CN107935840B - 4-hydroxyisophthalic acid derivative and synthetic method thereof - Google Patents

4-hydroxyisophthalic acid derivative and synthetic method thereof Download PDF

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CN107935840B
CN107935840B CN201711267698.3A CN201711267698A CN107935840B CN 107935840 B CN107935840 B CN 107935840B CN 201711267698 A CN201711267698 A CN 201711267698A CN 107935840 B CN107935840 B CN 107935840B
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hydroxyisophthalic acid
bromo
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吴东恩
孙柏旺
王曼凝
李雪莲
郭庆会
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Changzhou Vocational Institute of Engineering
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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 4-hydroxyisophthalic acid derivative and a synthesis method thereof, belonging to the field of organic chemistry and being a novel compound 5-bromo-4-hydroxyisophthalic acid arylamine compound synthesized by taking 4-hydroxyisophthalic acid as a raw material. The synthesis method takes 4-hydroxyisophthalic acid as a raw material and is prepared by the steps of methyl esterification, bromination, hydrolysis, amidation and the like, and the preparation method is simple and the compound has a novel structure. Biological activity tests show that the compound has stronger tumor cell inhibition activity.

Description

4-hydroxyisophthalic acid derivative and synthetic method thereof
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a 4-hydroxyisophthalic acid derivative and a synthetic method thereof
Background
In 1956, Hunt et al studied the synthesis of salicylic acid by Kolbe-schmitt method, and found that 4-hydroxyisophthalic acid was a major by-product in the reaction process, and purified 4-hydroxyisophthalic acid was separated (J Chem Soc.1956, 3099). The Chesher et al study found that 4-hydroxyisophthalic acid has antipyretic efficacy (Nature,1956,175: 206). Anup et al found that 4-hydroxyisophthalic acid was able to antagonize the production of intracellular free radicals and has antioxidant function to protect cells (Food Chemistry,2012,132: 1959). Haddadi et al further found that intracellular antioxidant function of 4-hydroxyisophthalic acid can affect the activity of neurotransmitter enzymes, and can be used as a candidate drug for treating neurodegenerative diseases (Neurochemistry International,2016,100: 78). Selleri et al studied the anti-platelet aggregation efficacy of 4-hydroxyisophthalic acid derivatives and developed the anti-platelet aggregation drug, picotamide (formula I) (US 3973026). Nathan et al synthesized a leukotriene receptor-2 receptor antagonist from 4-hydroxyisophthalic acid, and biological activity studies showed that The compound has good anti-myocardial ischemia effect (formula II) (The Journal of Pharmacology and Experimental Therapeutics,2011,339: 768). Gobert et al synthesized a protein tyrosine phosphatase inhibitor (formula III) using 4-hydroxyisophthalic acid as a raw material, and Biological activity studies showed that The compound had a good therapeutic effect on ulcerative colitis (The Journal of Biological Chemistry,2009,284(17): 11385).
Figure GDA0002840340590000011
Figure GDA0002840340590000021
Tumors are one of the diseases that seriously endanger human health. In 2015, 429.2 ten thousand new cancer cases and 281.4 ten thousand death cases exist in China, which is equivalent to 12000 new cancers and 7500 people dying from cancers every day. The chemical drug therapy is one of three major means for treating cancer, the development of the anti-tumor drug is always a research hotspot, and the research and development of new anti-tumor drugs have important significance. In order to further research the biological activity of the 4-hydroxyisophthalic acid derivatives, the inventor designs and synthesizes a class of 4-hydroxyisophthalic acid derivatives, and evaluates the biological efficacy of the 4-hydroxyisophthalic acid derivatives, and deduces that the compounds may show the anti-tumor activity. The activity of the compounds is further tested, and the compounds are found to have stronger inhibitory activity on gastric cancer cells (MGC-803 and SGC7901) and breast cancer cells (MDA-MB-231).
Disclosure of Invention
The invention aims to provide a novel 4-hydroxyisophthalic acid derivative, a synthetic method and application thereof. The synthesis method takes 4-hydroxyisophthalic acid as a raw material and is prepared by the steps of methyl esterification, bromination, hydrolysis, amidation and the like, and the preparation method is simple and the compound has a novel structure. Biological activity tests show that part of compounds have stronger tumor cell inhibition activity. The technical scheme of the invention is as follows:
the 4-hydroxyisophthalic acid derivative is characterized in that the structural general formula is
Figure GDA0002840340590000031
Wherein R is one or the combination of halogen, methyl, ethyl and trifluoromethyl.
