CN117534655A - 一种喹诺酮类化合物及其制备方法和用途 - Google Patents
一种喹诺酮类化合物及其制备方法和用途 Download PDFInfo
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- CN117534655A CN117534655A CN202311504831.8A CN202311504831A CN117534655A CN 117534655 A CN117534655 A CN 117534655A CN 202311504831 A CN202311504831 A CN 202311504831A CN 117534655 A CN117534655 A CN 117534655A
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- compound
- organic solvent
- alkali
- reaction
- dioxane
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- -1 Quinolone compound Chemical class 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 208000035143 Bacterial infection Diseases 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 5
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000006359 acetalization reaction Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical class ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- MVUMJYQUKKUOHO-AATRIKPKSA-N ethyl (e)-3-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)\C=C\N(C)C MVUMJYQUKKUOHO-AATRIKPKSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 150000005826 halohydrocarbons Chemical class 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 150000007660 quinolones Chemical class 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 abstract description 4
- 206010059866 Drug resistance Diseases 0.000 abstract description 3
- 229960003405 ciprofloxacin Drugs 0.000 abstract description 2
- 229940124307 fluoroquinolone Drugs 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229940072132 quinolone antibacterials Drugs 0.000 description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 1
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开一种喹诺酮类化合物及其制备方法和用途,属于医药技术领域,所述喹诺酮类化合物结构式为
Description
技术领域
本发明属于医药技术领域,尤其涉及一种喹诺酮类化合物及其制备方法和用途。
背景技术
耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA)具有多重耐药性,对多种一线抗生素均存在耐药现象,也被称为“超级细菌”。其引起的感染难以控制,给临床治疗带来了十分严峻的挑战。由于社区相关性MRSA的出现,全球性MRSA感染的发病率和死亡率急剧上升。欧洲每年大概有15万人感染MRSA,而亚洲则是全球感染率最高的地区之一。
自上世纪60年代,美国Sterling-winthrop研究所发现第一个喹诺酮类抗菌药萘啶酸以来,该类药物在治疗细菌感染方面一直发挥着非常重要的作用。全球抗菌药物市场中,喹诺酮类抗菌药仅次于β-内酰胺类抗生素。然而,随着喹诺酮类抗菌药物的长期使用,该类药物对MRSA也产生了一定的耐药性。
发明内容
为解决上述技术问题,本发明提出了一种喹诺酮类化合物及其制备方法和用途,本发明的喹诺酮类化合物对MRSA有抑制活性,且与现有喹诺酮类抗菌药物无交叉耐药性。
为实现上述目的,本发明提供了一种喹诺酮类化合物,结构式如(I)所示:
其中:R1选自氢,C1~6烷基,C3~7环烷基,C1~6烷氧基,被一个或多个卤原子取代的C1~6烷基;
R2选自H原子或F原子;
R3选自氢,C1~6烷基,C3~7环烷基,卤原子;取代基R3可以是邻位取代、间位取代或对位取代,也可以是单取代、双取代或多取代;
R4选自氢,C1~6烷基。
一种所述的喹诺酮类化合物的制备方法,包括以下步骤:
1)取代的苯乙酰氯与Meldrum酸在第一碱作用下缩合生成中间体2;
2)所述中间体2在第一酸中水解生成中间体3;
3)所述中间体3加热脱羧后,与叔丁醇反应生成中间体4;
4)所述中间体4与N,N-二甲基甲酰胺二甲缩醛反应得中间体5;
5)所述中间体5经所述第一酸水解脱羧,得到中间体6;
6)所述中间体6与盐酸胍反应得到中间体7;
7)化合物8与所述中间体7在钯催化剂、配体、第二碱存在下,于溶剂中反应得到化合物9;
8)所述化合物9在第三碱作用下水解,酸水调pH至2~3,过滤,水洗得化合物I-1,所述化合物I-1即喹诺酮类化合物;
或者,所述化合物9在第四碱作用下,与卤代烃反应生成化合物10,所述化合物10在所述第四碱作用下水解,酸水调pH至2~3,过滤,水洗得化合物I-2,所述化合物I-2即喹诺酮类化合物,其中:R1选自氢,C1~6烷基,C3~7环烷基,C1~6烷氧基,被一个或多个卤原子取代的C1~6烷基;R2选自H原子或F原子;R3选自氢,C1~6烷基,C3~7环烷基,卤原子;R4为C1~6烷基;
