CN111303057B - Phenazine derivative with nitrogen-containing side chain and preparation method and application thereof - Google Patents
Phenazine derivative with nitrogen-containing side chain and preparation method and application thereof Download PDFInfo
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- CN111303057B CN111303057B CN202010223202.8A CN202010223202A CN111303057B CN 111303057 B CN111303057 B CN 111303057B CN 202010223202 A CN202010223202 A CN 202010223202A CN 111303057 B CN111303057 B CN 111303057B
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 125000001791 phenazinyl group Chemical class C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 title claims 7
- -1 amine compound Chemical class 0.000 claims abstract description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 15
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 14
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 10
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- CYWWSTWTGNJCHK-UHFFFAOYSA-N OC1(CC=CC=C1)C=1NOC=CC1 Chemical compound OC1(CC=CC=C1)C=1NOC=CC1 CYWWSTWTGNJCHK-UHFFFAOYSA-N 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 1
- 150000002988 phenazines Chemical class 0.000 abstract description 23
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 229940124350 antibacterial drug Drugs 0.000 abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- SVRNCBGWUMMBQB-UHFFFAOYSA-N 1-hydroxyphenazine Chemical compound C1=CC=C2N=C3C(O)=CC=CC3=NC2=C1 SVRNCBGWUMMBQB-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- VVADQEJFUREKDN-UHFFFAOYSA-N N-[(4-fluorophenyl)methyl]phenazin-1-amine Chemical compound C1=CC=C2C(=C1)N=C3C=CC=C(C3=N2)NCC4=CC=C(C=C4)F VVADQEJFUREKDN-UHFFFAOYSA-N 0.000 description 8
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- JGCSKOVQDXEQHI-UHFFFAOYSA-N phenazine-1-carboxylic acid Chemical compound C1=CC=C2N=C3C(C(=O)O)=CC=CC3=NC2=C1 JGCSKOVQDXEQHI-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 4
- 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 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960003085 meticillin Drugs 0.000 description 4
- IIOCVQJXXRNWDD-UHFFFAOYSA-N 1-(1-methylpiperazin-2-yl)phenazine Chemical compound CN1CCNCC1C2=CC=CC3=NC4=CC=CC=C4N=C32 IIOCVQJXXRNWDD-UHFFFAOYSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- PFXKNWOHAOXEFO-UHFFFAOYSA-N 4-phenazin-1-ylmorpholine Chemical compound C1COCCN1C1=CC=CC2=NC3=CC=CC=C3N=C12 PFXKNWOHAOXEFO-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- KIYJZBMGYFAMHK-UHFFFAOYSA-N 1-benzyl-10h-phenoxazine Chemical compound C=1C=CC=2OC3=CC=CC=C3NC=2C=1CC1=CC=CC=C1 KIYJZBMGYFAMHK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- ZXVJZYDUDBBKSQ-UHFFFAOYSA-N C(C=C1)=CC=C1NC1=CC=CC2=C1NC1=CC=CC=C1O2 Chemical compound C(C=C1)=CC=C1NC1=CC=CC2=C1NC1=CC=CC=C1O2 ZXVJZYDUDBBKSQ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108010025955 Pyocins Proteins 0.000 description 2
- 125000005264 aryl amine group Chemical group 0.000 description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 2
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- 241000193388 Bacillus thuringiensis Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- GLGPSULEWSEHKK-UHFFFAOYSA-N N-benzylphenazin-1-amine Chemical compound C1=CC=C(C=C1)CNC2=CC=CC3=NC4=CC=CC=C4N=C32 GLGPSULEWSEHKK-UHFFFAOYSA-N 0.000 description 1
- YUBCTUYDGBLPAH-UHFFFAOYSA-N N-phenylphenazin-1-amine Chemical compound N(c1ccccc1)c1cccc2nc3ccccc3nc12 YUBCTUYDGBLPAH-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 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
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 229940097012 bacillus thuringiensis Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical group OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- MKQLBNJQQZRQJU-UHFFFAOYSA-N morpholin-4-amine Chemical compound NN1CCOCC1 MKQLBNJQQZRQJU-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/46—Phenazines
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry and pharmacology, and discloses a phenazine derivative with a nitrogen-containing side chain, a preparation method and application thereof, wherein the phenazine derivative has a chemical structural formula shown in formula (I), the phenazine derivative is prepared by reacting 1-hydroxy phenazine, trifluoromethanesulfonic anhydride and triethylamine in dichloromethane, and then phenazine-1-trifluoromethanesulfonate is prepared by taking toluene as a solvent and using Pd (OAc)2And carrying out Buchwald-Hartwig reaction with the corresponding amine compound or nitrogen-containing heterocyclic compound under the catalysis of DPE-phos to obtain the compound. The phenazine derivative with the nitrogen-containing side chain has strong antibacterial activity and can be used for preparing antibacterial drugs.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to a phenazine derivative with a nitrogen-containing side chain, a preparation method thereof and application thereof in preparing antibacterial drugs.
