An N-protected pyrrolotriazine C-glycoside compound and its preparation method

Abstract

This invention belongs to the field of organic synthesis technology and provides an N-protected pyrrolotriazine compound, its preparation method, and its application. Specifically, this invention discloses a method for preparing N-protected pyrrolotriazine compounds and their intermediates, and their application in the synthesis of cyano-containing carbon-nucleoside antiviral drugs. This invention has advantages such as shortening the synthetic route of carbon-nucleoside analogs; low cost; simple and efficient operation; high yield; high product purity; and avoiding the formation of difficult-to-remove amide or primary amine impurities, which is beneficial for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an N-protected pyrrolotriazine C-glycoside compound and its preparation method. Background Technology

[0002] Pyrrolotriazine compounds have been widely studied and applied due to their good drug-like properties. Some pyrrolotriazine compounds (Nature. 17; 531, 7594, 381-5) have shown good antiviral pharmacological activity.

[0003] Remdesivir, a pyrrolotriazine derivative, is an RNA-dependent RNA polymerase (RdRp) inhibitor. It works by inhibiting viral nucleic acid replication to achieve antiviral effects and was one of the first drugs marketed to treat SARS-CoV-2 infection since the outbreak of the pandemic. Despite its good clinical efficacy, remdesivir's application and accessibility are limited by its complex prodrug form, lengthy synthesis steps (J. Med. Chem. 2017, 60, 1648-1661), high price, and requirement for intravenous administration.

[0004] Chinese patent application CN113735862A, based on the structure of remdesivir, modified the main metabolite GS-441524 of remdesivir to develop a series of novel carbon-nucleoside small molecule drugs, such as ATV006 and ATV014. These compounds effectively improved the bioavailability of remdesivir, optimized its pharmacokinetic properties and drug-likeness, and, more importantly, demonstrated effective protection against current variant strains, including Delta and Omeprone strains, both in vivo and in vitro (Liu C., et al., Science Translational Medicine, 2022).

[0005] Since its discovery over two years ago, SARS-CoV-2 has continued to spread and undergo various mutations, and the virus is highly likely to continue coexisting with humans indefinitely. To meet the needs of subsequent clinical research and the human fight against SARS-CoV-2, research on the large-scale preparation processes of compounds such as ATV006 and ATV014 is of great significance. Therefore, rapidly developing and optimizing an efficient, low-cost, and industrially scalable synthetic route for compounds such as ATV006 and ATV014 is currently a crucial task in the synthesis and production of these drugs.

[0006] Although existing technologies exist for the preparation of carbon-nucleoside compounds, these methods suffer from problems such as low yield, high cost, and difficulty in removing impurities, as exemplified by the following reported methods.

[0007] In 2012, Gilead reported that bases Il or II-l, after temporary silyl protection with I-2, could undergo addition and reduction with ribonucleolus I-4 to obtain carbon-nucleoside analogs I-5 or II-3, which could be further used to synthesize remdesivir [Bioorganic & Medicinal Chemistry Letters 2012, 22(12), 4127-4132; Journal of Medicinal Chemistry 2014, 57(5), 1812-1825]. However, the yields from Il to I-5 or II-1 to II-3 were less than 20%.

[0008]

[0009] Gilead reported an improvement to the method in 2017: starting from base III-1, carbon-nucleoside analog I-5 can be obtained more reliably for further synthesis of remdesivir [Journal of Medicinal Chemistry 2017, 60(5), 1648-1661.], but the yield from III-1 to I-5 was only 40%, and expensive iodine-containing raw materials were used.

[0010]

[0011] Chinese patent application CN113754665A discloses a method for producing 5'-carboxylic acid ester-carbon-nucleoside analogs IV-4 (ATV014 (R = cyclohexyl); ATV006 (R = isopropyl)) by esterification of the 5'-hydroxyl group of remdesivir intermediate IV-1 with acetone fork and then deprotection. The following problems lead to operational inconvenience and impurity control issues: IV-1 has poor solubility in most organic solvents, making the reaction inconvenient; simultaneously, during the esterification of IV-2, the unprotected amino group results in the formation of amidated IV-3 impurity. Although most of the impurity can be removed by slurrying in ethanol, this results in a loss of yield; furthermore, the incompletely removed IV-3 impurity impurity leads to the presence of N-amidated IV-4 impurity in the final IV-4 product, which is difficult to remove and affects the quality of the final product.

[0012]

[0013] Chinese patent application CN113248508A discloses a route for N-protection of heterocyclic amine compounds using Boc or Cbz. Due to the instability of the Boc group in the reaction process, there are many impurities generated during the reaction, especially in V-5 (R=Boc), where Boc is easily removed to generate structure IV-1, and no NMR data or spectrum is provided for V-5 (R=Boc). At the same time, for the N-Cbz protection reaction, the overall yield of synthesizing V-5 (R=Cbz) is reduced to 12.3%, and Cbz in compound V-5 (R=Cbz) has a certain stability, making subsequent removal difficult under acid or basic conditions. Using Pd / C removal will generate byproducts of cyano group reduction, and the furan ring in this structure may have ring-opening issues.

[0014]

[0015] In the above formula: R = Boc or Cbz

[0016] The synthetic routes for representative carbon-nucleoside compounds reported above still suffer from drawbacks such as expensive raw materials, low yields, lengthy routes, and difficulty in removing impurities. Therefore, there is an urgent need for a low-cost, high-yield, quality-controllable method suitable for industrial production of compounds such as ATV014 and ATV006. Summary of the Invention Invention Overview

[0018] To address the aforementioned problems, this invention provides a method for preparing the compound shown in Formula J and its intermediates. The preparation method provided by this invention shortens the synthetic route for carbon-nucleoside analogs. The preparation method is low in cost, simple and efficient in operation, has high yield, high product purity, and avoids the generation of difficult-to-remove amide impurities or primary amine impurities, which is beneficial for industrial production.

[0019] On the other hand, the present invention provides intermediates for preparing compounds of formula J, such as compounds of formula A, B, C, D, E, F, G, or H, as well as specific compounds of each intermediate. Using the intermediates provided by the present invention, especially intermediate compounds with amino-substituted pivalamides, is beneficial for reducing the cost of preparation methods, simplifying operations, increasing product yield, improving product purity, and avoiding the generation of difficult-to-remove impurities.

[0020] In another aspect, the present invention provides a method for preparing the compound represented by formula F00. The method is a one-pot preparation method, which is simple to operate, has few operation steps, high yield, and is safe and environmentally friendly. Invention Details

[0022] To address the above problems, the present invention provides the following technical solution.

[0023] In a first aspect, the present invention provides a method for preparing a compound of formula J. In some embodiments, a method for preparing a compound of formula J includes the following steps:

[0024] 1) In the presence of a Lewis acid, the compound shown in formula D reacts with a ketal in a solvent to give the compound shown in formula E.

[0025] 2) Under the presence of a catalyst and solvent, and optionally a condensing agent, the compound shown in Formula E and the compound shown in Formula S5 undergo an esterification reaction at a certain temperature to obtain the compound shown in Formula H.

[0026] 3) Under acidic conditions, the compound shown in formula H undergoes an amino-ketal deprotection reaction in a solvent to yield the compound shown in formula J. This amino-ketal deprotection reaction is referred to as reaction i.

[0027] Under acidic or alkaline conditions, the compound shown in formula H undergoes an amino deprotection reaction in a solvent, followed by a ketal deprotection reaction under acidic conditions to obtain the compound shown in formula J. The amino deprotection reaction described in this step is referred to as reaction ii, and the ketal deprotection reaction described in this step is referred to as reaction iii.

[0028]

[0029] in, It is an amino protecting group. It is a hydroxyl protecting group.

[0030] R 4 Selected from substituted or unsubstituted C1-C 10 Straight-chain alkyl, substituted or unsubstituted C1-C 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2–C6 straight-chain alkenyl, substituted or unsubstituted C2–C6 branched alkenyl, substituted or unsubstituted C2–C6 straight-chain alkynyl, substituted or unsubstituted C2–C6 branched alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic groups,

[0031] X is selected from chlorine, hydroxyl, or -OC(O)R 4 .

[0032] In some embodiments, X is selected from chlorine or -OC(O)R 4The esterification reaction to obtain the compound shown in formula H includes the esterification reaction of the compound shown in formula E and the compound shown in formula S5 at a certain temperature in the presence of a catalyst and a solvent to obtain the compound shown in formula H.

[0033] In some embodiments, X is selected from hydroxyl groups, and the esterification reaction to obtain the compound shown in Formula H includes the esterification reaction of the compound shown in Formula E with the compound shown in Formula S5 at a certain temperature in the presence of a catalyst, solvent and condensing agent to obtain the compound shown in Formula H.

[0034] In some embodiments of the present invention, a method for preparing a compound of formula J includes the following steps:

[0035] 1) In the presence of a catalyst, the compound shown in formula D reacts with a ketal in a solvent to give the compound shown in formula F;

[0036] 2) In the presence of a condensing agent and a solvent, the compound shown in formula F undergoes an esterification reaction with the compound shown in formula S5-1 at a certain temperature to obtain the compound shown in formula G.

[0037] 3) Under the presence of acid and solvent, the compound shown in formula G undergoes a ketal deprotection reaction to obtain the compound shown in formula J. The ketal deprotection reaction described in this step is referred to as reaction iv.

[0038]

[0039] in, It is an amino protecting group. It is a hydroxyl protecting group;

[0040] R 4 Selected from substituted or unsubstituted C1-C10 straight-chain alkyl groups, substituted or unsubstituted C1-C 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2–C6 straight-chain alkenyl, substituted or unsubstituted C2–C6 branched alkenyl, substituted or unsubstituted C2–C6 straight-chain alkynyl, substituted or unsubstituted C2–C6 branched alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic.

[0041] In some embodiments of the present invention, the preparation method of the compound represented by formula D includes the following steps:

[0042] 1) Under certain temperature conditions, the compound of formula S1 and the compound shown in formula S3 undergo an amidation reaction in a solvent in the presence of a base and a catalyst to obtain the compound shown in formula A.

[0043] 2a) Under an inert gas atmosphere and at a certain temperature, the compound shown in formula A is mixed with organolithium and / or organomagnesium in a solvent, reacted, and the R group is removed. 2 The reaction solution 1 was obtained;

[0044] 2b) Under an inert gas atmosphere, the compound shown in formula S2 is mixed with a Lewis acid and a quaternary ammonium salt in a solvent, reacted, and cooled to a certain temperature to obtain reaction solution 2;

[0045] In step 2b), the Lewis acid is selected from at least one of anhydrous cerium trichloride, anhydrous lanthanum trichloride, and anhydrous neodymium trichloride, preferably neodymium trichloride; the quaternary ammonium salt is selected from at least one of tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, and hexadecyltrimethylammonium chloride, preferably tetrabutylammonium chloride;

[0046] 2c) Mix reaction solution 1 and reaction solution 2 and react at a certain temperature to obtain the compound shown in formula B;

[0047] 3) Under an inert gas atmosphere, the compound shown in formula B is mixed with an acid, a cyaniding reagent and a solvent, and then subjected to a cyanidation reaction to obtain the compound shown in formula C;

[0048] 4) Under an inert gas atmosphere, the compound shown in formula C is mixed with a Lewis acid and a solvent, and after a debenzylation reaction, the compound shown in formula D is obtained;

[0049]

[0050] in, R is an amino protecting group. 2 H or halogen; Y is selected from chlorine, hydroxyl, or -OC(O)R 1 .

