CN105732647B - A kind of chlorin e6Metal salt compound and its preparation method and application - Google Patents
A kind of chlorin e6Metal salt compound and its preparation method and application Download PDFInfo
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- CN105732647B CN105732647B CN201610213520.XA CN201610213520A CN105732647B CN 105732647 B CN105732647 B CN 105732647B CN 201610213520 A CN201610213520 A CN 201610213520A CN 105732647 B CN105732647 B CN 105732647B
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Abstract
The present invention relates to a kind of chlorin e6Metal salt compound, chemical constitution such as formula（I）It is shown, wherein R K+Or Na+Etc. common metal ions.Preparation method includes the following steps：（1）It using silkworm excrement crude chlorophyll as raw material, is dissolved in ether, concentrated hydrochloric acid is added, generate Phephorbide a；（2）Phephorbide a is reacted in highly basic methanol solution, rear generation chlorin e 6 mono-methyl after little water is added；（3）Gained chlorin e 6 mono-methyl reacts in highly basic alcoholic solution reaction reagent, and through isolating and purifying, obtains compound（I）.The present invention provides the raw materials in a kind of anti-gastric-ulcer, anti-anemia action and liver protection shengbai drug research field.（I）.
Description
Technical field
The invention belongs to dihydro porphin compound field, more 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 its derivative have sterilization, anti-mutagenesis, promote healing up of traumatic tissues, is anti-
Ulcer, promotes various bioactivity such as hematopoiesis function and optical dynamic therapy at liver protection.Therefore, the deep development of chlorophyll has
Hoping becomes completely new a medicine and health products large family.But so far, domestic and international biological medicine scientific and technological circle especially medicine
Educational circles not yet draws attention to this, and chlorophyll is still blank out in current pharmaceutical chemistry research.
Development antiulcer medicine is mainly by controlling gastric acid secretion, killing helicobacter pylori and protection
Three kinds of approach of stomach lining are come what is realized, and the drug of existing control hydrochloric acid in gastric juice and protection stomach lining is mostly palliative, and China's mesh
Preclinical therapy Gastric Ulcer Treatment is largely from external import or Counterfeit Item, and the treatment stomach of the innovation of few independent researches is burst
The new drug of ulcer.
China is hepatopathy big country, in recent years virus hepatitis, fatty liver, alcoholic liver disease, drug induced hepatic injury and liver cancer
Etc. hepatopathys increasingly becomed current one of the principal disease for threatening human survival health.The study found that the extract from silkworm excrement
The shortcomings of manufactured sodium copper chlorophyllin has good liver protection function, but its complicated component, and stability is poor greatly limits
Its application in the field.
Invention content
It is an object of the invention to propose a kind of chlorin e 6 metal salt compound and preparation method thereof, and then provide one
Raw material in kind anti-gastric-ulcer, anti-anemia action and liver protection shengbai drug research field.
The technical solution that the present invention is taken to achieve the above object is as described below.
Technical solution one：A kind of chlorin e 6 metal salt compound, chemical constitution such as formula（I）It is shown：
（I）
Wherein, R K+Or Na+Etc. common metal ions.
Technical solution two：As described in technical solution one such as formula（I）The preparation method of compound represented, including it is below
Step：
（1）It using silkworm excrement crude chlorophyll as raw material, is dissolved in ether, concentrated hydrochloric acid is added, generate Phephorbide a；
The wherein mass ratio of silkworm excrement crude chlorophyll and ether preferably 1:2~5, the mass ratio preferably 1 with concentrated hydrochloric acid:6~10, at room temperature
Stir 1.5~2.5h；
（2）Phephorbide a is reacted in highly basic methanol solution, rear generation chlorin e 6 list first after little water is added
Ester；The wherein concentration of highly basic methanol solution preferably 0.3%~0.6%, the mass ratio of Phephorbide a and highly basic methanol solution is preferred
1:50~150；
（3）Step（2）Gained chlorin e 6 mono-methyl reacts in highly basic alcoholic solution reaction reagent, and pure through detaching
Change, obtains compound（I）.
