CN116675685A - Pyridine-containing bisoxazolidone compound and synthetic method and application thereof - Google Patents
Pyridine-containing bisoxazolidone compound and synthetic method and application thereof Download PDFInfo
- Publication number
- CN116675685A CN116675685A CN202210182957.7A CN202210182957A CN116675685A CN 116675685 A CN116675685 A CN 116675685A CN 202210182957 A CN202210182957 A CN 202210182957A CN 116675685 A CN116675685 A CN 116675685A
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- CN
- China
- Prior art keywords
- methyl
- acetamide
- piperazin
- oxazolidinone
- fluoropyridin
- 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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- 150000001875 compounds Chemical class 0.000 title claims abstract description 102
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 42
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- -1 isovaleryl Chemical group 0.000 claims description 288
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 205
- 239000000543 intermediate Substances 0.000 claims description 161
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 158
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 126
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 111
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 60
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 25
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 10
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 6
- CISUDJRBCKKAGX-UHFFFAOYSA-N 3-fluoro-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1F CISUDJRBCKKAGX-UHFFFAOYSA-N 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- ZIJAZUBWHAZHPL-UHFFFAOYSA-N 6-chloropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=C(Cl)N=C1 ZIJAZUBWHAZHPL-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 125000005543 phthalimide group Chemical group 0.000 claims description 4
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 claims description 3
- NJLNZZDPGNPRDN-UHFFFAOYSA-N 4-(4-methylpiperidin-1-yl)pyrimidine Chemical compound C1CC(C)CCN1C1=CC=NC=N1 NJLNZZDPGNPRDN-UHFFFAOYSA-N 0.000 claims description 3
- NTVCMEJZWNSEFW-ICSRJNTNSA-N 4-(diaminomethylideneamino)-n-[[(2s)-1-[(2s)-3-hydroxy-2-(naphthalen-2-ylsulfonylamino)propanoyl]pyrrolidin-2-yl]methyl]butanamide Chemical compound NC(N)=NCCCC(=O)NC[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 NTVCMEJZWNSEFW-ICSRJNTNSA-N 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- VTRZVQDDNUFEHQ-IBGZPJMESA-N CC(NC[C@@H](CN1C(C=C2)=CN=C2N(CC2)CCN2C(NC2CCCCC2)=O)OC1=O)=O Chemical compound CC(NC[C@@H](CN1C(C=C2)=CN=C2N(CC2)CCN2C(NC2CCCCC2)=O)OC1=O)=O VTRZVQDDNUFEHQ-IBGZPJMESA-N 0.000 claims description 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 235000005152 nicotinamide Nutrition 0.000 claims description 3
- 239000011570 nicotinamide Substances 0.000 claims description 3
- 229960003966 nicotinamide Drugs 0.000 claims description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 3
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 3
- CYJBWQFWXJKKMS-UHFFFAOYSA-N 1-amino-3-chloropropan-2-ol Chemical compound NCC(O)CCl CYJBWQFWXJKKMS-UHFFFAOYSA-N 0.000 claims description 2
- WCXIFOFRSVXJQS-SFHVURJKSA-N CC(NC[C@@H](CN1C2=CC=C(N(CC3)CCN3S(C3=CC=C(C(F)(F)F)C=C3)(=O)=O)N=C2)OC1=O)=O Chemical compound CC(NC[C@@H](CN1C2=CC=C(N(CC3)CCN3S(C3=CC=C(C(F)(F)F)C=C3)(=O)=O)N=C2)OC1=O)=O WCXIFOFRSVXJQS-SFHVURJKSA-N 0.000 claims description 2
- FAENLOIAYHVMFT-INIZCTEOSA-N O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2CCN(CC2)C(=O)C=2OC=CC=2)N=C1 Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2CCN(CC2)C(=O)C=2OC=CC=2)N=C1 FAENLOIAYHVMFT-INIZCTEOSA-N 0.000 claims description 2
- DKIRUZSABDATAK-XZXOBPBMSA-N O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2CCN(CC2)C(=O)\C=C\C=2OC=CC=2)N=C1 Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(N2CCN(CC2)C(=O)\C=C\C=2OC=CC=2)N=C1 DKIRUZSABDATAK-XZXOBPBMSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- WDGCBNTXZHJTHJ-UHFFFAOYSA-N 2h-1,3-oxazol-2-id-4-one Chemical group O=C1CO[C-]=N1 WDGCBNTXZHJTHJ-UHFFFAOYSA-N 0.000 claims 4
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229960003581 pyridoxal Drugs 0.000 claims 1
- 235000008164 pyridoxal Nutrition 0.000 claims 1
- 239000011674 pyridoxal Substances 0.000 claims 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 abstract description 17
- 229960003907 linezolid Drugs 0.000 abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- 238000000338 in vitro Methods 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 3
- 238000009826 distribution Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 504
- 239000000047 product Substances 0.000 description 150
- 239000002904 solvent Substances 0.000 description 115
- 238000006243 chemical reaction Methods 0.000 description 110
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- 238000002360 preparation method Methods 0.000 description 90
- 239000012074 organic phase Substances 0.000 description 82
- 238000005481 NMR spectroscopy Methods 0.000 description 77
- 239000007787 solid Substances 0.000 description 76
- 238000002844 melting Methods 0.000 description 74
- 230000008018 melting Effects 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 239000012043 crude product Substances 0.000 description 54
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 45
- 238000000605 extraction Methods 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 36
- 239000000243 solution Substances 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 238000012544 monitoring process Methods 0.000 description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 20
- 238000005406 washing Methods 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
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- 238000000926 separation method Methods 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 210000003705 ribosome Anatomy 0.000 description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- SWKPKONEIZGROQ-UHFFFAOYSA-N 4-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1 SWKPKONEIZGROQ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 2
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- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) 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)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a pyridine-containing bisoxazolidone compound and a synthesis method and application thereof. The structural general formula of the pyridine-containing bisoxazolidone compound provided by the invention is shown as a general formula I. According to the invention, the benzene ring of the ring B of linezolid is replaced by pyridine heterocycle, the distribution of electron cloud is changed by introducing the pyridine ring, the alkalinity of molecules is increased, and the ring C is further modified. In order to further improve the antibacterial activity, the invention has the advantage that fluorine is connected to the pyridine ring of part of the product, so that the antibacterial activity is obviously improved. The in vitro antibacterial activity test shows that the pyridine-containing bisoxazolidone compound provided by the invention has definite antibacterial activity, and is hopeful to be a substitute of linezolid in clinic.
Description
Technical Field
The invention relates to an oxazolidinone compound containing a pyridine structure, or an optical isomer, pharmaceutically acceptable salt and/or solvate thereof, and further relates to a synthesis method of the compound and application of the compound as an antibacterial agent, belonging to the pyridine-containing bisoxazolidinone compound and application thereof.
Background
For many years, the massive discovery of clinically resistant bacteria, multidrug resistant bacteria and cross-resistant bacteria has led to a dramatic rise in mortality from infectious diseases. After the production of the multi-drug resistant bacteria, only three drugs of quinupristin, linezolid and daptomycin are marketed in Europe. Among them, linezolid is approved by the FDA as a lead compound among oxazolidinones for clinical treatment of multidrug resistant strains such as methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) infections since 2000. The mechanism of action is to bind to ribosomal 50S methylene, thereby inhibiting the onset of the complex ribosomal 70S subunit to take effect and ultimately inhibiting the synthesis of bacterial proteins. This unique mechanism of action enables it to treat drug-resistant bacterial infections and is not prone to cross-resistance by other drugs. In recent years, the production of several linezolid-resistant strains has also been reported, in cases triggered by mutations in the 50S large subunit ribosomal immune region protein region, or by the exclusion of drugs due to endogenous ribosomal methyltransferase efflux pumps. With the emergence of the drug resistance problem, the structure of the compound needs to be further optimized, and more novel compounds are designed to overcome the drug resistance.
In order to reasonably modify the structure of the linezolid, the molecular structure of the linezolid can be divided into four components according to the naming method of the oxazolidinone medicine as shown in figure 1: 1) A ring, a five membered heterocycle consisting of an oxazolidone structure; 2) A B ring, an aromatic ring attached to the N atom of the oxazolidinone ring, a 3) C ring, a morpholine ring attached to the benzene ring, a flexible ring, which is not structurally a planar rigid structure; 4) The C-5 side chain, consisting of a functional group attached to the C-5 position on the oxazolidinone, is generally in an isostatically position with the A ring.
At present, the modification of the C-5 side chain is not enumerated, and many reports on modification of the introduction of heterocycle into the ring A, C of linezolid are also available. For example, there are reports of changing morpholine ring (C ring) to pyridine ring and introducing 1,2, 4-dioxazole heterocycle at the distal end, and changing oxazolidinone ring (a ring) to five-membered aromatic heterocycle isoxazole to maintain bioactivity (fig. 2). To date, attempts and inventions for modifying benzene rings (B rings) are rare, and no drug with particularly good antibacterial effect is found. The problem of bacterial resistance of linezolid has been common in clinic for a long time, and there is a need to provide an antibacterial compound with novel structure capable of replacing linezolid.
Disclosure of Invention
The invention aims to provide a pyridine-containing bisoxazolidone compound with antibacterial activity;
the second object of the invention is to provide a method for synthesizing the pyridine-containing bisoxazolidone compound;
the invention also provides a preparation method of the pyridine-containing bisoxazolidone compound.
The above object of the present invention is achieved by the following technical solutions:
the invention firstly provides a pyridine-containing bisoxazolidone compound, which has a structural formula shown in a general formula I:
wherein X is 1 And X 2 Each independently selected from O or N;
R 1 、R 3 are substituents of different species from each other and include, but are not limited to, acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furanylAny one of acyl, 2-tetrahydrofuranyl, 3-pyridineformyl, 6-chloropyridine-3-formyl, 2-furanoyl, 3-pyridineacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino; r is R 2 Is hydrogen or F.
R 4 Any one selected from acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridine acryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino.
The compounds of formula I of the present invention contain chiral centers and thus enantiomers and racemates are present, and accordingly, the present invention also includes racemates, optically active isomers, polymorphic forms or mixtures thereof of the compounds of formula I, which compounds possess the useful properties described herein. The invention also relates to two enantiomers of useful nature and to mixtures containing both isomers.
The invention also includes solvates of the compounds of formula I, wherein the solvent of the solvate may be ethanol, water, etc., and wherein water may be present in varying amounts, such as monohydrate, hemihydrate, one hemihydrate, dihydrate or trihydrate, etc.
The compounds of formula I of the present invention may form pharmaceutically acceptable salts thereof with acids. The acid may comprise an inorganic or organic acid, with salts formed with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid.
The invention also includes prodrugs of the compounds of formula I. Prodrugs are derivatives of the compounds of formula I according to the invention, which may themselves have little or no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
As a specific embodiment of the present invention, the compound of formula I may be any one of the following specific compounds, but the following specific compounds are not meant to limit the present invention in any way:
(S) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } -3-phenylpropionamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } cyclohexanecarboxamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } nicotinamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } furan-2-carboxamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } -4- (trifluoromethyl) benzamide;
n- { [ (S) -3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } tetrahydrofuran-2-carboxamide;
(R) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } methanesulfonamide;
(R) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } benzenesulfonamide;
(S) -1-cyclohexyl-3- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } urea;
(S) -3-methyl-N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } butanamide;
(S) -1- (4-chlorophenyl) -3- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidin-5-yl ] methyl } urea;
(S) -N- {3- [6- (4-propionylpiperazin-1-yl) pyridin-3-yl-2-oxazolidin-5-yl ] methyl } acetamide;
(S) -N- [ ({ 3- [6- (4-cyclohexanecarbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- [ (3- (6- {4- [4- (trifluoromethyl) benzoyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidone-5-yl) methyl ] acetamide;
(S) -N- [ (3- {6- [4- (6-chloronicotinamide) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- {6- [4- (furan-2-carbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-) methyl ] acetamide;
(S) -N- [ (3- {6- [4- (3-phenylpropionyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidin-5-yl) methyl ] acetamide;
(S, E) -N- [ (3- (6- {4- [3- (furan-2-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- [ (3- (6- (4- { [4- (trifluoromethyl) phenyl ] sulfonyl } piperazin-1-yl) pyridin-3-yl) -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- { [3- (6- {4- [ (4-methoxyphenyl) sulfonyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S) -N- { [3- (6- {4- [ (4-nitrophenyl) sulfonyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidin-5-yl ] methyl } acetamide;
(S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] pyridin-2-yl } -N-cyclohexylpiperazine-1-carboxamide;
(S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] pyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide;
(S) -N- ({ 3- [ 5-fluoro-6- (4-propionylpiperazin-1-yl) pyridin-3-yl ] -2-oxazolidinone-5-yl } methyl) acetamide;
(S) -N- [ (3- {6- [4- (cyclohexanecarbonyl) piperazin-1-yl ] -5-fluoropyridin-3-yl } -2-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- { 5-fluoro-6- [4- (3-phenylpropionyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide;
(S, E) -N- { [3- (5-fluoro-6- {4- [3- (furan-2-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S, E) -N- { [3- (5-fluoro-6- {4- [3- (pyridin-3-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] -3-fluoropyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide;
(S) -N- ((3- (6- (4- (2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (4-chloropyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (benzylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-morpholinpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (methylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2- (isopropylamino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2- ((3-morpholinopropyl) amino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (4-methylpiperidin-1-yl) pyrimidine) 4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (naphthalen-1-ylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- ((2, 2-difluoroethyl) amino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (quinolin-5-ylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (phenylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (allylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((-3- (6- (4- (2- (propargylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- ((6-chloropyridin-3-yl) amino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (6-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -4- (4- (5- (5- (acetamidomethyl) -2-oxazolidinone-3-yl) -3-fluoropyridin-2-yl) piperazin-1-yl) -2- (methylsulfanyl) pyrimidine-5-acetic acid ethyl ester;
(S) -N- ((3- (5-fluoro-6- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4, 6-dichloropyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2, 6-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (5-bromopyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2, 5-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (5-bromo-2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2, 5, 6-trichloropyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-chloro-5-methylpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-chloro-5-fluoropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-aminopyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (4-aminopyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -2, 2-dichloro-N- (3- (6- (4- (2, 5-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (5-bromo-2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) -2, 2-dichloroacetamide;
(S) -2, 2-dichloro-N- ((3- (6- (4- (2-chloro-5-methylpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -2, 2-dichloro-N- ((3- (6- (4- (2-chloro-5-fluoropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide.
The present invention further provides methods of synthesis of compounds of formula I including, but not limited to, any of the following methods (I), (ii) or (iii).
A method for synthesizing a compound of formula I, said method comprising:
(1) 2-chloro-5-nitropyridine reacts with morpholine to prepare an intermediate A-1; (2) Reducing the intermediate A-1 by palladium carbon and hydrogen to generate an intermediate A-2; (3) Introducing Cbz protecting group on the amino group of the intermediate A-2 to obtain an intermediate A-3; (4) The intermediate A-3 and (R) - (-) -glycidyl butyl are cyclized to generate a product A-4 of an oxazolidone ring; (5) introducing methanesulfonyl into the product A-4 to generate A-5; (6) reacting A-5 with potassium phthalimide to produce A-6; (7) Removing phthalimide groups from the A-6 in a methanol solution to obtain A-7; (8) Connecting different substituents on the amino group of the intermediate A-7 to obtain the compound;
as a preferred embodiment of the above synthetic method of the present invention, in the reaction liquid of n-butyllithium and tetrahydrofuran at 78 ℃ in the step (4), the intermediates A-3 and (R) - (-) -glycidyl butyl ester are lower Wen Huange to form the product A-4 of oxazolidone ring;
In the step (7), removing phthalimide groups from the A-6 in a methanol solution to obtain A-7;
the substituent in the step (8) is selected from any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridylacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino.
(II) the invention provides another synthesis method of the compound of the general formula I, which comprises the following steps:
(1) 2-chloro-5-nitropyridine reacts with 1-Boc-piperazine to prepare an intermediate B-1; (2) reducing intermediate B-1 to intermediate B-2; (3) Introducing Cbz protecting group into the intermediate B-2 to obtain an intermediate B-3; (4) Reflux-extracting 1-amino-3-chloropropane-2-ol with acetic anhydride to obtain a ring-closing intermediate B-4; (5) The intermediate B-3 and the intermediate B-4 are cyclized to generate a product B-5 of an oxazolidone ring; (6) Boc removal of B-5 to give intermediate B-6; (7) The intermediate B-6 is further connected with different substituents to obtain the compound; the substituent includes, but is not limited to, any of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridine acryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino.
As a preferred embodiment of the above-mentioned method of the present invention according to the above-mentioned method of the above-mentioned item (II), the intermediate B-1 is reduced with palladium on carbon and ammonium formate to produce the intermediate B-2 in the step (2); in the step (4), 1-amino-3-chloropropane-2-alcohol and acetic anhydride are refluxed under the catalysis of triethylamine to obtain a ring-closing intermediate B-4; the B-5 in the step (6) is separated from Boc by trifluoroacetic acid to obtain an intermediate B-6.
