CN109678870A - A kind of biologically active podophyllotoxin derivative and preparation method thereof - Google Patents
A kind of biologically active podophyllotoxin derivative and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
The present invention provides a kind of biologically active podophyllotoxin derivative and preparation method thereof, which is 1- phenyl -8- (3,4,5- trihydroxy) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one, the podophyllotoxin derivative has good water solubility, has safety to normal cell, significantly inhibits to tumour cell；The preparation method of the podophyllotoxin derivative is simple, safely, be easy to operate and control.
Description
Technical field
The present invention relates to technical field of medicine synthesis, specially a kind of biologically active podophyllotoxin derivative and its
Preparation method.
Background technique
Podophyllotoxin is white crystalline powder, is a kind of wooden lipid anti-tumor drug ingredient, Etoposide and is replaced at present
Buddhist nun moors the podophyllotoxin derivatives such as glycosides and has become a clinical line anti-tumor drug, podophyllotoxin derivative Anticancer Effect and Mechanism
It is divided into two kinds: first is that inhibiting the assembling of tubulin and interfering the cell division of mid-term phase, second is that by inhibiting topoisomerase II
Inhibit cancer cell DNA replication dna.The podophyllotoxin derivatives such as Etoposide and Teniposide are for treating carcinoma of testis, small thin in clinic
The tumor diseases such as born of the same parents' lung cancer and leukaemia.Although having synthesized podophyllotoxin derivative with certain anti-tumor activity, deposit
Bone marrow suppression, gastrointestinal reaction, the poorly water-soluble the problems such as.
Summary of the invention
In consideration of it, the present invention provides a kind of biologically active podophyllotoxin derivative and preparation method thereof, the ghost
Mortar toxin derivant has good water solubility, has safety to normal cell, there is apparent inhibition to make tumour cell
With；The preparation method of the podophyllotoxin derivative is simple, safely, be easy to operate and control.
Technical scheme is as follows:
A kind of biologically active podophyllotoxin derivative, molecular structural formula are as follows:
Wherein, R is phenyl, p-methylphenyl or p-hydroxybenzene.
The preparation method of above-mentioned biologically active podophyllotoxin derivative, steps are as follows:
(1) podophyllotoxin is dissolved in tetrahydrofuran, reaction temperature is cooled to -20 DEG C, and diisopropylaminoethyl is slowly added dropwise
The tetrahydrofuran solution of lithium is cooled to -40 DEG C after dripping, and N is slowly added dropwise, and N- dibutyl formamide after dripping, is kept
20min is reacted under the conditions of -60 DEG C, then heats to -40 DEG C, 20min is reacted under the conditions of -40 DEG C, 0 DEG C is finally risen to, 0
30min is reacted under the conditions of DEG C, is subsequently poured into ice water, dilute hydrochloric acid solution is slowly added dropwise, and adjusting reaction solution pH is neutrality, is then used
Methylene chloride extraction reaction solution is multiple, and 6- aldehyde radical-podophyllotoxin is obtained after concentration of reaction solution；The podophyllotoxin and diisopropyl
Base lithium amide and N, the inventory molar ratio of N- dibutyl formamide are 1:2:10；
(2) 6- aldehyde radical-podophyllotoxin and triethylamine are dissolved in methylene chloride, is slowly added dropwise under the conditions of -5 DEG C to toluene
Sulfonic acid chloride is warmed to room temperature after dripping, and reacts 2h, and TLC monitors raw material fully reacting, a certain amount of water is added, separates organic phase,
Water phase is extracted with dichloromethane again, merges organic phase, obtains 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-Podophyllum emodi var chinense after steaming organic phase
Toxin；The inventory molar ratio of the 6- aldehyde radical-podophyllotoxin and triethylamine and paratoluensulfonyl chloride is 1:3:2；
(3) in the reaction flask with water segregator, 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin and anhydrous chlorine
Change calcium to be added in anhydrous benzene, then phenylhydrazine be added into reaction kettle, is to slowly warm up to flow back, the water of generation is removed in reaction process,
