CN106608835B - Hypocrellin derivant and its preparation method and application containing long chain quaternary - Google Patents
Hypocrellin derivant and its preparation method and application containing long chain quaternary Download PDFInfo
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- AMUZUAPDHKLOLU-UHFFFAOYSA-N CCCCCCCCCCCC[N](C)(C)CCCCCCN Chemical compound CCCCCCCCCCCC[N](C)(C)CCCCCCN AMUZUAPDHKLOLU-UHFFFAOYSA-N 0.000 description 1
- PWHBBUVAAQIXFR-UHFFFAOYSA-N CCCCCCCCC[N](C)(C)CCCCN Chemical compound CCCCCCCCC[N](C)(C)CCCCN PWHBBUVAAQIXFR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention discloses a kind of hypocrellin derivant and its preparation method and application containing long chain quaternary.Shown in the general structure of the derivative such as formula (1) or formula (2)：Wherein, X N, O or S；2≤m≤20,0≤n≤10,1≤p≤2, m, n, p are positive integer；R1、R2And R3Respectively contain the alkyl of 1 20 carbon atoms；A‑For F‑、Cl‑、Br‑、I‑Ion；HA is hypocrellin A；HB is hypocrelline B.The present invention modifies hypocrellin using the quaternary ammonium salt of long-chain for the first time, enhance its water-soluble and biocompatibility, the analog derivative has good fat water amphiphilic, can be effectively combined negative electrical charge species in organism, especially has good nucleophilicity to tumour cell.Such band long chain quaternary hypocrellin derivant can be directly dissolved in physiological saline and make preparation medicine, improve medicinal effects, the drug for exploitation hypocrellin treating cancer and anti-cancer virus provides possibility.
Description
Technical field
The present invention relates to the photosensitizer drug technical fields of optical dynamic therapy.Containing long chain quaternary ammonium more particularly, to one kind
Hypocrellin derivant of salt and its preparation method and application.
Background technology
Photodynamic therapy (Photodynamic Therapy, abbreviation PDT) is a kind of needle developed rapidly in recent years
To the selective therapy new technology of neovascular pathological tissues, which irradiates biological group dyed by photosensitizer using light
It knits, generates photochemical effect, to generate therapeutic effect to these diseases.Photodynamic therapy has become after operation, radiotherapy and change
The tumor therapeuticing method of the 4th kind of specific type then is treated, it is advantageous that its high efficiency and safety, under light illumination
It can continuously generate into ten million high response can active oxygen species, so as to cause the damage of sick cell and tissue or bad
Single target molecule can only extremely be killed with traditional drug and compared has significant high efficiency.On the other hand, photochemical therapy has
The two-way choice for having drug polarization and illumination positioning, reduces the damage to normal cell, greatly reduces toxic side effect,
Increase safety.PDT not only achieves significant achievement in clinical anticancer, while being also used for non-tumorous type disease, such as
The treatment of the diseases such as condyloma acuminatum, psoriasis, nevus flammeus, rheumatoid arthritis, fundus flavimaculatus lesion.PDT it is antiviral, kill
There has also been successful applications for bacterium, light power pesticide etc., and start to be difficult to cure to certain conventional treatments benign common
Pathological development achieves many breakthrough progress.
PDT is a kind of new disease treatment means based on the interaction of light, photosensitizer and oxygen, photosensitizer (light
Dynamic therapy drug) research be the key that influence optical dynamic therapy.Photosensitizer can absorb photon and be excited, and will absorb
Luminous energy by energy transmission to another component molecule generate photoreactive species.In the photosensitizer being currently known, for clinic
Mainly Porphyrin-Based Sensitizer and phthalocyanines photosensitizer, the drug of commercialization has Photofrin, Visudyne, Photosens
Deng.Visdyne is the currently the only photo-dynamical medicine for being approved by the fda in the United States for old macular degeneration treatment, it
Chemical composition be benzoporphyrin mono-acid ring A (DPD-MA), red light district maximum absorption wavelength in 689nm, the group of this wavelength
Penetration depth is knitted up to 5mm.The drug price is sufficiently expensive, and market price reaches 1500 dollars/15mg.For clinical phthalocyanines
Photosensitizer Photosens, most prominent advantage are stronger in red light district (600-700nm) absorption, and extinction coefficient usually compares
Other photosensitizers are order of magnitude greater.However, Porphyrin-Based Sensitizer and the most outstanding problem of phthalocyanines photosensitizer are geometrical isomerisms
The separation of body is difficult, it is difficult to obtain the pure compound of one pack system；Relative complex component is also unfavorable for the drug metabolism in later stage, poison
Manage the assessment of analysis.Other clinical or preclinical study photosensitizers include mainly dihydro porphin, chlorophyll class, quinones
Deng wherein quinones photosensitive drug is found in succession from last century the eighties, such as cercosporin, hypericin, Jia Rang chambers
Rhzomorph, hypocrellin A and B prime etc., have all had been found active anticancer.Wherein hypocrellin is by Yunnan Province of China plateau elevation
4000 meters, the natural photosensitizer extracted in a kind of red bacterium of parasitical fungi-bamboo on arrow bamboo, phototoxicity is good, dark toxicity is low, internal
Metabolism is fast, chemical constitution is clear, is with a wide range of applications.
Natural hypocrellin includes mainly hypocrellin A (Hypocrellin A, abbreviation HA) and hypocrelline B
(Hypocrellin B, abbreviation HB).In recent years, people to the optical physics of hypocrellin, photochemistry and photo-biological property done compared with
For detailed research (Medicinal Chemistry, 2010,10,332-341；Progress in Chemistry,20,
1345-1352), think that hypocrellin is a kind of photosensitizer having wide application prospects.However the main absorption wave of hypocrellin
Long range in 450-550nm, inhale also less than 1 millimeter at optical dynamic therapy window (600-900nm) by this wavelength energy tissue penetration
It is weaker to receive light ability.Past more than ten years there are many for hypocrellin chemical modification (New J.Chem., 2002,
26,1130–1136；J.Org.Chem.2003,68,2048-2050；2001,61,122-128；
Photochem.Photobiol.,2001,74,143-148；Dyes and Pigments,1999,41,93-100；
Bioorg.Med.Chem.Let.,2004,14,1499-1501；2012,22,5003-5007).Comparatively, chemical modification
Hypocrellin derivant it is different degrees of improve its red light absorption, but still than phthalocyanines photosensitizer order of magnitude lower, institute
To be evaluated from light absorption angle, optical dynamic treatment of tumor does not have apparent advantage.Later researcher has found that normal-butyl ammonia is repaiied
To 600-700nm, molar extinction coefficient significantly increases the apparent red shift of its absorbing wavelength of the hypocrellin of decorations, and this phenomenon is again from it
It is confirmed on its amido modified hypocrellin (n-hexylamine, hexamethylene ammonia, aniline, Bian ammonia, ethylaminoethanol etc.)
