- Interconversion of nicotine enantiomers during heating and implications for smoke from combustible cigarettes, heated tobacco products, and electronic cigarettes
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Physiological properties of (R)-nicotine have differences compared with (S)-nicotine, and the subject of (S)- and (R)-nicotine ratio in smoking or vaping related items is of considerable interest. A Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) method for the analysis of (S)- and (R)-nicotine has been developed and applied to samples of nicotine from different sources, nicotine pyrolyzates, several types of tobacco, smoke from combustible cigarettes, smoke from heated tobacco products, e-liquids, and particulate matter obtained from e-cigarettes aerosol. The separation was achieved on a Chiracel OJ-3 column, 250 × 4.6 mm with 3-μm particles using a nonaqueous mobile phase. The detection was performed using atmospheric pressure chemical ionization (APCI) in positive mode. The only transition measured for the analysis of nicotine was 163.1 → 84.0. The method has been summarily validated. For the analysis, the samples of tobacco and smoke from combustible cigarettes were subject to a cleanup procedure using solid phase extraction (SPE). It was demonstrated that nicotine upon heating above 450°C for several minutes starts decomposing, and some formation of (R)-enantiomer from a sample of 99% (S)-nicotine is observed. An analogous process takes place when a 99% (R)-nicotine is heated and forms low levels of (S)-nicotine. This interconversion has the effect of slightly increasing the content of (R)-nicotine in smoke compared with the level in tobacco for combustible cigarettes and for heated tobacco products. The (S)/(R) ratio of nicotine enantiomers in e-liquids was identical with the ratio for the particulate phase of aerosols generated by e-cigarette vaping.
- Moldoveanu, Serban C.
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p. 667 - 677
(2022/02/02)
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- Synthesis method of nicotine
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The invention belongs to the technical field of nicotine synthesis, and particularly relates to a synthesis method of nicotine. The invention discloses a synthesis method of nicotine. The synthesis method comprises the following steps: S1, synthesizing 1-(1-butenyl)-3-nicotyl-2-pyrrolidone, namely reacting 1-(1-butenyl)-pyrrolidone with nicotine ethyl ester under the condition of NaH catalysis by using an N,N-dimethyl formamide solution carrier to obtain the 1-(1-butenyl)-3-nicotyl-2-pyrrolidone; S2, synthesizing 3-cyclopentenyl amino-pyridine, namely concentrating the 1-(1-butenyl) 3-nicotinyl-2-pyrrolidone obtained in the step S1 under a certain condition, so as to obtain the 3-cyclopentenyl amino-pyridine, S3, synthesis of a nicotine precursor: introducing hydrogen into 3-cyclopentenyl amino-pyridine under the action of a Pd/C catalyst to obtain the nicotine precursor; and S4, synthesizing nicotine, namely obtaining nicotine from the nicotine precursor obtained in S3 under the action of formaldehyde and formic acid, wherein the chemical formulas are shown in specification.
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- Method for preparing nicotine
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The invention relates to a method for preparing nicotine. The method comprises the following steps: (1) adding N-Cbz pyrrolidone, nicotinate, an alkaline catalyst and a reaction solvent into a reaction container, carrying out a reaction, quenching until the system is neutral, and removing the reaction solvent to obtain a first solid mixture; (2) adding the first solid mixture into an acidic solution, and carrying out a reflux reaction to obtain a second reaction mixture; and (3) adding formic acid or formate solid and a formaldehyde solution into the second reaction mixture, reacting, and purifying the product to obtain racemic nicotine. The preparation method disclosed by the invention has high yield, and the prepared racemic nicotine and the S-nicotine have high purity.
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Paragraph 0060-0065
(2020/04/22)
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- Synthesis method of racemic nicotine
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The invention discloses a synthesis method of racemic nicotine. The method comprises the following steps: S1, introducing 3-(1-pyrrolin-2-yl) pyridine, a solvent and hydrogen into a first fixed bed reactor filled with a metal catalyst, and cooling at an outlet to obtain a crude product 3-(1-pyrrolidin-2-yl) pyridine mixed solution; and S2, taking the crude product 3-(1-pyrrolidine-2-yl) pyridine and a methylation reagent to pass through a solid second fixed bed reactor filled with a solid base catalyst, and cooling at an outlet to obtain racemic nicotine. The continuous flow fixed bed method is used for preparing racemic nicotine so that the continuity of production is realized, the reaction time is shortened, the reaction operation is simplified, the solvent consumption is reduced, the discharge of waste water and waste liquid is reduced, and the catalyst is convenient to recover.