(III) the invention provides a third synthesis method of a compound of the general formula I, which comprises the following steps:
(1) 3-fluoro-2-hydroxypyridine is connected with nitro to obtain an intermediate C-1; (2) refluxing and chloridizing the intermediate C-1 to obtain an intermediate C-2; (3) Intermediate C-2 reacts with 1-Boc-piperazine to prepare intermediate C-3; (4) reducing intermediate C-3 to intermediate C-4; (5) Introducing the intermediate C-4 into a Cbz protecting group to obtain an intermediate C-5; (6) Reflux of 1-amino-3-chloropropane-2-alcohol and acetic anhydride under the catalysis of triethylamine to obtain a ring-closing intermediate B-4; (7) The intermediate C-5 and the intermediate B-4 for ring closure are cyclized to generate a product C-6 of an oxazolidone ring; (8) C-6 is Boc removed to give intermediate C-7; (9) The intermediate C-7 is further connected with different substituents to obtain the compound.
As a preferred embodiment of the above-mentioned method of the present invention of the above-mentioned item (III), in the step (1), 3-fluoro-2-hydroxypyridine is nitrated with concentrated nitric acid to obtain an intermediate C-1; in step (2), intermediate C-1 is treated with POCl 3 、PCl 5 Reflux chlorination to obtain intermediate C-2; in the step (4), reducing the intermediate C-3 by palladium carbon and ammonium formate to generate an intermediate C-4; under ice bath in the step (8), removing Boc from the C-6 with trifluoroacetic acid to obtain an intermediate C-7; the substituents described in step (9) include, but are not limited to, acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionylAny one of a group, a 4-trifluoromethylbenzoyl group, a 3-picolyl group, a 2-furoyl group, a 2-tetrahydrofuranoyl group, a 3-picolyl group, a 6-chloropyridine-3-formyl group, a 2-furoyl group, a 3-pyridylacryloyl group, a methanesulfonyl group, a benzenesulfonyl group, a 4-trifluoromethylbenzenesulfonyl group, a 4-nitrobenzenesulfonyl group, a 4-methoxybenzenesulfonyl group, a cyclohexylamino group, or a 4-chloroanilino group.
It is another object of the present invention to provide a pharmaceutical composition for inhibiting bacterial infection, which is prepared by combining a prophylactically or therapeutically effective amount of the compound of formula I, or an enantiomer, racemate, solvate, pharmaceutically acceptable salt or prodrug thereof with an acid according to claim 1, with a pharmaceutically acceptable carrier; after a pharmaceutically acceptable dosage of the compound of the general formula I is matched with a pharmaceutically acceptable carrier or auxiliary material, the compound is prepared into any one of proper pharmaceutical compositions according to a preparation method conventional in the art. Generally, the compositions are suitable for oral administration and injection administration, as well as other methods of administration. The composition can be in the form of liquid preparation such as tablet, capsule, powder, granule, lozenge, suppository or oral liquid. The pharmaceutical compositions according to the invention may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of a compound of the general formula I, according to different methods of administration. Wherein the auxiliary materials can be antioxidant complexing agent, filler, framework material and the like; the pharmaceutically acceptable carrier is one or more of xylitol, mannitol, lactose, fructose, dextran, glucose, polyvinylpyrrolidone, low molecular dextran, sodium chloride, calcium gluconate or calcium phosphate, preferably mannitol or lactose.
At present, many reports on modification of linezolid are focused on modification of the side chain of the 5 th position of the A ring, the C ring or the A ring, or other heterocycles are introduced into the molecule, and modification of the benzene ring of the B ring is very little, and the benzene ring of the B ring is kept unchanged. According to the invention, the benzene ring of the ring B of the linezolid is replaced by the pyridine heterocycle, the distribution of electron cloud is changed by introducing the pyridine ring, and the alkalinity of molecules is increased.
Examples 1 to 12 according to the invention show that, after replacement of the B ring with a pyrimidine ring, the side chains form amide, sulfonamide and urea compounds, which have only a certain effect on Staphylococcus aureus ATCC25923 with little or no activity on other bacteria, on the premise that the C ring is unchanged. The C ring was later modified to give compounds (examples 13-24) with improved antimicrobial spectra and efficacy against a variety of bacteria, but with generally weaker efficacy. The antimicrobial activity of the products (examples 25-30) after attachment of fluorine to the pyridine ring was further improved and the MIC values of some of the compounds were close to the efficacy of linezolid. Although the antibacterial effect is slightly weaker than that of linezolid, the problem of bacterial drug resistance in clinic is quite common for a long time, and in this case, the compound has a novel structure and is expected to become a substitute of linezolid in clinic.
The in vitro antibacterial activity test shows that the pyridine-containing bisoxazolidone compounds provided by the invention have definite antibacterial activity.
Drawings
Figure 1 is a schematic representation of four components of the molecular structure of linezolid.
FIG. 2 is an example of the modification of the C-5 side chain of linezolid in the prior art.
FIG. 3 shows a synthetic route pattern of the pyridine-containing bisoxazolidinone compound.
FIG. 4 is a diagram of another synthetic route for a compound comprising a pyridine bisoxazolidinone compound, provided by the invention.
FIG. 5 is a third synthetic route for a compound comprising a pyridine bisoxazolidinone compound.
FIG. 6 is a synthetic route pattern of the compounds prepared in examples 31-58 provided herein.
FIG. 7 is a synthetic route diagram of the compounds prepared in examples 59-62 provided herein.
FIG. 8 shows the molecular structural formula of the pyridine-containing bisoxazolidinone compound.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions can be made in the details and form of the invention without departing from the spirit and scope of the invention, but these modifications and substitutions are intended to be within the scope of the invention.
TABLE 1 structural formulas and chemical names of Compounds synthesized in examples 1-30
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Preparation of intermediates A-1 to A-8 in preparation example 1
1. Preparation of intermediate A-1
3.11mL of morpholine (35.7 mmol) and 5mL of triethylamine (35.7 mmol) were added to 80mL of dichloromethane at room temperature with 4.79g of 2-chloro-5-nitropyridine (29.7 mmol) and stirred overnight at room temperature. TLC detection was complete, extraction with dichloromethane and water (3×100 mL) and the organic phases combined and evaporated to dryness to give the crude product. Silica gel column chromatography separation [ V (PE): v (EA) =1: 1]Obtain the intermediate A-1 of the target product. The product was a yellow solid with a yield of 66.1% and a melting point of 144.2-144.9 ℃. 1 H-NMR(400MHz, CDCl 3 )δ9.04(d,J＝2.8Hz,1H),8.23(dd,J＝9.6,2.8Hz,1H),6.57(d,J＝9.6Hz,1H),3.88–3.79 (m,4H),3.79–3.70(m,4H)。 13 C-NMR(75MHz,DMSO-d 6 )δ160.2,145.9,134.5,132.8,105.6, 65.8,44.7。
2. Preparation of intermediate A-2
6.73g of Compound A-1 (32.2 mmol) was dissolved in 300mL of dichloromethane, and 1.01g of palladium on carbon (15%) and 6.09g of ammonium formate (96.6 mmol) were added under nitrogen and stirred at room temperature to react overnight. TLC monitoring of reaction completion, removal of palladium on carbon by suction filtration through celite, washing of the celite with dichloromethane after suction filtration, combining the organic phases, removal of solvent by distillation under reduced pressure, removal of solvent with dichloromethane and water (3X 200)
mL) and the organic phases are combined, washed with saturated brine and distilled under reduced pressure to obtain a crude product, which is separated by silica gel column chromatography [ V (dichloromethane): v (methanol) =80: 1 ]Obtaining the target product intermediate A-2. The product was a bronze solid with a yield of 86% and a melting point of 146.3-149.6 ℃. 1 H-NMR(400MHz,CDCl 3 )δ7.80(d,J＝2.8Hz,1H),7.01(dd,J＝8.8,2.8Hz,1H), 6.57(d,J＝8.8Hz,1H),3.95–3.69(m,4H),3.43–3.23(m,4H),3.22–3.05(s,2H)。 13 C-NMR(75 MHz,DMSO-d 6 )δ152.8,138.0,124.9,108.7,66.5,47.3。
3. Preparation of intermediate A-3
0.179g of Compound A-2 (1 mmol) was added to [ V (acetone): v (water) =2: 1](4.5 mL) was dissolved, 0.17mL of benzyl chloroformate (1.2 mmol) and 0.127g of sodium carbonate (1.2 mmol) were added, stirred overnight under ice-bath conditions, TLC was monitored to complete the reaction, the solvent was distilled off under reduced pressure, ethyl acetate and water (3X 20 mL) were added for extraction, the organic phases were combined, saturated brine was used for washing, and the solvent was distilled off under reduced pressure to give the target product intermediate A-3. The product was a brown solid with a yield of 97.3% and a melting point of 163.1-166.0 ℃. 1 H-NMR (400MHz,CDCl 3 )δ8.08(d,J＝2.8Hz,1H),7.77(s,1H),7.45–7.29(m,5H),6.62(d,J＝9.2Hz, 1H),5.19(s,2H),3.98–3.63(m,4H),3.56–3.30(m,4H)。 13 C-NMR(75MHz,DMSO-d 6 )δ155.7, 153.7,138.4,136.6,129.2,128.4,128.0,127.0,126.4,107.0,65.9,65.8,45.7。
4. Preparation of intermediate A-4
1.64g of Compound A-3 (5.24 mmol) was dissolved in 20mL of anhydrous tetrahydrofuran at-78deg.C, nitrogen was introduced for protection, 4.2mL of n-butyllithium (2 mmol) was added to the flask at-78deg.C, and after stirring for 50min, 0.88mL of (R) - (-) -glycidyl butyl ester (6.288 mmol) dissolved in 5mL of anhydrous tetrahydrofuran was added thereto, and the mixture was allowed to react at-78deg.C for 1 hour, and then naturally warmed to room temperature, and stirred for 16 h. TLC was used to monitor completion of the reaction, the solvent was evaporated under reduced pressure, extracted with ethyl acetate and water (3X 40 mL), the organic phases were combined,washing with saturated salt water, and distilling under reduced pressure to remove solvent to obtain the intermediate A-4. The product was a yellow solid with a yield of 68.5% and a melting point of 160.2-162.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.24(d,J＝2.8Hz,1H),7.86(dd,J＝9.2,2.8Hz,1H), 6.89(d,J＝9.2Hz,1H),5.20(t,J＝5.6Hz,1H),4.71–4.66(m,1H),4.06–4.01(m,1H),3.80– 3.77(m,1H),3.71–3.69(m,4H),3.65–3.64(m,1H),3.59–3.53(m,1H),3.40–3.38(m,4H)。 13 C-NMR(75MHz,DMSO-d 6 )δ156.0,154.0,138.1,128.9,126.7,107.0,73.5,65.9,61.7,46.1, 45.5。
5. Preparation of intermediate A-5
279mg of Compound A-4 (1 mmol) was dissolved in 10mL of methylene chloride, 0.12mL of methanesulfonyl chloride (1.5 mmol) and 0.28mL of triethylamine (2 mmol) were added, the reaction was carried out overnight under ice-bath conditions, TLC was monitored to be complete, the solvent was evaporated to dryness, ethyl acetate and water extraction (3X 10 mL) were combined, the organic phases were combined, saturated brine was washed, the solvent was distilled off under reduced pressure to give a crude product, and [ V (petroleum ether) was separated by silica gel column chromatography: v (ethyl acetate) =5: 1]Obtaining the target product intermediate A-5. The product is a pale yellow solid, the yield is 99.4%, and the melting point is 254.0-254.4 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.23(d,J＝2.8Hz,1H),7.82(dd,J＝9.2, 2.8Hz,1H),6.90(d,J＝9.2Hz,1H),5.02–4.96(m,1H),4.53–4.44(m,2H),4.17–4.12(m,1H), 3.80–3.76(m,1H),3.71–3.69(m,4H),3.41–3.39(m,4H),3.26(s,3H)。 13 C-NMR(100MHz, DMSO-d 6 )δ156.8,154.7,139.3,130.1,126.6,107.5,70.8,70.3,66.4,46.6,45.9,37.3。
6. Preparation of intermediate A-6
840mg of compound A-5 (2.35 mmol) was dissolved in N, N-dimethylformamide (20 mL), 522.35mg of potassium phthalimide (2.82 mmol) and 498.2mg of anhydrous sodium carbonate (4.7 mmol) were added, and the mixture was stirred in an oil bath at 80℃for 2 hours, the completion of the reaction was monitored by TLC, N-dimethylformamide was washed by extraction with ethyl acetate and water (3X 10 mL), the organic phases were combined, washed with saturated brine and the solvent was distilled off under reduced pressure to obtain the target product intermediate A-6. The product is pale yellow solid, the yield is 96.4%, and the melting point is 206.0-208.1 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.19(d,J＝2.8Hz,1H),7.93–7.86(m, 4H),7.77(dd,J＝9.2,2.8Hz,1H),6.88(d,J＝9.2Hz,1H),4.97–4.90(m,1H),4.18–4.14(m,1H), 4.04–3.98(m,1H),3.94–3.85(m,2H),3.71–3.68(m,4H),3.40–3.38(m,4H)。 13 C-NMR(100 MHz,DMSO-d 6 )δ168.3,156.8,154.7,139.3,135.1,132.0,130.0,126.7,123.7,107.4,70.8,66.4, 48.5,45.9,40.1。
7. Preparation of intermediate A-7
0.98g of Compound A-6 (2.4 mmol) was dissolved in methylamine alcohol solution (25 mL), placed in a reaction kettle, placed in an oil bath under 80 ℃ and stirred for 4h, TLC monitored the reaction to completion, evaporated to dryness, extracted with ethyl acetate and water (3X 5 mL), the organic phases were combined, washed with saturated common salt water, distilled under reduced pressure to remove the solvent to give crude product, and separated by silica gel column chromatography [ V (dichloromethane): v (methanol) =30: 1 ]The desired product intermediate A-7 was obtained as a white solid in 34.3% yield with a melting point of 185.4-187.7deg.C. 1 H-NMR (400MHz,DMSO-d 6 )δ8.24(d,J＝2.8Hz,1H),7.85(dd,J＝9.2,2.8Hz,1H),6.89(d,J＝9.2Hz, 1H),4.67–4.60(m,1H),4.05–4.00(m,1H),3.83–3.80(m,1H),3.71–3.69(m,4H),3.40–3.38 (m,4H),3.01(s,2H),2.92–2.82(m,2H)。 13 C-NMR(75MHz,DMSO-d 6 )δ156.1,154.7,138.4, 129.2,126.6,106.9,73.7,65.9,47.2,45.5,43.9。
Preparation of intermediates B-1 to B-6 in preparation example 2
1. Preparation of intermediate B-1
6.65g N-Boc-piperazine (35.7 mmol) and 5mL triethylamine (35.7 mmol) were added to 4.79g 2-chloro-5-nitropyridine (29.7 mmol) in 80mL dichloromethane at room temperature and stirred overnight at room temperature. TLC detection was complete, extraction with dichloromethane and water (3×100 mL) and the organic phases combined and evaporated to dryness to give the crude product. Silica gel column chromatography separation [ V (PE): v (EA) =1: 1] to obtain the target product intermediate B-1. The product was a yellow solid with a yield of 67.0% and a melting point of 160.5-163.3 ℃.
2. Preparation of intermediate B-2
9.93g of Compound B-1 (32.2 mmol) were dissolved in 300mL of dichloromethane, 1.01g of palladium on carbon (15%) and 6.09g of ammonium formate (96.6 mmol) were added under nitrogen and stirred at room temperature and reacted overnight. TLC monitoring reaction completion, removing palladium carbon by suction filtration through celite, washing the celite with dichloromethane after suction filtration, combining the organic phases, distilling off the solvent under reduced pressure, extracting with dichloromethane and water (3X 200 mL), combining the organic phases, washing with saturated common salt water, distilling under reduced pressure to obtain crude product, separating by silica gel column chromatography [ V (dichloromethane): v (methanol) =80: 1] to obtain the target product intermediate B-2, wherein the product is bronze oily matter.
3. Preparation of intermediate B-3
0.278g of Compound B-2 (1 mmol) was added to [ V (acetone): v (water) =2: 1] (4.5 mL) was dissolved, 0.17mL of benzyl chloroformate (1.2 mmol) and 0.127g of sodium carbonate (1.2 mmol) were added, stirred overnight under ice-bath conditions, TLC was monitored to be complete, the solvent was distilled off under reduced pressure, ethyl acetate and water (3X 20 mL) were added for extraction, the organic phases were combined, saturated brine was used for washing, and the solvent was distilled off under reduced pressure to obtain the target product intermediate B-3. The product was a brown solid with a yield of 92.7% and a melting point of 125.8-128.8 ℃.
4. Preparation of intermediate B-4
7.0g (S) -1-amino-3-chloro-2-propanol hydrochloride (47.9 mmol) was dissolved in 200mL of dichloromethane, 20mL of triethylamine (143.7 mmol) was added, 11.32mL of acetic anhydride (119.86 mmol) was added to the flask under reflux at 35℃and the reaction was completed after stirring for 2 hours, dichloromethane and water extraction (3X 200 mL), the organic phases were combined, saturated brine was used, the solvent was distilled off under reduced pressure to give a yellow oily mixture, and petroleum ether was added to recrystallize to give the desired product intermediate B-4. The product was a white solid with a yield of 86.5% and a melting point of 31.4-31.9 ℃.
