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CN117126199B - A method for synthesizing fluororemdesivir - Google Patents

A method for synthesizing fluororemdesivir Download PDF

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CN117126199B
CN117126199B CN202310552338.7A CN202310552338A CN117126199B CN 117126199 B CN117126199 B CN 117126199B CN 202310552338 A CN202310552338 A CN 202310552338A CN 117126199 B CN117126199 B CN 117126199B
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ethylbutyl
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CN117126199A (en
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严楠
蒋清辉
杨舒
张向梅
邹安茹
章晓炜
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Jiangxi Normal University
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract

本发明公开了一种氟代瑞德西韦合成方法。该方法以氟代五元糖(2‑脱氧‑2‑氟‑3,5‑二‑O‑苄基‑D‑核糖酸‑γ‑内酯或2‑脱氧‑2‑氟‑3,5‑二‑O‑苄基‑D‑阿拉伯呋喃糖酸‑γ‑内酯)为起始原料，通过糖碳苷化、氰基化、脱苄基保护基以及磷酸化四个步骤，即得2‑乙基丁基((S)‑(((2R,3R,4R,5R)‑5‑(4‑氨基吡咯并[2,1‑f][1,2,4]三嗪‑7‑基)‑5‑氰基)‑4‑氟‑3‑羟基四氢呋喃‑2‑基)甲氧基)(苯氧基)磷酰基)‑L‑丙氨酸和2‑乙基丁基((S)‑(((2R,3R,4S,5R)‑5‑(4‑氨基吡咯并[2,1‑f][1,2,4]三嗪‑7‑基)‑5‑氰基)‑4‑氟‑3‑羟基四氢呋喃‑2‑基)甲氧基)(苯氧基)磷酰基)‑L‑丙氨酸两种代瑞德西韦；该合成方法路线短，步骤操作简单，收率相对较高，为核苷类药物的合成或者改性的设计提供全新合成途径。

The invention discloses a method for synthesizing fluorinated remdesivir. The method uses fluorinated pentasaccharide (2-deoxy-2-fluoro-3,5-di-O-benzyl-D-ribonucleic acid-γ-lactone or 2-deoxy-2-fluoro-3,5-di-O-benzyl-D-arabinofuranosononic acid-γ-lactone) as a starting 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-hydroxytetrahydrofuranose through four steps of sugar carbonylation, cyanation, removal of benzyl protecting group and phosphorylation. The invention discloses two generations of remdesivir, namely, 2-((S)-(((2R,3R,4S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine; the synthetic method has a short route, simple steps and relatively high yield, and provides a new synthetic route for the synthesis or modification design of nucleoside drugs.

Description

Fluororad West-Wei synthesis method
Technical Field
The invention relates to a drug synthesis method, in particular to a synthesis method of fluoro-Ruidexivir (2-ethylbutyl ((S) - (((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-yl) -5-cyano) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine compound or 2-ethylbutyl ((S) - ((2R, 3R,4S, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-yl) -5-cyano) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine compound, belonging to the technical field of drug synthesis.
Background
In 1950, 2-bromo-2-chloro-1, 1-trifluoroethane was used as inhalation anesthetic, which shows that fluorine-regulated bioactive molecules have the potential of (Ostercamp DL,B.R.,Chemical Aspects of General Anesthesia:Part I.From Ether to Halothane1.Journal of Chemical Education 2006,83,1821);1953 years, josef Fried and Emily Sabo find that 9 alpha-fluorocortisone (shown in the following reaction) is more than 10 times higher than cortisol anti-inflammatory activity, which shows that introduction of fluorine atoms at designated positions on drug molecules can improve drug property of the drug molecules for (Sabo,J.F.a.E.F.,9-α-Fluoro derivatives of cortisone and hydrocortisone.J.Am.Chem.Soc.1954,76,1455);1957 years, robert Duschinsky and the like to synthesize fluorine-containing drug 5-fluorouracil (shown in the reaction), and the drug molecules are used as antitumor drugs, and show high anti-cancer activity by inhibiting thymidylate synthase, so that the discovery of two fluorine-containing drugs of thymidylate (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). is prevented, the foundation of greater and greater effect of fluorine in life science is laid, and the effect of fluorine is cut off to
The general trend in the number of fluorine-containing drugs approved by the U.S. food and drug administration at the end of 2020 is the growing (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-containing pharmaceuticals approved by the FDA in2020:Synthesis and biological activity.Chinese Chemical Letters 2021). because of the nature of fluorine, which can change its various properties by introducing fluorine into the drug molecule, so fluorine has great significance for the modification of nucleoside drugs.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a chemical synthesis method of a fluoro-Ruidexivir compound, which has the characteristics of short route, simple step operation, relatively high yield and the like, and provides a brand-new way for the synthesis or modification design of nucleoside drugs.
