CN103102284A - Preparation of 4-trifluoromethyl-2, 6-dinitrobenzene salicylaldoxime derivative and its application in anticancer therapeutic drugs - Google Patents
Preparation of 4-trifluoromethyl-2, 6-dinitrobenzene salicylaldoxime derivative and its application in anticancer therapeutic drugs Download PDFInfo
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- CN103102284A CN103102284A CN2011103513424A CN201110351342A CN103102284A CN 103102284 A CN103102284 A CN 103102284A CN 2011103513424 A CN2011103513424 A CN 2011103513424A CN 201110351342 A CN201110351342 A CN 201110351342A CN 103102284 A CN103102284 A CN 103102284A
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- 0 *c1cc(C(F)(F)F)cc(C(C2)C2Cc2c3)c1Oc2c(C=NOCc(cccc1)c1Cl)cc3Cl Chemical compound *c1cc(C(F)(F)F)cc(C(C2)C2Cc2c3)c1Oc2c(C=NOCc(cccc1)c1Cl)cc3Cl 0.000 description 1
- WWTFFBZRBMVCBR-JBQSXSRFSA-N O=Nc1cc(C(F)(F)F)cc(N=O)c1Oc(c(Cl)c1)c(/C=N/OCc(c(Cl)c2)ccc2Cl)cc1Cl Chemical compound O=Nc1cc(C(F)(F)F)cc(N=O)c1Oc(c(Cl)c1)c(/C=N/OCc(c(Cl)c2)ccc2Cl)cc1Cl WWTFFBZRBMVCBR-JBQSXSRFSA-N 0.000 description 1
- VUZQUGQENZBEMD-BRJLIKDPSA-N [O-][N+](c1cc(C(F)(F)F)cc([N+]([O-])=O)c1Oc1c(/C=N/OCc2ccccc2)cccc1)=O Chemical compound [O-][N+](c1cc(C(F)(F)F)cc([N+]([O-])=O)c1Oc1c(/C=N/OCc2ccccc2)cccc1)=O VUZQUGQENZBEMD-BRJLIKDPSA-N 0.000 description 1
- KODGRBDAJZWOPD-HIUVJMHLSA-N [O-][NH+]1[ClH]c2cc(Cl)cc(/C=N/OCc(cccc3)c3F)c2Oc2c1cc(C(F)(F)F)cc2[N+]([O-])=O Chemical compound [O-][NH+]1[ClH]c2cc(Cl)cc(/C=N/OCc(cccc3)c3F)c2Oc2c1cc(C(F)(F)F)cc2[N+]([O-])=O KODGRBDAJZWOPD-HIUVJMHLSA-N 0.000 description 1
Abstract
The invention relates to a 4-trifluoromethyl-2, 6-dinitrobenzene salicylaldoxime derivative, which is characterized by having the following general formula. In the structural formula, R1 can be hydrogen, 5-chlorine, 3, 5-dichloro, 5-bromo, and 3, 5-dibromo, and R2 can be hydrogen, 2-fluoro, 2-chloro, and 2, 4-dichloro. The 4-trifluoromethyl-2, 6-dinitrobenzene salicylaldoxime derivative provided in the invention can resist tubulin polymerization and inhibit the proliferation of MCF7, HepG2, A549 cells. Therefore, the salicylaldoxime compound provided in the invention can serve as a potential antitumor drug. The invention discloses its preparation method.
Description
Technical field
The present invention relates to salicylaldoxime compounds and preparation method thereof and antitumor drug.
Background technology
Cancer is one of principal disease of serious threat human health.The non-equilibrium coupling of Cell apoptosis and proliferation and transfer diffusion thereof are the bases that malignant tumour occurs.And microtubule--the main component of cytoskeleton-play an important role aspect cellular activity, it has the chromosomal effect of traction in the cell mitogen process.Under standard state, microtubule is in tubulin dimeric ' polymerization-depolymerization ' running balance.Balance is destroyed will stop normally carrying out of cell cycle, cause apoptosis.So, be important channel and the means of tumor disease therapeutic take tubulin as the Chemotherapy target spot.
Research finds, some contain the medicine of schiff bases C=N group can be in conjunction with tubulin, thereby affect microtubule polymerization or depolymerization prevention cell cycle, causes apoptosis.For example, it is active that aminooimidazole Shiff base derivative (effectively suppressing gastric carcinoma cells NUGC-3 and murine leukemia cell P388 increment), triazole Shiff base derivative (significantly suppressing human liver cancer cell BEL-7402, SMMC-7721, BEL-7402 increment), presence of Schiff-base complex and albendazole etc. all have obvious microtubulin-resisting, and finally block cell cycle progression, cell death inducing.Before studies show that, aldehyde substituting group anticarcinogenic effect is better than the amine substituting group, and Schiff base is better than other aldehydes.In addition, dinitroanilines is mainly expressed by the interference to a-in eukaryotic cell and b-microtubule protein gene, hinders the tubulin polymerization effect, thus cell death inducing.
In previous work, we have synthesized a collection of various substituent salicylic aldehyde series schiff bases, and have tested its biological activity, in this literary composition, these salicylic aldehyde schiff bases and dinitro-p-trifluorotoluene compounds have formed a series of new compound without report by substitution reaction.Just be based on drug effect and the compatibility research thereof of above multiple group, inferring that these new compounds may embody schiff bases and the synergetic property of dinitro-p-trifluorotoluene compounds in antitumor.We have tested the activity of this batch compound, and find that it has good restraining effect to MCF7, HepG2, A549, thereby and can suppress the cell cycle with the tubulin effect, cause apoptosis.