(Photochem.Photobiol.,2003,78,411-415；Bioorg.Med.Chem.Let.,2011,11,2045-2047；
J.Photochem.Photobiol.B:1998,44,21-28)。
Amido modified hypocrellin has shown preferable optical physics, photochemistry and photobiology property, however this
The water solubility and biocompatibility of class compound are relatively poor, it is also necessary to be further improved.It is well known that capilary class disease
Target body is the intensive microvessel network of heteroplasia of focal zone, and blood fortune is abundant, more sensitive to photodynamic action；When optical dynamic therapy, medicine
Object must transport to lesion in a manner of intravenous injection by blood circulation system.However, hypocrellin is that a kind of lipophilicity is organic
Molecule, solubility in water is very low, and directly intravenous injection understands self-assemble in blood and causes blood vessel blockage.Sulfonic acid replaces
Derivative (J.Photochem.Photobiol.B.Biol., 1993,17,195-201) can solve water-soluble ask
Topic, but due to during its is negatively charged and cell and tissue a large amount of negative electrical charge it is mutually exclusive, cellular uptake rate is relatively low, drops significantly
Low Photodynamic activity.Therefore, the target compound of design will not only meet light absorption condition as proposed above, also meet
The fat water of optimization is amphiphilic -- and the concentration requirement for both meeting intravenous injection injection ensures high cellular uptake rate again.
Accordingly, it is desirable to provide a kind of meeting light absorption condition, and the fat water with optimization is amphiphatic containing long chain quaternary ammonium
The hypocrellin derivant of salt.
Invention content
It is an object of the present invention to provide a kind of hypocrellin derivants containing long chain quaternary.
It is another object of the present invention to provide a kind of preparation methods of the hypocrellin derivant containing long chain quaternary.
Third object of the present invention is to provide a kind of application of the hypocrellin derivant containing long chain quaternary.
The present invention cannot meet light absorption condition simultaneously for existing hypocrellin derivant, and meet the fat water of optimization
Amphiphatic problem, it is proposed that technical scheme of the present invention.Applicant is put forward for the first time modifies the red bacterium of bamboo with the quaternary ammonium salt of long-chain
Element enhances its water-soluble and biocompatibility, improves the oil-water ratio of hypocrellin parent.The analog derivative has good fat
Water is amphiphilic, can be directly dissolved in physiological saline.Due to being quaternary ammonium salt structure, it is not easy to be influenced by pH value.Light dynamic characteristics passes through
Experiments have shown that this kind of substituted derivative can not only meet the water-soluble requirement needed for clinical application, but also bio-light power is lived
Property compared with parent, solve intravenous injection medication requirements hydrophily and the lipophilicity of cellular uptake requirement between contradiction.
It is worth noting that, people relate only to neutral products to the modification of hypocrellin in the prior art and anion (sulfonic group) produces
Object, and report is had no precedent for cation modified hypocrellin, which discloses for the first time in the present invention.
To reach above-mentioned first purpose, the present invention uses following technical proposals：
A kind of hypocrellin derivant containing long chain quaternary, the general structure such as formula (1) of the derivative or formula (2) institute
Show
Wherein, X N, O or S atom；2≤m≤20,0≤n≤10,1≤p≤2, m, n, p are positive integer；R1、R2And R3
It is separately the alkyl containing 1-20 carbon atom；A-For F-、Cl-、Br-、I-Ion；HA is hypocrellin A；HB is that bamboo is red
Bacterium B prime；The structural formula of the HA and HB is respectively as shown in formula (3) and formula (4)：
The connection type of HA and X is in formula (1)：2 marked in formula (3) are connected by C-N singly-bounds, or in formula
(3) 2 marked in are connected by C-O singly-bounds, 5 either marked in the formula (3) be connected by C-S singly-bounds or
17 marked in formula (3) are connected by C=N double bonds；Or 2 marked in the formula (3) simultaneously by C-N singly-bounds,
17 are connected by C=N double bonds；
The connection type of HB and X is in formula (2)：2 marked in formula (4) are connected by C-N singly-bounds, or in formula
(4) 2 marked in are connected by C-O singly-bounds, 5 either marked in the formula (4) be connected by C-S singly-bounds or
17 marked in formula (4) are connected by C=N double bonds；Or 2 marked in the formula (4) simultaneously by C-N singly-bounds,
17 are connected by C=N double bonds；
P=1 indicates that hypocrellin parent modifies a long chain quaternary；P=2 indicates that the modification of hypocrellin parent is two long
Chain quaternary ammonium salt.
To reach above-mentioned second purpose, the present invention uses following technical proposals：
A kind of preparation method of the hypocrellin derivant containing long chain quaternary, includes the following steps：
Hypocrellin and long chain quaternary ammonium salt derivative are dissolved in organic solvent, reaction is carried out in the dark under inert gas shielding,
Most afterwards through isolating and purifying, you can obtain the hypocrellin derivant containing long chain quaternary.
Preferably, the hypocrellin is hypocrellin A or hypocrelline B；The long chain quaternary ammonium salt derivative leads to
Formula is-X- (CH2)m-(OCH2CH2)n-N+(R1)(R2)(R3), wherein X is N, O or S atom, 2≤m≤20,0≤n≤10, m, n
It is positive integer, R1、R2And R3It is separately the alkyl containing 1-20 carbon atom.
Preferably, the organic solvent is one or more in acetonitrile, tetrahydrofuran, pyridine, methanol and ethyl alcohol.
Preferably, the R3For C4H9、C6H13、C8H17、C10H21Or C12H25。
Preferably, the structural formula of the long chain quaternary ammonium salt derivative is：
-NH-(CH2)2-N+(CH3)2(C10H21)、-NH-(CH2)2-N+(CH3)2(C8H17)、-NH-(CH2)3-N+(CH3)2
(C10H21)、-NH-(CH2)3-N+(CH3)2(C8H17)、-NH-(CH2)4-N+(C2H5)2(C10H21)、-NH-(CH2)4-N+(C2H5)2
(C8H17)、-O-(CH2)2-N+(CH3)2(C10H21)、-O-(CH2)2-N+(CH3)2(C8H17)、-NH-(CH2)2(OCH2)2-N+
(CH3)2(C8H17)、-NH-(CH2)2(OCH2)4-N+(CH3)2(C8H17)、-S-(CH2)2-N+(CH3)2(C10H21) or-S- (CH2)2-
N+(CH3)2(C8H17)。
It is highly preferred that the structural formula of the long chain quaternary ammonium salt derivative is X=N, m=2, n=0, R1With R2It is methyl,
R3For C10H21, synthetic route is as shown in Figure 3.