In order to achieve the technical object, the present invention provides a method for synthesizing a 2-ethylbutyl ((S) - (((2 r,3r,4r,5 r) -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, the method comprising the steps of:
1) 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-ribono-gamma-lactone and 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine are subjected to a glycosylation reaction to obtain an intermediate 3;
2) The intermediate 3 is subjected to cyanation reaction with trifluoroacetic acid, trifluoromethanesulfonic acid trimethylsilyl ester and trimethylcyano silane to obtain an intermediate 4;
3) Intermediate 4 is reacted through debenzylation protecting groups to obtain intermediate 5;
4) Intermediate 5 is phosphorylated with 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine to give a 2-ethylbutyl ((S) - (((2 r,3r,4r,5 r) -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 structural formula of the 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 compound is as follows:
The structures of the intermediates 3, 4 and 5 are as follows in sequence:
As a preferable scheme, the process of the sugar carbosulfation reaction comprises the steps of mixing a1, 2-bis (chlorodimethylsilyl) ethane solution with a 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine solution, stirring for 5-20 min, adding diisopropylamine, stirring for 3-10 min, placing in a low-temperature environment below-50 ℃ for at least 20min, slowly dropwise adding n-butyllithium, stirring for 15-60 min, dropwise adding a 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-ribonic acid-gamma-lactone solution, stirring for 1-5 h, adding a citric acid solution, heating to 0-5 ℃ and stirring for 10-30 min. The preparation method comprises the steps of adding a tetrahydrofuran solution of 1, 2-bis (chlorodimethylsilyl) ethane into a tetrahydrofuran solution of 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine at room temperature after replacing gas (adopting inert gas to replace air), stirring for 5-20 min, adding diisopropylamine, stirring for 3-10 min, placing in a low-temperature constant-temperature stirrer at-78 ℃ for cooling, stirring for at least 20min, slowly dripping n-butyllithium, stirring for 15-60 min, dissolving 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-ribonic acid-gamma-lactone in tetrahydrofuran, dripping into the system, stirring for 1-5 h, adding a 1M citric acid solution, heating to 0 ℃ and stirring for 10-30 min. Wherein the molar ratio of 1, 2-bis (chlorodimethylsilyl) ethane to 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine to diisopropylamine to 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone=0.5-1.5:1.0:0.5-1.5:1.0-3.0.
As a preferable scheme, the cyanation reaction comprises the steps of dissolving the intermediate 3 in a solvent, placing in a low-temperature environment below-50 ℃, stirring for at least 20min, adding trifluoroacetic acid, stirring for 5-30 min, dropwise adding trifluoromethylsilyl sulfonate, stirring for 10-60 min, adding trimethylcyanosilane, and stirring for 1-5 h. The preparation method comprises the steps of replacing gas, dissolving an intermediate 3 in dichloromethane, placing in a low-temperature constant-temperature stirrer at a temperature of-78 ℃ for cooling, stirring for at least 20min, adding trifluoroacetic acid, stirring for 5-30 min, dropwise adding trimethyl silicone triflate, stirring for 10-60 min, adding trimethyl cyanosilane, and stirring for 1-5 h. The molar ratio of the intermediate 3 to the trifluoroacetic acid to the trifluoromethylsilyl triflate to the trimethylcyanosilane=1.0:1.0-5.0:1.0-10.0:1.0-10.0.
As a preferable scheme, the process of the debenzylation protecting group reaction comprises the steps of dissolving the intermediate 4 in a solvent, placing the solvent in a low-temperature environment below-50 ℃, stirring for at least 20min, then dropwise adding boron trichloride, heating to-40 to-30 ℃, and stirring for 1-5 h. More specifically, after the gas is replaced, the intermediate 4 is dissolved in methylene dichloride, placed in a low-temperature constant-temperature stirrer at-78 ℃ for cooling, stirred for at least 20min, then added with boron trichloride dropwise, heated to-40 ℃ and stirred for 1-5 h. Wherein, the molar ratio of the intermediate 4 to the boron trichloride=1.0:1.0-10.0.
As a preferable scheme, the phosphorylation reaction comprises the steps of dissolving an intermediate 5 in a solvent and dissolving 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine in the solvent, placing in an ice bath environment, slowly dropwise adding dimethyl aluminum chloride, and stirring for 5-10 d at room temperature. The specific reaction process is that the gas is replaced, the intermediate 5 and 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine are dissolved in the propidium, and under the ice bath condition, the dimethyl aluminum chloride is slowly added dropwise, and the mixture is stirred for 5-10 days after being heated to room temperature.