[0051] In some embodiments of the present invention, the compound represented by formula D is prepared by the following method, including the following steps:

[0052]

[0053] The compound shown in Formula S3 and the compound shown in Formula S4 are subjected to an amidation reaction in the presence of a base and a catalyst to obtain the compound shown in Formula C; under an inert gas atmosphere, the compound shown in Formula C is mixed with a Lewis acid and subjected to a debenzylation reaction to obtain the compound shown in Formula D.

[0054] in, It is an amino protecting group; Y is selected from chlorine, hydroxyl, or -OC(O)R 1 .

[0055] In some embodiments, R 3 Selected from substituted or unsubstituted C1-C10 Straight-chain alkyl, substituted or unsubstituted C1-C 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2–C6 straight-chain alkenyl, substituted or unsubstituted C2–C6 branched alkenyl, substituted or unsubstituted C2–C6 straight-chain alkynyl, substituted or unsubstituted C2–C6 branched alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, or two R 3 Forms C3-C with adjacent carbon. 10 Saturated or unsaturated alkane carbocyclic groups.

[0056] In some embodiments, R 1 Selected from substituted or unsubstituted C1-C 10 Straight-chain alkyl, substituted or unsubstituted C1-C 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2–C6 straight-chain alkenyl, substituted or unsubstituted C2–C6 branched alkenyl, substituted or unsubstituted C2–C6 straight-chain alkynyl, substituted or unsubstituted C2–C6 branched alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic.

[0057] In some embodiments, R 2 It is selected from hydrogen, fluorine, chlorine, bromine or iodine.

[0058] In some preferred embodiments, R 1 Selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, or phenyl; R 3 Selected from methyl, ethyl, trifluoromethyl, or cyclohexyl; R 4 Selected from isopropyl or cyclohexyl; R 2 Selected from hydrogen, bromine, or iodine.

[0059] In some preferred embodiments, R 3 Selected from methyl, ethyl, cyclohexyl or two R 3 It forms cyclohexyl and cyclopentyl groups with adjacent carbon atoms;

[0060] In some preferred embodiments, R 1 Selected from tert-butyl or phenyl; R 2 Selected from hydrogen; R 3 Selected from methyl, ethyl, or cyclohexyl;

[0061] In some preferred embodiments, R 1 Selected from tert-butyl or phenyl; R 2 Selected from hydrogen; R 3 Selected from methyl, ethyl, and cyclohexyl; R 4 Selected from isopropyl or cyclohexyl.

[0062] In some embodiments, the solvent in the reaction to obtain the compound shown in Formula E includes at least one of the following: dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, 2,2-dimethoxypropane, 3,3-dimethoxypentane, methyl tert-butyl ether, N,N-dimethylformamide, dimethyl sulfoxide, n-hexane, n-heptane, tetrahydrofuran, diethyl ether, and acetonitrile.

[0063] In some embodiments, the catalyst in the reaction to obtain the compound of formula E includes at least one of p-toluenesulfonic acid or its hydrate, methanesulfonic acid, trifluoromethanesulfonic acid or its hydrate, zinc trifluoromethanesulfonate or its hydrate, and trifluoroacetic acid.

[0064] In some embodiments, the molar ratio of the catalyst to the compound shown in Formula D in the reaction for obtaining the compound shown in Formula E is 0.01:1.00 to 0.10:1.00. In some embodiments, the molar ratio of the catalyst to the compound shown in Formula D in the reaction for obtaining the compound shown in Formula E is 0.05:1.00 to 0.10:1.00. In some embodiments, the molar ratio of the catalyst to the compound shown in Formula D in the reaction for obtaining the compound shown in Formula E is 0.01:1.00, 0.02:1.00, 0.03:1.00, 0.04:1.00, 0.05:1.00, 0.06:1.00, 0.07:1.00, 0.08:1.00, 0.09:1.00, or 0.10:1.00.

[0065] In some embodiments, the ketal in the reaction that yields the compound of formula E includes at least one of 2,2'-dimethoxypropane, 3,3'-dimethoxypentane, benzophenone dimethyl ketal, and dicyclohexyl ketone dimethyl ketal.

[0066] In some embodiments, the solvent in the reaction to obtain the compound of formula F includes at least one of the following: dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, 2,2-dimethoxypropane, 3,3-dimethoxypentane, methyl tert-butyl ether, N,N-dimethylformamide, dimethyl sulfoxide, n-hexane, n-heptane, tetrahydrofuran, diethyl ether, and acetonitrile.

[0067] In some embodiments, the catalyst in the reaction to obtain the compound of formula F includes at least one of p-toluenesulfonic acid or its hydrate, methanesulfonic acid, trifluoromethanesulfonic acid or its hydrate, zinc trifluoromethanesulfonate or its hydrate, and trifluoroacetic acid.

[0068] In some embodiments, the molar ratio of the catalyst to the compound shown in Formula D in the reaction for obtaining the compound shown in Formula F is 1.0:1.0 to 2.0:1.0. In some embodiments, the molar ratio of the catalyst to the compound shown in Formula D in the reaction for obtaining the compound shown in Formula F is 1.0:1.0, 1.2:1.0, 1.5:1.0, or 2.0:1.0.

[0069] In some embodiments, the ketal in the reaction that yields the compound of formula F includes at least one of 2,2'-dimethoxypropane, 3,3'-dimethoxypentane, benzophenone dimethyl ketal, and dicyclohexyl ketone dimethyl ketal.

[0070] In some embodiments, the solvent in the reaction to obtain the compound shown in Formula C includes at least one of the following: dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, 2,2-dimethoxypropane, 3,3-dimethoxypentane, methyl tert-butyl ether, N,N-dimethylformamide, dimethyl sulfoxide, n-hexane, n-heptane, tetrahydrofuran, diethyl ether, and acetonitrile.

[0071] In some embodiments, the solvent in the reaction to obtain the compound shown in Formula D includes at least one of the following: methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, 2,2-dimethoxypropane, 3,3-dimethoxypentane, methyl tert-butyl ether, N,N-dimethylformamide, dimethyl sulfoxide, n-hexane, n-heptane, tetrahydrofuran, diethyl ether, and acetonitrile.

[0072] In some embodiments, the reaction temperature for obtaining the compound represented by Formula E is 5°C to 40°C. In some embodiments, the reaction temperature for obtaining the compound represented by Formula E is 15°C to 30°C. In some embodiments, the reaction temperature for obtaining the compound represented by Formula E is 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0073] In some embodiments, the reaction temperature for obtaining the compound represented by formula F is 5°C to 40°C. In some embodiments, the reaction temperature for obtaining the compound represented by formula F is 15°C to 30°C. In some embodiments, the reaction temperature for obtaining the compound represented by formula F is 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0074] In some embodiments, the solvent in the condensation reaction to obtain the compound represented by formula G includes at least one of acetonitrile, dichloromethane, chloroform, or 1,2-dichloroethane.

[0075] In some embodiments, the condensing agent in the condensation reaction to obtain the compound of formula G includes at least one of DCC (dicyclohexylcarbodiimide), DIC (N,N-diisopropylcarbodiimide), EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), and PyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate); preferably dicyclohexylcarbodiimide or N,N-diisopropylcarbodiimide.

[0076] In some embodiments, the catalyst in the condensation reaction to obtain the compound of formula G includes DMAP (4-dimethylaminopyridine), PPY (4-pyrrolidinylpyridine), and 9-AJ (9-azajulolidine).

[0077] In some embodiments, the condensation reaction to obtain the compound represented by formula G is carried out at a reaction temperature of 5°C to 40°C or 15°C to 30°C. In some embodiments, the condensation reaction to obtain the compound represented by formula G is carried out at a reaction temperature of 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.

[0078] In some embodiments, the solvent in the condensation reaction to obtain the compound represented by formula H includes at least one of acetonitrile, dichloromethane, chloroform, or 1,2-dichloroethane.

[0079] In some embodiments, the condensing agent in the condensation reaction to obtain the compound of formula H includes at least one of DCC (dicyclohexylcarbodiimide), DIC (N,N-diisopropylcarbodiimide), EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), and PyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate); preferably dicyclohexylcarbodiimide or N,N-diisopropylcarbodiimide.

[0080] In some embodiments, the catalyst in the condensation reaction to obtain the compound represented by formula H includes DMAP (4-dimethylaminopyridine), PPY (4-pyrrolidinylpyridine), and 9-AJ (9-azajulolidine).

[0081] In some embodiments, the condensation reaction to obtain the compound represented by Formula H is carried out at a reaction temperature of 5°C to 40°C. In some embodiments, the condensation reaction to obtain the compound represented by Formula H is carried out at a reaction temperature of 15°C to 30°C. In some embodiments, the condensation reaction to obtain the compound represented by Formula H is carried out at a reaction temperature of 5°C, 10°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0082] In some embodiments, the acid in reaction i, reaction ii, reaction iii, or reaction iv to obtain the compound represented by formula J independently includes at least one of sulfuric acid, hydrochloric acid, formic acid, acetic acid, p-toluenesulfonic acid or its hydrate, camphorsulfonic acid, methanesulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid.

[0083] In some embodiments, the base in reaction ii to obtain the compound represented by formula J includes at least one of ammonia water, ammonia methanol solution, ammonia ethanol solution, an aqueous solution of methylamine, an alcoholic solution of methylamine, or hydrazine hydrate.

[0084] In some embodiments, the solvent in reaction i, reaction ii, reaction iii, or reaction iv to obtain the compound represented by formula J independently comprises at least one of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, and water.

[0085] In some embodiments, the reaction temperature for reaction i to obtain the compound represented by formula J is 0°C to 40°C. In some embodiments, the reaction temperature for reaction i to obtain the compound represented by formula J is 10°C to 30°C. In some embodiments, the reaction temperature for reaction i to obtain the compound represented by formula J is 0°C, 10°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0086] In some embodiments, the reaction temperature for reaction ii, in which the compound of formula J is obtained, is 0–40°C. In some embodiments, the reaction temperature for reaction ii, in which the compound of formula J is obtained, is 10°C–30°C. In some embodiments, the reaction temperature for reaction ii, in which the compound of formula J is obtained, is 0°C, 10°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0087] In some embodiments, the reaction temperature of reaction iii to obtain the compound represented by formula J is 0–40°C. In some embodiments, the reaction temperature of reaction iii to obtain the compound represented by formula J is 10°C–30°C. In some embodiments, the reaction temperature of reaction iii to obtain the compound represented by formula J is 0°C, 10°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0088] In some embodiments, the reaction temperature for reaction iv to obtain the compound represented by formula J is 0°C to 40°C. In some embodiments, the reaction temperature for reaction iv to obtain the compound represented by formula J is 10°C to 30°C. In some embodiments, the reaction temperature for reaction iv to obtain the compound represented by formula J is 0°C, 10°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0089] In some embodiments, the base for the amidation reaction to obtain the compound of formula A includes at least one of triethylamine, pyridine, diethylisopropylamine, DBACO (triethylenediamine), DMAP (4-dimethylaminopyridine), DBU (1,8-diazabicycloundec-7-ene), LiOH (lithium hydroxide), NaOH (sodium hydroxide), Na2CO3 (sodium carbonate), K2CO3 (potassium carbonate), NaHCO3 (sodium bicarbonate), and KHCO3 (potassium bicarbonate).

