CN101250132B - Polyfluoro ortho-hydroxybenzamide derivatives and uses thereof - Google Patents
Polyfluoro ortho-hydroxybenzamide derivatives and uses thereof Download PDFInfo
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- CN101250132B CN101250132B CN2008100609230A CN200810060923A CN101250132B CN 101250132 B CN101250132 B CN 101250132B CN 2008100609230 A CN2008100609230 A CN 2008100609230A CN 200810060923 A CN200810060923 A CN 200810060923A CN 101250132 B CN101250132 B CN 101250132B
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Abstract
The invention relates to a new 5-(2', 4'-difluorophenyl)-N-(4''-nitro-3''-trifluoromethylphenyl) salicylamide type anti-tumor drug, as 5-(2', 4'-difluorophenyl)-N-(4''-nitro-3''-trifluoromethylphenyl) salicylamide represented as formula (I) and 5-(2', 4'-difluorophenyl)-N-(4''-nitro-3''-trifluoromethylphenyl) salicylamide carboxylic ester represented as formula (II). And the invention also relates to a relative preparation method and an application of relative derivative in anti-tumor drug. The 5-(2', 4'-difluorophenyl)-N-(4''-nitro-3''-trifluoromethylphenyl) salicylamide derivative, preparation method and application have the advantages that (1) the invention provides a new anti-tumor drug with significant anti-tumor activity, (2) the preparation method is simple and the invention provides research base for new drug selection.
Description
(1) technical field
The present invention relates to the novel substance that a class has anti-tumor activity: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, and this compounds is in preparation antitumor drug, the especially application in anti-liver cancer, anti-leukemia medicine.
(2) background technology
N-replaces fluorobenzene salicylamide compound and derivative is the fluorine compound.Because the fluorine atom radius is little, have maximum electronegativity again, formed C-F bond energy can be much bigger than c h bond, increased the stability of fluorochemicals; And because the volume of fluorine atom is little, thereby often think the non-classical isostere of H atom, easily produce antagonistic action, that is: do not disturb interaction between fluorine-containing medicine and corresponding cell receptor, can replace the eubolism medicine at molecular level, mix biomacromolecule to duplicity, it is synthetic to cause causing death.When introducing fluorine atom in the drug molecule, its electrical effect and mimic effect have not only changed the distribution of intramolecule electron density, and can also improve the fat-soluble and perviousness of compound, solvability on microbial film is enhanced, promote it to absorb in vivo and transmission speed, physiological action is changed.So fluorine-containing medicine has characteristics such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong.Because fluorine-containing medicine has good, unique, valuable performance, has been subjected to the favor of medical research person and relevant company.
The research and development of fluorine-containing medicine mainly concentrate in the research and development of fluorine-containing fragrance, heterogeneous ring compound, have good antitumor activity as 5 FU 5 fluorouracil, difuradin, flutamide etc.Therefore, the new compound research to fluorine-containing, as to have anti-tumor activity has very important significance.
(3) summary of the invention
The object of the invention provides the new polyfluoro ortho-hydroxybenzamide compounds with anti-tumor activity of a class: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, and the application of this compounds in antitumor especially medicines resistant to liver cancer of preparation and anti-leukemia medicine.
The technical solution used in the present invention is:
5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, structure is suc as formula shown in (III):
In the formula (III) Y be-OH or-OCOR, wherein R is aryl or the substituted aryl of the alkyl of C1～C6 or substituted alkyl, C6～C12; The phenyl of the alkyl of the preferred C1～C3 of R or substituted alkyl, C6～C8 or substituted-phenyl.Substituting group in described substituted alkyl and the substituted aryl is respectively done for oneself: methyl, ethyl, propyl group, phenyl, p-methylphenyl, 2,5-3,5-dimethylphenyl, a chloro-phenyl-, rubigan, 2,4-dichlorophenyl, 2,5-dichlorophenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-nitrophenyl, 4-trifluoromethyl etc.
