- A Nivalin industrial preparation method (by machine translation)
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The invention relates to a technical field of drug synthesis, in particular relates to a preparation method of the galanthamine hydrobromide. Preparation method of this invention comprises the following steps: (1) the racemate narwedine as raw materials, adding resolution solvent to get levorotation narwedine; (2) L narwedine [...] butyl boron lithium hydride reduction shall be galantamine free alkali, further and hydrobromic acid shall be galanthamine hydrobromide. (by machine translation)
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Paragraph 0041; 0042
(2019/02/27)
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- Total synthesis of (±)-galanthamine from GABA through regioselective aryne insertion
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The total synthesis of (±)-galanthamine is achieved in ～5% overall yield using a key regioselective aryne insertion reaction into a GABA (γ-amino butyric acid) derivative. The strategy presented involves only two sub-critical temperature reactions and less than five chromatographic purifications to achieve the synthesis of galanthamine.
- Venkatesh, Telugu,Mainkar, Prathama S.,Chandrasekhar, Srivari
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p. 2192 - 2198
(2019/02/27)
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- An Eleven-Step Synthesis of Galanthamine from Commercially Available Materials
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Narwedine, an immediate precursor to the therapeutically valuable alkaloid (–)-galanthamine, has been synthesised by engaging an iodinated isovanillin derivative in an intermolecular Mitsunobu reaction with a 2-cyclohexen-1-ol derivative. The resulting aryl ether participated in an exceptionally efficient intramolecular Heck reaction to give a tetracyclic lactol after the hydrolysis of the primary cyclisation product. This last compound is an advanced intermediate associated with the Magnus synthesis of narwedine and could be elaborated to narwedine itself under reductive amination conditions. As a result, an eleven-step synthesis of galanthamine has been established.
- Nugent, Jeremy,Banwell, Martin G.
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p. 5862 - 5867
(2016/12/18)
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- A total synthesis of galanthamine involving de novo construction of the aromatic C-ring
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The tetracyclic alkaloid galanthamine is used clinically in a number of countries for the symptomatic treatment of mild to moderate forms of Alzheimer's disease, and this feature coupled with its novel molecular architecture has prompted an extensive focus on its synthesis. The present study reports a new and distinct synthesis of galanthamine wherein the AB-ring substructure and associated quaternary carbon centre are constructed by using a palladium-catalyzed intramolecular Alder-ene reaction. The product of this process is engaged in a Tsuji-Trost-type reaction to generate a semicyclic diene that participates in a normal-electron-demand Diels-Alder reaction to generate, after oxidation of the initially formed adduct, the aromatic C-ring of the target alkaloid. Modified Bischler-Napieralski chemistry is then deployed to construct the seven-membered D-ring and thereby furnishing narwedine, an established precursor to both (+)- and (-)-galanthamine. The first synthesis of the alkaloid galanthamine is reported in which the aromatic C-ring is assembled from non-aromatic precursors. This was accomplished by a Diels-Alder cycloaddition reaction. The diene used embodies the AB-ring system (and associated quaternary carbon centre) and was constructed by intramolecular Alder-ene and Tsuji-Trost-type chemistries. The D-ring was closed by a modified Bischler-Napieralski reaction.
- Nugent, Jeremy,Matou?ová, Eli?ka,Banwell, Martin G.
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p. 3771 - 3778
(2015/06/16)
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- Thiol-Reactive Analogues of Galanthamine, Codeine, and Morphine as Potential Probes to Interrogate Allosteric Binding within Nicotinic Acetylcholine Receptors
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Alkaloids including galanthamine (1) and codeine (2) are reported to be positive allosteric modulators of nicotinic acetylcholine receptors (nAChRs), but the binding sites responsible for this activity are not known with certainty. Analogues of galanthamine (1), codeine (2), and morphine (3) with reactivity towards cysteine thiols were synthesized including conjugated enone derivatives of the three alkaloids 4-6 and two chloro-alkane derivatives of codeine 7 and 8. The stability of the enones was deemed sufficient for use in buffered aqueous solutions, and their reactivity towards thiols was assessed by determining the kinetics of reaction with a cysteine derivative. All three enone derivatives were of sufficient reactivity and stability to be used in covalent trapping, an extension of the substituted cysteine accessibility method, to elucidate the allosteric binding sites of galanthamine and codeine at nAChRs.