Background
The problem of bacterial resistance has emerged widely worldwide and has become increasingly serious since the 21 st century due to the widespread use of antibiotics, particularly with clinical abuse. Such as methicillin-resistant staphylococcus aureus, penicillin-resistant streptococcus pneumoniae, multidrug-resistant mycobacterium tuberculosis, and the like. There is an urgent need for new chemical structures and new mechanisms of action of antibacterial agents for the clinical treatment of infectious diseases. In recent years, phenazine is a heterocyclic compound with a unique bactericidal mechanism, and can target a biological membrane of bacteria to kill the bacteria.
The phenazine is applied to the dye at the earliest time, pyocin is the phenazine dye at the earliest time, and researches show that the compound has better antibacterial activity. Phenazine-1-carboxylic acid (PCA) is a simple, natural phenazine compound secreted by Pseudomonas aeruginosa, has broad-spectrum antibacterial activity, and can inhibit Candida albicans and Bacillus thuringiensis. The chemical structural formulas of pyocin and phenazine-1-carboxylic acid are shown as the following formulas.
Disclosure of Invention
In view of the above, the present invention aims to provide a phenazine derivative having a nitrogen-containing side chain, which has a heterocyclic side chain structure and a strong antibacterial activity and can be used for preparing antibacterial drugs.
The invention provides a phenazine derivative with a nitrogen-containing side chain, which has a structure shown in a formula (I):
wherein R represents a substituted or unsubstituted benzylamino group, C1-C6The aliphatic amine group, substituted or unsubstituted arylamine group, morpholinyl group, N-aminomorpholinyl group, hydroxyethylpiperazinyl group, N-methylpiperazinyl group, piperidinyl group, 4-hydroxypiperidinyl group, 3-hydroxypiperidinyl group, 4-piperidinylpiperidinyl group, tetrahydropyrrolyl group or imidazolyl group.
Further, the phenazine derivative has a structure shown in any one of formulas 2a to 2 f:
wherein the content of the first and second substances,
when R is 4-fluorobenzylamine, the phenazine derivative is a compound with a structure shown in a formula 2 a;
compound 2 a: 1- (4' -fluorobenzylamino) phenazine
When R is benzylamino, the phenazine derivative is a compound with a structure shown in a formula 2 b;
compound 2 b: 1-benzylaminophenazine
When R is anilino, the phenazine derivative is a compound with a structure shown in a formula 2 c;
compound 2 c: 1-anilinophenazine
When R is butylamino, the phenazine derivative is a compound with a structure shown in a formula 2 d;
compound 2 d: 1-butylamine phenazine
When R is morpholinyl, the phenazine derivative is a compound with a structure shown as a formula 2 e;
compound 2 e: 1-morpholinyl phenazine
When R is N-methylpiperazine, the phenazine is a compound with a structure shown in a formula 2 f;
compound 2 f: 1- (N-methylpiperazinyl) phenazine
The invention also provides a preparation method of the phenazine derivative with the nitrogen-containing side chain, which comprises the following steps:
1-hydroxy phenazine, trifluoromethanesulfonic anhydride and triethylamine react in dichloromethane to obtain phenazine-1-trifluoromethanesulfonate, which is then dissolved in toluene in Pd (OAc)2And under the catalysis of DPE-phos, carrying out Buchwald-Hartwig reaction with corresponding amine compounds or nitrogen-containing heterocyclic compounds to obtain phenazine derivatives with nitrogen-containing side chains,
wherein the reaction has the formula:
wherein R is selected from substituted or unsubstituted benzylamine group, C1-C6And one of the substituted or unsubstituted arylamine group, morpholinyl group, N-aminomorpholinyl group, hydroxyethylpiperazinyl group, N-methylpiperazinyl group, piperidinyl group, 4-hydroxypiperidinyl group, 3-hydroxypiperidinyl group, 4-piperidinylpiperidinyl group, tetrahydropyrrolyl group and imidazolyl group.
