CN111620903A - C-nucleoside analogue, preparation method and application of nitrile-containing C-nucleoside compound for synthesizing Rudexilvir - Google Patents
C-nucleoside analogue, preparation method and application of nitrile-containing C-nucleoside compound for synthesizing Rudexilvir Download PDFInfo
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- CN111620903A CN111620903A CN202010553524.9A CN202010553524A CN111620903A CN 111620903 A CN111620903 A CN 111620903A CN 202010553524 A CN202010553524 A CN 202010553524A CN 111620903 A CN111620903 A CN 111620903A
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- group
- compound
- alkyl
- nucleoside
- hydrocarbyl
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- 239000002777 nucleoside Substances 0.000 title claims abstract description 24
- 150000002825 nitriles Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229940127073 nucleoside analogue Drugs 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 45
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000003513 alkali Substances 0.000 claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 229910000077 silane Inorganic materials 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 29
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 28
- -1 2-naphthylmethyl group Chemical group 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 23
- 125000000524 functional group Chemical group 0.000 claims description 21
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 20
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 11
- 150000007517 lewis acids Chemical class 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 150000001340 alkali metals Chemical class 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- LCHWKMAWSZDQRD-UHFFFAOYSA-N silylformonitrile Chemical class [SiH3]C#N LCHWKMAWSZDQRD-UHFFFAOYSA-N 0.000 claims description 7
- JKNHZOAONLKYQL-UHFFFAOYSA-K tribromoindigane Chemical compound Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 claims description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- DANBQHLZCHUINA-UHFFFAOYSA-N [SiH4].N#CC#N Chemical compound [SiH4].N#CC#N DANBQHLZCHUINA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- CMWINYFJZCARON-UHFFFAOYSA-N 6-chloro-2-(4-iodophenyl)imidazo[1,2-b]pyridazine Chemical compound C=1N2N=C(Cl)C=CC2=NC=1C1=CC=C(I)C=C1 CMWINYFJZCARON-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 3
- BRPMJMJJONIAHU-UHFFFAOYSA-N lithium;pyrrolidine Chemical compound [Li].C1CCNC1 BRPMJMJJONIAHU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000004756 silanes Chemical class 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 3
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000894007 species Species 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241001115402 Ebolavirus Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- CUOKHACJLGPRHD-BXXZVTAOSA-N D-ribono-1,4-lactone Chemical group OC[C@H]1OC(=O)[C@H](O)[C@@H]1O CUOKHACJLGPRHD-BXXZVTAOSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940122277 RNA polymerase inhibitor Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FKOASGGZYSYPBI-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)alumanyl trifluoromethanesulfonate Chemical compound [Al+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F FKOASGGZYSYPBI-UHFFFAOYSA-K 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical group CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a C-nucleoside analogue, a preparation method of a nitrile-containing C-nucleoside compound for synthesizing Rudexilvir and application of the nitrile-containing C-nucleoside compound. The preparation method of the C-nucleoside analogue comprises the step of reacting a compound I with a compound II under the action of alkali to form a compound III, wherein the structural formulas of the compound I, the compound II and the compound III are sequentially shown as follows:
and
wherein R is1Is selected from-CH2-aryl or-Si-hydrocarbyl, R2And R3Each independently selected from any one of H and tert-butyloxycarbonyl, RaAnd RbAre all R1，R5Is H or trimethylsilyl. The method has the advantages of easily obtained raw materials, no ultralow temperature adopted as reaction conditions, capability of being carried out at conventional temperature, easiness in realization of the reaction conditions and capability of realizing large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a C-nucleoside analogue, a preparation method of a nitrile-containing C-nucleoside compound for synthesizing Rudexilvir and application of the nitrile-containing C-nucleoside compound.
Background
Reddesivir (Remdesivir) is a drug developed by Gilidae, Inc. (Gilead) in the United states against Ebola virus, has completed phase I and phase II clinical trials, is relatively safe in animals and humans, and is not yet marketed in any country or region. Reidesciclovir, a novel nucleoside analogue, is an RNA polymerase inhibitor that was originally developed to combat Ebola virus, and in 2019-nCoV treatment, Reidesciclovir is considered to be the most potent drug at present, and is now marketed in Japan and the United states as a fast channel approval after the initiation of clinical trials, under the chemical name (S) -2- (((S) - (((2R,3S,4R,5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid 2-ethylbutyl ester, as shown below:
the existing RudeSeviru synthetic route has few reports, and the key step is the connection of a D-ribonolactone fragment and a heterocyclic fragment. The documents J.Med.chem.2017,60,1648-1661 and CN107074902 report the relevant syntheses. The synthetic route is as follows:
however, this route involves two difficulties, first, the preparation of compound 2 is difficult, and when compound 3 is formed when the two parts of compound 1 and compound 2 are butted, the yield is low, resulting in very low overall synthesis efficiency. The literature reports that when X in compound 2 is bromine, the yield is only 25%. Secondly, the process has two steps of reaction which involves ultralow temperature reaction and needs to be carried out at the temperature of minus 78 ℃, the conditions are very harsh, and the industrial production difficulty is large.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a C-nucleoside analogue, a preparation method of a nitrile-containing C-nucleoside compound for synthesizing Rudexilvir and application of the nitrile-containing C-nucleoside compound. The embodiment of the invention provides a preparation method of a novel C-nucleoside analogue, the raw materials of the method are easy to obtain, the reaction condition does not need to adopt ultralow temperature, the method can be carried out at the conventional temperature, the reaction condition is easy to realize, and the method can be used for large-scale industrial production.
The invention is realized by the following steps:
in a first aspect, embodiments of the present invention provide a method for preparing a C-nucleoside analogue, comprising reacting compound I with compound II in the presence of a base to form compound III, wherein compound I can be any one of the compounds represented by the following structural formula:
the structural formula of compound II is shown below:
the compound III is one of the compounds shown in the following structural formula:
wherein R is1Is selected from-CH2-aryl or-Si-hydrocarbyl, R2And R3Each independently selected from any one of H and tert-butyloxycarbonyl, RaAnd RbAre all R1，RcIs alkyl or substituted phenyl, R5Is H or trimethylsilyl.
