WO2019001292A1 - 4'-硫代核苷的新型化合物的制备方法和此制备方法中的中间体 - Google Patents

4'-硫代核苷的新型化合物的制备方法和此制备方法中的中间体 Download PDF

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WO2019001292A1
WO2019001292A1 PCT/CN2018/091514 CN2018091514W WO2019001292A1 WO 2019001292 A1 WO2019001292 A1 WO 2019001292A1 CN 2018091514 W CN2018091514 W CN 2018091514W WO 2019001292 A1 WO2019001292 A1 WO 2019001292A1
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group
compound
formula
optionally substituted
reaction
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PCT/CN2018/091514
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English (en)
French (fr)
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周江峰
梁玉峰
王强
王涛
韩维彪
李友强
魏海东
葛建华
赵忠琼
文乾映
吴灵静
田强
赵明亮
曾宏
蔡家强
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201880028331.2A priority Critical patent/CN110573521B/zh
Publication of WO2019001292A1 publication Critical patent/WO2019001292A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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 present invention relates to a process for the preparation of novel compounds of 4'-thionucleosides and intermediates in the process.
  • WO 2016/155593 A1 discloses a novel class of 4'-thionucleosides having anticancer activity, having the structure of formula (I):
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-10 acyl
  • Q is a pyrimidine base or a purine base having the following structure:
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from A 3-8 membered saturated, unsaturated or aromatic ring of a hetero
  • WO 2016/155593 A1 also discloses a process for the preparation of a compound of formula (I) comprising the steps of:
  • radicals are as defined above, wherein the first step reaction is preferably carried out in the presence of POCl 3.
  • One aspect of the invention provides a method of preparing a compound of formula T-3,
  • the PG group is a silicon-containing protecting group
  • X is hydrogen, C 1-6 alkyl, halogen or CN;
  • Q is a pyrimidine base or a purine base having the following structure:
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted C 6-14 aryl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from a 3-8 membered saturated ring, an unsaturated ring or an
  • the method includes the following steps:
  • a first step reacting a compound of formula T-1 with a reagent comprising a PG group in the presence of an organic or inorganic base, optionally under the catalysis of a catalyst, to form a compound of formula T-2;
  • Step 2 The compound of formula T-2 is reacted under the catalysis of an organic or inorganic acid to form a compound of formula T-3.
  • Another aspect of the invention provides a process for the preparation of a compound of formula (I)-1,
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from a 3-8 membered saturated ring, an unsaturated ring or an
  • the method includes the following steps:
  • Step A reacting T-3 and R-1 in the presence of a hydroxyhydrogen removal reagent to provide a compound of formula T-4, preferably step A in an aprotic solvent;
  • Step B The compound of the formula T-4 is catalyzed by an organic acid or a mineral acid or in the presence of a fluorine-containing reagent to give a compound of the formula (I)-1, which is preferably carried out in a solvent.
  • Another aspect of the invention provides an intermediate involved in the above process.
  • This stereoisomer is difficult to be separated and removed, making the purification treatment of the final target product difficult.
  • the inventors of the present application conducted intensive studies on the above reactions, and inventively obtained the preparation method of the present invention, which avoids the generation of by-products in the prior art and provides a process superior to the prior art.
  • the method of the present invention has various advantages, for example, the reaction conditions of the present invention are mild, and many reaction steps of the present invention can be carried out at room temperature; the reaction cycle of the present invention is short, and it is convenient to control the reaction of each reaction.
  • Crystallization gives a solid product, which avoids the defect that the intermediate in the prior art is always oily, improves the quality of the final product by quality control of the intermediate, and ensures the controllability of industrial production; moreover, the present invention also has There are techniques for higher reaction selectivity, reduced impurities (e.g., undesired disubstituted products and stereoisomers); and finally, the present invention also increases target product yield and purity.
  • a compound of the invention generally refers to the formulas T-1, T-2, T-3, T-4, T-4', (I)-1, (I)- described herein.
  • Salts of the compounds described herein represent those salts which retain the properties of the parent compound which can be prepared by protonation of the proton accepting moiety and/or deprotonation of the proton donating moiety. It should be noted that proton accepting partial protonation results in the formation of a cationic species in which the cationic charge is balanced by the presence of physiological anions, while deprotonation of the proton supply moiety results in the formation of an anionic species, wherein the anionic charge is passed through the presence of physiological cations. balance.
  • Salts of the compounds of the invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts, including inorganic acids and organic acids.
  • a suitable inorganic acid is, for example, a mineral acid as defined in the chemical field, such as hydrochloric acid, sulfuric acid or phosphoric acid.
  • Suitable organic acids include organic sulfonic acids, organic carboxylic acids or amino acids, and the like, suitable organic sulfonic acids such as C 6-16 aryl sulfonic acid, C 6-16 heteroaryl sulfonic acid and C 1-16 alkyl sulfonic acid, Suitable organic carboxylic acids are, for example, mono- or polycarboxylic acids, including C 1-16 alkyl carboxylic acids, C 6-16 aryl carboxylic acids and C 4-16 heteroaryl carboxylic acids.
  • the organic carboxylic acid may also be, for example, an amino acid, and there are many suitable amino acids, particularly natural amino acids found as protein components.
  • the salt formed from the above acid include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, hydrogensulfate/sulfate, Borate, camphor sulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, Portuguese Uronic acid salt, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, cis.
  • Oleate malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate , palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannic acid, tartaric acid Salt, tosylate, trifluoroacetate and xinofoate.
  • Suitable base addition salts are formed from bases which form non-toxic salts, including inorganic bases and organic bases. Specific examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts , potassium salt, sodium salt, tromethamine salt and zinc salt.
  • stereoisomer means an isomer that differs only in the manner in which the atoms are spatially aligned.
  • ⁇ - refers to a specific stereochemical configuration of a substituent on an asymmetric carbon atom in the chemical structure shown.
  • the compounds of the invention have one or more chiral centers and various stereoisomeric configurations can exist. Due to the presence of these chiral centers, the compounds of the invention may exist as racemates, mixtures of enantiomers and individual enantiomers as well as mixtures of diastereomers and diastereomers. All such racemates, enantiomers and diastereomers are within the scope of "compounds of the invention”. "R” and "S” are commonly used in organic chemistry to represent the specific configuration of a chiral center.
  • the compounds of the invention may exist in the form of hydrates or solvates wherein the compounds of the invention comprise a polar solvent which is a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • a polar solvent which is a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • substituents or “optionally” means that it may or may not be present under the circumstances or conditions, the term includes instances where the substituent is present or absent; the “optional” also includes the presence of one Or an example of a plurality of such substituent substitutions.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded. The normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • the term "optionally substituted” includes the case where one is substituted with one or more substituents, and when “optionally substituted” means that a plurality of substituents are present, the substituents may be appropriately interposed with each other Connected to form a saturated ring, an unsaturated ring or an aromatic ring containing 0-3 hetero atoms selected from the group consisting of oxygen (O), nitrogen (N) and sulfur (S), said saturated ring, unsaturated ring or aromatic ring A ring may also be formed together with a substituted group.
  • the term “optionally substituted aryl” includes benzodihydrothiophenyl and a group having the following structure:
  • alkyl denotes an unbranched or branched chain or cyclic saturated monovalent hydrocarbon residue, preferably having from 1 to 14 carbon atoms (C 1-14 alkyl), more preferably 1 To 10 carbon atoms (C 1-10 alkyl group), more preferably 1 to 6 carbon atoms (C 1-6 alkyl group), particularly preferably 1 to 4 carbon atoms (C 1-4 alkyl group).
  • alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl Heptyl (eg, hept-4-yl) and octyl.
  • cycloalkyl refers to a saturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring. When it consists of two or more rings, the rings may be joined together in a fused manner.
  • the cycloalkyl group can have 3 to 10 atoms (C 3-10 cycloalkyl group) in the ring, preferably 3 to 8 ring atoms (C 3-8 cycloalkyl group), more preferably 3 to 6 ring atoms ( C 3-6 cycloalkyl), particularly preferably contains 3-4 ring atoms (C 3-4 cycloalkyl).
  • Cycloalkyl groups include, but are not limited to, monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged a system (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] decyl, decalinyl, etc.), optionally Substituted by one or more (such as 1 to 3) suitable substituents.
  • monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused
  • alkenyl denotes a hydrocarbon residue having 2 to 10 carbon atoms and having one or two olefinic double bonds, preferably having 2 to 8 carbon atoms (C 2-8 alkenyl), more It preferably contains 2 to 6 carbon atoms (C 2-6 alkenyl), particularly preferably 2 to 4 carbon atoms (C 2-4 alkenyl), unless otherwise specified.
  • alkenyl group include a vinyl group, a 1-propenyl group, a 2-propenyl group or a 2-butenyl group, and the like.
  • alkynyl denotes an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms (C 2-10 alkynyl) and having one or two triple bonds, preferably containing 2 to 8 carbon atoms (C 2-8 alkynyl), more preferably 2 to 6 carbon atoms (C 2-6 alkynyl), particularly preferably 2 to 4 carbon atoms (C 2-4 alkynyl), Except as specified.
  • alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl and the like.
  • amino denotes -NH 2
  • alkylamino represents -NR'R
  • R' and R are the same or different and are H or alkyl or cycloalkyl as defined above.
  • alkoxy denotes -O-alkyl, wherein alkyl is as defined above (eg, C 1-14 alkyl, C 1-10 alkyl, C 1-6 alkyl or C 1-4 alkane).
  • Base for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and their Structure, etc.
  • halogen or "halo" as used herein denotes fluoro, chloro, bromo or iodo.
  • haloalkyl denotes an alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are replaced by a halogen.
  • Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl Base, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloro Ethyl, 3-bromopropyl or 2,2,2-trifluoroethyl and the like.
  • haloalkoxy denotes an alkoxy group as defined above wherein 1, 2, 3 or more hydrogen atoms are replaced by halogen.
  • hydroxyalkyl denotes a radical of the formula -R-OH wherein R is alkylene.
  • alkylene denotes 1 to 10 carbon atoms (C 1-10 alkylene group), more preferably 1 to 6 carbon atoms (C 1-6 alkylene group), particularly preferably 1 a divalent saturated linear hydrocarbon group of 4 carbon atoms (C 1-4 alkylene) or 3 to 10 carbon atoms (C 3-10 alkylene), more preferably 3 to 8 carbon atoms (C 3-8 alkylene), particularly preferably a branched saturated divalent hydrocarbon group having 3 to 5 carbon atoms (C 3-5 alkylene), unless otherwise indicated.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
  • aryl refers to a group having at least one aromatic ring, that is, having a conjugated ⁇ -electron system, including monocyclic aryl groups, bicyclic aryl groups, and the like. It contains 6 to 14 carbon atoms (C 6-14 aryl) such as phenyl, naphthyl and the like.
  • the optionally substituted aryl group includes an aryl group substituted with a plurality of substituents, and the substituents may be appropriately bonded to each other to form a saturated ring containing 0 to 3 hetero atoms selected from oxygen, nitrogen and sulfur, an unsaturated ring and / or aromatic ring.
  • the aryl group preferably includes the following groups:
  • aralkyl denotes a radical R'R"-, wherein R' is aryl as defined herein, and R" is alkylene as defined herein, it being understood that the aralkyl moiety The point of attachment will be on the alkylene group.
  • the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, 4-fluorobenzyl, phenylethyl, phenylpropyl, and phenylbutyl.