[0090] In some embodiments, the catalysts for the amidation reaction to obtain the compound of formula A include DMAP (4-dimethylaminopyridine), PPY (4-pyrrolidinylpyridine), and 9-AJ (9-azajulolidine).

[0091] In some embodiments, the solvent for the amidation reaction to obtain the compound of formula A includes at least one of dichloromethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, water, toluene, xylene, or acetone.

[0092] In some embodiments, the specific temperature in step 2a) is -78℃ to -10℃. In some embodiments, the specific temperature in step 2a) is -78℃ to -30℃. In some embodiments, the specific temperature in step 2a) is -78℃, -70℃, -65℃, -60℃, -55℃, -50℃, -45℃, -40℃, -35℃, or -30℃.

[0093] In some embodiments, the temperature in step 2b) is 25°C to 70°C. In some embodiments, the temperature in step 2b) is 40°C to 60°C. In some embodiments, the temperature in step 2b) is 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C.

[0094] In some embodiments, the specific temperature in step 2c) is -60℃ to 25℃. In some embodiments, the specific temperature in step 2c) is -40℃ to 25℃. In some embodiments, the specific temperature in step 2c) is -60℃, -55℃, -50℃, -45℃, -40℃, -35℃, -30℃, -25℃, -20℃, -15℃, -10℃, -5℃, 0℃, 5℃, 10℃, 15℃, 20℃, or 25℃.

[0095] In some embodiments, the organolithium comprises at least one of lithium methyl, lithium n-butyl, lithium sec-butyl, lithium tert-butyl, or lithium diisopropylamino.

[0096] In some embodiments, the organomagnesium comprises at least one of isopropyl magnesium chloride-lithium chloride, isobutyl magnesium chloride-lithium chloride, and magnesium dichloride (2,2,6,6-tetramethylpiperidine) lithium salt.

[0097] In some embodiments, the inert gas in step 2a) or step 2b) is independently selected from at least one of nitrogen and argon.

[0098] In some embodiments, the solvent in step 2a) or step 2b) of obtaining the compound of formula B is independently selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, water, toluene, xylene, or acetone.

[0099] In some embodiments, the reaction temperature of the cyanidation reaction is -60°C to -20°C. In some embodiments, the reaction temperature of the cyanidation reaction is -40°C to -25°C.

[0100] In some embodiments, the acid in the cyanidation reaction includes at least one of trimethylsilyl trifluoromethanesulfonate, trifluoromethanesulfonic acid, trifluoroacetic acid, boron trifluoride-ethyl ether complex, or methanesulfonic acid.

[0101] In some embodiments, the cyaniding agent in the cyanidation reaction includes at least one of trimethylnitrile silane, TBSCN (tert-butyldimethylcyanosilane), zinc cyanide, sodium cyanide, or cuprous cyanide.

[0102] In some embodiments, the inert gas in the cyanidation reaction is nitrogen or argon.

[0103] In some embodiments, the Lewis acid in the debenzylation reaction that yields the compound of formula D includes boron trichloride or boron tribromide.

[0104] In some embodiments, the debenzylation reaction of obtaining the compound represented by Formula D is carried out at a reaction temperature of -78°C to -40°C. In some embodiments, the debenzylation reaction of obtaining the compound represented by Formula D is carried out at a reaction temperature of -78°C, -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, or -40°C.

[0105] In some embodiments, the C1-C 10 Straight-chain alkyl groups are C1 straight-chain alkyl, C2 straight-chain alkyl, C3 straight-chain alkyl, C4 straight-chain alkyl, C5 straight-chain alkyl, C6 straight-chain alkyl, C7 straight-chain alkyl, C8 straight-chain alkyl, C9 straight-chain alkyl, or C 10 Straight-chain alkyl groups.

[0106] In some embodiments, the C1-C 10Branched alkyl groups are C1 branched alkyl, C2 branched alkyl, C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl, or C 10 Branched alkyl groups.

[0107] In some embodiments, the C3-C 10 The cycloalkyl group is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl, C9 cycloalkyl, or C 10 cycloalkyl

[0108] In some embodiments, the C2–C6 straight-chain alkenyl groups are C2 straight-chain alkenyl, C3 straight-chain alkenyl, C3 straight-chain alkenyl, C4 straight-chain alkenyl, C5 straight-chain alkenyl, C6 straight-chain alkenyl, C7 straight-chain alkenyl, C8 straight-chain alkenyl, C9 straight-chain alkenyl, or C 10 Straight-chain alkenyl groups.

[0109] In some embodiments, the C2–C6 branched alkenyl groups are C2-C3-C4-C5-C6-C7-C8-C9-C6-C7-C8-C9-C6-C6-C7-C8-C9-C6-C6-C7-C8-C9-C6-C6-C7-C8-C9-C6-C6-C6-C7-C7-C8-C9-C6 ... 10 Branched alkenyl groups.

[0110] In some embodiments, the C2–C6 straight-chain alkynyl group is a C2 straight-chain alkynyl group, a C3 straight-chain alkynyl group, a C3 straight-chain alkynyl group, a C4 straight-chain alkynyl group, a C5 straight-chain alkynyl group, a C6 straight-chain alkynyl group, a C7 straight-chain alkynyl group, a C8 straight-chain alkynyl group, a C9 straight-chain alkynyl group, or a C6 straight-chain alkynyl group. 10 Straight-chain acetylene group.

[0111] In some embodiments, the C2–C6 branched alkynyl group is C2 branched alkynyl, C3 branched alkynyl, C3 branched alkynyl, C4 branched alkynyl, C5 branched alkynyl, C6 branched alkynyl, C7 branched alkynyl, C8 branched alkynyl, C9 branched alkynyl, or C... 10 Branched alkynyl group.

[0112] Secondly, the present invention provides a compound.

[0113] A compound comprising: the compound shown in Formula A, the compound shown in Formula B, the compound shown in Formula C, the compound shown in Formula D, the compound shown in Formula E, the compound shown in Formula F, the compound shown in Formula G, or the compound shown in Formula H.

[0114]

[0115] in,

[0116] R 3Selected from substituted or unsubstituted C1-C10 straight-chain alkyl groups, substituted or unsubstituted C1-C 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2–C6 straight-chain alkenyl, substituted or unsubstituted C2–C6 branched alkenyl, substituted or unsubstituted C2–C6 straight-chain alkynyl, substituted or unsubstituted C2–C6 branched alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, or two R 3 Forms C3-C with adjacent carbon. 10 Saturated or unsaturated alkane carbocyclic groups;

[0117] R 1 and R 4 Each is independently selected from substituted or unsubstituted C1-C10 straight-chain alkyl groups, and substituted or unsubstituted C1-C10 straight-chain alkyl groups. 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2–C6 straight-chain alkenyl, substituted or unsubstituted C2–C6 branched alkenyl, substituted or unsubstituted C2–C6 straight-chain alkynyl, substituted or unsubstituted C2–C6 branched alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic.

[0118] R 2 It is selected from hydrogen, fluorine, chlorine, bromine or iodine.

[0119] The compound shown in Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, Formula G, or Formula H can be used as an intermediate in the preparation of the compound shown in Formula J.

[0120] In some embodiments, R 1 Selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, or phenyl; R 4 Selected from isopropyl and cyclohexyl; R 2 Selected from hydrogen, bromine, or iodine; R 3 Selected from methyl, ethyl, cyclohexyl, or two R 3 Cyclohexyl and cyclopentyl groups formed with adjacent carbon atoms;

[0121] In some preferred embodiments, R 1 Selected from tert-butyl or phenyl; R 2 Selected from hydrogen; R 3 Selected from methyl, ethyl, or cyclohexyl.

[0122] In some embodiments of the present invention, the compound represented by formula A includes:

[0123]

[0124] In some embodiments of the present invention, the compound represented by formula B comprises:

[0125]

[0126] In some embodiments of the present invention, the compound represented by formula C includes:

[0127]

[0128] In some embodiments of the present invention, the compound represented by formula D comprises:

[0129]

[0130] In some embodiments of the present invention, the compound represented by formula E comprises:

[0131]

[0132]

[0133] In some embodiments of the present invention, the compound represented by formula F includes:

[0134]

[0135] In some embodiments of the present invention, the compound represented by formula G includes:

[0136]

[0137] In some embodiments of the present invention, the compound represented by formula H includes:

[0138]

[0139] Using the intermediates provided by this invention, especially intermediate compounds with amino substituents of pivalamide, is beneficial for reducing the cost of preparation methods, simplifying operations, increasing product yield, improving product purity, and avoiding the generation of impurities that are difficult to remove.

[0140] Thirdly, the present invention provides a method for preparing a compound represented by formula F00.

[0141] A method for preparing a compound of formula F00, comprising:

[0142]

[0143] Under alkaline conditions, the compound shown in formula S4 reacts with pivaloyl chloride in an organic solvent, and after post-treatment, the compound shown in formula CO2 is obtained.

[0144] Under an inert gas atmosphere, the compound represented by formula CO2 is mixed with a Lewis acid and a solvent, and after a debenzylation reaction and post-treatment, the compound represented by formula D02 is obtained.

[0145] Under acidic conditions, the compound shown in formula D02 reacts with 2,2-dimethoxypropane in an organic solvent. After post-treatment, the compound shown in formula E02 is obtained. Then, an acid or base is added to react the compound, and after post-treatment, the compound shown in formula F00 is obtained.

[0146] In some embodiments, the base in the step of obtaining the compound represented by formula C02 includes at least one of triethylamine, pyridine, tri-n-butylamine, diisopropylethylamine, dimethylbenzylamine, morpholine, and N-methylpiperidine.

[0147] In some embodiments, the organic solvent in the step of obtaining the compound represented by formula C02 includes at least one of dichloromethane, 1,2-dichloroethane, toluene, and tetrahydrofuran.

[0148] In some embodiments, the post-processing in the step of obtaining the compound represented by formula C02 includes: adding an acidic aqueous solution, extraction, separation, washing the organic solvent layer, and concentrating the organic solvent layer.

[0149] In some embodiments, the inert gas used in the preparation method of the compound represented by formula F00 includes nitrogen or argon.

[0150] In some embodiments, the Lewis acid in the preparation method of the compound represented by formula F00 includes at least one of boron trichloride and boron tribromide.

[0151] In some embodiments, the solvent in the step of obtaining the compound represented by formula D02 is at least one of dichloromethane and 1,2-dichloromethane.

[0152] In some embodiments, the post-processing in the step of obtaining the compound represented by formula D02 includes: quenching the reaction, concentrating, dissolving in tetrahydrofuran, adding tert-butyl methyl ether, centrifuging, obtaining a supernatant, and concentrating the obtained supernatant.

[0153] In some embodiments, the acid in the step of obtaining the compound of formula E02 includes at least one of sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, or their hydrates.

[0154] In some embodiments, the organic solvent in the step of obtaining the compound represented by formula E02 includes at least one of acetone and dichloromethane.

[0155] In some embodiments, the post-processing in the step of obtaining the compound represented by formula E02 includes: quenching reaction, extraction, and retention of the organic phase layer.

[0156] In some embodiments, the acid in the step of obtaining the compound represented by formula F00 includes at least one of sulfuric acid, hydrochloric acid, formic acid, acetic acid, p-toluenesulfonic acid or its hydrate, camphorsulfonic acid, methanesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid.

