WO2021175296A1 - 瑞德西韦的中间体及其制备方法 - Google Patents

瑞德西韦的中间体及其制备方法 Download PDF

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WO2021175296A1
WO2021175296A1 PCT/CN2021/079143 CN2021079143W WO2021175296A1 WO 2021175296 A1 WO2021175296 A1 WO 2021175296A1 CN 2021079143 W CN2021079143 W CN 2021079143W WO 2021175296 A1 WO2021175296 A1 WO 2021175296A1
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谢元超
胡天文
朱富强
田广辉
沈敬山
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中国科学院上海药物研究所
上海特化医药科技有限公司
苏州旺山旺水生物医药有限公司
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Publication of WO2021175296A1 publication Critical patent/WO2021175296A1/zh

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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the technical field of pharmacy, in particular to a remdesivir intermediate, a preparation method thereof and its use for preparing remdesivir.
  • Remdesivir is a new carbon nucleoside phosphoramidate prodrug developed by Gilead.
  • the compound has broad-spectrum anti-RNA virus activity and is currently in clinical research. stage. Nature.2016;531(7594):381-5 and J.Med.Chem.2017;60(5):1648-1661 have reported that the compound GS-5734 has a significant inhibitory effect on Ebola virus, and found it It is by inhibiting the RdRp (RNA-dependent RNA-polymerases) activity of Ebola virus to block virus replication.
  • RdRp RNA-dependent RNA-polymerases
  • compound GS-5734 also has potential inhibitory activity against other RNA viruses, such as hepatitis C virus (HCV), coronavirus (SARS, MERS), respiratory syncytial virus (RSV), Lassa fever virus (LASV) and so on.
  • HCV hepatitis C virus
  • SARS coronavirus
  • RSV respiratory syncytial virus
  • LASV Lassa fever virus
  • Civir preparation method
  • step A of preparing compound 3 by reacting compound 1 with compound 2 there are many impurities and are difficult to separate, and the yield is too low.
  • the product compound 3 needs to be purified by column chromatography.
  • the yields of steps E and F are also unsatisfactory, which is not conducive to large-scale industrial production.
  • the purpose of the present invention is to provide a method for synthesizing remdesivir and its intermediates with low cost, high yield and good product purity.
  • Another object of the present invention is to provide compounds that can be used as intermediates for the preparation of remdesivir.
  • the first aspect of the present invention provides a method for preparing a compound of formula V, the method comprising the steps:
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or a -CH(Ph)- group together ,
  • R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring;
  • R 3 is a hydroxyl protecting group
  • R 8 is -NHW, where W is H or an amino protecting group
  • PG is H or a silyl substituent.
  • the 5-7 membered carbocyclic ring is saturated.
  • the hydroxyl protecting group is selected from the group consisting of substituted or unsubstituted benzyl, substituted or unsubstituted naphthylmethylene Trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl-methoxy ( MOM), tetrahydropyranyl (THP), tert-butyl, allyl or a combination thereof;
  • the "substituted” means that one or more hydrogen atoms (2, 3, or 4) in the group are selected from the following Substituent group substitution: C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro.
  • the hydroxyl protecting group is selected from the following group: benzyl, naphthylmethylene Trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl-methoxy ( MOM), tetrahydropyranyl (THP), tert-butyl, allyl, or a combination thereof.
  • TMS Trimethylsilyl
  • TIPS triisopropylsilyl
  • TIPS triisopropylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • MOM methyl-methoxy
  • THP tetrahydropyranyl
  • tert-butyl allyl, or a combination thereof.
  • the silyl substituent is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS or TBS), Triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS) or a combination thereof.
  • one, two or three of R 1 , R 2 and R 3 are naphthyl methylene groups.
  • substitution refers to one or more hydrogen atoms (2, 3 or 4) in the group being substituted by a substituent selected from the following group: C1-C6 alkane Group, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen.
  • the R 1 and R 2 groups on adjacent carbon atoms can form -CH 2 -, -C(C4-C6 alkylene), or -CH(Ph)- together. .
  • R 1 and R 2 are the same.
  • R 1 , R 2 and R 3 are the same.
  • R 1 and R 2 together form -CH(Ph)-.
  • W is H.
  • W is an amino protecting group
  • the deprotection reaction in step (c) is optional.
  • R 8 is an amino group and PG is H, the deprotection reaction is not necessary in step (c).
  • R 8 is an amino group and PG is a silyl group.
  • R 8 is an amino group and PG is not H.
  • R 8 is an amino group and PG is hydrogen
  • R 1 , R 2 , and R 3 are not benzyl at the same time.
  • the R 8 is selected from the group consisting of amino, acetamido (NHAc), benzoylamino (NHBz) or NHBoc.
  • step (c) it further includes: when PG is a silyl substituent and/or W in R 8 is an amino protecting group, performing a deprotection reaction, that is, consecutively or dividedly in any order removal of the PG step silyl group substituted with an amino protecting group 8 and / or the removal of R, or the simultaneous removal of the amino protecting group PG and R & lt 8 (PG thereby becomes H, W becomes H).
  • the R 1 , R 2 , and R 3 groups are not affected in the deprotection reaction.
  • the deprotection agent is selected from the following group: fluorine reagent, alkali, acid, or a combination thereof.
  • the fluorine reagent is selected from the following group: tetrabutylammonium fluoride, triethylamine hydrogen trifluoride, and ammonium fluoride.
  • the deprotection agent is an acid, and the acid is selected from the group consisting of acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), Formic acid, hydrochloric acid, concentrated hydrochloric acid.
  • the acid is selected from the group consisting of acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), Formic acid, hydrochloric acid, concentrated hydrochloric acid.
  • the deprotection agent is a base, and the base is selected from the group consisting of organic bases, inorganic bases, magnesium Grignard reagents, lithium Grignard reagents, or a combination thereof.
  • the deprotection agent is a base, and the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, sodium methoxide, sodium ethoxide, methylmagnesium bromide, Methyl lithium and so on.
  • the deprotection agent can also be used directly as a reaction solvent.
  • step (c) in an inert solvent, in the presence of a deprotecting agent, the compound of formula IV undergoes a deprotection reaction and a cyclization reaction, thereby producing a compound of formula V.
  • step (c) before step (c), the method further includes the following steps:
  • R 4 and R 5 are each independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C2-C6 alkynyl Substituted C1-C6 alkoxy; or R 4 , R 5 and the connected nitrogen atoms together form a substituted or unsubstituted 4 to 8 member containing 1-2 N heteroatoms and 0-1 selected from O, or S Heterocycloalkyl of heteroatoms;
  • substituted means that one or more hydrogen atoms (2, 3 or 4) in the group are substituted by a substituent selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne Group, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl; and
  • X is halogen
  • R 1 , R 2 , R 3 , R 8 and PG are as defined above.
  • the R 4 , R 5 and the connected nitrogen atom together form a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group containing 2 N heteroatoms.
  • R 4 , R 5 and the connected nitrogen atom together form a 5- to 7-membered ring; preferably, the 5- to 7-membered ring is -N(CH 2 )x(CH 2 )y- Ring, -N(CH 2 )xO(CH 2 )y-ring or -N(CH 2 )x-NR 7- (CH 2 )y-ring, where x and y are each independently 1 ⁇ 3, R 7 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • X is chlorine, bromine or iodine.
  • step (b) the compound of formula II reacts with the compound of formula III in the presence of halosilane, coupling reagent and deprotonating reagent in an inert solvent to produce a compound of formula IV.
  • step (b) the sub-steps are included:
  • PG is H, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • PG is a silyl group
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the compound of formula A is N,O-dimethylhydroxylamine or its hydrochloride.
  • step (a) the compound of formula I reacts with HNR 4 R 5 in the presence of a deprotonation reagent and/or Lewis acid in an inert solvent to produce a compound of formula II-a.
  • step (a') in an inert solvent, in the presence of a deprotonation reagent and/or Lewis acid and base, the compound of formula I, HNR 4 R 5 , halosilane PG-X A reaction occurs to produce a compound of formula II.
  • step (a') includes the steps:
  • PG is a silyl substituent
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above.
  • step (a) or (a') the reaction has one or more of the following characteristics:
  • the deprotonation reagent is selected from the group consisting of magnesium-based deprotonation reagent, lithium-based deprotonation reagent, or a combination thereof;
  • the Lewis acid is selected from the group consisting of trimethylaluminum, dimethylaluminum chloride, or a combination thereof, preferably, trimethylaluminum; and/or
  • the base is selected from the following group: triethylamine, diisopropylamine, imidazole, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine , 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, or a combination thereof, preferably, the base is imidazole.
  • the magnesium-based deprotonation reagent is selected from the group consisting of methyl magnesium bromide (CH 3 MgBr), methyl magnesium chloride (CH 3 MgCl), ethyl magnesium bromide (CH 3 CH 2 MgBr), ethyl magnesium chloride (CH 3 CH 2 MgCl), vinyl magnesium chloride (CH 2 CHMgCl), isopropyl magnesium chloride (iPrMgCl), tert-butyl magnesium chloride (tBuMgCl), phenyl magnesium chloride (PhMgCl), or a combination thereof.
  • methyl magnesium bromide CH 3 MgBr
  • methyl magnesium chloride CH 3 MgCl
  • ethyl magnesium bromide CH 2 MgBr
  • ethyl magnesium chloride CH 3 CH 2 MgCl
  • vinyl magnesium chloride CHMgCl
  • isopropyl magnesium chloride iPrMgCl
  • tBuMgCl
  • the lithium-based deprotonation reagent is selected from the group consisting of n-butyl lithium (nBuLi), tert-butyl lithium (tBuLi), lithium hydride (LiH), ethyl lithium (EtLi), propylene Lithium (PrLi), Lithium Chloride (LiCl), Methyl Lithium (MeLi), Isopropyl Lithium (iPrLi), Phenyl Lithium (PhLi), Cyclohexane Lithium (cyHexLi), Lithium Diisopropylamide ( LDA), lithium amide, lithium hexamethyldisilane amide (LiHMDS), or a combination thereof.
  • the magnesium-based deprotonation reagent is selected from the group consisting of methyl magnesium bromide (CH 3 MgBr), ethyl magnesium chloride (CH 3 CH 2 MgCl), vinyl magnesium chloride (CH 2 CHMgCl) , Isopropyl magnesium chloride (iPrMgCl), (tert-butyl magnesium chloride) tBuMgCl, (phenyl magnesium chloride) PhMgCl, or a combination thereof.
  • step (b) the reaction has one or more of the following characteristics:
  • the halosilane is selected from the group consisting of fluorosilane, chlorosilane, bromosilane, iodosilane, or a combination thereof;
  • the coupling reagent is selected from the group consisting of magnesium coupling reagent, lithium coupling reagent, or a combination thereof; and/or
  • the deprotonation reagent is selected from the group consisting of magnesium-based deprotonation reagent, lithium-based deprotonation reagent, sodium hydride (NaH), CaH 2 , or a combination thereof.
  • the halogenated silane is selected from the group consisting of trimethylchlorosilane (TMSCl), trimethylsilyl iodide (TMSI), triethylchlorosilane (TESCl), tert-butyldimethylsilane Chlorosilane (TBDMSCl) or triisopropylchlorosilane (TIPSCl), more preferably, trimethylchlorosilane (TMSCl), triethylchlorosilane (TESCl), tert-butyldimethylchlorosilane (TBDMSCl) or Triisopropylchlorosilane (TIPSCl).
  • TMSCl trimethylchlorosilane
  • TMSI trimethylsilyl iodide
  • TIPSCl triethylchlorosilane
  • TIPSCl triisopropylchlorosilane
  • TIPSCl Triisopropylch
  • iPrMgCl isopropyl magnesium chloride lithium chloride complex
  • PrMgCl ⁇ LiCl propyl magnesium chloride lithium chloride complex
  • the lithium coupling reagent is selected from the group consisting of n-butyl lithium (nBuLi), tert-butyl lithium (tBuLi), ethyl lithium (EtLi), propyl lithium (PrLi), methyl Lithium (MeLi), isopropyl lithium (iPrLi), phenyl lithium (PhLi), cyclohexane lithium (cyHexLi), or a combination thereof.
  • an additive is further added, and the additive is selected from the group consisting of LiCl, Ca(OTf) 2 , CaCl 2 , MgCl 2 , CeCl 3 , LaCl 3 , YCl 3 , NdCl 3 , Or a combination thereof, preferably, the additive is selected from the following group: LiCl, Ca(OTf) 2 , CaCl 2 , MgCl 2 , CeCl 3 , LaCl 3 or a combination thereof.
  • the second aspect of the present invention provides a compound of formula IV,
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or a -CH(Ph)- group together ,
  • R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring;
  • R 3 is a hydroxyl protecting group
  • R 8 is -NHW, where W is H or an amino protecting group
  • PG is H or a silyl substituent.
  • R 8 is an amino group and PG is hydrogen
  • R 1 , R 2 , and R 3 are not benzyl at the same time.
  • one, two or three of R1, R2 and R3 are naphthylmethylene groups.
  • X is halogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and PG are as defined above.
  • step (b) the compound of formula II reacts with the compound of formula III in the presence of halosilane, coupling reagent and deprotonating reagent in an inert solvent to produce a compound of formula IV.
  • step (b) the sub-steps are included:
  • step (b-3) when PG in formula II is a silyl substituent, in step (b-3), the deprotonation reagent may not be present in the reaction system.
  • step (b-3) when PG in formula II is H, in step (b-3), a deprotonation reagent is also present in the reaction system.
  • PG is H, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • PG is a silyl group
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the fourth aspect of the present invention provides a compound of formula II,
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or -CH(Ph)- together.
  • Group, and R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring ;
  • R 3 is a hydroxyl protecting group
  • R 4 and R 5 are each independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C2-C6 alkynyl Substituted C1-C6 alkoxy; or R 4 , R 5 and the connected nitrogen atoms together form a substituted or unsubstituted 4 to 8 member containing 1-2 N heteroatoms and 0-1 selected from O, or S Heterocycloalkyl of heteroatoms; and
  • PG is H or a silyl substituent
  • substituted means that one or more hydrogen atoms (2, 3 or 4) in the group are substituted by a substituent selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne Group, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl.
  • PG is hydrogen
  • the R 4 , R 5 and the connected nitrogen atom together form a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group containing 2 N heteroatoms.
  • R 4 , R 5 and the connected nitrogen atom together form a 5- to 7-membered ring; preferably, the 5- to 7-membered ring is -N(CH 2 )x(CH 2 )y- Ring, -N(CH 2 )xO(CH 2 )y-ring or -N(CH 2 )x-NR 7- (CH 2 )y-ring, where x and y are each independently 1 ⁇ 3, R 7 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • the fifth aspect of the present invention provides a method for preparing the compound of formula II according to the fourth aspect of the present invention, the method comprising the steps:
  • PG is H, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • PG is a silyl group substituent
  • X is a halogen
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above.
  • step (a) the compound of formula I reacts with HNR 4 R 5 in the presence of a deprotonation reagent and/or Lewis acid in an inert solvent to produce a compound of formula II-a.