反应路线如下:
进一步地,所述化合物8的制备方法如下:
a.4-溴-取代苯甲酰氯1’与3-(N,N-二甲氨基)丙烯酸乙酯在三乙胺存在下于甲苯中反应生成中间体2’;
b.将所述中间体2’与胺在第一有机溶剂中反应生成中间体3’;
c.将所述中间体3’在第五碱作用下关环生成中间体8;
反应路线如下:
其中:R1选自氢,C1~6烷基,C3~7环烷基,C1~6烷氧基,被一个或多个卤原子取代的C1~6烷基,被一个或多个卤原子取代的C2~6烯基,被一个或多个卤原子取代的C3~6炔基;
R2选自H原子或F原子。
进一步地,在化合物8的制备方法中,步骤b中所述第一有机溶剂为二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺(DMF)、四氢呋喃、二氧六环、二甲基亚砜(DMSO)和C1~C4醇中的至少一种;
步骤b的反应温度为25~80℃;
步骤c中所述第五碱为碱金属的碳酸盐或有机碱;所述碱金属的碳酸盐为碳酸钠、碳酸钾或碳酸铯;所述有机碱为三乙胺、DBU(1,8-二氮杂二环十一碳-7-烯)或DIEPA(N,N-二异丙基乙胺)。
步骤c中所述第五碱作用下关环在第二有机溶剂中进行,所述第二有机溶剂为四氢呋喃、二氧六环、DMF、DMSO和C1~C4醇中的至少一种;
步骤c中的反应温度为25~110℃。
进一步地,在所述喹诺酮类化合物的制备方法中,步骤1)中所述第一碱为有机碱;缩合在第三有机溶剂中进行,所述第三有机溶剂为二氯甲烷、三氯甲烷、DMF、四氢呋喃、二氧六环和DMSO中的至少一种;缩合的反应温度为20~80℃;
步骤2)中所述第一酸为盐酸(HCl)、硫酸或者三氟乙酸。
进一步地,在所述喹诺酮类化合物的制备方法中,步骤3)中与叔丁醇反应在第四有机溶剂中进行,所述第四有机溶剂为四氢呋喃、二氧六环、DMF、DMSO、甲苯和二甲苯中的至少一种;反应温度为60~110℃;
步骤4)中,缩醛反应在所述第四有机溶剂中进行;所述缩醛反应的温度为60~110℃。
进一步地,在所述喹诺酮类化合物的制备方法中,步骤5)中,所述水解脱羧在第五有机溶剂中进行,所述第五有机溶剂为C1~C4醇、四氢呋喃、二氧六环、二氯甲烷和三氯甲烷中的至少一种;反应温度为20~50℃;
步骤6)中,与盐酸胍反应在第六有机溶剂中进行,所述第六有机溶剂为C1~C4醇、四氢呋喃和二氧六环中的至少一种;反应温度为60~100℃。
进一步地,在所述喹诺酮类化合物的制备方法中,步骤7)中,所述配体为2,2'-双-(二苯膦基)-1,1'-联萘、2-二环己膦基-2'-(N,N-二甲胺)-联苯、2-叔丁基磷-2',4',6'-三异丙基联苯、2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯、4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,1’-双二苯基膦二茂铁、2-(二叔丁基膦)联苯、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯、2-二叔丁基膦-2',4',6'-三异丙基-3,6-二甲氧基-1,1'-联苯、2-二环己基磷-2’,4’,6’-三异丙基联苯或2-双环己基膦-2',6'-二甲氧基联苯;
所述钯催化剂为醋酸钯、三(二亚苄基茚丙酮)二钯或氯化钯;
所述溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、甲苯、1,4-二氧六环、二丁醚和叔丁醇中的至少一种;
所述第二碱为碳酸钾、磷酸钾、碳酸铯、叔丁醇钾或六甲基二硅基氨基锂;
反应温度为80-110℃,反应时间为8-24h。
进一步地,在所述喹诺酮类化合物的制备方法中,步骤8)中,当在第三碱作用下水解时,所述第三碱为氢氧化锂、氢氧化钠或氢氧化钾;在第六有机溶剂中进行,所述第六有机溶剂为C1~C4醇、四氢呋喃、二氧六环、DMF和DMSO中的至少一种;反应温度为25~50℃;反应时间为0.5~8h;
当在第四碱作用下,与卤代烃反应时,所述第四碱为NaH、叔丁醇钾、叔丁醇钠、二异丙基氨基锂或正丁基锂;在第七有机溶剂中进行,所述第七有机溶剂为DMF、四氢呋喃、二氧六环和DMSO中的至少一种;反应温度为-20~60℃,反应时间为8-24h。
所述的喹诺酮类化合物在制备预防和/或治疗细菌感染药物中的应用。
与现有技术相比,本发明具有如下优点和技术效果:
本发明的喹诺酮类化合物结构新颖,具有良好的抗菌活性。本发明的喹诺酮类化合物还可以制备成药物组合物(该药物组合物含有有效剂量的上述喹诺酮类化合物及相关的药用载体),上述喹诺酮类化合物和上述药物组合物均可以用于制备预防和/或治疗细菌感染药物,具有显著的抗菌效果,且不产生耐药性。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值,以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
本发明实施例中的室温,如无特殊说明,均按25±2℃计。
本发明所用原料和试剂均通过购买得到。
实施例1中间体5的制备
冰浴下,将取代的苯乙酰氯1(42.0mmol)滴加至Meldrum酸(5.0g,35.0mmol)、吡啶(5.5g,70.0mmol)与二氯甲烷(50mL)的混合物中,室温搅拌过夜后(生成中间体2),加入1.2M HCl(50mL),室温搅拌0.5h,分液,有机相经水洗(15mL×1),饱和食盐水洗(15mL×1),无水硫酸钠干燥、过滤、浓缩,得中间体3,无需分离纯化,直接用于下一步反应;
将中间体3(35.0mmol)溶于叔丁醇(50mL),加热至90℃反应3h,冷却至室温,减压蒸馏除去溶剂,得中间体4,无需分离纯化,直接用于下一步反应;
将中间体4(35.0mmol)溶于甲苯(50mL),向其中加入N,N-二甲基甲酰氨基缩二甲醇(4.6g,38.5mmol),100℃下加热搅拌反应2h,减压蒸馏除去溶剂,残余物经柱层析(石油醚/乙酸乙酯=3/1,体积比)分离纯化得中间体5。
5a(R3=2-甲基):收率20%;1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),7.15-7.10(m,4H),4.04(s,2H),3.02-2.86(br,6H),2.27(s,3H),1.51(s,9H).