The invention also provides a method for synthesizing a 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, which comprises the following steps:
1) 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone and 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine are subjected to glycosylation reaction to obtain an intermediate 9;
2) The intermediate 9 is subjected to cyanation reaction with trifluoroacetic acid, trifluoromethanesulfonic acid trimethylsilyl ester and trimethylsilyl cyanide to obtain an intermediate 4 or an intermediate 10;
3) Intermediate 10 is reacted through debenzylation protecting groups to obtain intermediate 5 or intermediate 11;
4) Intermediate 11 is phosphorylated with 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine to give a 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;
wherein,
The structural formula of the 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 is as follows:
the structures of the intermediates 9, 10 and 11 are as follows in sequence:
As a preferable scheme, the process of the carboglycosylation reaction comprises the steps of mixing a1, 2-bis (chlorodimethylsilyl) ethane solution with a 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine solution, stirring for 5-20 min, adding diisopropylamine, stirring for 3-10 min, placing in a low-temperature environment below-50 ℃ for at least 20min, slowly dropwise adding n-butyllithium, stirring for 15-60 min, dropwise adding a 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone solution, stirring for 1-5 h, adding a citric acid solution, heating to 0-5 ℃ and stirring for 10-30 min. The preparation method comprises the steps of adding a tetrahydrofuran solution of 1, 2-bis (chlorodimethylsilyl) ethane into a tetrahydrofuran solution of 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine at room temperature after replacing gas (inert gas is adopted), stirring for 5-20 min, adding diisopropylamine, stirring for 3-10 min, placing in a low-temperature constant-temperature stirrer at-78 ℃ for cooling, stirring for at least 20min, slowly dripping n-butyllithium, stirring for 15-60 min, dissolving 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone in tetrahydrofuran, dripping into the system, stirring for 1-5 h, adding a 1M citric acid solution, heating to 0 ℃ and stirring for 10-30 min. Wherein the molar ratio of 1, 2-bis (chlorodimethylsilyl) ethane to 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine to diisopropylamine to 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone=0.5-1.5:1.0:0.5-1.5:1.0-3.0.
As a preferable scheme, the cyanation reaction comprises the steps of dissolving an intermediate 9 in a solvent, placing in a low-temperature environment below-50 ℃, stirring for at least 20min, adding trifluoroacetic acid, stirring for 5-30 min, dropwise adding trifluoromethylsilyl sulfonate, stirring for 10-60 min, adding trimethylcyanosilane, and stirring for 1-5 h. The method comprises the steps of replacing gas, dissolving an intermediate 9 in methylene dichloride, placing in a low-temperature constant-temperature stirrer at a temperature of-78 ℃ for cooling, stirring for at least 20min, adding trifluoroacetic acid, stirring for 5-30 min, dropwise adding trimethyl silicone triflate, stirring for 10-60 min, adding trimethyl cyanosilane, and stirring for 1-5 h. The molar ratio of the intermediate 9 to the trifluoroacetic acid to the trifluoromethylsilyl triflate to the trimethylcyanosilane=1.0:1.0-5.0:1.0-10.0:1.0-10.0.
As a preferable scheme, the process of the debenzylation protecting group reaction comprises the steps of dissolving an intermediate 10 in a solvent, placing the solvent in a low-temperature environment below-50 ℃, stirring for at least 20min, then dropwise adding boron trichloride, heating to-40 to-30 ℃, and stirring for 1-5 h. More specifically, after gas replacement, the intermediate 10 is dissolved in methylene dichloride, placed in a low-temperature constant-temperature stirrer at-78 ℃ for cooling, stirred for at least 20min, then added with boron trichloride dropwise, heated to-40 ℃ and stirred for 1-5 h. Wherein, the molar ratio of the intermediate 10 to the boron trichloride=1.0:1.0-10.0.
As a preferable scheme, the phosphorylation reaction comprises the steps of dissolving an intermediate 11 in a solvent and dissolving 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine in the solvent, placing in an ice bath environment, slowly dropwise adding dimethyl aluminum chloride, and stirring for 5-10 d at room temperature. The more specific reaction process is that after gas replacement, intermediate 11 and 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine are dissolved in propadines, and under the ice bath condition, dimethyl aluminum chloride is slowly added dropwise, and the mixture is heated to room temperature and stirred for 5-10 days.
