CN117105899A - Osthole 8-bit structure modified product and preparation method and application thereof - Google Patents
Osthole 8-bit structure modified product and preparation method and application thereof Download PDFInfo
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- CN117105899A CN117105899A CN202310985746.1A CN202310985746A CN117105899A CN 117105899 A CN117105899 A CN 117105899A CN 202310985746 A CN202310985746 A CN 202310985746A CN 117105899 A CN117105899 A CN 117105899A
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- HPUXDMUGCAWDFW-UHFFFAOYSA-N Osthole Natural products COc1ccc2CCC(=O)Oc2c1C=CC(=O)C HPUXDMUGCAWDFW-UHFFFAOYSA-N 0.000 title claims abstract description 32
- MBRLOUHOWLUMFF-UHFFFAOYSA-N osthole Chemical compound C1=CC(=O)OC2=C(CC=C(C)C)C(OC)=CC=C21 MBRLOUHOWLUMFF-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims description 60
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 241000588724 Escherichia coli Species 0.000 claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 17
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 16
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 10
- 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 claims abstract description 9
- 229940124307 fluoroquinolone Drugs 0.000 claims abstract description 9
- 229960003085 meticillin Drugs 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 102
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 40
- 238000001914 filtration Methods 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 32
- 238000001035 drying Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 229940125782 compound 2 Drugs 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 20
- 229940125904 compound 1 Drugs 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 17
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 16
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 16
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 8
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 8
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 8
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 8
- 229960002218 sodium chlorite Drugs 0.000 claims description 8
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- -1 HBTU Chemical compound 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 229940124350 antibacterial drug Drugs 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 244000052769 pathogen Species 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- 239000013543 active substance Substances 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 description 35
- 239000002904 solvent Substances 0.000 description 18
- 239000012153 distilled water Substances 0.000 description 12
- 230000001376 precipitating effect Effects 0.000 description 12
- 238000002390 rotary evaporation Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940125890 compound Ia Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 2
- LPNRUMVKXCLEBE-JXVRESAISA-L (3r)-4-[[(e)-2-[5-ethyl-4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethenyl]-oxidophosphoryl]-3-hydroxybutanoate Chemical compound CCC1=C(C=2C=CC=CC=2)N=C(C(C)C)C(\C=C\P([O-])(=O)C[C@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 LPNRUMVKXCLEBE-JXVRESAISA-L 0.000 description 2
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- LIDUGWDLSDKCLM-CSKARUKUSA-N 4-[[3-[[[(e)-6,6-dimethylhept-2-en-4-ynyl]-ethylamino]methyl]phenoxy]methyl-dimethylsilyl]benzonitrile Chemical compound CC(C)(C)C#C/C=C/CN(CC)CC1=CC=CC(OC[Si](C)(C)C=2C=CC(=CC=2)C#N)=C1 LIDUGWDLSDKCLM-CSKARUKUSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- XJTWGMHOQKGBDO-GOSISDBHSA-N N-[(3-Fluorophenyl)methyl]-1-[(1r)-1-Naphthalen-1-Ylethyl]piperidine-4-Carboxamide Chemical compound C1CN([C@H](C)C=2C3=CC=CC=C3C=CC=2)CCC1C(=O)NCC1=CC=CC(F)=C1 XJTWGMHOQKGBDO-GOSISDBHSA-N 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 229960001019 oxacillin Drugs 0.000 description 2
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 1
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The scheme discloses a osthole 8-bit structure remodelling substance shown in a general formula I in the technical field of organic chemistry,
Description
Technical Field
The invention belongs to the field of organic chemistry, and in particular relates to an osthole 8-bit structure modified product, a preparation method and application thereof.
Background
Antibacterial drugs are one of the great findings in the 20 th century, but abuse of antibacterial drugs leads to rapid emergence of clinical multi-drug resistant bacteria, which seriously affects daily production and life of people. At present, drug resistance of antibiotics has become a major medical and health problem worldwide. The sequential emergence of different resistant bacteria has led to an increasing incidence and mortality in patients with various infectious diseases and presents a great challenge for clinical treatment. Thus, new antibacterial agents are urgently needed to overcome these alarming resistance problems.