Reaction solution is filtered after reaction, dilute hydrochloric acid solution is added dropwise in reaction solution, is gradually precipitated by solid, filters reaction solution, and filter cake adds
Enter in methylene chloride, then adjusting reaction pH with solution of potassium carbonate is neutrality, solid is completely dissolved, then dry anti-with anhydrous sodium sulfate
Liquid is answered, through the isolated 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-Podophyllum emodi var chinense of silica gel column chromatography after concentration of reaction solution after suction filtration
Toxin；The inventory mass ratio of the 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin and anhydrous calcium chloride is 1:1；
(5) 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-podophyllotoxin and alkali compounds are added in DMF, nitrogen
Reaction system is protected, is heated to 80 DEG C, reacts 5h, TLC monitors raw material fully reacting, steams DMF, medicinal extract is obtained, into medicinal extract
Methylene chloride is added, is then washed with water three times, separates organic phase, water phase is extracted with dichloromethane again, merges organic phase, steams
Obtain 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a after organic phase, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':
5,6] benzo [1,2,3-de] furans [3,4-h] scolds -9 (11bH) -one；The 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imines
The inventory molar ratio of base-podophyllotoxin and alkali compounds is 1:2~4；
(6) 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':
5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one is put into tetrahydrofuran, is stirring evenly and then adding into anhydrous
Lithium bromide is warming up to 30 DEG C, and solution gradually becomes clarification after mixing evenly；Slow temperature rising reflux stops adding to raw material fully reacting
Heat is cooled to room temperature, and vacuum rotary steam removes tetrahydrofuran after washed reaction liquid, obtains concentrate, dichloro is added into concentrate
Methane, it is 3 ± 0.5 that dilute hydrochloric acid is added while stirring at room temperature and adjusts concentrate pH, is extracted, layering；By water phase methylene chloride
Merging organic phase after extraction, organic phase is concentrated, methanol is added after concentration, a large amount of solids are precipitated, continue to be concentrated and be added methanol,
It is heated to reflux and stirs to solid and dissolve, stop heating；Oil bath is cooled to room temperature to, stirring after mistake cooling with ice-water bath naturally
Filter, filter cake are washed with cold methanol, and 8- (3,4,5- trihydroxy phenyl) -11,11a- dihydro -8H- [1,3] dioxy is obtained after draining
[4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (8aH) -one.
The preparation method of above-mentioned biologically active podophyllotoxin derivative the step of in (5), the alkalization
Conjunction object is sodium hydroxide, potassium hydroxide or barium hydroxide.
The preparation method of above-mentioned biologically active podophyllotoxin derivative the step of in (5), the 4- is to toluene
The inventory molar ratio of sulfonate group -6- phenylhydrazine imido grpup-podophyllotoxin and alkali compounds is 1:3.
The preparation method of above-mentioned biologically active podophyllotoxin derivative the step of in (6), after obtaining concentrate,
Methylene chloride is added into concentrate, it is 3 that dilute hydrochloric acid is added while stirring at room temperature and adjusts concentrate pH.
By above-mentioned biologically active podophyllotoxin derivative anti-tumor aspect application.
The prior art is compared, the beneficial effects of the present invention are: (1) provide a kind of noval chemical compound podophyllotoxin derivative
And the preparation method of podophyllotoxin derivative；(2) podophyllotoxin derivative is soluble easily in water；(3) podophyllotoxin derivative pair
Normal cell has safety, significantly inhibits to tumour cell；(4) preparation method of the podophyllotoxin derivative
Simply, safely, be easy to operate and control.
Detailed description of the invention
Fig. 1 is podophyllotoxin molecule and tumour cell target point protein combination schematic diagram；
Fig. 2 is podophyllotoxin derivative molecule provided by the invention and tumour cell target point protein combination schematic diagram.
