CN115594662A - Preparation method of (S) -nicotine - Google Patents

Preparation method of (S) -nicotine Download PDF

Info

Publication number
CN115594662A
CN115594662A CN202211276431.1A CN202211276431A CN115594662A CN 115594662 A CN115594662 A CN 115594662A CN 202211276431 A CN202211276431 A CN 202211276431A CN 115594662 A CN115594662 A CN 115594662A
Authority
CN
China
Prior art keywords
nicotine
preparation
molar ratio
racemic
inorganic base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202211276431.1A
Other languages
Chinese (zh)
Inventor
廖霞俐
赵玉茹
陈加兴
张真东
杨伟
隋昭松
尹天竹
杨波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kunming University of Science and Technology
Original Assignee
Kunming University of Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kunming University of Science and Technology filed Critical Kunming University of Science and Technology
Priority to CN202211276431.1A priority Critical patent/CN115594662A/en
Publication of CN115594662A publication Critical patent/CN115594662A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a preparation method of (S) -nicotine, which takes 3-pyridine methylamine as a reaction raw material, converts the 3-pyridine methylamine into racemic nicotine through phase transfer allylation, hydroboration oxidation, cyclization and methylation, and then obtains the (S) -nicotine with high optical purity through L-tartrate resolution. The method has the advantages of simple and easy operation, cheap and easily-obtained reagents, green and environment-friendly reaction process, high purity and yield of the product nicotine, and suitability for industrial production.

