reduced to racemic nicotine.
  • the whole reaction synthesis route is relatively short, the operation is simple, the reaction conditions are mild, the aftertreatment is simple, the yield of the synthesized racemic nicotine is high, and it is suitable for large-scale industrial 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.
  • Embodiments 1-14 provide a preparation method of racemic nicotine, which will be described below by taking Embodiment 1 as an example.
  • step S2 add the crude methylnicotinamide obtained in step S1 into 100mL of dichloroethane, add 0.111g (0.0012mol, 1.2eq) of monochloroacetone, and then add 0.142g (0.0011mol, 1.1eq) of N , N-diisopropylethylamine, and reacted at 25°C with a stirring speed of 400rpm for 5h, after the reaction was completed, extracted with 200mL ethyl acetate-water (the volume ratio of ethyl acetate and water was 2:1), and the organic phase, and the solvent was removed by rotary evaporation of the organic phase to obtain the crude product of N-methyl-N-(2-oxopropyl)nicotinamide;
  • step S3 dissolve the crude N-methyl-N-(2-oxopropyl)nicotinamide obtained in step S2 in 100mL tetrahydrofuran, add 0.06g (0.0015mol, 1.5eq) NaOH, and heat at 25°C React at a stirring speed of 400rpm for 6h.
  • step S4 dissolve the crude 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one obtained in step S3 in 100 mL of tetrahydrofuran, and add 0.057 g (0.0015mol, 1.5eq) sodium borohydride, react at 0°C for 2h to reduce 1-methyl-5-(pyridin-3-yl)-1,2-dihydro-3H-pyrrol-3-one to racemic Nicotine was extracted with 200mL ethyl acetate-water (the volume ratio of ethyl acetate and water was 2:1), the organic phase was taken, and the organic phase was rotary evaporated to remove the solvent to obtain the crude product of racemic nicotine, which was finally purified by atmospheric distillation once. Afterwards, racemic nicotine was obtained with a yield of 76%.
  • Examples 2-5 differ from Example 1 only in that in the S1 step reaction, the amounts of methylamine hydrochloride and N,N-diisopropylethylamine are adjusted, as shown in Table 1. Show.
  • Examples 6-7 differ from Example 1 only in that: in the S1 step reaction, the type of base is adjusted, as shown in Table 2 for details.
  • Example 8 differs from Example 1 only in that: in the S1 step reaction, the type of methylamine is adjusted, as shown in Table 3.
  • Examples 9-12 differ from Example 1 only in that in the S2 step reaction, the amounts of monochloroacetone and N,N-diisopropylethylamine are adjusted, as shown in Table 4 for details.
  • Example 13-14 The only difference between Examples 13-14 and Example 1 is that in the S2 step reaction, the type of alkali organic base is adjusted, as shown in Table 5 for details.