Specific embodiment
Technical solution in order to enable those skilled in the art to better understand the present invention, below in conjunction with of the invention real
Example is applied, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is only
A part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, should fall within the scope of the present invention.
Embodiment 1 provides 6- aldehyde radical-podophyllotoxin preparation process；Embodiment 2 provides 4- p-methyl benzenesulfonic acid ester group-
6- aldehyde radical-podophyllotoxin preparation process；Embodiment 3 provides 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-podophyllotoxin
Preparation process；Embodiment 4-6 provide 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,
3] preparation process of dioxy [4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one；Embodiment 7 mentions
Supply 1- phenyl -8- (3,4,5- trihydroxy) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,6] benzo [1,2,
3-de] furans [3,4-h] cinnolines -9 (11bH) -one preparation process.
1 6- aldehyde radical of embodiment-podophyllotoxin preparation process
In reaction flask, podophyllotoxin 4g is dissolved in tetrahydrofuran 50mL, reaction temperature is cooled to -20 DEG C, slowly drips
The tetrahydrofuran solution 30mL for adding lithium diisopropylamine 2g, is cooled to -40 DEG C after dripping, and N, N- dibutyl first is slowly added dropwise
Amide 16g after dripping, keeps -60 DEG C of reaction 20min, is being warming up to -40 DEG C of reaction 20min, is finally rising to 0 DEG C of reaction
30min is finally poured into ice water 100mL, and under the conditions of 0 DEG C, dilute hydrochloric acid solution is slowly added dropwise, and adjusting reaction solution pH is neutrality,
Then it is multiple that reaction solution is extracted with dichloromethane, 6- aldehyde radical-podophyllotoxin 3.6g is obtained after concentration of reaction solution；1H NMR
(400MHz,CDCl3): δ 9.96 (s, 1H), 7.37 (d, J=4.0Hz, 1H), 7.31 (d, J=4.0Hz, 1H), 6.82 (s,
1H), 6.33 (s, 2H), 5.48 (d, J=8.0Hz, 1H), 4.76 (dd, J1=4.0Hz, J2=4.0Hz, 1H), 4.63 (d, J=
4.0Hz, 1H), 4.37 (t, J1=8.0Hz, J2=8.0Hz, 2H), 4.21 (dd, J1=12.0Hz, J2=4.0Hz, 1H),
3.62(s,6H),3.45(s,3H)；HRMS(ESI):443.1375[M+H]+。
2 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical of embodiment-podophyllotoxin preparation process
In 500mL reaction flask, 6- aldehyde radical-podophyllotoxin 4.5g and triethylamine 3g are dissolved in 20mL methylene chloride ,-
Paratoluensulfonyl chloride 3.8g is slowly added dropwise under the conditions of 5 DEG C, is warmed to room temperature after dripping, reacts 2h, TLC monitoring raw material has reacted
Entirely, a certain amount of water is added, separates organic phase, water phase is extracted with dichloromethane again, merges organic phase, obtains after steaming organic phase
4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin 5.1g；1H NMR(400MHz,CDCl3):δ10.03(s,1H),7.85-
7.81 (m, 2H), 7.35 (d, J=4.0Hz, 1H), 7.42-7.39 (m, 2H), 7.32 (d, J=4.0Hz, 1H), 6.82 (s,
1H), 6.33 (s, 2H), 5.48 (d, J=8.0Hz, 1H), 4.76 (dd, J1=4.0Hz, J2=4.0Hz, 1H), 4.63 (d, J=
4.0Hz, 1H), 4.35 (t, J1=8.0Hz, J2=4.0Hz, 2H), 4.21 (dd, J1=12.0Hz, J2=4.0Hz, 1H),
3.62(s,6H),3.45(s,3H),2.41(s,3H)；HRMS(ESI):597.1438[M+H]+。