  • aryloxy as used herein denotes -O-R, and R is aryl as defined above.
  • heterocyclyl refers to 3- to 3 (eg, one, two, three or four) heteroatoms selected from N, O, S and P and the remaining atoms are carbon atoms.
  • a 16-membered saturated or unsaturated ring group is
  • the 3-10 membered heterocyclic group is a group having 3 to 10 carbon atoms and a hetero atom in the ring, such as, but not limited to, an oxiranyl group, an aziridine group, an azetidinyl group ( Azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl Oryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • an oxiranyl group an aziridine group
  • an azetidinyl group Azetidinyl
  • oxetanyl tetrahydrofuranyl
  • dioxolinyl pyrrolidinyl
  • heteroaryl refers to a cyclic aromatic group having from 1 to 3 heteroatoms selected from N, O and S as ring atoms and the remaining ring atoms being carbon, wherein said ring is 4- A 16-membered monocyclic or fused ring, preferably a 5-12 membered monocyclic or fused ring, a 5-8 membered monocyclic or fused ring.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrrole , pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyridazinyl, pyridazinyl, pyridazine-1-(2H)-1-yl, pyrido[3,2 -d] pyridazine-5(6H)-8-yl, triazinyl and the like and their benzo derivatives.
  • heteroaryloxy denotes a radical of the formula heteroaryl-O-, wherein said heteroaryl is as defined above.
  • sulfonamido refers to a radical of the formula -SO 2 NR'R", wherein R' and R" are the same or different and are each independently hydrogen or alkyl or cycloalkyl as defined above.
  • carboxy refers to a group of the formula -COOH, and the term “carboxylate group” as used herein denotes -COOR, wherein each R independently represents an alkyl group as defined above.
  • each group or atom or ion group includes a group or atom or ion group of its isotopic substitution, for example, the "hydrogen” includes H, 2 H ( ⁇ ), 3 H( ⁇ );
  • the C 1-14 alkyl group includes the case where one or more carbon atoms or all are 12 C, 13 C, 14 C, and other examples include N, P, O isotopes.
  • a partial embodiment of the invention provides a method of preparing a compound of formula T-3,
  • the PG group is a silicon-containing protecting group
  • X is hydrogen, C 1-6 alkyl, halogen or CN;
  • Q is a pyrimidine base or a purine base having the following structure:
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted C 6-14 aryl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from a 3-8 membered saturated ring, an unsaturated ring or an
  • the method includes the following steps:
  • a first step reacting a compound of formula T-1 with a reagent comprising a PG group in the presence of an organic or inorganic base, optionally under the catalysis of a catalyst, to form a compound of formula T-2;
  • Step 2 The compound of formula T-2 is reacted under the catalysis of an organic or inorganic acid to form a compound of formula T-3.
  • T-1 can be prepared by methods known in the art, for example, in a manner similar to that disclosed in WO 2016/155593 A1.
  • Q is a pyrimidine base having the structure:
  • Z is hydrogen, methyl or halogen.
  • Q is a pyrimidine base of the formula:
  • Z is hydrogen, methyl or halogen.
  • Q is
  • Q is selected from
  • R 5 at each occurrence is independently selected from hydrogen, optionally substituted C 1-10 alkyl (e.g. heptan-4-yl) and phenyl.
  • Z is hydrogen, methyl, fluoro or chloro.
  • X is hydrogen or halogen
  • the halogen is fluorine, chlorine, bromine or iodine.
  • the PG group is selected from the group consisting of TMS-, TES-, TBDMS-, TBDPS-, TIPS-, IPDMS-, DEIPS-, TPS-, DPMS-, DTBMS-, and TBMPS-.
  • the reagent comprising a PG group is (TMS) 2 NH(HMDS) or (TMS) 2 O.
  • the reagent comprising a PG group is PG-LG, wherein LG is selected from the group consisting of hydrogen, halogen, triflate, diethylamino, and azide.
  • the reagent comprising a PG group is trimethylchlorosilane (TMSCl), trimethylbromosilane (TMSBr), trimethyliodosilane (TMSI), trimethylsulfonate trimethyl Silicone ester (TMSOTf), azidotrimethylsilane (TMSN 3 ), N,N-diethyltrimethylsilylamine (TMSNEt 2 ), triethylchlorosilane (TESCl), trifluoromethanesulfonic acid Triethylsilyl ester (TESOTf), tert-butyldiphenylchlorosilane (TBDPSCl), tert-butyldimethylsilyl chloride (TBDMSCl), t-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf), Triisopropylchlorosilane (TIPSCl) or triisopropyl methane
  • TBDMSCl is most preferred, which minimizes the formation of by-products in which two PG groups are simultaneously removed.
  • the organic base is selected from the group consisting of imidazole, triethylamine, pyridine, 2,6-lutidine, DBU, and DIPEA; and the inorganic base is an alkali metal (eg, lithium, sodium, potassium, etc.) Or hydroxides, carbonates (such as sodium carbonate or potassium carbonate) or bicarbonates of alkaline earth metals (such as magnesium or calcium).
  • alkali metal eg, lithium, sodium, potassium, etc.
  • the catalyst is selected from the group consisting of DMAP, KF, CsF, and a silver salt (eg, silver nitrate).
  • the first step reaction is carried out in a solvent which is any solvent which does not affect the progress of the reaction, such as DMF, THF, 1,4-dioxane, DCM, chloroform, tetrachlorination A mixture of any two or more of carbon, benzene, toluene, DMSO, acetonitrile, and the above solvents.
  • the molar ratio of the compound of the formula T-1 to the reagent comprising the PG group is 1:2-1:20, preferably 1:2-1: 10, more preferably 1:2-1:5.
  • the molar ratio of the compound of the formula T-1 to the organic base or inorganic base is 1:2-1:20, preferably 1:2-1. : 10, more preferably 1:2-1:5.
  • the molar ratio of the compound of the formula T-1 to the catalyst is 1:0-1:5, preferably 1:0-1:1, more It is preferably 1:0-1:0.5.
  • the first step reaction is carried out at a temperature of from -10 °C to 100 °C, preferably from 0 °C to 50 °C, more preferably from 10 °C to 30 °C.
  • the organic acid is selected from the group consisting of AcOH, TFA, and citric acid; and the inorganic acid is selected from the group consisting of HF, HCl, and HBr.
  • the second step reaction is carried out in a solvent which is any solvent that does not affect the progress of the reaction, such as an ether, an alcohol or an ester selected from the group consisting of water, containing 1 to 6 carbon atoms, and the like A mixture of any two or more of the solvents.
  • the ether having 1 to 6 carbon atoms includes, but is not limited to, diethyl ether, tetrahydrofuran or 1,4-dioxane;
  • the alcohol having 1 to 6 carbon atoms includes, but is not limited to, methanol.
  • Ethanol, n-propanol or isopropanol; and the ester having from 1 to 6 carbon atoms includes, but is not limited to, ethyl formate or ethyl acetate.
  • the second step of the reaction is carried out in a mixture of water and tetrahydrofuran wherein the volume ratio of water to tetrahydrofuran is 1:20, preferably 1:10, more preferably 1:5.
  • the second step of the reaction is carried out in a mixture of water, tetrahydrofuran and methanol, wherein the volume ratio of water, tetrahydrofuran and methanol is 1: (1-5): (1-5), preferably 1 :2:2.
  • the second step of the reaction is carried out in a mixture of water, tetrahydrofuran and ethyl acetate, wherein the volume ratio of water, tetrahydrofuran and methanol is 1: (1-5): (1-5), preferably It is 1:2:2.
  • the weight to volume ratio (g/ml) of the compound of the formula T-2 to the organic acid or inorganic acid is 1:0.2 to 1:20, preferably It is 1:0.5-1:10, more preferably 1:0.8-1:5.
  • the second step reaction is carried out at a temperature of from -10 °C to 100 °C, preferably from 0 °C to 50 °C, more preferably from 10 °C to 30 °C.
  • the compound of formula T-1 is preferably a compound of formula 1-T-1:
  • the compound of formula T-2 is preferably a compound of formula 1-T-2:
  • the invention provides a method of preparing a compound of Formula 1-T-3, the method comprising the steps of:
  • the first and second steps are as defined above.
  • a partial embodiment of the invention provides a process for the preparation of a compound of formula (I)-1,
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from a 3-8 membered saturated ring, an unsaturated ring or an
  • the method includes the following steps:
  • Step A reacting T-3 and R-1 in the presence of a hydroxyhydrogen removal reagent to provide a compound of formula T-4;
  • Step B The compound of formula T-4 is reacted under the catalysis of an organic or inorganic acid or in the presence of a fluorine-containing reagent to give a compound of formula (I)-1.
  • R-1 can be prepared by methods known in the art, for example, in a manner similar to that disclosed in WO 2016/155593 A1.
  • the compound of formula T-3 is obtained by the method described above.
  • Y is oxygen
  • R 1, R 2, R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl and optionally substituted aryl (preferably optionally substituted C 6- 14 aryl), said "optionally substituted” means unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl and C 6-14 aryl.
  • R 1 , R 2 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl and 4-fluorobenzyl.
  • R 3 is selected from an optionally substituted aryl group, preferably an optionally substituted C 6-14 aryl group, more preferably an optionally substituted phenyl group, and the "optionally substituted” means not Substituted or substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy, the substituents may be bonded to each other to form 0-3 (eg 1, 2 or 3) A 3-8 membered saturated ring, unsaturated ring or aromatic ring of O.
  • R 3 most preferably has the structure shown below:
  • portions, R 1, R 2, R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl and optionally substituted aryl; Wherein R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and may be a saturated ring, an unsaturated ring or an aromatic Sexual ring
  • Q is
  • X is hydrogen, C 1-6 alkyl, halogen or CN;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted C 6-14 aryl;
  • Z is hydrogen, methyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be each independently or may be bonded to each other to form a 0- 3 3-8-membered saturated, unsaturated or aromatic rings
  • Q is cytosine and has the structural formula:
  • X is hydrogen, C 1-6 alkyl, halogen or CN;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; wherein R 2 and R 6 The two may be linked to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from A 3-8 membered saturated, unsaturated or aromatic ring of a hetero
  • X is hydrogen, C 1-6 alkyl, halogen or CN;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; wherein R 2 and R 6 The two may be linked to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • Q is a ⁇ base with the following structure:
  • Z is hydrogen, methyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkynyl, alkenyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be each independently or may be bonded to each other to form a 0- 3 3-8-membered saturated, unsaturated or aromatic rings
  • the hydroxy hydrogen removal reagent is selected from the group consisting of lithium amide, organolithium reagents (eg, methyl lithium, phenyl lithium, n-butyl lithium, LDA, LiHMDS) , NaH, sodium amide, sodium methoxide, sodium ethoxide, NaHMDS, KH, potassium amide, KHMDS and Grignard reagent.
  • organolithium reagents eg, methyl lithium, phenyl lithium, n-butyl lithium, LDA, LiHMDS
  • the "Grignard reagent” means an organometallic compound containing a magnesium halide such as t-butylmagnesium chloride.
  • the step A reaction is carried out in an aprotic solvent, which is any solvent that does not affect the progress of the reaction, such as DMF, THF, 1,4-dioxane, DMSO, acetonitrile, acetone, And a mixture of any two or more of the above solvents.
  • an aprotic solvent which is any solvent that does not affect the progress of the reaction, such as DMF, THF, 1,4-dioxane, DMSO, acetonitrile, acetone, And a mixture of any two or more of the above solvents.
