CN104800228A - Applications of O-benzoyl-(4-trifluoromethyl) salicylamide compound in preparing drugs used for treating intestinal cancer - Google Patents
Applications of O-benzoyl-(4-trifluoromethyl) salicylamide compound in preparing drugs used for treating intestinal cancer Download PDFInfo
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- CN104800228A CN104800228A CN201510042140.XA CN201510042140A CN104800228A CN 104800228 A CN104800228 A CN 104800228A CN 201510042140 A CN201510042140 A CN 201510042140A CN 104800228 A CN104800228 A CN 104800228A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- salicylamide
- fluorobenzoyl
- preparation
- correction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 salicylamide compound Chemical class 0.000 title claims abstract description 62
- 201000002313 intestinal cancer Diseases 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 229960000581 salicylamide Drugs 0.000 title abstract description 137
- 208000005016 Intestinal Neoplasms Diseases 0.000 title abstract description 5
- 229940079593 drug Drugs 0.000 title abstract 2
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical class NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims description 219
- 239000000460 chlorine Substances 0.000 claims description 162
- 238000002360 preparation method Methods 0.000 claims description 80
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 108
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 80
- 238000012937 correction Methods 0.000 description 76
- 238000005481 NMR spectroscopy Methods 0.000 description 71
- 238000005160 1H NMR spectroscopy Methods 0.000 description 69
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 20
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 20
- 229960004889 salicylic acid Drugs 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- 239000012531 culture fluid Substances 0.000 description 10
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001263 acyl chlorides Chemical class 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 240000000203 Salix gracilistyla Species 0.000 description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- HJAIUBPFHBLXFF-UHFFFAOYSA-N (3-chloro-2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=C(Cl)C=CC=C1C(=O)C1=CC=CC=C1 HJAIUBPFHBLXFF-UHFFFAOYSA-N 0.000 description 4
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 description 4
- AVYGCQXNNJPXSS-UHFFFAOYSA-N 2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC=C1Cl AVYGCQXNNJPXSS-UHFFFAOYSA-N 0.000 description 4
- JMYSPFGUBNENSE-UHFFFAOYSA-N 2-(trifluoromethoxy)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC(F)(F)F JMYSPFGUBNENSE-UHFFFAOYSA-N 0.000 description 4
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 4
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 4
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- ULHFFAFDSSHFDA-UHFFFAOYSA-N 1-amino-2-ethoxybenzene Chemical compound CCOC1=CC=CC=C1N ULHFFAFDSSHFDA-UHFFFAOYSA-N 0.000 description 3
- XMLFPUBZFSJWCN-UHFFFAOYSA-N 2-Hydroxy-4-trifluoromethyl benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1O XMLFPUBZFSJWCN-UHFFFAOYSA-N 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 2
- PBGKNXWGYQPUJK-UHFFFAOYSA-N 4-chloro-2-nitroaniline Chemical compound NC1=CC=C(Cl)C=C1[N+]([O-])=O PBGKNXWGYQPUJK-UHFFFAOYSA-N 0.000 description 2
- UTKUVRNVYFTEHF-UHFFFAOYSA-N 4-nitro-3-(trifluoromethyl)aniline Chemical compound NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 UTKUVRNVYFTEHF-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- KPFGGEHCIZEMTD-UHFFFAOYSA-N n-chloro-4-nitroaniline Chemical compound [O-][N+](=O)C1=CC=C(NCl)C=C1 KPFGGEHCIZEMTD-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 1
- DVIHKVWYFXLBEM-UHFFFAOYSA-N 2-hydroxybenzoyl chloride Chemical compound OC1=CC=CC=C1C(Cl)=O DVIHKVWYFXLBEM-UHFFFAOYSA-N 0.000 description 1
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 0 Cc(c(O)c1*)c(C)c([O+])c1O Chemical compound Cc(c(O)c1*)c(C)c([O+])c1O 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides applications of an O-benzoyl-(4-trifluoromethyl) salicylamide compound represented by formula (I) in preparing drugs used for treating intestinal cancer.
Description
(1) technical field
The present invention relates to the application of a kind of O-benzoyl-(4-trifluoromethyl) salicylamide compounds in preparation treatment bowelcancer medicine.
(2) background technology
Chinese patent CN 201210055341.X " (4-substituted benzene formyl) fluorobenzene salicylamide compound is preparing the application in medicament for resisting cervical cancer ", CN201210055273.7 " phenylacetyl fluorobenzene salicylamide compound is preparing the application in medicament for resisting cervical cancer " describe the O-benzoyl of diflunisal prepared by salicylic acid parent, the application of O-phenylacetyl fluorobenzene salicylamide compound in anti-cervical cancer respectively.Consider trifluoromethyl (CF
3) there is electron-withdrawing, the characteristic such as lipotropy and stable C-F key equally by force, effectively can change the acidity of compound, dipole moment, polarity and lipotropy after introduce trifluoromethyl in drug effect molecule, the metabolic stability of biomolecule can be strengthened simultaneously; And trifluoromethyl salicylic acid is relatively cheap, be easy to get.
It is active that this patent has anti-intestinal cancer by O-benzoyl-(4-trifluoromethyl) the salicylamide compounds obtained after carrying out structural modification to trifluoromethyl salicylic acid, and tool has very great significance.
(3) summary of the invention
The object of the invention is to provide the application of a kind of O-benzoyl-(4-trifluoromethyl) salicylamide compounds in preparation treatment bowelcancer medicine, and wherein said O-benzoyl-(4-trifluoromethyl) salicylamide compounds is such as formula shown in (I):
In formula I, R is halogen or nitro; R
1for hydrogen or chlorine; R
2for hydrogen or fluorine; R
3for H or ethyl; R
4for cyclohexyl, benzyl or structure are such as formula the substituted-phenyl shown in (A):
In formula (A), Q
1~ Q
5respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl, trifluoromethyl.
Preferably, in formula I, R is fluorine, chlorine or nitro; R
1for hydrogen or chlorine; R
2for hydrogen or fluorine; R
3for H, R
4for structure is such as formula the substituted-phenyl shown in (A), corresponding described O-benzoyl-(4-trifluoromethyl) salicylamide compounds is such as formula shown in (II):
Wherein: Q
1~ Q
5respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl, trifluoromethyl.
Further, the O-benzoyl of structure as shown in formula I-(4-trifluoromethyl) salicylamide compounds is one of compound in table 1:
Table 1:
| Compound | R | R 1 | R 2 | R 3 | R 4 | Q 1 | Q 2 | Q 3 | Q 4 | Q 5 |
| Ⅰ-1 | Cl | Cl | F | H | / | H | H | H | H | H |
| Ⅰ-2 | Cl | Cl | F | H | / | CH 3 | H | H | H | H |
| Ⅰ-3 | Cl | Cl | F | H | / | H | CH 3 | H | H | H |
| Ⅰ-4 | Cl | Cl | F | H | / | H | H | CH 3 | H | H |
| Ⅰ-5 | Cl | Cl | F | H | / | H | H | F | H | H |
| Ⅰ-6 | Cl | Cl | F | H | / | Cl | H | H | H | H |
| Ⅰ-7 | Cl | Cl | F | H | / | H | Cl | H | H | H |
| Ⅰ-8 | Cl | Cl | F | H | / | H | H | Cl | H | H |
| Ⅰ-9 | Cl | Cl | F | H | / | H | NO 2 | H | H | H |
| Ⅰ-10 | Cl | Cl | F | H | / | OCH 3 | H | H | H | H |
| Ⅰ-11 | Cl | Cl | F | H | / | H | H | OCH 3 | H | H |
| Ⅰ-12 | Cl | Cl | F | H | / | OC 2H 5 | H | H | H | H |
| Ⅰ-13 | Cl | Cl | F | H | / | F | H | F | H | H |
| Ⅰ-14 | Cl | Cl | F | H | / | Cl | H | H | Cl | H |
| Ⅰ-15 | Cl | Cl | F | H | / | Cl | H | NO 2 | H | H |
| Ⅰ-16 | Cl | Cl | F | H | / | H | CF 3 | NO 2 | H | H |
| Ⅰ-17 | Cl | Cl | F | H | CH 2C 6H 5 | / | / | / | / | / |
| Ⅰ-18 | Cl | Cl | F | H | Cyclohexyl | / | / | / | / | / |
| Ⅰ-19 | NO 2 | H | H | H | H | H | H | H | H | |
| Ⅰ-20 | NO 2 | H | H | H | / | CH 3 | H | H | H | H |
| Ⅰ-21 | NO 2 | H | H | H | / | H | CH 3 | H | H | H |
| Ⅰ-22 | NO 2 | H | H | H | / | H | H | CH 3 | H | H |
| Ⅰ-23 | NO 2 | H | H | H | / | H | H | F | H | H |
| Ⅰ-24 | NO 2 | H | H | H | / | Cl | H | H | H | H |
| Ⅰ-25 | NO 2 | H | H | H | / | H | Cl | H | H | H |
| Ⅰ-26 | NO 2 | H | H | H | / | H | H | Cl | H | H |
| Ⅰ-27 | NO 2 | H | H | H | / | NO 2 | H | H | H | H |
| Ⅰ-28 | NO 2 | H | H | H | / | H | NO 2 | H | H | H |
| Ⅰ-29 | NO 2 | H | H | H | / | OCH 3 | H | H | H | H |
| Ⅰ-30 | NO 2 | H | H | H | / | H | H | OCH 3 | H | H |
| Ⅰ-31 | NO 2 | H | H | H | / | OC 2H 5 | H | H | H | H |
| Ⅰ-32 | NO 2 | H | H | H | / | F | H | F | H | H |
| Ⅰ-33 | NO 2 | H | H | H | / | Cl | H | Cl | H | H |
| Ⅰ-34 | NO 2 | H | H | H | / | Cl | H | H | Cl | H |
| Ⅰ-35 | NO 2 | H | H | H | / | H | Cl | Cl | H | H |
| Ⅰ-36 | NO 2 | H | H | H | / | Cl | H | NO 2 | H | H |
| Ⅰ-37 | NO 2 | H | H | H | NO 2 | H | Cl | H | H | |
| Ⅰ-38 | NO 2 | H | H | H | CH 2C 6H 5 | / | / | / | / | / |
| Ⅰ-39 | NO 2 | H | H | H | Cyclohexyl | / | / | / | / | / |
| Ⅰ-40 | NO 2 | H | H | C 2H 5 | / | H | H | H | H | H |
| Ⅰ-41 | Cl | H | H | H | / | CH 3 | H | H | H | H |
| Ⅰ-42 | Cl | H | H | H | / | H | CH 3 | H | H | H |
| Ⅰ-43 | Cl | H | H | H | / | H | H | F | H | H |
| Ⅰ-44 | Cl | H | H | H | / | Cl | H | H | H | H |
| Ⅰ-45 | Cl | H | H | H | / | H | Cl | H | H | H |
| Ⅰ-46 | Cl | H | H | H | / | OCH 3 | H | H | H | H |
| Ⅰ-47 | Cl | H | H | H | / | OC 2H 5 | H | H | H | H |
| Ⅰ-48 | Cl | H | H | H | / | F | H | F | H | H |
| Ⅰ-49 | Cl | H | H | H | / | Cl | H | H | Cl | H |
| Ⅰ-50 | Cl | H | H | H | CH 2C 6H 5 | / | / | / | / | / |
| Ⅰ-51 | Cl | H | H | H | Cyclohexyl | / | / | / | / | / |
| Ⅰ-52 | F | H | H | H | H | H | H | H | H | |
| Ⅰ-53 | F | H | H | H | CH 3 | H | H | H | H | |
| Ⅰ-54 | F | H | H | H | H | CH 3 | H | H | H | |
| Ⅰ-55 | F | H | H | H | H | H | CH 3 | H | H | |
| Ⅰ-56 | F | H | H | H | H | H | F | H | H | |
| Ⅰ-57 | F | H | H | H | Cl | H | H | H | H | |
| Ⅰ-58 | F | H | H | H | H | Cl | H | H | H | |
| Ⅰ-59 | F | H | H | H | H | H | Cl | H | H | |
| Ⅰ-60 | F | H | H | H | OCH 3 | H | H | H | H | |
| Ⅰ-61 | F | H | H | H | H | H | OCH 3 | H | H | |
| Ⅰ-62 | F | H | H | H | F | H | F | H | H | |
| Ⅰ-63 | F | H | H | H | Cl | H | H | Cl | H |
| Ⅰ-64 | F | H | H | H | NO 2 | H | Cl | H | H | |
| Ⅰ-65 | F | H | H | H | H | CF 3 | NO 2 | H | H | |
| Ⅰ-66 | F | H | H | H | CH 2C 6H 5 | / | / | / | / | / |
| Ⅰ-67 | F | H | H | H | Cyclohexyl | / | / | / | / | / |
。
The preparation method of O-benzoyl-(4-trifluoromethyl) salicylamide compounds as shown in formula I of the present invention is as follows: the trifluoromethyl salicylic acid as shown in formula III and the substituted benzoyl chloride shown in formula IV react, and obtains the O-benzoyl shown in formula (V)-(4-trifluoromethyl) salicylic acid; Then, with SOCl
2the O-benzoyl shown in formula VI-(4-trifluoromethyl) bigcatkin willow acyl chlorides is obtained through chloride; Finally, with aminated compounds formula (VII) Suo Shi through amidation process, obtained O-benzoyl-(4-trifluoromethyl) salicylamide compounds Ru shown in (I).The equation of described reaction is shown below.
In formula IV, formula (V), formula VI, R is halogen or nitro; R
1for hydrogen or chlorine; R
2for hydrogen or fluorine;
In formula (VII), R
3for H or ethyl; R
4for cyclohexyl, benzyl or structure are such as formula the substituted-phenyl shown in (A):
In formula (A), Q
1~ Q
5respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl, trifluoromethyl.
Relevant synthetic method, can refer to Chinese patent CN102010366A and in Bioorg.Med.Chem.Lett.19 (2), content disclosed in 516-519 is upper.Concrete, described method recommends to carry out according to following steps:
(1) in toluene solvant, under catalyst A exists, acyl chloride reaction will be carried out such as formula the A of substituted benzoic acid chloride reagent (VIII) Suo Shi (preferably 80 DEG C) at 60 ~ 100 DEG C of temperature, usually reaction 3-8 hour; Reaction terminates rear steaming and desolventizes, and obtains the substituted benzoyl chloride as shown in formula IV, dissolves, obtain solution of acid chloride A stand-by by organic solvent A;
In formula (VIII), R is fluorine, chlorine or nitro; R
1for hydrogen or chlorine; R
2for hydrogen or fluorine; Described catalyst A is: DMF, pyridine, DMA; Described chloride reagent A is: thionyl chloride, phosphorus oxychloride, phosphorus pentachloride; Described organic solvent A is: oxolane, butanone, toluene; Described substituted benzoic acid is 1:1 ~ 3 with the ratio of the amount of substance of chloride reagent A, preferred 1:2.
(2) the 4-trifluoromethyl salicylic acid organic solvent B such as shown in formula III is dissolved, add organic amine A, then the solution of acid chloride A that step (1) is obtained is added, esterification is carried out under room temperature, usual reaction 6-16 hour, reaction terminates rear reactant liquor a separating treatment, obtains such as formula the O-benzoyl shown in (V)-(4-trifluoromethyl) salicylic acid;
Described organic amine A is: triethylamine, pyridine; Described organic solvent B is: oxolane, butanone, toluene;
The ratio of the amount of substance of described 4-trifluoromethyl salicylic acid as shown in formula III, the substituted benzoyl chloride in solution of acid chloride A is 1:1.The amount of substance of the substituted benzoyl chloride in solution of acid chloride A measures with the amount of substance of substituted benzoic acid.
The ratio of the amount of substance of described trifluoromethyl salicylic acid as shown in formula III, organic amine A is 1:1.
The method of described reactant liquor a separating treatment is: after reaction terminates, reactant liquor a filters, in filtrate, add dilute hydrochloric acid, stirring, crystallization, filter, filter cake washing with alcohol, drying, obtains the O-benzoyl shown in formula (V)-(4-trifluoromethyl) salicylic acid.
(3) in toluene solvant, under catalyst B exists, O-benzoyl-(4-trifluoromethyl) salicylic acid chloride reagent B (preferably 80 DEG C) at 60 ~ 100 DEG C of temperature that step (2) is obtained carries out acyl chloride reaction, usually reacts 3 ~ 10 hours; Reaction terminates rear steaming and desolventizes, and obtains the O-benzoyl shown in formula VI-(4-trifluoromethyl) bigcatkin willow acyl chlorides, dissolves, obtain solution of acid chloride B stand-by with organic solvent C;
Described catalyst B is: DMF, pyridine, DMA; Described chloride reagent B is: thionyl chloride, phosphorus oxychloride, phosphorus pentachloride; Described organic solvent C is: oxolane, acetone, butanone, toluene;
The ratio of the amount of substance of described O-benzoyl-(4-trifluoromethyl) salicylic acid, chloride reagent B is 1:1 ~ 3, preferred 1:2.
(4) aminated compounds formula (VII) Suo Shi is joined in organic solvent D, then the solution of acid chloride B that step (3) is obtained is added, carry out condensation reaction under room temperature, reaction terminates rear reactant liquor b separating treatment and obtains the O-benzoyl shown in formula I-(4-trifluoromethyl) salicylamide compounds.
Described organic solvent D is: oxolane, acetone, butanone, toluene; Described.
Shown in O-benzoyl shown in formula VI in described solution of acid chloride B-(4-trifluoromethyl) bigcatkin willow acyl chlorides and formula (VII), the ratio of the amount of substance of aminated compounds is 1:2.The amount of substance of the O-benzoyl shown in the formula VI in described solution of acid chloride B-(4-trifluoromethyl) bigcatkin willow acyl chlorides measures with O-benzoyl-(4-trifluoromethyl) salicylic amount of substance.
The method of described reactant liquor b separating treatment is: after reaction terminates, reactant liquor b filters, and adds water to filtrate, stirring, crystallization, filter, use butanone recrystallization after filter cake washing with alcohol, obtain the O-benzoyl shown in formula I-(4-trifluoromethyl) salicylamide compounds.
After tested, O-benzoyl of the present invention-(4-trifluoromethyl) salicylamide compounds obviously can suppress the growth of multiple colon-cancer cell under finite concentration, can be used as the treatment that antitumor drug is applied to intestinal cancer.
(4) detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1: preparation O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylic acid (V-1)
Chloro-for 20.9g (0.1mol) 2,4-bis-5-fluobenzoic acid, 24.0g (0.2mol) thionyl chloride, 60ml toluene and 4 DMF are dropped in reaction bulb, back flow reaction 6 hours, evaporated under reduced pressure, obtain yellow liquid, use 20ml acetone diluted, for subsequent use.
15.9g (0.077mol) 4-trifluoromethyl salicylic acid, 6.2g (0.077mol) pyridine, 50ml acetone is added in another reaction bulb, stir 30min, under ice bath, slowly add the solution of acid chloride obtained by previous step, stirring at normal temperature is spent the night.
Filter, add 100ml water to filtrate, stir 1h, sucking filtration, toluene wash, dry, obtain off-white color solid, be O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylic acid crude product, fusing point: 153-155 DEG C (correction), yield: 63.2%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.86(d,1H,J＝8.0Hz,5-H),7.98(s,1H,3-H),8.11(d,1H,J＝7.0Hz,3′-H),8.20(d,1H,J＝8.0Hz,6-H),8.24(d,1H,J＝9.5Hz,6′-H),13.79(s,1H,-COOH)。
Embodiment 2: preparation O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylic acid (V-2)
2 in embodiment 1 is replaced with 0.1mol Nitrodracylic acid, the chloro-5-fluobenzoic acid of 4-bis-, other operations are with embodiment 1, obtain O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylic acid crude product, fusing point: 141-143 DEG C (correction), yield: 51.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.87(d,1H,J＝8.5Hz,5-H),7.98(s,1H,3-H),8.20(d,1H,J＝8.0Hz,6-H),8.37(d,2H,J＝9.0Hz,3′,5′-H),8.44(d,2H,J＝9.0Hz,2′,6′-H),13.69(s,1H,-COOH)。
Embodiment 3: preparation O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylic acid (V-3)
2 in embodiment 1 is replaced with 0.1mol parachlorobenzoic-acid, the chloro-5-fluobenzoic acid of 4-bis-, other operations, with embodiment 1, obtain O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylic acid crude product, fusing point: 132-134 DEG C (correction), yield: 58.6%.
Embodiment 4: preparation O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylic acid (V-4)
2 in embodiment 1 is replaced with 0.1mol parafluorobenzoic acid, the chloro-5-fluobenzoic acid of 4-bis-, other operations, with embodiment 1, obtain O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylic acid crude product, fusing point: 170-172 DEG C (correction), yield: 77.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.46(t,2H,J＝8.5Hz,3′,5′-H),7.83(d,1H,J＝8.5Hz,5-H),7.91(s,1H,3-H),8.17(d,1H,J＝8.5Hz,6-H),8.21(d d,2H,J＝8.5Hz,2′,6′-H),13.59(s,1H,-COOH)。
Embodiment 5: preparation N-phenyl-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-1)
By 5.9g (0.015mol) O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylic acid crude product (V-1), 3.6g (0.03mol) thionyl chloride, 50ml toluene and 2 DMF drop in reaction bulbs, react 6 hours under 80 DEG C (correction), evaporated under reduced pressure, obtain yellow liquid, add 40ml acetone solution, obtained O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) bigcatkin willow acyl chlorides (VI-1) solution, for subsequent use.
Under ice bath, the mixed liquor of 2.8g (0.03mol) aniline/10ml acetone is joined in VI-1 solution made, normal-temperature reaction 10h; Filter, 100ml water is added to filtrate, stirring, crystallization, filter, washing with alcohol, butanone recrystallization, obtain white N-phenyl-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-1), fusing point: 160-161 DEG C (correction), yield: 75.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.15(t,1H,J＝7.5Hz,4″-H),7.34(t,2H,J＝8.0Hz,3″,5″-H),7.53(d,2H,J＝8.0Hz,2″,6″-H),7.59(d,1H,J＝6.5Hz,3′-H),7.61(s,1H,3-H),7.70(d,1H,J＝7.5Hz,5-H),7.91(d,1H,J＝8.5Hz,6′-H),7.92(s,1H,-NH),7.94(d,1H,J＝8.0Hz,6-H)。
Embodiment 6: preparation N-(2-aminomethyl phenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-2)
The aniline in embodiment 5 is replaced with 0.03mol ortho-aminotoluene, other operations are with embodiment 5, obtain N-(2-aminomethyl phenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-2), fusing point: 149-151 DEG C (correction), yield: 76.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.24(s,3H,-CH
3),7.13(t,1H,J＝7.5Hz,4″-H),7.21(d,1H,J＝7.5Hz,3″-H),7.25(t,1H,J＝7.5Hz,5″-H),7.58(s,1H,3-H),7.60(d,1H,J＝5.5Hz,3′-H),7.61(s,1H,-NH),7.72(d,1H,J＝78.5Hz,6″-H),7.78(d,1H,J＝7.0Hz,5-H),7.92(d,1H,J＝9.0Hz,6′-H),7.96(d,1H,J＝7.0Hz,6-H)。
Embodiment 7: preparation N-(3-aminomethyl phenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-3)
The aniline in embodiment 5 is replaced with 0.03mol meta-aminotoluene, other operations are with embodiment 5, obtain N-(3-aminomethyl phenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-3), fusing point: 150-152 DEG C (correction), yield: 82.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.35(s,3H,-CH
3),6.98(d,1H,J＝7.5Hz,4″-H),7.21(t,1H,J＝8.0Hz,5″-H),7.31(d,1H,J＝8.0Hz,6″-H),7.36(s,1H,2″-H),7.60(d,1H,J＝6.0Hz,3′-H),7.61(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),7.79(s,1H,-NH),7.91(d,1H,J＝9.0Hz,6′-H),7.94(d,1H,J＝8.0Hz,6-H)。
Embodiment 8: preparation N-(4-aminomethyl phenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-4)
The aniline in embodiment 5 is replaced with 0.03mol para-totuidine, other operations are with embodiment 5, obtain N-(4-aminomethyl phenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-4), fusing point: 160-162 DEG C (correction), yield: 60.4%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.34(s,3H,-CH
3),7.14(d,2H,J＝8.0Hz,3″,5″-H),7.40(d,2H,J＝8.0Hz,2″,6″-H),7.60(s,1H,3-H),7.61(d,1H,J＝7.0Hz,3′-H),7.69(d,1H,J＝8.0Hz,5-H),7.78(s,1H,-NH),7.91(d,1H,J＝8.5Hz,6′-H),7.94(d,1H,J＝8.0Hz,6-H)。
Embodiment 9: preparation N-(4-fluorophenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-5)
The aniline in embodiment 5 is replaced with 0.03mol para-fluoroaniline, other operations are with embodiment 5, obtain N-(4-fluorophenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-5), fusing point: 166-168 DEG C (correction), yield: 75.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.03(t,2H,J＝8.5Hz,3″,5″-H),7.49(d d,2H,J＝9.0Hz,2″,6″-H),7.60(s,1H,3-H),7.60(d,1H,J＝7.0Hz,3′-H),7.70(d,1H,J＝8.0Hz,5-H),7.91(d,1H,J＝8.5Hz,6′-H),7.93(s,1H,-NH),7.95(d,1H,J＝8.0Hz,6-H)。
Embodiment 10: preparation N-(2-chlorphenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-6)
The aniline in embodiment 5 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 5, obtain N-(2-chlorphenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-6), fusing point: 133-135 DEG C (correction), yield: 60.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.10(t,1H,J＝8.0Hz,4″-H),7.31(t,1H,J＝8.0Hz,5″-H),7.37(d,1H,J＝8.0Hz,3″-H),7.61(d,1H,J＝6.0Hz,3′-H),7.63(s,1H,3-H),7.73(d,1H,J＝8.5Hz,5-H),7.92(d,1H,J＝9.0Hz,6′-H),8.04(d,1H,J＝8.0Hz,6-H),8.38(s,1H,-NH),8.44(d,1H,J＝8.0Hz,6″-H)。
Embodiment 11: preparation N-(3-chlorphenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-7)
The aniline in embodiment 5 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 5, obtain N-(3-chlorphenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-7), fusing point: 169-171 DEG C (correction), yield: 76.4%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.14(d,1H,J＝8.0Hz,4″-H),7.25(t,1H,J＝8.0Hz,5″-H),7.36(d,1H,J＝8.0Hz,6″-H),7.62(s,1H,2″-H),7.62(d,1H,J＝6.5Hz,3′-H),7.64(s,1H,3-H),7.72(d,1H,J＝8.0Hz,5-H),7.84(s,1H,-NH),7.91(d,1H,J＝8.5Hz,6′-H),7.94(d,1H,J＝8.0Hz,6-H)。
Embodiment 12: preparation N-(4-chlorphenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-8)
The aniline in embodiment 5 is replaced with 0.03mol parachloroanilinum, other operations are with embodiment 5, obtain N-(4-chlorphenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-8), fusing point: 170-172 DEG C (correction), yield: 79.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.31(d,2H,J＝9.0Hz,3″,5″-H),7.48(d,2H,J＝8.5Hz,2″,6″-H),7.61(s,1H,3-H),7.61(d,1H,J＝6.5Hz,3′-H),7.71(d,1H,J＝8.0Hz,5-H),7.84(s,1H,-NH),7.91(d,1H,J＝8.5Hz,6′-H),7.93(d,1H,J＝8.0Hz,6-H)。
Embodiment 13: preparation N-(3-nitrobenzophenone)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-9)
The aniline in embodiment 5 is replaced with 0.03mol 3-nitroaniline, other operations are with embodiment 5, obtain N-(3-nitrobenzophenone)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-9), fusing point: 180-182 DEG C (correction), yield: 89.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.52(t,1H,J＝8.5Hz,5″-H),7.63(s,1H,3-H),7.63(d,1H,J＝6.0Hz,3′-H),7.71(d,1H,J＝8.0Hz,5-H),7.92(d,1H,J＝8.5Hz,6′-H),7.63(d,1H,J＝7.5Hz,4″-H),7.98(d,1H,J＝6.5Hz,6″-H),8.01(d,1H,J＝8.0Hz,6-H),8.20(s,1H,2″-H),8.34(s,1H,-NH)。
Embodiment 14: preparation N-(2-methoxyphenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-10)
The aniline in embodiment 5 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 5, obtain N-(2-methoxyphenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-10), fusing point: 142-144 DEG C (correction), yield: 89.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):3.78(s,3H,-OCH
3),6.87(d,1H,J＝8.5Hz,3″-H),6.98(t,1H,J＝7.5Hz,5″-H),7.08(t,1H,J＝7.5Hz,4″-H),7.59(d,1H,J＝6.5Hz,3′-H),7.61(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),7.93(d,1H,J＝9.0Hz,6′-H),8.01(d,1H,J＝8.0Hz,6-H),8.44(d,1H,J＝8.0Hz,6″-H),8.49(s,1H,-NH)。
Embodiment 15: preparation N-(4-methoxyphenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-11)
The aniline in embodiment 5 is replaced with 0.03mol 4-aminoanisole, other operations are with embodiment 5, obtain N-(4-methoxyphenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-11), fusing point: 152-154 DEG C (correction), yield: 75.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):3.81(s,3H,-OCH
3),6.87(d,2H,J＝9.0Hz,3″,5″-H),7.42(d,2H,J＝9.0Hz,2″,6″-H),7.60(s,1H,3-H),7.61(d,1H,J＝6.5Hz,3′-H),7.68(d,1H,J＝8.0Hz,5-H),7.81(s,1H,-NH),7.92(d,1H,J＝9.0Hz,6′-H),7.93(d,1H,J＝8.0Hz,6-H)。
Embodiment 16: preparation N-(2-ethoxyl phenenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-12)
The aniline in embodiment 5 is replaced with 0.03mol 2-phenetidine, other operations are with embodiment 5, obtain N-(2-ethoxyl phenenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-12), fusing point: 134-136 DEG C (correction), yield: 75.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):1.38(t,3H,J＝7.0Hz,-CH
3),3.63(q,2H,J＝7.0Hz,-CH
2),6.87(d,1H,J＝8.5Hz,3″-H),6.98(t,1H,J＝7.5Hz,5″-H),7.07(t,1H,J＝8.0Hz,4″-H),7.58(d,1H,J＝6.5Hz,3′-H),7.62(s,1H,3-H),7.71(d,1H,J＝8.0Hz,5-H),7.91(d,1H,J＝9.0Hz,6′-H),7.95(d,1H,J＝8.0Hz,6-H),8.45(s,1H,-NH),8.46(d,1H,J＝8.5Hz,6″-H)。
Embodiment 17: preparation N-(2,4 difluorobenzene base)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-13)
With 0.03mol 2,4-difluoroaniline replaces the aniline in embodiment 5, other operations are with embodiment 5, obtain N-(2,4-difluorophenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-13), fusing point: 144-146 DEG C (correction), yield: 75.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):6.86(t,1H,J＝9.0Hz,3″-H),6.90(t,1H,J＝9.0Hz,5″-H),7.63(d,1H,J＝6.5Hz,3′-H),7.63(s,1H,3-H),7.73(d,1H,J＝8.0Hz,5-H),7.93(d,1H,J＝8.5Hz,6′-H),8.04(d,1H,J＝7.5Hz,6-H),8.06(s,1H,-NH),8.29(q,1H,J＝8.5Hz,6″-H)。
Embodiment 18: preparation N-(2,5-Dichlorobenzene base)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-14)
With 0.03mol 2,5-dichloroaniline replaces the aniline in embodiment 5, other operations are with embodiment 5, obtain N-(2,5-Dichlorobenzene base)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-14), fusing point: 143-145 DEG C (correction), yield: 64.1%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.09(d,1H,J＝8.5Hz,4″-H),7.30(d,1H,J＝8.5Hz,3″-H),7.62(d,1H,J＝6.5Hz,3′-H),7.63(s,1H,6″-H),7.74(d,1H,J＝8.0Hz,5-H),7.92(d,1H,J＝8.5Hz,6′-H),8.04(d,1H,J＝8.0Hz,6-H),8.39(s,1H,3-H),8.56(s,1H,-NH)。
Embodiment 19: preparation N-(2-chloro-4 nitrophenyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-15)
The aniline in embodiment 5 is replaced with the chloro-4-nitroaniline of 0.03mol 2-, other operations are with embodiment 5, obtain N-(2-chloro-4 nitrophenyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-15), fusing point: 161-163 DEG C (correction), yield: 74.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.63(d,1H,J＝6.5Hz,3′-H),7.66(s,1H,3-H),7.77(d,1H,J＝9.0Hz,5-H),7.91(d,1H,J＝8.5Hz,6′-H),8.07(d,1H,J＝8.0Hz,6-H),8.21(d d,1H,J＝9.0Hz,5″-H),8.31(s,1H,3″-H),8.67(s,1H,-NH),8.76(d,1H,J＝9.5Hz,6″-H)。
Embodiment 20: preparation N-(4-nitro-3-trifluoromethyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-16)
The aniline in embodiment 5 is replaced with 0.03mol 4-nitro-3-trifluoromethylaniline, other operations are with embodiment 5, obtain N-(4-nitro-3-trifluoromethyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-16), fusing point: 176-178 DEG C (correction), yield: 40.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.64(d,1H,J＝6.5Hz,3′-H),7.65(s,1H,3-H),7.75(d,1H,J＝8.0Hz,5-H),7.91(s,1H,2″-H),7.93(d,1H,J＝8.5Hz,6′-H),7.98(d,1H,J＝8.0Hz,6-H),8.01(d,1H,J＝8.5Hz,6″-H),8.05(d,1H,J＝8.5Hz,5″-H),8.32(s,1H,-NH)。
Embodiment 21: preparation N-(benzyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-17)
The aniline in embodiment 5 is replaced with 0.03mol benzylamine, other operations are with embodiment 5, obtain N-(benzyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-17), fusing point: 157-159 DEG C (correction), yield: 60.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):4.57(d,2H,J＝3.5Hz,-CH
2),6.52(s,1H,-NH),7.23(m,5H,Ar″-H),6.52(s,1H,-NH),7.53(s,1H,3-H),7.55(d,1H,J＝6.0Hz,3′-H),7.65(d,1H,J＝7.5Hz,5-H),7.75(d,1H,J＝9.0Hz,6′-H),7.92(d,1H,J＝8.0Hz,6-H)。
Embodiment 22: preparation N-(cyclohexyl)-O-(the chloro-5-fluorobenzoyl of 2,4-bis-)-(4-trifluoromethyl) salicylamide (I-18)
The aniline in embodiment 5 is replaced with 0.03mol cyclohexylamine, other operations are with embodiment 5, obtain N-(cyclohexyl)-O-(2, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylamide (I-18), fusing point: 174-176 DEG C (correction), yield: 22.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):1.10(m,1H,4″-CH
2),1.14(m,2H,3″,5″-CH
2),1.33(m,2H,3″,5″-CH
2),1.60(m,1H,4″-CH
2),1.67(m,2H,2″,6″-CH
2),1.91(m,2H,2″,6″-CH
2),3.89(m,1H,1″-CH),5.95(d,1H,J＝9.0Hz,-NH),7.53(s,1H,3-H),7.63(d,1H,J＝8.0Hz,5-H),7.64(d,1H,J＝6.5Hz,3′-H),7.80(d,1H,J＝8.0Hz,6-H),7.98(d,1H,J＝8.5Hz,6′-H)。
Embodiment 23: preparation N-phenyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-19)
The O-(2 in embodiment 5 is replaced with 0.015molO-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylic acid, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylic acid crude product, other operations are with embodiment 5, obtain N-phenyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-19), fusing point: 168-171 DEG C (correction), yield: 80.6%.
1h nuclear magnetic resonance map is analyzed as follows:
H NMR(500MHz,DMSO,δppm):7.14(t,1H,J＝7.5Hz,4″-H),7.31(t,2H,J＝8.0Hz,3″,5″-H),7.48(d,2H,J＝8.0Hz,2″,6″-H),7.64(s,1H,3-H),7.72(d,1H,J＝8.0Hz,5-H),7.79(s,1H,-NH),7.94(d,1H,J＝8.0Hz,6-H),8.34(d,2H,J＝9.5Hz,2″,6″-H),8.36(d,2H,J＝10.0Hz,3″,5″-H)。
Embodiment 24: preparation N-(2-aminomethyl phenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-20)
The aniline in embodiment 23 is replaced with 0.03mol ortho-aminotoluene, other operations are with embodiment 23, obtain N-(2-aminomethyl phenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-20), fusing point: 183-185 DEG C (correction), yield: 66.1%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):2.19(s,3H,-CH
3),7.11(t,1H,J＝7.5Hz,4″-H),7.19(d,1H,J＝7.5Hz,3″-H),7.20(t,1H,J＝8.5Hz,5″-H),7.56(s,1H,3-H),7.63(s,1H,-NH),7.73(d,1H,J＝7.5Hz,6″-H),7.73(d,1H,J＝7.5Hz,5-H),7.95(d,1H,J＝7.5Hz,6-H),8.34(d,2H,J＝9.5Hz,3′,5′-H),8.36(d,2H,J＝9.5Hz,2′,6′-H)。
Embodiment 25: preparation N-(3-aminomethyl phenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-21)
The aniline in embodiment 23 is replaced with 0.03mol meta-aminotoluene, other operations are with embodiment 23, obtain N-(3-aminomethyl phenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-21), fusing point: 171-173 DEG C (correction), yield: 82.6%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.31(s,3H,-CH
3),6.96(d,1H,J＝7.5Hz,4″-H),7.18(t,1H,J＝8.0Hz,5″-H),7.24(d,1H,J＝8.0Hz,6″-H),7.33(s,1H,2″-H),7.63(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),7.75(s,1H,-NH),7.93(d,1H,J＝8.0Hz,6-H),8.34(d,2H,J＝9.0Hz,3′,5′-H),8.24(d,2H,J＝9.5Hz,2′,6′-H)。
Embodiment 26: preparation N-(4-aminomethyl phenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-22)
The aniline in embodiment 23 is replaced with 0.03mol para-totuidine, other operations are with embodiment 23, obtain N-(4-aminomethyl phenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-22), fusing point: 175-178 DEG C (correction), yield: 45.1%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.31(s,3H,-CH
3),7.11(d,2H,J＝8.0Hz,3″,5″-H),7.35(d,2H,J＝8.5Hz,2″,6″-H),7.62(s,1H,3-H),7.68(d,1H,J＝8.0Hz,5-H),7.82(s,1H,-NH),7.94(d,1H,J＝8.0Hz,6-H),8.32(d,2H,J＝9.0Hz,3′,5′-H),8.23(d,2H,J＝9.0Hz,2′,6′-H)。
Embodiment 27: preparation N-(4-fluorophenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-23)
The aniline in embodiment 23 is replaced with 0.03mol para-fluoroaniline, other operations are with embodiment 23, obtain N-(4-fluorophenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-23), fusing point: 151-152 DEG C (correction), yield: 83.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.13(t,2H,J＝9.0Hz,3″,5″-H),7.62(d d,2H,J＝9.0Hz,2″,6″-H),7.90(d,1H,J＝8.0Hz,5-H),8.01(d,1H,J＝8.0Hz,6-H),8.05(s,1H,3-H),8.32(d,2H,J＝9.0Hz,3′,5′-H),8.40(d 2H,J＝9.0Hz,2′,6′-H),10.71(s,1H,-NH)。
Embodiment 28: preparation N-(2-chlorphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-24)
The aniline in embodiment 23 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 23, obtain N-(2-chlorphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-24), fusing point: 138-140 DEG C (correction), yield: 77.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.09(t,1H,J＝8.0Hz,4″-H),7.30(t,1H,J＝8.0Hz,5″-H),7.35(d,1H,J＝8.0Hz,3″-H),7.65(s,1H,3-H),7.75(d,1H,J＝8.0Hz,5-H),8.04(d,1H,J＝8.0Hz,6-H),8.34(s,1H,-NH),8.38(d,1H,J＝8.0Hz,6″-H),8.40(d,2H,J＝9.0Hz,3′,5′-H),8.50(d,2H,J＝9.0Hz,2′,6′-H)。
Embodiment 29: preparation N-(3-chlorphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-25)
The aniline in embodiment 23 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 23, obtain N-(3-chlorphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-26), fusing point: 151-154 DEG C (correction), yield: 56.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.12(d,1H,J＝8.0Hz,4″-H),7.22(t,1H,J＝8.0Hz,5″-H),7.30(d,1H,J＝8.0Hz,6″-H),7.60(s,1H,3-H),7.64(s,1H,2″-H),7.71(d,1H,J＝8.0Hz,5-H),7.83(s,1H,-NH),7.92(d,1H,J＝8.0Hz,6-H),8.35(d,2H,J＝9.5Hz,3′,5′-H),8.50(d,2H,J＝9.5Hz,2′,6′-H)。
Embodiment 30: preparation N-(4-chlorphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-26)
The aniline in embodiment 23 is replaced with 0.03mol parachloroanilinum, other operations are with embodiment 23, obtain N-(4-chlorphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-26), fusing point: 155-157 DEG C (correction), yield: 61.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.29(d,2H,J＝7.5Hz,3″,5″-H),7.43(d,2H,J＝8.5Hz,2″,6″-H),7.63(s,1H,3-H),7.72(d,1H,J＝8.0Hz,5-H),7.82(s,1H,-NH),7.93(d,1H,J＝7.5Hz,6-H),8.36(s,4H,Ar′-H)。
Embodiment 31: preparation N-(2-nitrobenzophenone)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-27)
The aniline in embodiment 23 is replaced with 0.03mol ortho-nitraniline, other operations are with embodiment 23, obtain N-(2-nitrobenzophenone)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-27), fusing point: 144-146 DEG C (correction), yield: 66.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.43(t,1H,J＝8.5Hz,4″-H),7.56(d,1H,J＝8.0Hz,5-H),7.72(t,1H,J＝8.0Hz,5″-H),7.94(d,1H,J＝8.5Hz,6-H),7.96(d,1H,J＝7.5Hz,3″-H),8.03(d,1H,J＝8.0Hz,6″-H),8.09(s,1H,3-H),8.34(d,2H,J＝9.0Hz,3′,5′-H),8.40(d,2H,J＝9.0Hz,2′,6′-H),11.09(s,1H,-NH)。
Embodiment 32: preparation N-(3-nitrobenzophenone)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-28)
The aniline in embodiment 23 is replaced with 0.03mol meta nitro aniline, other operations are with embodiment 23, obtain N-(3-nitrobenzophenone)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-28), fusing point: 193-195 DEG C (correction), yield: 44.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.60(t,1H,J＝8.5Hz,5″-H),7.94(d,1H,J＝8.0Hz,5-H),7.96(d,1H,J＝8.0Hz,4″-H),7.97(d,1H,J＝8.0Hz,6″-H),8.08(d,1H,J＝8.0Hz,6-H),8.09(s,1H,3-H),8.32(d,2H,J＝9.0Hz,3′,5′-H),8.39(d,2H,J＝9.0Hz,2′,6′-H),8.60(s,1H,2″-H),11.14(s,1H,-NH)。
Embodiment 33: preparation N-(2-methoxyphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-29)
The aniline in embodiment 23 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 23, obtain N-(2-methoxyphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-29), fusing point: 178-180 DEG C (correction), yield: 24.6%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):3.65(s,3H,-OCH
3),6.89(t,1H,J＝7.5Hz,5″-H),7.01(d,1H,J＝8.5Hz,3″-H),7.12(t,1H,J＝8.5Hz,4″-H),7.74(d,1H,J＝7.5Hz,6″-H),7.88(d,1H,J＝8.0Hz,5-H),8.02(d,1H,J＝8.0Hz,6-H),8.04(s,1H,3-H),8.35(d,2H,J＝8.5Hz,3′,5′-H),8.41(d d,2H,J＝9.0Hz,2′,6′-H),9.79(s,1H,-NH)。
Embodiment 34: preparation N-(4-methoxyphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-30)
The aniline in embodiment 23 is replaced with 0.03mol 4-aminoanisole, other operations are with embodiment 23, obtain N-(4-methoxyphenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-30), fusing point: 171-173 DEG C (correction), yield: 85.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):3.71(s,3H,-OCH
3),6.86(d,2H,J＝9.0Hz,3″,5″-H),7.51(d,2H,J＝9.0Hz,2″,6″-H),7.88(d,1H,J＝8.0Hz,5-H),8.00(d,1H,J＝8.0Hz,6-H),8.03(s,1H,3-H),8.32(d,2H,J＝8.0Hz,3′,5′-H),8.41(d,2H,J＝8.0Hz,2′,6′-H),10.51(s,1H,-NH)。
Embodiment 35: preparation N-(2-ethoxyl phenenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-31)
The aniline in embodiment 23 is replaced with 0.03mol 2-phenetidine, other operations are with embodiment 23, obtain N-(2-ethoxyl phenenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-31), fusing point: 154-155 DEG C (correction), yield: 50.6%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):1.25(t,3H,J＝6.5Hz,-CH
3),3.98(q,2H,J＝6.5Hz,-CH
2),6.87(t,1H,J＝7.5Hz,5″-H),7.01(d,1H,J＝8.0Hz,3″-H),7.10(t,1H,J＝8.0Hz,4″-H),7.70(d,1H,J＝7.0Hz,6″-H),7.89(d,1H,J＝8.0Hz,5-H),8.00(d,1H,J＝8.0Hz,6-H),8.05(s,1H,3-H),8.33(d,2H,J＝9.0Hz,3′,5′-H),8.40(d,2H,J＝8.5Hz,2′,6′-H),9.70(s,1H,-NH)。
Embodiment 36: preparation N-(24-difluorophenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-32)
With 0.03mol 2,4-difluoroaniline replaces the aniline in embodiment 23, other operations are with embodiment 23, obtain N-(2,4-difluorophenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-32), fusing point: 156-158 DEG C (correction), yield: 58.6%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.06(t,1H,J＝8.5Hz,3″-H),7.29(t,1H,J＝8.5Hz,5″-H),7.54(q,1H,J＝8.5Hz,6″-H),7.90(d,1H,J＝8.0Hz,5-H),8.03(d,1H,J＝8.5Hz,6-H),8.05(s,1H,3-H),8.33(d,2H,J＝8.5Hz,3′,5′-H),8.41(d,2H,J＝8.5Hz,2′,6′-H),10.49(s,1H,-NH)。
Embodiment 37: preparation N-(2,4-Dichlorobenzene base)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-33)
With 0.03mol 2,4-dichloroaniline replaces the aniline in embodiment 23, other operations are with embodiment 23, obtain N-(2,4-Dichlorobenzene base)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-33), fusing point: 138-140 DEG C (correction), yield: 61.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.26(d d,1H,J＝8.0Hz,5″-H),7.38(s,1H,3″-H),7.64(s,1H,3-H),7.75(d,1H,J＝7.5Hz,5-H),8.03(d,1H,J＝8.0Hz,6-H),8.29(s,1H,-NH),8.37(d,1H,J＝6.5Hz,6″-H),8.38(s,4H,Ar′-H)。
Embodiment 38: preparation N-(2,5-Dichlorobenzene base)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-34)
With 0.03mol 2,5-dichloroaniline replaces the aniline in embodiment 23, other operations are with embodiment 23, obtain N-(2,5-Dichlorobenzene base)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-34), fusing point: 154-156 DEG C (correction), yield: 54.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.06(d d,1H,J＝8.5Hz,4″-H),7.29(d,1H,J＝8.5Hz,3″-H),7.65(s,1H,3-H),7.76(d,1H,J＝8.0Hz,5-H),8.03(d,1H,J＝8.0Hz,6-H),8.38(s,4H,Ar′-H),8.51(s,1H,6″-H)。
Embodiment 39: preparation N-(3,4-Dichlorobenzene base)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-35)
With 0.03mol 3,4-dichloroaniline replaces the aniline in embodiment 23, other operations are with embodiment 23, obtain N-(3,4-Dichlorobenzene base)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-35), fusing point: 197-199 DEG C (correction), yield: 57.4%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.30(d,1H,J＝9.0Hz,5″-H),7.37(d,1H,J＝8.5Hz,6″-H),7.64(s,1H,3-H),7.72(d,1H,J＝6.5Hz,5-H),7.74(s,1H,2″-H),7.92(d,1H,J＝8.0Hz,6-H),7.93(s,1H,-NH),8.35(d,2H,J＝9.0Hz,3′,5′-H),8.38(d,2H,J＝9.5Hz,2′,6′-H)。
Embodiment 40: preparation N-(2-chloro-4 nitrophenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-36)
The aniline in embodiment 23 is replaced with the chloro-4-nitroaniline of 0.03mol 2-, other operations are with embodiment 23, obtain N-(2-chloro-4 nitrophenyl)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-36), fusing point: 162-165 DEG C (correction), yield: 44.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.93(d,1H,J＝8.0Hz,5-H),7.98(d,1H,J＝9.0Hz,6″-H),8.08(d,1H,J＝8.0Hz,6-H),8.10(s,1H,3-H),8.22(d d,1H,J＝9.0Hz,5″-H),8.34(d,2H,J＝9.0Hz,3′,5′-H),8.35(s,1H,3″-H),8.41(d,2H,J＝9.0Hz,2′,6′-H),10.76(s,1H,-NH)。
Embodiment 41: preparation N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-37)
The aniline in embodiment 23 is replaced with 0.03mol 4-chloro-2-nitroaniline, other operations are with embodiment 23, obtain N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-37), fusing point: 142-144 DEG C (correction), yield: 40.6%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.58(d,1H,J＝8.5Hz,5″-H),7.82(d d,1H,J＝9.0Hz,6″-H),7.95(d,1H,J＝8.0Hz,5-H),8.02(d,1H,J＝8.0Hz,6-H),8.06(s,1H,3-H),8.09(s,1H,3″-H),8.33(d,2H,J＝9.0Hz,3′,5′-H),8.40(d,2H,J＝9.0Hz,2′,6′-H),11.16(s,1H,-NH)。
Embodiment 42: preparation N-benzyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-38)
The aniline in embodiment 23 is replaced with 0.03mol benzylamine, other operations are with embodiment 23, obtain N-benzyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-38), fusing point: 170-172 DEG C (correction), yield: 42.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):4.37(d,2H,J＝6.0Hz,-CH
2),7.16～7.22(m,5H,Ar″-H),7.83(d,1H,J＝8.0Hz,5-H),7.90(d,1H,J＝8.0Hz,6-H),7.97(s,1H,3-H),8.24(d,2H,J＝8.0Hz,3′,5′-H),8.37(d,2H,J＝8.0Hz,2′,6′-H),9.20(t,1H,J＝6.0Hz,-NH)。
Embodiment 43: preparation N-cyclohexyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-39)
The aniline in embodiment 23 is replaced with 0.03mol cyclohexylamine, other operations are with embodiment 23, obtain N-cyclohexyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-39), fusing point: 171-173 DEG C (correction), yield: 36.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):1.05(m,1H,4″-CH
2),1.13(m,2H,3″,5″-CH
2),1.20(m,2H,3″,5″-CH
2),1.51(m,1H,4″-CH
2),1.62(m,4H,2″,6″-CH
2),3.56(m,1H,1″-CH),7.78(s,2H,5,6-H),7.94(s,1H,3-H),8.32(d,2H,J＝9.0Hz,3′,5′-H),8.44(d,2H,J＝9.0Hz,2′,6′-H),8.48(d,1H,J＝8.0Hz,-NH)。
Embodiment 44: preparation N-ethyl, N-phenyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-40)
The aniline in embodiment 23 is replaced with 0.03mol N-ethylaniline, other operations are with embodiment 23, obtain N-ethyl, N-phenyl-O-(4-Nitrobenzol formyl)-(4-trifluoromethyl) salicylamide (I-40), fusing point: 134-135 DEG C (correction), yield: 75.6%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):2.17(t,3H,J＝7.0Hz,-CH
3),3.79(q,2H,J＝7.0Hz,-CH
2),7.22(d,2H,J＝8.0Hz,3″,5″-H),7.23(s,1H,4″-H),7.28(t,2H,J＝7.5Hz,2″,6″-H),7.51(d,1H,J＝8.5Hz,5-H),7.53(d,1H,J＝8.5Hz,6-H),7.82(s,1H,3-H),8.36(d,2H,J＝9.0Hz,3′,5′-H),8.59(d,2H,J＝9.0Hz,2′,6′-H)。
Embodiment 45: preparation N-(2-aminomethyl phenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-41)
The O-(2 in embodiment 6 is replaced with 0.015mol O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylic acid, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylic acid crude product, other operations are with embodiment 6, obtain N-(2-aminomethyl phenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-41), fusing point: 168-169 DEG C (correction), yield: 26.1%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.13(s,3H,-CH
3),7.12(t,1H,J＝8.0Hz,4″-H),7.15(t,1H,J＝8.0Hz,5″-H),7.21(d,1H,J＝9.0Hz,6″-H),7.23(d,1H,J＝8.0Hz,3″-H),7.69(d,2H,J＝9.0Hz,3′,5′-H),7.87(d,1H,J＝7.5Hz,5-H),7.98(s,1H,3-H),8.00(d,1H,J＝8.0Hz,6-H),8.11(d,2H,J＝8.5Hz,2′,6′-H),10.12(s,1H,-NH)。
Embodiment 46: preparation N-(3-aminomethyl phenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-42)
The o-toluidine in embodiment 45 is replaced with 0.03mol m-toluidine, other operations are with embodiment 45, obtain N-(3-aminomethyl phenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-42), fusing point: 160-161 DEG C (correction), yield: 40.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):2.25(s,3H,-CH
3),6.89(d,1H,J＝7.5Hz,4″-H),7.18(t,1H,J＝8.0Hz,5″-H),7.37(d,1H,J＝8.5Hz,6″-H),7.42(s,1H,2″-H),7.66(d,2H,J＝8.5Hz,3′,5′-H),7.86(d,1H,J＝8.0Hz,5-H),7.95(d,1H,J＝8.0Hz,6-H),7.99(s,1H,3-H),8.09(d,2H,J＝8.5Hz,2′,6′-H),10.52(s,1H,-NH)。
Embodiment 47: preparation N-(4-fluorophenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-43)
The o-toluidine in embodiment 45 is replaced with 0.03mol para-fluoroaniline, other operations are with embodiment 45, obtain N-(4-fluorophenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-43), fusing point: 165-167 DEG C (correction), yield: 25.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.13(t,2H,J＝9.0Hz,3″,5″-H),7.61(d d,2H,J＝9.0Hz,2″,6″-H),7.42(d,2H,J＝8.5Hz,3′,5′-H),7.87(d,1H,J＝8.5Hz,5-H),7.98(d,1H,J＝8.0Hz,6-H),7.99(s,1H,3-H),8.08(d,2H,J＝8.5Hz,2′,6′-H),10.66(s,1H,-NH)。
Embodiment 48: preparation N-(2-chlorphenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-44)
The o-toluidine in embodiment 45 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 45, obtain N-(2-chlorphenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-44), fusing point: 157-158 DEG C (correction), yield: 44.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.07(t,1H,J＝8.0Hz,4″-H),7.28(t,1H,J＝8.5Hz,5″-H),7.34(d,1H,J＝8.0Hz,3″-H),7.49(d,2H,J＝8.5Hz,3′,5′-H),7.61(s,1H,3-H),7.71(d,1H,J＝8.5Hz,5-H),8.08(d,1H,J＝8.5Hz,6-H),8.14(d,2H,J＝8.5Hz,2′,6′-H),8.43(d,1H,J＝8.5Hz,6″-H),8.46(s,1H,-NH)。
Embodiment 49: preparation N-(3-chlorphenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-45)
The o-toluidine in embodiment 45 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 45, obtain N-(3-chlorphenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-45), fusing point: 149-150 DEG C (correction), yield: 32.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.14(d,1H,J＝8.0Hz,4″-H),7.33(t,1H,J＝8.0Hz,5″-H),7.50(d,1H,J＝9.0Hz,6″-H),7.43(d,2H,J＝9.0Hz,3′,5′-H),7.76(s,1H,3-H),7.88(d,1H,J＝8.0Hz,5-H),7.99(d,1H,J＝8.5Hz,6-H),8.01(s,1H,2″-H),8.09(d,2H,J＝8.5Hz,2′,6′-H),10.79(s,1H,-NH)。
Embodiment 50: preparation N-(2-methoxyphenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-46)
The o-toluidine in embodiment 45 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 45, obtain N-(2-methoxyphenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-46), fusing point: 134-136 DEG C (correction), yield: 41.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):3.65(s,3H,-OCH
3),6.90(t,1H,J＝7.5Hz,4″-H),7.01(d,1H,J＝8.0Hz,3″-H),7.12(t,1H,J＝8.5Hz,5″-H),7.68(d,2H,J＝8.5Hz,3′,5′-H),7.77(d,1H,J＝7.5Hz,5-H),7.84(d,1H,J＝8.0Hz,6-H),7.98(s,1H,3-H),7.99(d,1H,J＝9.0Hz,6″-H),8.12(d,2H,J＝8.5Hz,2′,6′-H),9.71(s,1H,-NH)。
Embodiment 51: preparation N-(2-ethoxyl phenenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-47)
The o-toluidine in embodiment 45 is replaced with 0.03mol 2-phenetidine, other operations are with embodiment 45, obtain N-(2-ethoxyl phenenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-47), fusing point: 131-132 DEG C (correction), yield: 78.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):1.24(t,3H,J＝7.0Hz,-CH
3),3.98(q,2H,J＝7.0Hz,-CH
2),6.88(t,1H,J＝7.5Hz,4″-H),7.02(d,1H,J＝8.5Hz,3″-H),7.10(t,1H,J＝8.5Hz,5″-H),7.67(d,2H,J＝8.5Hz,3′,5′-H),7.73(d,1H,J＝7.5Hz,5-H),7.86(d,1H,J＝8.0Hz,6-H),7.96(d,1H,J＝8.0Hz,6″-H),7.99(s,1H,3-H),8.11(d,2H,J＝8.5Hz,2′,6′-H),9.63(s,1H,-NH)。
Embodiment 52: preparation N-(2,4 difluorobenzene base)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-48)
With 0.03mol 2,4-difluoroaniline replaces the o-toluidine in embodiment 45, other operations are with embodiment 45, obtain N-(2,4-difluorophenyl)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-48), fusing point: 147-148 DEG C (correction), yield: 23.4%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.07(t,1H,J＝8.5Hz,3″-H),7.29(t,1H,J＝8.5Hz,5″-H),7.54(q,1H,J＝9.0Hz,6″-H),7.68(d,2H,J＝9.0Hz,3′,5′-H),7.87(d,1H,J＝8.0Hz,5-H),7.99(s,1H,3-H),8.00(d,1H,J＝8.0Hz,6-H),8.10(d,2H,J＝8.5Hz,2′,6′-H),10.44(s,1H,-NH)。
Embodiment 53: preparation N-(2,5-Dichlorobenzene base)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-49)
With 0.03mol 2,5-dichloroaniline replaces the o-toluidine in embodiment 45, other operations are with embodiment 45, obtain N-(2,5-Dichlorobenzene base)-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-49), fusing point: 140-141 DEG C (correction), yield: 50.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.34(d,1H,J＝8.5Hz,4″-H),7.54(d,1H,J＝8.5Hz,3″-H),7.63(s,1H,6″-H),7.68(d,2H,J＝8.5Hz,3′,5′-H),7.89(d,1H,J＝8.5Hz,5-H),8.00(s,1H,3-H),8.02(d,1H,J＝8.5Hz,6-H),8.12(d,2H,J＝8.5Hz,2′,6′-H),10.48(s,1H,-NH)。
Embodiment 54: preparation N-benzyl-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-50)
The o-toluidine in embodiment 45 is replaced with 0.03mol benzylamine, other operations are with embodiment 45, obtain N-benzyl-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-50), fusing point: 168-170 DEG C (correction), yield: 30.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):4.36(d,2H,J＝6.0Hz,-CH
2),7.18～7.21(m,5H,Ar″-H),7.65(d,2H,J＝8.5Hz,3′,5′-H),7.82(d,1H,J＝8.5Hz,5-H),7.86(d,1H,J＝8.0Hz,6-H),7.91(s,1H,3-H),8.04(d,2H,J＝8.5Hz,2′,6′-H),9.14(t,1H,J＝6.0Hz,-NH)。
Embodiment 55: preparation N-cyclohexyl-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-51)
The o-toluidine in embodiment 45 is replaced with 0.03mol cyclohexylamine, other operations are with embodiment 45, obtain N-cyclohexyl-O-(4-chlorobenzoyl)-(4-trifluoromethyl) salicylamide (I-51), fusing point: 182-184 DEG C (correction), yield: 18.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):1.01(m,1H,4″-CH
2),1.09(m,2H,3″,5″-CH
2),1.20(m,2H,3″,5″-CH
2),1.51(m,1H,4″-CH
2),1.61(m,4H,2″,6″-CH
2),3.60(m,1H,1″-CH),7.71(d,2H,J＝8.5Hz,3′,5′-H),7.78(s,1H,5-H),7.78(s,6-H),7.88(s,1H,3-H),8.11(d,2H,J＝8.5Hz,2′,6′-H),8.41(d,1H,J＝8.0Hz,-NH)。
Embodiment 56: preparation N-phenyl-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-52)
The O-(2 in embodiment 5 is replaced with 0.015mol O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylic acid, the chloro-5-fluorobenzoyl of 4-bis-)-(4-trifluoromethyl) salicylic acid crude product, other operations are with embodiment 5, obtain N-phenyl-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-52), fusing point: 157-161 DEG C (correction), yield: 76.7%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.14(t,1H,J＝7.5Hz,4″-H),7.21(t,2H,J＝8.5Hz,3′,5′-H),7.31(t,2H,J＝8.0Hz,3″,5″-H),7.47(d,2H,J＝8.0Hz,2″,6″-H),7.60(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),8.00(s,1H,-NH),8.03(d,1H,J＝8.0Hz,6-H),8.24(d d,2H,J＝8.5Hz,2′,6′-H)。
Embodiment 57: preparation N-(2-aminomethyl phenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-53)
The aniline in embodiment 56 is replaced with 0.03mol ortho-aminotoluene, other operations are with embodiment 56, obtain N-(2-aminomethyl phenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-53), fusing point: 150-153 DEG C (correction), yield: 79.4%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.17(s,3H,-CH
3),7.11(t,1H,J＝8.5Hz,4″-H),7.17(d,1H,J＝8.5Hz,3″-H),7.20(t,1H,J＝8.5Hz,5″-H),7.20(t,2H,J＝8.5Hz,3′,5′-H),7.58(s,1H,3-H),7.70(s,1H,-NH),7.70(d,1H,J＝8.5Hz,6″-H),7.78(d,1H,J＝8.0Hz,5-H),8.02(d,1H,J＝8.0Hz,6-H),8.22(d d,2H,J＝8.5Hz,2′,6′-H)。
Embodiment 58: preparation N-(3-aminomethyl phenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-54)
The aniline in embodiment 56 is replaced with 0.03mol meta-aminotoluene, other operations are with embodiment 56, obtain N-(3-aminomethyl phenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-54), fusing point: 161-163 DEG C (correction), yield: 78.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.31(s,3H,-CH
3),6.95(d,1H,J＝7.5Hz,4″-H),7.18(t,1H,J＝8.0Hz,5″-H),7.22(t,2H,J＝8.5Hz,3′,5′-H),7.23(d,1H,J＝8.5Hz,6″-H),7.30(s,1H,2″-H),7.60(s,1H,3-H),7.70(d,1H,J＝8.0Hz,5-H),7.94(s,1H,-NH),8.03(d,1H,J＝8.0Hz,6-H),8.24(d d,2H,J＝8.5Hz,2′,6′-H)。
Embodiment 59: preparation N-(4-aminomethyl phenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-55)
The aniline in embodiment 56 is replaced with 0.03mol para-totuidine, other operations are with embodiment 56, obtain N-(4-aminomethyl phenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-55), fusing point: 179-183 DEG C (correction), yield: 71.9%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):2.31(s,3H,-CH
3),7.11(d,2H,J＝8.0Hz,3″,5″-H),7.21(t,2H,J＝8.5Hz,3′,5′-H),7.34(d,2H,J＝8.5Hz,2″,6″-H),7.59(s,1H,3-H),7.69(d,1H,J＝8.0Hz,5-H),7.94(s,1H,-NH),8.03(d,1H,J＝8.0Hz,6-H),8.23(d d,2H,J＝9.0Hz,2′,6′-H)。
Embodiment 60: preparation N-(4-fluorophenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-56)
The aniline in embodiment 56 is replaced with 0.03mol para-fluoroaniline, other operations are with embodiment 56, obtain N-(4-fluorophenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-56), fusing point: 149-154 DEG C (correction), yield: 82.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.15(t,2H,J＝9.0Hz,3″,5″-H),7.42(t,2H,J＝9.0Hz,3′,5′-H),7.63(d d,2H,J＝9.0Hz,2″,6″-H),7.87(d,1H,J＝8.0Hz,5-H),7.98(d,1H,J＝8.0Hz,6-H),7.99(s,1H,3-H),8.16(d d,2H,J＝9.0Hz,2′,6′-H),10.66(s,1H,-NH)。
Embodiment 61: preparation N-(2-chlorphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-57)
The aniline in embodiment 56 is replaced with 0.03mol o-chloraniline, other operations are with embodiment 56, obtain N-(2-chlorphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-57), fusing point: 132-134 DEG C (correction), yield: 77.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):7.08(t,1H,J＝8.0Hz,4″-H),7.20(t,2H,J＝8.5Hz,3′,5′-H),7.29(t,1H,J＝8.0Hz,5″-H),7.34(d,1H,J＝8.0Hz,3″-H),7.60(s,1H,3-H),7.72(d,1H,J＝8.5Hz,5-H),8.10(d,1H,J＝8.0Hz,6-H),8.24(d d,2H,J＝9.0Hz,2′,6′-H),8.44(d,1H,J＝8.0Hz,6″-H),8.49(s,1H,-NH)。
Embodiment 62: preparation N-(3-chlorphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-58)
The aniline in embodiment 56 is replaced with 0.03mol m-chloroaniline, other operations are with embodiment 56, obtain N-(3-chlorphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-58), fusing point: 141-143 DEG C (correction), yield: 77.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.15(d,1H,J＝8.0Hz,4″-H),7.34(t,1H,J＝8.5Hz,5″-H),7.43(t,2H,J＝8.5Hz,3′,5′-H),7.51(d,1H,J＝8.0Hz,6″-H),7.76(s,1H,3-H),7.89(d,1H,J＝8.5Hz,5-H),7.99(d,1H,J＝8.0Hz,6-H),8.00(s,1H,2″-H),8.17(d d,2H,J＝8.5Hz,2′,6′-H),10.79(s,1H,-NH)。
Embodiment 63: preparation N-(4-chlorphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-59)
The aniline in embodiment 56 is replaced with 0.03mol parachloroanilinum, other operations are with embodiment 56, obtain N-(4-chlorphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-59), fusing point: 173-176 DEG C (correction), yield: 78.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.37(d,2H,J＝9.0Hz,3″,5″-H),7.42(t,2H,J＝8.5Hz,3′,5′-H),7.65(d,2H,J＝9.0Hz,2″,6″-H),7.88(d,1H,J＝8.0Hz,5-H),7.99(d,1H,J＝8.0Hz,6-H),7.99(s,1H,3-H),8.16(d d,2H,J＝8.5Hz,2′,6′-H),10.75(s,1H,-NH)。
Embodiment 64: preparation N-(2-methoxyphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-60)
The aniline in embodiment 56 is replaced with 0.03mol 2-aminoanisole, other operations are with embodiment 56, obtain N-(2-methoxyphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-60), fusing point: 145-148 DEG C (correction), yield: 83.1%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):3.63(s,3H,-OCH
3),6.83(d,1H,J＝8.0Hz,3″-H),6.99(t,1H,J＝7.5Hz,5″-H),7.07(t,1H,J＝7.5Hz,4″-H),7.19(t,2H,J＝8.5Hz,3′,5′-H),7.60(s,1H,3-H),7.69(d,1H,J＝8.0Hz,5-H),8.12(d,1H,J＝8.0Hz,6-H),8.25(d d,2H,J＝8.5Hz,2′,6′-H),8.47(d,1H,J＝8.0Hz,6″-H),8.68(s,1H,-NH)。
Embodiment 65: preparation N-(4-methoxyphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-61)
The aniline in embodiment 56 is replaced with 0.03mol 4-aminoanisole, other operations are with embodiment 56, obtain N-(4-methoxyphenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-61), fusing point: 160-162 DEG C (correction), yield: 81.5%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,CDCl
3,δppm):3.79(s,3H,-OCH
3),6.84(d,2H,J＝8.5Hz,3″,5″-H),7.22(t,2H,J＝8.5Hz,3′,5′-H),7.36(d,2H,J＝9.0Hz,2″,6″-H),7.59(s,1H,3-H),7.69(d,1H,J＝8.0Hz,5-H),7.89(s,1H,-NH),8.02(d,1H,J＝8.0Hz,6-H),8.24(d d,2H,J＝9.0Hz,2′,6′-H)。
Embodiment 66: preparation N-(2,4 difluorobenzene base)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-62)
With 0.03mol 2,4-difluoroaniline replaces the aniline in embodiment 56, other operations are with embodiment 56, obtain N-(2,4-difluorophenyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-62), fusing point: 135-140 DEG C (correction), yield: 83.3%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.08(t,1H,J＝8.5Hz,3″-H),7.31(t,1H,J＝8.5Hz,5″-H),7.44(t,2H,J＝9.0Hz,3′,5′-H),7.56(q,1H,J＝8.5Hz,6″-H),7.87(d,1H,J＝8.0Hz,5-H),7.98(s,1H,3-H),7.99(d,1H,J＝9.0Hz,6-H),8.18(d d,2H,J＝9.0Hz,2′,6′-H),10.44(s,1H,-NH)。
Embodiment 67: preparation N-(2,5-Dichlorobenzene base)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-63)
With 0.03mol 2,5-dichloroaniline replaces the aniline in embodiment 56, other operations are with embodiment 56, obtain N-(2,5-Dichlorobenzene base)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-63), fusing point: 154-157 DEG C (correction), yield: 66.4%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.35(d,1H,J＝8.5Hz,4″-H),7.45(t,2H,J＝8.5Hz,3′,5′-H),7.54(d,1H,J＝8.5Hz,3″-H),7.62(s,1H,6″-H),7.89(d,1H,J＝8.0Hz,5-H),8.00(s,1H,3-H),8.02(d,1H,J＝8.0Hz,6-H),8.20(d d,2H,J＝8.5Hz,2′,6′-H),10.47(s,1H,-NH)。
Embodiment 68: preparation N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-64)
The aniline in embodiment 56 is replaced with 0.03mol 4-chloro-2-nitroaniline, other operations are with embodiment 56, obtain N-(the chloro-2-nitrobenzophenone of 4-)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-64), fusing point: 121-123 DEG C (correction), yield: 47.2%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.43(t,2H,J＝8.5Hz,3′,5′-H),7.58(d,1H,J＝9.0Hz,5-H),7.83(d,1H,J＝9.0Hz,5″-H),7.93(d,1H,J＝8.5Hz,6″-H),7.99(d,1H,J＝8.0Hz,6-H),8.02(s,1H,3-H),8.07(s,1H,3″-H),8.18(d d,2H,J＝8.5Hz,2′,6′-H),11.12(s,1H,-NH)。
Embodiment 69: preparation N-(4-nitro-3-trifluoromethyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-65)
The aniline in embodiment 56 is replaced with 0.03mol 4-nitro-3-trifluoromethylaniline, other operations are with embodiment 56, obtain N-(4-nitro-3-trifluoromethyl)-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-65), fusing point: 196-198 DEG C (correction), yield: 44.0%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):7.42(t,2H,J＝9.0Hz,3′,5′-H),7.93(d,1H,J＝8.0Hz,5-H),8.04(s,1H,3-H),8.07(d,1H,J＝8.0Hz,6-H),8.15(d,1H,J＝9.0Hz,6″-H),8.17(d d,2H,J＝9.0Hz,2′,6′-H),8.20(s,1H,2″-H),8.21(d,1H,J＝9.0Hz,5″-H),11.40(s,1H,-NH)。
Embodiment 70: preparation N-benzyl-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-66)
The aniline in embodiment 56 is replaced with 0.03mol benzylamine, other operations are with embodiment 56, obtain N-benzyl-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-66), fusing point: 161-163 DEG C (correction), yield: 69.8%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):4.37(d,2H,J＝6.0Hz,-CH
2),7.18～7.22(m,5H,Ar″-H),7.42(t,2H,J＝8.5Hz,3′,5′-H),7.81(d,1H,J＝8.0Hz,5-H),7.86(d,1H,J＝8.0Hz,6-H),7.90(s,1H,3-H),8.12(d d,2H,J＝8.5Hz,2′,6′-H),9.14(t,1H,J＝6.0Hz,-NH)。
Embodiment 71: preparation N-cyclohexyl-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-67)
The aniline in embodiment 56 is replaced with 0.03mol cyclohexylamine, other operations are with embodiment 56, obtain N-cyclohexyl-O-(4-fluorobenzoyl)-(4-trifluoromethyl) salicylamide (I-67), fusing point: 188-190 DEG C (correction), yield: 36.1%.
1h nuclear magnetic resonance map is analyzed as follows:
1H NMR(500MHz,DMSO,δppm):1.05(m,1H,4″-CH
2),1.14(m,2H,3″,5″-CH
2),1.20(m,2H,3″,5″-CH
2),1.52(m,1H,4″-CH
2),1.64(m,4H,2″,6″-CH
2),3.60(m,1H,1″-CH),7.45(t,2H,J＝8.5Hz,3′,5′-H),7.78(d,1H,J＝8.0Hz,6-H),7.78(d,1H,J＝8.0Hz,5-H),7.87(s,1H,3-H),8.19(d d,2H,J＝8.5Hz,2′,6′-H),8.41(d,1H,J＝8.0Hz,-NH)。
Embodiment 72 ~ 138:O-benzoyl-anti-intestinal cancer active testing of (4-trifluoromethyl) salicylamide Compound ira vitro
A. principle: the succinate dehydrogenase in living cells mitochondrion can make exogenous Thiazolyl blue (MTT) be reduced to water-insoluble bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) energy dissolved cell, measures first a ceremonial jade-ladle, used in libation light absorption value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly can reflect proliferative conditions and the number change of cell.Within the scope of certain cell number, the amount that MTT crystallization is formed is directly proportional to cell number.
B. cell: people's colon-cancer cell strain (HCT-116), people's colon-cancer cell strain (DLD-1), the strain of people's colon-cancer cell (Colo-320) (all purchased from Shanghai Inst. of Life Science, CAS)
C. experimental procedure
1) preparation of sample: Compound I-14 ~ I-36 prepared by Example 18 ~ 40, every 1mg sample 20 μ L DMSO dissolve, get 2 μ L, 1000 μ L culture fluid (preparation see culture fluid in the cultivation of step (2) cell below) dilution again, be made into the sample liquid of 100 μ g/mL, then use culture fluid serial dilution to working concentration 10 μ g/mL and 1 μ g/mL.
The preparation of 5mg/mLMTT: with normal saline configuration MTT solution, concentration is 5mg/mL.
2) cultivation of cell
The preparation of culture fluid: containing 800,000 units of Penicillin, 1.0g streptomycin, 10% inactivated fetal bovine serum in every 1000mLRPMI-1640 culture fluid (Hangzhou Ji Nuo company).
The cultivation of cell: tumor cell HCT-116, DLD-1, Colo-320 are inoculated in respectively in culture fluid, puts 37 DEG C (corrections), 5%CO
2cultivate in incubator, 3 ~ 5d goes down to posterity.
3) working sample is to the inhibitory action of growth of tumour cell
By cell ethylenediaminetetraacetic acid (EDTA)-trypsinization liquid (0.25% pancreatin, 0.02%EDTA, with the configuration of Hank ' s buffer) digestion, and to be diluted to cell concentration with culture fluid be 3 × 10
4/ mL, is added in 96 porocyte culture plates, and every hole 100 μ L, puts 37 DEG C (corrections), 5%CO
2after cultivating 24h in incubator, incline culture fluid, and add the sample with culture fluid dilution, every hole 200 μ L, each concentration adds 3 holes, puts 37 DEG C (corrections), 5%CO
2cultivate in incubator, in cell culture well, the MTT of 5mg/mL is added after 72h, every hole 10 μ L, puts 37 DEG C (corrections) and hatches 3h, add DMSO, every hole 150 μ L, with agitator (Haimen kylin Medical Instruments factory, QL-9001) vibration, first a ceremonial jade-ladle, used in libation is dissolved completely, light absorption value is detected at 490nm wavelength place with enzyme-linked immunosorbent assay instrument (BIO-RAD company of the U.S., 680 types).The culture fluid cultured cells of cisplatin control sample and same concentration DMSO is contained as blank under similarity condition, according to formula (1) calculation sample to the suppression ratio of growth of tumour cell, and the suppression ratio of compounds on cell growth under each concentration, the half-inhibition concentration (IC of each sample is calculated with SPSS software (purchased from American SPSS Inc.)
50), result is as shown in table 2:
Computing formula: suppression ratio (%)=(OD
blank-OD
sample)/OD
blank× 100% formula (1)
Table 2: each compound is to the IC of HCT-116, DLD-1, Colo-320
50value (mg/L)
Claims (4)
1. the application of O-benzoyl-(4-trifluoromethyl) the salicylamide compounds as shown in formula I in preparation treatment bowelcancer medicine:
In formula I, R is halogen or nitro; R
1for hydrogen or chlorine; R
2for hydrogen or fluorine; R
3for H or ethyl; R
4for cyclohexyl, benzyl or structure are such as formula the substituted-phenyl shown in (A):
In formula (A), Q
1~ Q
5respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl or trifluoromethyl.
2. apply as claimed in claim 1, R in wherein said formula I
3for H, R
4for structure is such as formula the substituted-phenyl shown in (A), corresponding described O-benzoyl-(4-trifluoromethyl) salicylamide compounds is such as formula shown in (II):
Wherein: R is fluorine, chlorine or nitro; R
1for hydrogen or chlorine; R
2for hydrogen or fluorine; Q
1~ Q
5respective is independently H, methyl, fluorine, chlorine, nitro, methoxyl group, ethyoxyl or trifluoromethyl.
3. apply as claimed in claim 1, wherein said O-benzoyl-(4-trifluoromethyl) salicylamide compounds one of compound listed by table 1:
Table 1:
。
4. apply as claimed in claim 3, wherein said O-benzoyl-(4-trifluoromethyl) salicylamide compounds is compounds I-14 ~ I-36.
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| US4545942A (en) * | 1980-03-22 | 1985-10-08 | Sankyo Company, Limited | Amino-acid derivatives, their preparation and their use as pharmaceuticals |
| CN101502523A (en) * | 2009-03-06 | 2009-08-12 | 浙江工业大学 | Application of benzoyl fluorobenzene salicylamide compound in preparing anti-tumor medicament |
| CN102600182A (en) * | 2012-03-05 | 2012-07-25 | 浙江工业大学 | Application of phenylacetyl fluorobenzene salicylamide compound in preparation of lung-cancer-resisting medicament |
| CN102614198A (en) * | 2012-03-05 | 2012-08-01 | 浙江工业大学 | Application of (4-substituted benzene formyl) fluorobenzene salicylamide compound in preparation of anti-lung-cancer medicines |
| US20130225529A1 (en) * | 2012-02-27 | 2013-08-29 | Basil Rigas | Phospho-ester derivatives and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS57120564A (en) * | 1981-01-19 | 1982-07-27 | Sankyo Co Ltd | Amino acid derivative |
| CN101955442B (en) * | 2010-09-30 | 2013-06-05 | 浙江工业大学 | Benzoyl fluorobenzene salicylamide compound and application thereof |
| WO2013056915A1 (en) * | 2011-10-18 | 2013-04-25 | Syngenta Participations Ag | Microbiocidal pyrazole derivatives |
| CN102614200B (en) * | 2012-03-05 | 2013-09-11 | 浙江工业大学 | Application of (4-substituted benzoyl) fluorobenzene salicylamide compound in preparation of medicine for resisting breast cancer |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4545942A (en) * | 1980-03-22 | 1985-10-08 | Sankyo Company, Limited | Amino-acid derivatives, their preparation and their use as pharmaceuticals |
| CN101502523A (en) * | 2009-03-06 | 2009-08-12 | 浙江工业大学 | Application of benzoyl fluorobenzene salicylamide compound in preparing anti-tumor medicament |
| US20130225529A1 (en) * | 2012-02-27 | 2013-08-29 | Basil Rigas | Phospho-ester derivatives and uses thereof |
| CN102600182A (en) * | 2012-03-05 | 2012-07-25 | 浙江工业大学 | Application of phenylacetyl fluorobenzene salicylamide compound in preparation of lung-cancer-resisting medicament |
| CN102614198A (en) * | 2012-03-05 | 2012-08-01 | 浙江工业大学 | Application of (4-substituted benzene formyl) fluorobenzene salicylamide compound in preparation of anti-lung-cancer medicines |
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