3 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup of embodiment-podophyllotoxin preparation process
In the reaction flask with water segregator, 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin 6g and anhydrous chlorination
Calcium 6g is added in anhydrous benzene 30mL, then phenylhydrazine 1.6g is added into reaction kettle, is to slowly warm up to flow back, and life is removed in reaction process
At water, filter reaction solution after reaction, dilute hydrochloric acid solution be added dropwise in reaction solution, is gradually precipitated by solid, filter reaction solution,
Filter cake is added in methylene chloride, then adjusting reaction pH with solution of potassium carbonate is neutrality, and solid is completely dissolved, then uses anhydrous sodium sulfate
Dry reaction liquid, through the isolated 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imines of silica gel column chromatography after concentration of reaction solution after suction filtration
Base-podophyllotoxin 5.5g；Anal.Calcd for C36H34N2O10S:C,62.96；H,4.99；N,4.08.Found:C,
62.61；H,4.87；N,4.11；HRMS(ESI):687.1935[M+H]+。
Embodiment 4 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4',
5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one preparation process (1)
In 500mL reaction flask, 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-podophyllotoxin 7g and sodium hydroxide
1.2g is added in DMF50mL, nitrogen protection reaction system, is heated to 80 DEG C, reacts 5h, and TLC monitors raw material fully reacting, steams
DMF is added methylene chloride 10mL, is washed three times with water 20mL, separates organic phase, and water phase uses methylene chloride 10mL to extract again, closes
And organic phase, steam obtain after organic phase -8,8a, 11,11a- tetrahydro -1H- of 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) [1,
3] dioxy [4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] (11bH) -one of cinnolines -9 3.9g；1H NMR(400MHz,
CDCl3): δ 8.39 (s, 1H), 7.71-7.66 (m, 2H), 7.45 (d, J=8.0Hz, 1H), 7.15 (t, J1=8.0Hz, J=
8.0Hz, 2H), 6.96 (d, J=4.0Hz, 2H), 6.35 (s, 2H), 5.41 (d, J=8.0Hz, 1H), 4.63 (d, J=4.0Hz,
1H), 4.19 (t, J1=8.0Hz, J2=8.0Hz, 2H), 4.02 (d, J=16.0Hz, 1H), 3.11 (d, J=4.0Hz, 1H),
3.10-3.05(m,1H),3.69(s,6H),3.38(s,3H)；Anal.Calcd for C29H26N2O7:C,67.70；H,5.09；
N,5.44.Found:C,67.51；H,5.22；N,5.31；HRMS(ESI):515.1773[M+H]+。
Embodiment 5 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4',
5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one preparation process (2)
The difference of the present embodiment and embodiment 4 are as follows: use the sodium hydroxide in potassium hydroxide 1.7g alternate embodiment 4
1.2g, acquisition 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,
6] benzo [1,2,3-de] furans [3,4-h] (11bH) -one of cinnolines -9 is 4.9g.
Embodiment 6 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4',
5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one preparation process (3)
The difference of the present embodiment and embodiment 4 are as follows: use the sodium hydroxide in anhydrous barium hydroxide 3.5g alternate embodiment 4
1.2g, acquisition 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,
6] benzo [1,2,3-de] furans [3,4-h] (11bH) -one of cinnolines -9 is 5.1g.