  • step (a') in an inert solvent, in the presence of a deprotonation reagent and/or Lewis acid and base, the compound of formula I, HNR 4 R 5 , halosilane PG-X A reaction occurs to produce a compound of formula II.
  • step (a') includes the steps:
  • PG is a silyl substituent
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or a -CH(Ph)- group together ,
  • R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring;
  • R 3 is a hydroxyl protecting group
  • R 4 and R 5 are each independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C2-C6 alkynyl Substituted C1-C6 alkoxy; or R 4 , R 5 and the connected nitrogen atoms together form a substituted or unsubstituted 4 to 8 member containing 1-2 N heteroatoms and 0-1 selected from O, or S Heterocycloalkyl of heteroatoms;
  • R 8 is -NHW, where W is H or an amino protecting group
  • PG is H or a silyl substituent
  • Each X is independently halogen
  • substituted means that one or more hydrogen atoms (2, 3 or 4) in the group are substituted by a substituent selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne Group, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl.
  • PG is a silyl substituent.
  • R 8 is an amino group.
  • step (a) when PG in the compound of formula II is a silyl substituent, step (a) also includes a haloalkyl group.
  • the method further includes the steps:
  • radcivir which uses a compound of formula IV as an intermediate to prepare radcivir.
  • the use of the compound of formula II or the compound of formula IV is provided as an intermediate for the preparation of remdesivir.
  • the method of the present invention has the advantages of easy availability of raw materials, mild reaction conditions, safety, no harm to human health and the environment, and low production cost.
  • the present invention also has the advantages of high reaction product yield, high purity, and less impurities, which is convenient for economy and convenience.
  • the intermediates of the present invention (especially the compound of formula IV) can be used as intermediates to further prepare remdesivir. The present invention has been completed on this basis.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “substantially consisting of” or “consisting of”.
  • room temperature refers to a temperature of 4-40°C, preferably 25 ⁇ 5°C.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-6 represents 1-6 carbons, including those containing 2, Alkyl groups of 3, 4, 5 or 6 carbon atoms, preferably 1-3 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.
  • alkenyl refers to an unsaturated alkyl group having one or more double bonds, including alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms.
  • alkynyl refers to an unsaturated alkyl group having one or more triple bonds, including alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms.
  • Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1, 4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers.
  • cycloalkyl includes cycloalkyls having 3, 4, 5, or 6 ring carbon atoms, which may be in the form of a fused ring, a spiro ring, or a bridged ring.
  • heterocycloalkyl refers to a cycloalkyl group containing one to three heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized, including those having Heterocycloalkyl groups of 4, 5, 6, 7 or 8 ring atoms.
  • alkylene by itself or as part of another substituent refers to a divalent group derived from an alkane, such as -CH 2 CH 2 CH 2 CH 2 -.
  • alkoxy or “alkyloxy”, “alkylamino” or “alkylamino” and “alkylthio” or “alkylthio” (or thioalkoxy ) Is used in its conventional sense to refer to those alkyl groups attached to the rest of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • the alkyl group can be the same or different, and can also be combined with each other.
  • the nitrogen atoms connected to the alkyl group combine to form a 3-7 membered ring. Therefore, the group represented by -NR4R5 includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
  • halo or halogen by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl or polyhaloalkyl.
  • C 1-4 haloalkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.
  • aryl means a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together or covalently linked.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.
  • substituted means that one or more hydrogen atoms (2, 3 or 4) in the group are substituted by a substituent selected from the following group: C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl.
  • protecting group refers to a group part of a compound that masks or changes the properties of a functional group or the properties of the compound as a whole.
  • the chemical substructure of protecting groups varies greatly.
  • One function of the protecting group is to be used as an intermediate in the synthesis of the parent drug.
  • Chemical protecting groups and protection/deprotection strategies are well known in the art. See “Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). See also Protective Groups in Organic Chemistry, Peter GM Wuts and Theodora W. Greene, 4th edition, 2006.
  • Protecting groups are often used to mask the reactivity of certain functional groups to help the efficiency of desired chemical reactions, such as the preparation and destruction of chemical bonds in an orderly and planned manner.
  • the protection of compound functional groups also changes other physical properties of the protected functional groups, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools.
  • the chemically protected intermediate itself may be Biologically active or inactive.
  • hydroxyl protecting group refers to a protecting group that can be used to protect a hydroxyl group (-OH).
  • the hydroxy protecting group includes but is not limited to: substituted or unsubstituted benzyl, substituted or unsubstituted naphthylmethylene Trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl-methoxy ( MOM), tetrahydropyranyl (THP), tert-butyl or allyl;
  • substitution refers to the substitution of one or more hydrogen atoms (2, 3, or 4) in the group by selected from the following group Group substitution: C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro.
  • amino protecting group refers to a protecting group that can be used to protect an amino group (-NH 2 ).
  • the amino protecting group includes, but is not limited to: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl ( Teoc), alkyl acyl (such as acetyl), benzoyl, etc.
  • deprotecting agent refers to any agent capable of removing a protecting group.
  • the deprotection agent will depend on the type of protecting group used. Representative deprotection agents are known in the art and can be found in Protective Groups in Organic Chemistry, Peter G.M. Wuts and Theodora W. Greene, 4th Ed., 2006.
  • reaction mixture refers to the process of bringing at least two different substances into contact so that they are mixed together and can be reacted.
  • the term "coupling agent” refers to an agent capable of coupling two different compounds.
  • the coupling agent can be catalytic or stoichiometric.
  • the coupling agent may be a lithium-based coupling agent, an aluminum-based coupling agent, or a magnesium-based coupling agent such as Grignard reagent.
  • halosilane refers to a silane having at least one halogen group attached to a silicon atom.
  • Representative halosilanes have the formula halogen-Si(R) 3 , where each R group can be alkyl (C1-C6 alkyl), alkenyl (C2-C6 alkenyl), cycloalkyl (C3- C8 cycloalkyl), phenyl or other silicon-containing groups.
  • halogenated silanes include, but are not limited to, trimethylchlorosilane (TMSCl), trimethylsilyl iodide (TMSI), triethylchlorosilane (TESCl), tert-butyldimethylchlorosilane (TBDMSCl) or triiso Propylchlorosilane (TIPSCl).
  • TMSCl trimethylchlorosilane
  • TMSI trimethylsilyl iodide
  • TCSl triethylchlorosilane
  • TDMSCl tert-butyldimethylchlorosilane
  • TIPSCl triiso Propylchlorosilane
  • the term "deprotonation reagent” refers to a substance capable of deprotonating (H) from a molecule to produce its conjugate base.
  • the deprotonation reagent may be a magnesium-based deprotonation reagent, a lithium-based deprotonation reagent, or a combination thereof.
  • Exemplary magnesium-based deprotonation reagents include, but are not limited to, methyl magnesium bromide (CH 3 MgBr), methyl magnesium chloride (CH 3 MgCl), ethyl magnesium bromide (CH 3 CH 2 MgBr), ethyl magnesium chloride ( CH 3 CH 2 MgCl), vinyl magnesium chloride (CH 2 CHMgCl), isopropyl magnesium chloride (iPrMgCl), tert-butyl magnesium chloride (tBuMgCl), phenyl magnesium chloride (PhMgCl), or a combination thereof.
  • Exemplary lithium-based deprotonation reagents include, but are not limited to, n-butyl lithium (nBuLi), tert-butyl lithium (tBuLi), lithium hydride (LiH), ethyl lithium (EtLi), propyl lithium (PrLi), chlorine Lithium (LiCl), Methyl Lithium (MeLi), Isopropyl Lithium (iPrLi), Phenyl Lithium (PhLi), Cyclohexane Lithium (cyHexLi), Lithium Diisopropylamide (LDA), Lithium Amide, Six Lithium methyl disilane amide (LiHMDS), or a combination thereof.
  • nBuLi n-butyl lithium
  • tBuLi lithium hydride
  • EtLi ethyl lithium
  • PrLi propyl lithium
  • any suitable inert solvent can be used in the method of the present invention.
  • Representative inert solvents include, but are not limited to, pentane, different pentane, hexane, different hexane, heptane, different heptane, petroleum ether, cyclopentane, different cyclohexane, benzene, toluene, Xylene, benzotrifluoride, halogenated benzenes such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, dichloromethane, chloroform, DMF, acetone, ethyl acetate, diethyl ether, tetrahydrofuran or a combination thereof.
  • the solvent may be tetrahydrofuran, toluene, DMF, or a combination thereof.
  • the reaction in the method of the present invention can be carried out at any suitable temperature.
  • the reaction temperature can be about -78°C to about 100°C, or about -50°C to about 100°C, or about -25°C to about 50°C, or about -10°C to about 25°C, or about 0°C. °C to about 20°C. In some embodiments, the reaction temperature may be about 0°C to about 20°C.
  • compound of formula V refers to a compound of formula V or a pharmaceutically acceptable salt or co-crystal thereof.
  • a compound of formula V refers to a compound of formula V or a pharmaceutically acceptable salt thereof.
  • compound of formula (number) refers to a compound of the formula and its pharmaceutically acceptable salts or co-crystals.
  • a compound of formula (number) refers to a compound of the formula and a pharmaceutically acceptable salt thereof.
  • HNR 4 R 5 also includes its salt form, such as hydrochloride and the like.
  • each step can provide the target compound or a pharmaceutically acceptable salt thereof in any suitable yield.
  • the target compound e.g., formula II, formula IV, formula V or remdesivir, etc.
  • the target compound can be at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, Produced in 90% or at least about 95% yield.
  • the method of the present invention can provide the target compound or its pharmaceutically acceptable salt in any purity.
  • the target compound can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%.
  • the target compound can be prepared with a purity of at least 95%.
  • the target compound can be prepared with a purity of at least 98%.
  • the target compound can be prepared with a purity of at least 99%.
  • the present invention provides a compound of formula II,
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or -CH(Ph)- together.
  • Group, and R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring ;
  • R 3 is a hydroxyl protecting group
  • R 4 and R 5 are each independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C2-C6 alkynyl Substituted C1-C6 alkoxy; or R 4 , R 5 and the connected nitrogen atoms together form a substituted or unsubstituted 4 to 8 member containing 1-2 N heteroatoms and 0-1 selected from O, or S Heterocycloalkyl of heteroatoms; and
  • PG is H or a silyl substituent
  • substituted means that one or more hydrogen atoms (2, 3 or 4) in the group are substituted by a substituent selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne Group, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl.
  • PG is hydrogen
  • the R 4 , R 5 and the connected nitrogen atom together form a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group containing 2 N heteroatoms.
  • R 4 , R 5 and the connected nitrogen atom together form a 5- to 7-membered ring; preferably, the 5- to 7-membered ring is -N(CH 2 )x(CH 2 )y- Ring, -N(CH 2 )xO(CH 2 )y-ring or -N(CH 2 )x-NR 7- (CH 2 )y-ring, where x and y are each independently 1 ⁇ 3, R 7 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • R 1 and R 2 together form
  • PG is H, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • PG is a silyl group substituent
  • X is a halogen
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above.
  • step (a) the compound of formula I reacts with HNR 4 R 5 in the presence of a deprotonation reagent and/or Lewis acid in an inert solvent to produce a compound of formula II-a.
  • step (a') in an inert solvent, in the presence of a deprotonation reagent and/or Lewis acid and base, the compound of formula I, HNR 4 R 5 , halosilane PG-X A reaction occurs to produce a compound of formula II.
  • Magnesium-based deprotonation reagents include but are not limited to methyl magnesium bromide (CH 3 MgBr), methyl magnesium chloride (CH 3 MgCl), ethyl magnesium bromide (CH 3 CH 2 MgBr), ethyl magnesium chloride (CH 3 CH 2 MgCl), vinyl magnesium chloride (CH 2 CHMgCl), isopropyl magnesium chloride (iPrMgCl), tert-butyl magnesium chloride (tBuMgCl), phenyl magnesium chloride (PhMgCl), or a combination thereof.
  • Lithium-based deprotonation reagents include, but are not limited to, n-butyllithium (nBuLi), tert-butyllithium (tBuLi), lithium hydride (LiH), ethyllithium (EtLi), propyllithium (PrLi), lithium chloride ( LiCl), methyl lithium (MeLi), isopropyl lithium (iPrLi), phenyl lithium (PhLi), cyclohexane lithium (cyHexLi), lithium diisopropylamide (LDA), lithium amide, hexamethyl two Lithium Silaneamide (LiHMDS) or a combination thereof.
  • nBuLi n-butyllithium
  • tBuLi tert-butyllithium
  • LiH lithium hydride
  • EtLi ethyllithium
  • PrLi propyllithium
  • LiCl lithium chloride
  • the Lewis acid includes, but is not limited to, trimethylaluminum and dimethylaluminum chloride.
  • the deprotonation reagent may be isopropylmagnesium chloride (iPrMgCl), tert-butylmagnesium chloride (tBuMgCl), and the Lewis acid may be trimethylaluminum.
  • the deprotonation reagent or Lewis acid may be present in any suitable amount.
  • the deprotonation reagent or Lewis acid may be present in an amount of at least 1.0 equivalent (mol/mol) to the compound of formula I, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol/mol).
  • the deprotonation reagent or Lewis acid may also be present in an amount of about 1.0 to about 10.0 equivalents (mol/mol) to the compound of formula I, for example about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 to about 3.0 equivalents ( mol/mol).
  • HNR 4 R 5 or its salt may be present in any suitable amount.
  • HNR 4 R 5 or its salt may be present in an amount of at least 1.0 equivalent (mol/mol) between 0 and the compound of formula I, or may be present in an amount of about 1.0 to about 10.0 equivalent (mol/mol) with the compound of formula I, For example, about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 to about 3.0 equivalents (mol/mol).
  • the method includes the steps: in an inert solvent, in the presence of a deprotonation reagent or Lewis acid and base, the compound of formula I, HNR 4 R 5 and halosilane react to produce the formula II compound.
  • the method includes: 1) reacting a compound of formula I with HNR 4 R 5 in the presence of a deprotonating reagent and/or Lewis acid in an inert solvent to produce a compound of formula II-a; 2) optionally The compound of formula II-a is isolated and obtained; 3) in an inert solvent, in the presence of a base, the compound of formula II-a is reacted with a halosilane to produce a compound of formula II.
  • any suitable halosilane can be used in the method for preparing the compound of formula II.
  • the halosilane may be fluorosilane, chlorosilane, bromosilane, or iodosilane.
  • the silane moiety can have any suitable substituents, such as alkyl, alkenyl, alkynyl, cycloalkyl, or phenyl.
  • halogenated silanes include, but are not limited to, trimethylchlorosilane (TMSCl), trimethylsilyl iodide (TMSI), triethylchlorosilane (TESCl), tert-butyldimethylchlorosilane (TBDMSCl), or trimethylchlorosilane (TMSCl).
  • TMSCl trimethylchlorosilane
  • TIPSCl trimethylchlorosilane
  • the halosilane may be a chlorosilane.