The synthesis process of 4-hydroxy isophthalic acid derivative includes methyl esterification, bromination, hydrolysis, acyl chlorination and reaction with substituted arylamine.
A synthesis method of a 4-hydroxyisophthalic acid derivative comprises the following steps:
Figure GDA0002840340590000032
step 1. preparation of dimethyl 4-hydroxyisophthalate (Compound a):
4-hydroxyisophthalic acid and thionyl chloride are taken as raw materials and react in methanol to prepare 4-hydroxyisophthalic acid dimethyl ester;
the volume of methanol added into each mole of 4-hydroxyisophthalic acid is 2-5L, and the molar ratio of the 4-hydroxyisophthalic acid to the thionyl chloride is 1:5-1: 20. Preferably, 3L of methanol is added per mole of 4-hydroxyisophthalic acid, and the molar ratio of 4-hydroxyisophthalic acid to thionyl chloride is 1: 10.
Step 2. preparation of dimethyl 5-bromo-4-hydroxyisophthalate (Compound b):
under the condition of keeping out of the sun, 4-hydroxy isophthalic acid dimethyl ester and N-bromosuccinimide react in N, N-Dimethylformamide (DMF) to synthesize 5-bromo-4-hydroxy isophthalic acid dimethyl ester;
the molar ratio of the 4-hydroxyisophthalic acid dimethyl ester to the N-bromosuccinimide is 1:1-1:5, and the reaction temperature is 30-50 ℃. Preferably, the molar ratio of the dimethyl 4-hydroxyisophthalate to the N-bromosuccinimide is 1:2, and the reaction temperature is 30 ℃.
Step 3. preparation of 5-bromo-4-hydroxyisophthalic acid (compound c):
(3) hydrolyzing dimethyl 5-bromo-4-hydroxyisophthalate under the action of alkali to prepare 5-bromo-4-hydroxyisophthalate;
the alkali reagent is sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and the like, and the molar ratio of the 5-bromine-4-hydroxyisophthalic acid dimethyl ester to the alkali is 1:3-1: 5. Preferably, the base used is sodium hydroxide and the molar ratio of dimethyl 5-bromo-4-hydroxyisophthalate to base is 1: 3.
Step 4. preparation of 5-bromo-4-hydroxyisophthaloyl dichloride (Compound d):
reacting 5-bromo-4-hydroxyisophthalic acid with thionyl chloride under the catalysis of a small amount of DMF to prepare 5-bromo-4-hydroxyisophthaloyl dichloride;
the volume of the thionyl chloride added to each mole of 5-nitro-4-hydroxyisophthalic acid is 1-4L, and DMF is used as catalytic amount. Preferably, 3L of thionyl chloride is added per mole of 5-bromo-4-hydroxyisophthalic acid.
Step 5. preparation of the target compound (compound e):
in an organic solvent, 5-bromo-4-hydroxy isophthaloyl dichloride and substituted aniline react under the action of alkali to generate a target compound with a structural formula (I).
The organic solvent is toluene, acetone, ethyl acetate, dichloromethane and the like; the substituted aniline is aniline containing one or a combination of halogen, methyl, ethyl and trifluoromethyl on a benzene ring; the alkali is potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, diisopropylethylamine or 4-dimethylaminopyridine, and the addition amount of the alkali is catalytic stoichiometric amount; the molar ratio of the 5-bromo-4-hydroxyisophthaloyl chloride to the substituted aniline is 1:2-1: 4. Preferably, the organic solvent used is toluene, the base used is triethylamine, and the molar ratio of 5-bromo-4-hydroxyisophthaloyl dichloride to substituted aniline is 1: 3.