The synthetic reaction route of the 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 compound of the present invention is as follows:
The specific reaction steps are as follows:
(1) Adding a tetrahydrofuran solution of 1, 2-bis (chlorodimethylsilyl) ethane into a tetrahydrofuran solution of 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine (compound 2) at room temperature, stirring for 10min, adding diisopropylamine, stirring for 5min, placing in a low-temperature constant-temperature stirrer for cooling at least for 20min, slowly dripping n-butyllithium, stirring for 30min, dissolving 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-ribonic acid-gamma-lactone (compound 1) in tetrahydrofuran, dripping into the system, stirring for 2h, adding a 1M citric acid solution, heating to 0 ℃, stirring for 20min, separating an organic phase, concentrating under reduced pressure to obtain a crude product intermediate 3, and purifying by column chromatography to obtain the intermediate 3, wherein the molar ratio of 1, 2-bis (chlorodimethylsilyl) ethane to the compound 2 is 1=0.5-1.5:1.0.0.0:1.0-0.0:0.0.0-0:1:1-0.0:0;
(2) Replacing gas, dissolving the intermediate 3 in dichloromethane, placing in a low-temperature constant-temperature stirrer at-78 ℃ for cooling, stirring for at least 20min, adding trifluoroacetic acid, stirring for 10min, dropwise adding trimethyl silicone triflate, stirring for 30min, adding trimethyl cyanosilane, and stirring for 2h. Quenching reaction, heating to room temperature, separating an organic phase, concentrating under reduced pressure, and performing silica gel column chromatography to obtain an intermediate 4, wherein the molar ratio of the intermediate 3 is trifluoroacetic acid to trifluoromethylsilyl triflate to trimethylcyanosilane=1.0:1.0-5.0:1.0-10.0:1.0-10.0;
(3) Replacing gas, dissolving the intermediate 4 in dichloromethane, placing the dichloromethane in a low-temperature constant-temperature stirrer for cooling at-78 ℃, stirring for at least 20min, dropwise adding boron trichloride, heating to-40 ℃, stirring for 2h, cooling to-78 ℃, dropwise adding dry methanol, dissolving dry triethylamine in the dry methanol, then dropwise adding the dry triethylamine into a reaction system, heating to room temperature after the dropwise adding is finished, concentrating under reduced pressure, and performing silica gel column chromatography to obtain an intermediate 5, wherein the molar ratio of the intermediate 4 to the boron trichloride=1.0:1.0-10.0;
(4) Displacing gas, dissolving an intermediate 5 and a photochemically pure compound 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine (compound 6) in pyridine, slowly dropwise adding dimethyl aluminum chloride under ice bath condition, stirring for 7d at room temperature, adding 30% of L-tartaric acid solution for quenching reaction, adding ethyl acetate for dilution, separating an organic phase, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound 7, wherein the molar ratio of the intermediate 5 to the compound 6 to the dimethyl aluminum chloride=1.0:1.0 to 5.0:0.1 to 1.0.
The synthetic reaction route of the 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 of the present invention is as follows:
The specific reaction steps are as follows:
(1) Adding a tetrahydrofuran solution of 1, 2-bis (chlorodimethylsilyl) ethane into the tetrahydrofuran solution of 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine (compound 2) at room temperature, stirring for 10min, adding diisopropylamine, stirring for 5min, placing in a low-temperature constant-temperature stirrer for cooling at-78 ℃ for at least 20min, slowly dripping n-butyllithium, stirring for 30min, dissolving 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranoic acid-gamma-lactone (compound 8) in tetrahydrofuran, dripping into the system, stirring for 2h, adding a 1M citric acid solution, heating to 0 ℃, stirring for 20min, separating an organic phase, concentrating under reduced pressure to obtain a crude product intermediate 9, and purifying by column chromatography to obtain the intermediate 9, wherein the molar ratio of 1, 2-bis (chlorodimethylsilyl) ethane is that the diisopropylamine is that the compound 2 is 8=0.5-1.5:1.1.0.0:0.5-0.1:0.0.5:0-0;
(2) Replacing gas, dissolving the intermediate 9 in dichloromethane, placing in a low-temperature constant-temperature stirrer at-78 ℃ for cooling, stirring for at least 20min, adding trifluoroacetic acid, stirring for 10min, dropwise adding trimethyl silicone triflate, stirring for 30min, adding trimethyl cyanosilane, and stirring for 2h. Quenching reaction, heating to room temperature, separating an organic phase, concentrating under reduced pressure, and performing silica gel column chromatography to obtain an intermediate 10, wherein the molar ratio of the intermediate 9 is trifluoroacetic acid to trifluoromethylsilyl triflate to trimethylcyanosilane=1.0:1.0-5.0:1.0-10.0:1.0-10.0;
(3) Replacing gas, dissolving the intermediate 10 in dichloromethane, placing the dichloromethane in a low-temperature constant-temperature stirrer for cooling at-78 ℃, stirring for at least 20min, dropwise adding boron trichloride, heating to-40 ℃, stirring for 2h, cooling to-78 ℃, dropwise adding dry methanol, dissolving dry triethylamine in the dry methanol, then dropwise adding the dry triethylamine into a reaction system, heating to room temperature after the dropwise adding is finished, concentrating under reduced pressure, and performing silica gel column chromatography to obtain an intermediate 11, wherein the molar ratio of the intermediate 10 to the boron trichloride is 1.0:1.0-10.0;
(4) Displacing gas, dissolving an intermediate 11 and a photochemically pure compound 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine (compound 6) in pyridine, slowly dropwise adding dimethyl aluminum chloride under ice bath condition, stirring for 7d at room temperature, adding 30% of L-tartaric acid solution for quenching reaction, adding ethyl acetate for dilution, separating an organic phase, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound 12, wherein the molar ratio of the intermediate 11 to the compound 6 to the dimethyl aluminum chloride=1.0:1.0-5.0:0.1-1.0.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
The invention successfully synthesizes two fluoro-Ruidexiwei drugs of 2-ethylbutyl ((S) - (((2R, 3R,4R, 5R) -5- (4-amino pyrrolo [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-amino pyrrolo [2,1-f ] [1,2,4] triazine-7-yl) -5-cyano) -4-fluoro-3-hydroxy tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine by a chemical method, and provides a brand new approach for nucleoside drug modification and design.
The synthesis method has the advantages of short route, simple step operation and relatively high yield (the reaction yield of each step reaches more than 55), and is beneficial to realizing the expansion of production.
Drawings
FIG. 1 is 1H NMR(400MHz,methanol-d4, 25 ℃ of 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-alanine compound.
FIG. 2 is 19F NMR(376MHz,methanol-d4, 25 ℃ of 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-alanine compound.
FIG. 3 is 19F NMR(376MHz,methanol-d4, 25 ℃ of 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-alanine compound.
FIG. 4 is 31P NMR(162MHz,methanol-d4, 25 ℃ of 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-alanine compound.
FIG. 5 is 31P NMR(162MHz,methanol-d4, 25 ℃ of 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-alanine compound.
FIG. 6 is 13C NMR(100MHz,methanol-d4, 25 ℃ of 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-alanine compound.
Detailed Description
The following specific examples are intended to further illustrate the present invention, but not to limit the scope of the claims.
The chemical reagents referred to in the examples below are conventional, commercially available, analytically pure reagents unless otherwise specified.
Example 1
(1) Synthesis of intermediate 3
4-Amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine (Compound 2) (321 mg, 1.015 mmol) was weighed into a dry 50mL round-bottom flask, displaced three times with a displacement gas, tetrahydrofuran (25.8 mL) was added and stirred at room temperature for 5min, 1, 2-bis (chlorodimethylsilyl) ethane (358.7 mg,1.667 mmol) was weighed into a dry 5mL round-bottom flask, dried tetrahydrofuran (1.6 mL) was added and dissolved and added into the reaction system, stirred at room temperature for 10min, diisopropylamine (234. Mu.L, 1.667 mmol) was added, stirred at room temperature for 5min, cooled in a low temperature constant temperature stirrer at-78℃for at least 20min, n-hexane,4.07mL, 6.015 mmol) was slowly dropped into n-butyllithium (1.6M in n-hexane mmol), stirred for 30min, 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-ribo-gamma-lactone (Compound) (1.9 g, 1.029 mL) was added into a round-bottom flask, dried for 1.02 mL, and stirred at room temperature for 1.0 h monitored.
Monitoring the completion of the reaction, quenching the reaction by adding 1M citric acid solution (16 mL), heating to 0 ℃, separating the organic phase, concentrating under reduced pressure to obtain a crude product, dissolving, adding silica gel for sample mixing, and performing silica gel column chromatography to obtain an intermediate 3 (426 mg,60%, petroleum ether: ethyl acetate=1:2, R f =0.25).
(2) Synthesis of intermediate 4
Intermediate 3 (426 mg, 0.227 mmol) was weighed into a 25mL reaction flask, displaced three times with gas, dichloromethane (12 mL) was added, stirred and dissolved, placed in a-78 ℃ low temperature constant temperature stirrer, cooled, stirred for at least 20min, trifluoroacetic acid (208. Mu.L, 2.721 mmol) was added, stirred for 10min, trimethylsilicone triflate (0.98 mL,5.442 mmol) was added dropwise, stirred for 30min, trimethylcyanosilane (0.68 mL,5.442 mmol) was added, stirred for 2h, and TLC monitored for reaction.
Monitoring the completion of the reaction, quenching the reaction, warming to room temperature, separating the organic phase, concentrating under reduced pressure, stirring, and subjecting to silica gel column chromatography to give intermediate 4 (319 mg,60%, petroleum ether: ethyl acetate=1:2, r f =0.7).
(3) Synthesis of intermediate 5
Intermediate 4 (231 mg,0.488 mmol) was weighed into a 25mL bottle, the gas was replaced three times, dichloromethane (2.7 mL) was added, stirred and dissolved, placed in a-78 ℃ low temperature constant temperature stirrer, stirred for at least 20min, boron trichloride (1M in methylene chloride,3.71mL,3.71mmol) was added dropwise, the temperature was raised to-40 ℃, stirred for 2h, and TLC monitored for reaction.