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Paragraph 0049-0052
(2021/01/04)
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- ENANTIOMERIC SEPARATION OF RACEMIC NICOTINE BY ADDITION OF AN O,O'-DISUBSTITUTED TARTARIC ACID ENANTIOMER
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The present invention relates to a method of separating racemic nicotine of Formula (l-a) as a mixture of the (R)- and (S)-enantiomers into the enantiomerically pure (S)- and (R)-nicotine represented by Formula (l-b) and (l-c), by adding a mixture of the L- and the D-enantiomer of a O,O'-disubstituted tartaric acid, wherein the molar ratio of the L- to the D-enantiomer is from 80:20 to 95:5, and obtaining the (S)-nicotine of formula (l-b), or by adding O,O'-dibenzoyl-D-tartaric acid and obtaining the (R)-nicotine of formula (l-c).
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Page/Page column 8; 17
(2019/07/13)
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- PREPARATION OF RACEMIC NICOTINE BY REACTION OF ETHYL NICOTINATE WITH N-VINYLPYRROLIDONE IN THE PRESENCE OF AN ALCOHOLATE BASE AND SUBSEQUENT PROCESS STEPS
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The present invention relates to a method of preparing racemic nicotine comprising: (i) reacting ethyl nicotinate and N-vinylpyrrolidone in the presence of an alcoholate base to 3-nicotinoyl-1-vinylpyrrolidin-2-one; (ii) reacting the 3-nicotinoyl-1-vinylpyrrolidin-2-one with an acid to myosmine; (iii) reducing the myosmine to nornicotine using a reducing agent; and (iv) methylating the nornicotine to obtain the racemic nicotine.
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Page/Page column 14-16
(2019/07/13)
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- Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists
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Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant Kivalue of 15.7?nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302. In addition, compound 1c also showed potent κ antagonist activity with κ IC50?=?9.32?nM in [35S]GTP-γ-S functional assay. The potential use of the representative compounds as antidepressants was also investigated. The most potent compound 1c not only exhibited potent antidepressant activity in the mice forced swimming test, but also displayed the effect of anti-anxiety in the elevated plus-maze test.
- Wang, Junwei,Song, Qiao,Xu, Anhua,Bao, Yu,Xu, Yungen,Zhu, Qihua
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- NICOTINE COMPOSITION FOR VAPING DEVICES AND VAPING DEVICES EMPLOYING THE SAME
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A composition suitable for use in a vaping device includes a nicotine product that includes a synthetic nicotine that is substantially free of one or more contaminants and/or impurities normally associated with tobacco-derived nicotine. For example, the synthetic nicotine is substantially free of one or more of nicotine-1'- N-oxide, nicotyrine, nornicotyrine, 2',3-bipyridyl, cotinine, anabasine, and/or anatabine. The composition further comprises one or more pharmaceutically acceptable excipients, additives and/or solvents.
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Paragraph 0080; 0081
(2017/08/01)
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- NICOTINE REPLACEMENT THERAPY PRODUCTS COMPRISING SYNTHETIC NICOTINE
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A composition suitable for use in nicotine replacement therapy products includes a nicotine product that includes a synthetic nicotine that is substantially free of one or more contaminants and/or impurities normally associated with tobacco-derived nicotine. For example, the synthetic nicotine is substantially free of one or more of nicotine-1′-N-oxide, nicotyrine, nornicotyrine, 2′,3-bipyridyl, cotinine, anabasine, and/or anatabine. The composition further comprises one or more pharmaceutically acceptable excipients, additives and/or carriers. The nicotine replacement therapy products may include any number of such products, including transdermal nicotine delivery patches, nicotine gums, synthetic chewing tobacco, synthetic snuff, and synthetic strips (e.g., dissolvable synthetic tobacco). Additionally, a method of treating nicotine addiction includes administering a nicotine replacement composition, e.g., via a nicotine replacement therapy product, to a user.
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Paragraph 0095
(2017/08/01)
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- A Hofmann Rearrangement-Ring Expansion Cascade for the Synthesis of 1-Pyrrolines: Application to the Synthesis of 2,3-Dihydro-1H-pyrrolo[2,1-a]isoquinolinium Salts
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Treatment of cyclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene, PhI(OCOCF3)2, resulted in the formation of 1-pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate. Further elaboration of this methodology to the synthesis of 2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinium salts has also been described.