Some preferred compounds of the invention are as follows:
Figure GDA0002840340590000051
the synthesis method of the invention takes 4-hydroxyisophthalic acid as a raw material, and prepares the 4-hydroxyisophthalic acid derivative through the steps of methyl esterification, bromination, hydrolysis, arylamidation and the like. The 5-bromo-4-hydroxyisophthalic acid (compound c) reported in the literature is obtained by direct bromination of a bromine simple substance using 4-hydroxyisophthalic acid as a raw material (J Chem Soc.1956, 3099). Because the benzene ring contains two carboxyl groups, the solubility of the 4-hydroxyisophthalic acid in a solvent is very poor, the reaction is complex when the 4-hydroxyisophthalic acid is directly brominated and substituted due to the positioning effect of the two carboxyl groups on the benzene ring, and the yield of the 5-bromo-4-hydroxyisophthalic acid product is very low. In order to overcome the poor solubility of the 4-hydroxyisophthalic acid and the positioning effect of two carboxyl groups on a benzene ring, the invention firstly prepares the dimethyl 4-hydroxyisophthalate (compound a) by methyl esterification reaction of the 4-hydroxyisophthalic acid. The solubility of the 4-hydroxy isophthalic acid dimethyl ester in a solvent is better, and the positioning effects of the substituent groups of the two ester groups are consistent. The bromine simple substance has high toxicity, and in order to avoid using the bromine simple substance, the method adopts N-bromosuccinimide (NBS) as a bromination reagent, and introduces a bromine substituent on a 4-hydroxyisophthalic acid methyl ester benzene ring to prepare the 5-bromine-4-hydroxyisophthalic acid dimethyl ester (compound b). By selecting a proper NBS bromination solvent, the bromination process of the method has mild reaction conditions and simple post-treatment. The 5-bromo-4-hydroxyisophthalic acid methyl ester is subjected to alkaline hydrolysis to prepare 5-bromo-4-hydroxyisophthalic acid (compound c). The solubility of 5-bromo-4-hydroxyisophthalic acid in a solvent is poor, and the yield is low when the 5-bromo-4-hydroxyisophthalic acid is directly reacted with arylamine. In order to overcome the problem of poor reaction activity of the 5-bromo-4-hydroxyisophthalic acid, the invention chlorinates the 5-bromo-4-hydroxyisophthalic acid (compound d), and then reacts with aromatic amine to prepare a product (compound e), thereby improving the product yield.
Human breast cancer MDA-MB-231 cells, human gastric cancer MGC-803 cells and human gastric cancer SGC-7901 cells are used as target cells, cis-platinum is used as a positive control drug, and a tetramethyl azozolium (MTT) colorimetric method is adopted to test the in-vitro inhibitory activity of the synthesized compound on tumor cells. The compound (I) has the activity of inhibiting the proliferation of tumor cells, and the activity of part of the compound is superior to that of the positive control cisplatin.
Advantageous effects
The invention relates to a novel compound 5-bromo-4-hydroxyisophthaloyl arylamine compound synthesized by taking 4-hydroxyisophthalic acid as a raw material. The compound takes 4-hydroxyisophthalic acid as a raw material, and 5-bromo-4-hydroxyisophthaloyl arylamine compounds are prepared by methyl esterification, bromination, hydrolysis and acyl arylamine. Two carboxyl groups exist on a 4-hydroxyisophthalic acid benzene ring, two products exist in the direct esterification reaction with methanol under the catalysis of strong acid, the reaction exists in balance, and the product yield is low. In the patent, 4-hydroxyisophthalic acid and methanol react in thionyl chloride to prepare 4-hydroxyisophthalic acid dimethyl ester, so that the reaction time is shortened, and the product yield (86%) is improved. According to the invention, N-bromosuccinimide (NBS) is used for brominating the 4-hydroxy dimethyl isophthalate, so that bromine with high toxicity is avoided. Meanwhile, by optimizing reaction conditions and selecting a proper reaction solvent, the reaction temperature is reduced (30 ℃), the post-treatment process is simple, the product, namely the 5-bromo-4-hydroxyisophthalic acid dimethyl ester, can be obtained by directly filtering, and the product yield is high (87%). The 5-bromo-4-hydroxyisophthalic acid dimethyl ester is hydrolyzed to prepare 5-bromo-4-hydroxyisophthalic acid, and the solubility of the 5-bromo-4-hydroxyisophthalic acid in an organic solvent is poor, so that the activity is poor when the 5-bromo-4-hydroxyisophthalic acid is directly reacted with arylamine. The invention prepares 5-bromo-4-hydroxyisophthalamide by reacting 5-bromo-4-hydroxyisophthalic acid with thionyl chloride for acyl chlorination and then reacting with arylamine. The method improves the activity of 5-bromine-4-hydroxyl isophthalic acid reaction and improves the product yield (about 60 percent). Through the test of the biological activity of the compound, the tumor inhibition activity of part of the 5-nitro-4-hydroxy isophthalic acid acyl arylamine compound is stronger than that of cisplatin, which shows that the compound structure has potential value as an antitumor drug.
