CN1594307A - Extraction separation for Nepal irid isoflavone from kudzu, process for preparing sulfonated compounds thereof , and their pharmaceutical uses - Google Patents
Extraction separation for Nepal irid isoflavone from kudzu, process for preparing sulfonated compounds thereof , and their pharmaceutical uses Download PDFInfo
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Abstract
The invention provides a process for extracting Nepal iris isoflavone from wild pueravia flower and a process for preparing Nepal iris isoflavone-3'-sulfonic acid sodium, wherein the extraction and separation process consists of solubilizing agent, heating up and returning flow, or ultrasonic wave abstraction, subjecting the extractive to n-butyl alcohol extraction, diluted acid hydrolysis, filtering, recrystallizing and drying. And the preparing process comprises charging Nepal iris isoflavone into the solution, charging sulphonating agent for reaction, purifying through the conventional separation method. The invention also provides a medicament and composition for treating cardiovascular and cerebrovascular diseases.
Description
Technical field
The invention belongs to the heterogeneous ring compound technical field, be specifically related to heterocycle not hydrogenant contain six-membered ring, Sauerstoffatom is arranged as ring hetero atom is only arranged, with other ring condensed heterocycle compounds.
Background technology
Radix Puerariae (Pueraria lobata (wild) Ohwi) is a pulse family Pueraria lobota platymiscium, and china natural resources is extensive, is mainly used in the Kaiyang expelling pathogenic factors from muscles and skin, promoting eruption antidiarrheal, and anti-tired pain relieving, it is cold to cure the wound, warm headache Xiang Qiang, hypertension, stenocardia etc.The Chinese medicine FI puerariae is the dried flower flower bud of leguminous plants Pueraria lobota, has another name called the Pueraria lobota barriness, and pharmacopeia puts down in writing that its property is sweet, and cold is used for relieving acute alcoholism and recuperating the spleen, the wine that cures the wound heating, and polydipsia, anorexia, discharging fresh blood stool etc. are spitted blood in the contrary acid regurgitation of vomitting.FI puerariae is the conventional medicament of China, is used to alleviate symptoms such as vomiting after drinking for a long time, and its main effective constituent is isoflavone compounds.Irisolidone (Irisolidone, 5,7-dihydroxyl-4 ', 6-dimethoxy isoflavones) and be the aglycon of the main active ingredient Kakkalide (Kakkalide) of Chinese medicine Flos Pueraria omeiensis, Kakkalide is poisoned to alleviation of alcohol and the protection liver injury has better curative effect.The bibliographical information Irisolidone has intensive and suppresses the Hp effect, and the MIC of bacteriostatic action is only than the high order of magnitude of tsiklomitsin.Irisolidone is a kind of good newtype drug precursor, has the potential using value.Simultaneously, isoflavone is because water-soluble and fat-soluble all lower, when medicinal, can only make medicinal preparation for oral administration and can not make injection, because theirs is water-soluble very low, have influence on drug utilization degree and effective time, in order to reach therapeutic purpose, during clinical use, patient's dose is big, take medicine and just can observe result of treatment after 1～2 week, thus the invention provides a kind of water-soluble isoflavone compounds Irisolidone-3 '-sodium sulfonate and preparation method thereof.Extraction and separation method about Irisolidone in the Flos Pueraria omeiensis, only adopt preparative chromatography to separate preparation at present, the invention provides a kind ofly with Flos Pueraria omeiensis extract n-butanol extraction, extract directly prepares the method for Irisolidone through dilute acid hydrolysis by recrystallization.
Summary of the invention
The object of the present invention is to provide a kind of from Flos Pueraria omeiensis the method for extraction separation Irisolidone.
Another object of the present invention is to overcome the medicinal shortcoming of Irisolidone, and a kind of water-soluble high new compound with pharmaceutical use is provided: Irisolidone-3 '-sodium sulfonate.
Further purpose of the present invention be to provide a kind of prepare Irisolidone-3 '-method of sodium sulfonate.
The 4th purpose of the present invention is to provide a kind of medicine and composition for the treatment of the heart, cerebrovascular disease.
The 5th purpose of the present invention is to provide a kind of above-claimed cpd and the application of composition in the medicine of the preparation treatment heart, cerebrovascular disease.
Irisolidone of the present invention and Irisolidone-3 '-chemical name of sodium sulfonate is respectively 5,7-dihydroxyl-6,4 '--dimethoxy isoflavones and 5,7-dihydroxyl-6,4 '--dimethoxy isoflavones-3 '-sodium sulfonate, their chemical structure is used following formula (I) and formula (II) expression respectively:
Formula (I) formula (II)
The operational path of extraction separation Irisolidone may further comprise the steps from Flos Pueraria omeiensis:
(1) exsiccant Flos Pueraria omeiensis, the solvent reflux or the ultrasonic extraction of 4～6 times of amounts of adding, the heating and refluxing extraction time is each 2 hours, the ultrasonic extraction time is each 30 minutes, filters, time extracting solution and the filter residue of extraction of winning.The solvent that filter residue adds 4～6 times of amounts again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.
