WO2021056811A1 - Dérivé de sel d'imine, son procédé de préparation et procédé de préparation de nicotine - Google Patents

Dérivé de sel d'imine, son procédé de préparation et procédé de préparation de nicotine Download PDF

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WO2021056811A1
WO2021056811A1 PCT/CN2019/121980 CN2019121980W WO2021056811A1 WO 2021056811 A1 WO2021056811 A1 WO 2021056811A1 CN 2019121980 W CN2019121980 W CN 2019121980W WO 2021056811 A1 WO2021056811 A1 WO 2021056811A1
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reaction
nicotine
solution
acid
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欧军
韩魁元
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Shenzhen Helgetech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3834—Aromatic acids (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the present invention relates to the field of organic synthesis preparation, in particular to an imine salt derivative, a preparation method thereof and a preparation method of nicotine.
  • Nicotine commonly known as nicotine, is an alkaloid that exists in Solanaceae (Solanum) and an important component of tobacco. It is also a typical nicotinic acetylcholine receptor agonist. The central nervous system has a regulatory role.
  • Nicotine can make people addicted or dependent. Repeated use of nicotine also increases heart speed and blood pressure and reduces appetite. Large doses of nicotine can cause vomiting and nausea, and death can occur in severe cases. At the same time, nicotine and its derivatives are effective drugs for treating Parkinson's syndrome, Alzheimer's disease, schizophrenia, epilepsy and depression.
  • the starting materials of the method are very expensive, and the intermediate pyrrolidol reduction step has the problems of incomplete reaction and low conversion rate, which is not suitable for industrial large-scale production.
  • the object of the present invention is to provide an imine salt derivative which can synthesize nicotine.
  • Another object of the present invention is to provide a method for preparing imine salt derivatives using niacin as the main raw material
  • Another object of the present invention is to provide a preparation method for preparing nicotine by using imine salt derivatives, which has low starting materials, mild reaction conditions, and high nicotine synthesis yield.
  • novel imine salt derivative of the present invention is represented by the following general formula (I) or (II):
  • X 1 and X 2 are respectively represented as acid radical anions.
  • the X 1 and X 2 represent the same acid radical ion; or the X 1 and X 2 represent different acid radical ions.
  • X 1 and/or X 2 respectively represent inorganic acid anions or organic acid anions, that is, X 1 and X 2 can be non-polar acid anions at the same time, or there can be no organic acid anions at the same time, or X 1 and X 2 can be organic Acid radical anion, the other is inorganic acid radical anion.
  • the present invention also provides a preparation method of imine salt derivatives, including the following steps:
  • reaction solution is cooled to below 10°C for extraction treatment, and the organic layers are combined; and the organic layer is concentrated under reduced pressure at 50-65°C to obtain 1-methyl-3-nicotinoyl -2-pyrrolidone;
  • the catalyst is thionyl chloride or oxalyl chloride.
  • the first quencher is an alkaline aqueous solution.
  • the extractant is an acidic aqueous solution.
  • the present invention further provides a method for preparing nicotine, which includes the following steps:
  • the general formula described in claim 1 is The iminium salt derivative and reducing agent are added to the solvent for reduction reaction, and the general formula is The racemic nicotine solution;
  • the reducing agent is one of sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate, hydrogen, and palladium/carbon.
  • the second quencher is an alkaline substance.
  • the extractant is one or more of ether solvents, ester solvents or chlorinated hydrocarbon solvents.
  • the beneficial effects of the present invention are: the first niacin, common organic acids and/or inorganic acids are used as raw materials, and the imine salt is synthesized under relatively mild process conditions (such as room temperature, about 100°C reflux reaction, extraction treatment, etc.)
  • relatively mild process conditions such as room temperature, about 100°C reflux reaction, extraction treatment, etc.
  • Starting material reducing agents eg, sodium thiosulfate, sodium borohydride, potassium borohydride, lithium tetrahydroaluminum, formic acid, ammonium formate, potassium formate
  • the reaction temperature is controlled at -10 to 100°C, even at room temperature
  • the intermediate of the imine salt derivative is reduced to obtain racemic nicotine. Therefore, compared with the existing nicotine synthesis process, the method has the advantages of mild synthesis process conditions, simple equipment requirements, and the product has the advantages of high purity and synthesis rate, and is particularly suitable for industrial production.