[0157] In some embodiments, the base in the step of obtaining the compound represented by formula F00 includes at least one of ammonia water, ammonia methanol solution, ammonia ethanol solution, an aqueous solution of methylamine, an alcoholic solution of methylamine, or hydrazine hydrate.

[0158] In some embodiments, the post-processing in the step of obtaining the compound of formula F00 includes: separation, retaining the organic phase layer, washing the organic phase layer, concentration, adding an alkane solvent to induce crystallization, centrifugation or filtration to obtain a precipitate or filter cake, washing the precipitate or filter cake with a mixed solution of n-heptane and ethyl acetate, and drying to obtain the compound of formula F00.

[0159] In some embodiments, the alkane solvent in the preparation method of the compound represented by formula F00 includes at least one of n-hexane, n-heptane, or petroleum ether.

[0160] In some embodiments, in the step of obtaining the compound represented by formula C02, the molar ratio of the base to the compound represented by formula S4 is 1.0:1.0–1.5:1.0. In some embodiments, in the step of obtaining the compound represented by formula C02, the molar ratio of the base to the compound represented by formula S4 is 1.0:1.0, 1.1:1.0, 1.2:1.0, 1.3:1.0, 1.35:1.00, 1.4:1.0, or 1.5:1.0.

[0161] In some embodiments, in the step of obtaining the compound represented by formula CO2, the molar ratio of the pivaloyl chloride to the compound represented by formula S4 is 1.0:1.0–1.4:1.0. In some embodiments, in the step of obtaining the compound represented by formula CO2, the molar ratio of the pivaloyl chloride to the compound represented by formula S4 is 1.0:1.0, 1.1:1.0, 1.15:1.00, 1.2:1.0, 1.3:1.0, or 1.4:1.0.

[0162] In some embodiments, in the step of obtaining the compound represented by formula C02, the mass ratio of the compound represented by formula S4 to the organic solvent is 1:4–1:10. In some embodiments, in the step of obtaining the compound represented by formula C02, the mass ratio of the compound represented by formula S4 to the organic solvent is 1:4, 1:5, 1:5.2, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0163] In some embodiments, in the step of obtaining the compound represented by formula D02, the molar ratio of the Lewis acid to the compound represented by formula C02 is 3.1:1.0–5.0:1.0. In some embodiments, in the step of obtaining the compound represented by formula D02, the molar ratio of the Lewis acid to the compound represented by formula C02 is 3.1:1.0, 4.0:1.0, or 5.0:1.0.

[0164] In some embodiments, in the step of obtaining the compound represented by formula D02, the mass ratio of the compound represented by formula C02 to the solvent is 1:7–1:12. In some embodiments, in the step of obtaining the compound represented by formula D02, the mass ratio of the compound represented by formula C02 to the solvent is 1:7, 1:8, 1:9, 1:10, 1:11, or 1:12.

[0165] In some embodiments, in the step of obtaining the compound represented by formula E02, the molar ratio of the acid to the compound represented by formula D02 is 0.5:1.0–2.0:1.0. In some embodiments, in the step of obtaining the compound represented by formula E02, the molar ratio of the acid to the compound represented by formula D02 is 0.5:1.0, 1.0:1.0, 1.5:1.0, 1.6:1.0, 1.7:1.0, 1.8:1.0, 1.9:1.0, or 2.0:1.0.

[0166] In some embodiments, in the step of obtaining the compound represented by formula E02, the molar ratio of 2,2-dimethoxypropane to the compound represented by formula D02 is 3:1–10:1. In some embodiments, in the step of obtaining the compound represented by formula E02, the molar ratio of 2,2-dimethoxypropane to the compound represented by formula D02 is 3:1, 4:1, 5:1, 6:1, 6.2:1.0, 6.5:1.0, 7:1, 8:1, 9:1, or 10:1.

[0167] In some embodiments, in the step of obtaining the compound represented by formula E02, the mass ratio of the compound represented by formula D02 to the organic solvent is 1:8–1:15. In some embodiments, in the step of obtaining the compound represented by formula E02, the mass ratio of the compound represented by formula D02 to the organic solvent is 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, or 1:15.

[0168] In some embodiments, in the step of obtaining the compound represented by formula F00, the molar ratio of the acid or base to the compound represented by formula D02 is independently 1:1–5:1. In some embodiments, in the step of obtaining the compound represented by formula F00, the molar ratio of the acid or base to the compound represented by formula D02 is independently 1:1, 2:1, 3:1, 4:1, or 5:1.

[0169] In some embodiments, the reaction temperature for obtaining the compound represented by formula CO2 is 0°C–40°C. In some embodiments, the reaction temperature for obtaining the compound represented by formula CO2 is 10°C–30°C.

[0170] In some embodiments, the reaction temperature for obtaining the compound represented by formula D02 is -78°C to -40°C. In some embodiments, the reaction temperature for obtaining the compound represented by formula D02 is -78°C to -50°C. In some embodiments, the reaction temperature for obtaining the compound represented by formula D02 is -78°C, -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, or -40°C.

[0171] In some embodiments, the reaction temperature for obtaining the compound of formula E02 is 0°C–40°C. In some embodiments, the reaction temperature for obtaining the compound of formula E02 is 0°C–30°C. In some embodiments, the reaction temperature for obtaining the compound of formula E02 is 0°C–25°C. In some embodiments, the reaction temperature for obtaining the compound of formula E02 is 0°C–20°C. In some embodiments, the reaction temperature for obtaining the compound of formula E02 is 10°C–20°C.

[0172] In some embodiments, the reaction temperature for obtaining the compound represented by formula F00 is 0°C–40°C. In some embodiments, the reaction temperature for obtaining the compound represented by formula F00 is 10°C–30°C.

[0173] Beneficial effects

[0174] Compared with the prior art, a certain embodiment of the present invention includes at least one of the following beneficial effects:

[0175] (1) The method of the present invention shortens the synthetic route of carbon-nucleoside analogs (such as compounds shown in formula J).

[0176] (2) Compared with the compounds represented by formula IV-1 (see background art), the compounds represented by formulas A, B, C, D, E or H of the present invention use -C(=O)R 1 As an amino protecting group, especially R 1More preferably, it is tert-butyl, which helps to avoid the generation of amide impurities on heterocycles that are difficult to remove (such as the impurities of formula IV-3 or IV-4 described in the background art) during the further synthesis of formula J, thereby improving product purity and product safety.

[0177] (3) Compared with other amino protecting groups, such as Boc or Cbz used in CN113248508, this application uses -C(=O)R 1 As an amino protecting group, the group R 1 Preferably, it is composed of methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, or phenyl groups; R group 1 The preferred formulation is tert-butyl, which is beneficial for increasing product yield, purity, and safety.

[0178] (4) The amino protecting group on the compound shown in formula A is -C(=O)R 1 Especially when R 1 The presence of tert-butyl group facilitates the reaction of the compound shown in formula A with the compound shown in formula S2 to synthesize the compound shown in formula B without the need for a halogen atom as a substituent. This significantly reduces costs (halogen substitution is costly). Furthermore, it helps to improve the yield and purity of the product compound shown in formula B and subsequent compounds (such as compounds shown in formulas C, D, E, F, H and / or J), demonstrating promising prospects for industrialization.

[0179] (5) Using more economical and cheaper pyrrolotriazine heterocyclic compounds without amino temporary protection (such as compounds shown in formula S1 or S4) or pyrrolotriazine heterocyclic compounds without halogen substitution (such as compounds shown in formula S1 and A15) as raw materials, carbon-nucleoside analogs are synthesized efficiently by reacting with ribonucleoside. This new route is simpler and more efficient in reaction operation, and the reaction yield is significantly improved. Therefore, the synthesis cost is greatly reduced.

[0180] (6) The method of the present invention has lower cost, better quality control and is more suitable for industrial production.

[0181] (7) The compound shown in formula F00 is prepared by a one-pot method, which is simple to operate, has few operation steps, high yield, and is safe and environmentally friendly.

[0182] Terminology Explanation

[0183] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings:

[0184] The term "multiple" means two or more, such as two, three, four or five.

[0185] In this invention, expressions such as "compound A", "compound of formula A" and "compound shown in formula A" have the same meaning, and other compounds are similarly referred to in this way.

[0186] In this invention, "room temperature" refers to ambient temperature, ranging from approximately 10°C to approximately 40°C. In some embodiments, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 35°C; in some embodiments, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 30°C; in other embodiments, "room temperature" refers to a temperature ranging from approximately 25°C to approximately 30°C; and in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0187] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0188] The terms "optional" or "optionally" refer to an event or situation that may, but is not necessarily, occur, as described below, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optionally condensing agent" means that a condensing agent may or may not be present.

[0189] In the foregoing description of this invention, all figures disclosed herein, whether or not the words “approximately” or “about” are used, are approximate values. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0190] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0191] In this invention, "substitution" refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of halogens, C1-C10 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, or C6-C10 aryl groups.

[0192] "Alkyl" is a hydrocarbon containing a positive, secondary, tertiary, or cyclic carbon atom. For example, alkyl can have 1 to 10 carbon atoms (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or C1 alkyl). 10 Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0193] "Alkenyl" refers to a group containing at least one unsaturated site, i.e., carbon-carbon sp. 2 Hydrocarbons with double bonds consisting of a positive, secondary, tertiary carbon atom, or a cyclic carbon atom. For example, alkenyl groups can have 2 to 10 carbon atoms (C2-C4). 10 alkenyl), 2 to 12 carbon atoms (C2-C)12 Alkenyl groups, such as C2-alkenyl, C3-alkenyl, C4-alkenyl, C5-alkenyl, C6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C... 10 alkenyl, C 11 alkenyl or C 12 Alkenyl (or 2 to 6 carbon atoms, C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7) and 5-hexenyl (-CH2CH2CH2CH2CH=CH2), propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, etc.

[0194] "Alynyl" is a hydrocarbon containing at least one unsaturated carbon atom, namely a carbon-carbon sp triple bond, or a cyclic carbon atom. For example, an alkynyl group can have 2 to 10 carbon atoms (C2-C4). 10 alkynyl group), 2 to 12 carbon atoms (C2-C) 12 Alkynyl groups, such as C2-alkynyl, C3-alkynyl, C4-alkynyl, C5-alkynyl, C6-alkynyl, C7-alkynyl, C8-alkynyl, C9-alkynyl, C 10 alkynyl group, C 11 alkynyl or C 12 Alkyne group (or 2 to 6 carbon atoms, C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C=CH), propynylate (-CH2C=CH), and the like.

[0195] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms (e.g., C6 aryl, C7 aryl, C8 aryl, C9 aryl, C2 aryl, C3 aryl, C4 aryl, C5 aryl ...2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20 Aryl groups (6 to 14 carbon atoms or 6 to 10 carbon atoms). Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc., and similar groups.

[0196] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group comprises 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms); in another embodiment, the cycloalkyl group comprises 3 to 8 carbon atoms; and in yet another embodiment, the cycloalkyl group comprises 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0197] The term "substituted" refers to alkyl, aryl, arylalkyl, heterocyclic, heteroaryl, carbocyclic, etc., such as "substituted C1-C". 10 Alkyl, substituted C6-C 20 "Aryl", "Substituted arylalkyl", "Substituted C1-C" 20 "Heterocyclic" and "substituted carbocyclic" refer to C1-C rings in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents, respectively. 10 Alkyl, C6-C 20 Aryl, arylalkyl, C1-C 20 Heterocyclic, carbocyclic. Unless otherwise stated, when the term “substituted” is used in conjunction with a group having two or more moieties capable of substitution, such as an arylalkyl group, the substituent may be attached to the aryl moieties, alkyl moieties, or both.

