CN102924426B - 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde, synthesis method and application of 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde - Google Patents
3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde, synthesis method and application of 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde Download PDFInfo
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- CN102924426B CN102924426B CN201210455312.2A CN201210455312A CN102924426B CN 102924426 B CN102924426 B CN 102924426B CN 201210455312 A CN201210455312 A CN 201210455312A CN 102924426 B CN102924426 B CN 102924426B
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- salicylic aldehyde
- chlorosalicylaldehyde
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Abstract
The invention discloses a 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde, a synthesis method and an application of 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde. The synthesis method of 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde comprises the following steps: weighing equivalent mole amount of 5-chlorosalicylaldehyde and 3,4-methylenedioxyphenethylamine hydrochloride to dissolve in an organic solvent, and performing condensation reaction within a range from 45 DEG C to a boiling point of the organic solvent; cooling after finishing the reaction; standing and crystallizing; separating out crystals and drying to obtain the product. The applicant investigates the activity of 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde for inhibiting the proliferation of eight human tumor cell strains to prove that the in-vitro antitumor activity has a certain selectivity; the activity for inhibiting the proliferation of HepG2 tumor strain is obvious, and the potential pharmaceutical value is good. The structure of 3,4-methylenedioxyphenethylamine hydrochloride-5-chlorosalicylaldehyde is represented by a formula shown in the description.
Description
Technical field
The present invention relates to medical technical field, be specifically related to homopiperony lamine contracting 5-chloro-salicylic aldehyde and synthetic method and application.
Background technology
Schiff's base is the very important organic compound of a class, and its constitutional features is to contain imines or azomethine characteristic group (RC=N-), is conventionally formed by amine and active carbonyl group condensation.The function and application field of Schiff's base is very extensive, comprises multiple fields such as medicine and pharmacology, biology, material, aspect study of pharmacy, is wherein one of hot research field.
Existing result of study fully shows, Schiff's base has biological activity and pharmacologically active widely, as antitumor, antibacterial, antiviral, anti-malarial, diminish inflammation and antipyretic etc.The peculiar imine group of Schiff's base or azomethine group are quite common in the compound of nature and growth and synthetic, and a lot of research also shows that the imine group in these compounds plays keying action in the biological activity performance of Schiff's base; The functional group that imido grpup both sides connect is for the diversity of Schiff's base activity provides larger selection space.Show if any report, homopiperony lamine and derivative Schiff's base thereof have had certain anti-microbial activity in the time of micro-molar concentration, can significantly suppress the growth (Pandeya S N, et al.1999) of trichophyton (MIC=820～980 μ M) and acrothesium floccosum (MIC=200～930 μ M).But have not yet to see the relevant report of the synthetic and activity research of the New Schiff Base take homopiperony lamine and 5-chloro-salicylic aldehyde as architecture basics.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new schiff base compounds, and homopiperony lamine contracting 5-chloro-salicylic aldehyde and synthetic method and application take homopiperony lamine and 5-chloro-salicylic aldehyde as architecture basics are specifically provided.
Homopiperony lamine contracting 5-chloro-salicylic aldehyde of the present invention, its structural formula is shown below:
Above-mentioned homopiperony lamine contracting 5-chloro-salicylic aldehyde's synthetic method is: take and equate that 5-chloro-salicylic aldehyde and the homopiperony lamine of amount of substance are dissolved in organic solvent, to the boiling temperature of organic solvent, carry out condensation reaction in 45 ℃, cooling after reacting completely, leave standstill crystallization, isolate crystal, dry, obtain homopiperony lamine contracting 5-chloro-salicylic aldehyde.
In above-mentioned synthetic method,
Described organic solvent can be any one or the two or more combination being selected from methylene dichloride, ethanol, methyl alcohol and chloroform.In the time that organic solvent is above-mentioned two or more combination, the proportioning between them can be any proportioning.Organic solvent is preferably first used before use
molecular sieve dewaters, thereby is more conducive to the carrying out of reaction.The consumption of organic solvent can be determined as required, be generally and can dissolve 5-chloro-salicylic aldehyde and the homopiperony lamine of participating in reaction, 5-chloro-salicylic aldehyde and 0.01mol homopiperony lamine 30～200mL organic solvent that can be specifically 0.01mol dissolve, and preferably dissolve with 30～100mL.In the time that the input amount of organic solvent is larger, after stopped reaction, can be first by the methods such as underpressure distillation remove majority of organic solvent (be generally remove account for organic solvent input amount 80～95%), then by cooling reaction solution, can separate out equally target product crystal after leaving standstill.
