CN115286640A - Compound with fused ring N, O-acetal skeleton and preparation method and application thereof - Google Patents
Compound with fused ring N, O-acetal skeleton and preparation method and application thereof Download PDFInfo
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- CN115286640A CN115286640A CN202210352965.1A CN202210352965A CN115286640A CN 115286640 A CN115286640 A CN 115286640A CN 202210352965 A CN202210352965 A CN 202210352965A CN 115286640 A CN115286640 A CN 115286640A
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- compound
- acetal skeleton
- fused ring
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
- -1 p-toluenesulfonyl Chemical group 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 125000004122 cyclic group Chemical group 0.000 claims description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 24
- 150000002466 imines Chemical class 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000010791 quenching Methods 0.000 claims description 16
- 230000000171 quenching effect Effects 0.000 claims description 15
- GOQJMMHTSOQIEI-UHFFFAOYSA-N hex-5-yn-1-ol Chemical compound OCCCCC#C GOQJMMHTSOQIEI-UHFFFAOYSA-N 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 150000007524 organic acids Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000007131 anti Alzheimer effect Effects 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000012300 argon atmosphere Substances 0.000 claims description 2
- 238000011161 development Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- IFPWCRBNZXUWGC-UHFFFAOYSA-M gold(1+);triphenylphosphane;chloride Chemical compound [Cl-].[Au+].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 IFPWCRBNZXUWGC-UHFFFAOYSA-M 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- URGUJYLTSUVAFP-UHFFFAOYSA-N [N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.[N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.[Ag+2] Chemical compound [N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.[N-](S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F.[Ag+2] URGUJYLTSUVAFP-UHFFFAOYSA-N 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 125000003367 polycyclic group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 239000011259 mixed solution Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 5
- 229940125773 compound 10 Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 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 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical compound [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229910003771 Gold(I) chloride Inorganic materials 0.000 description 3
- 239000012670 alkaline solution Substances 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000002084 enol ethers Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 229940124810 Alzheimer's drug Drugs 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ZQMAXZJZBIKOAG-UHFFFAOYSA-N upenamide Natural products C1CCCC(OC23)CC(=O)N2CCCC32C(O)C=CCC2C=CC=CC=CCN2CCCC3C2OC1CC3 ZQMAXZJZBIKOAG-UHFFFAOYSA-N 0.000 description 1
- ZQMAXZJZBIKOAG-AQSBWVGUSA-N upenamide Chemical compound C1CCCC(OC23)CC(=O)N2CCCC32C(O)C=CCC2\C=C\C=C\C=C\CN2CCCC3C2OC1CC3 ZQMAXZJZBIKOAG-AQSBWVGUSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
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- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a compound with a fused ring N, O-acetal skeleton, and a preparation method and application thereof. The compound having a fused ring N, O-acetal skeleton has a structure represented by the following formula:
wherein R is 1 Selected from phenyl and/or substituted phenyl, R 2 Selected from hydrogen or methoxy, R 3 Selected from p-toluenesulfonyl or methanesulfonyl, X is selected from CH 2 、CH 2 CH 2 And O is any one ofN is selected from 1 or 2. The preparation method provided by the invention has the advantages of mild reaction conditions, low catalyst consumption, simple and convenient operation, wide substrate universality and the like. A series of compounds with a new structure and a polycyclic N, O-acetal skeleton can be synthesized by a one-pot reaction in high yield, high area and high stereoselectivity.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a compound with a fused ring N, O-acetal skeleton, and a preparation method and application thereof.
Background
The fused ring N, O-acetal skeleton is widely present in a plurality of natural products or drug molecules with important physiological activity. For example, the alkaloid Perlinadine A with a tetracyclic structure skeleton has obvious cytotoxicity and antibacterial activity; CCR5 is thought to be involved in the pathway of HIV virus entry into macrophages and T cells, and therefore the development of CCR5 inhibitors would be promising for the treatment of HIV infection; the alkaloid Upenamide with macrocyclic N, O-acetal backbone is useful as HIV inhibitor. Therefore, the efficient and universal N, O-acetal skeleton synthesis method has been widely concerned by organic synthesizers and pharmacologists. Unfortunately, this aspect of research is not complete. To date, most synthetic methods have relied on cycloaddition of cyclic enamines (previously prepared or formed in situ) with activated unsaturated carbonyl compounds. E.g. 2009
Substituted aniline, formaldehyde and dicarbonyl compound are used as raw materials, cyclic enamine is formed in situ through aldol condensation-Friedel-crafts alkylation reaction, and then Diles-Alder cycloaddition reaction is carried out on the enamine and oxadiene formed in situ to construct the compound with N, O-acetal core skeletonA compound; in 2014, xupolithu et al quickly synthesized a series of fused-ring N, O-acetal compounds by cycloaddition reaction of cyclic enamine formed by in-situ activation of alkynylamine by transition metal catalysis and beta-keto ester activated by Lewis acid catalyst; in 2020, the terrayon group constructed such compounds using the cycloaddition-rearrangement tandem reaction process of α -azidocarbonyl compounds and cyclic enamines.
In view of the novel framework structure characteristics and abundant physiological activities of the fused-ring N, O-acetal compound, it is an urgent problem to develop a new method for rapidly constructing the fused-ring N, O-acetal compound.