  • the molar ratio of the compound of the formula T-3 to the compound of the formula R-1 is from 1:1 to 1:10, preferably from 1:1 to 1. : 5, more preferably 1:1 to 1:2.
  • the molar ratio of the compound of the formula T-3 to the hydroxyhydrogen removal reagent is from 1:1 to 1:20, preferably from 1:1 to 1: 10, more preferably 1:1 to 1:5.
  • the reaction in the step A reaction, it is preferred to first bring the compound of the formula T-3 and the hydroxyhydrogen removal reagent at -50 ° C to 50 ° C, preferably -20 ° C to 40 ° C, Preferably, the reaction is carried out at a temperature of from -10 ° C to 30 ° C to remove the hydroxy hydrogen in the compound of the formula T-3; then at -50 ° C to 30 ° C, preferably -20 ° C to 20 ° C, more preferably -15
  • the compound of the formula R-1 is added at a temperature of from ° C to 15 ° C, and the reaction is carried out at a temperature of from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C, more preferably from 10 ° C to 30 ° C after the addition.
  • the organic acid used in the step B reaction is selected from the group consisting of AcOH, TFA and citric acid; the inorganic acid used in the step B reaction is selected from the group consisting of HF, HCl and HBr; and the step B
  • the fluorine-containing reagent used in the reaction is selected from the group consisting of boron trifluoride, potassium fluoride, tetrabutylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, and boron trifluoride diethyl ether, and the above reagents. Any two or more.
  • the fluorine-containing reagent is preferably a combination of potassium fluoride and tetrabutylammonium fluoride, or boron trifluoride etherate.
  • the step B reaction is carried out in a solvent which is any solvent which does not affect the progress of the reaction, such as a nitrile, an ether, an alcohol or an ester selected from water, containing 1 to 6 carbon atoms, and A mixture of any two or more of the above solvents.
  • a solvent which is any solvent which does not affect the progress of the reaction, such as a nitrile, an ether, an alcohol or an ester selected from water, containing 1 to 6 carbon atoms, and A mixture of any two or more of the above solvents.
  • the nitrile having 1 to 6 carbon atoms includes, but is not limited to, acetonitrile or propionitrile; and the ether having 1 to 6 carbon atoms includes, but is not limited to, diethyl ether, tetrahydrofuran or 1,4-diene.
  • the step B reaction is carried out in a mixture of water and tetrahydrofuran, acetonitrile or a mixture of water and acetonitrile.
  • the step B is reacted at -50 ° C to 50 ° C, preferably -30 ° C to 50 ° C, -30 ° C to 40 ° C, -30 ° C to 30 ° C or -30 ° C to 20 ° C, more preferably It is carried out at a temperature of -20 ° C to 0 ° C.
  • the reaction when the fluorine-containing reagent used in the reaction of the step B is boron trifluoride etherate, the reaction is preferably at 10 ° C to 30 ° C, such as 25 ⁇ 5 ° C, 20 ⁇ 5 ° C or 15 The reaction is carried out at ⁇ 5 ° C; when the fluorine-containing reagent used in the reaction of the step B is a combination of potassium fluoride and tetrabutylammonium fluoride, the reaction is carried out at a temperature of -20 ° C ⁇ 10 ° C.
  • Some embodiments of the present invention provide a method of preparing a compound of Formula (I)-1', the method comprising the steps of:
  • steps A' and B' are as defined for step A and step B, respectively.
  • the compound of formula T-3 is preferably a compound of formula 1-T-3:
  • the compound of formula T-4' is preferably a compound of formula 1-T-4:
  • the compound of formula R-1' is preferably a compound of formula 1-R-1:
  • the invention provides a method of preparing a compound of Formula 1, the method comprising the steps of:
  • step A and step B are as defined above.
  • a partial embodiment of the invention provides a compound, or a salt, solvate, stereoisomer or polymorph thereof, having the structure of formula T-2:
  • the compound is preferably:
  • a partial embodiment of the invention provides a compound, or a salt, solvate, stereoisomer or polymorph thereof, having the structure of formula T-3:
  • the compound is preferably:
  • a partial embodiment of the invention provides a compound, or a salt, solvate, stereoisomer or polymorph thereof, having the structure of formula T-4:
  • the compound is preferably:
  • the present invention encompasses the technical solutions obtained by arbitrarily combining the various embodiments described above without being bound by the individual embodiments.
  • a compound of formula 1-T-1 (0.9 kg), THF (7.2 L), 4-(dimethylamino)pyridine (0.15 kg) and imidazole (1.17 kg) were sequentially added to a 30 L glass reactor, stirred and cooled to At about 10 ° C, tert-butyldimethylsilyl chloride (2.59 kg) was added in portions, and after the addition, the reaction was carried out at 15 ° C to 25 ° C. After the TLC reaction was completed, the reaction mixture was poured into cold water (11 L, 0 ° C to 10 ° C) with stirring. After the addition was completed, the mixture was extracted with dichloromethane, and the organic layer was collected and concentrated to give the formula 1 as a brown oil. The compound of -T-2 (2.6 kg) was used in the next reaction without isolation purification.
  • a compound of formula 1-T-1 (0.9 kg), N,N-dimethylformamide (7.2 L), 4-(dimethylamino)pyridine (0.15 kg) and tribrane were sequentially added to a 30 L glass reactor.
  • the amine (1.74 kg) was stirred and cooled to about 10 ° C, and tert-butyldimethylsilyl chloride (2.59 kg) was added in portions. After the addition, the reaction was carried out at 0 ° C to 10 ° C. After the TLC reaction was completed, the reaction mixture was poured into cold water (11 L, 0 ° C to 10 ° C) with stirring. After the addition was completed, the mixture was extracted with dichloromethane, and the organic layer was collected and concentrated to give the formula 1 as a brown oil.
  • the compound of -T-2 (2.4 kg) was used in the next reaction without isolation purification.
  • a compound of formula 1-T-1 (0.9 kg), dichloromethane (7.2 L), 4-(dimethylamino)pyridine (0.15 kg) and pyridine (1.36 kg) were sequentially added to a 30 L glass reactor, and stirred. The temperature was lowered to about 10 ° C, tert-butyldimethylsilyl chloride (2.59 kg) was added in portions, and after the addition, the reaction was carried out at 20 ° C to 35 ° C. After the TLC reaction was completed, the reaction mixture was poured into cold water (11 L, 0 ° C to 10 ° C) with stirring. After the addition was completed, the mixture was extracted with dichloromethane, and the organic layer was collected and concentrated to give the formula 1 as a brown oil. The compound of -T-2 (2.8 kg) was used in the next reaction without isolation purification.
  • a compound of formula 1-T-1 (0.9 kg), 1,4-dioxane (7.2 L), 4-(dimethylamino)pyridine (0.15 kg) and sodium carbonate were sequentially added to a 30 L glass reactor. 1.82 kg), stirred and cooled to about 10 ° C, t-butyldimethylsilyl chloride (2.59 kg) was added in portions, and after the addition, the reaction was carried out at 40 ° C to 50 ° C. After the TLC reaction was completed, the reaction mixture was poured into cold water (11 L, 0 ° C to 10 ° C) with stirring. After the addition was completed, the mixture was extracted with dichloromethane, and the organic layer was collected and concentrated to give the formula 1 as a brown oil. The compound of -T-2 (2.8 kg) was used in the next reaction without isolation purification.
  • Step 2 - Method 1 Synthesis of a compound of formula 1-T-3
  • a compound of the formula 1-T-2 (1.68 kg) and tetrahydrofuran (3.4 L) were added to a 10 L glass reaction flask 1, and tetrahydrofuran (3.4 L) and trifluoroacetic acid (1.7 L) were added to another 30 L glass reactor 2. And purified water (1.7L). After the temperature of the reaction liquid in the reaction flask 1 and the reaction vessel 2 are both lowered to less than 10 ° C, the reaction liquid in the reaction flask 1 is poured into the reaction vessel 2, and after the completion of the addition, the temperature is naturally raised to 20 ° C to 25 ° C. TLC detected the reaction completely.
  • reaction liquid in the reaction vessel 2 was added to 10 L of cold water, and extracted with ethyl acetate.
  • the organic layer was combined, and the organic layer was adjusted to pH about 7 with sodium bicarbonate solid, and the organic layer was concentrated to dryness to give an oil.
  • a crude product of 1-T-3 compound was obtained by reacting 2-aminoethyl acetate.
  • n-heptane 8.7 L was added, and then the mixture was cooled to about 5 ° C, stirred and crystallized, filtered, and the obtained solid was dried to constant weight to obtain a compound of formula 1-T-3 as a gray solid ( 1.09kg, yield 85%, purity 99.15%).
  • the compound of formula 1-T-2 (1.68 kg) and methanol (3.4 L) were added to a 10 L glass reaction flask 1, and tetrahydrofuran (3.4 L), AcOH (1.7 L) and purified were added to another 30 L glass reactor 2. Water (1.7L). After the temperature of the reaction liquid in the reaction flask 1 and the reaction vessel 2 are all lowered to less than 0 ° C, the reaction liquid in the reaction flask 1 is poured into the reaction vessel 2, and after the completion of the addition, the temperature is naturally raised to 0 ° C to 15 ° C. TLC detected the reaction completely.
  • reaction liquid in the reaction vessel 2 was added to 10 L of cold water, extracted with ethyl acetate, and the organic layer was combined.
  • the organic layer was adjusted to pH about 7 with sodium bicarbonate solid, then washed with water (7.0 L) and layered.
  • the organic layer was concentrated to dryness to give a crude material of compound of formula 1-T-3 as an oil.
  • the nuclear magnetic data and mass spectral data of the obtained compound were confirmed to be consistent with the data of the compound of the second step - method 1.
  • a compound of formula 1-T-2 (1.68 kg) and ethyl acetate (3.4 L) were added to a 10 L glass reaction flask 1, and tetrahydrofuran (3.4 L) and HCl (1.7 L) were added to another 30 L glass reactor 2. And purified water (1.7L). After the temperature of the reaction liquid in the reaction flask 1 and the reaction vessel 2 are both reduced to less than 5 ° C, the reaction liquid in the reaction flask 1 is poured into the reaction vessel 2, and after the completion of the addition, the temperature is naturally raised to 30 ° C to 50 ° C to react. The reaction was complete by TLC.
  • reaction liquid in the reaction vessel 2 was added to 10 L of cold water, extracted with ethyl acetate, and the organic layer was combined.
  • the organic layer was adjusted to pH about 7 with sodium bicarbonate solid, then washed with water (7.0 L) and layered.
  • the organic layer was concentrated to dryness to give a crude material of compound of formula 1-T-3 as an oil.
  • n-heptane 8.7 L was added, and then the mixture was cooled to about 5 ° C, stirred and crystallized, filtered, and the obtained solid was dried to constant weight to obtain a compound of formula 1-T-3 as a gray solid ( 1.13 kg, yield 88%, purity 99.35%).
  • the nuclear magnetic data and mass spectral data of the obtained compound were confirmed to be consistent with the data of the compound of the second step - method 1.
  • the reaction mixture was kept at a temperature below 10 ° C, and a saturated ammonium chloride solution (2.5 L) was added dropwise. After the dropwise addition was completed, the reaction mixture was concentrated to dryness under reduced pressure, and water (10 L) and n-heptane (10 L) were added to Extracted with methyl tert-butyl ether, the combined organic layers were concentrated to dryness to give crystals of the compound of formula 1-T-4 as a brown oil (1.70 kg, yield 99%, purity 99.44%).
