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WO2018210297A1 - 一种艾日布林中间体及其制备方法 - Google Patents

一种艾日布林中间体及其制备方法 Download PDF

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WO2018210297A1
WO2018210297A1 PCT/CN2018/087247 CN2018087247W WO2018210297A1 WO 2018210297 A1 WO2018210297 A1 WO 2018210297A1 CN 2018087247 W CN2018087247 W CN 2018087247W WO 2018210297 A1 WO2018210297 A1 WO 2018210297A1
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formula
compound
reaction
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group
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PCT/CN2018/087247
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English (en)
French (fr)
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张富尧
李火明
张歆宁
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上海时莱生物技术有限公司
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Priority to US16/613,329 priority Critical patent/US11186570B2/en
Priority to JP2019563797A priority patent/JP7102649B2/ja
Priority to EP18801562.2A priority patent/EP3626723B1/en
Publication of WO2018210297A1 publication Critical patent/WO2018210297A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to an eribulin intermediate and a preparation method thereof.
  • Eribulin (as shown in Formula I) is a structurally optimized derivative of the macrolide lactone halichondrin B extracted from the marine natural product Halichondria okadai, and is a soft sponge compound microtubule dynamics inhibitor. Since the FDA first approved the use of Halaven injection of methanesulfonate for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy regimens on November 15, 2010, Eisai has been actively expanding Eric Brin New indications. On January 28, 2016, the FDA approved its use for second-line treatment for unresectable or metastatic liposarcoma, making it the world's first new anticancer drug that significantly prolongs the survival of patients with advanced soft tissue sarcoma.
  • Halaven can induce tumor vascular remodeling, increase vascular perfusion and permeability in the core area of the tumor, and reduce hypoxia in the tumor microenvironment in advanced breast cancer tumor tissues. degree.
  • Halaven improves epithelial cell status and reduces the ability of breast cancer cells to migrate.
  • Ai Riblin has a complex molecular structure with 40 carbon atoms, 19 of which have chiral centers.
  • the current market supply of drugs can only be achieved through a fully synthetic route.
  • the route is very complex, so the synthetic route is designed and synthesized.
  • Process development presents significant challenges, especially with precise and highly selective control of individual chiral centers.
  • eribulin is mainly achieved by convergent synthesis of three intermediates of comparable complexity whose basic structure can be referred to compounds VIIIA, VI and XIa. Specifically, a derivative of the compound VIII is coupled with a derivative of the compound VI to obtain a derivative of the compound VB, and after several conversions, it is condensed with a derivative of the compound XIa, and finally converted into eribulin.
  • a derivative of the compound VIII is coupled with a derivative of the compound VI to obtain a derivative of the compound VB, and after several conversions, it is condensed with a derivative of the compound XIa, and finally converted into eribulin.
  • fragment splicing there are a large number of functional group manipulation steps. Therefore, the development of effective and rapid fragment splicing strategy has become the focus of many synthetic chemists.
  • Zhengda Tianqing Company discloses an intermediate as shown in Formula VE in the patent CN105713031A.
  • the currently reported synthetic strategy has a large commonality, that is, the oxidation state at the C14 position is basically an alcohol, and the oxidation state needs to be adjusted by adding an oxidant during the subsequent reaction. Therefore, more synthetic strategies are needed to enrich and optimize the total synthesis of Eribulin.
  • the present invention proceeds from the C14 acetal protected intermediate VIII through the first fragment. After splicing, intermediate V with acetal protection at the C14 position was obtained. Therefore, in the subsequent conversion, only the hydrolysis reaction is used to obtain the aldehyde functional group, thereby avoiding the oxidation state adjustment of the carbon atom at the position, and reducing the oxidation reaction step, making the synthesis route more green and efficient.
  • the reaction conditions are mild, the synthesis yield is high and the purification is simple, and it is suitable for large-scale production of the eribulin intermediate represented by the formula IV.
  • the present invention provides a compound of formula III,
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group;
  • R 1 and R 2 are an acetal protecting group or a thioacetal protecting group, and each independently is a C 1-10 alkyloxy group or a C 1-10 alkyl fluorenyl group, or R 1 and R 2 are common thereto
  • the linked carbon atoms are combined to form a cyclic acetal or a cyclic thioacetal;
  • R 1 and R 2 are preferably combined with the carbon atom to which they are attached to form a cyclic acetal or a cyclic thio acetal, more preferably substituted or non-substituted.
  • the Ar may be a phenyl group or a phenyl group substituted in the para-C 1-4 alkyl group (e.g., methyl, ethyl, n-propyl or isopropyl). It may also be a phenyl group substituted with a phenyl group, a p-methylphenyl group or a para-ethyl group.
  • said R 1 and R 2 may each independently be a C 1-5 alkyloxy group (e.g., a C 1-3 alkyloxy group, such as a methoxy group, Ethoxy, n-propoxy or isopropoxy); or, R 1 and R 2 may be combined with the carbon atom to which they are attached to form a 5-7 membered cyclic acetal (5-membered cyclic acetal)
  • a 5-7 membered cyclic acetal 5-membered cyclic acetal
  • 6-membered cyclic acetal R 10 and R 11 are each independently H or C 1-3 alkyl (such as methyl) and R 10 and R 11 are not simultaneously hydrogen) or 5-7 membered cyclic thioal (e.g. ).
  • said R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal.
  • the compound shown in Formula III can be selected from any of the following structures:
  • Ar is preferably phenyl, p-methylphenyl or para-ethyl substituted phenyl; R 1 and R 2 are common to them The attached carbon atoms combine to form an ethylene glycol acetal or a propylene glycol acetal.
  • the present invention also provides a process A for the preparation of a compound of formula III, which comprises the steps of subjecting a compound of formula V to intramolecular cyclization to give a compound of formula III; said intramolecular cyclization
  • the reaction is preferably carried out under basic conditions;
  • R 1 and R 2 are as defined above for the compound of formula III;
  • R 3 is hydrogen or a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group.
  • the R 3 may be a methylsulfonyl group.
  • the intramolecular cyclization reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the field, and may also be a C 6 -C 10 alkane solvent (such as n-hexane, n-heptane), an aromatic hydrocarbon solvent (such as toluene), an ether solvent (such as tetrahydrofuran).
  • ether solvent such as tetrahydrofuran.
  • an ester solvent such as t-butyl acetate or isopropyl acetate.
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the compound represented by the formula V may have a molar concentration in the organic solvent of 0.001 to 5 mol/L.
  • the base in the basic condition may be sodium hydride, potassium t-butoxide, sodium t-butoxide, butyl lithium, LDA, LiHMDS, KHMDS and NaHMDS.
  • the amount of the base used in the basic conditions may be a conventional amount for such a reaction in the art.
  • the molar ratio of the base to the compound of the formula V may be from 1 to 10:1.
  • the progress of the intramolecular cyclization reaction can be carried out by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC). Monitoring is carried out, generally as the end point of the reaction when the compound as shown in Formula V is no longer reacted.
  • the reaction temperature of the intramolecular cyclization reaction may be a conventional temperature of such a reaction in the art, for example, -30 to 30 °C.
  • the preparation method A of the compound of the formula III may comprise the following steps:
  • the base is added dropwise to the organic solution of the compound of the formula V at -30 to 30 ° C, and the reaction is further stirred under the conditions for 10 min to 6 h; after the TLC detection reaction is completed, the saturated ammonium chloride aqueous solution is added to the reaction solution. The reaction was quenched, extracted with ethyl acetate and concentrated to give a compound of formula III.
  • the organic solvent is preferably toluene, n-hexane, n-heptane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, acetic acid.
  • tert-butyl ester and isopropyl acetate is preferably toluene, n-hexane, n-heptane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, acetic acid.
  • tert-butyl ester and isopropyl acetate isopropyl acetate.
  • the base is preferably sodium hydride, potassium t-butoxide, sodium t-butoxide, butyl lithium, LDA, LiHMDS, KHMDS and NaHMDS. One or more.
  • the invention also provides a further preparation method B of the compound of formula III, which comprises the steps of: subjecting a compound of formula VA to intramolecular cyclization to give a compound of formula III; said intramolecular ring
  • the reaction is preferably carried out in the presence of a Lewis acid and a Lewis base;
  • R 1 and R 2 are as defined above for the compound of formula III;
  • Y is a halogen, preferably chlorine, bromine or iodine.
  • the Y may be chlorine.
  • the intramolecular cyclization reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the field, and may also be an aromatic hydrocarbon solvent (such as toluene), a nitrile solvent (such as acetonitrile), an ether solvent (such as tetrahydrofuran), and an ester solvent (such as acetic acid B).
  • an aromatic hydrocarbon solvent such as toluene
  • a nitrile solvent such as acetonitrile
  • an ether solvent such as tetrahydrofuran
  • an ester solvent such as acetic acid B
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the compound represented by the formula VA may have a molar concentration in the organic solvent of 0.001 to 5 mol/L.
  • the Lewis acid may be silver oxide and/or silver salt, and may also be silver oxide, silver perchlorate, silver trifluoromethanesulfonate, tetrafluorocarbon.
  • One or more of silver borate and silver hexafluorophosphate for example, silver oxide, silver trifluoromethanesulfonate, silver tetrafluoroborate or silver hexafluorophosphate.
  • the amount of the Lewis acid used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the Lewis acid to the compound represented by the formula VA may be from 0.1 to 10:1.
  • the Lewis base may be 2,6-di-tert-butyl-4-methylpyridine, 2,6-lutidine, 2,4.
  • One or more of 6-trimethylpyridine and pyridine may be used.
  • the amount of the Lewis base used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the Lewis base to the compound represented by the formula VA may be from 0.1 to 10:1.
  • the progress of the intramolecular cyclization reaction can be carried out by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC).
  • the monitoring is carried out, generally as the end point of the reaction when the compound as shown in the formula VA is no longer reacted.
  • the reaction temperature of the intramolecular cyclization reaction may be a conventional temperature of such a reaction in the art, for example, 0 to 60 °C.
  • the preparation method B of the compound of the formula III may comprise the following steps:
  • the Lewis acid and the Lewis base are added to the organic solution of the compound VA at 0 to 60 ° C, and the reaction is further stirred under the conditions for 6 to 48 hours; after the TLC detection reaction is completed, the reaction solution is quenched by adding a saturated aqueous solution of ammonium chloride. Extracted with ethyl acetate and concentrated to give compound III.
  • the organic solvent is preferably one of toluene, tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate and t-butyl acetate. A variety.
  • the Lewis acid is preferably silver oxide, silver perchlorate, silver trifluoromethanesulfonate, silver tetrafluoroborate and silver hexafluorophosphate.
  • the Lewis acid is preferably silver oxide, silver perchlorate, silver trifluoromethanesulfonate, silver tetrafluoroborate and silver hexafluorophosphate.
  • silver oxide, silver trifluoromethanesulfonate, silver tetrafluoroborate or silver hexafluorophosphate silver oxide, silver trifluoromethanesulfonate, silver tetrafluoroborate or silver hexafluorophosphate.
  • the Lewis base is preferably 2,6-di-tert-butyl-4-methylpyridine or 2,6-lutidine.
  • 2,4,6-trimethylpyridine and pyridine are preferred.
  • the invention also provides a compound of formula V,
  • R 1 and R 2 are as defined in the compound of the above formula III;
  • R 3 is hydrogen or a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group.
  • the R 3 may be a methylsulfonyl group.
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal;
  • Ar is a phenyl group, P-methylphenyl or phenyl substituted in the para-ethyl group;
  • R 3 is methylsulfonyl.
  • the compound of formula V can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of the formula V, wherein a compound of the formula VI and a compound of the formula VII are subjected to NHK reaction to obtain the compound of the formula V;
  • R 1 , R 2 and R 3 are as defined in the compound represented by the above formula V;
  • X is a halogen or a leaving group, preferably a chlorine, bromine, iodine or triflate group.
  • the X may be chlorine, bromine or iodine, and may also be iodine.
  • the NHK reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the field, and may also be an ester solvent (such as ethyl acetate), a nitrile solvent (such as acetonitrile), an ether solvent (such as methyl tert-butyl ether, tetrahydrofuran).
  • an ester solvent such as ethyl acetate
  • a nitrile solvent such as acetonitrile
  • an ether solvent such as methyl tert-butyl ether, tetrahydrofuran.
  • 2-methyltetrahydrofuran 2-methyltetrahydrofuran
  • a sulfoxide solvent such as dimethyl sulfoxide
  • a halogenated hydrocarbon solvent such as a chlorinated hydrocarbon solvent such as dichloromethane.
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art, and for
  • the NHK reaction can be carried out in the presence of a halogenated chromium salt and/or a halogenated nickel salt.
  • the halogenated chromium salt may be a chlorochromium salt (such as chromium dichloride or chromium trichloride).
  • the halogenated nickel salt may be a nickel chloride salt such as nickel dichloride.
  • the halogenated chromium salt or the halogenated nickel salt may be used in a conventional amount for such a reaction in the art, for example, the molar ratio of the halogenated chromium salt to the compound represented by the formula VII may be The molar ratio of the halogenated nickel salt to the compound of the formula VII may be from 0.0001 to 10:1 in the range of from 0.01 to 10:1.
  • the NHK reaction can be carried out in the presence of a base.
  • the base may be one or more of triethylamine, pyridine, 2,6-lutidine, 2,4,6-lutidine, proton sponge and diisopropylethylamine.
  • the amount of the base used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the base to the compound of the formula VII may be from 1 to 20:1.
  • the molar ratio of the compound of the formula VII to the compound of the formula VI may be from 0.1 to 10:1.
  • the NHK reaction can be carried out in the presence of a ligand.
  • the ligand may be a conventional ligand for such reactions in the art, and may also be and / or
  • the amount of the ligand used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the ligand to the compound of the formula VII may be from 0.1 to 10:1.
  • the progress of the NHK reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC).
  • a conventional test method in the art such as TLC, HPLC, GC or NMR, preferably TLC.
  • the compound represented by the formula VII is used as the end point of the reaction when it is no longer reacted.
  • the reaction temperature of the NHK reaction may be a conventional temperature of such a reaction in the art, for example, 0 to 60 °C.
  • the preparation method of the compound represented by Formula V may comprise the following steps:
  • the organic solvent is preferably ethyl acetate, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, dimethyl sulfoxide or 2-methyltetrahydrofuran. And one or more of dichloromethane.
  • the base is preferably triethylamine, pyridine, 2,6-lutidine, 2,4,6-lutidine.
  • One or more of a proton sponge and diisopropylethylamine are preferred.
  • the ligand may be any organic compound that is organic or inorganic.
  • the ligand may be any organic compound that is organic or inorganic.
  • the invention also provides a compound as shown in formula VA,
  • R 1 and R 2 are as defined in the compound of the above formula III;
  • Y is a halogen, preferably chlorine, bromine or iodine.
  • the Y may be chlorine.
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal;
  • Ar is a phenyl group, P-methylphenyl or phenyl substituted in the para-ethyl group;
  • Y is chlorine.
  • the compound of formula VA can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of the formula VA, which comprises the steps of: subjecting a compound of the formula VI and a compound of the formula VIIA to NHK reaction;
  • R 1 , R 2 and Y are as defined in the compound represented by the above formula VA;
  • X is a halogen or a leaving group, preferably a chlorine, bromine, iodine or triflate group.
  • the X may be chlorine, bromine or iodine, and may also be iodine.
  • the NHK reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the field, and may also be an ester solvent (such as ethyl acetate), a nitrile solvent (such as acetonitrile), an ether solvent (such as methyl tert-butyl ether, tetrahydrofuran).
  • an ester solvent such as ethyl acetate
  • a nitrile solvent such as acetonitrile
  • an ether solvent such as methyl tert-butyl ether, tetrahydrofuran.
  • 2-methyltetrahydrofuran 2-methyltetrahydrofuran
  • a sulfoxide solvent such as dimethyl sulfoxide
  • a halogenated hydrocarbon solvent such as a chlorinated hydrocarbon solvent such as dichloromethane.
  • the organic solvent may be used in an amount conventionally used in the field for such a reaction.
  • the NHK reaction can be carried out in the presence of a halogenated chromium salt and/or a halogenated nickel salt.
  • the halogenated chromium salt may be a chlorochromium salt (such as chromium dichloride or chromium trichloride).
  • the halogenated nickel salt may be a nickel chloride salt such as nickel dichloride.
  • the halogenated chromium salt or the halogenated nickel salt may be used in a conventional amount for such a reaction in the art, for example, the molar ratio of the halogenated chromium salt to the compound represented by the formula VIIA may be The molar ratio of the halogenated nickel salt to the compound of the formula VIIA may be from 0.0001 to 10:1 in the range of from 0.01 to 10:1.
  • the molar ratio of the compound represented by the formula VIIA to the compound represented by the formula VI may be from 0.1 to 10:1.
  • the NHK reaction can be carried out in the presence of a base.
  • the base may be one or more of triethylamine, pyridine, 2,6-lutidine, 2,4,6-lutidine, proton sponge and diisopropylethylamine.
  • the amount of base used can be a conventional amount for such reactions in the art.
  • the molar ratio of the base to the compound VIIA may range from 1 to 20:1.
  • the NHK reaction can be carried out in the presence of a ligand.
  • the ligand may be a conventional ligand for such reactions in the art, and may also be and / or
  • the amount of the ligand used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the ligand to the compound represented by the formula VIIA may be from 0.1 to 10:1.
  • the progress of the NHK reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC). Generally, when the compound represented by the formula VIIA is no longer reacted, it is used as a reaction end point.
  • a conventional test method in the art such as TLC, HPLC, GC or NMR, preferably TLC.
  • the reaction temperature of the NHK reaction may be a conventional temperature of such a reaction in the art, for example, 0 to 60 °C.
  • the method for preparing the compound of the formula VA may comprise the following steps:
  • the compound of the formula VI and the compound of the formula VIIA, the ligand, the chromium dichloride (or chromium trichloride) and the nickel dichloride are added to the reaction flask, and the organic solvent and the alkali are dissolved.
  • the reaction system is stirred in an oil bath at 0-60 ° C for 2 to 48 hours; after the TLC detection reaction is completed, the reaction is quenched by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate.
  • the compound, or a compound of formula VA was used in the next step without purification.
  • the organic solvent is preferably ethyl acetate, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, dimethyl sulfoxide or 2-methyltetrahydrofuran. And one or more of dichloromethane.
  • the base is preferably triethylamine, pyridine, 2,6-lutidine, 2,4,6-lutidine.
  • One or more of a proton sponge and diisopropylethylamine are preferred.
  • the ligand may be
  • the present invention provides a compound of formula VII,
  • R 1 , R 2 and R 3 are as defined in the compound represented by the above formula V;
  • X is a halogen or a leaving group, preferably a chlorine, bromine, iodine or triflate group.
  • the X may be chlorine, bromine or iodine, and may also be iodine.
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal; R 3 is methyl sulfonate.
  • Acyl; X is iodine.
  • the compound of formula VII can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of formula VII, which comprises the steps of: subjecting compound VIII to a hydroxy protecting reaction to give said compound of formula VII;
  • R 1 , R 2 , R 3 and X are as defined in the compound of the above formula VII, and R 3 is not hydrogen.
  • the hydroxy protecting reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the field, and may also be an ester solvent (such as ethyl acetate), a nitrile solvent (such as acetonitrile), an aromatic hydrocarbon solvent (such as toluene), an ether solvent (such as One or more of tetrahydrofuran, 2-methyltetrahydrofuran), an amide solvent such as N,N-dimethylformamide, and a halogenated hydrocarbon solvent such as a chlorinated hydrocarbon solvent such as dichloromethane.
  • the organic solvent may be used in an amount conventionally used in the field.
  • the molar concentration of the compound VIII in the organic solvent may be from 0.01 to 5 mol/L.
  • the hydroxy protecting reaction can be carried out in the presence of a base.
  • the base may be one or more of triethylamine, pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine and diisopropylethylamine.
  • the amount of the base used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the base to the compound VIII may be from 1 to 20:1.
  • the hydroxy protecting reaction may be carried out in the presence of a sulfonylating agent, which may be methanesulfonyl chloride or methanesulfonic anhydride.
  • a sulfonylating agent which may be methanesulfonyl chloride or methanesulfonic anhydride.
  • P-toluenesulfonyl chloride, p-toluenesulfonic anhydride or trifluoromethanesulfonic anhydride may also be methanesulfonyl chloride or methanesulfonic anhydride.
  • the amount of the sulfonylating agent to be used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the sulfonylating agent to the compound of the formula VIII may be from 1 to 10:1.
  • the progress of the hydroxy protecting reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR, preferably TLC). It is generally used as the end point of the reaction when the compound represented by the formula VIII is no longer reacted.
  • the reaction temperature of the hydroxy protecting reaction may be a conventional temperature of the reaction of the field, for example, -40 to 50 ° C, and further, for example, -10 to 20 °C.
  • the method for preparing the compound of the formula VII may comprise the following steps:
  • the organic solvent is preferably ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide. And one or more solvents in dichloromethane.
  • the base is preferably triethylamine, pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine and One or more of diisopropylethylamine.
  • the sulfonylating agent is preferably methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride or trifluoromethylsulfonate.
  • Anhydride is preferably methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride or trifluoromethylsulfonate.
  • the invention also provides a compound of formula VIIA,
  • R 1 , R 2 and X are as defined above in the compound of formula VII;
  • Y is a halogen, preferably chlorine, bromine or iodine.
  • the Y may be chlorine.
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal;
  • X is iodine; It is chlorine.
  • the compound of formula VIIA can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of formula VIIA, which comprises the steps of: subjecting a compound of formula VII to a substitution reaction to give said compound of formula VIIA;
  • R 1 , R 2 , X and Y are as defined in the compound of the above formula VIIA;
  • R 3 is hydrogen or a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group.
  • the R 3 may be a methylsulfonyl group.
  • the substitution reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the field, and may also be an ester solvent (such as ethyl acetate), a nitrile solvent (such as acetonitrile), an aromatic hydrocarbon solvent (such as toluene), an ether solvent (such as Tetrahydrofuran), amide solvents (such as N,N-dimethylformamide, N,N-dimethylpropenyl urea) and halogenated hydrocarbon solvents (such as chlorinated hydrocarbon solvents, such as dichloromethane) One or more.
  • an ester solvent such as ethyl acetate
  • a nitrile solvent such as acetonitrile
  • an aromatic hydrocarbon solvent such as toluene
  • an ether solvent such as Tetrahydrofuran
  • amide solvents such as N,N-dimethylformamide, N,N-dimethylpropenyl urea
  • the organic solvent is N,N-dimethylpropenyl urea or N,N-dimethylformamide.
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the molar concentration of the compound VII in the organic solvent may be 0.01 to 5 mol/L.
  • the substitution reaction can be carried out in the presence of a halogenating agent.
  • the halogenating agent may be a conventional reagent for such a reaction in the art, wherein a chlorinating agent such as lithium chloride, sodium chloride, tributylbenzylammonium chloride, ammonium chloride or tetrabutylammonium chloride Bromo reagents such as lithium bromide, sodium bromide, tributylbenzylammonium bromide, ammonium bromide or tetrabutylammonium bromide, iodide reagents such as lithium iodide, sodium iodide, tributylbenzyl iodide Ammonium, ammonium iodide or tetrabutylammonium iodide.
  • the halogenating agent is tributylbenzylammonium chloride or tetrabutylammonium chloride.
  • the halogenating agent can be used in a conventional amount for such a reaction in the art.
  • the molar ratio of the halogenating agent to the compound of the formula VII can be from 1 to 50.
  • the progress of the substitution reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC). Generally, when the compound VII is no longer reacted, it is used as a reaction end point.