5b(R3=3-甲基):收率66%;1H NMR(400MHz,Chloroform-d)δ7.56(s,1H),7.23-7.12(m,1H),7.11-6.98(m,3H),3.98(s,2H),3.07-2.75(br,6H),2.30(s,3H),1.52(s,9H).
5c(R3=4-甲基):收率53%;1H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.12(d,J=8.0Hz,2H),7.07(d,J=8.0Hz,2H),3.98(s,2H),3.05-2.74(br,6H),2.29(s,3H),1.52(s,9H).
5d(R3=3,4-二甲基):收率56%;1H NMR(400MHz,Chloroform-d)δ7.54(s,1H),7.04-7.00(m,2H),6.95(dd,J=7.6,2.0Hz,1H),3.95(s,2H),3.07-2.73(br,6H),2.21(s,3H),2.20(s,3H),1.53(s,9H).
5e(R3=2-氯):收率24%;1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.39-7.32(m,1H),7.30-7.13(m,3H),4.17(s,2H),3.15-2.83(br,6H),1.51(s,9H).
5f(R3=3-氯):收率28%;1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.30-7.23(m,3H),7.14-7.10(m,1H),4.00(s,2H),3.18-2.71(br,6H),1.52(s,9H).
5g(R3=4-氯):收率39%;1H NMR(400MHz,Chloroform-d)δ7.58(s,1H),7.24(d,J=8.1Hz,2H),7.17(d,J=8.1Hz,2H),3.99(s,2H),3.22-2.67(br,6H),1.52(s,9H).
5h(R3=3,4-二氯):收率30%;1H NMR(400MHz,Chloroform-d)δ7.62(s,1H),7.35(d,J=2.0Hz,1H),7.33(d,J=8.2Hz,1H),7.08(dd,J=8.2,2.0Hz,1H),3.97(s,2H),3.29-2.68(br,6H),1.52(s,9H).
5i(R3=2,4-二氟):收率48%;1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.25-7.15(m,1H),6.87-6.73(m,2H),4.03(s,2H),3.27-2.72(br,6H),1.52(s,9H).
实施例2中间体7的制备
将中间体5(2mmol)溶于二氯甲烷(8mL),加入过量三氟乙酸,室温搅拌过夜,除去溶剂,加入饱和NaHCO3水溶液,乙酸乙酯萃取,有机相水洗,盐水洗,干燥,浓缩,得中间体6,无需分离纯化,直接用于下一步反应;
将中间体6(2mmol)、盐酸胍(0.4g,4mmol)溶于无水乙醇(5mL),室温搅拌下向其中加入乙醇钠(0.4g,6mmol)的无水乙醇(5mL)溶液,加热至80℃搅拌过夜,冷却至室温,硅藻土过滤,除去溶剂,残余物经95%乙醇(体积分数)重结晶得中间体7。
7a(R3=2-甲基):收率67%;1H NMR(400MHz,Chloroform-d)δ8.12(d,J=5.1Hz,1H),7.20-7.14(m,4H),6.25(d,J=5.1Hz,1H),5.02(s,2H),3.93(s,2H),2.25(s,3H).
7b(R3=3-甲基):收率47%;1H NMR(400MHz,Chloroform-d)δ8.14(d,J=5.1Hz,1H),7.23-7.18(m,1H),7.07-7.02(m,3H),6.41(d,J=5.1Hz,1H),5.11(s,2H),3.87(s,2H),2.33(s,3H).
7c(R3=4-甲基):收率12%;1H NMR(400MHz,Chloroform-d)δ8.13(d,J=5.1Hz,1H),7.13-7.12(m,4H),6.40(d,J=5.1Hz,1H),5.12(s,2H),3.86(s,2H),2.33(s,3H).
7d(R3=3,4-二甲基):收率43%;1H NMR(400MHz,Chloroform-d)δ8.13(d,J=5.1Hz,1H),7.07(d,J=7.6Hz,1H),7.01(s,1H),6.97(d,J=7.6Hz,1H),6.41(d,J=5.1Hz,1H),5.05(s,2H),3.84(s,2H),2.23(s,6H).
7e(R3=2-氯):收率43%;1H NMR(400MHz,Chloroform-d)δ8.15(d,J=5.1Hz,1H),7.41-7.38(m,1H),7.28-7.20(m,3H),6.35(d,J=5.1Hz,1H),5.04(s,2H),4.06(s,2H).
7f(R3=3-氯):收率47%;1H NMR(400MHz,Chloroform-d)δ8.17(d,J=5.0Hz,1H),7.25-7.20(m,3H),7.14-7.11(m,1H),6.41(d,J=5.0Hz,1H),5.18(s,2H),3.87(s,2H).