Preferably, the molar ratio of the hypocrellin and long chain quaternary ammonium salt derivative is 1:2~10, concretely 1:
2、1:3、1:4、1:6 or 1:10；The temperature of reaction is 30-60 DEG C；The time of reaction is 6-12 hours.Reaction needs inert gas
As carried out under argon gas or nitrogen protection, and to be protected from light.
It is highly preferred that the organic solvent is acetonitrile or tetrahydrofuran；The hypocrellin and long chain quaternary ammonium salt derivative
Molar ratio be 1:4；The temperature of reaction is 50 DEG C；The time of reaction is 8 hours.
Preferably, the process isolated and purified is：
Except dereaction organic solvent obtains residue, residue is dissolved with dichloromethane；Diluted hydrochloric acid aqueous solution is used successively
And water washing；Then that organic layer is dry, filtering, removing solvent obtain crude product；By crude product purified by silica gel plate layer chromatography to get
To the hypocrellin derivant containing long chain quaternary.
Preferably, solvent used when silica gel plate layer chromatography is the mixing containing acetone, ethyl acetate, ethyl alcohol and diethylamine
Liquid, acetone in the mixed liquor, ethyl acetate, ethyl alcohol and diethylamine volume ratio be 20:1:1:1~3.
Preferably, the process isolated and purified is：
It except dereaction organic solvent, obtains black-and-blue solid residue and is dissolved with dichloromethane, with isometric dilute hydrochloric acid
Aqueous solution (5%) wash three times, washing it is primary, organic layer is dry with anhydrous magnesium sulfate, filtering, removes solvent and obtains crude product.
Gained crude product purified by silica gel plate layer chromatography method further detaches, and solvent is acetone：Ethyl acetate：Ethyl alcohol：(volume ratio is diethylamine
20:1:1:1~3) 20, are preferably in a proportion of:1:1:1, obtain the hypocrellin derivant containing long chain quaternary, yield 10~
30%, product is black-and-blue solid.
To reach above-mentioned third purpose, the present invention uses following technical proposals：
A kind of hypocrellin derivant containing long chain quaternary as described above is as the photosensitizer medicament in optical dynamic therapy
The application of object.
The hypocrellin derivant containing long chain quaternary of gained of the invention, absorption spectrum wavelength in 630nm or so, than
Hypocrellin parent (450-550nm) red shift significantly, shows preferable light absorpting ability, molar extinction coefficient 5000-
10000M-1cm-1；It is water-soluble preferably, and storing solution in 10uM~1mM concentration ranges can be configured in physiological saline.
Compared with hypocrellin A, hypocrelline B parent, the hypocrellin derivant of the invention containing long chain quaternary
In introduce quaternary ammonium salt and greatly strengthen its water solubility, the chain length by changing aliphatic chain adjusts oil-water ratio so that such
Derivative has good fat water amphiphilic, also has good biological compatibility in cell or tissue；Such compound with
Quaternary ammonium form exists, and is not easy to be influenced by pH, can be used in complicated organism；This kind of hypocrellin with normal salt can have
Negative electrical charge species in the combination organism of effect especially have good nucleophilicity to tumour cell；By adjust quaternary ammonium salt and
The distance between hypocrellin parent changes phototherapy effect.Therefore, such band long chain quaternary hypocrellin derivant can be straight
It connects and is dissolved in physiological saline and makes preparation medicine, improve medicinal effects；And be made of natural products, toxic side effect is not will produce, to open
The drug of hair hypocrellin treating cancer and anti-cancer virus is laid a good foundation.
Beneficial effects of the present invention are as follows：
1) from natural product extraction, raw material is easy to get, is at low cost, can largely prepare, no the hypocrellin raw material in the present invention
Containing any toxic side effect, it is easy to be metabolized；
2) synthesis and separation method are simple, without expensive reaction raw materials, complicated separation means；
3) hypocrellin derivant of the substitution of amino containing long chain quaternary prepared by is inhaled compared to hypocrellin parent
It receives the notable red shift of spectrum and molar extinction coefficient greatly increases, active oxygen can be efficiently generated under the conditions of photosensitive；The bright middle introducing of this law
Quaternary ammonium salt greatly strengthens its water solubility, and by adjusting the length adjustment oil-water ratio of its aliphatic chain, which has
Good fat water is amphiphilic：It can be directly dissolved in physiological saline, also there is good biological compatibility in cell or tissue；
4) positive charge aliphatic chain has certain targeting, can be effectively combined many negative electrical charge species in organism；
5) first generation Porphyrin-Based Sensitizer and second generation phthalocyanines photosensitizer of the photosensitizer and Clinical practice in the present invention
It compares, absorbing wavelength and absorbing ability are completely suitable, it is important that product is easily isolated, purifies, structure is clear, overcomes porphin
Quinoline and phthalocyanines photosensitizer are not readily separated and form labyrinth and be difficult to determining problem, have good targeting and very high
The ability of light power killing tumor cells.
Description of the drawings
Specific embodiments of the present invention will be described in further detail below in conjunction with the accompanying drawings.
Fig. 1 shows the general structure of hypocrellin A or hypocrellin B derivatives of the invention containing long chain quaternary.
Prepared by the hypocrelline B HB (a) and embodiment 4 extracted Fig. 2 shows the embodiment of the present invention 2 contains long chain quaternary
Hypocrellin B derivatives HB2 (b) absorption spectrum comparison diagram.
Fig. 3 shows the synthetic reaction route map of the long chain quaternary ammonium salt derivative in the embodiment of the present invention 3.
Fig. 4 shows the synthetic reaction route of the hypocrellin B derivatives containing long chain quaternary in the embodiment of the present invention 4
Figure.
Fig. 5 shows the synthetic reaction route of the hypocrellin B derivatives containing long chain quaternary in the embodiment of the present invention 12
Figure.
Fig. 6 shows the synthetic reaction route map of the hypocrellin B derivatives containing quaternary ammonium salt in the embodiment of the present invention 13.
Fig. 7 shows the synthetic reaction route of the hypocrellin B derivatives containing long chain quaternary in the embodiment of the present invention 15
Figure.