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Process for preparing dimethyl 4-hydroxyisophthalate compound of FIG. 11H NMR spectrum
FIG. 2 Process for preparing dimethyl 5-bromo-4-hydroxyisophthalate, compound of FIG. 21H NMR spectrum
Process for preparing 5-bromo-4-hydroxyisophthalic acid compound of FIG. 31H NMR spectrum
FIG. 4 Compound N1,N3Process for preparing (bis (4-fluorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 5 Compound N1,N3Process for preparing (bis (2-fluorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 6 Compound N1,N3Process for preparing (2-chlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 7 Compound N1,N3Process for preparing (3-chlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 8 Compound N1,N3Process for preparing (4-chlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 9 Compound N1,N3Process for preparing (2-chlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 10 Compound N1,N3Process for preparing (3-bromophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 11 Compound N1,N3Process for preparing (4-bromophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 12 Compound N1,N3Process for preparing (bis (2-iodophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 13 Compound N1,N3Process for preparing (bis (4-iodophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 14 Compound N1,N3Process for preparing (bis (2, 4-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR atlas
FIG. 15 Compound N1,N3Process for preparing (2, 4-difluorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 16 Compound N1,N3Process for preparing (bis (4-bromo-2-methylphenyl) -4-hydroxy-5-bromoisophthalamide)1H NMR spectrum
FIG. 17 Compound N1,N3Process for preparing (bis (3, 4-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 18 Compound N1,N3Process for preparing (bis (3-fluoro-4-iodophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 19 Compound N1,N3Process for preparing (bis (3-chloro-4-fluorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectra
FIG. 20 Compound N1,N3Process for preparing (bis (3, 4-dimethylphenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 21 Compound N1,N3Process for preparing (bis (3, 4-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
FIG. 22 Compound N1,N3Process for preparing (bis (2-fluoro-5-bromophenyl) -4-hydroxy-5-bromoisophthalamide)1H NMR spectrum
FIG. 23 Compound N1,N3Process for preparing (bis (2, 6-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide1H NMR spectrum
Detailed Description
The present invention will be further described with reference to the following specific examples. It is to be understood that the following examples are illustrative of the invention only and are not intended to limit the scope of the invention.
Example 1N1,N3Synthesis of (4-fluorophenyl) -4-hydroxy-5-bromoisophthalamide
Synthesis of 1.14-Hydroxyisophthalic acid dimethyl ester
15g (82.4mmol) of 4-hydroxyisophthalic acid are added to 150mL of anhydrous methanol. 75g (630.5mmol) of thionyl chloride slowly with stirring at room temperatureDropping into the solution within 30 min. After dropping, the temperature is raised until the solution is refluxed slowly. The reaction was monitored by TLC (petroleum ether: ethyl acetate 3:1) and after 4 hours the reaction was complete. After cooling to room temperature, a white solid precipitated. The solid was filtered and the filter cake was washed with copious amounts of water and dried under vacuum. The obtained solid was dissolved in 100mL of ethyl acetate, and the ethyl acetate solution was washed with 80mL of a saturated sodium bicarbonate solution, 50mL of distilled water, and 50mL of a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and rotary-evaporated to obtain 14g of a white solid (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)。
Synthesis of 1, 25-bromo-4-hydroxyisophthalic acid dimethyl ester
10g (41.61mmol) of dimethyl 4-hydroxyisophthalate were added to 100mL of N, N-dimethylformamide under exclusion of light. 11.11g (62.42mmol) of N-bromosuccinimide were added to the above solution with stirring at room temperature. After the addition, the reaction solution was heated to 35 ℃. After continuing the reaction for 5 hours, the heating was stopped and the reaction mixture was cooled to room temperature. 80mL of distilled water was added to the reaction mixture under stirring, and a white solid was precipitated. Stirring was continued for 30 min, filtered and the filter cake was washed with cold ethanol. The filter cake was collected and dried in vacuo to yield 11.52g of a white solid (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)。
Synthesis of 1.35-bromo-4-hydroxyisophthalic acid
8g (27.68mmol) of dimethyl 5-bromo-4-hydroxyisophthalate were added to 80mL of an aqueous potassium hydroxide solution (potassium hydroxide 6.20g/110.72 mmol). The reaction mixture was heated under reflux to form a white emulsion at the beginning, and the white solid was gradually dissolved as the reaction proceeded. After refluxing for 2 hours, the heating was stopped and the reaction mixture was cooled to room temperature. And adding 10% hydrochloric acid into the reaction solution to adjust the pH of the solution to 1-2, and separating out a white solid. Filtration was carried out, and the filter cake was washed with distilled water and methanol, respectively, and the filter cake was collected and dried under vacuum to obtain 5.9g of a white solid (yield 82%).1H NMR(DMSO-d6):δ(ppm)8.45(d,1H,Ar),8.49(d,1H,Ar)。
