CN1827574A - Chemical synthesis process for hypericin and derivatives thereof - Google Patents
Chemical synthesis process for hypericin and derivatives thereof Download PDFInfo
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- CN1827574A CN1827574A CN 200610076217 CN200610076217A CN1827574A CN 1827574 A CN1827574 A CN 1827574A CN 200610076217 CN200610076217 CN 200610076217 CN 200610076217 A CN200610076217 A CN 200610076217A CN 1827574 A CN1827574 A CN 1827574A
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Abstract
The invention discloses a method for chemosynthesis of the hypericin and its derivant. The said method includes the following steps: 1) dissolving 1, 3, 8-trihydroxy-6-methyl anthraquinone in the analytical pure glacial acetic acid,then adding concentrated hydrochloric acid with 36-40 % of zinc bichloride dehydrate, reacting for 1-4 hours at the temperature of less than 125 DEG C, cooling, and obtaining the 1, 3, 8-trihydroxy-6-methyl anthranone; 2) making 1, 3, 8-trihydroxy-6-methyl anthranone, pyridine, piperidine, nitrogen-oxygen pyridine and ferrisulphas hepthydrate react free of light for 0.5-3 hours at the temperature of 100-130 DEG C, then dissolving the reaction products in the acetone, illuminating them by a halogen lamp for 12-24 hours, thickening and dissolving them in the skellysolve B, filtering the deposition, and obtaining the hypericin. The method has advantages of that its operation is simple and reasonable, its cost is cheap, its productivity is high, its actual applied value is higher, so its actual value is broad.
Description
Technical field
The present invention relates to the chemical synthesis process of compound and derivative thereof, particularly relate to the chemical synthesis process of hypericin and derivative thereof.
Background technology
Hypericin (hypericin, 4,4,5,5,7,7-hexahydroxy--2,2-dimethyl-meta-meso-naphthadianthrene ketone, formula 1 seen in chemical structural formula), be the bioactive material of tool in the Herba Hyperici perforati (Hypericum perforatum L.), have antiviral, antidepressant and photo-activity.
Because the content of hypericin in the Herba Hyperici perforati herb only has about 4/10000ths, at present, the content of hypericin in its extract that extracts from Herba Hyperici perforati also is no more than 1% both at home and abroad, therefore, even if improve extraction process, the content of the hypericin of extract, separating neither be very high, but also can destroy a large amount of natural vegetations or take a large amount of arable lands.In order to improve hypericin content, to realize the industrialization of hypericin and derivative (as sulfonic acid class, amine, heterocyclic derivative) thereof, just the researchist considers to realize this goal from the angle of chemosynthesis.
At present, existing abroad many reports about the hypericin chemical synthesis route, the first with 3, the 5-dimethoxy p-methyl is raw material, whole synthetic route needed for 12 steps, and productive rate only is 6-9%; Its two be with Schuttgelb as starting raw material, Schuttgelb is directly changed into former hypericin, under visible light radiation, changes into hypericin more then, has problems such as the Schuttgelb productive rate is lower but transform for the first time.All there is big defective in said synthesis route, therefore presses for an economy, and is easy and simple to handle, reasonable, the chemical synthesis route of the hypericin that relative productive rate is higher.
Summary of the invention
It is lower to the purpose of this invention is to provide a kind of cost, easy and simple to handle, reasonable, the hypericin that relative productive rate is higher and the chemical synthesis process of derivative thereof.
The chemical synthesis process of hypericin provided by the present invention can may further comprise the steps:
1) with 1,3,8-trihydroxy--6-tectoquinone (Schuttgelb) is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, and reaction is 1-4 hour under not being higher than 125 ℃, and cooling obtains 1,3,8-trihydroxy--6-methyl anthrone; Described 1,3,8-trihydroxy--6-tectoquinone and SnCl
2.2H
2The mol ratio of O is 1: 4-6; The volume ratio of acetate and hydrochloric acid is 1.5-3: 1;
2) with 1,3,8-trihydroxy--6-methyl anthrone and pyridine, piperidines, nitrogen oxy picolinate and FeSO
47H
2O is dissolved in acetone with reaction product again 100-130 ℃ of following lucifuge reaction 0.5-3 hour, with halogen lamp irradiation 12-24 hour, concentrates, and uses n-hexane dissolution, and filtering-depositing obtains hypericin; Described 1,3,8-trihydroxy--6-methyl anthrone and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 1: 5-7: 0.1-0.18; The volume ratio of pyridine and piperidines is 10-11: 1.
In the synthetic method of above-mentioned hypericin, step 2) the nitrogen oxy picolinate in can adopt any one in this compounds, as nitrogen oxygen pyrazine, nitrogen oxygen pyridazine etc.
In addition, 1,3 in the step 1), 8-trihydroxy--6-tectoquinone can be synthetic by following step:
1) ethyl formate is mixed with acetone, splashes into the anhydrous diethyl ether that contains the sodium silk, stir, treat that the sodium silk reacts completely after, leave standstill 12-24h, leach the lark solid precipitation, obtain acetyl acetaldehyde; The mol ratio of described ethyl formate and acetone and sodium silk is 4-6: 4-8: 1-5; The volumetric molar concentration of sodium silk in anhydrous diethyl ether is 0.5-3mol/L;
2) acetyl acetaldehyde is mixed with methyl aceto acetate, place 12-24h under the room temperature, add the dehydrated alcohol that contains the sodium silk, reacted 10-14 hour down at 65-100 ℃, leave standstill 12-24h, leach precipitation, therefrom isolate organic acid, behind the recrystallization, obtain 2-hydroxy-4-methyl phenylformic acid; The mol ratio of described acetyl acetaldehyde and methyl aceto acetate and sodium is 0.5-1.3: 0.6-2: 0.5-1.5; The volumetric molar concentration of sodium in dehydrated alcohol is 0.6-2mol/L;
3) 2-hydroxy-4-methyl phenylformic acid is dissolved in the dehydrated alcohol, dripping mass percentage concentration is the NaOH solution of 8-20%, drip methyl-sulfate not being higher than under 10 ℃ the temperature then, again reaction system was reacted 3-8 hour down at 20-90 ℃, cooling, acidifying is filtered, recrystallization obtains 2-methoxyl group-4-tolyl acid; The mol ratio of described 2-hydroxy-4-methyl phenylformic acid and methyl-sulfate is 0.3-1.2: 0.5-1.5; The volume ratio of ethanol and NaOH solution is 1-3: 0.2-1.5;