It is to be noted that R provided in the examples of the present invention1、RaAnd RbAre all-CH2-and-Si-is linked to oxygen.
In alternative embodiments, R1middle-CH2-the aromatic group of the aromatic group is selected from any one of a fused aromatic group and a non-fused aromatic group;
preferably, R1middle-CH2The aryl group of the aryl group is any one selected from the group consisting of a 2-naphthyl group, a 1-naphthyl group, a phenyl group, and a p-methoxyphenyl group;
preferably, R1The hydrocarbyl of the medium-Si-hydrocarbyl is selected from any one of saturated alkyl and aromatic base substituted by the saturated alkyl;
preferably, R1The hydrocarbyl group of the mid-Si-hydrocarbyl group is selected from any one of the functional groups consisting of t-butyldimethyl, triisopropyl, triethyl, and t-butyldiphenyl;
most preferably, R1Selected from 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl and tert-butyldiphenylAny one of a functional group consisting of a silicon group, a triisopropylsilicon group, a triethylsilicon group, a benzyl group and a p-methoxybenzyl group;
preferably, RcThe alkyl in (A) is a C1-C8 alkyl group; preferably, it is
And
any one of the above;
preferably, RcWherein the substituted phenyl group is
Wherein R is4Any one of functional groups selected from the group consisting of alkyl groups, halogens, alkoxy groups, and nitro groups.
In the groups represented by the formulae in the examples of the present invention, the black bold line indicates the linking site thereof, for example
The middle black heavy line indicates the position of the oxygen linkage.
In an alternative embodiment, compound III is selected from any one of the compounds of the formula:
preferably, R4The alkyl group in (1) is selected from C1-C5 alkyl, more preferably methyl or ethyl;
preferably, R4The alkoxy in (A) is selected from C1-C5 alkoxy, more preferably methoxy;
preferably, R4In (1) halogenThe element is selected from fluorine or chlorine.
In alternative embodiments, the base is a strong organic base;
preferably, the strong organic base is a strong organic base containing an alkali metal;
preferably, the alkali metal comprises lithium;
preferably, the alkali metal-containing organic strong base includes any one of n-butyllithium, t-butyllithium, sec-butyllithium, lithium diisopropylamide, and lithium pyrrolidine.
In an alternative embodiment, the conditions of the reaction are: at a temperature of-20 ℃ to 25 ℃ for 1 to 5 hours, compound I: compound II: the molar ratio of the alkali is 1-1.5: 1: 1-3;
preferably, the reaction conditions are: at a temperature of 0 ℃ to 25 ℃ for 2 hours, compound I: compound II: the molar ratio of the base is 1.1: 1: 1.1-2.2;
preferably, the step of forming said compound III comprises: mixing the compound II with alkali and then mixing with the compound I for reaction;
preferably, the step of forming said compound III comprises: adding a silane substance;
preferably, the step of adding the silane species comprises: mixing the compound II with the alkali, then mixing with the silane substance, and then mixing and reacting with the compound I;
preferably, the step of adding the silane species comprises: mixing the compound II with the alkali, then mixing with the compound I, and then mixing and reacting with the silane substances;
preferably, the silane species is an alkyl-substituted silane species; more preferably trimethylchlorosilane;
preferably, the amount of the silane-based substance added is 2 to 3 times equivalent, preferably 2 times equivalent, of the amount of the compound II added.
In a second aspect, the embodiments of the present invention provide a nitrile-containing C-nucleoside compound for use in the synthesis of reidesavir, which is prepared from compound III prepared by the method for preparing a C-nucleoside analogue according to any one of the preceding embodiments, wherein the nitrile-containing C-nucleoside compound is one of the compounds represented by the following structural formula:
preferably, R1middle-CH2-the aromatic group of the aromatic group is selected from any one of a fused aromatic group and a non-fused aromatic group;
preferably, R1middle-CH2The aryl group of the aryl group is any one selected from the group consisting of a 2-naphthyl group, a 1-naphthyl group, a phenyl group, and a p-methoxyphenyl group;
preferably, R1The hydrocarbyl of the medium-Si-hydrocarbyl is selected from any one of saturated alkyl and aromatic base substituted by the saturated alkyl;
preferably, R1The hydrocarbyl group of the mid-Si-hydrocarbyl group is selected from any one of the functional groups consisting of t-butyldimethyl, triisopropyl, triethyl, and t-butyldiphenyl;
most preferably, R1Any one of functional groups selected from the group consisting of 2-naphthylmethyl group, 1-naphthylmethyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, triisopropylsilyl group, triethylsilyl group, benzyl group and p-methoxybenzyl group;
preferably, RcThe alkyl in (A) is a C1-C8 alkyl group; preferably, it is
And
any one of the above;
preferably, RcWherein the substituted phenyl group is
Wherein R is4Any one of functional groups selected from the group consisting of alkyl groups, halogens, alkoxy groups, and nitro groups.
In an alternative embodiment, the method comprises the following steps: the compound III prepared by the preparation method of the C-nucleoside analogue is subjected to synthesis reaction to form the nitrile-containing C-nucleoside compound.
In an alternative embodiment, the step of synthesizing the reaction comprises: reacting the compound III with a cyanogen silane substance under the catalysis of Lewis acid to form the nitrile-containing C-nucleoside compound;
preferably, the cyanosilanes are alkyl substituted cyanosilanes, preferably trimethylcyanosilane;
preferably, said compound III: the cyanogen silane substance: the mole ratio of the Lewis acid is 1: 2-5: 0.1 to 2, preferably 1: 4: 1;
preferably, the lewis acid includes any one of boron trifluoride etherate, aluminum trifluoromethanesulfonate, zinc trifluoromethanesulfonate, titanium tetrachloride, anhydrous tin tetrachloride, indium tribromide, and anhydrous ferric trichloride.