Summary of the invention
The object of the present invention is to provide a class salicylaldehyde oxime compounds and their preparation method and purposes.Technical scheme of the present invention is as follows:
1. a class salicylaldoxime derivative is characterized in that it has following general formula:
In structural formula, R1 is: hydrogen, 5-chlorine, 3,5-dichloro, 5-bromine, 3,5-dibromo.
R2 is: hydrogen, 2-fluorine, 2-chlorine, 2,4-dichloro.
2. method for preparing above-mentioned salicylaldoxime analog derivative, it is comprised of the following step:
Step 1. preparation Phenylmethoxyamine hydrochloride:
(1) azanol of Tetra hydro Phthalic anhydride protection is synthetic
Concrete synthetic method: be furnished with mechanical stirrer, in the 500ml three neck round-bottomed flasks of reflux condensing tube, adding respectively two kinds of raw materials of 0.2 mole, adding the 150ml pyridine in system, in 80 ℃ of reactions spend the night (the TLC detection reaction is carried out degree).Question response is complete, adds in a large amount of water, separate out after product with chloroform dissolving after washing activated carbon decolorizing, anhydrous magnesium sulfate drying, the filtering siccative, after solvent evaporated product.
(2) azanol replaces the benzyl chloride reaction
In 250ml three neck round-bottomed flasks; add the azanol of 0.2mol protection, then add the 2mol/L aqueous sodium hydroxide solution, complete to solid reaction; control ph between 8-9; adding mol ratio is the benzyltriethylammoinium chloride of 5% amount, then drips the chloroformic solution of benzyl chloride, to reacting completely; tell organic layer; water layer merges organic layer after extracting three times, and anhydrous magnesium sulfate drying is spin-dried for solvent and gets crude product.
(3) deprotection reaction
Get 250ml three neck round-bottomed flasks, take second step product 20g, then add 150ml ethanol, after sample is dissolved fully, be cooled to 0 ℃, drip hydrazine hydrate in system, to the disappearance of raw material point, product is standby through column chromatography for separation.
(4) salt-forming reaction
In methylene dichloride, cryosel is bathed and is cooled to-5 ℃ of left and right with the benzyloxy amine solvent, and passes into dry hydrogenchloride (laboratory self-control), controls gas flow rate, and tail gas absorbs with strong caustic, and ventilation body to product is all separated out.After blowing hydrogenchloride with nitrogen, filtration can obtain Phenylmethoxyamine hydrochloride.
Step 2. preparation schiff bases (salicylaldoxime):
With substituting group Phenylmethoxyamine hydrochloride (5.0mmol), be dissolved in dehydrated alcohol, slowly splash into equivalent triethylamine (5.0mmol), add again substituting group salicylic aldehyde (5.0mmol), magnetic stirs, normal-temperature reaction 0.5h (the TLC detection reaction is carried out degree), and product is separated out with solid.Suction filtration after reaction finishes, and rinse solids 3 times with dehydrated alcohol, the dry substituting group schiff bases (salicylaldoxime) that gets.With dehydrated alcohol with the product recrystallization.
Step 3. preparation 4-chloro-3, the 5-dinitro-p-trifluorotoluene:
Preparation 4-chloro-3, the 5-dinitro-p-trifluorotoluene
Nitration mixture is added in the round-bottomed flask that 4-chloro-3-nitro-trifluoromethyl toluene is housed that (＞2.5: 1), magnetic stirs, in 115 ℃ of reaction 4h (the TLC detection reaction is carried out degree).Question response finishes, and naturally cooling, standing demix, separatory discard the pale brown color acid layer of lower floor, then extracts 3 times with ethyl acetate and saturated sodium bicarbonate washing, and Rotary Evaporators is drained extraction liquid, gained solid ethyl alcohol recrystallization.
Step 4. is synthesized 4-trifluoromethyl-2,6-dinitrobenzene salicylaldoxime analog derivative
Add 4mmol K in the 50ml flask
2CO
3, and 2mmol substituting group schiff bases, 2mmol4-chloro-3, the 5-dinitro-p-trifluorotoluene, and be dissolved in the 20mml dehydrated alcohol, magnetic stirs, normal-temperature reaction 1h (TLC detection).Question response finishes, and with vacuum, solvent is drained, and residual solid in flask is dissolved in the 30ml ethyl acetate, with saturated common salt water washing extraction 3 times.Vacuum is drained extraction liquid, obtains the residual solid ethyl alcohol recrystallization, obtains final product.
4-trifluoromethyl-2 of the present invention, 6-dinitrobenzene salicylaldoxime analog derivative have the effect that suppresses MCF-7, A549, HepG2 cell proliferation.So 4-trifluoromethyl-2 of the present invention, 6-dinitrobenzene salicylaldoxime analog derivative can be done potential antitumor drug.