When condensation reaction, adopt thin-layer chromatography (TLC) to follow the tracks of detection condensation reaction whether completely, extremely completely approximately need to 1～12h in the reaction of said temperature scope internal condensation.The temperature of carrying out condensation reaction is preferably 65～80 ° of C, extremely completely approximately 3～6h of reaction under this condition.
After reacting completely, normally reaction solution is cooled to 10～25 ℃ and leaves standstill crystallization.The standing time is generally 1～12h.The described dry vacuum-drying of employing conventionally, temperature general control is at 25～50 ° of C.
The productive rate of preparing homopiperony lamine contracting 5-chloro-salicylic aldehyde by aforesaid method is in 70～90% left and right, and the homopiperony lamine contracting 5-chloro-salicylic aldehyde who makes can reach the object being further purified by the method for solvent recrystallization, and described solvent is identical with aforementioned organic solvent.
The present invention also comprises that above-mentioned homopiperony lamine contracting 5-chloro-salicylic aldehyde is in the application of preparing in antitumor drug.
The present invention also comprises the antitumor drug of preparing as effective constituent take above-mentioned homopiperony lamine contracting 5-chloro-salicylic aldehyde.
Compared with prior art, take homopiperony lamine and 5-chloro-salicylic aldehyde as architecture basics, obtain homopiperony lamine contracting 5-chloro-salicylic aldehyde by aldehyde amine dehydration condensation, synthetic method is simple, reaction conditions is gentle, and reaction raw materials is cheap and easy to get; Applicant also investigates the proliferation inhibition activity of homopiperony lamine contracting 5-chloro-salicylic aldehyde to 8 kinds of human tumor cell lines, result shows that its anti tumor activity in vitro has certain selectivity, proliferation inhibition activity to specific tumors strain is remarkable, demonstrate good potential pharmaceutical use, be expected to the preparation for various antitumor drugs.
Accompanying drawing explanation
Fig. 1 is the infrared spectra spectrogram of the product that makes of the embodiment of the present invention 1;
Fig. 2 is the UV spectrum spectrogram of the product that makes of the embodiment of the present invention 1;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the product that makes of the embodiment of the present invention 1;
Fig. 4 is the carbon-13 nmr spectra figure of the product that makes of the embodiment of the present invention 1;
Fig. 5 is the negative ion peak spectrogram of the electrospray ionization mass spectrum of the product that makes of the embodiment of the present invention 1.
Embodiment
With specific embodiment, the invention will be further described below, but the present invention is not limited to these embodiment.
Get that in the dehydrated alcohol that the 5-chloro-salicylic aldehyde of 0.01mol and the homopiperony lamine of 0.01mol be dissolved in 30mL, (dehydrated alcohol is used before using
molecular sieve dehydration), gained liquid under agitation condition under 78 ℃ of conditions back flow reaction to completely (TLC follows the tracks of detection, about 3h), after stopped reaction, reaction solution is fully cooled to 15 ℃, leaves standstill 6h, separate out yellow needle-like crystal, filter, gained crystal is vacuum-drying 6h under room temperature condition, obtains yellow solid product, productive rate 90%.
To yellow solid product obtained above carry out respectively infrared spectra, UV spectrum,
1h and
13c nuclear magnetic resonance spectrum and electrospray ionization mass spectrum evaluation, their spectrogram is respectively as shown in Fig. 1,2,3,4 and 5, and concrete spectral characteristic is as follows:
Infrared spectra: (KBr, cm
-1) 3440 (ν
n-H), 2912,2846 (ν
ar-H), 1637 (ν
c=N), 1484 (ν
c=C), 1249,1196 (ν
c-O), 1038 (ν
c-N);
UV spectrum (H
2o): ε
max=1.67 × 10
4lmol
-1cm
-1(236nm);
Nuclear magnetic resonance spectrum (hydrogen spectrum):
1h NMR (500MHz, CDCl
3) δ 13.45 (s, 1H, OH), 8.16 (s, 1H, CH=N), 7.26 (dd, J=8.9,2.6Hz, 1H, H-Ar), 7.18 (d, J=2.5Hz, 1H, H-Ar), 6.92 (d, J=8.8Hz, 1H, H-Ar), 6.76 (d, J=7.9Hz, 1H, H-Ar), 6.72 (s, 1H, H-Ar), 6.66 (d, J=7.9Hz, 1H, H-Ar), 5.95 (s, 2H, OCH
2o), 3.83 (t, J=6.9Hz, 2H, CH
2), 2.95 (t, J=7.0Hz, 2H, CH
2);
Nuclear magnetic resonance spectrum (carbon spectrum):
13c NMR (125MHz, CDCl
3) δ 163.96,159.80,147.73,146.13,132.73,132.02,130.33,123.04,121.85,119.44,118.60,109.15,108.31,100.90,61.19,36.97;
Electrospray ionization mass spectrum: m/z 302.1[M-H]
-.