Monitoring the completion of the reaction, cooling to-78 ℃, dropwise adding dry methanol (1.08 mL), dissolving dry triethylamine (1.4 mL) in dry methanol (2.2 mL), then dropwise adding the mixture into a reaction system, heating to room temperature after the completion of the dropwise adding, concentrating under reduced pressure, dissolving with methanol, adding silica gel for sample mixing, and carrying out column chromatography with ethyl acetate silica gel to obtain a product of 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 percent, petroleum ether: ethyl acetate=1:4, R f =0.2).
[α]D 25＝-51.1(c 1.0,C2H5OH);m.p.:166-169°C;
1H-NMR(400MHz,methanol-d4):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);
13C-NMR(100MHz,methanol-d4):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;
19F NMR(376MHz,methanol-d4):δ-197.79--197.98(m,1F);
19F NMR(376MHz,methanol-d4):δ-197.88(s,1F);
HRMS(ESI)m/z calcd for C12H12FN5O3Na+(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, 0.3411 mmol) were added to a 10mL round bottom flask, the gas was displaced three times, dry pyridine (1.7 mL) was added, the temperature was reduced under ice bath conditions and stirred for 10min, dimethylaluminum chloride (1M in heptane, 86. Mu.L, 0.086 mmol) was slowly added dropwise, stirred for 7d at room temperature, and TLC monitored for reaction.
The completion of the reaction was monitored, the reaction was quenched by addition of 30% l-tartaric acid solution (1 mL), diluted with ethyl acetate, the organic phase was separated, concentrated preshrunk samples under reduced pressure, and silica gel column chromatography gave compound 7 (66 mg,64%, petroleum ether: ethyl acetate=1:4, r f =0.4).
1H NMR(400MHz,methanol-d4):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);
19F NMR(376MHz,methanol-d4):δ-196.98--197.18(m,1F);
19F NMR(376MHz,methanol-d4):δ-197.08(s,1F);
31PNMR(162MHz,methanol-d4):δ3.68-3.54(m,1P);
31PNMR(162MHz,methanol-d4):δ3.61(s,1P);
13C NMR(100MHz,methanol-d4):δ174.99,174.94,157.17,152.16,125.10,148.59,130.76,126.13,123.31,123.26,121.35,121.31,118.21,115.78,115.70,112.33,102.77,94.62,92.63,82.39,82.31,79.41,79.20,70.57,70.40,68.09,66.27,66.22,51.50,41.67,24.19,20.61,20.54,11.33,11.28;
HRMS(ESI)m/z calcd for C27H34FN6O7PNa+(M+Na)+627.2103,found 627.2107.
Example 2
(1) Synthesis of intermediate 9
Referring to A.U, patent 2015238851A1 uses reaction condition 4, while the yield is low, only 20%, but the target product is obtained, and the screening spot plate for the following reaction conditions has a control spot. NaH is added in the reaction condition 5, the yield is improved to 41%, the material is added in an enlarged way by 10 times, and the yield is reduced to 34%. Reaction condition 7, initial attempt, yields only 42%. The reaction solvent is increased, the concentration of the reaction system is reduced, and the yield reaches 68% by using the reaction condition 8. The conditions are amplified by 10 times for feeding, and the yield is not obviously changed. The optimal reaction condition for the ligation of unnatural bases to ribose centers is therefore condition 8. The following table shows:
The following is a specific embodiment in which 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine (compound 2) (433.4 mg,2.0446 mmol) is weighed into a dry 50mL round bottom flask, the gas is replaced three times, dry tetrahydrofuran (20 mL) is added under nitrogen protection, stirring is carried out at room temperature for 5min, 1, 2-bis (chlorodimethylsilyl) ethane (484.2 mg,2.249 mmol) is weighed into a dry 5mL round bottom flask, dry tetrahydrofuran (3 mL) is added to dissolve and add into the reaction system, stirring is carried out at room temperature for 10min, diisopropylamine (0.32 mL,2.249 mmol) is added, stirring is carried out at room temperature for 5min, cooling is carried out in a low-temperature constant-temperature stirrer at-78 ℃, stirring is carried out for at least 20min, after dropwise addition of n-butyllithium (1.6M in n-hexane mL,8.792 mmol) is carried out, stirring is carried out at-78 ℃ for 30min after dropwise addition is completed, 2-deoxy-2-fluoro-3-diethyl lactone (3 mL) is added into a dry 5mL round bottom flask, stirring is carried out at room temperature for 2.149 mmol, dropwise, stirring is carried out at room temperature for 2 min, 2.127 mg, cooling is carried out in a constant temperature stirrer, and stirring is carried out at 2mL, cooling is carried out at 35 mmol, 2g, 2-3 mL is carried out at 35 mmol, and dropwise, 2-3 mL is monitored by monitoring, and then the temperature is added into a dry ethyl lactone is added into a dry flask.
The reaction was monitored for completion, quenched by the addition of 1M citric acid solution (16 mL), warmed to 0 ℃, the organic phase separated, concentrated under reduced pressure to give the crude product, dissolved, stirred with silica gel, and column chromatographed on silica gel to give intermediate 9 (552 mg,68%, petroleum ether: ethyl acetate=1:2, r f =0.25).
(2) Synthesis of intermediate 10
The cyanation reaction of 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 carried out, and when the reaction temperature was controlled to-78 ℃ at the beginning, a solid was precipitated during the reaction, the reaction was carried out in accordance with the reaction operation, and the starting material was found to be unreacted by the dot plate, and the yield was 60% (reaction condition 1). The reaction was again attempted with 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) in 65% yield (upper half of reaction condition 2) as in the experimental case. Analyzing the reason that the raw materials are not reacted, because the feed equivalent ratio of the cyanation reaction in the synthesis of the Ruidexivir can be used for completely reacting the raw materials, and combining the solid in the reaction process, the raw materials are not well dissolved into the solvent at the temperature of-78 ℃, so that the temperature raising measure is adopted. 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) is taken as a reaction substrate, the reaction temperature is slowly increased from-78 ℃, the solid dissolution condition is observed until the temperature is-40 ℃, the solution is clear, trifluoroacetic acid is added, after stirring for a while, trimethyl silicone triflate and trimethyl cyanosilane are added, and stirring is carried out for 2 hours until the raw materials are completely reacted, and the yield is 83% (the lower half of the reaction condition 2). Next, the cyanation reaction temperature was controlled at-40℃as shown in the following table:
The following is a specific embodiment, intermediate 9 (50 mg,0.108 mmol) was weighed into a dry 10mL round bottom flask, replaced with gas three times, dried dichloromethane (1.4 mL) was added under nitrogen protection, stirred and dissolved, placed in a-78 ℃ low temperature constant temperature stirrer for cooling, stirred for at least 20min, trifluoroacetic acid (24 μl,0.323 mmol) was added, stirred for 10min, trimethylsilyl triflate (117 μl,0.648 mmol) was added dropwise, stirred for 30min, trimethylcyanosilane (81 μl,0.648 mmol) was added, stirred for 2h, TLC monitored reaction, and plates were crawled with petroleum ether: ethyl acetate=1:2.
Monitoring the completion of the reaction, quenching the reaction, warming to room temperature, separating the organic phase, concentrating under reduced pressure, stirring, and subjecting to silica gel column chromatography to give intermediate 10 (33 mg,65%, petroleum ether: ethyl acetate=1:2, r f =0.7).
(3) Synthesis of intermediate 11
Intermediate 10 (189 mg,0.399 mmol) was weighed into a dry 25mL round bottom flask, the gas was replaced three times, dry dichloromethane (2.2 mL) was added under nitrogen protection, stirred and dissolved, placed in a-78 ℃ low temperature constant temperature stirrer to cool down, stirred for at least 20min, boron trichloride (1M in methylene chloride,3.04mL,3.04mmol) was added dropwise, the temperature was raised to-40 ℃ after the dropwise addition, stirred for 2h, tlc monitored for reaction, and petroleum ether: ethyl acetate=1:1 climbing plate was used.
Monitoring the completion of the reaction, cooling to-78 ℃, dropwise adding dry methanol (0.88 mL), dissolving dry triethylamine (1.44 mL) in the dry methanol (1.76 mL), then dropwise adding the solution into a reaction system, heating to room temperature after the completion of the dropwise adding, concentrating under reduced pressure, dissolving with methanol, adding silica gel for sample mixing, and performing column chromatography with ethyl acetate silica gel to obtain an intermediate 11 (105 mg,90%, petroleum ether: ethyl acetate=1:4, R f =0.2).
1HNMR(400MHz,methanol-d4):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);
13C-NMR(100MHz,methanol-d4):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;
19F NMR(376MHz,methanol-d4):δ-186.37--186.55(m,1F);
19F NMR(376MHz,methanol-d4):δ-186.46(s,1F);
HRMS(ESI)m/z calcd for C12H12FN5O3Na+(M+Na)+316.0816,found 316.0818.
(4) Synthesis of Compound 12
Intermediate 11 (50 mg,0.171 mmol) and the photochemically pure compound 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine (compound 6) (169 mg, 0.3411 mmol) were added to a 10mL round bottom flask, the gas was displaced three times, dry pyridine (1.7 mL) was added, the temperature was reduced under ice bath conditions and stirred for 10min, dimethylaluminum chloride (1M in heptane, 86. Mu.L, 0.086 mmol) was slowly added dropwise, stirred for 7d at room temperature, and TLC monitored for reaction.
