CN107935840A - A kind of 4 Hydroxy M Phthalic Acid derivatives and synthetic method - Google Patents
A kind of 4 Hydroxy M Phthalic Acid derivatives and synthetic method Download PDFInfo
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- CN107935840A CN107935840A CN201711267698.3A CN201711267698A CN107935840A CN 107935840 A CN107935840 A CN 107935840A CN 201711267698 A CN201711267698 A CN 201711267698A CN 107935840 A CN107935840 A CN 107935840A
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- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention discloses a kind of 4 Hydroxy M Phthalic Acid derivatives and synthetic method, belong to organic chemistry filed, the present invention be using 4 Hydroxy M Phthalic Acids between a kind of new 5 bromine of compound, 4 hydroxyl of Material synthesis phenyl-diformyl aromatic amine compound.The synthetic method using 4 Hydroxy M Phthalic Acids as raw material, through esterification, bromination, hydrolysis, amidatioon and etc. be made, preparation method is simple, and compound structure is novel.Biological activity test shows there is stronger inhibiting tumour cells activity.
Description
Technical field
The invention belongs to organic chemistry filed, and in particular to be 4 hydroxyisophthalic acid derivative and synthetic method
Background technology
1956, Hunt had found 4 hydroxyisophthalic acid when studying Kolbe-schmitt method salicylate processes
It is the Main By product of reaction process, and sub-argument has gone out 4 hydroxyisophthalic acid sterling (J Chem Soc.1956,3099).
The researchs such as Chesher find 4 hydroxyisophthalic acid have effects that to bring down a fever (Nature, 1956,175：206).Anup etc. is studied
It was found that 4 hydroxyisophthalic acid can resist the generation of intracellular free radicals, there is the anti-oxidation function (Food of protection cell
Chemistry,2012,132:1959).Haddadi etc. further study show that, 4 hydroxyisophthalic acid in the cell anti-
Oxidative function can influence the activity of neurotransmitters enzyme, can be as the drug candidate for the treatment of nerve degenerative diseases
(Neurochemistry International,2016,100：78).Selleri etc. have studied 4 hydroxyisophthalic acid and spread out
Platelet aggregation-against effect of biology, and have developed medicament for resisting platelet aggregation picotamide (formula one) (US 3973026).
Nathan etc. has synthesized a kind of receptor antagonist of leukotriene receptor -2 using 4 hydroxyisophthalic acid as raw material, and bioactivity is ground
Study carefully and show that the compound has effects that good (the The Journal of Pharmacology and that resist myocardial ischemia (formula two)
Experimental Therapeutics,2011,339:768).Gobert etc. is using 4 hydroxyisophthalic acid as raw material, synthesis
A kind of protein tyrosine phosphatase inhibitor (formula three), bioactivity research show that the compound has ulcerative colitis
Good therapeutic effect (The Journal of Biological Chemistry, 2009,284 (17):11385).
One picotamide chemical structural formula of formula
Leukotriene receptor -2 antagonist of the formula two using 4 hydroxyisophthalic acid as Material synthesis
Protein tyrosine phosphatase inhibitor of the formula three using 4 hydroxyisophthalic acid as Material synthesis
Tumour is one of disease for seriously endangering human health.China in 2015 have 429.2 ten thousand new cancer cases and
281.4 ten thousand deaths, cancer is died of equivalent to daily 12000 new cancer strickens, 7500 people.Chemotherapy is that cancer is controlled
One of three big means treated, the exploitation of antitumor drug is always research hotspot, and researching and developing new antitumor drug has weight
Want meaning.In order to further study the bioactivity of 4 hydroxyisophthalic acid derivative, inventor's design has synthesized a kind of 4-
Hydroxy M Phthalic Acid derivative, and biological effect evaluation is carried out to it, infer that these compounds may show antitumor work
Property.The activity of these compounds is further tested, finds it to stomach cancer cell (MGC-803 and SGC7901) and breast cancer cell
(MDA-MB-231) there is stronger inhibitory activity.
The content of the invention
It is an object of the invention to provide a kind of new 4 hydroxyisophthalic acid derivative and their synthetic method
With purposes.The synthetic method using 4 hydroxyisophthalic acid as raw material, through esterification, bromination, hydrolysis, amidatioon and etc. system
, preparation method is simple, and compound structure is novel.Biological activity test shows that part of compounds has stronger tumour cell
Inhibitory activity.Technical scheme is as follows：
A kind of 4 hydroxyisophthalic acid derivative, it is characterised in that general structure is
R is halogen, methyl, ethyl, one kind or combinations thereof in trifluoromethyl in formula.
A kind of synthetic method of 4 hydroxyisophthalic acid derivative, this method are using 4 hydroxyisophthalic acid as original
Material, by esterification, bromination, hydrolysis, chloride and with substituted aromatic amines reaction and etc. synthesis.
A kind of synthetic method of 4 hydroxyisophthalic acid derivative, specifically synthesizes according to following steps：
Step 1. prepares 4 hydroxyisophthalic acid dimethyl ester (compound a)：
Using 4 hydroxyisophthalic acid and thionyl chloride as raw material, react 4 hydroxyisophthalic acid two is made in methyl alcohol
Methyl esters；
The volume that every mole of 4 hydroxyisophthalic acid adds methanol is 2-5L, 4 hydroxyisophthalic acid and thionyl chloride
Molar ratio be 1:5-1:20.Preferably, the volume that every mole of 4 hydroxyisophthalic acid adds methanol is 3L, 4- hydroxyl isophthalic
The molar ratio of dioctyl phthalate and thionyl chloride is 1:10.