  • the reaction temperature of the substitution reaction may be a conventional temperature of such a reaction in the art, for example, -40 to 80 ° C, and further, for example, -20 to 60 ° C. .
  • the method for preparing the compound of the formula VIIA may comprise the following steps:
  • the halogenating agent is added to an organic solvent of the compound shown by VII at -20 to 60 ° C, and the reaction is stirred at -20 to 60 ° C for 1 to 48 hours. After the TLC reaction was completed, the reaction was quenched by water, extracted with ethyl acetate, and concentrated to give a compound as shown in VIIA.
  • the organic solvent is preferably ethyl acetate, acetonitrile, toluene, dichloromethane, N,N-dimethylformamide, N, One or more of N-dimethylpropenylurea (DMPU) and tetrahydrofuran (for example, N,N-dimethylpropenylurea or N,N-dimethylformamide).
  • DMPU N-dimethylpropenylurea
  • tetrahydrofuran for example, N,N-dimethylpropenylurea or N,N-dimethylformamide.
  • the halogenating agent is preferably lithium chloride, sodium chloride, tributylbenzylammonium chloride, ammonium chloride, tetrabutyl.
  • Ammonium chloride lithium bromide, sodium bromide, tributylbenzylammonium bromide, ammonium bromide, tetrabutylammonium bromide, lithium iodide, sodium iodide, tributylbenzylammonium iodide, ammonium iodide Or tetrabutylammonium iodide (such as tributylbenzylammonium chloride or tetrabutylammonium chloride).
  • the invention also provides a compound of formula II,
  • R 1 and R 2 are an acetal protecting group or a thioacetal protecting group, and each independently is a C 1-10 alkyloxy group or a C 1-10 alkyl fluorenyl group, or R 1 and R 2 are The carbon atoms to which they are linked together form a cyclic acetal or a cyclic thioacetal; R 1 and R 2 are preferably combined with the carbon atom to which they are attached to form a cyclic acetal or a cyclic thioacetal, more preferably a substitution. Or an unsubstituted ethylene glycol acetal or a substituted or unsubstituted propylene glycol acetal;
  • X is a halogen or a leaving group, preferably a chlorine, bromine, iodine or triflate group.
  • the R 1 and R 2 may each independently be a C 1-5 alkyloxy group (such as a C 1-3 alkyloxy group, such as a methoxy group, Ethoxy, n-propoxy or isopropoxy); or, R 1 and R 2 may be combined with the carbon atom to which they are attached to form a 5-7 membered cyclic acetal (5-membered cyclic acetal)
  • a 5-7 membered cyclic acetal such as 6-membered cyclic acetal R 10 and R 11 are each independently H or C 1-3 alkyl (e.g. methyl) and R 10 and R 11 are not simultaneously hydrogen) or a 5-7 membered cyclic thioacetal (e.g. ).
  • said R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal.
  • the X may be iodine.
  • X is iodo; R 1 R 2 and the carbon atom to which they are attached combine to form ethylene acetal or propylene acetal.
  • the compound of formula II can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of formula II, which comprises the steps of: subjecting a compound of formula IX to a reduction elimination reaction to obtain the compound of formula II;
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group.
  • the Ar may be a phenyl group or the para position may be substituted by a C 1-4 alkyl group (such as methyl, ethyl, n-propyl or isopropyl). Phenyl.
  • the Ar may be a phenyl group, a p-methylphenyl group or a phenyl group in which the para position is substituted with an ethyl group.
  • the reduction elimination reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the art, such as an ether solvent such as tetrahydrofuran.
  • the amount of the organic solvent used is a conventional amount for such a reaction in the art.
  • the compound of the formula IX may have a molar concentration of 0.001 to 5 mol/L in the organic solvent.
  • the reduction elimination reaction may be carried out in the presence of a reducing agent, and the reducing agent may be bismuth diiodide, chromium dichloride, trichlorochloride.
  • the reducing agent may be bismuth diiodide, chromium dichloride, trichlorochloride.
  • chromium, manganese powder and zinc powder such as bismuth iodide, chromium dichloride-manganese powder or zinc powder.
  • the amount of the reducing agent used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the reducing agent to the compound represented by the formula IX may be from 1 to 20:1.
  • the progress of the reduction elimination reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC). Generally, when the compound represented by the above formula IX is no longer reacted, it is used as a reaction end point.
  • a conventional test method in the art such as TLC, HPLC, GC or NMR, preferably TLC.
  • the reaction temperature of the reduction elimination reaction may be a conventional temperature of such a reaction in the art, for example, -78 to 30 °C.
  • the method for preparing the compound of formula II may comprise the following steps:
  • the reducing agent is added dropwise to the THF solution of the compound of the formula IX at -78 to 30 ° C, and the reaction is stirred at -78 to 30 ° C for 10 to 12 hours. After the TLC detection reaction was completed, the reaction was quenched by adding an aqueous solution of potassium carbonate, extracted with ethyl acetate, and concentrated to give a compound of formula II.
  • the reducing agent is preferably one of cerium diiodide, chromium dichloride, chromium trichloride, manganese powder and zinc powder. Or a variety (such as bismuth iodide, chromium dichloride-manganese powder or zinc powder).
  • the present invention also provides a process M for the preparation of a compound of formula IV, which comprises the steps of: hydrolyzing a compound of formula II to give a compound of formula IV;
  • the hydrolysis reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the art, for example, a halogenated hydrocarbon solvent (such as a chlorinated hydrocarbon solvent, such as dichloromethane).
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the molar concentration of the compound II in the organic solvent may be 0.001 to 5 mol/L.
  • the hydrolysis reaction may be carried out in the presence of a hydrolysis reagent, which may be hydrochloric acid or p-toluenesulfonic acid.
  • a hydrolysis reagent which may be hydrochloric acid or p-toluenesulfonic acid.
  • P-toluenesulfonic acid pyridinium salt, boron trifluoride etherate, TMSOTf, tetraisopropyl titanate, titanium tetrachloride, pyridine, 2,6-lutidine and 2,4,6-trimethylpyridine
  • One or more e.g., one or more of 2,6-lutidine, pyridine, and TMSOTf, such as 2,6-lutidine and TMSOTf, such as pyridine and TMSOTf).
  • the amount of the hydrolysis reagent may be a conventional amount for such a reaction in the art.
  • the progress of the hydrolysis reaction may be carried out by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably, Monitoring for TLC) is generally carried out as the end point of the reaction when the compound of the formula II described above is no longer reacted.
  • a conventional test method in the art such as TLC, HPLC, GC or NMR, preferably, Monitoring for TLC
  • the reaction temperature of the hydrolysis reaction may be a conventional temperature of such a reaction in the art, for example, -30 to 40 °C.
  • the preparation method M of the compound represented by Formula IV may comprise the following steps:
  • the hydrolysis reagent is sequentially added to a dichloromethane solution of the compound of the formula II at -30 to 40 ° C, and the reaction is further stirred for 1 to 24 hours after the addition. After the TLC detection reaction was completed, the reaction mixture was quenched by the addition of 1N hydrochloric acid, and extracted with ethyl acetate, and concentrated to give a compound of formula IV.
  • the hydrolysis reagent is preferably hydrochloric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, boron trifluoride etherate, TMSOTf, titanium.
  • TMSOTf titanium.
  • One or more of tetraisopropyl acid ester, titanium tetrachloride, pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine for example, 2,6-lutidine, pyridine
  • TMSOTf such as 2,6-lutidine and TMSOTf, such as pyridine and TMSOTf.
  • the invention also provides a compound of formula IX,
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group.
  • the Ar may be a phenyl group or a phenyl group substituted in the para-C 1-4 alkyl group (e.g., methyl, ethyl, n-propyl or isopropyl).
  • the Ar may be a phenyl group, a p-methylphenyl group or a phenyl group in which the para position is substituted with an ethyl group.
  • Ar is preferably a phenyl group, a p-methylphenyl group or a para-ethyl substituted phenyl group; R 1 and R 2 are common thereto The attached carbon atoms combine to form an ethylene glycol acetal or a propylene glycol acetal; X is iodine.
  • the compound of formula IX can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of formula IX, which comprises the steps of: subjecting a compound of formula X to an oxidation reaction;
  • Ar, X, R 1 and R 2 are as defined in the compound represented by the above formula IX.
  • the oxidation reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the art, such as a chlorinated hydrocarbon solvent (such as a chlorinated hydrocarbon solvent, such as dichloromethane) and/or a sulfoxide solvent (such as dimethyl sulfoxide).
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the compound of the formula X may have a molar concentration in the organic solvent of 0.001 to 5 mol/L.
  • the oxidizing agent in the oxidation reaction may be a conventional oxidizing agent such as Dess-Martin oxidizing agent, Swern oxidizing agent, IBX oxidizing agent, TEMPO-NaClO and TEMPO.
  • a conventional oxidizing agent such as Dess-Martin oxidizing agent, Swern oxidizing agent, IBX oxidizing agent, TEMPO-NaClO and TEMPO.
  • -PhI(OAc) 2 such as Dess-Martin oxidant, IBX oxidant, TEMPO-NaClO or TEMPO-PhI(OAc) 2
  • the amount of the oxidizing agent used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the oxidizing agent to the compound represented by the formula X may be from 1 to 20:1.
  • the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, GC or NMR, preferably TLC).
  • a conventional test method in the art such as TLC, HPLC, GC or NMR, preferably TLC.
  • the compound represented by the above formula X is used as the end point of the reaction when it is no longer reacted.
  • the reaction temperature of the oxidation reaction may be a conventional temperature of such a reaction in the art, for example, -20 to 60 °C.
  • the method for preparing the compound of the formula IX may comprise the following steps:
  • the oxidizing agent is added to the organic solvent of the compound represented by the formula X at -20 to 60 ° C, and the reaction is further stirred at the temperature for 1 to 6 hours; after the TLC detection reaction is completed, the solution is quenched with an aqueous solution of sodium thiosulfate and sodium hydrogencarbonate. Off. Extracted with ethyl acetate and concentrated to give a compound of formula IX.
  • the oxidizing agent is preferably a Dess-Martin oxidizing agent, a Swern oxidizing agent, an IBX oxidizing agent, TEMPO-NaClO, and TEMPO-PhI(OAc) 2
  • One or more such as Dess-Martin oxidant, IBX oxidant, TEMPO-NaClO or TEMPO-PhI (OAc) 2 ).
  • the present invention also provides a process for the preparation of a compound of formula XII, which comprises the steps of: subjecting a compound of formula IX to a hydrolysis reaction;
  • Ar, X, R 1 and R 2 are as defined in the compound represented by the above formula IX.
  • the hydrolysis reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the art, such as a halogenated hydrocarbon solvent (such as a chlorinated hydrocarbon solvent, such as dichloromethane), an aromatic hydrocarbon solvent (such as toluene), and a nitrile solvent ( One or more of such as acetonitrile.
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the molar concentration of the compound IX in the organic solvent may be 0.001 to 5 mol/L.
  • the hydrolysis reaction may be carried out in the presence of a hydrolysis reagent, which may be hydrochloric acid, p-toluenesulfonic acid or p-toluenesulfonic acid pyridinium salt.
  • a hydrolysis reagent which may be hydrochloric acid, p-toluenesulfonic acid or p-toluenesulfonic acid pyridinium salt.
  • the amount of the hydrolysis reagent may be a conventional amount for such a reaction in the art.
  • the molar ratio of the hydrolysis reagent to the compound of the formula IX may be from 0.1 to 20:1.
  • the progress of the hydrolysis reaction can be monitored by a conventional test method (such as TLC, HPLC, GC or NMR, preferably TLC) in the art.
  • a conventional test method such as TLC, HPLC, GC or NMR, preferably TLC
  • TLC TLC, HPLC, GC or NMR, preferably TLC
  • the reaction temperature of the hydrolysis reaction may be a conventional temperature of such a reaction in the art, for example, -20 to 40 °C.
  • the preparation method of the compound represented by Formula XII may comprise the following steps:
  • the hydrolysis reagent is sequentially added to the organic solution of the compound of the formula IX at -20 to 40 ° C. After the addition, the reaction is further stirred for 1 to 12 hours; after the TLC detection reaction is completed, the reaction solution is quenched by adding 1 N hydrochloric acid. Extracted with ethyl acetate and concentrated to give a compound of formula XII.
  • the organic solvent is preferably one or more of dichloromethane, toluene and acetonitrile.
  • the hydrolysis reagent is preferably hydrochloric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, boron trifluoride etherate, TMSOTf, titanic acid.
  • tetraisopropyl ester titanium tetrachloride, ammonium cerium nitrate, pyridine, 2,6-lutidine and 2,4,6-trimethylpyridine (for example, 2,6-dimethyl One or more of pyridinium, TMSOTf and pyridinium p-toluenesulfonate and ammonium cerium nitrate).
  • the invention also provides a compound of formula X,
  • Ar, X, R 1 and R 2 are as defined in the compound represented by the above formula IX.
  • Ar is preferably a phenyl group, a p-methylphenyl group or a para-ethyl substituted phenyl group; R 1 and R 2 are combined with the carbon atom to which they are attached to form a glycol acetal or Propylene glycol acetal; X is iodine.
  • the compound of formula X can be selected from any of the following structures:
  • the present invention also provides a process for the preparation of a compound of the formula X, which comprises the steps of: subjecting a compound of the formula III to a condensation reaction with a compound of the formula XI under basic conditions;
  • Ar, X, R 1 and R 2 are as defined in the compound represented by the above formula X.
  • the condensation reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the art, and may also be a C 6 -C 10 alkane solvent (such as n-heptane) and/or an ether solvent (such as tetrahydrofuran, 2-methyltetrahydrofuran).
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art.
  • the molar concentration of the compound III in the organic solvent may be 0.001 to 5 mol/L.
  • the alkali in the alkaline condition may be a conventional base in the field, and may also be sodium hydride or butyl lithium (such as n-butyllithium, Isobutyl lithium or tert-butyl lithium), diisopropylethylamine, lithium diisopropylamide, potassium hexamethylsilylamine, lithium hexamethylsilylamide and hexamethylsilyl
  • One or more of the sodium amino groups for example, n-butyllithium, lithium diisopropylamide or lithium hexamethylsilylamide.
  • the amount of the base used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the base to the compound of the formula III may be from 0.5 to 5:1.
  • the molar ratio of the compound of the formula III to the compound of the formula XI may be from 0.1 to 10:1.
  • the progress of the condensation reaction can be monitored by a conventional test method (such as TLC, HPLC, GC or NMR, preferably TLC) in the art.
  • a conventional test method such as TLC, HPLC, GC or NMR, preferably TLC
  • the compound represented by the above formula III is no longer reacted, it is used as a reaction end point.
  • the reaction temperature of the condensation reaction may be a conventional temperature of such a reaction in the art, for example, -78 to 0 °C.
  • the method of preparing the compound of formula X comprises the steps of:
  • the organic solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and n-heptane.
  • the base is preferably sodium hydride, butyl lithium, diisopropylethylamine, lithium diisopropylamide or hexamethyl.
  • potassium silylamine, lithium hexamethylsilylamide, and sodium hexamethylsilylamide eg, n-butyllithium, diisopropylamine lithium, or hexamethylsilyl
  • Amino lithium eg, n-butyllithium, diisopropylamine lithium, or hexamethylsilyl
  • the present invention also provides a method K for preparing a compound of the formula IV, which comprises the steps of: subjecting a compound of the formula XII to a reduction elimination reaction to obtain a compound of the formula IV;
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group;
  • X is a halogen or a leaving group, preferably a chlorine, bromine, iodine or triflate group.
  • the Ar may be a phenyl group or a para-C 1-4 alkyl group (such as methyl, ethyl, n-propyl or isopropyl).
  • the substituted phenyl group may also be a phenyl group, a p-methylphenyl group or a phenyl group in which the para position is substituted with an ethyl group.
  • the X may be chlorine, bromine or iodine, and may also be iodine.
  • the reduction elimination reaction can be carried out in an organic solvent.
  • the organic solvent may be a conventional solvent for such a reaction in the art, such as an ether solvent such as tetrahydrofuran.
  • the amount of the organic solvent used is a conventional amount for such a reaction in the art.
  • the molar concentration of the compound XII in the organic solvent may be 0.001 to 5 mol/L.
  • the reduction elimination reaction may be carried out in the presence of a reducing agent, and the reducing agent may be bismuth diiodide, chromium dichloride, or the like.
  • the reducing agent may be bismuth diiodide, chromium dichloride, or the like.
  • One or more of chromium chloride, manganese powder and zinc powder such as bismuth iodide, chromium dichloride-manganese powder or zinc powder.
  • the amount of the reducing agent used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the reducing agent to the compound represented by the formula XII may be from 0.1 to 20:1.
  • the progress of the reduction elimination reaction can be carried out by a conventional test method (for example, TLC, HPLC, GC or NMR, preferably TLC) in the art.
  • the monitoring is generally carried out as the end point of the reaction when the compound represented by the above formula XII is no longer reacted.
  • the reaction temperature of the reduction elimination reaction may be a conventional temperature of such a reaction in the art, for example, from -50 to 30 °C.
  • the preparation method K of the compound represented by the formula IV may comprise the following steps:
  • the reducing agent is added dropwise to the organic solution of the compound of the formula XII at -50 ° C to 30 ° C, and the reaction is stirred at this temperature for 30 min to 4 h. After the TLC detection reaction was completed, the reaction was quenched by adding an aqueous solution of potassium carbonate, and the mixture was extracted with ethyl acetate.
  • the reducing agent is preferably one of cerium diiodide, chromium dichloride, manganese powder, zinc powder and chromium trichloride. Or a variety.
  • the present invention also provides a synthesis method P of an eribulin intermediate represented by Formula IV, which comprises the following steps:
  • Ar, X, R 1 and R 2 are as defined above.
  • the present invention also provides a method Q of synthesizing an eribulin intermediate represented by Formula IV, comprising the steps of:
  • Ar, X, R 1 and R 2 are as defined above.
  • the invention also provides a synthesis method A of the eribulin intermediate represented by formula IV, which comprises the following steps:
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group;
  • R 1 and R 2 are an acetal protecting group or a thioacetal protecting group, and each independently is a C 1-10 alkyloxy group or a C 1-10 alkyl fluorenyl group, or R 1 and R 2 are common thereto
  • the attached carbon atoms combine to form a cyclic acetal or a cyclic thioacetal.
  • R 1 and R 2 are preferably combined with a carbon atom to which they are attached to form a cyclic acetal or a cyclic thioacetal, more preferably a substituted or unsubstituted ethylene acetal or a substituted or unsubstituted propylene glycol acetal;
  • R 3 is a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group;
  • X is a halogen or a leaving group, preferably a chlorine, bromine, iodine or triflate group.
  • the Ar may be a phenyl group or a para to a C 1-4 alkyl group (e.g., methyl, ethyl, n-propyl group). Or isopropyl) substituted phenyl.
  • the Ar may also be a phenyl group, a p-methylphenyl group or a phenyl group in which the para position is substituted with an ethyl group.
  • the R 1 and R 2 may each independently be a C 1-5 alkyloxy group (e.g., a C 1-3 alkyl group).
  • An oxy group such as methoxy, ethoxy, n-propoxy or isopropoxy); or, R 1 and R 2 may be combined with the carbon atom to which they are attached to form a 5-7 membered ring Acetal (5-membered cyclic acetal such as 6-membered cyclic acetal R 10 and R 11 are each independently H or C 1-3 alkyl (such as methyl) and R 10 and R 11 are not simultaneously hydrogen) or 5-7 membered cyclic thioal (e.g. ).
  • said R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal.
  • the R 3 may be a methylsulfonyl group.
  • the X may be chlorine, bromine or iodine, and may also be iodine.
  • the synthetic method A of the eribulin intermediate represented by the formula IV may include the following steps:
  • hydroxy protecting reaction is preferably carried out under basic conditions; and the hydroxy protecting reaction using a reagent is preferably triethylamine or pyridine , sodium hydride, potassium carbonate, 2,4,6-trimethylpyridine, 2,6-lutidine, butyl lithium, diisopropylethylamine, diisopropylamino lithium, hexamethyl
  • a reagent is preferably triethylamine or pyridine , sodium hydride, potassium carbonate, 2,4,6-trimethylpyridine, 2,6-lutidine, butyl lithium, diisopropylethylamine, diisopropylamino lithium, hexamethyl
  • potassium silylamine, lithium hexamethylsilylamide, and sodium hexamethylsilylamide is preferably triethylamine or pyridine , sodium hydride, potassium carbonate, 2,4,6-trimethylpyridine, 2,6-lutidine, butyl lithium, diisopropy
  • a compound represented by formula V subjecting a compound represented by formula V to intramolecular cyclization to give a compound of formula III; said intramolecular cyclization reaction is preferably carried out under basic conditions; said intramolecular cyclization reaction is preferably carried out using a reagent Is triethylamine, pyridine, sodium hydride, potassium carbonate, 2,4,6-trimethylpyridine, 2,6-lutidine, butyllithium, diisopropylethylamine, diisopropylamine One or more of lithium, hexamethylsilylamino potassium, hexamethylsilylamide lithium, and hexamethylsilylamino sodium;
  • condensation reaction of a compound of the formula III with a compound of the formula XI to give a compound of the formula X;
  • the condensation reaction is preferably carried out under basic conditions; the condensation reaction is preferably sodium hydride.
  • the condensation reaction is preferably sodium hydride.
  • an oxidizing agent preferably Dess-Martin oxidizing agent, Swern oxidizing agent, IBX oxidizing agent, TEMPO-NaClO and TEMPO-PhI (OAc)
  • the compound shown in Formula IX is subjected to a reduction elimination reaction to obtain a compound as shown in Formula II; and the reduction-eliminating reaction is preferably a reagent using cesium diiodide, chromium dichloride, manganese powder, zinc powder, and trichlorochloride.
  • the reduction-eliminating reaction is preferably a reagent using cesium diiodide, chromium dichloride, manganese powder, zinc powder, and trichlorochloride.
  • a compound of the formula II is subjecting to a hydrolysis reaction to obtain a compound of the formula IV;
  • the hydrolysis reaction is preferably carried out under acidic or neutral conditions;
  • the hydrolysis reaction using a reagent is preferably hydrochloric acid or p-toluenesulfonic acid.
  • p-toluenesulfonic acid pyridinium salt, boron trifluoride etherate, TMSOTf, tetraisopropyl titanate, titanium tetrachloride, pyridine, 2,6-lutidine and 2,4,6-trimethylpyridine
  • a reagent is preferably hydrochloric acid or p-toluenesulfonic acid.
  • p-toluenesulfonic acid pyridinium salt boron trifluoride etherate, TMSOTf, tetraisopropyl titanate, titanium tetrachloride, pyridine, 2,6-lutid
  • Ar is preferably a phenyl group, a p-methylphenyl group or a para-ethyl substituted phenyl group;
  • X is iodine;
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal.
  • the invention also provides a method A of synthesizing a compound of formula IVa, which comprises the steps of:
  • the invention also provides a method B of synthesizing a compound of formula IVa, which comprises the steps of:
  • the invention also provides a method B for synthesizing the eribulin intermediate represented by the formula IV, which comprises the following steps:
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group;
  • R 1 and R 2 are an acetal protecting group or a thioacetal protecting group, and each independently is a C 1-10 alkyloxy group or a C 1-10 alkyl fluorenyl group, or R 1 and R 2 are common thereto
  • the linked carbon atoms are combined to form a cyclic acetal or a cyclic thioacetal;
  • R 1 and R 2 are preferably combined with the carbon atom to which they are attached to form a cyclic acetal or a cyclic thio acetal, more preferably substituted or non-substituted.