Embodiment 7 1- phenyl -8- (3,4,5- trihydroxy) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':
5,6] preparation process of benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one
In 500mL four-hole bottle, -8,8a, 11,11a- tetrahydro -1H- of 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) [1,
3] dioxy [4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one 5g adds under the protection of room temperature argon gas
Enter in tetrahydrofuran 50mL, be stirring evenly and then adding into anhydrous lithium bromide 3.5g, be warming up to 30 DEG C, stir 10min after solution by
Gradual change clarification；It is to slowly warm up to back flow reaction 0.5h, a large amount of solids generate, and TLC detects reaction raw materials and disappears；Stop heating, it is cold
But to room temperature, water 30mL is added, vacuum rotary steam removes most of tetrahydrofuran after stirring 20min, and methylene chloride 30mL, room is added
The lower 2N hydrochloric acid adjusting reaction solution to pH=3 or so of temperature stirring, extracts, layering, water phase is extracted twice with methylene chloride 20mL, is closed
And organic phase, water 50mL are washed twice, saturated salt solution 30mL washed once；Back-out most of two is concentrated in organic phase at 40 DEG C
Methanol 20mL is added in chloromethanes, has a large amount of solids to be precipitated, and continues to be concentrated into a small amount of volume, methanol 20mL is added, is slowly stirred
Under, it is heated to return stirring 1h, stops heating；Oil bath is cooled to room temperature, stirring 10min cooling with ice-water bath, filtering, filter naturally
Cake repeatedly, obtains -8,8a, 11,11a- tetrahydro -1H- of 1- phenyl -8- (3,4,5- trihydroxy) with cold methanol 10mL washing after draining
[1,3] dioxy [4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] (11bH) -one of cinnolines -9 4.2g；1H NMR
(400MHz,CDCl3): δ 8.33 (s, 1H), 7.67-7.61 (m, 2H), 7.49 (d, J=8.0Hz, 1H), 7.13 (dd, J1=
12.0Hz, J=8.0Hz, 2H), 6.98-6.95 (m, 2H), 6.32 (s, 2H), 5.46 (d, J=8.0Hz, 1H), 5.13-5.11
(m, 2H), 4.63 (d, J=4.0Hz, 1H), 4.33-4.32 (m, 1H), 4.19 (t, J1=8.0Hz, J2=8.0Hz, 2H),
4.02 (d, J=16.0Hz, 1H), 3.16 (d, J=4.0Hz, 1H), 3.08 (t, J1=8.0Hz, J=4.0Hz, 1H)；
Anal.Calcd for C26H20N2O7:C,66.10；H,4.27；N,5.93.Found:C,66.36；H,4.15；N,5.81；
HRMS(ESI):473.1326[M+H]+。
Embodiment 8
The method that we use computer drug Computer Aided Design, podophyllotoxin and resulting compound molecule respectively with swell
The target point protein of oncocyte carries out molecular docking, target spot serial number 1M17.We have found that podophyllotoxin provided by the invention is derivative
Object can be very good to enter inside target point protein pocket, and compound molecule is surrounded by target point protein residue amino acid, with target spot
Form very strong function and effect, in podophyllotoxin molecule, only hydroxyl and aspartic acid ASP831 form hydrogen bond action (as schemed
Shown in 1), and podophyllotoxin derivative molecule provided by the invention can respectively with lysine LYS721, leucine LEU694 and
Methionine MET769 forms hydrogen bond action (as shown in Figure 2).
The test of 9 anti-tumor activity of embodiment
Growth period lung cell A549 is collected, the anticancer activity of compound is measured with MTS method, is 4 × 10 by concentration4
The cell solution of a/mL, which is added in 96 porocyte culture plates, (to be obtained culture solution containing 10% tire calf serum in tissue culture plate to be made into
Individual cells suspension), after culture for 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of compound effects with various concentration
Then the mixture of MTS (final mass concentration 2mg/mL) and DMS (30 μM of final molar concentration) are directly added into containing thin by 72h
In the culture medium of born of the same parents, continue to set incubator incubation 4h.After acting on 4h, liquid is discarded supernatant, 150 μ LDMSO are added in every hole, vibrate, carefully
Born of the same parents' survival rate measures absorptivity of the metabolin of MTS effect under enzyme linked immunological monitor 490nm wavelength by it, podophyllotoxin
Plain derivative is 5 μm of olL to the inhibiting rate IC50 of the cell-1。
The detection of 10 cytotoxicity of embodiment
Influence of the target compound of various concentration to human fibroblasts survival rate is detected by CCK-8 method, as a result table
Bright, the target compound of various concentration is respectively with cell co-culture, and each concentration group is compared with negative control group compared with difference is without system
Meter learns meaning, and target compound has certain safety to human fibroblasts.
