CN105732647A - Chlorins e6 metal salt compound and preparing method and application thereof - Google Patents
Chlorins e6 metal salt compound and preparing method and application thereof Download PDFInfo
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- CN105732647A CN105732647A CN201610213520.XA CN201610213520A CN105732647A CN 105732647 A CN105732647 A CN 105732647A CN 201610213520 A CN201610213520 A CN 201610213520A CN 105732647 A CN105732647 A CN 105732647A
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- 0 CC(C*)[C@@]1CN*=C(C)C1 Chemical compound CC(C*)[C@@]1CN*=C(C)C1 0.000 description 2
- FNLUJDLKYOWMMF-UHFFFAOYSA-N CCNCC(C)C Chemical compound CCNCC(C)C FNLUJDLKYOWMMF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Abstract
The invention relates to a chlorins e6 metal salt compound.The chemical structure is shown in the formula (I) in the description, wherein R is common metal ions such as K+ or Na+.A preparing method comprises the following steps that firstly, silkworm excrement crude product chlorophyll serves as a raw material and is dissolved in diethyl ether, concentrated hydrochloric acid is added, and magnesium-removed chlorophyllin a is generated; secondly, magnesium-removed chlorophyllin a is reacted in a strong-base methanol solution, a little of water is added later to generate chlorins e6 mono-methyl ester; thirdly, obtained chlorins e6 mono-methyl ester is reacted in a strong-base alcoholic solution reaction reagent, and a compound (I) is obtained through separation and purification.The chlorins e6 metal salt compound is a raw material in the study field of medicine for resisting gastric ulcers, resisting anemia and protecting the liver and promoting leucopoiesis.
Description
Technical field
The invention belongs to chlorin compounds field, particularly to a kind of chlorin e6Metal salt compound and its preparation method and application.
Background technology
It has been proved that chlorophyll degradation product and derivant thereof have sterilization, antimutagenic, promotion healing up of traumatic tissues, antiulcer, protect the liver, promote many-sided biological activity such as hemopoietic function and optical dynamic therapy.Therefore, chlorophyllous deep development is expected to become a brand-new medicine and health product extended familys.But, up to now, this is not yet drawn attention by domestic and international biological medicine scientific and technological circle particularly pharmacy circle, and chlorophyll is still blank out in current pharmaceutical chemistry is studied.
Development antiulcer medicine is mainly by controlling gastric acid secretion, kill helicobacter pylori and protecting three kinds of approach of gastric mucosa to realize; the medicine of existing control gastric acid and protection gastric mucosa is cured the symptoms, not the disease mostly; and China's current clinical treatment Gastric Ulcer Treatment major part is from external import or Counterfeit Item, seldom there is the new drug of the treatment gastric ulcer of the innovation of independent research.
China is hepatopathy big country, and the hepatopathy such as viral hepatitis, fatty liver, alcoholic liver disease, drug induced hepatic injury and hepatocarcinoma has increasingly becomed one of current principal disease threatening human survival healthy in recent years.The shortcomings such as research finds, the sodium copper chlorophllin that extract is made from Bombyx mori L. has a good liver protection function, but its complicated component, poor stability greatly limit its application in this field.
Summary of the invention
It is an object of the invention to propose a kind of chlorin e 6 metal salt compound and preparation method thereof, and then a kind of anti-gastric-ulcer, anti-anemia action and the raw material protected the liver in shengbai drug research field are provided.
The technical scheme that the present invention takes for achieving the above object is as described below.
Technical scheme one: a kind of chlorin e 6 metal salt compound, chemical constitution as shown in the formula (I):
(I)
Wherein, R is K+Or Na+Etc. common metal ion.
Technical scheme two: the preparation method of the compound as shown in the formula (I) as described in technical scheme one, comprises the following steps:
(1) with silkworm excrement crude chlorophyll for raw material, it is dissolved in ether, adds concentrated hydrochloric acid, generate pheophorbide acid a；Wherein preferred 1:2～5 of mass ratio of silkworm excrement crude chlorophyll and ether, 1:6～10 preferred with the mass ratio of concentrated hydrochloric acid, stir 1.5～2.5h under room temperature；
(2) pheophorbide acid a is reacted in highly basic methanol solution, after rear addition little water, generate chlorin e 6 mono-methyl；The wherein concentration of highly basic methanol solution preferably 0.3%～0.6%, preferred 1:50～150 of mass ratio of pheophorbide acid a and highly basic methanol solution；
(3) step (2) gained chlorin e 6 mono-methyl reacts in highly basic alcoholic solution reaction reagent, and separated purification, obtains compound (I).