5. Preparation of intermediate B-5
466mg of compound B-3 (1.13 mmol) was dissolved in 3mL of anhydrous tetrahydrofuran, 1 drop of N, N-dimethylformamide and 0.1mL of methanol (2.49 mmol) were added to the reaction mixture, and 1.55mL of a lithium tert-butoxide tetrahydrofuran solution (2.2M, 3.39 mmol) was added to the flask at 0℃under nitrogen protection, followed by stirring for 30 minutes, and 437mg of B-4 (6.288 mmol) dissolved in 1mL of anhydrous tetrahydrofuran was added at room temperature and stirred for 18 hours at room temperature. TLC was used to monitor the completion of the reaction, the solvent was evaporated under reduced pressure, ethyl acetate and water were extracted (3X 40 mL), the organic phases were combined, saturated brine was used for washing, and the solvent was distilled off under reduced pressure to give a crude product. Silica gel column chromatography separation [ V (PE) ： V(EA)＝1：3]Obtain the target product intermediate B-5. The product was a brown solid with a yield of 66.0% and a melting point of 160.1-161.3 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.31(t,J＝6.0Hz,1H),8.21(d,J＝3.0Hz,1H),7.80(dd,J＝9.0,3.0 Hz,1H),6.91(d,J＝9.0Hz,1H),4.74–4.67(m,1H),4.08–4.05(m,1H),3.73–3.70(m,1H),3.45 –3.38(m,8H),1.84(s,3H),1.42(s,9H)。
6. Preparation of intermediate B-6
474mg of Compound B-5 (1.13 mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added to the flask at 0℃and stirred for 2h. TLC monitoring reaction is complete, triethylamine is added to be alkaline, and the solvent is evaporated to dryness under reduced pressure, so that a target product intermediate B-5 is obtained. The product was a brown oil.
Preparation of intermediates C-1 to C-6 in preparation example 3
1 preparation of intermediate C-1
10g of 3-fluoropyridin-2-ol (88.5 mmol) was dissolved in 66mL of concentrated sulfuric acid (1062 mmol) in portions over 30min in an ice-water bath, 12mL of concentrated nitric acid (177 mmol) was slowly added dropwise at 0℃under stirring overnight and naturally warmed to room temperature. After the reaction is finished, pouring ice water, stirring for 30min, and separating out a product intermediate C-1. The product was a yellow solid in 58.5% yield. Melting point 221.1-221.8 ℃. 1 H-NMR(400MHz,CDCl 3 )δ9.13(d,J＝2.4Hz,1H),8.31(dd,J＝7.2,2.4Hz,1H)。
2 preparation of intermediate C-2
7.4g of intermediate C-1 (46.8 mmol) was dissolved in 150mL of phosphorus oxychloride, and 14.6g of phosphorus pentachloride (70.3 mmol) was added in portions and slowly over 50min and stirred at 60℃for 2h. The reaction was completed, the solvent was distilled off, 40mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3X 50 mL). The organic phase was washed with saturated sodium carbonate and evaporated to dryness to give intermediate C-2. The product is yellow solid, and the yield is 52.1%, and the melting point is 38.5-39.7 ℃. 1 H-NMR(400MHz,CDCl 3 )δ9.13(d,J＝2.4Hz,1H),8.31(dd,J ＝7.2,2.4Hz,1H)。
3. Preparation of intermediate C-3
6.65g N-Boc-piperazine (35.7 mmol) and 5mL triethylamine (35.7 mmol) were added to 5.24g C-2 (29.7 mmol) in 80mL dichloromethane at room temperature and stirred overnight at room temperature. TLC detection was complete, extraction with dichloromethane and water (3×100 mL), the organic phases combined and evaporated to dryness to give the crude product. Silica gel column chromatography separation [ V (PE): v (EA) =1: 1]Obtain the target product intermediate C-3. The product was a yellow solid with a yield of 67.1% and a melting point of 160.6-163.3 ℃. 1 H NMR(300MHz,CDCl 3 )δ 8.89(dd,J＝2.4,1.2Hz,1H),8.00(dd,J＝13.2,2.4Hz,1H),3.89–3.79(m,4H),3.62–3.53(m, 4H),1.50(s,9H)。 13 C NMR(150MHz,DMSO-d 6 )δ154.3,151.6,145.9(d,J C-F ＝259.4Hz),141.1, 139.9,119.5,79.4,46.8,43.0,28.5。
4. Preparation of intermediate C-4
10.51g of Compound C-3 (32.2 mmol) were dissolved in 300mL of dichloromethane, 1.01g of palladium on carbon (15%) and 6.09g of ammonium formate (96.6 mmol) were added under nitrogen and stirred at room temperature and reacted overnight. TLC monitoring reaction completion, removing palladium carbon by suction filtration through celite, washing the celite with dichloromethane after suction filtration, combining the organic phases, distilling off the solvent under reduced pressure, extracting with dichloromethane and water (3X 200 mL), combining the organic phases, washing with saturated common salt water, distilling under reduced pressure to obtain crude product, separating by silica gel column chromatography [ V (dichloromethane): v (methanol) =80: 1]Obtaining the target product intermediate C-4. The product was a brown oil. 1 H NMR(600MHz,DMSO-d 6 )δ7.46 (d,J＝2.4Hz,1H),6.81(dd,J＝14.4,2.4Hz,1H),5.11(s,2H),3.43–3.41(m,4H),3.07–2.98(m, 4H),1.40(s,9H)。 13 C NMR(150MHz,DMSO-d 6 )δ154.4,151.3(d,J C-F ＝254.1Hz),142.3,140.9, 128.6,110.6,79.4,49.1,45.7,28.5。
5. Preparation of intermediate C-5
0.296g of Compound C-4 (1 mmol) was added to [ V (acetone): v (water) =2: 1 ](4.5 mL) was dissolved, 0.17mL of benzyl chloroformate (1.2 mmol) and 0.127g of sodium carbonate (1.2 mmol) were added, stirred overnight under ice-bath conditions, TLC was monitored to complete the reaction, the solvent was distilled off under reduced pressure, ethyl acetate and water (3X 20 mL) were added for extraction, the organic phases were combined, saturated brine was used for washing, and the solvent was distilled off under reduced pressure to give the target product, intermediate C-5. The product was a brown solid with a yield of 93.3% and a melting point of 163.3-165.5 ℃. 1 H NMR(600 MHz,DMSO-d 6 )δ9.93(s,1H),8.12(d,J＝2.4Hz,1H),7.70(dd,J＝14.4,2.4Hz,1H),7.43–7.34 (m,5H),5.16(s,2H),3.45–3.43(m,4H),3.24–3.20(m,4H),1.42(s,9H)。 13 C NMR(150MHz, DMSO-d 6 )δ154.4,154.0,149.41(d,J＝257.1Hz),145.3,145.2,136.8,133.0,129.0,128.6,128.5, 126.3,79.5,66.6,48.1,48.1,28.5。
6. Preparation of intermediate C-6
486mg of Compound C-5 (1.13 mmol) was dissolved in 3mL of anhydrous tetrahydrofuran, 1 drop of N, N-dimethylformamide and 0.1mL of methanol (2.49 mmol) were added to the reaction mixture, and 1.55mL of a lithium tert-butoxide tetrahydrofuran solution (2.2M, 3.39 mmol) was added to the flask at 0℃under nitrogen protection, followed by stirring for 30 minutes, 437mg of B-4 (6.288 mmol) dissolved in 1mL of anhydrous tetrahydrofuran was added at room temperature, and stirring was continued for 18 hours at room temperature. TLC was used to monitor the completion of the reaction, the solvent was evaporated under reduced pressure, ethyl acetate and water were extracted (3X 40 mL), the organic phases were combined, saturated brine was used for washing, and the solvent was distilled off under reduced pressure to give a crude product. Silica gel column chromatography separation [ V (PE): v (EA) =1: 3]Obtain the target product intermediate C-6. The product was a brown solid with a yield of 61.0% and a melting point of 161.1-163.3 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.12(d,J＝2.4Hz,1H),7.92(dd,J＝14.4, 2.4Hz,1H),4.78–4.71(m,1H),4.12–4.10(m,1H),3.74–3.71(m,1H),3.47–3.45(m,4H),3.42 –3.41(m,2H),3.31–3.26(m,4H),1.84(s,3H),1.42(s,9H)。
Example 1 preparation of (S) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide
100mg of Compound A-7 (0.36 mmol) was dissolved in 5mL of dichloromethane, 0.04mL of acetyl chloride (0.54 mmol), 0.064mL of triethylamine (0.432 mmol) and 1 drop of N, N-dimethylformamide were added thereto, stirred overnight under ice-bath conditions, monitored by TLC for completion of the reaction, and the solvent was evaporated to dryness to give the desired product (S) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } acetamide. The product is light brown solid, the yield is 20 percent, and the melting point is 148.8-152.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.24–8.21(m, 2H),7.80(dd,J＝9.2,2.8Hz,1H),6.89(d,J＝9.2Hz,1H),4.74–4.63(m,1H),4.09–4.05(m,1H), 3.71–3.67(m,5H),3.42–3.38(m,5H),1.84(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ169.9, 156.2,154.5,138.7,129.4,126.4,106.9,71.8,65.9,47.5,45.5,41.5,22.4。
Example 2 preparation of (S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } -3-phenylpropionamide
100mg of Compound A-7 (0.36 mmol) was dissolved in 10mL of methylene chloride, 65mg of phenylpropionic acid (0.432 mmol), 22mg of 4-dimethylaminopyridine (0.18 mmol), 103.4mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.54 mmol), stirring overnight at room temperature, TLC monitoring was complete, the solvent was evaporated, methylene chloride and water extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, and the solvent was distilled off by distillation under reduced pressure to give the objective product (S) -N- { [ (3- (6-morpholinopyridin-3-yl-2-oxazolidinone-5-yl)]Methyl } -3-phenylpropionamide. The product was a white solid with a yield of 33.4% and a melting point of 213.5-214.4 ℃. IR Vmax (cm) -1 ；KBr pellets):3332(-NH),2963(-CH),1735(C＝O),1656(C＝N),1429(C-N),1230(C-O)。 1 H-NMR(400MHz,DMSO-d 6 )δ8.24(t,J＝5.6Hz,1H),8.21(d,J＝2.8Hz,1H),7.79(dd,J＝9.2, 2.8Hz,1H),7.19(m,5H),6.89(d,J＝9.2Hz,1H),4.71–4.65(m,1H),4.04–3.99(m,1H),3.70(m, 4H),3.67–3.30(m,1H),3.47–3.20(m,6H),3.10–2.76(m,2H),2.43–2.40(m,2H)。 13 C-NMR(75 MHz,DMSO-d 6 )δ172.2,156.2,154.5,141.1,138.5,129.2,128.2,128.1,126.4,125.8,106.9, 71.8,65.9,47.3,45.5,41.3,36.8,31.0。
Example 3 preparation of (S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } cyclohexanecarboxamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 0.06mL of cyclohexane carboxylic acid (0.48 mmol), 24.4mg of 4-dimethylaminopyridine (0.2 mmol) and 115mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol) were added, stirred overnight at room temperature, TLC was monitored to complete the reaction, the solvent was evaporated, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, and the solvent was distilled off under reduced pressure to give the objective product (S) -N- { [ (3- (6-morpholinopyridin-3-yl-2-oxazolidinone-5-yl)]Methyl } cyclohexane carboxamide. The product was a white solid with a yield of 56.2% and a melting point of 183.3-184.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.20(d,J＝2.8Hz,1H),8.07(t,J＝5.6Hz,1H),7.79(dd,J＝9.2, 2.8Hz,1H),6.89(d,J＝9.2Hz,1H),4.74–4.68(m,1H),4.08–4.03(m,1H),3.74–3.66(m,5H), 3.48–3.41(m,1H),3.40–3.38(m,4H),3.36–3.33(m,1H),2.17–2.10(m,1H),1.66–1.58(m, 5H),1.38–0.94(m,5H)。 13 C-NMR(75MHz,DMSO-d 6 )δ176.6,156.6,155.0,138.9,129.7,126.9, 107.4,72.3,66.4,47.8,46.0,44.3,41.7,29.6,25.9,25.7。
Example 4 preparation of (S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } nicotinamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 73.8mg of nicotinic acid (0.6 mmol), 24.4mg of 4-dimethylaminopyridine (0.2 mmol) and 115mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol) were added, stirring overnight at room temperature, TLC was monitored to complete the reaction, the solvent was evaporated to dryness, methylene chloride and water extraction (3X 10 mL), the organic phases were combined, saturated brine was washed, and the solvent was distilled off under reduced pressure to give the desired product (S) -N- { [ (3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl) ]Methyl } nicotinamide. The product was a yellow solid with a yield of 43.6% and a melting point of 178.1-180.2 ℃. 1 H-NMR(400 MHz,DMSO-d 6 )δ9.04(t,J＝5.6Hz,1H),9.00(s,1H),8.71(d,J＝4.8Hz,1H),8.22(d,J＝2.8Hz, 1H),8.20–8.17(m,1H),7.81(dd,J＝9.2,2.8Hz,1H),7.53–7.50(m,1H),6.88(d,J＝9.2Hz,1H), 4.90–4.84(m,1H),4.17–4.12(m,1H),3.87–3.83(m,1H),3.71–3.64(m,6H),3.48–3.34(m, 4H)。 13 C-NMR(75MHz,DMSO-d 6 )δ165.6,156.2,154.5,152.0,148.4,138.6,135.0,129.5,129.3, 126.4,123.4,106.9,71.5,65.9,47.7,45.5,42.3。
Example 5 preparation of (S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } furan-2-carboxamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 67.2mg of 2-furoic acid (0.6 mmol), 24.4mg of 4-dimethylaminopyridine (0.2 mmol) and 115mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol) were added, stirred overnight at room temperature, TLC monitored to complete the reaction, the solvent was evaporated, methylene chloride and water extracted (3X 10 mL) and the mixture was combinedThe organic phase is washed by saturated common salt water, and the solvent is distilled off under reduced pressure to obtain the target product (S) -N- { [ (3- (6-morpholinopyridin-3-yl) -2-oxazolidone-5-yl)]Methyl } furan-2-carboxamide. The product was a white solid with a yield of 53.5% and a melting point of 173.0-173.4 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.69(t,J＝6.0Hz,1H),8.21(d,J＝2.8Hz,1H),7.85(d,J＝1.6 Hz,1H),7.79(dd,J＝9.2,2.8Hz,1H),7.15(d,J＝3.6Hz,1H),6.88(d,J＝9.2Hz,1H),6.64–6.62 (m,1H),4.81(m,1H),4.14–4.10(m,1H),3.83–3.80(m,1H),3.75–3.64(m,4H),3.62–3.53(m, 2H),3.45–3.32(m,4H)。 13 C-NMR(75MHz,DMSO-d 6 )δ158.8,156.7,155.0,148.0,145.7,139.2, 129.9,126.9,114.3,112.4,107.4,72.0,66.4,48.2,46.0,42.1。
Example 6 preparation of (S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidin-5-yl ] methyl } -4- (trifluoromethyl) benzamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 114.12mg of 4- (trifluoromethyl) benzoic acid (0.6 mmol), 24.4mg of 4-dimethylaminopyridine (0.2 mmol), 115mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol), stirred overnight at room temperature, monitored by TLC for completion of the reaction, the solvent was evaporated, methylene chloride and water extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, and the solvent was distilled off under reduced pressure to give the objective product (S) -N- { [ (3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl) ]Methyl } -4- (trifluoromethyl) benzamide. The product was a white solid with a yield of 37.8% and a melting point of 226.1-227.7 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.07(t,J＝5.6Hz,1H),8.22(d,J＝2.4Hz,1H), 8.05(d,J＝8.0Hz,2H),7.86(d,J＝8.0Hz,2H),7.81(dd,J＝9.2,2.4Hz,1H),6.88(d,J＝9.2Hz, 1H),4.91–4.84(m,1H),4.17–4.12(m,1H),3.86–3.82(m,1H),3.73–3.67(m,4H),3.65–3.62 (m,1H),3.42–3.36(m,4H). 13 C-NMR(75MHz,DMSO-d 6 )δ165.8,156.2,154.5,138.6,137.8, 131.5,129.3(q,J C-F ＝216.8Hz),128.2,126.4,125.5,106.9,71.5,65.9,47.7,45.5,42.5。
Example 7 preparation of N- { [ (S) -3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } tetrahydrofuran-2-carboxamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 69.6mg of tetrahydrofuran-2-carboxylic acid (0.6 mmol), 24.4mg of 4-dimethylaminopyridine (0.2 mmol) and 115mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol) were added, stirring overnight at room temperature, TLC was monitored to complete the reaction, the solvent was evaporated, methylene chloride and water extracted (3X 10 mL), the organic phases were combined, saturated brine was used, and the solvent was distilled off under reduced pressure to give the target product N- { [ (S) -3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } tetrahydrofuran-2-carboxamide. The product was a grey solid with a yield of 36.9% and a melting point of 130.0-132.2 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.21(d,J＝2.8Hz,1H),8.08(t,J＝5.6Hz,1H),7.80 (dd,J＝9.2,2.8,1.3Hz,1H),6.89(d,J＝9.2Hz,1H),4.78–4.71(m,1H),4.25–4.21(m,1H),4.09 –4.04(m,1H),3.91–3.72(m,3H),3.72–3.65(m,4H),3.53–3.42(m,2H),3.42–3.36(m,4H), 2.14–2.06(m,1H),1.87–1.68(m,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ173.4,156.2,154.5, 138.5,129.2,126.4,106.9,77.6,71.5,68.5,65.9,47.4,45.5,41.2,30.0,24.8。
Example 8 preparation of (R) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } methanesulfonamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 0.0325mL of methanesulfonyl chloride (0.42 mmol), 0.11mL of triethylamine (0.8 mmol) and 9.76mg of 4-dimethylaminopyridine (0.08 mmol) were added, the reaction was allowed to proceed overnight under ice-bath conditions, TLC was monitored for completion, the solvent was evaporated to dryness, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, the solvent was distilled off under reduced pressure to give a crude product, and silica gel column chromatography was used to separate [ V (methylene chloride): v (methanol) =80: 1 ]To obtain the target product (R) -N- { [3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl]Methyl methanesulfonamide. The product was a white solid with a yield of 60.0% and a melting point of 248.7-249.8 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.23(d,J＝2.8Hz,1H),7.82(dd,J＝9.2, 2.8Hz,1H),7.48(t,J＝6.4Hz,1H),6.90(d,J＝9.2Hz,1H),4.79–4.72(m,1H),4.12–4.08(m, 1H),3.79–3.75(m,1H),3.74–3.62(m,4H),3.46–3.33(m,4H),3.35–3.25(m,2H),2.95(s, 3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ156.2,154.5,138.7,129.5,126.4,107.0,71.7,65.9,47.2, 45.5,45.1,39.9。