Specific implementation mode
In order to illustrate more clearly of the present invention, the present invention is done further with reference to preferred embodiments and drawings
It is bright.Similar component is indicated with identical reference numeral in attached drawing.It will be appreciated by those skilled in the art that institute is specific below
The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
Hypocrellin used in the present invention can extract by the following method, can also be obtained by commercially available purchase.
Embodiment 1
The extraction of hypocrellin A (HA)：Extracting method opened the ginseng of great organic chemistry with reference to 252-254 pages of Zhao of volume 9 in 1989
Book is examined, is suitably modified.The specific method is as follows：
The red bacterium of 100g bamboos is crushed with pulverizer, is placed in Soxhlet extractor, with the continuously extraction one of 1000mL acetone as solvent
It is closely colourless to extracting solution, and extracting solution is filtered to remove the solid insoluble penetrated on a small quantity, is then spin-dried for removing acetone, uses 500mL
Dichloromethane dissolves, and 4 × 400mL distills water washing, isolates organic layer and is spin-dried for, solid residue is washed with 5 × 100mL petroleum ethers
It washs, spontaneous combustion air-dries the solid in air, then uses chloroform-petroleum ether recrystallization twice, gained crystal is that target product bamboo is red
Fungus beetle element (HA), purity is 98% or more.Using thin-layer silicon offset plate chromatography, with petroleum ether：Ethyl acetate：Absolute ethyl alcohol (30:
10:1) make solvent, can be further purified to obtain the hypocrellin A of high-purity.
Embodiment 2
The preparation of hypocrelline B (HB)：Hypocrelline B is dehydrated under alkaline condition by A prime and is obtained, preparation method ginseng
It examines 252-254 pages of Zhao of volume 9 in 1989 and opens the reference book of great organic chemistry, be suitably modified.The specific method is as follows：
1 gram of hypocrellin A is dissolved in the KOH aqueous solutions of 1000mL 1.5%, is protected from light after being stirred to react 24 hours, is used
Slightly excessive dilute hydrochloric acid neutralizes, and with chloroform recovery product, hypocrelline B 0.98g, yield 98% are obtained after isolating and purifying.
Long chain quaternary ammonium salt derivative used in the present invention similar to universal method by being made below, with X=N, m=2, n=0,
R1=R2=Me, R3=C10H21To arrange explanation.
Embodiment 3
Long chain quaternary ammonium salt derivative (X- (CH2)m-(OCH2CH2)n-N+(R1)(R2)(R3)；Wherein X=N, m=2, n=0,
R1=R2=Me, R3=C10H21) preparation, synthetic route chart is as shown in Fig. 3：
The preparation of intermediate 1：
N, N- dimethyl-ethylenediamine (4.4g, 0.05mol) and diethyl carbonate (7.10g, 0.06mol) are mixed in 100 millis
Round-bottomed flask is risen, reaction solution reacts 48h at 70 DEG C, and then vacuum distillation obtains flaxen liquid 7.20g, yield 89%.1H NMR(CDCl3,δ,ppm):5.45 (s ,-NH-, 1H), 4.10 (d, J=6.5Hz ,-CH2O,2H),3.24(s,-NH-CH2-,
2H),2.39(m,-CH2N, 2H), 2.22 (d, J=1.5Hz, CH3NCH3, 6H), 1.23 (t, J=6.5Hz ,-CH2CH3,3H).Institute
Shown in the structural formula such as formula (5) for stating intermediate S1：
The preparation of intermediate 2：
Intermediate 1 and 1- bromine certain herbaceous plants with big flowers alkane (15.25g, 0.05mol), which are reacted at 100 DEG C under 48h, reacts 72h.Crude product is with third
Ketone-ether (1:1) 2 total 15.83g of white crystal, yield about 68% are obtained.1H NMR(CDCl3,δ,ppm):6.73(s,CONH-,
1H), 4.10 (q, J=7.1Hz ,-CH2O-,2H),3.77(s,-CH2N+,4H),3.53(s,CH3N+,6H),3.39(s,-
NHCH2-,2H),1.78-1.67(m,-N+CH2CH2-,2H),1.31–1.20(m,-CH2, 29H), 0.88 (t, J=6.8Hz ,-
CH3,3H).MS(ESI+):m/z calcd for C23H50N2O2 +(M+H+),385.3794,found:385.3788.In described
Shown in the structural formula of mesosome 2 such as formula (6)：
The preparation of long chain quaternary ammonium salt derivative 3：
48% hydrobromic acids of 50mL and 50mL distilled water, heating reflux reaction are added in intermediate 2 (10.60g, 0.02mol)
72h.Revolving removes hydrobromic acid, solid residue ethyl alcohol：Ether (1:1) it is recrystallized to give white flock crystal 13.62g, is produced
Rate 69%.1H NMR(D2O,δ,ppm):5.34(s,NH2,2H),3.65(m,NH2CH2CH2-,2H),3.48(m,-N+CH2CH2-,
2H),3.38(m,NH2CH2-,2H),3.12(s,N+-CH3,6H),1.78(m,N+CH2CH2-,2H),1.37-0.99(m,-CH2-,
26H), 0.76 (t, J=6.5Hz ,-CH3,3H).MS(ESI+):m/z calcd for C20H46N2+(M+H+),313.3583,
found:313.3590.Shown in the structural formula such as formula (7) of the long chain quaternary ammonium salt derivative 3：
Embodiment 4
N, N- dimethyl-N-certain herbaceous plants with big flowers base ethylenediamine -2- amino hypocrelline Bs (X=NH, m=2, n=0, R1=R2=CH3,
R3=C10H21) preparation, synthetic route is as shown in Fig. 4.
It is prepared by hypocrelline B HB (100mg, 0.18mmol) and embodiment 3 long chain quaternary ammonium salt derivative 3 (224mg,
It 0.72mmol) is dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, 50 DEG C is heated under nitrogen protection, is protected from light and is stirred to react
10h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 200mL dichloromethane dissolves, and uses 50mL dilute successively
Aqueous hydrochloric acid solution washed once, distilled water washes twice, and organic layer is dry with anhydrous magnesium sulfate, filter, organic phase hangs dry obtain
Crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (body
Product is than being 20:1:1:3) two kinds of black-and-blue solid products, are respectively obtained, Rf values are respectively 0.38 and 0.62, and wherein Rf is
0.38 product turns out to be 2 bit amino substitution products by characterization, is denoted as HB2, yield 7.2%.