4) 2-methoxyl group-4-tolyl acid is dissolved in the dimethylbenzene, adds anhydrous AlCl
3After, thionyl chloride was reacted 0.5-8 hour down at 40-90 ℃ then, and excessive thionyl chloride is removed in distillation, and organic solvent dissolution and recrystallization obtain 2-methoxyl group-4-methyl benzoyl chloride; Described 2-methoxyl group-4-tolyl acid, anhydrous AlCl
3With the mol ratio of thionyl chloride be 0.3-1.5: 0.1-0.5: 0.2-2;
5) with 3, the 5-dimethoxy p-methyl is dissolved in the anhydrous trichloromethane, adds anhydrous AlCl
3Keep away and be cooled under the water condition below 0 ℃, under agitation condition, splash into the anhydrous trichloromethane that is dissolved with 2-methoxyl group-4-methyl benzoyl chloride, stir 12-36h under the room temperature after, the impouring mass percentage concentration is in the dilute hydrochloric acid frozen water of 3-9%, tell organic layer, the pressure reducing and steaming solvent is used the ether dissolution solute, washing, drying boils off ether, is the Me of 99.5-99.8% with throw out and mass percentage concentration
2SO
4Solution, Anhydrous potassium carbonate and acetone mix, reacted 4-8 hour down at 50-100 ℃, filter concentrated filtrate, adding volumetric molar concentration in concentrated solution again is the NaOH solution of 1-3mol/L, react 0.5-2h, acidifying, trichloromethane recrystallization down at 60-105 ℃, separate out 3,5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid; Described 3,5-dimethoxy p-methyl, anhydrous AlCl
3With the mol ratio of 2-methoxyl group-4-methyl benzoyl chloride be 1: 0.5-2: 0.4: 2; 3, the volumetric molar concentration of 5-dimethoxy p-methyl in anhydrous trichloromethane is 0.1-2mol/L, and the 2-methoxyl group-volumetric molar concentration of 4-methyl benzoyl chloride in anhydrous trichloromethane is 0.2-1.5mol/L; Me
2SO
4With the mol ratio of Anhydrous potassium carbonate be 1: 0.5-2, residue and Me
2SO
4The volume ratio of solution and acetone is 0.3-2: 0.2-1: 2-10; The volume ratio of concentrated solution and NaOH solution is 1: 10-25;
6) NaCl and anhydrous AlCl
3Mixing is kept away under the water condition heating and is made its fusion, and gradation adds 3 under the agitation condition, 5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid is warming up to 150-175 ℃ then, stirs reaction 0.5-1.5h down, reaction finishes postcooling, the dilute hydrochloric acid frozen water that adds 3-9%, filter collection precipitation is washed to neutrality, separate, obtain 1,3,8-trihydroxy--6-tectoquinone; Described 3,5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid, NaCl and anhydrous AlCl
3Mol ratio be 1-4: 0.5-1.5: 1-3.
Above-mentioned 1,3, in the synthetic method of 8-trihydroxy--6-tectoquinone, step 2) aperture of the used molecular sieve of filtering-depositing is 4A in, and the method for separating organic acid is a pH gradient separations method, and the solvent that recrystallization is used is a benzene.
Filtering-depositing filters with B in the step 3), and the acid that acidifying is used is the 4-6mol/L concentrated hydrochloric acid; The solvent that recrystallization is used is benzene and trichloromethane.
The solvent that the step 4) recrystallization is used is a hexanaphthene.
The acid that acidifying is used in the step 5) is the 4-6mol/L concentrated hydrochloric acid.
From the precipitation of the neutrality after washing, isolate 1,3,8-trihydroxy--6-tectoquinone with silica gel VLC in the step 6).
The present invention also provides the chemical synthesis process of hypericin heterocyclic, sulfonic acid class and amino derivative thereof.
Wherein, the method for synthesis type II hypericin heterocyclic derivative can may further comprise the steps:
1) with 1,3,8-trimethoxy-6-benzoglyoxaline anthraquinone is dissolved in the analytically pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the HBr of 45-47%, reacts 1-1.5 hour down at 100-130 ℃, and cooling adds in the frozen water, separates, and residue is weighed after washing vacuum-drying and obtained product; Described 1,3,8-trimethoxy-6-benzoglyoxaline anthraquinone and SnCl
2.2H
2The mol ratio of O is 1: 4-10; The volume ratio of glacial acetic acid and HBr is 1-4: 0.5-2;
2) with the product and the pyridine of step 1), piperidines, nitrogen oxy picolinate and FeSO
47H
2O was 110-130 ℃ of following lucifuge reaction 0.5-2 hour, again reaction product is dissolved in 1-4mol/L hydrochloric acid, stirred 20-50 minute under the room temperature, separate the back with the 3-9%HCl washing, after wash vacuum-drying with water, product is dissolved in behind the methyl alcohol with halogen lamp irradiation 0.5-2 hour, boil off solvent, fully stirring is dissolved in methyl alcohol, obtains formula II hypericin heterocyclic derivative; The product of described step 1) and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.5-1.5: 2-8: 0.1-0.8, and the ratio of pyridine and piperidines is 10-11: 1.
A kind of synthesis type III2, the method of 5-disulfonic acid base hypericin, be with hypericin and oleum (15-25 ℃) reaction at room temperature 1-3 hour, the mixture of ice and water dilution adds sodium-chlor until saturated, precipitation separation, to precipitate and use cold wash, vacuum-drying obtains 2,5-disulfonic acid base hypericin; The mol ratio of described hypericin and oleum is 1: 12-14.
R
1=SO
3H; R
2=H formula IV
A kind of synthesis type IV 2,5, the method for 9-trisulfonic acid base hypericin is that hypericin and oleum were reacted 0.5-1.5 hour at 75-85 ℃, the mixture of ice and water dilution, add sodium-chlor until saturated, precipitation separation will precipitate and use cold wash, vacuum-drying, obtain 2,5,9-trisulfonic acid base hypericin; The mol ratio of described hypericin and oleum is 1: 14-16.
R
1=SO
3H; R
2=SO
3H formula V
A kind of synthesis type V 2,5,9, the method of 12-tetrasulfonic acid base hypericin is hypericin and oleum to be reacted 1-2 hour the mixture of ice and water dilution at 75-85 ℃, add sodium-chlor until saturated, precipitation separation will precipitate and use cold wash, vacuum-drying, obtain 2,5,9,12-tetrasulfonic acid base hypericin; The mol ratio of described hypericin and oleum is 1: 25-27.