Embodiment
Embodiment one: the preparation of 5-chloro-2 (2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-chlorobenzyl) oxime (compound 1)
Be furnished with mechanical stirrer, in the 500ml three neck round-bottomed flasks of reflux condensing tube, adding respectively Tetra hydro Phthalic anhydride and the hydrazine hydrate of 0.2mol, and adding the 150ml pyridine in the system, in 80 ℃ of reactions spend the night (the TLC detection reaction is carried out degree).Question response is complete, adds in a large amount of water, separate out after product with chloroform dissolving after washing activated carbon decolorizing, anhydrous magnesium sulfate drying, the filtering siccative, after solvent evaporated product a.Get 0.2mol product a in round-bottomed flask, add again the 2mol/L aqueous sodium hydroxide solution, complete to solid reaction, control ph between 8-9, adding mol ratio is the benzyltriethylammoinium chloride of 5% amount, drip again the chloroformic solution of 1-chloro-2-(chloromethyl) benzene (being substituting group benzyl chlorine), to reacting completely, tell organic layer, water layer merges organic layer after extracting three times, anhydrous magnesium sulfate drying is spin-dried for solvent and gets crude product b.Take second step product b 20g, then add 150ml ethanol, after sample is dissolved fully, be cooled to 0 ℃, drip hydrazine hydrate in system, to the disappearance of raw material point, product c is standby through column chromatography for separation.Product c is dissolved in methylene dichloride, and cryosel is bathed and is cooled to-5 ℃ of left and right, and passes into dry hydrogenchloride (laboratory self-control), controls gas flow rate, and tail gas absorbs with strong caustic, and ventilation body to product is all separated out.After blowing hydrogenchloride with nitrogen, filtration can obtain product d 5-chlorine substituent Phenylmethoxyamine hydrochloride.With 2-benzyl chloride oxygen amine hydrochlorate (5.0mmol), be dissolved in dehydrated alcohol, slowly splash into equivalent triethylamine (5.0mmol), add again substituting group salicylic aldehyde (5.0mmol), magnetic stirs, normal-temperature reaction 0.5h (the TLC detection reaction is carried out degree), and product is separated out with solid.Suction filtration after reaction finishes, and rinse solids 3 times with dehydrated alcohol, purifying, the dry product e that gets.
Nitrosonitric acid with 95% and 98% the vitriol oil at least to be made into nitration mixture at 1: 1, under 50-55 ℃, slowly drip in the round-bottomed flask that the 4-chlorobenzotrifluoride is housed (＞1: 1), magnetic stirs, control temperature of reaction, wait to dropwise, temperature keeps 0.5h, after rise to about 70 ℃ and continue to react about 2h (the TLC detection reaction is carried out degree).Question response finishes, and naturally cooling, standing demix, separatory discard the pale brown color acid layer of lower floor, then extracts 3 times with ethyl acetate and saturated sodium bicarbonate washing, and Rotary Evaporators is drained extraction liquid, and gained solid ethyl alcohol recrystallization obtains product f.The same, nitration mixture is added in the round-bottomed flask that product f is housed that (＞2.5: 1), magnetic stirs, in 115 ℃ of reaction 4h (the TLC detection reaction is carried out degree).Question response finishes, and naturally cooling, standing demix, separatory discard the pale brown color acid layer of lower floor, then extracts 3 times with ethyl acetate and saturated sodium bicarbonate washing, and Rotary Evaporators is drained extraction liquid, and gained solid ethyl alcohol recrystallization obtains the g product.
Add 4mmol K2CO3 in the 50ml flask, and 2mmol product e, 2mmol product g, and be dissolved in the 20mml dehydrated alcohol, magnetic stirs, normal-temperature reaction 1h (TLC detection).Question response finishes, and with vacuum, solvent is drained, and residual solid in flask is dissolved in the 30ml ethyl acetate, with saturated common salt water washing extraction 3 times.Vacuum is drained extraction liquid, obtains the residual solid ethyl alcohol recrystallization, gets faint yellow solid.Productive rate: 97%, mp:159-160 ℃; 1H NMR (CDCl3,300MHz); (5.3870 s, 2H); (6.4478 d, J=8.79HZ, 1H); (7.1756-7.2134 m, 1H); (7.2591-7.3189 m, 2H); (3.7316 t, J=4.5750HZ, 1H); (7.4969 t, J=6.1650HZ, 1H); (7.9267 d, J=2.5500HZ, 1H); (8.4661 s, 2H); (8.5344 s, 1H) .ESI-MS:530.24 (C21H13Cl2F3N3O6[M+H]+) .Anal.Calcd for C21H12Cl2F3N3O6:C, 47.57; H, 2.28; Cl, 13.37; F, 10.75; N, 7.92; O, 18.10.Found:C, 47.11; H, 2.83; N, 7.34.
Embodiment two: the preparation of 5-chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2,4-dichloro benzyl) oxime (compound 2)
The preparation method is with embodiment one.The 5-chloro-salicylic aldehyde is constant, and 2,4-dichloro Phenylmethoxyamine hydrochloride replaces the 2-benzyl chloride oxygen amine hydrochlorate in example one.Obtain faint yellow solid.Productive rate: 85%, mp:166-167 ℃; 1HNMR (CDCl3,300MHz): 6.4487 (d, J=8.97HZ, 1H); (7.1768-7.2152 m, 1H); (7.2603-7.3012 m, 3H); (7.3865-7.4170 m, 1H); (7.4810-7.6066 m, 1H); (7.9279 d, J=0.15,1H); (8.4637 s, 2H); (8.5344 s, 1H) .ESI-MS:564.68 (C
21H
12Cl
3F
3N
3O
6[M+H]+) .Anal.Calcd for C21H11Cl3F3N3O6:C, 44.67; H, 1.96; Cl, 18.84; F, 10.09; N, 7.44; O, 17.00Found:C, 44.69; H, 1.93; N, 7.44.