Disclosure of Invention
The invention uses natural product osthole as raw material, applies related drug design and synthesis theory to carry out structural transformation on 8-bit to obtain serial 8-bit structural transformation products. The research results show that: part of the compounds have remarkable antibacterial activity on methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinolone-resistant escherichia coli (FREC), and are far superior to that of the reference drugs, oxacillin and norfloxacin.
The osthole 8-position structure remodelling in the scheme has a chemical structure as shown in a general formula I:
wherein R is a hydrocarbon group of 1 to 6 carbon atoms; or R is phenyl or substituted phenyl; or R is benzyl or substituted benzyl; or R is a thiomethyl group or a substituted thiomethyl group.
The osthole 8-position structure remodelling substance disclosed by the general formula I can be used for treating and/or preventing staphylococcus aureus (S.aureus).
The osthole 8-bit structure remodelling of the invention shown in the general formula I can be used for treating and/or preventing escherichia coli (E.coli).
The osthole 8-bit structure remodelling of the invention shown in the general formula I can be used for treating and/or preventing methicillin-resistant staphylococcus aureus (MRSA).
The osthole 8-position structure remodelling of the invention shown in the general formula I can be used for treating and/or preventing Fluoroquinolone Resistant Escherichia Coli (FREC).
Preferably, any of the following compounds has a strong inhibitory effect on staphylococcus aureus (s.aureus), escherichia coli (e.coli), methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinolone-resistant escherichia coli (FREC), and has an antibacterial activity superior to or equivalent to that of the control.
Compound ij: r=Compound ik: r= = ->Compound in: r= = ->Compound io: r= = ->Compound ip: r= = ->Compound iq: r= = ->
The osthole 8-bit structure modified product shown in the general formula I can be used in combination with clinical antibacterial drugs or antibacterial active ingredients.
The following synthetic schemes describe the preparation of the compounds of the invention of formula I:
the method comprises the following steps:
preparation of Compound 1: taking osthole as a starting material, adding selenium dioxide and DMSO, stirring for reaction, filtering to remove insoluble substances, extracting with ethyl acetate, washing, drying, concentrating an organic layer, and separating and purifying by silica gel column chromatography to obtain a compound 1;
preparation of compound 2: adding tertiary butanol and 2-methyl-2-butene into the compound 1, and stirring for reaction; dissolving sodium chlorite and sodium dihydrogen phosphate in water, dripping into a reaction system, concentrating after the reaction is finished to separate out solid, vacuum filtering, and drying to obtain a compound 2;
preparation of compound 3: adding Boc-L-phenylalanine, HBTU, DIPEA, amine compounds and DMF into a reaction vessel, stirring at room temperature, adding water to precipitate a solid, filtering under reduced pressure, and drying to obtain a compound 3;
preparation of Compound 4: adding the compound 3, dichloromethane and trifluoroacetic acid into a reaction container, stirring at room temperature for reaction, concentrating, adding saturated sodium bicarbonate solution, separating out solid, vacuum filtering, and drying to obtain a compound 4;
preparation of Compound I: adding the compound 2, HBTU, DIPEA, the compound 4 and DMF into a reaction vessel, stirring at room temperature, adding water to separate out solid, vacuum filtering, and separating and purifying by silica gel column chromatography to obtain osthole 8-site structure modified product shown in the compound I.
Further, the reaction was stirred at 100℃during the preparation of Compound 1.
Further, the reaction was stirred at 40℃during the preparation of Compound 2.
Further, in the preparation of the compound I, the compound 2 is prepared by the following molar ratio: HBTU: DIPEA: compound 4=0.25: 0.50 to 0.75:0.50 to 1.0:0.25 to 0.45.