  • Figure 1 is a flow chart of the imine salt synthesis process of the present invention
  • Figure 2 is a flow chart of the nicotine synthesis process of the present invention.
  • X 1 and X 2 are respectively represented as acid radical anions.
  • X 1 and X 2 are respectively represented as acid radical anions, and these acid radical ions may be inorganic acid radical ions or organic acid radical ions.
  • inorganic acid anions include, but are not limited to, chloride, sulfate, phosphate, carbonate, nitrate, perchlorate or borate ions; organic acid anions include but are not limited to carbon-containing C 1 -C 30 carboxylate ion (e.g., formate ion, methyl propionate ion, valerate ion, benzoate ion, p-dibenzoate ion, etc.), carbon-containing C 3 -C 30 sulfonate ion (e.g., methyl Sulfonate ion, phenyl sulfonate ion, sodium dodecyl sulfonate ion, etc.), or carbon-containing C 3 -C 30 phosphonate ion (
  • X 1 and X 2 may be the same acid ion, such as chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, Perchlorate ion, borate ion, carbon-containing C 1 -C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion, etc.; or
  • X 1 and X 2 may also be different acid ions; for example, X 1 is sulfate ion, X 2 is formate ion; X 1 is borate ion, X 2 is C 30 sulfonate ion; or X 1 is C 8 phosphonate ion, X 2 is perchlorate ion, etc.
  • X 1 and X 2 are the same acid radical ion or different acid radical ion needs to be determined according to the acid added twice before and after the preparation process. If the acid added twice before and after is the same substance, X 1 and X 2 are the same acid radical ion; otherwise, X 1 and X 2 are different acid radical ions.
  • the preparation method of the above-mentioned imine salt derivative is as follows:
  • the molar ratio of niacin to catalyst is 1:5, and the catalyst is thionyl chloride or oxalyl chloride, preferably thionyl chloride; toluene is used as a solvent to dissolve nicotinic acid and the catalyst, which is beneficial to the reaction.
  • niacin and the catalyst are insoluble in toluene at room temperature, it is necessary to heat to 50-80°C (preferably 70°C) and stir while heating during the dissolution process.
  • the oil temperature heating method is used for 10min-60min, preferably 30min. A colorless and transparent mixed solution was obtained.
  • an alcohol solvent such as methanol, propanol, ethylene glycol, etc.
  • it may also be an ether solvent, or an aldehyde solvent, or a chloroform solvent or the like.
  • the first quencher is added to the reactor, and an alkaline aqueous solution is selected.
  • the solute can be one of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • One or more than two types; the first quencher is used to neutralize the acid radical ions in the reactant to ensure that the reaction stops and avoid the production of other by-products.
  • an ester extractant such as ethyl acetate, methyl acetate, ethyl propionate, etc.
  • the extractant can also be an ether solvent (e.g., diethyl ether, dimethyl diethyl ether, etc.). ), or one or more of chlorinated hydrocarbons (e.g., dichloroethane, tetrachloromethane, etc.) solvents.
  • the extraction is generally repeated multiple times, and the organic layer obtained after the extraction is concentrated under reduced pressure to remove the solvent to obtain methyl nicotinate.
  • the methyl nicotinate is dissolved in an organic solvent to obtain a methyl nicotinate solution, and it is determined that there is no significant exotherm.
  • the first organic solvent includes toluene, tetrahydrofuran or 1,2-dioxane.
  • alkaline reagents include sodium hydride, potassium hydride, sodium ethoxide, potassium and sodium tert-butoxide, or potassium and butyl lithium, lithium bis(trimethylsilyl)amide (LiHMDS) and lithium diisopropylamide ( One or more of LDA).
  • the second organic solvent includes one or more of toluene, tetrahydrofuran and 1,2-dioxane.
  • the obtained reaction liquid is cooled to below 10°C, the extractant is added dropwise, and acidic aqueous solutions (eg, niacin, nitric acid, sulfuric acid, phosphoric acid, and organic acids with C 3 ⁇ C 30) are selected.
