- Preparation method of nicotine and intermediate thereof
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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.
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- Synthesis method of (R, S-) nicotine
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The invention belongs to the technical field of medical intermediates, and particularly relates to a synthesis method of (R, S-) nicotine. The method comprises the following steps: (1) taking methyl nicotinate and N-butenyl pyrrolidone as raw materials, and preparing N-butenyl-3-benzoyl-1-pyrrolidone through a condensation reaction; (2) after the reaction is finished, carrying out hydrolysis reaction, cooling, adjusting the pH value to be alkaline, extracting, separating out an organic phase, concentrating and distilling to obtain an enamine intermediate; and (3) carrying out a reduction reaction on the enamine intermediate under illumination with the wavelength of 200-400nm by using a metal oxide or a complex as a reduction catalyst to obtain the target product (R, S-) nicotine. According to the method, use of the metal catalyst is innovatively proposed, reaction is initiated by illumination with specific wavelength to prepare the (R, S-) nicotine, and the method is simple and convenient to operate, high in yield, low in cost and suitable for industrial large-scale production.
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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 0047; 0053-0062
(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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- Enantioselective Synthesis of Nicotine via an Iodine-Mediated Hofmann-L?ffler Reaction
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An iodine-mediated Hofmann-L?ffler reaction has been developed that enables the first enantioselective synthesis of nicotine based on this synthetic methodology. The effect of the free pyridine core on the involved electrophilic iodine reagents was explored in detail. The final synthesis proceeds under moderate reaction conditions that tolerate the free pyridine core. The same synthetic sequence is also applicable to a number of derivatives with higher substituted pyridine cores, including bipyridine derivatives.
- Del Castillo, Estefanía,Mu?iz, Kilian
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supporting information
p. 705 - 708
(2019/02/07)
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- Direct α-C-H bond functionalization of unprotected cyclic amines
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Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N-H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (-)-solenopsin A.
- Chen, Weijie,Ma, Longle,Paul, Anirudra,Seidel, Daniel
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p. 165 - 169
(2018/02/06)
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- N-Heterocyclic Carbene Iron(III) Porphyrin-Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides
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Metal-catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N-heterocyclic carbene ligands which catalyzes the intramolecular C(sp3)–H amination of a wide variety of alkyl azides under microwave-assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re-bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis-octahydroindole, and leelamine derivatives.
- Shing, Ka-Pan,Liu, Yungen,Cao, Bei,Chang, Xiao-Yong,You, Tingjie,Che, Chi-Ming
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p. 11947 - 11951
(2018/09/11)
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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 0094
(2017/08/01)
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- A PROCESS FOR THE PREPARATION OF NICOTINE
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The present invention relates to a process for the preparation of racemic nicotine from 3- pyridylaldehyde using a one-pot or step-wise method. The process comprises the following steps: Stetter reaction, reduction-cyclisation and methylation.
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Page/Page column 6; 7
(2017/08/01)
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- Methods of using QIAPINE
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Uses of QIAPINE? to treat internal bleeding, such as subdural hematoma and subarachinoid hemorrhage, and ocular bleeding, such as such as hyphema and vitreous hemorrhage, in a subject are described. Also described are uses of QIAPINE? to treat vision loss resulting from hyphema or vitreous hemorrhage.
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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 0038; 0039
(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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- 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 3
(2012/08/28)
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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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- One-pot synthesis of polysubstituted pyrrolidines from aminonitriles
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α-Aminonitriles with a mono- or unsubstituted amino group as well as α-(alkylideneamino)nitriles can be employed as easily accessible α-aminocarbanion equivalents. Their α-deprotonation yields stabilized carbanions, which undergo smooth 1,4-addition to α,β- unsaturated carbonyl compounds. The resulting δ-keto-α-aminonitriles can be reductively cyclized to form polysubstituted pyrrolidines. Georg Thieme Verlag Stuttgart.
- Meyer, Nino,Werner, Frank,Opatz, Till
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p. 945 - 956
(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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- An immunotherapeutic program for the treatment of nicotine addiction: Hapten design and synthesis
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People continue to smoke and use tobacco products despite well-established hazardous consequences. The most contributing factor is the addictive nature of nicotine. There is no highly effective treatment for the problem of nicotine dependence. Immunotherapy offers an alternative to conventional approaches. The chemistry necessary for a comprehensive immunopharmacological program is presented. Haptens for the generation of antibodies specific for naturally occurring (S)-nicotine, (S)- and (R)-nornicotine, and the metabolite (S)-cotinine were prepared with high optical purity. Preliminary data for antinicotine antibodies are reported.
- Isomura,Wirsching,Janda
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p. 4115 - 4121
(2007/10/03)
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- Regioselective alkylation of N-(diphenylmethylidine)-3-(aminomethyl)pyridine: A simple route to minor tobacco alkaloids and related compounds
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A simple synthetic route to minor tobacco alkaloids and related compounds is described involving regioselective alkylation of N-(diphenylmethylidine)-3-(aminomethyl)pyridme with a suitable dielectrophile.
- Deo, Niranjan M.,Crooks, Peter A.
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p. 1137 - 1140
(2007/10/03)
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- A [3 + 2] and [4 + 3] cycloaddition approach to N-heterocycles via Pd-catalyzed TMM reactions with imines
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The question of cycloadditions of (trimethylenemethane) palladium complexes to heteroation is probed in the context of pyrrolidine syntheses. Whereas simple imines fail to react, imines possessing an electron-withdrawing group at either the carbon or nitrogen enhance the electrophilicity of the imine sufficiently to make it an excellent accetor. Palladium(0) complexes catalyze cycloadditions of 2-((trimethylsilyl)methyl)allyl esters to N-tosyl- and N-nitroimines. The stronger electron-withdrawing nature of the nitre group permits nitrimines derived from relatively hindered ketones to participate. Conjugated cisoid imines lead to [4 + 3] cycloadditions - a process azepine synthesis. Substituted TMM precursors cycloadd with high regioselectivity. The result. are consistent with a two-step addition process. Some of the simple examples explored to determine the scope and limitations of the process reveal simple syntheses of proline and nicotine analogues. The successful employment of imines as direct acceptors for TMM-PdL2 opens a new chapter on metal-catalyzed cycloadditions.
- Trost, Barry M.,Marrs, Christopher M.
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p. 6636 - 6645
(2007/10/02)
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- Tungstate-Catalyzed Oxidation of Secondary Amines to Nitrones. α-Substitution of Secondary Amines via Nitrones
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The sodium tungstate catalyzed oxidation of secondary amines with hydrogen peroxide gives the corresponding nitrones.Acyclic and cyclic nitrones can be obtained from secondary amines in a single step in good to escellent yields.The oxidation of secondary amines in the presence of alkenes gives isoxazolidines by 1,3-dipolar cycloaddition of nitrones.Introduction of a substituent at the α-position of secondary amines can be performed upon oxidation of secondary amines and subsequent treatment with various nucleophiles.
- Murahashi, Shun-Ichi,Mitsui, Hitoshi,Shiota, Tatsuki,Tsuda, Tomoyasu,Watanabe, Shoji
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p. 1736 - 1744
(2007/10/02)
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- A NOVEL THREE CARBON-AMINO GRIGNARD REAGENT: ITS USE IN AN EFFICIENT PYRROLIDINE SYNTHESIS
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A novel primary amino protected Grignard reagent has been developed; 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-propyl magnesium bromide 1a.Its usefulness is illustrated in the synthesis of 2-substituted pyrrolidines.
- Basha, Fatima Z.,DeBernardis, John F.
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p. 5271 - 5274
(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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- 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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