- 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 0043; 0044
(2019/02/27)
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- METHOD FOR PREPARATION OF PURIFIED GALANTAMINE HYDROBROMIDE
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The invention concerns a method for preparation of purified galantamine hydrobromide, i.e. extraction of galantamine from plant raw material, its conversion into hydrobromide and its purification. The method consists of extraction from Leucojum aestivum or Narcissus Carlon cv in aqueous medium or in medium of low alcohol, alkalized with calcium hydroxide to pH 9 - 12 at a temperature of 30 - 40°C of galantamine base, after filtration and concentration it is extracted 2 to 4 times with methyl isobutyl ketone, ethyl acetate or butyl acetate or with n-butanol in a ratio of extract/extractant of 8:1 during the extractions in water medium, and respectively 2:1 during the extractions in the presence of simple alcohol. Concentration of the collected organic extracts from 1/20 to 1/30 of the initial volume and replacement of the solvent with ethanol. Conversion of the obtained galantamine base during treatment with hydrobromic acid to galantamine hydrobromide which at a temperature of 80 - 85°C in aqueous medium is purified with activated carbon. Filtration of the purified solution, cooling down to 20-25°C and alkalization with ammonium hydroxide to pH 9-12. Extraction of the obtained galantamine base 2-4 times with methyl isobutyl ketone, ethyl acetate or butyl acetate in a ratio of alkaline water solution/organic solvent of 2:1 to 3:1 and after concentration from 1/5 to 1/10 of the initial volume, cooling and treating with selective reagent for N-desmethyl galantamine under stirring for 7-10 hours, followed by extraction with mineral acid to pH 2-3 in aqueous medium, alkalization of the acid water extract of the galantamine salt at pH 9-12, extraction of the released galantamine base with methyl isobutyl ketone, ethyl acetate or butyl acetate in a ratio of aqueous solution/organic solvent of 2:1 to 3:1, replacement of the solvent with ethanol and processing with hydrobromic acid and obtaining galantamine hydrobromide with HPLC grade more than 99% and high yield of about 90 - 92% of the content of Galantamine hydrobromide in the technical product.
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Page/Page column 5-9
(2019/12/15)
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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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- 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 11
(2009/01/24)
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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 4; 12
(2009/01/20)
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- A POLYMORPHIC FORM OF NARWEDINE AND ITS USE IN THE SYNTHESIS OF GALANTAMINE
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The present invention relates a polymorphic form of narwedine (Form B) and processes for the preparation thereof. Also provided is a process for the synthesis of galantamine using a polymorph of narwedine (Form B).
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Page/Page column 17
(2010/11/08)
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- PROCESS FOR THE PREPARATION OF PURE GALANTAMINE
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The invention relates to processes for the preparation of pure galantamine or pharmaceutically acceptable salts thereof. More particularly, it relates to the preparation of pure galantamine hy-drobromide. The invention also relates to pharmaceutical compositions that include the pure galantamine or pharmaceutically acceptable salts thereof and use of said compositions for treating Alzheimer's disease, dementia, mania, fatigue syndrome, and schizophrenia.
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Page/Page column 10
(2010/10/19)
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- Preparation of (-)-galantamine hydrobromide
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A process for preparing (?)-galantamine hydrobromide.
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Page/Page column 8
(2008/06/13)
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- Processes for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro-[3a, 3, 2-ef][2]benzazepine
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The invention relates to processes for the preparation of 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine, or derivatives thereof. Furthermore, the invention also relates to the compounds formed during the preparation of 4a, 5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine.
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- Optical resolution of narwedine-type compounds
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A process for the asymmetric transformation of a racemic compound of formula (I) wherein R1is H or a alkyl group having up to 20 carbon atoms, R2is H, or an alkyl, aryl, alkaryl or aralkyl group having up to 20 carbon atoms, and X is H, a halogen atom, tert-butyl, or any other removable substituent, comprises reaction of racemic compound (I) with an enantiomerically-enriched acid HY*, wherein Y* is a chiral group, to form a diastereomeric salt of compound (I) having Y* as a counterion. The salt obtained can then be reduced to give enantiomerically-enriched galanthamine, or a derivative thereof.
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Page column 6
(2008/06/13)
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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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- 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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