7g(R3=4-氯):收率63%;1H NMR(400MHz,Chloroform-d)δ8.16(d,J=5.1Hz,1H),7.28(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),6.40(d,J=5.1Hz,1H),5.00(s,2H),3.87(s,2H).
7h(R3=3,4-二氯):收率16%;1H NMR(400MHz,Chloroform-d)δ8.19(d,J=5.0Hz,1H),7.38(d,J=8.2Hz,1H),7.35(d,J=2.1Hz,1H),7.09(dd,J=8.2,2.1Hz,1H),6.42(d,J=5.0Hz,1H),5.01(s,2H),3.84(s,2H).
7i(R3=2,4-二氟):收率44%;1H NMR(400MHz,Chloroform-d)δ8.17(d,J=5.1Hz,1H),7.25-7.17(m,1H),6.87-6.79(m,2H),6.41(d,J=5.1Hz,1H),5.02(s,2H),3.89(s,2H).
实施例3中间体8的合成
在冰浴下,将3-(N,N-二甲氨基)丙烯酸乙酯(2.9g,20mmol)滴加到4-溴-苯甲酰氯1’(20mmol)、三乙胺(7.1g,70mmol)和甲苯(40mL)的混合溶液中,110℃加热搅拌过夜,冷却至室温,过滤,除去溶剂,残余物经柱层析分离纯化得中间体2’。
2’-1(R2=F,X=F):收率67%;1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.36(dd,J=8.3,6.0Hz,1H),7.26(dd,J=8.8,5.3Hz,1H),4.02(q,J=7.1Hz,2H),3.33(s,3H),2.89(s,3H),1.01(t,J=7.1Hz,3H).
2’-2(R2=H,R=Br):收率62%;1H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.71(d,J=1.8Hz,1H),7.44(dd,J=8.2,1.8Hz,1H),7.22(d,J=8.2Hz,1H),3.93(q,J=7.1Hz,2H),3.34(s,3H),2.98(s,3H),0.91(t,J=7.1Hz,3H)。
将中间体2’(13.5mmol)及各种取代的胺(17.5mmol)在THF(10mL)中,于50℃下,搅拌3h,浓缩,得中间体3’,无需分离纯化,直接用于下一步反应。
将中间体3’(13.5mmol)、K2CO3(4.7g,33.7mmol)加入DMF(15mL)中,于60-90℃搅拌过夜,冷却后,倒入冰水中,过滤,水洗,得中间体8。
8-1(R2=F,R1=环丙基):收率90%;1H NMR(400MHz,Chloroform-d)δ8.55(s,1H),8.16-8.12(m,2H),4.39(q,J=7.1Hz,2H),3.50-3.44(m,1H),1.41(t,J=7.1Hz,3H),1.38-1.35(m,2H),1.20-1.14(m,2H).
8-2(R2=H,R1=环丙基):收率96%;1H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.34(d,J=8.6Hz,1H),8.07(d,J=1.7Hz,1H),7.55(dd,J=8.6,1.7Hz,1H),4.40(q,J=7.1Hz,2H),3.47-3.41(m,1H),1.41(t,J=7.1Hz,3H),1.38-1.33(m,2H),1.18-1.12(m,2H).
实施例4中间体9的合成
将中间体7(0.6mmol)、中间体8(0.5mmol)、三(二亚苄基丙酮)二钯(18.3mg,0.02mmol)、2-二环己基磷-2’,4’,6’-三异丙基联苯(28.6mg,0.06mmol)、无水碳酸钾(165.9mg,1.2mmol)加入至无水甲苯(8mL)中,110℃加热反应24h,冷却至室温,硅藻土过滤,浓缩,经柱层析分离纯化得中间体9。
9-1(R3=2-甲基,R2=F,R1=环丙基):收率44%;1H NMR(400MHz,Chloroform-d)δ9.44(d,J=6.9Hz,1H),8.56(s,1H),8.39(d,J=5.1Hz,1H),8.16(d,J=11.7Hz,1H),7.76(d,J=4.3Hz,1H),7.23-7.21(m,2H),7.21-7.15(m,2H),6.58(d,J=5.1Hz,1H),4.40(q,J=7.1Hz,2H),4.09(s,2H),3.42-3.36(m,1H),2.28(s,3H),1.41(t,J=7.1Hz,3H),1.27-1.25(m,2H),1.16-1.11(m,2H).
9-2(R3=3-甲基,R2=F,R1=环丙基):收率49%;1H NMR(400MHz,Chloroform-d)δ9.42(d,J=7.0Hz,1H),8.54(s,1H),8.41(d,J=5.1Hz,1H),8.11(d,J=11.7Hz,1H),7.79(d,J=4.3Hz,1H),7.22(td,J=7.3,1.2Hz,1H),7.10-7.03(m,3H),6.73(d,J=5.1Hz,1H),4.38(q,J=7.1Hz,2H),4.04(s,2H),3.42-3.36(m,1H),2.33(s,3H),1.40(t,J=7.1Hz,3H),1.29-1.23(m,2H),1.16-1.10(m,2H).