  • the halosilane may be trimethylchlorosilane (TMSCl), triethylchlorosilane (TESCl), tert-butyldimethylchlorosilane (TBDMSCl), or triisopropylchlorosilane (TIPSCl) .
  • the halosilane may be trimethylchlorosilane (TMSCl).
  • the halosilane can be present in any suitable amount.
  • the halosilane may be present in an amount of at least 1.0 equivalent (mol/mol) relative to the compound of formula II-a, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalent ( mol/mol).
  • the halogenated silane may also be present in an amount of about 1.0 to about 10.0 equivalents (mol/mol) relative to the compound of formula II-a, for example, about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 to about 2.0 equivalents (mol/mol) /mol).
  • the halosilane may be present in an amount of about 1.0 to about 5.0 equivalents (mol/mol) relative to the compound of formula II-a.
  • the halosilane may be present in an amount of about 1.0 to about 2.0 equivalents (mol/mol) relative to the compound of formula II-a.
  • the base includes, but is not limited to, triethylamine, diisopropylamine, imidazole, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4 , 6-collidine, 4-dimethylaminopyridine and quinuclidine.
  • the base is imidazole.
  • the base can be present in any suitable amount.
  • the base is present in an amount of at least 1.0 equivalent (mol/mol) relative to the compound of formula II-a.
  • the base is present in an amount of about 1.0 to about 4.0 equivalents (mol/mol) relative to the compound of formula II-a.
  • the present invention also provides a compound of formula IV,
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or a -CH(Ph)- group together ,
  • R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring;
  • R 3 is a hydroxyl protecting group
  • R 8 is -NHW, where W is H or an amino protecting group
  • PG is H or a silyl substituent.
  • the present invention provides a method for preparing a compound of formula IV, the method comprising the steps:
  • the PG is H or a silyl substituent
  • X is halogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined above.
  • step (b) the compound of formula II reacts with the compound of formula III in an inert solvent in the presence of a halogenated silane, a deprotonation reagent and a coupling reagent to produce a compound of formula IV.
  • step (b) the sub-steps are included:
  • an additive is added to promote the reaction, and the additive includes but not limited to LiCl, Ca(OTf) 2 , CaCl 2 , MgCl 2 , CeCl 3 , LaCl 3 , YCl 3 , NdCl 3 , or a combination thereof.
  • the additive is LiCl, Ca(OTf) 2 , CaCl 2 , MgCl 2 , CeCl 3 , LaCl 3 or a combination thereof.
  • step (b-3) when PG in formula II is a silyl substituent, in step (b-3), there may be no deprotonation reagent.
  • step (b-3) when PG in formula II is H, in step (b-3), a deprotonation reagent is also present in the reaction system.
  • the above method includes the steps: 1) forming a mixture of the compound of formula III, halosilane, deprotonation reagent, and solvent; 2) adding a coupling reagent to the mixture of step 1); 3) adding step 2 ) The resulting mixture is mixed with a compound of formula II-a and a deprotonating agent to obtain a compound of formula IV.
  • the deprotonation reagent can deprotonate the compound of formula II-a as follows:
  • M is metallic lithium, magnesium, sodium or calcium, preferably, M is metallic lithium or magnesium.
  • the "one-pot method” is used to prepare the compound of formula IV from the compound of formula II-a and the compound of formula III.
  • halosilane can be used in the method.
  • the halosilane can be present in any suitable amount.
  • the halosilane may also be present in an amount of about 1.0 to about 10.0 equivalents (mol/mol) relative to the compound of formula III, for example, about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 to about 2.0 equivalents (mol/mol). /mol).
  • iPrMgCl isopropyl magnesium chloride
  • iPrMgCl LiCl isopropyl magnesium chloride lithium chloride complex
  • PrMgCl LiCl propyl
  • the magnesium coupling agent, lithium coupling agent, or a combination thereof may be present in any suitable amount.
  • the aforementioned coupling agent may be present in an amount of at least 1.0 equivalent (mol/mol) relative to the compound of formula III.
  • the coupling agent may also be present in an amount of about 1.0 to about 10.0 equivalents (mol/mol) relative to the compound of formula III, such as about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 to about 2.0 equivalents (mol/mol) /mol).
  • the compound equivalent (mol/mol) ratio of the compound of formula II (II-a) and the compound of formula III is 0.5:1 to 1:2; preferably, the compound equivalent of the compound of formula II (II-a) and the compound of formula III is The (mol/mol) ratio is 1:1.5 to 1.5:1.
  • the deprotonation reagent in each step is a magnesium-based deprotonation reagent, a lithium-based deprotonation reagent, sodium hydride (NaH), CaH 2 or a combination thereof
  • the magnesium-based deprotonation reagent includes but is not limited to methyl bromide Magnesium (CH 3 MgBr), methyl magnesium chloride (CH 3 MgCl), ethyl magnesium bromide (CH 3 CH 2 MgBr), ethyl magnesium chloride (CH 3 CH 2 MgCl), vinyl magnesium chloride (CH 2 CHMgCl), iso Propyl magnesium chloride (iPrMgCl), tert-butyl magnesium chloride (tBuMgCl), phenyl magnesium chloride (PhMgCl), or a combination thereof.
  • Lithium-based deprotonation reagents include, but are not limited to, n-butyllithium (nBuLi), tert-butyllithium (tBuLi), lithium hydride (LiH), ethyllithium (EtLi), propyllithium (PrLi), lithium chloride ( LiCl), methyl lithium (MeLi), isopropyl lithium (iPrLi), phenyl lithium (PhLi), cyclohexane lithium (cyHexLi), lithium diisopropylamide (LDA), lithium amide, hexamethyl two Lithium Silaneamide (LiHMDS) or a combination thereof.
  • nBuLi n-butyllithium
  • tBuLi tert-butyllithium
  • LiH lithium hydride
  • EtLi ethyllithium
  • PrLi propyllithium
  • LiCl lithium chloride
  • the deprotonation reagent can also overlap with the aforementioned coupling agent (magnesium coupling reagent, lithium coupling reagent or a combination thereof).
  • the deprotonation reagent can be present in any suitable amount.
  • the aforementioned deprotonation reagent may be present in an amount of at least 1.0 equivalent (mol/mol) relative to the compound of formula II (II-a).
  • the deprotonation reagent may also be present in an amount of about 1.0 to about 10.0 equivalents (mol/mol) relative to the compound of formula II (II-a), for example, about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 To about 2.0 equivalents (mol/mol).
  • the preparation method of the compound of formula IV includes the following steps;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , PG and X are as defined above.
  • step a and step b can be performed by a one-pot method.
  • the present invention provides a method for preparing a compound of formula V, the method comprising the steps:
  • R 1 and R 2 are each independently a hydroxyl protecting group, or the R 1 and R 2 groups on adjacent carbon atoms can form a -C(R 6 ) 2 -group or a -CH(Ph)- group together ,
  • R 6 is each independently H, C1-C8 alkyl, phenyl or substituted phenyl, or two R 6 and the attached C atom together form a substituted or unsubstituted 5-7 membered carbocyclic ring;
  • R 3 is a hydroxyl protecting group
  • R 8 is -NHW, where W is H or an amino protecting group
  • PG is H or a silyl substituent.
  • step (c) it further includes: when PG is a silyl substituent and/or W in R 8 is an amino protecting group, performing a deprotection reaction, that is, consecutively or dividedly in any order removal of the PG step silyl group substituted with an amino protecting group 8 and / or the removal of R, or the simultaneous removal of the amino protecting group PG and R & lt 8 (PG thereby becomes H, W becomes H).
  • the R 1 , R 2 , and R 3 groups are not affected in the deprotection reaction.
  • the deprotection reaction can be carried out simultaneously or continuously in any order or in steps.
  • the deprotecting agent used to remove the silyl substituent and the amino protecting group may be the same or different.
  • the deprotecting agent can be any suitable reagent that removes the protective group PG alone, removes the protective group in R 8 alone, or removes the protective group in PG and R 8 at the same time, such as a fluorine reagent, a base, an acid, or a combination thereof .
  • the fluorine reagent includes, but is not limited to, tetrabutylammonium fluoride, triethylamine hydrogen trifluoride, ammonium fluoride and the like.
  • the acid includes, but is not limited to, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), formic acid, hydrochloric acid, concentrated hydrochloric acid, and the like.
  • the base may be an organic base, an inorganic base, a magnesium Grignard reagent, or a lithium Grignard reagent.
  • Representative bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, sodium methoxide, sodium ethoxide, methyl Base magnesium bromide, methyl lithium, etc.
  • the deprotection agent can also be used directly as a reaction solvent.
  • the deprotection agent may be present in any suitable amount.
  • the deprotection agent may be present in an amount of at least 1.0 equivalent (mol/mol) relative to the compound of formula IV.
  • the deprotection agent may also be present in an amount of about 1.0 to about 10.0 equivalents (mol/mol) relative to the compound of formula IV, for example, about 1.0 to about 5.0 equivalents (mol/mol), or about 1.0 to about 2.0 equivalents (mol/mol) /mol).
  • the preparation method of compound V of the present invention includes the steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , PG and X are as defined above.
  • Each reaction step can be carried out stepwise or continuously.
  • the preparation method of compound V of the present invention includes the steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , PG and X are as defined above.
  • reaction steps can be carried out stepwise or continuously.
  • the compound of formula IV can be isolated by post-treatment, and then the aforementioned deprotection reaction can be carried out to obtain the compound of formula V, or the deprotecting agent can be directly added in the post-treatment process to obtain the compound of formula V.
  • the compound of formula II and compound of formula IV of the present invention can be used as intermediates for the preparation of remdesivir.
  • the present invention also provides a method for preparing radcivir, which comprises using the compound of formula IV as an intermediate to prepare radcivir.
  • the method may also include other steps commonly used in the art to prepare remdesivir from the compound of formula V.
  • the compound of formula V or its pharmaceutically acceptable salt obtained by this method can refer to the literature (J.Med.Chem.2017,60,1648-61; Nature.2016,531,381-5; Bioorg.Med.Chem. Lett. 2012, 22, 2705-7; WO2016069826) is used in the preparation of Redecive.
  • the present invention provides a new intermediate for the preparation of radcivir and its use.
  • the method for preparing radcivir by using the intermediate has easy-to-obtain raw materials, simple process, and mild reaction conditions suitable for industrial production.
  • the method of the present invention has simple and easy operation, stable process and easy control.
  • the reaction product has high yield and good purity.
  • the compound of formula V prepared from formula IV has a high yield and less impurities, and the reaction can be completed in one step, which is suitable for a one-pot method.
  • the post-reaction processing is convenient, safe, does not cause harm to human health and the environment, and the production cost is low.
  • 2,3,5-Tribenzyloxy-D-ribonic acid-1,4-lactone 1 (20.0g, 47.8mmol) and N,O-dimethylhydroxylamine hydrochloride (7.0g, 71.7mmol, 1.5 eq) was added to anhydrous tetrahydrofuran (70mL), under ice bath, 2M isopropylmagnesium chloride (71.7mL, 143.4mmol, 3eq) was added dropwise, after the addition, the reaction was continued at this temperature until the reaction was complete.
  • reaction solution was slowly poured into 1M dilute hydrochloric acid (150 mL), extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and brine in sequence, dried and concentrated to obtain compound 2a, 24.1 g of oily substance, and the obtained amount exceeded the theoretical value.
  • N,O-Dimethylhydroxylamine hydrochloride (1.56g, 16.0mmol, 1.6eq) was added to dichloromethane (15mL), stirred at minus 5 degrees Celsius, and 2M trimethylaluminum (10mL, 20mmol, 2eq) was slowly added dropwise ), after the addition, stir under ice bath for 30 minutes, and then add 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone 1 (4.2g, 10.0mmol) in dichloromethane ( 10mL), TLC monitors until the reaction is complete.
  • the reaction solution was added to an aqueous solution of sodium potassium tartrate, dichloromethane was added, stirred, and the organic phase was separated. The organic phase was washed with a saturated aqueous sodium chloride solution, dried and concentrated to obtain 4.8 g of an oily substance with a yield of 100%.
  • the 1 H NMR spectrum is the same as the product of Example 1.
  • 2,3,5-Tribenzyloxy-D-ribonic acid-1,4-lactone 1 (4.2g, 10.0mmol) and N-methylpiperazine (1.5g, 15.0mmol, 1.5eq) were added to tetrahydrofuran (20mL), under ice bath, drop 2M isopropylmagnesium chloride (15.0mL, 30.0mmol, 3eq), after the addition, gradually warm to room temperature and react until the reaction is complete.
  • the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and brine in sequence, dried and concentrated to obtain 3.5 g of an oily substance with a yield of 67.5%.
  • reaction solution was raised to minus 10 degrees Celsius, and 1.3M isopropylmagnesium chloride and lithium chloride solution (1.9mL, 2.5mmol, 1.1eq) was added, stirred for 1h, and 3a-1 (1.36g, 2.3mmol, 1eq) in tetrahydrofuran was added (3mL), the reaction solution was slowly raised to room temperature and stirred, and TLC monitored until the product no longer increased.
  • the reaction solution was added to saturated aqueous ammonium chloride solution, stirred for 5 minutes, extracted with ethyl acetate, and the organic layer was separated.
  • the crude product of 4a-1 was added to tetrahydrofuran (10 mL), 50% trifluoroacetic acid aqueous solution (1 mL) was added, stirred at room temperature, and TLC monitored until the starting material disappeared.
  • the reaction solution was added to water (15 mL), extracted with ethyl acetate, and the organic layer was separated.
  • the organic layer was washed with saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution, dried, concentrated, and separated by silica gel column chromatography to obtain a foamy solid 0.91 g, further beating with a mixed solvent of methyl tertiary ether and n-heptane to obtain 0.70 g of a white powdery solid with a yield of 55%.
  • reaction solution was added to a saturated aqueous ammonium chloride solution, stirred for 5 minutes, and then extracted with ethyl acetate to separate the organic layer.
  • the organic layer was washed with a saturated aqueous sodium chloride solution, dried, and concentrated to obtain a crude product of 4a-2.
  • reaction solution was added to a saturated aqueous ammonium chloride solution, and after stirring for 5 minutes, it was extracted with ethyl acetate to separate the organic layer.
  • the organic layer was washed with a saturated aqueous sodium chloride solution, dried, and concentrated to obtain a crude product of 4a-3.
  • Tetrahydrofuran solution (0.5mL, 1.0mmol, 1eq), 20 minutes later, add 1.3M isopropyl magnesium chloride lithium chloride tetrahydrofuran solution (1.9mL, 2.5mmol, 1.1eq), stir at minus 10 degrees Celsius for 1h, add 3a-3 (0.55 g, 1.0 mmol, 1 eq) in tetrahydrofuran solution (3 mL), the temperature of the reaction solution was slowly raised to room temperature, and TLC monitored until the product no longer increased. Add 1M dilute hydrochloric acid to the reaction solution to make the reaction system acidic, and stir under ice bath for about 1 hour.
  • reaction solution was added to a saturated aqueous ammonium chloride solution, and after stirring for 5 minutes, it was extracted with ethyl acetate to separate the organic layer.