(2) add suitable quantity of water in the paste of extracting for (1) and stir into suspension, the proportion that makes suspension is between 1.15～1.30, use the n-butanol extraction 3～5 times of 0.5～0.8 times of volume of suspension respectively, the extraction liquid of 3～5 propyl carbinols is evaporated to dried solids.
(3) give in the solids of (3) n-butanol extraction, 2～5% hydrochloric acid that adding solids weight is 3 times or the hydrolysis of sulfuric acid reflux 1 hour have precipitation to occur, this precipitation of decompress filter also washes with water to nearly neutrality, the oven dry, use the dehydrated alcohol recrystallization, suction filtration, dry compound formula (I).
Among the preparation method of the present invention's extraction separation Irisolidone from Flos Pueraria omeiensis, the solvent of extraction is water or methyl alcohol or ethanol or water and methanol mixture or water and alcoholic acid mixture.In water and methanol mixture or water and the alcoholic acid mixture volume of water and methyl alcohol or alcoholic acid volume ratio be arbitrarily than.
Among the preparation method of the present invention's extraction separation Irisolidone from Flos Pueraria omeiensis, the exsiccant Flos Pueraria omeiensis, the mode that adds solvent extraction both can be a reflux, also can be ultrasonic extraction.Ultrasonic wave can cause the cavatition of solvent, and cavatition produces partial High Temperature High Pressure, can enhancing substance dissolving power in solvent.The macroscopical turbulence that acoustic streaming that ultrasonic cavitation produces and shockwave can cause system and the high velocity impact of solid particulate make the attenuation of mass transfer frictional belt, and rate of mass transfer increases.Compare with conventional solvent extraction, the supersound extraction time is short, productive rate is high, mild condition; Special roles such as hyperacoustic pulverizing, stirring can be broken the cell walls of vegetable drug, so that solvent is penetrated in the crude drug cell as early as possible, stripping is chemical ingredients wherein.The ultrasonic extraction time of the present invention is only used 30 minutes at every turn, saves extraction time than heating reflux method.
The content of Irisolidone is not high in Flos Pueraria omeiensis, and the glycosides of Irisolidone---the content of Kakkalide is than higher, the Flos Pueraria omeiensis extract is added suitable quantity of water stir into the suspension n-butanol extraction, can change Kakkalide and Irisolidone over to propyl carbinol mutually, with separating of realization and water-soluble impurity.Again with the n-butyl alcohol extract of Flos Pueraria omeiensis with 2～5% hydrochloric acid or sulphuric acid hydrolysis, Kakkalide is hydrolyzed into Irisolidone, help improving the productive rate of Irisolidone like this.
The preparation method of the present invention's extraction separation Irisolidone from Flos Pueraria omeiensis has advantage with short production cycle, that product yield is high, equipment is simple and product cost is low.
Adopt chemical reaction prepare Irisolidone of the present invention-3 '-method of sodium sulfonate is as follows:
(1) in reactor, adds solvent and Irisolidone, make Irisolidone be dissolved in the solvent fully under stirring, add sulphonating agent again, make Irisolidone and sulphonating agent carry out chemical reaction, the mol ratio of used Irisolidone and sulphonating agent is 1: 1～1: 10, making the temperature of reaction solution with register is 20～100 ℃, reacted 20 minutes～10 hours, Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant.
(2) (1) post reaction mixture is cooled to room temperature, the sodium chloride solution that adds 1～5 times of amount 10～20% of reactant cumulative volume, fully stir, leave standstill and generate precipitation, use conventional separation method, (II) separates with formula, obtains crude product, 1～5 times of amount 10～20% sodium chloride solution that adds the crude product amount again make its purifying, obtain the pure product of formula (II) compound.
Formula (II)
Irisolidone of the present invention-3 '-preparation method of sodium sulfonate in, the used sulphonating agent of chemical reaction can be the vitriol oil or chlorsulfonic acid or oleum or sulphur trioxide.
Irisolidone of the present invention-3 '-preparation method of sodium sulfonate in, the solvent that reacts used is 70～98% sulfuric acid.
Irisolidone of the present invention-3 '-preparation method of sodium sulfonate in, the preferred temperature of sulfonation reaction is 40～80 ℃, the preferred time of chemical reaction is 2～8 hours.
Irisolidone of the present invention-3 '-preparation method of sodium sulfonate in, the optimum temps of chemical reaction is 60 ℃, the Best Times of chemical reaction is 4 hours.
Pharmaceutical composition of the present invention contains the above-claimed cpd formula (I) or the compound formula (II) for the treatment of significant quantity and is active ingredient, and contains one or more pharmaceutically acceptable carriers.