Step 2. prepares bromo- 4 hydroxyisophthalic acid dimethyl ester (the compound b) of 5-：
Under the conditions of lucifuge, 4 hydroxyisophthalic acid dimethyl ester is with N- bromo-succinimides in n,N-Dimethylformamide
(DMF) the reaction synthesis bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- in；
The molar ratio of 4 hydroxyisophthalic acid dimethyl ester and N- bromo-succinimides is 1:1-1:5, reaction temperature 30-
50℃.Preferably, the molar ratio of 4 hydroxyisophthalic acid dimethyl ester and N- bromo-succinimides is 1:2, reaction temperature is
30℃。
Step 3. prepares the bromo- 4 hydroxyisophthalic acids of 5- (compound c)：
(3) the bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- hydrolysis under alkali effect prepares the bromo- 4- hydroxyls isophthalic diformazans of 5-
Acid；
The base reagent is for sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide etc., the bromo- 4- hydroxyls isophthalic two of 5-
The molar ratio of formic acid dimethyl ester and alkali is 1:3-1:5.Preferably, alkali used is sodium hydroxide, the bromo- 4- hydroxyls isophthalic diformazans of 5-
The molar ratio of dimethyl phthalate and alkali is 1:3.
Step 4. prepares bromo- 4- hydroxyls m-phthaloyl chloride (the compound d) of 5-：
The bromo- 4 hydroxyisophthalic acids of 5- react under a small amount of DMF catalytic action with thionyl chloride prepares the bromo- 4- hydroxyls of 5-
M-phthaloyl chloride；
The volume that every mole of 5- nitro -4 hydroxyisophthalic acid adds thionyl chloride is 1-4L, and DMF is catalytic amount.
Preferably, the volume that the bromo- 4 hydroxyisophthalic acids of every mole of 5- add thionyl chloride is 3L.
Step 5. prepares target compound (compound e)：
In organic solvent, the bromo- 4- hydroxyls m-phthaloyl chlorides of 5- react generating structure with substituted aniline under alkali effect
Formula (I) target compound.
The organic solvent is toluene, acetone, ethyl acetate, dichloromethane etc.；The substituted aniline is on phenyl ring
Contain one kind or the aniline of combinations thereof in halogen, methyl, ethyl, trifluoromethyl；The alkali is potassium carbonate, bicarbonate
Sodium, saleratus, triethylamine, pyridine, diisopropylethylamine or 4-dimethylaminopyridine, its amount added are catalytic amount chemistry meter
Amount；The molar ratio of the bromo- 4- hydroxyls m-phthaloyl chlorides of 5- and substituted aniline is 1:2-1:4.Preferably, organic solvent used is first
Benzene, alkali used are triethylamine, and the molar ratio of the bromo- 4- hydroxyls m-phthaloyl chlorides of 5- and substituted aniline is 1:3.
The part preferred compound of the present invention is as follows：
The synthetic method of the present invention is using 4 hydroxyisophthalic acid as raw material, by esterification, bromination, hydrolysis, fragrant acyl
Amination and etc. prepare 4 hydroxyisophthalic acid derivative.The bromo- 4- hydroxyls isophthalic M-phthalic acid (chemical combination of 5- of document report
Thing c) obtains (J Chem Soc.1956,3099) using 4 hydroxyisophthalic acid as raw material, with the direct bromination of bromine simple substance.Due to
Contain two carboxyls on phenyl ring, causing 4 hydroxyisophthalic acid, solubility is very poor in a solvent, and two carboxyls determines on phenyl ring
Reaction is complicated when position effect causes 4 hydroxyisophthalic acid direct bromination substitution reaction, the bromo- 4 hydroxyisophthalic acid productions of 5-
Product yield is extremely low.In order to overcome the orientation effect of 4 hydroxyisophthalic acid poor solubility and two carboxyls on phenyl ring, this hair
It is bright that 4 hydroxyisophthalic acid esterification reaction of organic acid is prepared into 4 hydroxyisophthalic acid dimethyl ester (compound a) first.4- hydroxyls
Solubility is preferable in a solvent for dimethyl isophthalate, and the Orientation Effect of Substituting Groups of two ester groups is consistent.The poison of bromine simple substance
Property it is larger, in order to avoid use bromine simple substance, this method uses N- bromo-succinimides (NBS) as bromide reagent, in 4- hydroxyls
Bromine substituent is introduced on M-phthalic acid methyl esters phenyl ring to prepare bromo- 4 hydroxyisophthalic acid dimethyl ester (the compound b) of 5-.It is logical
Cross and select suitable NBS bromination solvents, the bromination process reaction condition of the method for the present invention is gentle, and post processing is simple.The bromo- 4- hydroxyls of 5-
Base M-phthalic acid methyl esters basic hydrolysis can prepare the bromo- 4 hydroxyisophthalic acids of 5- (compound c).Between the bromo- 4- hydroxyls of 5-
Solubility is poor in a solvent for phthalic acid, directly relatively low with yield during arylamine reaction.In order to overcome the bromo- 4- hydroxyls isophthalic two of 5-
The problem of formic acid reactivity is poor, the present invention by the bromo- 4 hydroxyisophthalic acid chlorides of 5- (compound d), afterwards and aromatic amine
Reaction prepares product, and (compound e), improves product yield.