Example 9 preparation of (R) -N- { [3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } benzenesulfonamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 0.0325mL of benzenesulfonyl chloride (0.42 mmol), 0.11mL of triethylamine (0.8 mmol) and 9.76mg of 4-dimethylaminopyridine (0.08 mmol) were added, the reaction was allowed to proceed overnight under ice-bath conditions, TLC was monitored to complete, the solvent was evaporated to dryness, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, the solvent was distilled off under reduced pressure to give a crude product, and silica gel column chromatography was used to separate [ V (methylene chloride): v (methanol) =80: 1]To obtain the target product (R) -N- { [3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } benzenesulfonamide. The product is yellow solid with a melting point of 121.3-123.8 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.27–8.11(m,2H),7.93–7.74(m,3H),7.70–7.50(m, 3H),6.90(d,J＝9.2Hz,1H),4.75–4.67(m,1H),4.10–4.03(m,1H),3.78–3.73(m,1H),3.79– 3.62(m,4H),3.41–3.38(m,4H),3.13–3.10(m,2H)。 13 C-NMR(75MHz,DMSO-d 6 )δ156.7, 154.8,140.9,139.1,133.0,129.9,129.8,126.9,126.8,107.5,72.0,66.4,47.6,46.0,45.8。
Example 10 preparation of (S) -1-cyclohexyl-3- { [3- (6-morpholin-pyridin-3-yl) -2-oxazolidin-5-yl ] methyl } urea
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 0.1mL of cyclohexylisocyanate (0.8 mmol) and 0.083mL of triethylamine (0.6 mmol) were added, the reaction was carried out overnight under ice-bath conditions, TLC was monitored to complete the reaction, the solvent was evaporated to dryness, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, and the solvent was distilled off under reduced pressure to give the objective product (S) -1-cyclohexyl-3- { [3- (6-morpholin-pyridin-3-yl) -2-oxazolidone-5-yl ]Methyl } urea. The product was a white solid with a yield of 47.1% and a melting point of 181.4-185.3 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.22(d,J＝2.8Hz,1H),7.80(dd,J＝9.2,2.8Hz, 1H),6.88(d,J＝9.2Hz,1H),6.07(t,J＝6.0Hz,1H),5.90(d,J＝8.0Hz,1H),4.71–4.65(m,1H), 4.07–4.03(m,1H),3.76–3.61(m,5H),3.44–3.35(m,4H),3.37–3.31(m,3H),1.81–1.37(m, 5H),1.30–0.90(m,5H)。 13 C-NMR(75MHz,DMSO-d 6 )δ157.4,156.2,154.6,138.7,129.3,126.5, 106.9,72.6,65.9,47.7,47.3,45.5,42.1,33.1,25.3,24.3。
Example 11 preparation of (S) -3-methyl-N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } butanamide
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 0.066mL of 3-methylbutanoic acid (0.6 mmol), 24.4mg of 4-dimethylaminopyridine (0.2 mmol) and 115mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol) were added, the reaction was stirred at room temperature overnight, TLC was monitored to complete the reaction, the solvent was evaporated to dryness, methylene chloride and water extraction (3X 10 mL), the organic phases were combined, saturated brine was used, the solvent was distilled off under reduced pressure to give a crude product, and [ V (methylene chloride) was separated by silica gel column chromatography: v (methanol) =120: 1]To obtain the target product (S) -3-methyl-N- { [3- (6-morpholinopyridin-3-yl) -2-oxazolidone-5-yl]Methyl } butanamide. The product was a white solid with a yield of 39.6% and a melting point of 184.4-187.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ 8.21(d,J＝2.8Hz,1H),8.17(t,J＝5.6Hz,1H),7.80(dd,J＝9.2,2.8Hz,1H),6.89(d,J＝9.2Hz, 1H),4.75–4.69(m,1H),4.10–4.05(m,1H),3.75–3.61(m,5H),3.51–3.40(m,2H),3.43–3.35 (m,4H),2.05–1.85(m,2H),0.83(dd,J＝8.4,6.4Hz,6H)。 13 C-NMR(75MHz,DMSO-d 6 )δ172.3, 156.2,154.5,138.5,129.3,126.4,106.9,71.8,65.9,47.4,45.5,44.5,41.2,25.5,22.2。
Example 12 preparation of (S) -1- (4-chlorophenyl) -3- { [3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } urea
111mg of Compound A-7 (0.4 mmol) was dissolved in 10mL of methylene chloride, 122.88mg of 1-chloro-4-phenylisocyanate (0.8 mmol) and 0.83mL of triethylamine (0.6 mmol) were added, the reaction was carried out overnight under ice-bath conditions, TLC was monitored to be complete, the solvent was evaporated, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined, saturated brine was washed, the solvent was distilled off under reduced pressure to give a crude product, and [ V (methylene chloride) was separated by silica gel column chromatography: v (methanol) =80: 1 ]To obtain the target product (S) -1- (4-chlorphenyl) -3- { [3- (6-morpholinopyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } urea. The product was a white solid in 57.4 yield% and melting point 229.1-229.5 ℃. 1 H-NMR (400MHz,DMSO-d 6 )δ8.81(s,1H),8.24(d,J＝2.0Hz,1H),7.82(dd,J＝9.2,2.0Hz,1H),7.65(s, 1H),7.31–7.09(m,2H),6.96–6.87(m,2H),6.59(t,J＝5.6Hz,2H),4.81–4.75(m,1H),4.13– 4.08(m,1H),3.80–3.72(m,1H),3.72–3.67(m,4H),3.49–3.46(m,2H),3.42–3.35(m,4H)。 13 C-NMR(75MHz,DMSO-d 6 )δ155.2,152.2,141.0,138.6,133.2,130.3,121.7,120.9,117.7,116.8, 106.9,72.2,65.9,47.3,45.5,42.0。
Example 13 preparation of (S) -N- {3- [6- (4-propionylpiperazin-1-yl) pyridin-3-yl-2-oxazolidinone-5-yl ] methyl } acetamide
159.5mg of compound B-6 (0.5 mmol) was dissolved in 5mL of dichloromethane, 57. Mu.L of acetyl chloride (0.65 mmol), 48. Mu.L of triethylamine (0.65 mmol) and 2mL of dichloromethane were added thereto, stirred overnight under ice-bath conditions, TLC was monitored to be complete, dichloromethane and water were extracted (3X 10 mL), the organic phases were combined, washed with saturated brine, distilled under reduced pressure to remove the solvent and the crude product was obtained, PE/EA recrystallized to give the target product (S) -N- {3- [6- (4-propionylpiperazin-1-yl) pyridin-3-yl-2-oxazolidin-5-yl)]Methyl } acetamide. The product is a brown solid with a melting point of 105.4-108.5 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.25(t,J＝6.0Hz, 1H),8.22(d,J＝2.8Hz,1H),7.81(dd,J＝9.2,2.8Hz,1H),6.92(d,J＝9.2Hz,1H),4.73–4.69(m, 1H),4.09–4.06(m,1H),3.71–3.68(m,1H),3.60–3.50(m,4H),3.50–3.49(m,2H),3.44–3.40 (m,4H),2.36(q,J＝7.2Hz,2H),1.01(t,J＝7.2Hz,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6, 155.6,150.6,139.0,129.6,127.0,125.2,108.0,72.3,47.9,45.8,44.9,42.0,22.9。
Example 14 preparation of (S) -N- [ ({ 3- [6- (4-cyclohexanecarbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide
159.5mg of Compound B-6 (0.5 mmol) was dissolved in 5mL of dichloromethane, 128mg of cyclohexane carboxylic acid (1 mmol), 12.2mg of 4-dimethylaminopyridine (0.1 mmol) and 143.6mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.75 mmol) were added, stirred overnight under ice-bath conditions, the reaction was complete monitored by TLC, dichloromethane and water extraction (3X 10 mL) were combined Washing the organic phase with saturated saline, distilling under reduced pressure to remove solvent to obtain crude product, and recrystallizing PE/EA to obtain target product (S) -N- [ ({ 3- [6- (4-cyclohexanecarbonyl) piperazin-1-yl)]Pyridin-3-yl } -2-oxazolidinone-5-yl) methyl]Acetamide. The product is a brown solid with a melting point of 164.7-165.3 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.25(t,J＝6.0Hz,1H),8.22(d,J＝2.8Hz,1H), 7.81(dd,J＝9.2,2.8Hz,1H),6.92(d,J＝9.2Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.71 –3.68(m,1H),3.65–3.51(m,5H),3.49–3.48(m,2H),3.42–3.38(m,4H),1.84(s,3H),1.74– 1.53(m,5H),1.35–1.29(m,5H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6,156.2,155.1,141.8, 139.2,128.9,128.7,107.7,72.3,48.0,45.6,45.4,44.9,42.0,41.1,34.4,31.2,22.9。
Example 15 preparation of (S) -N- [ (3- (6- {4- [4- (trifluoromethyl) benzoyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidone-5-yl) methyl ] acetamide
475mg of p-trifluoromethyl benzoic acid (2.5 mmol) is reacted with 1 drop of N, N-dimethylformamide for 30min, 5mL of dichloromethane is added to dissolve the thionyl chloride after the thionyl chloride is distilled off, 159.5mg of compound B-6 (0.5 mmol) is added under the ice bath condition, the mixture is stirred overnight under the ice bath condition, TLC monitors that the reaction is complete, dichloromethane and water are extracted (3X 10 mL), organic phases are combined, the mixture is washed by saturated saline solution, the solvent is distilled off by reduced pressure distillation to obtain a crude product, and PE/EA is recrystallized to obtain a target product (S) -N- [ (3- (6- {4- [4- (trifluoromethyl) benzoyl)]Piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl) methyl]Acetamide. The product is white solid with a melting point of 167.3-169.1 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.24(t,J＝5.6Hz,1H),8.23(d,J＝2.8 Hz,1H),7.84(d,J＝8.0Hz,2H),7.82(dd,J＝9.2,2.8Hz,1H),7.68(d,J＝8.0Hz,2H),6.92(d,J＝ 9.2Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.78–3.72(m,2H),3.71–3.68(m,1H),3.56 –3.52(m,4H),3.42–3.40(m,4H),1.84(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6,158.6, 155.7,155.0,139.4,138.9,133.5,129.9(q,J C-F ＝251.2Hz),129.0,127.2,108.0,72.3,46.2,45.9, 44.9,42.0,22.9。
EXAMPLE 16 preparation of (S) -N- [ (3- {6- [4- (6-chloronicotinamide) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide
472.5mg of 6-chloronicotinic acid (3 mmol) is reacted for 30min by adding 5mL of thionyl chloride and 1 drop of N, N-dimethylformamide, after the thionyl chloride is distilled off, 5mL of dichloromethane is added for dissolution, 159.5mg of compound B-6 (0.5 mmol) is added under ice bath condition and stirred overnight under ice bath condition, TLC monitors that the reaction is complete, dichloromethane and water are extracted (3X 10 mL), the organic phases are combined and washed with saturated saline solution, the solvent is distilled off under reduced pressure to obtain crude product, and silica gel column chromatography is carried out to separate [ V (dichloromethane): v (methanol) =80: 1]To obtain the target product (S) -N- [ (3- {6- [4- (6-chloronicotinamide) piperazin-1-yl)]Pyridin-3-yl } -2-oxazolidinone-5-yl) methyl]Acetamide. The product was a yellow oil-like substance, 1 H-NMR(400MHz,DMSO-d 6 )δ8.52(d,J＝2.4Hz,1H),8.25(t,J＝6.0Hz,1H),8.23(d, J＝2.8Hz,1H),7.96(dd,J＝8.0,2.4Hz,1H),7.82(dd,J＝9.2,2.8Hz,1H),7.64(d,J＝8.0Hz,1H), 6.93(d,J＝9.2Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.71–3.68(m,1H),3.61–3.55 (m,2H),3.48–3.45(m,4H),3.42–3.40(m,4H),1.84(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ 170.6,163.3,155.7,155.0,138.9,130.3,129.9,127.0,126.6,115.1,108.0,72.3,56.2,47.9,44.9,42.0, 22.9。
EXAMPLE 17 preparation of (S) -N- [ (3- {6- [4- (furan-2-carbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide
336mg of p-trifluoromethylbenzoic acid (3 mmol) is reacted for 30min by adding 5mL of thionyl chloride and 1 drop of N, N-dimethylformamide, after the thionyl chloride is distilled off, 5mL of dichloromethane is added for dissolution, 159.5mg of compound B-6 (0.5 mmol) is added under the ice bath condition, stirring is carried out overnight under the ice bath condition, TLC monitors that the reaction is complete, dichloromethane and water are extracted (3X 10 mL), organic phases are combined, and the organic phases are washed by saturated saline, the solvent is distilled off by reduced pressure distillation to obtain a crude product, PE/EA is recrystallized to obtain a target product (S) -N- [ (3- {6- [4- (furan-2-carbonyl) piperazin-1-yl) ]Pyridin-3-yl } -2-oxazolidinone-5-yl) methyl]Acetamide. The product is white solid with melting point of 191.2-191.8 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.25(t,J＝6.0Hz,1H),8.23(d,J＝2.8Hz,1H),7.87(d,J＝1.6 Hz,1H),7.82(dd,J＝9.2,2.8Hz,1H),7.04(d,J＝3.6Hz,1H),6.93(d,J＝9.2Hz,1H),6.65(dd,J ＝3.6,1.6Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.78–3.74(m,2H),3.71–3.69(m,1H), 3.69–3.46(m,4H),3.42–3.40(m,4H),1.85(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.7, 166.4,156.1,155.1,151.5,148.7,139.1,131.5,130.0,126.9,124.8,107.8,72.3,48.0,46.2,42.0, 22.9。
Example 18 preparation of (S) -N- [ (3- {6- [4- (3-phenylpropionyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide
79.75mg of Compound B-6 (0.25 mmol) was dissolved by adding 5mL of methylene chloride, 56.3mg of phenylpropionic acid (0.375 mmol), 6.1mg of 4-dimethylaminopyridine (0.05 mmol) and 72mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.375 mmol) were further added, stirred overnight under ice bath conditions, the reaction was completed by TLC monitoring, methylene chloride and water extraction (3X 10 mL), the organic phases were combined, and washed with saturated brine, and the solvent was distilled off by distillation under reduced pressure to obtain the crude product PE/EA, which was recrystallized to give the objective product (S) -N- [ (3- {6- [4- (3-phenylpropionyl) piperazin-1-yl)]Pyridin-3-yl } -2-oxazolidinone-5-yl) methyl]Acetamide. The product is a grey solid with a melting point of 133.2-133.3 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.25(t,J＝6.0Hz,1H),8.21(d,J ＝2.8Hz,1H),7.80(dd,J＝9.2,2.8Hz,1H),7.31–7.23(m,5H),6.90(d,J＝9.2Hz,1H),4.73– 4.69(m,1H),4.09–4.06(m,1H),3.70–3.68(m,1H),3.65–3.49(m,6H),3.42–3.40(m,4H),2.84 (t,J＝7.6Hz,2H),2.67(t,J＝7.6Hz,2H),1.84(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.5, 164.7,154.8,151.7,149.9,148.2,145.4,133.0,129.5,115.4,114.5,113.0,72.6,48.5,47.6,45.3,41.9, 22.9。
Example 19 preparation of (S, E) -N- [ (3- (6- {4- [3- (furan-2-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidin-5-yl) methyl ] acetamide
191.4mg of Compound B-6 (0.6 mmol) was dissolved in 5mL of dichloromethane, 166mg of furoic acid (1.2 mmol), 14.6mg of 4-dimethylaminopyridine (0.12 mmol) and 172mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.9 mmol) were further added, stirred overnight under ice-bath conditions, and TLC was monitored to be complete, dichloromethane and Extracting with water (3X 10 mL), mixing the organic phases, washing with saturated saline, distilling under reduced pressure to remove solvent to obtain crude PE/EA, and recrystallizing to obtain target product (S, E) -N- [ (3- (6- {4- [3- (furan-2-yl) acryloyl)]Piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl) methyl]Acetamide. The product is yellow solid with a melting point of 182.1-184.2 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.26(t,J＝6.0Hz,1H),8.23(d, J＝2.8Hz,1H),7.84–7.71(m,2H),7.37(d,J＝15.2Hz,1H),6.97(d,J＝15.2Hz,1H),6.93(d,J＝ 9.2Hz,1H),6.88(d,J＝3.2Hz,1H),6.64–6.60(m,1H),4.73–4.69(m,1H),4.09–4.06(m,1H), 3.76–3.72(m,2H),3.73–3.63(m,4H),3.53–3.50(m,5H),1.85(s,3H). 13 C-NMR(75MHz, DMSO-d 6 )δ174.2,170.6,156.3,155.1,139.2,130.0,126.8,107.7,72.3,48.0,42.0,29.6,26.1,25.6, 22.9。
Example 20 preparation of (S) -N- [ (3- (6- (4- { [4- (trifluoromethyl) phenyl ] sulfonyl } piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl ] acetamide
144mg of Compound B-6 (0.358 mg) was dissolved in 10mL of methylene chloride, 131mg of p-trifluoromethylbenzenesulfonyl chloride (0.537 mmol) and 0.14mL of triethylamine (1 mmol) were further added thereto, stirred overnight under ice-bath conditions, TLC was monitored to be complete, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined and washed with saturated brine, the solvent was distilled off under reduced pressure to give a crude product, and [ V (methylene chloride) ] was isolated by silica gel column chromatography: v (methanol) =80: 1]Obtaining the target product (S) -N- [ (3- (6- (4- { [4- (trifluoromethyl) phenyl)]Sulfonyl } piperazin-1-yl) pyridin-3-yl) -2-oxazolidinone-5-yl methyl]Acetamide. The product is a brown solid with a melting point of 226.4-226.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.23(t,J＝6.0Hz,1H),8.18(d,J＝2.8Hz,1H),8.04(d, J＝8.4Hz,2H),7.99(d,J＝8.4Hz,2H),7.78(dd,J＝9.2,2.8Hz,1H),6.89(d,J＝9.2Hz,1H),4.71 –4.67(m,1H),4.06–4.03(m,1H),3.68–3.65(m,1H),3.58–3.56(m,4H),3.40–3.38(m,2H), 3.06–3.04(m,4H),1.83(s,3H). 13 C-NMR(75MHz,DMSO-d 6 )δ170.7,159.0,156.2,155.1,146.3, 139.2,130.1,126.8,116.3,111.8,107.7,72.3,48.0,46.2,45.6,42.0,22.9。