Detailed Description
The invention is further described in connection with the following examples, which are not intended to be limiting, but rather to be construed according to the invention.
The preparation of the compound of the general formula I is carried out according to the following synthetic route:
wherein TFA is triethylamine, HBTU is O-benzotriazol-tetramethylurea hexafluorophosphate and DIPEA is N, N-diisopropylethylamine.
The chemical structure of the osthole 8-position structure modification in the general formula I is shown in the following table 1:
TABLE 1
Example 1: preparation of Compound Ia
(1) Preparation of Compound 1: taking a 100mL reaction bottle, adding 9.0mmol of selenium dioxide, 50.0mL of DMSO and 3.0mmol of osthole, stirring at 100 ℃ for reaction, tracking by TLC, filtering, removing insoluble substances, extracting by ethyl acetate, washing by saturated saline water, drying by anhydrous sodium sulfate, filtering, rotationally evaporating to concentrate the solvent to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain the compound 1.
(2) Preparation of compound 2: taking a 100mL reaction bottle, adding 1.0mmol of compound 1, 20.0mL of tertiary butanol and 10.0mL of 2-methyl-2-butene, and reacting at 40.0 ℃; then 9.0mmol of sodium chlorite and 7.0mmol of sodium dihydrogen phosphate are dissolved in 25.0mL of water, and are added dropwise to a reaction system, TLC tracking is carried out, after the reaction is finished, the solvent is concentrated by rotary evaporation, solid is separated out, and the compound 2 is prepared by vacuum suction filtration and drying.
(3) Preparation of compound 3 a: a50 mL reaction flask was taken, 1.2mmol of Boc-L-phenylalanine, 2.5mmol of HBTU, 3.5mmol of DIPEA, 1.0mmol of aniline and 5.0mL of DMF were added, and the reaction was stirred at room temperature and followed by TLC until the reaction was completed. Adding a proper amount of distilled water, precipitating solid, vacuum filtering, and drying to obtain the compound 3a.
(4) Preparation of compound 4 a: a50 mL reaction flask was taken, 1.0mmol of compound 3a, 5.0mL of dichloromethane and 15.0mmol of trifluoroacetic acid were added, the reaction was stirred at room temperature, followed by TLC, and the reaction was completed. Concentrating the solvent by rotary evaporation, adding saturated sodium bicarbonate solution, precipitating solid, vacuum filtering, and drying to obtain the compound 4a.
(5) Preparation of Compound Ia: a50 mL reaction bottle is taken, 0.25mmol of compound 2, 0.625mmol of HBTU, 0.875mmol of DIPEA, 0.3mmol of compound 4a and 2.5mL of DMF are weighed, the reaction is stirred at room temperature, TLC tracking is carried out, a proper amount of distilled water is added after the reaction is finished, a solid is separated out, the vacuum suction filtration is carried out, and the compound Ia is prepared for separation and purification by a thin layer chromatography.
Example 2: preparation of Compound Ik
(1) Preparation of Compound 1: taking a 100mL reaction bottle, adding 9.0mmol of selenium dioxide, 50.0mL of DMSO and 3.0mmol of osthole, stirring at 100 ℃ for reaction, tracking by TLC, filtering, removing insoluble substances, extracting by ethyl acetate, washing by saturated saline water, drying by anhydrous sodium sulfate, filtering, rotationally evaporating to concentrate the solvent to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain the compound 1.
(2) Preparation of compound 2: taking a 100mL reaction bottle, adding 1.0mmol of compound 1, 20.0mL of tertiary butanol and 10.0mL of 2-methyl-2-butene, and reacting at 40.0 ℃; then 9.0mmol of sodium chlorite and 7.0mmol of sodium dihydrogen phosphate are dissolved in 25.0mL of water, and are added dropwise to a reaction system, TLC tracking is carried out, after the reaction is finished, the solvent is concentrated by rotary evaporation, solid is separated out, and the compound 2 is prepared by vacuum suction filtration and drying.