It is thin as target using human breast carcinoma MDA-MB-231 cells, human gastric cancer MGC-803 cells, Human gastric cancer SGC-7901 cells
Born of the same parents, cis-platinum are positive control drug, using the synthesized compound on tumor cell of tetramethyl azo azoles salt (MTT) colorimetric method test
External inhibitory activity.After tested, compound of the invention (I) has the activity for suppressing tumor cell proliferation, which part
The activity of compound is better than positive control cis-platinum.
Beneficial effect
The present invention is a kind of bromo- 4- hydroxyls isophthalic of new compound 5- using 4 hydroxyisophthalic acid as Material synthesis
Two formyl aromatic amine compounds.Such compound is using 4 hydroxyisophthalic acid as raw material, by esterification, bromination, hydrolysis, acyl virtue
Amination is prepared for phenyl-diformyl aromatic amine compound between the bromo- 4- hydroxyls of 5-.There are two carboxyls on 4 hydroxyisophthalic acid phenyl ring,
With there are two kinds of products, and reacting during methanol direct esterification reaction and there is balance under strong acid catalyst, product yield is relatively low.This is specially
4 hydroxyisophthalic acid and methanol react this dicarboxylic acid dimethyl ester between preparation 4- hydroxyls in thionyl chloride in profit, shorten anti-
Between seasonable, product product yield (86%) is improved.The present invention is using N- bromo-succinimides (NBS) to 4- hydroxyls isophthalic two
Formic acid dimethyl ester carries out bromination, avoids using the larger bromine simple substance of toxicity.At the same time by optimizing reaction condition, selection is suitable
Reaction dissolvent, reduces reaction temperature (30 DEG C), and last handling process is simple, the bromo- 4 hydroxyisophthalic acid dimethyl esters of product 5-
Directly filtering is i.e. available, and product yield is high (87%).It is bromo- that the bromo- 4 hydroxyisophthalic acid diformazan ester hydrolysis of 5- prepares 5-
4 hydroxyisophthalic acid, the solubility of the bromo- 4 hydroxyisophthalic acids of 5- in organic solvent is poor, directly and arylamine reaction
When activity it is poor.The bromo- 4 hydroxyisophthalic acids of 5- and thionyl chloride are reacted chloride by the present invention, are prepared afterwards with arylamine reaction
The bromo- 4- hydroxyls isophtalamides of 5-.The activity of the bromo- 4 hydroxyisophthalic acid reactions of 5- is the method increase, improves production
Product yield (60% or so).By to compound biological activity test, part 5- nitros -4 hydroxyisophthalic acid acyl aryl amination
The tumors inhibition activity of compound is better than cis-platinum, this shows that the compound structure of the present invention has potentially as antitumor drug
Value.
Brief description of the drawings
Fig. 1 compound 4-hydroxy base dimethyl isophthalate1H NMR spectras
The bromo- 4 hydroxyisophthalic acid dimethyl esters of Fig. 2 compounds 5-1H NMR spectras
The bromo- 4 hydroxyisophthalic acids of Fig. 3 compounds 5-1H NMR spectras
Fig. 4 compound Ns1,N3- two (4- fluorophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Fig. 5 compound Ns1,N3- two (2- fluorophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Fig. 6 compound Ns1,N3- two (2- chlorphenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Fig. 7 compound Ns1,N3- two (3- chlorphenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Fig. 8 compound Ns1,N3- two (4- chlorphenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Fig. 9 compound Ns1,N3- two (2- chlorphenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 10 compound Ns1,N3- two (3- bromophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 11 compound Ns1,N3- two (4- bromophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 12 compound Ns1,N3- two (2- iodophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 13 compound Ns1,N3- two (4- iodophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 14 compound Ns1,N3- two (2,4- dichlorophenyl) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 15 compound Ns1,N3- two (2,4- difluorophenyl) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 16 compound Ns1,N3- two (the bromo- 2- aminomethyl phenyls of 4-) -4- hydroxyl -5- bromine isophtalamides1H NMR scheme
Spectrum
Figure 17 compound Ns1,N3- two (3,4- dichlorophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 18 compound Ns1,N3- two (the fluoro- 4- iodophenyls of 3-) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 19 compound Ns1,N3- two (the chloro- 4- fluorophenyls of 3-) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras)
Figure 20 compound Ns1,N3- two (3,4- 3,5-dimethylphenyl) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 21 compound Ns1,N3- two (3,4- dichlorophenyl) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 22 compound Ns1,N3- two (the fluoro- 5- bromophenyls of 2-) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Figure 23 compound Ns1,N3- two (2,6- dichlorophenyls) -4- hydroxyl -5- bromine isophtalamides1H NMR spectras
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described.It is to be understood that following embodiments are merely to illustrate this
Invention is not for the scope of the present invention.
1 N of embodiment1,N3- two (4- fluorophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
The synthesis of 1.1 4 hydroxyisophthalic acid dimethyl esters
15g (82.4mmol) 4 hydroxyisophthalic acid is added in 150mL absolute methanols.It is stirred at room temperature under state, 75g
(630.5mmol) thionyl chloride is slowly instilled in above-mentioned solution, is dripped off in 30 minutes.Drop finishes, and is warming up to solution and slowly flows back.
