Preparation method for asymmetric synthesis of nucleoside prodrug intermediate or prodrug based on P (V) precursor copper catalysis

Abstract

The invention provides a preparation method for asymmetrically synthesizing a nucleoside prodrug intermediate or prodrug based on copper catalysis of a P (V) precursor, which comprises the following steps of: reacting a nucleoside compound with racemic phosphamide under a metal catalysis condition in the presence of an organic solvent, alkali, a chiral ligand, a # imgabs0 # molecular sieve and a catalyst; a series of phosphorus center chiral nucleoside prodrug intermediates or prodrugs are generated. The asymmetric synthesis method provided by the invention is simple to operate, economical and efficient, and the obtained target compound has the characteristics of good substrate universality and high diastereoselectivity, and has good application potential in the fields of virus resistance and tumor resistance.

Description

Technical Field

[0001] The present invention belongs to the technical field of synthesis of medicines and pharmaceutical intermediates, and specifically relates to a nucleoside prodrug intermediate or prodrug and an asymmetric preparation method thereof, and in particular relates to a preparation method of a nucleoside prodrug intermediate or prodrug (Protides) by copper-catalyzed asymmetric synthesis based on a P(V) precursor. Background Art

[0002] In the context of the global pandemic of the new coronavirus, achieving efficient asymmetric synthesis of promising drug molecules in clinical trials will strongly support the rapid development of clinical trials, thereby timely verifying the efficacy and safety of drugs and saving more lives. Nearly half of the antiviral drugs currently on the market are nucleoside analogs. However, the phosphate group of nucleotides is negatively charged, has low lipid solubility in the body, and has low metabolic activation efficiency. McGuigan et al. creatively developed nucleoside prodrug technology in the 1990s, transforming the phosphate group of nucleotides into an electrically neutral amide / ester structure, which not only improves the lipophilicity of the compound and makes it easy to penetrate the cell membrane, but also greatly improves its metabolic activation efficiency, allowing it to be efficiently converted into the corresponding nucleoside triphosphate (NTP) in the cell. As an active species, NTP binds to its target, the viral RNA polymerase, and blocks RNA replication. The specific mechanism of action is as follows: in vivo, after the prodrug molecule I passes through the cell membrane, its ester group is hydrolyzed under the catalysis of carboxypeptidase, and the resulting intermediate II then undergoes intramolecular nucleophilic substitution and spontaneous hydrolysis to generate anion IV. Under the catalysis of phosphoamidase, IV is hydrolyzed again to generate phosphate / phosphonate anion V, which then undergoes two-step phosphorylation to generate nucleoside triphosphate NTP. Nucleoside prodrug technology greatly improves the efficiency of NTP generation in cells, thereby significantly enhancing the pharmacodynamic activity.

[0003]

[0004] Currently, many prodrugs have been used in the clinical treatment of viral infections such as hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and new coronavirus (SARS-CoV-2). Representative drugs are as follows:

[0005]

[0006] It can be found that the above nucleoside prodrugs all have phosphorus (V) chiral center structures, so how to design and construct the phosphorus chiral center has become a top priority in drug research and development. Taking the anti-hepatitis C drug sofosbuvir as an example, the optically pure (Sp) isomer has an in vitro anti-HCV activity that is 18 times that of its (Rp) isomer.

[0007] Currently, there are three main methods for achieving efficient stereoselective synthesis of nucleoside prodrugs: (1) chiral auxiliary group-assisted synthesis of nucleoside prodrugs; (2) using optically pure phosphoramide precursors to synthesize nucleoside prodrugs; and (3) using racemic P(V) precursors to synthesize nucleoside prodrugs.

[0008] Meier et al. have reported a class of chiral auxiliary group-substituted P(V) coupling precursors (reaction route as follows), which can be used for stereoselective synthesis of prodrugs, but the substrate application range is narrow and the precursor itself also requires multi-step synthesis and purification.

[0009]

[0010] At present, phosphoramide p-nitrophenolate and phosphoramide pentafluorophenolate are the two most commonly used precursors. These two precursors have certain stability and are easy to store and prepare. However, in their synthesis process, a diastereomeric mixture is often obtained, which requires optical purification to achieve the required optical purity. The purification methods mainly include the phosphotriesterase mutant enzyme resolution method of Pseudomonas deficient and the dynamic kinetic resolution method driven by crystallization. Alkyl Grignard reagents, Lewis acids or organic bases are often used as coupling reagents.

[0011]

[0012] Despite the above progress, people still hope to avoid the splitting of the precursor and directly generate the desired configuration of the phosphorus chiral center during the prodrug coupling process. DiRocco and Professor Zhang Wanbin both used organic small molecule catalysts chiral bicyclic imidazoles to achieve the asymmetric synthesis of nucleoside prodrugs. DiRocco improved the reaction activity and stereoselectivity by increasing the rigidity of the chiral bicyclic imidazole link, while Professor Zhang chose to increase the steric hindrance of the catalyst to achieve the goal of chiral control.

[0013] DiRocco, 2017

[0014]

[0015] Zhang, 2020

[0016]

[0017] In addition to the above organic small molecule catalytic methods, McGuigan reported the copper-catalyzed stereoselective coupling of ProTide. The introduction of BEN ligand did not significantly improve the yield and chirality.

[0018]

[0019] However, the poor substrate compatibility of the reported methods, the cumbersome and expensive ligand synthesis, and the inability to quantify small molecule catalysis have severely limited the asymmetric preparation of nucleoside prodrugs, and other asymmetric catalytic methods have rarely been reported. Therefore, it is of great significance to develop new stereoselective synthesis methods for nucleoside prodrugs.

[0020] We use chiral cyclohexanediamine ligands, which have easy-to-obtain raw materials and simple synthesis steps. It can be obtained by only one step of reductive amination and hydrochloric acid. The use of Lewis acid catalysis not only has a good yield, but more importantly, the reaction has excellent stereoselectivity, which may greatly promote the development of nucleoside prodrugs in antiviral and anti-tumor aspects.

[0021] Summary of the invention

[0022] In view of the deficiencies of the prior art, the present invention provides a nucleoside prodrug intermediate or a nucleoside prodrug and an asymmetric preparation method thereof.

[0023] The objective of the present invention is achieved through the following technical solutions:

[0024] In a first aspect, the present invention provides a nucleoside prodrug intermediate or a nucleoside prodrug, wherein the nucleoside prodrug intermediate comprises a compound structure shown in Formula I, Formula II or Formula III; the nucleoside prodrug comprises a compound structure shown in Formula IV;

[0025]

[0026] Among them, R 1 is any one of methyl, 2-ethylbutyl, isopropyl, tert-butyl, cyclohexyl and benzyl;

[0027] R 2 Any one of methyl, isopropyl, and methylthioethyl;

[0028] R 3 for Any of the following, where R 9 is any one of hydrogen, halogen, and methoxy;

[0029] R 4 Uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine, 6-chloroadenine, pyrrole

[0030] Any of [2,1-f][1,2,4]triazine-4-amine;

[0031] R 5 Any of hydrogen and cyano;

[0032] R 6is any one of azido, benzyloxy, and tert-butyldimethylsilyl;

[0033] R 7 Any one of hydrogen, halogen, and tert-butyldimethylsilyl;

[0034] R 8 It is either hydrogen or methyl.

[0035] Preferably, the nucleoside prodrug intermediate includes any one of a different substituted phosphoramide nucleoside prodrug intermediate, a different base substituted nucleoside prodrug intermediate, a deoxynucleoside and other nucleoside prodrug intermediates;

[0036] The structures of the different substituted phosphoramide nucleoside prodrug intermediates are shown in Formula I-1, Formula I-2, and Formula I-3; the structures of the different base substituted nucleoside prodrug intermediates are shown in Formula I-4; the structures of the deoxynucleosides and other nucleoside prodrug intermediates are shown in Formula II-1 and Formula III-1;

[0037] The nucleoside prodrugs include deoxynucleosides and other nucleoside prodrugs, and the structures are shown in the following formula II-1, formula IV-1, and formula IV-1;

[0038]

[0039]

[0040] Among them, R 1 is any one of methyl, 2-ethylbutyl, isopropyl, tert-butyl, cyclohexyl and benzyl;

[0041] R 2 Any one of methyl, isopropyl, and methylthioethyl;

[0042] R 4 is any one of uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine, 6-chloroadenine, and pyrrolo[2,1-f][1,2,4]triazine-4-amine;

[0043] R 5 Any of hydrogen and cyano;

[0044] R 6 is any one of azido, benzyloxy, and tert-butyldimethylsilyl;

[0045] R 7 Any one of hydrogen, halogen, and tert-butyldimethylsilyl;

[0046] R 8 is any of hydrogen or methyl;

[0047] R9 It is any of hydrogen, halogen and methoxy.

[0048] In formula II-1, when R 6 is an azido group, R 7 When it is a halogen, it is a prodrug;

[0049] When R 6 is an azido group, R 7 When it is hydrogen, it is a prodrug intermediate.

[0050] In a second aspect, the present invention provides a method for preparing a nucleoside prodrug intermediate or a nucleoside prodrug, comprising the following steps:

[0051] In organic solvents, bases, chiral ligands, In the presence of molecular sieves and catalysts, nucleoside compounds are reacted with racemic phosphoramide under metal catalysis conditions to generate nucleoside prodrug intermediates or nucleoside prodrugs.

[0052] Preferably, the reaction temperature is -10°C to 10°C, and the reaction time is 50 to 70 hours. More preferably, the reaction temperature is 0°C, and the reaction time is 60 hours.

[0053] Preferably, the nucleoside compound is selected from at least one of 2',3'-isopropylidene uridine, 5-fluoro-2',3'-isopropylidene uridine, 5-bromo-2',3'-isopropylidene uridine, 2',3'-isopropylidene thymidine, 2',3'-isopropylidene adenosine, 6-chloro-2',3'-isopropylidene adenosine, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, remdesivir intermediate, cordycepin, and 1-((3a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furo[3,4-d][1,3]dioxol]-6-yl)pyrimidine-2,4(1H,3H)-dione.