Example 21 preparation of (S) -N- { [3- (6- {4- [ (4-methoxyphenyl) sulfonyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide
159.5g of Compound B-6 (0.5 mmol) was dissolved in 10mL of dichloromethane, 155mg of p-methoxybenzenesulfonyl chloride (0.75 mmol) and 0.14mL of triethylamine (1 mmol) were added thereto, stirred overnight under ice-bath conditions, TLC monitored for completion of the reaction, dichloromethane and water extracted (3X 10 mL), the organic phases were combined and washed with saturated brine, the solvent was distilled off under reduced pressure to give a crude product, and silica gel column chromatography was carried out to separate [ V (dichloromethane): v (methanol) =80: 1]Obtaining the target product (S) -N- { [3- (6- {4- [ (4-methoxyphenyl) sulfonyl)]Piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } acetamide. The product was a brown solid with a melting point of 175.8-177.1 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.23(t,J＝6.0Hz,1H),8.17(d,J＝2.8Hz,1H),7.77(dd,J＝9.2, 2.8Hz,1H),7.69(d,J＝8.8Hz,2H),7.16(d,J＝8.8Hz,2H),6.87(d,J＝9.2Hz,1H),4.71–4.67 (m,1H),4.06–4.03(m,1H),3.84(s,3H),3.68–3.66(m,1H),3.57–3.55(m,4H),3.40–3.39(m, 2H),2.94–2.92(m,4H),1.83(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6,157.4,156.5,155.1, 139.1,130.0,126.6,107.7,72.3,49.7,48.0,45.4,43.5,33.6,25.6。
Example 22 preparation of (S) -N- { [3- (6- {4- [ (4-nitrophenyl) sulfonyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidin-5-yl ] methyl } acetamide
159.5g of Compound B-6 (0.5 mmol) was dissolved in 10mL of dichloromethane, 222mg of p-nitrobenzenesulfonyl chloride (1 mmol) and 0.14mL of triethylamine (1 mmol) were further added, stirred overnight under ice-bath conditions, TLC was monitored to be complete, dichloromethane and water extracts (3X 10 mL) were combined, the organic phases were combined and washed with saturated brine, the solvent was distilled off under reduced pressure to give the crude product, and silica gel column chromatography was carried out to separate [ V (dichloromethane): v (methanol) =80: 1 ]Obtaining the target product (S) -N- { [3- (6- {4- [ (4-nitrophenyl) sulfonyl)]Piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } acetamide. The product was a brown solid, melting point 209.0-209.3 ℃. 1 H- NMR(400MHz,DMSO-d 6 )δ8.44(d,J＝8.8Hz,1H),8.24(t,J＝6.0Hz,1H),8.17(d,J＝2.8Hz, 1H),8.04(d,J＝8.8Hz,2H),7.77(dd,J＝9.2,2.8Hz,1H),6.89(d,J＝9.2Hz,1H),4.74–4.67(m, 1H),4.05–4.02(m,1H),3.69–3.65(m,1H),3.59–3.57(m,4H),3.42–3.38(m,2H),3.08–3.06 (m,4H),1.83(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6,156.4,155.3,140.0,139.2,130.0, 128.6,126.7,125.8,121.5,107.8,72.3,48.0,45.4,43.8,42.0,22.9。
Example 23 preparation of (S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] pyridin-2-yl } -N-cyclohexylpiperazine-1-carboxamide
159.5g of Compound B-6 (0.5 mmol) was dissolved in 10mL of methylene chloride, 0.13mL of cyclohexylisocyanate (1 mmol) and 0.1mL of triethylamine (0.75 mmol) were added thereto, stirred overnight under ice-bath conditions, TLC monitored for completion of the reaction, methylene chloride and water extraction (3X 10 mL), the organic phases were combined and washed with saturated brine, the solvent was distilled off under reduced pressure to give a crude product, and silica gel column chromatography was carried out [ V (methylene chloride): v (methanol) =80: 1]Obtaining the target product (S) -4- {5- [5- (acetamidomethyl) -2-oxazolidone-3-yl]Pyridin-2-yl } -N-cyclohexylpiperazine-1-carboxamide. The product was a white solid, m.p.216.0-216.7 ℃. 1 H-NMR(400MHz, DMSO-d 6 )δ8.22(d,J＝2.8Hz,1H),7.80(dd,J＝9.2,2.8Hz,1H),6.92(d,J＝9.2Hz,1H),6.25(t, J＝6.0Hz,1H),5.67(d,J＝8.0Hz,1H),4.73–4.69(m,1H),4.09–4.05(m,1H),3.72–3.68(m, 1H),3.40–3.35(m,10H),1.84(s,3H),1.78–1.47(m,5H),1.32–1.00(m,5H)。 13 C-NMR(75 MHz,DMSO-d 6 )δ170.6,156.2,151.7,139.2,129.4,126.8,114.5,107.7,72.3,48.0,45.9,45.40, 42.0,42.0,22.9。
Example 24 preparation of (S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] pyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide
114g of Compound B-6 (0.358 mmol) was dissolved in 10mL of methylene chloride, 109.6mg of p-chlorophenyl isocyanate (0.716 mmol) and 0.1mL of triethylamine (0.75 mmol) were further added thereto, stirred overnight under ice-bath conditions, TLC was monitored to be complete, methylene chloride and water were extracted (3X 10 mL), the organic phases were combined and washed with saturated brine, the solvent was distilled off under reduced pressure to give a crude product, and [ V (methylene chloride) ] was separated by silica gel column chromatography: v (methanol) =80: 1 ]Obtaining the target product (S) -4- {5- [5- (acetamidomethyl) -2-oxazolidone-3-base group]Pyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide. The product was a white solid, m.p.248.2-249.1 ℃. 1 H- NMR(400MHz,DMSO-d 6 )δ8.73(s,1H),8.25(t,J＝6.0Hz,1H),8.23(d,J＝2.8Hz,1H),7.82(dd, J＝9.2,2.8Hz,1H),7.52(d,J＝8.8Hz,2H),7.29(d,J＝8.8Hz,2H),6.95(d,J＝9.2Hz,1H),4.73 –4.69(m,1H),4.09–4.07(m,1H),3.71–3.69(m,1H),3.67–3.53(m,4H),3.52–3.48(m,4H), 3.42–3.41(m,2H),1.85(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6,168.3,156.2,155.1, 140.4,139.1,130.0,128.3,126.9,126.0,107.8,72.4,48.0,42.0,22.9。
Example 25 preparation of (S) -N- ({ 3- [ 5-fluoro-6- (4-propionylpiperazin-1-yl) pyridin-3-yl ] -2-oxazolidinone-5-yl } methyl) acetamide
After 140mg of intermediate C-6 (0.32 mmol) was dissolved in 5mL of dichloromethane and 1mL of trifluoroacetic acid was added at 0℃for 2 hours, TLC was monitored for completion of the reaction, triethylamine was added to the reaction system at 0℃to adjust pH to neutrality, and the solvent was distilled off under reduced pressure. Under ice-water bath, 0.7mL TEA,5mL dichloromethane and 36. Mu.L propionyl chloride (0.416 mmol) were added, the reaction was allowed to stand overnight, naturally warmed to room temperature, and TLC was checked for completion. Extracted with dichloromethane and water (3X 10 mL) and the organic phases combined and evaporated to dryness. PE/EA recrystallization yields (S) -N- ({ 3- [ 5-fluoro-6- (4-propionylpiperazin-1-yl) pyridin-3-yl)]-2-oxazolidinone-5-yl } methyl) acetamide, the product is a brown solid, melting point 173.0-173.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.25(t,J＝6.0Hz,1H),8.13(d,J＝2.4Hz, 1H),7.92(dd,J＝14.4,2.4Hz,1H),4.77–4.73(m,1H),3.76–3.68(m,1H),3.59–3.70(m,4H), 3.43–3.41(m,2H),3.29–3.28(m,1H),3.11–3.09(m,4H),2.36(q,J＝7.6Hz,2H),1.84(s,3H), 1.01(t,J＝7.6Hz,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.6,152.9,139.1,129.1,128.6,125.9, 121.5,120.3,72.6,48.0,47.6,46.2,44.0,41.9,22.9,9.1。
EXAMPLE 26 preparation of (S) -N- [ (3- {6- [4- (cyclohexanecarbonyl) piperazin-1-yl ] -5-fluoropyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide
48mg of intermediate C-6 (0.11 mmol) was dissolved in 2mL of dichloromethane, 0.5mL of trifluoroacetic acid was added at 0deg.C for 2h, after which the reaction was monitored by TLC for completion and was followed by reaction at 0deg.C Triethylamine is added into the system to adjust the pH value to be neutral, and the solvent is distilled off under reduced pressure. 3mg of 4-dimethylaminopyridine, 33mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.16 mmol) and 30mg of cyclohexane carboxylic acid (0.22 mmol) were added under an ice-water bath, and the temperature was raised to 90℃overnight, and TLC detection was complete. Extracted with dichloromethane and water (3X 10 mL) and the organic phases combined and evaporated to dryness. PE/EA recrystallization yields (S) -N- [ (3- {6- [4- (cyclohexanecarbonyl) piperazin-1-yl)]-5-fluoropyridin-3-yl } -2-oxazolidinone-5-yl) methyl]Acetamide, product is brown solid, melting point 198.1-199.4 ℃. 1 H-NMR(400MHz, DMSO-d 6 )δ8.23(t,J＝6.0Hz,1H),8.13(d,J＝2.0Hz,1H),7.92(dd,J＝14.4,2.0Hz,1H),4.77– 4.73(m,1H),4.13–4.10(m,1H),3.74–3.72(m,1H),3.63–3.57(m,4H),3.43–3.41(m,2H),3.29 –3.27(m,4H),2.66–2.56(m,1H),1.84(s,3H),1.75–1.59(m,5H),1.43–1.20(m,5H)。 13 C- NMR(75MHz,DMSO-d 6 )δ174.0,170.5,154.8,148.3,145.8,133.0,129.9,115.4,72.6,48.6,47.6, 45.0,41.9,41.2,29.6,26.1,25.6,22.9。
EXAMPLE 27 preparation of (S) -N- [ (3- { 5-fluoro-6- [4- (3-phenylpropionyl) -1-yl ] pyridin-3-yl } -2-oxazolidone-5-yl) methyl ] acetamide
140mg of intermediate C-6 (0.32 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added at 0℃for 2 hours, TLC was monitored for completion of the reaction, triethylamine was added to the reaction system at 0℃for pH adjustment to neutrality, and the solvent was distilled off under reduced pressure to obtain intermediate C-7. 270mg of phenylpropionic acid (3.6 mmol) was dissolved in 4mL of thionyl chloride, 1 drop of N, N-dimethylformamide was added thereto, the temperature was raised to 70℃for 2 hours, and the reaction was completed and the thionyl chloride was distilled off. The evaporated product was dissolved in 5mL of dichloromethane in an ice-water bath, 0.7mL of triethylamine and 108mg of intermediate C-7 (0.32 mmol) were added, the reaction was allowed to stand overnight, naturally warmed to room temperature, and after 2h, the reaction was complete by TLC detection and the system was clean. Extraction with dichloromethane and water (3X 10 mL) and evaporation of the organic phase combined gives (S) -N- [ (3- { 5-fluoro-6- [4- (3-phenylpropionyl) -1-yl) ]Pyridin-3-yl } -2-oxazolidinone-5-yl) methyl]Acetamide, product is brown solid, melting point 143.0-143.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.28(t,J＝6.0Hz,1H),8.12(d,J＝2.4Hz,1H),7.92 (dd,J＝14.4,2.4Hz,1H),7.30–7.20(m,5H),4.77–4.73(m,1H),4.13–4.11(m,1H),3.75–3.72 (m,1H),3.60–3.58(m,2H),3.43–3.38(m,4H),3.28–3.26(m,4H),2.67(t,J＝7.6Hz,2H),2.53 (t,J＝7.6Hz,1H),1.84(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ172.0,170.5,170.0,154.8,150.0, 148.3,145.9,139.0,133.0,128.7,127.9,115.5,72.6,47.6,46.2,44.9,41.9,26.0,22.9。
Example 28 preparation of (S, E) -N- { [3- (5-fluoro-6- {4- [3- (furan-2-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidin-5-yl ] methyl } acetamide
110mg of intermediate C-6 (0.25 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added at 0℃for 2 hours, TLC was monitored for completion of the reaction, triethylamine was added to the reaction system at 0℃for pH adjustment to neutrality, and the solvent was distilled off under reduced pressure to obtain intermediate C-7. 84.25mg of intermediate C-7 (0.25 mmol) was dissolved in 5mL of dichloromethane, 6.1mg of 4-dimethylaminopyridine (0.05 mmol), 72.3mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 mmol) and 69.5mg of 2-tetrahydrofuranacrylic acid (0.5 mmol) were added, the reaction was carried out overnight, and the completion of the reaction was detected by TLC. Extracted with dichloromethane and water (3X 10 mL) and the organic phases combined and evaporated to dryness. PE/EA recrystallization gives (S, E) -N- { [3- (5-fluoro-6- {4- [3- (furan-2-yl) acryloyl)]Piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } acetamide, the product is white solid, and the melting range is 200.7-202.3 ℃. 1 H-NMR(400MHz, DMSO-d 6 )δ8.16(t,J＝6.0Hz,1H),8.06(d,J＝2.4Hz,1H),7.86(dd,J＝14.4,2.4Hz,1H),7.73(d, J＝1.6Hz,1H),7.30(d,J＝15.2Hz,1H),6.89(d,J＝15.2Hz,1H),6.81(d,J＝3.2Hz,1H),6.54 (dd,J＝3.2,1.6Hz,1H),4.75–4.58(m,1H),4.06–4.03(m,1H),3.79–3.58(m,5H),3.36–3.33 (m,2H),3.31–3.27(m,4H),1.77(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ170.5,164.6,154.8, 150.6,149.9,145.7,138.7,135.0,133.0,131.4,124.3,120.7,72.6,47.6,46.1,41.9,22.9。
Example 29 preparation of (S, E) -N- { [3- (5-fluoro-6- {4- [3- (pyridin-3-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidin-5-yl ] methyl } acetamide
140mg of intermediate C-6 (0.32 mmol) was dissolved in 5mL of methylene chloride, and 1mL of trifluoroacetic acid was added at 0℃to react for 2 hoursTLC monitors the completion of the reaction, triethylamine is added into the reaction system at 0 ℃ to adjust the pH to be neutral, and the solvent is distilled off under reduced pressure to obtain an intermediate C-7. 536mg of 3-pyridineacrylic acid (3.6 mmol) was dissolved in 4mL of thionyl chloride, 1 drop of N, N-dimethylformamide was added, the temperature was raised to 70℃for 2 hours, the reaction was completed, and the thionyl chloride was distilled off. The evaporated product was dissolved in 5mL of dichloromethane under ice-water bath, added with 0.7mL of triethylamine and 108mg of intermediate C-7 (0.32 mmol), reacted overnight, naturally warmed to room temperature and after 2h the reaction was complete by TLC. Extraction with dichloromethane and water (3X 10 mL) and evaporation of the combined organic phases and recrystallization with PE/EA gave (S, E) -N- { [3- (5-fluoro-6- {4- [3- (pyridin-3-yl) acryloyl)]Piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl]Methyl } acetamide, the product is a brown solid with a melting point of 201.5-202.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ8.90(d,J＝2.0Hz,1H),8.56(dd,J＝ 4.8,2.0Hz,1H),8.25(t,J＝6.0Hz,1H),8.21(d,J＝8.4Hz,1H),8.15(d,J＝2.4Hz,1H),7.94(dd, J＝14.4,2.4Hz,1H),7.56(d,J＝15.2Hz,1H),7.47(d,J＝15.2Hz,1H),7.46(dd,J＝8.4,4.8Hz, 1H),4.78–4.74(m,1H),4.13–4.10(m,1H),3.90–3.88(m,2H),3.75–3.72(m,4H),3.43–3.41 (m,4H),3.12–3.08(m,1H),1.85(s,3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ174.2,170.6,158.8, 154.8,149.9,148.2,145.8,141.8,133.0,130.1,126.4,118.7,116.7,115.5,72.6,45.1,41.9,35.7,34.4, 31.2,30.8,22.9。
Example 30 preparation of (S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] -3-fluoropyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide
100mg of intermediate C-6 (0.23 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added at 0℃for 2 hours, TLC was monitored for completion of the reaction, triethylamine was added to the reaction system at 0℃for pH adjustment to neutrality, and the solvent was distilled off under reduced pressure to obtain intermediate C-7. 77.51mg of intermediate C-7 (0.23 mmol) was dissolved in 5mL of dichloromethane under an ice-water bath, 0.7mL of TEA and 70.5mg of propionyl chloride (0.46 mmol) were added, the reaction was allowed to stand overnight, naturally warmed to room temperature, and TLC detection was complete. Extracted with dichloromethane and water (3X 10 mL) and the organic phases combined and evaporated to dryness. PE/EA recrystallization yields (S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ]-3-fluoropyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide, yieldThe product is brown solid, m.p.218.7-220.2 ℃. 1 H-NMR (400MHz,DMSO-d 6 )δ8.73(s,1H),8.25(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz,1H),7.94(dd,J＝ 14.4,2.4Hz,1H),7.48(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H),4.78–4.74(m,1H),4.13–4.10 (m,1H),3.75–3.72(m,1H),3.67–3.56(m,4H),3.43–3.41(m,2H),3.40–3.34(m,4H),1.85(s, 3H)。 13 C-NMR(75MHz,DMSO-d 6 )δ172.1,170.6,158.8,156.3,155.1,139.2,130.1,128.7,127.9, 126.7,107.7,72.3,48.0,42.0,41.1,26.0,22.9。
TABLE 2 structural formulas and chemical names of the Compounds prepared in examples 31-62
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Example 31 (S) -N- ((3- (6- (4- (2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
And example 32 preparation of (S) -N- ((3- (6- (4- (4-chloropyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
After 218mg of intermediate C-6 (0.5 mmol) was dissolved in 5mL of dichloromethane and 1mL of trifluoroacetic acid was added at 0℃for 2 hours, TLC was monitored for completion of the reaction, triethylamine was added to the reaction system at 0℃to adjust pH to neutrality, and the solvent was distilled off under reduced pressure. To the system was added 3mL of ethanol for dissolution, 0.14mL of triethylamine (1 mmol) and 97mg of 2, 4-dichloropyrimidine (0.65 mmol) were added, and the reaction was refluxed overnight, and TLC was monitored to complete the reaction. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol): v (triethylamine) =50: 1:1], to obtain example 31 and example 32.