2- bit amino substitution product HB2 characterize datas are as follows：1HNMR(CDCl3,δ,ppm):6.76(s,ArH,1H),6.66
(S,ArH,1H),4.06(S,OCH3,3H),4.02(CH,1H),4.01(S,OCH3,3H),3.98(S,OCH3,3H),3.68(m,
NHCH2-,2H),3.48(m,-N+CH2,2H),3.23(CH,1H),3.18(s,N+CH3,6H),2.32(S,COCH3,3H),1.95
(S,CH3,3H),1.41-1.02(m,CH2-,19H),0.78(t,CH3,3H).MS(ESI+):m/z calcd for
C43H53N2O8 +(M+H+),725.4,found:726.3. ultraviolet maximum absorption wavelength：470nm,636nm.The 2- bit aminos take
Shown in structural formula such as formula (8) for product HB2：
The component that above-mentioned Rf is 0.62 continues to use acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20:1:1:1) plate
Chromatography, it is respectively 0.28 (17 Schiff products, be denoted as HB17) and 0.42 (substitution of 2 bit aminos and 17 to obtain Rf values
Two substitution products of position Schiff product, are denoted as HB2-17), yield is respectively 6.5% and 3.8%.
17 Schiff product HB17 characterize datas are as follows：1HNMR(CDCl3,δ,ppm):6.63(s,ArH,1H),
6.58 (S, ArH, 1H), 5.32 (S, N=CH, 1H), 4.08 (S, OCH3,3H),4.06(S,OCH3,3H),4.00(CH,1H),
3.97(S,2OCH3,6H),3.62(m,NHCH2-,2H),3.54(m,-N+CH2,2H),3.20(CH,1H),3.16(s,N+-CH3,
6H),1.92(S,CH3,3H),1.38-1.03(m,-CH2-,19H),0.76(t,-CH3,3H).MS(ESI+):m/z calcd
for C44H55N2O8 +(M+H+),739.4,found:741.2. ultraviolet maximum absorption wavelength：478nm,642nm.Described 17
Shown in the structural formula of Schiff product such as formula (9)：
Two substitution product HB2-17 characterize datas of 2 and 17 simultaneous reactions are as follows：MS(ESI+):m/z calcd
for C57H84N4O7 2+(M2+/2),469.5,found:470.2；Ultraviolet maximum absorption wavelength：482nm,638nm.The diamino
Shown in the structural formula of base substitution product such as formula (10)：
Prepared by the hypocrelline B HB (a) and embodiment 4 extracted Fig. 2 shows the embodiment of the present invention 2 contains long chain quaternary
Hypocrellin B derivatives HB2 (b) absorption spectrum comparison diagram.The hypocrellin containing long chain quaternary can be obtained from figure
Its maximum absorption spectrum wavelength of derivative is in 630nm or so, than hypocrellin parent (450nm) red shift significantly, shows preferably
Light absorpting ability, molar extinction coefficient 5000-10000M-1cm-1。
Embodiment 5
N, N- dimethyl-N-certain herbaceous plants with big flowers base ethylenediamine 2- amino hypocrellin As (X=NH, m=2, n=0, R1=R2=CH3,R3
=C10H21) preparation：
It is prepared by hypocrellin A HB (100mg, 0.18mmol) and embodiment 3 long chain quaternary ammonium salt derivative (112mg,
It 0.36mmol) is dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, 50 DEG C is heated under nitrogen protection, is protected from light and is stirred to react 8h,
After completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL dichloromethane dissolves, water-soluble with 50mL dilute hydrochloric acid
Liquid washs three times, then is washed with distilled water primary, and organic layer is dry with anhydrous magnesium sulfate, filtering, organic phase are hanged and dry slightly produced
Product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio
It is 20:1:1:1) two kinds of black-and-blue solid products, are obtained, be denoted as respectively 2- bit amino substitution products S1 (yield 5.4%,
0.36) and 17 Schiff product S2 (yield 12.5%, Rf 0.65) Rf is.
2- bit amino substitution product S1 characterize datas are as follows：MS(ESI+):m/z calcd for C43H55N2O9 +(M+H+),
743.9,found:745.1. ultraviolet maximum absorption wavelength：465nm,628nm.
17 Schiff product product S2 characterize datas are as follows：MS(ESI+):m/z calcd for C44H57N2O9 +(M
+H+),757.9,found:759.2. ultraviolet maximum absorption wavelength：469nm,632nm.
Embodiment 6
N, N- dimethyl-N-certain herbaceous plants with big flowers base propane diamine 2- amino hypocrelline Bs (X=NH, m=3, n=0, R1=R2=CH3,R3
=C10H21) preparation：
By hypocrelline B HB (100mg, 0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=N, m=3, n=
0, R1=R2=CH3, R3=C10H21) (236mg, 0.72mmol) be dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen is protected
It is heated to 45 DEG C under shield, is protected from light and is stirred to react 6h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL
Dichloromethane dissolves, and is washed three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water primary, organic layer anhydrous magnesium sulfate
Dry, filtering, organic phase, which are hanged, dry obtains crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：
Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：1) two kinds of black-and-blue solid products, are obtained, are denoted as 2- respectively
(yield 10.6%, Rf are by amino substitution product S3 (yield 4.8%, Rf 0.32) and 17 Schiff product S4
0.55)。
2- bit amino substitution product S3 characterize datas are as follows：MS(ESI+):m/z calcd for C44H57N2O9 +(M+H+),
755.9,found:757.8. ultraviolet maximum absorption wavelength：475nm,638nm.
17 Schiff product product S4 characterize datas are as follows：MS(ESI+):m/z calcd for C45H59N2O9 +(M
+H+),769.9,found:772.5. ultraviolet maximum absorption wavelength：476nm,640nm.
Embodiment 7
N, N- dimethyl-N-certain herbaceous plants with big flowers base propane diamine 2- amino hypocrellin As (X=NH, m=3, n=0, R1=R2=CH3,R3
=C10H21) preparation：
By hypocrellin A HB (100mg, 0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=N, m=3, n=
0, R1=R2=CH3, R3=C10H21) (236mg, 0.72mmol) be dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen is protected
It is heated to 45 DEG C under shield, is protected from light and is stirred to react 6h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL
Dichloromethane dissolves, and is washed three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water primary, organic layer anhydrous magnesium sulfate
Dry, filtering, organic phase, which are hanged, dry obtains crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：
Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：1) two kinds of black-and-blue solid products, are obtained, are denoted as 2- respectively
(yield 9.8%, Rf are by amino substitution product S5 (yield 4.8%, Rf 0.28) and 17 Schiff product S6
0.55)。
2- bit amino substitution product S5 characterize datas are as follows：MS(ESI+):m/z calcd for C44H55N2O8 +(M+H+),
737.9,found:739.8. ultraviolet maximum absorption wavelength：472nm,634nm.