  • R 3 is a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group
  • X is a halogen or a leaving group Preferably, it is chlorine, bromine, iodine or a triflate group.
  • the synthetic method B of the eribulin intermediate represented by the formula IV may include the following steps:
  • the compound represented by the formula VIII is subjected to a hydroxy protecting reaction to obtain a compound represented by the formula VII; the hydroxy protecting reaction is preferably carried out under basic conditions; and the hydroxy protecting reaction using a reagent is preferably triethylamine or pyridine.
  • a reagent is preferably triethylamine or pyridine.
  • the intramolecular cyclization reaction is preferably carried out under basic conditions; and the intramolecular cyclization reaction using a reagent is preferably Sodium hydride, butyl lithium, diisopropylethylamine, lithium diisopropylamide, potassium hexamethylsilylamine, lithium hexamethylsilylamide and sodium hexamethylsilylamide
  • a reagent is preferably Sodium hydride, butyl lithium, diisopropylethylamine, lithium diisopropylamide, potassium hexamethylsilylamine, lithium hexamethylsilylamide and sodium hexamethylsilylamide
  • condensation reaction of a compound of the formula III with a compound of the formula XI to obtain a compound of the formula X;
  • the condensation reaction is preferably carried out under basic conditions; and the condensation reaction is preferably a triethylamine , pyridine, sodium hydride, potassium carbonate, 2,4,6-trimethylpyridine, 2,6-lutidine, butyl lithium, diisopropylethylamine, diisopropylamino lithium, six One or more of potassium methylsilylamino, lithium hexamethylsilylamide, and sodium hexamethylsilylamide;
  • an oxidizing agent preferably Dess-Martin oxidizing agent, Swern oxidizing agent, IBX oxidizing agent, TEMPO-NaClO and TEMPO-PhI (OAc) 2
  • a hydrolysis reaction preferably carried out under acidic or neutral conditions; and the reagent is preferably hydrochloric acid, p-toluenesulfonic acid, or the like.
  • the hydrolysis reaction is preferably carried out under acidic or neutral conditions; and the reagent is preferably hydrochloric acid, p-toluenesulfonic acid, or the like.
  • the compound represented by the formula XII is subjected to a reduction elimination reaction to obtain a compound represented by the formula IV; and the reduction-eliminating reaction is preferably a reagent of diiodide, chromium dichloride, manganese powder, zinc powder and trichlorination. One or more of chromium.
  • Ar is preferably a phenyl group, a p-methylphenyl group or a para-ethyl substituted phenyl group.
  • X is iodine; R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal.
  • the invention also provides a method C of synthesizing a compound of formula IVa, which comprises the steps of:
  • a compound represented by the formula XIIa is subjected to a reduction elimination reaction in the presence of cesium diiodide to obtain a compound represented by the formula IVa.
  • the invention also provides a method of synthesizing D of a compound of formula IVa, comprising the steps of:
  • a compound represented by the formula XIId is subjected to a reduction elimination reaction in the presence of cesium diiodide to obtain a compound represented by the formula IV.
  • the invention also provides a synthesis method C of the eribulin intermediate represented by formula IV, which comprises the following steps:
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group;
  • R 1 and R 2 are an acetal protecting group or a thioacetal protecting group, and each independently is a C 1-10 alkyloxy group or a C 1-10 alkyl fluorenyl group, or R 1 and R 2 are common thereto
  • the linked carbon atoms are combined to form a cyclic acetal or a cyclic thioacetal;
  • R 1 and R 2 are preferably combined with the carbon atom to which they are attached to form a cyclic acetal or a cyclic thio acetal, more preferably substituted or non-substituted.
  • R 3 is a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group
  • X is a halogen or a leaving group Preferred as chlorine, bromine, iodine or triflate
  • Y is a halogen, preferably chlorine, bromine or iodine.
  • the Y may be chlorine.
  • the synthetic method C of the eribulin intermediate represented by Formula IV may include the following steps:
  • the compound represented by the formula VIII is subjected to a hydroxy protecting reaction to obtain a compound represented by the formula VII; the hydroxy protecting reaction is preferably carried out under basic conditions; and the hydroxy protecting reaction using a reagent is preferably triethylamine or pyridine.
  • a reagent is preferably triethylamine or pyridine.
  • substitution reaction is preferably lithium chloride, sodium chloride, tributylbenzylammonium chloride, ammonium chloride or the like.
  • the substitution reaction is preferably lithium chloride, sodium chloride, tributylbenzylammonium chloride, ammonium chloride or the like.
  • a compound represented by formula VA subjecting a compound represented by formula VA to intramolecular cyclization to give a compound of formula III; said intramolecular cyclization reaction is preferably carried out under Lewis acid conditions; said Lewis acid is preferably silver oxide, high chloride One or more of silver acid, silver trifluoromethanesulfonate, silver tetrafluoroborate, and silver hexafluorophosphate;
  • condensation reaction is preferably carried out under basic conditions; and the condensation reaction is preferably a triethylamine , pyridine, sodium hydride, potassium carbonate, 2,4,6-trimethylpyridine, 2,6-lutidine, butyl lithium, diisopropylethylamine, diisopropylamino lithium, six One or more of potassium methylsilylamino, lithium hexamethylsilylamide, and sodium hexamethylsilylamide;
  • an oxidizing agent preferably Dess-Martin oxidizing agent, Swern oxidizing agent, IBX oxidizing agent, TEMPO-NaClO and TEMPO-PhI (OAc) 2
  • the compound represented by the formula IX is subjected to a reduction elimination reaction to obtain a compound represented by the formula II; and the reduction-eliminating reaction is preferably a reagent of diiodide, chromium dichloride, manganese powder, zinc powder, trichlorination. Chrome, etc.
  • the hydrolysis reaction is preferably carried out under acidic or neutral conditions; and the hydrolysis reaction is preferably a reagent of hydrochloric acid or p-toluenesulfonic acid; P-toluenesulfonic acid pyridinium salt, boron trifluoride etherate, TMSOTf, tetraisopropyl titanate, titanium tetrachloride, pyridine, 2,6-lutidine and 2,4,6-trimethylpyridine One or more.
  • Ar is preferably a phenyl group, a p-methylphenyl group or a para-ethyl substituted phenyl group.
  • X is iodine;
  • Y is chlorine;
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal. .
  • the invention also provides a method E of synthesizing a compound of formula IVa, which comprises the steps of:
  • the invention also provides a method F for the synthesis of a compound of formula IVa:
  • the invention also provides a method D for synthesizing the eribulin intermediate represented by formula IV, which comprises the following steps:
  • Ar is a C 1-10 alkyl-substituted or alkyloxy-substituted or unsubstituted aryl group; preferably a phenyl group substituted or unsubstituted with a C 1-10 alkyl group;
  • R 1 and R 2 are an acetal protecting group or a thioacetal protecting group, and each independently is a C 1-10 alkyloxy group or a C 1-10 alkyl fluorenyl group, or R 1 and R 2 are common thereto
  • the linked carbon atoms are combined to form a cyclic acetal or a cyclic thioacetal;
  • R 1 and R 2 are preferably combined with the carbon atom to which they are attached to form a cyclic acetal or a cyclic thio acetal, more preferably substituted or non-substituted.
  • R 3 is a hydroxy protecting group, preferably a methylsulfonyl group, a p-tolylsulfonyl group or a trifluoromethanesulfonyl group
  • X is a halogen or a leaving group Preferred as chlorine, bromine, iodine or triflate
  • Y is a halogen, preferably chlorine, bromine or iodine.
  • the Y may be chlorine.
  • the synthetic method D of the eribulin intermediate represented by the formula IV may include the following steps:
  • the compound represented by the formula VIII is subjected to a hydroxy protecting reaction to obtain a compound represented by the formula VII; the hydroxy protecting reaction is preferably carried out under basic conditions; and the hydroxy protecting reaction using a reagent is preferably triethylamine or pyridine.
  • a reagent is preferably triethylamine or pyridine.
  • substitution reaction is preferably lithium chloride, sodium chloride, tributylbenzylammonium chloride, ammonium chloride or the like.
  • the substitution reaction is preferably lithium chloride, sodium chloride, tributylbenzylammonium chloride, ammonium chloride or the like.
  • a compound represented by formula VA subjecting a compound represented by formula VA to intramolecular cyclization to give a compound of formula III; said intramolecular cyclization reaction is preferably carried out under Lewis acid conditions; said Lewis acid is preferably silver oxide, high chloride One or more of silver acid, silver trifluoromethanesulfonate, silver tetrafluoroborate, and silver hexafluorophosphate;
  • condensation reaction of a compound of the formula III with a compound of the formula XI to give a compound of the formula X;
  • the condensation reaction is preferably carried out under basic conditions; the reaction is preferably sodium hydride or butyl.
  • an oxidizing agent preferably Dess-Martin oxidizing agent, Swern oxidizing agent, IBX oxidizing agent, TEMPO-NaClO and TEMPO-PhI (OAc) 2
  • the hydrolysis reaction is preferably carried out under acidic or neutral conditions; and the hydrolysis reaction is preferably hydrochloric acid or p-toluenesulfonic acid; P-toluenesulfonic acid pyridinium salt, boron trifluoride etherate, TMSOTf, tetraisopropyl titanate, titanium tetrachloride, pyridine, 2,6-lutidine and 2,4,6-trimethylpyridine One or more;
  • the compound represented by the formula XII is subjected to a reduction elimination reaction to obtain a compound represented by the formula IV; and the reduction-eliminating reaction is preferably a reagent of diiodide, chromium dichloride, manganese powder, zinc powder and trichlorination. One or more of chromium.
  • Ar is preferably a phenyl group, a p-methylphenyl group or a para-ethyl substituted phenyl group.
  • X is iodine;
  • Y is chlorine;
  • R 1 and R 2 are combined with the carbon atom to which they are attached to form an ethylene glycol acetal or a propylene glycol acetal.
  • the invention also provides a method G of synthesizing a compound of formula IVa, which comprises the steps of:
  • a compound represented by the formula XIIa is subjected to a reduction elimination reaction in the presence of cesium diiodide to obtain a compound represented by the formula IV.
  • the invention also provides a method H of synthesizing a compound of formula IVa, which comprises the steps of:
  • reaction steps can also be used to prepare a compound of formula IV by short-circuiting; for example, by purchasing the intermediate of Formula III above, and then following the procedures provided in the above methods. a compound of formula IV.
  • the present invention provides a process for the preparation of eribulin which first produces a compound of formula II, formula III or formula V according to the method provided by the aforementioned invention, and then according to known methods.
  • Eribulin is prepared by a compound of formula II, formula III or formula V, which can be referred to the literature: J. Am. Chem. Soc. 2009, 131, 15636; Angew. Chem. Intl. Ed. 2009, 48, 2346; Synlett. 2013, 24, 323; Synlett. 2013, 24, 327; Synlett. 2013, 24, 333.
  • the ethylene glycol acetal is Propylene glycol acetal is
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-B 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpent
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy , heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio or oxo.
  • Alkyloxy means "RO-" wherein R is a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms.
  • R is a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-B 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy , heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio or oxo.
  • Alkyl fluorenyl means "RS-" wherein R is a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms.
  • R is a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-B 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbuty
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy , heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio or oxo.
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
  • the base and naphthyl are most preferably phenyl.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • the hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
  • the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl silicon, silicon-tert-butyldiphenylsilyl and the like; may be a C 1-10 alkyl or substituted alkyl, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl Ethyl ethyl, 2-tetrahydropyranyl (THP), etc.; may be (C 1-10 alkyl or aryl) acyl group, for example: formyl, acety
  • the acetal protecting group of the present invention is a suitable group for acetal protection known in the art, see the acetal protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts). .
  • the acetal protecting group may be a C 1-10 alkyloxy group, for example: dimethyl acetal, diethyl acetal, diisopropyl acetal, ethylene glycol acetal , propylene glycol acetal, and the like.
  • the thioacetal protecting group of the present invention is a suitable group for thioacetal protection known in the art, see thioacetal in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts). Protection group.
  • the acetal protecting group may be a C 1-10 alkyl fluorenyl group, for example: dimethyl thio acetal, diethyl acetal acetal, ethylene dithiol acetal, propylene dithiol acetal Wait.
  • the leaving group of the present invention is a suitable leaving group known in the art.
  • the leaving group may be a methanesulfonate group, a p-methylphenylsulfonate group or a trifluoromethanesulfonate group or the like.
  • Triethylamine (2.6 g) was first added to a solution of VIIIf (2.8 g, 5.4 mmol) in toluene (30 mL) at 10 ° C, then MsCl (2.3 g) was slowly added. After the addition was completed, the reaction was continued to stir under the conditions for 1 h. After the reaction was completed by TLC, the reaction mixture was evaporated, evaporated, evaporated
  • Triethylamine (2.3 g) was first added to a solution of VIIIg (1.9 g, 3.5 mmol) in DMF (30 mL) at 10 ° C, then methanesulfonic anhydride (1.7 g) was slowly added. After the addition was completed, the reaction was continued to stir under the conditions for 6 h. After the reaction was completed by TLC, the reaction mixture was evaporated, evaporated, evaporated
  • Examples 10 to 18 are compounds of the formula V
  • VIIf (0.87 g, 1.7 mmol), VIa (1.5 g), Ligand 1 (2.8 g), chromium dichloride (1.6 g) and nickel dichloride (0.21 g) were added to the reaction flask, and ethyl acetate was added. (10 mL) and 2,6-lutidine (0.44 g) were dissolved, and the reaction system was stirred at 20 ° C for 18 hours. After the TLC reaction was completed, the reaction was quenched with saturated aqueous sodium hydrogen carbonate, and ethyl acetate was evaporated.