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

提供一种消旋尼古丁的制备方法，包括如下步骤：烟酰氯和甲胺在碱性条件下得甲基烟酰胺，再与一氯丙酮缩合得N-甲基-N-(2-氧丙基)烟酰胺，再进行自身的羟醛缩合反应得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮，最后还原得消旋尼古丁。提供了一种合成消旋体尼古丁的新路线，采用廉价易得的烟酰氯和甲胺为起始原料，原材料成本低，整个反应合成路线较短，操作简单，反应条件温和，后处理简单，合成的消旋尼古丁的产率高，适合工业化大规模生产。

Description

一种消旋尼古丁的制备方法 技术领域
本发明涉及有机合成技术领域，尤其是涉及一种消旋尼古丁的制备方法。
背景技术
尼古丁作为电子烟的主要成分之一，其来源主要是烟草提取物和人工化学合成。从烟草等植物中提取纯化的尼古丁受原材料和气候等影响较多，很难进行大规模工业化生产，且还含有除尼古丁外的其他致癌烟草化合物类杂质，影响电子烟的吸食者健康。而人工化学方法合成尼古丁可以有效避免从烟草等植物中提取尼古丁的上述问题。
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1所示：
Figure PCTCN2021115397-appb-000001
反应式1
反应式1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。
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 PCTCN2021115397-appb-000002
反应式2
反应式2的制备方法，中间需要使用格氏试剂，操作条件较苛刻，不适合工业化生产，且产率和纯度较低。
发明内容
为了改善消旋尼古丁反应条件苛刻的问题，提高消旋尼古丁的产率和纯度，本申请 提供一种消旋尼古丁的制备方法。
第一方面，本申请提供一种消旋尼古丁的制备方法，采用如下技术方案实现：
一种消旋尼古丁的制备方法，包括如下步骤：
S1、烟酰氯和甲胺在碱的作用下反应，得甲基烟酰胺；
S2、甲基烟酰胺与一氯丙酮在有机碱作用下缩合，得N-甲基-N-(2-氧丙基)烟酰胺；
S3、N-甲基-N-(2-氧丙基)烟酰胺进行自身的羟醛缩合反应，得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮；
S4、1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮与还原剂反应，得消旋尼古丁。
通过采取上述技术方案，烟酰氯和甲胺是廉价易得的原料，烟酰氯和甲胺在碱性条件下得甲基烟酰胺，再与一氯丙酮缩合得N-甲基-N-(2-氧丙基)烟酰胺，再进行自身的羟醛缩合反应得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮，最后还原得消旋尼古丁。本申请以烟酰氯和甲胺为起始原材料，成本较低，是一条合成消旋尼古丁的新路线，整个反应合成路线较短，操作简单，反应条件温和，后处理简单，合成的消旋尼古丁的产率高，适合工业化大规模生产。
优选的，所述S1步骤中，所述烟酰氯、甲胺和碱的摩尔比为1:(1.5～2.5):(3～5)；更优选的，所述烟酰氯、甲胺和碱的摩尔比为1:2:4。
优选的，所述S1步骤中，所述甲胺选自一甲胺、甲胺盐酸盐、甲胺氢溴酸盐和甲胺氢碘酸盐中的任一种；优选的，所述甲胺为甲胺盐酸盐。
优选的，所述S1步骤中，所述碱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任一种。
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，所述胺选自N,N-二异丙基乙胺、三乙胺、N,N-二乙基乙胺中的任一种；优选的，所述胺为N,N-二异丙基乙胺或三乙胺。
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。
优选的，所述碱为胺或碳酸盐；进一步优选的，所述碱为N,N-二异丙基乙胺、三乙胺和碳酸钾中的任一种。
本申请中，所述S1步骤中使用的溶剂包括但不限于四氢呋喃。
本申请中，所述S1步骤的反应温度为20～30℃；优选的，所述S1步骤的反应温度为25℃。
本申请中，所述S1步骤的反应时间为2.5～3.5h；优选的，所述S1步骤的反应时间为3h。
本申请中，所述S1步骤中，烟酰氯、甲胺和碱反应后需要用酸调节体系至微酸性，然后萃取，旋蒸除去溶剂，得甲基烟酰胺粗品，无需纯化即可进行下一步反应。其中，可以用0.1mol/L盐酸调节体系的pH为6；萃取可以使用乙酸乙酯进行萃取。
