CN102050826B - Method for separating galanthamine - Google Patents

Abstract

The invention discloses a method for separating galantamine: first detecting the content of galantamine in the total alkaloid extract of Lycoris, and combining the total alkaloid extract of Lycoris with L-(-)-dibenzoyl Mix tartaric acid, use 75~95% ethanol as a solvent, fully react at 70~100°C to obtain a clear solution, then cool to -10~25°C, stand until crystallization, filter and take the filter cake with recrystallization solvent A After recrystallization, add alkali aqueous solution to the obtained crude crystal, adjust the pH value to 7~9 for decomposition, add _CHCl3 for extraction, take the organic layer and evaporate the solvent to obtain the crude galantamine; then dissolve it with acetone, add HBr aqueous solution, and filter To obtain galantamine hydrobromide, recrystallize with recrystallization solvent B to obtain pure galantamine. The separation efficiency of the present invention is high, only one crystallization is required, the yield of galantamine can be between 80-90%, and the purity can be between 90-99%. Moreover, the operation is simple, the repeatability is good, the implementation cost is low, the pollution is less, and it is beneficial to industrial scale-up.

Description

A method for separating galantamine

(1) Technical field

The invention relates to a method for separating galantamine, in particular to a method for separating galantamine from many other alkaloids from plant extracts containing amaryllidaceae alkaloids.

(2) Background technology

Galantamine, also known as Galanthamine, is a tetracyclic alkaloid with a tertiary amine, is a reversible cholinesterase inhibitor, and can be widely used in senile dementia (AD), myasthenia gravis, intestinal paralysis, and polio sequelae. Galantamine is often used clinically in the form of hydrobromide, and was launched in 2003. With the increase of the global elderly population and the increasing disease burden caused by Alzheimer's disease, galantamine, as a central cholinesterase inhibitor with mild effect and mild adverse reactions, has received renewed attention.

Galantamine was originally extracted from the dry bulbs of Snow Lotus, and later found in Tianshan Snow Lotus and the same family of Narcissus and Amaryllis. Among the wild resources, Hudixiao (also known as Huanghua Lycoris, Tiesaijian), Huanjinhua and Luscallions have higher galantamine content, among which Hudixiao bulbs have the highest content. But in recent years, due to unplanned excavation, outdated cultivation techniques, and low bulb reproduction numbers, the wild resources of Lycoris have gradually decreased.

At present, there are many ways to obtain galantamine. Lycoris contains about 0.1‰ of galantamine. Our technicians have successfully extracted monomer galantamine from lycoris through a large number of experiments, small tests and pilot tests. Min, then add hydrobromic acid to synthesize galantamine hydrobromide, and finally recrystallize with absolute ethanol to obtain fine-quality galantamine hydrobromide, so the separation of galantamine from plant materials is still a large-scale manufacturing An effective alternative approach, but the traditional separation and purification methods are complex and costly.

Patent 200910027243.3 describes that coarse powder from Lycoris bulbs is added into a _CO2 supercritical extractor, extracted with HCl- _CHCl3 , separated through an alumina chromatographic column, eluted, collected, concentrated, recrystallized, washed, and dried. Patent 200910232806.2 provides an improvement to this method, adjusting the pH to 9-10 with the extract, adding ethyl acetate for extraction, dehydrating with anhydrous sodium sulfate, filtering, and crystallizing instead of column separation. However, supercritical fluid CO ₂ The extraction method only reduces the impurities in the crude extraction, but cannot subdivide each Lycoris alkaloid component. If supercritical separation and purification is used, the process is cumbersome, and the equipment and instruments used make the cost higher.

Patent 03142010.9 describes the separation of Lycoris crude extract by high-speed countercurrent chromatography. Although it can avoid the problems of carrier adsorption, loss and denaturation, it is only suitable for a small amount of separation in the laboratory.

