CN1172933C - Prepn of matrine, oxymatrine and sophoxidine from flavescent sophora root - Google Patents

Abstract

The present invention relates to a technology for producing matrine, oxymatrine and sophoxidine from kuh-seng, which is characterized in that matrine crude products and sophoridine crude products are respectively formed by that kuh-seng is carried out on extraction, concentration, alkalization, recovery, solvent extraction, acid back extraction, deposition and separation after dried and crushed, and the matrine crude products and sophoridine crude products are recrystalled and dried to obtain matrine products and sophoridine products. Oxymatrine products can be obtained by that the matrine is carried out on oxidization, hydration, pressure reducing, distillation, crystallization, filtering, recrystallization and drying. The three types of products are medical manufacturing raw materials which can be used for preparing medicine for treating the disease, such as hepatitis b, hepatitis c, white cell deterioration, heart rate aberration, cancer, etc. The present invention has the advantages of simple productive process, low cost and high purity degree, and is suitable for large scale commercial production.

Description

A kind of production technique that from kuh-seng, prepares matrine, Oxymatyine and sophorine

Technical field

The present invention relates to a kind of from kuh-seng preparation can be used for matrine, the Oxymatyine of medical material, the production technique of sophorine.

Background technology

Kuh-seng is a kind of herbal medicine commonly used, in the successive dynasties book on Chinese herbal medicine works record is arranged more, is the dry root of cassia leguminous plant kuh-seng (Sophora flavscens Alt.), has effects such as heat-clearing, dehumidifying, desinsection, diuresis; China extensively distributes, aboundresources, contained alkaloid composition is considered to main biological activity wherein in the kuh-seng, at present from kuh-seng isolation identification 17 kinds of alkaloid compositions, be mainly: sophocarpine (Sophocarpine), matrine (matrine), sophorine (sophoridine), Oxymatyine (oxymatrine), Sophocarpidin (oxysophcarpine), this in five alkaloid account for more than 90% of total alkaloids, pharmacological evaluation and clinical application prove, kuh-seng and preparation thereof can be treated acute bacillary dysentery, trichomoniasis, bronchial asthma and asthmatic bronchitis, oedema and ascites, the treatment tetter, heart disorder and viral myocarditis, hypnosis and treatment mania, particularly Oxymatyine can be treated tumor radiotherapy, the white corpuscle that chemotherapy causes lowly reaches the leukopenia that other reason causes, the chronic viral hepatitis B and third liver are being applied to require Oxymatyine bulk drug purity more than 98% when clinical; Sophorine has antitumour activity to multiple animal-transplanted tumor, clinical suede cancer malignant mole, lung cancer, digestive tract cancer antitumous effect obviously stablized, and be a kind of of great value PTS.

From Herba Sophorae alopecuroidis, extract matrine at present mostly, Oxymatyine or sophorine, from kuh-seng, extract matrine, the bibliographical information of Oxymatyine or sophorine is few, and all be from kuh-seng, once can only extract a kind of alkaloid, CN1073681A for example, open day is on June 30th, 1993, reported the method for from kuh-seng, extracting matrine with the freezing vacuum method, from kuh-seng, once extract matrine, the bibliographical information of Oxymatyine and sophorine is not found so far, and traditional preparation technology, the program complexity, the cost height, be difficult to form commercial scale production, can not reach the purity more than 98%, hinder matrine greatly, Oxymatyine, sophorine is in pharmacy and application clinically.

Summary of the invention

The purpose of this invention is to provide a kind of novel process that from kuh-seng, prepares matrine, Oxymatyine, sophorine simultaneously, and technology is simple, cost is low, purification degree is high.