Therefore, can determine that above-mentioned yellow solid product is homopiperony lamine contracting 5-chloro-salicylic aldehyde, its molecular formula is C
16h
14clNO
3, molecular weight is 303.5g/mol, its chemical structural formula is as follows:
Embodiment 2
(methylene dichloride is used before using in the methylene dichloride of 100mL to get the 5-chloro-salicylic aldehyde of 0.01mol and the homopiperony lamine mixed dissolution of 0.01mol
molecular sieve dehydration), gained solution is stirring reaction (TLC follows the tracks of detection, about 12h) extremely completely at 45 ℃, after stopped reaction, most of dichloromethane solvent (account for methylene dichloride consumption 90%) is removed in underpressure distillation, remaining reaction solution is fully cooled to 10 ℃, leaves standstill 12h, separates out yellow needle-like crystal, filter, gained crystal room temperature condition glance sideways vacuum-drying 2h, obtains yellow solid product, productive rate 75%.
Above-mentioned yellow solid product is carried out to Spectrum Analysis, and its spectral characteristic is identical with the product that embodiment 1 makes, and therefore, can determine that the yellow solid product that the present embodiment makes is homopiperony lamine contracting 5-chloro-salicylic aldehyde.
Embodiment 3
(volume ratio of chloroform and anhydrous methanol is 1:1, before chloroform and anhydrous methanol use, uses in chloroform/anhydrous methanol mixed solvent of 200mL to get the 5-chloro-salicylic aldehyde of 0.01mol and the homopiperony lamine mixed dissolution of 0.01mol
molecular sieve dehydration), gained solution is stirring reaction (TLC follows the tracks of detection, about 1h) extremely completely at 60 ℃, after stopped reaction, remove most of solvent (account for consumption of organic solvent 90%) by vacuum distillation method, remaining reaction solution is fully cooled to 25 ℃ of room temperatures, leaves standstill 1h, separates out yellow needle-like crystal, filter, vacuum-drying 24h under gained crystal room temperature condition, obtains homopiperony lamine contracting 5-chloro-salicylic aldehyde, productive rate 70%.
(anhydrous methanol is used before using in the anhydrous methanol solvent of 100mL to get the 5-chloro-salicylic aldehyde of 0.01mol and the homopiperony lamine mixed dissolution of 0.01mol
molecular sieve dehydration), gained solution refluxes stirring reaction to complete (TLC follows the tracks of detection, about 4h), after stopped reaction at 65 ℃, remove most of methanol solvate (account for anhydrous methanol consumption 80%) by vacuum distillation method, remaining reaction solution is fully cooled to 15 ℃, leaves standstill 4h, separates out yellow needle-like crystal, filter, vacuum-drying 6h under gained crystal room temperature condition, obtains homopiperony lamine contracting 5-chloro-salicylic aldehyde, productive rate 82%.
In order to absolutely prove the purposes of homopiperony lamine contracting 5-chloro-salicylic aldehyde of the present invention in pharmacy, applicant has carried out anti tumor activity in vitro experiment to homopiperony lamine contracting 5-chloro-salicylic aldehyde.