  • the organic layer was washed with a saturated aqueous sodium chloride solution, dried, and concentrated to obtain a crude product of 4a-3.
  • the crude product of 4a-3 was added to tetrahydrofuran (10 mL), 50% trifluoroacetic acid aqueous solution (1 mL) was added, and the mixture was stirred at room temperature. TLC monitored until the starting material disappeared. The reaction solution was added to water (15 mL), extracted with ethyl acetate, and the organic layer was separated.
  • Tetrahydrofuran solution (0.5 mL, 1.0 mmol, 1 eq), 20 minutes later, 1.3 M isopropyl magnesium chloride lithium chloride tetrahydrofuran solution (1.9 mL, 2.5 mmol, 1.1 eq) was added, and the mixture was stirred at minus 10 degrees Celsius for 1 h.
  • Step A 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine (1.3g, 5.0mmol) was added to anhydrous tetrahydrofuran (6mL), added at minus 10 degrees Celsius Trimethylchlorosilane (1.1g, 10.0mmol, 2.0eq), after stirring for 10 minutes, slowly add 3M methylmagnesium bromide ether solution (3.3mL, 10.0mmol, 2.0eq) dropwise, after the addition, stir for 20 minutes, Subsequently, 1.3M isopropyl magnesium chloride lithium chloride tetrahydrofuran solution (5.0 mL, 6.5 mmol, 1.3 eq) was added, the reaction temperature was controlled between minus 10 degrees Celsius and 0 degrees Celsius, and the mixture was stirred for about 1 hour.
  • Step B 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone 1 (2.1g, 5.0mmol) and N,O-dimethylhydroxylamine hydrochloride (0.88g, 9.0 mmol, 1.8eq) was added to anhydrous tetrahydrofuran (10mL), under ice bath, slowly added 2M isopropylmagnesium chloride tetrahydrofuran solution (9.0mL, 18mmol, 3.6eq), stirred for 3h, then added 2M isopropylmagnesium chloride ( 2.5 mL, 5.0 mmol, 1.0 eq), 20 minutes later, add the solution of step A to the reaction solution.
  • 2M isopropylmagnesium chloride 2.5 mL, 5.0 mmol, 1.0 eq
  • reaction solution was added to a saturated aqueous ammonium chloride solution, stirred for 10 minutes, extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1M dilute hydrochloric acid, saturated sodium bicarbonate and sodium chloride solution in turn, dried and concentrated Obtain an oily substance, add methyl tertiary ether, precipitate insoluble matter after standing, and filter to obtain 1.6 g of white solid.
  • Step A 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone 1 (2.1g, 5.0mmol) and N,O-dimethylhydroxylamine hydrochloride (0.88g, 9.0 mmol, 1.8eq) was added to anhydrous tetrahydrofuran (10mL), under ice bath, slowly added 2M isopropylmagnesium chloride tetrahydrofuran solution (9.0mL, 18mmol, 3.6eq), stirred for 3h, then added 2M isopropylmagnesium chloride ( 2.5mL, 5.0mmol, 1.0eq), stirred for 20 minutes.
  • Step B 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine (1.3g, 5.0mmol) was added to anhydrous tetrahydrofuran (6mL), added at minus 10 degrees Celsius Trimethylchlorosilane (1.1g, 10.0mmol, 2.0eq), after stirring for 10 minutes, slowly add 3M methylmagnesium bromide ether solution (3.3mL, 10.0mmol, 2.0eq) dropwise, after the addition, stir for 20 minutes, Then add 1.3M isopropyl magnesium chloride lithium chloride tetrahydrofuran solution (5.0mL, 6.5mmol, 1.3eq), control the reaction temperature between minus 10 degrees Celsius to 0 degrees Celsius, stir for about 1 hour, and then add the reaction solution of step A, After the addition, the reaction was slowly raised to room temperature, and TLC monitored until the product no longer increased.
  • Trimethylchlorosilane 1.1g, 10.0mmol, 2.0eq
  • reaction solution was added to a saturated aqueous ammonium chloride solution, stirred for 10 minutes, extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1M dilute hydrochloric acid, saturated sodium bicarbonate and sodium chloride solution in turn, dried and concentrated An oil was obtained, methyl tertiary ether was added, and the insoluble matter was precipitated after standing, and filtered to obtain 1.7 g of white solid with a yield of 62%.

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Abstract

本发明提供了瑞德西韦(Remdesivir)的中间体及其制备方法。所述制备方法具有成本低、收率高、产品纯度好等优点，可实现瑞德西韦的高效合成。各式中，R 1、R 2、R 3、R 4、R 5、R 8、PG和X如说明书所定义。

Description

瑞德西韦的中间体及其制备方法 技术领域
本发明涉及制药技术领域，具体涉及瑞德西韦中间体、其制备方法和其用于制备瑞德西韦的用途。
背景技术
瑞德西韦(Remdesivir,GS-5734)是由吉利德科学公司(Gilead)开发的一种新型碳核苷氨基磷酸酯前药，该化合物具有广谱的抗RNA病毒活性，目前正处于临床研究阶段。Nature.2016；531(7594):381-5和J.Med.Chem.2017；60(5):1648-1661两篇文章先后报道化合物GS-5734对Ebola病毒具有显著的抑制作用，并发现其是通过抑制Ebola病毒的RdRp(RNA-dependent RNA-polymerases)活性以阻断病毒复制。此外，化合物GS-5734对其他RNA类病毒也具有潜在的抑制活性，如丙肝病毒(HCV)、冠状病毒(SARS、MERS)、呼吸道合胞病毒(RSV)、拉沙热病毒(LASV)等。
2020年伊始，新型冠状病毒(COVID-19)爆发后，瑞德西韦成功救治一名美国感染人员，其抗新型冠状病毒的疗效受到广泛关注。2020年2月我国学者在Cell Research(2020,0:1–3)上报道了瑞德西韦体外抗COVID-19的活性，其EC 50为0.77μM，显著优于广谱抗病毒药物利巴韦林(EC 50＝109.5μM)和法匹拉韦(EC 50＝61.88μM)，表现出了良好的抗新型冠状病毒应用前景。由于该药物已完成抗Ebola临床II试验，且其安全性也已得到验证，因此其特批的针对新型冠状病毒III期临床试验已于2020年2月4日在中国展开。
现有文献(J.Med.Chem.2017,60,1648-61；Nature.2016,531,381-5；Bioorg.Med.Chem.Lett.2012,22,2705-7；WO2016069826)已报道了关于瑞德西韦的如下制备方法：
Figure PCTCN2021079143-appb-000001
但该路线存在诸多不足，例如，由化合物1与化合物2反应制备化合物3的步骤A过程中杂质多且不易分离，收率过低，产品化合物3需要通过柱层析纯化获得。步骤E和步骤F也收率不理想，不利于工业化大生产。
因此，本领域急需提供一种成本低、收率高、产品纯度好的瑞德西韦及其中间体的合成方法。
发明内容
本发明的目的是提供一种成本低、收率高、产品纯度好的瑞德西韦及其中间体的合成方法。
本发明另一目的是提供可用做制备瑞德西韦的中间体的化合物。
本发明第一方面提供了一种制备式V化合物的方法，所述方法包括步骤：
(c)式IV化合物发生脱保护反应和成环反应，生成式V化合物；
Figure PCTCN2021079143-appb-000002
其中，
R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 8为-NHW，其中，W为H或氨基保护基；和
PG为H或硅烷基取代基。
在另一优选例中，所述的5-7元碳环是饱和的。
在另一优选例中，所述羟基保护基选自下组：取代或未取代的苄基、取代或未取代的萘基亚甲基
Figure PCTCN2021079143-appb-000003
三甲基硅基(TMS)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、甲基-甲氧基(MOM)、四氢吡喃基(THP)、叔丁基、烯丙基或其组合；所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C1-C6烷氧基、卤素、硝基。
在另一优选例中，所述羟基保护基选自下组：苄基、萘基亚甲基
Figure PCTCN2021079143-appb-000004
三甲基硅基(TMS)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、甲基-甲氧基(MOM)、四氢吡喃基(THP)、叔丁基、烯丙基、或其组合。
在另一优选例中，所述硅烷基取代基选自下组：三甲基硅基(TMS)、三乙基硅基(TES)、叔丁基二甲基硅基(TBDMS或TBS)、三异丙基硅基(TIPS)、叔丁基二苯基硅基(TBDPS)或其组合。
在另一优选例中，R 1、R 2和R 3中的一个、二个或三个为萘基亚甲基。
在另一优选例中，对于R1和R2而言，所述的取代指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、卤素。
在另一优选例中，所述的在相邻碳原子上的R 1和R 2基团可以一起形成-CH 2-、-C(C4-C6亚烷基)、或-CH(Ph)-。
在另一优选例中，R 1和R 2是相同的。
在另一优选例中，R 1、R 2和R 3是相同的。
在另一优选例中，R 1和R 2一起形成-CH(Ph)-。
在另一优选例中，W为H。
在另一优选例中，W为氨基保护基。
在另一优选例中，步骤(c)中脱保护反应是任选的，当R 8为氨基且PG为H时，则步骤(c)中不必进行脱保护反应。
在另一优选例中，R 8为氨基且PG为硅烷基。
在另一优选例中，R 8为氨基且PG不为H。
在另一优选例中，当R 8为氨基且PG为氢时，R 1、R 2、R 3不同时为苄基。
在另一优选例中，所述R 8选自下组：氨基、乙酰氨基(NHAc)、苯甲酰氨基(NHBz)或NHBoc。
在另一优选例中，在步骤(c)中，还包括：当PG为硅烷基取代基和/或R 8中的W为氨基保护基时，进行脱保护反应，即按任意顺序连续或分步脱除PG中硅烷基取代基、和/或脱除R 8中的氨基保护基，或者同时脱除PG和R 8中的氨基保护基(从而使PG变为H，W变为H)。
在另一优选例中，在所述的脱保护反应中，不影响R 1、R 2、R 3基团。
在另一优选例中，所述脱保护剂选自下组：氟试剂、碱、酸，或其组合。
在另一优选例中，所述氟试剂选自下组：四丁基氟化铵、三乙胺三氟化氢、氟化铵。
在另一优选例中，所述脱保护剂为酸，且所述酸选自下组：乙酸、硫酸、甲磺酸、对甲苯磺酸、三氟甲磺酸、三氟乙酸(TFA)、甲酸、盐酸、浓盐酸。
在另一优选例中，所述脱保护剂为碱，且所述碱选自下组：有机碱、无 机碱、镁格氏试剂、锂格氏试剂，或其组合。
在另一优选例中，所述脱保护剂为碱，且所述碱选自下组：氢氧化锂、氢氧化钠、氢氧化钾、氨、甲醇钠、乙醇钠、甲基溴化镁、甲基锂等。所述脱保护剂也可以直接作为反应溶剂。
在另一优选例中，在步骤(c)中，在惰性溶剂中，在脱保护剂存在下，式IV化合物发生脱保护反应和成环反应，从而生成式V化合物。
在另一优选例中，在步骤(c)前，还包括步骤：
(b)式II化合物和式III化合物反应，生成式IV化合物；
Figure PCTCN2021079143-appb-000005
式中，
R 4、R 5各自独立地选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、或取代或未取代的C1-C6烷氧基；或R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元含有1-2个N杂原子和0-1个选自O、或S杂原子的杂环烷基；
其中所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基；和
X为卤素；
R 1、R 2、R 3、R 8和PG如上定义。
在另一优选例中，所述的R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元的含2个N杂原子的杂环烷基。
在另一优选例中，R 4、R 5和相连的氮原子一起形成5至7元环；较佳地，所述5至7元环为-N(CH 2)x(CH 2)y-环、-N(CH 2)xO(CH 2)y-环或-N(CH 2)x-NR 7-(CH 2)y-环，其中，x、y各自独立地为1～3，R 7为氢、C1～C6烷基、C3-C6环烷基。
在另一优选例中，X为氯、溴或碘。
在另一优选例中，在步骤(b)中，在惰性溶剂中，在卤代硅烷和偶联试剂和去质子化试剂存在下，式II化合物与式III化合物发生反应，生成式IV化合物。
在另一优选例中，在步骤(b)中，包括子步骤：