(3) Preparation of compound 3 k: a50 mL reaction flask was taken, 1.2mmol of Boc-L-phenylalanine, 2.5mmol of HBTU, 3.5mmol of DIPEA, 1.0mmol of 3-nitroaniline and 5.0mL of DMF were added, and the reaction was stirred at room temperature and followed by TLC. Adding a proper amount of distilled water, precipitating solid, carrying out vacuum filtration, and drying to obtain the compound 3k.
(4) Preparation of compound 4 k: a50 mL reaction flask was taken, 1.0mmol of compound 3k, 5.0mL of dichloromethane and 15.0mmol of trifluoroacetic acid were added, the reaction was stirred at room temperature, followed by TLC, and the reaction was completed. Concentrating the solvent by rotary evaporation, adding saturated sodium bicarbonate solution, precipitating solid, vacuum filtering, and drying to obtain the compound 4k.
(5) Preparation of Compound Ik: taking a 50mL reaction bottle, weighing 0.25mmol of compound 2, 0.625mmol of HBTU, 0.875mmol of DIPEA, 0.3mmol of compound 4k and 2.5mL of DMF, stirring at room temperature for reaction, tracking by TLC, adding a proper amount of distilled water after the reaction is finished, separating out solids, carrying out vacuum suction filtration, and separating and purifying by a preparation thin layer chromatography to obtain the compound Ik.
Example 3: preparation of Compound In
(1) Preparation of Compound 1: taking a 100mL reaction bottle, adding 9.0mmol of selenium dioxide, 50.0mL of DMSO and 3.0mmol of osthole, stirring at 100 ℃ for reaction, tracking by TLC, filtering, removing insoluble substances, extracting by ethyl acetate, washing by saturated saline water, drying by anhydrous sodium sulfate, filtering, rotationally evaporating to concentrate the solvent to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain the compound 1.
(2) Preparation of compound 2: taking a 100mL reaction bottle, adding 1.0mmol of compound 1, 20.0mL of tertiary butanol and 10.0mL of 2-methyl-2-butene, and reacting at 40.0 ℃; then 9.0mmol of sodium chlorite and 7.0mmol of sodium dihydrogen phosphate are dissolved in 25.0mL of water, and are added dropwise to a reaction system, TLC tracking is carried out, after the reaction is finished, the solvent is concentrated by rotary evaporation, solid is separated out, and the compound 2 is prepared by vacuum suction filtration and drying.
(3) Preparation of compound 3 n: a50 mL reaction flask was taken, 1.2mmol of Boc-L-phenylalanine, 2.5mmol of HBTU, 3.5mmol of DIPEA, 1.0mmol of 4-chloroaniline and 5.0mL of DMF were added, and the reaction was stirred at room temperature and followed by TLC. Adding a proper amount of distilled water, precipitating solid, vacuum filtering, and drying to obtain the compound 3n.
(4) Preparation of compound 4 n: a50 mL reaction flask was taken, 1.0mmol of compound 3n, 5.0mL of dichloromethane and 15.0mmol of trifluoroacetic acid were added, the reaction was stirred at room temperature, followed by TLC, and the reaction was completed. Concentrating the solvent by rotary evaporation, adding saturated sodium bicarbonate solution, precipitating solid, vacuum filtering, and drying to obtain the compound 4n.
(5) Preparation of Compound In: taking a 50mL reaction bottle, weighing 0.25mmol of compound 2, 0.625mmol of HBTU, 0.875mmol of DIPEA, 0.3mmol of compound 4n and 2.5mL of DMF, stirring at room temperature for reaction, tracking by TLC, adding a proper amount of distilled water after the reaction is finished, separating out solids, carrying out vacuum suction filtration, and separating and purifying by a preparation thin layer chromatography to obtain the compound I < n >.