  • the reaction mixture was kept at a temperature below 10 ° C, and a saturated ammonium chloride solution (2.5 L) was added dropwise. After the dropwise addition was completed, the reaction mixture was concentrated to dryness under reduced pressure, and water (10 L) and n-heptane (10 L) were added to Extracted with methyl tert-butyl ether, the combined organic layers were concentrated to dryness to give crystals of the compound of formula 1-T-4 as a brown oil (1.70 kg, yield 99%, purity 99.30%).
  • the nuclear magnetic data and mass spectral data of the obtained compound were confirmed to be consistent with the data of the compound of the third step - method 1.
  • the nuclear magnetic data and mass spectral data of the obtained compound were confirmed to be consistent with the data of the compound of the third step - method 1.
  • a compound of formula 1-T-4 (1.54 kg), tetrahydrofuran (7.7 kg), potassium fluoride (144.7 g) and purified water (135.5 g) were added to a 30 L glass reactor, and the reaction was stirred to dissolve and It was cooled to -20 ° C, tetrabutylammonium fluoride (425.7 g) was added, and after the completion of the addition, the reaction was maintained at a temperature of -20 ° C. After the reaction was monitored by TLC, citric acid (616.0 g) was added to quench the reaction.
  • reaction liquid was concentrated, purified water (135.5 g) was added, and the mixture was extracted with dichloromethane, and the organic phase was combined, then the organic phase was concentrated, and the concentrate was purified by column chromatography to give compound 1 (yield 26.5%, purity 99.89%) ).
  • the nuclear magnetic data and mass spectral data of the obtained compound were confirmed to be consistent with the data of the compound of the fourth step-method 1.
  • reaction solution is added dropwise to sodium hydrogencarbonate (1.48 kg) and water (5.0 L) at 5 ⁇ 5 ° C to pH 7-8, extracted with ethyl acetate, and the organic phase is combined, then the organic phase Washing with 0.1 M sodium carbonate solution, concentrating under reduced pressure at 40 ° C to 45 ° C to dry oily crude product, and then the crude product is purified by methyl t-butyl ether and acetonitrile to give compound 1 (by compound 1-T-4) The yield of the pure product was calculated to be 65.8%, and the purity was 99.61%).
  • the nuclear magnetic data and mass spectral data of the obtained compound were confirmed to be consistent with the data of the compound of the fourth step-method 1.
  • Compound 1 can be synthesized according to any combination of the respective methods of the above four steps, for example, by the combination of the first step - the method 1, the second step - the method 1, the third step - the method 1 and the fourth step - the method 1 One step - method 1, second step - method 1, third step - method 1 and fourth step - combination of method 2, or by first step - method 1, second step - method 1, third step - method 1 and the combination of the fourth step - method 3 to synthesize.
  • the reaction conditions of the present invention are mild, and many reaction steps of the present invention can be carried out at room temperature; the reaction cycle of the present invention is short, and it is convenient to control the reaction time of each reaction, and is suitable for large-scale synthesis ( In particular, it is suitable to synthesize in a single reaction in an amount of more than 50 g, preferably more than 100 g, to save production costs; the process of the invention has a plurality of quality control nodes, which can obtain solid products by crystallization, thereby avoiding the present
  • the intermediate is always an oily defect, and the quality of the final product is improved by controlling the quality of the intermediate to ensure the controllability of industrial production; in addition, the present invention has higher reaction selectivity than the prior art.
  • the present invention also increases the target product yield and purity.
  • the reaction time is only about 4 hours, and the impurities of the obtained product can be removed by washing or the like, and the operation is simple, and the purity of the obtained product is high.

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Abstract

公开了按照路线I制备式T-3的化合物的方法，所述方法包括以下步骤：第一步，将式T-1的化合物与包含PG基团的试剂在有机碱或无机碱存在下，任选地在催化剂的催化下反应，生成式T-2的化合物；以及第二步，将式T-2的化合物在有机酸或无机酸的催化下反应，生成式T-3的化合物。还公开了按照路线II制备式(I)-1的化合物的方法，所述方法包括以下步骤：步骤A，使T-3和R-1在羟基氢移除试剂的存在下反应，得到式T-4的化合物；以及步骤B，将式T-4的化合物在有机酸或无机酸的催化下，或者在含氟试剂的存在下反应，得到式(I)-1的化合物。另外，还公开了上述制备方法中的中间体。

Description

4’-硫代核苷的新型化合物的制备方法和此制备方法中的中间体 发明领域
本发明涉及4’-硫代核苷的新型化合物的制备方法和此制备方法中的中间体。
发明背景
WO 2016/155593 A1公开了一类具有抗癌活性的4’-硫代核苷的新型化合物，其具有式(I)的结构：
Figure PCTCN2018091514-appb-000001
其中：
X为氢、C 1-6烷基、卤素、N 3、OH、CN或SH；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
R 4选自氢和任选取代的C 1-10酰基；
Q为结构如下的嘧啶碱基或嘌呤碱基：
Figure PCTCN2018091514-appb-000002
R 5每次出现时独立地选自氢、任选取代的C 1-10烷基和任选取代的环烷基；并且
Z为氢、任选取代的C 1-10烷基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环。
WO 2016/155593 A1还公开了一种制备式(I)的化合物的方法，其包括以下步骤：
Figure PCTCN2018091514-appb-000003
其中各基团如上所定义，其中第一步反应优选在POCl 3的存在下进行。
发明概述
本发明的一个方面提供制备式T-3的化合物的方法，
Figure PCTCN2018091514-appb-000004
其中：
PG基团为含硅保护基；
X为氢、C 1-6烷基、卤素或CN；
Q为结构如下的嘧啶碱基或嘌呤碱基：
Figure PCTCN2018091514-appb-000005
R 5每次出现时独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的C 6-14芳基；并且
Z为氢、任选取代的C 1-10烷基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；
所述方法包括以下步骤：
第一步：将式T-1的化合物与包含PG基团的试剂在有机碱或无机碱存在下，任选地在催化剂的催化下反应，生成式T-2的化合物；以及
第二步：将式T-2的化合物在有机酸或无机酸的催化下反应，生成式T-3的化合物。
本发明的另一方面提供制备式(I)-1的化合物的方法，
Figure PCTCN2018091514-appb-000006
其中：
PG、X和Q如上所定义；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、 氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；
所述方法包括以下步骤：