The preparation method comprises the following steps:
(1) dissolving 1-hydroxyphenyloxazine in dichloromethane, and sequentially adding triethylamine and trifluoromethanesulfonic anhydride at 0 ℃ to react to obtain a first reaction solution;
(2) reacting the first reactionDiluting the solution with organic solvent, washing with water, washing with saturated salt solution, and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain light yellow solid, wherein the organic solvent is at least one of ethyl acetate, diethyl ether and benzene;
(3) the pale yellow solid was dissolved in toluene and Pd (OAc) was added successively2DPE-phos and Cs2CO3Then adding an amine compound or a nitrogen-containing heterocyclic compound, reacting under the protection of nitrogen, and sequentially carrying out MgSO (MgSO) on a second reaction solution after the reaction is finished4Drying, drying under reduced pressure, and performing column chromatography to obtain phenazine derivative with nitrogen-containing side chain;
wherein the amine compound is one of benzylamine, arylamine and C1-C6 fatty amine; the nitrogen-containing heterocyclic compound is one of morpholine, N-amino morpholine, hydroxyethyl piperazine, N-methyl piperazine, piperidine, 4-hydroxypiperidine, 3-hydroxypiperidine, 4-piperidyl piperidine, tetrahydropyrrole and imidazole.
Preferably, in step (1) of the preparation method provided by the invention, the molar ratio of the 1-hydroxyphenyloxazine to the triethylamine to the trifluoromethanesulfonic anhydride is 1:3: 1.5.
Preferably, in step (1) of the preparation method provided by the invention, the reaction time of the reaction is 3 h.
Preferably, in the step (3) of the production method provided by the present invention, the phenazine-1-trifluoromethanesulfonate, the amine compound, Pd (OAc)2、DPE-phos、Cs2CO3In a molar ratio of 1:3: 0.2: 0.3: 2.5.
preferably, in the step (3) of the production method provided by the present invention, the phenazine-1-triflate, the nitrogen-containing heterocyclic compound, Pd (OAc)2、DPE-phos、Cs2CO3In a molar ratio of 1:3: 0.2: 0.3: 2.5.
preferably, in the step (3) of the preparation method provided by the invention, the reaction temperature is 100 ℃, and the reaction time is 8 h.
The invention also provides an application of the phenazine derivative with the nitrogen-containing side chain or the phenazine derivative with the nitrogen-containing side chain prepared by the preparation method in preparing antibacterial drugs.
The phenazine derivative with the nitrogen-containing side chain provided by the invention can be applied to the preparation of drugs for treating infectious diseases, wherein the infectious diseases are infectious diseases of human beings or animals caused by multi-drug resistant bacteria infection.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the NMR of 1- (4' -fluorobenzylamino) phenazine (2a) provided in example 1 of the present invention1H, spectrogram;
FIG. 2 shows the NMR of 1- (4' -fluorobenzylamino) phenazine (2a) provided in example 1 of the present invention13And C, spectrum.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
980mg (5mmol) of 1-hydroxyphenyloxazine are weighed out and placed in a 25mL round-bottomed flask, 10mL of anhydrous dichloromethane and 1.5g (15mmol) of triethylamine are added and dissolved with stirring at-30 ℃. 2.2g (7.5mmol) of trifluoromethanesulfonic anhydride are metered in and slowly added dropwise at 0 ℃. After the dropwise addition, the reaction is continued for 3 hours at 0 ℃. After the TLC detection reaction is finished, water is added to quench the reaction. The reaction solution was diluted with 30mL of DCM and washed with water. The organic phase was dried over anhydrous sodium sulfate to remove water, the solvent was evaporated under reduced pressure, and the residue was purified by dichloromethane: the ethyl acetate 50:1 is passed through the column to obtain 1.60g of light green solid product phenazine-1-triflate with the yield of 97%.
164mg (0.5mmol) of phenazine-1-triflate are weighed into a 25mL round bottom flask, 187mg (1.5mmol) of 4-fluorobenzylamine, 22mg (0.1mmol) of Pd (OAc) are added)2，81mg(0.15mmol)DPE-phos,407mg(1.25mmol)Cs2CO320mg (0.2mmol) of triethylamine. 5mL of toluene was added and dissolved by stirring, and the reaction was carried out for 8 hours at 100 ℃ under nitrogen. After the TLC detection reaction is finished, the solvent is directly evaporated under reduced pressure. Mixing with dichloromethane: the yield of the red solid product 1- (4' -fluorobenzylamino) phenazine is 67 percent by passing petroleum ether 2:1 through a column.