  • acidic aqueous solutions eg, niacin, nitric acid, sulfuric acid, phosphoric acid, and organic acids with C 3 ⁇ C 30
  • Is used to stop the condensation reaction neutralize the alkali solution in the reaction system at the same time, and adjust the pH of the reaction system solution to be 8-9, and then perform repeated extraction and separation with EA solvent to obtain the organic layer and combine it for subsequent extraction.
  • the acid substance can be an organic acid or an inorganic acid, wherein the acid radical anion corresponding to the inorganic acid includes but not limited to chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, perchlorate ion or boric acid Root ion.
  • the acid radical anions corresponding to organic acids include, but are not limited to, carbon-containing C 1 -C 30 carboxylate ions, carbon-containing C 3 -C 30 sulfonate ions, or carbon-containing C 3 -C 30 phosphonate ions.
  • the acid substance is added to 1-methyl-3-nicotinoyl-2-pyrrolidone to perform exothermic reaction first to obtain a light yellow reaction liquid, and then reflux reaction at 110°C for 24h; after the reflux reaction stops, the reaction system The temperature is lowered to 10°C; then the reaction system solution is subjected to vacuum distillation treatment to remove water, and acetone is added to recrystallize for purification treatment, and the general formula is The imine salt derivative.
  • the recrystallization purification is carried out by adding acetone, ethanol or ethyl acetate to the reaction solution after the vacuum distillation treatment for recrystallization purification treatment.
  • X 1 and X 2 are the same acid radical anion; if the acid substance added in the reflux reaction in step j is mixed with acid substance, then X 1 and X 2 are different acid radical anions.
  • the nicotine salt compound prepared by the above method is used to prepare nicotine, and the process flow is as follows:
  • the general formula is The imine salt derivative of and the reducing agent are added to the solvent to perform the reduction reaction to obtain racemic nicotine; wherein, X 1 and X 2 are both acid radical anions;
  • X 1 and X 1 may be inorganic acid anions or organic acid anions.
  • inorganic acid anions include, but are not limited to, chloride, sulfate, phosphate, carbonate, nitrate, perchlorate or borate ions
  • organic acid anions include but are not limited to carbon-containing C 1 -C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion.
  • the reducing agent is generally selected to be an inorganic acidic substance or an organic acidic substance; for example, sodium thiosulfate, sodium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, formic acid, ammonium formate, potassium formate; or a reducing agent It is possible to select a substance that can provide acid radical ions through the reduction reaction, for example, one of hydrogen and palladium/carbon.
  • X 1 and X 2 can be the same acid ion, such as chloride ion, sulfate ion, phosphate ion, carbonate ion, nitrate ion, perchlorate ion, borate ion, carbon-containing C 1- C 30 carboxylate ion, carbon-containing C 3 -C 30 sulfonate ion or carbon-containing C 3 -C 30 phosphonate ion, etc.; or
  • X 1 and X 2 may also be different acid ions; for example, X 1 is sulfate ion, X 2 is formate ion; X 1 is borate ion, X 2 is C 30 sulfonate ion; or X 1 is C 8 phosphonate ion, X 2 is perchlorate ion, etc.
  • the imine salt derivative is a cyclic organic substance, and solvents such as alcohol solvents, ether solvents, ester solvents, or chlorinated hydrocarbons are generally selected for dissolution.
  • solvents such as alcohol solvents, ether solvents, ester solvents, or chlorinated hydrocarbons
  • other organic solvents aldehyde-based solvents, ketone-based solvents, etc.
  • inorganic solvents such as water
  • the temperature of the reduction reaction can be controlled at room temperature of -10 to 100°C, preferably 25°C, so that the temperature control operation is convenient, and no additional heating or cooling control equipment is required.
  • the molar ratio of the intermediate to the reducing agent is controlled at 1:50; according to the chemical reaction rate mechanism, the excess of reactants is beneficial to speed up the reaction speed and convert the reactants into products as much as possible.
  • an excessive amount of reducing agent with low raw material price to convert the intermediate into more target product racemic nicotine.
  • the reducing agent reactant is excessive.
  • the target product racemic nicotine has been obtained; if the excessive reducing agent reactant continues to exist, it will, Further reaction produces undesirable products, so it is necessary to add a quencher.
  • the principle of quenching is to react with another compound that is more likely to react with the excess compound.
  • the reducing agent reactant is an acidic reactant, and the most likely reaction of an acidic substance is an acid-base reaction. Therefore, an alkaline substance is selected as the quencher.