Preferably, Y is-OH, described derivative be 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide, structure is suc as formula shown in (I):
Perhaps, described Y is-OCOR, described derivative be 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide carboxylicesters, structure is suc as formula shown in (II):
In the formula (II), R is the alkyl of C1～C6, the aryl of C6～C12.Comparatively preferred, R is the alkyl of C1～C3, the aryl of C6～C8.More preferred, R is a methyl or phenyl.
Compound of the present invention can adopt method well known in the art to prepare, and perhaps is prepared with reference to the method among the CN10102910A.
Concrete, The compounds of this invention is the preparation method can be: with fluorobenzene bigcatkin willow acyl chlorides (IV) is raw material, in organic solvent, under 0～160 ℃, carry out substitution reaction with 4-nitro-3-5-trifluoromethylaniline, obtain compound: 5-(2 ', 4 '-difluorophenyl)-N-shown in the described structural formula (I) (4 "-nitro-3 "-trifluoromethyl) salicylic amide.
Prepare described 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) method of salicylic amide carboxylicesters, with carboxylic acidylate fluorobenzene bigcatkin willow acyl chlorides (V) is raw material, in organic solvent, under 0～160 ℃, carry out substitution reaction with 4-nitro-3-5-trifluoromethylaniline, obtain compound: 5-(2 ', 4 '-difluorophenyl)-N-shown in the described structural formula (II) (4 "-nitro-3 "-trifluoromethyl) the salicylic amide carboxylicesters; Wherein, R is aryl or the substituted aryl of the alkyl of C1～C6 or substituted alkyl, C6～C12.
It is one of following that described organic solvent is preferably: the aromatic hydrocarbon of the nitrile of the ketone of C3～C8, the ether of C4～C8, C2～C4, the halohydrocarbon of C1～C3, C6～C8, the alkane of C4～C8 or the acid amides of C2～C5.
One of described organic solvent is more preferably following: acetone, ether, tetrahydrofuran (THF), acetonitrile, methylene dichloride, methyl-sulphoxide, benzene, hexanaphthene, N, dinethylformamide or chloroform.The quality of described tetrahydrofuran (THF) is carboxylic acidylate difunisal or difunisal quality 4～20 times.
Described raw material acidylate fluorobenzene bigcatkin willow acyl chlorides or fluorobenzene bigcatkin willow acyl chlorides be preferably 1: 0.5 with the ratio of 4-nitro-3-5-trifluoromethylaniline mole number～and 5.
Described amidate action temperature is preferably at normal temperatures carries out, and the reaction times is preferably 0.5～5h.
Described 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide (I) prepares as follows:
(a) preparation fluorobenzene bigcatkin willow acyl chlorides (IV): in chloroform or methylene dichloride, react and obtain fluorobenzene bigcatkin willow acyl chlorides by difunisal and sulfur oxychloride; The quality of described chloroform or methylene dichloride is 4～20 times of difunisal quality.
Reaction formula is as follows:
(b) 5-(2 ' shown in the preparation formula (I), 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide: with fluorobenzene bigcatkin willow acyl chlorides (IV) is raw material, in organic solvent, under the normal temperature, carry out substitution reaction with 4-nitro-3-5-trifluoromethylaniline, obtain 5-(2 ', 4 '-difluorophenyl)-N-shown in the described formula (I) (4 "-nitro-3 "-trifluoromethyl) salicylic amide; Described organic solvent is one of following: acetone, ether, tetrahydrofuran (THF), acetonitrile, methylene dichloride, methyl-sulphoxide, benzene, hexanaphthene, N, dinethylformamide or chloroform, described acidylate fluorobenzene bigcatkin willow acyl chlorides is 1: 0.5～5 with the ratio of 4-nitro-3-5-trifluoromethylaniline mole number; The quality of described organic solvent is 4～20 times of fluorobenzene bigcatkin willow acyl chlorides quality.
Reaction formula is as follows:
Described 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide carboxylicesters (II) prepares as follows:
(a) preparation acidylate difunisal (VI): in chloroform or methylene dichloride, react and obtain the acidylate difunisal by difunisal and carboxyl acyl chloride; The quality of described chloroform or methylene dichloride is 4～20 times of difunisal quality.
