CN119119000A - Aromatic oligoamide folded body with protected aminoalkoxy side chain and preparation method and application thereof - Google Patents
Aromatic oligoamide folded body with protected aminoalkoxy side chain and preparation method and application thereof Download PDFInfo
- Publication number
- CN119119000A CN119119000A CN202411245255.4A CN202411245255A CN119119000A CN 119119000 A CN119119000 A CN 119119000A CN 202411245255 A CN202411245255 A CN 202411245255A CN 119119000 A CN119119000 A CN 119119000A
- Authority
- CN
- China
- Prior art keywords
- compound
- aromatic
- oligoamide
- folded body
- side chain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 48
- 125000002431 aminoalkoxy group Chemical group 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 69
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 18
- 150000001263 acyl chlorides Chemical group 0.000 claims description 16
- 229940126214 compound 3 Drugs 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical group O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229940125773 compound 10 Drugs 0.000 claims description 5
- 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 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 3
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims 2
- 230000003993 interaction Effects 0.000 abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000007306 functionalization reaction Methods 0.000 abstract description 4
- 229920002521 macromolecule Polymers 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 109
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- -1 aliphatic amino acid Chemical class 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- GQIRIWDEZSKOCN-UHFFFAOYSA-N 1-chloro-n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C(Cl)=C(C)C GQIRIWDEZSKOCN-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000000429 assembly Methods 0.000 description 2
- 230000000712 assembly Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- LTKWJTJJGNNDAY-UHFFFAOYSA-N 2-amino-6-tert-butyl-1h-pyrimidin-4-one Chemical compound CC(C)(C)C1=CC(O)=NC(N)=N1 LTKWJTJJGNNDAY-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- RNAAXKYOTPSFGV-UHFFFAOYSA-N 8-fluoroquinoline Chemical compound C1=CN=C2C(F)=CC=CC2=C1 RNAAXKYOTPSFGV-UHFFFAOYSA-N 0.000 description 1
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229920002677 supramolecular polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/008—Supramolecular polymers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- C07D401/14—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 three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an aromatic oligoamide folding body with a protected amino alkoxy side chain, a preparation method and application thereof, wherein the aromatic oligoamide folding body has the following structure: r' is independently selected from the group consisting of linear alkyl, branched alkyl, and in each repeating unit Wherein m=0 to 2, andAt least 1 occurrence, R' is selected from the group consisting of straight chain alkyl, branched alkyl andN=1 to 8. Compared with the prior art, the aromatic oligoamide folding body prepared by the invention has the protected amino alkoxy side chain, has good amino reaction activity after removing the protecting group, can conveniently obtain a folding body sequence with further functionalization with various reagents so as to construct a supermolecule secondary assembly system, and is hopeful to reveal a biological macromolecule interaction mechanism.
Description
Technical Field
The invention relates to the technical field of aromatic oligoamide folding compounds, in particular to an aromatic oligoamide folding body with a protected amino alkoxy side chain, a preparation method and application thereof.
Background
The system which is obtained by constructing the same kind or different molecules by utilizing interaction forces such as hydrogen bond, cation-pi interaction, pi-pi stacking interaction and the like and exceeds the molecular level, namely the supermolecule system is a research hot spot with wide application prospect. The system is not only expected to simulate the functions of biological macromolecules and realize the slow release of medicines, but also provides a plurality of new ideas for the research of chemical basis.
The secondary assembly of the supermolecule system is more the leading edge of research and has more practical application possibility. By modifying the supramolecular system, interactions between a plurality of supramolecular systems can occur again (the strength of the interaction force is usually weaker than that of the first-order interaction force of the supramolecular system), the overall bonding strength of the secondary assembly is obviously increased, and a system with multiplied molecular weight is expected to be obtained, and the supramolecular polymer is an example.
The multi-level structure of proteins is an example of such secondary assembly, and the interaction between peptide bonds of polypeptides and hydrophobic interactions of amino acid residues can lead to secondary structures such as alpha-helices, while the interaction between these secondary structures (secondary assembly) can lead to tertiary and quaternary structures such as protein domains.