  • Examples 19 to 22 are compounds of the formula VA
  • VIIAb (1.2 g, 2.56 mmol), VIa (2.1 g), ligand 2 (3.8 g), chromium dichloride (1.9 g) and nickel dichloride (0.29 g) were added to the reaction flask, and tetrahydrofuran (30 mL) was added. And triethylamine (0.62 g) was dissolved, and the reaction system was stirred at 60 ° C for 4 hours. After the TLC reaction was completed, the reaction was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate.
  • Examples 23 to 35 are compounds of the formula III
  • Examples 36 to 39 are compounds of the formula X
  • Lithium diisopropylamide lithium (1.0 M in hexane, 0.6 mL) was added dropwise to a solution of IIIb (0.5 g, 0.54 mmol) in 2-methyltetrahydrofuran (10 mL) at -78 ° C, and the reaction was continued under the conditions Stir for 1 h.
  • a solution of compound XIa (0.49 g) in THF (4 mL). After the TLC reaction was completed, the reaction was quenched by aqueous saturated aqueous ammonium chloride, extracted with methyl tert-butyl ether, concentrated and evaporated with dichloromethane, and the crude compound Xb was directly used for the next reaction.
  • Examples 40 to 43 are compounds of the formula IX
  • Zinc powder (600 mg) and acetic acid (600 mg) were added to a solution of IXd (100 mg, 0.06 mmol) in THF (3 mL) at 30 ° C, and the mixture was stirred at this temperature for 6 h. After the TLC detection reaction was completed, the reaction was quenched by the addition of aqueous potassium carbonate. After ethyl acetate extraction, the concentrate was purified by column to afford compound IIa (63 mg).
  • Examples 52-56 are the synthesis of compounds of formula IVa
  • Zinc powder (200 mg) and acetic acid (200 mg) were added to a solution of XIId (50 mg, 0.03 mmol) in THF (2 mL), and the mixture was stirred at this temperature for 2 h. After the TLC reaction was completed, the reaction was quenched by the addition of an aqueous solution of potassium carbonate. After ethyl acetate extraction, the concentrate was purified by column to afford compound IVa (35 mg).
  • 2,6-lutidine (0.12 g) and TMSOTf (0.26 g) were added to a solution of IIa (80 mg, 0.05 mmol) in dichloromethane (2 mL) at -30 ° C under ice-cooling. The reaction was stirred for a further 24 h. After the reaction was completed by TLC, 1N hydrochloric acid was added to the reaction mixture to quench the reaction. After ethyl acetate extraction, the concentrate was purified by column to afford compound IVa (56 mg).

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Abstract

一种艾日布林中间体及其制备方法被公开，具体而言，如式II、式III和式V所示的化合物及其制备方法被公开，其中，Ar为C1-10烷基取代或烷基氧基取代或非取代的芳基；R1，R2为缩醛保护基团或者硫缩醛保护基团；R3为氢或者羟基保护基；X为卤素或者离去基团，其制备方法具有反应条件温和，选择性高，易于纯化，合成成本低廉等优点，适于大规模生产。

Description

一种艾日布林中间体及其制备方法
本申请要求申请日为2017年5月17日的中国专利申请CN201710350260.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种艾日布林中间体及其制备方法。
背景技术
艾日布林(如式I所示)是对海洋天然产物Halichondria okadai中提取的大环内酯类化合物halichondrin B进行结构优化的衍生物，是一种软海绵素类微管动力学抑制剂。自从2010年11月15日FDA首次批准甲磺酸艾日布林(Halaven)注射液用于治疗至少接受过两种化疗方案的转移性乳腺癌患者以来，卫材公司积极拓展艾日布林的新适应症。2016年1月28日FDA批准其用于二线治疗不能手术切除或转移性脂肪肉瘤，成为全球首个可显著延长晚期软组织肉瘤患者生存的新型抗癌药。目前该药已获批用于全球60多个国家的转移性乳腺癌的治疗，以及美国、日本和欧盟批准用于不可切除性或转移性软组织肉瘤。此外，卫材于也在2016年8月向中国食品和药品监督管理总局提交了Halaven治疗局部晚期或转移性乳腺癌的新药申请。近期的非临床研究和转化研究表明，除了具有抗有丝分裂效果外，Halaven在晚期乳腺癌肿瘤组织中还能够诱导肿瘤血管重塑、提高肿瘤核心区域的血管灌注和渗透性、降低肿瘤微环境缺氧程度。此外，Halaven还能改善上皮细胞状态，降低乳腺癌细胞的迁移能力。
Figure PCTCN2018087247-appb-000001
艾日布林分子结构复杂，含有40个碳原子，其中19个碳原子具有手性中心，目前的市场药物供应只能通过全合成的途径来实现，路线非常复杂，因此对合成路线设计和合成工艺开发存在非常大的挑战，尤其需要对各个手性中心进行精确地高选择性控制。
Figure PCTCN2018087247-appb-000002
目前对艾日布林的合成主要是通过对复杂程度相当的三个中间体(其基本结构可参照化合物VIIIA，VI和XIa)进行汇聚式合成来实现的。具体地，化合物VIII的衍生物与化合物VI的衍生物发生偶联获得化合物VB的衍生物之后，经过几步转化，再与化合物XIa的衍生物进行缩合，最终转化为艾日布林。在片段拼接的过程中，存在着大量的官能团操纵步骤，因此，发展有效快速的片段拼接策略，成为了众多合成化学家们关注的焦点。
卫材公司在专利WO2005118565A1中进行第一次片段拼接时，合成了如式VC所示的中间体。该中间体的C14位为被保护的醇官能团，该官能团需要经过一次氧化反应形成醛之后，才能进行第二次片段拼接。
Figure PCTCN2018087247-appb-000003
美国哈佛大学的Kishi实验室在文献中报道了如式VD所示的中间体。与化合物VC比较，C23位的甲烷磺酸酯基被替换为构型翻转的氯原子，从而更换了关环的条件。
Figure PCTCN2018087247-appb-000004
正大天晴公司在专利CN105713031A中公开了如式VE所示的中间体。
Figure PCTCN2018087247-appb-000005
加拿大Alphora研究公司在专利WO2013142999A1中合成了如式VF所示的中间体。在该中间体中，他们预先在C35位引入了艾日布林最终产物中所含的胺基官能团，但是C14位的氧化态仍然是醇。
Figure PCTCN2018087247-appb-000006
综上所述，当前所报道的合成策略存在较大的共通性，即C14位的氧化态基本上都是醇，该氧化态需要在后续反应的过程中通过加入氧化剂来进行调整。因此亟需更多的合成策略来丰富和优化艾日布林的全合成。
发明内容
本发明的目的是提供一种艾日布林中间体及其制备方法。
针对现有如式V所示的艾日布林中间体的合成方法比较单一，对C14位氧化态需要进行调整的现状，本发明从C14位缩醛保护的中间体VIII出发，经过第一次片段拼接后，获得了C14位为缩醛保护的中间体V。因此在后续的转化中，仅需使用水解反应获得醛官能团，从而避免了对该位置碳原子的氧化态调整，减少了氧化反应的步骤，使得合成 路线更加绿色高效。在中间体V、III和II的合成过程中，反应条件温和，合成收率高且纯化简便，适于大规模生产如式IV所示的艾日布林中间体。
本发明提供一种如式III所示的化合物，
Figure PCTCN2018087247-appb-000007
其中，Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛；R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛。
所示的如式III所示的化合物中，所述的Ar可为苯基或对位被C 1-4烷基(如甲基、乙基、正丙基或异丙基)取代的苯基，还可为苯基、对甲基苯基或对位乙基取代的苯基。
所示的如式III所示的化合物中，所述的R 1和R 2可以各自独立地为C 1-5烷基氧基(如C 1-3烷基氧基，再如甲氧基、乙氧基、正丙氧基或异丙氧基)；或者，所述的R 1和R 2可与它们共同连接的碳原子联合形成5-7元环状缩醛(5元环状缩醛如
Figure PCTCN2018087247-appb-000008
6元环状缩醛如
Figure PCTCN2018087247-appb-000009
R 10和R 11各自独立地为H或C 1-3烷基(如甲基)且R 10和R 11不同时为氢)或5-7元环状硫缩醛(如
Figure PCTCN2018087247-appb-000010
)。优选地，所述的R 1和 R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
所示的如式III所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000011
本发明一个优选的实施方案中，所示的如式III所示的化合物中，Ar优选为苯基、对甲基苯基或对位乙基取代的苯基；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
本发明还提供一种如式III所示化合物的制备方法A，其包括如下步骤：将式V所示的化合物进行分子内环化反应得到如式III所示的化合物；所述分子内环化反应优选在碱性条件下进行；
Figure PCTCN2018087247-appb-000012
其中，Ar、R 1和R 2如上述的如式III所示的化合物中定义；
R 3为氢或者羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基。
所述的如式III所示化合物的制备方法A中，所述的R 3可为甲磺酰基。
所述的如式III所示化合物的制备方法A中，所述的分子内环化反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为C 6-C 10烷烃溶剂(如正己烷、正庚烷)、芳烃类溶剂(如甲苯)、醚类溶剂(如四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚)和酯类溶剂(如乙酸叔丁酯、乙酸异丙酯)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的式V所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式III所示化合物的制备方法A中，所述的碱性条件中碱可为氢化钠、叔丁醇钾、叔丁醇钠、丁基锂、LDA、LiHMDS、KHMDS和NaHMDS中的一种或多种。所述的碱性条件中碱的用量可为本领域该类反应的常规用量，例如所述的碱与所述的如式V所示的化合物的摩尔比例可为1～10:1。
所述的如式III所示的化合物的制备方法A中，所述的分子内环化反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的如式V所示的化合物不再反应时作为反应终点。
所述的如式III所示的化合物的制备方法A中，所述的分子内环化反应的反应温度可为本领域该类反应的常规温度，例如为-30～30℃。
本发明的一个优选的实施方案中，所述的如式III所示化合物的制备方法A可包含以下步骤：
-30～30℃下向如式V所示的化合物的有机溶液中滴加碱，反应继续在此条件下搅拌10min～6h；TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，浓缩后分离得到如式III所示的化合物。
所述的如式III所示化合物的制备方法A的优选的实施方案中，所述有机溶剂优选甲苯、正己烷、正庚烷、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、乙酸叔丁酯和乙酸异丙酯中的一种或多种。
所述的如式III所示化合物的制备方法A的优选的实施方案中，所述碱优选氢化钠、叔丁醇钾、叔丁醇钠、丁基锂、LDA、LiHMDS、KHMDS和NaHMDS中的一种或多种。
本发明还提供另一种如式III所示化合物的制备方法B，其包括下列步骤：将式VA所示的化合物进行分子内环化反应得到如式III所示的化合物；所述分子内环化反应优选在路易斯酸和路易斯碱的存在下进行；
Figure PCTCN2018087247-appb-000013
其中，Ar、R 1和R 2如上述的如式III所示的化合物中定义；
Y为卤素，优选为氯、溴或碘。
所述的如式III所示化合物的制备方法B中，所述的Y可为氯。
所述的如式III所示化合物的制备方法B中，所述的分子内环化反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为芳烃类溶剂(如甲苯)、腈类溶剂(如乙腈)、醚类溶剂(如四氢呋喃)和酯类溶剂(如乙酸乙酯、乙酸叔丁酯、乙酸异丙酯)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的式VA所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式III所示化合物的制备方法B中，所述的路易斯酸可为氧化银和/或银盐，还可为氧化银、高氯酸银、三氟甲烷磺酸银、四氟硼酸银和六氟磷酸银中的一种或多种(例如氧化银、三氟甲烷磺酸银、四氟硼酸银或六氟磷酸银)。所述的路易斯酸的用量可为本领域该类反应的常规用量，例如所述的路易斯酸与所述的式VA所示的化合物的摩尔比例可为0.1～10:1。
所述的如式III所示化合物的制备方法B中，所述的路易斯碱可为2,6-二叔丁基-4-甲基吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶和吡啶中的一种或多种。所述的路易斯碱的用量可为本领域该类反应的常规用量，例如所述的路易斯碱与所述的式VA所示的化合物的摩尔比例可为0.1～10:1。
所述的如式III所示的化合物的制备方法B中，所述的分子内环化反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的如式VA所示的化合物不再反应时作为反应终点。
所述的如式III所示的化合物的制备方法B中，所述的分子内环化反应的反应温度可为本领域该类反应的常规温度，例如为0～60℃。
本发明的一个优选的实施方案中，所述的如式III所示的化合物的制备方法B可包含以下步骤：
0～60℃下向化合物VA的有机溶液中加入路易斯酸和路易斯碱，反应继续在此条件下搅拌6～48h；TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，浓缩后分离得到化合物III。
所述的如式III所示的化合物的制备方法B的优选的实施方案中，所述有机溶剂优选甲苯、四氢呋喃、乙腈、乙酸乙酯、乙酸异丙酯和乙酸叔丁酯中的一种或多种。
所述的如式III所示的化合物的制备方法B的优选的实施方案中，所述路易斯酸优选氧化银、高氯酸银、三氟甲烷磺酸银、四氟硼酸银和六氟磷酸银中的一种或多种(例如氧化银、三氟甲烷磺酸银、四氟硼酸银或六氟磷酸银)。
所述的如式III所示的化合物的制备方法B的优选的实施方案中，所述路易斯碱优选2,6-二叔丁基-4-甲基吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶和吡啶中的一种或多种。
本发明还提供一种如式V所示的化合物，
Figure PCTCN2018087247-appb-000014
其中，Ar、R 1和R 2如上述的式III所示的化合物中定义；
R 3为氢或者羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基。
所述的如式V所示的化合物中，所述的R 3可为甲磺酰基。
本发明一个优选的实施方案中，所述的如式V所示的化合物中，R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛；Ar为苯基、对甲基苯基或对位被乙基取代的苯基；R 3为甲磺酰基。
所述的如式V所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000015
本发明还提供一种如式V所示的化合物的制备方法，将如式VI所示的化合物和如式VII所示的化合物进行NHK反应得到所述的如式V所示的化合物；
Figure PCTCN2018087247-appb-000016
其中，Ar、R 1、R 2和R 3如上述的式V所示的化合物中定义；
X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
所述的如式V所示的化合物的制备方法中，所述的X可为氯、溴或碘，还可为碘。
所述的如式V所示的化合物的制备方法中，所述的NHK反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为酯类溶剂(如乙酸乙酯)、腈类溶剂(如乙腈)、醚类溶剂(如甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃)、亚砜类溶剂(如二甲亚砜)和卤代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如式VII所示的化合物在所述的有机溶剂中的摩尔浓度可为0.01～5mol/L。
所述的如式V所示的化合物的制备方法中，所述的NHK反应可在卤代铬盐和/或卤代镍盐的存在下进行。所述的卤代铬盐可为氯代铬盐(如二氯化铬、三氯化铬)。所述的卤代镍盐可为氯代镍盐(如二氯化镍)。所述的卤代铬盐或所述的卤代镍盐的用量可为本领域该类反应的常规用量，例如所述的卤代铬盐与所述的式VII所示的化合物的摩尔比例可为0.01～10:1，所述的卤代镍盐与所述的式VII所示的化合物的摩尔比例可为0.0001～10:1。
所述的如式V所示的化合物的制备方法中，所述的NHK反应可在碱存在的条件下进行。所述的碱可为三乙胺、吡啶、2,6-二甲基吡啶、2,4,6-二甲基吡啶、质子海绵和二异丙基乙基胺中的一种或多种。所述的碱的用量可为本领域该类反应的常规用量，例如所述的碱与所述的式VII所示的化合物的摩尔比例可为1～20:1。
所述的如式V所示的化合物的制备方法中，所述的式VII所示的化合物与所述的式VI所示的化合物的摩尔比例可为0.1～10:1。
所述的如式V所示的化合物的制备方法中，所述的NHK反应可在配体的存在下进行。所述的配体可为本领域该类反应常规的配体，还可为
Figure PCTCN2018087247-appb-000017
和/或
Figure PCTCN2018087247-appb-000018
所述的配体的用量可为本领域该类反应的常规用量，例如所述的的配体与所述的式VII所示的化合物的摩尔比例可为0.1～10:1。
所述的如式V所示的化合物的制备方法中，所述的NHK反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的如式VII所示的化合物不再反应时作为反应终点。
所述的如式V所示的化合物的制备方法中，所述的NHK反应的反应温度可为本领域该类反应的常规温度，例如为0～60℃。
本发明的一个优选的实施方案中，所述的如式V所示的化合物的制备方法可包含以下步骤：
向反应瓶中加入所述的如式VI所示的化合物、所述的如式VII所示的化合物、配体、二氯化铬(或三氯化铬)和二氯化镍，加入有机溶剂和碱溶解，反应体系放到0～60℃的油浴中搅拌2～48小时；TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩后分离得到化合物V，或化合物V不经纯化，直接用于下一步反应。
所述的如式V所示的化合物的制备方法的优选的实施方案中，所述有机溶剂优选乙酸乙酯、乙腈、甲基叔丁基醚、四氢呋喃、二甲亚砜、2-甲基四氢呋喃和二氯甲烷中的一种或多种。
所述的如式V所示的化合物的制备方法的优选的实施方案中，所述碱优选为三乙胺、吡啶、2,6-二甲基吡啶、2,4,6-二甲基吡啶、质子海绵和二异丙基乙基胺中的一种或多种。
所述的如式V所示的化合物的制备方法的优选的实施方案中，所述的配体可为
Figure PCTCN2018087247-appb-000019
本发明还提供一种如式VA所示的化合物，
Figure PCTCN2018087247-appb-000020
其中，Ar、R 1和R 2如上述的式III所示的化合物中定义；
Y为卤素，优选为氯、溴或碘。
所述的如式VA所示的化合物中，所述的Y可为氯。
本发明一个优选的实施方案中，所述的如式VA所示的化合物中，R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛；Ar为苯基、对甲基苯基或对位被乙基取代的苯基；Y为氯。
所述的如式VA所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000021
本发明还提供一种如式VA所示的化合物的制备方法，其包括如下步骤：将如式VI所示的化合物和如式VIIA所示的化合物进行NHK反应制得；
Figure PCTCN2018087247-appb-000022
其中，Ar、R 1、R 2和Y如上述的式VA所示的化合物中定义；
X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
所述的如式VA所示的化合物的制备方法中，所述的X可为氯、溴或碘，还可为碘。
所述的如式VA所示的化合物的制备方法中，所述的NHK反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为酯类溶剂(如乙酸乙酯)、腈类 溶剂(如乙腈)、醚类溶剂(如甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃)、亚砜类溶剂(如二甲亚砜)和卤代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如式VIIA所示的化合物在所述的有机溶剂中的摩尔浓度可为0.01～5mol/L。
所述的如式VA所示的化合物的制备方法中，所述的NHK反应可在卤代铬盐和/或卤代镍盐的存在下进行。所述的卤代铬盐可为氯代铬盐(如二氯化铬、三氯化铬)。所述的卤代镍盐可为氯代镍盐(如二氯化镍)。所述的卤代铬盐或所述的卤代镍盐的用量可为本领域该类反应的常规用量，例如所述的卤代铬盐与所述的式VIIA所示的化合物的摩尔比例可为0.01～10:1，所述的卤代镍盐与所述的式VIIA所示的化合物的摩尔比例可为0.0001～10:1。
所述的如式VA所示的化合物的制备方法中，所述的式VIIA所示的化合物与所述的式VI所示的化合物的摩尔比例可为0.1～10:1。
所述的如式VA所示的化合物的制备方法中，所述的NHK反应可在碱存在的条件下进行。所述的碱可为三乙胺、吡啶、2,6-二甲基吡啶、2,4,6-二甲基吡啶、质子海绵和二异丙基乙基胺中的一种或多种。所述的碱的用量可为本领域该类反应的常规用量。例如所述的碱与所述的化合物VIIA的摩尔比可为1-20:1。
所述的如式VA所示的化合物的制备方法中，所述的NHK反应可在配体的存在下进行。所述的配体可为本领域该类反应常规的配体，还可为
Figure PCTCN2018087247-appb-000023
和/或
Figure PCTCN2018087247-appb-000024
所述的配体的用量可为本领域该类反应的常规用量，例如所述的的配体与所述的式VIIA所示的化合物的摩尔比例可为0.1～10:1。
所述的如式VA所示的化合物的制备方法中，所述的NHK反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的如式VIIA所示的化合物不再反应时作为反应终点。
所述的如式VA所示的化合物的制备方法中，所述的NHK反应的反应温度可为本领域该类反应的常规温度，例如为0～60℃。
本发明的一个优选的实施方案中，所述的如式VA所示的化合物的制备方法可包含以下步骤：
向反应瓶中加入所述的如式VI所示的化合物和如式VIIA所示的化合物、配体、二氯化铬(或三氯化铬)和二氯化镍，加入有机溶剂和碱溶解，反应体系放到0～60℃的油浴中搅拌2～48小时；TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩后分离得到如式VA所示的化合物，或如式VA所示的化合物不经纯化，直接用于下一步反应。
所述的如式VA所示的化合物的制备方法的优选的实施方案中，所述有机溶剂优选乙酸乙酯、乙腈、甲基叔丁基醚、四氢呋喃、二甲亚砜、2-甲基四氢呋喃和二氯甲烷中的一种或多种。
所述的如式VA所示的化合物的制备方法的优选的实施方案中，所述碱优选为三乙胺、吡啶、2,6-二甲基吡啶、2,4,6-二甲基吡啶、质子海绵和二异丙基乙基胺中的一种或多种。
所述的如式VA所示的化合物的制备方法的优选的实施方案中，所述的配体可为
Figure PCTCN2018087247-appb-000025
本发明提供一种如式VII所示的化合物，
Figure PCTCN2018087247-appb-000026
其中，R 1、R 2和R 3如上述的式V所示的化合物中定义；
X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
所述的如式VII所示的化合物中，所述的X可为氯、溴或碘，还可为碘。
本发明一个优选的实施方案中，所述的如式VII所示的化合物中，R 1和R 2与它们共 同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛；R 3为甲磺酰基；X为碘。
所述的如式VII所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000027
本发明还提供一种如式VII所示的化合物的制备方法，其包括如下步骤：将化合物VIII进行羟基保护反应得到所述的如式VII所示的化合物；
Figure PCTCN2018087247-appb-000028
其中，R 1、R 2、R 3和X如上述的式VII所示的化合物中定义，且R 3不为氢。
所述的如式VII所示的化合物的制备方法中，所述的羟基保护反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为酯类溶剂(如乙酸乙酯)、腈类溶剂(如乙腈)、芳烃类溶剂(如甲苯)、醚类溶剂(如四氢呋喃、2-甲基四氢呋喃)、酰胺类溶剂(如N,N-二甲基甲酰胺)和卤代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的 化合物VIII在所述的有机溶剂中的摩尔浓度可为0.01～5mol/L。
所述的如式VII所示的化合物的制备方法中，所述的羟基保护反应可在碱存在的条件下进行。所述的碱可为三乙胺、吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶和二异丙基乙胺中的一种或多种。所述的碱的用量可为本领域该类反应的常规用量，例如所述的碱与所述的化合物VIII的摩尔比可为1～20：1。
所述的如式VII所示的化合物的制备方法中，所述的羟基保护反应可在磺酰化试剂存在的条件下进行，所述的磺酰化试剂可为甲烷磺酰氯，甲烷磺酸酐，对甲苯磺酰氯，对甲苯磺酸酐或三氟甲基磺酸酐，还可为甲烷磺酰氯或甲烷磺酸酐。所述的磺酰化试剂的用量可为本领域该类反应的常规用量，例如所述的磺酰化试剂与所述的如式VIII所示的化合物的摩尔比例可为1～10:1。
所述的如式VII所示的化合物的制备方法中，所述的羟基保护反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的如式VIII所示的化合物不再反应时作为反应终点。
所述的如式VII所示的化合物的制备方法中，所述的羟基保护反应的反应温度可为本领域该类反应的常规温度，例如为-40～50℃，再例如为-10～20℃。
本发明的一个优选的实施方案中，所述的如式VII所示的化合物的制备方法可包含以下步骤：
在-30～40℃下，向式VIII所示的化合物的有机溶剂中先加入碱，然后再慢慢加入磺酰化试剂，加完后，反应继续在此条件下搅拌15min～6h，TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩后分离得到如式VII所示的化合物。
所述的如式VII所示的化合物的制备方法的优选的实施方案中，所述有机溶剂优选乙酸乙酯、乙腈、甲苯、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺和二氯甲烷中的一种或多种溶剂。
所述的如式VII所示的化合物的制备方法的优选的实施方案中，所述碱优选三乙胺、吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶和二异丙基乙胺中的一种或多种。
所述的如式VII所示的化合物的制备方法的优选的实施方案中，所述磺酰化试剂优选甲烷磺酰氯、甲烷磺酸酐、对甲苯磺酰氯、对甲苯磺酸酐或三氟甲基磺酸酐。
本发明还提供一种如式VIIA所示的化合物，
Figure PCTCN2018087247-appb-000029
其中，其中，R 1、R 2和X如上述的如式VII所示的化合物中定义；
Y为卤素，优选为氯、溴或碘。
所述的如式VIIA所示的化合物中，所述的Y可为氯。
本发明一个优选的实施方案中，所述的如式VIIA所示的化合物中，R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛；X为碘；Y为氯。
所述的如式VIIA所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000030
本发明还提供一种如式VIIA所示的化合物的制备方法，其包括如下步骤：将如式VII所示的化合物进行取代反应得到所述的如式VIIA所示的化合物；
Figure PCTCN2018087247-appb-000031
其中，R 1、R 2、X和Y如上述的式VIIA所示的化合物中定义；
R 3为氢或者羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基。
所述的如式VIIA所示的化合物的制备方法中，所述的R 3可为甲磺酰基。
所述的如式VIIA所示的化合物的制备方法中，所述的取代反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为酯类溶剂(如乙酸乙酯)、 腈类溶剂(如乙腈)、芳烃类溶剂(如甲苯)、醚类溶剂(如四氢呋喃)、酰胺类溶剂(如N,N-二甲基甲酰胺、N,N-二甲基丙烯基脲)和卤代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)中的一种或多种。例如，所述的有机溶剂为N,N-二甲基丙烯基脲或N,N-二甲基甲酰胺。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的化合物VII在所述的有机溶剂中的摩尔浓度可为0.01～5mol/L。
所述的如式VIIA所示的化合物的制备方法中，所述的取代反应可在卤化试剂的存在下进行。所述的卤代试剂可为本领域该类反应的常规试剂，其中，氯代试剂如氯化锂、氯化钠、三丁基苄基氯化铵、氯化铵或四丁基氯化铵，溴代试剂如溴化锂、溴化钠、三丁基苄基溴化铵、溴化铵或四丁基溴化铵，碘代试剂如碘化锂、碘化钠、三丁基苄基碘化铵、碘化铵或四丁基碘化铵。例如，所述的卤代试剂为三丁基苄基氯化铵或四丁基氯化铵。所述的卤代试剂的用量可为本领域该类反应的常规用量，例如所述的卤代试剂与所述的如式VII所示的化合物的摩尔比可为1-50。
所述的如式VIIA所示的化合物的制备方法中，所述的取代反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的化合物VII不再反应时作为反应终点。
所述的如式VIIA所示的化合物的制备方法中，所述的取代反应的反应温度可为本领域该类反应的常规温度，例如为-40～80℃，再例如为-20～60℃。
本发明的一个优选的实施方案中，所述的如式VIIA所示的化合物的制备方法可包含以下步骤：
-20～60℃下，向如VII所示的化合物的有机溶剂中加入卤化试剂，反应在-20～60℃下搅拌1～48h。TLC检测反应完全后，加入水淬灭反应，乙酸乙酯萃取，浓缩后分离得到如VIIA所示的化合物。