17 Schiff product product S6 characterize datas are as follows：MS(ESI+):m/z calcd for C45H57N2O8 +(M
+H+),751.9,found:753.8. ultraviolet maximum absorption wavelength：478nm,635nm.
Embodiment 8
N, N- dimethyl-N-certain herbaceous plants with big flowers base propane diamine 2- amino hypocrelline Bs (X=NH, m=3, n=0, R1=R2=CH3,R3
=C12H25) preparation：
By hypocrelline B HB (100mg, 0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=N, m=3, n=
0, R1=R2=CH3, R3=C12H25) (256mg, 0.72mmol) be dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen is protected
It is heated to 50 DEG C under shield, is protected from light and is stirred to react 12h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue is used
100mL dichloromethane dissolves, and wash three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water once, and organic layer is with anhydrous
Magnesium sulfate is dry, filtering, organic phase hang and dry obtain crude product.Gained crude product is further detached with silica gel plate chromatography, solvent
For acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：2) two kinds of black-and-blue solid products, are obtained, are remembered respectively
For 2- bit amino substitution products S7 (yield 5.5%, Rf 0.28) and 17 Schiff product S8 (yield 12.2%,
0.48) Rf is.
2- bit amino substitution product S7 characterize datas are as follows：MS(ESI+):m/z calcd for C46H61N2O9 +(M+H+),
779.9,found:782.2. ultraviolet maximum absorption wavelength：472nm,652nm.
17 Schiff product product S8 characterize datas are as follows：MS(ESI+):m/z calcd for C47H63N2O9 +(M
+H+),793.8,found:795.6. ultraviolet maximum absorption wavelength：475nm,652nm.
Embodiment 9
N, N- dimethyl-N-certain herbaceous plants with big flowers base butanediamine 2- amino hypocrellin As (X=NH, m=4, n=0, R1=R2=CH3,R3
=C10H21) preparation：
By hypocrellin A HB (100mg, 0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=NH, m=4, n=
0, R1=R2=CH3, R3=C10H21) (248mg, 0.72mmol) be dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen is protected
It is heated to 45 DEG C under shield, is protected from light and is stirred to react 6h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL
Dichloromethane dissolves, and is washed three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water primary, organic layer anhydrous magnesium sulfate
Dry, filtering, organic phase, which are hanged, dry obtains crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：
Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：1) two kinds of black-and-blue solid products, are obtained, are denoted as 2- respectively
(yield 8.8%, Rf are by amino substitution product S9 (yield 9.2%, Rf 0.35) and 17 Schiff product S10
0.56)。
2- bit amino substitution product S9 characterize datas are as follows：MS(ESI+):m/z calcd for C45H57N2O8 +(M+H+),
751.9,found:754.0. ultraviolet maximum absorption wavelength：468nm,637nm.
17 Schiff product product S10 characterize datas are as follows：MS(ESI+):m/z calcd for C46H59N2O8 +
(M+H+),763.9,found:765.8. ultraviolet maximum absorption wavelength：475nm,640nm.
Embodiment 10
N, N- dimethyl-N-certain herbaceous plants with big flowers base propane diamine 2- amino hypocrelline Bs (X=NH, m=4, n=0, R1=R2=CH3,R3
=C10H21) preparation：
By 100mg hypocrelline Bs HB (0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=N, m=4, n=0,
R1=R2=CH3, R3=C10H21) (248mg, 0.72mmol) be dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen protection
Under be heated to 50 DEG C, be protected from light and be stirred to react 12h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL
Dichloromethane dissolves, and is washed three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water primary, organic layer anhydrous magnesium sulfate
Dry, filtering, organic phase, which are hanged, dry obtains crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：
Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：1) two kinds of black-and-blue solid products, are obtained, are denoted as 2- respectively
Amino substitution product S11 and 17 Schiff product S12.The Rf values of the two be respectively 0.30 (2 bit amino substitution product) and
0.55 (17 Schiff products), yield is respectively 4.8% and 15.5%.
2- bit amino substitution product S11 characterize datas are as follows：MS(ESI+):m/z calcd for C45H59N2O9 +(M+H+),767.9,found:769.2. ultraviolet maximum absorption wavelength：468nm,650nm.
17 Schiff product product S12 characterize datas are as follows：MS(ESI+):m/z calcd for C46H61N2O9 +
(M+H+),781.8,found:784.6. ultraviolet maximum absorption wavelength：470nm,650nm.
Embodiment 11
N, N- dimethyl-N-certain herbaceous plants with big flowers base butanediamine 2- amino hypocrellin As (X=NH, m=4, n=0, R1=R2=CH3,R3
=C12H25) preparation：
By hypocrellin A HB (100mg, 0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=N, m=4, n=
0, R1=R2=CH3, R3=C12H25) (248mg, 0.72mmol) be dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen is protected
It is heated to 45 DEG C under shield, is protected from light and is stirred to react 6h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL
Dichloromethane dissolves, and is washed three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water primary, organic layer anhydrous magnesium sulfate
Dry, filtering, organic phase, which are hanged, dry obtains crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：
Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：1) two kinds of black-and-blue solid products, are obtained, are denoted as 2- respectively
Amino substitution product S13 and 17 Schiff product S14.The Rf values of the two be respectively 0.35 (2 bit amino substitution product) and
0.56 (17 Schiff products), yield is respectively 9.2% and 8.8%.
2- bit amino substitution product S13 characterize datas are as follows：MS(ESI+):m/z calcd for C45H57N2O8 +(M+H+),751.9,found:754.0. ultraviolet maximum absorption wavelength：468nm,637nm.
17 Schiff product product S14 characterize datas are as follows：MS(ESI+):m/z calcd for C46H59N2O8 +
(M+H+),763.9,found:765.8. ultraviolet maximum absorption wavelength：475nm,640nm.
Embodiment 12
N, N- dimethyl-N-certain herbaceous plants with big flowers base ammonium-triethylene-glycol -2- amino hypocrelline Bs (X=NH, m=2, n=2, R1
=R2=CH3, R3=C10H21) preparation, synthetic route is as shown in Fig. 5.