Unlike the folds of (quasi) polypeptide sequences obtained by aliphatic amino acid condensation, aromatic oligoamide folds benefit from the rigid structure of the aromatic parent nucleus and pi-pi stacking, not only show better conformational stability, but also enable the construction of unique supramolecular assemblies such as helical molecular capsules and folded pseudorotaxane.
Meanwhile, secondary interaction in a supermolecular system is constructed by means of multiple hydrogen bond interaction, metal multidentate coordination and the like, so that a huge supermolecular system is obtained, and the method becomes an important field for revealing biological macromolecule interaction in chemical biology and supermolecular chemistry.
However, the introduction of structural units capable of forming secondary assemblies into a supramolecular system often requires complex organic synthesis methods and expensive activating reagents, and the functionalization is achieved after activation of reactive sites with poor reactivity.
Disclosure of Invention
The invention aims to provide an aromatic oligoamide folding body with a protected amino alkoxy side chain, a preparation method and application thereof, wherein the protected amino alkoxy side chain of the aromatic oligoamide folding body can be subjected to deprotection under mild conditions, a folding body sequence with further functional groups can be conveniently obtained, and the folding body can be used for constructing a supermolecule secondary assembly system.
The aim of the invention can be achieved by the following technical scheme:
in one aspect, the present invention provides an aromatic oligoamide fold with protected aminoalkoxy side chains, the aromatic oligoamide fold having the structure:
r' is independently selected from the group consisting of linear alkyl, branched alkyl, and in each repeating unit (T-butoxycarbonyl protected aminoalkyl) wherein m=0 to 2, andAt least 1 occurrence;
R' is selected from the group consisting of linear alkyl branched alkyl (9-Fluorenylmethyl);
n=1 to 8.
In the present invention,The position of the cleavage of the group, i.e. the O atom is attached to the C atom on the left side of the structural formula of the aromatic oligoamide fold.
Preferably, said R' is independently selected from the group consisting of propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, isopentyl and in each repeating unitWherein m=0 to 2, andAt least 1 occurrence.
Preferably, said compound wherein R' is selected from the group consisting of propyl, isopropyl, butyl, isobutyl, tert-butyl and
Preferably, the aromatic oligoamide fold comprises a compound A1, A2 or A3, wherein A1 has the structural formula:
the structural formula of A2 is as follows:
the structural formula of A3 is as follows:
In a second aspect, the present invention provides a process for the preparation of an aromatic oligoamide fold with protected aminoalkoxy side chains as described above.
Preferably, when the aromatic oligoamide folded body is a compound A1, the preparation process comprises the following steps of taking a compound 7 as a starting material, firstly reacting with 1-chloro-N, N, 2-trimethylacrylamide in an organic solvent to obtain acyl chloride residual solid, and then reacting the acyl chloride residual solid with a mixture of diisopropylethylamine and a compound 8 to obtain the compound A1, wherein the reaction scheme is as follows:
wherein the structural formula of the compound 8 is
Preferably, when the aromatic oligoamide folded body is a compound A2, the preparation process comprises the following steps of taking a compound 3 as a raw material, firstly reacting with 1-chloro-N, N, 2-trimethylacrylamide in an organic solvent to obtain acyl chloride residual solid, and then reacting the acyl chloride residual solid with a mixture of diisopropylethylamine and a compound 9 to obtain the compound A2, wherein the reaction scheme is as follows:
Wherein the structural formula of the compound 3 is Compound 9 has the structural formula
Preferably, the specific preparation process of the compound 3 comprises the following steps of taking the compound 1 as a raw material, reacting with diisopropylethylamine and isopropyl chloroformate in an organic solvent to obtain a compound 2, and reacting the compound 2 with tetrahydrofuran and sodium hydroxide to obtain the compound 3, wherein the reaction scheme is as follows:
Preferably, when the aromatic oligoamide folded body is a compound A3, the preparation process comprises the following steps of taking a compound 6 as a raw material, firstly reacting with 1-chloro-N, N, 2-trimethylacrylamide in an organic solvent to obtain acyl chloride residual solid, and then reacting the acyl chloride residual solid with a mixture of diisopropylethylamine and a compound 10 to obtain the compound A3, wherein the reaction scheme is as follows:
Wherein the structural formula of the compound 6 is Compound 10 has the structural formula
Preferably, the specific preparation process of the compound 6 comprises the following steps of taking the compound 3 as a raw material, reacting with 1-chloro-N, N, 2-trimethylacrylamide in an organic solvent to obtain acyl chloride residual solid, reacting the acyl chloride residual solid with the compound 4 and diisopropylethylamine to obtain a compound 5, adding lithium hydroxide monohydrate into a tetrahydrofuran solution to react the compound 5 to obtain the compound 6, wherein the reaction scheme is as follows:
In a third aspect, the invention also provides the use of an aromatic oligoamide fold with protected aminoalkoxy side chains as described above for constructing a supramolecular secondary assembly system.