Description

Preparation method of (S) -nicotine
Technical Field
The invention belongs to the technical field of fine chemical engineering, and particularly relates to a method for preparing (S) -nicotine by using 3-pyridylmethylamine as a raw material.
Background
Nicotine (the english name Nicotine, the chemical name is 1-methyl-2- (3' -pyridine) pyrrolidine), also known as Nicotine, and natural Nicotine is in (S) -configuration. In 1828, (S) -nicotine was first extracted from tobacco leaves by the German chemists Posselt and Reimann. In 1843, melsens determined the nicotine chemical formula. In 1893, pinner determined nicotine structure. In 1904, nicotine was first synthesized by Pictet and Crepieux.
Nicotine is a key component of tobacco alkaloid and has wide application in tobacco related products. Meanwhile, nicotine and its derivatives, nicotinic acid, nicotinamide, nicotinate, etc., have various physiological activities, such as the effects of treating depression, anxiety, alzheimer's disease, parkinson's disease, epilepsy and other nerve diseases.
However, the source of (S) -nicotine mainly depends on the extraction and purification of plant components such as tobacco, and this method is subject to great uncertainty, not only by the quality and source of tobacco, but also by the control of relevant policies. Therefore, the development of the artificial synthesis method of (S) -nicotine with industrial production potential has important application value.
Patents and literature on nicotine synthesis, document j. Org. Chem. 1990, 55 (6), 1736-1744, report the synthesis of racemic nicotine in four steps starting from pyrrolidine, as shown in the following formula:
Figure 405534DEST_PATH_IMAGE001
the reference relates to a very dangerous reagent of tert-butyl lithium and reaction conditions of-120 ℃, and meanwhile, the noble metal is adopted for reduction, so that the production cost is high, and the industrial production is not facilitated.
Patent document US 2010209006A1 reports a process for the preparation of racemic nicotine starting from methyl nicotinate via a four-step reaction, as shown in the following formula:
Figure 826151DEST_PATH_IMAGE002
the route requires the use of sodium hydride, a hazardous reagent, and the N-butenyl pyrrolidone used in the route is relatively expensive and is not suitable for industrial scale-up.
Patent document CN 110357853B provides a synthesis method of racemic nicotine, which comprises preparing grignard reagent of 3-bromopyridine from 3-bromopyridine and magnesium chips, adding N-methylpyrrolidone into the system to obtain enamine intermediate, and then performing reduction reaction in the presence of metal reduction catalysts such as Pd/C, pt/C and raney nickel to obtain racemic nicotine, as shown in the following formula:
Figure 236403DEST_PATH_IMAGE003
the route needs to use a Grignard reagent, relates to reaction conditions such as noble metal reduction and the like, and has high cost and is not beneficial to industrial scale-up production.
Patent document CN 111511726a reports a method for preparing (S) -nicotine, which comprises reacting racemic nicotine with ethyl nicotinate and N-vinyl pyrrolidone in four steps, and further resolving it with dibenzoyl tartaric acid to obtain (S) -nicotine:
Figure 349853DEST_PATH_IMAGE004
the route has the disadvantages of complicated steps, long production period and high production cost.
Document j, am. chem, soc. 2015, 137 (1), 90-93 and patent document CN 104341390a establish a highly efficient asymmetric hydrogenation reaction using a cyclic imine of a pyridyl moiety and an iridium catalyst of a chiral spirophosphine-oxazoline ligand to obtain (S) -nicotine;
Figure 275084DEST_PATH_IMAGE006
the iridium metal catalyst used in the route is expensive and complex to prepare, and is not beneficial to industrial production.
Patent document CN 113896713A reports asymmetric reduction using a metal iridium catalyst, followed by methylation to obtain (S) -nicotine;
Figure 437075DEST_PATH_IMAGE007
the iridium catalyst used in the route is expensive and complex in preparation, and is not beneficial to industrial production.
Patent document CN 114671852a reports a method for preparing optically pure (S) -nicotine, which uses ethyl nicotinate and N-vinyl pyrrolidone as raw materials, and performs enantioselective reduction and methylation reaction by imine reductase to obtain (S) -nicotine;
Figure 498572DEST_PATH_IMAGE008
the route uses flammable and difficult-to-store sodium metal, so that the reaction conditions are harsh and the operation is dangerous; the enzyme is used for reduction, the reaction time is long, the enzyme is not easy to store and is easy to inactivate, and the method is not suitable for industrial production.
Patent document CN 113979993A reports a method for preparing optically pure (S) -nicotine, in which 3-pyridinecarboxaldehyde and (R) -tert-butylsulfinamide are condensed in the presence of a catalytic substance to obtain chiral imine, thereby obtaining (S) -nicotine;
Figure 782922DEST_PATH_IMAGE009
the circuit is complex, the production cost is high, the yield is low, and the industrial production is not facilitated.
Patent document CN114437029a reports a method for preparing optically pure (S) -nicotine, in which 3-bromopyridine and magnesium or n-butyllithium are used to prepare grignard reagent or lithium reagent, 4-chlorobutanal and chiral tert-butyl sulfinamide are reacted, and (R) -nicotine and (S) -nicotine are prepared through cyclization and methylation;