One, the proliferation inhibition activity experiment of homopiperony lamine contracting 5-chloro-salicylic aldehyde to 8 kinds of human tumor cell lines:
1, cell strain and cell cultures
Human lung carcinoma cell NCI-H460, stomach cancer cell MGC80-3, human liver cancer cell BEL-7402, HepG2, cervical cancer cell HeLa 229, transitional cell bladder carcinoma cell line T-24, ovarian cancer cell SK-OV-3, the ovarian cancer cell of resistance to cis-platinum SK-OV-3/DDP are selected in this experiment
All cells strain is all cultivated in RPMI-1640 or DMEM nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, puts 37 ℃ containing volumetric concentration 5%CO
2in incubator, cultivate.Inverted microscope observation of cell growing state, 0.25% tryptic digestion goes down to posterity, take the logarithm vegetative period cell for experiment.
2, the preparation of testing compound
Homopiperony lamine salicylaldehyde used is 2 gained of product dehydrated alcohol recrystallization that the embodiment of the present invention 1 makes, its purity >=95%, its DMSO liquid storage (concentration is 0.001mol/L) is diluted to five concentration gradients successively by RMPI1640 substratum, be respectively 40,20,10,5,2.5 μ mol/L, wherein solubility promoter DMSO final concentration≤1%.First test under 10 μ mol/L or 20 μ mol/L concentration homopiperony lamine contracting 5-chloro-salicylic aldehyde for the inhibiting rate of different tumor cell proliferations, be considered as primary dcreening operation result (wherein, to SK-OV-3/DDP, T-24, HepG2 cell strain, primary dcreening operation concentration is 20 μ mol/L, is 10 μ mol/L to the primary dcreening operation concentration of all the other cell strains).Test respectively again target product under different gradient concentrations the propagation of various tumour cells is suppressed to degree, in order to the Fitting Calculation half-inhibition concentration, i.e. IC
50value.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of taking the logarithm vegetative period, after tryptic digestion, with being mixed with containing the nutrient solution of 10% calf serum the cell suspension that concentration is 5000/mL, be inoculated in 96 well culture plates with every hole 190 μ L, make cell density to 1000～10000 to be measured/hole (the aseptic PBS of marginal pore fills);
(2) 5%CO
2, hatch 24h for 37 ℃, at the bottom of being paved with hole to cell monolayer, every hole adds the medicine 10 μ L of finite concentration gradient, and each concentration gradient is established 4 multiple holes;
(3) 5%CO
2, hatch 48 hours, under inverted microscope, observe for 37 ℃;
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) stop cultivating, carefully suck nutrient solution in hole, every hole adds 150 μ L DMSO fully to dissolve first a ceremonial jade-ladle, used in libation precipitation, after vibrator mixes, is 570nm at microplate reader wavelength, and reference wavelength is the optical density value that 450nm measures each hole;
(6) zeroing hole (substratum, MTT, DMSO), control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO) are set simultaneously.
(7) according to the optical density value (OD value) recording, judge viable cell quantity, OD value is larger, and cytoactive is stronger.Utilize formula:
The inhibiting rate of computerized compound to growth of tumour cell.Its test result is as shown in table 1 below:
Table 1: the growth inhibition ratio (%) of homopiperony lamine contracting 5-chloro-salicylic aldehyde to different tumor cell lines
Note: to SK-OV-3/DDP, T-24, HepG2 cell strain, primary dcreening operation concentration is 20 μ mol/L, is 10 μ mol/L to the primary dcreening operation concentration of all the other cell strains; "-" represents non-activity; " ND " represents undetermined.
Further by Bliss software, the inhibiting rate data of five concentration gradients are carried out to matching, obtain the half-inhibition concentration (IC of product to different tumor lines
50value, the μ mol/L of unit), result is as shown in table 2 below:
Table 2: the IC of homopiperony lamine contracting 5-chloro-salicylic aldehyde to two kinds of human tumor cell lines
50value (μ M)
From anti tumor activity in vitro test result, homopiperony lamine contracting 5-chloro-salicylic aldehyde shows different proliferation inhibition activities for different human tumor cell lines.From primary dcreening operation result, except cervical cancer cell HeLa 229 cells are not had activity, other 7 kinds of tumor lines are all shown to certain inhibition activity, but overall activity a little less than, as to the inhibiting rate of ovarian cancer cell SK-OV-3, lung carcinoma cell NCI-H460, stomach cancer cell MGC80-3 all lower than 20%; But compound shows higher activity to transitional cell bladder carcinoma cell line T-24, liver cancer cell HepG2, under 20 μ mol/L concentration, inhibiting rate approaches or exceedes 50%, reaches respectively 46.81 ± 1.84 and 57.92 ± 3.16.In addition, it should be noted that compound has obvious inhibition to human ovarian cancer cisplatin resistance strain SK-OV-3/DDP active, inhibiting rate is 30.91 ± 0.32, on the contrary inhibiting rate to SK-OV-3 (12.08 ± 0.06) higher than it.This with for ovarian cancer a line clinical chemotherapy medicine---the active function of cis-platinum is contrary, show that they are completely different from the Anticancer Effect and Mechanism of cis-platinum, be conducive to it and effectively overcome the resistance of tumor line to cis-platinum.