The present invention is achieved by the following scheme:

Extract total alkaloids is according to very easily water-soluble principle behind contained alkaloid in the plant and the sour salify from kuh-seng, the kuh-seng of pulverizing is wetting with dilute sulphuric acid, make alkaloid salify wherein, extract with the alkaloid of enough water after again salify, water is evaporated, make total alkaloids become paste; Under unbound state, be soluble in organic solvent according to total alkaloids again, be insoluble in the principle of water, total alkaloids is alkalized with sodium hydroxide, make alkaloid become unbound state, wherein Oxymatyine and Sophocarpidin are reduced into matrine and sophocarpine, pass through organic solvent extraction, make alkaloid transfer to organic phase, strip with acid then, make alkaloid change aqueous phase over to, and exist with the form of salt from organic phase; When dissociating alkaloid with alkali, matrine at first crystallizes out; Mother liquor also can obtain matrine, sophorine through separating; Through recrystallization, get matrine and sophorine product; Matrine can generate Oxymatyine after peroxidation.Therefore excessive matrine and hydrogen peroxide carries out oxidizing reaction, can obtain Oxymatyine, and make hydrogen peroxide all change into water, do not bring other impurity in the material into; Concentrating under reduced pressure is removed most of water again, and crystallization, recrystallization obtain the Oxymatyine product.

The concrete production method of the present invention is as follows:

1. with the kuh-seng drying and crushing, granularity is the 10-60 order, uses 0.5%H ₂SO ₄Wetting, place more than 2 hours.With the wetting raw material stainless steel multi-function extractor of packing into, below 80 ℃, with water extraction 3 times, 3 water consumptions amount to 10 times of kuh-seng raw material, united extraction liquid, and the material slag discards;

2. extracting solution is condensed into the medicinal extract shape with double-effect evaporator, proportion 〉=1.2;

3. medicinal extract alkalizes to PH 〉=9 with alkali lye, adds reductive agent again, check that with thin-layer chromatography wherein the spot of Oxymatyine and Sophocarpidin disappears till;

4. be taken to till lifeless matter alkali detects in the medicinal extract with organic solvent extracting through above-mentioned 3 medicinal extract of handling, water layer discarded, organic solvent extraction liquid is stripped with acid solution, till organic layer lifeless matter alkali reaction, make alkaloid all change water layer over to, isolate water layer, organic solvent can be used repeatedly;

5. contain alkaloidal water layer and alkalize to PH=10-11 with alkali lye, the solution layering, lower layer of water discards, and upper strata total alkaloids cream is placed, and crystallization goes out matrine, filters, and gets the matrine crude product;

6. mother liquor also can get matrine crude product and sophorine crude product through anti-distributions chromatographic separation more than 7 grades, merges 5,6 gained matrine crude products, and recrystallization gets the matrine product repeatedly, and the sophorine crude product gets the sophorine product through recrystallization;

7. above-mentioned 6 gained matrine products and hydrogen peroxide are added reactor, dissolve under 50 ℃, 60 ℃ are reacted complete to hydrogen peroxide consumption, concentration of reaction solution below 80 ℃ is to there being crystalline particle to occur, add the acetone crystallization, use acetone recrystallization again, get the Oxymatyine product.

Wherein reductive agent is a Sodium Pyrosulfite; Alkali lye is sodium hydroxide, potassium hydroxide, ammonium hydroxide, yellow soda ash; Organic solvent is a kind of in trichloromethane, methylene dichloride, the benzene,toluene,xylene; The used acid of acid solution reextraction is sulfuric acid or hydrochloric acid.

The concrete grammar that thin-layer chromatography of the present invention is measured is:

Get thin-layer chromatography silica gel special G, be modulated into the emulsifiable paste shape with 2%NaOH solution, make thin layer plate,, the sample and the reference substance thereof of sophorine, Oxymatyine and matrine are put in the thin layer plate bottom 100 ℃ of activation 1 hour, with chloroform: acetone: methyl alcohol=3: 2: 1 is developping agent, carry out thin-layer chromatography, with the Dragendorff's reagent colour developing of improvement, the Rf value is respectively sophorine 0.67 again, Oxymatyine 0.29, matrine 0.79.

Be not difficult to find out that from above content advantage of the present invention is:

1 once feeds intake can get three kinds of products simultaneously, greatly reduces cost

2 technologies are simple, are fit to suitability for industrialized production

3 quality are good, inclusion-free, purity height, and three kinds of products all reach more than 98%

For advantage of the present invention is described better, be illustrated by following experiment:

Experiment one

Get 0.5 kilogram of gained Oxymatyine of the present invention, test for No. 001 by (1998) traditional Chinese medicines marking-up, the gained result is as follows;

Interventions Requested standard code assay

[proterties] becomes white or off-white color crystalline powder white crystalline powder

[discriminating] (1) should be the positive reaction positive reaction

(2) should be the positive reaction positive reaction

[inspection]

Moisture must not cross 8.5% 7.5%

It is 0.4% up to specification that residue on ignition must not be crossed

It is 10/10000ths up to specification that heavy metal must not be crossed

Related substance % should be up to specification

[assay] must not be less than 98.0% 99.5% conclusions by dry product: this product is checked above-mentioned project No. 001 by (1998) traditional Chinese medicines marking-up, and the result is up to specification.