Reaction formula is as follows:
(b) preparation acidylate fluorobenzene bigcatkin willow acyl chlorides (V): in chloroform or methylene dichloride, reaction obtains acidylate fluorobenzene bigcatkin willow acyl chlorides by acidylate difunisal (VI) and sulfur oxychloride; The quality of described chloroform or methylene dichloride is 4～20 times of acidylate difunisal quality.
Reaction formula is as follows:
(c) 5-(2 ' shown in the preparation formula (II), 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide carboxylicesters: with acidylate fluorobenzene bigcatkin willow acyl chlorides (V) is raw material, in organic solvent, under the normal temperature, carry out substitution reaction with 4-nitro-3-5-trifluoromethylaniline, obtain 5-(2 ', 4 '-difluorophenyl)-N-shown in the described formula (II) (4 "-nitro-3 "-trifluoromethyl) the salicylic amide carboxylicesters; Described organic solvent is one of following: acetone, ether, tetrahydrofuran (THF), acetonitrile, methylene dichloride, methyl-sulphoxide, benzene, hexanaphthene, N, dinethylformamide or chloroform, described acidylate fluorobenzene bigcatkin willow acyl chlorides is 1: 0.5～5 with the ratio of 4-nitro-3-5-trifluoromethylaniline mole number; The quality of described organic solvent is 4～20 times of acidylate fluorobenzene bigcatkin willow acyl chlorides quality.
Reaction formula is as follows:
The invention still further relates to 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) application of salicylic amide derivative in preparation antitumor drug especially medicines resistant to liver cancer or anti-leukemia medicine, specifically be 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide and the application of carboxylicesters in preparation antitumor drug especially medicines resistant to liver cancer thereof, and 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide and acetic ester and the application of butyric ester in the preparation anti-leukemia medicine.After tested, 5-(2 ' of the present invention, 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide and carboxylicesters thereof can significantly suppress the growth of tumour cell under finite concentration, can be used as the treatment that antitumor drug is applied to tumor diseases such as liver cancer.
Beneficial effect of the present invention is mainly reflected in: (1) provides a kind of antitumor drug new, that obvious anti-tumor activity is arranged, for new medicament screen provides the research basis, has the major application prospect; (2) preparation flow is simple, is beneficial to industrialization production.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide (I)
With diflunisal (that is: 5-(2,4 difluorobenzene base) Whitfield's ointment, CAS accession number: 22494-42-4) 2.5g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is fluorobenzene bigcatkin willow acyl chlorides (IV) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned fluorobenzene bigcatkin willow acyl chlorides complete soln, normal-temperature reaction 3-5 hour.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide 3.5g, fusing point: 175-179 ℃ (proofreading and correct);
1HNMR(400MHz，CDCl
3)：δ6.957(t，J＝8.0，1H，3’-H)、6.995(t，J＝8.0，1H，5’-H)、7.163(d，J＝8.0，1H，3-H)、7.397(q，1H，6’-H)、7.632(d，J＝8.0，1H，4-H)、7.676(s，1H，2”-H)、8.050(d，J＝8.0，1H，5”-H)、8.096(s，1H，6-H)、8.105(d，J＝8.0，1H，6”-H)、8.288(s，1H，-NH)、11.298(s，1H，-OH)；
EIMS：m/z＝438(M
+)。
Embodiment 2:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide acetic ester (II-1)
Add diflunisal 15g (0.06mol), methylene dichloride 50ml, pyridine 4.8g (0.06mol) successively in reaction flask, stir, dripping acetyl chloride 4.8g (0.06mol) stirs normal-temperature reaction 2～3h.After reaction was finished, with dilute hydrochloric acid (1M) washing, suction filtration, drying got white solid 17.2g, is acetylfuoridezene Whitfield's ointment (VI-1) crude product (purity 〉=85%), fusing point: 163～166 ℃ (proofreading and correct), and standby.EIMS：m/z＝292(M