Compound of the present invention and pharmaceutical composition can be used for preparing the application in the treatment heart, the cerebrovascular disease medicament.
Effective constituent Irisolidone-3 of the present invention '-sodium sulfonate or the Irisolidone preparation treatment heart, cerebrovascular disease medicament use with the form of conventional medicinal preparations; Described conventional medicinal preparations contain Irisolidone-3 as activeconstituents '-sodium sulfonate or Irisolidone, this activeconstituents in preparation with pharmaceutically acceptable carrier as being suitable in the stomach and intestine and the solid or the liquid excipient of the organic or inorganic of parenteral admin mix.Irisolidone-3 '-the sodium sulfonate medicinal preparations can be solid form such as tablet, granule, pulvis, capsule; Also can be liquid form such as injection, suspension agent, syrup and emulsion etc.; The Irisolidone medicinal preparations can be solid form such as tablet, granule, pulvis, capsule.
Can contain auxiliary substance, stablizer in the above-mentioned preparation, wetting agent and other additive commonly used are as lactose, citric acid, tartrate, stearic acid, Magnesium Stearate, terra alba, sucrose, W-Gum, talcum powder, gelatin, agar, pectin, peanut oil, sweet oil, theobroma oil, ethylene glycol, glucose, vovocan, Xylotox and xitix etc.
Above-mentioned preparation can be made according to the preparation technology of various preparation routines.
It is 0.1～99.5% activeconstituents that pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be 0.5～95% activeconstituents.
Activeconstituents Irisolidone-3 of the present invention '-sodium sulfonate makes the oral pharmaceutical of various formulations, Irisolidone is made the various formulation oral pharmaceutical except that liquid preparation, become human oral, Irisolidone in the medicine-3 '-content of sodium sulfonate or Irisolidone should be 150mg every day, three times on the one, Irisolidone-3 in each medicine '-content of sodium sulfonate or Irisolidone is 50mg, 14 days is a course of treatment, treats 2～3 courses of treatment.Adult's intramuscular injection, Irisolidone in the medicine-3 '-sodium sulfonate content should be 80mg every day, and twice, 14 day on the one is a course of treatment, treats 2 courses of treatment; Intravenous drip, adult's consumption, Irisolidone in the medicine-3 '-content of sodium sulfonate should be 80mg every day, and once-a-day, 14 days is a course of treatment, treats 2 courses of treatment.Oral pharmaceutical or injectable drug, children is taken the circumstances into consideration decrement.
The contriver with activeconstituents Irisolidone-3 of the present invention '-sodium sulfonate and Irisolidone consignment test unit carried out the test of pesticide effectiveness, test-results show activeconstituents Irisolidone-3 of the present invention '-sodium sulfonate and Irisolidone have oxygen lack resistant function preferably to small white mouse.If with Irisolidone-3 '-sodium sulfonate and Irisolidone be used for clinical trial, expection will have better therapeutic effect.
The present invention adopt the electrophilic substitution sulfonation reaction prepare Irisolidone-3 '-sodium sulfonate, advantage such as it is easy to have technology, and used equipment is simple, the yield height of product and production cost are low.
Description of drawings
Fig. 1 is the infrared spectrogram of Irisolidone of the present invention.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of Irisolidone of the present invention.
Fig. 3 is an Irisolidone of the present invention
13C mr spectrogram.
Fig. 4 be Irisolidone of the present invention-3 '-infrared spectrogram of sodium sulfonate.
Fig. 5 be Irisolidone of the present invention-3 '-the hydrogen nuclear magnetic resonance spectrogram of sodium sulfonate.
In Fig. 1 and Fig. 4, X-coordinate is a wave number, and ordinate zou is a specific absorption.In Fig. 2, Fig. 3 and Fig. 5, X-coordinate is chemical shift, and unit is ppm, and ordinate zou is a peak heights.
Embodiment
The present invention is described in more detail below in conjunction with drawings and Examples, but the invention is not restricted to these embodiment.
One, Irisolidone prepares embodiment
Get the Flos Pueraria omeiensis powder and add reactor, add 5 times of water gagings again, reflux 2 hours is filtered, time extracting solution and the filter residue of extraction of winning.The water that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.15, uses the n-butanol extraction 4 times of 0.6 times of volume of suspension respectively, and the extraction liquid of 4 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 5% hydrochloric acid reflux hydrolysis that adding solids weight is 3 times 1 hour, there is precipitation to occur, this precipitation of decompress filter also washes with water to nearly neutrality, and dehydrated alcohol recrystallization 3 times are used in oven dry, suction filtration, dry the pure product of formula (I), light yellow needle-like crystal, fusing point are 237-238 ℃, and extraction yield is 0.8%.
Referring to Fig. 1, the Irisolidone molecular structure of present embodiment is as follows through the infrared spectrometer test result:
IR(KBr)ν：3449.6，2956.4，1460.5，1659.3，1619.6，1575.8，1513.8，1065.8cm
-1.