TLC (petroleum ethers:Ethyl acetate=3:1) monitoring reaction, 4 it is small when after the reaction was complete.After being cooled to room temperature, there is white solid analysis
Go out.Cross filter solid, filter cake after massive laundering with being dried in vacuo.Obtained solid is dissolved in 100mL ethyl acetate, and ethyl acetate is molten
Liquid respectively with after 80mL saturated sodium bicarbonate solutions, 50mL distilled water, 50mL saturated common salt water washings, dry by anhydrous sodium sulfate,
Filtering, revolving obtain 14g white solids (yield 82%).1H NMR(CDCl3):δ(ppm)3.29(s,3H,CH3),3.27(s,
3H,CH3), 7.02 (d, 1H, Ar), 8.12 (dd, 1H, Ar), 8.58 (d, 1H, Ar), 11.19 (s, 1H, OH).
The synthesis of the bromo- 4 hydroxyisophthalic acid dimethyl esters of 1.2 5-
Under the conditions of lucifuge, 10g (41.61mmol) 4 hydroxyisophthalic acids dimethyl ester adds the N of 100mL, N- dimethyl
In formamide.Under the conditions of being stirred at room temperature, 11.11g (62.42mmol) N- bromo-succinimides are added in above-mentioned solution.Add
Finish, reaction solution is warming up to 35 DEG C.The reaction was continued 5 it is small when after, stop heating, be cooled to room temperature.Under stirring, in reaction solution
80mL distilled water is added, there is white solid precipitation.Continue stirring 30 minutes, filtering, filter cake is washed with cold ethanol.Collect filter cake,
Vacuum drying, obtains 11.52g white solids (yield 82%).1H NMR(CDCl3):δ(ppm)3.93(s,3H,CH3),4.03
(s,3H,CH3), 7.27 (d, 1H, Ar), 8.45 (dd, 1H, Ar).
The synthesis of the bromo- 4 hydroxyisophthalic acids of 1.3 5-
The bromo- 4 hydroxyisophthalic acid dimethyl esters of 8g (27.68mmol) 5- add 80mL potassium hydroxide aqueous solutions and (contain hydrogen-oxygen
Change potassium 6.20g/110.72mmol) in.It is heated to reflux, just starts the white milkiness shape of reaction solution, with the progress of reaction, white
Solid gradually dissolves.After when back flow reaction 2 is small, stops heating, be cooled to room temperature.10% hydrochloric acid conditioning solution is added in reaction solution
PH to 1-2, separates out white solid.Filtering, filter cake are washed with distilled water, methanol respectively, collect filter cake, vacuum drying, obtains
5.9g white solids (yield 82%).1H NMR(DMSO-d6):δ(ppm)8.45(d,1H,Ar),8.49(d,1H,Ar)。
1.4 N1,N3- two (2- fluorophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
The bromo- 4 hydroxyisophthalic acids of 2.0g (7.6mmol) 5- are taken, a few drop DMF is instilled, 25mL protochlorides is slowly added dropwise
Sulfone, 65 DEG C of oil bath, vigorous reflux in bottle, spherical condensation tube top connect gas concentration unit, and rear gas absorption plant uses hydrogen
Aqueous solution of sodium oxide.React 8 it is small when after, TLC detection find the bromo- 4 hydroxyisophthalic acid fundamental reactions of 5- it is complete.Revolving is removed
Thionyl chloride is removed, single port bottle obtains liquid substrate, spare.By the 2- fluoroanilines (28.5mmol) of 3.2g, 2.8g (28.5mmol)
Triethylamine is dissolved in 40mL toluene the ice bath stirring under conditions of nitrogen protection until all dissolvings.Substrate is dissolved in 20mL bis- again
Chloromethanes adds constant pressure funnel, is slowly added dropwise under condition of ice bath in the toluene solution dissolved with 2- fluoroanilines, in this process
In, there are a large amount of white cigarettes to generate.After being added dropwise, be stirred at room temperature 5 it is small when.Thin-layer chromatography detects, and substrate reactions finish.Filter, it is right
Filter cake and filtrate are detected analysis, and product is present in filter cake.Filter cake is dissolved in stirring and dissolving in tetrahydrofuran, is filtered to remove
Insoluble triethylamine hydrochloride, filtrate is rotated to obtain product, is weighed after dry and obtains 2.0g solids, pillar layer separation (oil
Ether：Ethyl acetate=5:1), product as white crystals, yield 61.7%.1H NMR (400MHz, DMSO) δ=10.48 (s, 1H,
NH), 10.34 (s, 1H, NH), 8.21 (d, J=1.9Hz, 2H, Ar), 7.78-7.21 (m, 8H, Ar).
2 N of embodiment1,N3- two (4- fluorophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
The synthesis of 2.1 4 hydroxyisophthalic acid dimethyl esters
20g (109.9mmol) 4 hydroxyisophthalic acid is added in 330mL absolute methanols.It is stirred at room temperature under state, 130g
(1099mmol) thionyl chloride is slowly instilled in above-mentioned solution, is dripped off in 40 minutes.Drop finishes, and is warming up to solution and slowly flows back.
TLC (petroleum ethers:Ethyl acetate=3:1) monitoring reaction, 3 it is small when after the reaction was complete.After being cooled to room temperature, there is white solid analysis
Go out.Cross filter solid, filter cake after massive laundering with being dried in vacuo.Obtained solid is dissolved in 120mL ethyl acetate, and ethyl acetate is molten
Liquid respectively with after 90mL saturated sodium bicarbonate solutions, 70mL distilled water, 70mL saturated common salt water washings, dry by anhydrous sodium sulfate,
Filtering, revolving obtain 15g white solids (yield 86%).1H NMR(CDCl3):δ(ppm)3.29(s,3H,CH3),3.27(s,
3H,CH3), 7.02 (d, 1H, Ar), 8.12 (dd, 1H, Ar), 8.58 (d, 1H, Ar), 11.19 (s, 1H, OH).