Disclosure of Invention
The invention mainly aims to provide a compound with a fused ring N, O-acetal skeleton, a preparation method and application thereof, so as to overcome the defects of the prior art.
In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:
the embodiment of the invention provides a compound with a fused ring N, O-acetal skeleton, which has a structure shown in a formula (I):
wherein R is 1 Selected from phenyl or substituted phenyl, R 2 Selected from hydrogen or methoxy, R 3 Selected from p-toluenesulfonyl or methanesulfonyl, X is selected from CH 2 、CH 2 CH 2 And O, n is selected from 1 or 2.
The embodiment of the present invention further provides a preparation method of the compound having a fused ring N, O-acetal skeleton, which includes: in protective atmosphere, reacting a uniformly mixed reaction system containing alkynol, cyclic unsaturated imine, metal catalyst, organic acid and organic solvent at 5-60 ℃ for 4-24 h to obtain the compound with the fused ring N, O-acetal skeleton.
The embodiment of the invention also provides application of the compound with the polycyclic N, O-acetal skeleton in preparation of HIV inhibitors, medicines for treating osteoporosis or medicines for developing anti-Alzheimer's disease medicines.
Compared with the prior art, the invention has the beneficial effects that: the preparation method of the compound with the fused ring N, O-acetal skeleton provided by the invention has the advantages of mild reaction conditions, low catalyst consumption, simple and convenient operation, wide substrate universality and the like, and can synthesize a series of compounds with the fused ring N, O-acetal skeleton with novel structures in a high-yield, high-area and high-stereoselectivity manner through one-pot reaction.
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 embodiments or the description of the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and it is also possible for those skilled in the art to obtain other drawings based on the drawings without creative efforts.
FIG. 1 is a schematic view showing the reaction scheme of a compound having a fused cyclic N, O-acetal skeleton according to an exemplary embodiment of the present invention;
FIG. 2a is a NMR spectrum of Compound 1 obtained in example 1 of the present invention;
FIG. 2b is the NMR C-spectrum of Compound 1 obtained in example 1 of the present invention;
FIG. 3a is a NMR spectrum of Compound 2 obtained in example 2 of the present invention;
FIG. 3b is a NMR spectrum of Compound 2 obtained in example 2 of the present invention;
FIG. 4a is a NMR spectrum of Compound 3 obtained in example 3 of the present invention;
FIG. 4b is a NMR spectrum of Compound 3 obtained in example 3 of the present invention;
FIG. 4c is an X-ray single crystal diffractogram of Compound 3 obtained in example 3 of the present invention;
FIG. 5a is a NMR spectrum of Compound 4 obtained in example 4 of the present invention;
FIG. 5b is a NMR spectrum of Compound 4 obtained in example 4 of the present invention;
FIG. 6a is a NMR spectrum of Compound 5 obtained in example 5 of the present invention;
FIG. 6b is a NMR spectrum of Compound 5 obtained in example 5 of the present invention;
FIG. 7a is a NMR spectrum of Compound 6 obtained in example 6 of the present invention;
FIG. 7b is a NMR carbon spectrum of Compound 6 obtained in example 6 of the present invention;
FIG. 8a is a NMR spectrum of Compound 7 obtained in example 7 of the present invention;
FIG. 8b is a NMR spectrum of Compound 7 obtained in example 7 of the present invention;
FIG. 9a is a NMR spectrum of Compound 8 obtained in example 8 of the present invention;
FIG. 9b is a NMR spectrum of Compound 8 obtained in example 8 of the present invention;
FIG. 10a is a NMR spectrum of Compound 9 obtained in example 9 of the present invention;
FIG. 10b is the NMR C-spectrum of Compound 9 obtained in example 9 of the present invention;
FIG. 10c is an X-ray single crystal diffractogram of Compound 9 obtained in example 9 of the present invention;
FIG. 11a is a NMR spectrum of Compound 10 obtained in example 10 of the present invention;
FIG. 11b is a NMR spectrum of Compound 10 obtained in example 10 of the present invention;
FIG. 11c is an X-ray single crystal diffractogram of Compound 10 obtained in example 10 of the present invention;
FIG. 12a is a NMR spectrum of Compound 11 obtained in example 11 of the present invention;
FIG. 12b is a NMR carbon spectrum of Compound 11 obtained in example 11 of the present invention;
FIG. 13a is a NMR spectrum of Compound 12 obtained in example 12 of the present invention;
FIG. 13b is a NMR carbon spectrum of Compound 12 obtained in example 12 of the present invention;
FIG. 14a is a NMR spectrum of Compound 13 obtained in example 13 of the present invention;
FIG. 14b is a NMR carbon spectrum of Compound 13 obtained in example 13 of the present invention.
Detailed Description
In view of the defects of the prior art, the inventor of the present invention has long studied and largely practiced to propose the technical solution of the present invention, which will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the 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.
Specifically, as one aspect of the technical scheme of the invention, the invention relates to a compound with a fused ring N, O-acetal skeleton, which has a structure shown in a formula (I):
wherein R is 1 Selected from phenyl or substituted phenyl, R 2 Selected from hydrogen or methoxy, R 3 Selected from p-toluenesulfonyl or methanesulfonyl, X is selected from CH 2 、CH 2 CH 2 And O, n is selected from 1 or 2.