Embodiment three: 3, the preparation of 5-two chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-chlorobenzyl) oxime (compound 3)
The preparation method is with embodiment one.Replace 5-chloro-salicylic aldehyde in example one with 3,5-dichloro-salicylaldehyde, 2-benzyl chloride oxygen amine hydrochlorate is constant.Obtain yellow solid.White?powder，59％，mp154-156℃；1HNMR(CDCl
3300MHz)：5.3724(s，2H)；7.2640-7.2945(m，1H)；7.3299(d，J＝2.55HZ，1H)；7.3871-7.4176(m，1H)；7.4420-7.5103(m，1H)；7.8267(d，J＝2.55HZ，1H)；8.2993(s，2H)；8.4423(s，1H).ESI-MS：564.68(C21H12Cl3F3N3O6，[M+H]+).Anal.Calcd?forC21H11Cl3F3N3O6：C，44.67；H，1.96；Cl，18.84；F，10.09；N，7.44；O，17.00.Found：C，44.65；H，1.99；N，7.42.
Embodiment four: 3, the preparation of 5-two chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2,4-dichloro benzyl) oxime (compound 4)
The preparation method is with embodiment one.Replace 5-chloro-salicylic aldehyde in example one with 3,5-dichloro-salicylaldehyde, replace 2-benzyl chloride oxygen amine hydrochlorate in example one with 2,4-dichloro Phenylmethoxyamine hydrochloride.Obtain faint yellow solid.Productive rate: 75%, mp170-171 ℃; 1HNMR (CDCl
3, 300MHz): 5.2964 (d, J=9.69HZ, 2H); (7.2640-7.2945 m, 1H); (7.3299 d, J=2.55HZ, 1H); (7.3871-7.4420 m, 1H); (7.4591-7.5103 m, 1H); (7.7960 d, J=2.55HZ, 1H); (8.2893 s, 2H); (8.4423 s, 1H) .ESI-MS:599.13 (C
21H
11Cl
4F
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
10Cl
4F
3N
3O
6: C, 42.10; H, 1.68; Cl, 23.67; F, 9.51; N, 7.01; O, 16.02.Found:C, 42.08; H, 1.69; N, 7.61.
Embodiment five: 5-bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-chlorobenzyl) oxime
The preparation of (compound 5)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 5-bromosalicylaldehyde replacement example one, 2-benzyl chloride oxygen amine hydrochlorate is constant.Obtain faint yellow solid.Productive rate: 68%, mp:108-109 ℃; 1HNMR (CDCl
3, 300MHz): 5.3905 (s, 2H); (6.3903 d, J=8.85HZ, 1H); (7.2607-7.3028 m, 2H); (7.3223-7.3601 m, 1H); (7.4005 t, J=4.575HZ, 1H); (7.4915 d, J=6.39,1H); (8.0767 d, J=2.40HZ, 1H); (8.4696 s, 2H); (8.5287 s, 1H) .ESI-MS:574.69 (C
21H
13BrClF
3N
3O
6[M+H]+) .Anal.Calcd forC
21H
12BrClF
3N
3O
6: C, 43.89; H, 2.10; Br, 13.90; Cl, 6.17; F, 9.92; N, 7.31; O, 16.70.Found:C, 43.79; H, 2.15; N, 7.38.
Embodiment six: the preparation of 5-bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2,4-dichloro benzyl) oxime (compound 6)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 5-bromosalicylaldehyde replacement example one, replace 2-benzyl chloride oxygen amine hydrochlorate with 2,4-dichloro Phenylmethoxyamine hydrochloride.Obtain faint yellow solid.Productive rate: 73%, mp:117-125 ℃; 1HNMR (CDCl
3, 300MHz): 5.3319 (s, 2H); (6.3933 d, J=8.79HZ, 1H); (7.2775 d, J=10.05,1H); (7.3283-7.3655 m, 1H); (7.4297 t, J=7.68HZ, 2H); (8.0489 d, J=3.12,1H); (8.43954 d, J=11.88HZ, 3H) .ESI-MS:609.13 (C
21H
12BrCl
2F
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
11BrCl
2F
3N
3O
6: C, 41.41; H, 1.82; Br, 13.12; Cl, 11.64; F, 9.36; N, 6.90; O, 15.76.Found:C, 41.44; H, 1.78; N, 6.97.
Embodiment seven: 3, the preparation of 5-two bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-chlorobenzyl) oxime (compound 7)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 3,5-Dibromosalicylaldehyde replacement example one, 2-benzyl chloride oxygen amine hydrochlorate is constant.Obtain faint yellow solid.Productive rate: 59%, mp:112-114 ℃; 1H NMR (CDCl
3, 300MHz): 5.3481 (d, J=9.51,2H); (6.4526 d, J=8.76HZ, 1H); (7.1847-7.2225 m, 1H); (7.2813 t, J=5.04,1H); (7.4284 t, 3.93HZ, 2H); (7.9014 d, J=2.73HZ, 1H); (8.4673 s, 2H); (8.5216 s, 1H) .ESI-MS:653.58 (C
21H
12Br
2ClF
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
11Br
2ClF
3N
3O
6: C, 38.59; H, 1.70; Br, 24.45; Cl, 5.42; F, 8.72; N, 6.43; O, 14.69.Found:C, 38.63; H, 1.56; N, 6.37.