所述的如式VIIA所示的化合物的制备方法的优选的实施方案中，所述有机溶剂优选为乙酸乙酯、乙腈、甲苯、二氯甲烷、N,N-二甲基甲酰胺、N,N-二甲基丙烯基脲(DMPU)和四氢呋喃中的一种或多种(例如N,N-二甲基丙烯基脲或N,N-二甲基甲酰胺)。
所述的如式VIIA所示的化合物的制备方法的优选的实施方案中，所述卤化试剂优选为氯化锂、氯化钠、三丁基苄基氯化铵、氯化铵、四丁基氯化铵、溴化锂、溴化钠、三丁基苄基溴化铵、溴化铵、四丁基溴化铵、碘化锂、碘化钠、三丁基苄基碘化铵、碘化铵或四丁基碘化铵(例如三丁基苄基氯化铵或四丁基氯化铵)。
本发明还提供一种如式II所示的化合物，
Figure PCTCN2018087247-appb-000032
其中，R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛；R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛；
X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
所述的如式II所示的化合物中，所述的R 1和R 2可以各自独立地为C 1-5烷基氧基(如C 1-3烷基氧基，再如甲氧基、乙氧基、正丙氧基或异丙氧基)；或者，所述的R 1和R 2可与它们共同连接的碳原子联合形成5-7元环状缩醛(5元环状缩醛如
Figure PCTCN2018087247-appb-000033
6元环状缩醛如
Figure PCTCN2018087247-appb-000034
R 10和R 11各自独立地为H或C 1-3烷基(如甲基)且R 10和R 11不同时为氢)或5-7元环状硫缩醛(如
Figure PCTCN2018087247-appb-000035
)。优选地，所述的R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
所述的如式II所示的化合物中，所述的X可为碘。
本发明一个优选的实施方案中，所述的如式II所示的化合物中，X为碘；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
所述的如式II所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000036
本发明还提供一种如式II所示的化合物的制备方法，其包括如下步骤：将如式IX所示的化合物进行还原消除反应得到所述的如式II所示的化合物；
Figure PCTCN2018087247-appb-000037
其中，X、R 1和R 2如上述的式II所示的化合物中定义；
Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基。
所述的如式II所示的化合物的制备方法中，所述的Ar可为苯基或对位被C 1-4烷基(如甲基、乙基、正丙基或异丙基)取代的苯基。优选地，所述的Ar可为苯基、对甲基苯基或对位被乙基取代的苯基。
所述的如式II所示的化合物的制备方法中，所述的还原消除反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，例如醚类溶剂(如四氢呋喃)。所 述的有机溶剂的用量为本领域该类反应的常规用量，例如所述的式IX所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式II所示的化合物的制备方法中，所述的还原消除反应可在还原剂存在的条件下进行，所述的还原剂可为二碘化钐，二氯化铬，三氯化铬，锰粉和锌粉中的一种或多种(如二碘化钐、二氯化铬-锰粉或锌粉)。所述的还原剂的用量可为本领域该类反应的常规用量，例如所述的还原剂与所述的式IX所示的化合物的摩尔比例可为1～20:1。
所述的如式II所示的化合物的制备方法中，所述的还原消除反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的式IX所示的化合物不再反应时作为反应终点。
所述的如式II所示的化合物的制备方法中，所述的还原消除反应的反应温度可为本领域该类反应的常规温度，例如为-78～30℃。
本发明的一个优选的实施方案中，所述的如式II所示的化合物的制备方法可包含以下步骤：
-78～30℃下，在如式IX所示的化合物的THF溶液中逐滴加入还原剂，反应在-78～30℃下搅拌10min～12h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩后分离得到如式II所示的化合物。
所述的如式II所示的化合物的制备方法的优选的实施方案中，所述还原剂优选为二碘化钐、二氯化铬、三氯化铬、锰粉和锌粉中的一种或多种(如二碘化钐、二氯化铬-锰粉或锌粉)。
本发明还提供一种如式IV所示的化合物的制备方法M，其包括如下步骤：将式II所示的化合物进行水解反应得到如式IV所示的化合物；
Figure PCTCN2018087247-appb-000038
其中，X、R 1和R 2的定义如上述的式II所示的化合物中所述。
所述的如式IV所示的艾日布林中间体的合成方法M中，所述的水解反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，例如为卤代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)。所述的有机溶剂的用量可为本领域该类反应的常规用量， 例如所述的化合物II在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式IV所示的艾日布林中间体的合成方法M中，所述的水解反应可在水解试剂存在的条件下进行，所述的水解试剂可为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种(例如2,6-二甲基吡啶、吡啶和TMSOTf中的一种或多种，再例如2,6-二甲基吡啶与TMSOTf，再例如吡啶和TMSOTf)。所述的水解试剂的用量可为本领域该类反应的常规用量，例如所述的水解试剂与所述的式II所示的化合物的摩尔比例可为0.1:20～1。
所述的如式IV所示的艾日布林中间体的合成方法M中，所述的水解反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的式II所示的化合物不再反应时作为反应终点。
所述的如式IV所示的艾日布林中间体的合成方法M中，所述的水解反应的反应温度可为本领域该类反应的常规温度，例如为-30～40℃。
本发明一个优选的实施方案中，所述的如式IV所示的化合物的制备方法M可包含如下步骤：
-30～40℃下向如式II所示的化合物的二氯甲烷溶液中依次加入水解试剂，加完后反应继续搅拌1～24h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取，浓缩后分离得到如式IV所示的化合物。
所述的如式IV所示的化合物的制备方法M的优选的实施方案中，所述水解试剂优选为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶的一种或多种(例如2,6-二甲基吡啶、吡啶和TMSOTf中的一种或多种，再例如2,6-二甲基吡啶与TMSOTf，再例如吡啶和TMSOTf)。
本发明还提供一种如式IX所示的化合物，
Figure PCTCN2018087247-appb-000039
其中，X、R 1和R 2如上述的式II所示的化合物中定义；
Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基。
所述的如式IX所示的化合物中，所述的Ar可为苯基或对位被C 1-4烷基(如甲基、乙基、正丙基或异丙基)取代的苯基。优选地，所述的Ar可为苯基、对甲基苯基或对位被乙基取代的苯基。
本发明一个优选的实施方案中，所述的如式IX所示的化合物中，Ar优选为苯基、对甲基苯基或对位乙基取代的苯基；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛；X为碘。
所述的如式IX所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000040
本发明还提供一种如式IX所示的化合物的制备方法，其包括如下步骤：将如式X所示的化合物进行氧化反应制得；
Figure PCTCN2018087247-appb-000041
其中，Ar、X、R 1和R 2如上述的式IX所示的化合物中定义。
所述的如式IX所示的化合物的制备方法中，所述的氧化反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，例如氯代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)和/或亚砜类溶剂(如二甲亚砜)。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的如式X所示的化合物在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式IX所示的化合物的制备方法中，所述的氧化反应中氧化剂可为本领域该类反应常规的氧化剂，例如Dess-Martin氧化剂、Swern氧化剂、IBX氧化剂、TEMPO-NaClO和TEMPO-PhI(OAc) 2中的一种或多种(如Dess-Martin氧化剂、IBX氧化剂、TEMPO-NaClO或TEMPO-PhI(OAc) 2)。所述的氧化剂的用量可为本领域该类反应的常规用量，例如所述的氧化剂与所述的式X所示的化合物的摩尔比例可为1～20:1。
所述的如式IX所示的化合物的制备方法中，所述的氧化反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的式X所示的化合物不再反应时作为反应终点。
所述的如式IX所示的化合物的制备方法中，所述的氧化反应的反应温度可为本领域该类反应的常规温度，例如为-20-60℃。
本发明的一个优选的实施方案中，所述的如式IX所示的化合物的制备方法可包含以下步骤：
在-20～60℃下如式X所示的化合物的有机溶剂中加入氧化剂，反应在该温度下继续搅拌1～6h；TLC检测反应完全后，用硫代硫酸钠和碳酸氢钠的水溶液淬灭。乙酸乙酯萃取，浓缩后分离得到如式IX所示的化合物。
所述的如式IX所示的化合物的制备方法中的优选的实施方案中，所述氧化剂优选为Dess-Martin氧化剂、Swern氧化剂、IBX氧化剂、TEMPO-NaClO和TEMPO-PhI(OAc) 2中的一种或多种(如Dess-Martin氧化剂、IBX氧化剂、TEMPO-NaClO或 TEMPO-PhI(OAc) 2)。
本发明还提供了一种如式XII所示的化合物的制备方法，其包括如下步骤：将如式IX所示的化合物进行水解反应制得；
Figure PCTCN2018087247-appb-000042
其中，Ar、X、R 1和R 2如上述的式IX所示的化合物中定义。
所述的如式XII所示的化合物的制备方法中，所述的水解反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，例如为卤代烃类溶剂(如氯代烃类溶剂，再如二氯甲烷)、芳烃类溶剂(如甲苯)和腈类溶剂(如乙腈)中的一种或多种。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的化合物IX在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式XII所示的化合物的制备方法中，所述的水解反应可在水解试剂存在的条件下进行，所述的水解试剂可为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、硝酸铈铵、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种(例如2,6-二甲基吡啶、TMSOTf和对甲苯磺酸吡啶盐和硝酸铈铵中的一种或多种)。所述的水解试剂的用量可为本领域该类反应的常规用量，例如所述的水解试剂与所述的式IX所示的化合物的摩尔比例可为0.1～20:1。
所述的如式XII所示的化合物的制备方法中，所述的水解反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的式IX所示的化合物不再反应时作为反应终点。
所述的如式XII所示的化合物的制备方法中，所述的水解反应的反应温度可为本领域该类反应的常规温度，例如为-20～40℃。
本发明的一个优选的实施方案中，所述的如式XII所示的化合物的制备方法可包含以下步骤：
-20～40℃下向如式IX所示的化合物的有机溶液中依次加入水解试剂，加完后反应继续搅拌1～12h；TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取，浓缩后分离得到如式XII所示的化合物。
所述的如式XII所示的化合物的制备方法的优选的实施方案中，所述有机溶剂优选 二氯甲烷、甲苯和乙腈中的一种或多种。
所述的如式XII所示的化合物的制备方法的优选的实施方案中，所述水解试剂优选为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、硝酸铈铵、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种(例如2,6-二甲基吡啶、TMSOTf和对甲苯磺酸吡啶盐和硝酸铈铵中的一种或多种)。
本发明还提供一种如式X所示的化合物，
Figure PCTCN2018087247-appb-000043
其中，Ar、X、R 1和R 2如上述的式IX所示的化合物中定义。
本发明一个优选的实施方案中，Ar优选为苯基、对甲基苯基或对位乙基取代的苯基；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛；X为碘。
所述的如式X所示的化合物可选自以下任一结构：
Figure PCTCN2018087247-appb-000044
本发明还提供一种如式X所示的化合物的制备方法，其包括如下步骤：将如式III所示的化合物与如式XI所示的化合物在碱性条件下进行缩合反应制得；
Figure PCTCN2018087247-appb-000045
其中，Ar、X、R 1和R 2如上述的式X所示的化合物中定义。
所述的如式X所示的化合物的制备方法中，所述的缩合反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，还可为C 6-C 10烷烃溶剂(如正庚烷)和/或醚类溶剂(如四氢呋喃、2-甲基四氢呋喃)。所述的有机溶剂的用量可为本领域该类反应的常规用量，例如所述的化合物III在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式X所示的化合物的制备方法中，所述的碱性条件中碱可为本领域该类反应常规的碱，还可为氢化钠、丁基锂(如正丁基锂、异丁基锂或叔丁基锂)、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种(例如正丁基锂、二异丙基胺基锂或六甲基硅基胺基锂)。所述的碱的用量可为本领域该类反应的常规用量，例如所述的碱与所述的式III所示的化合物的摩尔比例可为0.5～5:1。
所述的如式X所示的化合物的制备方法中，所述的式III所示的化合物与所述的式XI所示的化合物的摩尔比例可为0.1～10:1。
所述的如式X所示的化合物的制备方法中，所述的缩合反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的式III所示的化合物不再反应时作为反应终点。
所述的如式X所示的化合物的制备方法中，所述的缩合反应的反应温度可为本领域该类反应的常规温度，例如为-78-0℃。本发明的一个优选的实施方案中，所述的如式X所示的化合物的制备方法包含以下步骤：
-78～0℃下，向如式III所示的化合物的有机溶液中滴加碱的溶液，反应继续在此条件下搅拌15min～1h，然后向上述体系中加入化合物XI的THF溶液，并继续搅拌30min～4h；TLC检测反应完全后，加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，浓缩后分 离得到如式X所示的化合物。
所述的如式X所示的化合物的制备方法的优选的实施方案中，所述有机溶剂优选四氢呋喃、2-甲基四氢呋喃和正庚烷中的一种或多种。
所述的如式X所示的化合物的制备方法的优选的实施方案中，所述碱优选氢化钠、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种(例如正丁基锂、二异丙基胺基锂或六甲基硅基胺基锂)。
本发明还提供一种如式IV所示的化合物的制备方法K，其包括如下步骤：将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；
Figure PCTCN2018087247-appb-000046
其中Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
所述的如式IV所示的化合物的制备方法K中，所述的Ar可为苯基或对位被C 1-4烷基(如甲基、乙基、正丙基或异丙基)取代的苯基，还可为苯基、对甲基苯基或对位被乙基取代的苯基。
所述的如式IV所示的化合物的制备方法K中，所述的X可为氯、溴或碘，还可为碘。
所述的如式IV所示的化合物的制备方法K中，所述的还原消除反应可在有机溶剂中进行。所述的有机溶剂可为本领域该类反应的常规溶剂，例如醚类溶剂(如四氢呋喃)。所述的有机溶剂的用量为本领域该类反应的常规用量，例如所述的化合物XII在所述的有机溶剂中的摩尔浓度可为0.001～5mol/L。
所述的如式IV所示的化合物的制备方法K中，所述的还原消除反应可在还原剂存在的条件下进行，所述的还原剂可为二碘化钐、二氯化铬、三氯化铬、锰粉和锌粉中的一种或多种(如二碘化钐、二氯化铬-锰粉或锌粉)。所述的还原剂的用量可为本领域该类反应的常规用量，例如所述的还原剂与所述的式XII所示的化合物的摩尔比例可为 0.1～20:1。
所述的如式IV所示的化合物的制备方法K中，所述的还原消除反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR，较佳地为TLC)进行监控，一般以所述的式XII所示的化合物不再反应时作为反应终点。
所述的如式IV所示的化合物的制备方法K中，所述的还原消除反应的反应温度可为本领域该类反应的常规温度，例如为-50～30℃。
本发明一个优选的实施方案中，所述的式IV所示的化合物的制备方法K可包含如下步骤：
-50℃～30℃下，在式XII所示的化合物的有机溶液中逐滴加入还原试剂，反应在该温度下搅拌30min-4h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得如IV所示的化合物。
所述的式IV所示的化合物的制备方法K的优选的实施方案中，所述还原试剂优选为二碘化钐、二氯化铬、锰粉、锌粉和三氯化铬中的一种或多种。
本发明还提供了一种如式IV所示的艾日布林中间体的合成方法P，其包括如下步骤：
1)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；
2)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
3)将式IX所示的化合物进行还原消除反应得到如式II所示的化合物；
4)将式II所示的化合物进行水解反应得到如式IV所示的化合物；
Figure PCTCN2018087247-appb-000047
其中，Ar、X、R 1和R 2的定义如上所述。
所述的如式IV所示的艾日布林中间体的合成方法P中，各步反应条件均如上所述。
本发明还提供了一种如式IV所示的艾日布林中间体的合成方法Q，其包括如下步骤：其包括如下步骤：
1)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；
2)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
3)将式IX所示的化合物进行水解反应得到如式XII所示的化合物；
4)将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；
Figure PCTCN2018087247-appb-000048
其中，Ar、X、R 1和R 2的定义如上所述。
所述的如式IV所示的艾日布林中间体的合成方法Q中，各步反应条件均如上所述。
本发明还提供了一种如式IV所示的艾日布林中间体的合成方法A，其包括如下步骤：
Figure PCTCN2018087247-appb-000049
其中，Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛。R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代 或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛；R 3为羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基；X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。所述的如式IV所示的艾日布林中间体的合成方法A中，所述的Ar可为苯基或对位被C 1-4烷基(如甲基、乙基、正丙基或异丙基)取代的苯基。所述的Ar还可为苯基、对甲基苯基或对位被乙基取代的苯基。
所述的如式IV所示的艾日布林中间体的合成方法A中，所述的R 1和R 2可以各自独立地为C 1-5烷基氧基(如C 1-3烷基氧基，再如甲氧基、乙氧基、正丙氧基或异丙氧基)；或者，所述的R 1和R 2可与它们共同连接的碳原子联合形成5-7元环状缩醛(5元环状缩醛如
Figure PCTCN2018087247-appb-000050
6元环状缩醛如
Figure PCTCN2018087247-appb-000051
R 10和R 11各自独立地为H或C 1-3烷基(如甲基)且R 10和R 11不同时为氢)或5-7元环状硫缩醛(如
Figure PCTCN2018087247-appb-000052
)。优选地，所述的R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
所述的如式IV所示的艾日布林中间体的合成方法A中，所述的R 3可为甲磺酰基。
所述的如式IV所示的艾日布林中间体的合成方法A中，所述的X可为氯、溴或碘，还可为碘。
所述的如式IV所示的艾日布林中间体的合成方法A中，各步反应条件均如上所述。
所述的如式IV所示的艾日布林中间体的合成方法A可包括以下步骤：
1)将如式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；所述羟基保护反应优选在碱性条件下进行；所述羟基保护反应采用试剂优选为三乙胺、吡啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
2)将如式VII所示的化合物与式VI所示的化合物进行NHK反应得到如式V所示的化合物；所述的NHK反应采用试剂优选二氯化铬、三氯化铬和三溴化铬中的一种或多种；
3)将如式V所示的化合物进行分子内环化反应得到如式III所示的化合物；所述分子内环化反应优选在碱性条件下进行；所述分子内环化反应采用试剂优选为三乙胺、吡 啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
4)将如式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；所述缩合反应优选在碱性条件下进行；所述缩合反应采用试剂优选为氢化钠、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
5)将如式X所示的化合物进行氧化反应得到如式IX所示的化合物；所述氧化反应采用氧化剂优选为Dess-Martin氧化剂、Swern氧化剂、IBX氧化剂、TEMPO-NaClO和TEMPO-PhI(OAc) 2中的一种或多种；
6)将如式IX所示的化合物进行还原消除反应得到如式II所示的化合物；所述还原消除反应采用试剂优选为二碘化钐、二氯化铬、锰粉、锌粉和三氯化铬中的一种或多种；
7)将如式II所示的化合物进行水解反应得到如式IV所示的化合物；所述水解反应优选在酸性或者中性条件下进行；所述水解反应采用试剂优选为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种。
本发明一个优选的实施方案中，所述的如式IV所示的艾日布林中间体的合成方法中，Ar优选为苯基、对甲基苯基或对位乙基取代的苯基；X为碘；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
本发明还提供一种如式IVa所示的化合物的合成方法A，其包括如下步骤：
Figure PCTCN2018087247-appb-000053
1)将式VIIIa所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIa所示的化合物；
2)将式VIIa所示的化合物与式VIa所示的化合物在二氯化铬的存在下进行NHK反应得到如式Va所示的化合物；
3)将式Va所示的化合物在六甲基硅基氨基钾的存在下进行分子内环化反应得到如 式IIIa所示的化合物；
4)将式IIIa所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xa所示的化合物；
5)将式Xa所示的化合物在Dess-Martin氧化剂的存在下进行氧化反应得到如式IXa所示的化合物；
6)将式IXa所示的化合物在二碘化钐的存在下进行还原消除反应得到如式IIa所示的化合物；
7)将式IIa所示的化合物在TMSOTf和2，6-二甲基吡啶的存在下进行水解反应得到如式IVa所示的化合物。
所述的如式IVa所示的化合物的合成方法A中，各步反应条件均如上所述。
本发明还提供一种如式IVa所示化合物的合成方法B，其包括如下步骤：
Figure PCTCN2018087247-appb-000054
1)将式VIIIa所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIa所示的化合物；
2)将式VIIa所示的化合物与式VIb所示的化合物在二氯化铬的存在下进行NHK反应得到如式Vh所示的化合物；
3)将式Vh所示的化合物在六甲基硅基氨基钾的存在下进行分子内环化反应得到如式IIIh所示的化合物；
4)将式IIIh所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xc所示的化合物；
5)将式Xc所示的化合物在TEMPO氧化剂的存在下进行氧化反应得到如式IXc所示的化合物；
6)将式IXc所示的化合物在二氯化铬和锰粉的存在下进行还原消除反应得到如式IIa所示的化合物；
7)将式IIa所示的化合物在硝酸铈铵的存在下进行水解反应得到如式IV所示的化合物。
所述的如式IVa所示化合物的合成方法B中，各步反应条件均如上所述。
本发明还提供一种如式IV所示的艾日布林中间体的合成方法B，其包括如下步骤：
Figure PCTCN2018087247-appb-000055
其中，Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛；R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代 或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛；R 3为羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基；X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
所述的如式IV所示的艾日布林中间体的合成方法B中，所述的Ar、R 1、R 2、R 3和X的定义可如上述的如式IV所示的艾日布林中间体的合成方法B中所述。
所述的如式IV所示的艾日布林中间体的合成方法B可包括以下步骤：
1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；所述羟基保护反应优选在碱性条件下进行；所述羟基保护反应采用试剂优选为三乙胺、吡啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶，丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂或六甲基硅基胺基钠中的一种或多种；
2)将式VII所示的化合物与式VI所示的化合物进行NHK反应得到如式V所示的化合物；所述NHK反应采用试剂优选二氯化铬、三氯化铬和三溴化铬中的一种或多种；
3)将式V所示的化合物进行分子内环化反应得到如式III所示的化合物；所述分子内环化反应优选在碱性条件下进行；所述分子内环化反应采用试剂优选为氢化钠、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
4)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；所述缩合反应优选在碱性条件下进行；所述缩合反应采用试剂优选为三乙胺、吡啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
5)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；所述氧化反应采用氧化剂优选为Dess-Martin氧化剂、Swern氧化剂、IBX氧化剂、TEMPO-NaClO和TEMPO-PhI(OAc) 2中的一种或多种；
6)将式IX所示的化合物进行水解反应得到如式XII所示的化合物；所述水解反应优选在酸性或者中性条件下进行；所述反应采用试剂优选为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种；
7)将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；所述还原消除反应采用试剂优选为二碘化钐、二氯化铬、锰粉、锌粉和三氯化铬中的一种或多种。
所述的如式IV所示的艾日布林中间体的合成方法B中，各步反应条件均如上所述。
本发明一个优选的实施方案中，所述的如式IV所示的艾日布林中间体的合成方法B中，Ar优选为苯基、对甲基苯基或对位乙基取代的苯基；X为碘；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
本发明还提供一种如式IVa所示化合物的的合成方法C，其包括如下步骤：
Figure PCTCN2018087247-appb-000056
1)将式VIIIa所示的化合物在碱性条件下与甲烷磺酸酐反应得到如式VIIa所示的化 合物；
2)将式VIIa所示的化合物与式VIa所示的化合物在二氯化铬的存在下进行NHK反应得到如式Va所示的化合物；
3)将式Va所示的化合物在六甲基硅基氨基钾的存在下进行分子内环化反应得到如式IIIa所示的化合物；
4)将式IIIa所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xa所示的化合物；
5)将式Xa所示的化合物在TEMPO氧化剂的存在下反应得到如式IXa所示的化合物；
6)将式IXa所示的化合物在TMSOTf和2,6-二甲基吡啶的存在下进行水解反应得到如式XIIa所示的化合物；
7)将式XIIa所示的化合物在二碘化钐的存在下进行还原消除反应得到如式IVa所示的化合物。
所述的如式IVa所示化合物的的合成方法C中，各步反应条件均如上所述。
本发明还提供一种如式IVa所示化合物的合成方法D，其包括如下步骤：
Figure PCTCN2018087247-appb-000057
1)将式VIIIa所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIa所示的化合物；
2)将式VIIa所示的化合物与式VIc所示的化合物在二氯化铬的存在下进行NHK反应得到如式Vi所示的化合物；
3)将式Vi所示的化合物在六甲基硅基氨基钾的存在下进行分子内环化反应得到如 式IIIi所示的化合物；
4)将式IIIi所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xd所示的化合物；
5)将式Xd所示的化合物在Dess-Martin氧化剂的存在下反应得到如式IXd所示的化合物；
6)将式IXd所示的化合物在TMSOTf和2,6-二甲基吡啶的存在下进行缩醛水解反应得到如式XIId所示的化合物；
7)将式XIId所示的化合物在二碘化钐的存在下进行还原消除反应得到如式IV所示的化合物。
所述的如式IVa所示化合物的的合成方法D中，各步反应条件均如上所述。
本发明还提供了一种如式IV所示的艾日布林中间体的合成方法C，其包括如下步骤：
Figure PCTCN2018087247-appb-000058
其中，Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛；R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛；R 3为羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基；X为卤素或者离去基团，优选为氯、溴、碘或三 氟甲磺酸酯基；
Y为卤素，优选为氯、溴或碘。
所述的如式IV所示的艾日布林中间体的合成方法C中，所述的Ar、R 1、R 2、R 3和X的定义可如上述的如式IV所示的艾日布林中间体的合成方法B中所述。
所述的如式IV所示的艾日布林中间体的合成方法C中，所述的Y可为氯。
具体来说，所述的如式IV所示的艾日布林中间体的合成方法C可包括以下步骤：
1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；所述羟基保护反应优选在碱性条件下进行；所述羟基保护反应采用试剂优选为三乙胺、吡啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
2)将式VII所示的化合物进行取代反应得到如式VIIA所示的化合物；所述取代反应采用试剂优选氯化锂、氯化钠、三丁基苄基氯化铵、氯化铵、四丁基氯化铵、溴化锂、溴化钠、三丁基苄基溴化铵、溴化铵、四丁基溴化铵、碘化锂、碘化钠、三丁基苄基碘化铵、碘化铵或四丁基碘化铵；
3)将式VIIA所示的化合物与式VI所示的化合物进行NHK反应得到如式VA所示的化合物；所述NHK反应采用试剂优选二氯化铬、三氯化铬和三溴化铬中的一种或多种；
4)将式VA所示的化合物进行分子内环化反应得到如式III所示的化合物；所述分子内环化反应优选在路易斯酸条件下进行；所述路易斯酸优选为氧化银、高氯酸银、三氟甲烷磺酸银、四氟硼酸银和六氟磷酸银中的一种或多种；
5)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；所述缩合反应优选在碱性条件下进行；所述缩合反应采用试剂优选为三乙胺、吡啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