[0198] As used herein, “heterocyclic” or “heterocyclic group” includes, but is not limited to, those heterocycles described in, as examples, in Paquette, Leo A.: Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9: The Chemistry of Heterocyclic Compounds, A Series of Monographs^ (John Wiley & Sons, New York, 1950 to present), particularly Volumes 13, 14, 16, 19, and 28 and J. Am. Chem. Soc. (1960) 82: 5566. In a specific embodiment of the invention, “heterocyclic” includes “carbon ring” as defined herein, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N, or S). The term “heterocyclic” or “heterocyclic group” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclic groups include, for example, heterocycles substituted by any substituent including a carbonyl group disclosed herein.

[0199] Examples of heterocyclic compounds include, but are not intended to limit, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophene, sulfur-oxidized tetrahydrothiophene, pyrimidinyl, furanyl, thiophene, pyrroloyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thionaphthyl, indole, indoleenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinoneyl, pyrroloalkyl, 2-pyrroloalkyloneyl, pyrrolophyllyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, acrylonitrile (azacyclooctane), triazine, 6H-1,2,5-thiadiazine, 2H,6H-1,5,2-dithiazine, thiophene, thiaanthryl, pyranyl, isobenzofuran alkyl, chromenyl, ketonel, phenolflavinyl, 2H-pyrroloyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indazinyl, isoyndolyl, 3H-indolyl, 1H-indazolyl, purinel, 4H-quinazinyl, phthalazinyl, naphthidyl, quinoxalinyl, quinazolinyl, cinnaphthyl, pteridinyl, 4aH-carbazoleyl, carbazoleyl, β-carbolinyl, phenanthridinel, acridinel Pyrimidinyl, phenanthroline, phenazinyl, phenothiazinyl, furazinyl, phenoxazinyl, isochromyl, chromanyl, imidazoalkyl, imidazoline, pyrazolyl, pyrazolyl, piperazinyl, dihydroindolyl, isodihydroindolyl, quininecycloyl, morpholinyl, oxazolyl, benzotriazolyl, benzoisooxazolyl, hydroxyindolyl, benzooxazolyl, indigo acyl, and bis-tetrahydrofuranyl.

[0200] "Heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included on the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all those aromatic rings listed in the definition of "heterocyclic group," including pyridinyl, pyrroloyl, oxazolyl, indolyl, isoydinolyl, purinyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl, carbazoyl, imidazoyl, thiazoyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazolyl, etc.

[0201] In this invention, "mmol" represents millimole; "mol" represents mole; "Kg" represents kilogram; "g" represents gram; "eq" represents equivalent; "L" represents liter; "mL" represents milliliter; "℃" represents degree Celsius; "h" represents hour; "min" represents minute; and "w / w" represents weight ratio. Detailed Implementation

[0202] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0203] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0204] In the embodiments, the present invention has developed the following detection method and uses the following detection method for detection:

[0205] Method 1: Purity Analysis Method

[0206]

[0207]

[0208] Method 2: Mass spectrometry

[0209]

[0210] Certain abbreviations and acronyms were used in describing the experimental details. While most of them are understandable to those skilled in the art, the table below contains a list of these abbreviations and acronyms.

[0211] abbreviation meaning abbreviation meaning ACN Acetonitrile DCU Dicyclohexylurea DCC Dicyclohexylcarbodiimide TsOH p-Toluenesulfonic acid DCM dichloromethane NaCl Sodium chloride DMAP 4-Dimethylaminopyridine <![CDATA[Na2SO4]]> Sodium sulfate EA Ethyl acetate <![CDATA[NaHCO3]]> Sodium bicarbonate EDMA N,N-Dimethylethylamine <![CDATA[CH3CN]]> Acetonitrile MeOH methanol DIC diisopropylcarbodiimide PE petroleum ether BzCl Benzoyl chloride rt room temperature <![CDATA[BCl3]]> boron trichloride TEA Triethylamine <![CDATA[TsOH·H2O]]> p-Toluenesulfonic acid monohydrate THF Tetrahydrofuran <![CDATA[Na2CO3]]> Sodium carbonate TLC Thin-layer chromatography HPLC High performance liquid chromatography

[0212] Example 1: Preparation of pyrrolo[2,1-f][1,2,4]triazine-4-acetamide (A13)

[0213]

[0214] Pyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-1) (6.7 g, 50 mmol), 4-dimethylaminopyridine (0.12 g, 1 mmol, 0.02 eq), and pyridine (4.75 g, 60 mmol, 1.2 eq) were mixed with dichloromethane (65 mL), cooled to -5 °C, and acetyl chloride (4.12 g, 52.5 mmol, 1.05 eq) was added. The mixture was stirred and reacted at room temperature for 5 h. The pH was adjusted to 7–8 with 1 N hydrochloric acid aqueous solution, allowed to stand, and separated. The organic phase was collected, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, respectively, dried with sodium sulfate, filtered, concentrated under reduced pressure, dried, and separated by column chromatography to obtain compound A13 (grayish-white solid, 6.8 g, 77% yield, 99% purity). A suitable amount of the obtained compound A13 was analyzed by mass spectrometry, and the result was: MS (ESI): 177.1 [M+H]. + .

[0215] Example 2: Preparation of 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-acetamide (A14)

[0216]

[0217] 7-Iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-2) (13.0 g, 50 mmol), 4-dimethylaminopyridine (0.12 g, 1 mmol, 0.02 eq), and pyridine (4.75 g, 60 mmol, 1.2 eq) were mixed with dichloromethane (65 mL), cooled to -5 °C, and acetyl chloride (4.12 g, 52.5 mmol, 1.05 eq) was added. The mixture was stirred and reacted at room temperature for 5 h. The pH was adjusted to 7-8 with 1 N hydrochloric acid aqueous solution. The mixture was allowed to stand, separated, and the organic phase was collected. The organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered, concentrated under reduced pressure, dried, and separated by column chromatography to obtain compound A14 (pale yellow solid, 12.2 g, 81% yield, 98% purity). A suitable amount of the obtained compound A14 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 303.0 [M+H] + .

[0218] Example 3: Preparation of pyrrolo[2,1-f][1,2,4]triazine-4-pentaventramide (A15)

[0219]

[0220] Pyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-1) (13.4 g, 100 mmol), 4-dimethylaminopyridine (0.24 g, 2 mmol, 0.02 eq), and triethylamine (12.2 g, 120 mmol, 1.2 eq) were mixed with dichloromethane (70 mL), added, and cooled to -5 °C. Pteropenoyl chloride (13.3 g, 110 mmol, 1.1 eq) was added, and the mixture was stirred and reacted at room temperature for 6 h. 10 mL of 1 N dilute hydrochloric acid was added and stirred for 5 min. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to give compound A15 (a grayish-white solid, 21.2 g, 97% yield, 99% purity). An appropriate amount of the obtained compound A15 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 219.2 [M+H] + .

[0221] Example 4: Preparation of 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-pentaventramide (A08)

[0222]

[0223] 7-Iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-2) (13.0 g, 50 mmol), 4-dimethylaminopyridine (0.12 g, 1 mmol, 0.02 eq), and triethylamine (6.1 g, 60 mmol, 1.2 eq) were mixed with dichloromethane (65 mL), cooled to -5 °C, and pentanoyl chloride (6.6 g, 55 mmol, 1.1 eq) was added. The mixture was stirred and reacted at 0 °C for 4 h. 5 mL of 1N dilute hydrochloric acid was added and stirred for 5 min. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain compound A08 (pale yellow solid, 15.8 g, 92% yield, 99% purity). A suitable amount of the obtained compound A08 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 345.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d) 6 )δ10.32(s,1H),8.43(s,1H),7.13(d,J=4.9Hz,1H),7.08(d,J=4.7Hz,1H),1.28(s,9H).

[0224] Example 5: Preparation of pyrrolo[2,1-f][1,2,4]triazine-4-benzamide (A17)

[0225]

[0226] Pyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-1) (6.7 g, 50 mmol) was mixed with dichloromethane (65 mL), and 1N NaOH (60 mL, 60 mmol, 1.2 eq) was added. The mixture was cooled to -5 °C, and benzoyl chloride (7.7 g, 55 mmol, 1.1 eq) was added. The mixture was stirred and reacted at room temperature for 4 h. 5 mL of 1N dilute hydrochloric acid was added and stirred for 5 min. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain compound A17 (pale yellow solid, 11.7 g, 98% yield, 99% purity). A suitable amount of the obtained compound A17 was analyzed by mass spectrometry, and the result was: MS (ESI): 239.1 [M+H]. + .

[0227] Example 6: Preparation of 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-benzamide (A18)

[0228]

[0229] 7-Iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-2) (13.2 g, 50 mmol) was mixed with dichloromethane (65 mL), and 1N NaOH (60 mL, 60 mmol, 1.2 eq) was added. The mixture was cooled to -5 °C, and benzoyl chloride (7.7 g, 55 mmol, 1.1 eq) was added. The mixture was stirred and reacted at room temperature for 4 h. 5 mL of 1N dilute hydrochloric acid was added and stirred for 5 min. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain compound A18 (pale yellow solid, 16.8 g, 92% yield, 99% purity). A suitable amount of the obtained compound A18 was analyzed by mass spectrometry, and the result was: MS (ESI): 365.0 [M+H]. + .

[0230] Example 7: Preparation of 2,2,2-trifluoro-N-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)acetamide (A01)

[0231]

[0232] Pyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-1) (13.4 g, 100 mmol), 4-dimethylaminopyridine (0.6 g, 5 mmol, 0.05 eq), and triethylamine (15.2 g, 150 mmol, 1.5 eq) were mixed with dichloromethane (100 mL), cooled to -5 °C, and trifluoroacetic anhydride (27.3 g, 130 mmol, 1.3 eq) was added. The mixture was stirred and reacted at room temperature for 2 h. The pH was adjusted to 7–8 with 1 N hydrochloric acid aqueous solution, allowed to stand, and separated. The organic phase was collected, washed with saturated sodium bicarbonate aqueous solution, washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to obtain compound A01 (a pale yellow liquid, 11.0 g, 48%, purity 98%). A suitable amount of the obtained compound A01 was analyzed by mass spectrometry, and the result was: MS (ESI): 231.0 [M+H]. + .

[0233] Example 8: Preparation of 2,2,2-trifluoro-N-(7-iodopyrrole[2,1-f][1,2,4]triazine-4-yl)acetamide (A05)

[0234]

[0235] 7-Iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (S1-2) (26.0 g, 100 mmol), 4-dimethylaminopyridine (0.6 g, 5 mmol, 0.05 eq), and triethylamine (15.2 g, 150 mmol, 1.5 eq) were mixed with dichloromethane (100 mL), cooled to -5 °C, and trifluoroacetic anhydride (27.3 g, 130 mmol, 1.3 eq) was added. The mixture was stirred and reacted at room temperature for 2 h. The pH was adjusted to 7-8 by adding 1 N hydrochloric acid aqueous solution. The mixture was allowed to stand, separated, and the organic phase was collected. The organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to obtain compound A05 (a light yellow solid, 18.9 g, 53% yield, 98% purity). A suitable amount of the obtained compound A05 was analyzed by mass spectrometry, and the result was: MS (ESI): 357.1 [M+H] + .