The nuclear magnetic resonance detection of 1- (4' -fluorobenzylamino) phenazine (2a) is shown in fig. 1 and fig. 2, and the results are:1H NMR(400MHz,CDCl3):δ8.19-8.17(m,2H,ArH),7.78-7.76(m,2H,ArH),7.62-7.60(m,1H,ArH),7.53-7.36(m,3H,ArH),7.11-6.99(m,2H,ArH),6.85-6.82(m,1H，NH),6.55-6.52(m,1H,ArH),4.59(d,J＝5.8Hz,2H,CH2).13C NMR(100MHz,CDCl3):δ163.4,160.9,144.3,143.8,140.7,135.1,134.3,132.6,130.4,129.5,129.4,129.3,129.0,128.9,115.7,115.6,115.5,102.9,47.1.HRMS(ESI):m/z calcd for C19H15FN3:304.1245；found:304.1249[M+H]+.
example 2
1-Benzylphenoxazine (2b) was prepared according to the method of example 1 above, substituting 187mg (1.5mmol) of 4-fluorobenzylamine for 160mg (1.5mmol) of benzylamine, and the physicochemical data for this compound were:
2b：1H NMR(400MHz,CDCl3):δ8.23(t,J＝8Hz,2H,ArH),7.85-7.76(m,2H,ArH),7.65(t,J＝8Hz,1H,ArH),7.51-7.49(m,3H,ArH),7.41(t,J＝8Hz,2H,ArH),7.35(d,J＝8Hz,1H,ArH),6.90(s,1H,ArH),6.63(d,J＝8Hz,1H,ArH),4.65(s,2H,CH2).13C NMR(100MHz,CDCl3):δ144.5,144.3,143.7,140.7,138.6,135.2,132.7,130.3,129.6,129.3,128.8,127.5,127.4,115.3,102.8,47.8.MS(ESI)m/z＝286.1[M+H]+；HRMS(ESI):m/z calcd for C19H16N3:286.1337；found:286.1339[M+H]+.
example 3
1-Anilinophenoxazine (2c) was prepared according to the method of example 1 above, replacing 187mg (1.5mmol) of 4-fluorobenzylamine with 140mg (1.5mmol) of aniline and the physicochemical data for this compound were:
2c：1H NMR(400MHz,CDCl3):δ8.41(s,1H,ArH),8.23-8.21(m,2H,ArH),7.81-7.79(m,2H,ArH),7.68-7.66(m,1H,ArH),7.61-7.59(m,1H,ArH),7.50-7.37(m,5H,ArH),7.11-7.09(m,1H,ArH).13C NMR(100MHz,CDCl3):δ144.3,143.9,141.2,140.9,140.3,135.3,132.1,130.5,129.8,129.5,129.4,123.0,120.6,117.7,105.5.HRMS(ESI):m/z calcd for C18H14N3:272.1182；found:272.1185[M+H]+.
example 4
When 187mg (1.5mmol) of 4-fluorobenzylamine is exchanged for 109mg (1.5mmol) of butylamine according to the method of example 1 above, 1-butyamine phenazine (2d) is prepared, the physicochemical data for this compound being:
2d：1H NMR(400MHz,CDCl3):δ8.23-8.13(m,2H,ArH),7.76-7.74(m,2H,ArH),7.67-7.65(m,1H,ArH),7.45-7.39(m,1H,ArH),6.58-6.56(m,1H,ArH),6.41(t,J＝5.7Hz,1H,NH),3.37-3.35(m,2H,CH2),1.89-1.76(m,2H,CH2),1.55-1.53(m,2H,CH2),1.03(t,J＝7.4Hz,3H,CH3).13C NMR(100MHz,CDCl3):δ144.9,144.4,143.7,140.6,135.2,132.9,130.2,129.6,129.2,129.1,114.5,101.9,43.2,31.2,20.5,14.0.HRMS(ESI):m/zcalcd for C16H18N3:252.1495；found:252.1493[M+H]+.
example 5
When 187mg (1.5mmol) of 4-fluorobenzylamine is exchanged for 130mg (1.5mmol) of morpholine according to the method of example 1 above, 1-morpholinophenazine (2e) is prepared with the physicochemical data:
2e:1H NMR(400MHz,CDCl3):δ8.31-8.11(m,2H,-ArH),7.96-7.66(m,4H,-ArH),7.18-7.09(m,1H,-ArH),4.19-4.01(m,2H,CH2),3.60-3.47(m,2H,CH2).13C NMR(100MHz,CDCl3):δ149.1,144.7,142.8,141.2,138.8,130.9,130.6,130.2,129.8,129.1,123.2,114.9,67.1,52.6.HRMS(ESI):m/z calcd for C16H16N3O:266.1288；found:266.1289[M+H]+.