Embodiment eight: 3, the preparation of 5-two bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2,4-dichloro benzyl) oxime (compound 8)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 3,5-Dibromosalicylaldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in 2,4-dichloro Phenylmethoxyamine hydrochloride replacement example one.Obtain yellow solid.Productive rate: 66%, mp:157-159 ℃; 1HNMR (CDCl
3, 300MHz): 7.2439 (s, 1H); (7.3644 t, J=9.615HZ, 1H); (7.4133-7.4414 m, 2H); (7.6399 t, J=2.28,2H); (7.9706 d, J=2.19,1H); (8.2717 s, 2H); (8.4052 s, 1H) .ESI-MS:688.03 (C
21H
11Br
2Cl
2F
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
10Br
2Cl
2F
3N
3O
6: C, 36.66; H, 1.46; Br, 23.23; Cl, 10.31; F, 8.28; N, 6.11; O, 13.95.Found:C, 36.73; H, 1.48; N, 6.07.
Embodiment nine: the preparation of 2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-chlorobenzyl) oxime (compound 9)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in salicylic aldehyde replacement example one, 2-benzyl chloride oxygen amine hydrochlorate is constant.Obtain yellow solid.Productive rate: 58%, mp:141-142 ℃; 1H NMR (CDCl
3, 300MHz): 6.4971-6.5276 (m, 1H); (7.1402-7.2262 m, 1H); (7.2329-7.2652 m, 1H); (7.2744-7.2896 m, 2H); (7.2963-7.3213 m, 2H); (7.3865-7.4170 m, 1H); (7.5084-7.5395 m, 1H); (7.8693-7.9669 m, 1H); (8.4564 m, 2H); (8.6271 m, 1H) .ESI-MS:495.79 (C
21H
14ClF
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
13ClF
3N
3O
6: C, 50.87; H, 2.64; Cl, 7.15; F, 11.50; N, 8.48; O, 19.36.Found:C, 50.78; H, 2.69; N, 8.63.
Embodiment ten: the preparation of 2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2,4-dichloro benzyl) oxime (compound 10)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in salicylic aldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in 2,4-dichloro Phenylmethoxyamine hydrochloride replacement example one.Obtain faint yellow solid.Productive rate: 67%, mp:142-143 ℃; 1HNMR (CDCl
3, 300MHz): 5.3447 (d, J=7.02,2H); (6.5002-6.5306 m, 1H); (7.1427-7.2335 m, 1H); (7.2396-7.2670 m, 1H); (7.2737-7.2945 m, 1H); (7.4206 d, J=2.19HZ, 1H); (7.4582 d, J=8.25HZ, 1H); (7.9096-7.9413 m, 1H); (8.4612 s, 2H); (8.6149 s, 1H) .ESI-MS:530.24 (C
21H
13Cl
2F
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
12Cl
2F
3N
3O
6: C, 47.57; H, 2.28; Cl, 13.37; F, 10.75; N, 7.92; O, 18.10.Found:C, 47.55; H, 2.31; N, 7.90.
Embodiment 11: the preparation of 5-chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(benzyl) oxime (compound 11)
The preparation method is with embodiment one.The 5-chloro-salicylic aldehyde is constant, with the 2-benzyl chloride oxygen amine hydrochlorate in Phenylmethoxyamine hydrochloride replacement example one.Obtain yellow solid.Productive rate: 89%, mp:143-146 ℃; 1H NMR (CDCl
3, 300MHz): 5.2450 (s, 2H); (7.0765 d, J=9.03,1H); (7.3652-7.4450 m, 6H); (7.7633 d, J=2.55,1H); (8.4692 s, 1H); (8.9398 s, 2H); ESI-MS:495.79 (C
21H
14ClF
3N
3O
6[M+H]+) .Anal.Calcd forC
21H
13ClF
3N
3O
6: C, 50.87; H, 2.64; Cl, 7.15; F, 11.50; N, 8.48; O, 19.36.Found:C, 50.79; H, 2.64; N, 8.43.
Embodiment 12: the preparation of 5-chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-luorobenzyl) oxime (compound 12)
The preparation method is with embodiment one.The 5-chloro-salicylic aldehyde is constant, with the 2-benzyl chloride oxygen amine hydrochlorate in 2-fluorine Phenylmethoxyamine hydrochloride replacement example one.Obtain yellow powder.Productive rate: 78%, mp:122-126 ℃; 1HNMR (CDCl
3, 300MHz): 5.2925 (s, 2H); (7.0760 d, J=8.97,1H); (7.2055-7.2670 m, 2H); (7.3914-7.4481 m, 2H); (5.2060 t, J=7.59HZ, 1H); (7.755 d, J=2.76HZ, 1H); (8.4576 s, 1H); (8.9367 s, 2H) .ESI-MS:513.78 (C
21H
13ClF
4N
3O
6[M+H]+) .Anal.CalcdforC
21H
12ClF
4N
3O
6: C, 49.09; H, 2.35; Cl, 6.90; F, 14.79; N, 8.18; O, 18.68.Found:C, 49.11; H, 2.33; N, 8.03.
Embodiment 13: the preparation of 5-bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(benzyl) oxime (compound 13)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 5-bromosalicylaldehyde replacement example one, a Phenylmethoxyamine hydrochloride replaces the 2-benzyl chloride oxygen amine hydrochlorate in example one.Obtain yellow powder.Productive rate: 92%, mp:130-139 ℃; 1HNMR (CDCl
3, 300MHz): 7.2575 (d, J=19.92HZ, 2H); (6.9994 d, J=8.76HZ, 1H); (7.3310-7.4402 m, 5H); (7.5176-7.5554 m, 1H); (7.8882 d, J=2.58,1H); (8.4588 s, 1H); (8.9294 s, 2H) .ESI-MS:540.24 (C
21H
14BrF
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
13BrF
3N
3O
6: C, 46.69; H, 2.43; Br, 14.79; F, 10.55; N, 7.78; O, 17.77.Found:C, 46.70; H, 2.46; N, 7.73.