1.4 N1,N3Synthesis of (bis (2-fluorophenyl) -4-hydroxy-5-bromoisophthalamide
2.0g (7.6mmol) of 5-bromo-4-hydroxyisophthalic acid is taken, a few drops of DMF are added dropwise, 25mL of thionyl chloride is slowly added dropwise, the oil bath is carried out at 65 ℃, the interior of the bottle is subjected to violent reflux, a gas recovery device is connected above the spherical condenser tube, and a tail gas absorption device adopts sodium hydroxide aqueous solution. After 8 hours of reaction, TLC detection showed that the 5-bromo-4-hydroxyisophthalic acid was essentially completely reacted. Removing thionyl chloride by rotary evaporation, and obtaining a liquid substrate in a single-mouth bottle for later use. 3.2g of 2-fluoroaniline (28.5mmol) and 2.8g (28.5mmol) of triethylamine are dissolved in 40mL of toluene and stirred in an ice bath under nitrogen protection until all the components are dissolved. And dissolving the substrate in 20mL of dichloromethane, adding the dichloromethane into a constant-pressure dropping funnel, and slowly dropping the dichloromethane into a toluene solution dissolved with 2-fluoroaniline under the ice bath condition, wherein a large amount of white smoke is generated in the process. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. And (5) detecting by using thin-layer chromatography, and finishing the reaction of the substrate. And (4) performing suction filtration, and detecting and analyzing the filter cake and the filtrate to obtain a product existing in the filter cake. The filter cake was dissolved in tetrahydrofuran and stirred to dissolve, insoluble triethylamine hydrochloride was removed by filtration, the filtrate was rotary evaporated to give the product, which was dried and weighed to give 2.0g of a solid, which was isolated by column chromatography (petroleum ether: ethyl acetate 5:1) as white crystals with a yield of 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)。
Example 2N1,N3Synthesis of (4-fluorophenyl) -4-hydroxy-5-bromoisophthalamide
Synthesis of 2.14-Hydroxyisophthalic acid dimethyl ester
20g (109.9mmol) of 4-hydroxyisophthalic acid are added to 330mL of anhydrous methanol. While stirring at room temperature, 130g (1099mmol) of thionyl chloride was slowly dropped into the above solution, and the dropping was completed within 40 minutes. After dropping, the temperature is raised until the solution is refluxed slowly. The reaction was monitored by TLC (petroleum ether: ethyl acetate 3:1) and after 3 hours the reaction was complete. After cooling to room temperature, a white solid precipitated. The solid was filtered and the filter cake was washed with copious amounts of water and dried under vacuum. The resulting solid was dissolved in 120mL of ethyl acetate, and the ethyl acetate solution was obtainedAfter washing with 90mL of saturated sodium bicarbonate solution, 70mL of distilled water, and 70mL of saturated brine, respectively, the mixture was dried over anhydrous sodium sulfate, filtered, and rotary-evaporated to obtain 15g of a white solid (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)。
Synthesis of 2, 25-bromo-4-hydroxyisophthalic acid dimethyl ester
15g (62.41mmol) of dimethyl 4-hydroxyisophthalate were added, protected from light, to 120mL of N, N-dimethylformamide. 22.23g (124.82mmol) of N-bromosuccinimide were added to the above solution with stirring at room temperature. After the addition, the reaction solution was heated to 30 ℃. After continuing the reaction for 4 hours, the heating was stopped and the reaction mixture was cooled to room temperature. While stirring, 90mL of distilled water was added to the reaction mixture, and a white solid was precipitated. Stirring was continued for 35 min, filtered and the filter cake was washed with cold ethanol. The filter cake was collected and dried in vacuo to yield 15.87g of a white solid (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)。
Synthesis of 2.35-bromo-4-hydroxyisophthalic acid
10g (34.61mmol) of dimethyl 5-bromo-4-hydroxyisophthalate were added to 90mL of an aqueous solution of sodium hydroxide (sodium hydroxide 3.32g/103.83 mmol). The reaction mixture was heated under reflux to form a white emulsion at the beginning, and the white solid was gradually dissolved as the reaction proceeded. After refluxing for 2.5 hours, the heating was stopped and the reaction mixture was cooled to room temperature. And adding 10% hydrochloric acid into the reaction solution to adjust the pH of the solution to 1-2, and separating out a white solid. Filtration was carried out, and the filter cake was washed with distilled water and methanol, respectively, and the filter cake was collected and dried under vacuum to obtain 7.9g of a white solid (yield 88%).1H NMR(DMSO-d6):δ(ppm)8.45(d,1H,Ar),8.49(d,1H,Ar)。
2.4 N1,N3Synthesis of (4-fluorophenyl) -4-hydroxy-5-bromoisophthalamide