[0054] Preferably, the phosphoramide is selected from (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-alanine methyl ester, (chloro(phenoxy)phosphoryl)-L-alanine-2-ethylbutyl ester, (chloro(phenoxy)phosphoryl)-L-alanine cyclohexyl ester, (chloro(phenoxy)phosphoryl)-L-alanine tert-butyl ester, (chloro(phenoxy)phosphoryl)-L-alanine benzyl ester, (chloro(phenoxy)phosphoryl)-L-valine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-valine methyl ester, (chloro(phenoxy)phosphoryl)-L-methionine isopropyl ester, (chloro(4-methoxyphenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(4-fluorophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(4-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(3-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(2-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(1-naphthyloxy)phosphoryl)-L-alanine isopropyl ester, (chloro(ethoxy)phosphoryl)-L-alanine isopropyl ester, and (chloro(1-naphthyloxy)phosphoryl)-L-alanine benzyl ester.

[0055] Preferably, the molar ratio of the nucleoside-containing compound to the phosphoramide is 1:1.5-2.5, and more preferably the molar ratio is 1:2.3.

[0056] Preferably, the organic solvent is selected from ethylene glycol dimethyl ether, tetrahydrofuran, and acetonitrile; the base is selected from diisopropylethylamine, Et3N, and DBU, and more preferably the organic solvent is ethylene glycol dimethyl ether.

[0057] Preferably, the catalyst is selected from copper acetylacetonate, Cu(OTf)2, CuBr2, Ni(OTf)2, Fe(OTf)3, and more preferably the catalyst is copper acetylacetonate.

[0058] Preferably, the chiral ligand is selected from ligand L1 and ligand L2, and the ligand structure is as follows:

[0059]

[0060] The molar ratio of the catalyst to the nucleoside compound is 0.1:1;

[0061] The molar ratio of diisopropylethylamine to nucleoside compound is 2.3-3:1;

[0062] The molar ratio of the chiral ligand to the nucleoside compound is 0.15-0.2:1.

[0063] In a third aspect, the present invention further provides a nucleoside prodrug A, wherein the nucleoside prodrug A is prepared by the nucleoside prodrug intermediate according to claim 1; the compound structure of the nucleoside prodrug is shown in the following formula II:

[0064]

[0065] Among them, R 1 is any one of methyl, 2-ethylbutyl, isopropyl, tert-butyl, cyclohexyl and benzyl;

[0066] R 2 Any one of methyl, isopropyl, and methylthioethyl;

[0067] R 3 for Any of the following, where R 9 is any one of hydrogen, halogen, and methoxy;

[0068] R 4 Uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine, 6-chloroadenine, pyrrole

[0069] Any of [2,1-f][1,2,4]triazine-4-amine;

[0070] R 5 Any of hydrogen and cyano;

[0071] R 6 is any one of azido, benzyloxy, tert-butyldimethylsilyl, and hydroxyl;

[0072] R 7 Any one of hydrogen, halogen, tert-butyldimethylsilyl, and hydroxyl;

[0073] And R 6 and R 7 At least one of the groups is a hydroxyl group;

[0074] R 8 It is either hydrogen or methyl.

[0075] In a fourth aspect, the present invention further provides a method for preparing a nucleoside prodrug A, comprising the following steps:

[0076] The prodrug intermediate of claim 1 is reacted with ultra-dry THF to form a reaction system, and concentrated hydrochloric acid is added at 0° C., and then the temperature is raised to room temperature and the reaction is carried out overnight to obtain the nucleoside prodrug A; or

[0077] After nitrogen replacement of the prodrug intermediate of claim 1 in a reaction bottle, TFA is added at 0° C. to form a reaction system, and then the temperature is raised to room temperature and the reaction is carried out overnight to obtain the nucleoside prodrug A.

[0078] Compared with the prior art, the present invention has the following beneficial effects:

[0079] (1) The synthetic method provided by the present invention is simple to operate and has high diastereoselectivity. The target compound obtained has the characteristics of good functional group compatibility and wide substrate universality.

[0080] (2) The synthesis method provided by the present invention has a short synthesis step of the chiral ligand and the raw materials are cheap and readily available. The product nucleoside prodrug can greatly improve the lipid solubility and metabolic activation efficiency of the drug and has good application potential in the antiviral and anti-tumor fields. DETAILED DESCRIPTION

[0081] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements may be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0082] In a specific embodiment of the present invention, a method for preparing a nucleoside prodrug intermediate or a nucleoside prodrug is provided, wherein the method comprises: In the presence of molecular sieves and catalysts, nucleoside compounds are reacted with racemic phosphoramide under metal catalysis to generate nucleoside prodrugs.

[0083] The specific preparation steps are:

[0084] In a reaction vessel, chiral ligands, metal catalysts, nucleoside compounds, phosphoramide, After the molecular sieve, the reaction system is placed in a glove box, and then an organic solvent and a base are added in sequence. The reaction device is sealed, taken out of the glove box, and stirred at 0°C for 60 hours to obtain a nucleoside prodrug intermediate or a nucleoside prodrug.

[0085] In a specific embodiment, the nucleoside compound is selected from at least one of 2',3'-isopropylidene uridine, 5-fluoro-2',3'-isopropylidene uridine, 5-bromo-2',3'-isopropylidene uridine, 2',3'-isopropylidene thymidine, 2',3'-isopropylidene adenosine, 6-chloro-2',3'-isopropylidene adenosine, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, remdesivir intermediate, cordycepin, and 1-((3a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furo[3,4-d][1,3]dioxol]-6-yl)pyrimidine-2,4(1H,3H)-dione.

[0086] In a specific embodiment, the phosphoramide is selected from (chloro((phenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-alanine methyl ester, (chloro(phenoxy)phosphoryl)-L-alanine-2-ethylbutyl ester, (chloro(phenoxy)phosphoryl)-L-alanine cyclohexyl ester, (chloro(phenoxy)phosphoryl)-L-alanine tert-butyl ester, (chloro(phenoxy)phosphoryl)-L-alanine benzyl ester, (chloro(phenoxy)phosphoryl)-L-valine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-valine methyl ester, (chloro(phenoxy)phosphoryl)-L-alanine-2-ethylbutyl ester, (chloro(phenoxy)phosphoryl)-L-alanine cyclohexyl ester, (chloro(phenoxy)phosphoryl)-L-alanine tert-butyl ester, (chloro(phenoxy)phosphoryl)-L-alanine benzyl ester, (chloro(phenoxy)phosphoryl)-L-valine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-valine methyl ester, (chloro(phenoxy)phosphoryl)-L -methionine isopropyl ester, (chloro(4-methoxyphenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(4-fluorophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(4-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(3-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(2-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(1-naphthyloxy)phosphoryl)-L-alanine isopropyl ester, (chloro(ethoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(1-naphthyloxy)phosphoryl)-L-alanine benzyl ester.

[0087] In a specific embodiment, the molar ratio of the nucleoside compound to the phosphoramide is 1:2.3.

[0088] In a specific embodiment, the organic solvent is selected from ethylene glycol dimethyl ether, the base is selected from diisopropylethylamine, and the catalyst is selected from copper acetylacetonate.

[0089] The molar ratio of the diisopropylethylamine to the nucleoside compound is 2.3:1, the molar ratio of the copper acetylacetonate to the nucleoside compound is 0.1:1, and the molar ratio of the chiral ligand to the nucleoside compound is 0.15:1.

[0090] The chiral ligand is selected from ligand L1 and ligand L2, and the ligand structure is as follows:

[0091]

[0092] Under the above conditions, the corresponding nucleoside prodrug intermediates or nucleoside prodrugs can be prepared.

[0093] Taking 2',3'-isopropylidene uridine (Compound 1) as an example, the reaction formula for its reaction with (chloro((phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 2) to generate a nucleoside prodrug (Compound 3) is as follows:

[0094]

[0095] The reaction principle of the present invention is:

[0096]

[0097] Lewis acid catalysis is an important reaction mechanism in organic chemistry, which can promote the reaction of organic matter, accelerate the reaction rate, and improve the yield and selectivity of the reaction. The basic principle of Lewis acid catalysis is that Lewis acid coordinates with the electrophilic center in the reactant to form a complex, which enhances the reactivity of the reactant molecule and promotes the reaction. Introducing a suitable chiral ligand into the system can further achieve chirality control in the form of a complex with Lewis acid.

[0098] Example 1

[0099] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl)-L-alanine (compound 3a), the structure of which is shown below:

[0100]

[0101] The specific preparation steps of the 3a compound are as follows:

[0102] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro((phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3a (45.9 mg, 83% yield); 1H NMR (500MHz, CDCl3): δ9.09(s,1H),7.33–7.30(m,3H),7.22–7.15(m,3H),5.78(d ,J=2.9Hz,1H),5.71(dd,J=8.1,2.0Hz,1H),5.01(m,1H),4.79(dd,J=6.4,2.9Hz,1 H),4.59(dd,J=6.4,2.9Hz,1H),4.39–4.30(m,3H),4.01–3.88(m,2H),1.56(s,3H) ,1.35(d,J=7.0Hz,3H),1.32(s,3H),1.24(d,J=6.3Hz,3H),1.22(d,J=6.3Hz,3H). 13 C NMR (126MHz, CDCl3): δ173.2,173.1,163.1,150.7,150.6,150.0,141.3,129.8,125.2,120.1,120.1,114 .6,102.6,93.1,84.8,84.7,84.2,80.4,69.5,66.2,66.2,50.5,50.5,27.1,25.2,21.7,21.6,21.0,21.0. 31 P NMR (202MHz, CDCl3): δ2.74, 2.62. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =14.614min(major):t R =14.983min(minor),97:3dr.

[0103] Example 2

[0104] This embodiment provides a methyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl)-L-alanine (compound 3b), the structure of which is shown below:

[0105]

[0106] The specific preparation steps of the 3b compound are as follows:

[0107] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol), (chloro((phenoxy)phosphoryl)-L-alanine methyl ester (63.9 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3b (44.6 mg, 85% yield); 1 H NMR (500MHz, CDCl3): δ9.39(s,1H),7.33–7.30(m,3H),7.21–7.15(m,3H),5.78(d,J=2.9Hz,1H),5.71(d,J=8.1Hz,1H),4.80(dd,J=6 .4,2.8Hz,1H),4.62(dd,J=6.4,2.9Hz,1H),4.35(m,3H),4.09–3.96(m,2H),3.71(s,3H),1.56(s,3H),1.36(d,J=7,3H),1.32(s,3H). 13 C NMR (126MHz, CDCl3): δ174.2,174.1,163.3,150.6,150.6,150.1,141.4,129.8,125.2,120.1,120.1 ,114.6,102.7,93.1,84.8,84.8,84.2,80.5,66.3,66.2,52.6,50.3,50.3,27.1,25.2,20.93,20.89. 31 P NMR (202MHz, CDCl3): δ2.62, 2.44. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =13.204min(major):t R =13.609min(minor),95:5dr.