优选的，所述S2步骤中，所述甲基烟酰胺、一氯丙酮和有机碱的摩尔比为1:(1.1～2):(1.1～1.5)；更优选的，所述甲基烟酰胺、一氯丙酮和有机碱的摩尔比为1:(1.1～1.3):(1.05～1.15)；最优选的，所述甲基烟酰胺、一氯丙酮和有机碱的摩尔比为1:1.2:1.1。
优选的，所述S2步骤中，所述有机碱为胺或碱金属烷氧化物；更优选的，所述有机碱为胺。
优选的，所述S2步骤中，所述胺为N,N-二异丙基乙胺。
本申请中，所述S2步骤中使用的溶剂包括但不限于二氯乙烷。
本申请中，所述S2步骤的反应温度为20～30℃；优选的，所述S2步骤的反应温度为25℃。
本申请中，所述S2步骤的反应时间为4～6h；优选的，所述S2步骤的反应时间为5h。
本申请中，所述S2步骤中，甲基烟酰胺与一氯丙酮反应结束后可以用乙酸乙酯进行萃取，有机相除去溶剂，得到N-甲基-N-(2-氧丙基)烟酰胺粗品，无需纯化即可进行下一步反应。
本申请中，所述S3步骤中使用的溶剂包括但不限于四氢呋喃。
本申请中，所述S3步骤中，所述N-甲基-N-(2-氧丙基)烟酰胺进行自身的羟醛缩合反应需要在碱性条件下进行；该碱性条件使用的碱包括但不限于氢氧化钠、氢氧化钾、氢氧化锂、氢氧化镁、氢氧化铯和氢氧化钡中的任一种；优选的，所述N-甲基-N-(2-氧丙基) 烟酰胺进行自身的羟醛缩合反应需要氢氧化钠的催化。
本申请中，所述S3步骤中，所述N-甲基-N-(2-氧丙基)烟酰胺和氢氧化钠的摩尔比为1:(1.2～1.7)；优选的，所述N-甲基-N-(2-氧丙基)烟酰胺和氢氧化钠的摩尔比为1:1.5。
本申请中，所述S3步骤的反应温度为20～30℃；优选的，所述S3步骤的反应温度为25℃。
本申请中，所述S3步骤的反应时间为5～8h；优选的，所述S3步骤的反应时间为6h。
本申请中，所述S3步骤中，N-甲基-N-(2-氧丙基)烟酰胺进行自身的羟醛缩合反应后需要加酸调节体系的pH为中性，然后萃取，旋干溶剂，得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮粗品，可不用纯化进行下一步反应。
本申请中，所述S4步骤中，所述1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮和还原剂的摩尔比为1:(1～2)；优选的，所述1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮和还原剂的摩尔比为1:1.5。
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。
优选的，所述S4步骤中，所述还原剂为金属硼氢化物；更优选的，所述还原剂为硼氢化钠。
本申请中，所述S4步骤中使用的溶剂包括但不限于四氢呋喃。
本申请中，所述S4步骤的反应温度为-5～5℃；优选的，所述S4步骤的反应温度为0℃。
本申请中，所述S4步骤的反应时间为1～3h；优选的，所述S4步骤的反应时间为2h。
本申请中，所述S4步骤中，1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮与还原剂还原后可以用乙酸乙酯萃取，旋干溶剂，得消旋尼古丁粗品，然后进行精制纯化，得消旋尼古丁。
综上所述，本申请具有以下有益效果：
本申请采用廉价易得的烟酰氯和甲胺为起始原料，原材料成本低，提供了一种合成消旋体尼古丁的新路线，烟酰氯和甲胺在碱性条件下得甲基烟酰胺，再与一氯丙酮缩合得N-甲基-N-(2-氧丙基)烟酰胺，再进行自身的羟醛缩合反应得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡 咯-3-酮，最后还原得消旋尼古丁。整个反应合成路线较短，操作简单，反应条件温和，后处理简单，合成的消旋尼古丁的产率高，适合工业化大规模生产。
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1-14提供了一种消旋尼古丁的制备方法，以下以实施例1为例进行说明。
实施例1提供的消旋尼古丁的制备方法，其中，甲胺为甲胺盐酸盐，其合成路线如反应式3所示：
Figure PCTCN2021115397-appb-000003
反应式3
具体的制备步骤为：
S1、在25℃，向100mL四氢呋喃中加入0.142g(0.001mol，1eq)烟酰氯和0.135g(0.002mol，2eq)甲胺盐酸盐，然后加入0.517g(0.004mol，4eq)N,N-二异丙基乙胺，并在25℃以400rpm的搅拌速度反应3h，反应结束后用0.1mol/L盐酸调节体系的pH为7，用200mL乙酸乙酯-水(乙酸乙酯和水的体积比为2:1)萃取，取有机相，有机相旋蒸除去溶剂，得甲基烟酰胺粗品；