In an alternative embodiment, the conditions of the synthesis reaction are: the temperature is-20 to 25 ℃, and the time is 1 to 10 hours;
preferably, the conditions of the synthesis reaction are: the temperature was 0 ℃ and the time was 3 hours.
In a third aspect, the embodiments of the present invention provide an application of the nitrile-containing C-nucleoside compound and the C-nucleoside analog described in the foregoing embodiments in the synthesis of reidoxir.
The embodiment of the invention has the following beneficial effects: the examples of the present invention were prepared by using R in Compound II2And R3Different substituents are adopted, the acid and the alkali are different, so that the compound II can be directly reacted with alkali without being halogenatedThe reaction is carried out under the conventional temperature which is easy to realize without hydrogen extraction and then ester carbonyl of the compound I is directly attacked, so that the reaction is carried out at the conventional temperature which is easy to realize, the reaction yield is improved, the reaction condition is improved, and the reaction is milder and is easy to operate.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
In the prior art, ultralow temperature (-78 ℃) is needed in the process of synthesizing the Reidesciclovir, the temperature is difficult to realize industrially, and even if the Reidesciclovir is realized, the requirement on equipment is high, the production cost of the Reidesciclovir is obviously increased, and meanwhile, raw materials for synthesizing the Reidesciclovir are adopted
The synthesis is difficult, the production cost is increased, and the yield of the intermediate for synthesizing the Reidcvir by the raw material is low, so that the synthesis yield of the entire Reidcvir is also low. The inventors have found, through studies, that starting materials which are not substituted by halogen (x) are used
The reaction can be carried out, the reaction yield can be increased, and the reaction conditions are milder.
Specifically, the embodiment of the invention provides a preparation method of a C-nucleoside analogue, which comprises the following steps:
reacting a compound I with a compound II under the action of a base to form a compound III, wherein the compound I can adopt any one of compounds shown in the following structural formula:
the structural formula of compound II is shown below:
the compound III is one of the compounds shown in the following structural formula:
wherein R is1Is selected from-CH2-aryl or-Si-hydrocarbyl, R2And R3Each independently selected from any one of H and tert-butyloxycarbonyl, RaAnd RbAre all R1，RcIs alkyl or substituted phenyl R5Is H or trimethylsilyl.
It is to be noted that when the group to which oxygen in the compound I is bonded corresponds to RaAnd RbWhen the oxygen in the correspondingly formed compound III is correspondingly attached to the group RaAnd RbWhen the group to which oxygen in the compound I is attached corresponds to RcWhen the oxygen in the correspondingly formed compound III is correspondingly attached to the group Rc。
Further, R in the above formula1middle-CH2-the aromatic group of the aromatic group is selected from any one of a fused aromatic group and a non-fused aromatic group; r1middle-CH2The aryl group of the aryl group is any one selected from the group consisting of a 2-naphthyl group, a 1-naphthyl group, a phenyl group, and a p-methoxyphenyl group; r1The hydrocarbon group of the medium-Si-hydrocarbon group is selected from any one of a saturated alkyl group and a saturated alkyl group-substituted aromatic groupSeed growing; r1The hydrocarbyl group of the mid-Si-hydrocarbyl group is selected from any one of the functional groups consisting of t-butyldimethyl, triisopropyl, triethyl, and t-butyldiphenyl; most preferably, R1Selected from any one of functional groups consisting of 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl and p-methoxybenzyl.
Further, RcThe alkyl in (A) is a C1-C8 alkyl group; preferably, it is
And
any one of the above;
preferably, RcWherein the substituted phenyl group is
Wherein R is4Any one of functional groups selected from the group consisting of alkyl groups, halogens, alkoxy groups, and nitro groups.
In this case, the compound III may be selected from any one of the compounds represented by the following formulae:
The embodiment of the invention controls R in the compound II2And R3The substituent group is hydrogen or not, the acidity and alkalinity of the compound are controlled, the compound II can directly react with alkali without halogenating, the hydrogen is extracted, then the compound II reacts with ester carbonyl of the compound I to form the compound III, the halogenated compound II is not needed to be formed, the reaction temperature of the compound II for forming the compound III does not need to adopt ultralow temperature, the reaction can be carried out at the conventional temperature of, for example, -20 to 25 ℃, preferably 0 to 25 ℃, the production difficulty is reduced, meanwhile, the halogenated compound II is not needed, the yield of the reaction can be improved, and the enterprise benefit is increased.
The alkali adopted in the embodiment of the invention is organic strong alkali, and the organic strong alkali is organic strong alkali containing alkali metal; the alkali metal comprises lithium; preferably, the alkali metal-containing organic strong base includes any one of n-butyllithium, t-butyllithium, sec-butyllithium, lithium diisopropylamide, and lithium pyrrolidine. The organic strong base is favorable for pulling out hydrogen on the compound II, promoting the formation of the compound III, reducing the reaction temperature and improving the reaction yield.
It should be noted that the examples of the present invention only exemplify the strong organic bases containing lithium, and other organic bases containing alkali metals are also within the scope of the present invention as long as the above reaction can proceed.
Specifically, the reaction process is as follows: mixing the compound II with alkali and then mixing with the compound I for reaction; now mix compound II with alkali, can make alkali pull out compound II's hydrogen earlier, then form high active intermediate, then add compound I after, can react more fast, and avoid forming impurity, promote the yield of reaction to can further promote reaction temperature, avoid the ultra-low temperature. The temperature of the compound II mixed with the base should not be too high to avoid the generation of impurities during hydrogen extraction, and is preferably 0 ℃ although it may be lower than 0 ℃ or slightly higher than 0 ℃.
