EP4140992B1 - Verfahren zur herstellung von s-nikotin - Google Patents

Verfahren zur herstellung von s-nikotin Download PDF

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Publication number
EP4140992B1
EP4140992B1 EP21810886.8A EP21810886A EP4140992B1 EP 4140992 B1 EP4140992 B1 EP 4140992B1 EP 21810886 A EP21810886 A EP 21810886A EP 4140992 B1 EP4140992 B1 EP 4140992B1
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Prior art keywords
pyridin
nicotine
amino
butanone
present application
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French (fr)
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EP4140992A1 (de
EP4140992A4 (de
EP4140992C0 (de
Inventor
Jun Zou
Yang Zou
Meisen LIU
Weixian LUO
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Shenzhen Zinwi Biotech Co Ltd
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Shenzhen Zinwi Biotech Co Ltd
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Classifications

    • 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
    • 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
    • A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
    • 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

Definitions

  • the present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of S-nicotine.
  • S-Nicotine has a molecular formula of C 10 H 14 N 2 , a CAS number of 54-11-5 , and a structural formula of
  • S-nicotine is basically obtained by a chiral resolution method, but chiral resolution reagents are expensive, which is not conducive to industrial production.
  • 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.
  • 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.
  • Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-ylbutane-1.4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.
  • the patent application EP 3925955 A1 discloses a method for preparing nicotine. The nicotinic acid alkyl ester and N-methylpyrrolidone are subjected to a condensation reaction, and then added with a strong acid to obtain 4-methyamino-1-(3-pyridine)-butanonehydrochloride.
  • the 4-methylamino-1-(3-pyridine)-butanone hydrochloride is reacted with an amino-protecting reagent to obtain an intermediate.
  • a chiral alcohol is obtained through an asymmetric reduction.
  • the chiral alcohol is converted into the nicotine through a two-step reaction.
  • the patent application CN 104341390 A discloses asymmetric synthesis method of plant-based pesticides nicotine and quinine, in which hydrogenation precursor cyclic imine is obtained by using inexpensive and readily available 2,5-dibromopyridine as the starting material through two-step reactions, important hydrogenation product intermediates are obtained with high enantioselectivity under the induction of chiral catalyst iridium phosphine oxazoline, and the intermediates are reacted after two steps to obtain L-nicotine, while the intermediates can be converted to L-quinine after one step reaction.
  • 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.
  • the present application provides a preparation method of S-nicotine.
  • 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:
  • nicotinate and ⁇ -butyrolactone are used as raw materials, nicotinate and ⁇ -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.
  • the nicotinate is methyl nicotinate or ethyl nicotinate.
  • a molar ratio of the nicotinate to the ⁇ -butyrolactone to the base catalyst is 1: (1-2): (1.2-3); and more preferably, the molar ratio of the nicotinate to the ⁇ -butyrolactone to the base catalyst is 1: 1:2.
  • the alkali metal alkoxide includes, but is not limited to, any one of sodium tert-butoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
  • the alkaline earth metal hydride includes, but is not limited to, one or more of NaH, LiH, and KH.
  • the alkaline earth metal oxide includes, but is not limited to, one or more of Na 2 O, Li 2 O, and K 2 O.
  • the amine includes, but is not limited to, triethylamine and/or diisopropylethyl amine.
  • the metal salt of amine includes, but is not limited to, sodium bis(trimethylsilyl)amide and/or lithium diisopropylamide.
  • the hydroxide includes, but is not limited to, one or more of sodium hydroxide, lithium hydroxide, and magnesium hydroxide.
  • the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
  • the bicarbonate includes, but is not limited to, sodium bicarbonate and/or potassium bicarbonate.
  • the base catalyst is selected from any one of sodium tert-butoxide, NaH, and potassium tert-butoxide.
  • 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.
  • the reaction needs to be performed under an N 2 atmosphere, and an adding order of the nicotinate, the ⁇ -butyrolactone and the base catalyst is that: the ⁇ -butyrolactone is added first, followed by the base catalyst and finally the nicotinate.
  • the reaction temperature of the ⁇ -butyrolactone and the base catalyst is 0°C, and the reaction time is 30 min; and the reaction temperature of the nicotinate, the ⁇ -butyrolactone and the base catalyst is 25°C.