6)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；所述氧化反应采用氧化剂优选为Dess-Martin氧化剂、Swern氧化剂、IBX氧化剂、TEMPO-NaClO和TEMPO-PhI(OAc) 2中的一种或多种；
7)将式IX所示的化合物进行还原消除反应得到如式II所示的化合物；所述还原消除反应采用试剂优选为二碘化钐、二氯化铬、锰粉、锌粉、三氯化铬等；
8)将式II所示的化合物进行水解反应得到如式IV所示的化合物；所述水解反应优选在酸性或者中性条件下进行；所述水解反应采用试剂优选为盐酸、对甲苯磺酸、对甲 苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种。
所述的如式IV所示的艾日布林中间体的合成方法C中，各步反应条件均同上所述。
本发明一个优选的实施方案中，所述的如式IV所示的艾日布林中间体的合成方法C中，Ar优选为苯基、对甲基苯基或对位乙基取代的苯基；X为碘；Y为氯；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。。
本发明还提供一种如式IVa所示化合物的合成方法E，其包括如下步骤：
Figure PCTCN2018087247-appb-000059
1)将式VIIIb所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIb所示的化合物；
2)将式VIIb所示的化合物在三丁基苄基氯化铵的存在下进行氯代反应得到如式VIIAb所示的化合物；
3)将式VIIAb所示的化合物与式VIa化合物在二氯化铬的存在下进行NHK反应得到如式VAb所示的化合物；
4)将式VAb所示的化合物在四氟硼酸银的存在下下进行分子内环化反应得到如式IIIb所示的化合物；
5)将式IIIb所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xb所示的化合物；
6)将式Xb所示的化合物在Dess-Martin氧化剂的存在下反应得到如式IXb所示的化合物；
7)将式IXb所示的化合物在二碘化钐的存在下进行还原消除反应得到如式IIb所示的化合物；
8)将式IIb所示的化合物在TMSOTf和2,6-二甲基吡啶的存在下进行缩醛水解反应得到如式IVa所示的化合物。
所述的如式IVa所示化合物的合成方法E中，各步反应条件均如上所述。
本发明还提供一种如式IVa所示化合物的合成方法F：
Figure PCTCN2018087247-appb-000060
1)将式VIIIa所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIa所示的化合物；
2)将式VIIa所示的化合物在三丁基苄基氯化铵的存在下进行氯代反应得到如式VIIAa所示的化合物；
3)将式VIIAa所示的化合物与式VIb所示的化合物在二氯化铬的存在下进行NHK反应得到如式VAc所示的化合物；
4)将式VAc所示的化合物在四氟硼酸银的存在下进行分子内环化反应得到如式IIIh所示的化合物；
5)将式IIIh所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xc所示的化合物；
6)将式Xc所示的化合物在Dess-Martin氧化剂的作用下反应得到如式IXc所示的化合物；
7)将式IXc所示的化合物在二碘化钐的作用下进行还原消除反应得到如式IIa所示的化合物；
8)将式IIa所示的化合物在TMSOTf和2,6-二甲基吡啶的作用下进行缩醛水解反应得到如式IVa所示的化合物。
所述的如式IVa所示化合物的合成方法F中，各步反应条件均如上所述。
本发明还提供了一种如式IV所示的艾日布林中间体的合成方法D，其包括如下步骤：
Figure PCTCN2018087247-appb-000061
其中，Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛；R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛；R 3为羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基；X为卤素或者离去基团，优选为氯、溴、碘或三 氟甲磺酸酯基；
Y为卤素，优选为氯、溴或碘。
所述的如式IV所示的艾日布林中间体的合成方法B中，所述的Ar、R 1、R 2、R 3和X的定义可如上述的如式IV所示的艾日布林中间体的合成方法B中所述。
所述的如式IV所示的艾日布林中间体的合成方法D中，各步反应条件均如上所述。
所述的如式IV所示的艾日布林中间体的合成方法D中，所述的Y可为氯。
所述的如式IV所示的艾日布林中间体的合成方法D可包括以下步骤：
1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；所述羟基保护反应优选在碱性条件下进行；所述羟基保护反应采用试剂优选为三乙胺、吡啶、氢化钠、碳酸钾、2,4,6-三甲基吡啶、2,6-二甲基吡啶、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
2)将式VII所示的化合物进行取代反应得到如式VIIA所示的化合物；所述取代反应采用试剂优选氯化锂、氯化钠、三丁基苄基氯化铵、氯化铵、四丁基氯化铵、溴化锂、溴化钠、三丁基苄基溴化铵、溴化铵、四丁基溴化铵、碘化锂、碘化钠、三丁基苄基碘化铵、碘化铵或四丁基碘化铵；
3)将式VIIA所示的化合物与式VI所示的化合物进行NHK反应得到如式VA所示的化合物；所述NHK反应采用试剂优选二氯化铬、三氯化铬和三溴化铬中的一种或多种；
4)将式VA所示的化合物进行分子内环化反应得到如式III所示的化合物；所述分子内环化反应优选在路易斯酸条件下进行；所述路易斯酸优选为氧化银、高氯酸银、三氟甲烷磺酸银、四氟硼酸银和六氟磷酸银中的一种或多种；
5)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；所述缩合反应优选在碱性条件下进行；所述反应采用试剂优选为氢化钠、丁基锂、二异丙基乙基胺、二异丙基胺基锂、六甲基硅基胺基钾、六甲基硅基胺基锂和六甲基硅基胺基钠中的一种或多种；
6)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；所述氧化反应采用氧化剂优选为Dess-Martin氧化剂、Swern氧化剂、IBX氧化剂、TEMPO-NaClO和TEMPO-PhI(OAc) 2中的一种或多种；
7)将式IX所示的化合物进行水解反应得到如式XII所示的化合物；所述水解反应优选在酸性或者中性条件下进行；所述水解反应采用试剂优选为盐酸、对甲苯磺酸、对甲苯磺酸吡啶盐、三氟化硼乙醚、TMSOTf、钛酸四异丙酯、四氯化钛、吡啶、2,6-二甲基吡啶和2,4,6-三甲基吡啶中的一种或多种；
8)将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；所述还原消除反应采用试剂优选为二碘化钐、二氯化铬、锰粉、锌粉和三氯化铬中的一种或多种。
本发明一个优选的实施方案中，所述的如式IV所示的艾日布林中间体的合成方法D中，Ar优选为苯基，对甲基苯基或对位乙基取代的苯基；X为碘；Y为氯；R 1和R 2与它们共同连接的碳原子联合形成乙二醇缩醛或丙二醇缩醛。
本发明还提供一种如式IVa所示化合物的合成方法G，其包括如下步骤：
Figure PCTCN2018087247-appb-000062
1)将式VIIIb所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIb所示的化合物；
2)将式VIIb所示的化合物在四丁基氯化铵的存在下进行氯代反应得到如式VIIAb所示的化合物；
3)将式VIIAb所示的化合物与式VIa所示的化合物在二氯化铬的存在下进行NHK反应得到如式VAb所示的化合物；
4)将式VAb所示的化合物在六氟磷酸银的存在下进行分子内环化反应得到如式IIIb所示的化合物；
5)将式IIIb所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xb所示的化合物；
6)将式Xb所示的化合物在Dess-Martin氧化剂的存在下进行氧化反应得到如式IXb所示的化合物；
7)将式IXb所示的化合物在TMSOTf和2,6-二甲基吡啶的存在下进行缩醛水解反应得到如式XIIa所示的化合物；
8)将式XIIa所示的化合物在二碘化钐的存在下进行还原消除反应得到如式IV所示的化合物。
所述的如式IVa所示化合物的合成方法G中，各步反应条件均如上所述。
本发明还提供一种如式IVa所示化合物的合成方法H，其包括如下步骤：
Figure PCTCN2018087247-appb-000063
1)将式VIIIa所示的化合物在碱性条件下与甲烷磺酰氯反应得到如式VIIa所示的化合物；
2)将式VIIa所示的化合物在四丁基氯化铵的作用下进行氯代反应得到如式VIIAa所示的化合物；
3)将式VIIAa所示的化合物与式VIc所示的化合物在二氯化铬的存在下进行NHK反应得到如式VAd所示的化合物；
4)将式VAd所示的化合物在六氟磷酸银的存在下进行分子内环化反应得到如式IIIi 所示的化合物；
5)将式IIIi所示的化合物与式XIa所示的化合物在丁基锂或者二异丙基胺基锂的存在下进行缩合反应得到式Xd所示的化合物；
6)将式Xd所示的化合物在Dess-Martin氧化剂的存在下进行氧化反应得到如式IXd所示的化合物；
7)将式IXd所示的化合物在TMSOTf和2,6-二甲基吡啶的存在下进行缩醛水解反应得到如式XIId所示的化合物；
8)将式XIId所示的化合物在二碘化钐的存在下进行还原消除反应得到如式IV所示的化合物。
所述的如式IVa所示化合物的合成方法H中，各步反应条件均如上所述。
如果可以购得，也可使用上述反应步骤中的部分产物依更短路线制得式IV所示化合物；例如可通过购买前述式III所示的中间体，而后依照上述方法中提供的步骤制得式IV所示的化合物。
另一方面，本发明还提供了一种制备艾日布林的方法，该方法先依照本发明前述提供的方法制得式II、式III或式V所示的化合物，而后依照已知的方法经式式II、式III或式V所示的化合物制得艾日布林，所述方法可参照文献：J.Am.Chem.Soc.2009,131,15636；Angew.Chem.Intl.Ed.2009,48,2346；Synlett.2013,24,323；Synlett.2013,24,327；Synlett.2013,24,333。
本发明所使用的术语，除有相反的表述外，具有如下的含义。
在本发明中，乙二醇缩醛为
Figure PCTCN2018087247-appb-000064
丙二醇缩醛为
Figure PCTCN2018087247-appb-000065
“烷基”指饱和的脂族烃基团，包括1至10个碳原子的直链和支链基团，优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷基氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氧基、杂环烷基氧基、环烷硫基、杂环烷硫基或氧代。
“烷基氧基”指“RO-”，其中R为饱和的脂族烃基团，包括1至10个碳原子的直链和支链基团，优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷基氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氧基、杂环烷基氧基、环烷硫基、杂环烷硫基或氧代。
“烷基巯基”指“RS-”，其中R为饱和的脂族烃基团，包括1至10个碳原子的直链和支链基团，优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷基氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷基氧基、杂环烷基氧基、环烷硫基、杂环烷硫基或氧代。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选苯基和萘基，最优选苯基。芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基或杂环烷硫基。
本发明的羟基保护基是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯 甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。
本发明的缩醛保护基是本领域已知的适当的用于缩醛保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的缩醛保护基团。作为示例，优选地，所述的缩醛保护基可以是C 1-10烷基氧基，例如：二甲基缩醛，二乙基缩醛，二异丙基缩醛，乙二醇缩醛，丙二醇缩醛等。
本发明的硫缩醛保护基是本领域已知的适当的用于硫缩醛保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的硫缩醛保护基团。作为示例，优选地，所述的缩醛保护基可以是C 1-10烷基巯基，例如：二甲硫缩醛，二乙硫缩醛，乙二硫醇缩醛，丙二硫醇缩醛等。
本发明的离去基团是本领域已知的适当的可以离去的基团。作为示例，优选地，所述的离去基团可以是甲烷磺酸酯基、对甲基苯基磺酸酯基或三氟甲烷磺酸酯基等。
缩写表：
缩写 全称
DMP 戴斯-马丁氧化剂
OMs 甲烷磺酸酯基
Et 乙基
Me 甲基
iPr 异丙基
TBS 叔丁基二甲基硅基
DIBAL-H 二异丁基氢化铝
KHMDS 六甲基二硅基胺基钾
LiHMDS 六甲基二硅基胺基锂
NaHMDS 六甲基二硅基胺基钠
LDA 二异丙基胺基锂
NaH 氢化钠
MsCl 甲烷磺酰氯
Ms 2O 甲烷磺酸酐
TMSOTf 三甲基硅基三氟甲烷磺酸酯
SmI 2 二碘化钐
TEMPO 四甲基哌啶氮氧化物
PhI(OAc) 2 二乙酸碘苯
具体实施方式
以下将结合具体实例详细地解释本发明，使得本领域普通技术人员更全面地理解本发明，具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。
下表为实施例中所涉及的化合物的结构式：
Figure PCTCN2018087247-appb-000066
Figure PCTCN2018087247-appb-000067
Figure PCTCN2018087247-appb-000068
Figure PCTCN2018087247-appb-000069
实施例1～7为如式VII所示化合物的合成
实施例1：制备化合物VIIa
在室温下向VIIIa(8.17g,18mmol)的THF(150mL)溶液中先加入Et 3N(16.2g)，然后再慢慢加入MsCl(12.1g)。加完后，反应继续在此条件下搅拌1h。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIa(8.76g)。
MS(ESI)m/z:515(M+H +)。
1HNMR(400MHz，CDCl 3):δ6.36(d,J＝1.2Hz,1H),5.84(d,J＝1.6Hz,1H),5.01-4.99(m,1H),4.90-4.85(m,2H),4.72-4.65(m,1H),4.41-4.35(m,1H),4.08-4.01(m,1H),3.98-3.94(m,2H),3.87-3.83(m,2H),3.02(s,3H),2.71-2.64(m,1H),2.31-2.25(m,1H),2.10-2.02(m,1H),1.94-1.75(m,4H),1.73-1.51(m,6H),1.00(d,J＝6.4Hz,3H)。
实施例2：制备化合物VIIb
在-30℃下向VIIIb(1.02g,2.1mmol)的二氯甲烷(15mL)溶液中先加入吡啶(2.3g)，然后再慢慢加入Ms 2O(1.59g)。加完后，反应继续在此条件下搅拌3h。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIb(1.06g)。
MS(ESI)m/z:529(M+H +)。
1HNMR(400MHz，CDCl 3):δ6.36(s,1H),5.85(d,J＝1.3Hz,1H),5.00-4.98(m,1H),4.90-4.86(m,1H),4.72-4.65(m,1H),4.60-4.50(m,1H),4.42-4.38(m,1H),4.15–4.02(m, 2H),3.87–3.73(m,2H),3.02(s,3H),2.72-2.66(m,1H),2.54(d,J＝5.0Hz,1H),2.40–2.26(m,1H),2.19–2.06(m,2H),1.79–1.28(m,11H),1.01(d,J＝6.6Hz,3H)。
实施例3：制备化合物VIIc
在-10℃下向VIIIc(0.68g,1.3mmol)的乙酸乙酯(15mL)溶液中先加入2,6-二甲基吡啶(2.1g)，然后再慢慢加入Ms 2O(1.06g)。加完后，反应继续在此条件下搅拌30min。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIc(0.72g)。
MS(ESI)m/z:557(M+H +)。
1HNMR(400MHz，CDCl 3):δ6.36(s,1H),5.85(d,J＝1.2Hz,1H),5.00-4.96(m,1H),4.90-4.85(m,1H),4.73-4.65(m,1H),4.52-4.42(m,1H),4.42-4.37(m,1H),3.87–3.73(m,2H),3.38-3.30(m,2H),3.02(s,3H),2.72-2.65(m,1H),2.55(d,J＝5.0Hz,1H),2.40–2.25(m,1H),1.80–1.28(m,11H),1.18(s,3H),1.01(d,J＝6.6Hz,3H),0.71(s,3H)。
实施例4：制备化合物VIId
在40℃下向VIIId(2.6g,4.8mmol)的2-甲基四氢呋喃(30mL)溶液中先加入2,4,6-三甲基吡啶(4.2g)，然后再慢慢加入MsCl(3.9g)。加完后，反应继续在此条件下搅拌15min。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIId(2.73g)。
MS(ESI)m/z:561(M+H +)。
1H NMR(400MHz,Chloroform-d)δ6.36(s,1H),5.86(d,J＝1.3Hz,1H),5.04-5.00(m,1H),4.90-4.86(m,1H),4.73-4.65(m,1H),4.50-4.40(m,1H),4.19–4.00(m,1H),3.02(s,3H),2.99–2.78(m,4H),2.74-2.70(m,1H),2.45(d,J＝5.0Hz,1H),2.37–2.23(m,1H),2.20–2.05(m,2H),2.05–1.28(m,11H),1.01(d,J＝6.6Hz,3H)。
实施例5：制备化合物VIIe
在0℃下向VIIIe(3.2g,6.4mmol)的乙腈(30mL)溶液中先加入二异丙基乙胺(1.25g)，然后再慢慢加入MsCl(1.05g)。加完后，反应继续在此条件下搅拌2h。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIe(3.26g)。
MS(ESI)m/z:517(M+H +)。
1H NMR(400MHz,Chloroform-d)δ6.37(s,1H),5.76(d,J＝1.2Hz,1H),5.05-5.00(m,1H),4.90-4.85(m,1H),4.75-4.65(m,1H),4.40(dd,J＝7.0,3.9Hz,2H),3.34(d,J＝1.7Hz,6H),3.03(s,3H),2.38–2.25(m,1H),2.15-2.10(m,1H),1.83–1.28(m,11H),1.01(d,J＝6.6Hz,3H)。
实施例6：制备化合物VIIf
在10℃下向VIIIf(2.8g,5.4mmol)的甲苯(30mL)溶液中先加入三乙胺(2.6g)，然后再慢慢加入MsCl(2.3g)。加完后，反应继续在此条件下搅拌1h。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIf(2.9g)。
MS(ESI)m/z:545(M+H +)。
1H NMR(400MHz,Chloroform-d)δ6.36(s,1H),5.78(d,J＝1.2Hz,1H),5.04-5.00(m,1H),4.90-4.85(m,1H),4.75-4.65(m,1H),4.52(t,J＝5.5Hz,1H),4.41(brs,1H),3.72-3.47(m,4H),3.03(s,3H),2.75-2.68(m,1H),2.52(d,J＝5.0Hz,1H),2.41–2.26(m,1H),1.85–1.28(m,11H),1.23–1.18(m,6H),1.01(d,J＝6.6Hz,3H)。
实施例7：制备化合物VIIg
在10℃下向VIIIg(1.9g,3.5mmol)的DMF(30mL)溶液中先加入三乙胺(2.3g)，然后再慢慢加入甲烷磺酸酐(1.7g)。加完后，反应继续在此条件下搅拌6h。TLC检测反应完全后，反应液用饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIg(2.02g)。
MS(ESI)m/z:573(M+H +)。
1H NMR(400MHz,Chloroform-d)δ6.36(s,1H),5.77(d,J＝1.3Hz,1H),5.04-5.00(m,1H),4.92-4.88(m,1H),4.73-4.65(m,1H),4.57(t,J＝5.1Hz,1H),4.45-4.40(m,1H),3.90-3.82(m,2H),3.02(s,3H),2.75-2.66(m,1H),2.52(d,J＝5.0Hz,1H),2.41–2.26(m,1H),1.85–1.28(m,11H),1.26–1.09(m,12H),1.01(d,J＝6.6Hz,3H)。
实施例8～9为如式VIIA所示化合物的合成
实施例8：制备化合物VIIAa
-20℃下，溶解化合物VIIa(1.6g，3mmol)于N,N-二甲基丙烯基脲(DMPU)(20mL)中，加入三丁基苄基氯化铵(12g)。反应在室温下搅拌48h后，加水淬灭反应，乙酸乙 酯萃取，浓缩液过柱纯化得化合物VIIAa(1.43g)。
MS(ESI)m/z:455(M+H +)。
1H NMR(400MHz，CDCl 3):δ6.17(d,J＝1.2Hz,1H),5.73(d,J＝1.2Hz,1H),5.01-4.99(m,1H),4.92-4.83(m,2H),4.40-4.35(m,1H),4.10-4.00(m,1H),3.98-3.95(m,3H),3.87-3.85(m,2H),2.70-2.64(m,1H),2.30-2.25(m,1H),2.10-2.02(m,1H),1.94-1.73(m,4H),1.73-1.50(m,6H),1.00(d,J＝6.4Hz,3H)。
实施例9：制备化合物VIIAb
60℃下，溶解化合物VIIb(1.6g，2.9mmol)于N,N-二甲基甲酰胺(20mL)中，加入四丁基氯化铵(10g)。反应在该温度下搅拌1h后，加水淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物VIIAb(1.25g)。
MS(ESI)m/z:469(M+H +)
1H NMR(400MHz，CDCl 3):δ6.18(d,J＝1.2Hz,1H),5.72(d,J＝1.2Hz,1H),5.00-4.98(m,1H),4.92-4.86(m,1H),4.58-4.50(m,1H),4.43-4.38(m,1H),4.15–4.00(m,2H),3.97-3.91(m,1H),3.86–3.70(m,2H),2.70-2.65(m,1H),2.52(d,J＝5.0Hz,1H),2.40–2.25(m,1H),2.20–2.05(m,2H),1.80–1.29(m,11H),1.02(d,J＝6.6Hz,3H).
实施例10～18为如式V所示化合物的合成
实施例10：制备化合物Va
向反应瓶中加入VIIa(4.35g,8.5mmol)、VIa(5.7g)、配体1(13.1g)、二氯化铬(3.6g)和二氯化镍(1.05g)，加入四氢呋喃(60mL)和三乙胺(2.2g)溶解，反应体系在60℃下搅拌2小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Va(7.35g)。
MS(ESI)m/z:1017(M+H +)
1H NMR(400MHz,Chloroform-d)δ7.83(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),5.21(s,1H),4.99-4.86(m,1H),4.89-4.84(m,3H),4.79-4.76(m,1H),4.36-4.35(m,1H),4.19-4.16(m,1H),4.05-3.68(m,10H),3.57(dd,J＝10.4,5.2Hz,1H),3.47(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.04(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.75(q,J＝7.6Hz,2H),2.69-2.63(m,1H),2.59-2.55(m,1H),2.33-1.38(m,16H),1.27(t,J＝7.6Hz,3H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例11：制备化合物Vb
向反应瓶中加入VIIb(0.87g,1.6mmol)、VIa(1.3g)、配体2(3.1g)、二氯化铬(0.86g)和二氯化镍(0.12g)，加入2-甲基四氢呋喃(15mL)和二异丙基乙胺(0.43g)溶解，反应体系在30℃下搅拌4小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vb(1.32g)。
MS(ESI)m/z:1031(M+H +)
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),5.21(s,1H),5.00-4.86(m,1H),4.88-4.85(m,3H),4.80-4.72(m,1H),4.60-4.52(m,1H),4.45-4.40(m,1H),4.16-3.69(m,9H),3.58(dd,J＝10.4,5.2Hz,1H),3.45(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.05(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.74(q,J＝7.6Hz,2H),2.69-2.60(m,1H),2.60-2.55(m,1H),2.30-1.35(m,18H),1.27(t,J＝7.6Hz,3H),1.08(d,J＝7.6Hz,3H),0.88(s,9H),0.86(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例12：制备化合物Vc
向反应瓶中加入VIIc(0.87g,1.6mmol)、VIa(1.3g)、配体1(2.6g)、三氯化铬(0.95g)，锰粉(1.2g)和二氯化镍(0.22g)，加入乙腈(10mL)和吡啶(0.36g)溶解，反应体系在10℃下搅拌24小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vc(1.16g)。
MS(ESI)m/z:1059(M+H +)。
1H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.21(s,1H),5.00-4.86(m,1H),4.90-4.85(m,3H),4.80-4.75(m,1H),4.52-4.42(m,2H),4.13-3.70(m,9H),3.57(dd,J＝10.4,5.2Hz,1H),3.45(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.15(dd,J＝14,4.8Hz,1H),3.06(dd,J＝14.4,9.6Hz,1H),3.02(s,3H),2.75(q,J＝7.6Hz,2H),2.69-2.60(m,1H),2.60-2.55(m,1H),2.32-1.35(m,16H),1.27(t,J＝7.6Hz,3H),1.19(s,3H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.71(s,3H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例13：制备化合物Vd
向反应瓶中加入VIId(0.87g,1.6mmol)、VIa(1.2g)、配体2(2.4g)、二氯化铬(1.2g) 和二氯化镍(0.12g)，加入二甲亚砜(10mL)和三乙胺(0.44g)溶解，反应体系在0℃下搅拌48小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vd(1.2g)。
MS(ESI)m/z:1063(M+H +)
1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.21(s,1H),4.99-4.86(m,1H),4.90-4.85(m,3H),4.79-4.76(m,1H),4.50-4.40(m,1H),4.19-3.68(m,7H),3.57(dd,J＝10.4,5.2Hz,1H),3.48(dd,J＝10,5.6Hz,1H),3.39(s,3H),3.18(dd,J＝14,4.8Hz,1H),3.04(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),3.00-2.78(m,4H),2.75(q,J＝7.6Hz,2H),2.69-2.65(m,1H),2.59-2.55(m,1H),2.45(d,J＝5.0Hz,1H),2.35-1.30(m,18H),1.27(t,J＝7.6Hz,3H),1.08(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例14：制备化合物Ve
向反应瓶中加入VIIe(0.87g,1.7mmol)、VIa(1.2g)、配体1(2.7g)、二氯化铬(1.2g)和二氯化镍(0.12g)，加入二氯甲烷(10mL)和三乙胺(0.44g)溶解，反应体系在20℃下搅拌36小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Ve(1.06g)。
MS(ESI)m/z:1019(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.21(s,1H),4.99-4.86(m,1H),4.89-4.84(m,3H),4.79-4.76(m,1H),4.41(dd,J＝7.0,4.0Hz,1H),4.19-4.15(m,1H),4.05-3.65(m,5H),3.57(dd,J＝10.4,5.2Hz,1H),3.47(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.35(s,3H),3.34(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.04(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.75(q,J＝7.6Hz,2H),2.60-2.55(m,1H),2.30-1.35(m,17H),1.27(t,J＝7.6Hz,3H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例15：制备化合物Vf
向反应瓶中加入VIIf(0.87g,1.7mmol)、VIa(1.5g)、配体1(2.8g)、二氯化铬(1.6g)和二氯化镍(0.21g)，加入乙酸乙酯(10mL)和2,6-二甲基吡啶(0.44g)溶解，反应体系在20℃下搅拌18小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vf(1.12g)。
MS(ESI)m/z:1047(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.83(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),5.21(s,1H),4.99-4.86(m,1H),4.90-4.85(m,3H),4.80-4.75(m,1H),4.53(t,J＝5.6Hz,1H),4.41(brs,1H),4.20-4.15(m,1H),4.05-3.65(m,9H),3.56(dd,J＝10.4,5.2Hz,1H),3.46(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.04(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.75(q,J＝7.6Hz,2H),2.73-2.55(m,2H),2.53(d,J＝5.0Hz,1H),2.40-1.35(m,16H),1.27(t,J＝7.6Hz,3H),1.20-1.15(m,6H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例16：制备化合物Vg
向反应瓶中加入VIIg(0.87g,1.6mmol)、VIa(1.5g)、配体1(2.3g)、二氯化铬(1.2g)和二氯化镍(0.16g)，加入甲基叔丁基醚(10mL)和三乙胺(0.36g)溶解，反应体系在40℃下搅拌15小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vg(1.1g)。
MS(ESI)m/z:1075(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.21(s,1H),4.99-4.86(m,1H),4.89-4.84(m,3H),4.78-4.75(m,1H),4.57(t,J＝5.2Hz,1H),4.45-4.40(m,1H),4.20-4.15(m,1H),4.05-3.65(m,7H),3.57(dd,J＝10.4,5.2Hz,1H),3.46(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.05(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.74(q,J＝7.6Hz,2H),2.74-2.66(m,1H),2.60-2.55(m,1H),2.52(d,J＝5.0Hz,1H),2.40-1.35(m,16H),1.27(t,J＝7.6Hz,3H),1.26-1.09(m,12H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.08(s,6H),0.05(s,3H),0.03(s,3H),0.00(s,6H).