Chemical synthesis method (for example Kametani al., J.Chem.Soc.C, 1971,6,1043-1047; Shimizu al., Heterocycles, 1977,8,277-282; ZL200810020491.0; CN201010129674.3) although can not Rely on plant resources to obtain galantamine, but this method has a long synthetic route, consumes a large amount of organic reagents, and pollutes the environment. What is obtained is only the racemate, and must be split to obtain the left-handed enantiomer. time, cost. Alumina chromatography or silicate chromatography, the procedures are cumbersome, time-consuming, solvent consumption is large, high cost, and the carrier will absorb part of the active ingredients; alkali concentration gradient method, the procedure is cumbersome, time-consuming, solvent consumption is large, and the cost is high ; The liquid-liquid extraction method has high purity, but it takes a long time, consumes a lot of solvent, and the procedure is cumbersome.

The key to restricting the further development and utilization of galantamine is to separate a single active ingredient from the total extract. At present, the reported bulbs contain 0.21% of the total alkaloids, of which lycorine accounts for 0.1%, followed by homolycorine (homolycorine), (polyflora) narcissine (tazettine), and galantamine accounts for 0.035% , lycoramine (lycoramine), lycorine (lycorenine), pseudolycorine (pseudolycorine) and hippeastrine (hippeastrine), the pith of the stem contains galantamine, polyfloral narcisine and trace amounts of lycorine Alliamine. It is difficult to remove impurities similar to alkaloids by using traditional separation technology, and it does not meet the current high-quality requirements of galantamine in various countries in the world. Therefore, the production process of separating and purifying galantamine with high efficiency, high purity and low cost has far-reaching implications. significance.

(3) Contents of the invention

The purpose of the present invention is to provide a method for separating the total alkaloid extract of Amaryllidaceae by using the inclusion method for the deficiencies of the prior art.

The research idea of the present invention is: because galantamine has high steric hindrance (non-coplanar phenyl groups) and easy-to-form hydrogen bond groups (hydroxyl, amino groups), there are many unique molecules that can recognize galantamine. Galantamine is alkaline and can be combined with L-(-)-dibenzoyl tartaric acid to form a salt. The amino group and carboxyl group are docked to form N ⁺ -H---O ^- , O ^- -H---N ⁺ Such a hydrogen bond form. Here the molecular docking of L-(-)-dibenzoyl tartaric acid and galantamine is the key, followed by reordering, forming close packing and crystallizing out of solution. The tartrate is esterified into L-(-)-dibenzoyl tartaric acid to increase its steric hindrance, thereby enhancing the selectivity of the host molecule to the guest molecule.

In order to solve the technical problems of the present invention, the present invention adopts the following technical solutions:

A method for separating galantamine, the method uses lycoris total alkaloid extract containing galantamine as raw material, and the lycoris total alkaloid extract is made from the bulb of lycoris with acid as extractant The extract obtained by extracting by dipping method is as follows: detect the content of galantamine in the total alkaloid extract of Lycoris, mix the total alkaloid extract of Lycoris with L-(-)-benzophenone Mix acyl tartaric acid, use 75-95% ethanol as a solvent, fully react at 70-100°C to obtain a clear solution, then cool to -10-25°C, stand until crystallization occurs, filter to obtain a filter cake and filtrate, filter After the cake is recrystallized with the recrystallization solvent A, the crude crystal obtained is added with an aqueous alkali solution to adjust the pH value to 7-9 for decomposition, then add _CHCl3 for extraction, take the organic layer and evaporate the solvent to obtain the crude galantamine; The crude product of galanthamine is dissolved in acetone, added to HBr aqueous solution, filtered to obtain galantamine hydrobromide, and recrystallized with recrystallization solvent B to obtain pure galantamine; the recrystallization solvent A or B are each independently Aqueous ethanol, methanol, absolute ethanol or acetone;

The molar ratio of galantamine contained in the Lycoris total alkaloid extract to L-(-)-dibenzoyltartaric acid and HBr in HBr aqueous solution is 1:1-4:1-2.

