Method for stereoselectively preparing cis-2-boryl-alpha-carbon glycoside compound

Abstract

The invention provides a method for stereoselectively preparing a cis-2-boryl-alpha-carbon glycoside compound, and particularly provides a method for preparing a compound as shown in a formula 1 in the specification. The method comprises the step of reacting a compound shown in a formula 2, a compound shown in a formula 3 and a compound shown in a formula 4 under the action of a nickel salt catalyst, an amino alcohol ligand and alkali to obtain a compound shown in a formula 1. The method is simple to operate. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of sugar chemistry, and in particular to a method for stereoselectively preparing cis-2-boryl-α-carbon glycoside compounds. Background Art

[0002] C-glycoside compounds are widely present in natural products and drug molecules. Existing methods for constructing such compounds usually require multi-step reactions, which are cumbersome and cannot effectively control stereoselectivity; or they are limited by raw materials, and the substrate range is extremely limited, which does not conform to the diversity of chemical synthesis and cannot meet the needs of modern high-throughput drug screening.

[0003] Therefore, it is necessary to study and find a method that has simple reaction steps, a wide range of readily available substrates, high regioselectivity and stereoselectivity, and introduces boron-containing functional groups to efficiently synthesize cis-2-boryl-α-carbon glycoside compounds. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. The present invention provides a simple, convenient and green method for stereoselectively preparing cis-2-boryl-α-carbon glycoside compounds.

[0005] In the first aspect of the present invention, the present invention provides a method for preparing a compound of Formula 1. According to an embodiment of the present invention, the method comprises reacting a compound of Formula 2, a compound of Formula 3 and a compound of Formula 4 under the action of a nickel salt catalyst, an amino alcohol ligand and a base to obtain a compound of Formula 1,

[0006]

[0007] R 1 is a cyano group, an ester group, a carbonyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, an amine group, an amide group, an ether group, an alkyl group, a heteroaryl group, an -alkylaryl group, an -alkyl-membered heteroaryl group, a cycloalkyl group or a heterocyclic group, wherein the ester group, the alkoxy group, the alkenyl group, the alkynyl group, the aryl group, the amine group, an amide group, an ether group, an alkyl group, a heteroaryl group, an -alkylaryl group, an -alkyl-membered heteroaryl group, a cycloalkyl group or a heterocyclic group is optionally substituted by 1, 2 or 3 R 1a replace;

[0008] R 1ais OH, cyano, ester, carbonyl, alkoxy, alkenyl, alkynyl, aryl, amine, amide, ether, alkyl, heteroaryl, -alkylaryl, -alkyl-membered heteroaryl, cycloalkyl, heterocyclyl or BPin, wherein the alkoxy, alkenyl, alkynyl, aryl, amine, amide, ether, alkyl, heteroaryl, -alkylphenyl, -alkyl-membered heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogens, cyano, ester, alkyl, Cbz or TBS;

[0009] X is a halogen;

[0010] R 4 and R 2 Same or different, R 2 and R 4 Connected by B atoms,

[0011] R 4 -R 2 It is a diboron reagent;

[0012] R 3 is a protecting group,

[0013] n is 0, 1, 2, 3, 4, 5, 6 or 7.

[0014] According to an embodiment of the present invention, the above method may further include at least one of the following additional technical features:

[0015] According to an embodiment of the present invention, in the nickel salt catalyst, the cation is Ni+, and the anion is selected from Cl – Br – ,I – , [CH3COO] – , [CF3COO] – , [acac] – and one or more of dibenzylideneacetone.

[0016] According to an embodiment of the present invention, the nickel salt catalyst is NiCl2 DME.

[0017] According to an embodiment of the present invention, the cation of the base is selected from Li + 、Na + , K + and Cs + One or more of .

[0018] According to an embodiment of the present invention, the anion of the base is selected from F – 、CO3 2– , [CH3COO] – , [CF3COO] – , [OMe] – and [O tBu] – One or more of .

[0019] According to an embodiment of the present invention, the base is LiOMe.

[0020] According to an embodiment of the present invention, the amino alcohol ligand is selected from one of the following compounds:

[0021]

[0022] Among them, R 10 is H, Me, Bn, Boc or Cbz;

[0023] R 20 , R 30 is independently H, Me, Bn or Ph.

[0024] According to an embodiment of the present invention, the amino alcohol ligand is

[0025] According to an embodiment of the present invention, R 3 It is OBn, Ome or OBMP.

[0026] According to an embodiment of the present invention, the compound shown in Formula 2 is

[0027] According to an embodiment of the present invention, R 4 and R 2 They are

[0028] According to an embodiment of the present invention, R 4 -R 2 for

[0029] According to an embodiment of the present invention, R 1 For cyano, ester, carbonyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, naphthyl, amine, amide, ether, C 1-6 Alkyl, 5-6 membered heteroaryl, -C 1-6 Alkylphenyl, -C 1-6 Alkyl naphthyl, -C 1-6 Alkyl-5-6 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the ester group, alkoxy group, alkenyl group, alkynyl group, aryl group, amino group, amide group, ether group, alkyl group, heteroaryl group, -alkylphenyl group, alkylnaphthyl group, -alkyl membered heteroaryl group, cycloalkyl group or heterocyclic group is optionally substituted by 1, 2 or 3 R 1areplace.

[0030] According to an embodiment of the present invention, R 1a OH, cyano, ester, carbonyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, naphthyl, amine, amide, ether, C 1-6 Alkyl, 5-6 membered heteroaryl, -C 1-6 Alkylphenyl, -C 1-6 Alkyl naphthyl, -C 1-6 Alkyl-5-6 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl or BPin, the ester group, alkoxy group, alkenyl group, alkynyl group, aryl group, amine group, amide group, ether group, alkyl group, heteroaryl group, -alkylphenyl group, alkylnaphthyl group, -alkyl membered heteroaryl group, cycloalkyl group or heterocyclyl group is optionally substituted by 1, 2 or 3 halogen, cyano group, ester group, alkyl group, Cbz or TBS.

[0031] According to an embodiment of the present invention, R 1 for

[0032] -CH2CH2CH2Cl, -CH2CH2CH2C(=O)OCH2CH3, -CH2CH2CH2CN, -CH2CH2CH2Bpin, -CH2CH2CH2NHCbz, -CH2CH2CH2OH,

[0033] According to an embodiment of the present invention, X is -F, Cl, Br or I.

[0034] According to an embodiment of the present invention, the compound shown in Formula 3 is

[0035] According to an embodiment of the present invention, the compound shown in Formula 1 is

[0036]

[0037] According to an embodiment of the present invention, the molar ratio of the compound represented by Formula 2, the compound represented by Formula 3 and the compound represented by Formula 4 is 1:2.0:2.0.

[0038] According to an embodiment of the present invention, the reaction process further comprises adding an additive, and the additive is a salt.

[0039] According to an embodiment of the present invention, the cation of the salt is Li+ 、Na + , K + Mg 2+ and nBu4N + One or more of .

[0040] According to an embodiment of the present invention, the anion of the salt is selected from F – , Cl – Br – ,I – and SO4 2– One or more of .

[0041] According to an embodiment of the present invention, the additive is nBu4NBr.

[0042] According to an embodiment of the present invention, the molar ratio of the nickel salt catalyst, the diamine ligand, the base, the additive and the compound represented by Formula 2 is 0.05:0.05:3.0:2.0:1.

[0043] According to an embodiment of the present invention, the reaction is carried out in a solvent.

[0044] According to an embodiment of the present invention, the solvent is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, and methyl tert-butyl ether acetone.

[0045] According to an embodiment of the present invention, the molar volume ratio of the compound represented by Formula 2 to the solvent is 1:5.

[0046] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0047] 1) The present invention provides a method for stereoselectively preparing cis-2-boryl-α-carbon glycoside compounds, which uses sugar ene, alkyl halide and biboron reagent, and prepares cis-cis-2-boryl-α-carbon glycoside compounds in a one-pot reaction under the action of metal nickel catalyst. The method can not only efficiently synthesize the target compound, but also has mild reaction conditions, strong substrate applicability, good functional group compatibility, and excellent regioselectivity and stereoselectivity;

[0048] 2) The method for stereoselectively preparing cis-2-boryl-α-carbon glycoside compounds provided by the present invention uses cheap and readily available raw materials, is easy to operate, can be scaled up to the gram level, and can efficiently synthesize cis-2-boryl-α-carbon glycoside compounds;

[0049] 3) The method for stereoselectively preparing cis-2-boryl-α-carbon glycoside compounds provided by the present invention contains a boron group in the synthesized product, and the target compound can be further stereoselectively transformed to simply and efficiently synthesize other functionalized cis-2-boryl-α-carbon glycoside compounds, providing a new method for synthesizing complex drug molecules and drug lead compounds.

[0050] Definitions and general terms

[0051] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0052] Those skilled in the art will appreciate that, according to the conventions used in the art, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.

[0053] The present invention will list the literature corresponding to the determined specific content in detail, and the embodiments are accompanied by structural formulas and chemical formulas. The present invention is expected to cover all options, variants and equivalents, which may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that are different from or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0054] The following definitions shall apply to the present invention unless otherwise indicated. For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version and Handbook of Chemicals, 75, th Ed, 1994. In addition, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated by reference.

[0055] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0056] Compounds as described herein may optionally be substituted with one or more substituents, such as the general formula compounds of the invention, or as the specific examples, subclasses, and classes of compounds encompassed by the invention in the examples. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given structure can be substituted with one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.The substituents described herein may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C (=O) O-alkyl, -alkylene-S (=O) 2-alkyl, -alkylene-S (=O) 2-amino, -S (=O) 2-alkyl, -S (=O) 2-amino, -S (=O) 2OH, -O-alkylene-C (=O) O-alkyl, -O-alkylene-S (=O) 2-alkyl, -O-alkylene -S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkylamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, - N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C (=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and the like.

[0057] The term "alkyl" as used herein includes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, saturated straight or branched monovalent hydrocarbon groups, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), t-butyl (t- -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, isopropylene, and the like.

[0058] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2Double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described in the present invention, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0059] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH) and the like.

[0060] The term "heteroatom" means one or more of O, S, N, P and Si, including C, N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring being substituted with a hydrogen, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl); or in the form of -CH2- in a heterocyclic ring being oxidized to form -C(=O)-.

[0061] The term "halogen" refers to F, Cl, Br or I.

[0062] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0063] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group can be independently unsubstituted or substituted with one or more substituents described in the present invention.

[0064] The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a sulfur atom. In some embodiments, the alkylthio group is C 1-4 Alkylthio; such examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, etc. And the alkylthio group can be independently unsubstituted or substituted with one or more substituents described in the present invention.

[0065] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an N atom. In some embodiments, the alkylamino group is C 1-4 Alkylamino; such examples include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino, etc. And the alkylamino group can be independently unsubstituted or substituted with one or more substituents described in the present invention.

[0066] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic carbon ring system containing 3-12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but never an aromatic ring. In one embodiment, the cycloalkyl contains 3-10 carbon atoms; in another embodiment, the cycloalkyl contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3-6 carbon atoms. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

[0067] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to saturated or partially unsaturated monocyclic, bicyclic or tricyclic rings containing 3-12 ring atoms, never aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3-10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3-8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5-8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3-6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5-6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4-6 ring atoms; unless otherwise specified, heterocyclyl may be carbon or nitrogen radical, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Thiazepine Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, cyclopentanesulfonyl and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted by one or more substituents described herein.

[0068] The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring contains 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl and anthracene. The aryl groups can be independently optionally substituted with one or more substituents described herein.

[0069] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.

[0070] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,4-thiodiazolyl, 1,2,3-thiodiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,3 ... The following bicyclic rings are also included, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0071] As described in the present invention, a substituent is connected to a ring by a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) represents that the substituent R can be substituted mono- or poly-substituted at any substitutable position on the pyridine ring.

[0072]

[0073] As described in the present invention, a linker bonded to a ring to form a ring system (as shown in formula b) represents that the linker bond can be connected to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be connected to the rest of the molecule.

[0074]

[0075] The "ester" of the present invention refers to an ester that can be hydrolyzed in vivo by the compound of formula (I) containing a hydroxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce the parent alcohol. The groups of the ester that can be hydrolyzed in vivo by the compound of formula (I) containing a hydroxyl group include, but are not limited to: a phosphate group, an acetoxymethoxy group, a 2,2-dimethylpropionyloxymethoxy group, an alkanoyl group, a benzoyl group, a phenylacetyl group, an alkoxycarbonyl group, a dialkylcarbamoyl group, and a N-(dialkylaminoethyl)-N-alkylcarbamoyl group.

[0076] In addition, it should be noted that, unless otherwise clearly indicated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently the same or different specific groups. In more detail, the description method "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other. DETAILED DESCRIPTION

[0077] The present invention is described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0078] The scheme of the present invention will be explained below in conjunction with the examples. Those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. Where specific techniques or conditions are not indicated in the examples, the techniques or conditions described in the literature in the art or in accordance with the product instructions are carried out. The methods used are conventional methods known in the art unless otherwise specified, and the consumables and reagents used are commercially available unless otherwise specified. Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the recorded content may also be applied to the present invention.

[0079] In the following examples, B2pin2 refers to pinacol diboron; NiCl2·DME refers to nickel chloride di(ethylene glycol dimethyl ether), LiOMe refers to lithium methoxide, nBu4NBr refers to tetrabutylammonium bromide, and NMP refers to N-methylpyrrolidone. L represents an amino alcohol ligand, which is selected from one of the following compounds:

[0080]

[0081] Among them, R 10 One selected from H, Me, Bn, Boc, Cbz, R 20 , R 30One independently selected from H, Me, Bn, Ph.