9-3(R3=4-甲基,R2=F,R1=环丙基):收率64%;1H NMR(400MHz,Chloroform-d)δ9.43(d,J=6.9Hz,1H),8.56(s,1H),8.40(d,J=5.1Hz,1H),8.16(d,J=11.7Hz,1H),7.74(d,J=4.3Hz,1H),7.15-7.14(m,4H),6.71(d,J=5.1Hz,1H),4.40(q,J=7.1Hz,2H),4.03(s,2H),3.41-3.35(m,1H),2.34(s,3H),1.41(t,J=7.1Hz,3H),1.28-1.23(m,2H),1.15-1.10(m,2H).
9-4(R3=3,4-二甲基,R2=H,R1=环丙基):收率89%;1H NMR(400MHz,Chloroform-d)δ8.81(s,1H),8.52(s,1H),8.35(d,J=5.1Hz,1H),8.34(d,J=8.8Hz,1H),8.20(s,1H),7.33(d,J=8.8Hz,1H),7.07(d,J=7.6Hz,1H),7.01(s,1H),6.98(d,J=7.6Hz,1H),6.66(d,J=5.1Hz,1H),4.36(q,J=7.1Hz,2H),3.96(s,2H),3.42-3.35(m,1H),2.23(s,6H),1.38(t,J=7.1Hz,3H),1.27-1.21(m,2H),1.12-1.07(m,2H).
9-5(R3=2-氯,R2=H,R1=环丙基):收率40%;1H NMR(400MHz,Chloroform-d)δ8.73(d,J=2.0Hz,1H),8.51(s,1H),8.37(d,J=5.1Hz,1H),8.33(d,J=8.8Hz,1H),8.17(s,1H),7.43-7.39(m,1H),7.37(dd,J=8.8,2.0Hz,1H),7.30-7.21(m,3H),6.61(d,J=5.1Hz,1H),4.36(q,J=7.1Hz,2H),4.17(s,2H),3.41-3.35(m,1H),1.38(t,J=7.1Hz,3H),1.28-1.22(m,2H),1.12-1.07(m,2H).
9-6(R3=3-氯,R2=H,R1=环丙基):收率50%;1H NMR(400MHz,Chloroform-d)δ8.74(d,J=2.0Hz,1H),8.51(s,1H),8.39(d,J=5.0Hz,1H),8.35(d,J=8.8Hz,1H),8.32(s,1H),7.39(dd,J=8.8,2.0Hz,1H),7.25-7.21(m,3H),7.15-7.11(m,1H),6.65(d,J=5.0Hz,1H),4.35(q,J=7.1Hz,2H),3.98(s,2H),3.41-3.35(m,1H),1.37(t,J=7.1Hz,3H),1.24-1.20(m,2H),1.11-1.06(m,2H).
9-7(R3=4-氯,R2=H,R1=环丙基):收率66%;1H NMR(400MHz,Chloroform-d)δ8.76(d,J=2.0Hz,1H),8.53(s,1H),8.38(d,J=5.1Hz,1H),8.37(d,J=8.8Hz,1H),8.03(s,1H),7.35(dd,J=8.8,2.0Hz,1H),7.28(d,J=8.3Hz,2H),7.19(d,J=8.3Hz,2H),6.64(d,J=5.1Hz,1H),4.36(q,J=7.1Hz,2H),3.99(s,2H),3.41-3.35(m,1H),1.38(t,J=7.1Hz,3H),1.28-1.21(m,2H),1.13-1.08(m,2H).
9-8(R3=3,4-di氯,R2=H,R1=环丙基):收率29%;1H NMR(400MHz,Chloroform-d)δ8.73(d,J=2.0Hz,1H),8.54(s,1H),8.40(d,J=5.0Hz,1H),8.38(d,J=8.0Hz,1H),7.93(s,1H),7.39-7.35(m,3H),7.10(dd,J=8.0,2.0Hz,1H),6.66(d,J=5.0Hz,1H),4.37(q,J=7.1Hz,2H),3.96(s,2H),3.43-3.37(m,1H),1.39(t,J=7.1Hz,3H),1.29-1.24(m,2H),1.14-1.10(m,2H).
9-9(R3=2,4-二氟,R2=H,R1=环丙基):收率68%;1H NMR(400MHz,Chloroform-d)δ8.75(d,J=2.0Hz,1H),8.55(s,1H),8.40-8.37(m,2H),7.80(s,1H),7.35(dd,J=8.8,2.0Hz,1H),7.25-7.21(m,1H),6.89-6.81(m,2H),6.65(d,J=5.0Hz,1H),4.38(q,J=7.1Hz,2H),4.02(s,2H),3.46-3.40(m,1H),1.40(t,J=7.1Hz,3H),1.32-1.27(m,2H),1.16-1.11(m,2H).
实施例5终产物I的制备
将中间体9(1mmol)溶于四氢呋喃(8mL),加入5M LiOH(5mL),50℃加热反应3h,冷却至室温,除去部分四氢呋喃,在冰浴、搅拌下,用4M HCl调pH≈2,过滤,水洗,烘干得终产物I。
I-1(R3=2-甲基,R2=F,R1=环丙基):收率96%;1H NMR(400MHz,Chloroform-d)δ9.63(d,J=6.8Hz,1H),8.78(s,1H),8.43(d,J=5.0Hz,1H),8.09(d,J=11.2Hz,1H),7.92(d,J=4.3Hz,1H),7.24-7.15(m,4H),6.65(d,J=5.0Hz,1H),4.11(s,2H),3.55-3.47(m,1H),2.28(s,3H),1.37-1.31(m,2H),1.23-1.16(m,2H).