The step of forming said compound III comprises: adding a silane substance;
if in compound II R2And R3When all hydrogen is contained, the step of adding the silane substance comprises the following steps: subjecting said compound IIMixing with the alkali, then mixing with the silane substances, and then mixing and reacting with the compound I; and after the compound II reacts with alkali, the silane substance is added, so that the silane substance can react with nitrogen on the compound II to form a silicon-based protective group, N is prevented from participating in subsequent reaction, and the yield and the purity of the compound III are ensured. The added silicon-based protecting group is easy to fall off in the subsequent post-treatment process, so that R on the compound III is further enabled2And R3Still hydrogen.
If in compound II R2And R3When hydrogen is not used at the same time, the silane substance may be added or not added, and if the silane substance is added, the step of adding the silane substance comprises the following steps: mixing the compound II with the alkali, then mixing with the compound I, and then mixing and reacting with the silane substances; at this point, the added silane species reacts with the N on compound II, but reacts with the OH in compound III to form OTMS, facilitating the subsequent formation of compound IV.
The silane substance is alkyl substituted silane substance; more preferably trimethylchlorosilane; the silane-based substance can ensure smooth reaction.
Although examples of the present invention only exemplify trimethylchlorosilane to form OTMS, the silane-based material is within the scope of the present invention as long as compound III can be reacted with the cyanosilane-based material to form CN.
The reaction conditions were: at a temperature of-20 ℃ to 25 ℃ for 1 to 5 hours, compound I: compound II: the molar ratio of the alkali is 1-1.5: 1: 1-3; preferably, the reaction conditions are: at a temperature of 0 ℃ to 25 ℃ for 2 hours, compound I: compound II: the molar ratio of the base is 1.1: 1: 1.1-2.2; the amount of the silane-based substance added is 2 to 3 equivalents, preferably 2 equivalents, of the amount of the compound II added. The reaction can be smoothly carried out by adopting the conditions, and the formation of the compound III is ensured.
According to the reaction conditions, the reaction temperature can be obviously increased by adopting the specific raw materials, the reaction is not carried out under the ultralow temperature (-78 ℃) condition, the reaction conditions are easy to realize, the production cost is saved, the production difficulty is reduced, and the yield can be increased.
The embodiment of the present invention further includes performing post-treatment on the reaction system after the reaction is finished to obtain the pure compound III, and the post-treatment method can adopt the existing post-treatment methods, such as extraction, washing, concentration, column chromatography, etc., and will not be described in detail herein.
The above reaction is carried out in a suitable organic solvent in embodiments of the present invention, which may be any suitable solvent, including but not limited to tetrahydrofuran and 2-methyltetrahydrofuran.
Further, the embodiment of the invention also provides a nitrile-containing C-nucleoside compound, which is one of the compounds shown in the following structural formula:
and
wherein R is1、R2、R3、Ra、RbAnd RcDefined groups with R in the above-mentioned Compounds I, II and III1、R2、R3、Ra、RbAnd RcDefined radicals are as in, in particular R1Is selected from-CH2-aryl or-Si-hydrocarbyl, R2And R3Each independently selected from any one of H and tert-butyloxycarbonyl, and R2And R3Not simultaneously hydrogen, Ra and Rb are both R1, and Rc is alkyl or substituted phenyl; preferably, R1middle-CH2-the aromatic group of the aromatic group is selected from any one of a fused aromatic group and a non-fused aromatic group; preferably, R1middle-CH2The aryl group of the aryl group is any one selected from the group consisting of a 2-naphthyl group, a 1-naphthyl group, a phenyl group, and a p-methoxyphenyl group; preferably, R1The hydrocarbon group of the medium-Si-hydrocarbon group is selected from any one of a saturated alkyl group and a saturated alkyl group-substituted aromatic groupSeed growing; preferably, R1The hydrocarbyl group of the mid-Si-hydrocarbyl group is selected from any one of the functional groups consisting of t-butyldimethyl, triisopropyl, triethyl, and t-butyldiphenyl; most preferably, R1Selected from any one of functional groups consisting of 2-naphthylmethyl, 1-naphthylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, triethylsilyl, benzyl and p-methoxybenzyl. RcThe alkyl in (A) is a C1-C8 alkyl group; preferably, it is
And
any one of the above; preferably, RcWherein the substituted phenyl group is
Wherein R is4Any one of functional groups selected from the group consisting of alkyl groups, halogens, alkoxy groups, and nitro groups.
The novel compound and the C-nucleoside analogue can be used for synthesizing the Reidesvir.
The embodiment of the invention also provides a preparation method of the compound, which comprises the step of carrying out synthesis reaction by using the compound III to form the compound. Specifically, under the catalysis of Lewis acid, the compound III reacts with a cyanogen silane substance to form the nitrile-containing C-nucleoside compound.
The reaction does not need ultralow temperature, and can be carried out only under the condition of relatively conventional temperature, such as-20 to 25 ℃, so that the difficulty of reaction synthesis can be further reduced. Specifically, the conditions of the synthesis reaction are as follows: the temperature is-20 to 25 ℃, and the time is 1 to 10 hours; preferably, the conditions of the synthesis reaction are: the temperature was 0 ℃ and the time was 3 hours.
Further, the above-mentioned cyanosilanes are alkyl-substituted cyanosilanes, preferably trimethylcyanosilane; preferably, said compound III: the cyanogen silane substance: the mole ratio of the Lewis acid is 1: 2-5: 0.1 to 2, preferably 1: 4: 1; preferably, the lewis acid includes any one of boron trifluoride etherate, aluminum trifluoromethanesulfonate, zinc trifluoromethanesulfonate, titanium tetrachloride, anhydrous tin tetrachloride, indium tribromide, and anhydrous ferric trichloride. The formation of the compound can be further ensured by adopting the substances and the conditions. Wherein the reaction can be carried out by using other Lewis acid, and the Lewis acid is also in the protection scope of the invention.
The reaction may be carried out in a suitable organic solvent, which may be any suitable solvent, including but not limited to toluene, dioxane, acetonitrile, THF, dichloromethane, and the like.
