CN117126199A - Synthesis method of fluoroRuidexivir - Google Patents

Abstract

The invention discloses a method for synthesizing fluoroRuidexivir. The method takes fluoro five-membered sugar (2-deoxidization-2-fluoro-3, 5-di-O-benzyl-D-ribonucleotide-gamma-lactone or 2-deoxidization-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone) as an initial raw material, and obtains 2-ethylbutyl ((S) - ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-yl) -5-cyano) -4-fluoro-3-hydroxy tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine and 2-ethylbutyl ((S) - ((2R, 3R,4S, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-yl) -5-cyano) -4-fluoro-3-hydroxy tetrahydrofuran-2-phenoxy) phosphoryl) L-two-renin; the synthesis method has the advantages of short route, simple step operation and relatively high yield, and provides a brand new synthesis path for the synthesis or modification design of nucleoside medicines.

Description

A kind of synthesis method of fluremdesivir

Technical field

The invention relates to a drug synthesis method, specifically to a kind of fluoro-remdesivir (2-ethylbutyl((S)-(((2R,3R,4R,5R))-5-(4-aminopyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorus Acyl)-L-alanine compound or 2-ethylbutyl ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound), belongs to the field of drug synthesis technology.

Background technique

In 1950, 2-bromo-2-chloro-1,1,1-trifluoroethane was used as an inhalation anesthetic, indicating the potential of fluorine to modulate biologically active molecules (Ostercamp DL, B.R., Chemical Aspects of General Anesthesia: Part I. From Ether to Halothane1 .Journal of Chemical Education 2006,83,1821); In 1953, Josef Fried and Emily Sabo discovered that 9α-fludrocortisone (shown in the reaction below) has more than 10 times more anti-inflammatory activity than cortisol, indicating that on the drug molecule Introducing fluorine atoms at designated positions can improve its medicinal properties (Sabo, J.F.a.E.F., 9-α-Fluoroderivatives of cortisone and hydrocortisone. J.Am.Chem.Soc. 1954, 76, 1455); In 1957, Robert Duschinsky and others synthesized fluorine-containing drugs. 5-Fluorouracil (as shown in the reaction), as an anti-tumor drug, shows high anti-cancer activity by inhibiting thymidylate synthase, thereby preventing cells from synthesizing thymidine (C. Heidelberger, N.K.C., P. Danneberg, D. Mooren, L. Griesbach, R. Duschinsky and R. J. Schnitzer, FLUORINATED PYRIMIDINES, A NEW CLASS OF TUMOUR-INHIBITORY COMPOUNDS. Nature 1957, 179, 663). The discovery of these two fluorine-containing drugs laid the foundation for the increasing role of fluorine in life sciences.

At the end of 2020, the general trend in the number of fluorinated drugs approved by the U.S. Food and Drug Administration is increasing (Johnson, B.M.; Shu, Y.Z.; Zhuo, X.; Meanwell, N.A., Metabolic and Pharmaceutical Aspects of Fluorinated Compounds. J Med Chem 2020 , 63, 6315-6386), (Yu, Y.; Liu, A.; Dhawan, G.; Mei, H.; Zhang, W.; Izawa, K.; Soloshonok, V.A.; Han, J., Fluorine- containingpharmaceuticals approved by the FDA in 2020:Synthesis and biological activity.Chinese Chemical Letters 2021). Due to the characteristics of fluorine, the introduction of fluorine into drug molecules can change its various properties, so fluorine is of great significance to the modification of nucleoside drugs.

Contents of the invention

In view of the shortcomings of the existing technology, the purpose of the present invention is to provide a chemical synthesis method of fluoro-remdesivir compounds, which has the characteristics of short route, simple steps and relatively high yield, and is good for nucleosides. The synthesis or modified design of drug-like drugs provides a completely new approach.

In order to achieve the above technical objectives, the present invention provides a 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]Triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-propyl A method for synthesizing amino acid compounds, the method includes the following steps:

1) Combine 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribono-γ-lactone and 4-amino-7-bromopyrrolo[2,1-F][1 ,2,4]Triazine obtains intermediate 3 through sugar carbonation reaction;

2) React intermediate 3 with trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate and trimethylsilyl cyanide through cyanation to obtain intermediate 4;

3) React intermediate 4 through debenzylation protecting group to obtain intermediate 5;

4) Phosphate the intermediate 5 with 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine to obtain 2-ethylbutyl Base ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- Cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound;

Wherein, the 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri The structural formula of the azine-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound is as follows:

The structures of intermediates 3, 4, and 5 are as follows:

As a preferred option, the process of the glycosidation reaction is: mixing 1,2-bis(chlorodimethylsilyl)ethane solution with 4-amino-7-bromopyrrolo[2,1-F ][1,2,4] Mix the triazine solution, stir for 5 to 20 minutes, then add diisopropylamine, stir for 3 to 10 minutes, then place it in a low temperature environment below -50°C, stir for at least 20 minutes, and then slowly add n-butylamine dropwise base lithium, stir for 15 to 60 minutes, then add 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribono-γ-lactone solution dropwise, stir for 1 to 5 hours, and then add lemon acid solution, raise the temperature to 0~5°C, and stir for 10~30 minutes. A more specific reaction process: at room temperature, after replacing the gas (using an inert gas to replace the air), add the tetrahydrofuran solution of 1,2-bis(chlorodimethylsilyl)ethane to 4-amino-7-bromopyrrole Add [2,1-F][1,2,4]triazine to a tetrahydrofuran solution and stir for 5 to 20 minutes; then add diisopropylamine and stir for 3 to 10 minutes; place it in a -78°C low temperature constant temperature stirrer to cool down and stir. For at least 20 minutes, slowly drop n-butyllithium and stir for 15 to 60 minutes; then dissolve 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribono-γ-lactone in tetrahydrofuran , add dropwise to the system, stir for 1 to 5 hours, add 1M citric acid solution, raise the temperature to 0°C, and stir for 10 to 30 minutes. Among them, the molar ratio of 1,2-bis(chlorodimethylsilyl)ethane:4-amino-7-bromopyrrolo[2,1-F][1,2,4]triazine:diisopropylamine: 2-Deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranosyl-γ-lactone=0.5～1.5:1.0:0.5～1.5:1.0～3.0.

As a preferred solution, the process of the cyanation reaction is: dissolve intermediate 3 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, then add trifluoroacetic acid, and stir for 5 to 30 minutes. Then add trimethylsilyl trifluoromethanesulfonate dropwise, stir for 10 to 60 minutes, then add trimethylsilyl cyanide, and stir for 1 to 5 hours. A more specific reaction process: After replacing the gas, dissolve intermediate 3 in methylene chloride, place it in a -78°C low-temperature stirrer to cool down, stir for at least 20 minutes, then add trifluoroacetic acid, stir for 5 to 30 minutes, and add trifluoroacetic acid dropwise. Trimethylsilyl methanesulfonate, stir for 10 to 60 minutes, then add trimethylsilyl cyanide, and stir for 1 to 5 hours. Molar ratio of intermediate 3: trifluoroacetic acid: trimethylsilyl trifluoromethanesulfonate: trimethylsilyl cyanide = 1.0: 1.0～5.0: 1.0～10.0: 1.0～10.0.

As a preferred option, the process of the benzyl protecting group reaction is as follows: dissolve intermediate 4 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, then add boron trichloride dropwise, and Raise the temperature to -40~-30℃ and stir for 1~5h. More specific reaction process: After replacing the gas, dissolve intermediate 4 in methylene chloride, place it in a -78°C low-temperature constant temperature stirrer to cool down, stir for at least 20 minutes, then add boron trichloride dropwise, raise the temperature to -40°C, and stir. 1～5h. Among them, the molar ratio of intermediate 4: boron trichloride = 1.0: 1.0 to 10.0.

As a preferred option, the process of the phosphorylation reaction is: dissolve intermediate 5 in a solvent and 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)- L-alanine is dissolved in the solvent and placed in an ice bath environment. Dimethylaluminum chloride is slowly added dropwise, and the mixture is raised to room temperature and stirred for 5 to 10 days. A more specific reaction process is: replace the gas, dissolve intermediate 5 and 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine in propylbutyl , under ice bath conditions, slowly add dimethylaluminum chloride dropwise, raise to room temperature and stir for 5 to 10 days.

The invention also provides a 2-ethylbutyl ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2, Synthesis of 4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound method, which includes the following steps:

1) Combine 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranosyl-γ-lactone and 4-amino-7-bromopyrrolo[2,1-F] [1,2,4] Triazine obtains intermediate 9 through sugar carbonation reaction;

2) React intermediate 9 with trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate and trimethylsilyl cyanide through cyanation to obtain intermediate 4 or intermediate 10;

3) React intermediate 10 through debenzylation protecting group to obtain intermediate 5 or intermediate 11;

4) Phosphate the intermediate 11 with 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine to obtain 2-ethylbutyl Base ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- Cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound;

in,

The 2-ethylbutyl ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine- The structural formula of 7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound is as follows:

The structures of intermediates 9, 10, and 11 are as follows:

As a preferred option, the process of the glycosidation reaction is: mixing 1,2-bis(chlorodimethylsilyl)ethane solution with 4-amino-7-bromopyrrolo[2,1-F ][1,2,4] Mix the triazine solution, stir for 5 to 20 minutes, then add diisopropylamine, stir for 3 to 10 minutes, then place it in a low temperature environment below -50°C, stir for at least 20 minutes, and then slowly add n-butylamine dropwise base lithium, stir for 15 to 60 minutes, then add dropwise 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranofuranoic acid-γ-lactone solution, stir for 1 to 5 hours, and then Add citric acid solution, raise the temperature to 0~5°C, and stir for 10~30 minutes. A more specific reaction process: at room temperature, after replacing the gas (using an inert gas to replace the air), add the tetrahydrofuran solution of 1,2-bis(chlorodimethylsilyl)ethane to 4-amino-7-bromopyrrole Add [2,1-F][1,2,4]triazine to a tetrahydrofuran solution and stir for 5 to 20 minutes; then add diisopropylamine and stir for 3 to 10 minutes; place it in a -78°C low temperature constant temperature stirrer to cool down and stir. At least 20 minutes, then slowly drop n-butyllithium, and stir for 15 to 60 minutes; then dissolve 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranosyl-γ-lactone in Add tetrahydrofuran dropwise to the system, stir for 1 to 5 hours, add 1M citric acid solution, raise the temperature to 0°C, and stir for 10 to 30 minutes. Among them, the molar ratio of 1,2-bis(chlorodimethylsilyl)ethane:4-amino-7-bromopyrrolo[2,1-F][1,2,4]triazine:diisopropylamine: 2-Deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranosyl-γ-lactone=0.5～1.5:1.0:0.5～1.5:1.0～3.0.