I-2(R3=3-甲基,R2=F,R1=环丙基):收率90%;1H NMR(400MHz,Chloroform-d)δ9.62(d,J=6.9Hz,1H),8.82(s,1H),8.45(d,J=5.0Hz,1H),8.14(d,J=11.3Hz,1H),7.87(d,J=4.4Hz,1H),7.23(t,J=7.5Hz,1H),7.10(d,J=7.7Hz,1H),7.06(s,1H),7.05(d,J=8.0Hz,1H),6.79(d,J=5.0Hz,1H),4.06(s,2H),3.52-3.46(m,1H),2.34(s,3H),1.35-1.30(m,2H),1.21-1.16(m,2H).
I-3(R3=4-甲基,R2=F,R1=环丙基):收率85%;1H NMR(400MHz,Chloroform-d)δ9.61(d,J=6.9Hz,1H),8.79(s,1H),8.45(d,J=5.0Hz,1H),8.09(d,J=11.4Hz,1H),7.90(d,J=4.2Hz,1H),7.15(s,4H),6.79(d,J=5.0Hz,1H),4.06(s,2H),3.53-3.46(m,1H),2.34(s,3H),1.35-1.30(m,2H),1.22-1.16(m,2H).
I-4(R3=3,4-二甲基,R2=H,R1=环丙基):收率81%;1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.07(d,J=2.0Hz,1H),8.64(s,1H),8.50(d,J=5.0Hz,1H),8.17(d,J=8.9Hz,1H),7.85(dd,J=8.9,2.0Hz,1H),7.09-7.06(m,2H),7.01(d,J=7.6Hz,1H),6.84(d,J=5.0Hz,1H),3.98(s,2H),3.70-3.64(m,1H),2.18(s,3H),2.17(s,3H),1.31-1.26(m,2H),1.20-1.15(m,2H).
I-5(R3=2-氯,R2=H,R1=环丙基):收率98%;1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.99(d,J=2.0Hz,1H),8.66(s,1H),8.53(d,J=5.0Hz,1H),8.16(d,J=8.9Hz,1H),7.87(dd,J=8.9,2.0Hz,1H),6.74(d,J=5.0Hz,1H),4.23(s,2H),3.71-3.63(m,1H),1.32-1.25(m,2H),1.21-1.15(m,2H).
I-6(R3=3-氯,R2=H,R1=环丙基):收率82%;1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.02(d,J=2.0Hz,1H),8.65(s,1H),8.55(d,J=5.0Hz,1H),8.19(d,J=8.9Hz,1H),7.87(dd,J=8.9,2.0Hz,1H),7.42(s,1H),7.39-7.27(m,3H),6.92(d,J=5.0Hz,1H),4.10(s,2H),3.71-3.64(m,1H),1.31-1.25(m,2H),1.20-1.15(m,2H).
I-7(R3=4-氯,R2=H,R1=环丙基):收率94%;1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.00(d,J=2.0Hz,1H),8.63(s,1H),8.49(d,J=5.0Hz,1H),8.16(d,J=9.0Hz,1H),7.83(dd,J=9.0,2.0Hz,1H),7.35(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),6.84(d,J=5.0Hz,1H),4.05(s,2H),3.67-3.61(m,1H),1.30-1.24(m,2H),1.18-1.12(m,2H).
I-8(R3=3,4-di氯,R2=H,R1=环丙基):收率92%;1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.98(d,J=2.0Hz,1H),8.65(s,1H),8.54(d,J=5.0Hz,1H),8.17(d,J=8.9Hz,1H),7.87(dd,J=8.9,2.0Hz,1H),7.62(d,J=2.0Hz,1H),7.59(d,J=8.3Hz,1H),7.31(dd,J=8.3,2.0Hz,1H),6.91(d,J=5.0Hz,1H),4.10(s,2H),3.71-3.65(m,1H),1.32-1.26(m,2H),1.21-1.15(m,2H).
I-9(R3=2,4-二氟,R2=H,R1=环丙基):收率72%;1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.96(d,J=2.0Hz,1H),8.64(s,1H),8.50(d,J=5.0Hz,1H),8.15(d,J=9.0Hz,1H),7.86(dd,J=9.0,2.0Hz,1H),7.45-7.39(m,1H),7.20-7.14(m,1H),7.07-7.02(m,1H),6.79(d,J=5.0Hz,1H),4.09(s,2H),3.69-3.63(m,1H),1.32-1.26(m,2H),1.18-1.14(m,2H).