(b-1)使式III化合物和卤代硅烷、去质子化试剂、溶剂混合，形成混合物b1；
(b-2)向所述混合物b1中加入偶联试剂，形成混合物b2；
(b-3)将所述混合物b2与式II化合物以及任选地去质子化试剂混合，进行反应，从而得到式IV化合物。
在另一优选例中，在步骤(b)之前，所述方法包括步骤(a)或(a')：
(a)式I化合物与式A化合物发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000006
其中，PG为H，R 1、R 2、R 3、R 4和R 5如上定义；
或者
(a')式I化合物与式A化合物与卤代硅烷发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000007
其中，PG为硅烷基，R 1、R 2、R 3、R 4和R 5如上定义。
在另一优选例中，式A化合物为N,O-二甲基羟胺或其盐酸盐。
在另一优选例中，在步骤(a)中，在惰性溶剂中，在去质子化试剂和/或路易斯酸存在下，式I化合物与HNR 4R 5发生反应，生成式II-a化合物。
在另一优选例中，在步骤(a')中，在惰性溶剂中，在去质子化试剂和/或路易斯酸和碱存在下，式I化合物、HNR 4R 5、卤代硅烷PG-X发生反应，生成式II化合物。
在另一优选例中，步骤(a')包括步骤：
(a'1)式I化合物与HNR 4R 5发生反应，生成式II-a化合物；和
Figure PCTCN2021079143-appb-000008
(a'2)式II-a化合物与卤代硅烷PG-X发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000009
式中，PG为硅烷基取代基；且
R 1、R 2、R 3、R 4、R 5如上定义。
在另一优选例中，步骤(a)或(a')中，所述反应具有一个或多个下述特征：
(1)所述去质子化试剂选自下组：镁基去质子化试剂、锂基去质子化试剂，或其组合；
(2)所述路易斯酸选自下组：三甲基铝、二甲基氯化铝，或其组合，较佳地，三甲基铝；和/或
(3)所述碱选自下组：三乙胺、二异丙基胺、咪唑、二异丙基乙基胺、N,N-二乙基苯胺、吡啶、2,6-二甲基吡啶、2,4,6-可力丁、4-二甲基氨基吡啶、奎宁环，或其组合，较佳地，所述碱为咪唑。
在另一优选例中，所述镁基去质子化试剂选自下组：甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)、乙基溴化镁(CH 3CH 2MgBr)、乙基氯化镁(CH 3CH 2MgCl)、乙烯基氯化镁(CH 2CHMgCl)、异丙基氯化镁(iPrMgCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)，或其组合。
在另一优选例中，所述锂基去质子化试剂选自下组：正丁基锂(nBuLi)、叔丁基锂(tBuLi)、氢化锂(LiH)、乙基锂(EtLi)、丙基锂(PrLi)、氯化锂(LiCl)、甲基锂(MeLi)、异丙基锂(iPrLi)、苯基锂(PhLi)、环己烷锂(cyHexLi)、二异丙基氨基锂(LDA)、氨基锂、六甲基二硅烷氨基锂(LiHMDS)，或其组合。
在另一优选例中，所述镁基去质子化试剂选自下组：甲基溴化镁(CH 3MgBr)、乙基氯化镁(CH 3CH 2MgCl)、乙烯基氯化镁(CH 2CHMgCl)、异丙基氯化镁(iPrMgCl)、(叔丁基氯化镁)tBuMgCl、(苯基氯化镁)PhMgCl，或其组合。
在另一优选例中，步骤(b)中，所述反应具有一个或多个下述特征：
(1)所述卤代硅烷选自下组：氟硅烷、氯硅烷、溴硅烷，碘硅烷，或其组合；
(2)所述偶联试剂选自下组：镁偶联试剂、锂偶联试剂，或其组合；和/或
(3)所述去质子化试剂选自下组：镁基去质子化试剂、锂基去质子化试剂、氢化钠(NaH)、CaH 2，或其组合。
在另一优选例中，所述卤代硅烷选自下组：三甲基氯硅烷(TMSCl)、三甲基碘硅烷(TMSI)、三乙基氯硅烷(TESCl)、叔丁基二甲基氯硅烷(TBDMSCl)或三异丙基氯硅烷(TIPSCl)，更佳地，三甲基氯硅烷(TMSCl)、三乙基氯硅烷(TESCl)、叔丁基二甲基氯硅烷(TBDMSCl)或三异丙基氯硅烷(TIPSCl)。
在另一优选例中，所述镁偶联试剂选自下组：异丙基氯化镁(iPrMgCl)、异丙基氯化镁氯化锂络合物(iPrMgCl·LiCl)、丙基氯化镁氯化锂络合物(PrMgCl·LiCl)、仲丁基氯化镁氯化锂络合物(sBuMgCl·LiCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)、乙烯基溴化镁(CH 2＝CHMgBr)、乙基溴化镁(CH 3CH 2MgBr)、甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)或其组合。
在另一优选例中，所述锂偶联试剂选自下组：正丁基锂(nBuLi)、叔丁基锂 (tBuLi)、乙基锂(EtLi)、丙基锂(PrLi)、甲基锂(MeLi)、异丙基锂(iPrLi)、苯基锂(PhLi)、环己烷锂(cyHexLi)，或其组合。
在另一优选例中，步骤(b)中，还加入添加剂，所述添加剂选自下组：LiCl、Ca(OTf) 2、CaCl 2、MgCl 2、CeCl 3、LaCl 3、YCl 3、NdCl 3、或其组合，较佳地，所述添加剂选自下组：LiCl、Ca(OTf) 2、CaCl 2、MgCl 2、CeCl 3、LaCl 3或其组合。
本发明的第二方面，提供了式IV化合物，
Figure PCTCN2021079143-appb-000010
其中，
R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 8为-NHW，其中，W为H或氨基保护基；和
PG为H或硅烷基取代基。
在另一优选例中，当R 8为氨基且PG为氢时，R 1、R 2、R 3不同时为苄基。
在另一优选例中，R1、R2和R3中的一个、二个或三个为萘基亚甲基。
本发明第三方面，提供了一种如权利要求4所述的式IV化合物的制备方法，所述方法包括步骤：
(b)式II化合物与式III化合物发生反应，生成式IV化合物；和
Figure PCTCN2021079143-appb-000011
式中，
X为卤素；
R 1、R 2、R 3、R 4、R 5、R 8和PG如上所定义。
在另一优选例中，在步骤(b)中，在惰性溶剂中，在卤代硅烷和偶联试剂和去质子化试剂存在下，式II化合物与式III化合物发生反应，生成式IV化合物。
在另一优选例中，在步骤(b)中，包括子步骤：
(b-1)使式III化合物和卤代硅烷、去质子化试剂、溶剂混合，形成混合物b1；
(b-2)向所述混合物b1中加入偶联试剂，形成混合物b2；
(b-3)将所述混合物b2与式II化合物以及任选地去质子化试剂混合，进行反应，从而得到式IV化合物。
在另一优选例中，当式II中的PG为硅烷基取代基时，在步骤(b-3)中，反应体系中可不存在去质子化试剂。
在另一优选例中，当式II中的PG为H时，在步骤(b-3)中，在反应体系中还存在去质子化试剂。
在另一优选例中，在步骤(b)之前，所述方法包括步骤(a)或(a')：
(a)式I化合物与式A化合物发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000012
其中，PG为H，R 1、R 2、R 3、R 4和R 5如上定义；
或者
(a')式I化合物与式A化合物与卤代硅烷发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000013
其中，PG为硅烷基，R 1、R 2、R 3、R 4和R 5如上定义。
本发明第四方面，提供了式II化合物，
Figure PCTCN2021079143-appb-000014
其中，R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2 基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 4、R 5各自独立地选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、或取代或未取代的C1-C6烷氧基；或R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元含有1-2个N杂原子和0-1个选自O、或S杂原子的杂环烷基；和
PG为H或硅烷基取代基；
其中所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基。
在另一优选例中，PG为氢。
在另一优选例中，所述的R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元的含2个N杂原子的杂环烷基。
在另一优选例中，R 4、R 5和相连的氮原子一起形成5至7元环；较佳地，所述5至7元环为-N(CH 2)x(CH 2)y-环、-N(CH 2)xO(CH 2)y-环或-N(CH 2)x-NR 7-(CH 2)y-环，其中，x、y各自独立地为1～3，R 7为氢、C1～C6烷基、C3-C6环烷基。
本发明第五方面，提供了一种本发明第四方面所述式II化合物的制备方法，所述方法包括步骤：
(a)式I化合物与式A化合物发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000015
其中，PG为H，R 1、R 2、R 3、R 4和R 5如上定义；
或者
(a’)式I化合物与式A化合物与卤代硅烷PG-X发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000016
其中，PG为硅烷基取代基，X为卤素；R 1、R 2、R 3、R 4、R 5如上定义。
在另一优选例中，在步骤(a)中，在惰性溶剂中，在去质子化试剂和/或路易斯酸存在下，式I化合物与HNR 4R 5发生反应，生成式II-a化合物。
在另一优选例中，在步骤(a')中，在惰性溶剂中，在去质子化试剂和/或路易斯酸和碱存在下，式I化合物、HNR 4R 5、卤代硅烷PG-X发生反应，生成式II化合物。
在另一优选例中，步骤(a')包括步骤：
(a'1)式I化合物与HNR 4R 5发生反应，生成式II-a化合物；和
Figure PCTCN2021079143-appb-000017
(a'2)式II-a化合物与卤代硅烷PG-X发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000018
式中，PG为硅烷基取代基；且
R 1、R 2、R 3、R 4和R 5如上定义。
本发明第六方面，还提供了一种制备化合物V的方法，所述方法包括步骤：
(a)式I化合物、HNR 4R 5进行取代反应，生成式II化合物；
Figure PCTCN2021079143-appb-000019
(b)式II化合物与式III化合物发生反应，生成式IV化合物；和
Figure PCTCN2021079143-appb-000020
(c)式IV化合物发生脱保护反应和成环反应，生成式V化合物；
Figure PCTCN2021079143-appb-000021
各式中，
R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 4、R 5各自独立地选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、或取代或未取代的C1-C6烷氧基；或R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元含有1-2个N杂原子和0-1个选自O、或S杂原子的杂环烷基；
R 8为-NHW，其中，W为H或氨基保护基；
PG为H或硅烷基取代基；和
各X独立地为卤素；
其中所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基。
在另一优选例中，PG为硅烷基取代基。
在另一优选例中，R 8为氨基。
在另一优选例中，当式II化合物中，PG为硅烷基取代基时，步骤(a)中还包括卤代烷基。
在另一优选例中，所述的方法还包括步骤：
(d)将式V化合物作为中间体，进一步制得瑞德西韦。
本发明第七方面，提供了一种瑞德西韦的制备方法，所述方法使用式IV化合物作为中间体来制备瑞德西韦。
本发明第八方面，提供了式II化合物或式IV化合物的用途，用做制备瑞德西韦的中间体。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方 案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选和测试，首次提供了新颖的中间体IV和II，并开发了进一步制备瑞德西韦的中间体V的制备方法。本发明方法的原料易得、反应条件温和、安全、不对人体健康与环境产生危害、生产成本低，此外，本发明还具有反应产物收率高、纯度高、杂质少等优点，便于经济、方便地进行工业化生产。本发明的中间体(尤其是式IV化合物)，可作为中间体进一步制备瑞德西韦。在此基础上完成了本发明。
术语
除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“室温”是指温度为4-40℃，较佳地，25±5℃。
除非另有表述，术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即，C1-6表示1-6个碳，包括含有2、3、4、5或6个碳原子的烷基，较佳地，1-3个碳)。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基等。
除非另有表述，术语“烯基”指具有一个或多个双键的不饱和烷基，包括具有2、3、4、5或6个碳原子的烯基。类似地，术语“炔基”指具有一个或多个三键的不饱和烷基，包括具有2、3、4、5或6个碳原子的烯基。此类不饱和烷基的例子包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基和更高级的同系物和异构体。
除非另有表述，术语环烷基包括具有3、4、5或6个环碳原子的环烷基，其可以是并环、螺环、桥环形式。术语“杂环烷基”是指含有一至三个选自N、O和S的杂原子的环烷基，其中氮和硫原子任选被氧化，且氮原子任选被季铵化，包括具有4、5、6、7或8个环原子的杂环烷基。
除非另有表述，术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团，例如-CH 2CH 2CH 2CH 2-。
除非另有表述，术语"烷氧基"或“烷基氧基”、"烷氨基""或“烷基氨基”和" 烷硫基"或“烷基硫基”(或硫代烷氧基)以其常规意义使用，指代分别经氧原子、氨基或硫原子连接于分子的其余部分的那些烷基。此外，对于二烷基氨基，烷基部分可以相同或不同，也可和与各烷基相连的氮原子组合形成3-7元环。因此，-NR4R5所示基团表示包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基(azetidinyl)等。
除非另有表述，术语“卤代”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴、或碘原子。此外，诸如“卤代烷基”等术语表示包括单卤代烷基或多卤代烷基。例如，术语“C 1-4卤代烷基”表示包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有表述，术语“芳基”表示多不饱和的(通常芳香性)的烃基，其可以是单环或稠合在一起或共价连接的多环(最多三环)。芳基的非限制性例子包括苯基、萘基和联苯基。
在本文中，除特别说明之处，术语“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基。
如本文所用，术语“保护基”是指掩蔽或改变官能团的性质或化合物整体的性质的化合物的基团部分。保护基的化学亚结构变化很大。保护基团的一个功能是用作合成亲本药物的中间体。化学保护基团和保护/去保护的策略是本领域公知的。参见“Protective Groups in Organic Chemistry”，Theodora W.Greene(John Wiley&Sons,Inc.,New York,1991)。另参见Protective Groups in Organic Chemistry，Peter GM Wuts and Theodora W.Greene，第4版，2006。保护基通常被用于掩盖某些官能团的反应性，以帮助所需化学反应的效率，例如以有序和计划的方式制备和破坏化学键。除反应性以外，化合物官能团的保护还改变了受保护的官能团的其他物理性质，如极性、亲脂性(疏水性)以及其他可通过常用分析工具测定的性质，化学保护的中间体本身可能是生物活性的或无活性的。
如本文所用，“羟基保护基”是指可用于保护羟基(-OH)的保护基。所述羟基保护基包括但并不限于：取代或未取代的苄基、取代或未取代的萘基亚甲基
Figure PCTCN2021079143-appb-000022
三甲基硅基(TMS)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、甲基-甲氧基(MOM)、四氢吡喃基(THP)、叔丁基或烯丙基；所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C1-C6烷氧基、卤素、硝基。