Embodiment 14: the preparation of 5-bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-luorobenzyl) oxime (compound 14)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 5-bromosalicylaldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in 2-fluorine Phenylmethoxyamine hydrochloride replacement example one.Obtain faint yellow solid.White powder, productive rate: 92%, mp:121-128 ℃; 1HNMR (CDCl
3, 300MHz): 5.3476 (t, J=10.515HZ, 2H); (6.3935 d, J=8.76HZ, 1H); (7.0726 m, 1H); (7.1893 d, J=7.5HZ, 1H); (7.3176-7.3682 m, 2H); (7.4828 t, J=7.305HZ, 1H); (8.0858 d, J=2.55HZ, 1H); (8.4834 d, J=3.12HZ, 3H) .ESI-MS:558.23 (C
21H
13BrF
4N
3O
6[M+H]+) .Anal.Calcd for C
21H
12BrF
4N
3O
6: C, 45.18; H, 2.17; Br, 14.31; F, 13.61; N, 7.53; O, 17.20.Found:C, 45.28; H, 2,15; N, 7.57.
Embodiment 15: the preparation of 3,5-, two chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(benzyl) oxime (compound 15)
The preparation method is with embodiment one.Replace 5-chloro-salicylic aldehyde in example one with 3,5-dichloro-salicylaldehyde, replace 2-benzyl chloride oxygen amine hydrochlorate in example one with Phenylmethoxyamine hydrochloride.Obtain yellow solid.Productive rate: 79%, mp:139-145 ℃; 1HNMR (CDCl
3, 300MHz): 5.2828 (d, J=10.62HZ, 2H); (6.3807 d, J=8.76HZ, 1H); (7.2591-7.4438 m, 5H); (8.0836 d, J=2.400HZ, 1H); (8.4713 d, J=6.0600HZ, 3H) .ESI-MS:530.24 (C
21H
13Cl
2F
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
12Cl
2F
3N
3O
6: C, 47.57; H, 2.28; Cl, 13.37; F, 10.75; N, 7.92; O, 18.10.Found:C, 47.54; H, 2.31; N, 7.89.
Embodiment 16: the preparation of 3,5-, two chloro-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-luorobenzyl) oxime (compound 16)
The preparation method is with embodiment one.Replace 5-chloro-salicylic aldehyde in example one with 3,5-dichloro-salicylaldehyde, replace 2-benzyl chloride oxygen amine hydrochlorate in example one with 2-fluorine Phenylmethoxyamine hydrochloride.Obtain yellow solid.Productive rate: 93%, mp:111-112 ℃; 1HNMR (CDCl
3, 300MHz): 5.2820 (t, J=10.095HZ, 2H); (7.0579-7.1335 m, 1H); (7.1716 d, J=7.5HZ, 1H); (7.2945-7.3707 m, 2H); (7.4391 t, J=7.395HZ, 1H); (7.8249 d, J=2.55HZ, 1H); (8.2881 s, 2H); (8.3917 s, 1H) .ESI-MS:548.23 (C
21H
11Cl
3F
4N
3O
6[M+H]+) .Anal.Calcd for C
21H
11Cl
2F
4N
3O
6: C, 46.01; H, 2.02; Cl, 12.93; F, 13.86; N, 7.66; O, 17.51.Found:C, 46.01; H, 2.01; N, 7.66
Embodiment 17: the preparation of 3,5-, two bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(benzyl) oxime (compound 17)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 3,5-Dibromosalicylaldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in Phenylmethoxyamine hydrochloride replacement example one.Obtain faint yellow solid.Productive rate: 89%, mp:123-124 ℃; 1HNMR (CDCl
3, 300MHz): 5.1225 (s, 2H); (7.2823-7.3725 m, 5H); (7.9041 d, J=2.19HZ, 1H); (8.0648 d, J=2.4HZ, 1H); (8.4100 s, 1H); (8.8307 s, 2H) .ESI-MS:619.14 (C
21H
13Br
2F
3N
3O
6[M+H]+) .Anal.Calcd for C
21H
12Br
2F
3N
3O
6: C, 40.74; H, 1.95; Br, 25.81; F, 9.21; N, 6.79; O, 15.50.Found:C, 40.73; H, 1.99; N, 6.76.
Embodiment 18: the preparation of 3,5-, two bromo-2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-luorobenzyl) oxime (compound 18)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in 3,5-Dibromosalicylaldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in 2-fluorine Phenylmethoxyamine hydrochloride replacement example one.Obtain yellow solid.Productive rate: 98%, mp:94-96 ℃; 1HNMR (CDCl
3, 300MHz): 5.2316 (d, J=37.32HZ, 2H); (7.1512-7.2298 m, 2H); (7.3615-7.4328 m, 2H); (7.9489 d, J=2.37HZ, 1H); (8.0708 d, J=2.40HZ, 1H); (8.4094 s, 1H); (8.8252 s, 2H) .ESI-MS:637.13 (C
21H
12Br
2F
4N
3O
6[M+H]+) .Anal.CalcdforC
21H
11Br
2F
4N
3O
6: C, 39.59; H, 1.74; Br, 25.08; F, 11.93; N, 6.60; O, 15.07.Found:C, 39.61; H, 1.74; N, 6.63.
