METODIEV, Danail Georgiev,DASKALOV, Hristo Petrov,KLISAROVA, Maria Nedkova,SHOPOVA, Lubenova Daniela,APOSTOLOVA, Petya Mitkova,ZAEKOVA, Galina Nikolova,KOTSEV, Ivaylo Todorov,STOYANOV, Nikolay Kirilov
申请号：
BGBG2019/000010
公开号：
WO2019/222817A1
申请日:
2019.05.13
申请国别(地区):
BG
年份:
2019
代理人:
摘要：
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 9