In some preferred embodiments, the R is 1 When the substituent is a substituted phenyl group, the number of the substituent in the substituted phenyl group is one or more.
Further, the substituents are independently selected from any one or a combination of two or more of alkyl, alkoxy, hydroxyl, halogen, nitro and ester groups, and are not limited thereto.
Further, the position of the substituent in the substituted phenyl group is any one of ortho, meta, or para, and is not limited thereto.
In another aspect of the embodiments of the present invention, there is also provided a method for producing the aforementioned compound having a fused-ring N, O-acetal skeleton, which comprises: in protective atmosphere, reacting a uniformly mixed reaction system containing alkynol, cyclic unsaturated imine, metal catalyst, organic acid and organic solvent at 5-60 ℃ for 4-24 h to obtain the compound with the fused ring N, O-acetal skeleton.
In some preferred embodiments, the molar ratio of the alkynol, cyclic unsaturated imine, metal catalyst and organic acid is 1 to 2:1:0.01 to 0.05:0.05 to 0.20.
In some preferred embodiments, the alkynol includes 4-pentyn-1-ol and/or 5-hexyn-1-ol, and is not limited thereto.
In some preferred embodiments, the alkynol has the structure shown below:
in some preferred embodiments, the cyclic unsaturated imine has the structure shown in formula (II):
wherein R is 1 Selected from phenyl or substituted phenyl, R 2 Selected from hydrogen or methoxy, R 3 Selected from p-toluenesulfonyl or methanesulfonyl, X is selected from CH 2 、CH 2 CH 2 And O.
In some preferred embodiments, the cyclic unsaturated imine has the structure shown below:
wherein R is 1 Is phenyl or substituted phenyl, R 2 Is hydrogen or methoxy, R 3 Is p-toluenesulfonyl or methanesulfonyl.
Further, said R 1 When the substituent is a substituted phenyl group, the number of the substituent is one or more, and the substituent is at least independently selected from the group consisting of alkylAny one or combination of more than two of base, alkoxy, hydroxyl, halogen, nitro and ester; the position of the substituent is ortho-position, meta-position or para-position.
In some preferred embodiments, the metal catalyst includes any one or a combination of two or more of palladium chloride, silver trifluoromethanesulfonate, silver bistrifluoromethanesulfonylimide, and triphenylphosphine gold chloride, without being limited thereto.
In some preferred embodiments, the organic acid includes any one or a combination of two or more of trifluoroacetic acid, benzoic acid, and binaphthol phosphate, without being limited thereto.
In some preferred embodiments, the organic solvent includes any one or a combination of two or more of 1, 2-dichloroethane, dichloromethane, acetonitrile, toluene, tetrahydrofuran, dioxane, and the like, and is not limited thereto.
In some preferred embodiments, the protective atmosphere includes an argon atmosphere and/or a nitrogen atmosphere, and is not limited thereto.
In some preferred embodiments, the preparation method further comprises: after the reaction is finished, quenching, extracting and purifying the obtained product.
Further, after the reaction is completed, the obtained reaction solution (the obtained product) is quenched with an alkaline solution, and then extracted with an organic solvent, and then subjected to concentration and extraction, and then subjected to separation and purification by column chromatography to obtain the compound having a fused ring N, O-acetal skeleton.
Further, the alkaline solution used for quenching is any one of saturated sodium bicarbonate, saturated sodium carbonate or 10% sodium hydroxide solution.
Further, the organic solvent used for extraction is any one of dichloromethane, chloroform, ethyl acetate or diethyl ether.
Furthermore, the eluent adopted by the column chromatography separation and purification is a mixed solution of ethyl acetate and petroleum ether.
In some more specific embodiments, the method for preparing the compound having a fused cyclic N, O-acetal skeleton comprises:
under the protection of inert gas, adding cyclic unsaturated imine and metal catalyst into organic solvent, then adding alkynol and organic acid in sequence, then reacting at 5-60 ℃ for 4-24h, tracking the reaction process by TLC, after the reaction is finished, adding alkaline solution into the reaction solution, extracting by organic solvent, combining organic phases, washing by water, drying, concentrating solvent, separating and purifying by column chromatography, and obtaining the target compound with N, O-acetal skeleton. The reaction equation of the method is as follows:
the reaction scheme of the invention is shown in figure 1: alkynol is subjected to intramolecular hydrogenation oxidation reaction under the action of a transition metal catalyst to produce an exocyclic enol ether intermediate A, the A is interconverted and then converted into an endocyclic enol ether B, and the B and cyclic unsaturated imine activated by organic acid are subjected to intermolecular cyclization reaction to obtain the compound with an N, O-acetal skeleton.
In another aspect of the embodiments of the present invention, the use of the aforementioned compound having a fused ring N, O-acetal skeleton in the preparation of HIV inhibitors, drugs for treating osteoporosis, or drugs for developing anti-alzheimer drugs is also provided.
By the technical scheme, the preparation method has the advantages of mild reaction conditions, low catalyst consumption, simple and convenient operation, wide substrate universality and the like, and a series of fused ring N, O-acetal compounds with a spiro structure and a novel structure can be synthesized in a high-yield, high-regioselectivity and high-stereoselectivity manner through a one-pot reaction.