步骤A：使T-3和R-1在羟基氢移除试剂的存在下反应，得到式T-4的化合物，所述步骤A优选在非质子溶剂中进行；以及
步骤B：将式T-4的化合物在有机酸或无机酸的催化下，或者在含氟试剂的存在下反应，得到式(I)-1的化合物，所述步骤B优选在溶剂中进行。
本发明另一方面提供上述方法中涉及的中间体。
本申请发明人发现，在WO 2016/155593 A1所公开的方法中，当R 4为氢时，
Figure PCTCN2018091514-appb-000007
还可以与
Figure PCTCN2018091514-appb-000008
中与四氢噻吩环直接连接的羟基反应，从而得到具有以下结构的双取代产物：
Figure PCTCN2018091514-appb-000009
具体而言，本申请发明人发现，在依照WO 2016/155593 A1中实施例8所公开的方法制备化合物C8的过程中，有以下双取代产物的生成，该产物的生成不仅降低了反应的收率，还影响了产物的纯度：
Figure PCTCN2018091514-appb-000010
同时，本申请发明人还发现在WO 2016/155593 A1中实施例8的方法中还有以下立体异构体(约10％)生成：
Figure PCTCN2018091514-appb-000011
该立体异构体难以被分离移除，从而使最终目标产物的纯化处理变得困难。
本申请发明人对上述反应进行了深入的研究，创造性地得到本发明的制备方法，其 既避免了现有技术中的副产物产生，又提供了比现有技术更优的工艺。
具体而言，本发明的方法具有多种优点，例如：本发明的反应条件温和，本发明的很多反应步骤在室温下即可进行；本发明的反应周期较短，便于控制每步反应的反应时间，适于大规模合成(特别地，适合以单次反应中最终产物的量大于50g，优选大于100g的规模合成)，节约生产成本；本发明的工艺中有多个质量控制节点，可以通过结晶得到固体产物，避免了现有技术中中间体始终为油状物的缺陷，通过对中间体的质量控制，提高终产物的品质，确保工业生产的可控性；此外，本发明还具有比现有技术更高的反应选择性，减少了杂质(例如不期望的双取代产物和立体异构体产生)；最后，本发明还提高了目标产物收率和纯度。
发明详细描述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义与本领域技术人员通常所理解的相同。提及本文中使用的技术指在本领域中通常所理解的技术，包括那些本领域技术人员的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
表述“如上所定义”表示在申请中提供的第一和/或最广泛的定义，以及上下文适宜的情况。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
本文中所述的“本发明的化合物”一般是指本文中所述式T-1、T-2、T-3、T-4、T-4’、(I)-1、(I)-1’所限定化合物的范围，或者其盐、溶剂化物、立体异构体或多晶型物。
本文中所述的化合物的盐表示保留母体化合物的性质的那些盐，其可通过下列方式制备：使质子接受部分质子化和/或使质子供给部分去质子化。应该注意，质子接受部分质子化导致形成阳离子类物质，其中该阳离子电荷通过生理阴离子的存在而平衡，而质子供给部分去质子化导致形成阴离子类物质，其中该阴离子电荷通过生理阳离子的存在而平衡。
本发明的化合物的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成无毒盐的酸来形成，其包括无机酸和有机酸。在本发明中，合适的无机酸例如是化学领域定义的无机酸，例如盐酸、硫酸或磷酸等。合适的有机酸包括有机磺酸、有机羧酸或氨基酸等，合适的有机磺酸例如C 6-16芳基磺酸、C 6-16杂芳基磺酸和C 1-16烷基磺酸，合适的有机羧酸例如是一元或多元羧酸，包括C 1-16烷基羧酸、C 6-16芳基羧酸和C 4-16杂芳基羧酸。所述有机羧酸还可以例如是氨基酸，合适的氨基酸有许多，特别是作为蛋白质组分而发现的天然氨基酸。由上述酸所成盐的具体实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成无毒盐的碱来形成，其包括无机碱和有机碱。具体实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的盐的方法为本领域技术人员已知的。
术语“立体异构体”表示仅在原子的空间排列的方式上不同的异构体。“α-”、“β-”是指所示化学结构中不对称碳原子上取代基的特定立体化学构型。
本发明的化合物具有一个或多个手性中心，并且可以存在各种立体异构体构型。由于这些手性中心的存在，本发明的化合物可以外消旋物、对映体混合物和各对映体以及非对映异构体和非对映异构体混合物的形式存在。所有这种外消旋物、对映体和非对映异构体均属于“本发明的化合物”的范围。“R”和“S”在有机化学中通常用于表示手性中心的具体构型。
本发明的化合物可以水合物或溶剂化物的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
术语“任选的”或“任选”是指在相应情况或条件下可以存在但不一定存在，该术语包括所述取代基存在或不存在的实例；所述“任选”也包括存在一个或多个所述取代基取代的实例。术语“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。在本发明的化合物中，术语“任选取代”包括存在被一个或多个取代基取代的情形，并且当“任选取代”是指存在多个取代基时，取代基之间可以适当地彼此相连构成含有选自0-3个选自氧(O)、氮(N)和硫(S)的杂原子的饱和环、不饱和环或芳香环，所述饱和环、不饱和环或芳香环还可以与被取代基团一起构成环，例如，术语“任选取代的芳基”具体实例包括苯并二氢噻吩基以及具有以下结构的基团：
Figure PCTCN2018091514-appb-000012
本文所用的术语“烷基”表示未分支或分支的链状或环状的饱和一价烃残基，优选地含有1至14个碳原子(C 1-14烷基)，更优选地含有1至10个碳原子(C 1-10烷基)，更优选含有1至6个碳原子(C 1-6烷基)，特别优选含有1至4个碳原子(C 1-4烷基)。烷基的实例包括但不限于低级烷基，包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或者戊基、异戊基、新戊基、己基、庚基(例如庚-4-基)和辛基。
本文所用的术语“环烷基”指饱和的非芳族单环或多环(诸如双环)烃环。当其由两个或以上的环组成时，所述环可以稠合的方式连接在一起。环烷基能够在环中含有3至10个原子(C 3-10环烷基)，优选3至8个环原子(C 3-8环烷基)，更优选含有3-6个环原子(C 3-6环烷基)，特别优选含有3-4个环原子(C 3-4环烷基)。环烷基包括但不限于单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。
本文所用的术语“烯基”表示具有2至10个碳原子并且具有一个或两个烯属双键的烃残基，优选地含有2至8个碳原子(C 2-8烯基)，更优选含有2至6个碳原子(C 2-6烯基)，特别优选含有2至4个碳原子(C 2-4烯基)，另有指定除外。烯基的实例包括乙烯基、1-丙烯基、2-丙烯基或2-丁烯基等。
本文所用的术语“炔基”表示未分支或分支的烃链基团，其具有2至10个碳原子(C 2-10炔基)，并且具有一或者两个叁键，优选地含有2至8个碳原子(C 2-8炔基)，更优选含有2至6个碳原子(C 2-6炔基)，特别优选含有2至4个碳原子(C 2-4炔基)，另有指定除外。炔基的实例是乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基或3-丁炔基等。
本文所用的术语“氨基”表示-NH 2，烷胺基表示–NR'R″，R'和R″相同或不同并且为H或如上所定义的烷基或环烷基。
本文所用的术语“烷氧基”表示-O-烷基，其中烷基如上所定义(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基，还包括它们的异构体等。
本文所用的术语“卤素”或“卤代”表示氟、氯、溴或碘。
本文所用的术语“卤代烷基”表示如上所定义的烷基，其中1、2、3或更多个氢原子被卤素取代。实例是1-氟甲基、1-氯甲基、1-溴甲基、1-碘甲基、三氟甲基、三氯甲基、三溴甲基、三碘甲基、1-氟乙基、1-氯乙基、1-溴乙基、1-碘乙基、2-氟乙基、2-氯乙基、2-溴乙基、2-碘乙基、2,2-二氯乙基、3-溴丙基或2,2,2-三氟乙基等。
本文所用的术语“卤代烷氧基”表示如上所定义的烷氧基，其中1、2、3或更多个氢原子被卤素取代。
本文所用的术语“酰基”表示式-C(＝O)R的基团，其中R是氢或者如上所定义的烷基(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)。
本文所用的术语“烷基羰基”表示式-C(＝O)R的基团，其中R是如上所定义的烷基(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)。
本文所用的术语“酰胺基”表示式-NC(＝O)R'R″基团，其中R'和R″相同或不同，并且是氢或者如上所定义的烷基(如C 1-14烷基、C 1-10烷基、C 1-6烷基或C 1-4烷基)。
本文所用的术语“羟基烷基”表示式-R-OH的基团，其中R是亚烷基。
本文所用的术语“亚烷基”表示含有1至10个碳原子(C 1-10亚烷基)，更优选含有1至6个碳原子(C 1-6亚烷基)，特别优选含有1至4个碳原子(C 1-4亚烷基)的二价饱和直链烃基团或者3至10个碳原子(C 3-10亚烷基)，更优选含有3至8个碳原子(C 3-8亚烷基)，特别优选含有3至5个碳原子(C 3-5亚烷基)的支链饱和二价烃基团，另有指示除外。亚烷基的实例包括但不限于亚甲基、亚乙基、亚丙基、2-甲基-亚丙基、亚丁基和2-乙基亚丁基等。
本文所用的术语“芳基”是指具有至少有一个芳环的基团，即有一个共轭π-电子系统，包括单环芳基和双环芳基等。其包含6-14个碳原子(C 6-14芳基)，例如：苯基、萘基等。任选取代的芳基包括被多个取代基取代的芳基，且取代基之间可以适当地相连构成含有0-3个选自氧、氮和硫的杂原子的饱和环、不饱环和/或芳香环。所述芳基优选包括以下基团：
Figure PCTCN2018091514-appb-000013
本文所用的术语“芳烷基”表示基团R′R″-，其中R′是如本文所定义的芳基，R″是如本文所定义的亚烷基，可以理解，芳烷基部分的连接点将位于亚烷基上。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、4-氟苄基、苯基乙基、苯基丙基和苯基丁基。
本文所用的术语“芳氧基”表示-O-R，R为如上所定义的芳基。
本文所用的术语“芳基羰基”表示式-C(＝O)Ar的基团，其中Ar是如上所定义的芳基。
本文所用的术语“杂环基”是指含有1-4个(例如一个、两个、三个或四个)选自N、O、S和P的杂原子且其余原子为碳原子的3-16元饱和环或不饱和环的基团。特别地，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
本文所用的术语“杂芳基”是指具有1至3个选自N、O和S的杂原子作为环原子且剩余环原子为碳的环状芳族基团，其中所述环为4-16元单环或稠合环，优选5-12元单环或稠合环、5-8元单环或稠合环。杂芳基的实例包括但不限于：呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、吡咯基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、哒嗪基、酞嗪基、酞嗪-1-(2H)-1-基、吡啶并[3,2-d]哒嗪-5(6H)-8-基、三嗪基等以及它们的苯并衍生物。
本文所用的术语“杂芳基羰基”定义类似于“芳基羰基”，其表示式-C(＝O)R的基团，其中R是如上所定义的杂芳基。
本文所用的术语“杂芳基氧基”表示式杂芳基-O-的基团，其中所述杂芳基如上所定义。
本文所用的术语“磺酰胺基”是指式-SO 2NR'R″的基团，其中R'和R″相同或不同，并且各自独立地是氢或如上定义的烷基或环烷基。
本文所用的术语“羧基”是指式-COOH的基团，本文所用的术语“羧酸酯基”表示-COOR，其中所述的R各自独立地表示如上所定义的烷基。
本发明所述的通式或具体化合物中，各基团或原子或离子团均包括其同位素替代的基团或原子或离子团，例如所述“氢”包括H、 2H(氘)、 3H(氚)；所述C 1-14烷基包括其中一个或多个碳原子或全部为 12C、 13C、 14C，其他示例包括N、P、O同位素的情况。
本申请中的缩写具有以下含义：
缩写 含义
AcOH 乙酸/醋酸
CsF 氟化铯
DBU 1,8-二氮杂双环[5.4.0]十一碳-7-烯
DCM 二氯甲烷
DEIPS- 二乙基异丙基硅烷基
DIPEA N,N-二异丙基乙胺
DMAP 4-(二甲氨基)吡啶
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DPMS- 二苯基甲基硅烷基
DTBMS- 二叔丁基甲基硅烷基
HCl 盐酸
HMDS 六甲基二硅氮烷
IPDMS- 二甲基异丙基硅烷基
KHMDS 双(三甲基硅基)氨基钾