Preferably, the protected aminoalkoxy side chains carried by the aromatic oligoamide fold can be deprotected under mild conditions, the exposed amino groups are highly reactive, can be further functionalized and used to construct supramolecular secondary assembly systems.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention relates to an aromatic oligoamide folding compound with a protected amino alkoxy side chain, which can be further derivatized to obtain the aromatic oligoamide folding compound for a supermolecule secondary assembly.
(2) The invention designs an aromatic oligoamide folded compound, which is based on 8-fluoroquinoline and pyridine monomers, wherein a protected amino alkoxy side chain carried by the aromatic oligoamide folded compound can be subjected to deprotection under mild conditions, and an exposed amino group has high reactivity.
(3) The aromatic oligoamide folding compound designed by the invention has the advantages that the specific position in the oligomeric sequence is provided with the protected amino alkoxy side chain, the amino reaction activity after removing the protecting group is good, and the folding body sequence with further functionalization can be conveniently obtained with various reagents, so as to construct a supermolecule secondary assembly system.
(4) The preparation method of the aromatic oligoamide folded compound has the advantages of mild reaction conditions, stable reaction, easy operation and good product yield.
Drawings
FIG. 1 is a structural formula of an aromatic oligoamide fold of the present invention;
FIG. 2 shows the synthetic routes of compounds 1 to 6 of the present invention;
FIG. 3 shows the synthetic routes of the compounds A1, A2 and A3 of the present invention (wherein A is the synthetic route of the compound A1, B is the synthetic route of the compound A2, C is the synthetic route of the compound A3, and D is the structural formula of the compounds 8 and 10).
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples. The present embodiment is implemented on the premise of the technical scheme of the present invention, and a detailed implementation manner and a specific operation process are given, but the protection scope of the present invention is not limited to the following examples.
Unless specifically indicated otherwise, the reagents, methods, apparatus and devices employed in the present invention are those conventional in the art. Reagents and materials used in the following examples are commercially available unless otherwise specified.
The structural formula of the aromatic oligoamide folding body with the protected amino alkoxy side chain is shown in figure 1.
The preparation method of the invention can be further represented by the preparation process of the representative compound as follows:
Wherein compound 4 is a conventional compound.
Example 1 Synthesis of Compounds 1 to 6, the synthetic route is shown in FIG. 2
Synthesis of Compound 1
A solution of 8-fluoro-4-isopropoxy-7-nitroquinoline-2-carboxylic acid methyl ester (1.29 g,4.0 mmol) in 72mL of methanol/glacial acetic acid (v/v=1:1) was heated to reflux, reduced iron powder (0.692 g,12.4 mmol) was added in portions over 20 minutes, the reflux reaction was continued for 20 minutes, the yellow insoluble matter was filtered off, the filtrate was distilled off to remove the solvent, extracted with CH 2Cl2, the reddish brown insoluble matter was filtered off, washed with brine, and the organic phase was dried over Na 2SO4 and distilled off to remove the solvent to give compound 1 as a yellow solid (1.09 g, yield 95%).
1H NMR(400MHz,CDCl3):δ/ppm＝7.86(dd,9.0/1.5Hz,1H),7.41(s,1H),7,10(dd,9.0/7.7Hz,1H),4.14(br,2H),4.06–4.00(m,5H),2.26(hept,6.7Hz,1H),1.12(d,6.7Hz,6H).