Referring to Fig. 2, the H in the Irisolidone molecular structural formula of present embodiment is as follows with the nuclear magnetic resonance analyser test result:
1H?NMR(DMSO-d
6，300MHz)：8.34(1H，s，H-C
2)，6.50(1H，s，H-C
8)，7.42(2H，d，J＝8.8Hz，H-C
2’，H-C
6’)，6.92(2H，d，J＝8.8Hz，H-C
3’，H-C
5’)，3.78(1H，s，C
6-OCH
3)，3.75(3H，s，C
4-OCH
3)，12.96(1H，s，5-OH)，10.8(1H，s，7-OH)。
Referring to Fig. 3, the 13C in the Irisolidone molecular structural formula of present embodiment is as follows with the nuclear magnetic resonance analyser test result:
1H?NMR(DMSO-d
6)：154.8(C-2)，122.0(C-3)，181.0(C-4)，153.0(C-5)，131.8(C-6)，157.8(C-7)，94.6(C-8)，105.4(C-8a)，153.6(C-4a)，123.4(C-1′)，130.6(C-2′，C-6′)，114.4(C-3′，C-5′)，159.8(C-4′)，60.4(6′-OCH
3)，55.6(4′-OCH
3)。
Get the FI puerariae powder and add reactor, add 6 times of water gagings again, ultrasonic extraction 30 minutes is filtered, time extracting solution and the filter residue of extraction of winning.The water that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.18, uses the n-butanol extraction 5 times of 0.5 times of volume of suspension respectively, and the extraction liquid of 5 propyl carbinols is evaporated to dried solids.N-butanol extraction gets in the solids, and the 4% hydrochloric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 0.9%.
Get the FI puerariae powder and add reactor, add 6 times of amount ethanol again, ultrasonic extraction 30 minutes is filtered, time extracting solution and the filter residue of extraction of winning.The ethanol that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.22, uses the n-butanol extraction 3 times of 0.8 times of volume of suspension respectively, and the extraction liquid of 3 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 2% sulfuric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 1.0%.
Get the FI puerariae powder and add reactor, add 4 times of amount methyl alcohol again, ultrasonic extraction 30 minutes is filtered, time extracting solution and the filter residue of extraction of winning.The ethanol that filter residue adds 4 times of amounts of Flos Pueraria omeiensis powder again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.15, uses the n-butanol extraction 4 times of 0.7 times of volume of suspension respectively, and the extraction liquid of 4 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 2% sulfuric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 1.1%.
Get the FI puerariae powder and add reactor, add 5 times of amount ethanol again, heating and refluxing extraction 2 hours is filtered, time extracting solution and the filter residue of extraction of winning.The ethanol that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.30, uses the n-butanol extraction 5 times of 0.6 times of volume of suspension respectively, and the extraction liquid of 5 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 5% hydrochloric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 0.9%.
Embodiment 6
Get the FI puerariae powder and add reactor, add 6 times of amount methyl alcohol again, heating and refluxing extraction 2 hours is filtered, time extracting solution and the filter residue of extraction of winning.The ethanol that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.20, uses the n-butanol extraction 4 times of 0.5 times of volume of suspension respectively, and the extraction liquid of 4 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 2% sulfuric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 1.0%.
Get the FI puerariae powder and add reactor, add 5 times of water gagings and ethanol volume ratio again and be 1: 1 mixture, heating and refluxing extraction 2 hours is filtered, the extracting solution and the filter residue of winning and time extracting.Water and 1: 1 mixture of ethanol that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extract twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.28, uses the n-butanol extraction 5 times of 0.7 times of volume of suspension respectively, and the extraction liquid of 5 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 2% hydrochloric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 0.9%.
Embodiment 8
Get the FI puerariae powder and add reactor, add 6 times of water gagings and methyl alcohol volume ratio again and be 1: 1 mixture, ultrasonic extraction 30 minutes is filtered, the extracting solution and the filter residue of winning and time extracting.Filter residue adds 5 times of water gagings of Flos Pueraria omeiensis powder again and 1: 1 mixture of methyl alcohol extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.25, uses the n-butanol extraction 3 times of 0.5 times of volume of suspension respectively, and the extraction liquid of 3 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 4% sulfuric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.Present embodiment extracts Irisolidone from Flos Pueraria omeiensis extraction yield is 1.0%.
Embodiment 9
Get the FI puerariae powder and add reactor, add 5 times of water gagings and ethanol volume ratio again and be 9: 1 mixture, ultrasonic extraction 30 minutes is filtered, the extracting solution and the filter residue of winning and time extracting.Water and 9: 1 mixture of ethanol that filter residue adds 5 times of amounts of Flos Pueraria omeiensis powder again extract twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.20, uses the n-butanol extraction 3 times of 0.7 times of volume of suspension respectively, and the extraction liquid of 3 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 4% hydrochloric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.The yield of Irisolidone is 0.9% in the present embodiment Flos Pueraria omeiensis.