LDA 二异丙基氨基锂
LiHMDS 双(三甲基硅基)氨基锂
NaHMDS 双(三甲基硅基)氨基钠
-OTf 三氟甲磺酸酯基
TBDMS-或TBS- 叔丁基二甲基硅烷基
TBDPS- 叔丁基二苯基硅烷基
TBMPS- 叔丁基甲氧基苯基硅烷基
TES- 三乙基硅烷基
TFA 三氟醋酸，或者三氟乙酸
THF 四氢呋喃
TIPS- 三异丙基硅烷基
TLC 薄层色谱法
TMS- 三甲基硅烷基
TPS- 三苯基硅烷基
本发明的部分实施方案提供制备式T-3的化合物的方法，
Figure PCTCN2018091514-appb-000014
其中：
PG基团为含硅保护基；
X为氢、C 1-6烷基、卤素或CN；
Q为结构如下的嘧啶碱基或嘌呤碱基：
Figure PCTCN2018091514-appb-000015
R 5每次出现时独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的C 6-14芳基；并且
Z为氢、任选取代的C 1-10烷基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；
所述方法包括以下步骤：
第一步：将式T-1的化合物与包含PG基团的试剂在有机碱或无机碱存在下，任选地在催化剂的催化下反应，生成式T-2的化合物；以及
第二步：将式T-2的化合物在有机酸或无机酸的催化下反应，生成式T-3的化合物。
在所述方法中，T-1可由本领域中已知的方法制备得到，例如以与WO 2016/155593  A1中公开的类似方法制备得到。
在部分实施方案中，Q为结构如下的嘧啶碱基：
Figure PCTCN2018091514-appb-000016
并且
Z为氢、甲基或卤素。
在另部分实施方案中，Q为下式所示的嘧啶碱基：
Figure PCTCN2018091514-appb-000017
并且
Z为氢、甲基或卤素。
在部分实施方案中，Q为
Figure PCTCN2018091514-appb-000018
在部分实施方案中，Q选自
Figure PCTCN2018091514-appb-000019
在部分实施方案中，R 5每次出现时独立地选自氢、任选取代的C 1-10烷基(如庚-4-基)和苯基。
在部分实施方案中，Z为氢、甲基、氟或氯。
在部分实施方案中，X为氢或卤素，所述卤素为氟、氯、溴或碘。
在部分实施方案中，所述PG基团选自TMS-、TES-、TBDMS-、TBDPS-、TIPS-、IPDMS-、DEIPS-、TPS-、DPMS-、DTBMS-和TBMPS-。
在部分实施方案中，所述包含PG基团的试剂为(TMS) 2NH(HMDS)或(TMS) 2O。
在部分实施方案中，所述包含PG基团的试剂为PG-LG，其中LG选自氢、卤素、三氟甲磺酸酯基、二乙基氨基和叠氮基。
在部分实施方案中，所述包含PG基团的试剂为三甲基氯硅烷(TMSCl)、三甲基溴硅烷(TMSBr)、三甲基碘硅烷(TMSI)、三氟甲磺酸三甲基硅酯(TMSOTf)、叠氮基三甲基硅烷(TMSN 3)、N,N-二乙基三甲基甲硅烷胺(TMSNEt 2)、三乙基氯硅烷(TESCl)、三氟甲磺酸三乙基硅酯(TESOTf)、叔丁基二苯基氯硅烷(TBDPSCl)、叔丁基二甲基氯硅烷(TBDMSCl)、三氟甲磺酸叔丁基二甲基硅酯(TBDMSOTf)、三异丙基氯硅烷(TIPSCl)或者三氟甲磺酸三异丙基硅酯(TIPSOTf)。
在上述包含PG基团的试剂中，TBDMSCl是最优选的，其最大程度地避免了其中两个PG基团同时被脱除的副产物的生成。
在部分实施方案中，所述有机碱选自咪唑、三乙胺、吡啶、2,6-二甲基吡啶、DBU和DIPEA；并且所述无机碱为碱金属(例如锂、钠、钾等)或碱土金属(例如镁或钙)的氢氧化物、碳酸盐(例如碳酸钠或碳酸钾)或碳酸氢盐。
在部分实施方案中，所述催化剂选自DMAP、KF、CsF和银盐(例如硝酸银)。
在部分实施方案中，所述第一步反应在溶剂中进行，所述溶剂为不影响反应进行的任意溶剂，例如DMF、THF、1,4-二氧六环、DCM、氯仿、四氯化碳、苯、甲苯、DMSO、乙腈，以及上述溶剂中的任意两种或更多种的混合物。
在部分实施方案中，在所述第一步反应中，所述式T-1的化合物与包含PG基团的试剂的摩尔比为1:2-1:20，优选为1:2-1:10，更优选为1:2-1:5。
在部分实施方案中，在所述第一步反应中，所述式T-1的化合物与所述有机碱或无机碱的摩尔比为1:2-1:20，优选为1:2-1:10，更优选为1:2-1:5。
在部分实施方案中，在所述第一步反应中，所述式T-1的化合物与所述催化剂的摩尔比为1:0-1:5，优选为1:0-1:1，更优选为1:0-1:0.5。
在部分实施方案中，所述第一步反应在-10℃至100℃，优选0℃至50℃，更优选10℃至30℃的温度下进行。
在部分实施方案中，所述有机酸选自AcOH、TFA和柠檬酸；并且所述无机酸选自HF、HCl和HBr。
在部分实施方案中，所述第二步反应在溶剂中进行，所述溶剂为不影响反应进行的任意溶剂，例如选自水、含有1-6个碳原子的醚、醇或酯，以及上述溶剂中的任意两种或更多种的混合物。在部分实施方案中，所述含有1-6个碳原子的醚包括但不限于乙醚、四氢呋喃或1,4-二氧六环；所述含有1-6个碳原子的醇包括但不限于甲醇、乙醇、正丙醇或异丙醇；并且所述含有1-6个碳原子的酯包括但不限于甲酸乙酯或乙酸乙酯。
在部分实施方案中，所述第二步反应在水和四氢呋喃的混合物中进行，其中水和四氢呋喃的体积比为1:20，优选为1:10，更优选为1:5。
在部分实施方案中，所述第二步反应在水、四氢呋喃和甲醇的混合物中进行，其中水、四氢呋喃和甲醇的体积比为1:(1-5):(1-5)，优选为1:2:2。
在部分实施方案中，所述第二步反应在水、四氢呋喃和乙酸乙酯的混合物中进行，其中水、四氢呋喃和甲醇的体积比为1:(1-5):(1-5)，优选为1:2:2。
在部分实施方案中，在所述第二步反应中，所述式T-2的化合物与所述有机酸或无机酸的重量体积比(g/ml)为1:0.2-1:20，优选为1:0.5-1:10，更优选为1:0.8-1:5。
在部分实施方案中，所述第二步反应在-10℃至100℃，优选0℃至50℃，更优选10℃至30℃的温度下进行。
在部分实施方案中，所述式T-1的化合物优选为式1-T-1的化合物：
Figure PCTCN2018091514-appb-000020
在部分实施方案中，所述式T-2的化合物优选为式1-T-2的化合物：
Figure PCTCN2018091514-appb-000021
在部分实施方案中，本发明提供制备式1-T-3的化合物的方法，所述方法包括以下步骤：
Figure PCTCN2018091514-appb-000022
其中第一步和第二步如上所定义。
本发明的部分实施方案提供制备式(I)-1的化合物的方法，
Figure PCTCN2018091514-appb-000023
其中：
PG、X和Q如上所定义；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；
所述方法包括以下步骤：
步骤A：使T-3和R-1在羟基氢移除试剂的存在下反应，得到式T-4的化合物；以及
步骤B：将式T-4的化合物在有机酸或无机酸的催化下，或者在含氟试剂的存在下反应，得到式(I)-1的化合物。
在所述方法中，R-1可由本领域中已知的方法制备得到，例如以与WO 2016/155593 A1中公开的类似方法制备得到。
在部分实施方案中，式T-3的化合物由上文中所述方法获得。
在部分实施方案中，Y为氧。
在部分实施方案中，R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基和任选取代的芳基(优选任选取代的C 6-14芳基)，所述“任选取代”是指未取代或者被一个或多个选自卤素、C 1-6烷基和C 6-14芳基的取代基取代。最优选地，R 1、R 2、R 6和R 7各自独立地选自氢、甲基、乙基、丙基、异丙基、苯基、苄基和4-氟苄基。
在部分实施方案中，R 3选自任选取代的芳基，优选为任选取代的C 6-14芳基，更优选为任选取代的苯基，所述“任选取代”是指未取代或者被一个或多个选自卤素、C 1-6烷基和C 1-6烷氧基的取代基取代，所述取代基可以彼此相连构成含有0-3(例如1、2或3)个O的3-8元饱和环、不饱和环或芳香环。R 3最优选具有如下所示的结构：
Figure PCTCN2018091514-appb-000024
在部分实施方案中，R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的芳基；其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
Q为胞嘧啶，其结构式如下：
Figure PCTCN2018091514-appb-000025
在部分实施方案中，Q为
Figure PCTCN2018091514-appb-000026
X为氢、C 1-6烷基、卤素或CN；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
R 5每次出现时独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的C 6-14芳基；并且
Z为氢、甲基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以各自独立，或者彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环。
在部分实施方案中，Q为胞嘧啶，其结构式如下：
Figure PCTCN2018091514-appb-000027
X为氢、C 1-6烷基、卤素或CN；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的芳基；其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；并且
Z为氢、任选取代的C 1-10烷基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环。
在部分实施方案中，
X为氢、C 1-6烷基、卤素或CN；
Y为氧或硫；
R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的芳基；其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
R 3选自任选取代的芳基和任选取代的杂芳基；
Q为结构如下的嘌呤碱基：
Figure PCTCN2018091514-appb-000028
并且
Z为氢、甲基或卤素；
上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、炔基、烯基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以各自独立，或者彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环。
在部分实施方案中，所述羟基氢移除试剂(或称作“拔氢试剂”)选自氨基锂、有机锂试剂(例如甲基锂、苯基锂、正丁基锂、LDA、LiHMDS)、NaH、氨基钠、甲醇钠、乙醇钠、NaHMDS、KH、氨基钾、KHMDS和格氏试剂。
所述“格氏试剂”是指含卤化镁的有机金属化合物，例如叔丁基氯化镁。
在部分实施方案中，所述步骤A反应在非质子溶剂中进行，所述溶剂为不影响反应 进行的任意溶剂，例如DMF、THF、1,4-二氧六环、DMSO、乙腈、丙酮，以及上述溶剂中的任意两种或更多种的混合物。
在部分实施方案中，在所述步骤A反应中，所述式T-3的化合物与所述式R-1的化合物的摩尔比为1:1-1:10，优选为1:1-1:5，更优选为1:1-1:2。
在部分实施方案中，在所述步骤A反应中，所述式T-3的化合物与所述羟基氢移除试剂的摩尔比为1:1-1:20，优选为1:1-1:10，更优选为1:1-1:5。
在部分实施方案中，在所述步骤A反应中，优选首先使所述式T-3的化合物与所述羟基氢移除试剂在-50℃至50℃，优选-20℃至40℃，更优选-10℃至30℃的温度下反应，以将所述式T-3的化合物中的羟基氢移除；然后在-50℃至30℃，优选-20℃至20℃，更优选-15℃至15℃的温度下加入所述式R-1的化合物，加入完毕后使反应在-10℃至100℃，优选0℃至50℃，更优选10℃至30℃的温度下进行。
在部分实施方案中，所述步骤B反应中所使用的有机酸选自AcOH、TFA和柠檬酸；所述步骤B反应中所使用的无机酸选自HF、HCl和HBr；并且所述步骤B反应中所使用的含氟试剂选自三氟化硼、氟化钾、四丁基氟化铵、四乙基氟化铵、四丙基氟化铵和三氟化硼乙醚，以及上述试剂中的任意两种或更多种。所述含氟试剂优选为氟化钾和四丁基氟化铵的组合，或者三氟化硼乙醚。
在部分实施方案中，所述步骤B反应在溶剂中进行，所述溶剂为不影响反应进行的任意溶剂，例如选自水、含有1-6个碳原子的腈、醚、醇或酯，以及上述溶剂中的任意两种或更多种的混合物。
在部分实施方案中，所述含有1-6个碳原子的腈包括但不限于乙腈或丙腈；所述含有1-6个碳原子的醚包括但不限于乙醚、四氢呋喃或1,4-二氧六环；所述含有1-6个碳原子的醇包括但不限于甲醇、乙醇、正丙醇或异丙醇；并且所述含有1-6个碳原子的酯包括但不限于甲酸乙酯或乙酸乙酯。