Synthesis of Compound 2
To a solution of compound 1 (500 mg,1.71 mmol) and diisopropylethylamine (1.11 g,8.55 mmol) in 15mL of anhydrous 1, 4-dioxane at 0 ℃ was added isopropyl chloroformate, heated to 80 ℃ and stirred overnight. The mixture was washed with water and extracted with methylene chloride, and purified by silica gel column chromatography (10% → 25% ethyl acetate/petroleum ether, v/v) to give compound 2 (460 mg, yield 71%).
1H NMR(600MHz,CDCl3):δ/ppm＝8.44(br,1H),7.94(d,9.3Hz,1H),7.44(s,1H),7.05(s,1H),5.01(hept,6.3Hz,1H),3.99(s,3H),3.98(d,6.4Hz,2H),2.21(hept,6.7Hz,1H),1.28(d,6.2Hz,6H),1.06(d,6.7Hz,6H).
Synthesis of Compound 3
To 18mL of tetrahydrofuran solution containing compound 2 (400 mg,1.06 mmol) was added 2mL of aqueous solution of sodium hydroxide (106 mg,2.64 mmol), and after stirring at room temperature for 3 hours, the mixture was treated with 5% (w/w) aqueous citric acid solution and extracted with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain compound 3 (395 mg, yield. About.100%) which was directly used in the next step after drying.
1H NMR(400MHz,CDCl3):δ/ppm＝8.55(t,8.2Hz,1H),8.04(dd,9.4/1.8Hz,1H),7.57(s,1H),7.12(br,1H),5.09(hept,6.3Hz,1H),4.08(d,6.5Hz,2H),2.35–2.24(m,1H),1.37(d,6.2Hz,6H),1.14(d,6.7Hz,6H).
Synthesis of Compound 5
To a solution of compound 3 (223 mg,0.61 mmol) in 4mL of anhydrous dichloromethane was added 1-chloro-N, N, 2-trimethylpropenamine (246 mg,1.84 mmol), the solvent was removed under reduced pressure after stirring at room temperature for 2 hours, and dried under vacuum for 3 hours. The acid chloride residue was transferred with 5mL of anhydrous dichloromethane to a solution of compound 4 (201 mg,0.51 mmol) and diisopropylethylamine (262 mg,2.03 mmol) in 2mL of anhydrous dichloromethane and stirred at room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give a crude product. Precipitation with dichloromethane and methanol afforded compound 5 as a white solid (330 mg, 87% yield).
1H NMR(600MHz,CDCl3):δ/ppm＝11.0(br,1H),8.93(dd,9.2Hz,6.5Hz,1H),8.51(br,1H),8.06(d,9.2Hz,1H),8.04(d,9.2Hz,1H),7.69(s,1H),7.57(s,1H),7.16(s,1H),5.10(hept,6.1Hz,1H),4.78(br,1H),4.38(t,5.9Hz,2H),4.11(d,6.6Hz,2H),4.09(s,3H,COOCH3),3.45(q,7.7Hz,2H,),2.31(hept,1H),2.24–2.16(m,2H),1.45(s,9H),1.38(d,6.3Hz,6H),1.15(d,6.7Hz,6H).
Synthesis of Compound 6
To a solution of compound 5 (275 mg,0.37 mmol) in 7mL of tetrahydrofuran was added a solution of lithium hydroxide monohydrate (39 mg,0.93 mmol) in 7mL of water, which was stirred at room temperature for 4 hours, treated with 5% (w/w) aqueous citric acid and extracted with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give compound 6 as a pale yellow solid (245 mg, yield 90%), which was used directly in the next step after drying.