实施例6:终产物II的制备
在氮气保护下,向中间体9(0.5mmol)的无水N,N-二甲基甲酰胺(4mL)溶液中加入氢化钠(13.2mg,0.55mmol)的无水N,N-二甲基甲酰胺(1mL)悬浮液,室温搅拌75min,加入碘甲烷(106.5mg,0.75mmol)的无水N,N-二甲基甲酰胺(1mL)溶液,室温搅拌过夜,硅藻土过滤,浓缩,经柱层析分离纯化得中间体10;
将中间体10(0.1mmol)溶于四氢呋喃(5mL),加入5M LiOH(3mL),50℃加热反应3h,冷却至室温,除去部分四氢呋喃,在冰浴、搅拌下,用4M HCl调pH≈2,二氯甲烷萃取,干燥,浓缩,得终产物II。
10-1(R4=甲基,R3=3,4-二甲基,R2=F,R1=环丙基):收率42%;1H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.22-8.19(m,2H),7.91(d,J=6.2Hz,1H),7.04(d,J=7.7Hz,1H),7.01(s,1H),6.97(d,J=7.7Hz,1H),6.52(d,J=5.0Hz,1H),4.41(q,J=7.1Hz,2H),3.84(s,2H),3.60(s,3H),3.40-3.34(m,1H),2.23(s,3H),2.22(s,3H),1.42(t,J=7.1Hz,3H),1.26-1.26(m,2H),1.16-1.12(m,2H).
10-2(R4=甲基,R3=3,4-二甲基,R2=H,R1=环丙基):收率41%;1H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.44(d,J=8.8Hz,1H),8.25(d,J=5.0Hz,1H),7.95(d,J=2.0Hz,1H),7.43(dd,J=8.8,2.0Hz,1H),7.06(d,J=7.6Hz,1H),7.02(s,1H),6.98(d,J=7.6Hz,1H),6.55(d,J=5.0Hz,1H),4.39(q,J=7.1Hz,2H),3.86(s,2H),3.68(s,3H),3.35-3.30(m,1H),2.24(s,3H),2.23(s,3H),1.42(t,J=7.1Hz,3H),1.25-1.20(m,2H),1.14-1.10(m,2H).
II-1(R4=甲基,R3=3,4-二甲基,R2=F,R1=环丙基):收率74%;1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),8.23(d,J=5.1Hz,1H),8.17(d,J=10.4Hz,1H),8.08(d,J=6.2Hz,1H),7.04(d,J=7.6Hz,1H),7.00(s,1H),6.95(d,J=7.6Hz,1H),6.57(d,J=5.1Hz,1H),3.85(s,2H),3.65(s,3H),3.54-3.45(m,1H),2.23(s,3H),2.22(s,3H),1.36-1.31(m,2H),1.23-1.18(m,2H).
II-2(R4=甲基,R3=3,4-二甲基,R2=H,R1=环丙基):收率92%;1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.39(d,J=8.8Hz,1H),8.29(d,J=5.0Hz,1H),8.13(s,1H),7.60(d,J=8.8Hz,1H),7.07(d,J=7.7Hz,1H),7.02(s,1H),6.98(d,J=7.7Hz,1H),6.63(d,J=5.0Hz,1H),3.89(s,2H),3.75(s,3H),3.49-3.41(m,1H),2.24(s,3H),2.23(s,3H),1.32-1.28(m,2H),1.20-1.17(m,2H).
生物活性测试
目标化合物对耐甲氧西林金黄色葡萄球菌(MRSA)的抑制活性结果见表1。
表1目标化合物的抗菌生物活性
表1中,ATCC33591为MRSA实验室标准株,MU50为对环丙沙星耐药的MRSA临床分离株。
由表1可见结构通式(I)中的化合物普遍具有强抗MRSA活性。
将上述任何一种化合物和常规药用载体制成药物组合物,可用于预防和/或治疗细菌感染的疾病。
以上,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.一种喹诺酮类化合物,其特征在于,结构式如(I)所示:
其中:R1选自氢,C1~6烷基,C3~7环烷基,C1~6烷氧基,被一个或多个卤原子取代的C1~6烷基;
R2选自H原子或F原子;
R3选自氢,C1~6烷基,C3~7环烷基,卤原子;
R4选自氢,C1~6烷基。
2.一种权利要求1所述的喹诺酮类化合物的制备方法,其特征在于,包括以下步骤:
1)取代的苯乙酰氯与Meldrum酸在第一碱作用下缩合生成中间体2;
2)所述中间体2在第一酸中水解生成中间体3;
3)所述中间体3加热脱羧后,与叔丁醇反应生成中间体4;
4)所述中间体4与N,N-二甲基甲酰胺二甲缩醛反应得中间体5;
5)所述中间体5经所述第一酸水解脱羧,得到中间体6;
6)所述中间体6与盐酸胍反应得到中间体7;
7)化合物8与所述中间体7在钯催化剂、配体、第二碱存在下,于溶剂中反应得到化合物9;
8)所述化合物9在第三碱作用下水解,酸水调pH至2~3,过滤,水洗得化合物I-1,所述化合物I-1即喹诺酮类化合物;
或者,所述化合物9在第四碱作用下,与卤代烃反应生成化合物10,所述化合物10在所述第四碱作用下水解,酸水调pH至2~3,过滤,水洗得化合物I-2,所述化合物I-2即喹诺酮类化合物;其中:R1选自氢,C1~6烷基,C3~7环烷基,C1~6烷氧基,被一个或多个卤原子取代的C1~6烷基;R2选自H原子或F原子;R3选自氢,C1~6烷基,C3~7环烷基,卤原子;R4为C1~6烷基;
