CN117105809B - Benzanilide compound and preparation method and application thereof - Google Patents
Benzanilide compound and preparation method and application thereof Download PDFInfo
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- CN117105809B CN117105809B CN202311361694.7A CN202311361694A CN117105809B CN 117105809 B CN117105809 B CN 117105809B CN 202311361694 A CN202311361694 A CN 202311361694A CN 117105809 B CN117105809 B CN 117105809B
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- bab159
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- ethyl acetate
- lithium
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- -1 Benzanilide compound Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 38
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- 101100108853 Mus musculus Anp32e gene Proteins 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- 239000013067 intermediate product Substances 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- BJYHBJUWZMHGGQ-UHFFFAOYSA-N 1,2-dichloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Cl)=C1Cl BJYHBJUWZMHGGQ-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical class Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000001979 organolithium group Chemical group 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000011089 carbon dioxide Nutrition 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- SZAVVKVUMPLRRS-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].C[CH-]C SZAVVKVUMPLRRS-UHFFFAOYSA-N 0.000 claims description 2
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 claims description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- NKBASRXWGAGQDP-UHFFFAOYSA-N 5-chlorosalicylic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1O NKBASRXWGAGQDP-UHFFFAOYSA-N 0.000 claims 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 30
- 239000003242 anti bacterial agent Substances 0.000 abstract description 12
- 241000894006 Bacteria Species 0.000 abstract description 8
- 241000193468 Clostridium perfringens Species 0.000 abstract description 7
- 229940088710 antibiotic agent Drugs 0.000 abstract description 7
- 238000006257 total synthesis reaction Methods 0.000 abstract description 7
- 241000191940 Staphylococcus Species 0.000 abstract description 6
- 241000193830 Bacillus <bacterium> Species 0.000 abstract description 5
- 241000194017 Streptococcus Species 0.000 abstract description 5
- 241000194033 Enterococcus Species 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 241000191967 Staphylococcus aureus Species 0.000 description 6
- 229940124350 antibacterial drug Drugs 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- ZVSKZLHKADLHSD-UHFFFAOYSA-N benzanilide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=CC=C1 ZVSKZLHKADLHSD-UHFFFAOYSA-N 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000035143 Bacterial infection Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000022362 bacterial infectious disease Diseases 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- 229960004889 salicylic acid Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- 241000295644 Staphylococcaceae Species 0.000 description 3
- 206010041925 Staphylococcal infections Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 229940041033 macrolides Drugs 0.000 description 3
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000304886 Bacilli Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000006041 probiotic Substances 0.000 description 2
- 230000000529 probiotic effect Effects 0.000 description 2
- 235000018291 probiotics Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 1
- AKLMFDDQCHURPW-ISIOAQNYSA-N Eravacycline Chemical compound C([C@H]1C[C@H]2[C@@H](C(C(C(N)=O)=C(O)[C@@]2(O)C(=O)C1=C(O)C1=C2O)=O)N(C)C)C1=C(F)C=C2NC(=O)CN1CCCC1 AKLMFDDQCHURPW-ISIOAQNYSA-N 0.000 description 1
- 239000005779 Fenpyrazamine Substances 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241000194021 Streptococcus suis Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000011482 antibacterial activity assay Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229950004877 eravacycline Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- UTOHZQYBSYOOGC-UHFFFAOYSA-N fenpyrazamine Chemical compound O=C1N(C(C)C)N(C(=O)SCC=C)C(N)=C1C1=CC=CC=C1C UTOHZQYBSYOOGC-UHFFFAOYSA-N 0.000 description 1
- 244000000058 gram-negative pathogen Species 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
- A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
- A01N37/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system having at least one carboxylic group or a thio analogue, or a derivative thereof, and one oxygen or sulfur atom attached to the same aromatic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Pest Control & Pesticides (AREA)
- Environmental Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- Epidemiology (AREA)
- Agronomy & Crop Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dentistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a benzanilide compound, a preparation method and application thereof, wherein the structure of the benzanilide compound is shown as the following formula (I): (I) . The benzanilide compound (BAB 159) prepared by the total synthesis strategy has broad-spectrum antibacterial activity, has obviously excellent antibacterial activity compared with common commercial antibiotics, has obviously more excellent antibacterial activity on bacteria including staphylococcus, enterococcus, bacillus, clostridium perfringens and streptococcus, and has potential for industrialization.
