22083-74-5

Basic information

• Product Name: (+/-)-NICOTINE
• Synonyms: 1-METHYL-2-(3-PYRIDYL)PYRROLIDINE;BLACK LEAF 40;(+/-)-NICOTINE;NICOTINE;(+-)-nicotin;(+-)-pyridin;(+)-3-[(2R)-1-Methyl-2-pyrrolidinyl]pyridine;(2R)-1-Methyl-2-(3-pyridyl)pyrrolidine
• CAS NO: 22083-74-5
• Molecular Formula: C₁₀H₁₄N₂
• Molecular Weight: 162.23
• Product Categories: Neurochemicals;Nicotine Derivatives;AgonistsIon Channels;Cholinergics;Ligand-Gated Ion Channels;Neurotransmitters;Nicotinic Acetylcholine Receptor Modulators
• Mol File: 22083-74-5.mol
• Article Data: 49

Chemical Properties

• Melting Point: -79 °C
• Boiling Point: 67°C/0.5 mm
• Flash Point: 101 °C
• Appearance: yellow/liquid
• Density: 1.02 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.0303mmHg at 25°C
• Refractive Index: 1.539
• Storage Temp.: Refrigerator
• Solubility: ethanol: 50 mg/mL
• PKA: 8.02(at 25℃)
• BRN: 82108
• CAS DataBase Reference: (+/-)-NICOTINE(CAS DataBase Reference)
• NIST Chemistry Reference: (+/-)-NICOTINE(22083-74-5)
• EPA Substance Registry System: (+/-)-NICOTINE(22083-74-5)

Safety Data

• Hazard Codes: T+,N
• Statements: 25-27-51/53
• Safety Statements: 36/37-45-61
• RIDADR: UN 1654 6.1/PG 2
• WGK Germany: 3
• RTECS: QS5257500
• Hazardous Substances Data: 22083-74-5(Hazardous Substances Data)

Usage

Chemical Properties

(+/-)-NICOTINE is Colourless Liquid

Uses

Different sources of media describe the Uses of 22083-74-5 differently. You can refer to the following data:
1. This is the unnatural isomer of Nicotine
2. (+/-)-NICOTINE is an alkaloid isolated from plants. It is an active stimulant, having both addictive and carcinogenic properties.
3. Nicotine is an alkaloid isolated from plants. Nicotine is an active stimulant, having both addictive and carcinogenic properties. Nicotine can be absorbed through the alimentary canal, respiratory tra ct and intact skin. Nicotine is used in the treatment of smoking withdrawal syndrome. Nicotine has been used as an anthelmintic.

Biochem/physiol Actions

Prototype nicotinic acetylcholine receptor agonist.

Purification Methods

(+/-)-NICOTINE is purified by fractional distillation. Its solubility in EtOH is ~5%. The picrate forms yellow needles from hot H2O and has m 219o. The methiodide has m 219o (from MeOH). [Craig J Am Chem Soc 55 2854 1933, Nakane & Hutchinson J Org Chem 43 3922 1978, Beilstein 23/6 V 64.] POISONOUS.

InChI:InChI=1/C10H14N2/c1-12-7-3-5-10(12)9-4-2-6-11-8-9/h2,4,6,8,10H,3,5,7H2,1H3

Synthetic route

formaldehyd (50-00-0) + formic acid (64-18-6) + rac-nornicotine (5746-86-1) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
Stage #1: formaldehyd; formic acid; rac-nornicotine In water at 85℃; for 20h; Stage #2: With sodium hydroxide In water pH=13;	99.1%

formaldehyd (50-00-0) + 3-(3,4-dihydro-2H-pyrrol-2-yl)-pyridine (53844-46-5) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With formic acid In water at 80℃; for 18h;	98%

D-nicotine (25162-00-9) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With 18-crown-6 ether; potassium tert-butylate at 80℃; for 1h; Reagent/catalyst; Temperature; Inert atmosphere;	96.5%
With sodium hydride In o-xylene for 15h; Reflux;	66.8%
With sodium hydride In o-xylene for 15h; Reflux;	66.8%

nicotin (54-11-5) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With 15-crown-5; sodium t-butanolate at 80℃; for 2h; Reagent/catalyst; Inert atmosphere;	94.7%
With sodium hydride In xylene for 6h; Heating;	66%
With potassium hydride In xylene for 1h; Product distribution; Heating; other reagent, solvent, reaction time;

formaldehyd (50-00-0) + rac-nornicotine (5746-86-1) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With sodium cyanoborohydride In acetonitrile	91%
With formic acid at 30℃; Reagent/catalyst;	91%
Stage #1: formaldehyd; rac-nornicotine With polymer-bound trimethyl ammonium cyanoborohydride In water for 4h; Stage #2: With Amberlyst 15 In dichloromethane for 1h; Stage #3: With ammonia In methanol for 2h;	88%

ethyl N-methyl-N-<4-chloro-4-(3-pyridyl)butnyl>carbamate (73130-52-6) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With sulfuric acid for 5h; Heating; further reagent;	90%