- Huang, He,Yang, Qinghua,Zhang, Qianqian,Wu, Jie,Liu, Yizhen,Song, Chuanjun,Chang, Junbiao
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p. 1130 - 1135
(2016/04/19)
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- PROCESS FOR THE PREPARATION OF (R,S)-NICOTINE
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A method of preparing (R,S)-nicotine, comprising reacting a nicotinate ester with N-vinyl-2-pyrrolidinone in the presence of a base and a solvent to form a first mixture, combining the first mixture with an acid to form a second mixture comprising an aqueous layer, separating the aqueous layer from second mixture, combining the separated aqueous layer with an acid to form a third mixture, combining the third mixture with a base to form a fourth mixture comprising myosamine, reducing myosamine to nornicotine using a reducing agent, and methylating the nornicotine to yield R,S-nicotine.
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Paragraph 0037
(2016/05/19)
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- A Process for the Preparation of (R,S)-Nicotine
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A process for (R,S)-nicotine is described. Condensation of 1-(but-1-enyl) pyrrolidin-2-one with nicotinic acid ester gave 1-(but-1-enyl)-3-nicotinoylpyrrolidin-2-one which on treatment with an acid and a base gave myosmine. Myosmine was converted to (R,S)-nicotine by reduction followed by N-methylation.
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Page/Page column 4
(2012/08/28)
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- The reaction of cyclic imines with the Ruppert-Prakash reagent. Facile approach to α-trifluoromethylated nornicotine, anabazine, and homoanabazine
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We have demonstrated that the Ruppert-Prakash reagent is able to react with a number of cyclic imines under acidic condition to afford the corresponding α-trifluoromethyl derivatives of nitrogen heterocycles. 5-7-Membered cyclic imines bearing various alkyl, aryl or heterocyclic group were successfully involved in this transformation. Novel trifluoromethylated analogues of nicotine, anabasine, and homoanabasine alkaloids were synthesized.
- Shevchenko, Nikolay E.,Vlasov, Katja,Nenajdenko, Valentine G.,R?schenthaler, Gerd-Volker
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scheme or table
p. 69 - 74
(2011/02/27)
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- COMPOUNDS AND METHODS FOR THE DIAGNOSIS AND TREATMENT OF AMYLOID ASSOCIATED DISEASES
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The invention is in general directed to compounds, such as tannic acid, nicotine, nicotine derivatives and pyrrolidine derivatives of nicotine, and methods for diagnosing, preventing or alleviating the symptoms of amyloid-associated diseases, for example, neuronal diseases, such as, for example, Alzheimer's disease, compounds and methods for inhibiting ion channel activity of beta amyloid, and methods of diagnostic imaging of A/3 fibrils.
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Page/Page column 42; 44
(2009/01/24)
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- Oxidative C-arylation of free (NH)-heterocycles via direct (sp3) C-H bond functionalization
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The development of a new chemical transformation, namely oxidative C-arylation of saturated (NH)-heterocycles, is described. This reaction combines dehydrogenation and arylation in one process, leading to cross-coupling of (NH)-heterocycles and haloarenes. Typical reaction conditions involve heating the reaction partners in anhydrous dioxane at 120-150 °C in the presence of RhCl(CO)[P(Fur)3]2 as the catalyst and Cs2CO3 as the base. Addition of tert-butylethylene as the hydrogen acceptor increases the chemical yield by diminishing the dehalogenation pathway. This method demonstrated a good substrate scope, allowing for cross-coupling of a variety of (NH)-heterocycles (e.g., pyrrolidine, piperidine, piperazine, morpholine) and halo(hetero)arenes to afford valuable heterocyclic products in one step. The preliminary mechanistic studies provided some insight regarding the key events in the proposed catalytic cycle, including β-hydride elimination of an amido rhodium complex and carbometalation of the resulting imine. A large kinetic isotope effect [KIE (kC-H/kC-D) = 4.3] suggests that one or both β-hydride elimination steps are rate determining. The central role for the phosphine ligand was established in controlling the partitioning between the oxidative C-arylation and N-arylation pathways. Copyright
- Sezen, Bengue,Sames, Dalibor
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p. 13244 - 13246
(2007/10/03)
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- Aqueous aldol catalysis by a nicotine metabolite
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Nornicotine, an endogenous tobacco alkaloid and minor nicotine metabolite, can catalyze aldol reactions at physiological pH. Catalysis appears to be due to a covalent enamine mechanism, an unprecedented reaction with small organic molecule catalysts in aqueous buffer. Kinetic parameters for nornicotine as well as other related alkaloids were measured and demonstrate that both the pyrrolidine and pyridine rings are critical for optimal catalysis. Substrate compatibility of this catalyst and its implications in vivo are discussed. Copyright
- Dickerson, Tobin J.,Janda, Kim D.