如本文所用，“氨基保护基”是指可用于保护氨基(-NH 2)的保护基。所述氨基保护基包括但并不限于：苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰 基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、烷基酰基(如乙酰基)、苯甲酰基等。
如本文所用，术语“脱保护剂”是指能够除去保护基的任何试剂。脱保护剂将取决于所使用的保护基团的类型。代表性的脱保护剂是本领域已知的，可以在Protective Groups in Organic Chemistry,Peter G.M.Wuts and Theodora W.Greene,4th Ed.,2006中找到。
如本文所用，术语“形成反应混合物”是指使至少两种不同物质接触的过程，以使得它们混合在一起并且可以反应。
如本文所用，术语“偶联剂”是指能够偶联两种不同化合物的试剂。偶联剂可以是催化量的或化学计量的。例如，偶联剂可以是锂基偶联剂、铝基偶联剂或镁基偶联剂如格氏试剂。示例性偶联剂包括但不限于异丙基氯化镁(iPrMgCl)、异丙基氯化镁氯化锂络合物(iPrMgCl·LiCl)、丙基氯化镁氯化锂络合物(PrMgCl·LiCl)、仲丁基氯化镁氯化锂络合物(sBuMgCl·LiCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)、乙烯基溴化镁(CH 2＝CHMgBr)、乙基溴化镁(CH 3CH 2MgBr)、甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)、正丁基锂(nBuLi)、叔丁基锂(tBuLi)、乙基锂(EtLi)、丙基锂(PrLi)、甲基锂(MeLi)、三甲基铝，或其组合。
如本文所用，术语“卤代硅烷”是指具有与硅原子连接的至少一个卤素基团的硅烷。代表性的卤代硅烷具有式卤素-Si(R) 3，其中每个R基团可以是烷基(C1-C6烷基)、烯基(C2-C6烯基)、环烷基(C3-C8环烷基)、苯基或其它含硅基团。具体的卤代硅烷包括但不限于三甲基氯硅烷(TMSCl)、三甲基碘硅烷(TMSI)、三乙基氯硅烷(TESCl)、叔丁基二甲基氯硅烷(TBDMSCl)或三异丙基氯硅烷(TIPSCl)。
如本文所用，术语“去质子化试剂”指能够从分子中脱去质子(H)产生其共轭碱的物质。例如所述去质子化试剂可以是镁基去质子化试剂、锂基去质子化试剂，或其组合。示例性的镁基去质子化试剂包括但不限于甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)、乙基溴化镁(CH 3CH 2MgBr)、乙基氯化镁(CH 3CH 2MgCl)、乙烯基氯化镁(CH 2CHMgCl)、异丙基氯化镁(iPrMgCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)，，或其组合。示例性的锂基去质子化试剂包括但不限于正丁基锂(nBuLi)、叔丁基锂(tBuLi)、氢化锂(LiH)、乙基锂(EtLi)、丙基锂(PrLi)、氯化锂(LiCl)、甲基锂(MeLi)、异丙基锂(iPrLi)、苯基锂(PhLi)、环己烷锂(cyHexLi)、二异丙基氨基锂(LDA)、氨基锂、六甲基二硅烷氨基锂(LiHMDS)，或其组合。
在本发明的方法中可以使用任何合适的惰性溶剂。代表性的惰性溶剂包括但不限于戊烷、不同的戊烷、己烷、不同的己烷、庚烷、不同的庚烷、石油醚、环戊烷、不同的环己烷、苯、甲苯、二甲苯、三氟甲苯，卤代苯如氯苯、氟苯、 二氯苯和二氟苯，二氯甲烷、氯仿、DMF、丙酮、乙酸乙酯、二乙醚、四氢呋喃或其组合。在一些实施方案中，溶剂可以是四氢呋喃、甲苯、DMF或其组合。
本发明的方法中的反应可以在任何合适的温度下进行。例如，反应温度可以是约-78℃至约100℃，或者为约-50℃至约100℃，或者为约-25℃至约50℃，或约-10℃至约25℃，或约0℃至约20℃。在一些实施方案中，反应温度可以是约0℃至约20℃。
本文所用的“式V化合物”是指式V化合物或其药学上可接受的盐或共晶体。在一些实施方案中，“式V化合物”是指式V化合物或其药学上可接受的盐。类似地，关于可分离的中间体，短语“式(编号)化合物”是指该式及其药学上可接受的盐或共晶体的化合物。在一些实施方案中，关于可分离的中间体，短语“式(编号)的化合物”是指该式及其药学上可接受的盐的化合物。HNR 4R 5也包括其盐形式，如盐酸盐等。
在本发明的方法中，各步骤可以以任何合适的产率提供目标化合物或其药学上可接受的盐。例如，目标化合物(如，式II、式IV、式V或瑞德西韦等)可以以至少约50％、55％、60％、65％、70％、75％、80％、85％、90％或至少约95％的产率制备。本发明的方法可以提供任何纯度的目标化合物或其药学上可接受的盐。例如，目标化合物可以以至少约90、95、96、97、98或至少约99％的纯度制备。在一些实施方案中，目标化合物可以至少95％的纯度制备。在一些实施方案中，目标化合物可以以至少98％的纯度制备。在一些实施方案中，目标化合物可以以至少99％的纯度制备。
如本文所用，
Figure PCTCN2021079143-appb-000023
代表连接位点。
式II化合物
本发明提供了一种式II化合物，
Figure PCTCN2021079143-appb-000024
其中，R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 4、R 5各自独立地选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、或取代或未取代的C1-C6烷氧 基；或R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元含有1-2个N杂原子和0-1个选自O、或S杂原子的杂环烷基；和
PG为H或硅烷基取代基；
其中所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基。
在另一优选例中，PG为氢。
在另一优选例中，所述的R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元的含2个N杂原子的杂环烷基。
在另一优选例中，R 4、R 5和相连的氮原子一起形成5至7元环；较佳地，所述5至7元环为-N(CH 2)x(CH 2)y-环、-N(CH 2)xO(CH 2)y-环或-N(CH 2)x-NR 7-(CH 2)y-环，其中，x、y各自独立地为1～3，R 7为氢、C1～C6烷基、C3-C6环烷基。
在另一优选例中，R 1和R 2一起形成
Figure PCTCN2021079143-appb-000025
式II化合物的制备方法
(a)式I化合物与式A化合物发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000026
其中，PG为H，R 1、R 2、R 3、R 4和R 5如上定义；
或者
(a’)式I化合物与式A化合物与卤代硅烷PG-X发生反应，生成式II化合物；
Figure PCTCN2021079143-appb-000027
其中，PG为硅烷基取代基，X为卤素；R 1、R 2、R 3、R 4、R 5如上定义。
在另一优选例中，在步骤(a)中，在惰性溶剂中，在去质子化试剂和/或路易斯酸存在下，式I化合物与HNR 4R 5发生反应，生成式II-a化合物。
在另一优选例中，在步骤(a')中，在惰性溶剂中，在去质子化试剂和/或路易斯酸和碱存在下，式I化合物、HNR 4R 5、卤代硅烷PG-X发生反应，生成式II化合物。
任何合适的去质子化试剂都可用于制备式II化合物。镁基去质子化试剂包括但不限于甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)、乙基溴化镁(CH 3CH 2MgBr)、乙基氯化镁(CH 3CH 2MgCl)、乙烯基氯化镁(CH 2CHMgCl)、异丙基氯化镁(iPrMgCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)或其组合。锂基去质子化试剂包括但不限于正丁基锂(nBuLi)、叔丁基锂(tBuLi)、氢化锂(LiH)、乙基锂(EtLi)、丙基锂(PrLi)、氯化锂(LiCl)、甲基锂(MeLi)、异丙基锂(iPrLi)、苯基锂(PhLi)、环己烷锂(cyHexLi)、二异丙基氨基锂(LDA)、氨基锂、六甲基二硅烷氨基锂(LiHMDS)或其组合。所述路易斯酸包括但不限于三甲基铝、二甲基氯化铝。在一些实施方案中，去质子化试剂可以是异丙基氯化镁(iPrMgCl)、叔丁基氯化镁(tBuMgCl)，路易斯酸可以是三甲基铝。
所述去质子化试剂或路易斯酸可以任何合适的量存在。例如，去质子化试剂或路易斯酸可以以与式I化合物至少1.0当量(mol/mol)的量存在，例如约1.0、2、3、4、5、6、7、8、9或约10.0当量(mol/mol)。去质子化试剂或路易斯酸也可以以与式I化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约3.0当量(mol/mol)。
HNR 4R 5或其盐可以任何合适的量存在。例如，HNR 4R 5或其盐可以以0与式I化合物至少1.0当量(mol/mol)的量存在，也可以以与式I化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约3.0当量(mol/mol)。
优选地，当PG不为氢时，该方法包括步骤：在惰性溶剂中，在去质子化试剂或路易斯酸和碱存在在，式I化合物、HNR 4R 5和卤代硅烷发生反应，生成式II化合物。
更具体地，该方法包括：1)在惰性溶剂中，在去质子化试剂和/或路易斯酸存在下，式I化合物和HNR 4R 5反应，生成式II-a化合物；2)非必须地分离得到式II-a化合物；3)在惰性溶剂中，在碱存在下，式II-a化合物和卤代硅烷反应生成式II化合物。如下所示：
Figure PCTCN2021079143-appb-000028
上述方法中，式II-a化合物后可分离后再进行步骤3)，
或采用“一锅法”从式I化合物制备得到式II化合物：
Figure PCTCN2021079143-appb-000029
在上述步骤3)中：任何合适的卤代硅烷可用在制备式II化合物的方法中。例如，卤代硅烷可以是氟硅烷、氯硅烷、溴硅烷或碘硅烷。硅烷部分可以具有任何合适的取代基，例如烷基、烯基、炔基、环烷基或苯基。示例性的卤代硅烷包括但不限于三甲基氯硅烷(TMSCl)、三甲基碘硅烷(TMSI)、三乙基氯硅烷(TESCl)、叔丁基二甲基氯硅烷(TBDMSCl)或三异丙基氯硅烷(TIPSCl)。在一些实施方案中，卤代硅烷可以是氯硅烷。在一些实施方案中，卤代硅烷可以是三甲基氯硅烷(TMSCl)、三乙基氯硅烷(TESCl)、叔丁基二甲基氯硅烷(TBDMSCl)或三异丙基氯硅烷(TIPSCl)。在一些实施方案中，卤代硅烷可以是三甲基氯硅烷(TMSCl)。
卤代硅烷可以任何合适的量存在。例如，卤代硅烷可以以相对于式II-a化合物至少1.0当量(mol/mol)的量存在，例如约1.0、2、3、4、5、6、7、8、9或约10.0当量(mol/mol)。卤代硅烷也可以以相对于式II-a化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约2.0当量(mol/mol)。在一些实施方案中，卤代硅烷可以以相对于式II-a化合物约1.0至约5.0当量(mol/mol)的量存在。在一些实施方案中，卤代硅烷可以以相对于式II-a化合物约1.0至约2.0当量(mol/mol)的量存在。
所述碱包括但不限于三乙胺、二异丙基胺、咪唑、二异丙基乙基胺、N,N-二乙基苯胺、吡啶、2,6-二甲基吡啶、2,4,6-可力丁、4-二甲基氨基吡啶和奎宁环。优选地，所述碱为咪唑。所述碱可以任何合适的量存在。所述碱以相对于式II-a化合物至少1.0当量(mol/mol)的量存在。优选地，所述碱以相对于式II-a化合物约1.0至约4.0当量(mol/mol)的量存在。
式IV化合物
本发明还提供了式IV化合物，
Figure PCTCN2021079143-appb-000030
其中，
R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 8为-NHW，其中，W为H、或氨基保护基；
PG为H或硅烷基取代基。
式IV化合物的制备方法
本发明提供了一种式IV化合物的制备方法，所述方法包括步骤：
(b)式II化合物与式III化合物发生反应，生成式IV化合物；和
Figure PCTCN2021079143-appb-000031
式中，
所述PG为H或硅烷基取代基；且
X为卤素；
R 1、R 2、R 3、R 4、R 5、R 8如上所定义。
在另一优选例中，在步骤(b)中，在惰性溶剂中，在卤代硅烷、去质子化试剂和偶联试剂存在下，式II化合物与式III化合物发生反应，生成式IV化合物。
在另一优选例中，在步骤(b)中，包括子步骤：
(b-1)使式III化合物和卤代硅烷、去质子化试剂、溶剂混合，形成混合物b1；
(b-2)向所述混合物b1中加入偶联试剂，形成混合物b2；
(b-3)将所述混合物b2与式II化合物以及任选的去质子化试剂混合，进行反应，从而得到式IV化合物。
在另一优选例中，在步骤(b-3)中加入添加剂促进反应，所述添加剂包括但不限于LiCl、Ca(OTf) 2、CaCl 2、MgCl 2、CeCl 3、LaCl 3、YCl 3、NdCl 3、或其组合。优选地，所述添加剂为LiCl、Ca(OTf) 2、CaCl 2、MgCl 2、CeCl 3、LaCl 3或其组合。
优选地，当式II中的PG为硅烷基取代基时，在步骤(b-3)中，可以不存在去质子化试剂。
在另一优选例中，当式II中的PG为H时，在步骤(b-3)中，在反应体系中还存在去质子化试剂。
在一些实施例中，上述方法包括步骤：1)使式III化合物和卤代硅烷、去质子化试剂、溶剂形成混合物；2)向步骤1)的混合物中加入偶联试剂；3)将步骤2)所得混合物与式II-a化合物以及去质子化试剂混合，从而得到式IV化合物。
Figure PCTCN2021079143-appb-000032
其中，去质子化试剂可将式II-a化合物进行如下去质子化：
Figure PCTCN2021079143-appb-000033
式中，M为金属锂、镁、钠或钙，优选地，M为金属锂或镁。
优选地，采用“一锅法”由式II-a化合物和式III化合物制备得到式IV化合物。
任何合适的卤代硅烷可用于所述方法中。所述卤代硅烷可以任何合适的量存在。例如，卤代硅烷也可以以相对于式III化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约2.0当量(mol/mol)。
任何合适的偶联剂可用于所述方法中。所述镁偶联剂包括但不限于异丙基氯化镁(iPrMgCl)、异丙基氯化镁氯化锂络合物(iPrMgCl·LiCl)、丙基氯化镁氯化锂络合物(PrMgCl·LiCl)、仲丁基氯化镁氯化锂络合物(sBuMgCl·LiCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)、乙烯基溴化镁(CH 2＝CHMgBr)、乙基溴化镁(CH 3CH 2MgBr)、甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)或其组合。所述镁偶联剂、锂偶联剂或其组合可以任何合适的量存在。例如，上述偶联剂可以以相对于式III化合物至少1.0当量(mol/mol)的量存在。例如，偶联剂也可以以相对于式III化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约2.0当量(mol/mol)。
所述式II(II-a)化合物和式III化合物化合物当量(mol/mol)比为0.5:1～1:2；优选地，所述式II(II-a)化合物和式III化合物化合物当量(mol/mol)比为1:1.5～1.5:1。
各步骤中所述去质子化试剂为镁基去质子化试剂、锂基去质子化试剂、氢化钠(NaH)、CaH 2或其组合，镁基去质子化试剂包括但不限于甲基溴化镁(CH 3MgBr)、甲基氯化镁(CH 3MgCl)、乙基溴化镁(CH 3CH 2MgBr)、乙基氯化镁 (CH 3CH 2MgCl)、乙烯基氯化镁(CH 2CHMgCl)、异丙基氯化镁(iPrMgCl)、叔丁基氯化镁(tBuMgCl)、苯基氯化镁(PhMgCl)或其组合。锂基去质子化试剂包括但不限于正丁基锂(nBuLi)、叔丁基锂(tBuLi)、氢化锂(LiH)、乙基锂(EtLi)、丙基锂(PrLi)、氯化锂(LiCl)、甲基锂(MeLi)、异丙基锂(iPrLi)、苯基锂(PhLi)、环己烷锂(cyHexLi)、二异丙基氨基锂(LDA)、氨基锂、六甲基二硅烷氨基锂(LiHMDS)或其组合。所述去质子化试剂也可以和前面所述偶联剂重合(镁偶联试剂、锂偶联试剂或其组合)。所述去质子化试剂可以任何合适的量存在。例如，上述去质子化试剂可以以相对于式II(II-a)化合物至少1.0当量(mol/mol)的量存在。例如，去质子化试剂也可以以相对于式II(II-a)化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约2.0当量(mol/mol)。
在另一优选例中，式IV化合物制备方法包括如下步骤；
Figure PCTCN2021079143-appb-000034
式中，
R 1、R 2、R 3、R 4、R 5、R 8、PG和X如上所定义。
优选地，当各PG为H时，步骤a和步骤b可以采用一锅法进行。
式V化合物的制备方法
本发明提供了一种制备式V化合物的方法，所述方法包括步骤：
(c)式IV化合物发生脱保护反应和成环反应，生成式V化合物；