The synthesis of the bromo- 4 hydroxyisophthalic acid dimethyl esters of 2.2 5-
Under the conditions of lucifuge, 15g (62.41mmol) 4 hydroxyisophthalic acids dimethyl ester adds the N of 120mL, N- dimethyl
In formamide.Under the conditions of being stirred at room temperature, 22.23g (124.82mmol) N- bromo-succinimides are added in above-mentioned solution.Add
Finish, reaction solution is warming up to 30 DEG C.The reaction was continued 4 it is small when after, stop heating, be cooled to room temperature.Under stirring, in reaction solution
90mL distilled water is added, there is white solid precipitation.Continue stirring 35 minutes, filtering, filter cake is washed with cold ethanol.Collect filter cake,
Vacuum drying, obtains 15.87g white solids (yield 87.6%).1H NMR(CDCl3):δ(ppm)3.93(s,3H,CH3),
4.03(s,3H,CH3), 7.27 (d, 1H, Ar), 8.45 (dd, 1H, Ar).
The synthesis of the bromo- 4 hydroxyisophthalic acids of 2.3 5-
It is (hydrogeneous that the bromo- 4 hydroxyisophthalic acid dimethyl esters of 10g (34.61mmol) 5- add 90mL sodium hydrate aqueous solutions
Sodium oxide molybdena 3.32g/103.83mmol) in.It is heated to reflux, just starts the white milkiness shape of reaction solution, with the progress of reaction, in vain
Color solid gradually dissolves.After when back flow reaction 2.5 is small, stops heating, be cooled to room temperature.The adjusting of 10% hydrochloric acid is added in reaction solution
PH value of solution separates out white solid to 1-2.Filtering, filter cake are washed with distilled water, methanol respectively, collect filter cake, vacuum drying, obtains
To 7.9g white solids (yield 88%).1H NMR(DMSO-d6):δ(ppm)8.45(d,1H,Ar),8.49(d,1H,Ar)。
2.4 N1,N3- two (4- fluorophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
The bromo- 4 hydroxyisophthalic acids of 3.0g (11.5mmol) 5- are taken, a few drop DMF is instilled, 35mL protochlorides is slowly added dropwise
Sulfone, 65 DEG C of oil bath, vigorous reflux in bottle, spherical condensation tube top connect gas concentration unit, and rear gas absorption plant uses hydrogen
Aqueous solution of sodium oxide.React 7 it is small when after, TLC detection find the bromo- 4 hydroxyisophthalic acid fundamental reactions of 5- it is complete.Revolving is removed
Thionyl chloride is removed, single port bottle obtains liquid substrate, spare.By the 4- fluoroanilines (23mmol) of 2.55g, three second of 2.4g (24mmol)
Amine is dissolved in 50mL toluene the ice bath stirring under conditions of nitrogen protection until all dissolvings.Substrate is dissolved in 30mL dichloromethanes again
Alkane adds constant pressure funnel, is slowly added dropwise under condition of ice bath in the toluene solution dissolved with 4- fluoroanilines, in the process, has
A large amount of white cigarette generations.After being added dropwise, be stirred at room temperature 4 it is small when.Thin-layer chromatography detects, and substrate reactions finish.Filter, to filter cake and
Filtrate is detected analysis, and product is present in filter cake.Filter cake is dissolved in stirring and dissolving in tetrahydrofuran, is filtered to remove insoluble
Triethylamine hydrochloride, filtrate is rotated to obtain product, is weighed after dry and obtains 2.0g solids, pillar layer separation (petroleum ether：Acetic acid
Ethyl ester=4:1), white crystal, yield 67%,1HNMR (400MHz, DMSO) δ=10.77 (s, 1H), 10.50 (s, 1H),
8.24-8.04(m,2H),7.77-7.53(m,8H)。
3 N of embodiment1,N3- two (2- chlorphenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2- chloroanilines are reacted, product as white crystals, yield with embodiment 2
52%,1H NMR (400MHz, DMSO) δ=10.73 (s, 1H, NH), 10.46 (s, 1H, NH), 8.20-8.06 (m, 2H, Ar),
7.76-7.56(m,8H,Ar)。
4 N of embodiment1,N3- two (3- chlorphenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 3- chloroanilines are reacted, product as white crystals, yield with embodiment 2
62%,1H NMR (400MHz, DMSO) δ=10.85 (s, 1H, NH), 10.58 (s, 1H, NH), 8.45-7.73 (m, 2H, Ar),
7.46-7.30(m,8H,Ar)。
5 N of embodiment1,N3- two (4- chlorphenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 4- chloroanilines are reacted, product as white crystals, yield with embodiment 2
68%,1H NMR (400MHz, DMSO) δ=10.15 (s, 1H), 10.13 (s, 1H), 8.14 (dd, J=49.9,5.1Hz, 2H),
7.75 (d, J=8.4Hz, 1H), 7.55-7.28 (m, 7H).
6 N of embodiment1,N3- two (2- bromophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2- bromanilines are reacted, product as white crystals, yield with embodiment 2
64%,1H NMR (400MHz, DMSO) δ=10.48 (s, 1H), 10.34 (s, 1H), 8.20-7.23 (m, 10H).
7 N of embodiment1,N3- two (3- bromophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 3- bromanilines are reacted, product as white crystals, yield with embodiment 2
71%,1H NMR (400MHz, DMSO) δ=10.77 (s, 1H, NH), 10.50 (s, 1H, NH), 8.21-8.07 (m, 2H, Ar),
7.77-7.54(m,8H,Ar)。
8 N of embodiment1,N3- two (4- bromophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 4- bromanilines are reacted, product as white crystals, yield with embodiment 2
66%,1H NMR (400MHz, DMSO) δ=10.77 (s, 1H), 10.77 (s, 1H), 10.50 (s, 1H), 10.50 (s, 1H),
8.25-8.06(m,2H),7.83-7.42(m,8H)。
9 N of embodiment1,N3- two (2- iodophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2- Iodoanilines are reacted, product light yellow crystal with embodiment 2, received
Rate 67%,1H NMR (400MHz, DMSO) δ=10.43 (s, 1H, NH), 10.41 (s, 1H, NH), 8.21 (d, J=1.9Hz,
2H, Ar), 7.51-7.44 (m, 5H, Ar), 7.09 (td, J=7.8,5.1Hz, 3H, Ar).
10 N of embodiment1,N3- two (4- iodophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 4- Iodoanilines are reacted, product as white crystals, yield with embodiment 2
57%,1H NMR (400MHz, DMSO) δ=10.73 (s, 1H, NH), 10.46 (s, 1H, NH), 8.24-8.02 (m, 2H, Ar),
7.78-7.54(m,8H,Ar)。
11 N of embodiment1,N3- two (the fluoro- 4- bromophenyls of 2-) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and the fluoro- 4- bromanilines of 2- are reacted, product as white is brilliant with embodiment 2
Body, yield 72%,1H NMR (400MHz, DMSO) δ=10.59 (s, 1H, NH), 10.41 (s, 1H, NH), 8.14 (dd, J=
46.6,5.0Hz,2H,Ar),7.78,7.43(m,6H,Ar)。
12 N of embodiment1,N3- two (2,4 dichloro benzene base) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2,4- dichloroaniline reacted, product as white crystals with embodiment 2,
Yield 51%,1H NMR (400MHz, DMSO) δ=10.95 (s, 1H), 10.63 (s, 1H), 8.24-8.06 (m, 4H), 7.72
(d, J=53.6Hz, 4H).
13 N of embodiment1,N3- two (2,4 difluorobenzene base) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2,4- difluoroaniline reacted, product as white crystals with embodiment 2,
Yield 51%,1H NMR (400MHz, DMSO) δ=10.57 (s, 1H), 10.44 (s, 1H), 8.30 (dd, J=114.8,
2.0Hz,2H),7.92-7.01(m,6H)。
14 N of embodiment1,N3- two (the bromo- 2- aminomethyl phenyls of 4-) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and the bromo- 2-aminotoluenes of 4- are reacted, product as white is brilliant with embodiment 2
Body, yield 59%,1H NMR (400MHz, DMSO) δ=10.48 (s, 1H, NH), 10.34 (s, 1H, NH), 8.27-8.04 (m,
2H, Ar), 7.37-7.20 (m, 6H, Ar), 2.50 (d, J=1.6Hz, 6H ,-CH3)。
15 N of embodiment1,N3- two (3,4- dichlorophenyls) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 3,4-DCA reacted, product as white crystals with embodiment 2,
Yield 65%,1H NMR (400MHz, DMSO) δ=10.67 (s, 1H, NH), 10.44 (s, 1H, NH), 8.57-8.14 (m, 2H,
Ar),7.47-7.21(m,6H,Ar)。
16 N of embodiment1,N3- two (the fluoro- 4- iodophenyls of 3-) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and the fluoro- 4- Iodoanilines of 3- are reacted, product as white is brilliant with embodiment 2
Body, yield 62%,1H NMR (400MHz, DMSO) δ=10.73 (s, 1H, NH), 10.46 (s, 1H, NH), 8.24-8.02 (m,
2H,Ar),7.78-7.54(m,6H,Ar)。
17 N of embodiment1,N3- two (the chloro- 4- fluorophenyls of 3-) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and the chloro- 4- fluoroanilines of 3- are reacted, product as white is brilliant with embodiment 2
Body, yield 52%,1H NMR (400MHz, DMSO) δ=10.75 (s, 1H, NH), 10.66 (s, 1H, NH), 8.28-8.42 (m,
2H,Ar),7.88-7.44(m,6H,Ar)。
18 N of embodiment1,N3- two (3,5- 3,5-dimethylphenyl) -4- hydroxyl -5- bromines isophtalamides synthesize
Operated with embodiment 2, the bromo- 4 hydroxyisophthalic acids of 5- and 3,5- dimethylaniline are reacted, product as white is brilliant
Body, yield 57%,1H NMR (400MHz, DMSO) δ=10.78 (s, 1H, NH), 10.57 (s, 1H, NH), 8.35-8.00 (m,
2H,Ar),7.73-7.84(m,6H,Ar),2.64-2.53(m,12H,-CH3)。
19 N of embodiment1,N3- two (3,5- dichlorophenyl) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 3,5- dichloroaniline reacted, product as white crystals with embodiment 2,
Yield 63%,1H NMR(400MHz,DMSO):δ=10.79 (s, 1H, NH), 10.69 (s, 1H, NH), 8.35-8.05 (m, 2H,
Ar),7.69-7.34(m,6H,Ar)。
20 N of embodiment1,N3- two (2,5- dichlorophenyl) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2,5- dichloroaniline reacted, product as white crystals with embodiment 2,
Yield 64%,1H NMR(400MHz,DMSO):δ=10.62 (s, 1H), 10.51 (s, 1H), 8.33 (dd, J=112.1,
2.0Hz,2H),7.95-7.30(m,6H)。
21 N of embodiment1,N3- two (the bromo- 2- fluorophenyls of 5-) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and the bromo- 2- fluoroanilines of 5- are reacted, product as white is brilliant with embodiment 2