EXAMPLE 2 Synthesis of aromatic oligoamide folder Compound A1 with protected amino alkoxy side chain, the synthetic route is shown in FIG. 3A
(1) Synthesis of Compound 7
To 20mL of 1, 4-dioxane solution containing compound 4 (803 mg,2.04 mmol) was added 100mL of a 5% (w/w) aqueous solution of sodium bicarbonate. 20mL of a1, 4-dioxane solution of fluorenylmethyl chloroformate (792 mg,3.06 mmol) was added dropwise over 30 minutes at 0 ℃. Stirring was continued at 0 ℃ for 1 hour and then at room temperature overnight. Adding methyl chloroformate until the reaction is complete, treating with 1M hydrochloric acid and extracting with dichloromethane, and purifying the crude product by silica gel flash column chromatography (10% -38% ethyl acetate/petroleum ether, v/v) to obtain the ester compound. To 125mL of an anhydrous ethyl acetate solution of the ester compound (1.00 g,1.6 mmol) was added lithium iodide (0.650 g,4.9 mmol) as a solid, and the mixture was stirred overnight at 80℃and concentrated, treated with 5% aqueous solution of citric acid (w/w) and extracted with methylene chloride, dried by organic phase drying, and then sonicated with methanol to disperse the yellow insoluble matter, and the yellow insoluble matter was filtered off as a crude product, and purified by flash column chromatography on silica gel (methylene chloride→12% methanol/methylene chloride, v/v) to give compound 7 as a yellow solid (635 mg, yield 65%).
1H NMR(400MHz,DMSO-d6):δ/ppm＝9.99(s,1H),7.90(t,8.8Hz,4H),7.80(d,7.5Hz,2H),7.52(s,1H),7.43(t,7.4Hz,2H),7.35(t,7.4Hz,2H),7.00(br,1H),4.49(d,6.9Hz,2H),4.32(q,7.0Hz,2H),3.19(q,6.6Hz,2H),1.99(t,6.4Hz,2H),1.35(s,9H).
(2) Synthesis of Compound 8, structural formula shown in FIG. 3D
To a solution of dimeric 8-fluoroquinoline carboxylic acid compound (0.227 g,0.83 mmol) in 10mL of anhydrous dichloromethane was added 1-chloro-N, N, 2-trimethylpropenamide (0.343g, 2.57 mmol), the solvent was removed under reduced pressure after stirring at room temperature for 3 hours, and dried under vacuum for 3 hours. The acid chloride residue was transferred to a solution of the amino compound containing the terpyridyl dichloro 8-fluoroquinolinamide (0.710 g,0.75 mmol) and diisopropylethylamine (0.41 g,3.15 mmol) in 5mL of anhydrous dichloromethane with 10mL of anhydrous dichloromethane and stirred overnight at room temperature. The solvent was removed by rotary evaporation to give the crude product. Purifying by silica gel flash column chromatography (10% -40% ethyl acetate/petroleum ether, v/v) to obtain tert-butoxycarbonyl protected amino compound. To a solution of the t-butoxycarbonyl-protected amino compound (0.250 g,0.16 mmol) in 1mL of anhydrous dichloromethane was added trifluoroacetic acid (0.50 mL), and after stirring at room temperature for 6 hours, the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, and extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to give compound 8 as a yellow solid (0.830 g, yield 70%).
1H NMR(600MHz,DMSO-d6):δ/ppm＝11.48(s,1H),11.30(s,1H),11.03(s,1H),10.40(s,1H),10.08(s,1H),9.93(s,1H),9.25(s,1H),8.48(s,1H),8.10–6.53(m,21H),4.36–4.13(m,6H),4.03(q,7.2Hz,2H),2.40–2.31(m,4H),1.41–1.20(m,33H),0.68(s,9H).
(3) Synthesis of Compound A1
To a solution of compound 7 (186 mg,0.31 mmol) in 3mL of anhydrous dichloromethane was added 1-chloro-N, N, 2-trimethylpropenamine (134 mg,1.00 mmol), the solvent was removed under reduced pressure after stirring at room temperature for 3 hours, and dried under vacuum for 3 hours. The acid chloride residue was transferred to a mixture containing compound 8 (380 mg,0.25 mmol) and diisopropylethylamine (143 mg,1.11 mmol) with 4.5mL of anhydrous dichloromethane and stirred at room temperature overnight. The crude product was purified by flash column chromatography on silica gel (10% → 40% ethyl acetate/petroleum ether, v/v) and precipitated with dichloromethane and methanol to give compound A1 as a white solid (325 mg, yield 61%).