  • an alkaline substance is added as the second quencher, such as one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. .
  • the concentration range of the second quencher (reactant) is selected from 0.1 to 10 mol/L. Because, the inhibitory effect of different concentration of the second quencher, its principle is consistent with the chemical reaction rate mechanism.
  • the chemical reaction rate (v) is equal to the decrease ( ⁇ c) of a certain reactant concentration per unit time ( ⁇ t), namely:
  • the second quencher is used as a reactant, and the concentration of the second quencher affects the rate of the quenching reaction, which directly reflects whether there is a significant inhibitory effect in a short time.
  • step S12 the reaction temperature is controlled at -5 after adding a quencher ⁇ 50°C, preferably room temperature 25°C.
  • step S3 in order to extract the nicotine substance from the nicotine precursor solution (ie, the reaction mixture solution), a solvent needs to be added to the nicotine precursor solution.
  • This solvent can more easily dissolve nicotine, and the solvent after dissolving nicotine It shows a layering phenomenon with the mixed solution, and then removes the mixed solution to obtain a solvent solution that dissolves nicotine; this solvent is also called an extractant.
  • the extractant is preferably ether solvents (such as diethyl ether, dimethyl diethyl ether, etc.), ester solvents (such as carboxylate, phenyl acetate, or methyl carbonate, etc.) or chlorinated hydrocarbon solvents (Eg, dichloroethane, tetrachloromethane, etc.) one or more than two.
  • ether solvents such as diethyl ether, dimethyl diethyl ether, etc.
  • ester solvents such as carboxylate, phenyl acetate, or methyl carbonate, etc.
  • chlorinated hydrocarbon solvents Eg, dichloroethane, tetrachloromethane, etc.
  • step S3 the reaction temperature control during the extraction process with the addition of extractant At -5 to 50°C, preferably at room temperature 25°C.
  • the first nicotinic acid, common organic acids and/or inorganic acids are used as raw materials to synthesize imine salt derivatives under relatively mild process conditions (such as room temperature, about 100°C reflux reaction, extraction treatment, etc.) And re-use of cheap initial raw material reducing agents (such as sodium thiosulfate, sodium borohydride, potassium borohydride, lithium tetrahydroaluminum, formic acid, ammonium formate, potassium formate), also under a relatively mild condition ( For example, the reaction temperature is controlled at -10 to 100°C, even at room temperature) to reduce the intermediate of the imine salt derivative to obtain racemic nicotine. Therefore, compared with the existing nicotine synthesis process, the method has the advantages of mild synthesis process conditions, simple equipment requirements, and the product has the advantages of high purity and synthesis rate, and is particularly suitable for industrial production.
  • relatively mild process conditions such as room temperature, about 100°C reflux reaction, extraction treatment, etc.
  • initial raw material reducing agents such as sodium thios
  • Example 2 The difference from Example 1 is that: the first quencher is an aqueous potassium hydroxide solution; the alcohol extractant is ethyl acetate; the alkaline reagent used in the condensation reaction is sodium ethoxide; the acid substance used in the reflux reaction is different. Sulfuric acid is used in the example.
  • Example 2 The difference from Example 1 is that the catalyst is acid chloride; the first quencher is sodium carbonate aqueous solution; the alcohol extractant is ethyl propionate; the alkaline reagents used in the condensation reaction are potassium and sodium tert-butoxide; the reflux reaction is used
  • the acid substance is different, and nitric acid is used in this example.
  • Nitric acid was added to the 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g) aqueous solution, exothermic heat, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water. It was recrystallized with ethanol to obtain the intermediate nitrate (1.4g).
  • Example 1 The difference from Example 1 is that: the first quencher is an aqueous ammonia solution; the ether extractant is ether; the alkaline reagents used in the condensation reaction are potassium and butyl lithium; the acid substance used in the reflux reaction is different. Perchloric acid is used in it.
  • Example 2 The difference from Example 1 is that the first quencher is potassium carbonate aqueous solution; the ether extractant is dimethyl diethyl ether; the alkaline reagent used in the condensation reaction is lithium bis(trimethylsilyl)amide (LiHMDS) ; The first and second organic solvents are respectively mixed solvents of toluene and tetrahydrofuran; the acid substances used in the reflux reaction are different, and boric acid is used in this embodiment.