Embodiment 19: the preparation of 2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(benzyl) oxime (compound 19)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in salicylic aldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in Phenylmethoxyamine hydrochloride replacement example one.Obtain yellow solid.Productive rate: 95%, mp:92-94 ℃;
1HNMR(CDCl
3，300MHz)：5.2267(s，2H)；6.9723(d，J＝8.22HZ，1H)；7.2081(t，J＝7.59HZ，1H)；7.3225-7.4493(m，6H)；7.8098(t，J＝3.84HZ，1H)；8.5124(s，1H)；8.9276(s，2H).ESI-MS：461.35(C
21H
15F
3N
3O
6[M+H]+).Anal.Calcd?for?C
21H
14F
3N
3O
6：C，54.67；H，3.06；F，12.35；N，9.11；O，20.81.Found：C，54.64；H，3.09；N，9.13.
Embodiment 20: the preparation of 2-(2,6-dinitrobenzene-4-(phenylfluoroform) phenoxy group) phenyl aldehyde-O-(2-luorobenzyl) oxime (compound 20)
The preparation method is with embodiment one.With the 5-chloro-salicylic aldehyde in salicylic aldehyde replacement example one, with the 2-benzyl chloride oxygen amine hydrochlorate in 2-fluorine Phenylmethoxyamine hydrochloride replacement example one.Obtain yellow solid.Productive rate: 98%, mp:98-100 ℃;
1HNMR(CDCl
3，300MHz)：5.3523(d，J＝8.40HZ，2H)；6.5023(d，J＝8.22HZ，1H)；7.4279(t，J＝9.135HZ，1H)；7.1699(t，J＝7.05HZ，2H)；7.2256-7.2737(m，1H)；7.2841-7.3640(m，1H)；7.4749-7.5243(m，1H)；7.9400-7.9717(m，1H)；8.4533(s，2H)；8.5783(s，1H).ESI-MS：479.34(C
21H
14F
4N
3O
6[M+H]+).Anal.Calcd?for?C
21H
13F
4N
3O
6：C，52.62；H，2.73；F，15.85；N，8.77；O，20.03.Found：C，52.52；H，2.70；N，8.73.
Embodiment 21: pyrazoline derivative is studied tumors inhibition activity
Adopting MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole blue] method measures the salicylaldoxime compounds to MCF7, HepG2, A549 and anti-tubulin 503nhibiting concentration, i.e. IC
50
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, after adding the tri-distilled water dissolving, NaHCO3 solution with 5.6% transfers pH value to 7.2-7.4, is settled at last 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na2HPO412H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing the D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: specimen is made into storing solution with a small amount of tri-distilled water dissolving, general 10 times of preparation storing solutions by the experiment maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO generally is no more than 0.05%-0.1%.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) cell cultures: be the adherent growth cell, cellar culture (contains 10% calf serum) in DMEM or RPMI-1640 nutrient solution, puts 37 ℃, 5%CO
2Cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then wash with the D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming makes attached cell split away off from the culturing bottle wall; Pipette in right amount to the fresh culture bottle, then replenish fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cell is hatched: the above-mentioned tumour cell in the vegetative period of taking the logarithm, transferring concentration of cell suspension is 2 * 10
4Individual/ml.Every hole adds cell suspension 100 μ l in 96 well culture plates, puts 37 ℃, 5%CO
2Cultivate 24h in incubator.After cultivating 24h, add liquid by design respectively.
(7) dosing: will test liquid and join respectively in each hole according to the concentration gradient of ultimate density, each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add the test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in 37 ℃, 5%CO
2Cultivate 48h in incubator.
(8) mensuration of survivaling cell: in having cultivated 96 orifice plates after 48h, every hole adds MTT 40 μ l (being made into the MTT of 2.5mg/ml with 40 μ l PBS).After 37 ℃ of placement 4h, remove supernatant liquor.Every hole adds 100 μ l extracting solutions (10%SDS-5% isopropylcarbinol-0.01M HCl).37 ℃ of overnight incubation, last, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD experiment-OD is blank)/(OD contrast-OD is blank)] * 100% (average optical of OD experiment expression testing drug group, the average optical of OD contrast expression control group, the average optical of the blank expression of OD control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, try to achieve its corresponding drug level on typical curve.
The IC that records
50Be shown in Table 1
(9) mensuration of medicine on the tubulin polymerization impact
Then 30 ℃ of precultures of ox brain tubulin solution with medicine and the 10 μ M of different concns are dissolved in the L-glutamic acid damping fluid are cooled to 0 ℃. and add GTP, mixture is transferred to the spectrophotometric Glass tubing of 0 ℃ of precooling.Be warmed up to 30 ℃, rely on turbidimeter method can observe the assembling of tubulin.The method of calculation of IC50 are after 20min is hatched, to suppress the concentration that tubulin assembles added medicine when reaching 50% degree.
The IC that records
50Be shown in Table 1
The general formula of Compound 1-20
The restraining effect of table 1.Compound 1-20 to MCF7, HepG2, the increment of A549 cell and tubulin
Claims (4)
1. a class 4-trifluoromethyl-2,6-dinitrobenzene salicylaldoxime analog derivative is characterized in that it has following general formula:
In structural formula, R1 is: hydrogen, 5-chlorine, 3,5-dichloro, 5-bromine, 3,5-dibromo.