X=OCH
2CH
2NHCOCH
3Formula VI
A kind of method of synthesis type VI hypericin amino derivative may further comprise the steps:
1) with 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, reacts 0.5-1.5 hour down at 110-130 ℃, and cooling adds icy salt solution, precipitation separation, and washing, vacuum-drying obtains product 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone; Described 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone and SnCl
2.2H
2The mol ratio of O is 0.5-1.5: 3-6; The volume ratio of acetate and hydrochloric acid is 2-10: 0.5-2;
2) 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone and pyridine, piperidines, nitrogen oxy picolinate and FeSO
47H
2O was 100-120 ℃ of following lucifuge reaction 0.5-3 hour, with concentrated hydrochloric acid aqueous solution (water: concentrated hydrochloric acid=10: 1) make its rapid cooling, precipitation separation, washing was dissolved in acetone with reaction product, with halogen lamp irradiation 1-10 hour, filter, filtrate concentrates, and through the silica gel column chromatography wash-out, obtains formula VI hypericin amino derivative; Described 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.2-1.5: 4.5-8: 0.1-0.4; The volume ratio of pyridine and piperidines is 10-11: 1.
A kind of method of synthesis type VII hypericin amino derivative may further comprise the steps:
1) with 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, reacts 0.5-1.5 hour down at 110-130 ℃, and cooling adds icy salt solution, precipitation separation, and washing, vacuum-drying obtains product 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone; Described 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone and SnCl
2.2H
2The mol ratio of O is 0.5-1.5: 3-6; The volume ratio of acetate and hydrochloric acid is 2-10: 0.5-2;
2) to the product 1,3 of step 1), add pyridine, piperidines, nitrogen oxy picolinate and FeSO in 8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone
47H
2O is 100-120 ℃ of following lucifuge reaction 0.5-3 hour, with concentrated hydrochloric acid aqueous solution (water: concentrated hydrochloric acid=10: 1) make its rapid cooling, precipitation separation, washing was dissolved in acetone with reaction product, with halogen lamp irradiation 1-10 hour, filter, filtrate concentrates, through silica gel column chromatography wash-out (CHCl
3: MeOH=4: 1), obtain product; The product of described step 1) and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.2-1.5: 4.5-8: 0.1-0.4; The volume ratio of pyridine and piperidines is 10-11: 1;
3) to step 2) product in add 4-6mol/L HCl, boiling water bath 0.25-0.75 hour, separate, through vacuum-drying, obtain formula VII hypericin amino derivative; Described step 2) the product and the mol ratio of hydrochloric acid are 0.2-1.5: 1-2.
A kind of method of synthesis type VIII hypericin amino derivative may further comprise the steps:
1) 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthraquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, reacts 0.5-3 hour down at 110-130 ℃, and cooling adds icy salt solution, and the precipitation separation washing in vacuum-drying, obtains product 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthrone; Described 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthraquinone and SnCl
2.2H
2The mol ratio of O is 0.5-1.5: 3-6; The volume ratio of acetate and hydrochloric acid is 2-10: 0.5-2;
2) product with step 1) joins piperidines, nitrogen oxy picolinate and be dissolved with FeSO
47H
2In the pyridine of O, at 100-120 ℃ of following lucifuge reaction 0.5-3 hour, cool to room temperature, with concentrated hydrochloric acid aqueous solution (water: concentrated hydrochloric acid=10: 1) make its rapid cooling, precipitation separation, the washing, with the abundant stirring and dissolving of reaction product in acetone, with halogen lamp irradiation 1-10 hour, filter, filtrate concentrates, and separates (methanol-eluted fractions) through Sephadex LH-20 column purification, obtain formula VIII hypericin amino derivative, the product of described step 4) and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.2-1.5: 4.5-8: 0.1-0.4; The volume ratio of pyridine and piperidines is 10-11: 1.
The invention provides the chemical synthesis process of a kind of hypericin and derivative thereof.This method has easy and simple to handle, reasonable, and is with low cost, the advantage that productive rate is high.If apply the present invention to suitability for industrialized production, can greatly satisfy the demand of market to hypericin and derivative thereof, also provide convenience simultaneously for the exploitation of hypericin and derivative related products thereof.In sum, the present invention has higher actual application value, and market outlook are wide.
Below in conjunction with specific embodiment the present invention is described in further details.
Description of drawings
Fig. 1 is the HMNR collection of illustrative plates of hypericin
Fig. 2 is the 2D ROESY collection of illustrative plates of hypericin
Embodiment
Method therefor is ordinary method if no special instructions among the following embodiment.
Synthesizing of embodiment 1, hypericin
The method synthetic hypericin of current series invention, detailed process may further comprise the steps:
1) acetyl acetaldehyde is synthetic
The chemical equation of synthesis of acetyl acetaldehyde is as follows:
Concrete grammar is: ethyl formate 18.5g (0.25mol) and acetone 17.4g (0.30mol) are mixed, slowly splash into and contain among the anhydrous diethyl ether 125mL that newly cuts sodium silk 6g (0.15mol), keep away water condition under and stir, treat that the sodium silk reacts completely after, placement 12-24h.Leach the lark solid precipitation,, get solid acetyl acetaldehyde 17.1g after the vacuum-drying with the anhydrous diethyl ether washing.After measured, acetyl acetaldehyde productive rate is 80%.
2) the 2-hydroxy-4-methyl is benzoic synthetic
The benzoic chemical equation of Synthetic 2-hydroxy-4-methyl is as follows:
Concrete grammar is: get acetyl acetaldehyde 25.8g (0.3mol), add methyl aceto acetate 42.25g (0.33mol), warmly make moltenly entirely, mixture is placed 18h under room temperature, add the dehydrated alcohol 200mL that contains 6.9g sodium (0.3mol), at 80 ℃ of following backflow 12h, place 12-24h, leach precipitation 40g, precipitate with washing with alcohol with the 4A molecular sieve, drain, water 100mL dissolving filter cake is used the 4A molecular sieve filtration, a small amount of washing, water layer is with 6mol hydrochloric acid adjust pH to 3, with pH gradient separations method separating organic acid, solvent flashing, benzene recrystallization, get white, needle-shaped crystals 18.4g, yield 40%.Product is carried out instrumental analysis, as a result IR (KBr) cm-1:3240-2850 (intramolecular hydrogen bond, bs), 1149 (C-OH), 1650 (C=O, intramolecular hydrogen bonds), 1636 (aromatic ring frames); MSm/z:152 (M+), 134 (M-H
2O); HNMR (CD
3Cl) δ ppm:10.35 (1H, s, OH, D
2O exchanges disappearance), 7.79 (1H, d, J5,6=8Hz, 6-H), 6.83 (1H, s, 3-H), 6.75 (1H, d, J5,6=8Hz, 5-H), 2.37 (3H, s, pH-CH
3), show to have obtained the correct 2-hydroxy-4-methyl phenylformic acid of structure.
3) 2-methoxyl group-4-tolyl acid is synthetic
The chemical equation of Synthetic 2-methoxyl group-4-tolyl acid is as follows:
Concrete grammar is: get 2-hydroxy-4-methyl phenylformic acid 15.2g (0.1mol), be dissolved in the 100mL dehydrated alcohol, dropwise add mass percentage concentration and be 10% NaOH solution 50mL, drip methyl-sulfate 12.6g (0.088mol) down not being higher than 10 ℃, heat up then, at backflow 4-6 below 55 ℃ hour, after the placement cooling, with the concentrated hydrochloric acid acidifying of 6mol/L, filter with B, benzene is used in the washing back: trichloromethane (1: 3) recrystallization obtains crystallization 8.27g, yield 50%.Product is carried out instrumental analysis, IR (KBr) cm-1:1245 as a result, 1034 (C-O-C stretching vibrations), 1450 (methyl C-H flexural vibration) show to have obtained the correct 2-methoxyl group-4-tolyl acid of structure.
4,2-methoxyl group-4-methyl benzoyl chloride is synthetic
The chemical equation of Synthetic 2-methoxyl group-4-methyl benzoyl chloride is as follows:
Tool
Concrete grammar is: get 2-methoxyl group-4-tolyl acid 4.98g (0.03mol), be dissolved in 100mL dimethylbenzene, add the anhydrous AlCl of 0.8g
3(0.006mol), dropwise add thionyl chloride 4.5g (0.0378mol), vigorous reaction produces a large amount of gases, and at 80 ℃ of following backflow 0.5-2 hours, after reacting completely, excessive SOCl was removed in distillation
2, recrystallization behind the dissolve with ethanol obtains crystallization 4.8g, yield 87%.Product is carried out instrumental analysis, IR (KBr) cm-1:1770 (C=O stretching vibration) as a result, 1250-1190 (C-Cl stretching vibration) shows to have obtained the correct 2-methoxyl group-4-methyl benzoyl chloride of structure.
5,1,6,8-trihydroxy--3-tectoquinone (Schuttgelb) synthetic
Utilize friedel-crafts reaction to synthesize 1,6, the chemical equation of 8-trihydroxy--3-tectoquinone is as follows:
Concrete grammar is: 1) get 3,5-dimethoxy p-methyl 1.96g (0.01mol) is dissolved among the anhydrous trichloromethane 50mL, adds the anhydrous AlCl of 1.602g
3(0.012mol), keep away the water device, cryosel is bathed and is cooled to below 0 ℃, stirs down and splashes into the anhydrous trichloromethane 20mL that is dissolved with 2-methoxyl group-4-methyl benzoyl chloride 2.03g (0.011mol), stirs 12-36h under the room temperature, in the dilute hydrochloric acid frozen water of impouring 6%, tell organic layer, pressure reducing and steaming solvent, ether dissolution, washing, anhydrous Na SO
4Drying leaches siccative, boils off ether, and it is 99.8% Me that residue adds mass percentage concentration
2SO
4Solution 3.5mL, Anhydrous potassium carbonate 4g (0.029mol), acetone 40mL refluxes, and filters, filtrate concentrates, residue adds the HCl acidifying of 6mol with 100mL 2N NaOH backflow 1h, separates out pale precipitation 3,5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid 1.08g, vacuum-drying; 2) with NaCl 0.58g (1mmol), the anhydrous AlCl of 2.67g
3(2mmol) mixing is kept away under the water condition heating and is made its fusion, and gradation adds 3 under the vigorous stirring; 5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid 1g (3mmol) is warming up to 170 ℃, vigorous stirring after adding; reaction finishes postcooling, adds rare HCl frozen water of 6%, filter collection precipitation; be washed to neutrality; silica gel VLC separates, and obtains 1,6; the orange needle crystal 0.2g of 8-trihydroxy--3-tectoquinone, productive rate 25%.Product is carried out instrumental analysis, IR (KBr) cm-1:3500-300 () as a result, 2900 (C-OH), 1585 (C=O, intramolecular hydrogen bonds), 1636 (aromatic ring frames); MS m/z:270 (M+); 271 (M+1); HNMR (CD
3Cl) δ ppm:7.57 (1H, s, 5H), 7.33 (1H, s, 7H), 7.25 (1H, d, J=0.98Hz, 4H), 6.66 (1H, d, J=0.98Hz, 2H), 2.46 (3H, d, CH
3), show to have obtained the correct Schuttgelb of structure.
6,1,3,8-trihydroxy--6-methyl anthrone synthetic
Synthesize 1,3, the chemical equation of 8-trihydroxy--6-methyl anthrone is as follows:
Concrete grammar is: get 1,3,8-trihydroxy--6-tectoquinone 1.25g (5mmol) is dissolved in the 70mL acetate, adds 33mL then and contains 5g SnCl
2.2H
2The concentrated hydrochloric acid of O (0.022mol) refluxed 3 hours under not being higher than 125 ℃, and cool to room temperature is separated out precipitation, uses filter paper filtering, obtains emodin anthrone 0.72g, productive rate 92%.Product is carried out instrumental analysis, IR (KBr): 1620cm-1 as a result,
1H-NMR (DMSO-d
6, 200MHz, δ ppm): 12.36 and 12.19 (2s, OH1 and OH2), 10.82 (s, OH3), 6.73 and 6.64 (2s, H5 and H7), 4.26 (s, CH
2), 2.29 (s, CH
3), 6.37 (H2), 6.26 (H4) .MS:m/e (%)=300 (21), 299 (48), 298 (100M
+), 283 (40), 255 (45), 240 (32), 225 (31), 197 (19), 149 (43), show obtained structure correct 1,3,8-trihydroxy--6-methyl anthrone.
7, hypericin is synthetic
The chemical equation of synthetic hypericin is as follows:
Concrete grammar is: get 1g 1,3,8-trihydroxy--6-methyl anthrone (4mmol) adds 22mL pyridine/piperidines mixed solution, 2.45g nitrogen oxy picolinate (27.2mmol), 0.16g FeSO
47H
2O (5.6mmol), inflated with nitrogen is heated to 115 ℃ of reactions with reaction mixture under the condition of lucifuge, reaction finishes the back and concentrates, use the silicagel column reaction product isolated, gains are dissolved in 200mL acetone,, concentrate with halogen lamp irradiation 12-24 hour, use n-hexane dissolution, with the filter paper filtering precipitation, obtain hypericin 1.25g, productive rate 62%.Product is carried out instrumental analysis, IR (KBr) cm-1:3550-3000 as a result, 1660; HNMR (CD
3Cl) (1H, s), 6.62 (1H, s), (2H, dd), (3H, t), wherein (solvent is CD to the HMNR collection of illustrative plates of hypericin to 1.19-1.04 to 2.9-2.68 to δ ppm:7.35
3Cl) as shown in Figure 1, (solvent is DMSO-d to 2D ROESY collection of illustrative plates
6) as shown in Figure 2, show to have obtained the correct hypericin of structure.
Synthesizing of embodiment 2, hypericin heterocyclic derivative
Be example now with hypericin heterocyclic derivative with above chemical structural formula, the synthetic method of hypericin heterocyclic derivative is described, promptly earlier synthetic its corresponding Schuttgelb heterocyclic derivative, the purpose product that obtains having the said structure formula again, detailed process may further comprise the steps:
1) 1,3,8-trihydroxy--6-benzoglyoxaline anthrone synthetic
With 166.6mg1,3,8-trimethoxy-6-benzoglyoxaline anthraquinone (0.402mmol) is dissolved in the 30mL glacial acetic acid, adds then and contains 725.6mgSnCl
2.2H
2The mass percentage concentration of O (3.216mmol) is 45% HBr15mL, and applying argon gas was refluxing 1.3 hours below 125 ℃, and cooling adds in the frozen water, separates, and residue is weighed after washing vacuum-drying and obtained product 130.2mg, and productive rate is 90%.Product is carried out instrumental analysis, H as a result
1NMR (DMSO-d
6): 13.49 (br.s, NH), 12.43 (s, 8-OH), 12.33 (s, 1-OH), 10.95 (s, 3-OH), 4.49 (s, 10-CH
2) IR (KBr, cm
-1): 3474 (br, OH, NH), 3053 (=CH
2), 2930,2862 (CH-aliph), 1622 (CO), 1602 (C=N), 1480,1381,1340,1277,1248,1171,1159,1060,845,744.
2) 10,11-bisbenzimidazole-10,11-dinor-hypericin synthetic
The product 73.2mg (0.204mmol) that takes by weighing step 1) adds 96.96mg nitrogen oxy picolinate (1.02mmol), 2.272mgFeSO
47H
2O (0.008mmol), 1.0mL pyridine, 0.1mL piperidines, applying argon gas, 120 ℃ of following lucifuges were reacted 1 hour, cool to room temperature, pour into 9mL 2mol/L hydrochloric acid at ambient temperature lucifuge stirred 30-40 minute, separate the back with 6%HCl washing three times, after wash with water, vacuum-drying is dissolved in behind the 1000mL methyl alcohol product with halogen lamp irradiation 1 hour, concentrates, the gained solid is promptly got final product 46.1mg with the abundant stirring and dissolving of methyl alcohol, productive rate is 70%, and product is carried out instrumental analysis, as a result Mp＞350 ℃; IR (KBr, cm
-1): 3416 (br., OH, NH), 2943,2840 (CH-aliph), 1667 (CO), 1659 (CO), 1598 (C=N), 1566,1486,1460,1427,1375,1350,1325,1222,1203,1070,1054,982,946,915,886,852,812,757657.
Synthesizing of embodiment 3, hypericin sulfonic acid analog derivative
Be example with the hypericin sulfonic acid analog derivative with above chemical structural formula now, the synthetic method of hypericin sulfonic acid analog derivative is described, concrete grammar is as follows:
1,2,5-disulfonic acid base hypericin synthetic
45mg hypericin (0.089mmol) and 105mg oleum (1.07mmol) were at room temperature reacted 2 hours, the frozen water dilution, add sodium-chlor until saturated, centrifugal, precipitation uses cold wash until neutrality, vacuum-drying, wash-out on the Sephadex-LH2O post, elutriant are methanol aqueous solution (methyl alcohol: water=4: 1), obtain 2,5-disulfonic acid base hypericin 8mg, productive rate is 10%; Product is carried out instrumental analysis, H as a result
1NMR (DMSO-d
6, 500MHz, ppm): 15.00 (s, 2H), 14.36 (s, 2H), 13.51 (s, 2H), 7.48 (s, CH-9,12), 2.74 (s, 6H, CH
3-10,11).
2,2,5,9-trisulfonic acid base hypericin synthetic
40mg hypericin (0.079mmol) and 116.7mg oleum (1.19mmol) were reacted 1 hour at 80 ℃, the frozen water dilution adds sodium-chlor until saturated, and is centrifugal, the precipitation cold wash, vacuum-drying obtains 2,5,9-trisulfonic acid base hypericin 38mg, productive rate is 49.7%, and product is carried out instrumental analysis, H as a result
1NMR (DMSO-d
6, 500MHz, ppm): 17.38 (s, 1H), 15.04 (s, 1H), 14.34 (s, 1H), 14.12 (s, 1H), 13.96 (s, 1H), 13.47 (s, 1H), 7.44 (s, CH-9), 2.98 (s, CH
3-11), 2.71 (s, CH
3-10).
3,2,5,9,12-tetrasulfonic acid base hypericin synthetic
50.4mg hypericin (0.1mmol) and 254.8mg oleum (2.6mmol) were reacted 1.5 hours at 80 ℃, and the frozen water dilution adds sodium-chlor until saturated, centrifugal, precipitation is used cold wash, and vacuum-drying obtains 2,5,9,12-tetrasulfonic acid base hypericin 78mg, productive rate is 74%, product is carried out instrumental analysis, H as a result
1NMR (DMSO-d
6, 500MHz, ppm): 17.34 (s, 2H), 14.05 (s, 2H), 14.03 (s, 2H), 2.96 (s, CH
3-10,11).
Synthesizing of embodiment 4, hypericin amino derivative
1、
Have the synthetic method of the hypericin amino derivative of above chemical structural formula, may further comprise the steps:
1) with 76.5mg 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone (0.20mmol) is dissolved in the 18mL analytical pure glacial acetic acid, adds 2.6mL then and contain 227.3mg SnCl
2.2H
2The mass percentage concentration of O (1.00mmol) is the concentrated hydrochloric acid of 36-38%, be heated to 120 ℃ and reacted 0.5 hour down, cooling adds icy salt solution, precipitation separation, washing in vacuum-drying, obtains product 67mg 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone. productive rate is 94%, and product is carried out instrumental analysis, H as a result
1NMR (DMSO-d
6, 200MHz, ppm): 12.32 (s, 1H, OH), 12.36 (s, 1H, OH), 10.87 (s, 1H, OH), 8.0 (bs, 1H, NH), 6.88 (s, 1H, ar-H), 6.41 (s, 1H, ar-H), 6.22 (d, J=1.8Hz, ar-H) 4.48 (s, 2H, CH
2-O), 4.31 (s, 2H, ar-CH
2-ar), 3.45 (t, J=5.6Hz, 2H, CH
2-NH), 3.26 (t, j=5.5Hz, 2H, CH
2-O), 1.81 (s, 3H, CH
3CONH).
2) 76.36mg 1,3, adds 1mL pyridine, 100 μ l piperidines, 130mg nitrogen oxy picolinate (1.44mmol) and 9.45mgFeSO in 8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone (0.21mmol)
47H
2O, 110 ℃ of following lucifuges reactions 1.5 hours, cool to room temperature, with concentrated hydrochloric acid aqueous solution (10: 1) it is lowered the temperature rapidly after, precipitation separation, washing in 650mL acetone, is shone the abundant stirring and dissolving of reaction product 2 hours with halogen lamp, filter, filtrate concentrates, through silica gel column chromatography wash-out (CHCl
3: MeOH=4: 1), obtain the hypericin amino derivative (X=OCH that 11mg has above chemical structural formula
2CH
2NHCOCH
3) productive rate is 13%; Product is carried out instrumental analysis, H as a result
1NMR (acetone-d
6, 200MHz, ppm): 18.84 (bs, OH-3), 14.83 and 14.27 (2s, OH-1, OH-8,13), 7.66 (s, H-9,12), 7.08 (bs, 2NH), 6.62 (s, H-2,5), 5.16 and 4.70 (J=12Hz, ar-CH
2O), 3.5 (m, 2CH
2N), 3.2 (m, 2CH
2O), 1.76 (s, 2CH
3).
2、
X＝OCH
2OCH
2NH
2
Synthetic method with hypericin amino derivative of above chemical structural formula, be the product 71.6mg (0.1mmol) that gets step 1, add 20mL 6mol/L HCl, reaction is 0.5 hour in boiling water bath, separate, through vacuum-drying, obtain the hypericin amino derivative (X=OCH that 9mg has above chemical structural formula
2OCH
2NH
2), productive rate is 15%; Product is carried out instrumental analysis, as a result IR (KBr, cm
-1): 3448,2923,1617,1465,1247,1112,951.
3、
Have the synthetic method of the hypericin amino derivative of above chemical structural formula, may further comprise the steps:
1) with 142mg 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthraquinone (0.4mmol) is dissolved in the 28mL analytical pure glacial acetic acid, adds 4mL then and contain 454.5mgSnCl
2.2H
2The mass percentage concentration of O (6mmol) is the concentrated hydrochloric acid of 36-38%, reacts 0.5 hour cooling down at 120 ℃, add icy salt solution, precipitation separation, washing is in vacuum-drying, obtain product 96mg 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthrone, productive rate is 93%, product is carried out instrumental analysis, H as a result
1NMR (acetone-d
6, 200MHz, ppm): 12.47 (s, 1H, OH), 12.37 (s, 1H, OH), 9.8 (bs, 1H, OH), 6.99 (s, 1H, ar-H), 6.88 (s, 1H, ar-H), 6.55 (s, 1H, ar-H), 6.35 (d, J=1.8Hz, ar-H), 4.66 (s, 2H, ar-CH
2-O), 4.38 (s, 2H, ar-CH
2-ar), 3.38-3.76 (m, 4H, CH
2-O and CH
2-Cl).
2) get 120mg step 1) product (0.36mmol), it is joined 200 μ l piperidines, 222.5mg nitrogen oxy picolinate (2.45mmol) and be dissolved with 14mg FeSO
47H
2In the 2mL pyridine of O, 110 ℃ of following lucifuge reactions 1.5 hours, cool to room temperature was with concentrated hydrochloric acid aqueous solution (water: concentrated hydrochloric acid=10: 1) make its rapid cooling, precipitation separation, washing in 800mL acetone, is shone the abundant stirring and dissolving of reaction product 2 hours with halogen lamp, filter, filtrate concentrates, and separates (methanol-eluted fractions) through Sephadex LH-20 column purification, obtains the synthetic method (X=OCH that 15mg has the hypericin amino derivative of above chemical structural formula
2CH
2NH (CH
2)
5), productive rate is 11%; Product is carried out instrumental analysis, H as a result
1NMR (DMSO-d
6, 200MHz, ppm): 14.83 and 14.32 (2s, OH-1,6 and OH-8,13), 7.52 (s, H-9,12), 6.53 (s, H-2,5), 5.1 and 4.6 (J=12Hz, ar-CH
2O), 3.5 (m, 4H, 2CH
2N), 3.3 (m, 4H, 2CH
2O), 2.8 (m, 8H, the NCH on the piperidines
2), 1.5 (m, 12H, the CH on the piperidines
2).
Claims (10)
1, a kind of chemical synthesis process of hypericin may further comprise the steps:
1) with 1,3,8-trihydroxy--6-tectoquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The 36-40% concentrated hydrochloric acid of O, reaction is 1-4 hour under not being higher than 125 ℃, and cooling obtains 1,3,8-trihydroxy--6-methyl anthrone; Described 1,3,8-trihydroxy--6-tectoquinone and SnCl
2.2H
2The mol ratio of O is 1: 4-6; The volume ratio of acetate and hydrochloric acid is 1.5-3: 1;
2) with 1,3,8-trihydroxy--6-methyl anthrone and pyridine, piperidines, nitrogen oxy picolinate and FeSO
47H
2O is dissolved in acetone with reaction product again 100-130 ℃ of following lucifuge reaction 0.5-3 hour, with halogen lamp irradiation 12-24 hour, concentrates, and uses n-hexane dissolution, and filtering-depositing obtains hypericin; Described 1,3,8-trihydroxy--6-methyl anthrone and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 1: 5-7: 0.1-0.18; The volume ratio of pyridine and piperidines is 10-11: 1.