Example 1
This example provides a preparation method of compound III-1, the specific synthetic route is as follows:
specifically, compound II (1.3g,1eq) was dissolved in anhydrous THF (6.5ml), cooled to 0 ℃ under argon protection, LDA (2M, 15ml, 3eq) was slowly added dropwise at this temperature, and after the addition was complete, stirred for 30 minutes. Chlorotrimethylsilane (2.17g, 2eq) was added and stirring was continued for 30 minutes. Then, a tetrahydrofuran solution (10ml) of Compound I-1(2.86g,1.1eq) was slowly added dropwise. After the addition was complete, stirring was continued for 1 hour at this temperature. The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with 1N diluted hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated brine each for 1 time. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is 0 to 10 percent of dichloromethane/methanol) to obtain the compound III-1(2.87g,52 percent yield).1H NMR(500MHz,d-DMSO)8.06(s,br,2H),7.97(s,1H), 7.22-7.33(m,11H),7.10-7.14(m,3H),6.97-6.98(m,2H),6.92(d,J＝5Hz,1H), 5.36(d,J＝6Hz,1H),5.06(d,J＝6Hz,1H),4.54(dd,J＝11Hz,3Hz,2H), 4.43-4.47(m,4H),3.98-4.00(m,1H),3.90(t,J＝5Hz,1H),3.66(m,1H),3.45 (dd,J＝10Hz,6.5Hz,1H)；Ms(+C,ESI):M＝552,Found 553(M+1)。
Example 2
This example provides a preparation method of compound III-2, the specific synthetic route is as follows:
specifically, compound II (1.3g,1eq) was dissolved in anhydrous THF (6.5ml), cooled to 0 ℃ under argon protection, LDA (2M, 15ml, 3eq) was slowly added dropwise at this temperature, and after the addition was complete, stirred for 30 minutes. Chlorotrimethylsilane (2.17g, 2eq) was added and stirring was continued for 30 minutes. Then, a tetrahydrofuran solution (10ml) of Compound I-2(3.32g,1.1eq) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 25 ℃ and stirring was continued at 25 ℃ for 1 hour. The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated brine 1 time each. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is 0 to 10 percent of dichloromethane/methanol) to obtain a compound III-2 (1.93g,38 percent yield).1H NMR(500MHz,d-DMSO)7.84(s,1H),7.69(s, br,2H),6.83(d,J＝4.5Hz,1H),6.63(d,J＝4.5Hz,1H),4.92(d,6.5Hz,1H), 4.67(dd,J＝3.0Hz,6.5Hz，1H),4.24(dd，J＝5Hz,8.5Hz，1H),3.75-3.82 (m,2H),1.55(s,3H)，1.29(s,3H)，0.82(s,9H)，0.02(s,6H)，0.00(s,9H)；Ms(+C,ESI):M＝508,Found 509(M+1)。
Example 3
This example provides a preparation method of compound III-2, the specific synthetic route is as follows:
specifically, compound II (1.34g,1eq) was dissolved in anhydrous THF (6.5ml), cooled to 0 ℃ under argon protection, LDA (2M, 20ml, 4eq) was slowly added dropwise at this temperature, and after the addition was complete, stirred for 1 hour. Chlorotrimethylsilane (3.26g, 3eq) was added and stirring was continued for 30 minutes. Then, a tetrahydrofuran solution (15ml) of Compound I-2(4.53g,1.5eq) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 25 ℃ and stirring was continued at 25 ℃ for 5 hours. Dropwise adding ammonium chloride aqueous solution to quench the reaction, extracting with ethyl acetate, and respectively using water, saturated sodium bicarbonate aqueous solution and saturated sodium bicarbonate aqueous solutionEach was washed with brine 1 time. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is 0 to 10 percent of dichloromethane/methanol) to obtain a compound III-2 (2.24g,44 percent yield).1H NMR(500MHz,d-DMSO)7.84(s,1H),7.69(s, br,2H),6.83(d,J＝4.5Hz,1H),6.63(d,J＝4.5Hz,1H),4.92(d,6.5Hz,1H), 4.67(dd,J＝3.0Hz,6.5Hz，1H),4.24(dd，J＝5Hz,8.5Hz，1H),3.75-3.82 (m,2H),1.55(s,3H)，1.29(s,3H)，0.82(s,9H)，0.02(s,6H)，0.00(s,9H)；Ms(+C,ESI):M＝508,Found 509(M+1)。
Example 4
This example provides a preparation method of compound III-2, the specific synthetic route is as follows:
specifically, compound II (1.34g,1eq) was dissolved in anhydrous THF (6.5ml), cooled to-20 ℃ under argon protection, n-BuLi (2M, 10ml, 2eq) was slowly added dropwise at this temperature, and after the addition was complete, stirring was carried out for 30 minutes. Chlorotrimethylsilane (2.17g, 2eq) was added, the temperature was slowly raised to 0 ℃ and stirring was continued for 30 minutes. Subsequently, the reaction mixture was cooled again to-20 ℃ and n-BuLi (2M, 5ml, 1eq) was slowly added dropwise, and after completion of the addition, the reaction mixture was stirred for 30 minutes and then a solution of Compound I-2(3.32g,1.1eq) in tetrahydrofuran (10ml) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 0 ℃ and stirring was continued at 0 ℃ for 1 hour. The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated brine 1 time each. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is 0 to 10 percent of dichloromethane/methanol) to obtain a compound III-2(1.22g,24 percent yield).1H NMR(500MHz, d-DMSO)7.84(s,1H),7.69(s,br,2H),6.83(d,J＝4.5Hz,1H),6.63(d,J＝ 4.5Hz,1H),4.92(d,6.5Hz,1H),4.67(dd,J＝3.0Hz,6.5Hz，1H),4.24(dd， J＝5Hz,8.5Hz，1H),3.75-3.82(m,2H),1.55(s,3H)，1.29(s,3H)，0.82(s,9H)， 0.02(s,6H)，0.00(s,9H)；Ms(+C,ESI):M＝508,Found 509(M+1)。
