WO2021217685A1 - 一种含六元环的核苷类化合物及其制备方法 - Google Patents
一种含六元环的核苷类化合物及其制备方法 Download PDFInfo
- Publication number
- WO2021217685A1 WO2021217685A1 PCT/CN2020/088682 CN2020088682W WO2021217685A1 WO 2021217685 A1 WO2021217685 A1 WO 2021217685A1 CN 2020088682 W CN2020088682 W CN 2020088682W WO 2021217685 A1 WO2021217685 A1 WO 2021217685A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- acid
- nucleoside
- preparing
- structural formula
- Prior art date
Links
- -1 nucleoside compound Chemical class 0.000 title claims abstract description 70
- 239000002777 nucleoside Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 229940125782 compound 2 Drugs 0.000 claims description 30
- 229940126214 compound 3 Drugs 0.000 claims description 30
- 239000012074 organic phase Substances 0.000 claims description 28
- 239000000706 filtrate Substances 0.000 claims description 27
- 238000004440 column chromatography Methods 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- 229940125898 compound 5 Drugs 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 239000007800 oxidant agent Substances 0.000 claims description 18
- 239000012141 concentrate Substances 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 14
- 150000002373 hemiacetals Chemical class 0.000 claims description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims description 13
- 229960000583 acetic acid Drugs 0.000 claims description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000007848 Bronsted acid Substances 0.000 claims description 11
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 11
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 11
- ZEBGLCLVPCOXIV-UHFFFAOYSA-N 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound NC1=NC=NN2C(I)=CC=C12 ZEBGLCLVPCOXIV-UHFFFAOYSA-N 0.000 claims description 10
- 239000002841 Lewis acid Substances 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 10
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 10
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 10
- 150000007517 lewis acids Chemical class 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 9
- 150000008045 alkali metal halides Chemical class 0.000 claims description 9
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000006264 debenzylation reaction Methods 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- 239000010703 silicon Substances 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 6
- WJTPULFEHRBUCP-UHFFFAOYSA-N trimethylsilyl perchlorate Chemical compound C[Si](C)(C)OCl(=O)(=O)=O WJTPULFEHRBUCP-UHFFFAOYSA-N 0.000 claims description 6
- 229910015900 BF3 Inorganic materials 0.000 claims description 5
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 5
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 5
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 5
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 5
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 5
- 238000012805 post-processing Methods 0.000 claims description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical group C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 238000007333 cyanation reaction Methods 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 239000005046 Chlorosilane Substances 0.000 claims 2
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- 239000000126 substance Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 241000711573 Coronaviridae Species 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 150000003833 nucleoside derivatives Chemical class 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical group [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- BRDWIEOJOWJCLU-LTGWCKQJSA-N GS-441524 Chemical compound C=1C=C2C(N)=NC=NN2C=1[C@]1(C#N)O[C@H](CO)[C@@H](O)[C@H]1O BRDWIEOJOWJCLU-LTGWCKQJSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 150000004756 silanes Chemical class 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AMFDITJFBUXZQN-KUBHLMPHSA-N (2s,3s,4r,5r)-2-(4-amino-5h-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol Chemical compound C=1NC=2C(N)=NC=NC=2C=1[C@@H]1N[C@H](CO)[C@@H](O)[C@H]1O AMFDITJFBUXZQN-KUBHLMPHSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- OFFWOVJBSQMVPI-RMLGOCCBSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O.N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 OFFWOVJBSQMVPI-RMLGOCCBSA-N 0.000 description 1
- FXZASCOMEUCXNB-UBFVSLLYSA-N O=C([C@@H]([C@@H]1OCc2ccccc2)OCc2ccccc2)OC[C@H]1OCc1ccccc1 Chemical compound O=C([C@@H]([C@@H]1OCc2ccccc2)OCc2ccccc2)OC[C@H]1OCc1ccccc1 FXZASCOMEUCXNB-UBFVSLLYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- WXJFKKQWPMNTIM-VWLOTQADSA-N [(2s)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid Chemical compound CCCCCCCCCCCCCCCCOCCCOP(O)(=O)CO[C@H](CO)CN1C=CC(N)=NC1=O WXJFKKQWPMNTIM-VWLOTQADSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229950005107 brincidofovir Drugs 0.000 description 1
- VQPFDLRNOCQMSN-UHFFFAOYSA-N bromosilane Chemical compound Br[SiH3] VQPFDLRNOCQMSN-UHFFFAOYSA-N 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 description 1
- 229950008454 favipiravir Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229950002031 galidesivir Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940120922 lopinavir and ritonavir Drugs 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 1
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LMYWWPCAXXPJFF-UHFFFAOYSA-P pyridinium dichromate Chemical group C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O LMYWWPCAXXPJFF-UHFFFAOYSA-P 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 1
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 description 1
- OSXXGBUMRXAAFP-UHFFFAOYSA-N tetramethylazanium;cyanide Chemical compound N#[C-].C[N+](C)(C)C OSXXGBUMRXAAFP-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000008957 viral persistence Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
-
- 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
Definitions
- the invention belongs to the field of chemical synthesis, and specifically relates to a nucleoside compound containing a six-membered ring and a preparation method thereof.
- Coronavirus was the first virus that was able to infect the respiratory and digestive tracts of animals and humans. Normally, it caused only mild symptoms of infection in healthy people with normal immunity. However, the SARS epidemic at the beginning of this century caused 8096 infections in 27 countries around the world and claimed 774 lives. Ten years later, the Middle East respiratory syndrome caused by MERS brought pain to 1728 patients and took 624 lives. Coronaviruses can be divided into four categories according to their genome and structure. Among them, ⁇ and ⁇ only infect skin such as animals, while ⁇ and ⁇ mainly infect songbirds. Both SARS and MERS belong to ⁇ -type coronaviruses. At the beginning of 2020, a certain number of pneumonia caused by the coronavirus occurred in Wuhan, China.
- nucleoside anti-tumor and anti-viral drugs have been extremely active.
- many nucleoside anti-tumor drugs have entered the market.
- many patents and documents have been reported (see WO 2015/069939 A1; WO 2017/184668 A1; ES 2 465 265 T3; CN 102015714 A).
- nucleoside drugs and analogues are basically devoted to the research of the five-membered sugar ring, and most of these nucleoside drugs are in neutral water and most organic
- solvents only dissolving in dimethyl sulfoxide and N,N-dimethylformamide
- the chair conformation of the six-membered ring structure may exhibit different pharmacological activities in vivo. Therefore, it is necessary to develop a nucleoside drug with better solubility and higher activity in vivo, and containing six-membered ring.
- the first aspect of the present invention provides a nucleoside compound containing a six-membered ring, and the structural formula of the nucleoside compound 7 is:
- R 1 is selected from In one of them, R 2 is a hydroxyl group or an alkynyl group.
- the structural formula of the six-membered ring-containing nucleoside compound 7 is
- the second aspect of the present invention provides a method for preparing the nucleoside compound, which includes the following steps: dissolving compound 1 in an organic solvent, adding BnX, alkali metal halide, and alkali metal salt to react, and post-processing to obtain Compound 2, the compound 1 is D-ribose, and X is Br or Cl; the nucleoside compound 7 is obtained by oxidation, substitution, cyanation, and debenzylation of compound 2;
- the method for preparing compound 3 includes the following steps: preparing compound 2 into a hemiacetal intermediate, and then reacting with an oxidizing agent for 3-12 hours to obtain compound 3;
- the method for preparing compound 3 includes the following steps: dissolving compound 2 in glacial acetic acid and stirring for 5-15 minutes, adding sulfuric acid and/or hydrochloric acid, and then heating the system to 70-90°C React for 4-6 hours.
- the oxidant is selected from at least one of pyridinium chlorochromate, pyridinium dichromate, Dess-Martin oxidant, and DMSO/(COCl) 2.
- the step S1 includes: dissolving 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine in dry tetrahydrofuran, and adding halosilane Or silicon ester, stir for 5-15 minutes, add phenyl magnesium halide, stir for 15-25 minutes, add alkyl magnesium halide, continue the reaction for 15-25 minutes, add the tetrahydrofuran solution of compound 3; after 5.5-6.5 hours of reaction, Quench, extract, combine the organic phases, wash and dry; then filter, concentrate the filtrate, and column chromatography to obtain compound 4; preferably, the halogenated silane is selected from trimethylchlorosilane, trimethylsilyl iodide, and trimethylsilyl At least one of bromosilane and triethylchlorosilane; the silicon ester is selected from at least one of trimethylsilyl trifluoromethanesulfonate and trimethylsilyl perch
- the Bronsted acid is selected from camphorsulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid, rich At least one of maleic acid.
- the Lewis acid is selected from trimethylchlorosilane, trimethylsilyl iodide, trimethylbromosilane, triethylchlorosilane, trimethyltrifluoromethanesulfonate At least one of silicone ester, trimethylsilyl perchlorate, and boron trifluoride ether.
- the preparation method of the six-membered ring nucleoside compound described in this application has a simple technical route and a simple route.
- the reagents used are all commonly used reagents, which are suitable for large-scale preparation and can be easily realized in the laboratory. -100g grade preparation.
- the present invention provides a nucleoside compound containing a six-membered ring.
- the structural formula of the nucleoside compound 7 is:
- R 1 is selected from One of; R 2 is hydroxy or alkynyl.
- the R 1 group plays a decisive role in the antiviral spectrum of nucleosides and nucleoside derivatives.
- the biological genetic material changes when the obtained nucleoside compound is inserted into the DNA or RNA chain. This interferes with the synthesis of the virus; and the substituent on the R 1 group cannot be too large, and if the substituent is too large, it will be inactive.
- the structural formula of the six-membered ring-containing nucleoside compound 7 is
- the six-membered ring-containing nucleoside compound 7 described in this application is similar in chemical structure to natural nucleosides, and can be faked in the body, thereby interfering with or directly acting on the biosynthesis of proteins and nucleic acids, thereby interfering with viruses, especially It is the synthesis of coronavirus; and the nucleoside compound 7 contains a six-membered ring, which has better solubility and higher activity in the body.
- the preparation method of the nucleoside compound includes the following steps: dissolving compound 1 in an organic solvent, adding BnX, alkali metal halide, alkali metal salt for reaction, and post-processing to obtain compound 2, wherein compound 1 is D-ribose, X is Br or Cl; nucleoside compound 7 is obtained by oxidation, substitution, cyanation, and debenzylation of compound 2; the structural formula of compound 2 is:
- the preparation method of the six-membered ring-containing nucleoside compound 7 includes the following steps:
- the method for preparing compound 3 includes the following steps: preparing compound 2 into a hemiacetal intermediate, and then reacting with an oxidizing agent for 3-12 hours to obtain compound 3;
- the oxidizing agent can be added in any suitable amount; preferably, the amount of the oxidizing agent is 1-2 times the amount of the compound 2 substance.
- the oxidant is selected from at least one of pyridinium chlorochromate, pyridinium dichromate, Dess-Martin oxidant, and DMSO/(COCl) 2.
- the pyridinium chlorochromate is referred to as PCC for short, and the CAS number is 26299-14-9, which can oxidize the hydroxyl group to an aldehyde group under neutral conditions at room temperature.
- the pyridine dichromate is abbreviated as PDC, and the CAS number is 20039-37-6.
- the Dess-Martin oxidant is called DMP for short, and its CAS number is 87413-09-0, which can oxidize primary alcohols into aldehydes and secondary alcohols into ketones.
- the preparation method of compound 3 includes the following steps: dissolving compound 2 in glacial acetic acid and stirring for 5-15 minutes, adding sulfuric acid and/or hydrochloric acid, and then heating the system to 70-90°C for 4-6 hours .
- the preparation method of compound 3 includes the following steps: dissolving compound 2 in glacial acetic acid and stirring for 5-15 minutes, adding sulfuric acid and/or hydrochloric acid, and then heating the system to 70-90°C for 4-6 hours .
- the preparation method of compound 2 includes the following steps: dissolving compound 1 in an organic solvent, adding BnX (X is Br or Cl), alkali metal halide, alkali metal salt for reaction, and post-treatment , Compound 2 was obtained.
- the compound 1 is D-ribose, and the structural formula is:
- BnX can be added in any suitable amount; preferably, the amount of the BnX substance is 4-5 times the amount of the compound 1 substance.
- the alkali metal halide can be added in any suitable amount; preferably, the amount of the alkali metal halide substance is 0.02-0.06 of the amount of the compound 1 substance.
- the alkali metal salt can be added in any suitable amount; preferably, the amount of the alkali metal salt is 3-6 times the amount of the compound 1 substance.
- the organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, toluene, and N,N-dimethylformamide.
- the BnX refers to PhCH 2 Br
- the BnX refers to PhCH 2 Cl
- the alkali metal halide is selected from at least one of sodium iodide, potassium iodide, sodium bromide, potassium bromide, sodium chloride, and potassium chloride.
- the alkali metal salt is selected from at least one of potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, and n-butyl lithium.
- the preparation method of the compound 2 includes the following steps: dissolving compound 1 in an organic solvent, adding BnX (X is Br or Cl) and an alkali metal halide; then adding an alkali metal salt, and the reaction temperature is controlled at 30 After reacting at ⁇ 35°C for 5-12 hours, quenching with water, extraction, combining the organic phases, washing, and drying the organic phases; then filtering, concentrating the filtrate, and column chromatography to obtain compound 2.
- the preparation method of the compound 2 includes the following steps: dissolving compound 1 in an organic solvent, adding BnX (X is Br or Cl) and an alkali metal halide; then adding the alkali metal salt in batches, and the reaction temperature Control at 30 ⁇ 35°C. After reacting for 5-12 hours, it was quenched by adding water, extracted three times with ethyl acetate, the organic phases were combined and washed twice with water, and washed once with saturated sodium chloride, and the organic phase was dried with anhydrous magnesium sulfate. Then filter, concentrate the filtrate, and column chromatography to obtain compound 2.
- the alkali metal salt can be added in any suitable batch, for example, the alkali metal salt is added in 2 batches; or the alkali metal salt is added in 3 batches; or the alkali metal salt is added in 4 batches.
- the step S1 includes: dissolving 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine in dry tetrahydrofuran, and adding halosilane Or silicon ester, stir for 5-15 minutes, add phenyl magnesium halide, stir for 15-25 minutes, add alkyl magnesium halide, continue the reaction for 15-25 minutes, add the tetrahydrofuran solution of compound 3; after 5.5-6.5 hours of reaction, Quench, extract, combine the organic phases, wash and dry; then filter, concentrate the filtrate, and column chromatography to obtain compound 4.
- 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine can be added in any suitable amount; preferably, the 7-iodopyrrolo[2,1-F
- the amount of the substance of ][1,2,4]triazine-4-amine is 0.8-1.1 times the amount of the substance of compound 3.
- the CAS number of 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine is 1770840-43-1.
- the halogenated silane is selected from at least one of trimethylchlorosilane, trimethyliodosilane, trimethylbromosilane, and triethylchlorosilane;
- the silicon ester is selected from trimethyltrifluoromethanesulfonate At least one of silicone ester and trimethylsilyl perchlorate.
- the phenyl magnesium halide is phenyl magnesium chloride.
- the alkyl magnesium halide is selected from at least one of isopropyl magnesium chloride, tert-butyl magnesium chloride, methyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium chloride, propyl magnesium bromide, and propyl magnesium chloride.
- the step S1 includes: dissolving 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine in dry tetrahydrofuran, adding halosilane or silicon ester, After stirring for 5-15 minutes, add phenyl magnesium halide. After stirring for 15-25 minutes, add alkyl magnesium halide.
- the Bronsted acid is a sulfonic acid compound and/or a carboxylic acid compound; preferably, the Bronsted acid is selected from camphorsulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, At least one of methanesulfonic acid, benzenesulfonic acid, and fumaric acid.
- the step S2 includes: dissolving compound 4 in methanol, adding Bronsted acid, stirring and reacting overnight, removing methanol, adding saturated sodium bicarbonate solution, extracting with ethyl acetate, combining the organic phases, washing, and drying ; Then filter, concentrate the filtrate, and column chromatography to obtain compound 5.
- the method for removing methanol is not particularly limited, for example, distillation under reduced pressure.
- the Bronsted acid can be added in any suitable amount; preferably, the amount of the Bronsted acid is 2-3 times the amount of the compound 4 substance.
- the step S2 includes: dissolving compound 4 in methanol, adding Bronsted acid, stirring and reacting overnight, removing the methanol, adding saturated sodium bicarbonate solution, extracting with ethyl acetate, and combining the organic phases with Wash with saturated sodium chloride and dry with anhydrous magnesium sulfate; then filter, concentrate the filtrate, and column chromatography to obtain compound 5.
- the Lewis acid is selected from trimethylchlorosilane, trimethylsilyl iodide, trimethylbromosilane, triethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl perchlorate, At least one of boron trifluoride ether.
- the cyanation reagent is selected from at least one of trimethylsilyl cyanide, tetrabutylammonium cyanide, tetramethylammonium cyanide, tetraethylammonium cyanide, sodium cyanide, and potassium cyanide.
- the Lewis acid can be added in any suitable amount; preferably, the amount of the Lewis acid substance is 2-4 times the amount of the compound 5 substance.
- the cyanating reagent can be added in any suitable amount; preferably, the amount of the cyaniding reagent is 4-5 times the amount of the compound 5 substance.
- the step S3 includes: dissolving compound 5 in dry dichloromethane, placing it in an ice salt bath, adding Lewis acid, stirring for 25-35 minutes, adding a cyanide reagent, and raising to room temperature for reaction After a certain period of time, it was quenched, extracted, combined the organic phases, washed, and dried; then filtered, concentrated the filtrate, and column chromatography to obtain compound 6.
- the step S3 includes: dissolving compound 5 in dry dichloromethane, placing it in an ice salt bath, adding Lewis acid, stirring for 25-35 minutes, adding a cyanide reagent, and naturally raising to room temperature and reacting for a certain period of time. , Quenched with saturated sodium bicarbonate, extracted with dichloromethane, combined the organic phases, washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate; then filtered, concentrated the filtrate, and column chromatography to obtain compound 6.
- Dissolve compound 6 in dry dichloromethane reduce to -(70-80)°C, add debenzylation reagent, raise to -(35-45)°C and react for 7-9 hours; add C1-C2 organic alcohol, and then continue The mixed solution of alkali and the C1-C2 organic alcohol is added, then the system is raised to room temperature, the solvent is evaporated under reduced pressure to obtain a crude product, which is washed with an organic compound to obtain nucleoside compound 7.
- the debenzylation reagent is selected from at least one of boron trichloride, boron trifluoride, boron tribromide, iron trichloride, aluminum trichloride, titanium tetrachloride, and tin tetrachloride.
- the base is selected from at least one of sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, sodium carbonate, and potassium carbonate.
- the C1-C2 organic alcohol is methanol and/or ethanol.
- the organic compound is selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, and chloroform.
- the drying method is not particularly limited.
- anhydrous calcium chloride, anhydrous sodium carbonate, etc. can also be used.
- the preparation method of the nucleoside compound 7 of the present invention has a simple technical route and simple route.
- the reagents used are all commonly used reagents, which are suitable for large-scale preparation, and can conveniently realize preparation of 10-100 grams in the laboratory. .
- stirring reaction overnight refers to stirring for 10-14 hours.
- a preparation method of nucleoside compound 7 containing six-membered ring comprising the following steps:
- THF refers to tetrahydrofuran
- DCM refers to dichloromethane
- 2.0M in THF means that the concentration of phenyl magnesium chloride in THF is 2.0 mol/L.
- a method for preparing six-membered ring-containing nucleoside compound 7 the specific steps are the same as in Example 1, the difference lies in:
- a method for preparing six-membered ring-containing nucleoside compound 7 the specific steps are the same as in Example 1, the difference lies in:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种含六元环的核苷类化合物7及其制备方法，化合物7结构式为：(I), 其中R 1选自（II)、(III)、 (IV)、 (V)中的一种；其中R 2为羟基或炔基。
Description
本发明属于化学合成领域，具体涉及一种含六元环的核苷类化合物及其制备方法。
冠状病毒最早是一种能够感染动物和人类呼吸道和消化道的病毒，通常情况下，在正常免疫能力的健康人群体中仅引起轻微的感染症状。然而在本世纪初的SARS疫情中，给全球27个国家造成了8096例感染，且夺取了774人的生命。十年后，MERS引起的中东呼吸综合征又给1728例患者带了了痛苦，带走了624条生命。冠状病毒根据基因组与结构可以分为四类，其中α和β仅感染肤如动物，而γ和σ主要感染鸣禽类。SARS和MERS均属于β型冠状病毒。2020年年初，在中国武汉地区又集中爆发了一定数量的冠状病毒引起的肺炎。这些冠状病毒给人类的健康带了一定的痛苦，甚至直接威胁生命。截至目前，人们还有找到有效的抗冠状病毒的有效方法和预防冠状病毒的疫苗。因此，研发抗冠状病毒的新药具有重要意义。
在过去的30年人们针对SARS和MERS的临床治疗中，尚缺乏有效的疗法，患者主要通过利巴韦林与各种干扰素结合治疗，有时也会通过使用治疗HIV的药物lopinavir和ritonavir治疗，甚至使用光谱抗生素治疗。在各种抗病毒的药物研究中，近年来小分子核苷(TEAD)抗病毒药物(如favipiravir和brincidofovir)已进入临床试验中。特别，一种具有核苷类似物Galidesivir也已进入临床研发阶段。遗憾的是这些现有的治疗方法中缺少能够治疗急性感染或病毒持续性和后遗症方面的方案。因此，开发应用方便、高效的治疗冠状病毒病的药物具有重要意义。
近年来，关于核苷类抗肿瘤、抗病毒类药物研究极为活跃，截至目前，已有多个核苷抗肿瘤药物进入市场。在抗病毒方面，已有多篇专利与文献进行报道(见WO 2015/069939 A1；WO 2017/184668 A1；ES 2 465 265 T3；CN 102015714 A)。特别，近年来，以GS-5734(式I所示)和GS-441524(式II所示)为代表的一类具有抗埃博拉病毒(ebov)活性的单磷酸酰胺前药引起了药物化学家的青睐(Nature 2016,531,381–385；J.Med.Chem.2017,60,1648-1661；Veterinary Microbiology 2018，219，226-233)。不巧的是，在这些核苷类药物及类似物分子 研究中，基本上都致力于五元糖环的研究，而绝大多数这类核苷类药物具有在中性水及绝大多数有机溶剂中都难溶解(仅在二甲亚砜、N,N-二甲基甲酰胺中溶解)的缺点，这为进一步临床化学药物的纯化、注射剂型等研究带来了不小的麻烦。然而，目前尚未由任何文献报道含有六元糖环的核苷类药物或者研究报道。从药物化学研究角度来说，六元环结构具有的椅式构象可能在体内表现出不同的药理活性。因此，开发一种溶解性较好的、体内活性更高的、含有六元环的核苷类药物十分必要。
发明内容
为了解决上述技术问题，本发明的第一个方面提供了一种含六元环的核苷类化合物，所述核苷类化合物7结构式为：
其中R
1选自
中的一种，R
2为羟基或炔基。
作为一种优选的技术方案，所述含六元环的核苷类化合物7结构式为
本发明的第二方面提供了所述的核苷类化合物的制备方法，包括以下步骤：将化合物1溶于有机溶剂中，加入BnX、碱金属卤化物、碱金属盐进行反应，后处理，得到化合物2，所述化合物1为D-核糖，X为Br或Cl；将化合物2经过氧化、取代、氰化、脱苄基得到核苷类化合物7；
所述化合物2的结构式为：
作为一种优选的技术方案，包括以下步骤：
S1.将化合物3与7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺进行反应得到化合物4；
S2.将化合物4与布朗斯台德酸进行反应处理，得化合物5；
S3.在化合物5中加入路易斯酸和氰化试剂，后处理得到化合物6；
S4.将化合物6进行脱苄基，即得核苷类化合物7；
所述化合物3的结构式为：
所述化合物4的结构式为：
所述化合物5的结构式为：
所述化合物6的结构式为：
作为一种优选的技术方案，所述化合物3的制备方法，包括以下步骤：将化合物2制备成半缩醛中间体，然后与氧化剂反应3-12小时得到化合物3；
所述化合物2的结构式为：
作为一种优选的技术方案，所述化合物3的制备方法，包括以下步骤：将化合物2溶于冰醋酸中搅拌5-15分钟，加入硫酸和/或盐酸，之后将体系加热至70-90℃反应4-6小时。冷却后用0.5-1.5M的氢氧化钠调pH至3.8-4.2，减压浓缩除去冰醋酸，然后经过萃取、合并有机相后洗涤、干燥、然后过滤、滤液浓缩、柱层析得到半缩醛中间体；将所述半缩醛中间体溶于干燥的二氯甲烷，加入氧化剂反应3-12小时，淬灭，经过萃取，合并有机相后洗涤、干燥；然后过滤、滤液浓缩、柱层析得到化合物3。
作为一种优选的技术方案，所述氧化剂选自氯铬酸吡啶盐，重铬酸吡啶，戴斯-马丁氧化剂，DMSO/(COCl)
2中的至少一种。
作为一种优选的技术方案，所述步骤S1包括：将7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺溶于干燥四氢呋喃，加入卤代硅烷或硅酯，搅拌5-15分钟后加入苯基卤化镁、搅拌反应15-25分钟后加入烷基卤化镁，继续反应15-25分钟后加入化合物3的四氢呋喃溶液；反应5.5-6.5小时后，淬灭，萃取，合并有机相后洗涤，干燥；然后过滤、滤液浓缩、柱层析得到化合物4；优选的，所述卤代硅烷选自 三甲基氯硅烷、三甲基碘硅烷、三甲基溴硅烷、三乙基氯硅烷中的至少一种；所述硅酯选自三氟甲磺酸三甲基硅酯、高氯酸三甲基硅酯中的至少一种。
作为一种优选的技术方案，步骤S2中，所述布朗斯台德酸选自樟脑磺酸，对甲基苯磺酸，一水合对甲基苯磺酸，甲磺酸，苯磺酸，富马酸中的至少一种。
作为一种优选的技术方案，步骤S3中，所说路易斯酸选自三甲基氯硅烷、三甲基碘硅烷、三甲基溴硅烷、三乙基氯硅烷、三氟甲磺酸三甲基硅酯、高氯酸三甲基硅酯、三氟化硼乙醚中的至少一种。
有益效果：本申请所述含六元环核苷类化合物的制备方法，其技术路线操作简单，路线简洁，所用的试剂均为常用试剂，可适合大规模制备，在实验室中可以方便实现10-100克级的制备。
为了解决上述问题，本发明提供了一种含六元环的核苷类化合物，所述核苷类化合物7结构式为：
其中R
1选自
中的一种；R
2为羟基或炔基。
R
1基团对核苷及核苷衍生物的抗病毒谱起着决定性的作用，通过改变R1基团，使得所述得到的核苷类化合物嵌入DNA或RNA链时，生物遗传物质发生变化，从而干扰病毒的合成；而且在R
1基团上取代基不能太大，如果取代基过 大则没有活性。
作为一种优选的实施方式，所述含六元环的核苷类化合物7结构式为
本申请所述含六元环的核苷类化合物7从化学结构上和天然核苷有相似之处，可以在体内以假乱真，从而干扰或直接作用于蛋白质、核酸的生物合成，从而干扰病毒，特别是冠状病毒的合成；而且所述核苷类化合物7含六元环，溶解性较好，在体内活性更高。
所述的核苷类化合物的制备方法，包括以下步骤：将化合物1溶于有机溶剂中，加入BnX、碱金属卤化物、碱金属盐进行反应，后处理，得到化合物2，所述化合物1为D-核糖，X为Br或Cl；将化合物2经过氧化、取代、氰化、脱苄基得到核苷类化合物7；所述化合物2的结构式为：
作为一种优选的实施方式，所述含六元环的核苷类化合物7的制备方法，包括以下步骤：
S1.将化合物3与7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺进行反应得到化合物4；
S2.将化合物4与布朗斯台德酸进行反应处理，得化合物5；
S3.在化合物5中加入路易斯酸和氰化试剂，后处理得到化合物6；
S4.将化合物6进行脱苄基，即得核苷类化合物7。
所述化合物4的结构式为：
所述化合物5的结构式为：
所述化合物6的结构式为：
步骤S1
作为一种实施方式，所述化合物3的制备方法，包括以下步骤：将化合物2制备成半缩醛中间体，然后与氧化剂反应3-12小时得到化合物3；
所述氧化剂可以任何合适的量加入；优选的，所述氧化剂的物质的量为化合物2物质的量的1-2倍。
其中，所述氧化剂选自氯铬酸吡啶盐，重铬酸吡啶，戴斯-马丁氧化剂，DMSO/(COCl)
2中的至少一种。
所述化合物2的结构式为：
所述化合物3的结构式为：
所述氯铬酸吡啶盐简称为PCC，CAS号为26299-14-9，在室温、中性的条件下可将羟基氧化为醛基。
所述重铬酸吡啶简称为PDC，CAS号为20039-37-6。
所述戴斯-马丁氧化剂简称为DMP，CAS号为87413-09-0，可将伯醇氧化成 醛、仲醇氧化成酮。
优选的，所述化合物3的制备方法，包括以下步骤：将化合物2溶于冰醋酸中搅拌5-15分钟，加入硫酸和/或盐酸，之后将体系加热至70-90℃反应4-6小时。冷却后用0.5-1.5M的氢氧化钠调pH至3.8-4.2，减压浓缩除去冰醋酸，然后经过萃取、合并有机相后洗涤、干燥、然后过滤、滤液浓缩、柱层析得到半缩醛中间体；将所述半缩醛中间体溶于干燥的二氯甲烷，加入氧化剂反应3-12小时，淬灭，经过萃取，合并有机相后洗涤、干燥；然后过滤、滤液浓缩、柱层析得到化合物3。
优选的，所述化合物3的制备方法，包括以下步骤：将化合物2溶于冰醋酸中搅拌5-15分钟，加入硫酸和/或盐酸，之后将体系加热至70-90℃反应4-6小时。冷却后用0.5-1.5M的氢氧化钠调pH至3.8-4.2，减压浓缩除去冰醋酸，然后用乙酸乙酯萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸镁干燥；然后过滤、滤液浓缩、柱层析得到半缩醛中间体；将所述半缩醛中间体溶于干燥的二氯甲烷，加入氧化剂反应3-12小时；淬灭，用二氯甲烷萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸镁干燥；然后过滤、滤液浓缩、柱层析得到化合物3。
作为一种实施方式，所述化合物2的制备方法，包括以下步骤：将化合物1溶于有机溶剂中，加入BnX(X为Br或Cl)、碱金属卤化物、碱金属盐进行反应，后处理，得到化合物2。
所述化合物1为D-核糖，结构式为：
BnX可以任何合适的量加入；优选的，所述BnX的物质的量为化合物1物质的量的4-5倍。
碱金属卤化物可以任何合适的量加入；优选的，所述碱金属卤化物的物质的量为化合物1物质的量的0.02-0.06。
碱金属盐可以任何合适的量加入；优选的，所述碱金属盐的物质的量为化合物1物质的量的3-6倍。
所述有机溶剂选自二氯甲烷、四氢呋喃、二甲基亚砜、乙腈、甲苯、N,N-二甲基甲酰胺中的至少一种。
所述X为Br时，所述BnX指PhCH
2Br；所述X为Cl时，所述BnX指PhCH
2Cl。
所述碱金属卤化物选自碘化钠，碘化钾，溴化钠，溴化钾，氯化钠，氯化钾中的至少一种。
所述碱金属盐选自碳酸钾，碳酸钠，叔丁醇钾，氢化钠，二异丙基氨基锂，正丁基锂中的至少一种。
优选的，所述化合物2的制备方法，包括以下步骤：将化合物1溶于有机溶剂中，加入BnX(X为Br或Cl)和碱金属卤化物；然后加入碱金属盐，反应温度控制在30～35℃，反应5-12小时后加水淬灭，萃取，合并有机相后洗涤，有机相干燥；然后过滤、滤液浓缩、柱层析得到化合物2。
更优选的，所述化合物2的制备方法，包括以下步骤：将化合物1溶于有机溶剂中，加入BnX(X为Br或Cl)和碱金属卤化物；然后分批加入碱金属盐，反应温度控制在30～35℃。反应5-12小时后加水淬灭，乙酸乙酯萃取三次，合并有机相后用水洗涤两次，饱和氯化钠洗涤一次，有机相用无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物2。其中，碱金属盐可以任何合适批次加入，例如，分2批加入碱金属盐；或分3批加入碱金属盐；或分4批加入碱金属盐。
作为一种优选的实施方式，所述步骤S1包括：将7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺溶于干燥四氢呋喃，加入卤代硅烷或硅酯，搅拌5-15分钟后加入苯基卤化镁、搅拌反应15-25分钟后加入烷基卤化镁，继续反应15-25分钟后加入化合物3的四氢呋喃溶液；反应5.5-6.5小时后，淬灭，萃取，合并有机相后洗涤，干燥；然后过滤、滤液浓缩、柱层析得到化合物4。
7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺可以任何合适的量加入；优选的，所述7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺的物质的量为化合物3物质的量的0.8-1.1倍。
其中，7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺的CAS号为1770840-43-1。
所述卤代硅烷选自三甲基氯硅烷、三甲基碘硅烷、三甲基溴硅烷、三乙基氯硅烷中的至少一种；所述硅酯选自三氟甲磺酸三甲基硅酯、高氯酸三甲基硅酯中的至少一种。
所述苯基卤化镁为苯基氯化镁。
所述烷基卤化镁选自异丙基氯化镁、叔丁基氯化镁、甲基氯化镁、乙基溴化 镁、乙基氯化镁、丙基溴化镁、丙基氯化镁中的至少一种。
更优选的，所述步骤S1包括：将7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺溶于干燥四氢呋喃，加入卤代硅烷或硅酯，搅拌5-15分钟后加入苯基卤化镁、搅拌反应15-25分钟后加入烷基卤化镁，继续反应15-25分钟后加入化合物3的四氢呋喃溶液；反应6小时后，加入饱和氯化铵淬灭，用乙酸乙酯萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸镁干燥；然后过滤、滤液浓缩、柱层析得到化合物4。
步骤S2
所述布朗斯台德酸为磺酸化合物和/或羧酸化合物；优选的，所述布朗斯台德酸选自樟脑磺酸，对甲基苯磺酸，一水合对甲基苯磺酸，甲磺酸，苯磺酸，富马酸中的至少一种。
优选的，所述步骤S2包括：将化合物4溶于甲醇，加入布朗斯台德酸，搅拌反应过夜，除去甲醇，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，合并有机相后洗涤，干燥；然后过滤、滤液浓缩、柱层析得到化合物5。
所述除去甲醇的方法没有特别限制，例如，减压蒸馏。
所述布朗斯台德酸可以任何合适的量加入；优选的，所述布朗斯台德酸的物质的量为化合物4物质的量的2-3倍。
更进一步优选的，所述步骤S2包括：将化合物4溶于甲醇，加入布朗斯台德酸，搅拌反应过夜，除去甲醇，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸镁干燥；然后过滤、滤液浓缩、柱层析得到化合物5。
步骤S3
所说路易斯酸选自三甲基氯硅烷、三甲基碘硅烷、三甲基溴硅烷、三乙基氯硅烷、三氟甲磺酸三甲基硅酯、高氯酸三甲基硅酯、三氟化硼乙醚中的至少一种。
所述氰化试剂选自三甲基氰硅烷，四丁基氰化铵、四甲基氰化铵、四乙基氰化铵、氰化钠、氰化钾中的至少一种。
所述路易斯酸可以任何合适的量加入；优选的，所述路易斯酸的物质的量为化合物5物质的量的2-4倍。
所述氰化试剂可以任何合适的量加入；优选的，所述氰化试剂的物质的量为 化合物5物质的量的4-5倍。
作为一种优选的实施方式，所述步骤S3包括：将化合物5溶于干燥二氯甲烷，置于冰盐浴中，加入路易斯酸，搅拌25-35分钟后加入氰化试剂，升至室温反应一定时间后，淬灭，萃取，合并有机相后洗涤，干燥；然后过滤、滤液浓缩、柱层析得到化合物6。
进一步优选的，所述步骤S3包括：将化合物5溶于干燥二氯甲烷，置于冰盐浴中，加入路易斯酸，搅拌25-35分钟后加入氰化试剂，自然升至室温反应一定时间后，加入饱和碳酸氢钠淬灭，用二氯甲烷萃取，合并有机相后用饱和氯化钠洗涤，无水硫酸镁干燥；然后过滤、滤液浓缩、柱层析得到化合物6。
步骤S4
将化合物6溶于干燥二氯甲烷，降至-(70-80)℃，加入脱苄基试剂，升至-(35-45)℃反应7-9小时；加入C1-C2有机醇，然后继续加入碱和所述C1-C2有机醇的混合溶液，之后将体系升至室温，减压蒸去溶剂得粗品，用有机化合物洗涤，即得核苷类化合物7。
所说脱苄基试剂选自三氯化硼、三氟化硼、三溴化硼、三氯化铁、三氯化铝、四氯化钛、四氯化锡中的至少一种。
所述碱选自氢氧化钠、氢氧化钾、三乙胺、二乙胺、碳酸钠、碳酸钾中的至少一种。
所述C1-C2有机醇为甲醇和/或乙醇。
所述有机化合物选自二氯甲烷、四氢呋喃、乙腈、氯仿中的至少一种。
本申请中，所述干燥的方式无特别限制，例如，还可以采用无水氯化钙、无水碳酸钠等。
本发明所述核苷类化合物7的制备方法，其技术路线操作简单，路线简洁，所用的试剂均为常用试剂，可适合大规模制备，在实验室中可以方便实现10-100克级的制备。
本申请中，所述搅拌反应过夜指搅拌10-14小时。
下面通过实施例对本发明进行具体描述。有必要在此指出的是，以下实施例只用于对本发明作进一步说明，不能理解为对本发明保护范围的限制，该领域的专业技术人员根据上述本发明的内容做出的一些非本质的改进和调整，仍属于本 发明的保护范围。
另外，如果没有其它说明，所用原料都是市售得到的。
实施例
实施例1
一种含六元环的核苷类化合物7的制备方法，包括以下步骤：
S1.所述化合物2的制备方法，包括以下步骤：将D-核糖(化合物1)(10g，66.6mmol)溶于300mL N,N-二甲基甲酰胺，加入溴化苄(36mL，299.7mmol)和碘化钾(445mg，2.7mmol)。等量分4批加入氢化钠(13.4g，333mmol，60％in oil)，反应温度控制在30～35℃之间。反应12小时后处理，加水淬灭，乙酸乙酯萃取三次，合并有机相后用水洗涤两次，饱和氯化钠洗涤一次，有机相用无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物2，所述化合物2的质量为14.6g，产率为43％。
将化合物2(9.3g，18.2mmol)溶于120mL冰醋酸，搅拌10分钟，加入稀硫酸(37mL，1M in H
2O)，之后将体系加热至80℃反应5小时。冷却后用1M的氢氧化钠调pH至4，减压浓缩除去冰醋酸，然后用乙酸乙酯萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到半缩醛中间体(所述半缩醛中间体的质量为5.8g，产率为76％)。将该中间体(5.1g，12.1mmol)溶于50mL干燥的二氯甲烷，加入DMP氧化剂(10.3g，24.2mmol)反应3小时。加入饱和碳酸氢钠和硫代硫酸钠固体淬灭反应，用二氯甲烷萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物3(所述化合物3的质量为4.7g，产率为92％)。1H NMR(400MHz,CDCl
3)δ:7.45-7.42(m,2H),7.41-7.38(m,5H),7.38-7.35(m,3H),7.35-7.31(m,3H),7.30-7.28(m,2H),5.12(d,J＝8.0Hz,1H),4.99(d,J＝8.0Hz,1H),4.91(d,J＝8.0Hz,1H),4.71(d,J＝8.0Hz,1H),4.56(d,J＝8.0Hz,1H),4.51-4.45(m,2H),4.32-4.29(m,1H),4.27-4.26(m,1H),3.88(d,J＝1.6Hz,1H),3.83(ddd,J＝6.8,4.0,1.2Hz,1H)ppm；
将化合物7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺(15g，57.7mmol)溶于350mL干燥四氢呋喃，加入三甲基氯硅烷(14.6mL，115.4mmol)，搅拌10分钟后将体系降至0℃，加入苯基氯化镁(58mL，2.0M in THF)，搅拌反应20分钟后加 入异丙基氯化镁(47mL，1.3M in THF)，继续反应20分钟后在20分钟内滴入100mL化合物3(24.5g，58.6mmol)的四氢呋喃溶液。该温度下反应6小时后处理，加入饱和氯化铵淬灭反应，用乙酸乙酯萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物4(所述化合物4的质量为16.8g，产率为52％)。1H NMR(400MHz,DMSO)δ：8.08(brs,2H),8.03(s,1H),7.38-7.35(m,2H),7.32-7.27(m,7H),7.26-7.20(m,5H),7.16-7.13(m,2H),6.94(d,J＝3.2Hz,1H),5.53(d,J＝3.2Hz,1H),4.69(d,J＝8.0Hz,1H),4.62(s,2H),4.59-4.55(m,2H),4.52(d,J＝8.0Hz,1H),4.50(d,J＝7.6Hz,1H),4.13-4.10(m,1H),3.85-3.81(m,1H),3.80-3.76(m,1H),3.62-3.57(m,1H)ppm。
S2.将化合物4(32g，59.4mmol)溶于300mL甲醇，加入一水合对甲基苯磺酸(28.2g，148.5mmol，CAS号为6192-52-5)，搅拌反应12h后处理，减压蒸去甲醇，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物5(化合物5的质量为28g，产率为85％)。1H NMR(400MHz,CDCl3)δ：7.78(s,1H),7.42-7.38(m,2H),7.37-7.28(m,5H),7.27-7.20(m,3H),7.09-7.02(m,2H),7.00-6.94(m,2H),6.74(d,J＝7.2Hz,1H),6.62(d,J＝4.4Hz,1H),5.73(s,2H),4.92(d,J＝12.8Hz,1H),4.84-4.78(m,2H),4.64-4.52(m,3H),4.37(d,J＝12.0Hz,1H),4.17-4.14(m,1H),4.11(d,J＝12.4Hz,1H),3.88-3.81(m,2H),2.93(s,3H)ppm。
S3.将化合物5(28g，49.5mmol)溶于200mL干燥二氯甲烷，置于冰盐浴中，加入三氟甲磺酸三甲基硅酯(28.7mL，148.5mmol)，搅拌30分钟后加入三甲基氰硅烷(29.7mL，222.8mmol)，自然升至室温搅拌反应12h。加入饱和碳酸氢钠淬灭反应，用二氯甲烷萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物6(化合物6的质量为25.5g，产率为92％)。1H NMR(400MHz,CDCl
3)δ:7.82(s,1H),7.40-7.30(m,7H),7.27-7.20(m,4H),7.10-7.05(m,1H),7.01-6.94(m,3H),6.77-6.72(m,2H),6.64-6.59(m,1H),5.92(brs,2H),5.00(s,1H),4.88(d,J＝12.4Hz,1H),4.79(d,J＝12.4Hz,1H),4.63-4.58(m,2H),4.45(d,J＝11.6Hz,1H),4.39(d,J＝13.6Hz,1H),4.24(d,J＝12.0Hz,1H),4.20-4.14(m,2H),3.95-3.90(m,1H)ppm。
S5.将化合物6(34.8g，62.0mmol)溶于250mL干燥二氯甲烷，降至-78℃，加入三氯化硼(236mL，1M in DCM)，升至-40℃反应8小时。加入120mL无水甲醇，然后继续加入三乙胺(87mL)和无水甲醇(120mL)的混合溶液，之后将体系升至室温，减压蒸去溶剂得粗品，用氯仿洗涤四次得核苷类化合物7(所述核苷类化合物7的质量为15.3g，产率为85％)。1H NMR(400MHz,DMSO)δ:7.84(s,1H),7.76(brs,2H),6.83(d,J＝4.4Hz,1H),6.63(d,J＝4.4Hz,1H),5.60(d,J＝5.2Hz,1H),5.34(d,J＝4.8Hz,1H),5.02(d,J＝8.8Hz,1H),4.67(d,J＝8.8Hz,1H),4.08(d,J＝12.8Hz,1H),3.98(d,J＝12.8Hz,1H),3.86-3.81(m,2H)ppm。
其中：THF指四氢呋喃；DCM指二氯甲烷。
2.0M in THF指苯基氯化镁在THF的浓度为2.0mol/L。
实施例2
一种含六元环的核苷类化合物7的制备方法，具体步骤同实施例1，不同点在于：
将化合物2(9.3g，18.2mmol)溶于120mL冰醋酸，搅拌10分钟，加入稀盐酸(37mL，1M in H
2O)，之后将体系加热至80℃反应5小时。冷却后用1M的氢氧化钠调pH至4，减压浓缩除去冰醋酸，然后用乙酸乙酯萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到半缩醛中间体(5.8g，76％)。将该中间体(5.1g，12.1mmol)溶于50mL干燥的二氯甲烷，加入氯铬酸吡啶盐(PCC氧化剂)(5.2g，24.2mmol)反应3小时。加入饱和碳酸氢钠和硫代硫酸钠固体淬灭反应，用二氯甲烷萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、滤液浓缩、柱层析得到化合物3(化合物3的质量为4.0g，产率为80％)。
实施例3
一种含六元环的核苷类化合物7的制备方法，具体步骤同实施例1，不同点在于：
S3.将化合物5(5g，8.8mmol)溶于40mL干燥二氯甲烷，置于冰盐浴中，加入三氟化硼乙醚(3.3mL，26.5mmol)，搅拌30分钟后加入三甲基氰硅烷(5.3mL，39.6mmol)，升至室温反应12h。加入饱和碳酸氢钠淬灭反应，用二氯甲烷萃取三次，合并有机相后用饱和氯化钠洗涤一次，无水硫酸镁干燥。然后过滤、 滤液浓缩、柱层析得到化合物6(化合物6的质量为2.7g，收率为54％)。
以上所述仅是本发明的较佳实施例而已，并非是对发明作其他形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或更改为等同变化的等效实施例，但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改，等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (10)
- 一种含六元环的核苷类化合物，其特征在于，所述核苷类化合物7结构式为：
其中R 1选自
中的一种；R 2为羟基或炔基。
- 如权利要求1所述的含六元环的核苷类化合物，其特征在于，所述含六元环的核苷类化合物7结构式为
- 一种如权利要求1或2所述的核苷类化合物的制备方法，其特征在于，包括以下步骤：将化合物1溶于有机溶剂中，加入BnX、碱金属卤化物、碱金属盐进行反应，后处理，得到化合物2，所述化合物1为D-核糖，X为Br或Cl；将化合物2经过氧化、取代、氰化、脱苄基得到核苷类化合物7；所述化合物2的结构式为：
- 如权利要求3所述的核苷类化合物的制备方法，其特征在于，包括以下步 骤：S1.将化合物3与7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺进行反应得到化合物4；S2.将化合物4与布朗斯台德酸进行反应处理，得化合物5；S3.在化合物5中加入路易斯酸和氰化试剂，后处理得到化合物6；S4.将化合物6进行脱苄基，即得核苷类化合物7；所述化合物3的结构式为：
所述化合物4的结构式为：
所述化合物5的结构式为：
所述化合物6的结构式为：
- 如权利要求4所述的核苷类化合物的制备方法，其特征在于，所述化合物3的制备方法，包括以下步骤：将化合物2制备成半缩醛中间体，然后与氧化剂反应3-12小时得到化合物3。
- 如权利要求4或5所述的核苷类化合物的制备方法，其特征在于，所述化合物3的制备方法，包括以下步骤：将化合物2溶于冰醋酸中搅拌5-15分钟，加入硫酸和/或盐酸，之后将体系加热至70-90℃反应4-6小时；冷却后用0.5-1.5M的氢氧化钠调pH至3.8-4.2，减压浓缩除去冰醋酸，然后经过萃取、合并有机 相后洗涤、干燥、然后过滤、滤液浓缩、柱层析得到半缩醛中间体；将所述半缩醛中间体溶于干燥的二氯甲烷，加入氧化剂反应3-12小时，淬灭，经过萃取，合并有机相后洗涤、干燥；然后过滤、滤液浓缩、柱层析得到化合物3。
- 如权利要求5或6所述的核苷类化合物的制备方法，其特征在于，所述氧化剂选自氯铬酸吡啶盐，重铬酸吡啶，戴斯-马丁氧化剂，DMSO/(COCl) 2中的至少一种。
- 如权利要求4所述的核苷类化合物的制备方法，其特征在于，所述步骤S1包括：将7-碘代吡咯并[2,1-F][1,2,4]三嗪-4-胺溶于干燥四氢呋喃，加入卤代硅烷或硅酯，搅拌5-15分钟后加入苯基卤化镁、搅拌反应15-25分钟后加入烷基卤化镁，继续反应15-25分钟后加入化合物3的四氢呋喃溶液；反应5.5-6.5小时后，淬灭，萃取，合并有机相后洗涤，干燥；然后过滤、滤液浓缩、柱层析得到化合物4；优选的，所述卤代硅烷选自三甲基氯硅烷、三甲基碘硅烷、三甲基溴硅烷、三乙基氯硅烷中的至少一种；所述硅酯选自三氟甲磺酸三甲基硅酯、高氯酸三甲基硅酯中的至少一种。
- 如权利要求4所述的核苷类化合物的制备方法，其特征在于，步骤S2中，所述布朗斯台德酸选自樟脑磺酸，对甲基苯磺酸，一水合对甲基苯磺酸，甲磺酸，苯磺酸，富马酸中的至少一种。
- 如权利要求4所述的核苷类化合物的制备方法，其特征在于，步骤S3中，所说路易斯酸选自三甲基氯硅烷、三甲基碘硅烷、三甲基溴硅烷、三乙基氯硅烷、三氟甲磺酸三甲基硅酯、高氯酸三甲基硅酯、三氟化硼乙醚中的至少一种。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16/924,239 US10988503B1 (en) | 2020-05-06 | 2020-07-09 | Six-membered ring-containing nucleoside compound and preparation method thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010342636.XA CN111454270B (zh) | 2020-04-27 | 2020-04-27 | 一种含六元环的核苷类化合物及其制备方法 |
| CN202010342636.X | 2020-04-27 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US16/924,239 Continuation US10988503B1 (en) | 2020-05-06 | 2020-07-09 | Six-membered ring-containing nucleoside compound and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2021217685A1 true WO2021217685A1 (zh) | 2021-11-04 |
Family
ID=71674708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2020/088682 WO2021217685A1 (zh) | 2020-04-27 | 2020-05-06 | 一种含六元环的核苷类化合物及其制备方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111454270B (zh) |
| WO (1) | WO2021217685A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022142477A1 (en) * | 2020-12-30 | 2022-07-07 | Southern University Of Science And Technology | Methods and modified nucleosides for treating coronavirus infections |
| CN114409655A (zh) * | 2022-01-26 | 2022-04-29 | 郑州大学 | 3′,4′-不饱和核糖c-核苷类似物及其制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029644A (zh) * | 2014-02-19 | 2016-10-12 | 富士胶片株式会社 | 硫代吡喃糖化合物及其制造方法 |
| CN107074902A (zh) * | 2014-10-29 | 2017-08-18 | 吉利德科学公司 | 制备核糖核苷的方法 |
| CN110330540A (zh) * | 2019-08-08 | 2019-10-15 | 木天(济南)生物科技有限公司 | 核苷盐及其制备方法 |
-
2020
- 2020-04-27 CN CN202010342636.XA patent/CN111454270B/zh active Active
- 2020-05-06 WO PCT/CN2020/088682 patent/WO2021217685A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029644A (zh) * | 2014-02-19 | 2016-10-12 | 富士胶片株式会社 | 硫代吡喃糖化合物及其制造方法 |
| CN107074902A (zh) * | 2014-10-29 | 2017-08-18 | 吉利德科学公司 | 制备核糖核苷的方法 |
| CN110330540A (zh) * | 2019-08-08 | 2019-10-15 | 木天(济南)生物科技有限公司 | 核苷盐及其制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| DOWNEY A. MICHAEL, RICHTER CELIN, POHL RADEK, MAHRWALD RAINER, HOCEK MICHAL: "Direct One-Pot Synthesis of Nucleosides from Unprotected or 5-O-Monoprotected D-Ribose", ORGANIC LETTERS, vol. 17, no. 18, 10 September 2015 (2015-09-10), US, pages 4604 - 4607, XP055861742, ISSN: 1523-7052, DOI: 10.1021/acs.orglett.5b02332 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111454270A (zh) | 2020-07-28 |
| CN111454270B (zh) | 2024-05-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018217236B2 (en) | Synthesis of polycyclic-carbamoylpyridone compounds | |
| WO2021022690A1 (zh) | 核苷盐及其制备方法 | |
| JP7123429B2 (ja) | 二環式縮合環系ヌクレオカプシド阻害剤および薬物としてｂ型肝炎を治療するためのその使用 | |
| WO2021217685A1 (zh) | 一种含六元环的核苷类化合物及其制备方法 | |
| CN114555077A (zh) | 作为抗病毒剂的Patentiflorin A类似物 | |
| CN114591303B (zh) | 高纯度的化合物及化合物的纯化或制备方法 | |
| CN105566322A (zh) | 一种莫西沙星杂质g化合物的制备方法 | |
| CN110483549B (zh) | 一种硝基咪唑吡喃类抗结核药物的制备方法 | |
| CN115650959A (zh) | 化合物的制备方法或纯化方法 | |
| CN112409183B (zh) | 山椒子烯酮及其衍生物、其制备方法和应用 | |
| CN105399737B (zh) | 噁唑烷酮类化合物及其用途 | |
| CN113321694A (zh) | N4-羟基胞苷衍生物及其制备方法和用途 | |
| CN107722101A (zh) | 甾体吡啶类衍生物及其制备方法和应用 | |
| CN108129366B (zh) | 抗病毒化合物、制备方法及其用途 | |
| CN114591302B (zh) | 化合物及化合物的制备方法 | |
| US10988503B1 (en) | Six-membered ring-containing nucleoside compound and preparation method thereof | |
| ES2554619T3 (es) | Proceso para sintetizar isoquinolinas sustituidas | |
| CN115518058A (zh) | N-环烷基取代的芳甲胺类化合物在制备抗病毒药物中的用途及结构和制备方法 | |
| WO2016145997A1 (zh) | 一种药物活性糖分子及其合成方法 | |
| Sriharsha et al. | Synthesis and antimicrobial activity of novel 1, 3-oxazolidine nucleoside analogues | |
| CN107417641B (zh) | 苯并噻二嗪类衍生物及其制备方法与应用 | |
| CN101812078A (zh) | 杂环并二氢吡啶化合物及其合成方法 | |
| CN100478349C (zh) | 氟化核苷类化合物、其制备方法及其应用 | |
| JP3259191B2 (ja) | ２，２′−アンヒドロアラビノシルチミン誘導体の合成法 | |
| CN112079785A (zh) | 一种新型抗流感病毒奥司他韦衍生物、其制备方法及用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20933250 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20933250 Country of ref document: EP Kind code of ref document: A1 |
|
| 32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 25/05/2023) |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20933250 Country of ref document: EP Kind code of ref document: A1 |