Example 4: preparation of Compound I o
(1) Preparation of Compound 1: taking a 100mL reaction bottle, adding 9.0mmol of selenium dioxide, 50.0mL of DMSO and 3.0mmol of osthole, stirring at 100 ℃ for reaction, tracking by TLC, filtering, removing insoluble substances, extracting by ethyl acetate, washing by saturated saline water, drying by anhydrous sodium sulfate, filtering, rotationally evaporating to concentrate the solvent to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain the compound 1.
(2) Preparation of compound 2: taking a 100mL reaction bottle, adding 1.0mmol of compound 1, 20.0mL of tertiary butanol and 10.0mL of 2-methyl-2-butene, and reacting at 40.0 ℃; then 9.0mmol of sodium chlorite and 7.0mmol of sodium dihydrogen phosphate are dissolved in 25.0mL of water, and are added dropwise to a reaction system, TLC tracking is carried out, after the reaction is finished, the solvent is concentrated by rotary evaporation, solid is separated out, and the compound 2 is prepared by vacuum suction filtration and drying.
(3) Preparation of compound 3 o: a50 mL reaction flask was taken, 1.2mmol of Boc-L-phenylalanine, 2.5mmol of HBTU, 3.5mmol of DIPEA, 1.0mmol of 2-fluoroaniline and 5.0mL of DMF were added thereto, and the reaction was stirred at room temperature and followed by TLC after completion of the reaction. Adding a proper amount of distilled water, precipitating solid, vacuum filtering, and drying to obtain the compound 3o.
(4) Preparation of compound 4 o: a50 mL reaction flask was taken, 1.0mmol of compound 3o, 5.0mL of dichloromethane and 15.0mmol of trifluoroacetic acid were added, the reaction was stirred at room temperature, followed by TLC, and the reaction was completed. Concentrating the solvent by rotary evaporation, adding saturated sodium bicarbonate solution, precipitating solid, vacuum filtering, and drying to obtain the compound 4o.
(5) Preparation of Compound I o: taking a 50mL reaction bottle, weighing 0.25mmol of compound 2, 0.625mmol of HBTU, 0.875mmol of DIPEA, 0.3mmol of compound 4o and 2.5mL of DMF, stirring at room temperature for reaction, tracking by TLC, adding a proper amount of distilled water after the reaction is finished, separating out solids, carrying out vacuum suction filtration, and separating and purifying by a preparative thin layer chromatography method to obtain the compound I o.
Example 5: preparation of Compound ip
(1) Preparation of Compound 1: taking a 100mL reaction bottle, adding 9.0mmol of selenium dioxide, 50.0mL of DMSO and 3.0mmol of osthole, stirring at 100 ℃ for reaction, tracking by TLC, filtering, removing insoluble substances, extracting by ethyl acetate, washing by saturated saline water, drying by anhydrous sodium sulfate, filtering, rotationally evaporating to concentrate the solvent to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain the compound 1.
(2) Preparation of compound 2: taking a 100mL reaction bottle, adding 1.0mmol of compound 1, 20.0mL of tertiary butanol and 10.0mL of 2-methyl-2-butene, and reacting at 40.0 ℃; then 9.0mmol of sodium chlorite and 7.0mmol of sodium dihydrogen phosphate are dissolved in 25.0mL of water, and are added dropwise to a reaction system, TLC tracking is carried out, after the reaction is finished, the solvent is concentrated by rotary evaporation, solid is separated out, and the compound 2 is prepared by vacuum suction filtration and drying.
(3) Preparation of compound 3 p: a50 mL reaction flask was taken, 1.2mmol of Boc-L-phenylalanine, 2.5mmol of HBTU, 3.5mmol of DIPEA, 1.0mmol of 4-fluoroaniline and 5.0mL of DMF were added thereto, and the reaction was stirred at room temperature and followed by TLC after completion of the reaction. Adding a proper amount of distilled water, precipitating solid, vacuum filtering, and drying to obtain the compound 3p.