Example 5
This example provides a preparation method of compound III-3, the specific synthetic route is as follows:
specifically, compound II-1(2.34g,1eq) was dissolved in anhydrous THF (15ml), cooled to 0 ℃ with an ice salt bath under argon protection, LDA (2M, 11ml,2.2eq) was slowly added dropwise at this temperature, slowly increased to 0 ℃ after addition, and stirred at 0 ℃ for 30 minutes. Then, a tetrahydrofuran solution (10ml) of Compound I-2(3.32g,1.1eq) was added dropwise. After the addition was complete, stirring was continued for 1 hour at this temperature. The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated brine 1 time each. Drying the organic phase, concentrating, and separating and purifying by column chromatography (the eluent is ethyl acetate/n-hexane is 20% -40%), to obtain compound III-3(3.06g, 57% yield).1H NMR(500MHz, d-DMSO)10.32(s,1H),8.11(s,1H),7.04(s,1H),6.75(d,J＝3Hz,1H), 6.65(s,1H),5.00(d,J＝6.0Hz,1H),4.74(d,J＝5.5Hz,1H),4.01(dd,J＝5.5 Hz,9Hz,1H),3.71(t,J＝4.5Hz,3H)，3.63(q,J＝5.0Hz,1H)，1.42(s,9H)， 1.07(s,3H)，1.01(s,3H)，0.81(s,9H),0.00(s,6H)；Ms(+C,ESI):M＝536, Found 537(M+1)。
Example 6
This example provides a preparation method of compound III-3', the specific synthetic route is as follows:
specifically, compound II-1(2.34g,1eq) was dissolved in anhydrous THF (10ml), cooled to 0 ℃ with an ice salt bath under argon protection, LDA (2M, 11ml,2.2eq) was slowly added dropwise at this temperature, slowly increased to 0 ℃ after addition, and stirred at 0 ℃ for 30 minutes. Then, a tetrahydrofuran solution (10ml) of Compound I-2(3.32g,1.1eq) was added dropwise. After the addition was complete, stirring was continued for 1 hour at this temperature. Then chlorotrimethylsilane (2.17g, 2eq) was added and stirring was continued for 1 hour. The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated brine 1 time each. Drying the organic phaseThen concentrating, and separating and purifying by column chromatography (the eluent is ethyl acetate/n-hexane is 20% -40%), so as to obtain the compound III-3' (2.80g, 46% yield).1H NMR(500MHz,d-DMSO)10.48 (s,1H),8.29(s,1H),7.24(d,J＝5Hz,1H),6.87(d,J＝5Hz,1H),4.94-1(d,J ＝6.5Hz,1H),4.71(q,J＝3Hz,1H),4.31(d,J＝3Hz,1H),3.81-3.83(m,2H)， 1.60(s,3H)，1.56(s,9H)，1.34(s,3H)，0.83(s,9H),0.04(s,3H)，0.02(s,3H)， 0.00(s,9H)；Ms(+C,ESI):M＝608,Found 609(M+1)。
Example 7
This example provides a preparation method of compound III-4, the specific synthetic route is as follows:
specifically, compound II-2(3.34g,1eq) was dissolved in anhydrous THF (15ml), cooled to 0 ℃ with an ice salt bath under argon protection, LDA (2M, 5.5ml,1.1eq) was slowly added dropwise at this temperature, slowly raised to 0 ℃ after addition was complete, and stirred at 0 ℃ for 30 minutes. Then, a tetrahydrofuran solution (10ml) of Compound I-2(3.32g,1.1eq) was added dropwise. After the addition was complete, stirring was continued for 1 hour at this temperature. Then chlorotrimethylsilane (2.17g, 2eq) was added and stirring was continued for 1 hour. The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated brine 1 time each. Drying the organic phase, concentrating, and separating and purifying by column chromatography (the eluent is ethyl acetate/n-hexane is 5% -20%), to obtain compound III-4(2.41g, 34% yield).1H NMR(500MHz,d-DMSO)8.72(s, 1H),7.17(d,J＝5Hz,1H),6.93(d,J＝4.5Hz,1H),4.91 d,J＝6.5Hz,1H), 4.77(dd,J＝2.5Hz,6.5Hz,1H),4.42(d,J＝3.0Hz,1H),3.88(t,J＝2.5Hz, 1H),3.39(s,1H),1.66(s,3H)，1.46(s,18H)，1.41(s,3H)，0.94(s,9H),0.10(s, 3H)，0.08(s,3H)，0.00(s,9H)；Ms(+C,ESI):M＝708,Found 709(M+1)。
Example 8
This example provides a method for preparing compound IV-1, the specific synthetic route is as follows:
specifically, compound III-3(2.68g,1eq) was dissolved in anhydrous dichloromethane (13ml), cooled to-10 ℃ under argon protection, and trimethylsilyl cyanide (1.98g, 4eq) was added followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (2.22g, 2eq), (trimethylsilyl trifluoromethanesulfonate being an OTMS with OH on compound III, which then forms CN with trimethylsilyl cyanide) and stirred for 10 minutes. Indium tribromide (1.77g, 1eq) was added and after addition was slowly raised to 0 ℃ and stirring continued for 3 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate. After stirring for 30 minutes, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine 1 time each. The organic phase is concentrated after being dried, and is separated and purified by column chromatography ((eluent is ethyl acetate/n-hexane is 20% -40%) to obtain a compound IV-1(2.04g, 75% yield).1H NMR(500MHz,d-DMSO)10.45(s,1H),8.20(d,1H),7.14(d, J＝4.5Hz,1H),6.78(d,J＝4.5Hz,1H),5.35(d,J＝5.50Hz,1H),4.86(d,J＝5.5Hz,1H),4.44(t,J＝5.0Hz,1H),3.76-3.79(m,2H),1.38(s,9H),1.02(s,3H)，0.79(s,9H)，0.61(s,3H)，0.00(s,6H)；Ms(+C,ESI):M＝545,Found 546(M+ 1)。