As a preferred solution, the process of the cyanation reaction is: dissolve intermediate 9 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, then add trifluoroacetic acid, and stir for 5 to 30 minutes. Then add trimethylsilyl trifluoromethanesulfonate dropwise, stir for 10 to 60 minutes, then add trimethylsilyl cyanide, and stir for 1 to 5 hours. A more specific reaction process: After replacing the gas, dissolve intermediate 9 in methylene chloride, place it in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, then add trifluoroacetic acid, stir for 5 to 30 minutes, and add trifluoroacetic acid dropwise. Trimethylsilyl methanesulfonate, stir for 10 to 60 minutes, then add trimethylsilyl cyanide, and stir for 1 to 5 hours. Molar ratio of intermediate 9: trifluoroacetic acid: trimethylsilyl trifluoromethanesulfonate: trimethylsilyl cyanide = 1.0: 1.0～5.0: 1.0～10.0: 1.0～10.0.

As a preferred solution, the process of the debenzylation protecting group reaction is: dissolve the intermediate 10 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, then add boron trichloride dropwise, and Raise the temperature to -40~-30℃ and stir for 1~5h. A more specific reaction process: After replacing the gas, dissolve intermediate 10 in methylene chloride, place it in a -78°C low-temperature constant temperature stirrer to cool down, stir for at least 20 minutes, then add boron trichloride dropwise, raise the temperature to -40°C, and stir. 1～5h. Among them, the molar ratio of intermediate 10: boron trichloride = 1.0: 1.0 to 10.0.

As a preferred option, the process of the phosphorylation reaction is: dissolve intermediate 11 in a solvent and 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)- L-alanine is dissolved in the solvent and placed in an ice bath environment. Dimethylaluminum chloride is slowly added dropwise, and the mixture is raised to room temperature and stirred for 5 to 10 days. A more specific reaction process is: after replacing the gas, dissolve intermediate 11 and 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine in Protein and D., under ice bath conditions, slowly add dimethylaluminum chloride dropwise, raise to room temperature and stir for 5 to 10 days.

2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine) of the present invention The synthesis reaction route of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound is as follows:

The specific reaction steps are as follows:

(1) At room temperature, replace the gas and add the tetrahydrofuran solution of 1,2-bis(chlorodimethylsilyl)ethane to 4-amino-7-bromopyrrolo[2,1-F][1, 2,4] triazine (compound 2) in tetrahydrofuran solution, stir for 10 minutes; add diisopropylamine, stir for 5 minutes; place in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, slowly drop n-butyllithium, and stir for 30 minutes ; Dissolve 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribono-γ-lactone (compound 1) in tetrahydrofuran, add dropwise to the system, stir for 2h; add 1M The citric acid solution was heated to 0°C and stirred for 20 minutes; the organic phase was separated, concentrated under reduced pressure to obtain the crude product Intermediate 3, which was further purified by column chromatography to obtain Intermediate 3; where the molar ratio was 1,2-bis(chlorodimethyl Silyl)ethane: Compound 2: Diisopropylamine: Compound 1=0.5～1.5: 1.0: 0.5～1.5: 1.0～3.0;

(2) Replace the gas, dissolve intermediate 3 in dichloromethane, place it in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, add trifluoroacetic acid, stir for 10 minutes, and add trimethyl trifluoromethanesulfonate dropwise Silyl ester, stir for 30 minutes, add trimethylsilyl cyanide, and stir for 2 hours. Quench the reaction, raise the temperature to room temperature, separate the organic phase, concentrate under reduced pressure, and perform silica gel column chromatography to obtain intermediate 4, in which the molar ratio of intermediate 3: trifluoroacetic acid: trimethylsilyl trifluoromethanesulfonate: trimethyl Silane cyanide=1.0: 1.0～5.0: 1.0～10.0: 1.0～10.0;

(3) Replace the gas, dissolve intermediate 4 in methylene chloride, place it in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, add boron trichloride dropwise, raise the temperature to -40°C, stir for 2 hours, and cool to - At 78°C, dry methanol was added dropwise; dry triethylamine was dissolved in dry methanol, and then dropped into the reaction system. After the dropwise addition was completed, the temperature was raised to room temperature, concentrated under reduced pressure, and silica gel column chromatography was performed to obtain intermediate 5, in which , molar ratio of intermediate 4: boron trichloride = 1.0: 1.0~10.0;

(4) Replace the gas and combine intermediate 5 with the photochemically pure compound 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine (compound 6) Dissolve in pyridine, slowly add dimethyl aluminum chloride dropwise under ice bath conditions, raise to room temperature and stir for 7 days, add 30% L-tartaric acid solution to quench the reaction, add ethyl acetate to dilute, separate the organic phase, and concentrate under reduced pressure , Compound 7 was obtained by silica gel column chromatography; wherein, the molar ratio of intermediate 5: compound 6: dimethylaluminum chloride = 1.0: 1.0~5.0: 0.1~1.0.