Description
Technical Field
The invention belongs to the field of antibacterial compounds, and particularly relates to a benzanilide compound as well as a preparation method and application thereof.
Background
The large-scale and irregular use of antibacterial drugs causes the problem of bacterial drug resistance to be prominent, clinical available drugs are deficient, and bacterial infection, especially multi-drug resistant bacterial infection, is difficult to treat. At present, small molecule antibacterial compounds remain the primary means of effectively treating bacterial infections. However, the development of novel antimicrobial compounds of natural product origin is slow, far below the rate of bacterial resistance development, due to the limitations of synthetic technology and productivity. The artificially synthesized antibacterial drug has the advantages of high synthesis speed, simple process, easy modification, and the like, and can break through the defects of limited structure types, low discovery frequency, long period, and the like of natural products. Therefore, the compound with antibacterial potential is synthesized through a total synthesis means, antibacterial structure skeletons are enriched, the development efficiency of the antibacterial compound is improved, and a lead compound foundation is provided for the development of the antibacterial compound.
In recent years, development of novel antibacterial compounds based on total synthesis means has received a great deal of attention in the field of drug creation. For example, the report of the J.Nature in 2016 shows that more than 300 macrolides (Nature, 2016, 533, 338; nature,2016, 533, 326) with antibacterial activity are obtained through a 'building block' chemical total synthesis strategy, so that analysis of the structure-activity relationship of the macrolides (ACC CHEM RES,2021, 54, 1635) is accelerated, and a foundation is laid for further designing and developing novel macrolides with excellent antibacterial activity. Meanwhile, the fully synthetic compounds are also effective against multiple resistant bacteria, as in 2021, a new class of antibacterial drugs oxepanoprolinamide synthesized based on lincoamide-like chemical building blocks and designed in structural orientation, which overcome Erm-, cfr-, and ABCF-mediated multidrug resistance and exhibit broad activity against gram-positive and gram-negative pathogens (Nature, 2021, 599, 507). The tetracycline antibacterial drug ERAVACYCLINE, approved by the FDA in 2018, is an excellent case for the clinical entrance of chemical total synthetic Drugs, which have good antibacterial activity against both common tetracycline-resistant gram-positive and gram-negative bacteria in vitro and in vivo (Drugs, 2016, 76, 567; drugs,2019, 79, 315;Nat Microbiol.2019, 4, 1450). The research shows that the chemical total synthesis mode can effectively enrich candidate libraries of antibacterial drugs, obtain broad-spectrum antibacterial compounds for overcoming various drug resistance mechanisms, lay a foundation for structure-activity analysis and further promote the research and development of novel antibacterial compounds.
The synthesis process is simple, the modifiable property is strong, and the modification and transformation of the benzanilide as a framework structure have been studied in various fields of anti-tumor, anti-virus, anti-bacterial and the like (Chem Sci, 2021, 12, 13450;Eur J Med Chem, 2022, 236, 114318;J Med Chem, 2020, 63, 12830). The benzanilide antibacterial agents which are practically used at present comprise fluoroamide and fenpyrazamine, the structures of which are shown as a compound of the formula A and a compound of the formula B respectively, but the benzanilide antibacterial agents are mainly used for fungal infection on plants in the pesticide field. At present, the application of the structure on bacterial infection is not reported.