By hypocrelline B HB (100mg, 0.18mmol) and corresponding long chain quaternary ammonium salt derivative (X=N, m=2, n=
2, R1=R2=CH3, R3=C10H21) (318mg, 0.80mmol) be dissolved in 30mL anhydrous acetonitriles, after being sufficiently mixed, nitrogen is protected
It is heated to 40 DEG C under shield, is protected from light and is stirred to react 8h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 100mL
Dichloromethane dissolves, and is washed three times with 50mL diluted hydrochloric acid aqueous solutions, then is washed with distilled water primary, organic layer anhydrous magnesium sulfate
Dry, filtering, organic phase, which are hanged, dry obtains crude product.Gained crude product is further detached with silica gel plate chromatography, and solvent is acetone：
Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20：1：1：1) two kinds of black-and-blue solid products, are obtained, are denoted as 2- respectively
(yield 8.6%, Rf are by amino substitution product S15 (yield 6.2%, Rf 0.40) and 17 Schiff product S16
0.60)。
2- bit amino substitution product S15 characterize datas are as follows：MS(ESI+):m/z calcd for C47H61BrN2O10 +(M+
H+),813.4,found:813.9；Ultraviolet maximum absorption wavelength：463nm,645nm.The structure of the 2- bit aminos substitution product
Shown in formula such as formula (11)：
17 Schiff product product S16 characterize datas are as follows：MS(ESI+):m/z calcd for C48H63N2O10 +
(M+H+),827.4,found:827.9. ultraviolet maximum absorption wavelength：468nm,652nm.17 Schiff products
Shown in structural formula such as formula (12)：
Embodiment 13
5- sulfydryls replace hypocrelline B (X=S, m=2, n=0, R1=R2=R3=C2H5) preparation, synthetic route
As shown in Fig. 6.
Hypocrelline B HB (100mg, 0.18mmol) and sulfydryl second ammonia triethyl ammonium salt (482mg, 2mmol) are added to
In 200mL ethyl alcohol-PBS buffer solutions (3/1, V/V, pH=11).Illumination reaction is passed through oxygen into reaction solution simultaneously, reaction
10h.Reaction solution concentrates, with chloroform extraction, washing three times, it is dry, crude product detaches to obtain product, yield 32% with thin-layer chromatography.
5- sulfydryl substitution product characterize datas are as follows：MS(ESI+):m/z calcd for C38H42NO9S+(M+H+),688.2,
found:690.1. ultraviolet maximum absorption wavelength：451nm,608nm.The structural formula such as formula of the 5- sulfydryl substitution product S17
(13) shown in：
Embodiment 14
2- oxygen replaces hypocrellin B derivatives (X=O, m=2, n=0, R1=R2=R3=C2H5) preparation.
Hypocrelline B HB (100mg, 0.18mmol) and ethylaminoethanol triethyl ammonium salt (450mg, 2mmol) are dissolved in
In 50mL THF, after being sufficiently mixed, it is heated to 50 DEG C under nitrogen protection, is protected from light and is stirred to react 12h, after completion of the reaction, revolving is gone
Except solvent.Black-and-blue solid residue 200mL dichloromethane dissolves, and washed once, steams with 50mL diluted hydrochloric acid aqueous solutions successively
Distilled water washes twice, and organic layer is dry with anhydrous magnesium sulfate, filtering, organic phase hang and dry obtain crude product.Gained crude product silica gel
Plate layer chromatography method further detaches, and solvent is acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20:1:1:1) indigo plant, is obtained
Black obtains solid product, yield 8.5%, and Rf values are respectively 0.48.Its characterize data is as follows：MS(ESI+):m/z calcd
for C37H40BrNO9 +(M+H+),721.1,found:722.8. ultraviolet maximum absorption wavelength：452nm,605nm.It is 2- described
Shown in the structural formula such as formula (14) of oxygen substitution product S18：
Embodiment 15
N, N- dimethyl-N-octyl butanediamine -2- amino hypocrelline Bs (X=NH, m=4, n=0, R1=R2=CH3,
R3=C8H17) preparation, synthetic route is as shown in Fig. 7.
By hypocrelline B HB (100mg, 0.18mmol) and long chain quaternary ammonium salt derivative NH2CH2CH2CH2CH2N(CH3)2
(C8H17) (414mg, 1.8mmol) be dissolved in 50mL anhydrous tetrahydro furans, after being sufficiently mixed, 60 are heated under nitrogen protection
DEG C, it is protected from light and is stirred to react 12h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue is molten with 200mL dichloromethane
Solution, twice, organic layer is dry, filtering, organic phase hang and dry obtain crude product for washing.Gained crude product is further with silica gel plate chromatography
Separation, solvent is acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20:1:1:1-20:1:1:3) three, are respectively obtained
Kind is black-and-blue to obtain solid product.
2 and 17 while substitution product S19 (yield 8.5%, Rf 0.21)；MS(ESI+):m/z,found:
1017.6；Ultraviolet maximum absorption wavelength：460nm,632nm.
2- bit amino substitution products S20 (yield 6.7%, Rf 0.50)；(ESI+):m/z,found:806.6. ultraviolet
Maximum absorption wavelength：456nm,628nm.
17 Schiff product product S21 (yield 4.5%, Rf 0.35)；MS(ESI+):m/z found:
819.5. ultraviolet maximum absorption wavelength：452nm,630nm.
Embodiment 16
N, N- dimethyl-N-octyl hexamethylene diamine -2- amino hypocrelline Bs (X=NH, m=6, n=0, R1=R2=CH3,
R3=C8H17) preparation.
By hypocrelline B HB (100mg, 0.18mmol) and long chain quaternary ammonium salt derivative NH2CH2CH2CH2CH2CH2CH2N
(CH3)2(C8H17) (462mg, 1.8mmol) be dissolved in 100mL anhydrous tetrahydro furans, after being sufficiently mixed, heated under nitrogen protection
To 60 DEG C, it is protected from light and is stirred to react 12h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 200mL dichloromethanes
Alkane dissolves, and twice, organic layer is dry, filtering, organic phase hang and dry obtain crude product for washing.Gained crude product with silica gel plate chromatography into
One step detaches, and solvent is acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20:1:1:1-20:1:1:3), respectively
To three kinds of black-and-blue solid products.
2 and 17 while substitution product S22 (yield 6.5%, Rf 0.24)；MS(ESI+):m/z,found:
1072.6；Ultraviolet maximum absorption wavelength：462nm,634nm.
2- bit amino substitution products S23 (yield 5.8%, Rf 0.56)；(ESI+):m/z,found:834.6. ultraviolet
Maximum absorption wavelength：458nm,630nm.
17 Schiff product product S24 (yield 7.5%, Rf 0.30)；MS(ESI+):m/z found:
848.5. ultraviolet maximum absorption wavelength：454nm,632nm.
Embodiment 17
N, N- dimethyl-N-Kui Ji hexamethylene diamine -2- amino hypocrelline Bs (X=NH, m=6, n=0, R1=R2=CH3,
R3=C10H21) preparation.