S2、在25℃，将S1步骤得到的甲基烟酰胺粗品加入100mL二氯乙烷中，加入0.111g(0.0012mol，1.2eq)一氯丙酮，再加入0.142g(0.0011mol，1.1eq)N,N-二异丙基乙胺，并在25℃以400rpm的搅拌速度反应5h，反应结束后用200mL乙酸乙酯-水(乙酸乙酯和水的体积比为2:1)萃取，取有机相，有机相旋蒸除去溶剂，得N-甲基-N-(2-氧丙基)烟酰胺粗品；
S3、在25℃，将S2步骤得到的N-甲基-N-(2-氧丙基)烟酰胺粗品溶于100mL四氢呋喃中，加入0.06g(0.0015mol，1.5eq)NaOH，并在25℃以400rpm的搅拌速度反应6h，反应结束 后用0.1mol/L盐酸调节体系的pH为7，用200mL乙酸乙酯-水(乙酸乙酯和水的体积比为2:1)萃取，取有机相，有机相旋蒸除去溶剂，得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮粗品；
S4、在0℃，将S3步骤得到的1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮粗品溶于100mL四氢呋喃中，加入0.057g(0.0015mol，1.5eq)硼氢化钠，在0℃反应2h将1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮还原为消旋尼古丁，用200mL乙酸乙酯-水(乙酸乙酯和水的体积比为2:1)萃取，取有机相，有机相旋蒸除去溶剂，得消旋尼古丁粗品，最后经一次常压蒸馏，精制后得消旋尼古丁，收率76％。
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2-5，与实施例1不同之处仅在于：所述S1步骤反应中，对甲胺盐酸盐和N,N-二异丙基乙胺的用量进行调整，具体如表1所示。
表1 S1步骤中甲胺盐酸盐和N,N-二异丙基乙胺的用量对反应的影响
Figure PCTCN2021115397-appb-000004
实施例6-7，与实施例1不同之处仅在于：所述S1步骤反应中，对碱的种类进行调整，具体如表2所示。
表2 S1步骤中碱的选择对反应的影响
编号 碱选择 消旋尼古丁的收率(％)
实施例1 N,N-二异丙基乙胺 76
实施例6 三乙胺 74
实施例7 碳酸钾 70
实施例8，与实施例1不同之处仅在于：所述S1步骤反应中，对甲胺的种类进行调整，具体如表3所示。
表3 S1步骤中甲胺的选择对反应的影响
编号 甲胺选择 消旋尼古丁的收率(％)
实施例1 甲胺盐酸盐 76
实施例8 甲胺氢溴酸盐 73
实施例9-12，与实施例1不同之处仅在于：所述S2步骤反应中，对一氯丙酮和N,N-二异丙基乙胺的用量进行调整，具体如表4所示。
表4 S2步骤中一氯丙酮和N,N-二异丙基乙胺的用量对反应的影响
Figure PCTCN2021115397-appb-000005
实施例13-14，与实施例1不同之处仅在于：所述S2步骤反应中，对碱有机碱的种类进行调整，具体如表5所示。
表5 S2步骤中碱的选择对反应的影响
编号 有机碱选择 消旋尼古丁的收率(％)
实施例1 N,N-二异丙基乙胺 76
实施例13 N,N-二乙基乙胺 66
实施例14 叔丁醇钠 74
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. 一种消旋尼古丁的制备方法，其特征在于，包括如下步骤：
    S1、烟酰氯和甲胺在碱的作用下反应，得甲基烟酰胺；
    S2、甲基烟酰胺与一氯丙酮在有机碱作用下缩合，得N-甲基-N-(2-氧丙基)烟酰胺；
    S3、N-甲基-N-(2-氧丙基)烟酰胺进行自身的羟醛缩合反应，得1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮；
    S4、1-甲基-5-(吡啶-3-基)-1,2-二氢-3H-吡咯-3-酮与还原剂反应，得消旋尼古丁。
  2. 根据权利要求1所述的一种消旋尼古丁的制备方法，其特征在于，所述S1步骤中，所述烟酰氯、甲胺和碱的摩尔比为1:(1.5～2.5):(3～5)。
  3. 根据权利要求1所述的一种消旋尼古丁的制备方法，其特征在于，所述S1步骤中，所述甲胺选自一甲胺、甲胺盐酸盐、甲胺氢溴酸盐和甲胺氢碘酸盐中的任一种。
  4. 根据权利要求1所述的一种消旋尼古丁的制备方法，其特征在于，所述S1步骤中，所述碱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任一种。
  5. 根据权利要求4所述的一种消旋尼古丁的制备方法，其特征在于，所述胺选自N,N-二异丙基乙胺、三乙胺、N,N-二乙基乙胺中的任一种。