+)。
With acetylfuoridezene Whitfield's ointment crude product 3.0g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is acetylfuoridezene bigcatkin willow acyl chlorides (V-1) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned acetylfuoridezene bigcatkin willow acyl chlorides complete soln, normal-temperature reaction 3-5 hour.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide acetic ester 3.8g, fusing point: 170-174 ℃ (proofreading and correct);
1HNMR(400MHz，CDCl
3)：δ2.405(s，3H，-CH
3)、6.970(t，J＝8.0，1H，3’-H)、7.012(t，J＝8.0，1H，5’-H)、7.299(d，J＝8.0，1H，3-H)、7.445(q，1H，6’-H)、7.727(d，J＝8.0，1H，4-H)、7.976(s，1H，2”-H)、8.047(t，J＝8.0，1H，5”-H)、8.063(t，J＝8.0，1H，6”-H)、8.079(s，1H，6-H)、8.472(s，1H，-NH)；
EIMS：m/z＝480(M
+)。
Embodiment 3:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide butyric ester (II-2)
In reaction flask, add diflunisal 15g (0.06mol), methylene dichloride 50ml, pyridine 4.8g (0.06mol) successively, stir, drip butyryl chloride 6.4g (0.06mol), stir normal-temperature reaction 2～3h.After reaction was finished, with dilute hydrochloric acid (1M) washing, suction filtration, drying got white solid 18.3g, is butyryl difunisal (VI-2) crude product (purity 〉=85%), fusing point: 181～185 ℃ (proofreading and correct), and standby.EIMS：m/z＝320(M
+)。
With butyryl difunisal crude product 3.2g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is butyryl fluorobenzene bigcatkin willow acyl chlorides (V-2) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned acetylfuoridezene bigcatkin willow acyl chlorides complete soln, normal-temperature reaction 3-5 hour.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide butyric ester 3.9g, fusing point: 184-188 ℃ (proofreading and correct); EIMS:m/z=508 (M
+).
Embodiment 4:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide benzoic ether (II-3)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip Benzoyl chloride 8.5g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 19.4g.Be benzoyl fluorobenzene Whitfield's ointment (VI-3) crude product (purity 〉=85%), fusing point: 167-172 ℃ (not proofreading and correct), standby.EIMS：m/z＝354(M
+)。
With benzoyl fluorobenzene Whitfield's ointment crude product 3.54g (0.01mol), sulfur oxychloride 1.8g and 30mlCH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is benzoyl fluorobenzene salicylyl chlorine (V-3) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add the above-mentioned benzoyl fluorobenzene salicylyl chlorine complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide benzoic ether 4.4g, fusing point: 196-199 ℃ (proofreading and correct);
1HNMR(400MHz，CDCl
3)：6.973(t，J＝8.4，1H，3’-H)、7.018(t，J＝7.6，1H，5’-H)、7.414(d，J＝8.8，1H，3-H)、7.481(q，J＝6.4，1H，6’-H)、7.598(t，J＝7.6，2H，3”’，5”’-H)、7.705(s，1H，2”-H)、7.763(m，2H，4”’，5”-H)、7.915(d，J＝8.0，1H，4-H)、8.025(d，J＝8.4，1H，6”-H)、8.150(s，1H，6-H)、8.245(d，J＝7.6，2H，2”’，6”’-H)、8.848(s，1H，-NH)；
EIMS：m/z＝542(M
+)。
Embodiment 5:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(2 " '-chloro-benzoic acid) ester (II-4)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 2-chloro-benzoyl chloride 10.5g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 21.4g.Be (2-chlorobenzoyl) difunisal (VI-4) crude product (purity 〉=85%), fusing point: 186-190 ℃ (not proofreading and correct), standby.EIMS：m/z＝388(M
+)。
With (2-chlorobenzoyl) difunisal crude product 3.89g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (2-chlorobenzoyl) fluorobenzene bigcatkin willow acyl chlorides (V-4) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (2-chlorobenzoyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(2 " '-chloro-benzoic acid) ester 4.7g, fusing point: 212-216 ℃ (proofreading and correct); EIMS:m/z=576 (M
+).
Embodiment 6:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(3 " '-methyl-phenylformic acid) ester (II-5)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 3-methyl benzoyl chloride 9.3g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 20.5g.Be (3-toluyl) difunisal (VI-5) crude product (purity 〉=85%), fusing point: 187-191 ℃ (not proofreading and correct), standby.EIMS：368(M
+)。
With (3-toluyl) difunisal crude product 3.68g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (3-toluyl) fluorobenzene bigcatkin willow acyl chlorides (V-5) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (3-toluyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(3 " '-tolyl acid) ester 4.5g, fusing point: 211-215 ℃ (proofreading and correct); EIMS:m/z=556 (M
+).
Embodiment 7:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(3 " '-fluorobenzoic acid) ester (II-6)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 3-fluorobenzoyl chloride 9.5g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 20.2g.Be (3-fluorobenzoyl) difunisal (VI-6) crude product (purity 〉=85%), fusing point: 184-188 ℃ (not proofreading and correct), standby.EIMS：372(M
+)。
With (3-fluorobenzoyl) difunisal crude product 3.72g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (3-fluorobenzoyl) benzoyl fluorobenzene salicylyl chlorine (V-6) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (3-fluorobenzoyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(3 " '-fluorobenzoic acid) ester 4.7g, fusing point: 206-210 ℃ (proofreading and correct); EIMS:m/z=560 (M
+).
Embodiment 8:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-tolyl acid) ester (II-7)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 4-methyl benzoyl chloride 9.3g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 20.2g.Be (4-toluyl) difunisal (VI-7) crude product (purity 〉=85%), fusing point: 179-183 ℃ (not proofreading and correct), standby.EIMS：368(M
+)。
With (4-toluyl) difunisal crude product 3.68g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (4-toluyl) fluorobenzene bigcatkin willow acyl chlorides (V-7) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (4-toluyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-tolyl acid) ester 4.6g, fusing point: 204-208 ℃ (proofreading and correct); EIMS:m/z=556 (M
+).
Embodiment 9:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-fluorobenzoic acid) ester (II-8)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 4-fluorobenzoyl chloride 9.5g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 20.3g.Be (4-fluorobenzoyl) difunisal (VI-8) crude product (purity 〉=85%), fusing point: 175-179 ℃ (not proofreading and correct), standby.EIMS：m/z＝372(M
+)。
With (4-fluorobenzoyl) difunisal crude product 3.72g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (4-fluorobenzoyl) fluorobenzene bigcatkin willow acyl chlorides (V-8) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (4-fluorobenzoyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-fluorobenzoic acid) ester 4.5g, fusing point: 199-203 ℃ (proofreading and correct); EIMS:m/z=542 (M
+).
Embodiment 10:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-chloro-benzoic acid) ester (II-9)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 4-chloro-benzoyl chloride 10.5g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 21.4g.Be (2-chlorobenzoyl) difunisal (VI-9) crude product (purity 〉=85%), fusing point: 183-188 ℃ (not proofreading and correct), standby.EIMS：m/z＝388(M
+)。
With (4-chlorobenzoyl) difunisal crude product 3.89g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (4-chlorobenzoyl) fluorobenzene bigcatkin willow acyl chlorides (V-9) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (4-chlorobenzoyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-chloro-benzoic acid) ester 4.8g, fusing point: 211-215 ℃ (proofreading and correct); EIMS:m/z=576 (M
+).
Embodiment 11:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(4 " '-nitrobenzoic acid) ester (II-10)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip Benzoyl chloride 11.1g 0.06mol), 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 19.4g.Be (4-oil of mirbane formyl) difunisal (VI-10) crude product (purity 〉=85%), fusing point: 203-207 ℃ (not proofreading and correct), standby.EIMS：m/z＝399(M
+)。
With (4-oil of mirbane formyl) difunisal crude product 3.99g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (4-oil of mirbane formyl) fluorobenzene bigcatkin willow acyl chlorides (V-10) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (4-oil of mirbane formyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide (4 " '-nitrobenzoic acid) ester 4.4g, fusing point: 228-232 ℃ (proofreading and correct); EIMS:m/z=587 (M
+).