Figure 929870DEST_PATH_IMAGE010
the route uses Grignard reagent or lithium reagent with harsh reaction conditions, so the reaction is dangerous and is not beneficial to industrial production.
Patent CN 113999201a reports a method for preparing optically pure (S) -nicotine, which uses 3-pyridine acetonitrile as a raw material, and pyrrolidone for reaction, and then palladium catalysis and ligand for asymmetric reduction to prepare (S) -nicotine.
Figure 597349DEST_PATH_IMAGE011
This route uses a palladium catalyst and expensive ligands and is not suitable for industrial production.
Disclosure of Invention
The invention provides a method for preparing (S) -nicotine by taking 3-pyridine methylamine as a raw material, which comprises the following steps:
Figure 575670DEST_PATH_IMAGE012
the method takes 3-pyridine methylamine and benzophenone or benzophenone imine as raw materials to obtain 3-pyridine methylamine benzophenone imine; 3-pyridine methylamine benzophenone imine and allyl bromide are subjected to alkylation under the condition of inorganic base and phase transfer catalyst; then (S) -nicotine is obtained through hydroboration oxidation, hydrolysis, halogenation, cyclization, methylation and resolution.
The method comprises the following specific processes:
(1) In the presence of a solvent, 3-pyridine methylamine and benzophenone or benzophenone imine are used as raw materials and react for 6 to 24h at the temperature of 25 to 100 ℃ to prepare 3-pyridine methylamine benzophenone imine;
the molar ratio of the 3-pyridine methylamine to the benzophenone or the benzophenone imine is 1.2 to 1;
(2) In an aprotic solvent, 3-pyridine methylamine benzophenone imine and allyl bromide are taken as raw materials, inorganic base and a phase transfer catalyst are added, and the reaction is carried out for 1 to 8 hours at the temperature of 15 to 25 ℃ to prepare an alkylation product;
the aprotic solvent is one of toluene, dichloromethane and chloroform; the inorganic base is one of potassium carbonate, sodium hydroxide, potassium hydroxide and cesium hydroxide, the molar ratio of the inorganic base to 3-pyridylmethylamine benzophenone imine is 3 to 1 to 6, the phase transfer catalyst is quaternary ammonium salt (comprising tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetraethylammonium iodide and benzyltriethylammonium bromide), the molar ratio of the quaternary ammonium salt to 3-pyridylmethylamine benzophenone imine is 1 to 5 to 1, and the molar ratio of allyl bromide to 3-pyridylmethylamine benzophenone imine is 1 to 1.8;
(3) Carrying out hydroboration oxidation on the alkylation product at the temperature of 10 to 40 ℃ to prepare an alcohol compound;
the hydroboration oxidation is realized in one of a dicyclohexylborane and sodium perborate system, a sodium borohydride-iodine system and a 30% hydrogen peroxide solution; wherein the molar ratio of dicyclohexylborane to sodium perborate in the dicyclohexylborane and sodium perborate system is 1:3, and the molar ratio of sodium borohydride to iodine in the sodium borohydride-iodine system is 2:1;
(4) Adding inorganic acid into an alcohol compound to remove a benzophenone protecting group, then adding a halogenating reagent, chlorinating at 20-80 ℃, and then adding inorganic base for cyclization to prepare racemic nornicotine;
the inorganic acid is 3mol/L dilute hydrochloric acid or 1mol/L dilute sulfuric acid; the molar ratio of the alcohol compound to the inorganic acid is 1 to 1; the inorganic base is one of sodium carbonate and potassium carbonate; the molar ratio of the alcohol compound to the inorganic base is 1 to 5 to 1; the halogenating agent is thionyl chloride;
(5) Methylating racemic nornicotine with a methylating agent to obtain racemic nicotine;
the methylating agent is a formic acid-formaldehyde mixture or methyl iodide; the molar ratio of racemic nornicotine to methylating agent is 1 to 2 to 1;
(6) Resolving racemic nicotine with dibenzoyl-L-tartrate to obtain (S) -nicotine; the mass ratio of the racemic nicotine to the dibenzoyl-L-tartrate is 1 to 1.
The invention has the advantages and technical effects that:
1. the method is simple and easy to operate, and the reagent is cheap and easy to obtain;
2. the reaction process is green and environment-friendly;
3. the product nicotine has high purity and yield, and is suitable for industrial production.
Drawings
FIG. 1 is a NMR spectrum of (S) -nicotine obtained in example 1;
fig. 2 is a liquid chromatography spectrum of racemic nicotine (a) and (S) -nicotine (b).
Detailed Description
The method of the present invention is further described below by way of examples, but the scope of the present invention is not limited by the examples, and the reagents used in the examples are all conventional commercially available reagents or reagents prepared by conventional methods without specific descriptions, and the methods used are all conventional methods without specific descriptions.
Example 1: the preparation method of (S) -nicotine is as follows
1. Adding 15mL of toluene into a 25mL round-bottom flask, adding 1.30.30 mL (13.2 mmol) of 3-pyridinemethylamine and 2.5g (14.0 mmol) of benzophenone under stirring, reacting overnight at 100 ℃, monitoring the reaction process by TLC, adding 40mL of water after the reaction is finished, extracting three times by using 30mL of ethyl acetate, collecting combined organic phases, drying by using anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, separating by using silica gel column chromatography, eluting by using petroleum ether-ethyl acetate mixed liquor with volume ratios of 20;