Body, yield 60%,1H NMR (400MHz, DMSO) δ=10.69 (s, 1H), 10.44 (s, 1H), 8.11 (dd, J 27.0,
7.6Hz,2H),7.89-7.31(m,6H)。
22 N of embodiment1,N3- two (2,6- dichlorophenyl) -4- hydroxyl -5- bromines isophtalamides synthesize
Operate, the bromo- 4 hydroxyisophthalic acids of 5- and 2,6-DCA reacted, product as white crystals with embodiment 2,
Yield 64%,1H NMR (400MHz, DMSO) δ=10.82 (s, 1H, NH), 10.58 (s, 1H, NH), 8.67-8.22 (m, 2H,
Ar),7.65-7.35(m,6H,Ar)。
Here is the pharmacological experiment and result of part of compounds of the present invention：
It is thin as target using human breast carcinoma MDA-MB-231 cells, human gastric cancer MGC-803 cells, Human gastric cancer SGC-7901 cells
Born of the same parents, cis-platinum are positive control drug, using the synthesized compound on tumor cell of tetramethyl azo azoles salt (MTT) colorimetric method test
External inhibitory activity, test method and experimental result：
Mtt assay surveys cell Proliferation
Cell recovery：Freeze-stored cell is taken out from liquid nitrogen container or -80 DEG C of refrigerators, 37 DEG C of waters bath with thermostatic control is placed on and constantly shakes
Fast melt is allowed to, draws cell into centrifuge tube, 8mL minimal mediums 1000rpm is added and centrifuges 5 minutes, abandoning supernatant.
Draw 1mL complete mediums to suspend cell again, be transferred in 25ml Tissue Culture Flasks.5mL complete mediums are supplemented, gently
Blow uniformly after be put into quiescent culture in cell incubator (37 DEG C, containing 5%CO2, 95% humidity).
Cell passes on：Cell attachment is grown, and culture medium in blake bottle is discarded when blake bottle about 80% density is covered with, and is used
3mL high pressures PBS washes cell once.550 μ L pancreatin digestive juices are added, softly rocking blake bottle makes all cells all touch digestion
Liquid, is placed 30 seconds to 2 minutes, micro- Microscopic observation Cytoplasmic shrinkage in incubator, when gap becomes larger between cell and cell,
Digestive juice is siphoned away at once, adds 5mL complete mediums, stops digestion.Culture bottle wall is gently blown and beaten with glass pipette, make cell with
Bottle wall separates.It is seeded to after cell count by required cell number in new blake bottle.
Cell cryopreservation：Selection is frozen in the cell of exponential phase, and carries out changing liquid freezing the previous day.By one
Draw into centrifuge tube 1000rpm after bottle cell dissociation to centrifuge 5 minutes, abandoning supernatant.Cell is resuspended with cells frozen storing liquid, point
It is filled in cryopreservation tube, cryopreservation tube is put into freezing storing box, be positioned in -80 DEG C of refrigerators, such as need to for a long time preserves, then be transferred to liquid nitrogen
In tank.
Cell count：Postdigestive cell suspending liquid drop to be measured is drawn on cell counting count board, is seen under low-powered microscope
Examine the cell number simultaneously in the block plaid of count plate corner.In calculating process, for not remembering in the cell use note of edge crimping
Under, right principle is not remembered on a note left side.
Cell number/mL=(four block plaid total number of cells/4) × 104× extension rate
Cytotoxicity experiment：
Take the logarithm human breast carcinoma MDA-MB-231 cells, human gastric cancer MGC-803 cells, the human gastric cancer SGC-7901 in growth period
5.0 × 10 are pressed for target cell3A/hole is inoculated in 96 orifice plates, and edge hole is filled with PBS, and Tissue Culture Plate is placed in 37 DEG C of cells
When being incubated 24 hours in incubator, after cell attachment, the dilution of compound complete medium equimultiple is separately added into 96 orifice plates,
Using cis-platinum as positive control.Cell be placed in 37 DEG C, continue in 5% CO2gas incubator culture 72 it is small when after, 10 μ are added per hole
The MTT liquid (concentration 5mg/mL) of L, when culture 4 is small, measures the absorption value in every hole at 490nm with microplate reader, calculates various concentrations
Under cell inhibitory rate, using Prism softwares do concentration-inhibiting rate curve calculate IC50Value, the results are shown in Table 1.In table 1
The same upper table of compound numbers.Above-mentioned experiment, each hole are equipped with three multiple holes.