Embodiment 12:
Preparation 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(2 " ', 4 " '-difluoro-benzoic acid) ester (II-11)
In reaction flask, add diflunisal 15g (0.06mol), CHCl successively
360ml, pyridine 9.6g (0.12mol) stir 30min, stir, and drip 2,4 difluorobenzene formyl chloride 10.6g (0.06mol), and 30min dropwises.Stir normal-temperature reaction 3～5h.After reaction is finished, with dilute hydrochloric acid (1M) washing, suction filtration.Filtrate is through extraction, recovery.Drying, altogether white solid 20.3g.Be (2,4 ,-two fluorobenzoyl) difunisal (VI-11) crude product (purity 〉=85%), fusing point: 179-183 ℃ (not proofreading and correct), standby.EIMS：m/z＝390(M
+)。
With (2,4 ,-fluorobenzoyl) difunisal crude product 3.90g (0.01mol), sulfur oxychloride 1.8g and 30ml CH
2Cl
2Add in the reaction flask back flow reaction 4 hours.After reaction was finished, evaporated under reduced pressure got faint yellow solid, is (2,4 ,-two fluorobenzoyl) fluorobenzene bigcatkin willow acyl chlorides (V-11) crude product (purity 〉=80%).With the dissolving of 30ml tetrahydrofuran (THF), standby.
4-nitro-3-5-trifluoromethylaniline 2.1g (0.01mol), pyridine 0.8g (0.01mol) and 20ml tetrahydrofuran (THF) are added in the reaction flask, slowly add above-mentioned (2,4 ,-two fluorobenzoyl) the fluorobenzene bigcatkin willow acyl chlorides complete soln that makes, normal-temperature reaction 3～6 hours.Filter, with the filtrate decompression evaporate to dryness, the butanone recrystallization, 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide-(2 " ', 4 " '-difluoro-benzoic acid) ester 4.7g, fusing point: 207-211 ℃ (proofreading and correct); EIMS:m/z=578 (M
+).
Embodiment 13: anti-BEL-7402 people's liver cancer biological activity test
With 5-(2 ', 4 '-difluorophenyl)-N-of embodiment 1～12 preparation (4 "-nitro-3 "-trifluoromethyl) the salicylic amide compounds carries out the anti-human liver cancer biological activity test.
Testing method: sulphonyl rhodamine B (SRB) protein staining method
Cell strain: BEL-7402 people's liver cancer
Action time: 72 hours
Result evaluation: invalid: 10
-5Mol/L＜50%;
Effectively: 10
-5Mol/L＞50%;
The external test result of anti-human liver cancer biological activity is as follows:
Table 1: to the inhibiting rate (%) of BEL-7402 hepatoma cell growth
Evaluation criteria according to the anti-tumor biological vitro test: compound (I), (II-1)～(II-9) and (II-11) have an anti-human liver cancer effect.
Embodiment 14: anti-HL-60 human leukemia biological activity test
With 5-(2 ', 4 '-difluorophenyl)-N-of embodiment 1～12 preparation (4 "-nitro-3 "-trifluoromethyl) the salicylic amide compounds carries out anti-human leukemia biological activity test.
Testing method: tetrazolium (MTT) reduction method
Cell strain: HL-60 human leukemia
Action time: 72 hours
Result evaluation: invalid: 10
-5Mol/L＜50%;
Effectively: 10
-5Mol/L＞50%;
The external test result of anti-human leukemia biological activity is as follows:
Table 2: to the inhibiting rate (%) of HL-60 human leukemia growth
Evaluation criteria according to the anti-tumor biological vitro test: compound (I), (II-1) and (II-2) have an anti-human leukemia effect.
Claims (10)
- (1.5-2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, structure is suc as formula shown in (III):In the formula (III) Y be-OH or-OCOR, wherein R is aryl or the substituted aryl of the alkyl of C1～C6 or substituted alkyl, C6～C12; Substituting group in described substituted alkyl and the substituted aryl is respectively done for oneself: methyl, ethyl, propyl group, phenyl, p-methylphenyl, 2,5-3,5-dimethylphenyl, a chloro-phenyl-, rubigan, 2,4-dichlorophenyl, 2,5-dichlorophenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-nitrophenyl or 4-trifluoromethyl.
- 2. 5-(2 ' according to claim 1,4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, it is characterized in that: described Y is-OH, described derivative is 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) salicylic amide, structure is suc as formula shown in (I):
- 3. 5-(2 ' according to claim 1,4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, it is characterized in that: described Y is-OCOR, described derivative is 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide carboxylicesters, structure is suc as formula shown in (II):In the formula (II), R is the alkyl of C1～C6, the aryl of C6～C12.
- 5-4. as claimed in claim 3 (2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative, it is characterized in that: R is a methyl or phenyl.
- As the described 5-of one of claim 1～4 (2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) the salicylic amide derivative is in the application of preparation in the antitumor drug.
- 6. application as claimed in claim 5 is characterized in that: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) application of salicylic amide in the preparation medicines resistant to liver cancer.
- 7. application as claimed in claim 5 is characterized in that: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) application of salicylic amide in the preparation anti-leukemia medicine.
- 8. application as claimed in claim 5 is characterized in that: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) application of salicylic amide carboxylicesters in the preparation medicines resistant to liver cancer.
- 9. application as claimed in claim 5 is characterized in that: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) application of salicylic amide acetic ester in the preparation anti-leukemia medicine.
- 10. application as claimed in claim 5 is characterized in that: 5-(2 ', 4 '-difluorophenyl)-N-(4 "-nitro-3 "-trifluoromethyl) application of salicylic amide butyric ester in the preparation anti-leukemia medicine.
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| CN101502524B (en) * | 2009-03-13 | 2011-01-05 | 浙江工业大学 | Application of acetyl-fluorobenzene salicylamide compound in preparing anti-tumor medicament |
| CN101955442B (en) * | 2010-09-30 | 2013-06-05 | 浙江工业大学 | Benzoyl fluorobenzene salicylamide compound and application thereof |
| CN102010348A (en) * | 2010-11-12 | 2011-04-13 | 李家明 | Salicylamide ester type derivative and preparation method and application thereof |
| CN102614199B (en) * | 2012-03-05 | 2013-06-19 | 浙江工业大学 | Application of (4-substituted benzoyl) fluorobenzene salicylamide compound in preparation of medicine for resisting cervical cancer |
| CN102614197B (en) * | 2012-03-05 | 2013-11-13 | 浙江工业大学 | Application of phenylacetyl fluorobenzene salicylamide compound in preparation of anti-cervical-cancer medicines |
| CN102526077B (en) * | 2012-03-05 | 2013-06-19 | 浙江工业大学 | Application of phenylacetyl fluorobenzene salicylamide compound for preparing anti-leukemia drugs |
| CN102600181B (en) * | 2012-03-05 | 2013-07-31 | 浙江工业大学 | Application of (4-substituted benzoyl) fluorobenzene salicylamide compound in preparing anti-leukemie medicament |
| US20210205292A1 (en) * | 2016-03-11 | 2021-07-08 | The Board Of Trustees Of The Leland Stanford Junior University | Inhibitors of creb-cbp interaction for treatment of leukemia |
| CN106748997A (en) * | 2016-11-18 | 2017-05-31 | 浙江工业大学 | 6 ethyoxyl fluorine chloronicotinoyl fluorobenzene salicylamide compounds and its application in anti-lung-cancer medicament is prepared |
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| US3382145A (en) * | 1965-10-13 | 1968-05-07 | Monsanto Co | Gastropodicidally effective substituted 5-halo-3-phenylsalicylanilides |
| CN101029010A (en) * | 2007-03-23 | 2007-09-05 | 浙江工业大学 | N-substituted-acetylfuoridezene salicylamide, its production and use |
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| CN101029010A (en) * | 2007-03-23 | 2007-09-05 | 浙江工业大学 | N-substituted-acetylfuoridezene salicylamide, its production and use |
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