(4) Preparation of compound 4 p: a50 mL reaction flask was taken, 1.0mmol of compound 3p, 5.0mL of dichloromethane and 15.0mmol of trifluoroacetic acid were added, the reaction was stirred at room temperature, followed by TLC, and the reaction was completed. Concentrating the solvent by rotary evaporation, adding saturated sodium bicarbonate solution, precipitating solid, vacuum filtering, and drying to obtain the compound 4p.
(5) Preparation of Compound ip: taking a 50mL reaction bottle, weighing 0.25mmol of compound 2, 0.625mmol of HBTU, 0.875mmol of DIPEA, 0.3mmol of compound 4p and 2.5mL of DMF, stirring at room temperature for reaction, tracking by TLC, adding a proper amount of distilled water after the reaction is finished, separating out solids, carrying out vacuum suction filtration, and separating and purifying by a preparation thin layer chromatography to obtain the compound IP.
Example 6: preparation of Compound Iq
(1) Preparation of Compound 1: taking a 100mL reaction bottle, adding 9.0mmol of selenium dioxide, 50.0mL of DMSO and 3.0mmol of osthole, stirring at 100 ℃ for reaction, tracking by TLC, filtering, removing insoluble substances, extracting by ethyl acetate, washing by saturated saline water, drying by anhydrous sodium sulfate, filtering, rotationally evaporating to concentrate the solvent to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain the compound 1.
(2) Preparation of compound 2: taking a 100mL reaction bottle, adding 1.0mmol of compound 1, 20.0mL of tertiary butanol and 10.0mL of 2-methyl-2-butene, and reacting at 40.0 ℃; then 9.0mmol of sodium chlorite and 7.0mmol of sodium dihydrogen phosphate are dissolved in 25.0mL of water, and are added dropwise to a reaction system, TLC tracking is carried out, after the reaction is finished, the solvent is concentrated by rotary evaporation, solid is separated out, and the compound 2 is prepared by vacuum suction filtration and drying.
(3) Preparation of compound 3 q: a50 mL reaction flask was taken, 1.2mmol of Boc-L-phenylalanine, 2.5mmol of HBTU, 3.5mmol of DIPEA, 1.0mmol of 3-trifluoromethylaniline and 5.0mL of DMF were added thereto, and the reaction was stirred at room temperature and followed by TLC to complete the reaction. Adding a proper amount of distilled water, precipitating solid, carrying out vacuum filtration, and drying to obtain the compound 3q.
(4) Preparation of compound 4 q: a50 mL reaction flask was taken, 1.0mmol of compound 3q, 5.0mL of dichloromethane and 15.0mmol of trifluoroacetic acid were added, the reaction was stirred at room temperature, followed by TLC, and the reaction was completed. Concentrating the solvent by rotary evaporation, adding saturated sodium bicarbonate solution, precipitating solid, vacuum filtering, and drying to obtain the compound 4q.
(5) Preparation of Compound Iq: a50 mL reaction bottle is taken, 0.25mmol of compound 2, 0.625mmol of HBTU, 0.875mmol of DIPEA, 0.3mmol of compound 4q and 2.5mL of DMF are weighed, the reaction is stirred at room temperature, TLC tracking is carried out, a proper amount of distilled water is added after the reaction is finished, a solid is separated out, the vacuum suction filtration is carried out, and the compound Iq is prepared for separation and purification by a thin layer chromatography.
The data for compound i are shown in table 2:
TABLE 2
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Antibacterial activity test of the present invention: the Minimum Inhibitory Concentrations (MIC) of the compounds of formula i against staphylococcus aureus (s.aureus), escherichia coli (e.coli), methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinolone-resistant escherichia coli (FREC) were determined by two-fold dilution using osthole, oxacillin, norfloxacin as control drugs and the data are shown in table 3.