[0108] Example 3

[0109] This embodiment provides a 2-ethylbutyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl)-L-alanine (compound 3c), the structure of which is shown below:

[0110]

[0111] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol), (chloro((phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (80.0 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3c (44.6 mg, 75% yield); 1 H NMR (500MHz, CDCl3): δ9.63(s,1H),7.33–7.30(m,3H),7.21–7.14(m,3H),5.79(d,J=3.0Hz,1H),5.71(d,J=8.0Hz,1H),4.79(dd,J=6.6,2.8Hz,1 H),4.60(dd,J=6.4,2.9Hz,1H),4.36-4.34(m,3H),4.11–3.99(m,4H),1. 56(s,3H),1.53–1.48(m,1H),1.39-1.29(m,10H),0.87(t,J=7.5Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.9,173.8,163.2,150.6,150.6,150.1,141.3,129.8,125.2,120.1,120.1,114.6,10 2.7,93.0,84.8,84.7,84.2,80.4,67.7,66.3,66.2,50.4,40.2,27.1,25.2,23.2,23.1,21.1,21.0,11.0,10.9. 31P NMR (202MHz, CDCl3): δ2.70, 2.51. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.759min(minor):t R =15.948min(major),97:3dr.

[0112] Example 4

[0113] This embodiment provides a cyclohexyl((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (compound 3d), the structure of which is shown below:

[0114]

[0115] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol), (chloro((phenoxy)phosphoryl)-L-alanine cyclohexyl ester (79.5 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3d (53.4 mg, 90% yield); 1H NMR (500MHz, CDCl3): δ9.08(s,1H),7.33–7.30(m,3H),7.21–7.15(m,3H),5.79(d,J=2.9Hz,1H),5.71(dd,J =8.0,1.8Hz,1H),4.80–4.75(m,2H),4.58(dd,J=6.4,3.0Hz,1H),4.37–4.32(m,3H),4.05–3.98(m,1H),3.95 -3.88(m,1H),1.83–1.78(m,2H),1.73–1.67(m,2H),1.53–1.51(m,4H),1.21–1.46(m,11H). 13 C NMR (126MHz, CDCl3): δ173.1,173.0,163.0,150.7,150.6,150.0,141.3,129.3,125.2,120.11,120.08,114. 6,102.6,93.0,84.8,84.7,84.2,81.0,74.2,66.22,66.18,50.9,31.8,30.8,27.1,25.2,23.5,21.11,21.07. 31 P NMR (202MHz, CDCl3): δ2.77, 2.60. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =16.091min(major):t R =16.341min(minor),96:4dr.

[0116] Example 5

[0117] This embodiment provides a tert-butyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl)-L-alanine (compound 3e), the structure of which is shown below:

[0118]

[0119] The specific preparation steps of the 3e compound are as follows:

[0120] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol), (chloro((phenoxy)phosphoryl)-L-alanine tert-butyl ester (73.5 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3e (53.4 mg, 90% yield); 1 H NMR (500MHz, CDCl3): δ9.42(s,1H),7.35–7.30(m,3H),7.22–7.14(m,3H),5.80(d,J=3.0Hz,1H),5.71(d,J=8.1Hz,1H),4.79(dd,J =6.4,3.0Hz,1H),4.56(dd,J=6.4,3.0Hz,1H),4.37–4.30(m,3H),3.99–3.87(m,2H),1.56(s,3H),1.44(s,9H),1.34–1.31(m,6H). 13 C NMR (126MHz, CDCl3): δ172.8,172.7,163.2,150.7,150.6,150.1,141.3,129.8,125.1,120.11,120.08,114 .6,102.7,92.9,84.8,84.7,84.2,82.2,80.4,66.20,66.16,50.90,50.88,27.9,27.1,25.2,21.08,21.04. 31 P NMR (202MHz, CDCl3): δ2.83, 2.72. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.185min(major):t R =15.483min(minor),95:5dr.

[0121] Example 6

[0122] This embodiment provides a benzyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl)-L-alanine (compound 3f), the structure of which is shown below:

[0123]

[0124] The specific preparation steps of the 3f compound are as follows:

[0125] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol), (chloro((phenoxy)phosphoryl)-L-alanine benzyl ester (81.6 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3f (40.9 mg, 68% yield); 1 H NMR (500MHz, CDCl3): δ9.27(s,1H),7.36-7.27(m,8H),7.18-7.13(m,3H),5.76(d,J=2.7Hz,1H),5.68(d,J=8.1Hz,1H),5.13(s,2H),4.78(dd,J=6.4 ,3.0Hz,1H),4.59(dd,J=6.5,2.8Hz,1H),4.34–4.28(m,3H),4.13–4.05(m ,1H),3.98–3.94(m,1H),1.55(s,3H),1.37(d,J=7.1Hz,3H),1.31(s,3H). 13C NMR (126MHz, CDCl3): δ173.5,173.4,163.2,150.62,150.56,150.1,141.0,135.2,129.8,128.7,128.5,128.3,125. 2,120.11,120.07,114.6,102.6,93.2,84.83,84.77,84.1,80.0,67.8,66.3,66.2,50.5,27.1,25.2,20.91,20.87. 31 P NMR (202MHz, CDCl3): δ2.57, 2.37. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.295min(major):t R =15.611min(minor),98:2dr.

[0126] Example 7

[0127] This example provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-1(2H))-yl)-dimethyltetrahydrofuran[3,4-d][1,3]dioxa-4-yl)methoxy)(phenoxy)phosphoryl)-L-valine (3 g compound), the structure of which is shown below:

[0128]

[0129] The specific preparation steps of the 3g compound are as follows:

[0130] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-valine isopropyl ester (76.8 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate 3 g (36.0 mg, 62% yield) of colorless liquid; 1H NMR (500MHz, CDCl3): δ9.40 (s, 1H), 7.33–7.30 (m, 3H), 7.22 (d, J = 7.9Hz, 2H), 7.16 (t, J = 7.4Hz, 1H), 5.81(d,J=3.1Hz,1H),5.73(d,J=8.1Hz,1H),5.04–4.99(m,1H),4.74(dd,J=6.4,2.9Hz,1H),4.48(dd ,J=6.5,3.1Hz,1H),4.38–4.28(m,3H),3.89(t,J=10.5Hz,1H),3.75(td,J=11.0,10.3,4.8Hz,1H),2. 12–2.09(m,1H),1.55(s,3H),1.30(s,4H),1.23(dd,J=9.8,6.2Hz,7H),0.88(dd,J=16.7,6.8Hz,6H). 13 C NMR (126MHz, CDCl3): δ172.33,172.30,163.2,150.81,150.76,150.1,141.1,129.8,125.2,120.11,120.07,114 .6,102.7,92.6,84.6,84.5,84.1,80.4,69.3,66.2,66.1,60.3,32.1,32.0,27.1,25.2,21.8,21.7,18.9,17.3. 31 P NMR (202MHz, CDCl3): δ3.75, 3.61. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.647min(major):t R =15.894min(minor),97:3dr.

[0131] Example 8

[0132] This embodiment provides a methyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-1(2H))-yl)-dimethyltetrahydrofuran[3,4-d][1,3]dioxa-4-yl)methoxy)(phenoxy)phosphoryl)-L-valine (3h compound), the structure of which is shown below:

[0133]

[0134] The specific preparation steps of the 3h compound are as follows:

[0135] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-valine methyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to obtain a colorless liquid 3h (27.7 mg, 50% yield); 1 H NMR (500MHz, CDCl3): δ8.87(s,1H),7.34-7.30(m,3H),7.21–7.15(m,3H),5.79( d,J=3.0Hz,1H),5.73(d,J=7.9Hz,1H),4.76(dd,J=6.6,2.9Hz,1H),4.53(dd,J=6 .5,2.9Hz,1H),4.36–4.30(m,3H),3.84–3.76(m,1H),3.73–3.68(m,4H),2.08–2 .02(m,1H),1.71(s,3H),1.56(s,3H),1.31(s,3H),0.88(dd,J=16.4,6.9Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.3,163.0,150.8,150.7,150.0,141.2,129.8,125.2,120.1,120.0,1 14.6,102.7,92.9,84.7,84.6,84.2,80.4,66.2,60.2,52.3,32.1,32.0,27.1,25.2,18.9,17.3. 31 P NMR (202MHz, CDCl3): δ3.53, 3.37. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =14.490min(major):t R =14.748min(minor),95:5dr.

[0136] Example 9

[0137] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-1(dihydro))-yl)-dimethyltetrahydrofuran[3,4-d][1,3]dioxa-4-yl)methoxy)(phenoxy)phosphoryl)-L-methionine (compound 3i), the structure of which is shown below:

[0138]

[0139] The specific preparation steps of the 3i compound are as follows:

[0140] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-methionine isopropyl ester (84.1 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3i (21.5 mg, 35% yield); 1 H NMR(500MHz, CDCl3): δ9.41(s,1H),7.37–7.29(m,3H),7.23–7.14(m,3H),5 .76-5.66(m,2H),5.04-4.97(m,1H),4.90–4.78(m,2H),4.39–4.28(m,3H),4 .18–4.11(m,1H),4.05–3.99(m,1H),2.48(t,J=7.4Hz,2H),2.05–1.98(m,4H ),1.92–1.84(m,1H),1.56(s,3H),1.34–1.31(m,3H),1.24(d,J=6.3Hz,6H). 13C NMR (126MHz, CDCl3): δ172.2,172.1,163.2,150.65,150.60,150.0,142.0,129.8,129.7,125.0,120.1,120.0,114.6, 102.7,94.1,85.42,85.36,84.3,80.5,69.6,66.41,66.38,53.7,33.84,33.80,29.6,27.1,25.3,21.74,21.70,15.3. 31 P NMR (202MHz, CDCl3): δ3.01, 2.76. HPLC (ShimadzuLC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =7.341min(major):t R =8.225min(minor),90:10dr.