1H NMR(400MHz,DMSO-d6):δ/ppm＝11.56(s,1H),11.27(s,1H),10.66(s,1H),10.34(s,1H),10.14(s,1H),10.03–9.90(m,2H),8.84(s,1H),8.40–8.24(m,2H),8.24–8.08(m,1H),7.94(d,7.6Hz,1H),7.85–7.64(m,5H),7.62–7.34(m,9H),7.34–6.96(m,13H),6.92–6.82(m,2H),6.80–6.63(m,3H),4.45–3.65(m,14H),2.42–2.30(m,4H),2.27–2.00(m,3H),1.48(s,9H),1.40–1.27(m,20H),1.21–1.13(m,6H),0.50(s,9H).
EXAMPLE 3 Synthesis of aromatic oligoamide folder Compound A2 with protected amino alkoxy side chain, the synthetic route is shown in FIG. 3B
(1) Synthesis of Compound 9
To a solution of A1 (100 mg,0.05 mmol) in 0.7mL of anhydrous dichloromethane was added 0.10mL of tris (2-aminoethylamine) (0.65 mmol), and after stirring at room temperature for 30 minutes, the mixture was washed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and compound 9 (86 mg, yield 93%) was purified by flash column chromatography on silica gel (10%. Fwdarw.55% ethyl acetate/petroleum ether, v/v) and used directly for the next step and condensation of acid chloride.
(2) Synthesis of Compound A2
To a solution of compound 3 (56 mg,0.15 mmol) in 1mL of anhydrous dichloromethane was added 1-chloro-N, 2-trimethylpropenamine (61 mg,0.46 mmol), and after stirring at room temperature for 3 hours, the solvent was removed under reduced pressure and dried under vacuum for 3 hours. The acid chloride residue was transferred to a mixture containing compound 9 (140 mg, 76. Mu. Mol) and diisopropylethylamine (39 mg,0.30 mmol) with 1.5mL of anhydrous dichloromethane and stirred at room temperature overnight. The crude product was purified by flash column chromatography on silica gel (dichloromethane→25% ethyl acetate/dichloromethane, v/v) to give compound A2 as a white solid (145 mg, 87% yield).
1H NMR(400MHz,DMSO-d6):δ/ppm＝11.68(s,1H),11.24(s,1H),10.37(s,1H),10.25(s,1H),10.15(s,2H),9.96–9.77(m,3H),8.82(s,1H),8.51–8.28(m,2H),8.07–7.95(m,2H),7.87–7.76(m,2H),7.75–7.64(m,2H),7.61–7.36(m,4H),7.33–7.10(m,8H),7.08–6.58(m,9H),4.49–4.25(m,4H),4.23–4.09(m,3H),4.07–3.92(m,3H),3.90–3.79(m,2H),2.32–2.09(m,7H),1.52(s,9H),1.45–1.29(m,15H),1.28–1.15(m,15H),0.87(d,6.2Hz,3H),0.54(d,6.3Hz,3H),0.34(s,9H).
EXAMPLE 4 Synthesis of aromatic oligoamide folder Compound A3 with protected amino alkoxy side chain, the synthetic route is shown in FIG. 3C
(1) Synthesis of Compound 10, having a structural formula shown in FIG. 3D
To a solution of dimeric 8-fluoroquinoline carboxylic acid compound (0.128 g,0.20 mmol) in 2mL of anhydrous dichloromethane was added 1-chloro-N, N, 2-trimethylpropenamide (0.091 g,0.68 mmol), the solvent was removed under reduced pressure after stirring at room temperature for 3 hours, and dried under vacuum for 3 hours. The acid chloride residue was transferred to a solution of compound 8 (0.250 g,0.17 mmol) and diisopropylethylamine (0.094 g,0.73 mmol) in 1mL of anhydrous dichloromethane and stirred at room temperature overnight. The solvent was removed by rotary evaporation to give the crude product. Purifying by silica gel flash column chromatography (10% -35% ethyl acetate/petroleum ether, v/v) to obtain tert-butoxycarbonyl protected amino compound. To a solution of the t-butoxycarbonyl-protected amino compound (0.250 g,0.12 mmol) in 1mL of anhydrous dichloromethane was added trifluoroacetic acid (0.45 mL), and after stirring at room temperature for 5 hours, the mixture was washed with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the solvent was removed by rotary evaporation to give the crude product. Purification by flash column chromatography on silica gel (10% -35% ethyl acetate/petroleum ether, v/v) afforded compound 8 as a yellow solid (0.830 g, 70%).