Taking 3.0g (11.5mmol) of 5-bromo-4-hydroxyisophthalic acid, dripping several drops of DMF (dimethyl formamide), slowly dripping 35mL of thionyl chloride, carrying out oil bath at 65 ℃, violently refluxing in a bottle, and placing on a spherical condenser tubeThe gas recovery device is connected with the gas recovery device, and the tail gas absorption device adopts sodium hydroxide aqueous solution. After 7 hours of reaction, the TLC detection showed that the 5-bromo-4-hydroxyisophthalic acid was substantially reacted to completion. Removing thionyl chloride by rotary evaporation, and obtaining a liquid substrate in a single-mouth bottle for later use. 2.55g of 4-fluoroaniline (23mmol) and 2.4g (24mmol) of triethylamine are dissolved in 50mL of toluene and stirred in an ice bath under nitrogen protection until all is dissolved. And dissolving the substrate in 30mL of dichloromethane, adding the dichloromethane into a constant-pressure dropping funnel, and slowly dropping the dichloromethane solution dissolved with the 4-fluoroaniline into the toluene solution under the ice bath condition, wherein a large amount of white smoke is generated in the process. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. And (5) detecting by using thin-layer chromatography, and finishing the reaction of the substrate. And (4) performing suction filtration, and detecting and analyzing the filter cake and the filtrate to obtain a product existing in the filter cake. Dissolving the filter cake in tetrahydrofuran, stirring to dissolve, filtering to remove insoluble triethylamine hydrochloride, rotary evaporating the filtrate to obtain the product, drying, weighing to obtain 2.0g of solid, separating by column chromatography (petroleum ether: ethyl acetate ═ 4:1), white crystal with yield of 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)。
example 3N1,N3Synthesis of (2-chlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid was reacted with 2-chloroaniline to give a white crystal product with a yield of 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)。
example 4N1,N3Synthesis of (3-chlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid and 3-chloroaniline were reacted to give a product as white crystals in a yield of 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)。
example 5N1,N3Synthesis of (4-chlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same procedure as in example 2 was repeated, except that 5-bromo-4-hydroxyisophthalic acid was reacted with 4-chloroaniline to give a product in the form of white crystals, which was then collectedThe rate is 68 percent,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)。
example 6N1,N3Synthesis of (2-bromophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid was reacted with 2-bromoaniline, and the product was white crystals, yield 64%,1H NMR(400MHz,DMSO)δ＝10.48(s,1H),10.34(s,1H),8.20-7.23(m,10H)。
example 7N1,N3Synthesis of (bis (3-bromophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid was reacted with 3-bromoaniline, and the product was white crystals, with a yield of 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)。
example 8N1,N3Synthesis of (4-bromophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid was reacted with 4-bromoaniline, and the product was white crystals, with a yield of 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)。
example 9N1,N3Synthesis of (2-iodophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid was reacted with 2-iodoaniline to give a product as pale yellow crystals in 67% yield,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)。
example 10N1,N3Synthesis of (4-iodophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid was reacted with 4-iodoaniline to give a product in the form of white crystals with a yield of 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)。
example 11N1,N3Synthesis of (bis (2-fluoro-4-bromophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid was reacted with 2-fluoro-4-bromoaniline to give a white crystal product with a yield of 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)。
example 12N1,N3Synthesis of (bis (2, 4-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid was reacted with 2, 4-dichloroaniline to give a white crystal as a product in a yield of 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)。
example 13N1,N3Synthesis of (E) -bis (2, 4-difluorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid was reacted with 2, 4-difluoroaniline to give a product as white crystals in a yield of 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)。
example 14N1,N3Synthesis of (4-bromo-2-methylphenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid and 4-bromo-2-methylaniline were reacted to give a product in the form of white crystals with a yield of 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)。
example 15N1,N3Synthesis of (E) -bis (3, 4-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid and 3, 4-dichloroaniline were reacted to give a product as white crystals in a yield of 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)。
example 16N1,N3Synthesis of (bis (3-fluoro-4-iodophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid and 3-fluoro-4-iodoaniline were reacted, and the product was white crystals, 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)。
example 17N1,N3Synthesis of (bis (3-chloro-4-fluorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid and 3-chloro-4-fluoroaniline were reacted to give a product in the form of white crystals with a yield of 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)。
