Chiral synthesis method for (-)-galantamin hydrobromide

A technology of galantamine hydrobromide and synthesis method, which is applied in the direction of asymmetric synthesis, organic chemical method, chemical instrument and method, etc., and can solve the problems of large environmental impact, difficulty of obtaining, unsuitable for large-scale production, etc.

Inactive Publication Date: 2008-08-13
泰州市宝嵘新材料有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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 fo

Method used

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  • Chiral synthesis method for (-)-galantamin hydrobromide
  • Chiral synthesis method for (-)-galantamin hydrobromide

Examples

Experimental program
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Effect test

Embodiment

[0024] N-(2-Bromo-5-hydroxy-4-methoxybenzyl)-4-hydroxyphenethylamine (2)

[0025] To a solution of 65 g (0.28 mol) of 6-bromoisovanillin dissolved in 300 ml of methanol, a (methanol) solution of 38 g (0.28 mol) of tyramine was added dropwise at room temperature.

[0026] The mixture was stirred for 5h.

[0027] Cool to 0°C, add NaBH in small portions 4 13.4g (0.34mol) (minimal foaming is preferred).

[0028] Then the reaction solution was stirred at room temperature for 5 h. (Tracking TLC: EtOAc / MSO, 1 / 3)

[0029] Methanol was distilled off under reduced pressure, and the oily residue was dissolved in ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate.

[0030] Reduced pressure to dryness gave 82.3 g (83.1%) of yellow oil 2 (as HCl salt, mp 229-230°C)

[0031] N-(2-Bromo-5-hydroxy-4-methoxybenzyl)-4-hydroxyphenethylmethylamine (3)

[0032] 250g (0.14mol) is dissolved in a mixture of 98%-100% formic acid 50ml and 36%-38% formaldehyde 50ml. Heat...

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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 ...

Claims

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Application Information

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IPC IPC(8): C07D491/06C07B53/00A61P25/28
Inventor 阎家麒高荣谢建平
Owner 泰州市宝嵘新材料有限公司
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