[0236] Example 9: Preparation method of N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (BO1)

[0237]

[0238] a) Under a nitrogen atmosphere, pyrrolo[2,1-f][1,2,4]triazine-4-acetamide (A13) (5.0 g, 28.4 mmol) was mixed with tetrahydrofuran (100 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (62.5 mmol, 25 mL, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the hydrogen at the 7-position, yielding reaction solution 1.

[0239] b) Under a nitrogen atmosphere, neodymium trichloride (8.5 g, 34.1 mmol, 1.2 eq), tetra-n-butylammonium chloride (9.5 g, 34.1 mmol, 1.2 eq) and tetrahydrofuran (100 mL) were mixed, heated under reflux for 0.5 h, cooled to room temperature, and 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (14.3 g, 34.1 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0240] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), react at -40℃ until the starting material is completely converted, add acetic acid (7.5 mL) and water (30 mL) sequentially to quench the reaction, stir, heat to room temperature, let stand, separate the layers, extract with isopropyl acetate, dry the organic phase with sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, separate the crude product by column chromatography to obtain compound B01 (6.4 g, 38% yield, purity 97%). A suitable amount of the obtained compound B01 was analyzed by mass spectrometry, and the result was: MS (ESI): 595.3 [M+H]. + .

[0241] Example 10: Preparation Method II of N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (BO1)

[0242]

[0243] a) Under a nitrogen atmosphere, 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-acetamide (A14) (10.0 g, 33 mmol) was mixed with tetrahydrofuran (100 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (73 mmol, 29 mL, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the iodine at the 7-position, yielding reaction solution 1.

[0244] b) Under a nitrogen atmosphere, neodymium trichloride (10.0 g, 40 mmol, 1.2 eq), tetra-n-butylammonium chloride (11.1 g, 40 mmol, 1.2 eq) and tetrahydrofuran (100 mL) were mixed, heated under reflux for 0.5 h, cooled to room temperature, and 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (16.7 g, 40 mmol) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0245] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), and react at -40℃ until the starting material is completely converted. Add acetic acid (10 mL) and water (40 mL) sequentially to quench the reaction, stir, heat to room temperature, allow to stand, separate the layers, and extract with isopropyl acetate. Dry the organic phase with sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Separate the crude product by column chromatography to obtain compound B01 (8.2 g, 42% yield, 98% purity). A suitable amount of the obtained compound B01 was analyzed by mass spectrometry, and the result was: MS (ESI): 595.3 [M+H]. + .

[0246] Example 11: Preparation method of N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (BO2)

[0247]

[0248] a) Under a nitrogen atmosphere, pyrrolo[2,1-f][1,2,4]triazine-4-pentanamide (A15) (10.9 g, 50 mmol) was mixed with tetrahydrofuran (100 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (110 mmol, 44 mL, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the hydrogen at the 7-position, yielding reaction solution 1.

[0249] b) Under a nitrogen atmosphere, neodymium trichloride (15.0 g, 60 mmol, 1.2 eq), tetra-n-butylammonium chloride (16.7 g, 60 mmol, 1.2 eq) and tetrahydrofuran (150 mL) were mixed, heated under reflux for 0.5 h, cooled to room temperature, and 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (25.1 g, 60 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0250] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), and react at -40℃ until the starting material is completely converted. Add acetic acid (15 mL) and water (60 mL) sequentially to quench the reaction, stir, heat to room temperature, allow to stand, separate the layers, extract with isopropyl acetate, dry the organic phase with sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and separate the crude product by column chromatography to obtain compound BO2 (26.7 g, 84% yield). Take an appropriate amount of the obtained compound BO2 for mass spectrometry and proton NMR spectroscopy. The results are: MS (ESI): 637.3 [M+H] + ; 1 H NMR(400MHz,Chloroform-d)δ8.37–7.78(m,2H),7.64–6.79(m,16H),5.42–5.22(m, 1H), 4.87–4.39 (m, 8H), 4.23–3.93 (m, 2H), 3.82–3.46 (m, 2H), 1.38 (d, J = 3.1Hz, 9H).

[0251] Example 12: Preparation Method II of N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (BO2)

[0252]

[0253] a) Under a nitrogen atmosphere, 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-pentaventilamide (A08) (10.32 g, 30 mmol) was mixed with tetrahydrofuran (60 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (66 mmol, 26.4 mL, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the iodine at the 7-position, yielding reaction solution 1.

[0254] b) Under a nitrogen atmosphere, neodymium trichloride (9.0 g, 36 mmol, 1.2 eq), tetra-n-butylammonium chloride (10.0 g, 36 mmol, 1.2 eq), and tetrahydrofuran (90 mL) were heated under reflux for 0.5 h, cooled to room temperature, and 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (15.0 g, 36 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0255] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), and react at -40℃ until the starting material is completely converted. Add acetic acid (9 mL) and water (36 mL) sequentially to quench the reaction, stir, allow to stand at room temperature, separate the layers, and extract with isopropyl acetate. Dry the organic phase with sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Separate the crude product by column chromatography to obtain compound BO2 (16.4 g, 86% yield). Analyze an appropriate amount of the obtained compound BO2 using mass spectrometry; the result is: MS (ESI): 637.3 [M+H]. + .

[0256] Example 13: Preparation of N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (BO3)

[0257]

[0258] a) Under a nitrogen atmosphere, pyrrolo[2,1-f][1,2,4]triazine-4-benzamide (A17) (7.1 g, 30 mmol) was mixed with tetrahydrofuran (60 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (66 mmol, 26.4 mL, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the hydrogen at the 7-position, yielding reaction solution 1.

[0259] b) Under a nitrogen atmosphere, neodymium trichloride (9.0 g, 36 mmol, 1.2 eq), tetra-n-butylammonium chloride (10.0 g, 36 mmol, 1.2 eq) and tetrahydrofuran (90 mL) were mixed and heated under reflux for 0.5 h. After cooling to room temperature, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (15.0 g, 36 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0260] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), and react at -40℃ until the starting material is completely converted. Add acetic acid (9 mL) and water (36 mL) sequentially to quench the reaction, stir, heat to room temperature, allow to stand, separate the layers, and extract with isopropyl acetate. Dry the organic phase with sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Separate the crude product by column chromatography to obtain compound B03 (15.1 g, 77% yield, 98% purity). A suitable amount of the obtained compound B03 was analyzed by mass spectrometry, and the result was: MS (ESI): 657.3 [M+H]. + .

[0261] Example 14: Preparation of N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (BO3)

[0262]

[0263] a) Under a nitrogen atmosphere, 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-benzamide (A18) (10.9 g, 30 mmol) was mixed with tetrahydrofuran (60 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (66 mmol, 26.4 mL, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the iodine at position 7, yielding reaction solution 1.

[0264] b) Under a nitrogen atmosphere, neodymium trichloride (9.0 g, 36 mmol, 1.2 eq), tetra-n-butylammonium chloride (10.0 g, 36 mmol, 1.2 eq) and tetrahydrofuran (90 mL) were mixed and heated under reflux for 0.5 h. After cooling to room temperature, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (15.0 g, 36 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0265] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), and react at -40℃ until the starting material is completely converted. Add acetic acid (9 mL) and water (36 mL) sequentially to quench the reaction, stir, heat to room temperature, allow to stand, separate the layers, and extract with isopropyl acetate. Dry the organic phase with sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Separate the crude product by column chromatography to obtain compound B03 (14.3 g, 73% yield, 98% purity). A suitable amount of the obtained compound B03 was analyzed by mass spectrometry, and the result was: MS (ESI): 657.3 [M+H]. + .

[0266] Example 15: Preparation method of N-(7-(3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-yl)pyrrole[2,1-f][1,2,4]triazine-4-yl)-2,2,2-trifluoroacetamide (BO4)

[0267]

[0268] a) Under a nitrogen atmosphere, 2,2,2-trifluoro-N-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)acetamide (A01) (2.3 g, 10 mmol) was mixed with tetrahydrofuran (10 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (9 mL, 22 mmol, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the hydrogen at position 7, yielding reaction solution 1.

[0269] b) Under a nitrogen atmosphere, neodymium trichloride (3.0 g, 12 mmol, 1.2 eq), tetra-n-butylammonium chloride (3.3 g, 12 mmol, 1.2 eq) and tetrahydrofuran (10 mL) were mixed and heated under reflux for 0.5 h. After cooling to room temperature, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (5.0 g, 12 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0270] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), react at -40℃, and monitor the reaction by HPLC until the starting material is completely converted. LC-MS analysis showed that MS(ESI) = 649.2 [M+H]. + The target molecular weight was observed. Acetic acid (2.5 mL) and water (10 mL) were then added sequentially to quench the reaction. The mixture was stirred, heated to room temperature, allowed to stand, separated, and extracted with isopropyl acetate. The organic phase was sampled and analyzed by HPLC, revealing a 9% peak of the target product. The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography, but no product with a molecular weight of 648 was collected.

[0271] Example 16: Preparation Method II of N-(7-(3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-yl)pyrrole[2,1-f][1,2,4]triazine-4-yl)-2,2,2-trifluoroacetamide (BO4)

[0272]

[0273] a) Under a nitrogen atmosphere, 2,2,2-trifluoro-N-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)acetamide (A05) (3.6 g, 10 mmol) was mixed with tetrahydrofuran (10 mL), cooled to -78 °C, and 2.5 M n-butyllithium tetrahydrofuran solution (9 mL, 22 mmol, 2.2 eq) was added. The mixture was reacted at -78 °C to -40 °C for 1 h to remove the iodine at position 7, yielding reaction solution 1.

[0274] b) Under a nitrogen atmosphere, neodymium trichloride (3.0 g, 12 mmol, 1.2 eq), tetra-n-butylammonium chloride (3.3 g, 12 mmol, 1.2 eq) and tetrahydrofuran (10 mL) were mixed and heated under reflux for 0.5 h. After cooling to room temperature, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (S2) (5.0 g, 12 mmol, 1.2 eq) were added and mixed. The mixture was then cooled to -40 °C to obtain reaction solution 2.

[0275] c) Mix reaction solution 1 obtained in step a) with reaction solution 2 obtained in step b), react at -40℃, and monitor the reaction by HPLC until the starting material is completely converted. LC-MS analysis showed that MS(ESI) = 649.2 [M+H]. + The target molecular weight was observed. Acetic acid (2.5 mL) and water (10 mL) were then added sequentially to quench the reaction. The mixture was stirred, heated to room temperature, allowed to stand, separated, and extracted with isopropyl acetate. The organic phase was sampled and analyzed by HPLC, revealing a 15% peak of the target product. The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography, but no product with a molecular weight of 648 was collected.

