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Synthesis method of galanthamine

A technology of galantamine and hydroxyl, applied in the field of synthesis of galantamine, can solve the problems of high price of galantamine, only 1.4%, high cost

Active Publication Date: 2013-12-04
TIANJIN HAIGELI TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is mainly used clinically for the treatment of myasthenia gravis and Alzheimer's disease (AD). Galantamine is a natural active alkaloid, mainly derived from plants of the Amaryllidaceae family such as Amaryllidaceae, Lycoris safflower, Daffodil, Snowflake Lian et al., due to limited resources, complex extraction process, and high cost, the price of galantamine has remained high for a long time. For this reason, researchers have been working on the total synthesis of galantamine.
[0003] In 1962, Barton et al simulated the biosynthesis method, using p-hydroxyphenylacetic acid and benzyl-protected isovanillin as starting materials, and obtained racemization through nine steps of benzylation, chlorination, condensation, hydrolysis, and oxidative cyclization. Body Narwedine (narwedine), and then through LiAlH 4 The mixture of galantamine and epigalantamine is obtained by reduction, wherein the oxidation ring synthesis yield is only 1.4%, and the total yield is less than 1%.

Method used

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  • Synthesis method of galanthamine
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Examples

Experimental program
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Effect test

Embodiment 1

[0024] N-(4-hydroxyphenethyl)-3-hydroxy-4-methoxy-6-bromobenzylamine (d)

[0025] 58g (0.25mol) of 6-bromoisovanillin (a) was dissolved in 280ml of methanol, 35g (0.25mol) of tyramine (b) was added at room temperature, and the reaction was stirred for 1 hour. Cool down to below 0°C, add 8.5g (0.225mol) sodium borohydride in batches, stir at 0°C for 1 hour, and stir at room temperature for 3 hours, evaporate the solvent under reduced pressure, add dichloromethane to dissolve, wash with water, and evaporate to dryness to obtain (d )75g, yield 85.2%.

Embodiment 2

[0027] N-methyl-N-(4-hydroxyphenethyl)-3-hydroxy-4-methoxy-6-bromobenzylamine (f)

[0028] Dissolve 50g (0.14mol) (d) in 250ml methanol, add 32ml of 37% formaldehyde, react at room temperature for 2 hours, cool down to 0°C, add 4.8g (0.126mol) sodium borohydride, react at 0°C for 3 hours, add 50ml The solid was precipitated in ice water and filtered to obtain 41.4 g of (f), with a yield of 80.6%.

Embodiment 3

[0030] Bronavirdine (g)

[0031] Dissolve 20g (0.055mol) (f) in 200ml of dichloromethane, add 1g of tetrabutylammonium bisulfate and appropriate amount of water at room temperature, add oxidant OXone (33g, 0.055mol), CaCl 2 (610.5mg, 5.5mmol), TEMPO (77mg, 0.55mmol), stirred at room temperature for 2 hours, stirred at 40°C for 2 hours, washed with water, concentrated to one-third volume, precipitated solid, stirred at room temperature for 3 hours, filtered to obtain ( g) 12.4 g, yield 62%.

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Abstract

The invention provides a new method for the preparation of (-)-galanthamine. The method includes the following steps: preparing N-methyl-N-(4-hydroxyl phenethyl)-3-hydroxyl-4-methoxyl-6-bretylium (f) by condensation of N-(4-hydroxyl phenethyl)-3-hydroxyl-4-methoxyl-6-bretylium (d) as a starting material and formaldehyde, then preparing bromo-narwedine (g) by catalytic oxidation using an oxidizing agent (Oxone / CaCl2 / TEMPO) and a phase-transfer catalyst, transforming the bromo-narwedine to levo bromo-narwedine (h) by Shieh method, obtaining bromo-(-)-galantamine (i) by asymmetric reduction, and then obtaining the (-)-galanthamine by hydrogenated debromination.

Description

[0001] Technical field: the invention belongs to the technical field of medicinal chemistry. Specifically relates to a method for synthesizing galantamine. Background technique: [0002] The chemical name of galantamine is: 11-methyl-3-methoxy-4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuran [3a, 3, 2-ef ][2]Benzazepine-6-ol. It is mainly used clinically for the treatment of myasthenia gravis and Alzheimer's disease (AD). Galantamine is a natural active alkaloid, mainly derived from plants of the Amaryllidaceae family such as Amaryllidaceae, Lycoris safflower, Daffodil, Snowflake Lian et al., due to limited resources, complicated extraction process and high cost, the price of galantamine has remained high for a long time, so researchers have been working on the total synthesis of galantamine. [0003] In 1962, Barton et al simulated the biosynthesis method, using p-hydroxyphenylacetic acid and benzyl-protected isovanillin as starting materials, and obtained racemization through ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107
Inventor 马德明刘喜凤吕家森马让
Owner TIANJIN HAIGELI TECH DEV
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