2-ethylbutyl ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine) of the present invention The synthesis reaction route of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound is as follows:

The specific reaction steps are as follows:

(1) At room temperature, replace the gas and add the tetrahydrofuran solution of 1,2-bis(chlorodimethylsilyl)ethane to 4-amino-7-bromopyrrolo[2,1-F][1, 2,4] triazine (compound 2) in tetrahydrofuran solution, stir for 10 minutes; add diisopropylamine, stir for 5 minutes; place in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, slowly drop n-butyllithium, and stir for 30 minutes ; Dissolve 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranofuranoic acid-γ-lactone (compound 8) in tetrahydrofuran, add it dropwise to the system, and stir for 2h; Add 1M citric acid solution, raise the temperature to 0°C, and stir for 20 minutes; separate the organic phase and concentrate under reduced pressure to obtain the crude product Intermediate 9, which is further purified by column chromatography to obtain Intermediate 9; where the molar ratio is 1,2-bis(chlorobis) Methylsilyl)ethane: Compound 2: Diisopropylamine: Compound 8=0.5～1.5: 1.0: 0.5～1.5: 1.0～3.0;

(2) Replace the gas, dissolve intermediate 9 in methylene chloride, place it in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, add trifluoroacetic acid, stir for 10 minutes, add trimethyl trifluoromethanesulfonate dropwise Silyl ester, stir for 30 minutes, add trimethylsilyl cyanide, and stir for 2 hours. Quench the reaction, raise the temperature to room temperature, separate the organic phase, concentrate under reduced pressure, and perform silica gel column chromatography to obtain intermediate 10, in which the molar ratio of intermediate 9: trifluoroacetic acid: trimethylsilyl trifluoromethanesulfonate: trimethyl Silane cyanide=1.0: 1.0～5.0: 1.0～10.0: 1.0～10.0;

(3) Replace the gas, dissolve intermediate 10 in methylene chloride, place it in a -78°C low temperature constant temperature stirrer to cool down, stir for at least 20 minutes, add boron trichloride dropwise, raise the temperature to -40°C, stir for 2 hours, and cool to - At 78°C, dry methanol was added dropwise; dry triethylamine was dissolved in dry methanol, and then dropped into the reaction system. After the dropwise addition was completed, the temperature was raised to room temperature, concentrated under reduced pressure, and silica gel column chromatography was performed to obtain intermediate 11, in which , molar ratio of intermediate 10: boron trichloride = 1.0: 1.0~10.0;

(4) Replace the gas and combine intermediate 11 with the photochemically pure compound 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine (compound 6) Dissolve in pyridine, slowly add dimethyl aluminum chloride dropwise under ice bath conditions, raise to room temperature and stir for 7 days, add 30% L-tartaric acid solution to quench the reaction, add ethyl acetate to dilute, separate the organic phase, and concentrate under reduced pressure , Compound 12 was obtained by silica gel column chromatography; wherein, the molar ratio of intermediate 11: compound 6: dimethylaluminum chloride = 1.0: 1.0~5.0: 0.1~1.0.

Compared with the existing technology, the technical solution of the present invention brings beneficial technical effects:

The present invention successfully synthesizes 2-ethylbutyl ((S)-((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2 ,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine and 2 -Ethylbutyl((S)-((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine Two fluorinated remdesivir drugs, Modification and design of nucleoside drugs provide new ways.

The synthesis method of the present invention has a short route, simple steps and relatively high yield (the reaction yield of each step reaches more than 55%), which is beneficial to expanding production.

Description of the drawings

Figure 1 shows 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine ¹ H NMR of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound (400MHz ,methanol-d ₄ ,25℃).

Figure 2 shows 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine) ¹⁹ F NMR of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound (376MHz ,methanol-d ₄ ,25℃).

Figure 3 shows 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine) ¹⁹ F NMR of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound (376MHz ,methanol-d ₄ ,25℃).

Figure 4 is 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine ³¹ P NMR of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound (162MHz ,methanol-d ₄ ,25℃).

Figure 5 is 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine ³¹ P NMR of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound (162MHz ,methanol-d ₄ ,25℃).

Figure 6 is 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine ¹³ C NMR of -7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound (100MHz ,methanol-d ₄ ,25℃).

Detailed ways

The following specific examples are intended to further illustrate the present invention, but are not intended to limit the scope of the claims.

Unless otherwise specified, the chemical reagents involved in the following examples are all conventional commercially available analytically pure reagents.

Example 1

(1) Synthesis of intermediate 3

Weigh 4-amino-7-bromopyrrolo[2,1-F][1,2,4]triazine (compound 2) (321 mg, 1.515 mmol) into a dry 50 mL round-bottomed flask, replace the gas three times, and add Tetrahydrofuran (25.8 mL), stir at room temperature for 5 min; weigh 1,2-bis(chlorodimethylsilyl)ethane (358.7 mg, 1.667 mmol) into a dry 5 mL round-bottomed flask, and add dry tetrahydrofuran (1.6 mL) Dissolve it and add it to the reaction system, stir at room temperature for 10 minutes, add diisopropylamine (234 μL, 1.667 mmol), stir at room temperature for 5 minutes, place it in a -78°C low-temperature stirrer to cool down, stir for at least 20 minutes, and slowly drip n-butylamine Lithium (1.6M in n-hexane, 4.07mL, 6.515mmol), stir for 30min; 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribo-γ-lactone ( Compound 1) (1.0g, 3.029mmol) was weighed into a dry 5mL round-bottomed flask, added tetrahydrofuran (1.6mL) to dissolve, added dropwise to the system, stirred for 2h, and monitored the reaction with TLC.

Monitor the completion of the reaction, add 1M citric acid solution (16 mL) to quench the reaction, raise the temperature to 0°C, separate the organic phase, concentrate under reduced pressure to obtain the crude product, dissolve it, add silica gel to mix the sample, and perform silica gel column chromatography to obtain intermediate 3 (421 mg, 60%, petroleum ether: ethyl acetate = 1:2, R _f = 0.25).

(2) Synthesis of intermediate 4

Weigh intermediate 3 (421 mg, 0.907 mmol) into a 25 mL reaction flask, replace the gas three times, add methylene chloride (12 mL), stir to dissolve, place in a -78°C low-temperature stirrer to cool down, stir for at least 20 min, and add trifluoroacetic acid (208μL, 2.721mmol), stir for 10min, add trimethylsilyl trifluoromethanesulfonate (0.98mL, 5.442mmol) dropwise, stir for 30min, add trimethylsilyl cyanide (0.68mL, 5.442mmol), stir for 2h. Reactions were monitored by TLC.

Monitor the completion of the reaction, quench the reaction, warm to room temperature, separate the organic phase, concentrate under reduced pressure, mix the sample, and obtain intermediate 4 (259 mg, 60%, petroleum ether: ethyl acetate = 1:2, R _f =0.7).

(3) Synthesis of intermediate 5

Weigh Intermediate 4 (231 mg, 0.488 mmol) into a 25 mL bottle, replace the gas three times, add methylene chloride (2.7 mL), stir to dissolve, place in a -78°C low-temperature stirrer to cool down, stir for at least 20 min, add trichloride dropwise Boron (1Min methylene chloride, 3.71mL, 3.71mmol) was heated to -40°C, stirred for 2 hours, and the reaction was monitored by TLC.

Monitor the completion of the reaction, cool down to -78°C, and add dry methanol (1.08 mL) dropwise; dissolve dry triethylamine (1.4 mL) in dry methanol (2.2 mL), and then drop it into the reaction system until the addition is completed. , warmed to room temperature, concentrated under reduced pressure, dissolved in methanol, added silica gel to mix the sample, and used ethyl acetate silica gel column chromatography to obtain the product 1-cyano-1-C-(4-aminopyrrolo[2,1-f ][1,2,4]triazin-7-yl)-2-deoxy-2-fluoro-D-ribose intermediate 5 (137 mg, 96%, petroleum ether: ethyl acetate = 1: 4, R _f = 0.2).

[α] _D ²⁵ =-51.1 (c 1.0, C ₂ H ₅ OH); mp: 166-169°C;

¹ H-NMR (400MHz, methanol-d ₄ ): δ7.89 (s, 1H), 7.00 (d, J = 4.8Hz, 1H), 6.90 (d, J = 4.8Hz, 1H), 5.47 (dd, J＝53.8,4.0Hz,1H),4.68(s,2H),4.30-4.21(m,2H),3.95(dd,J＝12.6,2.0Hz,1H),3.75(dd,J＝12.6,4.0Hz ,1H);

¹³ C-NMR (100MHz, methanol-d ₄ ): δ157.20, 148.53, 123.67 (d, J = 5.0Hz, 1C), 118.15, 116.18 (d, J = 7.2Hz, 1C), 112.47, 102.75, 93.69 (d ,J＝200.4Hz,1C),85.06,79.09(d,J＝20.5Hz,1C),70.52(d,J＝16.7Hz,1C),61.76;

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-197.79--197.98 (m, 1F);

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-197.88 (s, 1F);

HRMS(ESI)m/z calcd for C ₁₂ H ₁₂ FN ₅ O ₃ Na ⁺ (M+Na) ⁺ 316.0816,found 316.0816.

(4) Synthesis of compound 7

Intermediate 5 (50 mg, 0.171 mmol) and the photochemically pure compound 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine (compound 6) (169 mg, 0.341 mmol) was added to a 10 mL round-bottomed flask, replaced the gas three times, added dry pyridine (1.7 mL), cooled and stirred for 10 min in an ice bath, and slowly added dimethylaluminum chloride (1 M in heptane, 86 μL, 0.086 mmol), raised to room temperature and stirred for 7 days, and TLC monitored the reaction.

Monitor the completion of the reaction, add 30% L-tartaric acid solution (1mL) to quench the reaction, add ethyl acetate to dilute, separate the organic phase, concentrate under reduced pressure and mix the sample, silica gel column chromatography to obtain compound 7 (66mg, 64%, petroleum ether: Ethyl acetate=1:4, R _f =0.4).

¹ H NMR (400MHz, methanol-d ₄ ): δ7.89 (s, 1H), 7.35-7.30 (m, 2H), 7.24-7.16 (m, 3H), 5.48 (dd, J = 53.4, 4.1Hz, 1H),4.51-4.46(m,1H),4.39-4.23(m,3H),4.04-4.00(m,1H),3.95-3.91(m,2H),1.48-1.42(m,1H),1.34- 1.27(m,8H),0.87-0.83(m,6H);

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-196.98--197.18 (m, 1F);

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-197.08 (s, 1F);

³¹ PNMR (162MHz, methanol-d ₄ ): δ3.68-3.54 (m, 1P);

³¹ PNMR (162MHz, methanol-d ₄ ): δ3.61 (s, 1P);

¹³ C NMR (100MHz, methanol-d ₄ ): δ174.99,174.94,157.17,152.16,125.10,148.59,130.76,126.13,123.31,123.26,121.35,121.31,118.21,115.78,11 5.70,112.33,102.77,94.62,92.63, 82.39,82.31,79.41,79.20,70.57,70.40,68.09,66.27,66.22,51.50,41.67,24.19,20.61,20.54,11.33,11.28;

HRMS(ESI)m/z calcd for C ₂₇ H ₃₄ FN ₆ O ₇ PNa ⁺ (M+Na) ⁺ 627.2103, found 627.2107.

Example 2

(1) Synthesis of Intermediate 9

Referring to A.U. Patent 2015238851A1, reaction condition 4 was used. Although the yield was low, only 20%, the target product was obtained, which provided a control point for the subsequent screening of reaction conditions. When NaH was added in reaction condition 5, the yield increased to 41%. When the feed was amplified 10 times, the yield decreased to 34%. Reaction condition 7, when I first tried it, the yield was only 42%. Later, the reaction solvent was increased and the concentration of the reaction system was reduced. Using reaction conditions 8, the yield reached 68%. Under this condition, the feed was amplified 10 times, and the yield did not change significantly. Therefore, the optimal reaction condition for connecting unnatural bases to the ribose center is condition 8. As shown in the following table:

The following is a specific embodiment: 4-amino-7-bromopyrrolo[2,1-F][1,2,4]triazine (compound 2) (433.4mg, 2.0446mmol) was weighed into a dry 50mL round bottom Flask, replace the gas three times, add dry tetrahydrofuran (20mL) under nitrogen protection, stir at room temperature for 5 minutes; weigh 1,2-bis(chlorodimethylsilyl)ethane (484.2mg, 2.249mmol) into dry 5mL In a round-bottomed flask, add dry tetrahydrofuran (3 mL) to dissolve it and add it to the reaction system. Stir at room temperature for 10 min. Add diisopropylamine (0.32 mL, 2.249 mmol). Stir at room temperature for 5 min. Place at -78°C and stir at low temperature. Cool down the temperature in the device, stir for at least 20 minutes, slowly add n-butyllithium (1.6M in n-hexane, 5.5mL, 8.792mmol) dropwise. After the dropwise addition is completed, stir at -78°C for 30min; 2-deoxy-2- Fluoro-3,5-di-O-benzyl-D-arabinofuranosyl-γ-lactone (compound 8) (1.35g, 4.0893mmol) was weighed into a dry 5mL round-bottom flask, and dry tetrahydrofuran (3mL ) to dissolve and slowly drop it into the reaction system. After the dropwise addition is completed, stir at -78°C for 2 hours. Monitor the reaction with TLC and use petroleum ether: ethyl acetate = 1:2 to climb the plate.

Monitor the completion of the reaction, add 1M citric acid solution (16 mL) to quench the reaction, raise the temperature to 0°C, separate the organic phase, concentrate under reduced pressure to obtain the crude product, dissolve it, add silica gel to mix the sample, and perform silica gel column chromatography to obtain intermediate 9 (542 mg, 68%, petroleum ether: ethyl acetate = 1:2, R _f = 0.25).

(2) Synthesis of intermediate 10

p-1-C-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-deoxy-2-fluoro-3,5-di-O-benzyl D-ribose (intermediate 4) was subjected to a cyanolation reaction. When the reaction temperature was initially controlled to -78°C, solids would precipitate during the reaction. The reaction was carried out according to the reaction operation. It was found on the spot board that some raw materials had not been completely reacted. , the yield is 60% (reaction condition 1). 1-C-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-deoxy-2-fluoro-3,5-di-O-benzyl -D-arabinofuranose (intermediate 9), try the reaction again, the experimental phenomenon is the same, the yield is 65% (upper half of reaction condition 2). Analyze the reason why the raw materials have not been completely reacted, because the equivalent ratio of the cyanation reaction in the synthesis of remdesivir can complete the reaction of the raw materials. During the combined reaction, solids appear, and we realize that the raw materials cannot dissolve well at -78°C. into the solvent, so heating measures are taken. 1-C-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-deoxy-2-fluoro-3,5-di-O-benzyl Use methyl-D-arabinofuranose (intermediate 9) as the reaction substrate, slowly raise the reaction temperature from -78°C, and observe the dissolution of the solid until -40°C. When the solution is clear, add trifluoroacetic acid and stir for a while, then add trifluoroacetic acid. Trimethylsilyl fluomethanesulfonate and trimethylsilyl cyanide were stirred for 2 hours and found to be completely reacted with a yield of 83% (lower half of reaction conditions 2). Next, the temperature of the cyanation reaction was controlled at -40°C. The specific contents are as shown in the table below:

The following is a specific implementation: Weigh Intermediate 9 (50 mg, 0.108 mmol) into a dry 10 mL round-bottomed flask, replace the gas three times, add dry dichloromethane (1.4 mL) under nitrogen protection, stir to dissolve, and place at -78 Cool the temperature in a low temperature constant temperature stirrer at ℃, stir for at least 20 minutes, add trifluoroacetic acid (24 μL, 0.323 mmol), stir for 10 minutes, add trimethylsilyl trifluoromethanesulfonate (117 μL, 0.648 mmol) dropwise, stir for 30 minutes, add trifluoromethanesulfonate Methyl cyanide silane (81 μL, 0.648 mmol), stir for 2 hours, monitor the reaction with TLC, and use petroleum ether: ethyl acetate = 1:2 to climb the plate.