1H NMR(400MHz,DMSO-d6):δ/ppm＝11.69(s,1H),11.14(s,1H),10.47(s,1H),10.34(s,1H),10.10(s,2H),9.96(s,1H),9.92(s,1H),9.84(s,1H),8.77(s,1H),8.32(t,7.6Hz,1H),8.09–7.87(m,3H),7.85(d,7.5Hz,2H),7.78–7.14(m,13H),7.08–6.56(m,8H),4.37–3.81(m,12H),2.41–2.20(m,6H),1.43–1.15(m,36H),1.03(s,9H),0.38(s,9H).
(2) Synthesis of Compound A3
To a solution of compound 6 (125 mg,0.172 mmol) in 4.5mL of anhydrous dichloromethane was added 1-chloro-N, N, 2-trimethylpropenamine (61 mg,0.46 mmol), the solvent was removed under reduced pressure after stirring at room temperature for 3 hours, and dried under vacuum for 3 hours. The acid chloride residue was transferred to a mixture containing compound 10 (220 mg,0.115 mmol) and diisopropylethylamine (60 mg,0.46 mmol) with 7mL of anhydrous dichloromethane and stirred at room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution and extracted with methylene chloride, and purified by silica gel flash column chromatography (20% → 50% ethyl acetate/petroleum ether, v/v) and precipitated with methylene chloride and methanol to give compound A3 as a white solid (225 mg, yield 75%).
1H NMR(600MHz,CCl4/DMSO-d6＝1:5,v/v):δ/ppm＝11.45(s,1H),11.28–11.01(m,1H),10.93–10.55(m,1H),10.38–10.18(m,1H),10.15–9.47(m,5H),8.69(s,1H),8.14–6.41(m,32H),4.42–3.92(m,13H),3.47–3.31(m,2H),2.45–2.09(m,9H),1.53(s,9H),1.40–1.15(m,42H),0.85(br,3H),0.68–0.31(m,9H).
Example 5:
The protected side chain amino groups can be deprotected in a mild environment, and the exposed highly reactive amino groups can be reacted by simple steps to give further functionalized oligomeric sequences for use in constructing secondary assembled structures, examples of which are given below for deprotection, functionalization and secondary assembled supramolecular polymerization.
6-Tert-Butylisocytosine (100 mg,0.60 mmol) and N, N' -carbonyldiimidazole (146 mg,0.90 mmol) were dissolved in 2.5mL of 1, 4-dioxane and stirred at 60℃for 2 hours. The white precipitate was collected by filtration, thoroughly washed with acetone and dried in the shade to give an activated isocytosine compound (110 mg, yield 70%).
1H NMR(600MHz,CDCl3):δ/ppm＝12.63(br,1H,NHC＝O),12.49(br,1H,Ar-NH),8.71(s,1H,N-CH＝N),7.60(s,C(＝O)-N-CH＝CH-N),7.14(s,C(＝O)-N-CH＝CH-N),5.93(s,1H,C(＝O)-CH＝C),1.39(s,9H,tBu).
To 2.5mL of anhydrous 1, 4-dioxane solution containing Compound A3 (175 mg,0.065 mmol) was added 3.0mL of 1, 4-dioxane solution of hydrogen chloride, and the solvent was removed by rotary evaporation after stirring at room temperature for 4 hours to give the corresponding amine. After the amine was dissolved in 3.5mL of anhydrous dichloromethane, anhydrous triethylamine (29 mg,0.288 mmol) and activated isocytosine compound (26 mg,0.100 mmol) were added. After the mixture was stirred overnight at 35 ℃, washed with 1.0M aqueous hydrogen chloride, saturated aqueous sodium bicarbonate and brine, extracted with dichloromethane, purified by flash column chromatography on silica gel (0.5% → 3.0% methanol/dichloromethane, v/v) and precipitated with methanol/dichloromethane to give compound A4 as a white solid (135 mg, yield 75%).