。
Disclosure of Invention
In order to solve the problems of serious bacterial drug resistance, insufficient candidate antibacterial drugs and the like, the invention is based on a total synthesis mode to modify and replace substituent groups of the benzanilide with a mother nucleus structure, and screens out a compound BAB159 with optimal antibacterial activity, which has excellent antibacterial activity. Is a novel antibacterial agent which is expected to be industrialized. The invention solves the technical problems by the following technical proposal:
the first object of the present invention is to provide a benzanilide compound having the structure shown in the following formula (I):
(I)。
The compound shown in the formula (I) is named as BAB159, has excellent antibacterial activity, shows good antibacterial activity on staphylococcus aureus standard strain 25923 (Staphylococcus aureusATCC 25923), methicillin-resistant staphylococcus aureus (MRSA T144), has the Minimum Inhibitory Concentration (MIC) of 0.015 mug/mL, and meanwhile, shows that the compound shown in the formula (I) has better activity on five types of bacteria including staphylococcus, enterococcus, bacillus, clostridium perfringens and streptococcus clinically, and is superior to various antibiotics clinically used.
The second object of the present invention is to provide a process for preparing a benzanilide compound of the formula (I) described above, which comprises the following synthetic route:
。
Further, the preparation method of the benzanilide compound shown in the formula (I) comprises the following steps:
(S1) under the protection of inert atmosphere, 1, 2-dichloro-3- (trifluoromethyl) benzene reacts for 2-4 hours at the temperature of minus 80 ℃ to minus 60 ℃ in the presence of organolithium and organoamine, dry ice is poured into the reaction liquid, the reaction liquid is heated to room temperature and stirred for 12-24 hours, and an intermediate CPd1 is obtained after post treatment;
(S2) reacting the intermediate Cpd1 with tert-butanol in the presence of an azide compound to give the intermediate Cpd2;
(S3) adding ethyl acetate into the intermediate product Cpd2 for dissolution, adding saturated ethyl acetate hydrochloride, stirring, and precipitating a white solid to obtain an intermediate product Cpd3;
(S4) salicylic acid reacts with oxalyl chloride to obtain an acyl chloride intermediate;
(S5) reacting the intermediate Cpd3 with acyl chloride in the presence of potassium iodide at 60-80 ℃ for 15-20h, separating out solid, and carrying out post-treatment to obtain the compound BAB159 of the formula (I).
Further, in the step (S1), the molar ratio of 1, 2-dichloro-3- (trifluoromethyl) benzene, organolithium, and organoamine is 1:1-1.2:1-1.2. Further, in the step (S1), the inert atmosphere protection is selected from at least one of nitrogen and argon, the organic lithium is selected from at least one of n-butyllithium, tert-butyllithium, methyllithium, propyllithium, isopropyllithium and phenyllithium, and the organic amine is selected from at least one of diisopropylamine and triethylamine.
The post-treatment is that the reaction liquid is concentrated, water and ethyl acetate are added, acid is regulated, liquid is separated, the organic phase is concentrated, and pulping is carried out; acid adjustment is to adjust the pH to 2-4, such as 3; the volume ratio of water to ethyl acetate is 1:2-3, wherein the water addition amount is 1-1.5 times of the mass of the 1, 2-dichloro-3- (trifluoromethyl) benzene; the reagent used for beating is n-hexane.
Further, in the step (S2), the reaction condition is that the reaction is carried out for 10 to 20 hours under an inert atmosphere; the reaction solvent is at least one selected from dioxane, benzene and toluene, and the ratio of the volume usage of the solvent to the mass of the intermediate Cpd1 is 10-15mL:1g. The volume amount of tertiary butanol is such that the ratio of the mass of the intermediate Cpd1 is 3-6mL:1g. The reaction proceeds in the forward direction with a large excess of t-butanol. The azide compound is at least one selected from diphenyl azide phosphate and sodium azide, and the dosage of the azide compound is 1 to 1.5 times of the molar quantity of the intermediate product Cpd 1.
Further, in the step (S2), after the reaction is completed, the post-treatment is that the reaction solution is poured into ice, concentrated, extracted with ethyl acetate, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate volume ratio is 10-30:1, such as 20:1) to obtain an intermediate Cpd2.
