CN1035503A

CN1035503A - Productive technology for real cholinesterase inhibitor-fuding alkali

Info

Publication number: CN1035503A
Application number: CN 89101076
Authority: CN
Inventors: 徐择邻; 杨振生; 袁珊琴
Original assignee: TOXICANTS INST ACADEMY OF MILITARY MEDICAL SCIENCES
Current assignee: TOXICANTS INST ACADEMY OF MILITARY MEDICAL SCIENCES
Priority date: 1989-03-11
Filing date: 1989-03-11
Publication date: 1989-09-13

Abstract

The invention belongs to a kind of production technique of real cholinesterase inhibitor-Fuding alkali.It is characterized in that with the Phlegmariurus fordii (Bak) Ching-Bak being raw material, filter through aqueous hydrochloric acid earlier.After H ⁺Zeo-karb gets total alkaloids, directly adopts silicagel column low pressure wet method dress post, after chromatographic separation and refinement treatment, get final product highly purified Fuding alkali.

Description

Process for producing real cholinesterase inhibitor fuding alkali

The present invention relates to a production process of a new medicine of fuding alkali, a real cholinesterase inhibitor, which is prepared by separating and purifying chemical components of natural medicines.

The fuding alkali is also called huperzine A, and has the chemical name of (5R, 9R, 11E) -5-amino-11-ethylidene-5.6, 9.10-tetrahydro-7-methyl-5.9-methylene cycloocta (b) pyridine-ethyl (1H) ketone. The structural formula is as follows:

the product is a new compound separated from the whole herb of the taxus chinensis of huperziaceae in more than three thousand Chinese herbal medicines, has selective inhibition effect on true cholinesterase, is a novel medicine with high efficiency and low side effect for treating severe myasthenia, has better effect than the prior physostigmine and neostigmine which are commonly used clinically, and has the advantages of long effective time, good gastrointestinal absorption, good stability, easy entry into the center through blood brain barrier and the like. Meanwhile, the product also has the function of enhancing memory, and can be effectively used for treating senile dementia. In view of the new structure, wide application and rich medicine source of the product, the invention aims to develop a set of advanced separation method, is simple, convenient and feasible, has no environmental pollution, has purity meeting the specification requirement of Chinese pharmacopoeia and is suitable for mass production in factories.

The inventor analyzes and recognizes the theoretical knowledge of modern equipment and instruments and phytochemistry on the basis of the theoretical knowledge and practical experience of traditional Chinese medicine, and selects a simple and feasible production process which is suitable for mass production and is researched by the invention through years of experimental research and clinical verification.

The prior common separation technologies of natural medicinal chemical alkaloids are mostly solvent extraction, dry-wet column chromatography, gradient chromatography and the like. Experiments prove that the method can not successfully separate the alkaloid effective components with low content from the taxus chinensis.

The invention takes the south China masson pine as the raw material, firstly, the south China masson pine is filtered by hydrochloric acid water solution, and the acid water solution is filtered by H⁺Cation exchange resin to obtain total alkaloid, loading the total alkaloid onto silica gel column by low pressure wet method, separating to obtain primary pure fuding alkali by twice chromatography, and refining to obtain pure fuding alkali. The production process flow is as follows:

in the production process provided by the invention. Percolating crude drug powder with 1.5-2% hydrochloric acid solution, and passing percolate through H⁺Exchanging the type cation exchange resin into cation medicine resin. Washing with water, drying, wetting with 5-10% ammonia water for 24 hr, loading into continuous elution column, eluting with 95% ethanol, recovering ethanol to obtain total alkaloids, and loading into silica gel column by wet method under low pressureAnd (3) carrying out low-pressure elution (the pressure is 0.5-0.8 kg/square centimeter) on the column by using a mixed solution (100: 7 v/v) of absolute ethyl alcohol and acetic acid. Collecting by parts, collecting crude fuding alkali by a plate layer qualitative method, performing secondary low-pressure wet column packing, eluting with isopropanol-water (8: 2 v/v) solution at low pressure, and separating primary fuding alkali by a plate layer qualitative method. Will be as followsDissolving the fosdine in 2% hydrochloric acid aqueous solution, decoloring with 3-5% activated carbon, filtering to collect clear liquid, extracting with ethyl acetate twice to separate out acid water, adjusting the pH value (pH 7-8) with ammonia water, extracting with chloroform, adding neutral alumina into chloroform liquid, filtering, washing with water to separate out a chloroform layer, dehydrating with anhydrous sodium sulfate, recovering chloroform to obtain a white solid, and finally recrystallizing with isopropanol, aqueous solution and acetone respectively to obtain pure fosdine, wherein the yield is 0.06% and the purity is 96%.

Compared with the common alkaloid extraction process, the method has the following advantages:

1. simple operation and good separation effect.

2. The production conditions are safe and reliable, and explosive and flammable solvents are not used in the whole extraction process.

3. The required production process conditions are simple and economical. The used reagent is cheap and easy to obtain and can be repeatedly used.

4. No environmental pollution and suitability for batch production.

Example (b):

1. 100 kg of raw medicinal powder of the south China maitake fir. Percolating with 1.5-2% aqueous hydrochloric acid solution, and passing through H⁺Forming cation exchange resin into cation medicine resin, washing with water, drying, wetting with 5-10% ammonia water overnight, loading into continuous elution column, washing with 95% ethanol, and recovering ethanol to obtain 180 g total alkaloids.

2. 50G of the total alkaloids are taken, are filled into a column (0.5-0.8 kg/square centimeter) by a low-pressure wet method with 1000G of silica gel (G10-40 mu), and are eluted by absolute ethyl alcohol and glacial acetic acid (100: 7 v/v) at low pressure. The crude fudine alkali 8.5 g is obtained after fractional collection, plate layer characterization and ethanol recovery.

3. 8.5 g of crude fuding alkali is taken, and the crude fuding alkali is filled into a column by a low-pressure wet method by the same method, and is eluted by isopropanol and water (8: 2 v/v) at low pressure. 6.6 g of the primary pure fuding alkali is obtained after the plate layer is used for qualitative determination.

4. 6.6 g of the primary pure fogdrine is dissolved in 30 ml of 2%hydrochloric acid water solution, and 3-5% of activated carbon is added for decoloring. Extracting the filtrate twice with ethyl acetate, adjusting the pH value of the separated liquid medicine with ammonia water (pH 7-8), and extracting with chloroform for 3 times. And adding 10-15% neutral alumina into the combined chloroform solution, shaking, filtering, washing the chloroform solution with water to separate chloroform, and dehydrating with anhydrous sodium sulfate. After the chloroform is recovered, white solid is obtained, after recrystallization twice by using isopropanol and water (7: 2 v/v) solution, and then recrystallization is carried out by using acetone, 4.6 g of pure fuding alkali can be obtained, and the content is 96%.

Claims

1. A process for preparing the real cholinesterase inhibitor fogdridine features that the maitake fir is percolated by aqueous solution of hydrochloric acid and H⁺Separating out total alkaloids by cation resin exchange, directly loading into silica gel column with low pressure wet method, separating out primary fuding alkali by chromatography, and refining to obtain pure fuding alkali.

2. The process for producing fuding alkali according to claim 1, wherein the pressure required for packing silica gel into the column by the low pressure wet method is 0.5-0.8 kg/cm, and the specification of the silica gel is G10-40 μ.

3. The process for producing fuding base according to claim 1, wherein the refining (recrystallization) is carried out using isopropanol, water (7: 2 v/v) and acetone as the reagents.

4. Process for the production of fuding base according to claims 1, 2 and 3, characterisedin that the bulk of the organic solvent used is non-toxic ethanol and isopropanol.