Experiment two

Get 0.8 kilogram of gained matrine of the present invention, test by national drug standards WS-10001-(HD-0047) 2002, the gained result is as follows:

Interventions Requested standard code assay

[proterties] this product is white, needle-shaped crystals or white, needle-shaped crystals powder

Crystalline powder, odorless, bitter odorless, bitter

Specific optical rotation (25 ℃+) 31.0-36.0 34.3

[discriminating] (1), (2) are positive reaction (1), (2) positive reaction

[inspection]

Basicity (PH) 9.5-10.5 10.4

The clarity of solution and color are up to specification

Oxide compound %≤0.01 is up to specification

Weight loss on drying %≤1.0 are up to specification

Residue on ignition %≤0.1 is up to specification

Heavy metal≤20ppm is up to specification

Related substance %≤2.0 0.6

[assay] is by dry product 98.0%-101.0% 99.5% conclusion: this product is tested by national drug standards WS-10001-(HD-0047) 2002, and is up to specification.

Experiment three

Get 0.3 kilogram of method with reference to matrine of gained sophorine of the present invention (still can't calibrate standard at present) and test, the result is as follows;

The Interventions Requested assay

[proterties] white, needle-shaped crystals

[discriminating] (1), (2) positive reaction

[inspection]

Weight loss on drying % 0.8

Residue on ignition % 0.01

Heavy metal 10ppm

Related substance % 0.5

[assay] pressed dry product and calculated 98.8%

Conclusion: up to specification.

Description of drawings

Fig. 1 is the process flow sheet of preparation matrine, sophorine

Fig. 2 is the process flow sheet of preparation Oxymatyine

Embodiment:

Select the northwest to produce the high-quality kuh-seng, drying is pulverized 40 orders, gets 200 kilograms in kuh-seng powder, uses 0.5%H ₂SO ₄Solution 100L is wetting, places more than 2 hours, in the 2000L stainless steel multi-function extractor of packing into, adds 800L water for the first time, heats 75 ± 5 ℃, keeps this temperature, forces water cycle 2 hours, leaches solution; In multi-function extractor, add 600L water for the second time, heat 75 ± 5 ℃, keep this temperature, force water cycle 2 hours, leach solution; In multi-function extractor, add 500L water for the third time again, heat 75 ± 5 ℃, keep this temperature, force water cycle 2 hours, leach solution; Merge No. three times extracting solution, the leaching clear liquid uses double-effect evaporator at 80 ℃, and the following vacuum condition of-0.08MPa concentrates down, and evaporation removes and anhydrates, and makes it into the medicinal extract shape, and proportion 〉=1.2 get 95 kilograms of medicinal extract, and yield is 47.5%; Medicinal extract adds flaky sodium hydrate and transfers to PH 〉=9, adds the reductive agent Sodium Pyrosulfite again thin-layer chromatography is checked in the medicinal extract till the non-oxidation matrine and Sophocarpidin spot; Medicinal extract is with dichloromethane extraction 6 times, and each 150L is till the lifeless matter alkali reaction; Dichloromethane extraction liquid is stripped till the lifeless matter alkali reaction with 8% hydrochloric acid soln; Make alkaloid all change water layer over to, isolate water layer, organic solvent can be used repeatedly; Contain alkaloidal water layer and alkalize to PH=10-11 with sodium hydroxide, the solution layering, lower layer of water discards, and the upper strata is a total alkaloids cream; Total alkaloids cream is placed and to be spent the night, i.e. crystallization goes out matrine, filter the matrine crude product; Mother liquor also can obtain matrine crude product and sophorine crude product through anti-distributions chromatographic separation more than 7 grades, merges gained matrine crude product twice, through recrystallization repeatedly, 1.42 kilograms of pure product of matrine, content 98.3% (by dry product), water content 19.7%.