  6. 根据权利要求1所述的一种消旋尼古丁的制备方法，其特征在于，所述S2步骤中，所述甲基烟酰胺、一氯丙酮和有机碱的摩尔比为1:(1.1～2):(1.1～1.5)。
  7. 根据权利要求6所述的一种消旋尼古丁的制备方法，其特征在于，所述S2步骤中，所述甲基烟酰胺、一氯丙酮和有机碱的摩尔比为1:1.2:1.1。
  8. 根据权利要求1所述的一种消旋尼古丁的制备方法，其特征在于，所述S2步骤中，所述有机碱为胺或碱金属烷氧化物。
  9. 根据权利要求8所述的一种消旋尼古丁的制备方法，其特征在于，所述S2步骤中，所述胺为N,N-二异丙基乙胺。
  10. 根据权利要求1所述的一种消旋尼古丁的制备方法，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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN110357853A (zh) * 2019-08-05 2019-10-22 济南悟通生物科技有限公司 (r,s-)尼古丁的合成方法
CN111454203A (zh) * 2020-05-25 2020-07-28 山东京博生物科技有限公司 一种2-氯-n,n-二甲基烟酰胺的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8367837B2 (en) * 2011-02-14 2013-02-05 Divi's Laboratories, Ltd. Process for the preparation of (R,S)-nicotine
US9809567B2 (en) * 2014-12-09 2017-11-07 Njoy, Llc Synthesis and resolution of nicotine
US10421739B2 (en) * 2016-01-08 2019-09-24 Council Of Scientific & Industrial Research Process for the preparation of nicotine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN110357853A (zh) * 2019-08-05 2019-10-22 济南悟通生物科技有限公司 (r,s-)尼古丁的合成方法
CN111454203A (zh) * 2020-05-25 2020-07-28 山东京博生物科技有限公司 一种2-氯-n,n-二甲基烟酰胺的合成方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DOWLING MATTHEW S., JIAO WENHUA, HOU JIE, JIANG YUCHUN, GONG SHANGSHENG: "Modular Synthesis of 3,6-Disubstituted-1,2,4-triazines via the Cyclodehydration of β-Keto- N -acylsulfonamides with Hydrazine Salts", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 83, no. 7, 6 April 2018 (2018-04-06), pages 4229 - 4238, XP093028657, ISSN: 0022-3263, DOI: 10.1021/acs.joc.8b00254 *
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
See also references of EP4151629A4
SHURDHA ENDRIT; MILLER HANNAH A.; JOHNSON RUSSELL E.; BALAICH GARY J.; IACONO SCOTT T.: "Synthesis and thermal properties of a new styryl-functionalized pentafulvene glassy carbon precursor", TETRAHEDRON, ELSEVIER SIENCE PUBLISHERS, AMSTERDAM, NL, vol. 70, no. 34, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 5142 - 5147, XP028873387, ISSN: 0040-4020, DOI: 10.1016/j.tet.2014.05.109 *

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