2. adding 15mL of toluene into a 25mL round-bottom flask, adding 0.3g (1 mmol) of tetrabutylammonium bromide and 2.6g (66 mmol) of sodium hydroxide under stirring, adding 3g (11 mmol) of 3-pyridylmethylaminobenzophenoneimine, finally dropwise adding 1.14mL (13 mmol) of allyl bromide, reacting at 20 ℃, monitoring the reaction process by TLC, adding 40mL of water after the reaction is finished, extracting three times by using 40mL of ethyl acetate, collecting the combined organic phases, drying by using anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, performing alumina column chromatography, sequentially eluting by using petroleum ether-ethyl acetate mixed liquor with the volume ratio of 20 to 10, collecting eluent with the volume ratio of 10 to obtain an alkylation product, wherein the yield is 92%;
3. reacting BH 3 . SMe 2 Adding 9.6mL (19.2 mmol) of an alkylated product into a tetrahydrofuran solution of cyclohexene at 0 ℃ in an amount of 4mL (38.4 mmol) after stirring for 3h, adding 2g (6.4 mmol) of the alkylated product into the reaction solution, stirring at 25 ℃ for 20 h, adding water (20 mL) and sodium perborate tetrahydrate (5.9 g) into the obtained reaction solution, reacting at 10 ℃, monitoring the reaction progress by TLC, adding 50mL of water to dilute the reaction after the reaction is finished, adding 50mL of water, extracting with 40mL of ethyl acetate for three times, collecting the combined organic phases, drying with anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, separating by silica gel column chromatography, eluting with petroleum ether containing 80% of ethyl acetate, ethyl acetate and ethyl acetate containing 5% of methanol in turn, collecting the eluent eluted with ethyl acetate containing 5% of methanol to obtain an alcohol compound with a yield of 88%;
4. the resulting 2g (5.2 mmol) of the alcohol compound was dissolved in 3mol/L HCl (15 mL) and Et 2 O (15 mL), the obtained mixture is stirred vigorously for 30min at 20 ℃, after the reaction is finished, an aqueous layer is reserved, an organic layer is discarded, the obtained aqueous layer is concentrated under reduced pressure to obtain colorless oily liquid, thionyl chloride (15 mL) is added into the colorless oily liquid, the mixture is stirred for 30min at 20 ℃, then white solid obtained after vacuum concentration is placed into acetonitrile (80 mL) to react with 5g (47 mmol) of excessive sodium carbonate at 25 ℃, the reaction process is monitored, after the reaction is finished, 50mL of water is added, ethyl acetate 40mL is used for extraction for three times, the combined organic phase is collected and dried by anhydrous magnesium sulfate, the filtration is carried out, the organic phase is concentrated under reduced pressure, the organic phase is separated by silica gel column chromatography, the dichloromethane containing 3% of methanol and 1% of triethylamine is used for elution, the eluent is collected, and the yield of racemic nicotine is 82%;
5. dissolving 2.5g (0.01 mol) of racemic nornicotine in 10mL of ethanol, slowly adding 10g of formic acid aqueous solution (35 mass percent and containing 0.15mol of formic acid) and 6.5g of formaldehyde aqueous solution (35 mass percent and containing 0.15mol of formaldehyde) in ice bath, heating to 60 ℃ for reaction for 1h, adjusting the pH value of the system to 12-14 by using sodium hydroxide aqueous solution (30 mass percent), extracting by using toluene, collecting and combining organic phases, drying by using anhydrous magnesium sulfate, filtering, concentrating the organic phases under reduced pressure to obtain a racemic nicotine crude product, performing silica gel column chromatography separation, eluting by using dichloromethane containing 3 percent of methanol and 1 percent of triethylamine, collecting eluent to obtain a racemic nicotine pure product, wherein the yield is 98 percent, and is shown in figure 2a;
6. dissolving 5g of racemic nicotine and 11g of dibenzoyl-L-tartrate in 50mL of absolute ethanol, refluxing the mixture at 80 ℃ for 30min, cooling to 25 ℃, stirring for 12 h, separating out and filtering to obtain a precipitate, suspending the precipitate in 30mL of water and 30mL of toluene, dropwise adding ammonia to adjust the pH to 9-10, after phase separation, collecting a water phase, extracting twice with toluene, collecting and combining toluene phases, and concentrating under reduced pressure to obtain pure (S) -nicotine with the yield of 78%, wherein the yield of the pure (S) -nicotine is nuclear magnetic resonance hydrogen spectrum (600 MHz, CDCl and CDCl) 3 ) See fig. 1, 2b.
Example 2: the preparation method of (S) -nicotine is as follows
1. Adding 15mL of dichloromethane into a 25mL round-bottom flask, adding 1.30mL (13.2 mmol) of 3-picolylamine and 1.82mL (11.0 mmol) of benzophenone imine under stirring, reacting at 25 ℃, monitoring the reaction process by TLC (thin layer chromatography), adding 30mL of water after the reaction is finished, extracting with 30mL of ethyl acetate for three times, collecting and combining organic phases, drying by anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, cooling and crystallizing the product in petroleum ether, filtering, collecting crystals, and drying to obtain 3-picolylamine benzophenone imine with the yield of 98%;
2. adding 15mL of dichloromethane into a 25mL round-bottom flask, adding 0.6g (2 mmol) of benzyltriethylammonium bromide and 4.56g (33 mmol) of potassium hydroxide under stirring, adding 3g (11 mmol) of 3-pyridylmethylaminobenzophenonimine, finally dropwise adding 1.3mL (15 mmol) of allyl bromide, reacting at 25 ℃, monitoring the reaction process by TLC, adding 40mL of water after the reaction is finished, extracting three times by using 40mL of ethyl acetate, collecting combined organic phases, drying by using anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, separating by using silica gel column chromatography, sequentially eluting by using petroleum ether-ethyl acetate mixed liquor with the volume ratio of 10 to 5:1, collecting 5:1 eluent to obtain an alkylated product with the yield of 90%;
3. weighing 2.4g (63 mmol) of sodium borohydride, placing the sodium borohydride in a round-bottom flask, adding 10mL of tetrahydrofuran, and adding I under ice bath 2 Dripping tetrahydrofuran solution containing 2g (6.4 mmol) of alkylated product into the reaction solution, reacting at 40 deg.C, monitoring the reaction process, and after the reaction is finishedAdding 1mol/L sodium hydroxide solution slowly into a reaction bottle, quickly adding 30 mass percent hydrogen peroxide solution into reaction liquid, adding 40mL water after the reaction is finished, extracting with 40mL ethyl acetate for three times, combining organic phases, drying with anhydrous magnesium sulfate, filtering, decompressing and concentrating the organic phases, separating by silica gel column chromatography, eluting with petroleum ether containing 80 percent ethyl acetate, ethyl acetate and ethyl acetate containing 5 percent methanol in sequence, collecting the eluent of the ethyl acetate containing 5 percent methanol to obtain an alcohol compound with the yield of 78 percent;
4. 1g (2.6 mmol) of the alcohol compound was dissolved in 1mol/L dilute sulfuric acid (10 mL) and Et 2 O (10 mL), and the resulting mixture was stirred vigorously at 25 ℃ for 30min, and the resulting aqueous layer was separated and concentrated to give a colorless oily liquid; then stirring 1h of the colorless oily liquid in thionyl chloride (8 mL) at 80 ℃, then placing a white solid obtained by vacuum concentration in acetonitrile (80 mL) to react with excessive potassium carbonate 1.8g (13 mmol) at 25 ℃, monitoring the reaction process, after the reaction is finished, adding 30mL of water, extracting with 30mL of ethyl acetate for three times, combining organic phases, drying with anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, separating by silica gel column chromatography, eluting with dichloromethane containing 3% of methanol and 1% of triethylamine, collecting eluent to obtain racemic nornicotine, wherein the yield is 77%;
5. dissolving 5g (0.02 mol) of racemic nornicotine in 10mL of dichloromethane, adding 5.68 g (0.04 mol) of methyl iodide and 4.25 mL (0.03 mol) of triethylamine at room temperature, continuously reacting at 25 ℃ for 5 h, adjusting the pH value of a system to 12-14 by using an aqueous solution of sodium hydroxide (30 mass percent), standing for layering, removing an organic layer, extracting a water layer by using dichloromethane, evaporating dichloromethane extract under reduced pressure to dryness to obtain a crude racemic nicotine product, distilling at 130 ℃ under reduced pressure, collecting the fraction to obtain a pure racemic nicotine product, wherein the yield is 90%;
6. in step 6 of example 1, the yield of (S) -nicotine was 78%.
Example 3: the preparation method of (S) -nicotine is as follows
1. Same as example 1, step 1;
2. adding 10mL of dichloromethane into a 25mL round-bottom flask, adding 0.38 g (1.46 mmol) of tetrabutylammonium hydroxide and 3.70g (22 mmol) of cesium hydroxide under stirring, adding 2g (7.3 mmol) of 3-pyridylmethylamine benzophenone imine, finally dropwise adding 1.14mL (13 mmol) of allyl bromide, reacting at 25 ℃, monitoring the reaction process, adding 30mL of water after the reaction is finished, extracting three times by using 30mL of ethyl acetate, collecting the combined organic phases, drying by using anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure, separating by using a silica gel column chromatography, sequentially eluting by using petroleum ether-ethyl acetate mixed liquor with a volume ratio of 10 to 5:1, collecting 5:1 eluent to obtain an alkylated product, wherein the yield is 89%;
steps 3-6 are the same as steps 3-6 of example 1, pure (S) -nicotine, yield 75%.
Example 4: the preparation method of (S) -nicotine is as follows
1. Same as example 2, step 1;
2. 20mL chloroform was added to a 50mL round bottom flask, tetraethylammonium iodide 0.47 g (1.8 mmol) and potassium carbonate 5.14 g (37 mmol) were added with stirring, 3-pyridylmethylamine benzophenone imine 5g (18.3 mmol) was added, finally allyl bromide 2.58 mL (33 mmol) was added dropwise, the reaction was monitored at 25 ℃. After the reaction is finished, 50mL water is added, extraction is carried out for three times by using 50mL ethyl acetate, organic phases are combined and dried by anhydrous magnesium sulfate, filtration is carried out, the organic phase is concentrated under reduced pressure and separated by alumina column chromatography, elution is carried out by using petroleum ether-ethyl acetate mixed liquor with the volume ratio of 20 to 10.
Steps 3-6 are the same as steps 3-6 of example 2, pure (S) -nicotine, yield 78%.

Claims (6)

1. A process for the preparation of (S) -nicotine, characterized by the steps of:
(1) 3-pyridine methylamine and benzophenone or benzophenone imine are taken as raw materials and react for 6 to 24h at the temperature of 25 to 100 ℃ to prepare 3-pyridine methylamine benzophenone imine;
Figure DEST_PATH_IMAGE002
；
(2) In an aprotic solvent, 3-pyridine methylamine benzophenone imine and allyl bromide are taken as raw materials, inorganic base and a phase transfer catalyst are added, and the reaction is carried out for 1 to 8 hours at the temperature of 15 to 25 ℃ to prepare an alkylation product;
Figure DEST_PATH_IMAGE004
；
(3) Subjecting the alkylation product to hydroboration oxidation at 10 to 40 ℃ to prepare an alcohol compound;
Figure DEST_PATH_IMAGE006
；
(4) Adding inorganic acid into an alcohol compound to remove a benzophenone protecting group, then adding a halogenating reagent, chlorinating at 20-80 ℃, and then adding inorganic base for cyclization to prepare racemic nornicotine;
Figure DEST_PATH_IMAGE008
；
(5) Methylating racemic nornicotine with a methylating agent to obtain racemic nicotine;
Figure DEST_PATH_IMAGE010
；
(6) Resolving racemic nicotine with dibenzoyl-L-tartrate to obtain (S) -nicotine;
Figure DEST_PATH_IMAGE012
。
2. a process for the preparation of (S) -nicotine according to claim 1, characterized in that: the aprotic solvent in the step (2) is one of toluene, dichloromethane and chloroform; the inorganic base is one of potassium carbonate, sodium hydroxide, potassium hydroxide and cesium hydroxide, the molar ratio of the inorganic base to the 3-pyridinemethylamine benzophenone imine is 3 to 1, the phase transfer catalyst is a quaternary ammonium salt, the molar ratio of the quaternary ammonium salt to the 3-pyridinemethylamine benzophenone imine is 1 to 5 to 1, and the molar ratio of allyl bromide to the 3-pyridinemethylamine benzophenone imine is 1 to 1.8.
3. A process for the preparation of (S) -nicotine according to claim 2, characterized in that: the quaternary ammonium salt is one of tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetraethylammonium iodide and benzyltriethylammonium bromide.
4. A process for the preparation of (S) -nicotine according to claim 1, characterized in that: the hydroboration oxidation in the step (3) is realized in one of a dicyclohexylborane and sodium perborate system, a sodium borohydride-iodine system and a 30% hydrogen peroxide solution, and the halogenating agent is thionyl chloride.
5. A process for the preparation of (S) -nicotine according to claim 1, characterized in that: in the step (4), the inorganic acid is 3mol/L dilute hydrochloric acid or 1mol/L dilute sulfuric acid; the molar ratio of the alcohol compound to the inorganic acid is 1 to 1; the inorganic base is one of sodium carbonate and potassium carbonate; the molar ratio of the alcohol compound to the inorganic base is 1 to 5 to 1.
6. A process for the preparation of (S) -nicotine according to claim 1, characterized in that: the methylating agent in the step (5) is a formic acid-formaldehyde mixture or methyl iodide; the molar ratio of racemic nornicotine to methylating agent is 1 to 2 to 1.
CN202211276431.1A 2022-10-19 2022-10-19 Preparation method of (S) -nicotine Pending CN115594662A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211276431.1A CN115594662A (en) 2022-10-19 2022-10-19 Preparation method of (S) -nicotine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211276431.1A CN115594662A (en) 2022-10-19 2022-10-19 Preparation method of (S) -nicotine

Publications (1)

Publication Number Publication Date
CN115594662A true CN115594662A (en) 2023-01-13

Family

ID=84849738

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211276431.1A Pending CN115594662A (en) 2022-10-19 2022-10-19 Preparation method of (S) -nicotine

Country Status (1)

Country Link
CN (1) CN115594662A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114702475A (en) * 2022-05-17 2022-07-05 大连天源基化学有限公司 Synthesis process of single-configuration nicotine
CN116217544A (en) * 2023-05-08 2023-06-06 济南悟通生物科技有限公司 Synthesis method of (S) -nornicotine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011119722A2 (en) * 2010-03-23 2011-09-29 Rock Creek Pharmaceuticals, Inc. Use of anatabine to treat inflammation and methods of synthesizing anatabine
CN107286132A (en) * 2017-05-27 2017-10-24 宁波智锐新材料有限公司 A kind of preparation method for anatabine
CN111511726A (en) * 2017-12-22 2020-08-07 斯福瑞股份有限公司 Preparation of racemic nicotine by reaction of ethyl nicotinate with N-vinylpyrrolidone in the Presence of an alcoholate base and subsequent processing steps

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011119722A2 (en) * 2010-03-23 2011-09-29 Rock Creek Pharmaceuticals, Inc. Use of anatabine to treat inflammation and methods of synthesizing anatabine
CN107286132A (en) * 2017-05-27 2017-10-24 宁波智锐新材料有限公司 A kind of preparation method for anatabine
CN111511726A (en) * 2017-12-22 2020-08-07 斯福瑞股份有限公司 Preparation of racemic nicotine by reaction of ethyl nicotinate with N-vinylpyrrolidone in the Presence of an alcoholate base and subsequent processing steps

