193146-85-9

Upstream product

• 510-77-0 (-)-narwedine 
• 26601-10-5 (-)4a,5,9,10,11,12-hexhydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one 
• 357-70-0 Galantamine 
• 357-70-0 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef ][2]benzazepin-6-ol 
• 510-77-0 (4aS,8aS)-rel-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-6-one 
• 7318-55-0 (4aR,8aR)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one 
• 807362-55-6 (-)-galantamine tartarate 
• 934415-11-9 galantamine 
• 179107-93-8 N-(p-hydroxyphenylethyl)-N-(6-bromo-3-hydroxy-4-methoxybenzyl)amine 
• 2973-59-3 2-bromoisovanillin 
• 120-14-9 3,4-dimethoxy-benzaldehyde 
• 5392-10-9 2-bromo-4,5-dimethoxybenzaldehyde 
• 122584-18-3 N-(4-hydroxyphenethyl)-N-(2-bromo-5-hydroxy-4-methoxybenzyl)formamide 

Downstream Products

• 60755-80-8 O-Demethylgalantamine 
• 41303-74-6 N-desmethyl galantamine 
• 146274-40-0 (-)-(4aα,6β)-6-chloro-4a-5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-e,f][2]benzazepin 

Relevant academic research and scientific papers

METHOD FOR PREPARATION OF PURIFIED GALANTAMINE HYDROBROMIDE

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.

A Nivalin industrial preparation method (by machine translation)

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)

Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions

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.

Commercial scale process of galanthamine hydrobromide involving Luche reduction: Galanthamine process involving regioselective 1,2-reduction of α,β-unsaturated ketone

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 improved process for the preparation of galantamine hydrobromide

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

Syntheses and Preparations of Narwedine and Related Novel Compounds

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.

PROCESS FOR THE PREPARATION OF PURE GALANTAMINE

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.

A POLYMORPHIC FORM OF NARWEDINE AND ITS USE IN THE SYNTHESIS OF GALANTAMINE

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).

Preparation of (-)-galantamine hydrobromide

A process for preparing (?)-galantamine hydrobromide.

Processes for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro-[3a, 3, 2-ef][2]benzazepine

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.