Get the FI puerariae powder and add reactor, add 6 times of water gagings and methyl alcohol volume ratio again and be 1: 9 mixture, heating and refluxing extraction 2 hours is filtered, the extracting solution and the filter residue of winning and time extracting.Filter residue adds 4 times of water gagings of Flos Pueraria omeiensis powder again and 1: 9 mixture of methyl alcohol extracts twice according to the method for extracting the above-mentioned first time again.The extracting solution that extracts for three times merges, and underpressure distillation is to paste.Add suitable quantity of water in the paste and stir into suspension, the proportion that makes suspension is 1.20, uses the n-butanol extraction 4 times of 0.5 times of volume of suspension respectively, and the extraction liquid of 4 propyl carbinols is evaporated to dried solids.In the solids of n-butanol extraction, the 3% sulfuric acid reflux hydrolysis that adding solids weight is 3 times 1 hour has precipitation to occur.Other technological process is identical with embodiment 1.The yield of Irisolidone is 1.0% in the present embodiment Flos Pueraria omeiensis.
Two, Irisolidone-3 '-sodium sulfonate prepares embodiment
Embodiment 11
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 80% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the Irisolidone and the vitriol oil is 1: 5, after the stirrer stirring, making the temperature of reaction solution with register is 60 ℃, reacts 1 hour, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacting material, be cooled to room temperature, 10% sodium chloride aqueous solution that adds 5 times of reactant cumulative volumes fully stirs, and leaves standstill and separates out precipitation, filter, obtain Irisolidone-3 '-the sodium sulfonate crude product; With recrystallization method Irisolidone-3 '-10% sodium chloride aqueous solution that adds 5 times of amounts in the sodium sulfonate crude product carries out purifying, obtain Irisolidone-3 '-sodium sulfonate elaboration (productive rate 88%).
Adopt the Irisolidone-3 of this examples preparation '-sodium sulfonate, after tested, its physicochemical property is as follows:
Light yellow needle-like crystal, fusing point are 318 ℃ (decomposition); Solubleness in water is 7.4%, and is soluble in water; Thin layer shows light basket look fluorescence.
Referring to Fig. 4, the Irisolidone of present embodiment-3 '-the infrared spectrometer test result of sodium sulfonate is as follows:
IR(KBr)ν：3452.0，3069.7，2946.3，2843.9，1654.2，1625.6，1579.5，1496.4，1464.3，1367.4，1337.6，1262.1，1189.5，1156.4，1097.3，1071.5，1033.1，1001.7cm
-1。
Referring to Fig. 5, the Irisolidone of present embodiment-3 '-H of sodium sulfonate is as follows with the nuclear magnetic resonance analyser test result:
1H?NMR(DMSO-d
6，300MHz)：8.37(s，1H，H-C
2)，7.90(d，J＝2.2Hz，1H，H-C
2’)，7.49(dd，J＝2.2Hz，J＝8.6Hz，1H，H-C
6’)，7.06(d，J＝8.6Hz，1H，H-C
5’)，6.55(s，1H，H-C
8)，3.81(s，3H，C
6-OCH
3)，3.76(s，3H，C
4’-OCH
3)，13.03(s，1H，C
5-OH)，10.87(s，1H，C
7-OH)。
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 70% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the Irisolidone and the vitriol oil is 1: 8, after the stirrer stirring, making the temperature of reaction solution with register is 100 ℃, react 20 clocks, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain Irisolidone-3 '-sodium sulfonate precipitation, separate subsequently Irisolidone-3 '-sodium sulfonate, and make its purifying, separation and purifying are raw materials used to be 20% sodium chloride aqueous solution of 1 times of reactant cumulative volume, and other technological process is identical with embodiment 1.
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 98% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the Irisolidone and the vitriol oil is 1: 3, after the stirrer stirring, making the temperature of reaction solution with register is 20 ℃, reacted 10 hours, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain Irisolidone-3 '-the sodium sulfonate precipitation, separate subsequently Irisolidone-3 '-sodium sulfonate, and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 90% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent vitriol oil again, Irisolidone unit is 1: 1 with the mol ratio of the vitriol oil, after the stirrer stirring, making the temperature of reaction solution with register is 80 ℃, reacted 50 minutes, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain Irisolidone-3 '-the sodium sulfonate precipitation, separate subsequently Irisolidone-3 '-sodium sulfonate and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 85% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent vitriol oil again, Irisolidone unit is 1: 6 with the mol ratio of the vitriol oil, after the stirrer stirring, making the temperature of reaction solution with register is 20 ℃, reacted 10 hours, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions, place, Irisolidone-3 '-the sodium sulfonate precipitation, separate subsequently Irisolidone-3 '-sodium sulfonate and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
Embodiment 16
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 70% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent oleum again, Irisolidone and oleum mol ratio are 1: 3, after the stirrer stirring, be warming up to 50～55 ℃, reacted 1 hour, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 10% sodium chloride aqueous solution, obtain Irisolidone-3 '-the sodium sulfonate crude product, and make its purifying.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Embodiment 17
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 85% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, add the sulphonating agent chlorsulfonic acid again, Irisolidone and chlorsulfonic acid mol ratio are 1: 2, after the stirrer stirring, be warming up to 45～50 ℃, reacted 2 hours, reaction-ure mixture is cooled to room temperature, add 10% sodium chloride aqueous solution heating back and cooling, obtain Irisolidone-3 '-the sodium sulfonate crude product.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Embodiment 18
In the present embodiment, earlier Irisolidone is added in the reactor, also add solvent 80% sulfuric acid gradually with the stirrer stirring up to Irisolidone is fully dissolved, feed the sulphonating agent sulphur trioxide again, Irisolidone and sulphur trioxide mol ratio are 1: 2, after the stirrer stirring, be warming up to 45～50 ℃, reacted 2 hours, obtain Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 10% sodium chloride aqueous solution heating back and cooling, obtain Irisolidone-3 '-the sodium sulfonate crude product.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Three, Irisolidone-3 '-sodium sulfonate and Irisolidone example of formulations
With preparation Irisolidone of the present invention-3 '-sodium sulfonate or 1000 in Irisolidone tablet are that used raw material of example and ratio of adjuvant are as follows:
Irisolidone-3 '-sodium sulfonate or
Irisolidone 50g
Starch 250g
Starch slurry (10%) 85g
Magnesium Stearate 15g
Adopt the preparation technology of conventional tablet to make, every heavy 0.4g, every Irisolidone-3 '-content of sodium sulfonate or Irisolidone is 50mg.Usage: be grown up three times on the one, each 1 oral, children take the circumstances into consideration decrement.
With preparation Irisolidone of the present invention-3 '-sodium sulfonate or Irisolidone powder are that used raw material of example and ratio of adjuvant are as follows for 1000 bags:
Irisolidone-3 '-sodium sulfonate or
Irisolidone 40g
Lactose 2800g
Starch slurry (10%) 60g
Adopt the preparation technology of conventional powder to make, every bag heavy 3g, every Irisolidone-3 '-content of sodium sulfonate or Irisolidone is 40mg.Usage: be grown up three times on the one, each 1 sack clothes, children take the circumstances into consideration decrement.
Embodiment 21
With the preparation Irisolidone of the present invention-3 '-sodium sulfonate 1000ml injection is an example, used raw material and ratio of adjuvant are as follows:
Irisolidone-3 '-sodium sulfonate 50g
Water for injection adds to 1000ml
Adopt the preparation technology of conventional method injection to make, every bottle of 2ml, contain Irisolidone-3 '-sodium sulfonate 100mg.Usage: intramuscular injection, one day twice, each 1, intravenous drip, once-a-day, each 2.
The contriver with effective constituent Irisolidone-3 of the present invention '-sodium sulfonate and Irisolidone consignment test unit carried out the test of pesticide effectiveness, exemplify following experiment content and test-results thereof, prove with the pharmacological agent heart of the present invention's preparation, the validity of cerebrovascular disease.
The test of pesticide effectiveness
The ICR mouse is provided by the Traditional Chinese Medicine Research Institute, Shanxi Province Experimental Animal Center, body weight 20～22g, and in mouse 6-7 in age week, the animal conformity certification moves word 08-24 number for the doctor.
1. anti-hypoxia, ischemia resisting effect
(1) animal grouping and handle laboratory animal be divided at random blank group, positive drug control group, the heavy dose of group of Irisolidone and small dose group, Irisolidone-3 '-totally six groups of the heavy dose of group of sodium sulfonate and small dose group, every group of 12 mouse, blank group is irritated stomach and give equal-volume solvent (Xylo-Mucine suspension liquid) every day, and the heavy dose of and low dose of Irisolidone is respectively 150mgkg
-1D
-1, and 50mgkg
-1, Irisolidone-3 '-the heavy dose of and low dose of sodium sulfonate is respectively 150mgkg
-1D
-1, and 50mgkg
-1D
-1, gastric infusion, 7 days aftertreatment animals of successive administration.
(2) testing method of each index
The acute brain hypoxia test: by (1) described method grouping, with the positive medicine of nimodipine, dosage is 120mgkg
-1D
-1, behind the last administration 1h, breaking end rapidly from the mouse ear rear portion, the record mouse once breathes the time to the end from the broken end beginning.
The chemical hypoxia test: by (1) described method grouping, with the positive medicine of nimodipine, dosage is 120mgkg-1d-1, and behind the last administration 1h, each organizes equal abdominal injection Sodium Nitrite 200mgkg
-1, opening entry mouse survival time immediately.
Cardiac muscle specificity hypoxia test: on (1) described method packet by packet basis, increase model control group again.Blank group and model control group all give the equal-volume solvent, and with the positive medicine of propranolol hydrochloride, dosage is 120mgkg
-1D
-1, behind the last administration 40min, except that the blank group, all the other are respectively organized equal abdominal injection and give 10mgkg
-1Racemic isoproterenol, give Racemic isoproterenol 15min after, it is flat to place volume to be that 200mL is equipped with the wide-mouth of 10g sodica calx each group mouse, sealing, record mouse diing time.
(3) experimental result
Irisolidone-3 '-sodium sulfonate and Irisolidone to the effect of acute cerebral ischemia mouse, to the effect of chemical anoxic mouse and to the effect of myocardium specificity anoxic mouse see Table 1 respectively, table 2 and table 3.
Table 1 Irisolidone and sodium sulfonate thereof to the effect of acute cerebral ischemia mouse (x ± s, n=12)
Group dosage (mgkg
-1D
-1) survival time (s)
Blank group-20.28 ± 1.96
Nimodipine control group 120 23.45 ± 1.89
*
The heavy dose of group 150 22.37 ± 1.68 of Irisolidone
*
Irisolidone small dose group 50 23.49 ± 2.42
*
Irisolidone-3 '-the heavy dose of group 150 22.67 ± 2.50 of sodium sulfonate
*
Irisolidone-3 '-sodium sulfonate small dose group 50 22.25 ± 2.19
*
Annotate:
*Expression is compared with model control group
*P＜0.05,
*P＜0.01, down together
Table 2 Irisolidone and sodium sulfonate thereof to the effect of chemical anoxic mouse (x ± s, n=12)
Group dosage (mgkg
-1D
-1) survival time (min)
Blank group-11.93 ± 1.31
Nimodipine control group 120 14.95 ± 2.45
*
The heavy dose of group 150 14.74 ± 3.72 of Irisolidone
*
Irisolidone small dose group 50 13.43 ± 2.51
Irisolidone-3 '-the heavy dose of group 150 13.45 ± 1.70 of sodium sulfonate
*
Irisolidone-3 '-sodium sulfonate small dose group 50 13.36 ± 2.24
Table 3 Irisolidone and sodium sulfonate thereof to the effect of myocardium specificity anoxic mouse (x ± s, n=12)
Group dosage (mgkg
-1D
-1) survival time (min)
Blank group-40.83 ± 6.98
Model control group-21.93 ± 2.90
*
Nimodipine control group 120 27.76 ± 4.83
*
The heavy dose of group 150 28.03 ± 3.70 of Irisolidone
*
Irisolidone small dose group 50 29.12 ± 2.65
*
Irisolidone-3 '-the heavy dose of group 150 28.05 ± 6.02 of sodium sulfonate
*
Irisolidone-3 '-sodium sulfonate small dose group 50 25.32 ± 3.51
*
2. conclusion
Behind the mouse broken end, because cerebral blood supply stops, original blood and nutritive substance still can make brain function keep blink in the brain at short notice, and the mouse demonstration clocklike dehisces to breathe, and all medicines that the brain oxygen-consumption is reduced all can prolong mouse and breathe the time; After Sodium Nitrite enters in the body, can with the oxyphorase combination, make it lose the ability of carrying oxygen, thereby the histanoxia of causing causes animal dead; After giving Racemic isoproterenol, heart rate is accelerated, and myocardial contraction strengthens, and myocardial consumption of oxygen rises, and when anoxic, the myocardial cell comes to harm at first, thereby causes animal dead.Have to reduce and organize oxygen-consumption, vasodilation promotes blood flow rate, improves the utilization ratio of oxygen in the tissue, coronary artery dilator, and the medicine that reduces functions such as myocardial consumption of oxygen all can prolong the animal caused by anoxia dead time.This test as can be seen, Irisolidone-3 '-sodium sulfonate, Irisolidone all can prolong the anoxic death time of animal effectively, have significantly oxygen lack resistant function.In addition, after Irisolidone glucoside unit is sulfonated, improved significantly that it is water-soluble, its anti-anoxia ability and the first basically identical of Irisolidone glucoside.
Claims (8)
1. the method for the following formula of extraction separation (I) Irisolidone from elegant jessamine (Pueraia lobata (Willd)) is spent.