example 6
When 187mg (1.5mmol) of 4-fluorobenzylamine is exchanged for 150mg (1.5mmol) of N-methylpiperazine according to the process of example 1 above, 1- (N-methylpiperazinyl) phenazine (2f) is prepared, whose physicochemical data are:
2f：1H NMR(400MHz,CDCl3):δ8.31-8.15(m,2H,-ArH),7.91-7.68(m,4H,-ArH),7.18-7.09(m,1H,-ArH),3.58(s,4H,NH2),2.85(s,4H,CH2),2.46(s,3H,CH3).13C NMR(100MHz,CDCl3):δ149.2,144.7,143.3,142.8,141.2,131.0,130.5,130.3,129.7,129.1,122.8,115.0,55.2,52.1,46.2.HRMS(ESI):m/z calcd for C17H19N4:279.1604；found:279.1609[M+H]+.
in order to better understand the essence of the invention, the results of in vitro bacteriostasis experiments on three strains of escherichia coli ATCC25922, staphylococcus aureus ATCC29213 and methicillin-resistant staphylococcus aureus ATCC43300 by using the phenazine derivatives with nitrogen-containing side chains provided by the invention are respectively shown below, and the new application of the phenazine derivatives in the research field of antibacterial drugs is illustrated. The pharmaceutical examples present partial activity data for representative compounds. It must be noted that the pharmaceutical examples of the present invention are intended to illustrate the present invention and not to limit the present invention. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.
Example (b): in vitro bacteriostasis experiment
Experimental methods
And determining the half inhibitory concentration MIC of the compound to three strains of escherichia coli ATCC25922, staphylococcus aureus ATCC29213 and methicillin-resistant staphylococcus aureus ATCC43300 by adopting a broth microdilution method. First, the compound was diluted to different concentrations with dimethyl sulfoxide, 5. mu.L of each concentration of the drug solution was added to 195. mu.L of bacterial suspension (10)5CFU/mL), the final concentration of the compound in the medium was 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03, 0.015 μ g/mL in that order. The results were observed after 24 hours incubation at 37 ℃ and MIC values were calculated.
The MIC results are given in table 1 below.
TABLE 1 results of in vitro bacteriostatic experiments on compounds 2 a-2 f
As can be seen from Table 1, the phenazine derivative with nitrogen-containing side chain provided by the invention has important biological activity, has an inhibiting effect on the growth of three strains of Escherichia coli ATCC25922, Staphylococcus aureus ATCC29213 and methicillin-resistant Staphylococcus aureus ATCC43300, and is likely to be developed into a new antibacterial drug.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A phenazine derivative having a nitrogen-containing side chain, wherein the phenazine derivative having a nitrogen-containing side chain has a structure represented by formula 2 a:
2. a method for producing a phenazine derivative having a nitrogen-containing side chain, characterized in that the reaction formula of the production method is as follows:
wherein R is 4-fluorobenzylamino;
the preparation method comprises the following steps:
(1) dissolving 1-hydroxyphenyloxazine in dichloromethane, and sequentially adding triethylamine and trifluoromethanesulfonic anhydride at 0 ℃ to react to obtain a first reaction solution;
(2) the first reaction solution is addedDiluting with organic solvent, washing with water, washing with saturated salt water, and MgSO4Drying, drying under reduced pressure, and performing column chromatography to obtain phenazine-1-trifluoromethanesulfonate, wherein the organic solvent is at least one of ethyl acetate, diethyl ether and benzene;
(3) dissolving the phenazine-1-triflate in toluene, adding Pd (OAc) in sequence2DPE-phos and Cs2CO3Then adding 4-fluorobenzylamine, reacting under the protection of nitrogen to obtain a second reaction solution, and sequentially carrying out MgSO (MgSO) on the second reaction solution4Drying, drying under reduced pressure, and performing column chromatography to obtain the phenazine derivative with the nitrogen-containing side chain.
3. The process according to claim 2, wherein in the step (1), the molar ratio of 1-hydroxyphenyloxazine, triethylamine and trifluoromethanesulfonic anhydride is 1:3: 1.5.
4. The method according to claim 2, wherein the reaction time in the step (1) is 3 hours.
5. The process according to claim 2, wherein in the step (3), the phenazine-1-trifluoromethanesulfonate, 4-fluorobenzylamine, Pd (OAc)2、DPE-phos、Cs2CO3In a molar ratio of 1:3: 0.2: 0.3: 2.5.
6. the method according to claim 2, wherein in the step (3), the reaction temperature is 100 ℃ and the reaction time is 8 hours.
7. Use of a phenazine derivative having a nitrogen-containing side chain according to claim 1 or a phenazine derivative having a nitrogen-containing side chain prepared by the preparation method according to any one of claims 2 to 6 in the preparation of an antibacterial agent.
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