N-methylmyosmine (525-74-6) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; under 7500.75 Torr; Autoclave;	90%

1:1 complex of 1,1,6,6-tetraphenyl-hexa-2,4-diyne 1,6-diol and nicotine (125947-48-0) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
In acetone	86%

(RS) 1-methyl-2-(3'-pyridyl)pyrrolidine-2-carbaldehyde (180407-32-3) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With sodium hydroxide at 50℃; for 16h;	80%

methyl 2-(pyridin-3-yl)pyrrolidine-1-carboxylate (1253522-99-4) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux;	77%

4-methylamino-1-(3-pyridyl)butanone hydrochloride → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
Stage #1: 4-methylamino-1-(3-pyridyl)butanone hydrochloride In water at -5℃; for 5h; pH=8; Stage #2: With sodium tetrahydroborate In ethanol; water at -5 - 15℃; for 2h; Reagent/catalyst; Solvent; pH-value;	72%

1-methyl-2-(3-pyridinyl)-2-pyrrolidinol → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With sodium tetrahydroborate In ethanol; water at -5 - 15℃; for 2h; Reagent/catalyst; Temperature; Solvent;	72%

1-methyl-3-nicotinoyl-2-pyrrolidone (125630-28-6) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
Stage #1: 1-methyl-3-nicotinoyl-2-pyrrolidone With hydrogenchloride at 135℃; for 40h; Stage #2: With sodium tetrahydroborate; sodium hydroxide for 1.5h; pH=8; Concentration; Reagent/catalyst; Time; Temperature; Cooling with ice;	71%

3-Bromopyridine (626-55-1) + N-methylsuccinimide (1121-07-9) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
Stage #1: 3-Bromopyridine With n-butyllithium In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #2: N-methylsuccinimide In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #3: With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0 - 20℃; for 2h; Inert atmosphere;	65%

C12H18N2Si (1197362-42-7) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran Reflux;	60%

methylamine (74-89-5) + 4-Hydroxy-4-(3-pyridyl)-butanol → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium carbonate In water at 110℃; for 2h; Inert atmosphere; Microwave irradiation; Green chemistry;	50%

(1R,2S,5S)-2-Isopropyl-5-methylcyclohexyl 2-(pyridin-3-yl)pyrrolidine-1-carboxylate (1253523-06-6) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux;	47%

methylamine (74-89-5) + 4-Oxo-1-(3-pyridyl)-1-butanone (76014-80-7) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
Stage #1: methylamine; 4-Oxo-1-(3-pyridyl)-1-butanone With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran; dichloromethane at -78 - 20℃; Stage #2: With Amberlyst 15 In tetrahydrofuran; dichloromethane at 20℃; for 1h; Stage #3: With triethylamine In dichloromethane at 20℃; for 1h;	46%

nicotirine (487-19-4) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With palladium on activated charcoal; charcoal catalyst Hydrogenation;

tetrachloromethane (56-23-5) + 1-methyl-2-(3-pyridyl)-3-pyrroline (21446-40-2) + ethylene glycol (107-21-1) → nicotirine (487-19-4) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

1-methyl-2-(3-pyridyl)-3-pyrroline (21446-40-2) → nicotirine (487-19-4) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

4-methylamino-1-[3]pyridyl-butan-1-ol (2055-27-8, 76030-54-1) → methyl-(4-pyridin-3-yl-but-3-enyl)-amine (538-79-4) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With phosphorus pentoxide; xylene

Pseudooxynicotine (2055-23-4) → 4-methylamino-1-[3]pyridyl-butan-1-ol (2055-27-8, 76030-54-1) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With sodium tetrahydroborate In water pH 9.0;

N'-tert-Butyl-N-(4-chloro-1-pyridin-3-yl-butyl)-N-methyl-formamidine → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With hydrazine hydrate In ethanol; acetic acid at 25℃; Yield given;

rac-nornicotine (5746-86-1) → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
ESCHWEILER-method; Yield given;