example 18N1,N3Synthesis of (bis (3, 5-dimethylphenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid and 3, 5-dimethylaniline were reacted to give a product in the form of white crystals with a yield of 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)。
example 19N1,N3Synthesis of (bis (3, 5-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid and 3, 5-dichloroaniline were reacted to give a white crystal as a product with a yield of 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)。
example 20N1,N3Synthesis of (bis (2, 5-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, and 5-bromo-4-hydroxyisophthalic acid was reacted with 2, 5-dichloroaniline to give a product as white crystals in a yield of 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)。
example 21N1,N3Synthesis of (bis (5-bromo-2-fluorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid and 5-bromo-2-fluoroaniline were reacted to give a product in the form of white crystals with a yield of 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)。
example 22N1,N3Synthesis of (bis (2, 6-dichlorophenyl) -4-hydroxy-5-bromoisophthalamide
The same operation as in example 2 was carried out, 5-bromo-4-hydroxyisophthalic acid was reacted with 2, 6-dichloroaniline to give a product as white crystals in a yield of 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)。
the following are the pharmacological tests and results of some of the compounds of the invention:
the in vitro inhibitory activity of the synthesized compound on tumor cells is tested by using human breast cancer MDA-MB-231 cells, human gastric cancer MGC-803 cells and human gastric cancer SGC-7901 cells as target cells and cisplatin as a positive control drug and adopting a tetramethyl azoazolate (MTT) colorimetric method, and the test method and the experimental result are as follows:
MTT method for measuring cell proliferation
Cell recovery: taking out the frozen cells from a liquid nitrogen tank or a refrigerator at minus 80 ℃, putting the cells into a constant-temperature water bath at 37 ℃ to be continuously shaken to be quickly melted, sucking the cells into a centrifugal tube, adding 8mL of a basic culture medium, centrifuging at 1000rpm for 5 minutes, and removing supernatant. The cells were resuspended by pipetting 1mL of complete medium and transferred to a 25mL cell culture flask. Supplementing 5mL of complete medium, gently blowing, and standing in a cell culture box (37 deg.C, 5% CO)295% humidity).
Cell passage: cells grew adherently, the medium in the flask was discarded when the flask was about 80% full, and the cells were washed once with 3mL of high pressure PBS. Adding 550 mu L of pancreatin digestive juice, gently shaking the culture flask to make all cells contact with the digestive juice, placing in an incubator for 30 seconds to 2 minutes, observing cytoplasm shrinkage under a microscope, immediately sucking away the digestive juice when gaps between cells become larger, adding 5mL of complete culture medium, and stopping digestion. The culture flask wall was gently blown with a glass pipette to separate the cells from the flask wall. After cell counting, the desired number of cells was inoculated into a new flask.
Freezing and storing cells: cells in the logarithmic growth phase were selected for cryopreservation and the fluid was changed one day before cryopreservation. After digesting a flask of cells, sucking the solution into a centrifuge tube, centrifuging the solution at 1000rpm for 5 minutes, and discarding the supernatant. Resuspending cells with cell freezing solution, subpackaging into freezing tubes, placing the freezing tubes into a freezing box, placing in a refrigerator at-80 deg.C, and transferring into a liquid nitrogen tank if long-term storage is required.
Cell counting: and (3) sucking the digested cell suspension to be detected to drop on a cell counting plate, and observing and calculating the number of cells in the large square grids at the four corners of the counting plate under a low power microscope. In the calculation process, the principle of recording on the upper side and recording on the left side and recording on the right side is adopted for the cells with the edge lines.
Cell number/mL ═ number of large square lattice cells/4) × 104X dilution factor
Cytotoxicity experiments:
taking human breast cancer MDA-MB-231 cells, human gastric cancer MGC-803 cells and human gastric cancer SGC-7901 cells in logarithmic growth phase as target cells according to the ratio of 5.0 multiplied by 103And inoculating each cell/well into a 96-well plate, filling edge wells with PBS, placing the cell culture plate in a cell culture box at 37 ℃ for incubation for 24 hours, after cells adhere to the wall, diluting the compound with a complete culture medium in an equal time manner, and respectively adding the diluted compound into the 96-well plate, wherein cisplatin is used as a positive control. Culturing cells in a 5% carbon dioxide incubator at 37 deg.C for 72 hr, adding 10 μ L MTT solution (5 mg/mL) into each well, culturing for 4 hr, measuring the absorbance of each well at 490nm with microplate reader, calculating the cell inhibition rate at different concentrations, and calculating IC by using Prism software to obtain concentration-inhibition rate curve50The results are shown in Table 1. The compound numbers in Table 1 are as above. In the above experiment, each well was provided with three multiple wells.