| Target compound concentration (μ g/mL) | 0 | 2.5 | 5.0 | 7.5 | 10.0 |
| Cell survival rate (%) | 100±0 | 91.4 | 86.3 | 79.7 | 75.2 |
11 solubility experiment of embodiment
In 250mL volumetric flask, ringer's solution 100mL is added, by podophyllotoxin and compound 1- phenyl -8- (3,4,5-
Trihydroxy) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] scolds
Quinoline -9 (11bH) -one (podophyllotoxin derivative i.e. provided by the invention) take respectively 10mg, 50mg, 100mg, 250mg, 500mg,
750mg is separately added into volumetric flask, sees whether to dissolve under ultrasonic wave effect, and discovery podophyllotoxin 10mg can be completely molten
Solution, 50mg are partly dissolved, compound 1- phenyl -8- (3,4,5- trihydroxy) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy
[4', 5':5,6] benzo [1,2,3-de] furans [3,4-h] (11bH) -one of cinnolines -9 500mg can be completely dissolved, the portion 750mg
Divide dissolution.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (6)
1. a kind of biologically active podophyllotoxin derivative, molecular structural formula are as follows:
Wherein, R is phenyl, p-methylphenyl or p-hydroxybenzene.
2. preparing biologically active podophyllotoxin derivative method described in claim 1, which is characterized in that step is such as
Under:
(1) podophyllotoxin is dissolved in tetrahydrofuran, reaction temperature is cooled to -20 DEG C, and lithium diisopropylamine is slowly added dropwise
Tetrahydrofuran solution is cooled to -40 DEG C after dripping, and N is slowly added dropwise, and N- dibutyl formamide after dripping, is maintained at -60
20min is reacted under the conditions of DEG C, then heats to -40 DEG C, 20min is reacted under the conditions of -40 DEG C, finally rises to 0 DEG C, in 0 DEG C of item
30min is reacted under part, is subsequently poured into ice water, dilute hydrochloric acid solution is slowly added dropwise, adjusting reaction solution pH is neutrality, then uses dichloro
Methane extraction reaction solution is multiple, and 6- aldehyde radical-podophyllotoxin is obtained after concentration of reaction solution；The podophyllotoxin and diisopropyl ammonia
Base lithium and N, the inventory molar ratio of N- dibutyl formamide are 1:2:10；
(2) 6- aldehyde radical-podophyllotoxin and triethylamine are dissolved in methylene chloride, tolysulfonyl is slowly added dropwise under the conditions of -5 DEG C
Chlorine is warmed to room temperature after dripping, and reacts 2h, and TLC monitors raw material fully reacting, a certain amount of water is added, separates organic phase, water phase
It is extracted with dichloromethane again, merges organic phase, obtain 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin after steaming organic phase；
The inventory molar ratio of the 6- aldehyde radical-podophyllotoxin and triethylamine and paratoluensulfonyl chloride is 1:3:2；
(3) in the reaction flask with water segregator, 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin and anhydrous calcium chloride
It is added in anhydrous benzene, then phenylhydrazine is added into reaction kettle, be to slowly warm up to flow back, the water of generation is removed in reaction process, react
After filter reaction solution, dilute hydrochloric acid solution is added dropwise in reaction solution, is gradually precipitated by solid, filter reaction solution, filter cake be added two
In chloromethanes, then with solution of potassium carbonate adjust reaction pH be it is neutral, solid is completely dissolved, then with anhydrous sodium sulfate dry reaction
Liquid, through the isolated 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-podophyllotoxin of silica gel column chromatography after concentration of reaction solution after suction filtration
Element；The inventory mass ratio of the 4- p-methyl benzenesulfonic acid ester group -6- aldehyde radical-podophyllotoxin and anhydrous calcium chloride is 1:1；
(5) 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-podophyllotoxin and alkali compounds are added in DMF, nitrogen protection