在部分实施方案中，所述步骤B反应在水和四氢呋喃的混合物、乙腈或者水和乙腈的混合物中进行。
在部分实施方案中，所述步骤B反应在-50℃至50℃，优选-30℃至50℃、-30℃至40℃、-30℃至30℃或-30℃至20℃，更优选-20℃至0℃的温度下进行。
在部分实施方案中，当所述步骤B反应中所使用的含氟试剂为三氟化硼乙醚时，所述反应优选在10℃至30℃，例如25±5℃、20±5℃或15±5℃下进行；当所述步骤B反应中所使用的含氟试剂为氟化钾和四丁基氟化铵的组合时，所述反应在-20℃±10℃的温度下进行。
本发明的部分实施方案提供制备式(I)-1’的化合物的方法，所述方法包括以下步骤：
Figure PCTCN2018091514-appb-000029
其中各基团如上所定义，并且步骤A’和步骤B’分别如对于步骤A和步骤B所定义。
在部分实施方案中，所述式T-3的化合物优选为式1-T-3的化合物：
Figure PCTCN2018091514-appb-000030
在部分实施方案中，所述式T-4’的化合物优选为式1-T-4的化合物：
Figure PCTCN2018091514-appb-000031
在部分实施方案中，所述式R-1’的化合物优选为式1-R-1的化合物：
Figure PCTCN2018091514-appb-000032
在部分实施方案中，本发明提供制备式1的化合物的方法，所述方法包括以下步骤：
Figure PCTCN2018091514-appb-000033
其中步骤A和步骤B如上所定义。
本发明的部分实施方案提供化合物或者其盐、溶剂化物、立体异构体或多晶型物，所述化合物具有式T-2的结构：
Figure PCTCN2018091514-appb-000034
其中各基团如上所定义；并且
所述化合物优选为：
Figure PCTCN2018091514-appb-000035
本发明的部分实施方案提供化合物或者其盐、溶剂化物、立体异构体或多晶型物，所述化合物具有式T-3的结构：
Figure PCTCN2018091514-appb-000036
其中各基团如上所定义；并且
所述化合物优选为：
Figure PCTCN2018091514-appb-000037
本发明的部分实施方案提供化合物或者其盐、溶剂化物、立体异构体或多晶型物，所述化合物具有式T-4的结构：
Figure PCTCN2018091514-appb-000038
其中各基团如上所定义；并且
所述化合物优选为：
Figure PCTCN2018091514-appb-000039
本发明涵盖对上述各个实施方案进行任意组合所得的技术方案，而不受各个独立实施方案本身的约束。
实施例
结合以下实施例进一步描述本发明，但提供这些实施例并非意图限制本发明的范围。
除非另外说明，实施例中使用的原料和试剂可商购获得，或者根据WO 2016/155593 A1中公开的方法获得(例如1-T-1和1-R-1)。
Figure PCTCN2018091514-appb-000040
第一步-方法1：式1-T-2的化合物的合成
在30L玻璃反应釜中依次加入式1-T-1的化合物(0.9kg)、THF(7.2L)、4-(二甲氨基)吡啶(0.15kg)和咪唑(1.17kg)，搅拌并降温至10℃左右，分批加入叔丁基二甲基氯硅烷(2.59kg)，加入完毕后，在15℃至25℃下反应。TLC检测反应完全后，在搅拌下将反应液倒入冷水(11L，0℃至10℃)中，加入完毕后，用二氯甲烷萃取，收集并浓缩有机层，得到棕色油状物形式的式1-T-2的化合物(2.6kg)，将其在未分离纯化下用于下一步反应。
第一步-方法2：式1-T-2的化合物的合成
在30L玻璃反应釜中依次加入式1-T-1的化合物(0.9kg)、N,N-二甲基甲酰胺(7.2L)、4-(二甲氨基)吡啶(0.15kg)和三乙胺(1.74kg)，搅拌并降温至10℃左右，分批加入叔丁基二甲基氯硅烷(2.59kg)，加入完毕后，在0℃至10℃下反应。TLC检测反应完全后，在 搅拌下将反应液倒入冷水(11L，0℃至10℃)中，加入完毕后，用二氯甲烷萃取，收集并浓缩有机层，得到棕色油状物形式的式1-T-2的化合物(2.4kg)，将其在未分离纯化下用于下一步反应。
第一步-方法3：式1-T-2的化合物的合成
在30L玻璃反应釜中依次加入式1-T-1的化合物(0.9kg)、二氯甲烷(7.2L)、4-(二甲氨基)吡啶(0.15kg)和吡啶(1.36kg)，搅拌并降温至10℃左右，分批加入叔丁基二甲基氯硅烷(2.59kg)，加入完毕后，在20℃至35℃下反应。TLC检测反应完全后，在搅拌下将反应液倒入冷水(11L，0℃至10℃)中，加入完毕后，用二氯甲烷萃取，收集并浓缩有机层，得到棕色油状物形式的式1-T-2的化合物(2.8kg)，将其在未分离纯化下用于下一步反应。
第一步-方法4：式1-T-2的化合物的合成
在30L玻璃反应釜中依次加入式1-T-1的化合物(0.9kg)、1,4-二氧六环(7.2L)、4-(二甲氨基)吡啶(0.15kg)和碳酸钠(1.82kg)，搅拌并降温至10℃左右，分批加入叔丁基二甲基氯硅烷(2.59kg)，加入完毕后，在40℃至50℃下反应。TLC检测反应完全后，在搅拌下将反应液倒入冷水(11L，0℃至10℃)中，加入完毕后，用二氯甲烷萃取，收集并浓缩有机层，得到棕色油状物形式的式1-T-2的化合物(2.8kg)，将其在未分离纯化下用于下一步反应。
第二步-方法1：式1-T-3的化合物的合成
在10L玻璃反应瓶1中加入式1-T-2的化合物(1.68kg)和四氢呋喃(3.4L)，在另一个30L玻璃反应釜2中加入四氢呋喃(3.4L)、三氟醋酸(1.7L)和纯化水(1.7L)。将反应瓶1和反应釜2中的反应液温度均降至低于10℃后，将反应瓶1中的反应液倒入反应釜2中，加入完毕后，自然升温至20℃至25℃反应，TLC检测反应完全。
将反应釜2中反应液加入到10L冷水中，用乙酸乙酯萃取，合并有机层，将有机层用碳酸氢钠固体调节pH至7左右，将有机层浓缩至干燥，得油状物形式的式1-T-3的化合物的粗品。
向浓缩后的油状物中加入正庚烷(8.7L)，然后降温至约5℃搅拌析晶，过滤，将所得固体干燥至恒重，得灰色固体形式的式1-T-3的化合物(1.09kg，收率85％，纯度99.15％)。
1H-NMR(DMSO-d 6,400MHz):δ8.01(d,J＝3.2Hz,1H),7.34(d,J＝34.0Hz,2H),6.45-6.50(m,1H),5.80(d,J＝7.2Hz,1H),5.31-5.33(m,1H),4.87-5.02(m,1H),4.44-4.49(m,1H),3.57-3.72(m,2H),3.21-3.25(m,1H),0.87(s,9H),0.10(s,3H),0.08(s,3H).
MS：C 15H 27FN 3O 3SSi[M+H] +理论值为376.5，测定值为376.1。
第二步-方法2：式1-T-3的化合物的合成
在10L玻璃反应瓶1中加入式1-T-2的化合物(1.68kg)和甲醇(3.4L)，在另一个30L玻璃反应釜2中加入四氢呋喃(3.4L)、AcOH(1.7L)和纯化水(1.7L)。将反应瓶1中和反应釜2中反应液温度均降至低于0℃后，将反应瓶1中的反应液倒入反应釜2中，加入完毕后，自然升温至0℃至15℃反应，TLC检测反应完全。
将反应釜2中反应液加入到10L冷水中，用乙酸乙酯萃取，合并有机层，将有机层用碳酸氢钠固体调节pH至7左右，然后加入水(7.0L)洗涤并分层，将有机层浓缩至干，得油状物形式的式1-T-3的化合物的粗品。
向浓缩后的油状物中加入正庚烷(8.7L)，然后降温至约5℃搅拌析晶，过滤，将所得固体干燥至恒重，得灰色固体形式的式1-T-3的化合物(1.07kg，收率83％，纯度99.45％)。
经检测，所得化合物的核磁数据及质谱数据与第二步-方法1的化合物的数据一致。
第二步-方法3：式1-T-3的化合物的合成
在10L玻璃反应瓶1中加入式1-T-2的化合物(1.68kg)和乙酸乙酯(3.4L)，在另一个30L玻璃反应釜2中加入四氢呋喃(3.4L)、HCl(1.7L)和纯化水(1.7L)。将反应瓶1中和反应釜2中反应液温度均降至小于5℃后，将反应瓶1中的反应液倒入反应釜2中，加入完毕后，自然升温至30℃至50℃反应，TLC检测反应完全。
将反应釜2中反应液加入到10L冷水中，用乙酸乙酯萃取，合并有机层，将有机层用碳酸氢钠固体调节pH至7左右，然后加入水(7.0L)洗涤并分层，将有机层浓缩至干，得油状物形式的式1-T-3的化合物的粗品。
向浓缩后的油状物中加入正庚烷(8.7L)，然后降温至约5℃搅拌析晶，过滤，将所得固体干燥至恒重，得灰色固体形式的式1-T-3的化合物(1.13kg，收率88％，纯度99.35％)。
经检测，所得化合物的核磁数据及质谱数据与第二步-方法1的化合物的数据一致。
第三步-方法1：式1-T-4的化合物的合成
向30L玻璃反应瓶釜中加入式1-T-3的化合物(1.0kg)和四氢呋喃(2L)，用氮气保护，搅拌并降温至0℃以下，滴加1mol/L叔丁基氯化镁溶液(7L)，滴加完毕后，将反应物升温至20℃至30℃，保持1小时。然后分批加入式1-R-1的化合物(1.45kg)。加入完毕后，使反应在20℃至30℃下进行，直至TLC监测反应完全。
将反应物保持温度在10℃以下滴加饱和氯化铵溶液(2.5L)，滴加完毕后，将反应物减压浓缩至干，加入水(10L)和正庚烷(10L)，将水层用甲基叔丁基醚萃取，合并有机相，浓缩至干，得到棕色油状物形式的式1-T-4的化合物(1.70kg，收率99％，纯度99.44％)。
1H-NMR(DMSO-d 6,400MHz):δ7.88(d,J＝5.2Hz,1H),7.31-7.40(m,4H),7.16-7.22(m,3H),6.56-6.62(m,1H),6.09-6.14(m,1H),5.79(d,J＝7.6Hz,1H),4.85-5.04(m,2H),4.52-4.57(m,1H),4.21-4.32(m,1H),4.11-4.17(m,1H),3.73-3.84(m,1H),3.43-3.46(m,1H),1.24(d,J＝7.2Hz,3H),1.18(d,J＝2.0Hz,3H),1.16(d,J＝2.0Hz,3H),0.86(s,9H),0.08(s,3H),0.07(s,3H).
MS：C 27H 43FN 4O 7PSSi[M+H] +理论值为645.7，测定值为645.2。
第三步-方法2：式1-T-4的化合物的合成
向30L玻璃反应瓶釜中加入式1-T-3的化合物(1.0kg)和1,4-二氧六环(2L)，用氮气保护，搅拌并降温至0℃以下，滴加1mol/L正丁基锂溶液(7L)，滴加完毕后，将反应物升温至0℃至10℃，保持1小时。然后分批加入式1-R-1的化合物(1.45kg)。加入完毕后，使反应在20℃至30℃下进行，直至TLC监测反应完全。
将反应物保持温度在10℃以下滴加饱和氯化铵溶液(2.5L)，滴加完毕后，将反应物减压浓缩至干，加入水(10L)和正庚烷(10L)，将水层用甲基叔丁基醚萃取，合并有机相，浓缩至干，得到棕色油状物形式的式1-T-4的化合物(1.70kg，收率99％，纯度99.30％)。
经检测，所得化合物的核磁数据及质谱数据与第三步-方法1的化合物的数据一致。
第三步-方法3：式1-T-4的化合物的合成
向30L玻璃反应瓶釜中加入式1-T-3的化合物(1.0kg)和乙腈(2L)，用氮气保护，搅拌并降温至0℃以下，滴加NaH(106g)，滴加完毕后，将反应物升温至30℃至40℃，保持1小时。然后分批加入式1-R-1的化合物(1.45kg)。加入完毕后，使反应在20℃至30℃下进行，直至TLC监测反应完全。
在保持温度低于10℃下，向反应物滴加饱和氯化铵溶液(2.5L)，滴加完毕后，将反应物减压浓缩至干，加入水(10L)和正庚烷(10L)，将水层用甲基叔丁基醚萃取，合并有机相，浓缩至干，得到棕色油状物形式的式1-T-4的化合物(1.70kg，收率99％，纯度99.60％)。
经检测，所得化合物的核磁数据及质谱数据与第三步-方法1的化合物的数据一致。
第四步-方法1：化合物1的合成
向30L玻璃反应釜中加入式1-T-4的化合物(1.54kg)、四氢呋喃(7.7kg)、氟化钾(144.7g)和纯化水(135.5g)，将反应物搅拌使其溶解，并将其降温至-20℃，加入四丁基氟化铵(425.7g)，加入完毕后在保持温度为-20℃反应。TLC监测反应完全后，加入柠檬酸(616.0g)淬灭反应。
将反应液浓缩，加入纯化水(135.5g)，用二氯甲烷萃取，合并有机相，然后有机相浓缩，并将浓缩物通过柱色谱法纯化，得到化合物1(收率26.5％，纯度99.89％)。
HRMS：C 21H 29FN 4O 7PS[M+H] +测定值为531.1478。
1H NMR(400MHz,CD 3OD)δ8.06(dd,J＝7.4,1.6Hz,1H),7.37(t,J＝8.4Hz,2H),7.25(d,J＝8.8Hz,2H),7.20(t,J＝7.6Hz,1H),6.67(dd,J＝19.2,4.4Hz,1H),5.90(d,J＝7.6Hz,1H),5.05-4.90(m,2H),4.44-4.40(m,1H),4.38-4.34(m,1H),4.31-4.25(m,1H),3.95-3.87(m,1H),3.60-3.56(m,1H),1.35(d,J＝7.1Hz,3H),1.23(dd,J＝6.2,1.6Hz,6H).