Further, the method preferably includes: detecting the content of galantamine in the total alkaloid extract of Lycoris, mixing the total alkaloid extract of Lycoris with L-(-)-dibenzoyl tartaric acid, and using 75% Using ethanol as a solvent, fully reacted at 80°C to obtain a clear solution, then cooled to room temperature, left to stand until crystals precipitated, filtered to obtain a filter cake and filtrate, and after the filter cake was recrystallized with 85% ethanol, the crude crystal obtained was added to 10% NaOH aqueous solution, adjust the pH value to 8 for decomposition, then add _CHCl3 for extraction, take the organic layer and evaporate the solvent to obtain the crude product of galantamine; dissolve the crude product of galantamine with acetone, add HBr aqueous solution, and filter to obtain Galantamine hydrobromide was recrystallized with 50% ethanol to obtain pure galantamine.

In the method, the mass ratio of galantamine contained in the Lycoris total alkaloid extract to 75-95% ethanol solvent is 1:10-30.

The alkaline aqueous solution is NaOH solution, KOH solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution or potassium bicarbonate solution, preferably 10% NaOH solution.

The recrystallization solvent A is preferably 50-85% ethanol, and the recrystallization solvent B is preferably 35-65% ethanol.

Lycoris total alkaloid extract of the present invention is commercially available or extracted from Lycoris bulbs with acid as extractant through immersion method, usually according to the following method: take Lycoris bulbs, crush them without sieving, put them into Add 2‰ hydrochloric acid to the percolation cylinder to completely immerse the bulbs of Lycoris bulbs. Add hydrochloric acid solution at any time to ensure that the bulbs of Lycoris bulbs are fully soaked. After soaking for 8 to 12 hours, start to collect the percolation liquid, and constantly replenish the hydrochloric acid solution to ensure that the bulbs of Lycoris bulbs are fully soaked. Soak until the seepage turns from yellowish brown to dark green, and stop seepage. Combine all the percolates, adjust the pH to 6-7, filter to obtain the precipitate, and obtain the Lycoris total alkaloid extract.

The present invention fully reacts under the condition of 70-100°C temperature, and the reaction time is generally 30 minutes to 1 hour to obtain a clear solution; then cool to -10-25°C, and stand until crystallization occurs, and the crystallization time is generally between 6-8 hours.

Compared with the prior art, this method is based on the basic principle of supramolecular assembly, and utilizes the topological matching between the host molecule and the guest molecule, so that the alkaline galantamine can be selectively absorbed in the total alkaloid Form stable molecular crystals with L-(-)-dibenzoyl tartaric acid to achieve efficient and rapid separation. The main advantages are:

a) The efficiency of splitting is relatively high. Due to the high selectivity of molecular recognition, only one crystallization is required, the yield of galantamine can be between 80% and 90%, and the purity can be between 90% and 99%.

b) The operation is simple, the repeatability is good, the implementation cost is low, the pollution is less, and it is beneficial to industrial scale-up.

(4) Specific implementation methods

The technical solutions of the present invention will be further described below with specific examples, but the protection scope of the present invention is not limited thereto.

Preparation of Lycoris total alkaloids extract: take 8kg of Lycoris bulbs, crush them without sieve, moisten them with 2‰ HCl, put them into a percolating cylinder with absorbent cotton in advance, pour hydrochloric acid while loading, and wait until the Lycoris bulbs are packed into When the percolation cylinder is halfway through, stop loading the cylinder. Continue to add 2‰ HCl until the amaryllis bulbs are completely submerged, shake repeatedly, and add hydrochloric acid solution at any time to ensure that the amaryllis bulbs are fully soaked, and soak overnight. On the second day, the percolation liquid was collected, and the hydrochloric acid solution was continuously added until the percolation liquid turned from yellowish brown to dark green, and the percolation was stopped. Combine all the percolates, adjust the pH to 7, filter to obtain the precipitate, and obtain 1.2 kg of Lycoris total alkaloid extract.

Example 1

Lycoris total alkaloid extract (containing 10% of galantamine, 20% of other alkaloids, determined by HPLC) 5.0g and 0.6g of L-(-)-dibenzoyl tartaric acid (purchased from Jinan Biyoute Chemical Co., Ltd. Co., Ltd.), mixed with 15.0ml of 75% ethanol as solvent, heated to 80°C, and heated for 30min to obtain a clear solution. Then it was cooled to 25°C and crystals were precipitated [Crystal I: IR (KBr, cm ^-1 ) 3418, 3068, 3056, 2960, 1731, 1635, 1602, 1586, 1335, 1318, 1266, 1179, 1026, 1003, 937, 890, 710, 684, 650, 617. ¹ H NMR (DMSO-d ₆ ) δ8.046(d, 1H), 7.742(d, 1H), 7.619(d, 1H), 6.85(AB, 2H, J=9.6Hz), 6.15(d, 1H, J=7.9Hz), 5.95(dd, 1H, J=7.9Hz, J=3.2Hz), 5.922(d, 1H), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47 (bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90(s+m, 4H), 3.50(d, 1H, J=12.8Hz), 2.85( bs, 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J = 16.0 Hz)]. Filtration, while recovery of solvents and identification reagents, by-product mixed alkaloid filtrate. 0.46g of crystal I was recrystallized by adding 15.0ml of 85% ethanol, then filtered, and the ethanol solvent was recovered at the same time, then 10% NaOH was added dropwise to adjust the pH to 8 for decomposition, and 100mL _CHCl3 was added for extraction, and the organic layer was evaporated to remove the solvent, and finally obtained Galantamine crude product 0.44g. The crude product is dissolved in 15.0ml of acetone, and 0.7ml of 40% HBr solution is added, the obtained galantamine hydrobromide is filtered, recrystallized with 10.0ml of 50% ethanol, and finally dried to obtain 0.43g of its finished product: IR(KBr , cm ^-1 ) 3520, 2582, 2522, 1618, 1510, 1418, 1286, 1048, 1020, 810, 719, 613, 428. ¹ H NMR (DMSO-d ₆ ) δ6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J=7.9Hz), 5.95 (dd, 1H, J=7.9Hz, J=3.2Hz) , 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47(bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90( s+m, 4H), 3.50 (d, 1H, J = 12.8 Hz), 2.85 (bs, 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J = 16.0 Hz). The content of galantamine was determined by HPLC. Chromatographic conditions: chromatographic column ZorbaxC ₁₈ (250mm×0.46mm, 0.5μm); mobile phase V (water): V (methanol): V (glacial acetic acid) = 91:8:1; flow rate 1mL·min ^-1 ; column temperature 30°C; pressure 126bar; injection volume 1μL; detection wavelength 280nm. The purity is 98.3%, and the yield is 86.0%.

Example 2

Mix 6.4g of total alkaloids (containing 13% of galantamine and 18% of other alkaloids) with 3.0g of L-(-)-dibenzoyl tartaric acid, use 19.2ml of 85% ethanol as solvent, and heat to 100°C , Heated for 1h to obtain a clear solution. Then it was cooled to 10°C and crystals were precipitated [Crystal I: IR (KBr, cm ^-1 ) 3418, 3068, 3056, 2960, 1731, 1635, 1602, 1586, 1335, 1318, 1266, 1179, 1026, 1003, 937, 890, 710, 684, 650, 617. ¹ H NMR (DMSO-d ₆ ) δ8.046 (d, 1H), 7.742 (d, 1H), 7.619 (d, 1H), 6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J =7.9Hz), 5.95(dd, 1H, J=7.9Hz, J=3.2Hz), 5.922(d, 1H), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47( bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90(s+m, 4H), 3.50(d, 1H, J=12.8Hz), 2.85(bs , 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J=16.0Hz)]. Filtration, while recovery of solvents and identification reagents, by-product mixed alkaloid filtrate. 0.78g of crystal I was recrystallized by adding 19.2ml of 75% ethanol, and then filtered, while recovering the ethanol solvent, then adding 10% NaOH dropwise to adjust the pH to 7.5 for decomposition, adding 100mL _CHCl3 for extraction, taking the organic layer to evaporate the solvent, and finally Obtain 0.73g of crude galantamine. The crude product was dissolved in 19.2ml of acetone, and 0.6ml of 40% HBr solution was added, the obtained galantamine hydrobromide was filtered, recrystallized with 12.8ml of 65% ethanol, and finally dried to obtain its finished product 0.69g: IR ( KBr, cm ^-1 ) 3520, 2582, 2522, 1618, 1510, 1418, 1286, 1048, 1020, 810, 719, 613, 428. ¹ H NMR (DMSO-d ₆ ) δ6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J=7.9Hz), 5.95 (dd, 1H, J=7.9Hz, J=3.2Hz ), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47(bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90 (s+m, 4H), 3.50 (d, 1H, J = 12.8Hz), 2.85 (bs, 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J = 16.0Hz). The content of galantamine was determined by HPLC. Chromatographic conditions: chromatographic column ZorbaxC ₁₈ (250mm×0.46mm, 0.5μm); mobile phase V (water): V (methanol): V (glacial acetic acid) = 91:8:1; flow rate 1mL·min ^-1 ; column temperature 30°C; pressure 126bar; injection volume 1μL; detection wavelength 280nm. The purity is 98.8%, and the yield is 82.9%.

Example 3

Mix 7.3g of total alkaloids (containing 8% of galantamine and 19% of other alkaloids) with 0.8g of L-(-)-dibenzoyl tartaric acid, use 17ml of 95% ethanol as solvent, and heat to 70°C , Heated for 50 min to obtain a clear solution. Then it was cooled to -10°C and crystals were precipitated [Crystal I: IR (KBr, cm ^-1 ) 3418, 3068, 3056, 2960, 1731, 1635, 1602, 1586, 1335, 1318, 1266, 1179, 1026, 1003 , 937, 890, 710, 684, 650, 617. ¹ H NMR (DMSO-d ₆ ) δ8.046 (d, 1H), 7.742 (d, 1H), 7.619 (d, 1H), 6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J =7.9Hz), 5.95(dd, 1H, J=7.9Hz, J=3.2Hz), 5.922(d, 1H), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47( bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90(s+m, 4H), 3.50(d, 1H, J=12.8Hz), 2.85(bs , 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J=16.0Hz)]. Filtration, while recovery of solvents and identification reagents, by-product mixed alkaloid filtrate. Add 0.48g of crystal I to 21.9ml of 55% ethanol for recrystallization, then filter, recover the ethanol solvent at the same time, then add 10% NaOH dropwise to adjust the pH to 7 for decomposition, add 100mL _CHCl3 for extraction, take the organic layer to evaporate the solvent, and finally Obtain 0.45 g of crude galantamine. The crude product is dissolved in 21.9ml of acetone, and 0.6ml of 40% HBr solution is added, the galantamine hydrobromide obtained by filtration is recrystallized with 14.6ml of 35% ethanol, and finally dried to obtain 0.44g of its finished product: IR (KBr , cm ^-1 ) 3520, 2582, 2522, 1618, 1510, 1418, 1286, 1048, 1020, 810, 719, 613, 428. ¹ H NMR (DMSO-d ₆ ) δ6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J=7.9Hz), 5.95 (dd, 1H, J=7.9Hz, J=3.2Hz ), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47(bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90 (s+m, 4H), 3.50 (d, 1H, J = 12.8Hz), 2.85 (bs, 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J = 16.0Hz). The content of galantamine was determined by HPLC. Chromatographic conditions: chromatographic column ZorbaxC ₁₈ (250mm×0.46mm, 0.5μm); mobile phase V (water): V (methanol): V (glacial acetic acid) = 91:8:1; flow rate 1mL·min ^-1 ; column temperature 30°C; pressure 126bar; injection volume 1μL; detection wavelength 280nm. The purity is 99.3%, and the yield is 75.3%.

Example 4

Mix 8.2g of total alkaloids (containing 15% of galantamine and 22% of other alkaloids) with 4.9g of L-(-)-dibenzoyl tartaric acid, use 24.6ml of 90% ethanol as solvent, and heat to 80°C , heated for 45min to obtain a clear solution. Then it was cooled to 0°C and crystals were precipitated [Crystal I: IR (KBr, cm ^-1 ) 3418, 3068, 3056, 2960, 1731, 1635, 1602, 1586, 1335, 1318, 1266, 1179, 1026, 1003, 937, 890, 710, 684, 650, 617. ¹ H NMR (DMSO-d ₆ ) δ8.046 (d, 1H), 7.742 (d, 1H), 7.619 (d, 1H), 6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J =7.9Hz), 5.95(dd, 1H, J=7.9Hz, J=3.2Hz), 5.922(d, 1H), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47( bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90(s+m, 4H), 3.50(d, 1H, J=12.8Hz), 2.85(bs , 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J=16.0Hz)]. Filtration, while recovery of solvents and identification reagents, by-product mixed alkaloid filtrate. Add 1.12g of crystal I to 24.6ml of 85% ethanol for recrystallization, then filter, and recover the ethanol solvent at the same time, then add 10% NaOH dropwise to adjust the pH to 9 for decomposition, add 100mL _CHCl3 for extraction, take the organic layer to evaporate the solvent, and finally 1.05 g of crude galantamine was obtained. The crude product was dissolved in 24.6ml of acetone, and 1.5ml of 40% HBr solution was added, the obtained galantamine hydrobromide was filtered, recrystallized with 16.4ml of 50% ethanol, and finally dried to obtain its finished product 0.97g: IR ( KBr, cm ^-1 ) 3520, 2582, 2522, 1618, 1510, 1418, 1286, 1048, 1020, 810, 719, 613, 428. ¹ H NMR (DMSO-d ₆ ) δ6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J=7.9Hz), 5.95 (dd, 1H, J=7.9Hz, J=3.2Hz ), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47(bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90 (s+m, 4H), 3.50 (d, 1H, J = 12.8Hz), 2.85 (bs, 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J = 16.0Hz). The content of galantamine was determined by HPLC. Chromatographic conditions: chromatographic column ZorbaxC ₁₈ (250mm×0.46mm, 0.5μm); mobile phase V (water): V (methanol): V (glacial acetic acid) = 91:8:1; flow rate 1mL·min ^-1 ; column temperature 30°C; pressure 126bar; injection volume 1μL; detection wavelength 280nm. The purity is 99.1%, and the yield is 78.9%.

Example 5

Total alkaloids (containing galantamine 12%, other alkaloids 20%) 9.1g and 3.0g L-(-)-dibenzoyl tartaric acid are mixed, with 27.3ml 75% ethanol as solvent, heated to 90 °C, heated for 70 min to obtain a clear solution. Then it was cooled to 15°C and crystals were precipitated [Crystal I: IR (KBr, cm ^-1 ) 3418, 3068, 3056, 2960, 1731, 1635, 1602, 1586, 1335, 1318, 1266, 1179, 1026, 1003, 937, 890, 710, 684, 650, 617. ¹ H NMR (DMSO-d ₆ ) δ8.046 (d, 1H), 7.742 (d, 1H), 7.619 (d, 1H), 6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J =7.9Hz), 5.95(dd, 1H, J=7.9Hz, J=3.2Hz), 5.922(d, 1H), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47( bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90(s+m, 4H), 3.50(d, 1H, J=12.8Hz), 2.85(bs , 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J=16.0Hz)]. Filtration, while recovery of solvents and identification reagents, by-product mixed alkaloid filtrate. Crystal I 1.04 was recrystallized by adding 27.3ml of 50% ethanol, then filtered, and the ethanol solvent was recovered at the same time, then 10% NaOH was added dropwise to adjust the pH to 8.5 for decomposition, and 100mL _CHCl3 was added for extraction, and the organic layer was evaporated to remove the solvent, and finally obtained Galantamine crude product 0.98g. The crude product was dissolved in 27.3ml of acetone, and 1.5ml of 40% HBr solution was added, the obtained galantamine hydrobromide was filtered, recrystallized with 18.2ml of 45% ethanol, and finally dried to obtain 0.91g of its finished product: IR(KBr , cm ^-1 ) 3520, 2582, 2522, 1618, 1510, 1418, 1286, 1048, 1020, 810, 719, 613, 428. ¹ H NMR (DMSO-d ₆ ) δ6.85 (AB, 2H, J=9.6Hz), 6.15 (d, 1H, J=7.9Hz), 5.95 (dd, 1H, J=7.9Hz, J=3.2Hz ), 4.85(d, 1H, J=16.0Hz), 4.60(s, 1H), 4.47(bs, 1H), 4.35(d, 1H, J=16.0Hz), 4.10(bs, 1H), 3.70-3.90 (s+m, 4H), 3.50 (d, 1H, J = 12.8Hz), 2.85 (bs, 3H), 2.40-2.00 (m, 3H), 1.90 (d, 1H, J = 16.0Hz). The content of galantamine was determined by HPLC. Chromatographic conditions: chromatographic column ZorbaxC ₁₈ (250mm×0.46mm, 0.5μm); mobile phase V (water): V (methanol): V (glacial acetic acid) = 91:8:1; flow rate 1mL·min ^-1 ; column temperature 30°C; pressure 126bar; injection volume 1μL; detection wavelength 280nm. The purity is 98.9%, and the yield is 83.3%.

Claims (4)

1. method with form isolating galanthamine from short-tube lycoris total alkaloids medicinal extract of galanthamine hydrobromide, said method is a raw material with the short-tube lycoris total alkaloids medicinal extract that contains lycoremine, described short-tube lycoris total alkaloids medicinal extract is to be that extraction agent extracts the medicinal extract that obtains through soaking the method for filtering with acid by the short-tube lycoris bulb; It is characterized in that described method is: detect the content of lycoremine in the short-tube lycoris total alkaloids medicinal extract, short-tube lycoris total alkaloids medicinal extract is mixed with L-(-)-dibenzoyl tartaric acid, make solvent with 75～95% ethanol; 70～100 ℃ of fully reactions down, get settled solution, be cooled to-10～25 ℃ then; Leave standstill to separating out crystallization; Filtration obtains filter cake and filtrating, filter cake with recrystallization solvent A recrystallization after, the crystal bullion that obtains adds alkali aqueous solution; Adjust pH is 7～9 to decompose, and adds CHCl again ₃Extraction is got organic layer and is steamed to desolventize and obtain the lycoremine bullion; The lycoremine bullion is used acetone solution, and add the HBr aqueous solution, filter and obtain galanthamine hydrobromide,, obtain the pure article of galanthamine hydrobromide with recrystallization solvent B recrystallization; Said recrystallization solvent A or B independently are aqueous ethanolic solution, methyl alcohol, absolute ethyl alcohol or acetone separately;

The amount of substance of HBr is than being 1:1～4:1～2 in the lycoremine that contains in the said short-tube lycoris total alkaloids medicinal extract and L-(-)-dibenzoyl tartaric acid, the HBr aqueous solution.

2. the method for claim 1 is characterized in that described method is: detect the content of lycoremine in the short-tube lycoris total alkaloids medicinal extract, short-tube lycoris total alkaloids medicinal extract is mixed with L-(-)-dibenzoyl tartaric acid; Ethanol with 75% is made solvent, 80 ℃ of fully reactions down, gets settled solution; Be cooled to room temperature then, leave standstill, filter and obtain filter cake and filtrating to separating out crystallization; Filter cake with 85% ethyl alcohol recrystallization after; The crystal bullion that obtains adds the 10%NaOH aqueous solution, and adjust pH is 8 to decompose, and adds CHCl again ₃Extraction is got organic layer and is steamed to desolventize and obtain the lycoremine bullion; The lycoremine bullion is used acetone solution, and add the HBr aqueous solution, filter the galanthamine hydrobromide that obtains and use 50% ethyl alcohol recrystallization, obtain the pure article of galanthamine hydrobromide.

3. the method for claim 1, the lycoremine that it is characterized in that containing in the said short-tube lycoris total alkaloids medicinal extract is 1:10～30 with the ratio of the quality of 75～95% alcohol solvent.

4. the method for claim 1 is characterized in that said alkali aqueous solution is NaOH solution, KOH solution, sodium carbonate solution, solution of potassium carbonate, sodium hydrogen carbonate solution or potassium bicarbonate solution.