CN107973727B - 间二取代苯酚化合物及其制备方法与抗结核菌应用 - Google Patents
间二取代苯酚化合物及其制备方法与抗结核菌应用 Download PDFInfo
- Publication number
- CN107973727B CN107973727B CN201711310722.7A CN201711310722A CN107973727B CN 107973727 B CN107973727 B CN 107973727B CN 201711310722 A CN201711310722 A CN 201711310722A CN 107973727 B CN107973727 B CN 107973727B
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- China
- Prior art keywords
- benzyl
- hydroxyphenyl
- phenol compound
- disubstituted phenol
- phenyl
- 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.)
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- -1 M-disubstituted phenol compound Chemical class 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 241000193830 Bacillus <bacterium> Species 0.000 title abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 28
- 201000008827 tuberculosis Diseases 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 230000009467 reduction Effects 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 238000010520 demethylation reaction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- QXIIPLXNJAJOMR-UHFFFAOYSA-N 3-methoxy-5-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 QXIIPLXNJAJOMR-UHFFFAOYSA-N 0.000 claims description 5
- 230000017858 demethylation Effects 0.000 claims description 5
- MZMHAKPJHNLEJM-UHFFFAOYSA-N (4,4-dimethylcyclohexyl) N-(3-benzyl-5-hydroxyphenyl)carbamate Chemical compound CC1(CCC(CC1)OC(NC1=CC(=CC(=C1)O)CC1=CC=CC=C1)=O)C MZMHAKPJHNLEJM-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 claims description 4
- LQJSCZKHFFBHHN-UHFFFAOYSA-N N-(3-benzyl-5-hydroxyphenyl)-2,4-dichlorobenzamide Chemical compound C(C1=CC=CC=C1)C=1C=C(C=C(C=1)O)NC(C1=C(C=C(C=C1)Cl)Cl)=O LQJSCZKHFFBHHN-UHFFFAOYSA-N 0.000 claims description 4
- VIPLQYZKEJTVCK-UHFFFAOYSA-N N-(3-benzyl-5-hydroxyphenyl)-2-chlorobenzamide Chemical compound C(C1=CC=CC=C1)C=1C=C(C=C(C=1)O)NC(C1=C(C=CC=C1)Cl)=O VIPLQYZKEJTVCK-UHFFFAOYSA-N 0.000 claims description 4
- XMIGCFCBTULNLG-UHFFFAOYSA-N N-(3-benzyl-5-hydroxyphenyl)benzamide Chemical compound C(C1=CC=CC=C1)C=1C=C(C=C(C=1)O)NC(C1=CC=CC=C1)=O XMIGCFCBTULNLG-UHFFFAOYSA-N 0.000 claims description 4
- KKALUBSPOXMLCQ-UHFFFAOYSA-N N-(3-benzyl-5-hydroxyphenyl)thiophene-2-carboxamide Chemical compound C(C1=CC=CC=C1)C=1C=C(C=C(C=1)O)NC(=O)C=1SC=CC=1 KKALUBSPOXMLCQ-UHFFFAOYSA-N 0.000 claims description 4
- KGXWCUUOWNNNHZ-UHFFFAOYSA-N N-(3-hydroxy-5-phenoxyphenyl)benzamide Chemical compound OC=1C=C(C=C(C=1)OC1=CC=CC=C1)NC(C1=CC=CC=C1)=O KGXWCUUOWNNNHZ-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- BHJPKZMRLZAYLC-UHFFFAOYSA-N ethyl N-(3-benzyl-5-hydroxyphenyl)carbamate Chemical compound C(C)OC(NC1=CC(=CC(=C1)O)CC1=CC=CC=C1)=O BHJPKZMRLZAYLC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- WYCUESRFTDCWAZ-UHFFFAOYSA-N N-(3-benzyl-5-hydroxyphenyl)-4-methylbenzamide Chemical compound C(C1=CC=CC=C1)C=1C=C(C=C(C=1)O)NC(C1=CC=C(C=C1)C)=O WYCUESRFTDCWAZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 125000002560 nitrile group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical class 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical class 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical class 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 35
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 136
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 50
- 230000015572 biosynthetic process Effects 0.000 description 41
- 238000003786 synthesis reaction Methods 0.000 description 41
- AUAWCUYBKHAGGW-UHFFFAOYSA-N 5-amino-1-benzylcyclohexa-2,4-dien-1-ol Chemical compound C(C1=CC=CC=C1)C1(CC(=CC=C1)N)O AUAWCUYBKHAGGW-UHFFFAOYSA-N 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 33
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- 238000010828 elution Methods 0.000 description 31
- 239000003208 petroleum Substances 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 239000000284 extract Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000012043 crude product Substances 0.000 description 22
- 238000004896 high resolution mass spectrometry Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 6
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 6
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 description 5
- 235000011009 potassium phosphates Nutrition 0.000 description 5
- FHUSNGUPJXGLPL-UHFFFAOYSA-N 3-bromo-5-methoxyaniline Chemical compound COC1=CC(N)=CC(Br)=C1 FHUSNGUPJXGLPL-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 3
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 230000002365 anti-tubercular Effects 0.000 description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
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- 239000012453 solvate Substances 0.000 description 3
- OFUOYHFRYIXYLQ-UHFFFAOYSA-N 1-benzyl-3-methoxy-5-nitrobenzene Chemical compound COC=1C=C(C=C(C=1)[N+](=O)[O-])CC1=CC=CC=C1 OFUOYHFRYIXYLQ-UHFFFAOYSA-N 0.000 description 2
- YMSJHJFYMIGLAK-UHFFFAOYSA-N 1-benzyl-5-nitrocyclohexa-2,4-dien-1-ol Chemical compound C(C1=CC=CC=C1)C1(CC(=CC=C1)[N+](=O)[O-])O YMSJHJFYMIGLAK-UHFFFAOYSA-N 0.000 description 2
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- 229940126062 Compound A Drugs 0.000 description 2
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- CEOCVKWBUWKBKA-UHFFFAOYSA-N 2,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1Cl CEOCVKWBUWKBKA-UHFFFAOYSA-N 0.000 description 1
- HIQKOCLKQSNITC-UHFFFAOYSA-N 2-(4,4-dimethylcyclohexyl)acetic acid Chemical compound CC1(C)CCC(CC(O)=O)CC1 HIQKOCLKQSNITC-UHFFFAOYSA-N 0.000 description 1
- DNUYOWCKBJFOGS-UHFFFAOYSA-N 2-[[10-(2,2-dicarboxyethyl)anthracen-9-yl]methyl]propanedioic acid Chemical compound C1=CC=C2C(CC(C(=O)O)C(O)=O)=C(C=CC=C3)C3=C(CC(C(O)=O)C(O)=O)C2=C1 DNUYOWCKBJFOGS-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- WAKMMQSMEDJRRI-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC(C(Cl)=O)=CC(C(F)(F)F)=C1 WAKMMQSMEDJRRI-UHFFFAOYSA-N 0.000 description 1
- FSIVJDQJCGNKQS-UHFFFAOYSA-N 4-[4-(10-hydroxydecoxy)phenyl]benzonitrile Chemical compound C1=CC(OCCCCCCCCCCO)=CC=C1C1=CC=C(C#N)C=C1 FSIVJDQJCGNKQS-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- NHHQOYLPBUYHQU-UHFFFAOYSA-N 4-methylthiadiazole-5-carboxylic acid Chemical compound CC=1N=NSC=1C(O)=O NHHQOYLPBUYHQU-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 229910004068 NO2Cl Inorganic materials 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- OQQVFCKUDYMWGV-UHFFFAOYSA-N [5-[1-(phenylmethyl)-3-indazolyl]-2-furanyl]methanol Chemical compound O1C(CO)=CC=C1C(C1=CC=CC=C11)=NN1CC1=CC=CC=C1 OQQVFCKUDYMWGV-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000036981 active tuberculosis Diseases 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 208000015355 drug-resistant tuberculosis Diseases 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 201000006674 extrapulmonary tuberculosis Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- IJFXRHURBJZNAO-UHFFFAOYSA-N meta--hydroxybenzoic acid Natural products OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- VGKOARVVEXZTPU-UHFFFAOYSA-N n-methylpyrazin-2-amine Chemical compound CNC1=CN=CC=N1 VGKOARVVEXZTPU-UHFFFAOYSA-N 0.000 description 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- RYGUCYSSMOFTSH-UHFFFAOYSA-N oxane-4-carbonyl chloride Chemical compound ClC(=O)C1CCOCC1 RYGUCYSSMOFTSH-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
Classifications
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/26—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
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- C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/82—Amides; Imides in position 3
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- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明提供了一类通式为(Ⅰ)的间二取代苯酚化合物、其制备方法与应用。所述的间二取代苯酚化合物具有新的抗结核菌药母核结构和优秀的抗结核菌活性,特别是对耐药的变异结核菌株也具有很强的抑制活性。本发明还提供了所述的间二取代苯酚化合物的制备方法,该制备方法的原料廉价易得,无需使用高毒性和高污染试剂,反应步骤简单,可实现工业化生产;具有良好的药用前景。
Description
技术领域
本发明属于药物化学领域,特别涉及一类间二取代苯酚化合物及其制备方法与抗结核菌应用。
背景技术
结核病是由结核分枝杆菌引起的一种慢性致死性疾病,其每年致死人数已超过艾滋病,严重危害人类健康。目前,由于多药耐药和广泛耐药变异结核菌的出现,以及与HIV共同感染的结核病人的出现,大大增加了治疗肺结核的难度。临床上对一线抗结核药物异烟肼、利福平、吡嗪酰胺和链霉素产生耐药的病人比例已经接近15%,而二线药物由于副作用较大,并不适合长期用药。
因此,发现新结构、高选择性、与现有一线药物不产生交叉耐药性的抗结核新药物具有十分重要的临床应用价值。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足,提供一类间二取代苯酚化合物,所述的间二取代苯酚化合物具有抗结核菌活性。
本发明的第二目的在于提供一种药物组合物,包括所述的间二取代苯酚化合物或其药学可接受的盐、立体异构体或溶剂化物,以及任选的药学可接受的辅料、载体或赋形剂。
本发明的第三目的在于提供所述的间二取代苯酚化合物的制备方法。
本发明的第四目的在于提供所述的间二取代苯酚化合物在制备预防和/或治疗结核病的药物中的应用。
本发明的第五目的在于提供所述的间二取代苯酚化合物在制备预防和/或治疗分枝杆菌感染引起的疾病的药物中的应用。
本发明的目的通过下述技术方案实现:
通式Ⅰ所示的化合物,或其药学可接受的盐、立体异构体或溶剂化物,
其中,R1为甲基、乙基、乙烯基、C3~C8烷基及环烷基、甲氧基、苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基、喹啉基、噻唑基、噻二唑基、苯氧基、苄氧基、乙氧基、C3~C8烷基氧基及环烷基氧基、四氢吡喃基、四氢呋喃基;其中在苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基、喹啉基、噻唑基、苯氧基、苄氧基的芳香环上还可以有单取代或者多取代基,取代基可以是甲基、乙基、C3~C6烷基及环烷基、氟、氯、溴、甲氧基、硝基、三氟甲基、腈基、羟基;
R2为无取代、单取代或多取代的苯基、噻吩基、呋喃基、吡啶基、吡嗪基、嘧啶基、噻唑基、吡唑基、三氮唑基,取代基可以是甲基、氟、氯、溴、甲氧基、三氟甲基、腈基;
X为CH2、O、S、NH和NCH3。
所述的R1优选为C5~C8环烷基、苯基、苯基氧基、C5~C8环烷基氧基,其中在苯基、苯基氧基的苯环上还可以有单取代或者多取代,取代基可以是甲基、氯、氟。
所述的R2优选为苯基。
所述的X优选为CH2或NCH3。
进一步优选为以下化合物:
3-苄基-5-羟基苯基-氨基甲酸-4,4-二甲基环己酯;
N-(3-苄基-5-羟基苯基)-4,4-二甲基-环己烷甲酰胺;
N-(3-苄基-5-羟基苯基)-4-甲基苯甲酰胺;
N-(3-羟基-5-(甲基苯胺基)苯基)-环己烷甲酰胺;
N-(3-苄基-5-羟基苯基)环己基甲酰胺;
N-(3-苄基-5-羟基苯基)-2-(4,4-二甲基环己基)乙酰胺;
N-(3-苄基-5-羟基苯基)苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2-氯苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2,4-二氯苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2-氯烟酰胺;
N-(3-苄基-5-羟基苯基)噻吩-2-甲酰胺;
3-苄基-5-羟基苯基-氨基甲酸乙酯;
N-(3-羟基-5-苯氧基苯基)-苯甲酰胺;
N-(3-羟基-5-(甲基苯胺基)苯基)-苯甲酰胺;
N-(3-羟基-5-(甲基-2-吡啶基胺基)苯基)-苯甲酰胺;
N-(3-羟基-5-(甲基-2-吡嗪基胺基)苯基)-苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2-苯乙酰胺;
N-(3-苄基-5-羟基苯基)-4,4-二氟环己基甲酰胺;
N-(3-苄基-5-羟基苯基)四氢吡喃-4-甲酰胺。
一种药物组合物,包括所述的间二取代苯酚化合物或其药学可接受的盐、立体异构体或溶剂化物,以及任选的药学可接受的辅料、载体或赋形剂。
所述的间二取代苯酚化合物的制备方法,包括如下步骤:
当X为CH2时,采用3-硝基-5-甲氧基苯甲酸为原料,经过还原成醇、傅克烷基化、脱甲基、硝基还原和酰化反应制备得到所述的间二取代苯酚化合物;
具体地,包括如下步骤:
(1)以3-硝基-5-甲氧基苯甲酸为原料,经还原后得到3-硝基-5-甲氧基苄醇;
(2)3-硝基-5-甲氧基苄醇与芳香族化合物R2H发生傅克烷基化反应,得到化合物A;
(3)化合物A发生脱甲基反应,得到化合物B;
(4)还原化合物B中的硝基,得到化合物C;
(5)化合物C与R1COCl、或(R1CO)2O、或R1COOH发生反应,即得所述的间二取代苯酚化合物D。
合成路线如下:
所述的合成路线中的反应试剂和条件优选如下:
a.NaBH4、BF3.OEt2、THF或LiAlH4、THF;
b.R2H、AlCl3;
c.BBr3、CH2Cl2或NaH、EtSH、DMF;
d.还原剂优选为Pd/C催化加氢,或铁粉,或锌粉中的至少一种;进一步优选为10%Pd/C、H2,或铁粉、醋酸/甲醇/水,或锌粉、醋酸/甲醇/水;
e.R1COCl、Et3N、CH2Cl2,或(R1CO)2、Et3N、CH2Cl2,或R1COOH、亚磷酸三苯酯、甲苯。
当X为O、S、NH、NCH3时,采用3-溴-5-硝基苯甲醚为原料,经过硝基还原、酰化、偶联、脱甲基反应制备得到所述的间二取代苯酚化合物;
具体地,包括如下步骤:
(1)3-溴-5-硝基苯甲醚还原得到3-溴-5-甲氧基苯胺;
(2)3-溴-5-甲氧基苯胺与R1COCl,或(R1CO)2,或R1COOH发生酰化反应,得到化合物E;
(3)化合物E与R2XH发生偶联反应,得到化合物F;
(4)化合物F发生脱甲基反应,即得所述的间二取代苯酚化合物G。
合成路线如下:
所述的合成路线中的反应试剂和条件优选如下:
a.铁粉或锌粉、醋酸/甲醇/水;
b.R1COCl、Et3N、CH2Cl2,或(R1CO)2、Et3N、CH2Cl2,或R1COOH、亚磷酸三苯酯、甲苯;
c.R2XH、CuI、K3PO4、DMSO;
d.BBr3、CH2Cl2或NaH、EtSH、DMF。
所述的间二取代苯酚化合物或所述的药物组合物在制备预防和/或治疗结核病的药物中的应用。
所述的结核病包括肺结核或肺外结核。
所述的结核病包括活动性结核病、单耐药结核病、多耐药结核病或广泛耐多药结核病。
所述的间二取代苯酚化合物或所述的药物组合物在制备预防和/或治疗分枝杆菌感染引起的疾病的药物中的应用。
所述的分枝杆菌为结核分枝杆菌;进一步优选为结核分枝杆菌H37Rv,或对异烟肼和利福平耐药的临床分离结核分枝杆菌P103、R7、P91。
本发明相对于现有技术具有如下的优点及效果:
1.本发明提供了一类间二取代苯酚化合物,具有新的抗结核菌药母核结构和优秀的抗结核菌活性,特别是对耐药的变异结核菌株也具有很强的抑制活性。
2.本发明提供了上述的间二取代苯酚化合物的制备方法,采用3-硝基-5-甲氧基苯甲酸为原料,经过还原成醇、傅克烷基化、脱甲基、硝基还原和酰化反应制备得到所述的间二取代苯酚化合物;或者采用3-溴-5-硝基苯甲醚为原料,经过硝基还原、酰化、偶联、脱甲基反应制备得到。上述的合成路线原料廉价易得,不使用高毒性和高污染试剂,反应步骤简单,可实现工业化生产。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例中反应所用的原料可以由本领域技术人员根据已有知识制备得到,或可以通过商业途径购得。
实施例1合成N-(3-苄基-5-羟基苯基)-2-苯乙酰胺
在100mL两口瓶中,在氩气保护下加入硼氢化钠(1.6g,42mmol)和重蒸的四氢呋喃(20mL),在0℃下缓慢加入3-硝基-5-甲氧基苯甲酸(3.94g,20mmol),再加入三氟化硼乙醚溶液6.7mL。在室温下反应4h,反应液在冰浴冷却下用稀盐酸淬灭,然后用二氯甲烷(30mL×2)萃取。萃取液在减压下除去溶剂得到粗产物3-硝基-5-甲氧基苄醇3.6g,直接用于下一步反应。
在100mL圆底烧瓶中,加入无水三氯化铝(5.58g,42mmol)、无水苯20mL和二氯甲烷10mL,在冰浴条件下缓慢加入3-硝基-5-甲氧基苄醇(3.6g,20mmol),然后于80℃条件下回流5h。反应液冷却后倒入冰水中,用乙酸乙酯(30mL×2)萃取。萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色固体即1-苄基-3-硝基-5-甲氧基苯2.0g,产率41%。
在200mL两口瓶中,加入1-苄基-3-硝基-5-甲氧基苯(2.0g,8.2mmol)和重蒸的二氯甲烷50mL,在-78℃下缓慢加入三溴化硼二氯甲烷溶液42mL(1mol/L),然后在0℃条件下反应12h。反应液用饱和碳酸氢钠溶液淬灭,然后用二氯甲烷(30mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到黄色固体即1-苄基-3-硝基苯酚577mg,产率30%。
在100mL两口瓶中,加入1-苄基-3-硝基苯酚(577mg,2.5mmol)、20mL甲醇/二氯甲烷(V/V=1/1)混合溶剂和10%Pd/C(60mg),在一个大气压的氢气下反应2h。将反应液过滤,滤液在减压下除去溶剂得到灰色固体即1-苄基-3-氨基苯酚400mg,产率80%。
在25mL圆底烧瓶中,在冰浴条件下加入1-苄基-3-氨基苯酚(99.5mg,0.5mmol)、苯乙酰氯(73μL,0.55mmol)、三乙胺(76μL,0.55mmol)和重蒸的四氢呋喃2mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到红色固体即N-(3-苄基-5-羟基苯基)-2-苯乙酰胺113mg,产率71%。
1H NMR(400MHz,DMSO)δ9.94(s,1H),9.27(s,1H),7.32–7.17(m,10H),7.05(s,1H),6.81(s,1H),6.31(s,1H),3.76(s,2H),3.58(s,2H).13C NMR(100MHz,DMSO)δ169.36,158.03,143.08,141.52,140.60,136.55(s),129.50,129.18,128.82,128.72,126.93,126.40,111.37,110.84,104.63,43.84,41.75.高分辨质谱(ESI)C21H19NO2[M+H]+:理论值:318.1489,实测值:318.1478。
实施例2合成N-(3-苄基-5-羟基苯基)环己基甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在50mL圆底烧瓶中,冰浴冷却下加入1-苄基-3-氨基苯酚(99.5mg,0.5mmol)、环己烷甲酰氯(74μL,0.55mmol)、三乙胺(76μL,0.55mmol)和重蒸的四氢呋喃2mL,在室温下反应12h,反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即N-(3-苄基-5-羟基苯基)环己烷甲酰胺75mg,产率49%。
1H NMR(400MHz,DMSO)δ9.59(s,1H),9.24(s,1H),7.28(m,2H),7.19(m,3H),7.04(m,1H),6.84(m,1H),6.28(m,1H),3.77(s,2H),2.27(t,J=11.4Hz,1H),1.73(d,J=9.2Hz,4H),1.63(d,J=9.6Hz,1H),1.37(m,2H),1.30–1.14(m,3H).13C NMR(101MHz,DMSO)δ174.62,157.96,142.93,141.62,140.91,129.18,128.82,126.39,111.02,110.82,104.55,45.31,41.80,29.61,25.88,25.71。高分辨质谱(ESI)C20H24NO2[M+H]+:理论值:310.1802,实测值:310.1800。
实施例3合成N-(3-苄基-5-羟基苯基)-2-(4,4-二甲基环己基)乙酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、2-(4,4-二甲基环己基)乙酸(204mg,1.2mmol)、亚磷酸三苯酯(314μL,1.2mmol)和重蒸的甲苯5mL,在110℃反应12h。反应液减压除去溶剂,残余物用硅胶柱层析纯化(石油醚/二氯甲烷梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)-2-(4,4-二甲基环己烷)乙酰胺127mg,产率45%。
1H NMR(400MHz,DMSO)δ9.60(s,1H),9.21(s,1H),7.28(m,2H),7.18(m,3H),7.06(m,1H),6.79(m,1H),6.28(m,1H),3.78(s,2H),2.15(d,J=7.1Hz,2H),1.64(m,1H),1.49(m,2H),1.33(m,2H),1.19–1.10(m,4H),0.87(s,3H),0.86(s,3H).13C NMR(101MHz,DMSO)δ170.89,157.99,142.94,141.58,140.70,129.19,128.82,126.40,111.12,110.82,104.65,44.32,41.78,38.86,35.18,32.83,30.07,28.67,24.97.高分辨质谱(ESI)C23H29NO2[M+H]+:理论值:352.2271,实测值:352.2273.
实施例4合成N-(3-苄基-5-羟基苯基)-4,4-二氟环己基甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、4,4-二氟环己烷甲酸(197mg,1.2mmol)、亚磷酸三苯酯(314μL,1.2mmol)和重蒸的甲苯5mL,在110℃反应12h。反应液减压除去溶剂,残余物用硅胶柱层析纯化(石油醚/二氯甲烷梯度洗脱),得到黄色固体即N-(3-苄基-5-羟基苯基)-4,4-二氟环己烷甲酰胺126mg,产率37%。
1H NMR(400MHz,DMSO)δ9.75(s,1H),9.30(s,1H),7.28(m,2H),7.24–7.15(m,3H),7.03(m,1H),6.83(m,1H),6.30(m,1H),3.78(s,2H),2.42(t,J=10.6Hz,1H),2.08(d,J=8.7Hz,2H),1.86(d,J=10.6Hz,3H),1.75(m,1H),1.65(m,2H).13C NMR(101MHz,DMSO)δ173.17,157.99,143.04,141.58,140.64,129.19,128.84,126.41,124.13(t,1J=239Hz),111.25,110.85,104.62,42.41,41.77,32.72(t,2J=23Hz),26.08,25.99.高分辨质谱(ESI)C20H21NO2F2[M+H]+:理论值:346.1613,实测值:346.1604.
实施例5合成N-(3-苄基-5-羟基苯基)四氢吡喃-4-甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(159mg,0.8mmol)、四氢吡喃-4-甲酰氯(109μL,0.88mmol)、三乙胺(111μL,0.88mmol)和重蒸的四氢呋喃2mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)四氢吡喃-4-甲酰胺197mg,产率63%。
1H NMR(400MHz,MeOD)δ7.30–7.21(m,1H),7.16(m,1H),7.02(m,1H),6.79(m,1H),6.38(m,1H),3.98(dd,J=11.4,2.6Hz,2H),3.84(s,2H),3.45(td,J=11.7,2.1Hz,2H),2.57(tt,J=11.4,4.0Hz,1H),1.89–1.67(m,4H).13C NMR(101MHz,DMSO)δ173.29,157.98,142.99,141.58,140.73,129.19,128.83,126.40,111.20,110.91,104.66,66.87,42.19,41.79,29.33.高分辨质谱(ESI)C19H21NO3[M+H]+:理论值:312.1594,实测值:312.1602。
实施例6合成N-(3-苄基-5-羟基苯基)苯甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(99mg,0.5mmol)、苯甲酰氯(63μL,0.55mmol)、三乙胺(76μL,0.55mmol)和重蒸的四氢呋喃2mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)苯甲酰胺79mg,产率52%。
1H NMR(400MHz,DMSO)δ10.02(s,1H),9.29(s,1H),7.94–7.88(m,1H),7.59–7.53(m,1H),7.50(m,1H),7.29(m,1H),7.20(m,2H),7.06(m,1H),6.37(m,1H),3.83(s,1H).13CNMR(101MHz,DMSO)δ157.82,155.56,142.49,141.80,141.74,129.16,128.79,126.35,111.40,110.08,105.09,66.48,44.68,41.89.高分辨质谱(ESI)C20H18NO2[M+H]+:理论值:304.1332,实测值:304.1324。
实施例7N-(3-苄基-5-羟基苯基)-4-甲基苯甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(99.5mg,0.5mmol)、对甲基苯甲酰氯(73μL,0.55mmol)、三乙胺(76μL,0.55mmol)和重蒸的四氢呋喃2mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到淡红色固体即N-(3-苄基-5-羟基苯基)-4-甲基苯甲酰胺101mg,产率64%。
1H NMR(400MHz,DMSO)δ9.96(s,1H),9.32(s,1H),7.83(d,J=8.1Hz,2H),7.30(t,J=7.7Hz,4H),7.20(m,4H),7.05(s,1H),6.36(s,1H),3.82(s,2H),2.37(s,3H).13C NMR(101MHz,DMSO)δ165.69,157.93,142.89,141.89,141.63,140.66,132.66,129.29,129.20,128.85,128.14,126.42,112.10,111.70,105.80,41.85,21.46.高分辨质谱(ESI)C21H19NO2[M+H]+:理论值:318.1489,实测值:318.1488。
实施例8合成N-(3-苄基-5-羟基苯基)-3-羟基苯甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,加入1-苄基-3-氨基苯酚(99.5mg,0.5mmol)、间羟基苯甲酸(104mg,0.75mmol)、亚磷酸三苯酯(196.55μL,0.75mmol,)和重蒸的甲苯5mL,在110℃反应12h。反应液减压除去溶剂,残余物用硅胶柱层析纯化(石油醚/二氯甲烷梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)-3-羟基苯甲酰胺99mg,产率62%。
1H NMR(400MHz,DMSO)δ9.95(s,1H),9.68(s,1H),9.29(s,1H),7.37–7.25(m,5H),7.23(s,1H),7.22–7.16(m,3H),7.06(m,1H),6.95(dd,J=7.3,1.8Hz,1H),6.36(s,1H),3.82(s,2H).13C NMR(101MHz,DMSO)δ165.93,157.92,157.76,142.87,141.61,140.62,137.05,129.78,129.19,128.84,126.41,118.82,118.63,115.01,112.12,111.74,105.82,41.85;高分辨质谱(ESI)C20H17NO3[M+H]+:理论值:320.1281,实测值:320.1277。
实施例9合成N-(3-苄基-5-羟基苯基)-2-氯苯甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、2-氯苯甲酰氯(101μL,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃5mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)-2-氯苯甲酰胺140mg,产率52%。
1H NMR(400MHz,DMSO)δ10.29(s,1H),9.34(s,1H),7.57–7.45(m,3H),7.42(m,1H),7.29(m,2H),7.19(m,3H),7.15(m,1H),6.98(m,1H),6.98(m,1H),6.37(m,1H),3.82(s,1H).13C NMR(101MHz,DMSO)δ163.87,158.12,150.82,146.89,143.35,141.46,140.08,138.59,133.79,129.23,128.87,126.46,123.57,112.20,111.27,105.05,41.72;高分辨质谱(ESI)C20H17NO2Cl[M+H]+:理论值:338.0942,实测值:338.0942。
实施例10合成N-(3-苄基-5-羟基苯基)-3,5-双(三氟甲基)苯甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、3,5-双三氟甲基苯甲酰氯(159μL,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃5mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)-3,5-双(三氟甲基)苯甲酰胺168mg,产率48%。
1H NMR(400MHz,DMSO)δ10.48(s,1H),9.46(s,1H),8.58(s,1H),8.34(s,1H),7.30(m,1H),7.21(m,4H),7.02(s,1H),6.45(s,1H),3.86(s,1H).13C NMR(101MHz,DMSO)δ162.82,158.05,143.16,141.51,139.89,137.69,130.86(q,2J=33.4Hz),129.21,129.01(q,4J=1Hz),128.88,126.47,125.44(q,1J=272Hz),123.60(q,1J=272Hz),112.50,112.26,106.08,41.76;高分辨质谱(ESI)C22H16NO2F6[M+H]+:理论值:440.1080,实测值:440.1092。
实施例11合成N-(3-苄基-5-羟基苯基)-2,4-二氯苯甲酰胺
1-苄基-3-氨基苯酚的合成参加实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、2,4-二氯苯甲酰氯(123μL,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃5mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)-2,4-二氯苯甲酰胺205mg,产率55%。
1H NMR(400MHz,MeOD)δ7.55(d,J=1.9Hz,1H),7.49(d,J=8.2Hz,1H),7.41(dd,J=8.2,1.9Hz,1H),7.29–7.22(m,2H),7.22–7.12(m,5H),6.92(s,1H),3.87(s,2H).13C NMR(100MHz,MeOD)δ165.70,157.48,143.41,140.91,139.02135.95,135.26,131.76,129.69,129.37,128.57,128.08,127.14,125.75,112.12,111.96,105.11,41.43.高分辨质谱(ESI)C20H15NO2Cl2[M+H]+:理论值:372.0553,实测值:372.0561。
实施例12合成N-(3-苄基-5-羟基苯基)-2-氯烟酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、2-氯烟酰氯(154mg,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃5mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)-2-氯烟酰胺129mg,产率48%。
1H NMR(400MHz,DMSO)δ:10.42(s,1H),9.39(s,1H),8.51(d,J=4.7Hz,1H),8.02(d,J=7.4Hz,1H),7.54(dd,J=7.3,4.9Hz,1H),7.30(m,1H),7.21(m,1H),7.14(s,1H),6.94(s,1H),6.40(s,1H),3.84(s,1H).13C NMR(101MHz,DMSO)δ163.87,158.12,150.82,146.89,143.35,141.46,140.08,138.59,133.79,129.23,128.87,126.46,123.57,112.20,111.27,105.05,41.72;高分辨质谱(ESI)C19H16N2O2Cl[M+H]+:理论值:339.0895,实测值:339.0896。
实施例13合成N-(3-苄基-5-羟基苯基)噻吩-2-甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(99mg,0.5mmol)、2-噻吩甲酰氯(58.8μL,0.55mmol)、三乙胺(76.24μL,0.55mmol)和重蒸的四氢呋喃5mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即N-(3-苄基-5-羟基苯基)噻吩-2-甲酰胺94mg,产率61%。
1H NMR(400MHz,DMSO)δ10.01(s,1H),9.34(s,1H),7.99(d,J=3.3Hz,1H),7.82(d,J=4.8Hz,1H),7.36–7.25(m,2H),7.20(m,4H),7.16(s,1H),6.99(s,1H),6.38(s,1H),3.83(s,2H).13C NMR(101MHz,DMSO)δ160.21,157.99,143.02,141.56,140.74,140.12,132.15,129.42,129.20,128.86,128.45,126.44,112.10,111.93,105.87,41.81.高分辨质谱(ESI)C18H15NO2S[M+H]+:理论值:310.0896,实测值:310.0892。
实施例14合成N-(3-苄基-5-羟基苯基)-4-甲基-1,2,3-噻二唑-5-甲酰胺
1-苄基-3-氨基苯酚的合成参见实施例1。在25mL圆底烧瓶中,加入1-苄基-3-氨基苯酚(99mg,0.5mmol)、4-甲基-1,2,3-噻二唑-5-羧酸(108mg,0.75mmol)、亚磷酸三苯酯(197μL,0.75mmol)和重蒸的甲苯5mL,在110℃反应12h。反应液减压除去溶剂,残余物用硅胶柱层析纯化(石油醚/二氯甲烷梯度洗脱),得到黄色固体即N-(3-苄基-5-羟基苯基)-4-甲基-1,2,3-噻二唑-5-甲酰胺72mg,产率44%。
1H NMR(400MHz,DMSO)δ10.52(s,1H),9.43(s,1H),7.29(m,2H),7.22(m,3H),7.11(s,1H),6.93(s,1H),6.43(s,1H),3.84(s,2H),2.78(s,3H).13C NMR(101MHz,MeOD)δ159.28,158.18,157.64,144.18,143.49,140.84,138.69,128.58,128.07,125.75,112.49,112.09,105.40,41.40,12.01.高分辨质谱(ESI)C17H15N3O2S[M+H]+:理论值:326.0958,实测值:326.0956。
实施例15合成3-苄基-5-羟基苯基-氨基甲酸-4,4-二甲基环己酯
1-苄基-3-氨基苯酚的合成参见实施例1。在50mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、氯甲酸4,4-二甲基环己酯(167mg,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃20mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即3-苄基-5-羟基苯基-氨基甲酸-4,4-二甲基环己酯129mg,产率46%。
1H NMR(400MHz,DMSO)δ9.34(s,1H),9.23(s,1H),7.28(t,J=7.4Hz,2H),7.22–7.14(m,3H),6.80(d,J=10.9Hz,2H),6.23(s,1H),4.68–4.49(m,1H),3.76(s,2H),1.84–1.67(m,2H),1.59–1.47(m,2H),1.47–1.38(m,2H),1.32–1.19(m,2H),0.92(s,3H),0.91(s,3H).13C NMR(101MHz,DMSO)δ157.98,153.44,142.91,141.59,140.74,129.14,128.79,126.37,110.45,110.11,103.86,72.42,41.85,36.27,29.75,27.67.高分辨质谱(ESI)C22H27NO3[M+Na]+:理论值:376.1183,实测值:376.1873。
实施例16合成3-苄基-5-羟基苯基-氨基甲酸苄酯
1-苄基-3-氨基苯酚的合成参见实施例1。在50mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、氯甲酸苄酯(149mg,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃20mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即3-苄基-5-羟基苯基-氨基甲酸苄酯114mg,产率43%。
1H NMR(400MHz,DMSO)δ9.57(s,1H),9.26(s,1H),7.43–7.32(m,2H),7.31–7.24(m,1H),7.22–7.14(m,1H),6.83(s,1H),6.78(s,1H),6.24(s,1H),5.11(s,1H),3.77(s,1H).13C NMR(101MHz,DMSO)δ158.10,153.80,143.19,141.71,140.52,137.20,129.15,128.89,128.82,128.45,126.60,126.39,110.68,110.12,103.77,66.17,41.81.高分辨质谱(ESI)C21H19NO3[M+Na]+:理论值:356.1257,实测值:356.1257。
实施例17合成3-苄基-5-羟基苯基-氨基甲酸乙酯
1-苄基-3-氨基苯酚的合成参见实施例1。在50mL圆底烧瓶中,在冰浴冷却下加入1-苄基-3-氨基苯酚(160mg,0.8mmol)、氯甲酸乙酯(94mg,0.88mmol)、三乙胺(110μL,0.88mmol)和重蒸的四氢呋喃20mL,在室温下反应12h。反应液用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶柱层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体即3-苄基-5-羟基苯基-氨基甲酸乙酯104mg,产率48%。
1H NMR(400MHz,DMSO)δ9.40(s,1H),9.23(s,1H),7.28(t,J=7.4Hz,1H),7.18(d,J=7.7Hz,1H),6.79(d,J=19.2Hz,1H),6.22(s,1H),4.08(q,J=7.0Hz,1H),3.76(s,1H),1.21(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ158.09,153.89,143.02,141.57,140.64,129.14,128.81,126.38,110.52,110.12,103.76,60.43,41.81,14.99.高分辨质谱(ESI)C16H17NO3[M+Na]+:理论值:294.1101,实测值:294.1091。
实施例18合成N-(3-羟基-5-苯氧基苯基)-苯甲酰胺
在100mL圆底烧瓶中,加入1-溴-3-甲氧基硝基苯(4.64g,20mmol)、铁粉(5.6g,100mmol)、醋酸/甲醇/水混合溶剂20mL,在反应液中加入一滴浓盐酸,在109℃反应1h,然后在室温下反应4h。在反应液中加入20mL水,用乙酸乙酯(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱),得到黄色固体即3-溴-5-甲氧基苯胺2.15g,产率54%。
在100mL圆底烧瓶中,在冰浴冷却下加入3-溴-5-甲氧基苯胺(301mg,1.5mmol)、苯甲酰氯(190μL,1.65mmol)、三乙胺(228μL,1.65mmol)和重蒸的四氢呋喃15mL,在室温下反应12h。在反应液中加入15mL水,用乙酸乙酯(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱),得到白色固体N-(3-溴-5-甲氧基苯基)苯甲酰胺256mg,产率55%。
在100mL两口瓶中,加入苯酚(112mg,1.2mmol)、N-(3-溴-5-甲氧基苯)苯甲酰胺(244mg,0.8mmol)、磷酸钾(339mg,1.6mmol)、碘化亚铜(15mg)和无水DMSO15mL,在氩气保护下于110℃反应过夜。反应液冷却后加入15mL水,用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂,残余物用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到N-(3-甲氧基-5-苯氧基苯)苯甲酰胺140mg,产率55%。
在100mL圆底烧瓶中,加入N-(3-甲氧基-5-苯氧基苯基)苯甲酰胺(140mg,0.44mmol)和重蒸的二氯甲烷10mL,在-78℃下缓慢滴加三溴化硼二氯甲烷溶液2.2mL(1mol/L),加完后在0℃下继续反应12h。反应液用饱和碳酸氢钠淬灭,然后用二氯甲烷(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱),得到黄色固体即N-(3-羟基-5-苯氧基苯基)-苯甲酰胺53mg,产率40%。
1H NMR(400MHz,DMSO)δ10.16(s,1H),9.67(d,J=22.8Hz,1H),7.93(d,J=7.2Hz,2H),7.59(t,J=7.2Hz,1H),7.52(t,J=7.3Hz,2H),7.46–7.37(m,2H),7.22(s,1H),7.17(t,J=7.4Hz,1H),7.08(d,J=7.8Hz,2H),6.98(m,1H).13C NMR(100MHz,DMSO)δ166.10,159.17,158.35,156.89,141.62,135.45,131.99,130.43,128.78,128.12,123.99,119.55,102.94,101.68,101.58.高分辨质谱(ESI)C19H15NO3[M+H]+:理论值:306.1125,实测值:306.1113。
实施例19合成N-(3-羟基-5-苯胺基苯基)-苯甲酰胺
N-(3-溴-5-甲氧基苯基)-苯甲酰胺的合成参见实施例18。在100mL两口瓶中,加入苯胺(110μL,1.2mmol)、N-(3-溴-5-甲氧基苯)苯甲酰胺(244mg,0.8mmol)、磷酸钾(339mg,1.6mmol)、碘化亚铜(15mg)和无水DMSO 15mL,在氩气保护下于110℃反应过夜。反应液冷却后加入15mL水,用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂,残余物用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到N-(3-甲氧基-5-苯胺基苯基)-苯甲酰胺152mg,产率60%。
在100mL圆底烧瓶中,加入N-(3-甲氧基-5-苯胺基苯基)-苯甲酰胺(152mg,0.48mmol)和重蒸的二氯甲烷10mL,在-78℃下缓慢滴加三溴化硼二氯甲烷溶液2.4mL(1mol/L),加完后在0℃下继续反应12h。反应液用饱和碳酸氢钠淬灭,然后用二氯甲烷(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即N-(3-羟基-5-苯胺基苯基)-苯甲酰胺75mg,产率53%。
1H NMR(400MHz,CDCl3)δ9.98(s,1H),9.21(s,1H),8.05(s,1H),7.95–7.87(m,2H),7.60–7.54(m,1H),7.54–7.47(m,2H),7.27–7.17(m,2H),7.09(m,3H),6.86–6.78(m,2H),6.25(t,J=2.0Hz,1H).13C NMR(101MHz,DMSO)δ165.89,158.55,144.89,143.90,141.05,135.73,131.82,129.49,128.74,128.10,120.01,117.69,100.34,100.18,99.98.高分辨质谱(ESI)C19H16N2O2[M+H]+:理论值:305.1285,实测值:305.1279。
实施例20合成N-(3-羟基-5-(甲基苯胺基)苯基)-苯甲酰胺
N-(3-溴-5-甲氧基苯基)-苯甲酰胺的合成参见实施例18。在100mL两口瓶中,加入N-甲基苯胺(130μL,1.2mmol)、N-(3-溴-5-甲氧基苯基)苯甲酰胺(244mg,0.8mmol)、磷酸钾(339mg,1.6mmol)、碘化亚铜(15mg)和无水DMSO 15mL,在氩气保护下于110℃反应过夜。反应液冷却后加入15mL水,用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂,残余物用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到N-(3-甲氧基-5-(甲基苯胺基)苯基)-苯甲酰胺127mg,产率52%。
在100mL圆底烧瓶中,加入N-(3-甲氧基-5-(甲基苯胺基)苯基)-苯甲酰胺(152mg,0.48mmol)和重蒸的二氯甲烷10mL,在-78℃下缓慢滴加三溴化硼二氯甲烷溶液2.4mL(1mol/L),加完后在0℃下继续反应12h。反应液用饱和碳酸氢钠淬灭,然后用二氯甲烷(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即N-(3-羟基-5-(甲基苯胺基)苯基)-苯甲酰胺67mg,产率55%。
1H NMR(400MHz,DMSO)δ10.08(s,1H),9.36(s,1H),7.97(dd,J=21.2,7.8Hz,2H),7.61(t,J=7.2Hz,1H),7.54(t,J=7.4Hz,2H),7.34(t,J=7.5Hz,2H),7.09(d,J=8.2Hz,3H),7.00(t,J=7.2Hz,1H),6.95(s,1H),6.19(s,1H),6.19(s,1H),3.26(s,3H).13C NMR(101MHz,DMSO)δ165.88,158.54,150.16,149.11,141.11,135.60,131.86,129.62,128.74,128.08,121.88,121.44,103.38,102.89,101.30,40.56.高分辨质谱(ESI)C20H18N2O2[M+Na]+:理论值:341.1260,实测值:341.1240。
实施例21合成N-(3-羟基-5-(甲基-2-吡啶基胺基)苯基)-苯甲酰胺
N-(3-溴-5-甲氧基苯基)-苯甲酰胺的合成参见实施例18。在100mL两口瓶中,加入2-甲胺基吡啶(123μL,1.2mmol)、N-(3-溴-5-甲氧基苯基)-苯甲酰胺(244mg,0.8mmol)、磷酸钾(339mg,1.6mmol)、碘化亚铜(15mg)和无水DMSO 15mL,在氩气保护下于110℃反应过夜。反应液冷却后加入15mL水,用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂,残余物用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到N-(3-甲氧基-5-(甲基-2-吡啶基胺基)苯基)-苯甲酰胺117mg,产率48%。
在100mL圆底烧瓶中,加入N-(3-甲氧基-5-(甲基-2-吡啶基胺基)苯基)-苯甲酰胺(152mg,0.48mmol)和重蒸的二氯甲烷10mL,在-78℃下缓慢滴加三溴化硼二氯甲烷溶液2.4mL(1mol/L),加完后在0℃下继续反应12h。反应液用饱和碳酸氢钠淬灭,然后用二氯甲烷(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即N-(3-羟基-5-(甲基-2-吡啶基胺基)苯基)-苯甲酰胺64mg,产率57%。
1H NMR(400MHz,DMSO)δ10.14(s,1H),9.59(s,1H),8.16(dd,J=5.0,1.1Hz,1H),7.95–7.89(m,2H),7.58(dd,J=8.4,6.1Hz,1H),7.51(t,J=7.3Hz,2H),7.45(t,J=6.9Hz,1H),7.26(t,J=1.9Hz,1H),7.17(s,1H),6.70–6.65(m,1H),6.63(d,J=8.6Hz,1H),6.41(t,J=2.0Hz,1H),3.35(s,3H).13C NMR(101MHz,DMSO)δ166.02,158.95,158.62,148.03,147.80,141.51,137.31,135.43,132.03,128.82,128.12,113.77,109.70,108.77,108.46,104.94,38.41.高分辨质谱(ESI)C19H17N3O2[M+H]+:理论值:320.1394,实测值:320.1373。
实施例22合成N-(3-羟基-5-(甲基-2-吡嗪基胺基)苯基)-苯甲酰胺
N-(3-溴-5-甲氧基苯基)-苯甲酰胺的合成参见实施例18。在100mL两口瓶中,加入2-甲胺基吡嗪(114μL,1.2mmol)、N-(3-溴-5-甲氧基苯基)-苯甲酰胺(244mg,0.8mmol)、磷酸钾(339mg,1.6mmol)、碘化亚铜(15mg)和无水DMSO 15mL,在氩气保护下于110℃反应过夜。反应液冷却后加入15mL水,用乙酸乙酯(15mL×2)萃取,萃取液在减压下除去溶剂,残余物用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到N-(3-甲氧基-5-(甲基-2-吡嗪基胺基)苯基)-苯甲酰胺122mg,产率50%。
在100mL圆底烧瓶中,加入N-(3-甲氧基-5-(甲基-2-吡嗪基胺基)苯基)-苯甲酰胺(152mg,0.48mmol)和重蒸的二氯甲烷10mL,在-78℃下缓慢滴加三溴化硼二氯甲烷溶液2.4mL(1mol/L),加完后在0℃下继续反应12h。反应液用饱和碳酸氢钠淬灭,然后用二氯甲烷(20mL×2)萃取,萃取液在减压下除去溶剂得到粗产物,用硅胶层析纯化(石油醚/乙酸乙酯梯度洗脱)得到白色固体即N-(3-羟基-5-(甲基-2-吡嗪基胺基)苯基)-苯甲酰胺62mg,产率53%。
1H NMR(400MHz,DMSO)δ10.21(s,1H),9.73(s,1H),8.15(s,1H),8.01(s,1H),7.92(d,J=7.7Hz,2H),7.87(s,1H),7.58(t,J=7.0Hz,1H),7.52(t,J=7.3Hz,2H),7.32(s,1H),7.22(s,1H),6.47(s,1H),3.36(s,3H).13C NMR(101MHz,DMSO)δ166.07,159.23,154.66,146.24,141.97,141.72,135.35,133.17,133.03,132.05,128.82,128.11,108.72,108.47,105.74,38.21.高分辨质谱(ESI)C18H16N4O2[M+H]+:理论值:321.1346,实测值:321.1331。