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DEO, NIRANJAN M等: "Regioselective alkylation of N-(diphenylmethylidine)-3-(aminomethyl)pyridine: a simple route to minor tobacco alkaloids and related compounds", TETRAHEDRON LETTERS, vol. 37, no. 8, pages 1137 - 1140, XP004030090, DOI: 10.1016/0040-4039(96)00002-0 *
GIANFRANCO CAINELLI等: "Efficient Transamination under Mild Conditions: Preparation of Primary Amine Derivatives from Carbonyl Compounds via Imine Isomerization with Catalytic Amounts of Potassium tert-Butoxide", J.ORG.CHEM., vol. 61, pages 5134 - 5139 *
XIAOYAN QIAN等: "Palladium-Catalyzed Decarboxylative Generation and Asymmetric Allylation of α-Imino Anions", ORGANIC LETTERS, vol. 16, pages 5228 - 5231 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114702475A (en) * 2022-05-17 2022-07-05 大连天源基化学有限公司 Synthesis process of single-configuration nicotine
CN114702475B (en) * 2022-05-17 2023-12-26 大连天源基化学有限公司 Synthesis process of nicotine with single configuration
CN116217544A (en) * 2023-05-08 2023-06-06 济南悟通生物科技有限公司 Synthesis method of (S) -nornicotine
CN116217544B (en) * 2023-05-08 2023-08-29 济南悟通生物科技有限公司 Synthesis method of (S) -nornicotine

Similar Documents

Publication Publication Date Title
CN115594662A (en) Preparation method of (S) -nicotine
EP3925955A1 (en) Method for asymmetrically preparing nicotine
CN111704573B (en) Preparation method of rabeprazole chloride and intermediate thereof
WO2005044805A1 (en) A novel process for preparing donepezil and its derivatives
CN114702475A (en) Synthesis process of single-configuration nicotine
CN115073251B (en) Asymmetric catalytic synthesis method of nicotine
CN113979993A (en) Method for asymmetric synthesis of (S) -nicotine
CN113185465A (en) Preparation method of 4-ethyl-5-aminopyrimidine
CN114230553A (en) Asymmetric synthesis method of levo-nicotine
CN110937985A (en) Synthetic method of paradol
CN114213460B (en) Chiral nitrogen-phosphine compound for ketone asymmetric hydrogenation reaction or transfer hydrogenation reaction, preparation method and application
CN112250567B (en) Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol
Ren et al. Arylamine synthesis enabled by a photocatalytic skeletal-editing dehydrogenative aromatization strategy
WO2005076749A2 (en) A novel process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine
CN110790708B (en) Preparation method of Ailixipine intermediate
CN112645984B (en) Half-sandwich ruthenium complex containing phenyl benzoxazole structure and preparation method and application thereof
CN113788784B (en) Preparation method of 2-fluoro-3-trifluoromethyl pyridine
CN109651437A (en) A kind of chiral nitrogen phosphorus ligand and preparation method thereof and a kind of method for splitting racemization menthol
CN115650824B (en) Chiral diol and preparation method thereof, prepared catalyst and preparation method and application thereof
CN114085130B (en) Method for synthesizing ((1R,8S,9S, Z) -bicyclo [6.1.0] non-4-en-9-yl) methanol
WO2023007712A1 (en) (r,s)-nicotine production method
CN114262290B (en) 4-methylene pyrrolidine-2-thioketone compound, and synthetic method and application thereof
CN112300059B (en) Preparation method of PF-06651600 intermediate
CN116478052A (en) Method for synthesizing 1-naphthylamine derivative by copper catalysis
CN112375101A (en) Method for preparing chiral nitrogen-phosphorus ligand L-8 containing pyridocyclohexane

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination