1668-85-5Relevant articles and documents
Total synthesis of (±)-galanthamine from GABA through regioselective aryne insertion
Venkatesh, Telugu,Mainkar, Prathama S.,Chandrasekhar, Srivari
, p. 2192 - 2198 (2019)
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.
Dynamic diastereomeric salt resolution narwedine and its transformation to (-)-galanthamine
Chaplin, David A.,Johnson, Nicholas B.,Paul, Jane M.,Potter, Gerard A.
, p. 6777 - 6780 (1998)
Racemic narwedine may be resolved by means of a dynamic diastereomeric salt formation using di-p-toluoyl-D-tartaric acid. Both the 1:1 and 2:1 salts are formed in excellent yields and diastereomeric excesses. These salts are reduced in a highly diastereoselective and chemoselective manner to give (- )-galanthamine.
Commercial scale process of galanthamine hydrobromide involving Luche reduction: Galanthamine process involving regioselective 1,2-reduction of α,β-unsaturated ketone
Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Prabahar, Koilpillai Joseph,Handa, Vijay Kumar,Srinu, Kukunuri Naga Venkata Satya,Babu, Korupolu Raghu,Sanasi, Paul Douglas
, p. 406 - 412 (2013)
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.
An Eleven-Step Synthesis of Galanthamine from Commercially Available Materials
Nugent, Jeremy,Banwell, Martin G.
, p. 5862 - 5867 (2016)
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.
The application of a specific morphinan template to the synthesis of galanthamine
Yamamoto, Naoshi,Okada, Takahiro,Harada, Yukimasa,Kutsumura, Noriki,Imaide, Satomi,Saitoh, Tsuyoshi,Fujii, Hideaki,Nagase, Hiroshi
, p. 5751 - 5758 (2017/09/05)
(–)-Galanthamine (4) was synthesized from naltrexone (1) in 18 steps with 3% total yield by overcoming many specific side reactions derived from the 4,5-epoxymorphinan skeleton. The key features are cleavage of the D-ring by the Hofmann elimination and the following the one-pot C9–C10 and C9–14 bond cleavages concomitant with the C9 removal by the OsO4–NaIO4 combination reaction. Then, the treatment with zinc powder in acetic acid led to not only removal of the 2,2,2-trichloroethoxycarbonyl (Troc) group, but also reductive amination of the resulting imine to give the desired 7-membered ring.
Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions
Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Raghu Babu, Korupolu,Sanasi, Paul Douglas,Prabahar, Koilpillai Joseph
, p. 117 - 124 (2014/02/14)
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.
Synthesis and evaluation of (-)- and (+)-[11C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging
Kimura, Hiroyuki,Kawai, Tomoki,Hamashima, Yoshio,Kawashima, Hidekazu,Miura, Kenji,Nakaya, Yuta,Hirasawa, Makoto,Arimitsu, Kenji,Kajimoto, Tetsuya,Ohmomo, Yoshiro,Ono, Masahiro,Node, Manabu,Saji, Hideo
, p. 285 - 291 (2014/01/17)
Improved radiopharmaceuticals for imaging cerebral acetylcholinesterase (AChE) are needed for the diagnosis of Alzheimer's disease (AD). Thus, 11C-labeled (-)-galanthamine and its enantiomers were synthesized as novel agents for imaging the localization and activity of AChE by positron emission tomography (PET). C-11 was incorporated into (-)- and (+)-[ 11C]galanthamine by N-methylation of norgalanthamines with [ 11C]methyl triflate. Simple accumulation of 11C in the brain was measured in an in vivo biodistribution study using mice, whilst donepezil was used as a blocking agent in analogous in vivo blocking studies. In vitro autoradiography of rat brain tissue was performed to investigate the distribution of (-)-[11C]galanthamine, and confirmed the results of PET studies in mice. The radiochemical yields of N-methylation of (-)- and (+)-norgalanthamines were 13.7% and 14.4%, respectively. The highest level of accumulation of 11C in the brains of mice was observed at 10 min after administration (2.1% ID/g). Intravenous pretreatment with donepezil resulted in a 30% decrease in accumulation of (-)-[11C]galanthamine in the striatum; however, levels in the cerebellum were unchanged. In contrast, use of (+)-[11C]galanthamine led to accumulation of radioactivity in the striatum equal to that in the cerebellum, and these levels were unaffected by pretreatment with donepezil. In in vitro autoradiography of regional radioactive signals of brain sections showed that pretreatment with either (-)-galanthamine or donepezil blocked the binding of (-)-[11C] galanthamine to the striatum, while sagittal PET imaging revealed accumulation of (-)-[11C]galanthamine in the brain. These results indicate that (-)-[11C]galanthamine showed specific binding to AChE, whereas (+)-[11C]-galanthamine accumulated in brain tissue by non-specific binding. Thus, optically pure (-)-[11C]galanthamine could be a useful PET tracer for imaging cerebral AChE.
Total synthesis of (±)-Galanthamine via a C3-selective stille coupling and IMDA cycloaddition cascade of 3,5-dibromo-2-pyrone
Chang, Jay Hyok,Kang, Ho-Ung,Jung, In-Hak,Cho, Cheon-Gyu
supporting information; experimental part, p. 2016 - 2018 (2010/06/21)
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.
An improved process for the preparation of galantamine hydrobromide
-
Page/Page column 10, (2009/01/24)
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
Domino double Michael-Claisen cyclizations: A powerful general tool for introducing quaternary stereocenters at C(4) of cyclohexane-1,3-diones and total synthesis of diverse families of sterically congested alkaloids
Ishikawa, Teruhiko,Kudo, Kazuhiro,Kuroyabu, Ken,Uchida, Satoshi,Kudoh, Takayuki,Saito, Seiki
, p. 7498 - 7508 (2008/12/22)
(Chemical Equation Presented) Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids of biological interest such as (+)-aspidospermidine, (±)-galanthamine, (±)-lycoramine, and (±)-mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates under thermodynamically controlled conditions.