上述实施例制得的间二取代苯酚化合物的结构式和编号整理如表1:
表1实施例制得的代表性间二取代苯酚化合物
效果实施例实施例化合物的抗结核活性测定
1.平板法测定实施例化合物对结核分枝杆菌的最低抑菌浓度(MIC)
(1)结核分枝杆菌标准株H37Rv(广州市胸科医院提供)的液体培养:在7H9培养基(购买于Difco公司)中培养,37℃摇床长培养至菌液600nm下吸光值(OD600)为0.3~0.7,得到结核菌H37Rv培养液。
(2)配制不同浓度待测化合物的7H11培养基(购买于Difco公司)平板:将待测化合物用DMSO溶解,配制成适当浓度的初溶液,用7H11培养基进行稀释,每种化合物各10个浓度梯度,在96孔板中每孔加入100μL,待测化合物的终浓度分别为10,5,2.5,1.25,0.625,0.312,0.15,0.075,0.0375,0.019μg/mL。
(3)每孔接种100μL结核菌H37Rv培养液,每板均设有抗菌药异烟肼的阳性对照孔和不含有测试药物的DMSO替代阴性对照孔,将96孔板加盖后置于37℃培养。第三天后观察每孔中结核菌的生长情况并记录结果,第七天后再观察记录一次进行确认。分析数据,得出各化合物对于结核分枝杆菌H37Rv生长的最低抑制浓度(MIC),结果如下表2。
表2实施例化合物对结核分枝杆菌H37Rv的最低抑制浓度(MIC)
由表2结果可知,实施例化合物对结核菌H37Rv的生长具有很强的抑制作用,其中化合物2、3、7、15的MIC值分别达到0.625μg/mL、0.312μg/mL、1.25μg/mL、0.625μg/mL。
2.实施例化合物对临床分离的多药耐药结核菌株的最低抑制浓度(MIC)
P103、R7和P91为从广州市胸科医院临床分离的耐药结核分支杆菌株,所述的菌株对于常用的抗结核药物异烟肼和利福平耐药。
表3实施例化合物对多药耐药结核菌株的最低抑制浓度MIC
a H表示异烟肼;R表示利福平
由表3可知,化合物2和化合物3对于上述多药耐药结核菌株的生长也具有很强的抑制作用。
对比例
以下通过对比实施例说明本发明的间二取代苯酚化合物的结构特殊性与其抗结核菌活性密切相关,破坏该结构特殊性将导致得到的化合物完全或者很大程度上丧失抗结核菌活性。化合物6对于结核菌H37RV具有强的抑制活性(MIC=5μg/mL),然而去掉苯甲酰胺基,或者去掉3位苄基,或者将5位羟基甲基化,或者用羧基替换5位羟基,或者3位苄基氧化后得到的相应化合物都基本丧失了对于结核菌H37RV的生长抑制活性,这些对比结果充分说明了本发明的间二取代苯酚化合物的结构特殊性是其具备抗结核活性的关键。
对比化合物
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
1.一类通式为(Ⅰ)的间二取代苯酚化合物或其药学可接受的盐,
其中,R1为甲基、乙基、乙烯基、C3~C8烷基及环烷基、甲氧基、苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基、喹啉基、噻唑基、噻二唑基、苯氧基、苄氧基、乙氧基、C3~C8烷基氧基及环烷基氧基、四氢吡喃基、四氢呋喃基;或在芳香环上有单取代或者多取代基的苯基、萘基、噻吩基、呋喃基、吡啶基、嘧啶基、喹啉基、噻唑基、苯氧基、苄氧基,所述的取代基为甲基、乙基、C3~C6烷基及环烷基、氟、氯、溴、甲氧基、硝基、三氟甲基、腈基、羟基中的至少一种;
R2为无取代、单取代或多取代的苯基、噻吩基、呋喃基、吡啶基、吡嗪基、嘧啶基、噻唑基、吡唑基、三氮唑基,所述的取代基为甲基、氟、氯、溴、甲氧基、三氟甲基、腈基中的至少一种;
X为CH2、O、NH和NCH3;
所述的间二取代苯酚化合物不包含如下结构的化合物:
2.根据权利要求1所述的通式为(Ⅰ)的间二取代苯酚化合物或其药学可接受的盐,其特征在于:
所述的R1为C5~C8环烷基、苯基、苯基氧基、C5~C8环烷基氧基;或在苯环上有单取代或者多取代的苯基、苯基氧基,所述的取代基为甲基、氯、氟中的至少一种。
3.根据权利要求1所述的通式为(Ⅰ)的间二取代苯酚化合物或其药学可接受的盐,其特征在于:
所述的R2为苯基。
4.根据权利要求1所述的通式为(Ⅰ)的间二取代苯酚化合物或其药学可接受的盐,其特征在于:
所述的X为CH2或NCH3。
5.根据权利要求1所述的通式为(Ⅰ)的间二取代苯酚化合物或其药学可接受的盐,其特征在于,所述的间二取代苯酚化合物选自如下化合物之一:
3-苄基-5-羟基苯基-氨基甲酸-4,4-二甲基环己酯;
N-(3-苄基-5-羟基苯基)-4,4-二甲基-环己烷甲酰胺;
N-(3-苄基-5-羟基苯基)-4-甲基苯甲酰胺;
N-(3-羟基-5-(甲基苯胺基)苯基)-环己烷甲酰胺;
N-(3-苄基-5-羟基苯基)环己基甲酰胺;
N-(3-苄基-5-羟基苯基)-2-(4,4-二甲基环己基)乙酰胺;
N-(3-苄基-5-羟基苯基)苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2-氯苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2,4-二氯苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2-氯烟酰胺;
N-(3-苄基-5-羟基苯基)噻吩-2-甲酰胺;
3-苄基-5-羟基苯基-氨基甲酸乙酯;
N-(3-羟基-5-苯氧基苯基)-苯甲酰胺;
N-(3-羟基-5-(甲基苯胺基)苯基)-苯甲酰胺;
N-(3-羟基-5-(甲基-2-吡啶基胺基)苯基)-苯甲酰胺;
N-(3-羟基-5-(甲基-2-吡嗪基胺基)苯基)-苯甲酰胺;
N-(3-苄基-5-羟基苯基)-2-苯乙酰胺;
N-(3-苄基-5-羟基苯基)-4,4-二氟环己基甲酰胺;
N-(3-苄基-5-羟基苯基)四氢吡喃-4-甲酰胺。
6.一种药物组合物,其特征在于:
包括权利要求1~5任一项所述的间二取代苯酚化合物或其药学可接受的盐,以及任选的药学可接受的辅料、载体或赋形剂。
7.权利要求1~5任一项所述的间二取代苯酚化合物的制备方法,其特征在于,
当X为CH2时,包括如下步骤:采用3-硝基-5-甲氧基苯甲酸为原料,经过还原成醇、傅克烷基化、脱甲基、硝基还原和酰化反应制备得到所述的间二取代苯酚化合物;
或者,
当X为O、NH、NCH3时,包括如下步骤:采用3-溴-5-硝基苯甲醚为原料,经过硝基还原、酰化、偶联、脱甲基反应制备得到所述的间二取代苯酚化合物。
8.权利要求1~5任一项所述的间二取代苯酚化合物或其药学可接受的盐或权利要求6所述的药物组合物的应用,其特征在于:
在制备预防和/或治疗结核病的药物中的应用。
9.权利要求1~5任一项所述的间二取代苯酚化合物或其药学可接受的盐或权利要求6所述的药物组合物的应用,其特征在于:
所述的应用为在制备预防和/或治疗结核分枝杆菌感染引起的疾病的药物中的应用。
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AR076880A1 (es) * | 2009-05-18 | 2011-07-13 | Orion Corp | Inhibidores de proteasa, composiciones farmaceuticas que los contienen y su uso. |
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