Example 31 was a brown solid with a yield of 5.8% and a melting point of 171.1-173.1 ℃. 1 H NMR(600MHz,DMSO-d 6 ) δ8.32(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz,1H),8.11(d,J＝6.0Hz,1H),7.94(dd,J＝14.4,2.4Hz, 1H),6.88(d,J＝6.0Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.79–3.72(m,5H),3.46– 3.40(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.6,163.0,160.0,158.0,154.8, 149.1(d,J C-F ＝257.1Hz),145.6,133.0,130.0,115.4,102.9,72.6,55.4,47.6,47.4,41.9,22.9。
Example 32 was a white solid with a yield of 40.4% and a melting point of 160.0-161.1 ℃. 1 H NMR(600MHz,DMSO-d 6 ) δ8.35(d,J＝5.4Hz,1H),8.25(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz, 1H),6.77(d,J＝5.4Hz,1H),4.79–4.72(m,1H),4.14–4.10(m,1H),3.89–3.81(m,4H),3.76–3.60(m,1H),3.46–3.39(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,161.5, 160.5,154.8,149.1(d,J C-F ＝257.1Hz),145.9,133.0,130.0,128.7,115.4,109.7,72.6,47.7,46.1, 43.7,41.9,22.9。
Example 33 preparation of (S) -N- ((3- (6- (4- (2- (benzylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 5mL of dioxane, 17.1mg of p-toluenesulfonic acid monohydrate (0.09 mmol) and 0.36mL of benzylamine (3.33 mmol) were added at room temperature, the temperature was raised and refluxed, the reaction was monitored by TLC for completion, and the solvent was distilled off under reduced pressure. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol): v (triethylamine) =100: 1:1]The product of example 33 was obtained. The product was a white solid with a yield of example 33 of 41.5% and a melting point of 202.7-204.6 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J ＝6.0Hz,1H),8.13(d,J＝2.4Hz,1H),7.93(dd,J＝14.4,2.4Hz,1H),7.82(d,J＝6.0Hz,1H),7.32 –7.24(m,5H),7.22–7.16(m,1H),6.07(d,J＝6.0Hz,1H),4.79–4.72(m,1H),4.14–4.10(m, 1H),3.74–3.72(m,1H),3.74–3.64(m,4H),3.47–3.38(m,2H),3.36–3.34(m,4H),1.84(s, 3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.6,162.3,154.8,150.0(d,J C-F ＝256.7Hz),146.0, 145.9,141.7,133.0,129.8,128.5,127.6,126.8,115.5,115.4,72.6,47.8,44.5,43.5,41.9,22.9。
Example 34 preparation of (S) -N- ((3- (6- (4- (2-morpholinpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 5mL of morpholine, 17.1mg of p-toluenesulfonic acid monohydrate (0.09 mmol) was added at room temperature, the reaction was refluxed at elevated temperature, and the reaction was completed by TLC. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure, and recrystallizing with ethyl acetate to give example 34 as a white solid with a yield of 46.1% and a melting point of 191.3-192.1deg.C. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝ 6.0Hz,1H),8.13(d,J＝2.4Hz,1H),7.96–7.90(m,2H),6.17(d,J＝6.0Hz,1H),4.79–4.72(m, 1H),4.13–4.10(m,1H),3.74–3.72(m,1H),3.70–3.69(m,4H),3.64–3.63(m,8H),3.47–3.35 (m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.6,161.6,157.1,154.8,150.0(d, J C-F ＝256.7Hz),146.0,133.0,129.9,115.5,115.4,94.1,72.6,66.6,47.7,44.4,43.6,41.9,22.9。
Example 35 preparation of (S) -N- ((3- (6- (4- (2- (methylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
200mg of example 31 (0.44 mmol) was dissolved in 4mL of methanol solution and reacted at room temperature for 3 days, the TLC monitored the completion of the reaction and the ethanol was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, evaporating the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 35 was obtained as a pale yellow solid in 40 yield5%, melting point 193.3-195.1 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.27(t,J＝6.0Hz,1H),8.14(d,J ＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),7.86(d,J＝6.6Hz,1H),7.31–7.30(s,1H),6.31(d,J ＝6.6Hz,1H),4.78–4.73(m,1H),4.13–4.10(m,1H),3.84–3.78(s,4H),3.75–3.73(m,1H),3.43 –3.42(m,6H),2.82(d,J＝4.8Hz,3H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5, 162.0,154.8,149.1(d,J C-F ＝257.1Hz),145.7,145.7,133.0,133.0,130.0,115.6,115.5,72.6,47.7, 47.6,43.9,41.9,28.1,22.9。
Example 36 preparation of (S) -N- ((3- (5-fluoro-6- (4- (2- (isopropylamino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
200mg of example 31 (0.44 mmol) was dissolved in 4mL of isopropylamine solution and reacted at 50℃under sealing for 3 days, and TLC monitored the completion of the reaction and the isopropylamine was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 36 was obtained as a pink solid in a yield of 44.4% and melting point 196.8-199.5 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H), 8.13(d,J＝2.4Hz,1H),7.93(dd,J＝14.4,2.4Hz,1H),7.82(d,J＝6.0Hz,1H),6.31(s,1H),6.04 (d,J＝6.0Hz,1H),4.79–4.72(m,1H),4.12–4.10(m,1H),4.04–3.95(m,1H),3.74–3.72(m, 1H),3.68–3.66(m,4H),3.49–3.36(m,5H),1.84(s,3H),1.12(d,J＝6.6Hz,6H),1.08–0.94(m, 1H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.7,161.7,157.2,154.8,149.1(d,J C-F ＝256.3Hz), 146.0,133.0,129.9,115.5,115.4,72.6,47.8,47.7,47.6,43.5,42.2,41.9,23.1,22.9。
Example 37 preparation of (S) -N- ((3- (5-fluoro-6- (4- (2- ((3-morpholinopropyl) amino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 144mg of 3-aminopropyl morpholine (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction and dioxane was distilled offA ring. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =50: 1]The product of example 37 was obtained as a brown oil in 48.7% yield. 1 H NMR(600MHz,DMSO-d 6 )δ8.28(t,J＝6.0Hz,1H),8.12(d,J＝2.4Hz,1H),7.92(dd,J＝14.4, 2.4Hz,1H),7.81(d,J＝6.0Hz,1H),6.57(s,1H),6.03(d,J＝6.0Hz,1H),4.77–4.73(m,1H),4.12 –4.09(m,1H),3.75–3.73(m,1H),3.67–3.65(m,4H),3.57–3.56(m,4H),3.44–3.42(m,4H), 3.38–3.35(m,4H),3.27–3.23(m,2H),2.33–2.30(m,4H),1.85(s,3H),1.66–1.64(m,2H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.6,162.7,162.3,157.2,154.8,149.1(d,J C-F ＝257.1Hz),145.9, 132.9,129.8,115.5,115.3,72.6,66.7,56.7,53.8,47.7,46.1,43.5,41.9,26.5,22.9,7.6。
Example 38 preparation of (S) -N- ((3- (6- (4- (4-methylpiperidin-1-yl) pyrimidine) 4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 0.12mL of 4-methylpiperidine (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =40: 1]The product of example 38 was obtained as a pink solid in a yield of 64.4% and a melting point of 198.1-200.5 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.13(d,J＝2.4Hz, 1H),7.93(dd,J＝14.4,2.4Hz,1H),7.89(d,J＝6.0Hz,1H),6.08(d,J＝6.0Hz,1H),4.79–4.72(m, 1H),4.62–4.59(m,2H),4.13–4.10(m,1H),3.74–3.72(m,1H),3.68–3.66(m,4H),3.43–3.41 (m,2H),3.41–3.37(m,4H),2.77–2.73(m,2H),1.84(s,3H),1.64–1.56(m,2H),1.04–0.98(m, 2H),0.91(d,J＝6.6Hz,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.7,161.4,157.1,154.8, 149.1(d,J C-F ＝256.3Hz),146.0,133.0,129.9,115.5,115.4,93.2,72.6,47.7,44.0,43.6,41.9,34.1, 31.3,22.9,22.4。
Example 39 preparation of (S) -N- ((3- (6- (4- (2- (naphthalen-1-ylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 143mg of 1-naphthylamine (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction, and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 39 was obtained as a brown solid in yield of 59.3%, melting point 221.8-223.1 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.60(s,1H),8.35(t,J＝6.0Hz,1H),8.13–8.11 (m,2H),7.99–7.90(m,3H),7.80(d,J＝7.2Hz,1H),7.74(d,J＝8.4Hz,1H),7.54–7.50(m,3H), 6.42(d,J＝6.6Hz,1H),4.77–4.75(m,1H),4.12–4.09(m,1H),3.78–3.75(m,1H),3.73–3.71 (m,4H),3.43–3.42(m,2H),3.38–3.34(m,4H),1.85(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ 170.6,162.1,154.8,152.4,149.1(d,J C-F ＝257.1Hz),146.0,145.7,134.9,134.4,133.0,130.0,128.7, 128.6,126.4,126.1,126.0,125.1,123.4,121.7,115.6,115.4,95.8,72.6,63.1,52.5,22.9,7.7。
Example 40 preparation of (S) -N- ((3- (6- (4- (2- ((2, 2-difluoroethyl) amino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 0.07mL of 2, 2-difluoroethylamine (1 mmol) were added, the reaction was sealed at 75℃overnight, TLC monitored for completion of the reaction, and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1 ]The product of example 40 was obtained as a pink solid in a yield of 66.7%, melting point 228.1-231.2 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.13(d,J ＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),7.87(d,J＝6.0Hz,1H),7.02(s,1H),6.20(d,J＝6.0 Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.76–3.73(m,1H),3.73–3.68(m,5H),3.68– 3.58(m,2H),3.46–3.38(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.5, 154.8,149.1(d,J C-F ＝257.2Hz),145.9,145.8,133.1,133.0,129.9,115.6,115.4,72.6,47.7,47.64, 43.9(t,J＝26.7Hz),43.7,43.6,41.9,22.9。
Example 41 preparation of (S) -N- ((3- (6- (4- (2- (quinolin-5-ylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 150mg of 5-aminoquinoline (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 41 was obtained as a white solid in 43% yield with a melting point of 226.2-232.2 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.15(s,1H),8.87(dd,J＝4.2,1.8Hz,1H),8.53– 8.48(m,1H),8.24(t,J＝6.0Hz,1H),8.15–8.12(m,1H),7.99–7.90(m,2H),7.87(dd,J＝7.2,1.2 Hz,1H),7.77–7.71(m,2H),,7.489–7.47(m,1H),6.33(d,J＝6.0Hz,1H),4.79–4.72(m,1H), 4.13–4.10(m,1H),3.74–3.72(m,1H),3.68–3.66(m,4H),3.43–3.41(m,2H),3.39–3.37(m, 4H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.5,161.1,157.3,154.8,149.7(d,J C-F ＝259.1Hz),148.3,145.9,136.9,133.0,132.6,129.9,129.6,124.7,123.6,120.7,120.6,115.6,115.4, 107.8,95.9,72.6,47.7,43.5,41.9,22.9。
Example 42 preparation of (S) -N- ((3- (6- (4- (2- (phenylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 91.15. Mu.L of aniline (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction and dioxane was distilled off. Extracting with dichloromethane and water (3X 10 mL), the organic phases were combined, the solvent was distilled off under reduced pressure to give a crude product, which was separated by silica gel column chromatography [ V (methylene chloride): v (methanol) =30: 1]The product of example 42 was obtained as a white solid in 43% yield with melting point 190.6-194.4 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.17(s,1H),8.24(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz, 1H),8.00(d,J＝6.0Hz,1H),7.95(dd,J＝14.4,2.4Hz,1H),7.73–7.68(m,2H),7.30–7.24(m, 2H),6.92(t,J＝7.2Hz,1H),6.36(d,J＝6.0Hz,1H),4.79–4.72(m,1H),4.14–4.11(m,1H),3.79 –3.77(m,4H),3.75–3.72(m,1H),3.48–3.39(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO- d 6 )δ170.5,165.2,162.5,154.8,149.1(d,J C-F ＝256.2Hz),145.7,141.2,140.8,133.0,129.8,128.9, 121.8,119.4,117.3,115.6,95.8,72.6,47.7,43.8,41.9,22.9。
Example 43 preparation of (S) -N- ((3- (6- (4- (2- (allylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 75. Mu.L of 2-allylamine (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 43 was obtained as a white solid in a yield of 68.1% with a melting point of 182.1-184.6 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.25(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz, 1H),7.94(dd,J＝14.4,2.4Hz,1H),7.85(d,J＝6.6Hz,1H),7.51–7.08(m,1H),6.28(d,J＝6.0Hz, 1H),5.92–5.86(m,1H),5.19(d,J＝17.4Hz,1H),5.08(d,J＝10.2Hz,1H),4.77–4.73(m,1H), 4.13–4.10(m,1H),3.93–3.91(m,2H),3.78–3.75(m,4H),3.74–3.72(m,1H),3.43–3.39(m, 6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.0,154.8,149.1(d,J C-F ＝257.5Hz), 145.8,138.1,136.4,133.0,130.0,128.5,126.0,115.6,115.4,72.6,47.6,43.9,43.4,41.9,22.9,21.2。
Example 44 preparation of (S) -N- ((3- (6- (4- (2- (propargylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of example 31 (0.33 mmol) was dissolved in 4mL of dioxane solution, 11.4mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 69. Mu.L of 2-propargylamine (1 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction, and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1 ]The product of example 44 was obtained as a white solid in a yield of 44.9% and melting point 185.6-188.7 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.29(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz,1H), 7.94(dd,J＝14.4,2.4Hz,1H),7.88(d,J＝6.0Hz,1H),7.22(s,1H),6.23(d,J＝6.0Hz,1H),5.33(s, 1H),4.77–4.73(m,1H),4.13–4.10(m,1H),4.04–4.03(m,2H),3.78–3.72(m,4H),3.44–3.34 (m,7H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.4,154.8,149.1(d,J C-F ＝256.9 Hz),145.9,145.8,133.1,133.0,130.0,115.6,115.4,72.6,63.1,52.5,47.7,43.7,41.9,30.6,22.9, 7.7。
Example 45 preparation of (S) -N- ((3- (6- (4- (2- ((6-chloropyridin-3-yl) amino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
200mg of example 31 (0.44 mmol) was dissolved in 4mL of dioxane solution, 17mg of p-toluenesulfonic acid monohydrate (0.09 mmol) and 171mg of 2-propargylamine (1.3 mmol) were added, the reaction was refluxed overnight, TLC monitored for completion of the reaction, and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 45 was obtained as a white solid in a yield of 45.8% and a melting point of 134.4-135.6 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.46(s,1H),8.74(d,J＝3.0Hz,1H),8.27– 8.19(m,2H),8.14(d,J＝2.4Hz,1H),8.05(d,J＝6.0Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),7.40 (d,J＝9.0Hz,1H),6.40(d,J＝6.0Hz,1H),4.79–4.72(m,1H),4.14–4.11(m,1H),3.78–3.71(m, 5H),3.47–3.42(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.5,159.5,157.1, 154.8,149.1(d,J C-F ＝256.5Hz),145.8,141.3,140.2,137.9,133.0,129.9,129.2,124.2,115.6,115.4, 96.6,72.6,47.6,43.7,41.9,22.9。
Example 46 preparation of (S) -N- ((3- (6- (4- (6-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC was monitored to complete the reaction, triethylamine was added to adjust the basicity, the product was dissolved in 4mL of ethanol solution after the solvent was distilled off, 83. Mu.L of triethylamine (0.6 mmol) and 60mg of 4, 6-dichloropyrimidine (0.4 mmol) were added, the reaction was refluxed overnight, TLC was monitored to complete the reaction, and ethanol was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1 ]The product of example 46 was obtained as a white solid in a yield of 45.1% with a melting point of 190.0-191.1 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.37(s,1H),8.24(t,J＝6.0Hz,1H),8.14(d,J ＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),7.02(s,1H),4.79–4.72(m,1H),4.14–4.10(m,1H), 3.81–3.75(m,4H),3.74–3.71(m,1H),3.43–3.42(m,6H),1.84(s,3H)。 13 C NMR(150MHz, DMSO-d 6 )δ170.5,162.7,159.7,158.5,154.8,148.2(d,J C-F ＝256.7Hz),145.6,133.0,129.99,115.6, 102.3,72.6,47.6,47.5,43.8,41.9,22.9。
Example 47 preparation of (S) -4- (4- (5- (5- (acetamidomethyl) -2-oxazolidinone-3-yl) -3-fluoropyridin-2-yl) piperazin-1-yl) -2- (methylthio) pyrimidine-5-acetic acid ethyl ester
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC was monitored to be complete, triethylamine was added to adjust the basicity, the solvent was distilled off, the product was dissolved in 4mL of ethanol solution, 83. Mu.L of triethylamine (0.6 mmol) and 93mg of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (0.4 mmol) were added, the reaction was refluxed overnight, TLC was monitored to be complete, and ethanol was distilled off. Extracting with dichloromethane and water (3×10 mL), mixing the organic phases, and distilling under reduced pressure to remove solvent to obtain crude productSilica gel column chromatography separation [ V (dichloromethane): v (methanol) =50: 1]The product of example 47 was obtained as a white solid in a yield of 50.6% and a melting point of 210.1-213.1 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.45(s,1H),8.26(t,J＝6.0 Hz,1H),8.11(d,J＝2.4Hz,1H),7.92(dd,J＝14.4,2.4Hz,1H),4.79–4.72(m,1H),4.36–4.17(m, 2H),4.14–4.09(m,1H),3.76–3.72(m,1H),3.68–3.66(m,4H),3.46–3.44(m,4H),3.43–3.41 (m,2H),2.48(s,3H),1.85(s,3H),1.37–1.25(m,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ172.6, 170.5,165.9,159.8,159.3,154.8,149.0(d,J C-F ＝257.0Hz),145.6,132.9,129.8,115.3,105.7,72.6, 61.4,47.6,47.5,47.3,41.9,22.9,14.5,14.1。