[0141] Example 10

[0142] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (4-methoxyphenoxy) phosphoryl)-L-alanine (compound 3j), the structure of which is shown below:

[0143]

[0144] The specific preparation steps of the 3j compound are as follows:

[0145] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(4-methoxyphenoxy)phosphoryl)-L-alanine isopropyl ester (77.2 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f=0.50) to separate the colorless liquid 3j (50.2 mg, 86% yield); 1 H NMR (500MHz, CDCl3): δ9.65 (s, 1H), 7.36 (d, J = 8.1Hz, 1H), 7.14–7.10 (m, 2H), 6.83 –6.80(m,2H),5.80(d,J=2.9Hz,1H),5.72(d,J=8.1Hz,1H),5.03–4.98(m,1H),4.79 (dd,J=6.4,3.1Hz,1H),4.64(dd,J=6.4,2.9Hz,1H),4.36–4.32(m,3H),4.05–3.95 (m,2H),3.76(s,3H),1.56(s,3H),1.36–1.32(m,6H),1.23(dd,J=11.8,6.3Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.25,173.19,163.4,156.8,150.2,144.2,144.1,141.4,121.01,121.98 114.7,114.6,102.7,93.0,84.82,84.75,84.2,80.5,69.4,66.2,66.2,55.6,50.5,27.1,25.2,21.7,21.6,21.0,20.9. 31 P NMR (202MHz, CDCl3): δ3.18, 3.08..HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =14.613min(major):t R =14.946min(minor),95:5dr.

[0146] Embodiment 11

[0147] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (4-fluorophenoxy) phosphoryl)-L-alanine (3k compound), the structure of which is shown below:

[0148]

[0149] The specific preparation steps of the 3k compound are as follows:

[0150] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(4-fluorophenoxy)phosphoryl)-L-alanine isopropyl ester (74.4 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3k (49.1 mg, 86% yield); 1 H NMR (500MHz, CDCl3): δ9.72(s,1H),7.35(d,J=8.1Hz,1H),7.19–7.16(m,2H),6.99(t,J=8.3Hz,2H),5.74–5.68(m,2H),5.02–4.97(m,1H),4.8 4–4.81(m,2H),4.35–4.33(m,3H),4.10(t,J=10.4Hz,1H),3.99–3.94(m ,1H),1.56(s,3H),1.33(d,J=5.9Hz,6H),1.22(dd,J=10.8,6.3Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.2,173.1,163.4,160.7,158.7,150.2,146.51,146.49,146.45,146.43,141.9,121.67,121.63,121.60 ,121.57,116.3,116.2,114.6,102.7,93.8,85.2,85.1,84.2,80.6,69.4,66.33,66.29,50.4,27.1,25.2,21.7,21.6,21.0,20.9. 31 PNMR (202MHz,CDCl3):δ2.99. 19 F NMR (471MHz, CDCl3): δ-117.69, -117.92. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R=14.891min(major):t R =15.163min(minor),96:4dr.

[0151] Example 12

[0152] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (4-bromophenoxy) phosphoryl)-L-alanine (compound 31), the structure of which is shown below:

[0153]

[0154] The specific preparation steps of the 31 compound are as follows:

[0155] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(4-bromophenoxy)phosphoryl)-L-alanine isopropyl ester (88.5 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3l (58.7 mg, 93% yield); 1 H NMR (500MHz, CDCl3): δ9.72(s,1H),7.42(d,J=8.3Hz,2H),7.33(d,J=8.1Hz,1H),7.11(d,J=8.3Hz,2H),5.73–5.71(m,2H),5.02–4.95(m,1H) ,4.83(s,2H),4.35–4.32(m,3H),4.13(t,J=10.6Hz,1H),3.98–3.93(m,1H),1.56(s,3H),1.34(d,J=4.2Hz,6H),1.22(dd,J=10.4,6.3Hz,6H). 13C NMR (126MHz, CDCl3): δ173.1,173.0,163.4,150.2,149.8,149.7,141.9,132.7,122.1,122.0,118.0,114. 6,102.7,94.0,85.3,85.2,84.2,80.6,69.5,66.4,66.3,50.42,50.41,27.1,25.2,21.7,21.6,21.0,20.9. 31 PNMR (202MHz, CDCl3): δ2.71, 2.65HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.783min(major):t R =16.033min(minor),95:5dr.

[0156] Example 13

[0157] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (3-bromophenoxy) phosphoryl)-L-alanine (3m compound), the structure of which is shown below:

[0158]

[0159] The specific preparation steps of the 3m compound are as follows:

[0160] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(3-bromophenoxy)phosphoryl)-L-alanine isopropyl ester (88.5 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3m (54.9 mg, 87% yield); 1H NMR (500MHz, CDCl3): δ9.67(s,1H),7.39(s,1H),7.32–7.28(m,2H),7.20-7.16(m,2H),5.74–5.67(m,2H),5.03–4.98(m,1H),4.84–4. 78(m,2H),4.36–4.35(m,3H),4.15(t,J=10.5Hz,1H),3.99–3.95(m,1H),1.56(s,3H),1.39–1.34(m,6H),1.23(dd,J=12.2,6.3Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.1,173.0,163.4,151.2,151.1,150.2,141.8,130.8,128.3,123.65,123.61,122.6,119.1, 119.0,114.7,102.8,93.7,85.13,85.07,84.2,80.5,69.5,66.44,66.39,50.4,27.1,25.3,21.7,21.6,20.95,20.91. 31 P NMR (202MHz, CDCl3): δ2.63, 2.58. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.713min(major):t R =15.963min(minor),94:6dr.

[0161] Embodiment 14

[0162] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (2-bromophenoxy) phosphoryl)-L-alanine (3n compound), the structure of which is shown below:

[0163]

[0164] The specific preparation steps of the 3n compound are as follows:

[0165] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(2-bromophenoxy)phosphoryl)-L-alanine isopropyl ester (88.5 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3n (11.4 mg, 18% yield); 1 H NMR (500MHz, CDCl3): δ9.07(m,1H),7.51–7.42(m,2H),7.31–7.20(m,2H),6.98(t,J=7.7Hz,1H),5.75–5.61(m,2H),4.97–4.89(m,1H),4 .82–4.76(m,1H),4.70–4.48(m,1H),4.37–4.26(m,3H),4.03–3.78(m,2H),1.50(d,J=7.8Hz,3H),1.33–1.24(m,6H),1.18–1.13(m,6H). 13 C NMR (126MHz, CDCl3): δ173.02,172.96,172.9,172.8,163.1,163.0,150.0,147.84,147.80,147.7,1 47.6,141.5,141.0,133.6,133.5,128.8,126.3,121.68,121.67,121.31,121.29,114.7,114.5,114. 4,114.3,102.9,102.7,93.4,92.5,85.0,84.9,84.34,84.28,84.1,80.5,80.3,69.5,69.4,66.81,66.72,66.52,66.48,50.38,50.37,50.35,50.34,27.1,25.3,21.73,21.68,21.6,21.1,21.02,20.98. 31P NMR (202MHz, CDCl3): δ2.76, 2.67. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =64.261min(major):t R =65.198min(minor),34:66dr.

[0166] Embodiment 15

[0167] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (1-naphthyloxy) phosphoryl)-L-alanine (3o compound), the structure of which is shown below:

[0168]

[0169] The specific preparation steps of the 3o compound are as follows:

[0170] In a 10 mL reaction bottle, ligand L2 (4.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(1-naphthyloxy)phosphoryl)-L-alanine isopropyl ester (81.8 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3o (30.8 mg, 51% yield); 1H NMR (500MHz, CDCl3): δ9.06 (s, 1H), 8.11–8.09 (m, 1H), 7.85–7.83 (m, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.58–7 .51(m,3H),7.40(t,J=7.9Hz,1H),6.96(d,J=8.0Hz,1H),5.70(d,J=3.4Hz,1H),5.48(dd,J=8.1,2.1Hz, 1H),5.01–4.96(m,1H),4.63(dd,J=6.5,3.2Hz,1H),4.42–4.37(m,1H),4.35–4.29(m,2H),4.20(dd,J=6 .4,3.4Hz,1H),4.11–4.04(m,2H),1.52(s,3H),1.36(d,J=7.9,3H),1.27(s,3H),1.20(d,J=6.3Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.3,173.2,163.0,149.9,146.7,146.6,140.7,134.7,128.0,126.9,126.6,126.31,126.26,125.53,125.04,12 1.3,115.18,115.16,114.7,102.6,92.3,84.3,84.2,83.7,80.1,69. 5,66.22,66.18,50.61,50.60,27.1,25.2,21.7,21.6,21.05,21.01. 31 P NMR (202MHz, CDCl3): δ3.26, 2.91. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.687min(major):t R =15.950min(minor),95:5dr.

[0171] Example 16

[0172] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(2,4-diketo-3,4-dihydropyrimidin-(2H))-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (ethoxy) phosphoryl)-L-alanine (3p compound), the structure of which is shown below:

[0173]

[0174] The specific preparation steps of the 3p compound are as follows:

[0175] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropyl uridine (28.4 mg, 0.1 mmol), (chloro(ethoxy)phosphoryl)-L-alanine isopropyl ester (59.2 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3p (41.4 mg, 82% yield); 1 H NMR (500MHz, CDCl3): δ9.65 (s, 1H), 7.47–7.40 (m, 1H), 5.82 (d, J = 1.6Hz, 1H), 5. 74(d,J=8.1Hz,1H),5.05–5.00(m,1H),4.91–4.85(m,2H),4.36–4.33(m,1H),4.2 5–4.22(m,2H),4.13–4.03(m,2H),3.88–3.82(m,1H),3.75(t,J=10.2Hz,1H),1. 57(s,3H),1.39–1.35(m,6H),1.30(t,J=7.1Hz,3H),1.25(dd,J=8.8,6.2Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.41,173.36,163.4,150.2,141.6,114.6,102.7,93.3,85.15,85.09,84. 4,80.6,69.2,65.70,65.66,62.93,62.89,50.1,27.2,25.3,21.7,21.6,21.06,21.02,16.2,16.1. 31 P NMR (202MHz, CDCl3): δ7.45, 7.30. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R=64.103min(major):t R =74.743min(minor),92:8dr.