  • the hydrochloric acid is concentrated hydrochloric acid, and the concentration of the concentrated hydrochloric acid is 12 mol/L.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the molar ratio of the 4-chloro-1-(3-pyridin)-1-butanone to the animation reagent is 1: 2.
  • the amination reagent is ammonium hydroxide or formamide; and more preferably, the amination reagent is formamide.
  • 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.
  • 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.
  • the 4-amino-1-(3-pyridin)-1-butanone prepared at S2 needs to be dissolved in the organic solvent II.
  • the organic solvent II is tetrahydrofuran.
  • 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).
  • 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.
  • 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.
  • an extraction agent is methylene chloride
  • 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.
  • the reaction temperature of S4 is -10 to 10°C; and more preferably, the reaction temperature of S4 is 0°C.
  • reaction time of S4 is 20 to 40 min; and preferably, the reaction time of S4 is 30 min.
  • the chlorination reagent is selected from oxalyl chloride, thionyl chloride, PC13, and PC15.
  • the molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxalyl chloride is 1: 1.5.
  • 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.
  • the base is hydroxide or carbonate.
  • 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.
  • the carbonate includes, but is not limited to, one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
  • the base is sodium hydroxide.
  • 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.
  • 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.
  • the amine methylation reagent is methyl iodide.
  • 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.
  • 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.
  • the pH needs to be adjusted to 6 by using an acid, extraction is performed, an organic phase is dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude S-nicotine.
  • the purification is distillation purification, and specifically includes: performing atmospheric distillation extraction two times to obtain a levorotatory sample with high purity.
  • the present application provides a novel route for synthesizing S-nicotine by using cheap and readily available nicotinate and ⁇ -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.
  • 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.
  • Embodiments 1 to 20 provide a preparation method of S-nicotine, which will be described below by taking Embodiment 1 as an example.
  • Embodiment 1 provides a preparation method of S-nicotine, wherein nicotinate is methyl nicotinate, and a synthetic route is shown as Reaction Formula 1:
  • 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.
  • Embodiments 2 to 3 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. Table 1 Effect of selection of base catalyst on the yield of S-nicotine 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
  • Embodiment 4 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.
  • Table 2 Effect of selection of amination reagent on the yield of S-nicotine Serial number Selection of amination reagent Yield of S-nicotine (%) Embodiment 1 Formamide 52 Embodiment 4 Ammonium hydroxide 48
  • Embodiments 5 to 6 and Embodiment 1 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. Table 3 Effect of usage amount of amination reagent on the yield of S-nicotine Serial number Equivalent quantity (eq) of amination reagent Yield of S-nicotine (%) Embodiment 1 2 52 Embodiment 5 3 48 Embodiment 6 1 45
  • Embodiments 7 to 9 and Embodiment 1 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.
  • Table 4 Effect of usage amount of (+)-B-diisopinocampheyl chloroborane on the yield of S-nicotine 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
  • Embodiments 10 to 12 and Embodiment 1 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. Examples 11 and 12 are only comparative examples which are not examples according to the invention. Table 5 Effect of selection of organic solvent II on the yield of S-nicotine 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
  • Embodiments 13 to 15 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. Table 6 Effect of reaction temperature on the yield of S-nicotine 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
  • Embodiments 16 to 17 and Embodiment 1 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. Table 7 Effect of reaction temperature on the yield of S-nicotine Serial number Reaction temperature (°C) Yield of S-nicotine (%) Embodiment 1 0 52 Embodiment 16 10 43 Embodiment 17 -10 48
  • Embodiments 18 to 19 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. Table 8 Effect of usage amount of oxalyl chloride on the yield of S-nicotine 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
  • Embodiment 20 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%.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • Plural Heterocyclic Compounds (AREA)
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Claims (6)