Example 48 preparation of (S) -N- ((3- (5-fluoro-6- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC was monitored to complete the reaction, triethylamine was added to adjust the basicity, the solvent was distilled off, the product was dissolved in 4mL of ethanol solution, 83. Mu.L of triethylamine (0.6 mmol) and 51mg of 2-chloro-5-methylpyrimidine (0.4 mmol) were added, the reaction was refluxed overnight, TLC was monitored to complete the reaction, and ethanol was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =50: 1 ]The product of example 47 was obtained as a white solid in a yield of 49.4% with a melting point of 195.1-197.3 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.26–8.23(m,3H),8.13(d,J＝2.4Hz,1H), 7.93(dd,J＝14.4,2.4Hz,1H),4.77–4.73(m,1H),4.13–4.10(m,1H),3.85–3.80(m,4H),3.76– 3.70(m,1H),3.43–3.37(m,6H),2.10(s,3H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ 160.7,158.2,154.8,149.2(d,J C-F ＝255.3Hz),146.1,133.0,130.0,119.1,115.5,115.4,72.6,47.9, 46.2,43.9,22.9,14.1,9.1。
Example 49 (S) -N- ((3- (6- (4, 6-dichloropyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) ethyl)
Preparation of amide and example 50 (S) -N- ((3- (6- (4- (2, 6-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added for basicity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 83. Mu.L of triethylamine (0.6 mmol) and 45. Mu.L of 2,4, 6-trichloropyrimidine (0.4 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, dioxane was evaporated. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate) =1: 3] to give the product of example 49 and the product of example 50, respectively, as white solids in yields of 13.8% and 44.7%, respectively, with melting points of 191.3-192.5 ℃ and 195.2-197.1 ℃, respectively.
Example 49 product: 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz, 1H),7.94(dd,J＝14.4,2.4Hz,1H),6.98(s,1H),4.77–4.73(m,1H),4.14–4.10(m,1H),3.88– 3.84(m,4H),3.75–3.72(m,1H),3.44–3.41(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 ) δ170.5,161.6,160.5,154.8,148.2(d,J＝256.7Hz),145.7,132.9,130.0,115.4,108.2,72.6,47.6, 47.5,43.9,41.9,22.9。
Example 50 product: 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz, 1H),7.94(dd,J＝14.4,2.4Hz,1H),7.08(s,1H),4.77–4.74(m,1H),4.13–4.10(m,1H),3.87– 3.71(m,5H),3.44–3.42(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,163.4, 159.6,159.0,154.8,149.1(d,J C-F ＝257.1Hz),145.5,133.0,130.0,115.4,101.4,72.6,47.6,47.4, 43.7,41.9,22.9。
example 51 preparation of (S) -N- ((3- (6- (4- (5-bromopyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) is dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid is added for reaction for 2 h under ice bath condition, TLC monitors that the reaction is complete, triethylamine is added for alkalinity,after evaporation of the solvent, the product was dissolved in 4mL of dioxane solution, 83. Mu.L of triethylamine (0.6 mmol) and 174mg of 2-chloro-5-bromopyrimidine (0.4 mmol) were added, the reaction was refluxed overnight, TLC monitored the completion of the reaction and dioxane was evaporated. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 51 was obtained as a white solid in a yield of 47.6% with a melting point of 196.1-196.3 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.50(s,2H),8.24(t,J＝6.0Hz, 1H),8.13(d,J＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),4.77–4.73(m,1H),4.14–4.10(m, 1H),3.88–3.83(m,4H),3.74–3.71(m,1H),3.43–3.33(m,6H),1.84(s,3H)。 13 C NMR(150 MHz,DMSO-d 6 )δ170.5,166.3,160.0,158.5,154.8,150.8(d,J C-F ＝253.7Hz),133.0,129.9,115.3, 106.1,72.6,47.6,43.8,41.9,39.0,22.9。
Example 52 preparation of (S) -N- ((3- (6- (4- (2, 5-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added for basicity, the solvent was distilled off, the product was dissolved in 4mL of dioxane solution, 83. Mu.L of triethylamine (0.6 mmol) and 46. Mu.L of 2,4, 5-trichloropyrimidine (0.4 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1 ]The product of example 52 was obtained as a white solid in a yield of 48.6%, melting point 193.5-194.2 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.35(s,1H),8.24(t,J＝6.0Hz, 1H),8.14(d,J＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),4.77–4.73(m,1H),4.14–4.10(m, 1H),3.91–3.86(m,4H),3.75–3.72(m,1H),3.51–3.46(m,4H),3.43–3.41(m,2H),1.84(s, 3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,160.4,159.1,157.1,154.8,148.3(d,J C-F ＝256.7Hz), 133.0,130.0,115.5,115.1,72.6,47.6,47.6,47.0,41.9,22.9。
Example 53 preparation of (S) -N- ((3- (6- (4- (5-bromo-2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 83. Mu.L of triethylamine (0.6 mmol) and 50. Mu.L of 2, 4-dichloro-5-bromopyrimidine (0.4 mmol) were added, reaction was carried out overnight at 70℃and TLC monitoring was complete, dioxane was evaporated off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol) =30: 1]The product of example 53 was obtained as a white solid in a yield of 82.8% with a melting point of 196.7-197.6 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.46(s,1H),8.24(t,J＝6.0Hz, 1H),8.14(d,J＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),4.77–4.73(m,1H),4.14–4.10(m, 1H),3.87–3.83(m,4H),3.75–3.72(m,1H),3.50–3.46(m,4H),3.43–3.41(m,2H),1.84(s, 3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,162.7,161.8,157.8,154.8,149.1(d,J C-F ＝257.1Hz), 145.6,133.0,130.0,115.5,104.1,72.6,47.6,47.6,47.3,41.9,22.9。
Example 54 preparation of (S) -N- ((3- (5-fluoro-6- (4- (2, 5, 6-trichloropyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide
130mg of intermediate C-6 (0.3 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 83 μl of triethylamine (0.6 mmol) and 85mg of 2,4,5, 6-tetrachloropyrimidine (0.4 mmol) were added, reaction was carried out overnight at 70℃and TLC monitoring was complete, dioxane was evaporated. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate) =1: 5 ]The product of example 54 was obtained as a white solid in a yield of 71.4% with a melting point of 210.0-211.1 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.14(d,J ＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.92–3.81 (m,4H),3.75–3.72(m,1H),3.52–3.47(m,4H),3.44–3.39(m,2H),1.84(s,3H)。 13 C NMR(150 MHz,DMSO-d 6 )δ170.5,161.9,159.0,155.1,154.8,149.1(d,J C-F ＝255.8Hz),145.6,133.0,129.8, 115.4,112.4,72.6,47.8,47.6,47.5,41.9,22.9。
Example 55 preparation of (S) -N- ((3- (6- (4- (2-chloro-5-methylpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
80mg of intermediate C-6 (0.18 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 2mL of dioxane solution after evaporation of the solvent, 100. Mu.L of triethylamine (0.72 mmol) and 28. Mu.L of 2, 4-dichloro-5-methylpyrimidine (0.24 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, dioxane was evaporated off. The crude product was obtained by extraction with dichloromethane and water (3X 10 mL), the organic phases combined, distillation under reduced pressure and solvent removal, and recrystallization from petroleum ether ethyl acetate gave the product of example 55 as a white solid with a yield of 58.9% and a melting point of 198.8-200.8 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz,1H),8.06(s, 1H),7.93(dd,J＝14.4,2.4Hz,1H),4.79–4.72(m,1H),4.14–4.10(m,1H),3.74–3.72(m,1H), 3.70–3.65(m,4H),3.48–3.44(m,4H),3.43–3.41(m,2H),2.24(s,3H),1.84(s,3H)。 13 C NMR (150MHz,DMSO-d 6 )δ170.5,165.0,160.0,157.2,154.8,149.1(d,J C-F ＝257.1Hz),145.8,133.0, 130.0,116.2,115.4,72.6,47.8,47.6,46.9,41.9,22.9,17.3。
Example 56 preparation of (S) -N- ((3- (6- (4- (2-chloro-5-fluoropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
80mg of intermediate C-6 (0.18 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice bath conditions for 2 h, TLC was monitored to be complete, triethylamine was added to adjust the basicity, the product was dissolved in 2mL of dioxane solution after the solvent was distilled off, 100. Mu.L of triethylamine (0.72 mmol) and 40mg of 2, 4-dichloro-5-fluoropyrimidine (0.24 mmol), at 50℃overnight, TLC monitored the completion of the reaction and distilled off dioxane. The crude product was obtained by extraction with dichloromethane and water (3X 10 mL), the organic phases combined, distillation under reduced pressure and solvent removal, and recrystallization from petroleum ether ethyl acetate gave the product of example 55 as a white solid with a yield of 70.1% and a melting point of 204.4-205.5 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.25–8.21(m,2H),8.14(d,J＝2.4Hz,1H),7.94(dd,J ＝14.4,2.4Hz,1H),4.79–4.72(m,1H),4.14–4.10(m,1H),3.90–3.86(m,4H),3.75–3.71(m, 1H),3.48–3.46(m,4H),3.43–3.41(m,2H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5, 154.8,153.5,152.5,149.1(d,J C-F ＝257.0Hz),147.1(d,J C-F ＝256.4Hz),145.6,144.7,133.0,130.0, 115.6,72.6,47.6,45.8,41.9,40.5,22.9。
Example 57 preparation of (S) -N- ((3- (6- (4- (2-aminopyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of intermediate C-6 (0.35 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 200. Mu.L of triethylamine (1.4 mmol) and 58.3mg of 2-amino-4-chloropyrimidine (0.45 mmol) were added, reaction was carried out overnight at 70℃and TLC monitoring was complete, dioxane was evaporated off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol): v (triethylamine) =30: 1:1]The product of example 57 was obtained as a white solid in a yield of 60.9% and melting point 195.6-196.7 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.28–8.25 (m,1H),8.15(d,J＝2.4Hz,1H),7.97–7.88(m,3H),7.89(dd,J＝7.8,2.4Hz,1H),6.57(d,J＝7.8 Hz,1H),4.78–4.74(m,1H),4.14–4.11(m,1H),3.75–3.72(m,1H),3.47–3.46(m,4H),3.43– 3.41(m,4H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 )δ170.5,161.7,155.1,154.8,149.1(d, J C-F ＝256.4Hz),145.4,143.4,133.0,130.1,115.6,115.5,95.4,72.7,47.6,47.5,41.9,22.9.。
Example 58 preparation of (S) -N- ((3- (6- (4- (4-aminopyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
150mg of intermediate C-6 (0.35 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 34 mg paratoluenesulfonic acid monohydrate (0.175 mmol) and 136mg of 4-amino-2-chloropyrimidine (1.05 mmol) were added, reaction was carried out overnight at 70℃and TLC monitoring was complete, dioxane was evaporated. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (dichloromethane): v (methanol): v (triethylamine) =30: 1:1]The product of example 58 was obtained as a white solid in a yield of 60.9% with a melting point of 196.6-197.7 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ 8.25(t,J＝6.0Hz,1H),8.14(d,J＝2.4Hz,1H),7.94(dd,J＝14.4,2.4Hz,1H),7.77(d,J＝6.0Hz, 1H),7.48–7.10(m,2H),5.94(d,J＝6.0Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.80–3.78(m,4H),3.75–3.72(m,1H),3.43–3.40(m,6H),1.84(s,3H)。 13 C NMR(150MHz,DMSO-d 6 ) δ170.5,164.5,154.8,149.1(d,J C-F ＝256.7Hz),145.9,138.1,133.0,130.0,128.5,126.0,115.6,72.6, 47.7,43.9,41.9,22.9,21.3。
Preparation of intermediate D-1
1.00g of 1-amino-3-chloropropane-2-ol hydrochloride (6.85 mmol) was dissolved in methylene chloride (50 mL), 1.63mL of dichloroacetyl chloride (17.1 mmol) and 2.86mL of triethylamine (20.55 mmol) were added, stirred overnight under reflux, the reaction mixture was cooled, 20mL of water was added, methylene chloride (3X 20 mL) was added for extraction, the organic phases were combined, washed with saturated brine, concentrated by distillation under reduced pressure, and cooled and precipitated by adding petroleum ether at-78℃to give the desired product, namely D-1. The product was a yellow solid with a yield of 87.7% and a melting point of 37.4-39.7 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ8.80(t,J＝6.0Hz,1H),6.83(s,1H),6.45(s,1H),5.25–5.21(m,1H), 3.96–3.77(m,2H),3.51–3.49(m,2H)。
Preparation of intermediate D-2
100mg of the mixture is converted into a solution at 0 DEG CCompound C-5 (0.23 mmol) was dissolved in 2mL of anhydrous tetrahydrofuran, nitrogen was introduced for protection, 100mg of lithium t-butoxide (1.15 mmol) was added to the three-necked flask at-78℃and stirred for 20min, then 232mg of intermediate D-1 (0.7 mmol) dissolved in 1mL anhydrous tetrahydrofuran was added thereto, the reaction was carried out at-78℃for 1 hour, and then the temperature was naturally raised to room temperature and stirred for 16h. TLC monitoring reaction completion, water quenching, vacuum evaporation of solvent, ethyl acetate and water extraction (3X 40 mL), combining organic phase, saturated salt water washing, vacuum distillation evaporation of solvent to obtain crude product, silica gel column chromatography separation [ V (petroleum ether): v (ethyl acetate) =1: 1]Obtaining the target product intermediate D-2. The product was a white solid with a yield of 68.5% and a melting point of 150.1-153.2 ℃. 1 H NMR(600 MHz,DMSO-d 6 )δ8.98(t,J＝6.0Hz,1H),8.11(d,J＝2.4Hz,1H),7.91(dd,J＝14.4,2.4Hz,1H), 6.50(s,1H),4.86–4.82(m,1H),4.17–4.14(m,1H),3.75–3.73(m,1H),3.55–3.54(m,2H),3.46 –3.45(m,4H),3.29–3.28(m,4H),1.42(s,9H)。
Example 59 preparation of (S) -2, 2-dichloro-N- (3- (6- (4- (2, 5-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
100mg of intermediate D-2 (0.2 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added for basicity, the solvent was distilled off, the product was dissolved in 4mL of dioxane solution, 111. Mu.L of triethylamine (0.8 mmol) and 30. Mu.L of 2,4, 5-trichloropyrimidine (0.26 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate) =1: 1 ]The product of example 59 was obtained as a white solid in a yield of 45.9% and a melting point of 100.7-101.5 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.07(t,J＝6.0Hz,1H),8.34(s, 1H),8.13(d,J＝2.4Hz,1H),7.93(dd,J＝14.4,2.4Hz,1H),6.54(s,1H),4.85–4.83(m,1H),4.17 –4.14(m,1H),3.89–3.87(m,4H),3.78–3.75(m,1H),3.56–3.53(m,2H),3.49–3.47(m,4H)。 13 C NMR(150MHz,DMSO-d 6 )δ165.0,160.4,159.0,157.1,154.6,149.0(d,J C-F ＝256.3Hz),145.7, 133.1,129.8,115.6,115.1,72.1,67.1,52.5,47.0,42.7,7.7。
Example 60 preparation of (S) -N- ((3- (6- (4- (5-bromo-2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) -2, 2-dichloroacetamide
100mg of intermediate D-2 (0.2 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 111. Mu.L of triethylamine (0.8 mmol) and 33. Mu.L of 2, 4-dichloro-5-bromopyrimidine (0.26 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, dioxane was evaporated. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate) =1: 1]The product of example 60 was obtained as a white solid in a yield of 33.9% and a melting point of 104.1-104.8 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.01(t,J＝6.0Hz,1H), 8.46(s,1H),8.13(d,J＝2.4Hz,1H),7.93(dd,J＝14.4,2.4Hz,1H),6.51(s,1H),4.86–4.82(m, 1H),4.17–4.14(m,1H),3.86–3.84(m,4H),3.78–3.73(m,1H),3.56–3.54(m,2H),3.49–3.47 (m,4H)。 13 C NMR(150MHz,DMSO-d 6 )δ165.0,162.0,157.8,154.6,149.1(d,J C-F ＝257.1Hz), 145.7,133.0,129.9,115.6,115.5,104.1,72.1,67.1,47.6,47.3,46.1,42.7。
Example 61 preparation of (S) -2, 2-dichloro-N- ((3- (6- (4- (2-chloro-5-methylpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
100mg of intermediate D-2 (0.2 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added to adjust alkalinity, the product was dissolved in 4mL of dioxane solution after evaporation of the solvent, 111. Mu.L of triethylamine (0.8 mmol) and 30. Mu.L of 2, 4-dichloro-5-methylpyrimidine (0.26 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, dioxane was evaporated off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate) =1: 1 ]The product of example 61 was obtained as a white solidThe yield of the product is 47.6%, and the melting point is 157.0-157.6 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.04(t,J＝6.0Hz,1H), 8.13(d,J＝2.4Hz,1H),8.06(s,1H),7.92(dd,J＝14.4,2.4Hz,1H),6.53(s,1H),4.86–4.82(m, 1H),4.17–4.14(m,1H),3.77–3.75(m,1H),3.68–3.66(m,4H),3.56–3.51(m,2H),3.47–3.44 (m,4H),2.24(s,3H). 13 C NMR(150MHz,DMSO-d 6 )δ165.0,160.1,157.2,154.6,149.1(d,J C-F ＝ 256.4Hz),145.8,133.1,129.8,116.2,115.6,115.5,72.1,67.1,47.8,46.9,46.0,42.7,17.3.