Further, in the step (S3), the intermediate Cpd2, ethyl acetate were dissolved, and the ratio of the amounts of saturated ethyl acetate hydrochloride was 1g:6-10mL:6-10mL.
Further, in the step (S4), the molar ratio of salicylic acid to oxalyl chloride is 1:1.1-1.3, such as 1:1.2. The reaction solvent is at least one of dichloromethane, chloroform and ethyl acetate. DMF was also added as catalyst, the volume addition of DMF and the mass ratio of salicylic acid were 5-10mL:100g, preferably 5-8mL:100g.
Further, in step (S5), the molar ratio of the intermediate Cpd3, the acid chloride intermediate, and potassium iodide is 1:1.1-1.3:1.5-2. The reaction solvent is at least one of acetonitrile, methanol, ethanol or pyridine. The post-treatment is to filter the precipitated solid, dissolve the filter cake with ethyl acetate, wash with water until the pH is neutral, spin-dry, pulp with at least one solvent of dichloromethane, chloroform and diethyl ether, and filter to obtain the product BAB159.
The third object of the invention is to provide the application of the benzanilide compound shown in the formula (I) in the aspect of preparing antibacterial agents.
Further, the antibacterial agent has an inhibitory/killing effect on bacteria including: staphylococci, enterococci, bacillus, clostridium perfringens and streptococcus.
The compound BAB159 prepared by the total synthesis strategy has broad-spectrum antibacterial activity, and compared with common commercial antibiotics, the compound BAB159 has obviously excellent antibacterial activity on bacteria including staphylococcus, enterococcus, bacillus, clostridium perfringens and streptococcus.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum (solvent DMSO) of the compound BAB159 obtained in example 5;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound BAB159 obtained in example 5;
FIG. 3 is a high resolution mass spectrum of the compound BAB159 obtained in example 5 in positive ion mode;
fig. 4 is a high resolution mass spectrum of the compound BAB159 obtained in example 5 in negative ion mode.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. The following examples facilitate a better understanding of the present invention, but are not intended to limit the same. The experimental methods in the following examples are conventional methods unless otherwise specified.
The staphylococcus aureus standard strain S. aureusATCC 25923 and 25923 is purchased from China general microbiological culture collection center (CGMCC), and the methicillin-resistant staphylococcus aureus MRSA T144 is obtained by separation in the laboratory.
The specific strains of the invention in tables 2 and 3 were obtained from clinical isolates. Wherein the staphylococcus is mainly derived from tumor hospital isolation and dairy farm environmental samples; enterococci include human, animal, and probiotic products; the bacillus is mainly a probiotic source; streptococcus is mainly swine origin; clostridium perfringens is primarily of chicken origin. The strain numbers are laboratory internal numbers.
Example 1: synthesis of Compound Cpd1
Tetrahydrofuran was added to the three-necked flask and stirred to replace nitrogen, the temperature was lowered to-75 ℃, wen Dijia 29.8.8 g of butyllithium (1 eq) was controlled, wen Di g of diisopropylamine (47.1 g) was controlled, and 10 min g of diisopropylamine was stirred. Then, 100 g (1 eq) of 1, 2-dichloro-3- (trifluoromethyl) benzene was added dropwise, and the reaction was continued for two hours at the end of the addition. Pouring the reaction solution into dry ice, naturally heating to room temperature, stirring overnight, concentrating the reaction solution to remove tetrahydrofuran, adding 100mL of water and 200mL of ethyl acetate, adjusting the pH to 3, separating the solution, concentrating the organic phase to obtain a crude product of the product, pulping the organic phase with normal hexane, and filtering to obtain 72g of intermediate product Cpd1, wherein the yield is 60%.
。
Example 2: synthesis of Compound Cpd2
Cpd 172 g (1 eq) was added to a single-necked flask, 720mL of dioxane was uniformly dissolved, tert-butanol 350 mL, triethylamine 112 g (4 eq), 115 g of diphenyl azide phosphate (1.5 eq) were sequentially added, and the reaction was carried out overnight after the nitrogen substitution was completed three times. The reaction solution was poured into ice, concentrated ethyl acetate was extracted, and the organic phase was stirred (petroleum ether: ethyl acetate=20:1) to give 72 g of intermediate Cpd2 in 78.4% yield.
。
Example 3: synthesis of Compound Cpd3
Cpd2 72g is added into a single-mouth bottle, 720 mL ethyl acetate is added for dissolution, 720 mL saturated ethyl acetate hydrochloride is added for stirring overnight, and a white solid which is gradually separated out is the product. The solid obtained by filtration was 57g of intermediate Cpd3 in 98% yield.
。
Example 4: synthesis of acid chlorides
100 G salicylic acid is dissolved in 1L of dichloromethane, 8 ml of N, N-dimethylformamide is added, 1.2eq of oxalyl chloride is added under the ice bath condition, the reaction is carried out for 2 hours at room temperature, the reaction becomes clear, and the acyl chloride compound is obtained after the central control is finished and is dried in a spinning way for later use.
。
Example 5: synthesis of Compound BAB159
Cpd 350 g (1 eq) and acetonitrile were added to a single-necked flask, stirred well, potassium iodide (62 g (2 eq)) was added, and then the acid chloride compound 43 g (acetonitrile was dissolved) (1.2 eq) prepared in example 4 was slowly added, followed by reaction at 80℃for 16 hours. Standing overnight, filtering, dissolving the filter cake with ethyl acetate, washing with water twice, drying the organic phase, spin-drying the obtained product, pulping with dichloromethane, and filtering the solid to obtain the product BAB159 with a yield of 38.4%.
。
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum (solvent DMSO) of the compound BAB159 obtained in example 5. FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound BAB159 obtained in example 5. Fig. 3 is a high resolution mass spectrum of the compound BAB159 obtained in example 5 in positive ion mode. Fig. 4 is a high resolution mass spectrum of the compound BAB159 obtained in example 5 in negative ion mode.
From FIGS. 1 to 4, it can be judged that the structure of the compound obtained in example 5 is represented by formula (I).
Example 6: determination of bacteriostatic Activity of benzanilide derivative BAB159
Minimum Inhibitory Concentration (MIC) determinations of the benzanilide compound BAB159 of formula (I) and commercial antibiotics were made with reference to the micro broth dilution recommended by the american clinical laboratory standardization committee (CLSI 2022), and MIC result determinations were performed primarily with reference to the CLSI M100-32st Edition (2022) standard.
The test compound is dissolved in dimethyl sulfoxide (DMSO), 100. Mu.L of MHB broth medium is added into a 96-well U-shaped plate, 100. Mu.L of a certain concentration of the compound is added into the first column of the 96-well U-shaped plate, and the double ratio is diluted to the 10 th column. Single colonies of the test strain were picked up in BHI broth and grown to the logarithmic bacterial growth phase on a 37 ℃ shaker. The bacteria were adjusted to a turbidity of 0.5 by a Mirabilimeter and diluted 100-fold (about 10 6 CFU/mL) with MHB broth, 100. Mu.L of the above bacteria was added to a 96-well U-plate. Columns 11 and 12 contained only MHB broth and test bacterial liquid, respectively, as negative and positive controls. The 96-well U-shaped plate is placed in a 37 ℃ incubator for 16-18 h, and the experimental result is read, and the lowest macroscopic drug concentration for inhibiting the bacterial growth is taken as the MIC value of the compound. The results are shown in table 1 below:
table 1 antibacterial activity test
。
As can be seen from the data in Table 1, compared with the common commercial antibiotics, the compound of the formula (I) prepared by the invention has obviously excellent antibacterial activity, and has lower minimum antibacterial concentration on staphylococcus aureus standard strain 25923 (Staphylococcus aureusATCC 25923) and methicillin-resistant staphylococcus aureus (MRSA T144). Meanwhile, antibacterial activity assays of the antifungal agents fluoroamide and fenacet having the same parent nucleus structure found that they did not have antibacterial activity.