By hypocrelline B HB (100mg, 0.18mmol) and long chain quaternary ammonium salt derivative NH2CH2CH2CH2CH2CH2CH2N
(CH3)2(C10H21) (513mg, 1.8mmol) be dissolved in 100mL anhydrous tetrahydro furans, after being sufficiently mixed, under nitrogen protection plus
Heat is protected from light to 60 DEG C and is stirred to react 12h, after completion of the reaction, revolving removal solvent.Black-and-blue solid residue 200mL dichloros
Methane dissolves, and twice, organic layer is dry, filtering, organic phase hang and dry obtain crude product for washing.Gained crude product silica gel plate chromatography
Further separation, solvent is acetone：Ethyl acetate：Ethyl alcohol：Diethylamine (volume ratio 20:1:1:1-20:1:1:3), respectively
Obtain three kinds of black-and-blue solid products.
2 and 17 while substitution product S25 (yield 7.5%, Rf 0.28)；MS(ESI+):m/z,found:
1128.2；Ultraviolet maximum absorption wavelength：463nm,636nm.
2- bit amino substitution products S26 (yield 6.8%, Rf 0.58)；(ESI+):m/z,found:861.5；It is ultraviolet
Maximum absorption wavelength：460nm,632nm.
17 Schiff product product S27 (yield 8.5%, Rf 0.40)；MS(ESI+):m/z found:
876.5. ultraviolet maximum absorption wavelength：456nm,634nm.
Obviously, the above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be pair
The restriction of embodiments of the present invention may be used also on the basis of the above description for those of ordinary skill in the art
To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is every to belong to this hair
Row of the obvious changes or variations that bright technical solution is extended out still in protection scope of the present invention.
Claims (10)
1. a kind of hypocrellin derivant containing long chain quaternary, it is characterised in that：The general structure of the derivative such as formula (1)
Or shown in formula (2)：
Wherein, X N, O or S atom；2≤m≤20,0≤n≤10,1≤p≤2, m, n, p are positive integer；R1、R2And R3Respectively
It independently is the alkyl containing 1-20 carbon atom；A-For F-、Cl-、Br-、I-Ion；HA is hypocrellin A；HB is the red bacterium second of bamboo
Element；The structural formula of the HA and HB is respectively as shown in formula (3) and formula (4)：
The connection type of HA and X is in formula (1)：The 2 substitution-OCH marked in formula (3)3, X and 2 carbon atom it is mono- by C-N
Key is connected, or the 2 substitution-OCH marked in formula (3)3, X be connected by C-O singly-bounds with 2 carbon atoms, Huo Zhe
5 marked in formula (3) are connected by C-S singly-bounds, or 17 marked in formula (3) are connected by C=N double bonds；
Or the 2 substitution-OCH marked in formula (3) simultaneously3, X and 2 carbon atom pass through C=N double bonds by C-N singly-bounds, 17
It is connected；
The connection type of HB and X is in formula (2)：The 2 substitution-OCH marked in formula (4)3, X and 2 carbon atom it is mono- by C-N
Key is connected, or the 2 substitution-OCH marked in formula (4)3, X be connected by C-O singly-bounds with 2 carbon atoms, Huo Zhe
5 marked in formula (4) are connected by C-S singly-bounds, or 17 marked in formula (4) are connected by C=N double bonds；
Or the 2 substitution-OCH marked in formula (4) simultaneously3, X and 2 carbon atom pass through C=N double bonds by C-N singly-bounds, 17
It is connected.
2. a kind of preparation method of the hypocrellin derivant containing long chain quaternary as described in claim 1, which is characterized in that
Include the following steps：
Hypocrellin and long chain quaternary ammonium salt derivative are dissolved in organic solvent, reaction is carried out in the dark under inert gas shielding, finally
Through isolating and purifying, you can obtain the hypocrellin derivant containing long chain quaternary.
3. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 2, feature exist
In：The hypocrellin is hypocrellin A or hypocrelline B；The quaternary ammonium salt of the long chain quaternary ammonium salt derivative replaces base junction
Structure general formula is：-X-(CH2)m-(OCH2CH2)n-N+(R1)(R2)(R3), wherein X be N, O or S atom, 2≤m≤20,0≤n≤
10, m, n is positive integer, R1、R2And R3It is separately the alkyl containing 1-20 carbon atom.
4. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 2, feature exist
In：The organic solvent is one or more in acetonitrile, tetrahydrofuran, pyridine, methanol and ethyl alcohol.
5. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 2, feature exist
In：The molar ratio of the hypocrellin and long chain quaternary ammonium salt derivative is 1:2~10.
6. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 2, feature exist
In：The temperature of reaction is 30-60 DEG C；The time of reaction is 6-12 hours.
7. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 2, feature exist
In：The organic solvent is acetonitrile, tetrahydrofuran or pyridine；The hypocrellin and feeding intake for long chain quaternary ammonium salt derivative are rubbed
You are than being 1:4；The temperature of reaction is 50 DEG C；The time of reaction is 8 hours.
8. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 2, feature exist
In the process isolated and purified is：
Except dereaction organic solvent obtains residue, residue is dissolved with dichloromethane；Successively use diluted hydrochloric acid aqueous solution and
Water washing；Then that organic layer is dry, filtering, removing solvent obtain crude product；By crude product purified by silica gel plate layer chromatography to get to containing
The hypocrellin derivant of long chain quaternary.
9. a kind of preparation method of hypocrellin derivant containing long chain quaternary according to claim 8, feature exist
In：Solvent used is the mixed liquor containing acetone, ethyl acetate, ethyl alcohol and diethylamine, the mixing when silica gel plate layer chromatography
Acetone in liquid, ethyl acetate, ethyl alcohol and diethylamine volume ratio be 20:1:1:1~3.
10. a kind of hypocrellin derivant containing long chain quaternary as described in claim 1 is in preparing optical dynamic therapy
Application in photosensitizer drug.
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| US15/769,789 US11154548B2 (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, and preparation method and application thereof |
| JP2018521084A JP2018536643A (en) | 2015-10-21 | 2016-10-21 | Mono- or poly-substituted oil-water amphiphilic hypocrellin derivatives and method for producing and using the same |
| PCT/CN2016/102832 WO2017067497A2 (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, preparation method therefor, and uses thereof |
| EP16856928.3A EP3366669A4 (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, preparation method therefor, and uses thereof |
| CA3002695A CA3002695C (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, preparation method therefor, and uses thereof |
| JP2020143916A JP7479997B2 (en) | 2015-10-21 | 2020-08-27 | Mono- or poly-substituted oil-water amphiphilic hypocrellin derivatives and their uses |
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