TABLE 1 inhibition of three tumor cells by test samples
Compound (I) 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
As can be seen from table 1, under this experimental condition, the inhibitory activity of compounds 6,8,9,10,12,14,15,18,21 was stronger against human breast cancer cell MDA-MB-231 than that of the positive control; the inhibitory activity of the compound 5,6,8,9,10,14,15 and 18 on gastric cancer cells MGC-803 is stronger than that of a positive control; the inhibitory activity of the compound 5,8,9,10,12,14,15,18,19 and 21 on gastric cancer cells SGC-7901 is stronger than that of a positive control.

Claims (9)

1. A4-hydroxyisophthalic acid derivative characterized in that said 4-hydroxyisophthalic acid derivative has the following structure:
Figure FDA00029713560200000112
2. a method for synthesizing a 4-hydroxyisophthalic acid derivative as claimed in claim 1, characterized in that:
Figure FDA0002971356020000021
step (1) preparing dimethyl 4-hydroxyisophthalate as shown in formula a:
4-hydroxyisophthalic acid and thionyl chloride are taken as raw materials and react in methanol to prepare 4-hydroxyisophthalic acid dimethyl ester;
step (2) preparing dimethyl 5-bromo-4-hydroxyisophthalate as described in formula b:
under the condition of keeping out of the sun, 4-hydroxy isophthalic acid dimethyl ester and N-bromosuccinimide react in N, N-dimethylformamide to synthesize 5-bromo-4-hydroxy isophthalic acid dimethyl ester;
step (3) preparing 5-bromo-4-hydroxyisophthalic acid as shown in formula c:
hydrolyzing dimethyl 5-bromo-4-hydroxyisophthalate under the action of alkali to prepare 5-bromo-4-hydroxyisophthalate;
step (4) preparing 5-bromo-4-hydroxyisophthaloyl dichloride as described in formula d:
reacting 5-bromo-4-hydroxyisophthalic acid with thionyl chloride under the catalysis of a small amount of DMF to prepare 5-bromo-4-hydroxyisophthaloyl dichloride;
step (5) preparing a compound according to formula (e):
in an organic solvent, 5-bromo-4-hydroxyisophthaloyl chloride and substituted aniline react under the action of alkali to generate the compound shown in the formula (e), wherein the compound shown in the formula (e) is the compound shown in claim 1.
3. The method of synthesis according to claim 2, characterized in that: in the step (1), the volume of methanol added into each mole of 4-hydroxyisophthalic acid is 2-5L, and the molar ratio of 4-hydroxyisophthalic acid to thionyl chloride is 1:5-1: 20.
4. The method of synthesis according to claim 2, characterized in that: the volume of methanol added into each mole of 4-hydroxyisophthalic acid in the step (1) is 3L, and the molar ratio of the 4-hydroxyisophthalic acid to thionyl chloride is 1: 10.
5. The method of synthesis according to claim 2, characterized in that: the molar ratio of the 4-hydroxyisophthalic acid dimethyl ester to the N-bromosuccinimide in the step (2) is 1:1-1:5, and the reaction temperature is 30-50 ℃.
6. The method of synthesis according to claim 2, characterized in that: the molar ratio of the 4-hydroxyisophthalic acid dimethyl ester to the N-bromosuccinimide in the step (2) is 1:2, and the reaction temperature is 30 ℃.
7. The method of synthesis according to claim 2, characterized in that: the alkali reagent in the step (3) is sodium hydroxide, potassium hydroxide, barium hydroxide and calcium hydroxide, and the molar ratio of the 5-bromo-4-hydroxyisophthalic acid dimethyl ester to the alkali is 1:3-1: 5.
8. The method of synthesis according to claim 2, characterized in that: the alkali in the step (3) is sodium hydroxide, and the molar ratio of the 5-bromine-4-hydroxyisophthalic acid dimethyl ester to the alkali is 1: 3.
9. The method of synthesis according to claim 2, characterized in that: the volume of the thionyl chloride added into each mole of the 5-bromo-4-hydroxyisophthalic acid in the step (4) is 1-4L.
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