Reaction system is heated to 80 DEG C, reacts 5h, and TLC monitors raw material fully reacting, steams DMF, obtains medicinal extract, is added into medicinal extract
Then methylene chloride is washed with water three times, separate organic phase, and water phase is extracted with dichloromethane again, merges organic phase, steams organic
1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,6] are obtained after phase
Benzo [1,2,3-de] furans [3,4-h] scolds -9 (11bH) -one；The 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-ghost
The inventory molar ratio of mortar toxin and alkali compounds is 1:2~4；
(6) 1- phenyl -8- (3,4,5- 2,4,5-trimethoxyphenyl) -8,8a, 11,11a- tetrahydro -1H- [1,3] dioxy [4', 5':5,6]
Benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (11bH) -one is put into tetrahydrofuran, is stirring evenly and then adding into anhydrous bromination
Lithium is warming up to 30 DEG C, and solution gradually becomes clarification after mixing evenly；For slow temperature rising reflux to raw material fully reacting, stopping heating is cold
But to room temperature, vacuum rotary steam removes tetrahydrofuran after washed reaction liquid, obtains concentrate, methylene chloride is added into concentrate,
It is 3 ± 0.5 that dilute hydrochloric acid is added while stirring at room temperature and adjusts concentrate pH, is extracted, layering；After water phase is extracted with dichloromethane
Merge organic phase, organic phase is concentrated, methanol is added after concentration, a large amount of solids are precipitated, continue to be concentrated and be added methanol, heat back
It flows and stirs to solid and dissolve, stop heating；Oil bath is cooled to room temperature naturally and is cooled down with ice-water bath, is filtered after stirring, filter cake
Washed with cold methanol, obtained after draining 8- (3,4,5- trihydroxy phenyl) -11,11a- dihydro -8H- [1,3] dioxy [4', 5':5,
6] benzo [1,2,3-de] furans [3,4-h] cinnolines -9 (8aH) -one.
3. the preparation method of biologically active podophyllotoxin derivative as claimed in claim 2, which is characterized in that in step
Suddenly in (5), the alkali compounds is sodium hydroxide, potassium hydroxide or barium hydroxide.
4. the preparation method of biologically active podophyllotoxin derivative as claimed in claim 2, which is characterized in that in step
Suddenly in (5), the 4- p-methyl benzenesulfonic acid ester group -6- phenylhydrazine imido grpup-podophyllotoxin and alkali compounds inventory molar ratio
For 1:3.
5. the preparation method of biologically active podophyllotoxin derivative as claimed in claim 2, which is characterized in that in step
Suddenly in (6), after obtaining concentrate, methylene chloride is added into concentrate, dilute hydrochloric acid is added while stirring at room temperature and adjusts concentration
Liquid pH is 3.
6. biologically active podophyllotoxin derivative as described in claim 1 is in the application of anti-tumor aspect.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037379A (en) * | 2014-04-25 | 2015-11-11 | 上海医药工业研究院 | Podophyllotoxin derivative, and preparation method, medicine composition and application thereof |
| CN107652300A (en) * | 2017-09-20 | 2018-02-02 | 辽宁大学 | Podophyllotoxin analogue and its application containing 1,2,4 triazinone structures |
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2018
- 2018-12-28 CN CN201811627142.5A patent/CN109678870A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037379A (en) * | 2014-04-25 | 2015-11-11 | 上海医药工业研究院 | Podophyllotoxin derivative, and preparation method, medicine composition and application thereof |
| CN107652300A (en) * | 2017-09-20 | 2018-02-02 | 辽宁大学 | Podophyllotoxin analogue and its application containing 1,2,4 triazinone structures |
Non-Patent Citations (2)
| Title |
|---|
| 贾红光等，: "鬼臼毒素类抗肿瘤药物的研究", 《青海医学院学报》 * |
| 赵明等，: "鬼臼毒素衍生物的合成及其体外抗肿瘤活性", 《中国药物化学杂志》 * |
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