[0176] Embodiment 17

[0177] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-2,2-dimethyl-6-(5-methyl-2,4-diketo-3,4-dihydropyrimidin-1(2H))-yl)tetrahydrofuran-3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3q compound), the structure of which is shown below:

[0178]

[0179] The specific preparation steps of the 3q compound are as follows:

[0180] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylthymidine (29.8 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3q (41.4 mg, 73% yield); 1 H NMR (500MHz, CDCl3): δ9.32(s,1H),7.30(t,J=7.9Hz,2H),7.21–7.14(m,4H),5.78(d,J=2.9Hz,1H),5.02-4.97(m,1H),4.83(dd,J=6.5,3.3Hz,1 H),4.70(dd,J=6.5,2.9Hz,1H),4.37–4.34(m,3H),4.01–3.92(m,2H),1 .90(s,3H),1.56(s,3H),1.36–1.32(m,6H),1.22(dd,J=10.0,6.2Hz,6H) 13C NMR (126MHz, CDCl3): δ173.1,173.0,163.8,150.63,150.58,150.3,137.4,129.7,125.1,120.2,120.1,114.6,111.2,93. 0,84.7,84.6,84.0,80.5,77.3,77.1,76.8,69.4,66.37,66.30,50.42,50.41,27.1,25.3,21.7,21.6,21.02,20.98,12.4. 31 P NMR (202MHz, CDCl3): δ2.68, 2.53. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.019min(major):t R =15.297min(minor),96:4dr.

[0181] Embodiment 18

[0182] This embodiment provides an isopropyl (R)-(((3aR,4R,6R,6aR)-6-(5-fluoro-2,4-diketo-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran-[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3r compound), the structure of which is shown below:

[0183]

[0184] The specific preparation steps of the 3r compound are as follows:

[0185] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 5-fluoro-2',3'-isopropylidene uridine (30.2 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f=0.50) to separate the colorless liquid 3r (22.8 mg, 40% yield); 1 H NMR (500MHz, CDCl3): δ9.61 (s, 1H), 7.51 (d, J = 5.9Hz, 1H), 7.34-7.31 (m, 2H ),7.23(d,J=8.0Hz,2H),7.17(t,J=7.3Hz,1H),5.83(d,J=3.2Hz,1H),5.03– 4.98(m,1H),4.75(d,J=5.2Hz,1H),4.41–4.32(m,4H),4.03–3.96(m,2H),1. 55(s,1H),1.36(d,J=6.4Hz,3H),1.31(s,3H),1.23(dd,J=11.6,6.3Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.24,173.18,157.0,156.8,150.63,150.58,148.7,141.5,139.6,129.8,125.3,125.1,124 .9,120.04,120.00,114.7,92.3,84.4,84.3,84.0,80.3,69.5,66.2,66.1,50.5,27.1,25.2,21.7,21.6,20.9,20.8. 31 P NMR (202MHz, CDCl3): δ2.86,2.65. 19 FNMR (471MHz, CDCl3): δ-164.85, -164.95. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =14.731min(major):t R =15.066min(minor),95:5dr.

[0186] Embodiment 19

[0187] This embodiment provides an isopropyl (R)-(((3aR,4R,6R,6aR)-6-(5-bromo-2,4-diketo-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran-[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3s compound), the structure of which is shown below:

[0188]

[0189] The specific preparation steps of the 3s compound are as follows:

[0190] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 5-bromo-2',3'-isopropylidene uridine (36.3 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3s (34.7 mg, 55% yield); 1 H NMR (500MHz, CDCl3): δ9.56(s,1H),7.74(s,1H),7.30-7.33(m,2H),7.27–7.21( m,2H),7.17(t,J=7.3Hz,1H),5.79–5.78(m,1H),5.01(m,1H),4.72–4.71(m,1H) ,4.42–4.38(m,2H),4.35–4.31(m,2H),4.08–4.03(m,1H),3.95(t,J=10.5Hz,1H ),1.55(s,3H),1.37(d,J=7.0Hz,3H),1.30(s,3H),1.23(dd,J=10.7,6.3Hz,6H). 13 CNMR (126MHz, CDCl3): δ173.1,173.0,159.0,150.7,150.6,149.4,140.4,129.8,125.3,120.09,120.06,1 14.6,97.0,93.0,84.83,84.77,84.2,80.5,69.5,66.3,66.2,50.5,27.0,25.1,21.7,21.6,20.99,20.95. 31 P NMR (202MHz, CDCl3): δ2.84, 2.65. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.101min(major):tR =15.439min(minor),95:5dr.

[0191] Embodiment 20

[0192] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -L-alanine (3t compound), the structure of which is shown below:

[0193]

[0194] The specific preparation steps of the 3t compound are as follows:

[0195] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2',3'-isopropylidene adenosine (30.7 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate 3t of colorless liquid (36.3mg, 63% yield); 1 H NMR (500MHz, CDCl3): δ8.36 (s, 1H), 8.00 (s, 1H), 7.24 (t, J = 7.8Hz, 2H), 7.12 –7.06(m,3H),6.10(d,J=2.6Hz,1H),5.95(s,2H),5.10(dd,J=6.3,2.6Hz,1H) ,5.01–4.94(m,2H),4.54–4.52(m,1H),4.38–4.28(m,2H),3.97–3.92(m,2H), 1.60(s,3H),1.35(s,3H),1.28(d,J=5.6Hz,3H),1.21(dd,J=8.9,6.3Hz,6H). 13C NMR (126MHz, CDCl3): δ173.1,173.0,155.6,153.3,150.61,150.55,129.6,125.0,120.04,120.00,11 4.4,91.4,85.32,85.26,84.2,81.3,69.2,66.25,66.21,50.4,27.1,25.2,21.7,21.6,20.90,20.86. 31 P NMR (202MHz, CDCl3): δ2.77, 2.67. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =14.909min(major):t R =15.258min(minor),96:4dr.

[0196] Embodiment 21

[0197] This embodiment provides an isopropyl ((R)-(((3aR,4R,6R,6aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran [3, 4-d][1, 3] dioxol-4-yl) methoxy) (phenoxy) phosphoryl) -L-alanine (3u compound), the structure of which is shown below:

[0198]

[0199] The specific preparation steps of the 3u compound are as follows:

[0200] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 6-chloro-2',3'-isopropylidene adenosine (34.2 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3u (38.4 mg, 63% yield); 1H NMR (500MHz, CDCl3): δ7.87(s,1H),7.22–7.19(m,2H),7.08–7.04(m,3H),6 .17(s,2H),6.00–5.99(m,1H),4.99–4.97(m,1H),4.93–4.86(m,2H),4.42–4 .41(m,1H),4.28–4.25(m,,2H),3.90–3.84(m,1H),3.74(t,J=10.4Hz,1H),1 .53(s,3H),1.27(s,3H),1.22(d,J=7.0Hz,3H),1.14(dd,J=9.8,6.2Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.03,172.97,156.2,154.4,150.6,150.5,129.7,125.1,120.10,120.07,114. 7,90.7,85.1,85.0,84.0,81.1,69.3,66.22,66.18,50.43,50.41,27.1,25.3,21.7,21.6,20.93,20.89. 31 P NMR (202MHz, CDCl3): δ2.68, 2.59. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.760min(major):t R =16.004min(minor),96:4dr.

[0201] Embodiment 22

[0202] This embodiment provides an isopropyl ((R)-(((2S,3S,5R))-3-azido-5-(5-methyl-2,4-diketo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (compound 3v), the structure of which is shown below:

[0203]

[0204] The specific preparation steps of the 3v compound are as follows:

[0205] In a 10 mL reaction bottle, ligand L2 (4.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), zidovudine (26.7 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3v (49.3 mg, 92% yield); 1 H NMR (500MHz, CDCl3): δ9.14(s,1H),7.37–7.32(m,3H),7.24–7.18(m,3H),6.2 2(t,J=6.7Hz,1H),5.04–4.99(m,1H),4.39–4.33(m,3H),4.07–3.97(m,2H),3. 92–3.87(m,1H),2.35(ddd,J=13.9,6.3,4.1Hz,1H),2.12(dt,J=14.2,7.3Hz, 1H), 1.93 (d, J = 1.3Hz, 3H), 1.36 (d, J = 7.1Hz, 3H), 1.24 (dd, J = 8.9, 6.3Hz, 6H). 13 C NMR (126MHz, CDCl3): δ173.1,173.0,163.7,150.44,150.38,150.2,135.3,129.9,125.4,120.1,1 20.0,111.4,84.7,82.42,82.36,69.6,65.7,65.6,60.3,50.5,37.3,21.7,21.6,21.0,20.9,12.5. 31 PNMR (202MHz, CDCl3): δ3.11, 2.78. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =23.788min(major):t R =24.062min(minor),95:5dr.

[0206] Embodiment 23

[0207] This embodiment provides an isopropyl ((R)-(((2S,3S,5R))-3-benzyloxy-5-(5-methyl-2,4-diketo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3w compound), the structure of which is shown below:

[0208]

[0209] The specific preparation steps of the 3w compound are as follows:

[0210] In a 10 mL reaction bottle, add ligand L2 (4.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 3'-O-benzylthymidine (33.2 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3w (56.5 mg, 94% yield); 1 H NMR (500MHz, CDCl3): δ9.28(s,1H),7.39–7.29(m,8H),7.20–7.16(m,3H),6.33(dd, J=8.3,5.8Hz,1H),5.04–4.99(m,1H),4.56–4.48(m,2H),4.34(dd,J=6.3,2.9Hz,2H) ,4.26–4.21(m,2H),4.02–3.88(m,2H),2.38(ddd,J=13.8,5.9,2.2Hz,1H),1.92(s,3 H),1.81(ddd,J=14.0,8.2,6.1Hz,1H),1.36(d,J=6.9Hz,3H),1.23(t,J=6.8Hz,6H). 13C NMR (126MHz, CDCl3): δ173.04,172.98,163.9,150.6,150.5,150.4,137.3,135.4,129.8,128.6,128.0,127.7,125.3 ,120.1,120.0,111.2,84.9,83.0,82.9,78.6,71.7,69.5,66.32,66.29,50.5,37.3,21.7,21.6,21.02,20.98,12.6. 31 P NMR (202MHz, CDCl3): δ3.11, 2.78. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =16.102min(major):t R =16.271min(minor),94:6dr.