In order to further understand the present invention, the following method for constructing cyclic N, O-acetals by catalyzing cyclic unsaturated imines with alkynols with metals and organic acids is further described in detail with reference to several preferred embodiments, but the present invention is not limited to the following embodiments, and those skilled in the art can make insubstantial modifications and adjustments under the teaching of the core of the present invention and still fall within the scope of the present invention.
The experimental materials used in the examples used below were all available from conventional biochemical reagents companies, unless otherwise specified.
Example 1
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was carried out by the following steps:
under the protection of nitrogen, adding 2.5mL of dichloromethane into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine A and 1mol% of silver trifluoromethanesulfonate, stirring uniformly, sequentially adding 0.5mmol of 5-hexyne-1-ol and 5mol% of trifluoroacetic acid, reacting at 5 ℃, tracking by a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 24 h), quenching the reaction, extracting the dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (petroleum ether: a mixed solution of ethyl acetate with the volume ratio of 5:1 is an eluent), thus obtaining a compound 1 with a fused ring N, O-acetal skeleton.
Referring to FIGS. 2a and 2b, the NMR data of the acetal compound 1 obtained in this example are: 1 H NMR(600 MHz,CDCl 3 )δ7.98(d,J＝8.3Hz,2H),7.69(d,J＝7.7Hz,1H),7.37-7.25(m,3H),7.25-7.16 (m,5H),7.13(d,J＝7.3Hz,1H),3.95(d,J＝13.8Hz,1H),3.73(dd,J＝15.8,11.6Hz,1H),2.80(t, J＝18.7Hz,1H),2.74-2.60(m,2H),2.56(d,J＝14.3Hz,1H),2.45(s,3H),2.40(s,3H),2.00(d, J＝9.3Hz,2H),1.50(dd,J＝54.4,12.0Hz,3H),1.38(s,3H),1.29-1.04(m,1H)ppm. 13 C NMR (151MHz,CDCl 3 )δ＝142.93,140.33,139.56,136.50,135.53,135.11,134.40,132.43,129.36, 129.16,128.94,128.71,126.90,126.66,125.96,123.60,92.48,77.28,77.07,76.86,63.18,51.33, 44.87,27.49,27.37,24.95,24.02,21.57,21.20,16.83ppm.
example 2
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was carried out by the following steps:
under the protection of nitrogen, adding 2.5mL of dichloroethane into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine B and 2.5mol% of silver trifluoromethanesulfonate, stirring uniformly, sequentially adding 0.6mmol of 5-hexyne-1-ol and 10mol% of trifluoroacetic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium carbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting the trichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (petroleum ether: a mixed solution of ethyl acetate with the volume ratio of 5.
Referring to fig. 3a and 3b, the nmr data for compound 2 obtained in this example are: 1 H NMR(600MHz, CDCl 3 )δ7.97(d,J＝8.3Hz,2H),7.67(d,J＝7.7Hz,1H),7.40-7.27(m,5H),7.20(t,J＝7.3Hz, 1H),7.14(d,J＝7.3Hz,1H),7.08(d,J＝17.3Hz,2H),4.06–3.89(m,1H),3.85-3.62(m,1H), 2.97-2.65(m,3H),2.63-2.54(m,1H),2.46(s,3H),2.17-1.86(m,2H),1.57(dd,J＝50.6,38.7Hz, 4H),1.37(s,3H),1.31-1.11(m,1H)ppm. 13 C NMR(151MHz,CDCl 3 )δ＝162.71,161.09,143.02, 140.44,138.30,135.33,135.08,134.12,132.61,130.46,129.04,128.73,126.98,126.84,126.00, 123.50,115.62,92.62,77.27,77.06,76.85,63.01,50.87,45.16,27.68,27.36,25.11,24.10,21.61, 16.90ppm.
example 3
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, adding 2.5mL acetonitrile into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine C and 5mol% of silver trifluoromethanesulfonate, stirring uniformly, sequentially adding 0.75mmol of 5-hexyne-1-ol and 15mol% of trifluoroacetic acid, heating to 40 ℃ for reaction, tracking a TLC point plate, adding 2mL of 10% sodium hydroxide solution after the reaction is finished (about 8 hours), quenching the reaction, extracting for three times by ethyl acetate, combining organic phases, washing by water, drying by anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 5 is an eluent), thus obtaining a compound 3 with a fused N, O-acetal skeleton.
Referring to fig. 4a and 4b, the nmr data for compound 3 obtained in this example are: 1 H NMR(600MHz,CDCl 3 ) δ7.87(d,J＝8.3Hz,2H),7.58(d,J＝7.6Hz,1H),7.22(ddd,J＝21.2,20.2,8.9Hz,9H),7.12- 6.92(m,2H),3.84(d,J＝12.1Hz,1H),3.75-3.50(m,1H),2.91-2.53(m,3H),2.44(dd,J＝10.7, 8.0Hz,1H),2.34(s,3H),2.04-1.81(m,2H),1.77-1.33(m,4H),1.27(s,3H),1.11(dd,J＝39.8, 27.6Hz,2H)ppm. 13 C NMR(151MHz,CDCl 3 )δ＝142.97,142.63,140.37,135.47,135.11,134.24, 132.61,129.14,129.07,128.73,128.69,126.93,126.73,125.97,123.58,92.36,77.29,77.08,76.86, 63.17,51.64,45.10,27.73,27.45,25.10,24.12,21.62,16.95ppm.
FIG. 4c is an X-ray single crystal diffractogram of Compound 3 obtained in example 3 of the present invention.
Example 4
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, 2.5mL of dichloroethane is added into a round bottom flask containing 0.5mmol of cyclic unsaturated imine D and 3mol% of palladium chloride, after the dichloroethane is uniformly stirred, 0.1mmol of 5-hexyne-1-ol and 10mol% of trifluoroacetic acid are sequentially added, the reaction is carried out at room temperature, a TLC point plate is tracked, after the reaction is finished (about 10 hours), 2mL of saturated sodium bicarbonate solution is added to quench the reaction, dichloromethane is extracted for three times, organic phases are combined, washed by water, dried by anhydrous sodium sulfate, a solvent is concentrated, and the mixture is separated and purified by column chromatography (petroleum ether: a mixed solution of ethyl acetate with the volume ratio of 5.
Referring to fig. 5a and 5b, the nmr data for compound 4 obtained in this example are: 1 H NMR(600MHz,CDCl 3 ) δ7.86(d,J＝8.3Hz,2H),7.55(d,J＝7.6Hz,1H),7.41(d,J＝8.4Hz,2H),7.20(dd,J＝16.1,7.8 Hz,4H),7.14(d,J＝7.7Hz,2H),7.10(t,J＝7.0Hz,1H),7.03(d,J＝7.3Hz,1H),3.84(d,J＝11.0Hz,1H),3.62(t,J＝10.6Hz,1H),2.85-2.54(m,3H),2.48(d,J＝18.2Hz,1H),2.36(s,3H), 2.04-1.72(m,2H),1.59-1.34(m,6H),1.26(s,3H),1.21-0.96(m,2H)ppm. 13 C NMR(151MHz, CDCl 3 )δ＝143.05,141.79,140.32,135.25,135.07,133.62,132.86,131.84,130.75,129.04,128.74, 126.99,126.90,125.94,123.51,120.82,92.36,77.25,77.04,76.82,63.00,51.07,45.08,27.66, 27.38,25.08,24.10,21.62,16.90ppm.
example 5
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was carried out by the following steps:
adding 2.5mL dioxane into a round bottom flask containing 0.5mmol cyclic unsaturated imine E and 5mol% palladium chloride under the protection of nitrogen, stirring uniformly, then sequentially adding 0.1mmol 5-hexyne-1-ol and 20mol% trifluoroacetic acid, reacting at room temperature, tracking by a TLC point plate, adding 2mL saturated sodium bicarbonate solution after the reaction is finished (about 10 h), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (petroleum ether: a mixed solution of ethyl acetate with the volume ratio of 5.
Referring to fig. 6a and 6b, the nmr data for compound 5 obtained in this example are: 1 H NMR(600MHz,CDCl3) δ7.97(d,J＝8.3Hz,2H),7.71(d,J＝7.7Hz,1H),7.44(d,J＝9.0Hz,2H),7.38-7.23(m,5H), 7.20(t,J＝7.4Hz,1H),7.13(d,J＝7.3Hz,1H),3.96(dd,J＝11.9,4.9Hz,1H),3.86-3.57(m,1H), 2.81(td,J＝15.7,6.3Hz,1H),2.70(d,J＝10.8Hz,1H),2.58(dd,J＝13.1,5.0Hz,1H),2.45(s, 4H),2.20(s,1H),2.17-1.85(m,2H),1.49(t,J＝12.5Hz,4H),1.38(s,3H),1.31-1.08(m,1H) ppm. 13 C NMR(151MHz,CDCl3)δ＝144.99,143.18,139.99,135.28,134.91,133.21,132.97, 130.44,130.18,129.21,128.85,126.90,126.05,123.85,77.25,77.04,76.83,63.11,51.31,44.68, 27.66,27.45,24.96,24.18,21.64,16.92ppm.
example 6
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, adding 2.5mL of dioxane into a round bottom flask containing 0.5mmol of cyclic unsaturated imine E and 5mol% of palladium chloride, stirring uniformly, sequentially adding 0.1mmol of 5-hexyne-1-ol and 20mol% of trifluoroacetic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (petroleum ether: a mixed solution of ethyl acetate with the volume ratio of 5.
Referring to fig. 7a and 7b, the nmr data for compound 6 obtained in this example are: 1 H NMR(600MHz,CDCl3) δ7.87(d,J＝8.2Hz,2H),7.54(t,J＝7.2Hz,2H),7.49(d,J＝8.7Hz,1H),7.30(t,J＝7.1Hz,1H), 7.26-7.15(m,4H),7.06(ddd,J＝24.8,15.6,7.3Hz,3H),3.84(s,1H),3.56(d,J＝56.2Hz,2H), 2.86(s,1H),2.65(s,1H),2.45(s,1H),2.37(s,3H),1.99(s,1H),1.75(d,J＝33.2Hz,1H),1.46(d, J＝38.9Hz,6H),1.30(s,4H),0.99(d,J＝233.0Hz,2H).13C NMR(151MHz,CDCl3)δ＝142.96, 142.34,140.50,135.18,135.10,134.57,132.51,132.31,130.29,128.99,128.66,128.58,128.45, 126.88,126.06,123.31,92.64,77.25,77.04,76.82,63.28,49.28,46.06,27.53,27.27,25.17,23.97, 21.61,16.93.
example 7
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was carried out by the following steps:
under the protection of nitrogen, adding 2.5mL of dioxane into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine G and 5mol% of triphenylphosphine aurous chloride, stirring uniformly, sequentially adding 0.1mmol of 5-hexyne-1-ol and 20mol% of trifluoroacetic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (petroleum ether: a mixed solution of ethyl acetate with the volume ratio of 5.
Referring to fig. 8a and 8b, the nmr data for compound 7 obtained in this example are: 1H NMR (600mhz, cdcl3) δ 7.86 (d, J =8.2hz, 2h), 7.52 (d, J =8.4hz, 2h), 7.33 (s, 1H), 7.30-7.16 (m, 5H), 7.10 (t, J =7.3hz, 1h), 7.03 (d, J =7.3hz, 1h), 3.83 (d, J =11.6hz, 1h), 3.62 (t, J =12.0hz, 1h), 3.46 (d, J = 10.7hz, 1h), 2.86 (t, J =10.0hz, 1h), 2.65 (t, J =12.9hz, 1h), 2.47 (d, J =14.8hz, 1h), 2.37 (s, 3H), 1.98 (t, J =18.6hz, 1h), 1.72 (d, J =16.7hz, 1h), 1.61-1.36 (m, 5H), 1.28 (s, 3H), 1.27-1.10 (m, 1H). 13C NMR (151mhz, cdcl3) δ =143.14,140.33,139.42,135.52,135.02,133.84,133.14, 133.00,131.07,128.84,128.73,128.42,127.00,125.96,123.29,92.59,77.25,77.04,76.83,63.18, 45.98,27.59,27.14,25.08,24.12,21.57,16.98.
Example 8
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was carried out by the following steps:
under the protection of nitrogen, adding 2.5mL of tetrahydrofuran into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine H and 5mol% of bis (trifluoromethanesulfonyl) imide silver, stirring uniformly, then sequentially adding 0.1mmol of 5-hexyne-1-ol and 20mol% of trifluoroacetic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 5.
Referring to fig. 9a and 9b, the nmr data for compound 8 obtained in this example are: 1 H NMR(600MHz,CDCl 3 ) δ7.98(d,J＝8.3Hz,2H),7.71(d,J＝7.6Hz,1H),7.43-7.25(m,3H),7.22-6.94(m,5H),3.95(dd, J＝11.8,5.0Hz,1H),3.73(td,J＝12.1,3.2Hz,1H),2.81(t,J＝19.0Hz,1H),2.66(d,J＝10.9Hz, 1H),2.53(dd,J＝23.0,10.1Hz,2H),2.44(s,3H),2.30(d,J＝9.9Hz,6H),1.99(s,2H),1.64(s, 2H),1.57-1.27(m,6H),1.16(t,J＝14.8Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ＝142.93,140.30, 139.94,135.57,135.12,135.05,134.29,132.45,129.26,128.65,126.86,126.60,125.96,123.80, 92.40,77.26,77.05,76.83,63.21,51.28,44.85,27.70,27.36,25.07,24.16,21.62,19.84,19.50, 16.80.
example 9
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, adding 2.5mL of tetrahydrofuran into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine I and 5mol% of bis (trifluoromethanesulfonyl) imide silver, stirring uniformly, then sequentially adding 0.1mmol of 5-hexyne-1-ol and 20mol% of trifluoroacetic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 5.
Referring to fig. 10a and 10b, the nmr data for compound 9 obtained in this example is: 1 H NMR(600MHz, CDCl 3 )δ7.47(d,J＝7.7Hz,1H),7.38(s,4H),7.29(dd,J＝16.5,9.9Hz,2H),7.18(t,J＝7.3Hz, 1H),7.11(d,J＝7.2Hz,1H),4.10(d,J＝15.1Hz,1H),3.88(t,J＝12.0Hz,1H),3.45(s,3H),3.13 (t,J＝11.4Hz,1H),2.75(t,J＝12.9Hz,2H),2.54(d,J＝17.2Hz,1H),2.18-1.82(m,2H), 1.78-1.52(m,3H),1.46(s,3H),1.29(d,J＝12.2Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ＝142.63, 135.35,134.92,131.33,129.08,128.79,127.15,126.96,126.87,126.11,122.55,92.25,77.33, 77.11,76.90,63.73,51.70,45.80,44.98,27.74,27.17,25.25,24.17,17.07.
FIG. 10c is an X-ray single crystal diffractogram of Compound 9 obtained in example 9 of the present invention.
Example 10
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
adding 2.5mL of tetrahydrofuran into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine C, 5mol% of triphenylphosphine aurous chloride and 5mol% of silver trifluoromethanesulfonate under the protection of nitrogen, stirring uniformly, then sequentially adding 0.1mmol of 4-pentyne-1-ol and 20mol% of benzoic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatographic separation and purification (petroleum ether: ethyl acetate volume ratio is 5.
Referring to fig. 11a and 11b, the nmr data for compound 10 obtained in this example are: 1H NMR (600 MHz, CDCl) 3 )δ7.86(d,J＝8.2Hz,2H),7.57(d,J＝7.6Hz,1H),7.36-7.15(m,6H),7.13-6.99(m,2H), 6.88(dd,J＝44.8,7.3Hz,2H),3.70(t,J＝8.2Hz,1H),3.44-3.16(m,2H),2.77(t,J＝19.2Hz,1H), 2.50(dd,J＝45.6,15.6Hz,2H),2.39(s,3H),2.06(dd,J＝53.5,33.4Hz,1H),1.76(s,1H),1.65(s, 1H),1.58(s,3H),1.52(s,1H),1.31(d,J＝7.2Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ＝142.63, 141.81,138.81,134.45,134.21,133.74,131.15,128.94,128.77,128.58,127.68,127.37,127.29, 127.06,126.78,126.30,123.41,100.49,77.27,77.06,76.85,68.69,59.10,47.11,29.98,29.42, 28.01,26.42,21.56.
FIG. 11c is an X-ray single crystal diffractogram of Compound 10 obtained in example 10 of the present invention.
Example 11
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, adding 2.5mL of tetrahydrofuran into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine J, 5mol% of triphenylphosphine aurous chloride and 5mol% of bis (trifluoromethanesulfonyl) imide silver, stirring uniformly, then sequentially adding 0.1mmol of 4-pentyne-1-ol and 20mol% of binaphthol phosphate, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 5 is used as an eluent), thus obtaining the compound 11 with a fused ring N, O-acetal skeleton
Referring to fig. 12a and 12b, the nmr data for compound 11 obtained in this example are: 1 H NMR(600MHz, CDCl 3 )δ7.93(d,J＝6.9Hz,2H),7.89(dd,J＝45.2,7.5Hz,4H),7.86(d,J＝8.2Hz,2H),7.56(d, J＝7.7Hz,1H),7.56(d,J＝7.7Hz,1H),7.26(d,J＝8.1Hz,2H),7.23(dd,J＝38.6,10.0Hz,4H), 7.20(d,J＝12.0Hz,2H),7.08(t,J＝7.3Hz,1H),7.14-6.87(m,4H),7.02(s,1H),7.02-6.90(m, 2H),4.31(q,J＝7.1Hz,2H),4.31(q,J＝7.1Hz,2H),3.75(dd,J＝47.5,36.6Hz,1H),3.55–3.19 (m,2H),2.78(t,J＝19.2Hz,1H),2.52(dd,J＝30.7,7.6Hz,2H),2.40(s,3H),2.07(t,J＝17.3Hz, 1H),1.77(d,J＝18.1Hz,1H),1.59(d,J＝24.2Hz,5H),1.40-0.99(m,4H)； 13 C NMR(151MHz, CDCl 3 )δ＝149.35,143.26,138.37,135.04,133.27,130.14,129.28,128.96,128.18,127.12,127.00, 126.05,123.29,98.96,77.25,77.04,76.82,69.55,61.11,46.01,40.62,37.37,27.67,27.32,24.69, 21.58,14.38.
example 12
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, adding 2.5mL of tetrahydrofuran into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine K and 2mol% of silver trifluoromethanesulfonate, stirring uniformly, then sequentially adding 0.1mmol of 5-hexyne-1-ol and 10mol% of dinaphthol phosphate, reacting at 60 ℃, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 4 hours), quenching the reaction, extracting for three times by dichloromethane, combining organic phases, washing with water, drying by anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 5 is used as an eluent), thus obtaining a compound 11 with a fused N, O-acetal skeleton
Referring to fig. 13a and 13b, the nmr data for compound 12 obtained in this example are: 1 H NMR(600MHz, CDCl 3 ):δ＝7.85(d,J＝8.3Hz,2H),7.55(d,J＝7.6Hz,1H),7.37-7.14(m,7H),7.14-6.94(m,2H), 3.83(d,J＝13.7Hz,1H),3.69-3.42(m,1H),2.83-2.57(m,3H),2.47(d,J＝13.2Hz,1H),2.32(d, J＝43.4Hz,3H),1.88(dd,J＝51.2,23.4Hz,2H),1.69-1.33(m,4H),1.25(s,3H),1.20-0.93(m, 1H)ppm； 13 C NMR(151MHz,CDCl 3 ):δ＝143.06,141.26,140.30,135.23,135.02,133.70,132.67, 130.36,129.04,128.89,128.75,126.99,126.78,125.97,123.48,92.54,77.28,77.06,76.85,62.99, 50.97,44.98,27.67,27.45,25.09,24.10,21.57,16.91ppm.
example 13
In this example, the preparation method of the compound having a fused ring N, O-acetal skeleton was performed by the following steps:
under the protection of nitrogen, adding 2.5mL of tetrahydrofuran into a round-bottom flask containing 0.5mmol of cyclic unsaturated imine I and 5mol% of bis (trifluoromethanesulfonyl) imide silver, stirring uniformly, then sequentially adding 0.1mmol of 5-hexyne-1-ol and 20mol% of trifluoroacetic acid, reacting at room temperature, tracking a TLC point plate, adding 2mL of saturated sodium bicarbonate solution after the reaction is finished (about 10 hours), quenching the reaction, extracting with dichloromethane for three times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating a solvent, and performing column chromatography separation and purification (a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 5.
Referring to fig. 14a and 14b, the nmr data for compound 13 obtained in this example are: 1 H NMR(600MHz, CDCl 3 ):δ＝8.02(d,J＝7.8Hz,2H),7.89(d,J＝7.7Hz,1H),7.47-7.08(m,11H),3.85(d,J＝15.1 Hz,1H),3.63(d,J＝12.0Hz,1H),3.22(d,J＝22.6Hz,1H),3.06(dd,J＝57.6,16.8Hz,2H),2.46 (s,3H),2.35(s,1H),1.79-1.49(m,2H),1.39(s,4H),1.22(dd,J＝45.9,36.5Hz,2H)ppm； 13 C NMR(151MHz,CDCl 3 ):δ＝143.02,142.75,141.68,141.04,140.26,137.21,128.92,128.81, 128.61,128.58,127.12,126.06,124.90,123.28,122.30,93.32,77.30,77.09,76.88,63.20,48.44, 44.08,37.35,24.84,23.99,21.65,17.33ppm.
in addition, the inventors of the present invention have also made experiments with other raw materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.
It should be understood that the technical solutions of the present invention are not limited to the above specific embodiments, and any technical modifications made according to the technical solutions of the present invention fall within the protection scope of the present invention without departing from the spirit of the present invention and the scope of the claims.
Claims (10)
1. A compound having a fused-ring N, O-acetal skeleton, characterized in that the compound having a fused-ring N, O-acetal skeleton has a structure represented by the following formula (I):
wherein R is 1 Selected from phenyl or substituted phenyl, R 2 Selected from hydrogen or methoxy, R 3 Selected from p-toluenesulfonyl or methanesulfonyl, X is selected from CH 2 、CH 2 CH 2 And O, n is selected from 1 or 2.
2. The compound having a fused ring N, O-acetal skeleton according to claim 1, wherein: the R is 1 When the substituted phenyl is substituted, the number of the substituent groups in the substituted phenyl is one or more; preferably, the substituent is independently selected from any one or a combination of more than two of alkyl, alkoxy, hydroxyl, halogen, nitro and ester; preferably, the position of the substituent in the substituted phenyl group is any one of ortho-position, meta-position or para-position.
3. A process for producing a compound having a fused ring N, O-acetal skeleton according to claim 1 or 2, which comprises: in protective atmosphere, reacting a uniformly mixed reaction system containing alkynol, cyclic unsaturated imine, metal catalyst, organic acid and organic solvent at 5-60 ℃ for 4-24 h to obtain the compound with the fused ring N, O-acetal skeleton.
4. The production method according to claim 3, characterized in that: the molar ratio of the alkynol, the cyclic unsaturated imine, the metal catalyst and the organic acid is 1-2: 1: 0.01-0.05: 0.05-0.20.
5. The production method according to claim 3, characterized in that: the alkynol comprises 4-pentyne-1-ol and/or 5-hexyne-1-ol.
6. The production method according to claim 3, characterized in that: the cyclic unsaturated imine has a structure shown in a formula (II):
wherein R is 1 Selected from phenyl or substituted phenyl, R 2 Selected from hydrogen or methoxy, R 3 Selected from p-toluenesulfonyl or methanesulfonyl, X is selected from CH 2 、CH 2 CH 2 And O.
7. The production method according to claim 3, characterized in that: the metal catalyst comprises any one or the combination of more than two of palladium chloride, silver trifluoromethanesulfonate, bis-trifluoromethanesulfonimide silver and triphenylphosphine gold chloride.
8. The production method according to claim 3, characterized in that: the organic acid comprises one or the combination of more than two of trifluoroacetic acid, benzoic acid and binaphthol phosphate;
and/or the organic solvent comprises any one or the combination of more than two of 1, 2-dichloroethane, dichloromethane, acetonitrile, toluene, tetrahydrofuran and dioxane;
and/or the protective atmosphere comprises an argon atmosphere and/or a nitrogen atmosphere.
9. The method of claim 3, further comprising: after the reaction is finished, quenching, extracting and purifying the obtained product.
10. Use of the compound having a fused cyclic N, O-acetal skeleton according to claim 1 or 2 for the preparation of an HIV inhibitor, a drug for treating osteoporosis, or for the development of an anti-alzheimer's disease drug.
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| JORGE I. JIMÉNEZ, 等: "‘Upenamide: An Unprecedented Macrocyclic Alkaloid from the Indonesian Sponge Echinochalina sp.", J. ORG. CHEM., vol. 65, no. 25, pages 1 * |
| MAI SASAKI,: "Perinadine A, a Novel Tetracyclic Alkaloid from Marine-Derived Fungus Penicillium citrinum", ORG. LETT., vol. 7, no. 19 * |
| MALAMIDOU-XENIKAKI, ELIZABETH, 等: "Cycloaddition Reactions of Indanedioneketene with Electron-Rich Dienophiles: An Experimental and a Theoretical Study", JOURNAL OF ORGANIC CHEMISTRY, vol. 81, no. 06, pages 2383 - 2398 * |
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