The compounds of the invention, BAB159, were also tested for their antibacterial activity against staphylococci, enterococci, bacilli, clostridium perfringens and streptococci, expressed as Minimum Inhibitory Concentration (MIC) in μg/mL. The results are shown in tables 2 and 3 below. Table 3 shows the test results for each specific strain in Table 2.
TABLE 2 antibacterial spectra of BAB159
。
Note that: the positive control except enterococcus was linezolid, and the rest was vancomycin.
TABLE 3 specific antibacterial spectra of BAB159
。
As can be seen from tables 2 and 3, the compounds of formula (I) prepared according to the present invention have significantly superior antibacterial activity compared to the usual commercial antibiotics. It shows activity superior to positive control antibiotics against a variety of common pathogenic bacteria in the clinic including staphylococci, enterococci, bacilli, clostridium perfringens, streptococcus suis. At the same time, it has equivalent activity to clinically sensitive and drug-resistant strains.
Claims (6)
1. A preparation method of a benzanilide compound BAB159 is characterized in that the BAB159 has a structure shown in the following formula (I): (I)；
The synthetic route for BAB159 is as follows:
；
The preparation method of the BAB159 comprises the following steps:
(S1) under the protection of inert atmosphere, 1, 2-dichloro-3- (trifluoromethyl) benzene reacts for 2-4 hours at the temperature of minus 80 ℃ to minus 60 ℃ in the presence of organolithium and organoamine, dry ice is poured into the reaction liquid, the reaction liquid is heated to room temperature and stirred for 12-24 hours, and an intermediate product Cpd1 is obtained after post treatment; the organic lithium is at least one of n-butyl lithium, tertiary butyl lithium, methyl lithium, propyl lithium, isopropyl lithium and phenyl lithium; the organic amine is at least one selected from diisopropylamine and triethylamine;
(S2) reacting the intermediate Cpd1 with tert-butanol in the presence of an azide compound to give the intermediate Cpd2; the azide compound is at least one selected from diphenyl azide phosphate and sodium azide;
(S3) adding ethyl acetate into the intermediate product Cpd2 for dissolution, adding saturated ethyl acetate hydrochloride, stirring, and precipitating a white solid to obtain an intermediate product Cpd3;
(S4) reacting 5-chlorosalicylic acid with oxalyl chloride to obtain an acyl chloride intermediate;
(S5) reacting the intermediate CPd3 and an acyl chloride intermediate in the presence of potassium iodide at 60-80 ℃ for 15-20h, separating out solids, and carrying out post-treatment to obtain the product compound shown as the formula (I).
2. The method according to claim 1, wherein in the step (S1), the molar ratio of 1, 2-dichloro-3- (trifluoromethyl) benzene, organolithium, and organoamine is 1:1-1.2:1-1.2.
3. The preparation method according to claim 1, wherein in the step (S2), the reaction condition is an inert atmosphere for 10 to 20 hours; the reaction solvent is at least one selected from dioxane, benzene and toluene, and the ratio of the volume usage of the solvent to the mass of the intermediate Cpd1 is 10-15mL:1g; the volume amount of tertiary butanol is such that the ratio of the mass of the intermediate Cpd1 is 3-6mL:1g; the amount of azide compound is 1 to 1.5 times the molar amount of intermediate Cpd 1.
4. The preparation method according to claim 1, wherein in the step (S3), the ratio of the amounts of the intermediate Cpd2, ethyl acetate, and saturated ethyl acetate hydrochloride is 1g:6-10mL:6-10mL.
5. The method according to claim 1, wherein in the step (S4), the molar ratio of 5 chloro-salicylic acid to oxalyl chloride is 1:1.1-1.3; DMF was also added as catalyst, the volume addition of DMF and the mass ratio of 5 chloro-salicylic acid were 5-10mL:100g.
6. The preparation method according to claim 1, wherein in the step (S5), the molar ratio of the intermediate Cpd3, the acid chloride intermediate, and potassium iodide is 1:1.1-1.3:1.5-2.
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