Example 62 preparation of (S) -2, 2-dichloro-N- ((3- (6- (4- (2-chloro-5-fluoropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide
100mg of intermediate D-2 (0.2 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added under ice-bath conditions for 2 h, TLC monitoring was complete, triethylamine was added for basicity, the solvent was distilled off, the product was dissolved in 4mL of dioxane solution, 111. Mu.L of triethylamine (0.8 mmol) and 43mg of 2, 4-dichloro-5-fluoropyrimidine (0.26 mmol) were added, reaction was carried out overnight at 50℃and TLC monitoring was complete, and dioxane was distilled off. Extraction with dichloromethane and water (3X 10 mL), combining the organic phases, distilling off the solvent under reduced pressure to give the crude product, and column chromatography on silica gel [ V (petroleum ether): v (ethyl acetate) =1: 1]The product of example 62 was obtained as a white solid in a yield of 28.3% with a melting point of 126.9-127.6 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.03(t,J＝6.0Hz,1H),8.23(d, J＝6.6Hz,1H),8.13(d,J＝2.4Hz,1H),7.93(dd,J＝14.4,2.4Hz,1H),6.52(s,1H),4.86–4.82(m, 1H),4.17–4.14(m,1H),3.88–3.86(m,4H),3.77–3.74(m,1H),3.56–3.54(m,2H),3.49–3.46 (m,4H)。 13 C NMR(150MHz,DMSO-d 6 )δ165.0,154.6,153.4,152.5,149.1(d,J C-F ＝256.3Hz), 147.1(d,J C-F ＝256.4Hz),144.8,133.1,129.9,115.6,115.5,72.1,67.1,47.7,46.0,45.8,42.7。
Experimental example 1 in vitro antibacterial Activity experiment of the Compounds of the invention
1. Sample supply: the compounds synthesized in examples 1-62.
2. Experimental method
Samples were sterilized and diluted to a range of concentrations, up to 128 μg/mL, with MH broth. 100 μl MH broth was added to each row of wells 12 of the 96-well plate as a blank, 50 μl MH broth was added to well 11, and 50 μl of test solutions were added sequentially from well 10 to well 1 in order of low to high.
Selecting a proper amount of tested strain and standard strain, inoculating the strain into MH broth suitable for growth, culturing for 24 hours at 37 ℃, and diluting the grown bacterial liquid with the MH broth to serve as a tested bacterial liquid. Inoculating 50 mu L of bacterial liquid to the 1 st to 11 th holes, blowing and evenly mixing, and culturing for 18 to 24 hours at the temperature of 37 ℃. And observing the experimental result under a black background, wherein turbidity exists in the holes with bacteria growth or bacterial precipitation exists at the bottom, and the sterile growth hole culture solution is clear and transparent and has no precipitation. The lowest drug concentration contained in the aseptically grown wells is the lowest inhibitory concentration, i.e., MIC.
3. Experimental results
The results of the experiments are shown in tables 3 and 4
TABLE 3 Activity of the compounds prepared in examples 1-30 MIC (μg/mL) for gram-positive bacteria
Note that: ATCC-25923 is Staphylococcus aureus; ATCC-49619 is Streptococcus pneumoniae; ATCC-29212 is enterococcus faecalis; ATCC-6633 is bacillus subtilis; ATCC-35924 is Staphylococcus xylosus.
TABLE 4 Activity of the compounds prepared in examples 31-62 MIC (μg/mL) for gram-positive bacteria
Note that: ATCC-25923 is Staphylococcus aureus; ATCC-49619 is Streptococcus pneumoniae; BNCC-109047 is bacillus subtilis; ATCC-29212 is enterococcus faecalis; ATCC-35924 is Staphylococcus xylosus; ATCC-19111 is Listeria.
The in vitro antibacterial activity test shows that the pyridine-containing bisoxazolidone compounds provided by the invention have definite antibacterial activity.
Claims (10)
1. The pyridine-containing bisoxazolidone compound is characterized in that the structural formula is shown in the general formula I:
wherein X is 1 And X 2 Independently of each other selected from oxygen or nitrogen;
R 1 、R 3 is a substituent different from each other in kind, and includes, but is not limited to, any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridine acryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino;
R 2 hydrogen or fluorine;
R 4 any one selected from acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridine acryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino.
2. The enantiomer, racemate, solvate, and acid of a pyridoxal-containing compound of claim 1, wherein the enantiomer, racemate, solvate, and acid form a pharmaceutically acceptable salt or prodrug thereof.
3. The pyridine-containing bisoxazolidinone compound according to claim 1, wherein the compound of formula I is selected from any one of the following compounds:
(S) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } -3-phenylpropionamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } cyclohexanecarboxamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } nicotinamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } furan-2-carboxamide;
(S) -N- { [ (3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } -4- (trifluoromethyl) benzamide;
n- { [ (S) -3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } tetrahydrofuran-2-carboxamide;
(R) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } methanesulfonamide;
(R) -N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } benzenesulfonamide;
(S) -1-cyclohexyl-3- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } urea;
(S) -3-methyl-N- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } butanamide;
(S) -1- (4-chlorophenyl) -3- { [3- (6-morpholinpyridin-3-yl) -2-oxazolidin-5-yl ] methyl } urea;
(S) -N- {3- [6- (4-propionylpiperazin-1-yl) pyridin-3-yl-2-oxazolidin-5-yl ] methyl } acetamide;
(S) -N- [ ({ 3- [6- (4-cyclohexanecarbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- [ (3- (6- {4- [4- (trifluoromethyl) benzoyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidone-5-yl) methyl ] acetamide;
(S) -N- [ (3- {6- [4- (6-chloronicotinamide) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- {6- [4- (furan-2-carbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- [ (3- {6- [4- (3-phenylpropionyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidin-5-yl) methyl ] acetamide;
(S, E) -N- [ (3- (6- {4- [3- (furan-2-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- [ (3- (6- (4- { [4- (trifluoromethyl) phenyl ] sulfonyl } piperazin-1-yl) pyridin-3-yl) -2-oxazolidinone-5-yl) methyl ] acetamide;
(S) -N- { [3- (6- {4- [ (4-methoxyphenyl) sulfonyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S) -N- { [3- (6- {4- [ (4-nitrophenyl) sulfonyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidin-5-yl ] methyl } acetamide;
(S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] pyridin-2-yl } -N-cyclohexylpiperazine-1-carboxamide;
(S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] pyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide;
(S) -N- ({ 3- [ 5-fluoro-6- (4-propionylpiperazin-1-yl) pyridin-3-yl ] -2-oxazolidinone-5-yl } methyl) acetamide;
(S) -N- [ (3- { 5-fluoro-6- [4- (cyclohexanecarbonyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- { 5-fluoro-6- [4- (3-phenylpropionyl) piperazin-1-yl ] pyridin-3-yl } -2-oxazolidinone-5-yl) methyl ] acetamide;
(S, E) -N- { [3- (5-fluoro-6- {4- [3- (furan-2-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S, E) -N- { [3- (5-fluoro-6- {4- [3- (pyridin-3-yl) acryloyl ] piperazin-1-yl } pyridin-3-yl) -2-oxazolidinone-5-yl ] methyl } acetamide;
(S) -4- {5- [5- (acetamidomethyl) -2-oxazolidinone-3-yl ] -3-fluoropyridin-2-yl } -N- (4-chlorophenyl) piperazine-1-carboxamide;
(S) -N- ((3- (6- (4- (2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (4-chloropyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (benzylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-morpholinpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2- (methylamino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2- (isopropylamino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2- ((3-morpholinopropyl) amino) pyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (4-methylpiperidin-1-yl) pyrimidine) 4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (naphthalen-1-ylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- ((2, 2-difluoroethyl) amino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- (3- (6- (4- (2- (quinolin-5-ylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- (3- (6- (4- (2- (phenylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- (allylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- (3- (6- (4- (2- (propargylamino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2- ((6-chloropyridin-3-yl) amino) pyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (6-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -4- (4- (5- (5- (acetamidomethyl) -2-oxazolidinone-3-yl) -3-fluoropyridin-2-yl) piperazin-1-yl) -2- (methylsulfanyl) pyrimidine-5-acetic acid ethyl ester;
(S) -N- ((3- (5-fluoro-6- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4, 6-dichloropyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2, 6-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (5-bromopyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2, 5-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (5-bromo-2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (5-fluoro-6- (4- (2, 5, 6-trichloropyrimidin-4-yl) piperazin-1-yl) pyridin-3-yl) -2-oxazolidin-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-chloro-5-methylpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-chloro-5-fluoropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (2-aminopyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (4-aminopyrimidin-2-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -2, 2-dichloro-N- (3- (6- (4- (2, 5-dichloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -N- ((3- (6- (4- (5-bromo-2-chloropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidin-5-yl) methyl) -2, 2-dichloroacetamide;
(S) -2, 2-dichloro-N- ((3- (6- (4- (2-chloro-5-methylpyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide;
(S) -2, 2-dichloro-N- ((3- (6- (4- (2-chloro-5-fluoropyrimidin-4-yl) piperazin-1-yl) -5-fluoropyridin-3-yl) -2-oxazolidinone-5-yl) methyl) acetamide.
4. A method of synthesizing a compound of formula I according to claim 1, comprising:
(1) 2-chloro-5-nitropyridine reacts with morpholine to prepare an intermediate A-1; (2) Reducing the intermediate A-1 by palladium carbon and hydrogen to generate an intermediate A-2; (3) Introducing Cbz protecting group on the amino group of the intermediate A-2 to obtain an intermediate A-3; (4) The intermediate A-3 and (R) - (-) -glycidyl butyl are cyclized to generate a product A-4 of an oxazolidone ring; (5) introducing methanesulfonyl into the product A-4 to generate A-5; (6) reacting A-5 with potassium phthalimide to produce A-6; (7) Removing phthalimide groups from the A-6 in a methanol solution to obtain A-7; (8) Connecting different substituents on the amino group of the intermediate A-7 to obtain the compound;
5. The synthetic method according to claim 4, wherein in the step (4), in a reaction liquid of n-butyllithium and tetrahydrofuran at 78 ℃, intermediates A-3 and (R) - (-) -glycidyl butyl ester are lower Wen Huange to form a product A-4 of an oxazolidone ring;
in the step (7), removing phthalimide groups from the A-6 in a methanol solution to obtain A-7;
the substituent in the step (8) is selected from any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridylacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino.
6. A method of synthesizing a compound of formula I according to claim 1, comprising:
(1) 2-chloro-5-nitropyridine reacts with 1-Boc-piperazine to prepare an intermediate B-1; (2) reducing intermediate B-1 to intermediate B-2; (3) Introducing Cbz protecting group into the intermediate B-2 to obtain an intermediate B-3; (4) Reflux-extracting 1-amino-3-chloropropane-2-ol with acetic anhydride to obtain a ring-closing intermediate B-4; (5) The intermediate B-3 and the intermediate B-4 are cyclized to generate a product B-5 of an oxazolidone ring; (6) Boc removal of B-5 with trifluoroacetic acid to give intermediate B-6; (7) The intermediate B-6 is further connected with different substituents to obtain the compound; the substituent includes, but is not limited to, any of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridine acryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino;
7. The method according to claim 6, wherein in the step (2), the intermediate B-1 is reduced with palladium on carbon and ammonium formate to form an intermediate B-2; in the step (4), 1-amino-3-chloropropane-2-alcohol and acetic anhydride are refluxed under the catalysis of triethylamine to obtain a ring-closing intermediate B-4; the B-5 in the step (6) is separated from Boc by trifluoroacetic acid to obtain an intermediate B-6.
8. A method of synthesizing a compound of formula I according to claim 1, comprising:
(1) 3-fluoro-2-hydroxypyridine is connected with nitro to obtain an intermediate C-1; (2) refluxing and chloridizing the intermediate C-1 to obtain an intermediate C-2; (3) Intermediate C-2 reacts with 1-Boc-piperazine to prepare intermediate C-3; (4) reducing intermediate C-3 to intermediate C-4; (5) Introducing the intermediate C-4 into a Cbz protecting group to obtain an intermediate C-5; (6) Reflux of 1-amino-3-chloropropane-2-alcohol and acetic anhydride under the catalysis of triethylamine to obtain a ring-closing intermediate B-4; (7) The intermediate C-5 and the intermediate B-4 for ring closure are cyclized to generate a product C-6 of an oxazolidone ring; (8) C-6 is Boc removed to give intermediate C-7; (9) The intermediate C-7 is further connected with different substituents to obtain the compound;
9. the synthetic method according to claim 8, wherein in the step (1), 3-fluoro-2-hydroxypyridine is nitrated with concentrated nitric acid to obtain an intermediate C-1; in step (2), intermediate C-1 is treated with POCl 3 、PCl 5 Reflux chlorination to obtain intermediate C-2; in the step (4), reducing the intermediate C-3 by palladium carbon and ammonium formate to generate an intermediate C-4; under ice bath in the step (8), removing Boc from the C-6 with trifluoroacetic acid to obtain an intermediate C-7; the substituents described in step (9) include, but are not limited to, acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl,Any one of 4-trifluoromethylbenzoyl, 3-picolyl, 2-furoyl, 2-tetrahydrofuranoyl, 3-picolyl, 6-chloropyridine-3-formyl, 2-furoyl, 3-pyridine-acryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chloroanilino.
10. Use of a pyridine-containing bisoxazolidinone compound as defined in claim 1 or 3, an enantiomer, racemate, solvate, and acid to form a pharmaceutically acceptable salt or prodrug thereof in the manufacture of an anti-bacterial infection medicament.
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