[0211] Embodiment 24

[0212] This embodiment provides a ((R)-(((2S,3S,5R))-3-tert-butyldimethylsilyloxy-5-(5-methyl-2,4-diketo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (3x compound), the structure of which is shown below:

[0213]

[0214] The specific preparation steps of the 3x compound are as follows:

[0215] In a 10 mL reaction bottle, add ligand L2 (4.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 3'-O-(tert-butyldimethylsilyl)thymidine (35.6 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate into a colorless liquid 3x (50.0 mg, 80% yield); 1H NMR (500MHz, CDCl3): δ8.82(s,1H),7.29(s,1H),7.24(t,J=7.8Hz,2H),7.14(d,J=8.0Hz ,2H),7.09(t,J=7.4Hz,1H),6.23(t,J=7.0,1H),4.96–4.91(m,1H),4.34(dt,J=6.2,3.0H z,1H),4.27–4.19(m,2H),3.96–3.87(m,2H),3.76–3.72(m,1H),2.07(ddd,J=13.6,6.0, 2.9Hz,1H),1.84(s,3H),1.78–1.73(m,1H),1.18–1.14(m,6H),0.81(s,9H),0.00(s,6H). 13 C NMR (126MHz, CDCl3): δ173.0,172.9,163.7,150.6,150.5,150.2,135.5,129.8,125.3,120.1,120.0,111.1,85.53,85.47, 84.8,77.3,77.2,77.0,76.8,71.7,69.5,65.71,65.67,50.5,40.6,25.7,21.7,21.6,21.04,21.00,17.9,12.6,-4.7,-4.9. 31 P NMR (202MHz, CDCl3): δ2.89, 2.67. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =31.631min(major),t R =32.07min(minor),97:3dr.

[0216] Embodiment 25

[0217] This embodiment provides an isopropyl ((R)-(((2S,5R))-5-(5-methyl-2,4-diketo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3y compound), the structure of which is shown below:

[0218]

[0219] The specific preparation steps of the 3y compound are as follows:

[0220] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), stavudine (22.4 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3y (47.3 mg, 96.0% yield); 1 H NMR (500MHz, CDCl3): δ9.17(s,1H),7.34–7.30(m,3H),7.18–7.15(m,3H),7.0 5–7.03(m,1H),6.35(d,J=6.0Hz,1H),5.87(d,J=5.8Hz,1H),5.04–4.97(m,2H) ,4.40(ddd,J=11.7,6.7,2.8Hz,1H),4.32(ddd,J=11.7,6.0,2.8Hz,1H),3.95– 3.84(m,2H),1.83(s,3H),1.30(d,J=6.9Hz,3H),1.22(dd,J=11.5,6.3Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.11,173.05,163.9,150.9,150.3,150.2,136.0,133.3,129.7,127.4,125. 2,120.24,120.20,111.3,89.6,84.74,84.68,69.5,66.52,66.48,50.4,21.7,21.6,21.0,20.9,12.4. 31 P NMR (202MHz, CDCl3): δ3.37, 2.77. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.760min(major):t R =16.004min(minor),98:2dr.

[0221] Embodiment 26

[0222] This embodiment provides an isopropyl ((R)-(((3a'R,4'R,6'R,6a'R)-4'-(2,4-diketo-3,4-dihydropyrimidin-1(2H))-yl)tetrahydrospiro[cyclohexane-1,2'-furo[3,4-d][1,3]dioxole]-6'-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (compound 3z), the structure of which is shown below:

[0223]

[0224] The specific preparation steps of the 3z compound are as follows:

[0225] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 1-((3a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furo[3,4-d][1,3]dioxol]-6'-yl)pyrimidine-2,4(1H,3H)-dione (32.4 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3z (50.4 mg, 85.0% yield); 1 H NMR (500MHz, CDCl3): δ9.21 (s, 1H), 7.26–7.23 (m, 3H), 7.14 (d, J = 8.0Hz, 2H), 7.09 (t, J =7.4Hz,1H),5.74(d,J=3.0Hz,1H),5.64(d,J=8.0Hz,1H),4.93(m,1H),4.71(d,J=4.1H z,1H),4.50(dd,J=6.4,3.0Hz,1H),4.31–4.25(m,3H),3.94–3.88(m,2H),1.71-1.68(m ,2H),1.59–1.55(m,2H),1.47(m,4H),1.33–1.27(m,5H),1.16(dd,J=11.7,6.3Hz,6H). 13C NMR(126MHz, CDCl3):173.2,173.1,163.3,150.7,150.6,150.1,141.5,129.8,125.2,120.11,120.08,115.4,102.7, 93.0,84.8,84.7,83.6,80.1,69.4,66.30,66.26,50.49,50.47,36.9,34.6,24.9,23.9,23.5,21.7,21.6,21.0,20.9. 31 P NMR (202MHz, CDCl3): δ2.72, 2.58. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =16.160min(major):t R =16.642min(minor),97:3dr.

[0226] Embodiment 27

[0227] This embodiment provides a 2-ethylbutyl ((R)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3aa compound), the structure of which is shown below:

[0228]

[0229] The specific preparation steps of the 3aa compound are as follows:

[0230] In a 10 mL reaction bottle, add ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), remdesivir intermediate (33.1 mg, 0.1 mmol), (chloro(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (80.0 mg, 0.23 mmol), Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f=0.50) to separate the colorless liquid 3aa (41.1 mg, 64% yield); 1 H NMR (500MHz, CDCl3): δ7.95(s,1H),7.25(t,J=7.9Hz,2H),7.14–7.12(m,3H),6.91(d,J= 4.5Hz,1H),6.59(d,J=4.6Hz,1H),6.07(s,2H),5.28(d,J=6.7Hz,1H),4.92(dd,J=6.8,3. 7Hz,1H),4.62–4.60(m,1H),4.37(dddd,J=34.4,11.3,6.5,4.1Hz,2H),4.13–3.95(m,4H ),1.75(s,3H),1.50–1.45(m,1H),1.37(s,3H),1.34–1.26(m,8H),0.85(t,J=7.5Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.64,173.57,155.3,150.63,150.57,147.5,129.6,125.1,123.2,120.23,120.19,117.1,116.8,115.7 ,112.4,100.1,83.8,83.5,83.3,81.38,81.36,67.6,65.44,65.40,50.3,40.2,26.2,25.4,23.2,23.1,21.01,20.97,11.0,10.9. 31 P NMR (202MHz, CDCl3): δ2.66. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =16.475min,>99:1dr.

[0231] Embodiment 28

[0232] This embodiment provides a (R)-Remdesivir (3ab compound), the structure of which is shown below:

[0233]

[0234] The specific preparation steps of the 3ab compound are as follows:

[0235] In a 10 mL reaction bottle, the 3aa compound prepared in Example 27 (35.2 mg, 0.054 mmol) and ultra-dry THF (1.0 mL) were added. The reaction system was placed at 0°C, and concentrated hydrochloric acid (1 mL) was slowly added dropwise. After the addition was completed, the temperature was restored to room temperature and the reaction was allowed to proceed overnight. A saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic phase was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (DCM: MeOH = 5:1, R f =0.40) to separate the colorless liquid 3ab (22.8 mg, 69% yield); 1 H NMR (500MHz, CD3OD): δ7.87(s,1H),7.32–7.29(m,2H),7.18–7.15(m,3H),6.94–6 .91(m,2H),4.81(d,J=5.5Hz,1H),4.62(s,1H),4.47–4.40(m,2H),4.33(ddd,J=11 .2,5.7,4.0Hz,1H),4.22(t,J=5.5Hz,1H),4.06–3.98(m,2H),3.90-3.84(m,1H),1 .52–1.46(m,1H),1.38–1.31(m,5H),1.26(d,J=7.1Hz,3H),0.88(t,J=7.5Hz,6H). 13 C NMR (126MHz, CD3OD): δ173.8,173.7,155.7,150.8,150.7,146.8,129.3,124.7,124.2,120.03,120.00,116.7,116. 2,111.0,101.3,83.2,83.1,79.6,74.3,70.1,66.7,65.4,65.3,50.2,40.3,22.82,22.80,19.02,18.97,9.93,9.90. 31 P NMR (202MHz, CDCl3): δ3.57. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =15.329min,>99:1dr.

[0236] Embodiment 29

[0237] This embodiment provides a (R)-Stampidine (3ac compound), the structure of which is shown below:

[0238]

[0239] The specific preparation steps of the 3ac compound are as follows:

[0240] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), stavudine (22.4 mg, 0.1 mmol), (chloro(4-bromophenoxy)phosphoryl)-L-alanine methyl ester (82.0 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3ac (49.4 mg, 91% yield); 1 H NMR (500MHz, CDCl3): δ9.41(s,1H),7.43(d,J=8.8Hz,2H),7.30(d,J=1.5Hz,1H),7.12–7.01(m,3H),6.36–6.28(m,1H),5. 93-5.88(m,1H),5.05–5.00(m,1H),4.40–4.32(m,2H),4.07–3.92(m,2H),3.70(s,3H),1.81(s,3H),1.33(d,J=7.0Hz,3H). 13 C NMR (126MHz, CDCl3): δ174.1,174.0,164.0,150.9,149.4,149.3,135.9,133.2,132.7,127.5 ,122.11,122.07,118.2,111.2,89.6,84.6,84.5,66.63,66.59,52.7,50.2,20.9,20.8,12.4. 31 P NMR (202MHz, CDCl3): δ3.36, 2.69. HPLC (Shimadzu LC-2030) (AgilentXDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =27.020min(major):t R =29.423min(minor),97:3dr.