Example 9
This example provides a method for preparing compound IV-1, the specific synthetic route is as follows:
specifically, compound III-3' (3.04g,1eq) was dissolved in anhydrous dichloromethane (15ml), cooled to-10 ℃ under argon protection, added with trimethylsilyl cyanide (1.98g, 4eq), and stirred for 10 minutes. Indium tribromide (1.77g, 1eq) was added and after addition was slowly raised to 0 ℃ and stirring continued for 3 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate. After stirring for 30 minutes, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine 1 time each. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is ethyl acetate/n-hexane is 20% -40%), so that the compound IV-1(2.23g, 82% yield) is obtained.1H NMR(500MHz,d-DMSO)10.45(s,1H),8.20(d,1H),7.14(d, J＝4.5Hz,1H),6.78(d,J＝4.5Hz,1H),5.35(d,J＝5.50Hz,1H),4.86(d,J＝ 5.5Hz,1H),4.44(t,J＝5.0Hz,1H),3.76-3.79(m,2H),1.38(s,9H),1.02(s,3H)， 0.79(s,9H)，0.61(s,3H)，0.00(s,6H)；Ms(+C,ESI):M＝545,Found 546(M+ 1)。
Example 10
This example provides a method for preparing compound IV-1, the specific synthetic route is as follows:
specifically, compound III-3' (3.04g,1eq) was dissolved in anhydrous dichloromethane (15ml), cooled to-10 ℃ under argon protection, added with trimethylsilyl cyanide (1.98g, 4eq), and stirred for 10 minutes. Indium tribromide (0.18g, 0.1eq) was added and after addition was slowly raised to 0 ℃ and stirring was continued for 3 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate. After stirring for 30 minutes, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine 1 time each. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is ethyl acetate/n-hexane is 20% -40%), so that the compound IV-1(1.23g, 45% yield) is obtained.1HNMR(500MHz,d-DMSO)10.45(s,1H),8.20(d,1H),7.14(d, J＝4.5Hz,1H),6.78(d,J＝4.5Hz,1H),5.35(d,J＝5.50Hz,1H),4.86(d,J＝ 5.5Hz,1H),4.44(t,J＝5.0Hz,1H),3.76-3.79(m,2H),1.38(s,9H),1.02(s,3H)， 0.79(s,9H)，0.61(s,3H)，0.00(s,6H)；Ms(+C,ESI):M＝545,Found 546(M+ 1)。
Example 11
This example provides a method for preparing compound IV-1, the specific synthetic route is as follows:
specifically, compound III-3' (3.04g,1eq) was dissolved in anhydrous dichloromethane (15ml), cooled to-10 ℃ under argon protection, added with trimethylsilyl cyanide (1.98g, 4eq), and stirred for 10 minutes. Aluminum triflate (1.19g, 0.5eq) was added and after addition slowly increased to 0 ℃ and continuedStirred for 3 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate. After stirring for 30 minutes, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine 1 time each. Drying the organic phase, concentrating, and separating and purifying by column chromatography (the eluent is ethyl acetate/n-hexane is 20% -40%), to obtain compound IV-1(1.85g, 68% yield).1H NMR(500MHz,d-DMSO)10.45(s,1H),8.20(d,1H),7.14(d, J＝4.5Hz,1H),6.78(d,J＝4.5Hz,1H),5.35(d,J＝5.50Hz,1H),4.86(d,J＝ 5.5Hz,1H),4.44(t,J＝5.0Hz,1H),3.76-3.79(m,2H),1.38(s,9H),1.02(s,3H)， 0.79(s,9H)，0.61(s,3H)，0.00(s,6H)；Ms(+C,ESI):M＝545,Found 546(M+ 1)。
Example 12
This example provides a method for preparing compound IV-2, the specific synthetic route is as follows:
specifically, compound III-3(3.54g,1eq) was dissolved in anhydrous dichloromethane (15ml), cooled to-10 ℃ under argon protection, added with trimethylsilyl cyanide (1.98g, 4eq), and stirred for 10 minutes. Indium tribromide (1.77g, 1eq) was added and after addition was slowly raised to 0 ℃ and stirring continued for 3 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate. After stirring for 30 minutes, the mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine 1 time each. The organic phase is concentrated after being dried, and is separated and purified by column chromatography (the eluent is ethyl acetate/n-hexane is 5% -20%), so that the compound IV-2(1.39g, 43% yield) is obtained.1H NMR(500MHz,d-DMSO)10.45(s,1H),8.76(s,1H),7.27(d,J＝5Hz, 1H),6.93(d,J＝5Hz,1H),5.46(d,J＝6.50Hz,1H),4.98-5.00(m,1H), 4.61-4.64(m,1H),4.22(dd,J＝4.5Hz,7Hz，1H),4.08-4.11(m,1H),1.66(s, 3H),1.48(s,18H)，1.40(s,3H),0.85(s,9H)，0.00(s,6H)；Ms(+C,ESI): M＝645,Found 646(M+1)。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing a C-nucleoside analogue, which comprises reacting a compound I with a compound II under the action of a base to form a compound III, wherein the compound I can adopt any one of the compounds shown in the following structural formula:
the structural formula of compound II is shown below:
the compound III is one of the compounds shown in the following structural formula:
wherein R is1Is selected from-CH2-aryl or-Si-hydrocarbyl, R2And R3Each independently selected from any one of H and tert-butyloxycarbonyl, RaAnd RbAre all R1，RcIs alkyl or substituted phenyl, R5Is H or trimethylsilyl.