1H NMR(600MHz,CCl4/DMSO-d6＝1:5,v/v):δ/ppm＝11.66–9.45(m,9H),8.69(s,1H),8.21–6.33(m,26H),5.86(s,1H),4.55–3.92(m,12H),3.58(s,1H),2.43–2.13(m,7H),1.41–1.08(m,42H),0.85(br,3H),0.68–0.32(m,9H).
The nuclear magnetic resonance diffusion sequence spectrum of the 20mM deuterated chloroform solution of the compound A4 shows that the compound A4 can form a supermolecular polymer with the molecular weight of 100000 through the multiple hydrogen bond interaction of the allopyrimidinone unit, and the structural formula of the compound A4 is shown as follows.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411245255.4A CN119119000A (en) | 2024-09-06 | 2024-09-06 | Aromatic oligoamide folded body with protected aminoalkoxy side chain and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411245255.4A CN119119000A (en) | 2024-09-06 | 2024-09-06 | Aromatic oligoamide folded body with protected aminoalkoxy side chain and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN119119000A true CN119119000A (en) | 2024-12-13 |
Family
ID=93749074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202411245255.4A Pending CN119119000A (en) | 2024-09-06 | 2024-09-06 | Aromatic oligoamide folded body with protected aminoalkoxy side chain and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN119119000A (en) |
-
2024
- 2024-09-06 CN CN202411245255.4A patent/CN119119000A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4463454B2 (en) | Method for synthesizing a substantially monodispersed mixture of polymers having polyethylene glycol moieties | |
| JP7296396B2 (en) | Amanitin-antibody conjugate | |
| CN114409890A (en) | A kind of amino functionalized polyethylene glycol derivative and preparation method thereof | |
| JPWO2019189867A1 (en) | Applications for drug delivery of bisiminobiotin compounds | |
| JP2008530289A (en) | Process for the preparation of polyethylene glycols functionalized with alkoxyamines | |
| CN109824565B (en) | Light-responsive multifunctional chemical cross-linking agent and preparation method and application thereof | |
| CN108558692A (en) | A kind of preparation method of amides compound | |
| CN119119000A (en) | Aromatic oligoamide folded body with protected aminoalkoxy side chain and preparation method and application thereof | |
| EP3412700A1 (en) | Compounds | |
| CN103012176A (en) | Method for preparing long-chain alkyl 4-carboxyl anionic surfactant | |
| WO2023033017A1 (en) | Method for producing ganirelix or salt thereof | |
| CN119137111A (en) | Lipophilic reagent compounds for liquid phase synthesis of biomolecules | |
| JP2003516398A (en) | Macrocyclic compounds and their use | |
| JP7522726B2 (en) | Method for producing pyrrole-imidazole (poly)amide | |
| CN110437066A (en) | Synthetic method of carboxylic ester compound | |
| CN113264883B (en) | Method for rapidly synthesizing phenanthridine compounds | |
| JP2655907B2 (en) | Separating agent | |
| CN115636848B (en) | Method for synthesizing phosphorylcholine compound by one-pot method | |
| CN110172062B (en) | Synthesis method of monofluoro spiro compound and intermediate thereof | |
| JP6202431B2 (en) | Cage-type silsesquioxane derivatives | |
| AU2022424485A1 (en) | Method for producing oligonucleic acid compound | |
| CN111375068B (en) | Preparation method of polyethylene glycol polypeptide medicine | |
| CN107586265B (en) | Environment-friendly orthogonal protection diamino diacid compound, preparation method and application thereof | |
| CN101260135A (en) | A kind of synthetic method of higher fatty acid zidovudine ester | |
| CN117964685A (en) | Antibody drug conjugate, intermediate thereof, preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |