A process for the preparation of aryl carbon glycoside compounds

Abstract

This invention provides a process for preparing aryl C-glycoside compounds, belonging to the pharmaceutical field. The method includes the following steps: using compounds shown in formula (II) and formula (III) as raw materials, reacting to obtain the compound shown in formula (I). The method of this invention has wide applicability and can prepare various aryl C-glycosides. It can be used not only for preparing pyridine C-glycoside compounds but also for preparing selenoside drugs. The glycosyl donor used in the method of this invention has good stability, requires no protecting group, avoids lengthy protection / deprotection operations, reduces production costs, and reduces the amount of waste generated. The method of this invention can react rapidly at room temperature, under mild conditions, without the need for n-butyllithium or Grignard reagents, and does not require sub-zero temperatures, making it safe and environmentally friendly. The method of this invention yields high-purity products and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a process for preparing aryl C-glycoside compounds. Background Technology

[0002] Carbohydrates are another important class of life-giving substances besides nucleic acids and proteins. They are crucial information molecules within living organisms, participating in all temporal and spatial processes of life, especially multicellular life, including fertilization, implantation, differentiation, development, immunity, infection, metastasis, and aging. Carbohydrates play a vital role in intercellular recognition and interaction, water and electrolyte transport, cancer development and metastasis, immunity and immunosuppression, and cell aggregation. In recent years, the significant physiological activity of carbohydrate compounds has increasingly attracted the research interest of chemists. Glycosides are an important form of sugar found in nature, widely present in organisms, possessing unique biological activities and undertaking important physiological functions. Glycosides are a very important class of compounds formed by the condensation of the hemiacetal hydroxyl group of a sugar with a ligand, resulting in the loss of one molecule of water or other small molecules. The sugar portion is called the glycosyl group, and the non-sugar portion is called the ligand. Based on the type of atom attached to the carbon atom of the sugar ring by the ligand in the molecular structure of glycosides, they can be classified into oxyglycosides, nitrogen-containing glycosides, thioglycosides, and carbon-containing glycosides. Among them, C-glycosides refer to a class of compounds in which the oxygen atom outside the C-glycoside bond is replaced by a carbon atom. They are a class of sugar skeletons that are very widespread in nature. They are widely found in a variety of natural products and drug molecules. Compared with oxyglycosides and nitrogen glycosides, C-glycosides have better enzyme stability and hydrolysis resistance in organisms. Therefore, they have become an important alternative to natural oxyglycoside drugs.

[0003] International patent application WO2021013155A1 discloses a method for preparing carbon glycosides using allyl sulfone glycosyl donors and pyridine tetrafluoroborate as raw materials (synthetic route as follows). In this method, under a nitrogen atmosphere, glycosyl donor 3-1 (1.0 equiv), glycosyl acceptor pyridine tetrafluoroborate (2.0 equiv), photosensitizer Eosin Y (0.025 equiv.), and initiator sodium trifluoromethyl sulfinate (0.2 equiv.) are added to a catalytic reaction flask, followed by the addition of DMSO. The mixture is stirred at room temperature for 8 hours under Blue LED irradiation to obtain the carbon glycoside compound CX. However, this method can only be used to prepare pyridine-based carbon glycosides and cannot be used to prepare serotonin-type drugs.

[0004]

[0005] Stanozolidinediones, a type of hypoglycemic agent, selectively inhibit SGLT-2 (sodium-glucose cotransporter 2), reducing renal glucose reabsorption and increasing urinary glucose excretion, thereby lowering blood glucose levels in patients with type 2 diabetes. In addition to lowering blood sugar, stanozolidinediones can also reduce weight, lower blood pressure, protect the heart and kidneys, and lower uric acid. Furthermore, compared to other types of hypoglycemic agents, stanozolidinediones have no significant side effects and do not interfere with the insulin and glucagon secretion regulation pathways. These advantages make stanozolidinediones the first-line drugs for treating type 2 diabetes. Currently, there are nine stanozolidinediones on the market globally, four of which have been approved for marketing in China: dapagliflozin, canagliflozin, empagliflozin, and uapagliflozin. Empagliflozin, launched in 2014, achieved global sales exceeding $3 billion in 2019.

[0006] For empagliflozin-type drugs, the reported preparation methods include the following method for synthesizing empagliflozin (also known as epagliptin) disclosed by Shi Kejin et al. (Synthetic Process of Epalgliflozin, Chemical Research and Application, November 2016, Vol. 28, No. 11): Using 5-bromo-2-chlorobenzoic acid as a starting material, acylation, Friedel-Crafts acylation, nucleophilic substitution, and reduction yield the intermediate (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene. This intermediate is then condensed with 2,3,4,6-tetra-O-trimethylsilyl-D-glucopyranoside 1,5-lactone, etherified, and demethoxylated to obtain empagliflozin, with an overall yield of 29.8% and a purity of 99.13%. This method not only has a low yield but also requires a reaction temperature of -78°C during synthesis, which is difficult to control and unfavorable for industrial production. In order to improve the yield of empagliflozin drugs, researchers have improved the above process and reported an improved process for synthesizing empagliflozin (China Pharmaceutical Industry Journal, 2018, Vol. 49, No. 8): Phenol (2) reacts with (R)-3-hydroxytetrahydrofuran to obtain (S)-3-phenoxytetrahydrofuran, which is then reacted with 2-chloro-5-iodobenzyl bromide via Friedel-Crafts alkylation to obtain (S)-3-[4-(2-chloro-5-iodobenzyl)phenoxy]tetrahydrofuran (6). 6 and 2,3,4,6-tetra-O-acetyl-1-α-bromo-D-pyranose were condensed in the presence of n-butyllithium and cuprous iodide to give (2S,3R,4R,5S,6R)-2-[3-[4-[(S)-tetrahydrofuran-3-yloxy]benzyl]-4-chlorophenyl]-6-acetoxymethyl-3,4,5-triacetoxyepoxyhexane (8); finally, 8 was deacetylated with lithium hydroxide to give target compound 1 (i.e., empagliflozin), with an overall yield of 43.0% (based on 2) and a product purity of 99.21%. Although this method improves the product yield, it has the following problems: (1) The reaction route is lengthy and the economic cost increases. The glycosyl donor used has poor stability and the hydroxyl group on the glycosyl donor needs to be protected with a protecting group to prevent it from interfering with the key bonding steps. After the synthesis of compound 8, the protecting group is removed to obtain the target product empagliflozin; (2) The reaction temperature of -40℃ is harsh and the equipment requirements are high; (3) The overall yield needs to be further improved.

[0007]

[0008] Therefore, it is of great significance to develop a new method for preparing aryl C-glycosides, including levofloxacin drugs, with a simple reaction route, lower production cost, and mild reaction conditions. Summary of the Invention

[0009] The purpose of this invention is to provide a process for preparing aryl C-glycoside compounds.

[0010] The present invention provides a method for preparing the compound shown in formula (I), the method comprising the following steps: using the compound shown in formula (II) and the compound shown in formula (III) as raw materials, reacting to obtain the compound shown in formula (I);

[0011]

[0012] Where t is an integer from 0 to 5, R a Each is independently selected from LOH, LOCOR0, and C. 1～4 alkyl, Or two of the R's a Connect them into a ring;

[0013] R0 is C 1～4 alkyl;

[0014] X is a halogen;

[0015] The B ring is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl;

[0016] s is an integer from 0 to 5, R b Each C is independently selected from halogenated or non-halogenated C 1～4 Alkyl, halogenated or unhalogenated C 1～4 Alkoxy, COOR5, OCOR5, NHCOR5, CONHR5, COR5, NHR5, OR5, SR5, cyano, halogen, LOH, 5-6 member saturated heterocyclic group, 5-6 member saturated cycloalkyl group

[0017]

[0018] R6 is a hydrogen or amino protecting group;

[0019] R7 is hydrogen or C. 1～4 alkyl;

[0020] L is absent or has 1 to 4 methylene groups;

[0021] Ring A is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl;

[0022] p is an integer from 0 to 2, and R2 is independently selected from C. 1～4 Alkyl, C 1～4 Alkoxy, halogenated or unhalogenated phenyl, OR3, where R3 is a 5-6 membered saturated heterocyclic group or a 5-6 membered saturated cycloalkyl group.

[0023] The compounds shown in formula (II) and formula (III) of this invention are both readily available or can be synthesized by those skilled in the art.

[0024] Furthermore, the reaction is carried out in the presence of a Ni(I)-based catalyst, a Ru(II)-based photosensitizer, a Bpy-ligand complex, an initiator, and a base. The solvent for the reaction is an organic solvent. The reaction temperature is room temperature, the reaction time is 6–18 hours, the reaction is carried out under LED light irradiation, and the reaction is carried out under a nitrogen atmosphere.

[0025] And / or, the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the Ni(I)-based catalyst, the Ru(II)-based photosensitizer, the Bpy-ligand complex, the initiator and the base is (0.1–0.3):(0.05–0.20):(5%–15%):(0.5–1.5%):(9%–15%):(0.2–1.0):(0.1–0.7).

[0026] Further, the Ni(I)-based catalyst is NiBr2.DME, the Ru(II)-based photosensitizer is Ru(bpy)3Cl2.6H2O, the Bpy-ligand complex is diOMebpy, the initiator is sodium p-toluenesulfonate, the base is tetramethylguanidine, and the organic solvent is DMSO;

[0027] And / or, the reaction time is 12 hours, and the parameters of the LED lamp are: 10W, 455nm;

[0028] And / or, the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the Ni(I)-based catalyst, the Ru(II)-based photosensitizer, the Bpy-ligand complex, the initiator, and the base is 0.15:0.1:10%:1%:12%:0.6:0.4.

[0029] Furthermore, the compound shown in formula (II) is The compound shown in formula (III) is The compound shown in formula (I) is

[0030] Where X is a halogen;

[0031] R1 is a halogen, C 1～4 Alkyl or C 1～4 Alkoxy;

[0032] Ring A is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl;

[0033] p is an integer from 0 to 2, and R2 is independently selected from C. 1～4 Alkyl, C 1～4 Alkoxy, halogenated or unhalogenated phenyl, OR3, where R3 is a 5-6 membered saturated heterocyclic group or a 5-6 membered saturated cycloalkyl group.

[0034] Furthermore, the compound shown in formula (I) is one of the following compounds:

[0035]

[0036] Furthermore, the compound shown in formula (II) is The compound shown in formula (III) is The compound shown in formula (I) is

[0037] Where X is a halogen;

[0038] The B ring is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl;

[0039] q is an integer from 0 to 2, and R4 is independently selected from halogenated or non-halogenated C. 1～4 Alkyl, halogenated or unhalogenated C 1～4 Alkoxy, COOR5, OCOR5, NHCOR5, CONHR5, COR5, NHR5, OR5, SR5, cyano, halogen, LOH, 5-6 member saturated heterocyclic group, 5-6 member saturated cycloalkyl group

[0040] R5 is hydrogen or C. 1～4 Alkyl group, R6 is a hydrogen or amino protecting group, R7 is a hydrogen or C protecting group 1～4 Alkyl group, where L is absent or has 1 to 3 methylene groups.

[0041] Furthermore, It is one of the following structures:

[0042]

[0043] Wherein, R is methoxy, methyl, tert-butyl, OCF3, CF3 or COOMe.

[0044] Furthermore, the compound shown in formula (I) is one of the following compounds:

[0045]

[0046]

[0047] Furthermore, the compound shown in formula (II) is The compound shown in formula (III) is The compound shown in formula (I) is

[0048] Where X is a halogen;

[0049] R9 represents hydrogen, hydroxyl group, OCOCH3,

[0050] y is an integer from 1 to 4, R8 is independently selected from LOH, LOCOCH3, and methyl; L is absent or has 1 to 3 methylene groups.

[0051] Furthermore, the compound shown in formula (I) is one of the following compounds:

[0052]

[0053]

[0054] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided herein apply to the term throughout the specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0055] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C 1～4 Alkyl groups are straight-chain or branched alkyl groups containing 1 to 4 carbon atoms.

[0056] In this invention, "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system. The aryl group may be substituted or unsubstituted.

[0057] "Heteroaryl" refers to a heteroaryl group containing one or more heteroatoms. Heteratoms include oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0058] "Cycloalkyl" refers to a substituent in a saturated or unsaturated cyclic hydrocarbon; the cyclic hydrocarbon can be monocyclic or polycyclic. For example, "5- to 6-membered saturated cycloalkyl" refers to a saturated cycloalkyl ring with 5 to 6 carbon atoms.

[0059] "Fused cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.

[0060] "Heterocyclic group" refers to a substituent in a saturated or unsaturated cyclic hydrocarbon; the cyclic hydrocarbon can be monocyclic or polycyclic and carries at least one cyclic heteroatom (including but not limited to O, S, or N). For example, "5- to 6-membered saturated heterocyclic group" refers to a saturated heterocyclic group with 5 to 6 ring atoms.

[0061] "Heterocyclic fused ring group" refers to a polycyclic heterocyclic group in which two rings share two adjacent carbon atoms or heteroatoms.

[0062] Halogens are fluorine, chlorine, bromine or iodine.

[0063] Compared with the prior art, the preparation method of the present invention has the following beneficial effects:

[0064] (1) This invention is the first to propose a reaction route for preparing the aryl C-glycoside compound of formula (I) using the compounds shown in formula (II) and formula (III) as raw materials. The reaction mechanism of the synthesis method of this invention is different from the reaction mechanism in the prior art and is a new reaction mechanism.

[0065] (2) The method of the present invention has wide applicability and can prepare various aryl carbon glycosides. It can be used not only to prepare pyridine carbon glycoside compounds, but also to prepare selenoside drugs.

[0066] (3) The glycosyl donor raw material used in the method of the present invention is stable and does not require a protecting group, thus avoiding lengthy protection / deprotection operations, reducing production costs, and reducing the amount of "three wastes" generated.

[0067] (4) The method of the present invention uses a free radical reaction, which can react rapidly at room temperature. The conditions are mild, and no n-butyllithium or Grignard reagents are required. It does not need to be carried out at sub-zero temperatures, making it safe and environmentally friendly.

[0068] (5) The method of the present invention has high product yield and high purity;

[0069] (6) The reaction stereoselectivity of the present invention is feasible. The catalyst used in the present invention, after the transition metal is combined with the chiral ligand, can regulate the stereoconfiguration of the aryl glycoside, so that the reaction has excellent stereoselectivity.

[0070] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0071] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0072] Figure 1 Synthetic routes for empagliflozin, canagliflozin, dapagliflozin, and iodaggliflozin.

[0073] Figure 2 The synthetic routes for compounds 10a to 10y are shown.

[0074] Figure 3 The synthetic routes for compounds 12a to 12k are shown below. Detailed Implementation

[0075] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0076] The glycosyl donor raw materials used in the following examples can all be prepared according to the method described in the international patent application No. WO2021013155A1.

[0077] The following are examples of methods for preparing glycosyl donors:

[0078] Route 1:

[0079]

[0080] The glycosyl donor was synthesized according to the method in Route 1, specifically as follows:

[0081] Step 1: Thiourea (15 mmol, 1.1 g) and BF3·Et2O (30 mmol, 3.75 mL) were added sequentially to a 100 mL round-bottom flask containing SI-5 (10 mmol) and 25 mL CH3CN. The reaction solution was refluxed for 8 hours until TLC monitoring showed complete consumption of SI-5. Et3N (30 mmol, 5.2 mL) and 3-bromo-2-methylpropene (15 mmol, 1.5 mL) were added sequentially to the resulting solution. The resulting solution was stirred at 80 °C and the reaction progress was monitored by TLC. The resulting solution was concentrated and dissolved in CH2Cl2, and washed with water. The organic layer was separated, washed with brine, dried, and concentrated to obtain SI-6 in the form of a mixture, which could be used in the next step without further purification.

[0082] Step 2: Dissolve SI-6 in 20 mL of CH₂Cl₂ and cool at 0 °C. Add m-CPBA (25 mmol, 4.3 g) slowly to the reaction solution while stirring. Stir the mixture at room temperature for another 1 hour. Filter the resulting mixture and wash the filtrate with water. Separate the organic layer, wash with saturated Na₂SO₃ solution, saturated NaHCO₃ solution, and brine, then dry and concentrate. Perform rapid chromatography on the residue to obtain sulfone SI-7.

[0083] Step 3: Dissolve SI-7 in 20 mL of MeOH at 0 °C, then add LiOH (5 mmol, 120 mg). Stir the reaction at 0 °C for 4 hours. Add silica gel to the mixture and concentrate under vacuum. Dry load the resulting mixture onto a silica gel column and elute to obtain the corresponding glycosyl donor.

[0084] Route 2:

[0085]

[0086] Example 1: Preparation of Empagliflozin

[0087]

[0088] Empagliflozin was synthesized according to Route 2. The specific operation was as follows: glycosyl donor 1 (42 mg, 0.15 mmol), (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan (41 mg, 0.1 mmol), Ru(bpy)3Cl2.6H2O (0.8 mg, 1 mol%), NiBr2.DME (3.1 mg, 10 mol%), diOMebpy (2.6 mg, 12 mol%), TolSO2Na (sodium p-toluenesulfonate, 54 mg, 0.6 mmol), TMG (tetramethylguanidine, 25 μL, 0.4 mmol)) and DMSO (0.5 mL) were weighed and mixed into a screw-cap vial with a magnetic stir bar. The vial was filled with N2 and sealed with a Teflon-lined cap. The mixture was stirred at room temperature under a 10W, 455nm LED lamp for 12 hours until the reaction was complete.

[0089] The reaction solution was diluted with 10 mL of ethyl acetate and then washed with saturated brine. The organic phase was collected, and the aqueous phase was extracted three times with 6 mL of ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the residue was separated by silica gel chromatography (using a petroleum ether / ethyl acetate solution of 10:7 (v / v) as the eluent) to give the glycoside product empagliflozin. Single β-configuration, 26 mg, yield 57%, purity >95%.

[0090] 1H NMR(400MHz,CD3OD)δ7.37–7.31(m,2H),7.27(dd,J=8.1,2.1Hz,1H),7.13–7.0 6(m,2H),6.81–6.74(m,2H),4.94(ddt,J=6.2,4.1,1.9Hz,1H),4.08(d,J=9.7H z,1H),4.05–3.95(m,2H),3.94–3.80(m,5H),3.71–3.64(m,1H),3.48–3.34(m, 3H),3.30–3.24(m,1H),2.19(dtd,J=13.3,8.4,6.0Hz,1H),2.10–2.02(m,1H).

[0091] Example 2: Preparation of canagliflozin

[0092]

[0093] Following the method and raw material molar ratio of Example 1, the only difference was that iodobenzene compound 2 was replaced by 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene instead of 3s)-3-[4-[(5-iodo-2-methylphenyl)methyl]thiophene, and the volume ratio of petroleum ether / ethyl acetate in the silica gel chromatography eluent was modified to 10:5, yielding the glycoside product canagliflozin. Single β configuration, 32 mg, yield 71%, purity greater than 95%.

[0094] 1 H NMR (400MHz, CD3OD) δ7.54–7.48(m,2H),7.31(d,J=1.7Hz,1H),7.24(dd,J=7. 8,1.8Hz,1H),7.15(d,J=7.8Hz,1H),7.08(d,J=3.6Hz,1H),7.07–7.01(m,2H), 6.68(d,J=3.6Hz,1H),4.16–4.12(m,2H),4.11(d,J=9.3Hz,1H),3.88(dd,J=1 1.9,1.8Hz,1H),3.70(dd,J=11.9,5.0Hz,1H),3.51–3.35(m,4H),2.29(s,3H).

[0095] Example 3: Preparation of dapagliflozin

[0096]

[0097] Following the method and starting material molar ratio of Example 1, the only difference was that iodobenzene compound 2 was replaced by 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan, yielding the glycoside product dapagliflozin. Single β-configuration, 31 mg, yield 75%, purity >95%.

[0098] 1 H NMR (400MHz, CD3CN) δ7.37(d,J=8.2Hz,1H),7.30(d,J=2.1Hz,1H),7.24(dd,J=8.2,2.2Hz,1H),7.12 (d,J=8.6Hz,2H),6.86–6.80(m,2H),4.08(d,J=9.4Hz,1H),4.05–4.02(m,2H),3.99(q,J=7.1Hz,2H), 3.74(ddd,J=11.6,5.8,2.1Hz,1H),3.63–3.56(m,1H),3.45(d,J=3.1Hz,1H),3.36(dt,J=7.1,3.3Hz, 4H), 3.24 (td, J = 8.9, 4.7Hz, 1H), 3.13 (d, J = 4.8Hz, 1H), 2.73 (t, J = 6.2Hz, 1H), 1.33 (t, J = 7.0Hz, 3H).

[0099] Example 4: Preparation of Iggliflozin

[0100]

[0101] Following the method and starting material molar ratio of Example 1, the only difference was that iodobenzene compound 2 was replaced by 2-(5-bromo-2-fluorophenyl)methylbenzothiophene instead of 3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydro-furan, yielding the glycoside product igagliptin. Single β-configuration, 27 mg, yield 68%, purity >95%.

[0102] 1H NMR (400MHz, CD3OD) δ7.72(dd,J=8.1,1.2Hz,1H),7.69–7.60(m,1H),7.43(dd,J=7.4,2.2Hz,1H),7.35(ddd,J=8.5,5.0,2.3Hz,1H),7.32–7.19( m,2H),7.12–7.02(m,2H),4.34–4.18(m,2H),4.11(d,J=9.4Hz,1H),3.9 1–3.82(m,1H),3.73–3.63(m,1H),3.48–3.35(m,3H),3.33–3.31(m,1H).

[0103] Route 3:

[0104]

[0105] Example 5: Preparation of compounds 10a-10y

[0106] Compounds 10a–10y were synthesized according to Route 3. Specifically, the following procedures were followed: 0.15 mmol of glycosyl donor 1a, 0.1 mmol of compound 2, 0.8 mg of Ru(bpy)3Cl2·6H2O (1 mol%), 3.1 mg of NiBr2·DME (10 mol%), 2.6 mg of diOMebpy (12 mol%), 54 mg of TolSO2Na (0.6 mmol), 25 μL of TMG (0.4 mmol), and 0.5 mL of DMSO were weighed and placed into a screw-cap vial equipped with a magnetic stir bar. The vial was filled with N2 and sealed with a Teflon-lined cap. The mixture was stirred at room temperature under a 10 W, 455 nm LED lamp for 12 hours until the reaction was complete.

[0107] The reaction solution was diluted with 10 mL of ethyl acetate and then washed with saturated brine. The organic phase was collected, and the aqueous phase was extracted three times with 6 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure, and the residues were separated by silica gel chromatography (using a mixture of petroleum ether and ethyl acetate as the eluent) to give compounds 10a to 10y (the specific structures are shown in Table 1).

[0108] Table 1. Parameter control for the synthesis of compounds 10a–10y

[0109]

[0110]

[0111]

[0112] Table 2. Yields, purities, and structural characterization of compounds 10a–10y

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] Route 4:

[0126]

[0127] Example 6: Preparation of compounds 12a-12k

[0128] Compounds 12a-12k were synthesized according to Route 4. Specifically, the following procedures were followed: 0.15 mmol of glycosyl donor 11, 0.1 mmol of compound 2a, 0.8 mg of Ru(bpy)3Cl2·6H2O (0.8 mg, 1 mol%), 3.1 mg of NiBr2·DME (3.1 mg, 10 mol%), 2.6 mg of diOMebpy (2.6 mg, 12 mol%), 54 mg of TolSO2Na (0.6 mmol), 25 μL of TMG (0.4 mmol), and 0.5 mL of DMSO were weighed and placed into a screw-cap vial equipped with a magnetic stir bar. The vial was filled with N2 and sealed with a Teflon-lined cap. The mixture was stirred at room temperature under a 10 W, 455 nm LED lamp for 12 hours until the reaction was complete.

[0129] The reaction solution was diluted with 10 mL of ethyl acetate and then washed with saturated brine. The organic phase was collected, and the aqueous phase was extracted three times with 6 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure, and the residues were separated by silica gel chromatography (using a mixture of petroleum ether and ethyl acetate as eluent) to give compounds 12a–12k (the specific structures are shown in Table 3).

[0130] Table 3. Structures of compounds 12a-12k

[0131]

[0132]

[0133] Table 4. Yields, purities, and structural characterization of compounds 12a–12k

[0134]

[0135]

[0136]

[0137]

[0138]

[0139] Example 7: Synthesis of carbohydrate compounds 13a-13j

[0140] Route 5:

[0141]

[0142] 1. Synthesize compound 13a

[0143]

[0144] (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-methoxyphenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0145] Following Route 5, the mixture was prepared using glycosyl donor a (84 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2.6H2O (1.5 mg, 1 mol%), NiBr2.DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13a (single β configuration, 73 mg, 83%, purity >95%) as a white solid.

[0146] 1 H NMR (400MHz, CDCl3) δ7.30–7.23(m,2H),6.90–6.82(m,2H),5.32(t,J=9.4Hz, 1H),5.23(t,J=9.6Hz,1H),5.14(t,J=9.6Hz,1H),4.35(d,J=9.8Hz,1H),4.28( dd,J=12.3,4.7Hz,1H),4.15(dd,J=12.3,2.3Hz,1H),3.83(ddd,J=9.9,4.6,2. 2Hz,1H),3.79(s,3H),2.08(s,3H),2.06(s,3H),2.00(s,3H),1.80(s,3H).The 1 H NMR spectracoincide with the previous report.

[0147] 2. Synthesis of compound 13b

[0148] (2R,3S,4R,5S,6S)-5-acetamido-2-(acetoxymethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4-diyl diacetate

[0149] Following Route 5, the mixture was prepared using glycosyl donor b (97 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2.6H2O (1.5 mg, 1 mol%), NiBr2.DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13b (single β configuration, 44 mg, 50%, purity >95%) as a white solid.

[0150] 1 H NMR (400MHz, CDCl3) δ7.30–7.25(m,2H),6.89–6.83(m,2H),5.31–5.19(m,3H),4.36(d,J=10.2Hz,1H),4.31–4. 22(m,2H),4.13(dd,J=12.4,2.3Hz,1H),3.84–3.73(m,4H),2.08(s,3H),2.05(s,3H),2.04(s,3H),1.72(s,3H); 13 C NMR (101MHz, CDCl3) δ171.40,170.96,169.57,160.10,128.95,114.02,81.29,76.33,74. 53,68.85,62.70,55.37,54.98,23.23,20.95,20.89,20.83; HRMS(DART-TOF)calculated for C 21 H 27 NNaO9 + [M+Na] + m / z460.1578, found 460.1570.

[0151] 3. Synthesis of compound 13c

[0152] (2S,3S,4R,5S,6S)-2-(4-methoxyphenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate

[0153] Following Route 5, the following were used: glycosyl donor c (80 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol%), NiBr2·DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13c (β / α = 1:3, 53 mg, 70%, purity >95%) as a white solid.

[0154] α-anomer: 1 H NMR(400MHz, CDCl3), δ7.46–7.38(m,2H),6.99–6.91(m,2H),5.98(t,J=2.8Hz,1H),5.16(ddd,J=13.9,5.9,2.3Hz,2H),5.0 0(d,J=2.7Hz,1H),3.82(s,3H),3.65–3.56(m,1H),2.17(s,3H),2.05(s,3H),2.01(s,3H),1.27(d,J=6.4Hz,3H);β-anomer: 1 H NMR(400MHz, CDCl3), δ7.26–7.24(m,2H),6.86–6.81(m,2H),5.49(dd,J=3.0,1.3Hz,1H),5.20(dd,J=7.4,2.5Hz,1H),5.11(d ,J=3.0Hz,1H),4.69(s,1H),3.78(s,3H),3.73–3.64(m,1H),2.08(s,3H),1.98(s,3H),1.95(s,3H),1.33(d,J=6.1Hz,3H).The 1 HNMR spectra coincide with the previous report.

[0155] 4. Synthesis of compound 13d

[0156] (2S,3S,4S,5R)-2-(4-methoxyphenyl)tetrahydro-2H-pyr an-3,4,5-triyl triacetate

[0157] Following Route 5, the following were used: glycosyl donor d (76 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2.6H2O (1.5 mg, 1 mol%), NiBr2.DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13d (single β configuration, 56 mg, 77%, purity >95%) as a white solid.

[0158] 1 H NMR (400MHz, CDCl3) δ7.24(d,J=2.0Hz,2H),6.89–6.82(m,2H),5.32(t,J=9.5Hz,1H),5.15(dd,J=10.2,5.6Hz,1H),5. 09(t,J=9.5Hz,1H),4.31–4.19(m,2H),3.79(s,3H),3.44(t,J=11.0Hz,1H),2.06(s,3H),2.03(s,3H),1.80(s,3H).The 1 H NMRspectra coincide with the previous report.

[0159] 5. Synthesis of compound 13e

[0160] (2R,3R,4S,5R)-2-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0161] Following Route 5, the following were used: glycosyl donor e (76 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2.6H2O (1.5 mg, 1 mol%), NiBr2.DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13e as a white solid (β / α = 4:1, 58 mg, 79%, purity >95%).

[0162] β-anomer: 1 H NMR (400MHz, CDCl3) δ7.34–7.29(m,2H),6.89–6.85(m,2H),5.40(t,J=3.6Hz,1H),5.31(dd,J=9.7,3.1Hz,1H),4.93(dt,J=3 .9,1.9Hz,1H),4.57(d,J=9.7Hz,1H),3.99(d,J=1.9Hz,2H),3.79(s,3H),2.19(s,3H),2.18(s,3H),1.83(s,3H).α-anomer: 1 H NMR (400MHz, CDCl3) δ7.27–7.19(m,2H),6.85–6.81(m,2H),5.50(dd,J=3.3,1.3Hz,1H),5.36–5.33(m,1H),5.22(dd,J=10.3,3. 3Hz,1H),4.62(s,1H),4.32(dd,J=11.1,5.5Hz,1H),3.78(s,3H),3.46–3.36(m,1H),2.07(s,3H),2.00(s,3H),1.94(s,3H).The 1 H NMR spectra coincide with the previous report.

[0163] 6. Synthesis of compound 13f

[0164] (2R,3R,4R,5R)-2-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0165] Following Route 5, the following were used: glycosyl donor f (76 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol%), NiBr2·DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13f (β / α = 10:1, 59 mg, 80%, purity >95%) as a white solid.

[0166] 1H NMR (400MHz, CDCl3) δ7.36–7.28(m,2H),6.94–6.78(m,2H),5.44–5.36(m,2H),5.17(dd,J=10.1,3.5Hz,1H),4. 23(d,J=9.6Hz,1H),4.13(dd,J=13.2,2.1Hz,1H),3.83–3.76(m,4H),2.21(s,3H),2.01(s,3H),1.81(s,3H).The 1 H NMR spectra coincide with the previous report.

[0167] 7. 13g of the synthesized compound

[0168] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5S,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0169] Following Route 5, the following were prepared: glycosyl donor g (133 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol%), NiBr2·DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give 13 g of product as a white solid (β / α = 10:1, 118 mg, 81%, purity >95%).

[0170] 11H NMR (400 MHz, CDCl3), δ 7.25–7.19 (m, 2H), 6.89–6.81 (m, 2H), 5.48 (d, J = 4.0 Hz, 1H), 5.43–5.34 (m, 2H), 5.08 (t, J = 9.9 Hz, 1H), 4.97 (t, J = 9.7 Hz, 1H), 4.89 (dd, J = 10.6, 4.0 Hz, 1H), 4.48 (dd, J = 12.2, 2.5 Hz, 1H), 4.38 (d, J = 9.9 Hz, 1H), 4.28 (t, J = 3.9 Hz, 1H), 4.25 (t, J = 3.8 Hz, 1H), 4.12 (t, J = 9.3 Hz, 1H), 4.07 (dd, J = 12.4, 2.2 Hz, 1H), 4.00 (dt, J = 10.1, 3.0 Hz, 1H), 3.84–3.75 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.79 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 170.73, 170.67, 170.50, 170.08, 169.59, 169.44, 160.01, 128.52, 128.45, 113.96, 95.83, 79.50, 76.42, 73.53, 73.19, 70.15, 69.57, 68.65, 68.17, 63.45, 61.62, 55.37, 55.32, 21.13, 21.11, 21.01, 20.98, 20.85, 20.83, 20.83, 20.76, 20.74, 20.55; HRMS (DART-TOF) calculated for C 33 13 42 11 18 + [M + Na] + m / z 749.2263, found 749.2257.

[0171] 8. Synthesis of Compound 13h

[0172] (2R,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(4-methoxyphenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0173] Following Route 5, the following were used: glycosyl donor h (84 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol%), NiBr2·DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13h (single β configuration, 68 mg, 77%, purity >95%) as a white solid.

[0174] 1 H NMR (400MHz, CDCl3) δ7.32–7.29(m,2H),6.88–6.86(m,2H),5.52(dd,J=3.5,1.1Hz,1H),5.35(t,J=9.9Hz,1H),5.17(dd,J=10.1,3.4Hz ,1H),4.32(d,J=9.7Hz,1H),4.22–4.10(m,2H),4.09–4.01(m,1H),3.79(s,3H),2.20(s,3H),2.03(s,3H),1.99(s,3H),1.81(s,3H).The 1 H NMR spectra coincide with the previous report.

[0175] 9. Synthesis of compound 13i

[0176] (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0177] Following Route 5, the mixture was prepared with glycosyl donor i (84 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2.6H2O (1.5 mg, 1 mol%), NiBr2.DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13i (single β configuration, 49 mg, 56%, purity >95%) as a white solid.

[0178] 1 H NMR (400MHz, CDCl3) δ7.45–7.39(m,2H),7.00–6.90(m,2H),5.97(t,J=3.1Hz,1H ),5.34(t,J=8.9Hz,1H),5.18(dd,J=9.1,3.1Hz,1H),5.07(d,J=3.0Hz,1H),4.3 7(dd,J=12.1,6.0Hz,1H),4.12(dd,J=12.2,2.8Hz,1H),3.83(s,3H),3.75(ddd, J=8.8,6.0,2.8Hz,1H),2.16(s,3H),2.13(s,3H),2.06(s,3H),2.01(s,3H).The 1 H NMR spectracoincide with the previous report.

[0179] 10. Synthesize compound 13j

[0180] (2R,3R,4R,5R,6S)-2-(4-methoxyphenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate

[0181] Following Route 5, the following were used: glycosyl donor j (80 mg, 0.30 mmol), 4-methoxyiodobenzene (47 mg, 0.2 mmol), Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol%), NiBr2·DME (6.2 mg, 10 mol%), diOMebpy (5.2 mg, 12 mol%), TolSO2Na (107 mg, 0.6 mmol), TMG (50 μL, 0.4 mmol), and DMSO (1.0 mL). The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10:2) to give product 13j (β / α = 4:1, 58 mg, 79%, purity >95%) as a white solid.

[0182] 1 H NMR (400MHz, CDCl3) δ7.31(d,J=8.6Hz,2H),6.86(d,J=8.7Hz,2H),5.38–5.31(m,2H),5.17(dd,J=10.1,3.4Hz,1H),4.29(d ,J=9.7Hz,1H),3.94(qd,J=6.5,1.2Hz,1H),3.79(s,3H),2.23(s,3H),1.99(s,3H),1.80(s,3H),1.23(d,J=6.4Hz,3H).The 1 HNMR spectra coincide with the previous report.

[0183] The following experimental examples demonstrate the beneficial effects of the present invention.

[0184] Experiment Example 1: Screening Experiment for Reaction Conditions

[0185] 1. Experimental Methods

[0186] Route Six:

[0187]

[0188] The target compound (i.e., compound 12a in Example 6) in route six was synthesized according to the method of Example 6; then the reaction conditions were changed according to Table 5 to synthesize the target compound.

[0189] The yields of the target compound under different conditions were compared, and the results are shown in Table 5.

[0190] 2. Experimental Results

[0191] Table 5. Results of reaction condition screening

[0192]

[0193] The above experimental results show that the product yield obtained under the reaction conditions of Example 6 of the present invention is the highest.

[0194] In summary, this invention provides a process for preparing aryl C-glycoside compounds. The method of this invention has wide applicability and can prepare various aryl C-glycosides, including not only pyridine C-glycoside compounds but also levofloxacin-type drugs. The glycosyl donor used in this method has good stability, requires no protecting groups, avoids lengthy protection / deprotection operations, reduces production costs, and minimizes the generation of waste. The method of this invention can react rapidly at room temperature under mild conditions, without the need for n-butyllithium or Grignard reagents, and does not require sub-zero temperatures, making it safe and environmentally friendly. The method of this invention yields high-purity products and is suitable for industrial production.

Claims

1. A method for preparing the compound shown in formula (I), characterized in that: The method includes the following steps: using the compound shown in formula (II) and the compound shown in formula (III) as raw materials, reacting to obtain the compound shown in formula (I); the reaction is carried out in the presence of a Ni(I)-based catalyst, a Ru(II)-based photosensitizer, a Bpy-ligand complex, an initiator, and a base, and the reaction is carried out under the irradiation of an LED lamp; Where t is an integer from 0 to 5, R a Each is independently selected from LOH, LOCOR0, and C. 1~4 alkyl, , Or two of the R's a Connect them into a ring; R0 is C 1~4 alkyl; X is a halogen; The B ring is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl; s is an integer from 0 to 5, R b Each C is independently selected from halogenated or non-halogenated C 1~4 Alkyl, halogenated or unhalogenated C 1~4 Alkoxy, COOR5, OCOR5, NHCOR5, CONHR5, COR5, NHR5, OR5, SR5, cyano, halogen, LOH, 5-6 member saturated heterocyclic group, 5-6 member saturated cycloalkyl group , ; R5 is hydrogen or C. 1~4 alkyl; R6 is a hydrogen or amino protecting group; R7 is hydrogen or C. 1~4 alkyl; L is absent or has 1 to 4 methylene groups; Ring A is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl; p is an integer from 0 to 2, and R2 is independently selected from C. 1~4 Alkyl, C 1~4 Alkoxy, halogenated or unhalogenated phenyl, OR3, where R3 is a 5-6 member saturated heterocyclic group or a 5-6 member saturated cycloalkyl group.

2. The method according to claim 1, characterized in that: The solvent for the reaction is an organic solvent, the reaction temperature is room temperature, the reaction time is 6 to 18 hours, and the reaction is carried out under a nitrogen atmosphere. And / or, the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the Ni(I)-based catalyst, the Ru(II)-based photosensitizer, the Bpy-ligand complex, the initiator and the base is (0.1~0.3):(0.05~0.20):(5%~15%):(0.5~1.5%):(9%~15%):(0.2~1.0):(0.1~0.7).

3. The method according to claim 2, characterized in that: The Ni(I)-based catalyst is NiBr2.DME, the Ru(II)-based photosensitizer is Ru(bpy)3Cl2.6H2O, the Bpy-ligand complex is diOMebpy, the initiator is sodium p-toluenesulfonate, the base is tetramethylguanidine, and the organic solvent is DMSO. And / or, the reaction time is 12 hours, and the parameters of the LED lamp are: 10 W, 455 nm; And / or, the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the Ni(I)-based catalyst, the Ru(II)-based photosensitizer, the Bpy-ligand complex, the initiator and the base is 0.15:0.1:10%:1%:12%:0.6:0.

4.

4. The method according to any one of claims 1-3, characterized in that: The compound shown in formula (II) is The compound shown in formula (III) is The compound shown in formula (I) is ; Where X is a halogen; R1 is a halogen, C 1~4 Alkyl or C 1~4 Alkoxy; Ring A is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl; p is an integer from 0 to 2, and R2 is independently selected from C. 1~4 Alkyl, C 1~4 Alkoxy, halogenated or unhalogenated phenyl, OR3, where R3 is a 5-6 member saturated heterocyclic group or a 5-6 member saturated cycloalkyl group.

5. The method according to claim 4, characterized in that: The compound shown in formula (I) is one of the following compounds: 、 、 、 。 6. The method according to any one of claims 1-3, characterized in that: The compound shown in formula (II) is The compound shown in formula (III) is The compound shown in formula (I) is ; Where X is a halogen; R9 represents hydrogen, hydroxyl group, OCOCH3, or ; y is an integer from 1 to 4, R8 is independently selected from LOH, LOCOCH3, and methyl; L is either absent or has 1 to 3 methylene groups.

7. The method according to any one of claims 1-3, characterized in that: The compound shown in formula (I) is one of the following compounds: 。 8. A method for preparing the compound shown in formula (I), characterized in that: The method includes the following steps: using the compound shown in formula (II) and the compound shown in formula (III) as raw materials, reacting to obtain the compound shown in formula (I); the reaction is carried out in the presence of a Ni(I)-based catalyst, a Ru(II)-based photosensitizer, a Bpy-ligand complex, an initiator, and a base, and the reaction is carried out under LED irradiation; the compound shown in formula (II) is... The compound shown in formula (III) is The compound shown in formula (I) is ; Where X is a halogen; The B ring is a 5-6 membered aryl, a 5-6 membered heteroaryl, a fused cycloalkyl, or a heterofused cycloalkyl; q is an integer from 0 to 2, and R4 is independently selected from halogenated or non-halogenated C. 1~4 Alkyl, halogenated or unhalogenated C 1~4 Alkoxy, COOR5, OCOR5, NHCOR5, CONHR5, COR5, NHR5, OR5, SR5, cyano, halogen, LOH, 5-6 member saturated heterocyclic group, 5-6 member saturated cycloalkyl group ; R5 is hydrogen or C. 1~4 Alkyl group, R6 is a hydrogen or amino protecting group, R7 is a hydrogen or C protecting group 1~4 Alkyl group, where L is absent or has 1 to 3 methylene groups.

9. The method according to claim 8, characterized in that: The solvent for the reaction is an organic solvent, the reaction temperature is room temperature, the reaction time is 6 to 18 hours, and the reaction is carried out under a nitrogen atmosphere. And / or, the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the Ni(I)-based catalyst, the Ru(II)-based photosensitizer, the Bpy-ligand complex, the initiator and the base is (0.1~0.3):(0.05~0.20):(5%~15%):(0.5~1.5%):(9%~15%):(0.2~1.0):(0.1~0.7).

10. The method according to claim 9, characterized in that: The Ni(I)-based catalyst is NiBr2.DME, the Ru(II)-based photosensitizer is Ru(bpy)3Cl2.6H2O, the Bpy-ligand complex is diOMebpy, the initiator is sodium p-toluenesulfonate, the base is tetramethylguanidine, and the organic solvent is DMSO. And / or, the reaction time is 12 hours, and the parameters of the LED lamp are: 10 W, 455 nm; And / or, the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the Ni(I)-based catalyst, the Ru(II)-based photosensitizer, the Bpy-ligand complex, the initiator and the base is 0.15:0.1:10%:1%:12%:0.6:0.

4.

11. The method according to any one of claims 8-10, characterized in that: It is one of the following structures: Wherein, R is methoxy, methyl, tert-butyl, OCF3, CF3 or COOMe.

12. The method according to claim 11, characterized in that: The compound shown in formula (I) is one of the following compounds: 。

Images