2. The method of claim 1, wherein R is1middle-CH2-the aromatic group of the aromatic group is selected from any one of a fused aromatic group and a non-fused aromatic group;
preferably, R1middle-CH2The aryl group of the aryl group is any one selected from the group consisting of a 2-naphthyl group, a 1-naphthyl group, a phenyl group, and a p-methoxyphenyl group;
preferably, R1The hydrocarbyl of the medium-Si-hydrocarbyl is selected from any one of saturated alkyl and aromatic base substituted by the saturated alkyl;
preferably, R1The hydrocarbyl group of the mid-Si-hydrocarbyl group is selected from any one of the functional groups consisting of t-butyldimethyl, triisopropyl, triethyl, and t-butyldiphenyl;
most preferably, R1Any one of functional groups selected from the group consisting of 2-naphthylmethyl group, 1-naphthylmethyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, triisopropylsilyl group, triethylsilyl group, benzyl group and p-methoxybenzyl group;
preferably, RcThe alkyl in (A) is a C1-C8 alkyl group; preferably, it is
And
any one of the above;
preferably, RcWherein the substituted phenyl group is
Wherein R is4Any one of functional groups selected from the group consisting of alkyl groups, halogens, alkoxy groups, and nitro groups.
3. The method for producing a C-nucleoside analogue according to claim 1, wherein the compound III is selected from any one of compounds represented by the following formulae:
preferably, R4The alkyl group in (1) is selected from C1-C5 alkyl, more preferably methyl or ethyl;
preferably, R4The alkoxy in (A) is selected from C1-C5 alkoxy, more preferably methoxy;
preferably, R4The halogen in (1) is selected from fluorine or chlorine.
4. The method of claim 1, wherein the base is a strong organic base;
preferably, the strong organic base is a strong organic base containing an alkali metal;
preferably, the alkali metal comprises lithium;
preferably, the alkali metal-containing organic strong base includes any one of n-butyllithium, t-butyllithium, sec-butyllithium, lithium diisopropylamide, and lithium pyrrolidine.
5. The process for the preparation of a C-nucleoside analogue according to any one of claims 1 to 4, characterized in that the reaction conditions are: at a temperature of-20 ℃ to 25 ℃ for 1 to 5 hours, compound I: compound II: the molar ratio of the alkali is 1-1.5: 1: 1-3;
preferably, the reaction conditions are: at a temperature of 0 ℃ to 25 ℃ for 2 hours, compound I: compound II: the molar ratio of the base is 1.1: 1: 1.1-2.2;
preferably, the step of forming said compound III comprises: mixing the compound II with alkali and then mixing with the compound I for reaction;
preferably, the step of forming said compound III comprises: adding a silane substance;
preferably, the step of adding the silane species comprises: mixing the compound II with the alkali, then mixing with the silane substance, and then mixing and reacting with the compound I;
preferably, the step of adding the silane species comprises: mixing the compound II with the alkali, then mixing with the compound I, and then mixing and reacting with the silane substances;
preferably, the silane species is an alkyl-substituted silane species; more preferably trimethylchlorosilane;
preferably, the amount of the silane-based substance added is 2 to 3 times equivalent, preferably 2 times equivalent, of the amount of the compound II added.
6. A nitrile-containing C-nucleoside compound for use in the synthesis of reidecivir, which is prepared from compound III prepared by the method for preparing a C-nucleoside analog according to any one of claims 1 to 5, wherein the nitrile-containing C-nucleoside compound is one of the compounds represented by the following structural formula:
preferably, R1middle-CH2-the aromatic group of the aromatic group is selected from any one of a fused aromatic group and a non-fused aromatic group;
preferably, R1middle-CH2The aryl group of the aryl group is any one selected from the group consisting of a 2-naphthyl group, a 1-naphthyl group, a phenyl group, and a p-methoxyphenyl group;
preferably, R1The hydrocarbyl of the medium-Si-hydrocarbyl is selected from any one of saturated alkyl and aromatic base substituted by the saturated alkyl;
preferably, R1The hydrocarbyl group of the medium-Si-hydrocarbyl group is selected from t-butyldimethyl, triisopropyl, and tri-butylAny one of a group of functional groups consisting of ethyl groups and tert-butyldiphenyl groups;
most preferably, R1Any one of functional groups selected from the group consisting of 2-naphthylmethyl group, 1-naphthylmethyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, triisopropylsilyl group, triethylsilyl group, benzyl group and p-methoxybenzyl group;
preferably, RcThe alkyl in (A) is a C1-C8 alkyl group; preferably, it is
And
any one of the above;
preferably, RcWherein the substituted phenyl group is
Wherein R is4Any one of functional groups selected from the group consisting of alkyl groups, halogens, alkoxy groups, and nitro groups.
7. A method for preparing nitrile-containing C-nucleosides as in claim 6, comprising: the nitrile-containing C-nucleoside compound is formed by performing a synthetic reaction on the compound III prepared by the preparation method of the C-nucleoside analogue according to any one of claims 1 to 5.
8. The method of claim 7, wherein the step of performing a synthesis reaction comprises: reacting the compound III with a cyanogen silane substance under the catalysis of Lewis acid to form the nitrile-containing C-nucleoside compound;
preferably, the cyanosilanes are alkyl substituted cyanosilanes, preferably trimethylcyanosilane;
preferably, said compound III: the cyanogen silane substance: the mole ratio of the Lewis acid is 1: 2-5: 0.1 to 2, preferably 1: 4: 1;
preferably, the lewis acid includes any one of boron trifluoride etherate, aluminum trifluoromethanesulfonate, zinc trifluoromethanesulfonate, titanium tetrachloride, anhydrous tin tetrachloride, indium tribromide, and anhydrous ferric trichloride.
9. The method for preparing nitrile-containing C-nucleosides as claimed in claim 7 or 8, wherein the conditions of the synthesis reaction are: the temperature is-20 to 25 ℃, and the time is 1 to 10 hours;
preferably, the conditions of the synthesis reaction are: the temperature was 0 ℃ and the time was 3 hours.
10. Use of a C-nucleoside analogue according to claim 1 or a nitrile-containing C-nucleoside compound according to claim 6 for the synthesis of reidoxivir.
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