  • the first quencher is potassium carbonate aqueous solution
  • the ether extractant is dimethyl diethyl ether
  • the alkaline reagent used in the condensation reaction is lithium bis(trimethylsilyl)amide (LiHMDS) )
  • the first and second organic solvents are respectively mixed solvents of toluene and tetrahydrofuran; the acid substances used in the reflux reaction are different, and boric acid is used in this embodiment.
  • Example 1 The difference from Example 1 is that: the first quencher is an aqueous sodium bicarbonate solution; the chlorinated hydrocarbon extractant is dichloroethane; the alkaline reagent used in the condensation reaction is lithium diisopropylamide (LDA); The first and second organic solvents are 1,2-dioxane respectively; the acid substance used in the reflux reaction is different, and benzoic acid is used in this example.
  • the first quencher is an aqueous sodium bicarbonate solution
  • the chlorinated hydrocarbon extractant is dichloroethane
  • the alkaline reagent used in the condensation reaction is lithium diisopropylamide (LDA)
  • the first and second organic solvents are 1,2-dioxane respectively
  • the acid substance used in the reflux reaction is different, and benzoic acid is used in this example.
  • Benzoic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), exothermic, the reaction liquid was light yellow, refluxed at 110°C for 24h, cooled to 10°C, and distilled under reduced pressure to remove water It was recrystallized by adding ethyl acetate to obtain the intermediate benzoate (1.6g).
  • Example 2 The difference from Example 1 is that: the first quencher is an aqueous potassium bicarbonate solution; the alkaline reagents used in the condensation reaction are sodium hydride and sodium ethoxide; the first and second organic solvents are tetrahydrofuran; the acid substance used in the reflux reaction is not Similarly, camphor sulfonic acid is used in this example.
  • Camphorsulfonic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was reduced to 10°C and evaporated under reduced pressure. Water and ethanol were recrystallized to obtain the intermediate camphor sulfonate (1.8 g).
  • Example 2 The difference from Example 1 is that the first quencher is a mixed aqueous solution of potassium bicarbonate and potassium carbonate; the chlorinated hydrocarbon extractant is tetrachloromethane; the alkaline reagent used in the condensation reaction is potassium hydride; the first and second organic
  • the solvents were mixed solvents of toluene, tetrahydrofuran and 1,2-dioxane; the acid substances used in the reflux reaction were different, and a mixed acid of phenylphosphonic acid and nitric acid was used in this embodiment.
  • Phenylphosphonic acid was added to the aqueous solution of 1-methyl-3-nicotinoyl-2-pyrrolidone (2.0g), the reaction solution was light yellow, and the reaction was refluxed at 110°C for 24 hours. The temperature was lowered to 10°C and then distilled under reduced pressure. The water was removed, acetone was added for recrystallization, and the intermediate nitrophenyl phosphonate (1.61 g) was obtained.
  • the intermediate was selected as the hydrochloride salt of the intermediate prepared in Example 1.
  • the mixture of the intermediate hydrochloride (1.5g, 0.0088mol) and potassium formate (1.6g, 0.0052mol) was heated to reflux at 100°C for 2h in 10mL of absolute ethanol. After the reaction, the ethanol was left under reduced pressure. The residue was dissolved in water, and 3N sodium hydroxide solution was added to react at 25°C to make it neutral. The resulting oily substance was extracted with ether at 25°C, and the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.4 g of nicotine with a purity of 99.4%.
  • the intermediate was selected as the nitrate of the intermediate prepared in Example 3.
  • the intermediate was selected as the sulfate salt of the intermediate prepared in Example 2.
  • the intermediate perchlorate prepared in Example 4 was selected as the intermediate.
  • the intermediate was selected as the borate of the intermediate prepared in Example 5.
  • the mixture of borate (1.5g) and ammonium formate (1.4g) of the intermediate was heated to reflux at 90°C for 2h in 10 mL of ethyl acetate. After the reaction, the ethyl acetate was removed under reduced pressure, and the residue was dissolved in Water, and add 0.5mol/L potassium carbonate solution to make the reaction become neutral at 0°C. The resulting oily substance was extracted with ether at 0°C, the organic solvent was washed with saturated brine three times, and dried with anhydrous sodium sulfate. The inorganic matter was removed by filtration, and the residue was distilled under reduced pressure to obtain 1.41 g of nicotine with a purity of 99.3%.