Inhibitory action of 1 given the test agent of table to three kinds of tumour cells
| Compound | IC50(μM) | ||
| MDA-MB-231 | MGC-803 | SGC-7901 | |
| Cis-platinum | 49.98 | 46.92 | 47.73 |
| 5 | 31.33 | ＞ 100 | 50.92 |
| 6 | 28.44 | 63.24 | ＞ 100 |
| 8 | 30.96 | 67.38 | 46.47 |
| 9 | 19.16 | 35.36 | 49.79 |
| 10 | 24.82 | 40.29 | 27.16 |
| 12 | 20.94 | ＞ 100 | 77.99 |
| 14 | 28.17 | 37.90 | 47.26 |
| 15 | 13.92 | 19.81 | 50.51 |
| 18 | 35.66 | 42.51 | 39.83 |
| 19 | ＞ 100 | ＞ 100 | 31.99 |
| 21 | 46.21 | ＞ 100 | 41.78 |
By table 1 as it can be seen that under the experiment condition, for human breast cancer cell MDA-MB-231, compound 6,8,9,10,
12,14,15,18,21 inhibitory activity are better than positive reference substance；For stomach cancer cell MGC -803, compound 5,6,8,9,10,14,
15,18 inhibitory activity are better than positive reference substance；For stomach cancer cell SGC-7901, compound 5,8,9,10,12,14,15,18,
19,21 inhibitory activity are better than positive reference substance.
Claims (10)
1. a kind of 4 hydroxyisophthalic acid derivative, it is characterised in that general structure is
R is halogen, methyl, ethyl, one kind or combinations thereof in trifluoromethyl in formula.
2. 4 hydroxyisophthalic acid derivative according to claim 1, it is characterised in that：The 4- hydroxyls isophthalic two
Formic acid derivates are as follows：
A kind of 3. synthetic method of 4 hydroxyisophthalic acid derivative, it is characterised in that：
Step (1) prepares the 4 hydroxyisophthalic acid dimethyl ester as described in formula a：
Using 4 hydroxyisophthalic acid and thionyl chloride as raw material, react 4 hydroxyisophthalic acid diformazan is made in methyl alcohol
Ester；
Step (2) prepares the bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- as described in formula b：
Under the conditions of lucifuge, 4 hydroxyisophthalic acid dimethyl ester and N- bromo-succinimides are anti-in n,N-Dimethylformamide
The bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- should be synthesized；
Step (3) prepares the bromo- 4 hydroxyisophthalic acids of 5- as described in formula c：
The hydrolysis under alkali effect of the bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- prepares the bromo- 4 hydroxyisophthalic acids of 5-；
Step (4) prepares the bromo- 4- hydroxyls m-phthaloyl chlorides of 5- as described in formula d：
The bromo- 4 hydroxyisophthalic acids of 5- react under a small amount of DMF catalytic action with thionyl chloride prepares the bromo- 4- hydroxyls isophthalic of 5-
Dimethyl chloride；
Step (5) prepares the target compound as described in formula e：
In organic solvent, the reaction under alkali effect is generated such as formula (I) institute the bromo- 4- hydroxyls m-phthaloyl chlorides of 5- with substituted aniline
The target compound shown.
4. synthetic method according to claim 3, it is characterised in that：The step (1), every mole of 4- hydroxyls isophthalic two
The volume that formic acid adds methanol be 2-5L, and the molar ratio of 4 hydroxyisophthalic acid and thionyl chloride is 1:5-1:20.
5. synthetic method according to claim 4, it is characterised in that：Described every mole of 4- hydroxyls isophthalic two of step (1)
The volume that formic acid adds methanol be 3L, and the molar ratio of 4 hydroxyisophthalic acid and thionyl chloride is 1:10.
6. synthetic method according to claim 3, it is characterised in that：Described step (2) 4 hydroxyisophthalic acid two
The molar ratio of methyl esters and N- bromo-succinimides is 1:1-1:5,30-50 DEG C of reaction temperature.
7. synthetic method according to claim 6, it is characterised in that：Described step (2) 4 hydroxyisophthalic acid two
The molar ratio of methyl esters and N- bromo-succinimides is 1:2, reaction temperature is 30 DEG C.
8. synthetic method according to claim 3, it is characterised in that：Base reagent described in the step (3) is hydrogen-oxygen
Change sodium, potassium hydroxide, barium hydroxide, calcium hydroxide etc., the molar ratio of the bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- and alkali is 1:
3-1:5。
9. synthetic method according to claim 8, it is characterised in that：Alkali described in the step (3) is sodium hydroxide,
The molar ratio of the bromo- 4 hydroxyisophthalic acid dimethyl esters of 5- and alkali is 1:3.
10. synthetic method according to claim 3, it is characterised in that：Described every mole of 5- nitro -4- hydroxyl of step (4)
The volume that base M-phthalic acid adds thionyl chloride is 1-4L.
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| WO2011130383A1 (en) * | 2010-04-14 | 2011-10-20 | Comentis, Inc. | Compounds containing fused rings which inhibit beta-secretase activity and methods of use thereof |
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| CN106117078A (en) * | 2016-06-28 | 2016-11-16 | 东南大学 | The application in preparing antitumor drug of the 5 nitro 4 hydroxyl isophthaloyl aminated compoundss |
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| WO2011130383A1 (en) * | 2010-04-14 | 2011-10-20 | Comentis, Inc. | Compounds containing fused rings which inhibit beta-secretase activity and methods of use thereof |
| CN105884620A (en) * | 2016-04-22 | 2016-08-24 | 东南大学 | 4-Hydroxyl-1,3 di-phthalate derivatives and preparation and application thereof |
| CN106117078A (en) * | 2016-06-28 | 2016-11-16 | 东南大学 | The application in preparing antitumor drug of the 5 nitro 4 hydroxyl isophthaloyl aminated compoundss |
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