[0276] Example 17: Preparation of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (CO1)

[0277]

[0278] Under a nitrogen atmosphere, N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (BO1) (11.9 g, 20 mmol) was mixed with dichloromethane (120 mL), cooled to -40 °C, and trifluoromethanesulfonic acid (9.0 g, 60 mmol, 3.0 eq) was added. The mixture was stirred for 20 minutes, and then trimethylsilyl trifluoromethanesulfonate was added. An ester (26.7 g, 120 mmol, 6.0 eq) and a dichloromethane solution (60 mL) of trimethylcyanosilane (11.9 g, 120 mmol, 6.0 eq.) were reacted at -25 °C to -30 °C for 30 min. The reaction was quenched by adding potassium bicarbonate aqueous solution at -10 °C, and the mixture was stirred for 15 min. After standing, the mixture was separated, the organic phase was dried over sodium sulfate, filtered, and the filtrate was purified by column chromatography with ethyl acetate and petroleum ether to give compound C01 (5.6 g, 47% yield, 97% purity). A suitable amount of the obtained compound C01 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 604.3 [M+H] + ; 1 H NMR (400MHz, d) 6 -DMSO): δ10.97(s,1H),8.35(s,1H),7.42–7.22(m,16H),7.00(d,J=4.8Hz,1H),4.92(d,J=4.9Hz,1H),4.91–4.78(m,2H),4.62– 4.49 (m, 4H), 4.48–4.43 (m, 1H), 4.16 (t, J = 5.4Hz, 1H), 3.72 (dd, J = 11.1, 3.5Hz, 1H), 3.61 (dd, J = 11.1, 4.5Hz, 1H), 2.42 (s, 3H).

[0279] Example 18: Preparation of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (CO2)

[0280]

[0281] Under a nitrogen atmosphere, N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (BO2) (12.8 g, 20 mmol), dichloromethane (80 mL), and cooled to -40 °C were added. Trifluoromethanesulfonic acid (9.0 g, 60 mmol, 3.0 eq) and trimethylsilyl trifluoromethanesulfonate (B02) were then added. A solution of 26.7 g (120 mmol, 6.0 eq.) and trimethylcyanosilane (11.9 g, 120 mmol, 6.0 eq.) in dichloromethane (60 mL) was reacted at -25 °C to -30 °C for 15 min. The reaction was quenched by adding potassium bicarbonate aqueous solution at -10 °C, and the mixture was stirred for 15 min. After standing, the mixture was separated into layers. The organic phase was dried over sodium sulfate, filtered, and the filtrate was purified by column chromatography with ethyl acetate and petroleum ether to give compound CO2 (11.1 g, 86% yield). A suitable amount of the obtained compound CO2 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 646.2 [M+H]. + ; 1 H NMR (400MHz, DMSO-d) 6 )δ10.45(s,1H),8.41(s,1H),7.36–7.25(m,15H),7.01(d,J=4.9Hz,1H),6.97(d,J=4.8Hz,1H),4.95–4.86(m,2H),4.81(d,J=11.7Hz,1H ),4.62–4.49(m,4H),4.48–4.42(m,1H),4.16(t,J=5.4Hz,1H),3.71(dd,J=11.1,3.5Hz,1H),3.60(dd,J=11.1,4.5Hz,1H),1.31(s,9H).

[0282] Example 19: Preparation of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (CO3)

[0283]

[0284] Under a nitrogen atmosphere, N-(7-((3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (BO3) (13.1 g, 20 mmol) was mixed with dichloromethane (100 mL), cooled to -40 °C, and then trifluoromethanesulfonic acid (9.0 g, 60 mmol, 3.0 eq) and trimethylsilyl trifluoromethanesulfonate (2... A solution of 6.7 g (120 mmol, 6.0 eq.) of trimethylcyanosilane (11.9 g, 120 mmol, 6.0 eq.) in dichloromethane (60 mL) was reacted at -25 °C to -30 °C for 15 min. The reaction was quenched by adding potassium bicarbonate aqueous solution at -10 °C, and the mixture was stirred for 15 min. After standing, the mixture was separated, the organic phase was dried over sodium sulfate, filtered, and the filtrate was purified by column chromatography with ethyl acetate and petroleum ether to give compound CO3 (10.8 g, 81% yield, 99% purity). A suitable amount of the obtained compound CO3 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 666.3 [M+H]. + .

[0285] Example 20: Preparation Method II of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (CO1)

[0286]

[0287] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydrofuran-2-carboxynitrile (S4) (100 g, 178 mmol) and 4-dimethylaminopyridine (0.44 g, 3.6 mmol, 0.02 eq) were mixed with dichloromethane (400 mL), and triethylamine (21.6 g, 213.6 mmol (1.2 eq) was added, cooled to -5 °C, and acetyl chloride (15.4 g, 196 mmol, 1.1 eq) was added. The mixture was stirred and reacted at 0 °C for 6 hours. 18 mL of 1N dilute hydrochloric acid was added and stirred. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound C01 (pale yellow solid, 79.3 g, 83% yield, 99% purity). An appropriate amount of the obtained compound C01 was detected by mass spectrometry (MS (ESI): 604.3 [M+H)). + .

[0288] Example 21: Preparation Method II of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (CO2)

[0289]

[0290] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydrofuran-2-carboxynitrile (S4) (100 g, 178 mmol) and 4-dimethylaminopyridine (4.4 g, 3.6 mmol, 0.02 eq) were mixed with dichloromethane (400 mL), and triethylamine (21.6 g, 213.6 mmol) was added. 1.2 eq) was added, cooled to -5℃, and pivaloyl chloride (23.6 g, 196 mmol, 1.1 eq) was added. The mixture was stirred and reacted at 30℃ for 6 hours. 18 mL of 1N dilute hydrochloric acid was added and stirred. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, concentrated under reduced pressure, and dried to obtain compound CO2 (pale yellow viscous oil to solid, 109.2 g, 95% yield, 99% purity), which was directly used in subsequent reactions. An appropriate amount of the obtained compound CO2 was detected by mass spectrometry (ESI): 646.2 [M+H]. + .

[0291] Example 22: Preparation Method II of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (CO3)

[0292]

[0293] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydrofuran-2-carboxynitrile (S4) (100 g, 178 mmol) and 4-dimethylaminopyridine (4.4 g, 3.6 mmol, 0.02 eq) were mixed with dichloromethane (400 mL), and triethylamine (21.6 g, 2...) was added. 13.6 mmol (1.2 eq) was added, cooled to -5 °C, and benzoyl chloride (27.6 g, 196 mmol, 1.1 eq) was added. The mixture was stirred and reacted at 30 °C for 6 hours. 18 mL of 1N dilute hydrochloric acid was added and stirred for 5 minutes. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate aqueous solution, then washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting pale yellow solid CO3 (115 g, 97% yield, 99% purity) was dried to obtain CO3. A suitable amount of the obtained compound CO3 was analyzed by mass spectrometry (ESI): 666.8 [M+H]. + .

[0294] Example 23: Preparation method of N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)trifluoroacetamide (CO4)

[0295]

[0296] In a round-bottom flask, (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydrofuran-2-carboxynitrile (S4) (5 g, 8.9 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol, 0.02 eq) were added sequentially. The mixture was dissolved in dichloromethane (25 mL), and triethylamine (1.5 mL, 10.7 mmol, 1.2 eq) was added. The mixture was cooled to -5 °C, and trifluoroacetic anhydride (2.06 g, 9.8 mmol, 1.1 eq) was slowly added dropwise over 20 minutes. The mixture was stirred at 25 °C for 6 hours. HPLC was used to monitor the reaction until the starting material was completely converted, and LC-MS analysis showed an MS(ESI) of 649.2 [M+H]. + The target molecular weight was observed, with a peak area of ​​approximately 20%. The mixture was washed with purified water (20 mL), then with saturated sodium chloride solution (20 mL), dried over sodium sulfate, concentrated under reduced pressure, and separated by column chromatography. A clean target compound, CO4, was not obtained.

[0297] Example 24: Preparation of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide compound (DO1)

[0298]

[0299] Under a nitrogen atmosphere, N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (CO1) (3.0 g, 5 mmol) was mixed with dichloromethane (40 mL), cooled to -78 °C, and 1 M boron trichloride solution in dichloromethane (19 mL, 19 mmol, 3.8 eq) was added. The mixture was reacted at -50 °C for 1–2 h, and then methanol (10 mL) and triethylamine (1 The reaction was quenched with 10 mL of methanol solution (0 eq), heated to room temperature, concentrated under reduced pressure, washed three times with 10 mL of n-hexane, then 20 mL of dichloromethane and 15 mL of water were added. The mixture was stirred, allowed to stand, separated, and the organic phase was collected. The aqueous phase was extracted twice with 20 mL of dichloromethane. The organic phases were combined, washed with 20 mL of pure water, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane:methanol (V / V) = 15:1 to 12:1) to obtain compound D01 (0.9 g, 54% yield). A suitable amount of the obtained compound D01 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 332.2 [MH]. - .

[0300] Example 25: Preparation of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide compound (DO2)

[0301]

[0302] Under a nitrogen atmosphere, N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (CO2) (64.6 g, 100 mmol) was mixed with dichloromethane (800 mL), cooled to -78 °C, and 1 M dichloromethane solution of boron trichloride (380 mL, 380 mmol, 3.8 eq) was added. The mixture was reacted at -50 °C for 1-2 h. The reaction was quenched by adding 200 mL of methanol, followed by 10 eq of triethylamine in 200 mL of methanol. The mixture was heated to room temperature, concentrated under reduced pressure, washed three times with 200 mL of n-hexane, then 400 mL of dichloromethane and 300 mL of water were added. The mixture was stirred, allowed to stand, and separated. The organic phase was collected, and the aqueous phase was extracted twice with 400 mL of dichloromethane. The organic phases were combined, washed with 400 mL of pure water, dried over sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane:methanol (V / V) = 15:1–12:1) to obtain compound DO2 (31.2 g, 83% yield). A suitable amount of the obtained compound DO2 was analyzed by mass spectrometry, proton NMR, and carbon NMR. The results were: MS (ESI): 376.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d) 6 )δ10.41(s,1H),8.47(s,1H),7.18(d,J=4.7Hz,1H),6.99(d,J=4.7Hz,1H),6.23(d,J=6.2Hz,1H),5.25(d,J=5.5Hz,1H),4.92(t,J=5.6Hz,1H),4 .63(t,J=5.7Hz,1H),4.10(q,J=4.2Hz,1H),3.97(q,J=5.5Hz,1H),3.66( ddd,J=12.2,5.5,3.4Hz,1H),3.53(dt,J=12.2,5.2Hz,1H),1.30(s,9H); 13 C NMR (101MHz, DMSO-d) 6 )δ177.9,153.0,146.7,125.7,118.9,117.3,113.0,106.7,85.7,78.6,74.9,70.4,61.1,27.2.

[0303] Example 26: Preparation of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide compound (DO3)

[0304]

[0305] Under a nitrogen atmosphere, N-(7-((2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-cyanotetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (CO3) (6.7 g, 10 mmol) was mixed with dichloromethane (80 mL), cooled to -78 °C, and 1 M boron trichloride solution in dichloromethane (38 mL, 38 mmol, 3.8 eq) was added. The mixture was reacted at -50 °C for 1–2 h, followed by the addition of methanol (20 mL) and then triethylamine. The reaction was quenched with 10 eq of methanol (20 mL), heated to room temperature, concentrated under reduced pressure, washed three times with n-hexane (20 mL), then dichloromethane (40 mL) and water (30 mL) were added. The mixture was stirred, allowed to stand, separated, and the organic phase was collected. The aqueous phase was extracted twice with dichloromethane (40 mL). The organic phases were combined, washed with pure water (40 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane:methanol (V / V) = 15:1–12:1) to obtain compound DO3 (3.0 g, 76% yield). A suitable amount of the obtained compound DO3 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 396.1 [M+H] + .