  • the benzoate of the intermediate prepared in Example 6 was selected as the intermediate.
  • the intermediate was selected as the camphorsulfonate of the intermediate prepared in Example 7.
  • Example 8 the intermediate phenylphosphonate prepared in Example 8 was selected as the intermediate.
  • the borate of the intermediate prepared in Example 1 was selected as the intermediate.

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Abstract

La présente invention concerne un dérivé de sel d'imine, son procédé de préparation et un procédé de préparation de nicotine. Le procédé de préparation de nicotine comprend les étapes suivantes consistant à : ajouter un dérivé de sel d'imine de formule générale (I) ou (II) et un agent réducteur dans un solvant et mettre en œuvre la réaction pour obtenir une solution de nicotine racémique ; ajouter un second agent d'extinction dans la solution de nicotine racémique pour obtenir une solution d'un précurseur de nicotine ; et ajouter un agent d'extraction dans la solution de précurseur de nicotine, réaliser une concentration sous vide, et éliminer un solvant par séchage pour obtenir de la nicotine. Dans la présente invention, la nicotine racémique est obtenue par réduction d'un intermédiaire dérivé de sel d'imine, qui est synthétisé pour la première fois, à l'aide d'un agent réducteur peu coûteux dans des conditions relativement modérées. Par comparaison aux procédés de synthèse de nicotine existants, le procédé selon la présente invention a les avantages d'avoir des conditions de processus de synthèse modérées, des exigences d'équipement simples et des vitesses de synthèse et de pureté de produit élevées, et est particulièrement approprié pour une production industrielle.
PCT/CN2019/121980 2019-09-27 2019-11-29 Dérivé de sel d'imine, son procédé de préparation et procédé de préparation de nicotine Ceased WO2021056811A1 (fr)

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CN117362270A (zh) * 2022-07-01 2024-01-09 湖北和诺生物工程股份有限公司 一种消旋尼古丁的制备方法及左旋尼古丁的拆分方法
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102617547A (zh) * 2011-01-27 2012-08-01 上海特化医药科技有限公司 一种制备消旋尼古丁的方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102617547A (zh) * 2011-01-27 2012-08-01 上海特化医药科技有限公司 一种制备消旋尼古丁的方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GÄRTNER PETER, BICA KATHARINA, EINZINGER CHRISTIAN: "Synthesis of Partially Deuterated N -Nitrosamines ? New Standards in Tobacco-smoke Analysis", MONATSHEFTE FÜR CHEMIE / CHEMICAL MONTHLY, SPRINGER VIENNA, VIENNA, vol. 135, no. 5, 1 May 2004 (2004-05-01), Vienna, pages 549 - 555, XP055795773, ISSN: 0026-9247, DOI: 10.1007/s00706-003-0152-8 *
IDE, AKIO ET AL.: "Synthesis of 3-(1-methyl-2-pyrrolidinyl) quinoline", JOURNAL OF THE CHEMICAL SOCIETY OF JAPAN, vol. 91, no. 6, 31 December 1970 (1970-12-31) *
KOVACIC, PETER ET AL.: "Reduction potentials of imine-substituted, biologically active pyridines:possible relation to activity", FREE RADICAL RESEARCH COMMUNICATIONS, vol. 10, no. 3, 31 December 1990 (1990-12-31), ISSN: 8755-0199 *
WAGNER, F.F. COMINS, D.L.: "Recent advances in the synthesis of nicotine and its derivatives", TETRAHEDRON, ELSEVIER SIENCE PUBLISHERS, AMSTERDAM, NL, vol. 63, no. 34, 12 July 2007 (2007-07-12), AMSTERDAM, NL, pages 8065 - 8082, XP022149763, ISSN: 0040-4020, DOI: 10.1016/j.tet.2007.04.100 *
WU YAXIAN, WANG XIAO-YU, HE LI-QIN: "Synthesis of Nicomethanol Nicotinate", ANHUI CHEMICAL INDUSTRY, vol. 39, no. 4, 1 August 2013 (2013-08-01), pages 34 - 38, XP055796147, DOI: 10.3969/j.issn.1008-553X.2013.04.011 *

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