[0082] Specifically, L1 to L8 represent the following diamine ligands respectively:

[0083]

[0084] Example 1

[0085]

[0086] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucal (76 μL, 0.4 mmol) and benzyl bromide (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 2-((2R,3S,4R,5S,6R)-2-benzyl-4,5-dimethoxy-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (colorless oily liquid, yield 87%). 1 H NMR(600MHz,Chloroform-d)δ7.27–7.23(m,2H),7.20–7.14(m,3H),4.29(ddd,J=10.9,5.1,3 .7Hz,1H),3.69(ddd,J=8.6,4.5,2.8Hz,1H),3.62(dd,J=10.8,8.0Hz,1H),3.58(s,3H),3.55 (dd,J=10.4,4.4Hz,1H),3.52(s,3H),3.44(dd,J=10.4,2.8Hz,1H),3.29(s,3H),3.20–3.11( m,2H),2.69(dd,J=14.8,3.7Hz,1H),1.69(dd,J=10.7,5.1Hz,1H),1.27(d,J=8.9Hz,12H)ppm. 13C NMR (151MHz, Chloroform-d) δ139.37,129.08,128.34,126.13,83.55,81.93,80.44,74.39,72.25,71.49,59.91,59.65,59.13,36.32,25.05,24.79ppm. 11 B NMR(193MHz,Chloroform-d)δ30.77ppm.HRMS(ESI)calculated[M+H] + for C 22 H 36 BO6 + =407.2599,found:407.2605.

[0087] Example 2

[0088]

[0089] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and biboric acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 4-oxytrifluoromethylbenzyl bromide (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 2-((2R, 3S, 4R, 5S, 6R)-4,5-dimethoxy-6-(methoxymethyl)-2-(4-(trifluoromethoxy)benzyl)tetrahydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (colorless oily liquid, yield 82%). 11H NMR (400 MHz, Chloroform-d) δ 7.21–7.17 (m, 2H), 7.09 (dt, J = 7.4, 1.0 Hz, 2H), 4.23 (ddd, J = 11.0, 5.1, 3.6 Hz, 1H), 3.66 (ddd, J = 8.1, 4.7, 2.8 Hz, 1H), 3.62–3.57 (m, 1H), 3.56 (s, 3H), 3.54–3.51 (m, 1H), 3.50 (s, 3H), 3.44 (dd, J = 10.3, 2.8 Hz, 1H), 3.28 (s, 3H), 3.17 (dd, J = 14.8, 11.0 Hz, 1H), 3.09 (t, J = 8.2 Hz, 1H), 2.66 (dd, J = 14.9, 3.6 Hz, 1H), 1.66 (dd, J = 10.6, 5.1 Hz, 1H), 1.26 (d, J = 5.4 Hz, 12H) ppm. 13 13C NMR (101 MHz, Chloroform-d) δ 147.67, 138.23, 130.34, 121.87, 120.90 (t, J = 256.6 Hz), 119.32, 83.60, 81.75, 80.29, 74.15, 72.38, 71.48, 59.89, 59.60, 59.11, 35.70, 24.97, 24.76 ppm. 11 11B NMR (128 MHz, Chloroform-d) δ 32.05 ppm. 19 19F NMR (376 MHz, Chloroform-d) δ -57.82 ppm. HRMS (ESI) calculated + for C 23 H 35 BO7F3 + = 491.2422, found: 491.2430.

[0090] Example 3

[0091]

[0092] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and biboric acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 4-trifluoromethylbenzyl bromide (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 2-((2R, 3S, 4R, 5S, 6R)-4,5-dimethoxy-6-(methoxymethyl)-2-(4-(trifluoromethoxy)benzyl)tetrahydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (colorless oily liquid, yield 71%). 1 H NMR(600MHz,Chloroform-d)δ7.52–7.46(m,2H),7.29(d,J=8.0Hz,2H),4.26(ddd,J=11.1,5.1,3.6Hz, 1H),3.68(ddd,J=8.0,4.8,2.9Hz,1H),3.60(dd,J=10.5,7.9Hz,1H),3.56(s,3H),3.53(dd,J=10.3,4. 8Hz,1H),3.50(s,3H),3.44(dd,J=10.3,2.9Hz,1H),3.28(s,3H),3.23(dd,J=14.8,11.0Hz,1H),3.11( t,J=8.1Hz,1H),2.72(dd,J=14.8,3.5Hz,1H),1.67(dd,J=10.5,5.1Hz,1H),1.27(d,J=6.7Hz,12H)ppm. 13 C NMR(151MHz,Chloroform-d)δ143.63,129.41,128.49(q,J=32.2Hz),125.24(q,J=3.8Hz) 124.47(q,J=271.7Hz),83 .65,81.59,80.27,77.37,77.16,76.95,73.93,72.49,71.45,59.89,59.59,59.15,36.30,25.12,25.01,24.82ppm. 11 B NMR (128MHz, Chloroform-d) δ31.39ppm. 19F NMR(565MHz,Chloroform-d)δ-62.37ppm.HRMS(ESI)calculated[M+H] + for C 23 H 35 BO6F3 + =475.2473,found:475.2481.