第四步-方法2：化合物1的合成
向反应瓶中依次加入化合物1-T-4(5.28g,8.2mmol)和乙腈(30ml)，搅拌并加入三氟化硼乙醚(9.8g,82mmol)。在室温(20℃至30℃)下反应，直至TLC监控反应完全。用碳酸氢钠水溶液调节pH到7，用二氯甲烷萃取，合并有机相，浓缩至干，得固液混合物7.3g。将所述混合物经乙腈重结晶得化合物1(3.1g,收率73％，纯度99.93％)。
经检测，所得化合物的核磁数据及质谱数据与第四步-方法1的化合物的数据一致。
第四步-方法3：化合物1的合成
向5L反应瓶中依次加入化合物1-T-4粗品(500g，含纯品374g)和乙腈(3.0L)，搅拌溶解，加入纯化水(3.0ml)，降温至5±5℃，滴加三氟化硼乙醚(1.50kg)，控制温度在20℃以内，滴加完毕后，在15±5℃下反应，直至TLC监测反应完全。反应完毕后，将反应液滴加到5±5℃的碳酸氢钠(1.48kg)和水(5.0L)中至pH到7-8，用乙酸乙酯萃取，合并有机相，然后将有机相用0.1M碳酸钠溶液洗涤，在40℃至45℃下减压浓缩至干得油状粗品，将粗品依次用甲基叔丁基醚和乙腈打浆纯化，得到化合物1(按化合物1-T-4纯品的量计算收率为65.8％，纯度99.61％)。经检测，所得化合物的核磁数据及质谱数据与第四步-方法1的化合物的数据一致。
化合物1可以根据以上四个步骤各自方法的任意组合来合成，例如通过第一步-方法1、第二步-方法1、第三步-方法1以及第四步-方法1的组合，通过第一步-方法1、第二步-方法1、第三步-方法1以及第四步-方法2的组合，或者通过第一步-方法1、第二步-方法1、第三步-方法1以及第四步-方法3的组合来合成。
根据本发明的实验可知，本发明的反应条件温和，本发明的很多反应步骤在室温下即可进行；本发明的反应周期较短，便于控制每步反应的反应时间，适于大规模合成(特别地，适合以单次反应中最终产物的量大于50g，优选大于100g的规模合成)，节约生产成本；本发明的工艺中有多个质量控制节点，可以通过结晶得到固体产物，避免了现有技术中中间体始终为油状物的缺陷，通过对中间体的质量控制，提高终产物的品质，确保工业生产的可控性；此外，本发明还具有比现有技术更高的反应选择性，减少了杂质(例如不期望的双取代产物和立体异构体产生)；最后，本发明还提高了目标产物收率和纯度。例如在本发明的第二步反应中，反应时间仅需约4小时，所得产物的杂质通过洗涤等操作即可除去，操作简便，所得产物的纯度高。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (17)

  1. 制备式T-3的化合物的方法，
    Figure PCTCN2018091514-appb-100001
    其中：
    PG基团为含硅保护基；
    X为氢、C 1-6烷基、卤素或CN；
    Q为结构如下的嘧啶碱基或嘌呤碱基：
    Figure PCTCN2018091514-appb-100002
    优选为
    Figure PCTCN2018091514-appb-100003
    R 5每次出现时独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基和任选取代的C 6-14芳基；并且
    Z为氢、任选取代的C 1-10烷基或卤素；
    上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；
    所述方法包括以下步骤：
    第一步：将式T-1的化合物与包含PG基团的试剂在有机碱或无机碱存在下，任选地在催化剂的催化下反应，生成式T-2的化合物；以及
    第二步：将式T-2的化合物在有机酸或无机酸的催化下反应，生成式T-3的化合物。
  2. 权利要求1的方法，其中所述PG基团选自TMS-、TES-、TBDMS-、TBDPS-、TIPS-、IPDMS-、DEIPS-、TPS-、DPMS-、DTBMS-和TBMPS-。
  3. 权利要求1或2的方法，其中所述包含PG基团的试剂为PG-LG，其中LG选自氢、卤素、三氟甲磺酸酯基、二乙基氨基和叠氮基，所述PG-LG优选为三甲基氯硅烷(TMSCl)、三甲基溴硅烷(TMSBr)、三甲基碘硅烷(TMSI)、三氟甲磺酸三甲基硅酯(TMSOTf)、叠氮基三甲基硅烷(TMSN 3)、N,N-二乙基三甲基甲硅烷胺(TMSNEt 2)、三乙基氯硅烷(TESCl)、三氟甲磺酸三乙基硅酯(TESOTf)、叔丁基二苯基氯硅烷(TBDPSCl)、叔丁基二甲基氯硅烷(TBDMSCl)、三氟甲磺酸叔丁基二甲基硅酯(TBDMSOTf)、三异丙基氯硅烷(TIPSCl)或者三氟甲磺酸三异丙基硅酯(TIPSOTf)。
  4. 权利要求1-3中任一项的方法，其中所述有机碱选自咪唑、三乙胺、吡啶、2,6-二甲基吡啶、DBU和DIPEA；并且所述无机碱为碱金属(例如锂、钠、钾等)或碱土金属(例如镁或钙)的氢氧化物、碳酸盐(例如碳酸钠或碳酸钾)或碳酸氢盐。
  5. 权利要求1-4中任一项的方法，其中所述催化剂选自DMAP、KF、CsF和银盐(例 如硝酸银)。
  6. 权利要求1-5中任一项的方法，其中所述有机酸选自AcOH、TFA和柠檬酸；并且所述无机酸选自HF、HCl和HBr。
  7. 权利要求1-6中任一项的方法，其中所述第一步反应在溶剂中进行，所述溶剂选自DMF、THF、1,4-二氧六环、DCM、氯仿、四氯化碳、苯、甲苯、DMSO、乙腈，以及上述溶剂中的任意两种或更多种的混合物。
  8. 权利要求1-7中任一项的方法，其中所述第二步反应在溶剂中进行，所述溶剂选自水、含有1-6个碳原子的醚(例如四氢呋喃)、醇(例如甲醇、乙醇)或酯(例如乙酸乙酯)，以及上述溶剂中的任意两种或更多种的混合物(例如水和四氢呋喃的混合物；水、四氢呋喃和甲醇的混合物；或者水、四氢呋喃和乙酸乙酯的混合物)。
  9. 制备式(I)-1的化合物的方法，
    Figure PCTCN2018091514-appb-100004
    其中：
    PG、X和Q如权利要求1-8中任一项所定义；
    Y为氧或硫；
    R 1、R 2、R 6和R 7各自独立地选自氢、任选取代的C 1-10烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基和任选取代的杂芳基，其中R 2和R 6两者可以相连构成3-8元碳环，且所述碳环可以含有0-3个选自N、O和S的杂原子并可以是饱和环、不饱和环或芳香性环；
    优选地，R 1、R 2、R 6和R 7各自独立地选自氢、甲基、乙基、丙基、异丙基、苯基、苄基和4-氟苄基；
    R 3选自任选取代的芳基和任选取代的杂芳基，优选为苯基；
    上述“任选取代”是指未取代或者被一个或多个选自以下的取代基取代：卤素、烷基、氨基、烷胺基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟基烷基、烷氧基烷基、酰胺基、磺酰胺基、氰基、硝基、亚硝基、叠氮基、醛基、烯基、炔基、环烷基、芳基、芳烷基、芳氧基、杂芳基、杂芳基氧基、酰基、羧基、烷基羰基、芳基羰基、杂芳基羰基和羧酸酯基；所述取代基可以彼此相连构成含有0-3个选自N、O和S的杂原子的3-8元饱和环、不饱和环或芳香环；
    所述方法包括以下步骤：
    步骤A：使T-3和R-1在羟基氢移除试剂的存在下反应，得到式T-4的化合物，所述步骤A优选在非质子溶剂中进行，所述非质子溶剂例如DMF、THF、1,4-二氧六环、DMSO、乙腈、丙酮，以及上述溶剂中的任意两种或更多种的混合物；以及
    步骤B：将式T-4的化合物在有机酸或无机酸的催化下，或者在含氟试剂的存在下反应，得到式(I)-1的化合物，所述步骤B优选在溶剂中进行，所述溶剂例如选自水、含有1-6个碳原子的腈(例如乙腈)、醚(例如四氢呋喃)、醇或酯，以及上述溶剂中的任意两种或更多种的混合物。
  10. 权利要求9的方法，其中所述羟基氢移除试剂选自氨基锂、有机锂试剂(例如甲基锂、苯基锂、正丁基锂、LDA、LiHMDS)、NaH、氨基钠、甲醇钠、乙醇钠、NaHMDS、KH、氨基钾、KHMDS和格氏试剂(例如叔丁基氯化镁)。
  11. 权利要求9或10的方法，其中所述有机酸选自AcOH、TFA和柠檬酸；所述无机酸选自HF、HCl和HBr；并且所述含氟试剂选自三氟化硼(例如三氟化硼乙醚)、氟化钾、四丁基氟化铵、四乙基氟化铵、四丙基氟化铵，以及上述试剂中的任意两种或更多种，所述含氟试剂优选为氟化钾和四丁基氟化铵的组合，或者三氟化硼乙醚。
  12. 权利要求9-11中任一项的方法，其中所述步骤B反应在-50℃至50℃，优选-30℃至50℃、-30℃至40℃、-30℃至30℃或-30℃至20℃，更优选-20℃至0℃的温度下进行；
    优选地，当所述步骤B反应中所使用的含氟试剂为三氟化硼乙醚时，所述反应在10℃至30℃，例如25±5℃、20±5℃或15±5℃下进行；当所述步骤B反应中所使用的含氟试剂为氟化钾和四丁基氟化铵的组合时，所述反应在-20℃±10℃的温度下进行。
  13. 权利要求9-12中任一项的方法，其中所述步骤B反应在水和四氢呋喃的混合物、乙腈或者水和乙腈的混合物中进行。
  14. 权利要求9-13中任一项的方法，其中式T-3的化合物由权利要求1-8中任一项的方法获得。
  15. 化合物或者其盐、溶剂化物、立体异构体或多晶型物，所述化合物具有式T-2的结构：
    Figure PCTCN2018091514-appb-100005
    其中各基团如权利要求1或2中所定义；并且
    所述化合物优选为：
    Figure PCTCN2018091514-appb-100006
  16. 化合物或者其盐、溶剂化物、立体异构体或多晶型物，所述化合物具有式T-3的结构：
    Figure PCTCN2018091514-appb-100007
    其中各基团如权利要求1或2中所定义；并且
    所述化合物优选为：
    Figure PCTCN2018091514-appb-100008
  17. 化合物或者其盐、溶剂化物、立体异构体或多晶型物，所述化合物具有式T-4的结构：
    Figure PCTCN2018091514-appb-100009
    其中各基团如权利要求9中所定义；并且
    所述化合物优选为：
    Figure PCTCN2018091514-appb-100010
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