2, synthetic method according to claim 1 is characterized in that: 1,6 in the described step 1), and the synthetic method of 8-trihydroxy--3-tectoquinone may further comprise the steps:
1) ethyl formate is mixed with acetone, splashes into the anhydrous diethyl ether that contains the sodium silk, stir, treat that the sodium silk reacts completely after, leave standstill 12-24h, leach the lark solid precipitation, obtain acetyl acetaldehyde; The mol ratio of described ethyl formate and acetone and sodium silk is 4-6: 4-8: 1-5; The volumetric molar concentration of sodium silk in anhydrous diethyl ether is 0.5-3mol/L;
2) acetyl acetaldehyde is mixed with methyl aceto acetate, place 12-24h under the room temperature, add the dehydrated alcohol that contains the sodium silk, reacted 10-14 hour down at 65-100 ℃, leave standstill 12-24h, leach precipitation, therefrom isolate organic acid, behind the recrystallization, obtain 2-hydroxy-4-methyl phenylformic acid; The mol ratio of described acetyl acetaldehyde and methyl aceto acetate and sodium is 0.5-1.3: 0.6-2: 0.5-1.5; The volumetric molar concentration of sodium in dehydrated alcohol is 0.6-2mol/L;
3) 2-hydroxy-4-methyl phenylformic acid is dissolved in the dehydrated alcohol, dripping mass percentage concentration is the NaOH solution of 8-20%, drip methyl-sulfate not being higher than under 10 ℃ the temperature then, again reaction system was reacted 3-8 hour down at 20-90 ℃, cooling, acidifying is filtered, recrystallization obtains 2-methoxyl group-4-tolyl acid; The mol ratio of described 2-hydroxy-4-methyl phenylformic acid and methyl-sulfate is 0.3-1.2: 0.5-1.5; The volume ratio of ethanol and NaOH solution is 1-3: 0.2-1.5;
4) 2-methoxyl group-4-tolyl acid is dissolved in the dimethylbenzene, adds anhydrous AlCl
3After, thionyl chloride was reacted 0.5-8 hour down at 40-90 ℃ then, and excessive thionyl chloride is removed in distillation, and organic solvent dissolution and recrystallization obtain 2-methoxyl group-4-methyl benzoyl chloride; Described 2-methoxyl group-4-tolyl acid, anhydrous AlCl
3With the mol ratio of thionyl chloride be 0.3-1.5: 0.1-0.5: 0.2-2;
5) with 3, the 5-dimethoxy p-methyl is dissolved in the anhydrous trichloromethane, adds anhydrous AlCl
3Keep away and be cooled under the water condition below 0 ℃, under agitation condition, splash into the anhydrous trichloromethane that is dissolved with 2-methoxyl group-4-methyl benzoyl chloride, stir 12-36h under the room temperature after, the impouring mass percentage concentration is in the dilute hydrochloric acid frozen water of 3-9%, tell organic layer, the pressure reducing and steaming solvent is used the ether dissolution solute, washing, drying boils off ether, is the Me of 99.5-99.8% with throw out and mass percentage concentration
2SO
4Solution, Anhydrous potassium carbonate and acetone mix, reacted 4-8 hour down at 50-100 ℃, filter concentrated filtrate, adding volumetric molar concentration in concentrated solution again is the NaOH solution of 1-3mol/L, react 0.5-2h, acidifying, trichloromethane recrystallization down at 60-105 ℃, separate out 3,5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid; Described 3,5-dimethoxy p-methyl, anhydrous AlCl
3With the mol ratio of 2-methoxyl group-4-methyl benzoyl chloride be 1: 0.5-2: 0.4: 2; 3, the volumetric molar concentration of 5-dimethoxy p-methyl in anhydrous trichloromethane is 0.1-2mol/L, and the 2-methoxyl group-volumetric molar concentration of 4-methyl benzoyl chloride in anhydrous trichloromethane is 0.2-1.5mol/L; Me
2SO
4With the mol ratio of Anhydrous potassium carbonate be 1: 0.5-2, residue and Me
2SO
4The volume ratio of solution and acetone is 0.3-2: 0.2-1: 2-10; The volume ratio of concentrated solution and NaOH solution is 1: 10-25;
6) NaCl and anhydrous AlCl
3Mixing is kept away under the water condition heating and is made its fusion, and gradation adds 3 under the agitation condition, 5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid is warming up to 150-175 ℃ then, stirs reaction 0.5-1.5h down, reaction finishes postcooling, the dilute hydrochloric acid frozen water that adds 3-9%, filter collection precipitation is washed to neutrality, separate, obtain 1,3,8-trihydroxy--6-tectoquinone; Described 3,5-dimethoxy-2 (4-methyl-2-anisoyl) phenylformic acid, NaCl and anhydrous AlCl
3Mol ratio be 1-4: 0.5-1.5: 1-3.
3, synthetic method according to claim 2 is characterized in that: described step 2) middle is the molecular sieve filtration precipitation of 4A with the aperture; The method of separating organic acid is a pH gradient separations method; The recrystallization solvent is a benzene; Use the B filtering-depositing in the step 3); The acid that acidifying is used is the concentrated hydrochloric acid of 4-6mol/L; The recrystallization solvent is benzene and trichloromethane; Being used for the solvent that recrystallization uses in the step 4) is hexanaphthene; The acid that acidifying is used in the step 5) is the 4-6mol/L concentrated hydrochloric acid; From the precipitation of the neutrality after washing, isolate 1,3,8-trihydroxy--6-tectoquinone with silica gel VLC in the step 6).
4, a kind of method of synthesis type II hypericin heterocyclic derivative may further comprise the steps:
1) with 1,3,8-trimethoxy-6-benzoglyoxaline anthraquinone is dissolved in the analytically pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the HBr of 45-47%, reacts 1-1.5 hour down at 100-130 ℃, and cooling adds in the frozen water, separates, and residue is weighed after washing vacuum-drying and obtained product; Described 1,3,8-trimethoxy-6-benzoglyoxaline anthraquinone and SnCl
2.2H
2The mol ratio of O is 1: 4-10; The volume ratio of glacial acetic acid and HBr is 1-4: 0.5-2;
2) with the product and the pyridine of step 1), piperidines, nitrogen oxy picolinate and FeSO
47H
2O was 110-130 ℃ of following lucifuge reaction 0.5-2 hour, again reaction product is dissolved in 1-4mol/L hydrochloric acid, stirred 20-50 minute under the room temperature, separate the back with the 3-9%HCl washing, after wash vacuum-drying with water, product is dissolved in behind the methyl alcohol with halogen lamp irradiation 0.5-2 hour, boil off solvent, fully stirring is dissolved in methyl alcohol, obtains formula worker I hypericin heterocyclic derivative; The product of described step 1) and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.5-1.5: 2-8: 0.1-0.8, and the ratio of pyridine and piperidines is 10-11: 1.
5, a kind of synthetic formula III 2, the method for 5-disulfonic acid base hypericin is that hypericin and oleum were at room temperature reacted 1-3 hour, the mixture of ice and water dilution, add sodium-chlor until saturated, precipitation separation will precipitate and use cold wash, vacuum-drying obtains 2,5-disulfonic acid base hypericin; The mol ratio of described hypericin and oleum is 1: 12-14.
R
1＝H； R
2＝H
Formula III
6, a kind of synthesis type IV 2,5, the method for 9-trisulfonic acid base hypericin is that hypericin and oleum were reacted 0.5-1.5 hour at 75-85 ℃, the mixture of ice and water dilution, add sodium-chlor until saturated, precipitation separation will precipitate and use cold wash, vacuum-drying, obtain 2,5,9-trisulfonic acid base hypericin; The mol ratio of described hypericin and oleum is 1: 14-16.
Formula IV
7, a kind of synthesis type V 2,5,9, the method of 12-tetrasulfonic acid base hypericin is hypericin and oleum to be reacted 1-2 hour the mixture of ice and water dilution at 75-85 ℃, add sodium-chlor until saturated, precipitation separation will precipitate and use cold wash, vacuum-drying, obtain 2,5,9,12-tetrasulfonic acid base hypericin; The mol ratio of described hypericin and oleum is 1: 25-27.
R
1＝SO
3H； R
2＝SO
3H
Formula V
8, a kind of method of synthesis type VI hypericin amino derivative may further comprise the steps:
1) with 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, reacts 0.5-1.5 hour down at 110-130 ℃, and cooling adds icy salt solution, precipitation separation, and washing, vacuum-drying obtains product 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone; Described 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone and SnCl
2.2H
2The mol ratio of O is 0.5-1.5: 3-6; The volume ratio of acetate and hydrochloric acid is 2-10: 0.5-2;
2) 1,3,8-trihydroxy--6-(ω)-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone and pyridine, piperidines, nitrogen oxy picolinate and FeSO
47H
2O makes its rapid cooling with concentrated hydrochloric acid aqueous solution, precipitation separation, washing 100-120 ℃ of following lucifuge reaction 0.5-3 hour, reaction product is dissolved in acetone,, filters with halogen lamp irradiation 1-10 hour, filtrate concentrates, and through the silica gel column chromatography wash-out, obtains formula VI hypericin amino derivative; Described 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.2-1.5: 4.5-8: 0.1-0.4; The volume ratio of pyridine and piperidines is 10-11: 1.
Formula VI
9, a kind of method of synthesis type VII hypericin amino derivative may further comprise the steps:
1) with 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, reacts 0.5-1.5 hour down at 110-130 ℃, and cooling adds icy salt solution, precipitation separation, and washing, vacuum-drying obtains product 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone; Described 1,3,8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthraquinone and SnCl
2.2H
2The mol ratio of O is 0.5-1.5: 3-6; The volume ratio of acetate and hydrochloric acid is 2-10: 0.5-2;
2) to the product 1,3 of step 1), add pyridine, piperidines, nitrogen oxy picolinate and FeSO in 8-trihydroxy--6-(ω-2-acetylaminohydroxyphenylarsonic acid oxyethyl group-methyl) anthrone
47H
2O makes its rapid cooling 100-120 ℃ of following lucifuge reaction 0.5-3 hour with concentrated hydrochloric acid aqueous solution, precipitation separation, and washing is dissolved in acetone with reaction product, with halogen lamp irradiation 1-10 hour, filters, and filtrate concentrates, and through the silica gel column chromatography wash-out, obtains product; The product of described step 1) and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.2-1.5: 4.5-8: 0.1-0.4; The volume ratio of pyridine and piperidines is 10-11: 1;
3) to step 2) product in add 4-6mol/L HCl, boiling water bath 0.25-0.75 hour, separate, through vacuum-drying, obtain formula VII hypericin amino derivative; Described step 2) product and the mol ratio of HCl are 0.2-1.5: 1-2.
10, a kind of method of synthesis type VIII hypericin amino derivative may further comprise the steps:
1) 1,3,8-trihydroxy--6-(ω)-2-chloro-oxyethyl group-methyl) anthraquinone is dissolved in the analytical pure glacial acetic acid, adds then and contains SnCl
2.2H
2The mass percentage concentration of O is the concentrated hydrochloric acid of 36-40%, reacts 0.5-3 hour down at 110-130 ℃, and cooling adds icy salt solution, and the precipitation separation washing in vacuum-drying, obtains product 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthrone; Described 1,3,8-trihydroxy--6-(ω-2-chloro-oxyethyl group-methyl) anthraquinone and SnCl
2.2H
2The mol ratio of O is 0.5-1.5: 3-6; The volume ratio of acetate and hydrochloric acid is 2-10: 0.5-2;
2) product with step 1) joins piperidines, nitrogen oxy picolinate and be dissolved with FeSO
47H
2In the pyridine of O, at 100-120 ℃ of following lucifuge reaction 0.5-3 hour, cool to room temperature, make its rapid cooling with concentrated hydrochloric acid aqueous solution, precipitation separation, the washing, with the abundant stirring and dissolving of reaction product in acetone, with halogen lamp irradiation 1-10 hour, filter, filtrate concentrates, and separates through Sephadex LH-20 column purification, obtain formula VIII hypericin amino derivative, the product of described step 4) and nitrogen oxy picolinate and FeSO
47H
2The mol ratio of O is 0.2-1.5: 4.5-8: 0.1-0.4; The volume ratio of pyridine and piperidines is 10-11: 1.
X＝OCH
2CH
2NH(CH
2)
5
Formula VIII
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102126942A (en) * | 2010-12-22 | 2011-07-20 | 湖北工业大学 | Method for synthesizing hypericin |
| CN102180782A (en) * | 2011-03-23 | 2011-09-14 | 中国农业科学院兰州畜牧与兽药研究所 | Method for synthesizing hypericin |
| CN106588622A (en) * | 2016-12-16 | 2017-04-26 | 陕西嘉禾药业有限公司 | Hypericin synthesis method |
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| CN108084065A (en) * | 2017-11-21 | 2018-05-29 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of hypericin derivative and its preparation method and application |
| CN108863741A (en) * | 2017-05-11 | 2018-11-23 | 上海凯伟化工科技有限公司 | A kind of synthetic method of hypericin |
| CN116354810A (en) * | 2023-02-21 | 2023-06-30 | 浙江爱索拓标记医药科技有限公司 | Radioisotope carbon-14 multi-site marked emodin and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102126942A (en) * | 2010-12-22 | 2011-07-20 | 湖北工业大学 | Method for synthesizing hypericin |
| CN102126942B (en) * | 2010-12-22 | 2013-10-23 | 湖北工业大学 | Method for synthesizing hypericin |
| CN102180782A (en) * | 2011-03-23 | 2011-09-14 | 中国农业科学院兰州畜牧与兽药研究所 | Method for synthesizing hypericin |
| CN102180782B (en) * | 2011-03-23 | 2013-04-10 | 中国农业科学院兰州畜牧与兽药研究所 | Method for synthesizing hypericin |
| CN106588622A (en) * | 2016-12-16 | 2017-04-26 | 陕西嘉禾药业有限公司 | Hypericin synthesis method |
| CN108863741A (en) * | 2017-05-11 | 2018-11-23 | 上海凯伟化工科技有限公司 | A kind of synthetic method of hypericin |
| CN108084065A (en) * | 2017-11-21 | 2018-05-29 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of hypericin derivative and its preparation method and application |
| CN108084065B (en) * | 2017-11-21 | 2020-06-16 | 中国农业科学院兰州畜牧与兽药研究所 | Hypericin derivative and preparation method and application thereof |
| CN108084004A (en) * | 2017-12-08 | 2018-05-29 | 陕西嘉禾药业有限公司 | A kind of synthetic method of emodin anthrone |
| CN108084004B (en) * | 2017-12-08 | 2021-05-18 | 陕西嘉禾药业有限公司 | Method for synthesizing emodin anthrone |
| CN116354810A (en) * | 2023-02-21 | 2023-06-30 | 浙江爱索拓标记医药科技有限公司 | Radioisotope carbon-14 multi-site marked emodin and preparation method thereof |
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