Figure PCTCN2021079143-appb-000035
其中，
R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
R 3为羟基保护基；
R 8为-NHW，其中，W为H、或氨基保护基；和
PG为H或硅烷基取代基。
在另一优选例中，在步骤(c)中，还包括：当PG为硅烷基取代基和/或R 8中的W为氨基保护基时，进行脱保护反应，即按任意顺序连续或分步脱除PG中硅烷基取代基、和/或脱除R 8中的氨基保护基，或者同时脱除PG和R 8中的氨基保护基(从而使PG变为H，W变为H)。
在另一优选例中，在所述的脱保护反应中，不影响R 1、R 2、R 3基团。
典型地，当PG为硅烷基取代基且R 8为氨基保护基取代的氨基时，所述脱保护反应可同时进行或按任意顺序连续进行或分步骤进行。
用于脱除硅烷基取代基和氨基保护基的脱保护剂可以相同也可以不同。
所述脱保护剂可以是单独去除保护基PG，单独脱除R 8中的保护基，或者同时去掉PG和R 8中的保护基的任何合适的试剂，如氟试剂、碱、酸或其组合。所述氟试剂包括但不限于四丁基氟化铵、三乙胺三氟化氢、氟化铵等。所述酸包括但不限于乙酸、硫酸、甲磺酸、对甲苯磺酸、三氟甲磺酸、三氟乙酸(TFA)、甲酸、盐酸、浓盐酸等。所述碱可以是有机碱、无机碱、镁格氏试剂或锂格氏试剂，代表性的碱包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氨、甲醇钠、乙醇钠、甲基溴化镁、甲基锂等。所述脱保护剂也可以直接作为反应溶剂。
所述脱保护剂可以任何合适的量存在。例如，脱保护剂可以以相对于式IV化合物至少1.0当量(mol/mol)的量存在。例如，脱保护剂也可以以相对于式IV化合物约1.0至约10.0当量(mol/mol)的量存在，例如约1.0至约5.0当量(mol/mol)，或约1.0至约2.0当量(mol/mol)。
优选地，本发明的V化合物的制备方法，包括步骤：
Figure PCTCN2021079143-appb-000036
各式中，R 1、R 2、R 3、R 4、R 5、R 8、PG和X如上所定义。
各反应步骤可分步进行或连续进行。
优选地，本发明的V化合物的制备方法，包括步骤：
Figure PCTCN2021079143-appb-000037
式中，R 1、R 2、R 3、R 4、R 5、R 8、PG和X如上所定义。
反应步骤可分步进行或连续进行。由II制备IV反应结束后，可以后处理 分离出式IV化合物，然后进行前述脱保护基反应得到式V化合物，也可以在后处理过程中直接加入脱保护剂得到式V化合物。
瑞德西韦的制备方法
本发明的式II化合物和式IV化合物可以用作制备瑞德西韦的中间体。
本发明还提供了一种瑞德西韦的制备方法，所述方法包括使用式IV化合物作为中间体来制备瑞德西韦。
典型地，所述方法还可以包括本领域常用的从式V化合物制备瑞德西韦的其他步骤。例如，通过该方法得到的式V化合物或其药学上可接受的盐可参考文献(J.Med.Chem.2017,60,1648-61；Nature.2016,531,381-5；Bioorg.Med.Chem.Lett.2012,22,2705-7；WO2016069826)用于瑞德西韦的制备。
本发明的主要优点包括：
1.本发明提供了制备瑞德西韦的新中间体及其用途，通过利用该中间体制备瑞德西韦的方法原料易得、工艺简洁、反应条件温和适合工业化生产。
2.本发明的方法具有操作简单易行、工艺稳定、易于控制。
3.在本发明中中，反应产物收率高、纯度好。尤其是从式IV制得式V化合物具有很高的收率，且杂质少，并且该反应可以在一步完成，适合一锅法。
4.在本发明中，反应后处理方便、安全、不对人体健康与环境产生危害、生产成本低。
下面结合具体实施，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
Figure PCTCN2021079143-appb-000038
2,3,5-三苄氧基-D-核糖酸-1,4-内酯1(20.0g，47.8mmol)与N,O-二甲基羟胺盐酸盐(7.0g，71.7mmol，1.5eq)加入到无水四氢呋喃(70mL)中，冰浴下，滴加2M异丙基氯化镁(71.7mL，143.4mmol，3eq)，加毕，在该温度下继续反应直至反应完全。将反应液缓慢倒入1M稀盐酸(150mL)中，乙酸乙酯萃取，有机相依次有饱和碳酸氢钠和食盐水洗涤，干燥后浓缩，得化合物2a，油状物24.1g，所得量超过 理论值。 1H NMR(500MHz,DMSO-d6)：δ7.39–7.20(m,15H)，5.09(d,J＝4.9Hz,1H)，4.71–4.62(m,2H)，4.51–4.42(m,4H)，4.38(d,J＝11.5Hz,1H)，4.14–4.04(m,1H)，3.82(dd,J＝7.8,2.9Hz,1H)，3.66(dd,J＝9.9,4.5Hz,1H)，3.49(dd,J＝9.9,6.5Hz,1H)。
实施例2
Figure PCTCN2021079143-appb-000039
N,O-二甲基羟胺盐酸盐(1.56g，16.0mmol，1.6eq)加入到二氯甲烷(15mL)中，零下5摄氏度搅拌，缓慢滴加2M三甲基铝(10mL，20mmol，2eq)，加毕，冰浴下搅拌30分钟，随后加入2,3,5-三苄氧基-D-核糖酸-1,4-内酯1(4.2g，10.0mmol)的二氯甲烷溶液(10mL)，TLC监测直至反应完全。反应液加入到酒石酸钠钾的水溶液中，加入二氯甲烷，搅拌，分出有机相，有机相用饱和氯化钠水溶液洗涤，干燥后浓缩，得油状物4.8g，收率100％。 1H NMR谱图同实施例1产物。
实施例3
Figure PCTCN2021079143-appb-000040
2,3,5-三苄氧基-D-核糖酸-1,4-内酯1(4.2g，10.0mmol)与N-甲基哌嗪(1.5g，15.0mmol，1.5eq)加入到四氢呋喃(20mL)中，冰浴下，滴加2M异丙基氯化镁(15.0mL，30.0mmol，3eq)，加毕，逐渐升至室温反应直至反应完全。将反应液缓慢倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次有饱和碳酸氢钠和食盐水洗涤，干燥后浓缩，得油状物3.5g，收率67.5％。
实施例4
Figure PCTCN2021079143-appb-000041
化合物2a(4.79g，10mmol)和咪唑(1.36g，20mmol，2eq)加入到DMF(15mL)中，冰浴下，分批次加入叔丁基二甲基氯硅烷(1.81g，12mmol，1.2eq)，加毕，室温反应过夜。将反应液加入到水(150mL)中，乙酸乙酯萃取，分出有机层，有机层用饱和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得油状物4.2g，进一步柱层析纯化，得油状物3.2g，纯品收率54％。 1H NMR(600MHz,DMSO-d 6)δ 7.33–7.15(m,15H),4.71–4.63(m,1H),4.60(d,J＝11.4Hz,1H),4.46–4.38(m,3H),4.36–4.30(m,2H),4.22–4.17(m,1H),3.74(d,J＝8.6Hz,1H),3.62(dd,J＝10.0,4.1Hz,1H),3.49–3.41(m,4H),3.06(s,3H),0.82(s,9H),0.00(s,3H),-0.01(s,3H)。
实施例5
Figure PCTCN2021079143-appb-000042
化合物2a(5.0g，10.4mmol)和咪唑(1.42g，20.8mmol，2eq)加入到四氢呋喃(50mL)中，冰浴下，缓慢滴加三乙基氯硅烷(2.35g，15.6mmol，1.5eq)，加毕，反应液逐渐升至室温，1小时后反应完全。向反应液中加入饱和碳酸氢钠水溶液(10mL)，加入乙酸乙酯(30mL)，分出有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压蒸除溶剂后得到粗品，柱层析纯化，得到油状产物4.5g，收率75.8％。 1H NMR(500MHz,DMSO-d 6)δ7.38–7.18(m,15H),4.74–4.61(m,2H),4.50–4.44(m,3H),4.42(d,J＝11.4Hz,1H),4.37(d,J＝11.7Hz,1H),4.27–4.22(m,1H),3.82(d,J＝8.5Hz,1H),3.71(dd,J＝10.0,4.5Hz,1H),3.51(s,3H),3.48(dd,J＝10.0,6.8Hz,1H),3.12(s,3H),0.91(t,J＝8.0Hz,9H),0.61–0.54(m,6H)。
实施例6
Figure PCTCN2021079143-appb-000043
化合物2a(7.0g，14.6mmol)和咪唑(1.79g，26.3mmol，1.8eq)加入到二氯甲烷(50mL)中，冰浴下，缓慢滴加三甲基氯硅烷(2.06g，19.0mmol，1.3eq)，加毕，反应液逐渐升至室温，1小时后反应完全。过滤，滤液用饱和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得油状物6.5g，收率80.7％。 1H NMR(500MHz,DMSO-d 6)δ7.40–7.20(m,15H),4.71–4.64(m,1H),4.61(d,J＝11.4Hz,1H),4.51–4.45(m,3H),4.43(d,J＝11.4Hz,1H),4.38(d,J＝11.7Hz,1H),4.24–4.20(m,1H),3.77(dd,J＝8.0,2.1Hz,1H),3.67(dd,J＝10.1,4.0Hz,1H),3.53(s,3H),3.49(dd,J＝10.0,7.0Hz,1H),3.12(s,3H),0.08(s,9H)。
实施例7
Figure PCTCN2021079143-appb-000044
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.6g，2.3mmol)溶于四氢呋喃(3mL)中，零下20摄氏度下加入2.0M苯基氯化镁(1.2mL，2.3mmol，1eq)，搅拌10分钟后，滴加三甲基氯硅烷(0.25g，2.3mmol，1eq)，加完后搅拌15分钟，随后加入2.0M苯基氯化镁(1.2mL，2.3mmol，1eq)，滴完后搅拌20min。反应液温度升至零下10摄氏度，加入1.3M异丙基氯化镁氯化锂溶液(1.9mL，2.5mmol，1.1eq)，搅拌1h，加入3a-1(1.36g，2.3mmol，1eq)的四氢呋喃溶液(3mL)，反应液缓慢升至室温搅拌，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵水溶液中，搅拌5分钟后，乙酸乙酯萃取，分出有机层，有机层用稀盐酸和饱和氯化钠水溶液洗涤，干燥，浓缩，得4a-1粗品。少量产品纯化后获得氢谱， 1H NMR(500MHz,DMSO-d6)δ8.09(s,2H),7.96(s,1H),7.39–7.22(m,11H),7.18–7.07(m,3H),6.96–6.85(m,3H),5.40(d,J＝7.6Hz,1H),4.63–4.53(m,2H),4.52–4.42(m,3H),4.34(d,J＝11.7Hz,1H),4.26–4.17(m,1H),3.91(dd,J＝7.6,1.6Hz,1H),3.83(dd,J＝10.2,3.5Hz,1H),3.51(dd,J＝10.2,7.3Hz,1H),0.83(s,9H),0.02(s,3H),-0.05(s,3H)。
将4a-1粗品加入到四氢呋喃(10mL)中，加入50％三氟乙酸水溶液(1mL)，室温搅拌，TLC监测直至原料消失。反应液加入到水(15mL)中，乙酸乙酯萃取，分出有机层，有机层依次用饱和碳酸氢钠水溶液和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得泡沫状固体0.91g，进一步用甲叔醚和正庚烷混合溶剂打浆，得白色粉末状固体0.70g，收率55％。所得产物 1H NMR(500MHz,DMSO-d 6)δ8.07(s,2H),8.00(s,1H),7.38–7.23(m,11H),7.20–7.13(m,3H),7.04–6.98(m,2H),6.95(d,J＝4.5Hz,1H),5.39(d,J＝5.9Hz,1H),5.06(dd,J＝5.3Hz,1H),4.61–4.54(m,2H),4.51–4.43(m,4H),4.05–3.98(m,1H),3.94(t,J＝5.2Hz,1H),3.70(dd,J＝10.2,3.4Hz,1H),3.48(dd,J＝10.2,6.4Hz,1H)。
实施例8
Figure PCTCN2021079143-appb-000045
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(2.0g，7.7mmol)加入到无水四氢呋喃中(10mL)，冰浴下滴加2M苯基氯化镁(7.7mL，15.4mmol，2eq)，搅拌20分钟后，缓慢加入三甲基氯硅烷(0.84g，7.7mmol，1eq)，20分钟后，加入1.3M异丙基氯化镁氯化锂(6.3mL，7.7mmol，1.1eq)，搅拌30分钟后，降温至零下20摄氏度，滴加3a-2(4.57g，7.7mmol，1.0eq)的四氢呋喃溶液(15mL)，加毕，缓慢升至室温，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵水溶液中，搅拌5分钟后，乙酸乙酯萃取，分出有机层，有机层用饱氯化钠水溶液洗涤，干燥，浓缩，得4a-2粗品。
将4a-2粗品加入到四氢呋喃(15mL)中，加入50％三氟乙酸水溶液(3mL)，室温搅拌，TLC监测直至原料消失。反应液加入到(50mL)水中，乙酸乙酯萃取，分出有机层，有机层依次用饱和碳酸氢钠水溶液和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得泡沫状固体3.2g，收率75％。所得产物 1H NMR谱图与实施例7相同。
实施例9
Figure PCTCN2021079143-appb-000046
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.26g，1.0mmol)加入到无水四氢呋喃(3mL)中，零下20摄氏度下加入2.0M苯基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，搅拌10分钟后，滴加TMSCl(0.11g，1.0mmol，1eq)，加完后搅拌10分钟，随后加入2.0M苯基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，20分钟后，加入1.3M异丙基氯化镁氯化锂四氢呋喃溶液(1.9mL，2.5mmol，1.1eq)，零下10摄氏度下搅拌1h，加入3a-3(0.55g，1.0mmol，1eq)的四氢呋喃溶液(3mL)，反应液温度缓慢升至室温，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵水溶液中，搅拌5分钟后，用乙酸乙酯萃取，分出有机层，有机层用饱氯化钠水溶液洗涤，干燥，浓缩，得4a-3粗品。
将4a-3粗品加入到四氢呋喃(10mL)中，加入50％三氟乙酸水溶液(1mL)，室温搅拌，TLC监测直至原料消失。反应液加入到水(15mL)中，乙酸乙酯萃取，分出有机层，有机层依次用饱和碳酸氢钠水溶液和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得泡沫状固体0.43g，收率78％。所得产物 1H NMR谱图与实施例7相同。
实施例10
Figure PCTCN2021079143-appb-000047
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.26g，1.0mmol)加入到无水四氢呋喃(3mL)中，零下20摄氏度下加入2.0M苯基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，搅拌10分钟后，滴加三甲基氯硅烷(0.11g，1.0mmol，1eq)，加完后搅拌10分钟，随后加入2.0M苯基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，20分钟后，加入1.3M异丙基氯化镁氯化锂四氢呋喃溶液(1.9mL，2.5mmol，1.1eq)，零下10摄氏度下搅拌1h，加入3a-3(0.55g，1.0mmol，1eq)的四氢呋喃溶液(3mL)，反应液温度缓慢升至室温，TLC监测直至产物不再增多。向反应液加入1M稀盐酸，使反应体系为酸性，冰浴下搅拌1小时左右。加入乙酸乙酯(20mL)和水(20mL)，分出有机层，有机层依次用饱和碳酸氢钠和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得泡沫状固体0.44g，进一步用甲叔醚打浆，得白色粉末状固体0.34g，收率62％。所得产物 1H NMR谱图与实施例7相同。
实施例11
Figure PCTCN2021079143-appb-000048
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.52g，2.0mmol)加入到无水四氢呋喃(5mL)中，零下10摄氏度下加入三甲基氯硅烷(0.43g，4.0mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(1.33mL，4.0mmol，2.0eq)，加毕，搅拌20分钟，随后加入1.3M异丙基氯化镁氯化锂溶液(2mL，2.6mmol，1.3eq)，控制反应温度在零下10摄氏度到0摄氏度之间，搅拌1小时左右后，加入3a-3(1.1g，2.0mmol，1eq)的四氢呋喃溶液(4mL)，反应液逐渐升至室温，TLC检测直至产物不再增多。将反应液加入到饱和氯化铵水溶液中，搅拌5分钟后，用乙酸乙酯萃取，分出有机层，有机层用饱氯化钠水溶液洗涤，干燥，浓缩，得4a-3粗品。