The sophorine crude product gets 0.2 kilogram of sophorine product, content 98.5% (by dry product), water content 1.2% through recrystallization.

With 1.4 kilograms of the pure product of above-mentioned gained matrine, add hydrogen peroxide 600ml, after 50 ℃ of heating for dissolving of water-bath, 60 ℃ of reacting by heating of water-bath stir simultaneously, per 2 hours inspection content of hydrogen peroxide, reaction terminating when no hydrogen peroxide detects in solution; Using the vacuum decompression thickener, is thermal source with 80 ℃ of water, under the following vacuum condition of-0.08MPa, reaction solution has been concentrated into crystallization has separated out, and adds acetone 1500ml, stirs, and is placed to room temperature, and crystallization is separated out, and leaches crystallization, gets the Oxymatyine crude product; Use acetone recrystallization again, filter, vacuum-drying gets 0.95 kilogram of Oxymatyine product, content 98.5% (by dry product), and water content 6.5%, total yield is 0.475%.

Claims (5)

1. production technique for preparing matrine, Oxymatyine, sophorine from kuh-seng is characterized in that may further comprise the steps:

(1) with the kuh-seng drying and crushing, granularity is the 10-50 order, uses 0.5%H ₂SO ₄Wetting, place more than 2 hours, wetting raw material is packed in the stainless steel multi-function extractor, below 80 ℃, with water extraction 3 times, 3 water consumptions amount to 10 times of kuh-seng raw material, united extraction liquid, the material slag discards;

(2) extracting solution is condensed into the medicinal extract shape with double-effect evaporator, proportion 〉=1.2;

(3) medicinal extract alkalizes to PH 〉=9 with alkali lye, adds Sodium Pyrosulfite again, check that with thin-layer chromatography wherein the spot of Oxymatyine and Sophocarpidin disappears till;

(4) medicinal extract of handling through above-mentioned (3) is taken to till lifeless matter alkali detects in the medicinal extract with organic solvent extracting, water layer discarded, and organic solvent extraction liquid is stripped with acid solution, till organic layer lifeless matter alkali reaction, make alkaloid all change water layer over to, isolate water layer, organic solvent can be used repeatedly;

(5) contain alkaloidal water layer and alkalize to PH=10-11 with alkali lye, the solution layering, lower layer of water discards, and upper strata total alkaloids cream is placed, and crystallization goes out matrine, filters, and gets the matrine crude product;

(6) mother liquor also can get matrine crude product and sophorine crude product through anti-distributions chromatographic separation more than 7 grades, merges (5), (6) gained matrine crude product, and periodic crystallisation gets the matrine product, and recrystallization sophorine crude product gets the sophorine product;

(7) above-mentioned (6) gained matrine product and hydrogen peroxide are added reactor, dissolve under 50 ℃, 60 ℃ are reacted complete to hydrogen peroxide consumption, concentration of reaction solution below 80 ℃ is to there being crystalline particle to occur, add the acetone crystallization, use acetone recrystallization again, get the Oxymatyine product.

2. production technique according to claim 1 is characterized in that used alkali lye is sodium hydroxide, potassium hydroxide, ammonium hydroxide, yellow soda ash.

3. production technique according to claim 1, it is characterized in that used organic solvent is wherein a kind of in trichloromethane, methylene dichloride, the benzene,toluene,xylene.

4. production technique according to claim 1 is characterized in that the used acid of acid solution reextraction is sulfuric acid or hydrochloric acid.

5. production technique according to claim 1 is characterized in that the concrete grammar that thin-layer chromatography is measured is:

Get thin-layer chromatography silica gel special G, be modulated into the emulsifiable paste shape with 2%NaOH solution, make thin layer plate,, the sample and the reference substance thereof of sophorine, Oxymatyine and matrine are put in the thin layer plate bottom 100 ℃ of activation 1 hour, with chloroform: acetone: methyl alcohol=3: 2: 1 is developping agent, carry out thin-layer chromatography, with the Dragendorff's reagent colour developing of improvement, the Rf value is respectively sophorine 0.67 again, Oxymatyine 0.29, matrine 0.79.

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