[0241] Embodiment 30

[0242] This embodiment provides a benzyl ((R)-(((2S,3S,5R))-3-tert-butyldimethylsilyloxy-5-(5-fluoro-2,4-diketo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(1-naphthyloxy)phosphoryl)-L-alanine (3ad compound), the structure of which is shown below:

[0243]

[0244] The specific preparation steps of the 3ad compound are as follows:

[0245] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 5-fluoro-3'-tert-butyldimethylsilyloxyuridine (36.0 mg, 0.1 mmol), (chloro(1-naphthyloxy)phosphoryl)-L-alanine benzyl ester (92.9 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3ad (37.8 mg, 52% yield); 1 H NMR (500MHz, Acetone-d6): δ8.13(d,J=8.1Hz,1H),7.84(d,J=8.4Hz,1H),7.67–7.65(m,2H),7.54(d ,J=6.8Hz,1H),7.47-7.41(m,2H),7.37(t,J=7.9Hz,1H),7.28–7.20(m,5H),6.11(t,J=7.0Hz,1H),5. 20(t,J=10.9Hz,1H),5.05–4.97(m,2H),4.41-4.39(m,1H),4.32–4.24(m,2H),4.16–4.08(m,1H),4.0 0-3.98(m,1H),1.77–1.72(m,1H),1.28(d,J=7.2Hz,3H),1.23–1.17(m,1H),0.80(s,9H),0.00(s,6H) 13C NMR (126MHz, CDCl3): δ173.23,173.20,156.51,156.49,148.8,147.1,147. 0,141.1,139.5,136.1,134.9,128.4,128.1,128.0,127.8,126.7,126.3,12 5.56,125.55,124.6,124.0,123.7,121.7,115.14,115.14,85.9,85.8,85.0,72.2,66.4,65.9,65.8,50.6,39.9,25.2,19.72,19.67,17.6,-5.5,-5.6. 31 P NMR (202MHz, CDCl3): δ3.58, 3.18. 19 F NMR (471MHz, CDCl3): δ-163.50, -163.92. HPLC (Shimadzu LC-2030) (AgilentXDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =33.495min(major):t R =37.686min(minor),96:4dr.

[0246] Embodiment 31

[0247] This embodiment provides a (R)-NUC-3373 (3ae compound), the structure of which is shown below:

[0248]

[0249] The specific preparation steps of the 3ae compound are as follows:

[0250] In a 10 mL reaction bottle, the compound 3ad prepared in Example 30 (37.8 mg, 0.05 mmol) was added. After nitrogen replacement three times, TFA (1 mL) was added dropwise at 0°C, and then the system was warmed to room temperature and stirred overnight. A saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic phase was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography (DCM: MeOH = 5:1, R f =0.40) to separate the colorless liquid 3ae (23.3 mg, 76% yield); 1H NMR (500MHz, CD3OD): δ8.08–8.06(m,1H),7.82–7.80(m,1H),7.64(t,J=7.3Hz,2H),7.47–7 .42(m,3H),7.35(t,J=7.9Hz,1H),7.28–7.20(m,5H),6.08–6.05(m,1H),5.07–4.99(m,2H) ,4.56(s,1H),4.27–4.25(m,2H),4.21(dt,J=5.9,2.8Hz,1H),4.06–3.97(m,2H),2.02(ddd ,J=13.7,5.9,2.7Hz,1H),1.61(ddd,J=13.9,7.9,6.2Hz,1H),1.28(dd,J=7.2,1.4Hz,3H). 13 C NMR (126MHz, CDCl3): δ173.43,173.38,156.9,148.6,146.3,146.2,141.6,139.5,135.0,134.7,128.6,128.5,128.2,127.9,126.9,12 6.8,126.22,126.15,125.4,125.3,123.9,123.6,121.0,115.12,115.10,85.14,85.09,85.0,70.3,67.5,65.8,50.6,39.8,20.8,20.7. 31 P NMR (202 MHz, CDCl3): δ 4.64. 19 F NMR (471MHz, CDCl3): δ-167.18. HPLC (Shimadzu LC-2030) (AgilentXDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =22.977min(major):t R =24.463min(minor),96:4dr.

[0251] Embodiment 32

[0252] This embodiment provides an isopropyl ((R)-(((2R,3R,4R,5R))-3-tert-butyldimethylsilyloxy-5-(2,4-diketo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3af compound), the structure of which is shown below:

[0253]

[0254] The specific preparation steps of the 3af compound are as follows:

[0255] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), 2'-fluoro-2'-methyl-3'-tert-butyldimethylsilyloxyuridine (37.4 mg, 0.1 mmol), (chloro(1-phenoxy)phosphoryl)-L-alanine isopropyl ester (70.3 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3af (37.3 mg, 58% yield); 1 H NMR (500MHz, CDCl3): δ9.70 (s, 1H), 7.46 (d, J = 8.2Hz, 1H), 7.19 (t, J = 7.8Hz, 2H), 7.08 (d, J=8.0Hz,2H),7.04(t,J=7.4Hz,1H),6.05(d,J=18.4Hz,1H),5.54(d,J=8.1Hz,1H),4.91– 4.86(m,1H),4.48(dd,J=11.8,2.4Hz,1H),4.19–4.13(m,2H),3.98(d,J=6.5Hz,1H),3.88 –3.73(m,2H),1.19–1.14(m,6H),1.08(dd,J=16.2,6.3Hz,6H),0.77(s,9H),-0.05(s,6H). 13 C NMR (126MHz, CDCl3): δ173.64,173.58,163.4,150.42,150.37,150.2,139.1,125.3,120.11,120.07,102.9,100. 0,98.5,79.9,79.8,72.20,72.06,69.6,62.9,50.7,25.6,21.7,21.6,20.91,20.87,17.9,17.2,17.0,-4.3,-4.5. 31 P NMR (202MHz, CDCl3): δ2.90, 2.50. 19F NMR (471MHz, CDCl3): δ-163.41. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =18.046min(major):t R =18.886min(minor),99:1dr.

[0256] Embodiment 33

[0257] This embodiment provides a (R)-sofosbuvir (3ag compound), the structure of which is shown below:

[0258]

[0259] The specific preparation steps of the 3ag compound are as follows:

[0260] In a 10 mL reaction bottle, the compound 3af prepared in Example 32 (37.3 mg mg, 0.058 mmol) was added. After nitrogen replacement three times, TFA (1 mL) was added dropwise at 0°C, and then the system was warmed to room temperature and stirred overnight. Saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic phase was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography (DCM: MeOH = 5:1, R f =0.40) to separate the colorless liquid 3ag (23.9 mg, 78% yield), 1 H NMR (500MHz, CDCl3): δ7.22–7.18(m,3H),7.10(d,J=8.0Hz,2H),7.03(t,J=7. 4Hz,1H),6.05(d,J=19.0Hz,1H),5.44(d,J=8.1Hz,1H),4.91-4.86(m,1H),4.3 8–4.36(m,2H),4.29(t,J=10.7Hz,1H),4.00–3.97(m,1H),3.89-3.84(m,1H), 3.69(dd,J=23.6,9.3Hz,1H),1.24–1.14(m,6H),1.10(dd,J=11.1,6.2Hz,6H). 13C NMR (126MHz, CDCl3): δ173.45,173.39,163.5,150.45,150.40,150.35,130.0,125.4,119.89,119.85,102. 8,101.0,99.5,80.7,79.9,78.5,71.4,71.2,69.7,63.46,63.45,50.6,21.7,21.6,20.8,20.7,16.6,16.4. 31 P NMR (202 MHz, CDCl3): δ 3.74. 19 F NMR (471MHz, CDCl3): δ-161.96. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =13.526min(major):t R =13.901min(minor),99:1dr.

[0261] Embodiment 34

[0262] This embodiment provides a benzyl ((R)-(((2S,4R,5R))-5-(6-amino-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine (3ah compound), the structure of which is shown below:

[0263]

[0264] The specific preparation steps of the 3ah compound are as follows:

[0265] In a 10 mL reaction bottle, ligand L1 (7.4 mg, 0.015 mmol), copper acetylacetonate (2.6 mg, 0.01 mmol), cordycepin (36.6 mg, 0.1 mmol), (chloro(1-phenoxy)phosphoryl)-L-alanine benzyl ester (81.4 mg, 0.23 mmol) were added. Molecular sieves (20 mg), the reaction system was placed in a glove box, and then diisopropylethylamine (40.0 μL, 0.23 mmol, DIPEA) and ethylene glycol dimethyl ether (1.0 mL) were added in sequence. The reaction device was sealed, taken out of the glove box, and stirred at 0°C for 60 h. After the reaction was completed, column chromatography (DCM: MeOH = 10:1, R f =0.50) to separate the colorless liquid 3ah (49.2 mg, 72% yield); 1H NMR (500MHz, CDCl3): δ8.24(s,1H),8.03(s,1H),7.28–7.11(m,9H),7.04(t,J=7.3Hz,1H),6.10(s, 2H),5.86(d,J=1.7Hz,1H),5.06–5.01(m,2H),4.73–4.72(m,1H),4.61–4.58(m,1H),4.38–4.42(m, 1H),4.22–4.17(m,1H),4.11(t,J=10.5Hz,1H),4.04–3.96(m,1H),2.11(ddd,J=13.2,9.7,5.2Hz,1 H),1.85(ddd,J=13.1,5.9,2.2Hz,1H),1.25(d,J=7.1Hz,3H),0.82(s,9H),0.01(d,J=12.8Hz,6H). 13 C NMR (126MHz, CDCl3): δ173.40,173.35,155.5,152.8,150.62,150.57,149.3,138.9,135.3,129.7,128.6,128.4,128.2,1 25.0,120.22,120.18,120.0,92.3,79.0,78.9,76.3,67.2,66.82,66.78,50.4,34.3,25.7,20.9,20.8,17.9,-4.8,-5.0. 31 P NMR (202MHz, CDCl3): δ2.98. HPLC (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =13.868min(major):t R =14.55min(minor),97:3dr.

[0266] Embodiment 35

[0267] This embodiment provides a (R)-cordycepin (3ai compound), the structure of which is shown below:

[0268]

[0269] The specific preparation steps of the 3ai compound are as follows:

[0270] In a 10 mL reaction bottle, the compound 3ah prepared in Example 32 (49.2 mg mg, 0.072 mmol) was added. After nitrogen replacement three times, TFA (1 mL) was added dropwise at 0°C, and then the system was warmed to room temperature and stirred overnight. Saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic phase was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography (DCM: MeOH = 5:1, R f =0.40) to separate the colorless liquid 3ai (25.8 mg, 63% yield), 1 H NMR (500MHz, CDCl3): δ8.23(s,1H),8.15(s,1H),7.23–7.17(m,7H),7.08–7.03(m,3H),5. 92(d,J=1.8Hz,1H),5.00(d,J=2.6Hz,2H),4.63–4.61(m,1H),4.57–4.52(m,1H),4.30(ddd ,J=11.5,5.6,2.7Hz,1H),4.13(ddd,J=11.6,6.1,3.8Hz,1H),3.84–3.78(m,1H),2.21(ddd ,J=13.5,9.5,5.6Hz,1H),1.95(ddd,J=13.4,6.1,2.4Hz,1H),1.17(dd,J=7.2,1.3Hz,3H). 13 C NMR (126MHz, CDCl3): δ173.43,173.40,154.2,150.7,150.6,149.8,148.5,140.0,135.9,129.3,128.2,127 .90,127.87,124.8,120.1,120.0,119.1,91.9,79.2,79.1,75.3,66.8,66.7,66.5,50.3,33.2,18.9,18.8. 31 P NMR (202MHz, CDCl3): δ2.76. HPLC (Shimadzu LC-2030) (AgilentXDB-C18, H2O:MeOH=90.0:10.0, 0.5mL / min, 35℃, 254nm), t R =13.435min(major):t R =13.646min(minor),97:3dr.

[0271] Embodiment 35

[0272] This example investigates the yield and dr value of the compound 3a described in Example 1 prepared under different conditions. The specific preparation steps are basically the same as those in Example 1, except that the conditions in Table 1 below are changed. Experimental Group 1 is to prepare compound 3a under the same conditions as Example 1, and Experimental Groups 2-16 are to prepare compound 3a by changing some of the conditions.

[0273] Table 1

[0274]

[0275]

[0276] The yield and dr value results of each experimental group are shown in Table 1. The comparison of experimental group 1 and experimental group 2-4 using different reaction temperatures shows that when the temperature gradually increases (10℃, room temperature), the yield and dr are significantly reduced; although the dr at -10℃ is higher than 0℃, the yield decreases greatly. The comparison of experimental group 1 and experimental group 5-6 using different bases shows that the use of strong organic bases will increase the background reaction and cause the dr value to decrease. The comparison of experimental group 1 and experimental group 7-10 using different catalysts shows that the selection of different catalysts, including changing the metal type, will have a negative effect on the reaction. The comparison of experimental group 1 and experimental group 11 shows that the reaction activity and stereoselectivity are significantly reduced by reducing the feed amount of phosphoramide. The comparison of experimental group 1 and experimental group 12 shows that the reduction of catalyst loading has an adverse effect on the diastereoselectivity of the reaction, which is only 18:1. The comparison of experimental group 1 and experimental group 13-17 shows that the replacement of the ligand type with other bidentate nitrogen ligands cannot achieve stereoselective control.

[0277] Comparative Example 1

[0278] This comparative example provides a method for preparing a nucleoside prodrug (compound 3a), which is different from the method for preparing the experimental group 1 in Example 53 in that the chiral ligand L1 is not added in this comparative example. The results show that dr=1:1, and the stereoselectivity of the reaction cannot be controlled.

[0279] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A nucleoside prodrug intermediate or a nucleoside prodrug, characterized in that: The nucleoside prodrug intermediate includes a compound structure shown in Formula I, Formula II or Formula III; the nucleoside prodrug includes a compound structure shown in Formula IV; Among them, R 1 is any one of methyl, 2-ethylbutyl, isopropyl, tert-butyl, cyclohexyl and benzyl; R 2 Any one of methyl, isopropyl, and methylthioethyl; R 3 for Any of the following, where R 9 is any one of hydrogen, halogen, and methoxy; R 4 is any one of uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine, 6-chloroadenine, and pyrrolo[2,1-f][1,2,4]triazine-4-amine; R 5 Any of hydrogen and cyano; R 6 is any one of azido, benzyloxy, and tert-butyldimethylsilyl; R 7 Any one of hydrogen, halogen, and tert-butyldimethylsilyl; R 8 It is either hydrogen or methyl.

2. The nucleoside prodrug intermediate or nucleoside prodrug according to claim 1, characterized in that: The nucleoside prodrug intermediates include any one of different substituted phosphoramide nucleoside prodrug intermediates, different base substituted nucleoside prodrug intermediates, deoxynucleosides and other nucleoside prodrug intermediates; The structures of the different substituted phosphoramide nucleoside prodrug intermediates are shown in Formula I-1, Formula I-2, and Formula I-3; the structures of the different base substituted nucleoside prodrug intermediates are shown in Formula I-4; the structures of the deoxynucleosides and other nucleoside prodrug intermediates are shown in Formula II-1 and Formula III-1; The nucleoside prodrugs include deoxynucleosides and other nucleoside prodrugs, and the structures are shown in the following formula II-1, formula IV-1, and formula IV-1; Among them, R 1 is any one of methyl, 2-ethylbutyl, isopropyl, tert-butyl, cyclohexyl and benzyl; R 2 Any one of methyl, isopropyl, and methylthioethyl; R 4 is any one of uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine, 6-chloroadenine, and pyrrolo[2,1-f][1,2,4]triazine-4-amine; R 5 Any of hydrogen and cyano; R 6 is any one of azido, benzyloxy, and tert-butyldimethylsilyl; R 7 Any one of hydrogen, halogen, and tert-butyldimethylsilyl; R 8 is any of hydrogen or methyl; R 9 It is any of hydrogen, halogen and methoxy.

3. A method for preparing a nucleoside prodrug intermediate or a nucleoside prodrug according to claim 1 or 2, characterized in that: The following steps are involved: In organic solvents, bases, chiral ligands, In the presence of molecular sieves and catalysts, nucleoside compounds are reacted with racemic phosphoramide under metal catalysis conditions to generate nucleoside prodrug intermediates or nucleoside prodrugs.

4. The method for preparing the nucleoside prodrug intermediate or the nucleoside prodrug according to claim 1, characterized in that: The reaction temperature is -10°C to 10°C, and the reaction time is 50 to 70 hours.

5. The method for preparing the nucleoside prodrug intermediate or the nucleoside prodrug according to claim 3, characterized in that: The nucleoside compound is selected from at least one of 2',3'-isopropylidene uridine, 5-fluoro-2',3'-isopropylidene uridine, 5-bromo-2',3'-isopropylidene uridine, 2',3'-isopropylidene thymidine, 2',3'-isopropylidene adenosine, 6-chloro-2',3'-isopropylidene adenosine, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, remdesivir intermediate, cordycepin, and 1-((3a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furo[3,4-d][1,3]dioxol]-6-yl)pyrimidine-2,4(1H,3H)-dione.

6. The method for preparing a nucleoside prodrug intermediate or a nucleoside prodrug according to claim 3, characterized in that: The phosphoramide is selected from (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-alanine methyl ester, (chloro(phenoxy)phosphoryl)-L-alanine-2-ethylbutyl ester, (chloro(phenoxy)phosphoryl)-L-alanine cyclohexyl ester, (chloro(phenoxy)phosphoryl)-L-alanine tert-butyl ester, (chloro(phenoxy)phosphoryl)-L-alanine benzyl ester, (chloro(phenoxy)phosphoryl)-L-valine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-valine methyl ester, (chloro(phenoxy)phosphoryl)-L-methionine isopropyl ester, (chloro(phenoxy)phosphoryl)-L-methionine methyl ... ester, (chloro(4-methoxyphenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(4-fluorophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(4-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(3-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(2-bromophenoxy)phosphoryl)-L-alanine isopropyl ester, (chloro(1-naphthyloxy)phosphoryl)-L-alanine isopropyl ester, (chloro(ethoxy)phosphoryl)-L-alanine isopropyl ester, and (chloro(1-naphthyloxy)phosphoryl)-L-alanine benzyl ester.

7. The method for preparing the nucleoside prodrug intermediate or the nucleoside prodrug according to any one of claims 3 to 5, characterized in that: The molar ratio of the nucleoside-containing compound to the phosphoramide is 1:1.5-2.

5.

8. The method for preparing a nucleoside prodrug intermediate or a nucleoside prodrug according to claim 3, characterized in that: The organic solvent is selected from ethylene glycol dimethyl ether, tetrahydrofuran, and acetonitrile; the base is selected from diisopropylethylamine, Et3N, and DBU; the catalyst is selected from copper acetylacetonate, Cu(OTf)2, CuBr2, Ni(OTf)2, and Fe(OTf)3; the chiral ligand is selected from ligand L1 and ligand L2, and the ligand structure is as follows: The molar ratio of the catalyst to the nucleoside compound is 0.1:1; The molar ratio of diisopropylethylamine to nucleoside compound is 2.3-3:1; The molar ratio of the chiral ligand to the nucleoside compound is 0.15-0.2:

1.

9. A nucleoside prodrug A, characterized in that: The nucleoside prodrug A is prepared by the nucleoside prodrug intermediate according to claim 1; the compound structure of the nucleoside prodrug is shown in the following formula II: Among them, R 1 is any one of methyl, 2-ethylbutyl, isopropyl, tert-butyl, cyclohexyl and benzyl; R 2 Any one of methyl, isopropyl, and methylthioethyl; R 3 for Any of the following, where R 9 is any one of hydrogen, halogen, and methoxy; R 4 is any one of uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine, 6-chloroadenine, and pyrrolo[2,1-f][1,2,4]triazine-4-amine; R 5 Any of hydrogen and cyano; R 6 is any one of azido, benzyloxy, tert-butyldimethylsilyl, and hydroxyl; R 7 Any one of hydrogen, halogen, tert-butyldimethylsilyl, and hydroxyl; And R 6 and R 7 At least one of the groups is a hydroxyl group; R 8 It is either hydrogen or methyl.

10. A method for preparing the nucleoside prodrug A according to claim 9, characterized in that: The following steps are involved: The prodrug intermediate of claim 1 is reacted with ultra-dry THF to form a reaction system, and concentrated hydrochloric acid is added at 0° C., and then the temperature is raised to room temperature and the reaction is carried out overnight to obtain the nucleoside prodrug A; or After nitrogen replacement of the prodrug intermediate of claim 1 in a reaction bottle, TFA is added at 0° C. to form a reaction system, and then the temperature is raised to room temperature and the reaction is carried out overnight to obtain the nucleoside prodrug A.

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