将4a-3粗品加入到四氢呋喃(10mL)中，加入50％三氟乙酸水溶液(1mL)，室温搅拌，TLC监测直至原料消失。反应液加入到水(15mL)中，乙酸乙酯萃取，分出有机层，有机层依次用饱和碳酸氢钠水溶液和氯化钠水溶液洗涤，干燥，浓缩，硅胶柱层析分离，得泡沫状固体0.93g，进一步用甲叔醚和正庚烷混合溶剂打浆， 得白色粉末状固体0.76g，收率69％。所得产物 1H NMR谱图与实施例7相同。
实施例12
Figure PCTCN2021079143-appb-000049
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(1.35g，5.2mmol)加入到无水四氢呋喃(8mL)中，零下10摄氏度下加入三甲基氯硅烷(1.13g，10.4mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(3.5mL，10.4mmol，2.0eq)，加毕，搅拌20分钟，随后加入1.3M异丙基氯化镁氯化锂溶液(5.6mL，7.3mmol，1.4eq)，控制反应温度在零下10摄氏度到0摄氏度之间，搅拌1小时左右后，加入3a-3(2.9g，5.2mmol，1eq)的四氢呋喃溶液(4mL)，反应液逐渐升至室温，TLC检测直至产物不再增多。向反应液加入1M稀盐酸，使反应体系为酸性，冰浴下搅拌1小时左右。加入乙酸乙酯(50mL)和水(30mL)，分出有机层，有机层依次用饱和碳酸氢钠和氯化钠水溶液洗涤，干燥，浓缩，加入甲叔醚，静置，析出大量白色固体，过滤得白色固体1.7g；滤液浓缩后，硅胶柱层析分离，得泡沫状固体，进一步用甲叔醚和正庚烷混合溶剂打浆，得白色粉末状固体0.4g，固体合并，总收率73％。所得产物 1H NMR谱图与实施例7相同。
实施例13
Figure PCTCN2021079143-appb-000050
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.21g，1.0mmol)加入到无水四氢呋喃(4mL)中，零下15摄氏度下加入三甲基氯硅烷(0.22g，2.0mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(0.67mL，2.0mmol，2.0eq)，加毕，搅拌20分钟，降低温度至零下78摄氏度，缓慢滴加1.6M正丁基锂的己烷溶液(0.75mmol，1.2mmol，1.2eq)，加毕，搅拌5分钟，随后加入3a-3(0.55g，1.0mmol，1eq)的四氢呋喃溶液(4mL)，TLC监测反应至产物不再增多。向反应液中加入饱和氯化铵溶液，逐渐升至室温，加入1M稀盐酸，使反应体系为酸性，冰浴下搅拌1小时左右。乙酸乙酯萃取，分出有机层，有机层干燥，浓缩，硅胶柱层析分离，得泡沫状固体0.25g，收率45％。所得产 物 1H NMR谱图与实施例7相同。
实施例14
Figure PCTCN2021079143-appb-000051
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.26g，1.0mmol)加入到无水四氢呋喃(3mL)中，零下20摄氏度下加入2.0M苯基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，搅拌10分钟后，滴加三甲基氯硅烷(0.11g，1.0mmol，1eq)，加完后搅拌10分钟，随后加入2.0M苯基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，20分钟后，加入1.3M异丙基氯化镁氯化锂四氢呋喃溶液(1.9mL，2.5mmol，1.1eq)，零下10摄氏度下搅拌1h。化合物2a(0.48g，1.0mmol)加入到无水四氢呋喃(2mL)中，冰浴下，加入2M异丙基氯化镁四氢呋喃溶液(0.5mL，1.0mmol，1eq)，搅拌20分钟后加入到上述反应液中，缓慢升至室温反应，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵的水溶液中，搅拌10分钟后，用乙酸乙酯萃取，分出有机层，有机层干燥，浓缩，硅胶柱层析分离，得泡沫状固体0.36g，收率65％。所得产物 1H NMR谱图与实施例7相同。
实施例15
Figure PCTCN2021079143-appb-000052
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.52g，2.0mmol)加入到无水四氢呋喃(5mL)中，零下10摄氏度下加入三甲基氯硅烷(0.43g，4.0mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(1.33mL，4.0mmol，2.0eq)，加毕，搅拌20分钟，随后加入1.3M异丙基氯化镁氯化锂溶液(2mL，2.6mmol，1.3eq)，控制反应温度在零下10摄氏度到0摄氏度之间，搅拌1小时左右。化合物2a(0.96g，2.0mmol)加入到无水四氢呋喃(4mL)中，冰浴下，加入2M异丙基氯化镁四氢呋喃溶液(1.0mL，2.0mmol，1eq)，搅拌20分钟后加入到上述反应液中，缓慢升至室温反应，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵的水溶液中，搅拌10分钟后，用乙酸乙酯萃取，分出有机层，有机层干燥，浓缩，硅胶柱层析，得泡沫状固体0.94g，进一步用甲叔醚和正庚烷混合溶剂打浆，得白色粉末状固体 0.75g，收率68％。所得产物 1H NMR谱图与实施例7相同。
实施例16
Figure PCTCN2021079143-appb-000053
7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(0.52g，2.0mmol)加入到无水四氢呋喃(5mL)中，零下10摄氏度下加入三甲基氯硅烷(0.44g，4.0mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(1.33mL，4.0mmol，2.0eq)，加毕，搅拌20分钟，随后加入1.3M异丙基氯化镁氯化锂溶液(2mL，2.6mmol，1.3eq)，控制反应温度在零下10摄氏度到0摄氏度之间，搅拌1小时左右，备用。化合物2a(0.96g，2.0mmol)加入到无水四氢呋喃(4mL)中，冰浴下，加入2M异丙基氯化镁四氢呋喃溶液(1.0mL，2.0mmol，1eq)，搅拌20分钟后，将上述制备的格式试剂溶液滴加到该反应液中，加毕，缓慢升至室温反应，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵的水溶液中，搅拌10分钟后，用乙酸乙酯萃取，分出有机层，有机层依次用1M稀盐酸、饱和碳酸氢钠和氯化钠溶液洗涤，干燥后浓缩，硅胶柱层析分离，得泡沫状固体，进一步用甲叔醚和正庚烷混合溶剂打浆，得白色粉末状固体0.70g，收率63％。所得产物 1H NMR谱图与实施例7相同。
实施例17
Figure PCTCN2021079143-appb-000054
步骤A：7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(1.3g，5.0mmol)加入到无水四氢呋喃(6mL)中，零下10摄氏度下加入三甲基氯硅烷(1.1g，10.0mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(3.3mL，10.0mmol，2.0eq)，加毕，搅拌20分钟，随后加入1.3M异丙基氯化镁氯化锂四氢呋喃溶液(5.0mL，6.5mmol，1.3eq)，控制反应温度在零下10摄氏度到0摄氏度之间，搅拌1小时左右。
步骤B：2,3,5-三苄氧基-D-核糖酸-1,4-内酯1(2.1g，5.0mmol)和N,O-二甲基羟胺盐酸盐(0.88g，9.0mmol，1.8eq)加入到无水四氢呋喃(10mL)中，冰浴下，缓慢加入2M异丙基氯化镁四氢呋喃溶液(9.0mL，18mmol，3.6eq)，搅拌3h后，再加入2M异丙基氯化镁(2.5mL，5.0mmol，1.0eq)，20分钟后，将步骤A的溶液 加入到该反应液中。加毕，缓慢升至室温反应，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵的水溶液中，搅拌10分钟后，乙酸乙酯萃取，分出有机层，有机层依次用1M稀盐酸、饱和碳酸氢钠和氯化钠溶液洗涤，干燥后浓缩得到油状物，加入甲叔醚，静置后析出不溶物，过滤，得到白色固体1.6g，滤液浓缩后，硅胶柱层析，得到浅棕色泡沫状固体，进一步用甲叔醚打浆，得白色粉末状固体0.2g，固体合并，总收率65％。所得产物 1H NMR谱图与实施例7相同。
实施例18
Figure PCTCN2021079143-appb-000055
步骤A：2,3,5-三苄氧基-D-核糖酸-1,4-内酯1(2.1g，5.0mmol)和N,O-二甲基羟胺盐酸盐(0.88g，9.0mmol，1.8eq)加入到无水四氢呋喃(10mL)中，冰浴下，缓慢加入2M异丙基氯化镁四氢呋喃溶液(9.0mL，18mmol，3.6eq)，搅拌3h后，再加入2M异丙基氯化镁(2.5mL，5.0mmol，1.0eq)，搅拌20分钟。
步骤B：7-碘吡咯并[2,1-F][1,2,4]三嗪-4-胺(1.3g，5.0mmol)加入到无水四氢呋喃(6mL)中，零下10摄氏度下加入三甲基氯硅烷(1.1g，10.0mmol，2.0eq)，搅拌10分钟后，缓慢滴加3M甲基溴化镁乙醚溶液(3.3mL，10.0mmol，2.0eq)，加毕，搅拌20分钟，随后加入1.3M异丙基氯化镁氯化锂四氢呋喃溶液(5.0mL，6.5mmol，1.3eq)，控制反应温度在零下10摄氏度到0摄氏度之间，搅拌1小时左右，随后加入步骤A的反应液，加毕，缓慢升至室温反应，TLC监测直至产物不再增多。将反应液加入到饱和氯化铵的水溶液中，搅拌10分钟后，乙酸乙酯萃取，分出有机层，有机层依次用1M稀盐酸、饱和碳酸氢钠和氯化钠溶液洗涤，干燥后浓缩得到油状物，加入甲叔醚，静置后析出不溶物，过滤，得到白色固体1.7g，收率62％。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种制备式V化合物的方法，其特征在于，所述方法包括步骤：
    (c)式IV化合物发生脱保护反应和成环反应，生成式V化合物；
    Figure PCTCN2021079143-appb-100001
    其中，
    R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
    R 3为羟基保护基；
    R 8为-NHW，其中，W为H或氨基保护基；和
    PG为H或硅烷基取代基。
  2. 如权利要求1所述的方法，其特征在于，R 8为氨基且PG为硅烷基。
  3. 如权利要求1所述的方法，其特征在于，所述羟基保护基选自下组：取代或未取代的苄基、取代或未取代的萘基亚甲基
    Figure PCTCN2021079143-appb-100002
    三甲基硅基(TMS)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、甲基-甲氧基(MOM)、四氢吡喃基(THP)、叔丁基、烯丙基或其组合；所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C1-C6烷氧基、卤素、硝基。
  4. 如权利要求1所述的方法，其特征在于，所述硅烷基取代基选自下组：三甲基硅基(TMS)、三乙基硅基(TES)、叔丁基二甲基硅基(TBDMS或TBS)、三异丙基硅基(TIPS)、叔丁基二苯基硅基(TBDPS)或其组合。
  5. 如权利要求1所述的方法，其特征在于，所述R 8选自下组：氨基、乙酰氨基(NHAc)、苯甲酰氨基(NHBz)或NHBoc。
  6. 如权利要求1所述的方法，其特征在于，在步骤(c)中，在惰性溶剂中，在脱保护剂存在下，式IV化合物发生成环反应和脱保护反应，从而生成式V化合物。
  7. 式IV化合物，
    Figure PCTCN2021079143-appb-100003
    其中，
    R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
    R 3为羟基保护基；
    R 8为-NHW，其中，W为H或氨基保护基；和
    PG为H或硅烷基取代基。
  8. 一种如权利要求7所述的式IV化合物的制备方法，其特征在于，所述方法包括步骤：
    (b)式II化合物与式III化合物发生反应，生成式IV化合物；和
    Figure PCTCN2021079143-appb-100004
    式中，
    X为卤素；
    R 1、R 2、R 3、R 4、R 5、R 8和PG如权利要求7所定义。
  9. 如权利要求8所述的方法，其特征在于，在步骤(b)中，包括：在惰性溶剂中，在卤代硅烷和偶联试剂和去质子化试剂存在下，式II化合物与式III化合物发生反应，生成式IV化合物。
  10. 式II化合物，
    Figure PCTCN2021079143-appb-100005
    其中，R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个 取代或未取代的5-7元碳环；
    R 3为羟基保护基；
    R 4、R 5各自独立地选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、或取代或未取代的C1-C6烷氧基；或R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元含有1-2个N杂原子和0-1个选自O、或S杂原子的杂环烷基；和
    PG为H或硅烷基取代基；
    其中所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基。
  11. 一种权利要求10所述的式II化合物的制备方法，其特征在于，所述方法包括步骤：
    (a)式I化合物与式A化合物发生反应，生成式II化合物；
    Figure PCTCN2021079143-appb-100006
    其中，PG为H，R 1、R 2、R 3、R 4和R 5如上定义；
    或者
    (a’)式I化合物与式A化合物与卤代硅烷PG-X发生反应，生成式II化合物；
    Figure PCTCN2021079143-appb-100007
    其中，PG为硅烷基取代基，X为卤素；R 1、R 2、R 3、R 4、R 5如上定义。
  12. 如权利要求11所述的方法，其特征在于，在步骤(a)中，包括：在惰性溶剂中，在去质子化试剂和/或路易斯酸存在下，式I化合物与HNR 4R 5发生反应，生成式II-a化合物；
    在步骤(a')中，包括：在惰性溶剂中，在去质子化试剂和/或路易斯酸和碱存在下，式I化合物、HNR 4R 5、卤代硅烷PG-X发生反应，生成式II化合物。
  13. 一种制备化合物V的方法，其特征在于，所述方法包括步骤：
    (a)式I化合物、HNR 4R 5进行取代反应，生成式II化合物；
    Figure PCTCN2021079143-appb-100008
    (b)式II化合物与式III化合物发生反应，生成式IV化合物；和
    Figure PCTCN2021079143-appb-100009
    (c)式IV化合物发生脱保护反应和成环反应，生成式V化合物；
    Figure PCTCN2021079143-appb-100010
    各式中，
    R 1和R 2各自独立地为羟基保护基，或者在相邻碳原子上的R 1和R 2基团可以一起形成-C(R 6) 2-基团或者-CH(Ph)-基团，并且R 6各自独立地为H、C1-C8烷基、苯基或取代的苯基，或者两个R 6与相连的C原子共同构成一个取代或未取代的5-7元碳环；
    R 3为羟基保护基；
    R 4、R 5各自独立地选自下组：取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、或取代或未取代的C1-C6烷氧基；或R 4、R 5和相连的氮原子一起形成取代或未取代的4至8元含有1-2个N杂原子和0-1个选自O、或S杂原子的杂环烷基；
    R 8为-NHW，其中，W为H或氨基保护基；
    PG为H或硅烷基取代基；和
    各X独立地为卤素；
    其中所述“取代”指基团中一个或多个氢原子(2、3或4个)被选自下组的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、卤素、C1-C3卤代烷基、硝基、C6-C10芳基、苄基。
  14. 一种瑞德西韦的制备方法，其特征在于，所述方法包括使用式IV化合物作为中间体来制备瑞德西韦的步骤。
  15. 如权利要求10所述的式II化合物或如权利要求7所述的式IV化合物的用途，其特征在于，用做制备瑞德西韦的中间体。
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