- Gallagher, Ryan,Chebib, Mary,Balle, Thomas,McLeod, Malcolm D.
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p. 1834 - 1841
(2015/12/26)
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- CONSTRUCTS AND METHODS FOR BIOSYNTHESIS OF GALANTHAMINE
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The present disclosure relates generally to the identification of enzymes within the Amaryllidaceae alkaloid biosynthetic pathway as well as to engineering transgenic organisms for the production of galanthamine and/or hemanthamine and/or lycorine. Disclosed herein is the isolation and characterization of cDNAs and encoded norbelladine 4'-0-methyltransferase, CYP96T1-3, and norbelladine synthase/reductase involved in the biosynthesis of galanthamine and haemanthamine. The invention relates to a transgenic plant, comprising within its genome, and expressing, a heterologous nucleotide sequence coding for a class I O-methyltransferase, wherein the O-methyltransferase is norbelladine 4'-0-methyltransferase. In one embodiment, the norbelladine 4'-0-methyltransferase is selected from among NpN40MT1, NpN40MT2, NpN40MT3, NpN40MT4, and NpN40MT5. The invention further contemplates a method of making a transgenic plant.
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Paragraph 0126
(2016/06/08)
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- Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions
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A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galanthamine, (-)-galanthamine 1, (+)-galanthamine 2, (-)-epigalanthamine 3, and (+)-epigalanthamine 4, from (±)-narwedine 5 is reported. Thus (±)-narwedine 5 was resolved by dynamic kinetic resolution to obtain enantiomerically pure (-)-narwedine 6 and (+)-narwedine 7. Each enantiomerically pure isomer of narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine. In these reactions, the (-)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enantiomeric purity of >99.5%, whereas (-)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from a prochiral carbonyl group on the cyclic enone system.
- Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Raghu Babu, Korupolu,Sanasi, Paul Douglas,Prabahar, Koilpillai Joseph
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p. 117 - 124
(2014/02/14)
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- Commercial scale process of galanthamine hydrobromide involving Luche reduction: Galanthamine process involving regioselective 1,2-reduction of α,β-unsaturated ketone
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Effect of lanthanide chloride in the Luche regioselective 1,2-reduction of 1-bromo-11-formyl-nornarwedine (5) was studied. Thus, 1-bromo-11-formyl- nornarwedine (5) is reduced with sodium borohydride in the presence of lanthanide chloride to yield 1-bromo-11-formyl-galanthamine isomers (6), which is a key intermediate for the commercial production of highly pure galanthamine hydrobromide (1), a modern drug against Alzheimer's disease.
- Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Prabahar, Koilpillai Joseph,Handa, Vijay Kumar,Srinu, Kukunuri Naga Venkata Satya,Babu, Korupolu Raghu,Sanasi, Paul Douglas
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p. 406 - 412
(2013/06/05)
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- Two new alkaloids from Crinum asiaticum var. sinicum
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Two new alkaloids (1, 2) were isolated from the whole plants of Crinum asiaticum var. sinicum together with seven known alkaloids. The structures of the new alkaloids were elucidated by spectroscopic analyses and chemical conversions from known alkaloids. New alkaloid 1 was isolated for the first time as a natural product, although it has been prepared as a synthetic product.
- Kogure, Noriyuki,Katsuta, Noriko,Kitajima, Mariko,Takayama, Hiromitsu
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experimental part
p. 1545 - 1548
(2012/01/13)
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- METHOD FOR THE PRODUCTION OF HIGH-PURITY 4A, 5, 9, 10, 11, 12,-HEXAHYDRO-6H-BENZOFURO [3A, 3, 2-EF] [2] BENZAZEPINE, AND THE DERIVATIVES THEREOF
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A process for the production of extremely pure galanthamine or extremely pure galanthamine derivatives, whereby a start is made from racemic bromine narwedine, which is debrominated under palladium catalysis. The working-up of the reaction mixture, which is carried out in the presence of oxygen or peroxides, is essential to the process, so that the palladium catalyst is converted into an insoluble form, a form that can be easily separated. The further reaction is carried out by reduction of enantiomerically pure narwedine to form enantiomerically pure galanthamine, whereby it is then alkylated or dealkylated, so that a corresponding substitution on the ring-nitrogen atom is achieved. By further purification, such as recrystallization, residual portions of palladium of below 5 ppm are achieved, so that the direct use as a pharmaceutical raw material is made possible.
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Page/Page column 3
(2010/05/13)
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- Total synthesis of (±)-Galanthamine via a C3-selective stille coupling and IMDA cycloaddition cascade of 3,5-dibromo-2-pyrone
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Figure presented A new efficient synthetic route to (±)-galanthamine was devised by using a tandem C3-selective Stille coupling-IMDA cascade of 3,5-dibromo-2-pyrone as a key strategy.
- Chang, Jay Hyok,Kang, Ho-Ung,Jung, In-Hak,Cho, Cheon-Gyu
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supporting information; experimental part
p. 2016 - 2018
(2010/06/21)
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- SYNTHESIS OF MORPHINE AND RELATED DERIVATIVES
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The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.
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Page/Page column 86-87
(2010/12/17)
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- Concise syntheses of (-)-galanthamine and (±)-codeine via intramolecular alkylation of a phenol derivative
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(Figure Presented). A new solution-processable fabrication protocol using a soluble tetrabenzoporphyrin (BP) precursor and bis(dimethylphenylsilylmethyl) [60]fullerene (SIMEF) created three-layered p-i-n photovoltaic devices, in which the i-layer possesses a well-defined bulk heterojunction structure in which columnar BP crystals grow vertically from the bottom p-layer. The device showed a power conversion efficiency of 5.2% (VOC = 0.75 V; JSC = 10.5 mA/cm2; FF = 0.65).
- Magnus, Philip,Sane, Neeraj,Fauber, Benjamin P.,Lynch, Vince
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supporting information; experimental part
p. 16045 - 16047
(2010/02/16)
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- Syntheses and Preparations of Narwedine and Related Novel Compounds
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The present invention relates to a process for preparing racemic narwedine (which can be can be kinetically resolved) to yield (?)-narwedine and which is the biogenic precursor of (?)-galanthamine) and the use thereof as a starting material for producing (?)-galanthamine. The invention further includes processes for preparing (?)-galanthamine and (?)-galanthamine hydrobromide, as well as related novel compounds.
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Page/Page column 11
(2009/01/20)
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- An improved process for the preparation of galantamine hydrobromide
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The present invention relates to an improved process for the preparation of [4aS,6R,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol of Formula I
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Page/Page column 10; 11
(2009/01/24)
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- Biomimetic synthesis of (±)-galanthamine and asymmetric synthesis of (-)-galanthamine using remote asymmetric induction
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(±)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol coupling of N-(4-hydroxy)phenethyl-N-(3′, 4′,5′-trialkoxy)benzyl formamide (15b) as a key step. Because of the symmetrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole coupling product except for volatile components from the oxidizing agent. On the basis of the successful results of the above strategy, (-)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction, where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C-N bond of the tri-O-alkylated gallyl amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry for the synthesis of (-)-1.