Monitor the reaction to complete, quench the reaction, warm to room temperature, separate the organic phase, concentrate under reduced pressure, mix the sample, and obtain intermediate 10 (33 mg, 65%, petroleum ether: ethyl acetate = 1:2, R _f =0.7).

(3) Synthesis of intermediate 11

Weigh Intermediate 10 (189 mg, 0.399 mmol) into a dry 25 mL round-bottomed flask, replace the gas three times, add dry methylene chloride (2.2 mL) under nitrogen protection, stir to dissolve, and place in a -78°C low temperature constant temperature stirrer. Lower the temperature in medium, stir for at least 20 minutes, add boron trichloride (1M in methylene chloride, 3.04mL, 3.04mmol) dropwise. After the dropwise addition is completed, raise the temperature to -40°C, stir for 2h, monitor the reaction with TLC, use petroleum ether: ethyl acetate =1:1 climbing board.

Monitor the completion of the reaction, cool down to -78°C, and add dry methanol (0.88mL) dropwise; dissolve dry triethylamine (1.44mL) in dry methanol (1.76mL), then drop it into the reaction system, and the dropwise addition is complete , warmed to room temperature, concentrated under reduced pressure, dissolved in methanol, added silica gel to mix the sample, and used ethyl acetate silica gel column chromatography to obtain intermediate 11 (105 mg, 90%, petroleum ether: ethyl acetate = 1: 4, R _f =0.2).

¹ HNMR (400MHz, methanol-d ₄ ): δ7.88 (s, 1H), 6.91-6.88 (m, 2H), 5.67 (d, J = 49.6, Hz, 1H), 4.42-4.31 (m, 2H) ,3.83-3.75(m,2H);

¹³ C-NMR (100MHz, methanol-d ₄ ): δ157.03,148.27,122.99,116.98,116.88,116.79,111.64,102.73,100.57(d,J＝198.8Hz,1C),,88.61,79.47(d,J＝ 31.3Hz, 1C), 77.07 (d, J = 26.82Hz, 1C), 62.44;

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-186.37--186.55 (m, 1F);

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-186.46 (s, 1F);

HRMS(ESI)m/z calcd for C ₁₂ H ₁₂ FN ₅ O ₃ Na ⁺ (M+Na) ⁺ 316.0816, found 316.0818.

(4) Synthesis of compound 12

Intermediate 11 (50 mg, 0.171 mmol) and photochemically pure compound 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine (compound 6) (169 mg, 0.341 mmol) was added to a 10 mL round-bottomed flask, replaced the gas three times, added dry pyridine (1.7 mL), cooled and stirred for 10 min in an ice bath, and slowly added dimethylaluminum chloride (1 M in heptane, 86 μL, 0.086 mmol), raised to room temperature and stirred for 7 days, and TLC monitored the reaction.

Monitor the completion of the reaction, add 30% L-tartaric acid solution (1mL) to quench the reaction, add ethyl acetate to dilute, separate the organic phase, concentrate under reduced pressure and mix the sample, silica gel column chromatography to obtain compound 12 (58.8 mg, 57%, petroleum ether) : Ethyl acetate = 1: 4, R _f = 0.4)

¹ H NMR (400MHz, methanol-d ₄ ): δ7.89 (s, 1H), 7.36-7.16 (m, 5H), 6.90 (d, J = 4.6Hz, 1H), 6.82 (d, J = 4.6Hz ,1H),5.69(d,J＝49.14Hz,1H),4.50-4.27(m,4H),4.05-3.94(m,3H),1.50-1.42(m,1H),1.36-1.29(m,8H ),0.88-0.84(m,6H);

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-186.37--186.55 (m, 1F);

¹⁹ F NMR (376MHz, methanol-d ₄ ): δ-186.46 (s, 1F);

³¹ PNMR (162MHz, methanol-d ₄ ): δ3.50-3.35 (m, 1P);

³¹ PNMR (162MHz, methanol-d ₄ ): δ3.43 (s, 1P);

¹³ C NMR (100MHz, methanol-d ₄ ): δ174.96,174.92,158.85,157.03,152.21,152.14,148.40,130.79,126.13,121.42,124.37,116.58,116.50,111.67,10 2.76,101.14,99.18,86.47,79.51, 76.79,68.11,66.46,51.54,41.66,24.21,20.61,20.54,11.34,11.29;

HRMS(ESI)m/z calcd for C ₂₇ H ₃₄ FN ₆ O ₇ PNa ⁺ (M+Na) ⁺ 627.2103, found 627.2107.

The above are only preferred embodiments of the present invention. The present invention is not limited to the above-mentioned embodiments. As long as the technical effects of the present invention are achieved by the same means, they shall fall within the protection scope of the present invention. Various modifications and changes may be made to the technical solutions and/or implementations within the scope of the present invention.

Claims (10)

1. A 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri Synthetic method of azine-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound, It is characterized by: including the following steps: 1) Combine 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribono-γ-lactone and 4-amino-7-bromopyrrolo[2,1-F][1 ,2,4]Triazine obtains intermediate 3 through sugar carbonation reaction; 2) React intermediate 3 with trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate and trimethylsilyl cyanide through cyanation to obtain intermediate 4; 3) React intermediate 4 through debenzylation protecting group to obtain intermediate 5; 4) Phosphate the intermediate 5 with 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine to obtain 2-ethylbutyl Base ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- Cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound; Wherein, the 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri The structural formula of the azine-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound is as follows: The structures of intermediates 3, 4, and 5 are as follows: 2. A kind of 2-ethylbutyl ((S)-(((2R,3R,4R,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 1 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine A method for synthesizing acid compounds, characterized in that: the process of the sugar carbonation reaction is: mixing 1,2-bis(chlorodimethylsilyl)ethane solution with 4-amino-7-bromopyrrolo[2 ,1-F][1,2,4]Triazine solution is mixed, stir for 5 to 20 minutes, then add diisopropylamine, stir for 3 to 10 minutes, then place in a low temperature environment below -50°C, stir for at least 20 minutes, and then slowly Add n-butyllithium dropwise, stir for 15 to 60 minutes, then add 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribono-γ-lactone solution dropwise, and stir for 1 to 5 hours. , then add citric acid solution, raise the temperature to 0~5°C, and stir for 10~30 minutes. 3. a kind of 2-ethylbutyl ((S)-(((2R,3R,4R,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 1 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine The synthesis method of acid compounds is characterized in that: the cyanation reaction process is: dissolve intermediate 3 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, then add trifluoroacetic acid, and stir 5 to 30 minutes, then add trimethylsilyl trifluoromethanesulfonate dropwise, stir for 10 to 60 minutes, then add trimethylsilyl cyanide, and stir for 1 to 5 hours. 4. a kind of 2-ethylbutyl ((S)-(((2R,3R,4R,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 1 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine The synthesis method of acid compounds is characterized in that: the process of the debenzyl protecting group reaction is: dissolve intermediate 4 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, and then add trichloride dropwise Boronize, raise the temperature to -40~-30°C, and stir for 1~5 hours. 5. a kind of 2-ethylbutyl ((S)-(((2R,3R,4R,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 1 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine A method for synthesizing acid compounds, characterized in that: the process of the phosphorylation reaction is: dissolving intermediate 5 in a solvent and 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy) Phosphoryl)-L-alanine is dissolved in the solvent and placed in an ice bath environment. Dimethylaluminum chloride is slowly added dropwise, and the mixture is raised to room temperature and stirred for 5 to 10 days. 6. A 2-ethylbutyl ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri Synthetic method of azine-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound, It is characterized by: including the following steps: 1) Combine 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranosyl-γ-lactone and 4-amino-7-bromopyrrolo[2,1-F] [1,2,4] Triazine obtains intermediate 9 through sugar carbonation reaction; 2) React intermediate 9 with trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate and trimethylsilyl cyanide through cyanation to obtain intermediate 4 or intermediate 10; 3) React intermediate 10 through debenzylation protecting group to obtain intermediate 5 or intermediate 11; 4) Phosphate the intermediate 11 with 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine to obtain 2-ethylbutyl Base ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- Cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound; Wherein, the 2-ethylbutyl ((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri The structural formula of the azine-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine compound is as follows: The structures of intermediates 9, 10, and 11 are as follows: 7. A kind of 2-ethylbutyl ((S)-(((2R,3R,4S,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 6 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine A method for synthesizing acid compounds, characterized in that: the process of the sugar carbonation reaction is: mixing 1,2-bis(chlorodimethylsilyl)ethane solution with 4-amino-7-bromopyrrolo[2 ,1-F][1,2,4]Triazine solution is mixed, stir for 5 to 20 minutes, then add diisopropylamine, stir for 3 to 10 minutes, then place in a low temperature environment below -50°C, stir for at least 20 minutes, and then slowly Add n-butyllithium dropwise and stir for 15 to 60 minutes, then add 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranonoic acid-γ-lactone solution dropwise, and stir for 1 to 60 minutes. 5 hours, then add citric acid solution, raise the temperature to 0~5℃, and stir for 10~30min. 8. A kind of 2-ethylbutyl ((S)-(((2R,3R,4S,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 6 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine The synthesis method of acid compounds is characterized in that: the cyanation reaction process is: dissolve intermediate 9 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, then add trifluoroacetic acid, and stir 5 to 30 minutes, then add trimethylsilyl trifluoromethanesulfonate dropwise, stir for 10 to 60 minutes, then add trimethylsilyl cyanide, and stir for 1 to 5 hours. 9. A kind of 2-ethylbutyl ((S)-(((2R,3R,4S,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 6 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine The synthesis method of acid compounds is characterized in that: the process of the debenzyl protecting group reaction is: dissolve the intermediate 10 in a solvent, place it in a low temperature environment below -50°C, stir for at least 20 minutes, and then add trichloride dropwise Boronize, raise the temperature to -40~-30°C, and stir for 1~5 hours. 10. A kind of 2-ethylbutyl ((S)-(((2R,3R,4S,5R))-5-(4-aminopyrrolo[2,1-f][ according to claim 6 1,2,4]triazin-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine A method for synthesizing acid compounds, characterized in that: the process of the phosphorylation reaction is: dissolving intermediate 11 in a solvent and 2-ethylbutyl ((S)-(perfluorophenoxy)(phenoxy) Phosphoryl)-L-alanine is dissolved in the solvent and placed in an ice bath environment. Dimethylaluminum chloride is slowly added dropwise, and the mixture is raised to room temperature and stirred for 5 to 10 days.