And further IC
50value Data shows that its proliferation inhibition activity to liver cancer cell HepG2 is the highest too, IC
50value reaches 10.69 ± 0.42 μ M; And IC to transitional cell bladder carcinoma cell line T-24
50value also reaches 24.17 ± 1.05 μ M.
The above results shows, homopiperony lamine contracting 5-chloro-salicylic aldehyde has certain active selectivity to different people tumor cell line, in 8 kinds of screened tumour cells, it shows the highest toxicity selectivity to human liver cancer cell HepG2, has the value of further investigation exploitation.On the other hand, homopiperony lamine contracting 5-chloro-salicylic aldehyde is still starkly lower than cis-platinum to the proliferation inhibition activity of above-mentioned tumor cell line, but this toxicity that also shows homopiperony lamine contracting 5-chloro-salicylic aldehyde normal tissue cell also should be lower.
In sum, homopiperony lamine contracting 5-chloro-salicylic aldehyde of the present invention aggregate performance has gone out certain anti tumor activity in vitro, human liver cancer cell HepG2 is had to significant toxicity selectivity, there is good potential pharmaceutical use, be expected to the preparation for various antitumor drugs.
Claims (8)
1. homopiperony lamine contracting 5-chloro-salicylic aldehyde, its structural formula is shown below:
2. homopiperony lamine contracting 5-chloro-salicylic aldehyde's claimed in claim 1 synthetic method, it is characterized in that: take and equate that 5-chloro-salicylic aldehyde and the homopiperony lamine of amount of substance are dissolved in organic solvent, to the boiling temperature of organic solvent, carry out condensation reaction in 45 ℃, cooling after reacting completely, leave standstill crystallization, isolate crystal, dry, obtain homopiperony lamine contracting 5-chloro-salicylic aldehyde.
3. homopiperony lamine contracting 5-chloro-salicylic aldehyde's according to claim 2 synthetic method, is characterized in that: described organic solvent is selected from any one or the two or more combinations in methylene dichloride, dehydrated alcohol, methyl alcohol and chloroform.
4. homopiperony lamine contracting 5-chloro-salicylic aldehyde's according to claim 2 synthetic method, is characterized in that: the temperature of described condensation reaction is 60～70 ℃.
5. homopiperony lamine contracting 5-chloro-salicylic aldehyde's according to claim 2 synthetic method, is characterized in that: after reacting completely, reaction solution is cooled to 10～25 ℃.
6. homopiperony lamine contracting 5-chloro-salicylic aldehyde's according to claim 2 synthetic method, is characterized in that: the standing time is 1～12h.
7. homopiperony lamine contracting 5-chloro-salicylic aldehyde claimed in claim 1 is in the application of preparing in antitumor drug.
8. the antitumor drug of preparing as effective constituent take homopiperony lamine contracting 5-chloro-salicylic aldehyde claimed in claim 1.
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| CN101855218A (en) * | 2007-09-13 | 2010-10-06 | 康塞特医药品有限公司 | Synthesizing of deuterated catechol and benzo [d] [1,3] dioxole and derivative thereof |
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| CN101855218A (en) * | 2007-09-13 | 2010-10-06 | 康塞特医药品有限公司 | Synthesizing of deuterated catechol and benzo [d] [1,3] dioxole and derivative thereof |
Non-Patent Citations (3)
| Title |
|---|
| Medicinal Chemistry Letters》.2005,第16卷1380-1383. * |
| XIAOLI Bian et al.Synthesis and antihyperglycemic evaluation of various protoberberine derivatives.《Bioorganic & Medicinal Chemistry Letters》.2005,第16卷1380-1383. |
| XIAOLI Bian et al.Synthesis and antihyperglycemic evaluation of various protoberberine derivatives.《Bioorganic & * |
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