  1. Verfahren zur Herstellung von S-Nicotin, dadurch gekennzeichnet, dass es die folgenden Schritte umfasst:
    S1: Zugabe von Nikotinat und γ-Butyrolacton in ein organisches Lösungsmittel I, Durchführung einer Kondensation in Gegenwart eines basischen Katalysators, um ein Kondensationsprodukt zu erhalten, und Durchführung einer Cyclisierung des Kondensationsprodukts in Gegenwart von Salzsäure, um 4-Chlor-1-(3-pyridin)-1-butanon zu erhalten;
    S2: Umsetzen des 4-Chlor-1-(3-pyridin)-1-butanons mit einem Aminierungsreagenz unter alkalischen Bedingungen, um 4-Amino-1-(3-pyridin)-1-butanon zu erhalten;
    S3: Zugabe von 4-Amino-1-(3-pyridin)-1-butanon und (+)-B-Diisopinocampheylchlorboran in ein organisches Lösungsmittel II und Umsetzen bei -30 bis 10°C um (S)-4-Amino-1-(pyridin-3-yl)butan-1-ol zu erhalten;
    S4: Umsetzen des (S)-4-Amino-1-(pyridin-3-yl)butan-1-ols mit einem Chlorierungsreagenz, um (S)-4-Amino-1-(pyridin-3-yl)butyl-1-chlor zu erhalten;
    S5: Cyclisierung des (S)-4-Amino-1-(pyridin-3-yl)butyl-1-chlorins in Gegenwart einer Base, um S-Demethylnicotin zu erhalten; und
    S6: Umsetzen des S-Demethylnicotins mit einem Amin-Methylierungsreagenz, um rohes S-Nicotin zu erhalten, und Reinigen, um S-Nicotin zu erhalten;
    wobei bei S1 der Basenkatalysator aus einem oder mehreren von Alkalimetallalkoxid, Erdalkalimetallhydrid, Erdalkalimetalloxid, Amin, einem Metallsalz von Amin, Hydroxid, Carbonat und Bicarbonat ausgewählt ist;
    bei S3 das organische Lösungsmittel II ausgewählt ist aus einem oder mehreren von Tetrahydrofuran, Dimethyltetrahydrofuran und 1,4-Dioxan,
    bei S4 das Chlorierungsreagenz Oxalylchlorid ist, und ein molares Verhältnis des (S)-4-Amino-1-(pyridin-3-yl)butan-1-ols zum Oxalylchlorid 1:(1-3) ist, und
    bei S2 ein molares Verhältnis des 4-Chlor-1-(3-pyridin)-1-butanons zum Aminierungsreagenz 1:(1-3) ist.
  2. Verfahren zur Herstellung von S-Nicotin nach Anspruch 1, dadurch gekennzeichnet, dass bei S3 ein molares Verhältnis des 4-Amino-1-(3-pyridin)-1-butanons zum (+)-B-Diisopinocampheylchlorboran 1:(1-3) ist.
  3. Verfahren zur Herstellung von S-Nicotin nach Anspruch 4, dadurch gekennzeichnet, dass bei S4 die Reaktionstemperatur -10 bis 10°C beträgt.
  4. Verfahren zur Herstellung von S-Nikotin nach Anspruch 1, dadurch gekennzeichnet, dass bei S2 das Aminierungsreagenz Ammoniumhydroxid oder Formamid ist.
  5. Verfahren zur Herstellung von S-Nicotin nach Anspruch 1, dadurch gekennzeichnet, dass bei S1 ein molares Verhältnis des Nicotinats zum γ-Butyrolacton zum Basenkatalysator 1:(1-2):(1,2-3) beträgt.
  6. Verfahren zur Herstellung von S-Nikotin nach Anspruch 1, dadurch gekennzeichnet, dass bei S5 die Base Hydroxid oder Carbonat ist.
EP21810886.8A 2021-07-10 2021-08-16 Verfahren zur herstellung von s-nikotin Active EP4140992B1 (de)

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CN202110781163.8A CN113475739B (zh) 2021-07-10 2021-07-10 一种s-尼古丁的制备方法
PCT/CN2021/112793 WO2023284057A1 (zh) 2021-07-10 2021-08-16 一种s-尼古丁的制备方法

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CN114276204B (zh) * 2021-12-24 2024-02-27 大庆雾泰化工科技有限公司 一种(s)-(-)-尼古丁的制备方法
CN114437031B (zh) * 2022-02-16 2023-06-27 深圳市真味生物科技有限公司 一种6-甲基尼古丁的合成方法

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EP4140992A4 (de) 2023-12-06
CN113475739B (zh) 2022-11-11
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WO2023284057A1 (zh) 2023-01-19
CN113475739A (zh) 2021-10-08

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