实施例17：制备化合物Vh
向反应瓶中加入VIIa(0.87g,1.6mmol)、VIb(1.3g)、配体1(2.3g)、二氯化铬(1.1g)和二氯化镍(0.15g)，加入四氢呋喃(20mL)和三乙胺(0.32g)溶解，反应体系在30℃下搅拌12小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vh(1.2g)。
MS(ESI)m/z:989(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.99–7.92(m,2H),7.75–7.66(m,1H),7.65–7.59 (m,2H),5.20(s,1H),4.99-4.88(m,1H),4.89-4.85(m,3H),4.80-4.76(m,1H),4.36-4.35(m,1H),4.19-4.15(m,1H),4.05-3.68(m,10H),3.57(dd,J＝10.4,5.2Hz,1H),3.47(dd,J＝10,5.6Hz,1H),3.37(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.04(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.70-2.63(m,1H),2.59-2.55(m,1H),2.33-1.38(m,16H),1.08(d,J＝7.6Hz,3H),0.88(s,9H),0.88(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例18：制备化合物Vi
向反应瓶中加入VIIa(0.87g,1.6mmol)、VIc(1.4g)、配体2(2.1g)、二氯化铬(1.6g)和二氯化镍(0.23g)，加入2-甲基四氢呋喃(20mL)和质子海绵(0.36g)溶解，反应体系在30℃下搅拌24小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物Vi(1.1g)。
MS(ESI)m/z:1003(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),5.20(s,1H),5.00-4.88(m,1H),4.86-4.82(m,3H),4.80-4.76(m,1H),4.39-4.35(m,1H),4.19-4.15(m,1H),4.05-3.66(m,10H),3.57(dd,J＝10.2,5.2Hz,1H),3.46(dd,J＝10,5.6Hz,1H),3.37(s,3H),3.17(dd,J＝14,4.8Hz,1H),3.04(dd,J＝14.4,9.6Hz,1H),3.01(s,3H),2.70-2.65(m,1H),2.59-2.55(m,1H),2.46(s,3H),2.33-1.38(m,16H),1.08(d,J＝7.6Hz,3H),0.88(s,9H),0.88(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例19～22为如式VA所示化合物的合成
实施例19：制备化合物VAa
向反应瓶中加入VIIAa(1.2g,2.6mmol)、VIa(2.1g)、配体1(3.8g)、二氯化铬(1.9g)和二氯化镍(0.29g)，加入四氢呋喃(30mL)和三乙胺(0.62g)溶解，反应体系在20℃下搅拌12小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物VAa(1.7g)。
MS(ESI)m/z:957(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.83(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.21(s,1H),5.00-4.86(m,1H),4.89-4.82(m,3H),4.39-4.35(m,1H),4.20-4.15(m,1H),4.05-3.70(m,11H),3.55(dd,J＝10.4,5.2Hz,1H),3.48(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.15(dd,J＝14,4.8Hz,1H),3.05(dd,J＝14.4,9.6Hz,1H),2.75(q,J＝7.6Hz,2H), 2.69-2.63(m,1H),2.59-2.55(m,1H),2.33-1.38(m,16H),1.27(t,J＝7.6Hz,3H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例20：制备化合物VAb
向反应瓶中加入VIIAb(1.2g,2.56mmol)、VIa(2.1g)、配体2(3.8g)、二氯化铬(1.9g)和二氯化镍(0.29g)，加入四氢呋喃(30mL)和三乙胺(0.62g)溶解，反应体系在60℃下搅拌4小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物VAb(1.5g)。
MS(ESI)m/z:971(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),5.21(s,1H),5.00-4.85(m,1H),4.90-4.85(m,3H),4.82-4.75(m,1H),4.45-4.40(m,1H),4.15-3.65(m,10H),3.58(dd,J＝10.4,5.2Hz,1H),3.46(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.16(dd,J＝14,4.8Hz,1H),3.05(dd,J＝14.4,9.6Hz,1H),2.73(q,J＝7.6Hz,2H),2.69-2.65(m,1H),2.60-2.57(m,1H),2.30-1.35(m,18H),1.27(t,J＝7.6Hz,3H),1.07(d,J＝7.6Hz,3H),0.88(s,9H),0.87(s,9H),0.07(s,6H),0.05(s,3H),0.04(s,3H),0.00(s,6H).
实施例21：制备化合物VAc
向反应瓶中加入VIIAa(1.2g,2.6mmol)、VIb(2.1g)、配体1(3.8g)、二氯化铬(1.9g)和二氯化镍(0.29g)，加入2-甲基四氢呋喃(30mL)和二异丙基乙胺(0.85g)溶解，反应体系在0℃下搅拌48小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物VAc(1.3g)。
MS(ESI)m/z:929(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.97-7.88(m,2H),7.70-7.63(m,3H),5.22(s,1H),5.00-4.85(m,1H),4.90-4.80(m,3H),4.37-4.35(m,1H),4.18-4.13(m,1H),4.03-3.70(m,11H),3.54(dd,J＝10.4,5.2Hz,1H),3.48(dd,J＝10,5.6Hz,1H),3.38(s,3H),3.14(dd,J＝14,4.8Hz,1H),3.03(dd,J＝14.4,9.6Hz,1H),2.70-2.65(m,1H),2.60-2.52(m,1H),2.30-1.35(m,16H),1.05(d,J＝7.6Hz,3H),0.89(s,9H),0.87(s,9H),0.08(s,6H),0.05(s,3H),0.04(s,3H),0.01(s,6H).
实施例22：制备化合物VAd
向反应瓶中加入VIIAa(1.2g,2.6mmol)、VIc(2.1g)、配体2(3.8g)、二氯化铬(1.9g)和二氯化镍(0.29g)，加入2-甲基四氢呋喃(30mL)和质子海绵(1.2g)溶解，反应体系在30℃下搅拌24小时。TLC检测反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，浓缩液过柱纯化得化合物VAd(1.6g)。
MS(ESI)m/z:943(M+H +).
1H NMR(400MHz,Chloroform-d)δ7.80(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),5.23(s,1H),5.02-4.86(m,1H),4.88-4.81(m,3H),4.36-4.35(m,1H),4.18-4.10(m,1H),4.03-3.72(m,11H),3.53(dd,J＝10.4,5.2Hz,1H),3.46(dd,J＝10,5.6Hz,1H),3.39(s,3H),3.15(dd,J＝14,4.8Hz,1H),3.02(dd,J＝14.4,9.6Hz,1H),2.70-2.65(m,1H),2.60-2.50(m,1H),2.46(s,3H),2.30-1.35(m,16H),1.05(d,J＝7.6Hz,3H),0.89(s,9H),0.87(s,9H),0.08(s,6H),0.05(s,3H),0.04(s,3H),0.01(s,6H).
实施例23～35为如式III所示化合物的合成
实施例23：制备化合物IIIa
室温下，向化合物Va(2.0g,1.99mmol)的THF(75mL)溶液中滴加KHMDS(0.5M,6.0mL)，反应继续在此条件下搅拌30分钟。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIa(1.06g)。
MS(ESI)m/z:944(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),4.95–4.87(m,2H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝1.8Hz,1H),4.25(brs,1H),4.04–3.71(m,8H),3.70–3.45(m,4H),3.43(s,3H),3.39-3.32(m,1H),3.08–2.93(m,2H),2.74(q,J＝7.6Hz,2H),2.67–2.44(m,2H),2.26–1.32(m,16H),1.25(t,J＝7.6Hz,3H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.04(s,3H),0.03(s,3H).
实施例24：制备化合物IIIa
0℃下，向化合物VAa(1g,0.99mmol)的乙酸叔丁酯(20mL)溶液中加入2,6-二叔丁基-4-甲基吡啶(2.3g)和四氟硼酸银(2.6g)，反应继续在此条件下搅拌48h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIa(0.8g)。
MS(ESI)m/z:944(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),4.95–4.87(m,2H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝1.8Hz,1H),4.25(brs,1H),4.04–3.71(m,8H),3.70–3.45(m,4H),3.43(s,3H),3.39-3.32(m,1H),3.08–2.93(m,2H),2.74(q,J＝7.6Hz,2H),2.67–2.44(m,2H),2.26–1.32(m,16H),1.25(t,J＝7.6Hz,3H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.04(s,3H),0.03(s,3H).
实施例25：制备化合物IIIb
-30℃下，向化合物Vb(1.0g,0.97mmol)的THF(20mL)溶液中滴加LiHMDS(1M,3mL)，反应继续在此条件下搅拌6h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIb(0.62g)。
MS(ESI)m/z:957(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.89–7.78(m,2H),7.46–7.36(m,2H),4.88(d,J＝2.2Hz,1H),4.83(s,1H),4.76(d,J＝1.9Hz,1H),4.63(d,J＝2.2Hz,1H),4.55(t,J＝4.8Hz,1H),4.25(brs,1H),4.11-4.06(m,2H),3.99–3.46(m,10H),3.44(s,3H),3.38-3.32(m,1H),3.04–2.94(m,2H),2.75(q,J＝7.6Hz,2H),2.62-2.50(m,2H),2.27–1.30(m,18H),1.27(t,J＝7.6Hz,3H),1.05(d,J＝6.4Hz,3H),0.89(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例26：制备化合物IIIb
30℃下，向化合物VAb(1g,0.97mmol)的乙酸异丙酯(20mL)溶液中加入2，4，6-三甲基吡啶(2.6g)和六氟磷酸银(3.2g)，反应继续在此条件下搅拌12h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIb(0.7g)。
MS(ESI)m/z:944(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),4.95–4.87(m,2H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝1.8Hz,1H),4.25(brs,1H),4.04–3.71(m,8H),3.70–3.45(m,4H),3.43(s,3H),3.39-3.32(m,1H),3.08–2.93(m,2H),2.74(q,J＝7.6Hz,2H),2.67–2.44(m,2H),2.26–1.32(m,16H),1.25(t,J＝7.6Hz,3H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.04(s,3H),0.03(s,3H).
实施例27：制备化合物IIIc
-20℃下，向化合物Vc(1.0g,0.95mmol)的2-甲基四氢呋喃(20mL)溶液中滴加LDA(1M,2mL)，反应继续在此条件下搅拌3h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIc(0.66g)。
MS(ESI)m/z:985(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.89–7.79(m,2H),7.42(d,J＝8.3Hz,2H),4.88(d,J＝2.2Hz,1H),4.84(s,1H),4.77(d,J＝1.9Hz,1H),4.63(d,J＝2.2Hz,1H),4.44(dd,J＝4.5Hz,1H),4.25(brs,1H),4.01–3.47(m,10H),3.44(s,3H),3.43–3.31(m,3H),3.06–2.93(m,2H),2.75(q,J＝7.6Hz,2H),2.65–2.47(m,2H),2.26–1.32(m,16H),1.26(t,J＝7.6Hz,3H),1.18(s,3H),1.06(d,J＝6.4Hz,3H),0.89(s,18H),0.71(s,3H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例28：制备化合物IIId
-10℃下，向化合物Vd(1.0g,0.95mmol)的甲基叔丁基醚(20mL)溶液中滴加丁基锂(2.5M,1mL)，反应继续在此条件下搅拌2h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIId(0.58g)。
MS(ESI)m/z:989(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.89–7.79(m,2H),7.46–7.37(m,2H),4.89(d,J＝2.2Hz,1H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.65(d,J＝2.2Hz,1H),4.26-4.20(m,1H),4.05(t,17.2Hz,1H),4.00–3.47(m,8H),3.43(s,3H),3.40-3.32(m,1H),3.06–2.94(m,2H),2.94–2.79(m,4H),2.75(q,J＝7.6Hz,2H),2.66–2.46(m,2H),2.25–1.32(m,18H),1.27(t,J＝7.6Hz,3H),1.06(d,J＝6.2Hz,3H),0.89(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例29：制备化合物IIIe
0℃下，向化合物Ve(1.0g,0.98mmol)的甲苯(20mL)溶液中滴加NaHMDS(1.0M,1.5mL)，反应继续在此条件下搅拌30min。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIe(0.60g)。
MS(ESI)m/z:945(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.87–7.78(m,2H),7.47–7.36(m,2H),4.89(d,J＝2.1Hz,1H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝2.2Hz,1H),4.36(t,J＝5.6Hz,1H),4.00–3.47(m,8H),3.43(s,3H),3.38-3.33(m,1H),3.31(s,3H),3.30(s,3H),3.06– 2.95(m,2H),2.75(q,J＝7.6Hz,2H),2.67–2.44(m,2H),2.27–1.33(m,16H),1.27(J＝7.6Hz,3H),1.06(d,J＝6.4Hz,3H),0.89(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例30：制备化合物IIIf
10℃下，向化合物Vf(1.0g,0.96mmol)的正庚烷(20mL)溶液中加入叔丁醇钾(206mg)，反应继续在此条件下搅拌1h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIf(0.68g)。
MS(ESI)m/z:973(M+Na +)。
1H NMR(400MHz,Chloroform-d)δ7.88–7.78(m,2H),7.41(d,J＝8.2Hz,2H),4.88(d,J＝2.1Hz,1H),4.83(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝2.2Hz,1H),4.48(t,J＝5.6Hz,1H),4.25(brs,1H),3.97-3.92(m,1H),3.87–3.46(m,10H),3.43(s,3H),3.38-3.32(m,1H),3.06–2.93(m,2H),2.74(q,J＝7.6Hz,2H),2.65–2.46(m,2H),2.27–1.33(m,16H),1.26(t,J＝7.6Hz,3H),1.19(t,J＝7.0Hz,6H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例31：制备化合物IIIg
20℃下，向化合物Vg(1.0g,0.95mmol)的正己烷(20mL)溶液中滴加KHMDS(1.0M,1.5mL)，反应继续在此条件下搅拌30min。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIg(0.70g)。
MS(ESI)m/z:1001(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.90–7.79(m,2H),7.46–7.36(m,2H),4.88(d,J＝2.1Hz,1H),4.83(s,1H),4.76(d,J＝1.9Hz,1H),4.63(d,J＝2.2Hz,1H),4.55(t,J＝5.1Hz,1H),4.25(brs,1H),4.00–3.46(m,10H),3.43(s,3H),3.38-3.32(m,1H),3.09–2.91(m,2H),2.74(q,J＝7.6Hz,2H),2.64–2.46(m,2H),2.28–1.33(m,16H),1.27(t,J＝7.6Hz,3H),1.18(d,J＝6.0Hz,6H),1.13(d,J＝6.0Hz,6H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例32：制备化合物IIIh
-20℃下，向化合物Vh(1.0g,1.01mmol)的四氢呋喃(20mL)溶液中加入氢化钠(102mg)，反应继续在此条件下搅拌30min。TLC检测反应完全后，向反应液中加入饱 和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIh(0.59g)。
MS(ESI)m/z:915(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.98–7.93(m,2H),7.73–7.66(m,1H),7.65–7.58(m,2H),4.96–4.88(m,2H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝1.8Hz,1H),4.25(brs,1H),4.05–3.70(m,8H),3.73–3.44(m,4H),3.42(s,3H),3.39-3.32(m,1H),3.06–2.92(m,2H),2.66–2.42(m,2H),2.28–1.30(m,16H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例33：制备化合物IIIh
60℃下，向化合物VAc(1g,1.08mmol)的甲苯(20mL)溶液中加入2,6-二甲基吡啶(3.6g)和氧化银(4.5g)，反应继续在此条件下搅拌6h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIh(0.6g)。
MS(ESI)m/z:915(M+Na +).
1H NMR(400MHz,Chloroform-d)δ7.98–7.93(m,2H),7.73–7.66(m,1H),7.65–7.58(m,2H),4.96–4.88(m,2H),4.84(s,1H),4.76(d,J＝1.8Hz,1H),4.64(d,J＝1.8Hz,1H),4.25(brs,1H),4.05–3.70(m,8H),3.73–3.44(m,4H),3.42(s,3H),3.39-3.32(m,1H),3.06–2.92(m,2H),2.66–2.42(m,2H),2.28–1.30(m,16H),1.05(d,J＝6.4Hz,3H),0.88(s,18H),0.09(s,3H),0.08(s,3H),0.05(s,3H),0.04(s,3H).
实施例34：制备化合物IIIi
30℃下，向化合物Vi(1.0g,1.0mmol)的四氢呋喃(20mL)溶液中滴加叔丁醇钠(189mg)，反应继续在此条件下搅拌10min。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIi(0.72g)。
MS(ESI)m/z:929(M+Na +).
1H NMR(400MHz，CDCl 3)：δ7.81(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),4.89-4.64(m,5H),4.25(br,1H),3.99-3.93(m,3H),3.88-3.78(m,5H),3.69-3.64(m,1H),3.60-3.54(m,2H),3.50-3.35(m,5H),3.00-2.98(m,2H),2.63-2.51(m,2H),2.46(s,3H),2.24-2.15(m,3H),2.04-1.98(m,1H),1.90-1.50(m,12H),1.07(d,J＝6.4Hz,3H),0.89(s,18H),0.10(s,3H),0.09(s,3H),0.05(s,3H),0.04(s,3H).
实施例35：制备化合物IIIi
20℃下，向化合物VAd(1g,1.08mmol)的四氢呋喃(20mL)溶液中加入2,6-二叔丁基-4-甲基吡啶(3.8g)和三氟甲烷磺酸银(6.2g)，反应继续在此条件下搅拌36h。TLC检测反应完全后，向反应液中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIIi(0.7g)。
MS(ESI)m/z:929(M+Na +).
1H NMR(400MHz，CDCl 3)：δ7.81(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),4.89-4.64(m,5H),4.25(br,1H),3.99-3.93(m,3H),3.88-3.78(m,5H),3.69-3.64(m,1H),3.60-3.54(m,2H),3.50-3.35(m,5H),3.00-2.98(m,2H),2.63-2.51(m,2H),2.46(s,3H),2.24-2.15(m,3H),2.04-1.98(m,1H),1.90-1.50(m,12H),1.07(d,J＝6.4Hz,3H),0.89(s,18H),0.10(s,3H),0.09(s,3H),0.05(s,3H),0.04(s,3H).
实施例36～39为如式X所示化合物的合成
实施例36：制备化合物Xa
-50℃下，向IIIa(0.5g,0.55mmol)的THF(10mL)溶液中滴加正丁基锂(2.5M in hexane,0.36mL)，反应继续在此条件下搅拌30min。然后向上述体系中加入化合物XIa(0.490g)的THF(4mL)溶液，并继续搅拌1h。TLC检测反应完全后，加入饱和氯化铵水溶液淬灭反应，甲基叔丁基醚萃取后，浓缩并用二氯甲烷交换，粗产品化合物Xa直接用于下一步反应。
MS(ESI)m/z:1662(M+H +).
1H NMR(400MHz，CDCl 3):δ7.80(d,J＝8Hz,1H),7.68(d,J＝8Hz,1H),7.39(d,J＝8Hz,2H),6.88-6.78(m,1H),6.29-6.23(m,1H),4.99-4.63(m,6H),4.38-4.19(m,2H),4.09-3.35(m,21H),2.88-1.20(m,24H),1.20-0.84(m,49H),0.15-(-0.04)(m,30H).
实施例37：制备化合物Xb
-78℃下，向IIIb(0.5g,0.54mmol)的2-甲基四氢呋喃(10mL)溶液中滴加二异丙基胺基锂(1.0M in hexane,0.6mL)，反应继续在此条件下搅拌1h。然后向上述体系中加入化合物XIa(0.49g)的THF(4mL)溶液，并继续搅拌4h。TLC检测反应完全后，加入饱和氯化铵水溶液淬灭反应，甲基叔丁基醚萃取后，浓缩并用二氯甲烷交换，粗产品化合物Xb直接用于下一步反应。
MS(ESI)m/z:1676(M+H +).
1H NMR(400MHz，CDCl 3):δ7.80(d,J＝8Hz,1H),7.68(d,J＝8Hz,1H),7.39(d,J＝8Hz,2H),6.88-6.78(m,1H),6.29-6.23(m,1H),5.02-4.60(m,7H),4.40-4.16(m,2H),4.11-3.30(m,20H),2.90-1.20(m,26H),1.20-0.84(m,49H),0.15-(-0.04)(m,30H).
实施例38：制备化合物Xc
0℃下，向IIIh(0.5g,0.56mmol)的正庚烷(10mL)溶液中滴加六甲基硅基胺基锂(1.0M in hexane,0.6mL)，反应继续在此条件下搅拌15min。然后向上述体系中加入化合物XIa(0.49g)的THF(4mL)溶液，并继续搅拌30min。TLC检测反应完全后，加入饱和氯化铵水溶液淬灭反应，甲基叔丁基醚萃取后，浓缩并用二氯甲烷交换，粗产品化合物Xc直接用于下一步反应。
MS(ESI)m/z:1634(M+H +).
1H NMR(400MHz，CDCl 3):δ7.97-7.90(m,2H),7.70-7.58(m,1H),7.60-7.50(m,2H),6.88-6.78(m,1H),6.29-6.23(m,1H),4.99-4.63(m,6H),4.38-4.19(m,2H),4.09-3.35(m,21H),2.88-1.20(m,19H),1.15-0.84(m,49H),0.15-(-0.04)(m,30H).
实施例39：制备化合物Xd
-10℃下，向IIIi(0.5g,0.56mmol)的正庚烷(10mL)溶液中滴加六甲基硅基胺基钾(1.0M,0.6mL)，反应继续在此条件下搅拌15min。然后向上述体系中加入化合物XIa(0.49g)的THF(4mL)溶液，并继续搅拌2h。TLC检测反应完全后，加入饱和氯化铵水溶液淬灭反应，甲基叔丁基醚萃取后，浓缩并用二氯甲烷交换，粗产品化合物Xd直接用于下一步反应。
MS(ESI)m/z:1648(M+H +).
1H NMR(400MHz，CDCl 3):δ7.80-7.75(m,1H),7.68-7.65(m,1H),7.40-7.35(m,2H),6.88-6.78(m,1H),6.29-6.23(m,1H),4.99-4.63(m,6H),4.40-4.20(m,2H),4.09-3.35(m,21H),2.90-1.20(m,22H),1.15-0.85(m,49H),0.15-(-0.04)(m,30H).