The preparation method step（3）In, the temperature of reaction can be from the freezing point of solvent to the boiling temperature of solvent
The temperature changed in range, preferably 0~80 DEG C, further preferred 20~60 DEG C；The process of reaction may be used in this field often
Advise test method（Such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC）It determines, preferred reaction time
0.5~16h, further preferred 1~10h.
The preparation method step（3）Described in alcohol to be under room temperature be liquid C1-6Lower alcohol；It is preferred that methanol,
Ethyl alcohol, propyl alcohol or butanol.
The preparation method step（2）And step（3）Described in highly basic be potassium hydroxide or sodium hydroxide.
The preparation method step（3）The volume ratio of middle chlorin e 6 mono-methyl and reaction reagent is 1:10~150,
Mass ratio with highly basic is 5:3~25.
In the preparation method, the purifying is detached using silica gel column chromatography, and solvent is dichloromethane, three chloromethanes
One or more in alkane, carbon tetrachloride, methanol, ethyl alcohol, ethyl acetate, acetone and petroleum ether and wherein contain total volume 2%~
0.5% formic acid；1.2%~0.8% formic acid containing total volume preferably wherein.
Technical solution three：Chlorin e 6 metal salt compound as described in technical solution one is in anti-gastric-ulcer, anti-anemia action
With the application in liver protection shengbai drug research field.
The room temperature of the present invention refers to environment temperature, is 10~30 DEG C
The agents useful for same and raw material of the present invention is commercially available.
The present invention also provides described such as formula（1）Shown in chlorin e 6 metal salt compound quality standard.
The positive effect of the present invention is that：The present invention provides a kind of structures to define, the significant potential drug of activity
And its synthetic method, chlorin e 6 metal salt of the invention can be used for anti-gastric-ulcer, anti-anemia action and the research of liver protection shengbai drug
Raw material is provided in field.
Description of the drawings
Fig. 1 is chlorin e 6 metal salt-stable of the present invention（In 0~4 DEG C of refrigerator）Test result.
Fig. 2 is chlorin e 6 metal salt-stable of the present invention（At room temperature）Test result.
Specific embodiment
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
Product specification selects.
Embodiment 1：The preparation of chlorin e 6 trisodium salt
（1）Silkworm excrement crude chlorophyll 100g, is dissolved in 300ml ether, and 600ml hydrochloric acid is added, and stirs 2 hours, stands, takes
The dilution of 500ml water is added in lower layer's acid solution, and 10mol/L sodium hydroxide solutions are added dropwise to pH5~6, blackish green precipitation is precipitated, depressurize
Dry, it is about 20g to obtain Phephorbide a.
（2）It is about 5g to take Phephorbide a, is dissolved in 200ml methanol, and 0.5% sodium hydrate methanol solution 500ml is added,
It is stirred to react 5h, 3g sodium hydroxides and 30ml water, water-bath reflux 2h is added, hydrochloric acid is added dropwise to pH5~6, three times volume is added
Water, is precipitated precipitation after standing, decompression filter after through silica gel column chromatography（300-400 mesh, eluent：Dichloromethane, methanol, acetone,
Formic acid=10:1:1:0.7）, mainstream part is collected, about 1.2g2,7,12,18- tetramethyl -3- vinyl -8- ethyl -13- carboxyls-are obtained
15- methanoyl ethyl -17- carboxyl -17,18- chlorins.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）Above-mentioned chlorin e 6 mono-methyl 1.1g is taken, is dissolved in 15ml methanol, the sodium hydroxide water of 0.1mol/l is added
Solution, 65 DEG C of heating water bath react 8h, and pressurization filters, and the solid collected 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
By step in embodiment 1（3）Used in sodium hydroxide replace with potassium hydroxide chlorin e 6 three can be made
Sylvite, 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 metal salt-stable
Chlorin e 6 metal salt is taken respectively（By taking sodium salt as an example）With chlorin e 6（It purchases in the limited public affairs of Mayan reagent
Department）, take 1.0g to place at room temperature and in 0~4 DEG C of refrigerator respectively, measured by HPLC per sampling at regular intervals
The purity of the two, as a result respectively such as Fig. 1, shown in Fig. 2.
Chlorin e 6 metal salt（By taking sodium salt as an example）At normal temperatures and the stability at 0~4 DEG C and chlorin e 6
Compared to more stable, rate of change is slower.
Embodiment 4：The quality standard of chlorin e 6 metal salt
Molecular formula：C34H33N4O6R3
Wherein R is K or Na.
Its molecular weight is 662.68, R when R is Na when being K, and its molecular weight is 710.
Physical and chemical index such as table one：
Table one
| Project | Index |
| Ash content, 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 terms of As）, mg/kg ,≤ | 2 |
| Lead（Pb）, mg/kg ,≤ | 5 |
Ash test：1.0~2.0g of sample is taken, is set in the crucible of pre-burn, accurately weighed, slow calcination is to complete
Ashing, lets cool to room temperature；Unless otherwise specified, after adding 0.5~1.0ml of sulfuric acid that moistening, low-temperature heat is made to be eliminated to sulfuric acid vapor,
Processing to burn at 700~800 DEG C makes to be ashed completely, transplants in drier, lets cool to room temperature, after accurately weighed, then at 700~800 DEG C
Toast is burnt to constant weight.
The measurement of pH：The sample solution that compound concentration is 1%（1g is dissolved in 100ml water）, its pH is measured with acidometer
Value.
The measurement of absorbance and absorbance ratio：0.1g samples accurately are weighed, 0.0002g is accurate to, is dissolved in water, are moved into
Scale is added water in 100ml volumetric flasks to shake up.The above-mentioned aqueous solutions of 1ml are taken, phosphate buffer is used（pH7.5）It dilutes and is settled to
100ml, this is test liquid.Liquid of materialsing is placed in 1cm cuvettes, with phosphate buffer（pH7.5）Blank control is done, is used
Maximum absorption wave strong point of the spectrophotometer in two wave-length coverages of 405nm ± 3nm and 630nm ± 3nm measures absorbance.
（Absorbance should control between 0.3 ~ 0.7, otherwise should adjust test liquid concentration, then redeterminate absorbance.）
Test liquid a concentration of 1%, the suction measured with 1cm cuvettes, the maximum absorption wave strong point within the scope of 405nm ± 3nm
Luminosity is with 1% 1cm (405nm ± 3nm of Ε）Meter, by formula（A.1）It calculates：
In formula：
A 1--- the absorbance of practical measurement test liquid；
c 1--- the numerical value of the concentration of tested sample liquid（According to the loss on drying value of actual measurement sample, it is converted into terms of butt
Concentration）, unit is gram every milliliter（g/ml）.
A.4.4.2 absorbance ratio withw 1Meter, by formula（A.2）It calculates：
In formula：
Ε1% 1cm (405nm ± 3nm）1cm --- test liquid a concentration of 1%, with 1cm cuvettes, 405nm ±
The absorbance that maximum absorption wave strong point within the scope of 3nm measures；
Ε1% 1cm(630nm ± 3nm）1cm --- a concentration of 1 % of test liquid, with 1cm cuvettes, 630nm ±
The absorbance that maximum absorption wave strong point within the scope of 3nm measures, assay method is the same as 1% 1cm of Ε (405nm ± 3nm).
Experimental result is subject to the arithmetic mean of instantaneous values of parallel determinations.The survey independent twice obtained under the conditions of repeatability
The absolute difference for determining result must not exceed the 2% of arithmetic mean of instantaneous value.
HPLC purity tests：0.1g samples accurately are weighed, 0.0002g is accurate to, is placed in silicon ware, no more than 500 DEG C
Lower calcination with ~ 2 drop sulfuric acid moistening of 1 drop, is ashed again to carbon-free.The hydrochloric acid solution for being 10% with mass fraction divides 3 times（Every time
5ml）Dissolving ash content is boiled, and is filtered in 100ml volumetric flasks, is settled to scale with water after cooling, this is test liquid.
Mobile phase A：Acetonitrile, it is spare after ultrasound degassing with 0.45 μm of membrane filtration.
Mobile phase B：Acetonitrile：0.1%TFA=45:55（Volume ratio）It prepares, after mixing, with 0.45 μm of membrane filtration,
It is spare after ultrasound degassing.
Column temperature：25℃.
Flow rate of mobile phase：1ml/min.
Sample size：20μl.
The preparation of test liquid：Weigh chlorin E6Trisodium salt sample 0.012g, it is accurately weighed, 25ml volumetric flasks are placed in,
Methanol dissolves and is settled to scale, shakes up, and pipettes 1ml to 10ml volumetric flasks, Mobile phase B is settled to scale.It shakes up spare.
It measures：In 5.2.3 with reference under chromatographic condition, by two method gradient elution of table, test liquid is measured, when reservation
Between 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：Sample purity is calculated by area normalization method.
Loss on drying measures：2~4g of test sample is taken, is uniformly mixed, divides and takes about 0.5~lg, be placed in same in test sample
Under the conditions of dry and in the measuring cup weighed, it is accurately weighed, open bottle cap, be put into vacuum drying apparatus, be decompressed to 2.67kPa
(20mmHg) continues half an hour below, is placed at room temperature for 24 hours.Connection anhydrous calcium chloride drying tube is exported in vacuum drying apparatus, is beaten
Piston to be opened, waits for that interior external pressure is consistent, closure piston opens drier, covers bottle cap, takes out measuring cup accurately weighed weight rapidly,
Calculate the water content in test sample（%）.
Claims (8)
1. a kind of preparation method of chlorin e 6 metal salt compound, the chemical constitution of chlorin e 6 metal salt compound is such as
Formula（I）It is shown：
（I）
Wherein, R K+Or Na+, which is characterized in that include the following steps：
（1）It using silkworm excrement crude chlorophyll as raw material, is dissolved in ether, concentrated hydrochloric acid is added, generate Phephorbide a；
（2）Phephorbide a is reacted in highly basic methanol solution, rear generation chlorin e 6 mono-methyl after little water is added；
（3）Step（2）Gained chlorin e 6 mono-methyl is in alcoholic caustic potash or sodium hydroxide alcoholic solution reaction reagent
Reaction, and through isolating and purifying, obtain compound（I）.
2. preparation method as described in claim 1, which is characterized in that step（3）Described in alcohol be under room temperature be liquid
C1-6Lower alcohol.
3. preparation method as described in claim 1, which is characterized in that step（2）Described in highly basic be potassium hydroxide or hydrogen
Sodium oxide molybdena.
4. preparation method as described in claim 1, which is characterized in that step（3）Middle chlorin e 6 mono-methyl with react examination
The volume ratio of agent is 1:10~150.
5. preparation method as described in claim 1, which is characterized in that step（3）Described in reaction time for reacting be 1~
10h, reaction temperature are 20~60 DEG C.
6. preparation method as described in claim 1, which is characterized in that the purifying is detached using silica gel column chromatography, expansion
Agent is one or more in dichloromethane, chloroform, carbon tetrachloride, methanol, ethyl alcohol, ethyl acetate, acetone and petroleum ether
And the formic acid wherein containing total volume 2%~0.5%.
7. preparation method as claimed in claim 2, which is characterized in that the lower alcohol is methanol, ethyl alcohol, propyl alcohol or fourth
Alcohol.
8. preparation method as claimed in claim 6, which is characterized in that the solvent is dichloromethane, chloroform, four
One or more in chlorination carbon, methanol, ethyl alcohol, ethyl acetate, acetone and petroleum ether and wherein contain total volume 1.2%~0.8%
Formic acid.
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| KR102112819B1 (en) * | 2017-12-11 | 2020-05-19 | 동성제약주식회사 | Pharmaceutical compositions for treatment of high fat diet induced obesity and non-alcoholic steatohepatitis using trisodium Chlorin e6 as photosensitizer |
| RU2705199C1 (en) * | 2019-05-22 | 2019-11-06 | Илья Евгеньевич Жаров | METHOD OF PRODUCING TRIS-SODIUM SALT OF CHLORINE e6 |
| 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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| CN1097760A (en) * | 1994-06-03 | 1995-01-25 | 中国人民解放军第二军医大学 | Chlorin e 6Metal complex and synthetic method thereof |
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| KR101579299B1 (en) * | 2013-07-04 | 2015-12-21 | 다이아텍코리아 주식회사 | A novel Chlorin e6 monomethyl ester, synthesis method of the same, and use of the same |
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