Formula (I)
This method technological operation comprises: the Flos Pueraria omeiensis powder, the solvent reflux of 4～6 times of amounts of adding or ultrasonic extraction 3 times, united extraction liquid, be distilled to paste, add suitable quantity of water and stir into suspension, the proportion that makes suspension is between 1.15～1.30, use the n-butanol extraction 3～5 times of 0.5～0.8 times of volume of suspension respectively, the extraction liquid of propyl carbinol is merged, be evaporated to dried solids, this solids has precipitation to occur with 2～5% hydrochloric acid or the sulphuric acid hydrolysis of 3 times of solids weight, this precipitation of decompress filter also washes with water to nearly neutrality, oven dry is used the dehydrated alcohol recrystallization, suction filtration, dry formula (I).
2. following formula (II) compound:
Formula (II)
3. the solvent according to the described formula of claim 1 (I) extraction and separation method is water or methyl alcohol or ethanol or water and methanol mixture or water and alcoholic acid mixture.
4. the preparation method of claim 2 Chinese style (II) compound, this method may further comprise the steps:
(1). add solvent and formula (I) Irisolidone in the reactor, Irisolidone is dissolved in the solvent, add sulphonating agent again, Irisolidone and sulphonating agent carry out chemical reaction, the mol ratio of used Irisolidone and sulphonating agent is 1: 1～1: 10, making the temperature of reaction solution with register is 20～100 ℃, reacted 20 minutes～10 hours, Irisolidone-3 '-mixture of sulfonic acid and unreacted reactant.
(2). (1) post reaction mixture is cooled to room temperature, and pouring cumulative volume into is the sodium chloride solution of 3～8 times of amounts 10～20% of reaction mixture, fully stirs, and leaves standstill the generation light-yellow precipitate.Use conventional separation method, the compound separation of formula (II) is come out, obtain crude product, 1～5 times of amount 10～20% sodium chloride solution that adds the crude product amount again make its purifying, obtain the pure product of compound of formula (II).
Formula (I) formula (II)
5. according to the preparation method of the described claim formula of claim 4 (II) compound, wherein the temperature of reaction of Irisolidone and sulphonating agent is 20 ℃～100 ℃, and chemical time is 20 minutes～10 hours.
6. according to the preparation method of the described claim formula of claim 4 (II) compound, it is characterized in that: said solvent is 70～98% sulfuric acid; Said sulphonating agent is the vitriol oil or chlorsulfonic acid or oleum or sulphur trioxide.
7. a pharmaceutical composition for the treatment of the heart, cerebrovascular disease wherein has claim formula (II) compound or formula (I) compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.
8. claim formula (II) compound and formula (I) the compound application in the medicine of the preparation treatment heart, cerebrovascular disease.
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|---|---|---|---|---|
| CN100415732C (en) * | 2005-08-12 | 2008-09-03 | 东北师范大学 | Kudzuvine flower isoflavone , monomer tectoridin and tectorigenin extraction method and uses |
| CN100462361C (en) * | 2007-01-31 | 2009-02-18 | 陕西师范大学 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
| CN100471500C (en) * | 2005-07-04 | 2009-03-25 | 山东省医学科学院药物研究所 | Medicinal composition contg. glucoside of pueravia flower and its application |
| CN101239092B (en) * | 2008-03-14 | 2010-10-20 | 山东省医学科学院药物研究所 | Kudzuvine flower isoflavonoid extraction, its extracting method, medicinal composition and its use in pharmaceutical |
| CN101632656B (en) * | 2009-08-04 | 2010-11-03 | 山东省医学科学院药物研究所 | Preparation method of water-soluble irisolidone |
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| CN105153148A (en) * | 2015-06-18 | 2015-12-16 | 玉林师范学院 | Tryptanthrin alkaloid salt, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100471500C (en) * | 2005-07-04 | 2009-03-25 | 山东省医学科学院药物研究所 | Medicinal composition contg. glucoside of pueravia flower and its application |
| CN100415732C (en) * | 2005-08-12 | 2008-09-03 | 东北师范大学 | Kudzuvine flower isoflavone , monomer tectoridin and tectorigenin extraction method and uses |
| CN1911924B (en) * | 2006-08-18 | 2011-06-01 | 山东省医学科学院药物研究所 | Extraction method of Nepal eagle tail isoflavone, its derivative and medicipal composition using said derivative as active component |
| CN100462361C (en) * | 2007-01-31 | 2009-02-18 | 陕西师范大学 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
| CN101239092B (en) * | 2008-03-14 | 2010-10-20 | 山东省医学科学院药物研究所 | Kudzuvine flower isoflavonoid extraction, its extracting method, medicinal composition and its use in pharmaceutical |
| CN101632656B (en) * | 2009-08-04 | 2010-11-03 | 山东省医学科学院药物研究所 | Preparation method of water-soluble irisolidone |
| CN105153148A (en) * | 2015-06-18 | 2015-12-16 | 玉林师范学院 | Tryptanthrin alkaloid salt, and preparation method and application thereof |
| CN107417653A (en) * | 2017-08-22 | 2017-12-01 | 四川省中医药科学院 | Sulfonate of 6 hydroxy dye lignin 5 ' and its production and use |
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