实施例40～43为如式IX所示化合物的合成
实施例40：制备化合物IXa
-20℃下，向上述粗品化合物Xa的二氯甲烷溶液(5mL)中加入碳酸氢钠(0.23g)和DMP氧化剂(0.51g)。反应在室温下搅拌2h。TLC检测反应完全后，用硫代硫酸钠和碳 酸氢钠的水溶液淬灭。乙酸乙酯萃取后，浓缩液过柱纯化得化合物IXa(0.78g)，核磁显示为一组非对映异构体。
MS(ESI)m/z:1660(M+H +).
1H NMR(400MHz，CDCl 3)：δ7.79-7.77(m,1H),7.68-7.65(m,1H),7.38-7.36(m,2H),6.86-6.82(m,1H),6.29-6.25(m,1H),5.00-4.81(m,5H),4.66(d,J＝20.4Hz,1H),4.40-3.37(m,23H),2.89-2.48(m,6H),2.45-1.00(m,27H),0.88-0.80(m,45H),0.11-0.01(m,30H).
实施例41：制备化合物IXb
40℃下，向上述粗品化合物Xb的二氯甲烷溶液(5mL)中加入TEMPO(0.02g)和Ph(OAc) 2(0.43g)。反应在室温下搅拌6h。TLC检测反应完全后，用硫代硫酸钠和碳酸氢钠的水溶液淬灭。乙酸乙酯萃取后，浓缩液过柱纯化得化合物IXb(0.72g)。
MS(ESI)m/z:1674(M+H +).
1H NMR(400MHz，CDCl 3)：δ7.79-7.77(m,1H),7.68-7.65(m,1H),7.38-7.36(m,2H),6.86-6.82(m,1H),6.29-6.25(m,1H),5.00-4.81(m,5H),4.65(d,J＝20.4Hz,1H),4.60-3.35(m,23H),2.90-2.48(m,6H),2.45-1.00(m,29H),0.88-0.80(m,45H),0.11-0.00(m,30H).
实施例42：制备化合物IXc
20℃下，向上述粗品化合物Xc的二氯甲烷溶液(5mL)中加入TEMPO(0.02g)和NaClO(5mL)和碳酸氢钠饱和水溶液(5mL)。反应在室温下搅拌1h。TLC检测反应完全后，用硫代硫酸钠和碳酸氢钠的水溶液淬灭。乙酸乙酯萃取后，浓缩液过柱纯化得化合物IXc(0.66g)。
MS(ESI)m/z:1632(M+H +).
1H NMR(400MHz，CDCl 3):δ7.95-7.92(m,2H),7.55-7.81(m,3H),6.85-6.80(m,1H),6.30-6.25(m,1H),5.00-4.80(m,5H),4.67(d,J＝20.4Hz,1H),4.40-3.37(m,23H),2.89-2.48(m,6H),2.45-1.00(m,27H),0.88-0.80(m,45H),0.11-0.01(m,30H).
实施例43：制备化合物IXd
60℃下，向上述粗品化合物Xd的二甲亚砜溶液(5mL)中加入IBX氧化剂(1.2g)。反应在60℃下搅拌4h。TLC检测反应完全后，用硫代硫酸钠和碳酸氢钠的水溶液淬灭。乙酸乙酯萃取后，浓缩液过柱纯化得化合物IXd(0.59g)。核磁显示为一组非对映异构体。
MS(ESI)m/z:1646(M+H +).
1H NMR(400MHz，CDCl 3)：δ7.78-7.76(m,1H),7.68-7.64(m,1H),7.38-7.36(m,2H),6.86-6.82(m,1H),6.28-6.25(m,1H),5.01-4.80(m,5H),4.66(d,J＝20.4Hz,1H),4.42-3.34(m,23H),2.89-2.81(m,2H),2.65-2.48(m,2H),2.45-1.00(m,27H),0.88-0.80(m,45H),0.10-0.00(m,30H).
实施例44～47为如式XII所示化合物的合成
实施例44：制备化合物XIIa
冰水冷却的条件下向IXa(0.78g,0.47mmol)的二氯甲烷(10mL)溶液中依次加入2,6-二甲基吡啶(0.62g)和TMSOTf(1.3g)，加完后反应继续搅拌1h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物XIIa(0.625g)。核磁显示为一组非对映异构体。
MS(ESI)m/z:1615(M+H +).
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),7.78-7.68(m,1H),7.67-7.65(m,1H),7.39-7.35(m,2H),6.86-6.82(m,1H),6.29-6.25(m,1H),5.01-4.81(m,5H),4.34-3.43(m,18H),2.88-2.86(m,2H),2.85-1.02(m,31H),0.90-0.78(m,45H),0.13-0.01(m,30H).
实施例45：制备化合物XIIa
-20℃下向IXb(0.7g,0.42mmol)的二氯甲烷(10mL)溶液中依次加入吡啶(0.55g)和TMSOTf(1.2g)，加完后反应继续搅拌4h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物XIIa(0.58g)。
MS(ESI)m/z:1615(M+H +).
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),7.78-7.68(m,1H),7.67-7.65(m,1H),7.39-7.35(m,2H),6.86-6.82(m,1H),6.29-6.25(m,1H),5.01-4.81(m,5H),4.34-3.43(m,18H),2.88-2.86(m,2H),2.85-1.02(m,31H),0.90-0.78(m,45H),0.13-0.01(m,30H).
实施例46：制备化合物XIIc
30℃下向IXc(0.6g,0.37mmol)的甲苯(10mL)溶液中加入对甲苯磺酸吡啶盐(1.8g)，加完后反应继续搅拌12h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物XIIc(0.47g)。
MS(ESI)m/z:1588(M+H +).
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),7.93(d,J＝8.0Hz,2H),7.80-7.55(m,3H),6.87-6.81(m,1H),6.28-6.24(m,1H),5.05-4.81(m,5H),4.35-3.42(m,18H),2.88-2.85(m,2H),2.85-1.03(m,26H),0.90-0.75(m,45H),0.13-0.00(m,30H).
实施例47：制备化合物XIId
40℃下向IXd(0.6g,0.37mmol)的乙腈(10mL)溶液中加入硝酸铈铵(1.2g)，加完后反应继续搅拌6h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物XIId(0.51g)。
MS(ESI)m/z:1602(M+H +).
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),7.77-7.68(m,1H),7.68-7.65(m,1H),7.39-7.35(m,2H),6.87-6.80(m,1H),6.29-6.25(m,1H),5.05-4.80(m,5H),4.35-3.40(m,18H),2.88-2.85(m,2H),2.85-1.00(m,29H),0.90-0.75(m,45H),0.13-0.00(m,30H).
实施例48～51为如式II所示化合物的合成
实施例48：制备化合物IIa
-78℃下，在IXa(100mg,0.06mmol)的THF(3mL)溶液中逐滴加入SmI 2的THF溶液(0.1M in THF,2mL)，反应在该温度下搅拌10min。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIa(82mg)。
MS(ESI)m/z:1492(M+H +).
1H NMR(400MHz，CDCl 3):δ9.79(s,1H),6.85(dd,J＝14.4,3.6Hz,1H),6.28(dd,J＝14.4,1H),4.99(d,J＝2Hz,1H),4.89-4.85(m,3H),4.79(s,1H),4.34-4.33(m,1H),4.06-4.02(m,2H),3.89-3.43(m,11H),3.33(s,3H),3.23(d,J＝3.6Hz,1H),2.93(d,J＝9.6Hz,2Hz,1H),2.75-2.22(m,10H),2.09-1.26(m,16H),1.07(3H,d,J＝6.0Hz),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例49：制备化合物IIa
0℃下，在IXc(100mg,0.06mmol)的THF(3mL)溶液中加入二氯化铬(205mg)和锰粉(300mg)，反应在该温度下搅拌12h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIa(78mg)。
MS(ESI)m/z:1492(M+H +).
1H NMR(400MHz，CDCl 3):δ9.79(s,1H),6.85(dd,J＝14.4,3.6Hz,1H),6.28(dd,J＝14.4,1H),4.99(d,J＝2Hz,1H),4.89-4.85(m,3H),4.79(s,1H),4.34-4.33(m,1H),4.06-4.02(m,2H),3.89-3.43(m,11H),3.33(s,3H),3.23(d,J＝3.6Hz,1H),2.93(d,J＝9.6Hz,2Hz,1H),2.75-2.22(m,10H),2.09-1.26(m,16H),1.07(3H,d,J＝6.0Hz),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例50：制备化合物IIa
30℃下，在IXd(100mg,0.06mmol)的THF(3mL)溶液中加入锌粉(600mg)和醋酸(600mg)，反应在该温度下搅拌6h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIa(63mg)。
MS(ESI)m/z:1492(M+H +)
1H NMR(400MHz，CDCl 3):δ9.79(s,1H),6.85(dd,J＝14.4,3.6Hz,1H),6.28(dd,J＝14.4,1H),4.99(d,J＝2Hz,1H),4.89-4.85(m,3H),4.79(s,1H),4.34-4.33(m,1H),4.06-4.02(m,2H),3.89-3.43(m,11H),3.33(s,3H),3.23(d,J＝3.6Hz,1H),2.93(d,J＝9.6Hz,2Hz,1H),2.75-2.22(m,10H),2.09-1.26(m,16H),1.07(3H,d,J＝6.0Hz),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例51：制备化合物IIb
-30℃下，在IXb(100mg,0.06mmol)的THF(3mL)溶液中加入SmI 2(0.1M，3mL)，反应在该温度下搅拌2h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IIb(77mg)。
MS(ESI)m/z:1506(M+H +)。
1H NMR(400MHz，CDCl 3):δ9.78(s,1H),6.83(dd,J＝14.4,3.6Hz,1H),6.26(dd,J＝14.4,1H),5.00(d,J＝2Hz,1H),4.90-4.85(m,3H),4.78(s,1H),4.62-4.51(m,1H),4.42-4.38(m,1H),4.16-4.00(m,3H),3.90-3.42(m,9H),3.34(s,3H),3.21(d,J＝3.6Hz,1H),2.90(d,J＝9.6Hz,2Hz,1H),2.75-2.20(m,10H),2.10-1.20(m,18H),1.08(3H,d,J＝ 6.0Hz),0.95(s,9H),0.92(s,9H),0.90(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例52～56为如式IVa所示化合物的合成
实施例52：制备化合物IVa
-30℃下，在XIIa(86mg,0.05mmol)的THF(2mL)溶液中逐滴加入SmI 2的THF溶液(0.1M in THF,1mL)，反应在该温度下搅拌30min。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IVa(80mg)。
MS(ESI)m/z:1448(M+H +)。
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),6.86(dd,J＝15.0,8.0Hz,1H),6.28(d,J＝15.0Hz,1H),4.99-4.97(m,1H),4.89(dd,J＝8.0,3.0Hz,1H),4.88-3.64(m,13H),3.57(dd,J＝10.0,6.0Hz,1H),3.53-3.41(m,3H),3.33(s,3H),3.25(d,J＝2.8Hz,1H),2.95(dd,J＝10.0,2.0Hz,1H),2.77-1.06(m,26H),1.07(d,J＝6.0Hz,3H),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例53：制备化合物IVa
-50℃下，在XIIc(50mg,0.03mmol)的THF(2mL)溶液中加入二氯化铬(100mg)和锰粉(100mg)，反应在该温度下搅拌4h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IVa(39mg)。
MS(ESI)m/z:1448(M+H +)。
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),6.86(dd,J＝15.0,8.0Hz,1H),6.28(d,J＝15.0Hz,1H),4.99-4.97(m,1H),4.89(dd,J＝8.0,3.0Hz,1H),4.88-3.64(m,13H),3.57(dd,J＝10.0,6.0Hz,1H),3.53-3.41(m,3H),3.33(s,3H),3.25(d,J＝2.8Hz,1H),2.95(dd,J＝10.0,2.0Hz,1H),2.77-1.06(m,26H),1.07(d,J＝6.0Hz,3H),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例54：制备化合物IVa
30℃下，在XIId(50mg,0.03mmol)的THF(2mL)溶液中加入锌粉(200mg)和醋 酸(200mg)，反应在该温度下搅拌2h。TLC检测反应完全后，加入碳酸钾的水溶液淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IVa(35mg)。
MS(ESI)m/z:1448(M+H +)。
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),6.86(dd,J＝15.0,8.0Hz,1H),6.28(d,J＝15.0Hz,1H),4.99-4.97(m,1H),4.89(dd,J＝8.0,3.0Hz,1H),4.88-3.64(m,13H),3.57(dd,J＝10.0,6.0Hz,1H),3.53-3.41(m,3H),3.33(s,3H),3.25(d,J＝2.8Hz,1H),2.95(dd,J＝10.0,2.0Hz,1H),2.77-1.06(m,26H),1.07(d,J＝6.0Hz,3H),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例55：制备化合物IVa
冰水冷却的-30℃条件下向IIa(80mg,0.05mmol)的二氯甲烷(2mL)溶液中依次加入2,6-二甲基吡啶(0.12g)和TMSOTf(0.26g)，加完后反应继续搅拌24h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IVa(56mg)。
MS(ESI)m/z:1448(M+H +)。
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),6.86(dd,J＝15.0,8.0Hz,1H),6.28(d,J＝15.0Hz,1H),4.99-4.97(m,1H),4.89(dd,J＝8.0,3.0Hz,1H),4.88-3.64(m,13H),3.57(dd,J＝10.0,6.0Hz,1H),3.53-3.41(m,3H),3.33(s,3H),3.25(d,J＝2.8Hz,1H),2.95(dd,J＝10.0,2.0Hz,1H),2.77-1.06(m,26H),1.07(d,J＝6.0Hz,3H),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
实施例56：制备化合物IVa
40℃下向IIb(50mg,0.03mmol)的二氯甲烷(2mL)溶液中依次加入吡啶(0.15g)和TMSOTf(0.22g)，加完后反应继续搅拌1h。TLC检测反应完全后，向反应液中加入1N盐酸淬灭反应，乙酸乙酯萃取后，浓缩液过柱纯化得化合物IVa(33mg)。
MS(ESI)m/z:1448(M+H +)。
1H NMR(400MHz，CDCl 3)：δ9.78(s,1H),6.86(dd,J＝15.0,8.0Hz,1H),6.28(d,J＝15.0Hz,1H),4.99-4.97(m,1H),4.89(dd,J＝8.0,3.0Hz,1H),4.88-3.64(m,13H),3.57(dd, J＝10.0,6.0Hz,1H),3.53-3.41(m,3H),3.33(s,3H),3.25(d,J＝2.8Hz,1H),2.95(dd,J＝10.0,2.0Hz,1H),2.77-1.06(m,26H),1.07(d,J＝6.0Hz,3H),0.95(s,9H),0.92(s,9H),0.89(s,9H),0.88(s,9H),0.86(s,9H),0.12(s,3H),0.11(s,3H),0.10(s,3H),0.09(s,3H),0.08(s,3H),0.07(s,3H),0.06(s,3H),0.04(s,3H),0.03(s,3H),0.02(s,3H)。
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于本领域普通技术人员是显而易见的且包括在本发明的范围内。

Claims (25)

  1. 一种如式III所示的化合物，
    Figure PCTCN2018087247-appb-100001
    其中，Ar为C 1-10烷基取代或烷基氧基取代或非取代的芳基；优选为对位被C 1-10烷基取代或非取代的苯基；
    R 1和R 2为缩醛保护基团或者硫缩醛保护基团，且各自独立地为C 1-10烷基氧基或C 1-10烷基巯基，或者R 1和R 2与它们共同连接的碳原子联合形成环状缩醛或者环状硫缩醛；R 1和R 2优选为与它们共同连接的碳原子联合形成环状缩醛或环状硫缩醛，更优选为取代或非取代的乙二醇缩醛或取代或非取代的丙二醇缩醛。
  2. 一种如权利要求1所述的如式III所示的化合物的制备方法，其特征在于，其为方法A或方法B；
    方法A：包括如下步骤，将式V所示的化合物进行分子内环化反应得到如式III所示的化合物；
    Figure PCTCN2018087247-appb-100002
    方法B：包括下列步骤，将式VA所示的化合物进行分子内环化反应得到如式III所示的化合物；
    Figure PCTCN2018087247-appb-100003
    其中，Ar、R 1和R 2的定义如权利要求1所述；
    R 3为氢或者羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基；
    Y为卤素，优选为氯、溴或碘。
  3. 一种如式V所示的化合物，
    Figure PCTCN2018087247-appb-100004
    其中，Ar、R 1、R 2和R 3的定义如权利要求2所述。
  4. 一种如权利要求3所述的如式V所示的化合物的制备方法，其特征在于：将如式VI所示的化合物和如式VII所示的化合物进行NHK反应得到所述的如式V所示的化合物；
    Figure PCTCN2018087247-appb-100005
    其中，Ar、R 1、R 2和R 3的定义如权利要求3所述；
    X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
  5. 一种如式VA所示的化合物，
    Figure PCTCN2018087247-appb-100006
    其中，Ar、R 1和R 2的定义如权利要求2所述；
    Y为卤素，优选为氯、溴或碘。
  6. 一种如权利要求5所述的如式VA所示的化合物的制备方法，其特征在于：其包括如下步骤，将如式VI所示的化合物和如式VIIA所示的化合物进行NHK反应制得；
    Figure PCTCN2018087247-appb-100007
    其中，Ar、R 1、R 2和Y的定义如权利要求5所述；
    X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
  7. 一种如式VII所示的化合物，
    Figure PCTCN2018087247-appb-100008
    其中，R 1、R 2和R 3的定义如权利要求3所述；
    X为卤素或者离去基团，优选为氯、溴、碘或三氟甲磺酸酯基。
  8. 一种如权利要求7所述的如式VII所示的化合物的制备方法，其特征在于：其包括如下步骤，将化合物VIII进行羟基保护反应得到所述的如式VII所示的化合物；
    Figure PCTCN2018087247-appb-100009
    其中，R 1、R 2、R 3和X的定义如权利要求7所述，且R 3不为氢。
  9. 一种如式VIIA所示的化合物，
    Figure PCTCN2018087247-appb-100010
    其中，R 1、R 2和X的定义如权利要求7所述；
    Y为卤素，优选为氯、溴或碘。
  10. 一种如权利要求9所述的如式VIIA所示的化合物的制备方法，其特征在于：其包括如下步骤，将如式VII所示的化合物进行取代反应得到所述的如式VIIA所示的化合物；
    Figure PCTCN2018087247-appb-100011
    其中，R 1、R 2、X和Y的定义如权利要求9所述；
    R 3为氢或者羟基保护基，优选为甲磺酰基、对甲苯基磺酰基或三氟甲磺酰基。
  11. 一种如式II所示的化合物，
    Figure PCTCN2018087247-appb-100012
    其中，X、R 1和R 2的定义如权利要求4所述。
  12. 一种如权利要求11所述的如式II所示的化合物的制备方法，其特征在于：其包括如下步骤，将如式IX所示的化合物进行还原消除反应得到所述的如式II所示的化合物；
    Figure PCTCN2018087247-appb-100013
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  13. 一种如式IV所示的化合物的制备方法，其特征在于：其包括如下步骤，将式II所示的化合物进行水解反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100014
    其中，X、R 1和R 2的定义如权利要求4所述。
  14. 一种如式IX所示的化合物，
    Figure PCTCN2018087247-appb-100015
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  15. 一种如权利要求14所述的如式IX所示的化合物的制备方法，其特征在于：其包括如下步骤，将如式X所示的化合物进行氧化反应制得；
    Figure PCTCN2018087247-appb-100016
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  16. 一种如式XII所示的化合物的制备方法，其特征在于：其包括如下步骤，将如式IX所示的化合物进行水解反应制得；
    Figure PCTCN2018087247-appb-100017
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  17. 一种如式X所示的化合物，
    Figure PCTCN2018087247-appb-100018
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  18. 一种如权利要求17所述的如式X所示的化合物的制备方法，其特征在于：其包括如下步骤，将如式III所示的化合物与如式XI所示的化合物在碱性条件下进行缩合反应制得；
    Figure PCTCN2018087247-appb-100019
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  19. 一种如式IV所示的化合物的制备方法，其特征在于：其包括如下步骤：
    1)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；
    2)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
    3)将式IX所示的化合物进行还原消除反应得到如式II所示的化合物；
    4)将式II所示的化合物进行水解反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100020
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  20. 一种如式IV所示的化合物的制备方法，其特征在于，其包括如下步骤：
    1)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；
    2)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
    3)将式IX所示的化合物进行水解反应得到如式XII所示的化合物；
    4)将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100021
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  21. 一种如式IV所示的化合物的制备方法，其特征在于，其包括如下步骤：
    1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；
    2)将式VII所示的化合物与式VI所示的化合物进行NHK反应得到如式V所示的化合物；
    3)将式V所示的化合物进行分子内环化反应得到如式III所示的化合物；
    4)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合 物；
    5)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
    6)将式IX所示的化合物进行还原消除反应得到如式II所示的化合物；
    7)将式II所示的化合物进行水解反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100022
    其中，Ar、X、R 1和R 2的定义如权利要求4所述。
  22. 一种如式IV所示的化合物的制备方法，其特征在于，其包括如下步骤：
    1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；
    2)将式VII所示的化合物与式VI所示的化合物进行NHK反应得到如式V所示的化合物；
    3)将式V所示的化合物进行分子内环化反应得到如式III所示的化合物；
    4)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；
    5)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
    6)将式IX所示的化合物进行水解反应得到如式XII所示的化合物；
    7)将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100023
    其中，Ar、X、R 1、R 2和R 3的定义如权利要求4所述。
  23. 一种如式IV所示的化合物的制备方法，其特征在于，其包括如下步骤：
    1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；
    2)将式VII所示的化合物进行取代反应得到如式VIIA所示的化合物；
    3)将式VIIA所示的化合物与式VI所示的化合物进行NHK反应得到如式VA所示的化合物；
    4)将式VA所示的化合物进行分子内环化反应得到如式III所示的化合物；
    5)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合 物；
    6)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
    7)将式IX所示的化合物进行还原消除反应得到如式II所示的化合物；
    8)将式II所示的化合物进行水解反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100024
    其中，Ar、X、R 1、R 2和R 3的定义如权利要求4所述；
    Y为卤素，优选为氯、溴或碘。
  24. 一种如式IV所示的化合物的制备方法，其特征在于，包含如下步骤：
    1)将式VIII所示的化合物进行羟基保护反应得到如式VII所示的化合物；
    2)将式VII所示的化合物进行取代反应得到如式VIIA所示的化合物；
    3)将式VIIA所示的化合物与式VI所示的化合物进行NHK反应得到如式VA所示的化合物；
    4)将式VA所示的化合物进行分子内环化反应得到如式III所示的化合物；
    5)将式III所示的化合物与式XI所示的化合物进行缩合反应得到式X所示的化合物；
    6)将式X所示的化合物进行氧化反应得到如式IX所示的化合物；
    7)将式IX所示的化合物进行水解反应得到如式XII所示的化合物；
    8)将式XII所示的化合物进行还原消除反应得到如式IV所示的化合物；
    Figure PCTCN2018087247-appb-100025
    其中，Ar、X、R 1、R 2和R 3的定义如权利要求4所述；
    Y为卤素，优选为氯、溴或碘。
  25. 一种艾日布林的制备方法，其特征在于：其包括权利要求13、19、20、21、22、23和24中任一项所述的如式IV所示的化合物的制备方法，或者经如权利要求1所述的如式III所示的化合物、如权利要求3所述的如式V所示的化合物、如权利要求5所述的 如式VA所示的化合物或如权利要求11所述的如式II所示的化合物制备艾日布林的步骤。
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