TABLE 3 Table 3
As is clear from the above experimental results, the compounds of the general formula I to be protected according to the present invention have potent antibacterial activity and have broad spectrum. Some compounds have strong inhibitory effects on staphylococcus aureus (s.aureus), escherichia coli (e.coli), methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinolone-resistant escherichia coli (FREC), such as compounds ik and iq. In addition, some of the compounds have particularly remarkable antibacterial activity against methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinolone-resistant escherichia coli (FREC), and are superior to the reference drugs, such as compounds Ij, ik, in, io, ip and Iq, and the like. The high-activity compound of the derivative can be applied to the applications of resisting staphylococcus aureus (S.aureus), escherichia coli (E.coli), methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinolone-resistant escherichia coli (FREC); meanwhile, the antibacterial agent can also be combined with other antibacterial active substances.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.
Claims (8)
1. An osthole 8-position structure remodelling, which is characterized in that: the chemical structure of the compound is shown as a general formula I:
wherein R is a hydrocarbon group of 1 to 6 carbon atoms; or R is phenyl or substituted phenyl; or R is benzyl or substituted benzyl; or R is a thiomethyl group or a substituted thiomethyl group.
2. The method for preparing osthole 8-site structure modified substance according to claim 1, wherein the method comprises the following steps: the synthetic route of the general formula I is as follows:
the method specifically comprises the following steps:
preparation of Compound 1: taking osthole as a starting material, adding selenium dioxide and DMSO, stirring for reaction, filtering to remove insoluble substances, extracting with ethyl acetate, washing, drying, concentrating an organic layer, and separating and purifying by silica gel column chromatography to obtain a compound 1;
preparation of compound 2: adding tertiary butanol and 2-methyl-2-butene into the compound 1, and stirring for reaction; dissolving sodium chlorite and sodium dihydrogen phosphate in water, dripping into a reaction system, concentrating after the reaction is finished to separate out solid, vacuum filtering, and drying to obtain a compound 2;
preparation of compound 3: adding Boc-L-phenylalanine, HBTU, DIPEA, amine compounds and DMF into a reaction vessel, stirring at room temperature, adding water to precipitate a solid, filtering under reduced pressure, and drying to obtain a compound 3;
preparation of Compound 4: adding the compound 3, dichloromethane and trifluoroacetic acid into a reaction container, stirring at room temperature for reaction, concentrating, adding saturated sodium bicarbonate solution, separating out solid, vacuum filtering, and drying to obtain a compound 4;
preparation of Compound I: adding the compound 2, HBTU, DIPEA, the compound 4 and DMF into a reaction vessel, stirring at room temperature, adding water to separate out solid, vacuum filtering, and separating and purifying by silica gel column chromatography to obtain osthole 8-site structure modified product shown in the compound I.
3. The method for preparing osthole 8-site structure modified substance according to claim 2, wherein the method is characterized in that: the reaction was stirred at 100℃during the preparation of Compound 1.
4. The method for preparing osthole 8-site structure modified substance according to claim 2, wherein the method is characterized in that: the reaction was stirred at 40℃during the preparation of Compound 2.
5. The method for preparing osthole 8-site structure modified substance according to claim 2, wherein the method is characterized in that: in the preparation of the compound I, the compound 2 is prepared by the following molar ratio: HBTU: DIPEA: compound 4=0.25: 0.50 to 0.75:0.50 to 1.0:0.25 to 0.45.
6. Use of a osthole 8-position structure modification according to claim 1 in antibacterial drugs or in combination with antibacterial active ingredients.
7. Use of a osthole 8-position structure remodelling according to claim 1 in a medicament for the treatment and/or prophylaxis of any of the following pathogens: staphylococcus aureus (s.aureus), escherichia coli (e.coli), methicillin-resistant staphylococcus aureus (MRSA), fluoroquinolone-resistant escherichia coli (FREC).
8. Use of a osthole 8-position structure modification according to claim 7, wherein the osthole 8-position structure modification is any of the following compounds of general formula i according to claim 1:
compound ij:compound ik: />
Compound in:compound io: />
Compound ip:compound iq: />
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