Monitoring the completion of the reaction, quenching the reaction by adding 30% L-tartaric acid solution (1 mL), diluting with ethyl acetate, separating the organic phase, concentrating preshrunk under reduced pressure, and subjecting to silica gel column chromatography to give compound 12 (58.8 mg,57%, petroleum ether: ethyl acetate=1:4, R f =0.4)
1H NMR(400MHz,methanol-d4):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);
19F NMR(376MHz,methanol-d4):δ-186.37--186.55(m,1F);
19F NMR(376MHz,methanol-d4):δ-186.46(s,1F);
31PNMR(162MHz,methanol-d4):δ3.50-3.35(m,1P);
31PNMR(162MHz,methanol-d4):δ3.43(s,1P);
13C NMR(100MHz,methanol-d4):δ174.96,174.92,158.85,157.03,152.21,152.14,148.40,130.79,126.13,121.42,124.37,116.58,116.50,111.67,102.76,101.14,99.18,86.47,79.51,76.79,68.11,66.46,51.54,41.66,24.21,20.61,20.54,11.34,11.29;
HRMS(ESI)m/z calcd for C27H34FN6O7PNa+(M+Na)+627.2103,found 627.2107.
The present invention is not limited to the above embodiments, but is merely preferred embodiments of the present invention, and the present invention should be construed as being limited to the above embodiments as long as the technical effects of the present invention are achieved by the same means. Various modifications and variations are possible in the technical solution and/or in the embodiments within the scope of the invention.

Claims (2)

1. A method for synthesizing a 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 is characterized by comprising the following steps:
1) 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone and 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine are subjected to glycosylation reaction to obtain an intermediate 9;
2) The intermediate 9 is subjected to cyanation reaction with trifluoroacetic acid, trifluoromethanesulfonic acid trimethylsilyl ester and trimethylcyano silane to obtain an intermediate 10;
3) Intermediate 10 is reacted through debenzylation protecting groups to obtain intermediate 11;
4) Intermediate 11 is phosphorylated with 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine to give a 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;
Wherein the structural formula of the 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 is as follows:
the structures of the intermediates 9, 10 and 11 are as follows in sequence:
、、;
The process of the glycosylation reaction of the sugar comprises the steps of weighing 2.0446mmol of 4-amino-7-bromopyrrolo [2,1-F ] [1,2,4] triazine in a dried 50mL round bottom flask, displacing gas for three times, adding 20mL of dried tetrahydrofuran under the protection of nitrogen, and stirring for 5min at room temperature; weighing 2.399 mmol of 1, 2-bis (chlorodimethylsilyl) ethane in a dry 5mL round bottom flask, adding 3mL of dry tetrahydrofuran to dissolve the 1, 2-bis (chlorodimethylsilyl) ethane and adding the solution into a reaction system, stirring the solution for 10min at room temperature, adding 2.249mmol of diisopropylamine, stirring the solution for 5min at room temperature, placing the solution in a low-temperature constant-temperature stirrer for cooling, stirring the solution for at least 20min, slowly dropwise adding 8.792mmol of n-butyllithium, stirring the solution for 30min at-78 ℃ after the dropwise adding is finished, weighing 4.0893mmol of 2-deoxy-2-fluoro-3, 5-di-O-benzyl-D-arabinofuranonic acid-gamma-lactone in the dry 5mL round bottom flask, adding 3mL of dry tetrahydrofuran to dissolve the solution and slowly dropwise adding the solution into the reaction system, stirring the solution for 2h at-78 ℃ after the dropwise adding is finished, monitoring the reaction by TLC, adding 16mL of 1M citric acid solution for quenching the reaction, heating to 0 ℃, separating an organic phase, concentrating the organic phase under reduced pressure to obtain a crude product, dissolving, adding a silica gel column, and stirring the silica gel column to obtain an intermediate column 9;
Dissolving an intermediate 9 in a solvent, placing in a low-temperature environment below-50 ℃, stirring for at least 20min, adding trifluoroacetic acid, stirring for 5-30 min, dropwise adding trifluoromethylsilyl sulfonate, stirring for 10-60 min, adding trimethylcyanosilane, and stirring for 1-5 h;
the process of the debenzylation protecting group reaction comprises the steps of dissolving an intermediate 10 in a solvent, placing the solvent in a low-temperature environment below-50 ℃, stirring for at least 20min, then dropwise adding boron trichloride, heating to-40 to-30 ℃, and stirring for 1-5 h.
2. The method for synthesizing a 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 according to claim 1, wherein the phosphorylation reaction is carried out by dissolving intermediate 11 in a solvent and 2-ethylbutyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine in a solvent, placing in an ice bath environment, slowly dropwise adding dimethylaluminum chloride, and stirring at room temperature for 5-10 d.
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