- Node, Manabu,Kodama, Sumiaki,Hamashima, Yoshio,Katoh, Takahiro,Nishide, Kiyoharu,Kajimoto, Tetsuya
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p. 1662 - 1679
(2007/10/03)
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- An efficient synthesis of (±)-narwedine and (±)-galanthamine by an improved phenolic oxidative coupling
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Old problems, new ideas! The biometic phenol coupling of norbelladine derivatives such as 1 (Bn = benzyl) to form galanthamine (2), a drug used in the treatment of Alzheimer's disease, has been greatly improved by the use of the hypervalent-iodine oxidation regeant phenyliodine(III) bis(triflouroacetate) (PIFA).
- Node, Manabu,Kodama, Sumiaki,Hamashima, Yoshio,Baba, Takahiro,Hamamichi, Norimitsu,Nishide, Kiyoharu
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p. 3060 - 3062
(2007/10/03)
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- Development of a pilot scale process for the anti-alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion
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(-)-Galanthamine has been synthesised using an efficient nine-step procedure, which in large scale affords 12.4 (6.7-19.1)% overall yield. The process improvements and optimization of each step are described. Notable steps include (i) an oxidative phenol coupling and (ii) crystallisation-induced chiral conversion of (±)-narwedine to (-)-narwedine. This is a practical and cost-effective synthesis of (-)-galanthamine which is amenable to pilot plant scale-up to afford sufficient material for use in clinical trials.
- Kueenburg, Bernhard,Czollner, Laszlo,Frohlich, Johannes,Jordis, Ulrich
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p. 425 - 431
(2013/09/08)
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- Oxidative Intramolecular Phenolic Coupling Reaction Induced by a Hypervalent Iodine(III) Reagent: Leading to Galanthamine-Type Amaryllidaceae Alkaloids
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By extending our oxidative phenol-coupling reactions using a hypervalent iodine(III) reagent, a versatile synthetic procedure for the galanthamine-type Amaryllidaceae alkaloids was accomplished. The first total synthesis of (±)-sanguinine and the total syntheses of (±)-galanthamine, (±)- narwedine, (±)-lycoramine, and (±)-norgalanthamine were also successfully carried out.
- Kita, Yasuyuki,Arisawa, Mitsuhiro,Gyoten, Michiyo,Nakajima, Makiko,Hamada, Ryuji,Tohma, Hirofumi,Takada, Takeshi
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p. 6625 - 6633
(2007/10/03)
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- New kilogram-synthesis of the anti-Alzheimer drug (-)-galanthamine
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A concise, scalable synthesis of (-)-galanthamine, a drug being used for the treatment of Alzheimer's disease, is described. The yield of the critical phenolic coupling step was optimized to 45-50%. For the reduction of the aryl bromide, air-activated LiAlH4 was used and racemic narwedine was converted to (-)-narwedine by a second order asymmetric transformation.
- Czollner, Laszlo,Frantsits, Werner,Kueenburg, Bernhard,Hedenig, Ursula,Froehlich, Johannes,Jordis, Ulrich
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p. 2087 - 2088
(2007/10/03)
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- Chemical and pharmacological characterization of galanthamine, an acetylcholinesterase inhibitor, and its derivatives. A potential application in Alzheimer's disease ?
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We conducted structural and pharmacological studies of galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and 19 structural analogs.Systematic derivatization of galanthamine at the cyclohexene ring, tertialy amino, hydroxyl, methoxyl functions indicated that these structural features are essential for biological activity.Molecular modeling studies suggested that the low energy conformations of the analogs are similar to that of the parent.One derivative, galanthamine n-butyl carbamate, had an LD50 of over 100 mg/kg (ip) in mice.In a passive avoidanceparadigm, this analog improved performance in a dose-dependant fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice.In the same paradigm, the peak effect of the parent compound is a 6-fold higher dose.With this surprisingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's desease. galanthamine derivatives / molecular modeling / avetylcholinesterase inhibitor / Alzheimer's desease / passive avoidance / basal forebrain lesion
- Han, SY,Sweeney, JE,Bachman, ES,Schweiger, EJ,Forloni, G,et al.
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p. 673 - 687
(2007/10/02)
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