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p. 3220 - 3221
(2007/10/03)
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- Synthesis of 2-aryl-1-pyrrolines from arylnitriles
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Aromatic nitriles underwent addition of stabase-protected γ-aminopropylmagnesium bromide to afford the corresponding 1-pyrrolines in one step. Copyright
- Keppens, Marian,De Kimpe, Norbert,Fonck, Gwendolien
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p. 3097 - 3102
(2007/10/03)
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- Synthesis of cyclic imines via ethylenetetramethyldisilyl-protected ω-aminoimines. Application to the synthesis of alkaloids
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Cyclic imines, including several alkaloids such as myosmine, anabaseine and apoferrorosamine, were synthesized by α-alkylation of imines with ethylenetetramethyldisilyl-protected ω-bromoamines, followed by ring closure.
- De Kimpe, Norbert G.,Kepppens, Marian A.,Stevens, Christian V.
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p. 4693 - 4696
(2007/10/02)
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- Organometallic Ring-Opening Reactions of N-Acyl and N-Alkoxycarbonyl Lactams. Synthesis of Cyclic Imines
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The reactions of hexyl- and phenylmagnesium bromides with N-acyl and N-alkoxycarbonyl lactams in tetrahydrofuran at -78 deg C have been performed to determine the factors affecting the regioselectivity.N-Pivaloyl γ- and δ-lactams undergo the ring-opening reactions with both Grignard reagents, whereas on the N-benzoyl γ-lactam a complete selectivity is achieved only with phenylmagnesium bromide.The N-Cbz γ- and δ-lactams preferentially react at the exocyclic carbonyl group, especially with hexylmagnesium bromide.The N-Boc five- to eight-membered lactams undergo the ring-opening reaction to give N-Boc-ω-amino ketones, although the efficiency slightly decreases by increasing the ring size.The deprotection of the N-Boc-ω-amino ketones with trifluoroacetic acid easily affords the corresponding five- to seven-membered cyclic imines.Pyridine alkaloids containing the cyclic imine moiety have been prepared by a modified route, exploiting the more easily available pyridyllithium reagents, instead of the corresponding Grignard reagents.
- Giovannini, Arianna,Savoia, Diego,Umani-Ronchi, Achille
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p. 228 - 234
(2007/10/02)
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- PHOTO-INDUCED ELECTRON-TRANSFER OXIDATION OF NICOTINE
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Irradiation of nicotine in acetonitrile in the presence of TiO2 or 9,10-dicyanoanthracene under oxygen with a 100 W high pressure mercury lamp gave nicotyrine, cotinine,, and dehydronornicotine.A reaction mechanism leading to these products trough nicotine radical cation and superoxide anion is proposed.
- Yamada, Shuzo,Sakai, Toshiaki,Ohashi, Mamoru
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p. 287 - 290
(2007/10/02)
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- SYNTHESIS OF TOBACCO ALKALOIDS VIA TERTIARY AZIDES
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A convenient new synthesis of different tobacco alkaloids, such as nicotine and anabasine is described, using as key step the SCHMIDT reaction applied to tertiary alcohols.
- Alberici, Gilles F.,Andrieux, Jean,Adam, Gerard,Plat, Michel M.
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p. 1937 - 1940
(2007/10/02)
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- A Synthesis for Nornicotine- and Nicotine-2-carboxamide
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5-(2-Pyrrolidinyl)pyridine-2-carboxamide (6) (R = H) was prepared starting from readily available 4-oxo-4-(3-pyridyl)butyronitrile (4) in three steps in an overall yield of 33percent and was methylated in a Leuckart-Wallach reaction to yield 6 (R = CH3) in 68percent yield.The key step of the synthesis is the regioselective introduction of the carbamoyl group via Minisci reaction.
- Langhals, Elke,Langhals, Heinz,Ruechardt, Christoph
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p. 330 - 333
(2007/10/02)
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