反应路线如下:
3.根据权利要求2所述的喹诺酮类化合物的制备方法,其特征在于,所述化合物8的制备方法如下:
a.4-溴-取代苯甲酰氯1’与3-(N,N-二甲氨基)丙烯酸乙酯在三乙胺存在下于甲苯中反应生成中间体2’;
b.将所述中间体2’与胺在第一有机溶剂中反应生成中间体3’;
c.将所述中间体3’在第五碱作用下关环生成中间体8;
反应路线如下:
其中:R1选自氢,C1~6烷基,C3~7环烷基,C1~6烷氧基,被一个或多个卤原子取代的C1~6烷基;
R2选自H原子或F原子。
4.根据权利要求3所述的喹诺酮类化合物的制备方法,其特征在于,步骤b中所述第一有机溶剂为二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环、二甲基亚砜和C1~C4醇中的至少一种;
步骤b的反应温度为25~80℃;
步骤c中所述第五碱为碱金属的碳酸盐或有机碱;
步骤c中所述第五碱作用下关环在第二有机溶剂中进行,所述第二有机溶剂为四氢呋喃、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜和C1~C4醇中的至少一种;
步骤c中的反应温度为25~110℃。
5.根据权利要求2所述的喹诺酮类化合物的制备方法,其特征在于,步骤1)中所述第一碱为有机碱;缩合在第三有机溶剂中进行,所述第三有机溶剂为二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、二氧六环和二甲基亚砜中的至少一种;缩合的反应温度为20~80℃;
步骤2)中所述第一酸为盐酸、硫酸或者三氟乙酸。
6.根据权利要求2所述的喹诺酮类化合物的制备方法,其特征在于,步骤3)中与叔丁醇反应在第四有机溶剂中进行,所述第四有机溶剂为四氢呋喃、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、甲苯和二甲苯中的至少一种;反应温度为60~110℃;
步骤4)中,缩醛反应在所述第四有机溶剂中进行;所述缩醛反应的温度为60~110℃。
7.根据权利要求2所述的喹诺酮类化合物的制备方法,其特征在于,步骤5)中,所述水解脱羧在第五有机溶剂中进行,所述第五有机溶剂为C1~C4醇、四氢呋喃、二氧六环、二氯甲烷和三氯甲烷中的至少一种;反应温度为20~50℃;
步骤6)中,与盐酸胍反应在第六有机溶剂中进行,所述第六有机溶剂为C1~C4醇、四氢呋喃和二氧六环中的至少一种;反应温度为60~100℃。
8.根据权利要求2所述的喹诺酮类化合物的制备方法,其特征在于,步骤7)中,所述配体为2,2'-双-(二苯膦基)-1,1'-联萘、2-二环己膦基-2'-(N,N-二甲胺)-联苯、2-叔丁基磷-2',4',6'-三异丙基联苯、2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯、4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,1’-双二苯基膦二茂铁、2-(二叔丁基膦)联苯、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯、2-二叔丁基膦-2',4',6'-三异丙基-3,6-二甲氧基-1,1'-联苯、2-二环己基磷-2’,4’,6’-三异丙基联苯或2-双环己基膦-2',6'-二甲氧基联苯;
所述钯催化剂为醋酸钯、三(二亚苄基茚丙酮)二钯或氯化钯;
所述溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、甲苯、1,4-二氧六环、二丁醚和叔丁醇中的至少一种;
所述第二碱为碳酸钾、磷酸钾、碳酸铯、叔丁醇钾或六甲基二硅基氨基锂;
反应温度为80-110℃,反应时间为8-24h。
9.根据权利要求2所述的喹诺酮类化合物的制备方法,其特征在于,步骤8)中,当在第三碱作用下水解时,所述第三碱为氢氧化锂、氢氧化钠或氢氧化钾;在第六有机溶剂中进行,所述第六有机溶剂为C1~C4醇、四氢呋喃、二氧六环、N,N-二甲基甲酰胺和二甲基亚砜中的至少一种;反应温度为25~50℃;反应时间为0.5~8h;
当在第四碱作用下,与卤代烃反应时,所述第四碱为NaH、叔丁醇钾、叔丁醇钠、二异丙基氨基锂或正丁基锂;在第七有机溶剂中进行,所述第七有机溶剂为N,N-二甲基甲酰胺、四氢呋喃、二氧六环和二甲基亚砜中的至少一种;反应温度为-20~60℃,反应时间为8-24h。
10.权利要求1所述的喹诺酮类化合物在制备预防和/或治疗细菌感染药物中的应用。
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CN105873439A (zh) * | 2013-10-15 | 2016-08-17 | 詹森药业有限公司 | RORγt的烷基连接的喹啉基调节剂 |
CN108484577A (zh) * | 2018-03-05 | 2018-09-04 | 复旦大学 | 一种嘧啶-喹诺酮类杂合物及其制备方法和用途 |
CN110857293A (zh) * | 2018-08-24 | 2020-03-03 | 南京药捷安康生物科技有限公司 | 一种新型的喹啉衍生物抑制剂 |
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CN108484577A (zh) * | 2018-03-05 | 2018-09-04 | 复旦大学 | 一种嘧啶-喹诺酮类杂合物及其制备方法和用途 |
CN110857293A (zh) * | 2018-08-24 | 2020-03-03 | 南京药捷安康生物科技有限公司 | 一种新型的喹啉衍生物抑制剂 |
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