Chiral synthesis method for (-)-galantamin hydrobromide

Abstract

Ethamine compound is obtained by condensing starting materials of 6-bromoisovanillin and tyramine under catalysis of NaBH4 in carbinol. In formylation of ethamine compound, aminic acid and formaldehyde of same amount are used to produce formyl compound, with temperature between 90 DEG C. and 110 DEG C., 8h. Racemic bromonarwedine is obtain by oxidation and cyclization of the formyl compound. Racemic narwedine is obtained by reduction reaction under catalysis of NaCO2H, PPh3, Pd(OAc)2. Racemic narwedine is transformed into (-)-narwedine by a process of crystal inoculation. (-)-narwedine is reduced into unsaturated ketone by (-)-N-methyl ephedrine as chiral reagent, whereby optically active alcohol is obtained, and (-)-galanthamine is also obtained.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a novel method for chiral synthesis of (-)-galanthamine hydrobromide. Background technique [0002] Galanthamine is a left-handed chiral compound extracted from Lycoris squamigera Maxim and Lycoris aurea Herb or the same plants of the Amaryllidaceae family. It is a highly selective Sexual cholinesterase inhibitor, well tolerated, no hepatotoxicity. Clinically, it was originally used for the sequelae of polio and myasthenia gravis, and now it is used for the treatment of Alzheimer's disease, and it can also improve the memory impairment caused by dementia patients and brain organic diseases. Clinically used (-)-galantamine is usually prepared as hydrobromide. [0003] [0004] Alzheimer's disease is a progressive neurodegenerative disorder in the elderly, and its clinical manifestations are mainly memory loss and cognitive dysfunction. Alzheimer's disease is the ...

AI Technical Summary

Problems solved by technology

The main reason for the high production cost of extracting galantamine is that ① the raw material Lycoris is wild, difficult to collect, transportation, cooling, and processing are too cumbersome and labor-intensive

②The extraction and purification process consumes a large amount of solvents, which has a great impact on the environment and increases the cost of environmental governance. ③Limited by natural plant resources

[0009] 1) US 2006 / 0009640A1 and US 6369238B1 first prepare the export-oriented galantamine, and then use D-(+)-p-methyldibenzoyltartaric acid ((+)-para-toluoyltartaric acid monohydrate) for chiral transformation , low yield, high cost of chiral reagents, not suitable for large-scale production

[0010] 2) Organic Process Research & Development, 1999, 3, 425, when synthesizing (-)-galantamine from (-)-Navidine, the stereoselective reducing agent L-Selectride was used. There is no domestic manufacturer of L-Selectride, so it needs to be imported , are expensive and not readily available

[0011] 3) Yan Jiaqi: CN1554658A and Liu Tao et al: Zhejiang University Journal, 2006, 40:520 Preparation of racemic galantamine, which is not a natural product and has no selective cholinesterase inhibitory effect , and what is synthesized is not a product of racemic galantamine, there is also a racemic surface galantamine, the separation of the two is extremely difficult

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