In described preparation method step (3), the temperature of reaction can in from the freezing point of solvent to the boiling point temperature range of solvent the temperature of change, it is preferable that 0～80 DEG C, it is preferred that 20～60 DEG C；The process of reaction can adopt traditional test methods in this area (such as nuclear magnetic resonance, NMR, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) to determine, it is preferable that response time 0.5～16h, it is preferred that 1～10h.
The described alcohol described in preparation method step (3) is the C under room temperature for liquid1-6Lower alcohol；Preferred methanol, ethanol, propanol or butanol.
Highly basic described in described preparation method step (2) and step (3) is potassium hydroxide or sodium hydroxide.
In described preparation method step (3), chlorin e 6 mono-methyl is 1:10～150 with the volume ratio of reaction reagent, is 5:3～25 with the mass ratio of highly basic.
In described preparation method, described purification adopts silica gel column chromatography to separate, developing solvent be in dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol, ethyl acetate, acetone and petroleum ether one or more and wherein containing the formic acid of cumulative volume 2%～0.5%；Preferably wherein containing cumulative volume 1.2%～0.8% formic acid.
Technical scheme three: the chlorin e 6 metal salt compound as described in technical scheme one is in anti-gastric-ulcer, anti-anemia action and the application that protects the liver in shengbai drug research field.
The room temperature of the present invention refers to ambient temperature, is 10～30 DEG C
The agents useful for same of the present invention and raw material are all commercially.
Present invention also offers the quality standard of described chlorin e 6 metal salt compound as the formula (1).
The actively progressive effect of the present invention is in that: the invention provides a kind of structure significant potential drug clear and definite, active and synthetic method thereof, the chlorin e 6 slaine of the present invention can be used for anti-gastric-ulcer, anti-anemia action and protects the liver offer raw material in shengbai drug research field.
Accompanying drawing explanation
Fig. 1 is chlorin e 6 slaine stability (in the refrigerator of 0～4 DEG C) result of the test of the present invention.
Fig. 2 is chlorin e 6 slaine stability (at room temperature) result of the test of the present invention.
Specific embodiment
Mode by the examples below further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1: the preparation of chlorin e 6 trisodium salt
(1) silkworm excrement crude chlorophyll 100g, is dissolved in 300ml ether, adds 600ml hydrochloric acid, stirs 2 hours, standing, take off a layer acid solution, add the dilution of 500ml water, dropping 10mol/L sodium hydroxide solution is to pH5～6, precipitate out blackish green precipitation, drying under reduced pressure, obtain pheophorbide acid a and be about 20g.
(2) take pheophorbide acid a and be about 5g, it is dissolved in 200ml methanol, add 0.5% sodium hydrate methanol solution 500ml, stirring reaction 5h, add 3g sodium hydroxide and 30ml water, water-bath backflow 2h, hydrochloric acid drops to pH5～6, add triploid hydrops, precipitation is precipitated out after standing, through silica gel column chromatography (300-400 order after decompression sucking filtration, eluent: dichloromethane, methanol, acetone, formic acid=10:1:1:0.7), collect main flow part, obtain about 1.2g2, 7, 12, 18-tetramethyl-3-vinyl-8-ethyl-13-carboxyl-15-methanoyl ethyl-17-carboxyl-17, 18-chlorin.MS (ESI+) M/Z:612 (M+2) .611 (M+1), 1H-NMR(δ PPM, CDCL3): 1.63(3H), 1.75(3H), 2.25-2.30(4H), 3.29(3H), 3.47(3H) 3.62(3H), 3.73-3.77(2H), 3.80(3H), 4.56(2H), 5.01(2H), 6.15(1H), 6.34(1H), 8.05(1H), 8.86(1H), 9.59(1H), 9.77(1H).
(3) taking above-mentioned chlorin e 6 mono-methyl 1.1g, be dissolved in 15ml methanol, add the sodium hydrate aqueous solution of 0.1mol/l, heating in water bath 65 DEG C, react 8h, pressurize sucking filtration, and collecting the solid obtained is chlorin e 6 trisodium salt, 0.8g.MS (ESI+) M/Z:599 (M+2) .598 (M+1), 1H-NMR(δ PPM, CDCL3): 1.63(3H), 1.75(3H), 2.25-2.30(4H), 3.29(3H), 3.47(3H) 3.62(3H), 3.73-3.77(2H), 3.80(3H), 4.56(2H), 5.01(2H), 6.15(1H), 6.34(1H), 8.05(1H), 8.86(1H), 9.59(1H), 9.77(1H).
Embodiment 2: the preparation of chlorin e 6 tripotassium salt
Sodium hydroxide used in step (3) in embodiment 1 is replaced with potassium hydroxide and can prepare chlorin e 6 tripotassium salt, MS (ESI+) M/Z:599 (M+2) .598 (M+1), 1H-NMR(δ PPM, CDCL3): 1.63(3H), 1.75(3H), 2.25-2.30(4H), 3.29(3H), 3.47(3H) 3.62(3H), 3.73-3.77(2H), 3.80(3H), 4.56(2H), 5.01(2H), 6.15(1H), 6.34(1H), 8.05(1H), 8.86(1H), 9.59(1H), 9.77(1H).
Embodiment 3: chlorin e 6 slaine stability
Take chlorin e 6 slaine (for sodium salt) and chlorin e 6 (purchasing in Mayan reagent company limited) respectively, take 1.0g respectively to place at room temperature and in the refrigerator of 0～4 DEG C, often sample the purity being measured both by HPLC at regular intervals, result is respectively as shown in Fig. 1, Fig. 2.
Chlorin e 6 slaine (for sodium salt) at normal temperatures and the stability of 0～4 DEG C compared with chlorin e 6 more stable, rate of change is slower.
Embodiment 4: the quality standard of chlorin e 6 slaine
Molecular formula: C34H33N4O6R3
Wherein R is K or Na.
When R is Na, its molecular weight is 662.68, R when being K, and its molecular weight is 710.
Physical and chemical index is table one such as:
Table one
| Project | Index |
| Ash, w(%) | 25 |
| pH | 9.5～10.5 |
| Absorbance, >= | 2300 |
| Absorbance ratio | 4.0～5.0 |
| Purity testing, w(%), >= | 95 |
| Loss on drying, (%) ,≤ | 2 |
| Total arsenic (in As), mg/kg ,≤ | 2 |
| Plumbous (Pb), mg/kg ,≤ | 5 |
Ash test: take sample 1.0～2.0g, puts in the crucible of pre-burn, accurately weighed, and slow calcination, to complete ashing, lets cool to room temperature；Unless otherwise specified, add sulphuric acid 0.5～1.0ml and make to moisten, after low-temperature heat eliminates to sulfuric acid vapor, process to burn at 700～800 DEG C and make complete ashing, transplant in exsiccator, let cool to room temperature, after accurately weighed, then process at 700～800 DEG C and burn to constant weight.
The mensuration of pH: compound concentration is the sample solution (1g is dissolved in 100ml water) of 1%, measures its pH value with acidometer.
The mensuration of absorbance and absorbance ratio: accurately weigh 0.1g sample, be accurate to 0.0002g, be dissolved in water, adds water to scale in immigration 100ml volumetric flask and shakes up.Taking the above-mentioned aqueous solution of 1ml, dilute with phosphate buffer (pH7.5) and be settled to 100ml, this is test liquid.Liquid of materialsing is placed in 1cm cuvette, does blank with phosphate buffer (pH7.5), measures absorbance by spectrophotometer maximum absorption wave strong point in two wave-length coverages of 405nm ± 3nm and 630nm ± 3nm.(absorbance should control between 0.3 ~ 0.7, otherwise should adjust test liquid concentration, then redeterminate absorbance.)
Test liquid concentration is 1%, uses 1cm cuvette, and the absorbance that the maximum absorption wave strong point within the scope of 405nm ± 3nm records, in Ε 1%1cm (405nm ± 3nm), calculates by formula (A.1):
In formula:
A1The absorbance of practical measurement test liquid；
c1The numerical value (the loss on drying value according to actual measurement sample, be converted into the concentration in butt) of the concentration of tested sample liquid, unit is gram every milliliter (g/ml).
A.4.4.2 absorbance ratio is with w1Meter, calculates by formula (A.2):
In formula:
Ε 1%1cm (405nm ± 3nm) 1cm test liquid concentration is 1%, uses 1cm cuvette, the absorbance that the maximum absorption wave strong point within the scope of 405nm ± 3nm records；
Ε 1%1cm (630nm ± 3nm) 1cm test liquid concentration is 1%, uses 1cm cuvette, the absorbance that the maximum absorption wave strong point within the scope of 630nm ± 3nm records, and assay method is with Ε 1%1cm (405nm ± 3nm).
Experimental result is as the criterion with the arithmetic mean of instantaneous value of parallel determinations.The absolute difference of the twice independent measurement result obtained under repeatability condition must not exceed the 2% of arithmetic mean of instantaneous value.
HPLC purity test: accurately weigh 0.1g sample, be accurate to 0.0002g, is placed in silicon ware, and calcination is to carbon-free at less than 500 DEG C, moistening with 1 ~ 2 sulphuric acid, ashing again.Dividing 3 times (each 5ml) to boil dissolving ash with the hydrochloric acid solution that mass fraction is 10%, and filter in 100ml volumetric flask, be settled to scale with water after cooling, this is test liquid.
Mobile phase A: acetonitrile, with 0.45 μm of membrane filtration, ultrasonic degassed rear standby.
Mobile phase B: acetonitrile: 0.1%TFA=45:55(volume ratio) preparation, after mix homogeneously, with 0.45 μm of membrane filtration, ultrasonic degassed rear standby.
Column temperature: 25 DEG C.
Flow rate of mobile phase: 1ml/min.
Sample size: 20 μ l.
The preparation of test liquid: weigh chlorin E6Trisodium salt sample 0.012g, accurately weighed, it is placed in 25ml volumetric flask, methanol dissolves and is settled to scale, shakes up, and pipettes 1ml to 10ml volumetric flask, and Mobile phase B is settled to scale.Shake up standby.
Measure: under 5.2.3 reference color spectral condition, by table two method gradient elution, test liquid is measured, retention time 25min, record collection of illustrative plates.
Table two
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 0 | 100 |
| 20 | 100 | 0 |
| 25 | 100 | 0 |
Purity calculates: calculate sample purity by area normalization method.
Loss on drying measures: take test sample 2～4g, mix homogeneously, divide and take about 0.5～lg, it is placed in weighing botle that is dry under test sample similarity condition and that weigh, accurately weighed, open bottle cap, put in vacuum drying apparatus, being decompressed to 2.67kPa (20mmHg) and continue half an hour below, room temperature is placed 24 hours.Connect anhydrous calcium chloride drying tube in vacuum drying apparatus outlet, open piston, treat that interior external pressure is consistent, closure piston, open exsiccator, cover bottle cap, take out the rapid accurately weighed weight of weighing botle, calculate the water content (%) in test sample.
Claims (10)
1. a chlorin e 6 metal salt compound, it is characterised in that chemical constitution as shown in the formula (I):
(I)
Wherein, R is K+Or Na+。
2. the preparation method of compound as shown in the formula (I) as claimed in claim 1, it is characterised in that comprise the following steps:
(1) with silkworm excrement crude chlorophyll for raw material, it is dissolved in ether, adds concentrated hydrochloric acid, generate pheophorbide acid a；
(2) pheophorbide acid a is reacted in highly basic methanol solution, after rear addition little water, generate chlorin e 6 mono-methyl；
(3) step (2) gained chlorin e 6 mono-methyl reacts in highly basic alcoholic solution reaction reagent, and separated purification, obtains compound (I).
3. preparation method as claimed in claim 2, it is characterised in that the alcohol described in step (3) is the C under room temperature for liquid1-6Lower alcohol.
4. preparation method as claimed in claim 2, it is characterised in that step (2) and the highly basic described in step (3) are potassium hydroxide or sodium hydroxide.
5. preparation method as claimed in claim 2, it is characterised in that in step (3), chlorin e 6 mono-methyl is 1:10～150 with the volume ratio of reaction reagent.
6. preparation method as claimed in claim 2, it is characterised in that described in step (3), the response time of reaction is 1～10h, and reaction temperature is 20～60 DEG C.
7. preparation method as claimed in claim 2, it is characterized in that, described purification adopts silica gel column chromatography to separate, developing solvent be in dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol, ethyl acetate, acetone and petroleum ether one or more and wherein containing the formic acid of cumulative volume 2%～0.5%.
8. preparation method as claimed in claim 3, it is characterised in that described lower alcohol is methanol, ethanol, propanol or butanol.
9. preparation method as claimed in claim 6, it is characterised in that described developing solvent be in dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol, ethyl acetate, acetone and petroleum ether one or more and wherein containing cumulative volume 1.2%～0.8% formic acid.
10. chlorin e 6 metal salt compound as claimed in claim 1 is in anti-gastric-ulcer, anti-anemia action and the application that protects the liver in shengbai drug research field.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2705199C1 (en) * | 2019-05-22 | 2019-11-06 | Илья Евгеньевич Жаров | METHOD OF PRODUCING TRIS-SODIUM SALT OF CHLORINE e6 |
| CN111479589A (en) * | 2017-12-11 | 2020-07-31 | 东星制药株式会社 | Pharmaceutical composition for treating obesity and non-alcoholic steatohepatitis caused by high-fat diet using trisodium chlorin e6 photosensitizer |
| CN112521392A (en) * | 2019-09-18 | 2021-03-19 | 康俄(上海)医疗科技有限公司 | Purification method of chlorin e6 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111479589A (en) * | 2017-12-11 | 2020-07-31 | 东星制药株式会社 | Pharmaceutical composition for treating obesity and non-alcoholic steatohepatitis caused by high-fat diet using trisodium chlorin e6 photosensitizer |
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| CN112521392A (en) * | 2019-09-18 | 2021-03-19 | 康俄(上海)医疗科技有限公司 | Purification method of chlorin e6 |
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