[0093] Example 4

[0094]

[0095] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and methyl 4-bromomethylbenzoate (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain methyl 4-(((2R, 3S, 4R, 5S, 6R)-4,5-dimethoxy-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-2-yl)methyl)benzoate (colorless oily liquid, yield 72%). 1 HNMR(600MHz,Chloroform-d)δ7.92(d,J=8.2Hz,2H),7.24(d,J=8.3Hz,2H),4.27(ddd,J=11.0,5.0,3.7Hz, 1H),3.87(s,3H),3.66(ddd,J=7.9,4.6,2.9Hz,1H),3.59(dd,J=10.4,7.8Hz,1H),3.55(s,3H),3.52(dd,J= 10.3,4.6Hz,1H),3.49(s,3H),3.40(dd,J=10.3,2.9Hz,1H),3.27(s,3H),3.21(dd,J=14.7,11.0Hz,1H),3. 11(t,J=8.1Hz,1H),2.71(dd,J=14.7,3.7Hz,1H),1.65(dd,J=10.4,5.1Hz,1H),1.26(d,J=6.5Hz,12H)ppm. 13CNMR(151MHz,Chloroform-d)δ167.24,144.99,129.66,129.12,128.08,83.59,81.4 8,80.25,73.81,72.43,71.35,59.82,59.53,59.14,52.04,36.53,25.00,24.81ppm. 11 B NMR(193MHz,Chloroform-d)δ31.65ppm.HRMS(ESI)calculated[M+H] + for C 24 H 38 BO8 + =465.2654,found:465.2656.

[0096] Example 5

[0097]

[0098] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 1-bromo-3-chloropropane (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 2-((2R, 3S, 4R, 5S, 6R)-4,5-bisbenzyloxy-6-(benzyloxy)methyl)-2-(3-chloropropyl)tetrahydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (colorless oily liquid, yield 76%) 11H NMR (600 MHz, Chloroform-d) δ 7.36–7.21 (m, 13H), 7.18–7.13 (m, 2H), 4.88–4.81 (m, 2H), 4.75 (d, J = 11.1 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 4.51 (dd, J = 11.5, 6.9 Hz, 2H), 4.08 (dt, J = 8.3, 4.5 Hz, 1H), 3.89 (dd, J = 11.4, 8.3 Hz, 1H), 3.73 (dd, J = 10.4, 4.6 Hz, 1H), 3.68 (dd, J = 10.5, 2.6 Hz, 1H), 3.62 (dq, J = 7.4, 2.5 Hz, 1H), 3.50 (t, J = 6.9 Hz, 2H), 2.03–1.93 (m, 1H), 1.87–1.71 (m, 3H), 1.65–1.55 (m, 1H), 1.47 (ddt, J = 13.2, 10.0, 6.1 Hz, 1H), 1.20 (d, J = 3.5 Hz, 12H) ppm. 13 13C NMR (151 MHz, Chloroform-d) δ 139.34, 138.46, 138.40, 128.44, 128.37, 128.28, 127.87, 127.84, 127.68, 127.58, 127.38, 127.31, 83.52, 80.71, 79.25, 74.59, 74.14, 73.50, 73.39, 72.09, 69.59, 44.95, 32.29, 28.99, 25.08, 24.85, 23.26 ppm. 11 11B NMR (193 MHz, Chloroform-d) δ 32.45 ppm.

[0099] Example 6

[0100]

[0101] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and ethyl 4-bromobutyrate (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain the product 4-((2R, 3S, 4R, 5S, 6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-2-yl)butanoic acid ethyl ester (colorless oily liquid, yield 78%) 1 H NMR(600MHz,Chloroform-d)δ7.35–7.20(m,13H),7.17–7.12(m,2H),4.84(d,J=3.9Hz,2H),4.75(d,J=11.1Hz,1H),4.63(d ,J=12.2Hz,1H),4.53–4.48(m,2H),4.10(q,J=6.9Hz,3H),3.88(dd,J=11.5,8.4Hz,1H),3.74(dd,J=10.5,4.5Hz,1H),3.68( dd,J=10.5,2.2Hz,1H),3.65–3.59(m,1H),3.53(t,J=8.9Hz,1H),2.33(td,J=7.4,3.1Hz,2H),2.04–1.94(m,1H),1.88–1.7 6(m,2H),1.64(dq,J=9.6,6.8Hz,1H),1.31(dtd,J=13.9,6.4,3.3Hz,1H),1.24(t,J=7.1Hz,3H),1.19(d,J=2.7Hz,12H)ppm. 13C NMR(151MHz,Chloroform-d)δ173.56,139.36,138.52,138.39,128.41,128.36,128.26,127.87,127.83,127.63,127.55,127.3 7,127.28,83.50,80.73,79.25,74.57,74.17,73.51,73.44,72.02,69.51,60.26,33.88,29.11,25.05,24.84,21.45,14.35ppm. 11 B NMR(193MHz,Chloroform-d)δ32.45ppm.HRMS(ESI)calculated[M+H] + for C 39 H 52 BO8 + =659.3750,found:659.3764.

[0102] Example 7

[0103]

[0104] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 4-bromobutyronitrile (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 4-((2R, 3S, 4R, 5S, 6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-2-yl)butyronitrile (colorless oily liquid, yield 68%) 11H NMR (600 MHz, Chloroform-d) δ 7.34–7.21 (m, 13H), 7.15 (d, J = 8.4 Hz, 2H), 4.83 (q, J = 10.8 Hz, 2H), 4.75 (d, J = 11.2 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.53–4.46 (m, 2H), 4.08 (dd, J = 9.9, 7.3 Hz, 1H), 3.93–3.85 (m, 1H), 3.70 (dd, J = 9.5, 4.7 Hz, 1H), 3.68–3.59 (m, 2H), 3.48 (t, J = 8.7 Hz, 1H), 2.40–2.35 (m, 1H), 2.30 (s, 1H), 2.14–2.05 (m, 1H), 1.88–1.77 (m, 2H), 1.65 (q, J = 7.1 Hz, 2H), 1.21 (d, J = 1.9 Hz, 12H) ppm. 13 13C NMR (151 MHz, Chloroform-d) δ 139.04, 138.22, 138.12, 128.31, 128.28, 128.16, 127.67, 127.56, 127.50, 127.26, 127.23, 119.59, 119.47, 83.55, 80.16, 78.88, 74.36, 73.99, 73.34, 72.54, 72.18, 69.32, 28.39, 27.76, 24.98, 24.72, 22.05, 16.97, 16.67 ppm. 11 11B NMR (193 MHz, Chloroform-d) δ 33.71 ppm. HRMS (ESI) calculated + for C 37 H 47 BO6N + = 612.3491, found: 612.3503。

[0105] Example 8

[0106]

[0107] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 3-bromopropylboronic acid pinacol ester (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 2-((2R, 3S, 4R, 5S, 6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-2-(3-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)tetrahydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,4-dioxaborolan (colorless oily liquid, yield 45%). 1 H NMR(600MHz,Chloroform-d)δ7.36–7.20(m,13H),7.14(d,J=7.5Hz,2H),4.89–4.81(m,2H),4.75(d,J=11.1Hz,1H) ,4.65(d,J=12.1Hz,1H),4.51(dd,J=11.7,6.2Hz,2H),4.08(dt,J=9.6,4.5Hz,1H),3.92–3.86(m,1H),3.78–3.72( m,1H),3.67(d,J=10.5Hz,1H),3.65–3.61(m,1H),3.53(t,J=9.0Hz,1H),2.02–1.91(m,1H),1.84(dd,J=11.6,5.5H z,1H),1.61–1.52(m,1H),1.48–1.36(m,1H),1.23(d,J=1.4Hz,12H),1.19(d,J=6.4Hz,12H),0.86–0.70(m,2H)ppm. 13C NMR(151MHz,Chloroform-d)δ139.54,138.74,138.56,128.41,128.37,128.27,127.93,127.80,127.57,127.52,127.42,12 7.25,83.45,83.02,81.05,79.46,74.57,74.20,73.87,73.54,71.87,69.66,32.67,25.12,25.02,24.93,24.91,20.51ppm. 11 B NMR(193MHz,Chloroform-d)δ34.27ppm.HRMS(ESI)calculated[M+H] + for C 42 H 59 B2O8 + =713.4391,found:713.4403.

[0108] Example 9

[0109]

[0110] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 3-bromopropylcarbamic acid benzyl ester (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 ° C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain benzyl (2-((2R, 3S, 4R, 5S, 6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-2-yl)ethyl)carbamate (colorless oily liquid, yield 62%) 11H NMR (600 MHz, Chloroform-d) δ 7.39–7.19 (m, 18H), 7.11 (d, J = 5.4 Hz, 2H), 5.75 (d, J = 4.9 Hz, 1H), 5.06 (s, 2H), 4.81 (q, J = 11.0 Hz, 2H), 4.72 (d, J = 11.2 Hz, 1H), 4.45 (dd, J = 25.1, 9.6 Hz, 3H), 4.20–4.10 (m, 1H), 3.86 (t, J = 9.7 Hz, 1H), 3.76 (t, J = 8.3 Hz, 1H), 3.66–3.54 (m, 2H), 3.47 (dq, J = 13.0, 6.4, 6.0 Hz, 1H), 3.35 (t, J = 8.8 Hz, 1H), 3.21 (dd, J = 13.2, 5.5 Hz, 1H), 2.16 (dq, J = 12.4, 8.0, 7.0 Hz, 1H), 1.84–1.78 (m, 1H), 1.53 (dd, J = 12.5, 5.9 Hz, 1H), 1.18 (s, 12H) ppm. 13 13C NMR (151 MHz, Chloroform-d) δ 156.75, 139.15, 138.17, 138.03, 136.98, 128.50, 128.45, 128.38, 128.30, 128.08, 127.97, 127.92, 127.89, 127.75, 127.62, 127.37, 83.62, 80.44, 78.91, 74.49, 74.08, 73.36, 73.30, 72.37, 69.25, 66.44, 39.41, 29.76, 25.07, 24.83 ppm. 11 11B NMR (193 MHz, Chloroform-d) δ 32.81 ppm. HRMS (ESI) calculated [[M+H]] + for C 43 H 53 BO8N + = 722.3859, found: 722.3873。

[0111] Example 10

[0112]

[0113] In an argon-filled glove box, di(ethylene glycol dimethyl ether)nickel chloride (4.4 mg, 0.02 mmol), L1 (4.1 mg, 0.02 mmol), lithium methoxide (45.6 mg, 1.2 mmol) and diboronic acid pinacol ester (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone, and then 3,4,6-tri-O-methyl-D-glucitol (76 μL, 0.4 mmol) and 3-iodo-1-propanol (0.8 mmol) were added, followed by 1 mL of N-methylpyrrolidone. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography to obtain 3-((2R, 3S, 4R, 5S, 6R)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)tetrahydro-2H-pyran-2-yl)propan-1-ol (colorless oily liquid, yield 45%) 1 HNMR(600MHz,Chloroform-d)δ7.35–7.21(m,13H),7.15(d,J=7.9Hz,2H),4.84(q,J=10.8Hz,2H),4.75(d,J =11.0Hz,1H),4.59(d,J=12.2Hz,1H),4.50(t,J=11.0Hz,2H),4.12(ddd,J=11.6,5.3,2.8Hz,1H),3.90(dd,J =11.1,8.5Hz,1H),3.73–3.57(m,5H),3.47(t,J=8.8Hz,1H),2.18–2.09(m,1H),2.04(dh,J=11.4,6.3Hz,1H ),1.85(dd,J=11.4,5.4Hz,1H),1.65(dh,J=28.0,7.5Hz,2H),1.45–1.37(m,1H),1.20(d,J=5.4Hz,12H)ppm. 13 C NMR(151MHz,Chloroform-d)δ139.26,138.38,138.21,128.40,128.36,128.24,127.85,127.82,127.64,127.59,127 .36,127.27,83.49,80.66,79.10,74.53,74.10,73.84,73.46,72.11,69.53,62.21,29.63,26.15,24.99,24.81ppm. 11B NMR(193MHz,Chloroform-d)δ33.92ppm.HRMS(ESI)calculated[M+H] + for C 36 H 48 BO7 + =603.3488,found:603.3492.

[0114] The synthesis of cis-2-boryl-α-carbon glycoside compounds in the following Examples 11-22 was carried out with reference to the method steps of the above Example 2. The structures and names, NMR, HRMS data and yields of the synthesized compounds are shown in Table 1 below:

[0115] Table 1 Structure, name, NMR, HRMS and yield of products in Examples 11-22

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention, and all of these shall be included in the scope of protection of the present invention.

[0125] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

Claims

1. A method for preparing a compound represented by formula 1, characterized in that: The method comprises reacting a compound represented by Formula 2, a compound represented by Formula 3 and a compound represented by Formula 4 under the action of a nickel salt catalyst, an amino alcohol ligand and a base to obtain a compound represented by Formula 1. R 1 is a cyano group, an ester group, a carbonyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, an amine group, an amide group, an ether group, an alkyl group, a heteroaryl group, an -alkylaryl group, an -alkyl-membered heteroaryl group, a cycloalkyl group or a heterocyclic group, wherein the ester group, the alkoxy group, the alkenyl group, the alkynyl group, the aryl group, the amine group, an amide group, an ether group, an alkyl group, a heteroaryl group, an -alkylaryl group, an -alkyl-membered heteroaryl group, a cycloalkyl group or a heterocyclic group is optionally substituted by 1, 2 or 3 R 1a replace; R 1a is OH, cyano, ester, carbonyl, alkoxy, alkenyl, alkynyl, aryl, amine, amide, ether, alkyl, heteroaryl, -alkylaryl, -alkyl-membered heteroaryl, cycloalkyl, heterocyclyl or BPin, wherein the alkoxy, alkenyl, alkynyl, aryl, amine, amide, ether, alkyl, heteroaryl, -alkylphenyl, -alkyl-membered heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogens, cyano, ester, alkyl, Cbz or TBS; X is a halogen; R 4 and R 2 Same or different, R 2 and R 4 Connected by B atoms, R 4 -R 2 It is a diboron reagent; R 3 is a protecting group, n is 0, 1, 2, 3, 4, 5, 6 or 7.

2. The method according to claim 1, characterized in that In the nickel salt catalyst, the cation is Ni+ and the anion is selected from Cl – Br – ,I – , [CH3COO] – , [CF3COO] – , [acac] – and one or more of dibenzylideneacetone; Optionally, the nickel salt catalyst is NiCl2 DME.

3. The method according to claim 1, characterized in that The cation of the base is selected from Li + 、Na + , K + and Cs + One or more of; Optionally, the anion of the base is selected from F – 、CO3 2– , [CH3COO] – , [CF3COO] – , [OMe] – and [O t Bu] – One or more of; Optionally, the base is LiOMe.

4. The method according to claim 1, characterized in that: The amino alcohol ligand is selected from one of the following compounds: Among them, R 10 is H, Me, Bn, Boc or Cbz; R 20 , R 30 is independently H, Me, Bn or Ph; Optionally, the amino alcohol ligand is 5. The method according to claim 1, characterized in that R 3 is OBn, Ome, or OBMP; Optionally, the compound shown in Formula 2 is 6. The method according to claim 1, characterized in that R 4 and R 2 They are Optionally, R 4 -R 2 for 7. The method according to claim 1, characterized in that R 1 For cyano, ester, carbonyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, naphthyl, amine, amide, ether, C 1-6 Alkyl, 5-6 membered heteroaryl, -C 1-6 Alkylphenyl, -C 1-6 Alkyl naphthyl, -C 1-6 Alkyl-5-6 membered heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the ester group, alkoxy group, alkenyl group, alkynyl group, aryl group, amino group, amide group, ether group, alkyl group, heteroaryl group, -alkylphenyl group, alkylnaphthyl group, -alkyl membered heteroaryl group, cycloalkyl group or heterocyclic group is optionally substituted by 1, 2 or 3 R 1a replace; Optionally, R 1a OH, cyano, ester, carbonyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, naphthyl, amine, amide, ether, C 1-6 Alkyl, 5-6 membered heteroaryl, -C 1-6 Alkylphenyl, -C 1-6 Alkyl naphthyl, -C 1-6 Alkyl-5-6 membered heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl or BPin, wherein the ester, alkoxy, alkenyl, alkynyl, aryl, amine, amide, ether, alkyl, heteroaryl, -alkylphenyl, alkylnaphthyl, -alkyl membered heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 halogens, cyano, ester, alkyl, Cbz or TBS; Optionally, R 1 for -CH2CH2CH2Cl、-CH2CH2CH2C(=O)OCH2CH3、-CH2CH2CH2CN、-CH2CH2CH2Bpin、-CH2CH2CH2NHCbz、-CH2CH2CH2OH、 Optionally, X is -F, Cl, Br or I; Optionally, the compound shown in formula 3 is 8. The method according to claim 1, characterized in that The compound shown in formula 1 is 9. The method according to claim 1, characterized in that: The molar ratio of the compound represented by Formula 2, the compound represented by Formula 3 and the compound represented by Formula 4 is 1:2.0:2.

0.

10. The method according to claim 1, characterized in that The reaction process further includes adding an additive, wherein the additive is a salt; Optionally, the cation of the salt is Li + 、Na + , K + Mg 2+ and nBu4N + One or more of; Optionally, the anion of the salt is selected from F – , Cl – Br – ,I – and SO4 2– One or more of; Optionally, the additive is nBu4NBr; Optionally, the molar ratio of the nickel salt catalyst, the diamine ligand, the base, the additive and the compound represented by Formula 2 is 0.05:0.05:3.0:2.0:1; Optionally, the reaction is carried out in a solvent; Optionally, the solvent is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tert-butyl ether acetone; Optionally, the molar volume ratio of the compound represented by Formula 2 to the solvent is 1:5.

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