R2 is: hydrogen, 2-fluorine, 2-chlorine, 2,4-dichloro.
2. one kind prepares above-mentioned 4-trifluoromethyl-2, the method for 6-dinitrobenzene salicylaldoxime analog derivative, and it is comprised of the following step:
Step 1. preparation Phenylmethoxyamine hydrochloride:
(1) azanol of Tetra hydro Phthalic anhydride protection is synthetic
Be furnished with mechanical stirrer, in the 500ml three neck round-bottomed flasks of reflux condensing tube, adding respectively two kinds of raw materials of 0.2mol, adding the 150ml pyridine in system, in 80 ℃ of reactions spend the night (the TLC detection reaction is carried out degree).Question response is complete, adds in a large amount of water, separate out after product with chloroform dissolving after washing activated carbon decolorizing, anhydrous magnesium sulfate drying, the filtering siccative, after solvent evaporated product.
(2) azanol replaces the benzyl chloride reaction
In 250ml three neck round-bottomed flasks; add the azanol of 0.2mol protection, then add the 2mol/L aqueous sodium hydroxide solution, complete to solid reaction; control pH between 8-9; adding mol ratio is the benzyltriethylammoinium chloride of 5% amount, then drips the chloroformic solution of benzyl chloride, to reacting completely; tell organic layer; water layer merges organic layer after extracting three times, and anhydrous magnesium sulfate drying is spin-dried for solvent and gets crude product.
(3) deprotection reaction
Get 250ml three neck round-bottomed flasks, take second step product 20g, then add 150ml ethanol, after sample is dissolved fully, be cooled to 0 ℃, drip hydrazine hydrate in system, to the disappearance of raw material point, product is standby through column chromatography for separation.
(4) salt-forming reaction
In methylene dichloride, cryosel is bathed and is cooled to-5 ℃ of left and right with the benzyloxy amine solvent, and passes into dry hydrogenchloride (laboratory self-control), controls gas flow rate, and tail gas absorbs with strong caustic, and ventilation body to product is all separated out.After blowing hydrogenchloride with nitrogen, filtration can obtain Phenylmethoxyamine hydrochloride.
Step 2. preparation 4-chloro-3, the 5-dinitro-p-trifluorotoluene:
Preparation 4-chloro-3-nitro-trifluoromethyl toluene
Nitrosonitric acid with 95% and 98% the vitriol oil at least to be made into nitration mixture at 1: 1, under 50-55 ℃, slowly drip in the round-bottomed flask that the 4-chlorobenzotrifluoride is housed (＞1: 1), magnetic stirs, control temperature of reaction, wait to dropwise, temperature keeps 0.5h, after rise to about 70 ℃ and continue to react about 2h (the TLC detection reaction is carried out degree).Question response finishes, and naturally cooling, standing demix, separatory discard the pale brown color acid layer of lower floor, then extracts 3 times with ethyl acetate and saturated sodium bicarbonate washing, and Rotary Evaporators is drained extraction liquid, and gained solid ethyl alcohol recrystallization obtains final product.
Step 3. preparation schiff bases (salicylaldoxime):
With substituting group Phenylmethoxyamine hydrochloride (5.0mmol), be dissolved in dehydrated alcohol, slowly splash into equivalent triethylamine (5.0mmol), add again substituting group salicylic aldehyde (5.0mmol), magnetic stirs, normal-temperature reaction 0.5h (the TLC detection reaction is carried out degree), and product is separated out with solid.Suction filtration after reaction finishes, and rinse solids 3 times with dehydrated alcohol, the dry substituting group schiff bases (salicylaldoxime) that gets.With dehydrated alcohol with the product recrystallization.
Step 4. preparation 4-trifluoromethyl-2,6-dinitrobenzene salicylaldoxime analog derivative
In similar (1), nitration mixture is added in the round-bottomed flask that 4-chloro-3-nitro-trifluoromethyl toluene is housed that (＞2.5: 1), magnetic stirs, in 115 ℃ of reaction 4h (the TLC detection reaction is carried out degree).Question response finishes, and naturally cooling, standing demix, separatory discard the pale brown color acid layer of lower floor, then extracts 3 times with ethyl acetate and saturated sodium bicarbonate washing, and Rotary Evaporators is drained extraction liquid, and gained solid ethyl alcohol recrystallization obtains final product.
Step. synthetic salicylaldoxime end product
Add 4mmol K in the 50ml flask
2CO
3, and 2mmol substituting group schiff bases, 2mmol 4-chloro-3, the 5-dinitro-p-trifluorotoluene, and be dissolved in the 20mml dehydrated alcohol, magnetic stirs, normal-temperature reaction 1h (TLC detection).Question response finishes, and with vacuum, solvent is drained, and residual solid in flask is dissolved in the 30ml ethyl acetate, with saturated common salt water washing extraction 3 times.Vacuum is drained extraction liquid, obtains the residual solid ethyl alcohol recrystallization, obtains final product.
3. the preparation method of salicylaldoxime analog derivative claimed in claim 2.
4. the application of salicylaldoxime analog derivative claimed in claim 1 in the preparation antitumor drug.
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| CN113214087A (en) * | 2021-05-06 | 2021-08-06 | 山东科加工业技术研究院有限公司 | Preparation method and application of 4-chloro-3, 5-dinitro-benzotrifluoride |
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Application publication date: 20130515 |