(+-)-1-methyl-5-<3>pyridyl-pyrrolidin-2-one → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With tetrahydrofuran; lithium aluminium tetrahydride

3-<δ-methylamino-α-oxy-butyl>-pyridine → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With phosphorus; hydrogen iodide at 100℃; im Rohr; Behandeln des Reaktionsprodukts mit Alkalilauge und folgend Destillieren mit Wasserdampf;

<(-)-nicotine>-sulfate → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With water at 200℃;

dihydrometanicotine → 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5)

Conditions	Yield
With sodium hypobromide Behandeln des entstandenen N-Brom-dihydrometanicotins in konz. Schwefelsaeure bei 20grad und Erhitzen der Loesung auf 100grad;

3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → (+/-)-nornicotine hydrochloride

Conditions	Yield
With aluminum oxide; silica gel; potassium carbonate; sodium percarbonate; sodium salt of 2,4-dichloro-6-hydroxy-1,3,5-triazine In chloroform column chromatography;	95%

3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → nicotin (54-11-5)

Conditions	Yield
With borane-ammonia complex; 6-hydroxy-D-nicotine oxidase for 16h; Kinetics; Reagent/catalyst; Enzymatic reaction; enantioselective reaction;	93%
Stage #1: 3-(1-methyl-pyrrolidin-2-yl)-pyridine With O,O'-dibenzoyl-L-tartaric acid In ethanol Reflux; Stage #2: With ammonium hydroxide In water; toluene pH=9.8 - 10.4;	70.8%
Stage #1: 3-(1-methyl-pyrrolidin-2-yl)-pyridine In methanol Heating; Stage #2: With hydrogenchloride In methanol Further stages.;

1,3-propanesultone (1120-71-4) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → C13H20N2O3S

Conditions	Yield
for 0.00416667h; microvawe irradiation;	92%

3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → cotinine (15569-85-4)

Conditions	Yield
With Hg(II)-EDTA In dichloromethane for 17h; Heating; pH 8.0;	88%
With ethylenediaminetetraacetic acid; mercury(II) diacetate; acetic acid for 2h; steam-bath; further reagent;	70%
With iodosylbenzene; (5,10,15,20-tetraphenylporphyrinato)manganese(III) chloride In dichloromethane Mechanism; other catalysts;	22%
With iodosylbenzene; (5,10,15,20-tetraphenylporphyrinato)manganese(III) chloride In dichloromethane	22%
With ethylenediaminetetraacetic acid; mercury(II) diacetate

S-tert-butyl O-ethyl carbonodithioate (84380-38-1) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → 2-(tert-butyl)-5-(1-methylpyrrolidin-2-yl)pyridine (83218-45-5)

Conditions	Yield
With dilauryl peroxide; camphor-10-sulfonic acid In 1,2-dichloro-ethane at 85℃; for 1h; Sealed tube;	83%

bis(pinacol)diborane (73183-34-3) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → 3-(1-methylpyrrolidin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Conditions	Yield
Stage #1: bis(pinacol)diborane With C24H28ClIrN2O In n-heptane; isopropyl alcohol at 75℃; for 1h; Sealed tube; Inert atmosphere; Stage #2: 3-(1-methyl-pyrrolidin-2-yl)-pyridine In n-heptane; isopropyl alcohol Sealed tube; Inert atmosphere;	82%

triisopropylsilyl trifluoromethanesulfonate (80522-42-5) + di-tert-butylmagnesium (14627-81-7) + 3-(1-methyl-pyrrolidin-2-yl)-pyridine (22083-74-5) → C23H44N2Si

Conditions	Yield
Stage #1: triisopropylsilyl trifluoromethanesulfonate; 3-(1-methyl-pyrrolidin-2-yl)-pyridine In dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: di-tert-butylmagnesium In 1,4-dioxane; diethyl ether; dichloromethane at -85℃; for 16h; Inert atmosphere;	81%

Upstream product

• 487-19-4 nicotirine 
• 56-23-5 tetrachloromethane 
• 21446-40-2 1-methyl-2-(3-pyridyl)-3-pyrroline 
• 107-21-1 ethylene glycol 
• 2055-27-8 4-methylamino-1-[3]pyridyl-butan-1-ol 
• 50-00-0 formaldehyd 
• 5746-86-1 rac-nornicotine 
• 2055-23-4 Pseudooxynicotine 
• 73130-52-6 ethyl N-methyl-N-<4-chloro-4-(3-pyridyl)butnyl>carbamate 
• 125947-48-0 1:1 complex of 1,1,6,6-tetraphenyl-hexa-2,4-diyne 1,6-diol and nicotine 
• 54-11-5 nicotin 
• 180407-32-3 (RS) 1-methyl-2-(3'-pyridyl)pyrrolidine-2-carbaldehyde 
• 7732-18-5 water 
• 491-26-9 Nicotine-N-oxide 

Downstream Products

• 92036-80-1 dimethyl-[4-(1-methyl-[3]piperidyl)-butyl]-amine 
• 23158-10-3 N-methyl-N-(4-pyridin-3-yl-but-3-enyl)-benzamide 
• 27140-96-1 (S)-1-benzyl-3-(1-benzyl-1-methyl-pyrrolidinium-2-yl)-pyridinium; diiodide 
• 513-86-0 3-hydroxy-2-butanon 
• 120-94-5 1-Methylpyrrolidine 
• 487-19-4 nicotirine 
• 5337-62-2 3-(1-methylpyrrolidin-2-yl)piperidine 
• 100-54-9 pyridine-3-carbonitrile 
• 4673-31-8 3-propylpyridine 
• 59-67-6 nicotinic acid 
• 532-12-7 Myosmine 
• 111357-52-9 methyl-bis-(4-[3]pyridyl-butyl)-amine 
• 72430-94-5 3-(5-nitro-1⁽²⁾H-pyrazol-3-yl)-pyridine 
• 32726-84-4 2-aminonicotine 

Relevant articles and documents

On the biosynthesis of nicotine

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The preparation of tobacco constituents incorporating stable isotopes. I. The synthesis of d,l-nornicotine-1'-15N and d,l-nicotine-11-15N

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Racemization method and application of pyridine derivative

The invention belongs to the field of medicines, and particularly relates to a racemization method and application of a pyridine derivative. The method comprises the following steps: carrying out a racemization reaction on the pyridine derivative shown in the following formula I under the action of alkali and a phase transfer catalyst, and carrying out post-treatment to obtain a pyridine derivative racemate, wherein the formula I is shown in the specification. In the formula I, n is selected from -3, -2, -1, 0, 1, 2 and 3, and R represents hydrogen or a C1-C7 carbon-containing group. The alkali is at least one selected from potassium hydroxide, sodium hydroxide and alkali metal alkoxide. The phase transfer catalyst is selected from 18-crown 6-ether, 18-crown 6-ether derivatives, 15-crown 5-ether and 15-crown 5-ether derivatives. A reaction temperature is 20 DEG C to 200 DEG C. The racemization method of the pyridine derivative provided by the invention has the advantages of mild conditions, high racemization speed, few side reactions, high yield, low cost and high practical value, and is suitable for large-scale industrial production and application.

Preparation method of nicotine and intermediate thereof

The invention relates to a preparation method of nicotine and an intermediate thereof, wherein the intermediate has a structure as shown in a formula (II), X1, X2 and X3 are respectively and independently CR2R3, R1 is a C1-6 alkyl group, and R2 and R3 are each independently H or a C1-6 alkyl group. According to the invention, the preparation method of the nicotine and the intermediate thereof has the advantages of simple operation, mild reaction conditions, easily available raw materials, and high conversion rate, can effectively reduce the production cost of the nicotine, and has the potential of industrial production, and each reaction can be directly post-fed through simple post-treatment basically.

Preparation method of artificially synthesized (R, S)-nicotine salt

The invention discloses a preparation method of artificially synthesized (R, S)-nicotine salt. The method comprises: S1, taking 4-methylamino-1-(3-pyridine)-butanone hydrochloride and an alkaline substance, and carrying out a reaction at a temperature of -5-5 DEG C; S2, concentrating a reactant in the step S1, and adding a first refining solvent for refining, so as to obtain 1-methyl-2-(3-pyridine)-2-pyrrolidinol; S3, taking 1-methyl-2-(3-pyridine)-2-pyrrolidinol, adding a reducing agent, and carrying out a reaction at the temperature of 15-35 DEG C; and S4, concentrating the reactant in the step S3, adding a second refining solvent for refining, and then adding acid for reaction to obtain the artificially synthesized (R, S)-nicotine salt. The invention innovatively provides a two-step method for synthesizing the (R, S)-nicotine salt, and the prepared (R, S)-nicotine salt does not contain any other harmful tobacco compounds, has the advantages of simple process and high purity, and is suitable for industrial large-scale production.