[0306] Example 27: Preparation of N-(7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxo-4-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (E01)

[0307]

[0308] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (DO1) (3.3 g, 10 mmol, 1.0 eq), 2,2-dimethoxypropane (6.2 g, 60 mmol, 6.0 eq), and p-toluenesulfonic acid (0.17 g, 1 mmol, 0.1 eq) were mixed with dichloromethane (20 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, triethylamine (0.2 mL, 1.5 mmol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (V / V) = 30:1–20:1) to obtain compound E01 (2.3 g, 62% yield, 98% purity). An appropriate amount of the obtained compound E01 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 374.2 [M+H] + .

[0309] Example 28: Preparation of N-(7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxo-4-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (E02)

[0310]

[0311] Dichloromethane (200 mL) was added to the reactor at 25 °C, followed by N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (DO2) (37.3 g, 100 mmol, 1.0 eq) and 2,2-dimethoxypropane (62 g, 600 mmol). 6.0 eq) was added, followed by TsOH (p-toluenesulfonic acid) (1.7 g, 10 mmol, 0.1 eq). The reaction was stirred at 25 °C for 3–5 hours until completion. Then, triethylamine (2 mL, 15 mmol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (V / V) = 30:1–20:1) to obtain compound E02 (37.8 g, 91% yield). An appropriate amount of the obtained compound E02 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 416.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d) 6)δ10.50(s,1H),8.49(s,1H),7.17(d,J=4.8Hz,1H),7.00(d,J=4.8Hz,1H),5.37(d,J=6.5Hz,1H),5.04(t,J=5.6Hz,1H),4. 91(dd,J=6.5,2.9Hz,1H),4.38(td,J=5.2,2.9Hz,1H),3.54(qt,J=11.6,5.4Hz,2H),1.66(s,3H),1.39(s,3H),1.30(s,9H).

[0312] Example 29: Preparation of N-(7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxo-4-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (E03)

[0313]

[0314] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (DO3) (39.5 g, 100 mmol, 1.0 eq), 2,2-dimethoxypropane (62 g, 600 mmol, 6.0 eq), and TsOH (1.7 g, 10 mmol, 0.1 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, triethylamine (2 mL, 15 mmol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (V / V) = 30:1–20:1) to obtain compound E03 (37.0 g, 85% yield). A suitable amount of the obtained compound E03 was analyzed by mass spectrometry, and the result was: MS (ESI): 436.2 [M+H] + .

[0315] Example 30: Preparation of N-(7-((3aR,4R,6R,6aR)-4-cyano-2,2-diethyl-6-(hydroxymethyl)tetrahydrofurano[3,4-d][1,3]dioxo-4-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (E05)

[0316]

[0317] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)acetamide (DO1) (3.3 g, 10 mmol, 1.0 eq), 2,2-dimethoxypentane (7.9 g, 60 mmol, 6.0 eq), and TsOH (0.17 g, 1 mmol, 0.1 eq) were mixed with dichloromethane (20 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, triethylamine (0.2 mL, 1.5 mmol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (V / V) = 30:1–20:1) to obtain compound E05 (2.6 g, 65% yield). An appropriate amount of the obtained compound E05 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 402.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d) 6 ): δ10.97(s,1H),8.44(s,1H),7.31(d,J=4.8Hz,1H),7.15(d,J=4.8Hz,1H ),5.39(d,J=6.7Hz,1H),5.01(t,J=5.6Hz,1H),4.86(dd,J=6.6,3.6Hz,1H) ,4.30(td,J=5.6,3.6Hz,1H),3.54–3.44(m,2H),2.40(s,3H),1.94–1.84( m, 2H), 1.65 (q, J = 7.4Hz, 2H), 1.02 (t, J = 7.4Hz, 3H), 0.85 (t, J = 7.4Hz, 3H).

[0318] Example 31: Preparation of N-(7-((3aR,4R,6R,6aR)-4-cyano-2,2-diethyl-6-(hydroxymethyl)tetrahydrofurano[3,4-d][1,3]dioxo-4-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (E06)

[0319]

[0320] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (DO2) (37.5 g, 1.0 eq, 100 mmol), 2,2-dimethoxypentane (79 g, 6.0 eq, 600 mmol), and TsOH (1.7 g, 0.1 eq, 10 mmol) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, triethylamine (2 mL, 0.15 eq, 15 mmol) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (V / V) = 30:1–20:1) to obtain compound E06 (39.4 g, 89% yield). An appropriate amount of the obtained compound E06 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 444.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d) 6 )δ10.52(s,1H),8.49(s,1H),7.18(d,J=4.8Hz,1H),7.01(dd,J=4.8,1.7Hz,1H), 5.41(d,J=6.7Hz,1H),5.02(d,J=5.8Hz,1H),4.87(dd,J=6.8,3.7Hz,1H),4.37–4 .23(m,1H),3.50(ddq,J=16.9,12.2,6.0Hz,2H),1.89(q,J=7.6Hz,3H),1.65(t,J =7.4Hz, 4H), 1.30 (d, J = 1.7Hz, 9H), 1.01 (d, J = 5.4Hz, 3H), 0.86 (t, J = 7.1Hz, 3H).

[0321] Example 32: Preparation of N-(7-((3aR,4R,6R,6aR)-4-cyano-2,2-diethyl-6-(hydroxymethyl)tetrahydrofurano[3,4-d][1,3]dioxo-4-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (E07)

[0322]

[0323] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (DO3) (4.0 g, 10 mmol, 1.0 eq), 2,2-dimethoxypentane (7.9 g, 60 mmol, 6.0 eq), and TsOH (0.17 g, 1 mmol, 0.1 eq) were mixed with dichloromethane (20 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, triethylamine (0.2 mL, 1.5 mmol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (V / V) = 30:1–20:1) to obtain compound E07 (3.6 g, 78% yield, 99% purity). A suitable amount of the obtained compound E07 was analyzed by mass spectrometry, and the result was: MS (ESI): 464.2 [M+H] + .

[0324] Example 33: Preparation method of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxono-4-carboxynitrile (F00)

[0325]

[0326] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (DO2) (37.5 g, 100 mmol, 1.0 eq), 2,2-dimethoxypropane (62 g, 600 mmol, 6.0 eq), and p-toluenesulfonic acid monohydrate (24.7 g, 130 mmol, 1.3 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, n-heptane (80 mL) was added and stirred for 2 hours. The mixture was filtered, and the filter cake was collected. The filter cake was mixed with a mixture of saturated sodium bicarbonate aqueous solution (200 mL) and dichloromethane (200 mL). The pH of the aqueous phase was adjusted to 8–9 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and then separated. The aqueous phase was extracted once with dichloromethane (120 mL), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to give compound F00 (pale yellow to off-white solid, 30.8 g, 93% yield). A suitable amount of the obtained compound F00 was analyzed by mass spectrometry, and the result was: MS (ESI): 330.2 [MH]. - .

[0327] Example 34: Preparation Method II of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxo-4-carboxynitrile (F00)

[0328]

[0329] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (DO2) (37.5 g, 100 mmol, 1.0 eq), 2,2-dimethoxypropane (62 g, 600 mmol, 6.0 eq), and p-toluenesulfonic acid monohydrate (1.9 g, 10 mmol, 0.1 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, 28% ammonia water (47 g, 375 mmol, 3.75 eq.) was added and stirred for 2 hours. HPLC monitoring showed complete conversion of intermediate E02. The mixture was diluted with purified water (100 mL), allowed to stand, and then separated. The organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to 1 / 5 volume. Hexane (200 mL) was added to induce crystallization, filtered, and the filter cake was dried to obtain compound F00 (pale yellow to off-white solid, 31.8 g, 96% yield).

[0330] Example 35: Preparation method of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxo-4-carboxynitrile (F00)

[0331]

[0332] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (DO3) (39.5 g, 100 mmol, 1.0 eq), 2,2-dimethoxypropane (62 g, 600 mmol, 6.0 eq), and p-toluenesulfonic acid monohydrate (28.5 g, 150 mmol, 1.5 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 8–10 hours until the reaction was complete. Then, n-heptane (80 mL) was added and stirred for 2 hours. The mixture was then filtered, and the filter cake was collected. The filter cake was added to a mixture of saturated sodium bicarbonate aqueous solution (200 mL) and dichloromethane (200 mL). The pH of the aqueous phase was adjusted to 8–9 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and then separated. The aqueous phase was extracted once with DCM (3V, 120mL), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (200mL), dried over sodium sulfate, and the filtrate was concentrated under reduced pressure and dried to give compound F00 (pale yellow to off-white solid, 24.2g, 73% yield, 98%). A suitable amount of the obtained compound F00 was analyzed by mass spectrometry, and the result was: MS (ESI): 330.2 [MH]. - .

[0333] Example 36: Preparation method of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-diethyltetrahydrofurano[3,4-d][1,3]dioxono-4-carboxynitrile (F01)

[0334]

[0335] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (DO2) (37.5 g, 100 mmol, 1.0 eq), 3,3-dimethoxypentane (7.9 g, 60 mmol, 6.0 eq), and TsOH·H2O (p-toluenesulfonic acid monohydrate) (24.7 g, 130 mmol, 1.3 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, n-heptane (80 mL) was added and stirred for 2 hours. The mixture was filtered, and the filter cake was collected. The filter cake was mixed with a mixture of saturated sodium bicarbonate aqueous solution (200 mL) and dichloromethane (200 mL), stirred, and the pH of the aqueous phase was maintained at 8–9. The mixture was allowed to stand and then separated. The aqueous phase was extracted once with DCM (dichloromethane) (120 mL), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to give compound F01 (pale yellow to off-white solid, 31.6 g, 88% yield). A suitable amount of the obtained compound F01 was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 358.2 [MH]. - ; 1 H NMR (400MHz, DMSO-d) 6 )δ8.03–7.86(m,3H),6.94–6.88(m,2H),5.38(d,J=6.7Hz,1H),5.00(t,J=5.7Hz,1H),4.85(dd,J=6.8,3.8Hz,1H),4.26(td,J=5.6 ,3.7Hz,1H),3.48(qt,J=11.6,5.7Hz,2H),1.93–1.83(m,2H),1.65(q,J=7.4Hz,2H),1.00(t,J=7.4Hz,3H),0.84(t,J=7.4Hz,3H).

[0336] Example 37: Preparation Method II of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-diethyltetrahydrofurano[3,4-d][1,3]dioxo-4-carboxynitrile (F01)

[0337]

[0338] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)pentanamide (DO2) (37.5 g, 100 mmol, 1.0 eq), 3,3-dimethoxypentane (79 g, 600 mmol, 6.0 eq), and TsOH·H2O (p-toluenesulfonic acid monohydrate) (1.9 g, 10 mmol, 0.1 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, 28% ammonia water (47 g, 375 mmol, 3.75 eq.) was added and stirred for 2 hours. HPLC monitoring showed complete conversion of intermediate E06. The mixture was diluted with purified water (100 mL), allowed to stand, and then separated. The organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to 1 / 5 volume. Hexane (200 mL) was added to induce crystallization, filtered, and the filter cake was dried to obtain compound F01 (pale yellow to off-white solid, 33.8 g, 94% yield).

[0339] Example 38: Preparation method of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-diethyltetrahydrofurano[3,4-d][1,3]dioxo-4-carboxynitrile (F01)

[0340]

[0341] N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-)pyrrolo[2,1-f][1,2,4]triazine-4-)benzamide (DO3) (39.5 g, 100 mmol, 1.0 eq), 3,3-dimethoxypentane (79 g, 600 mmol, 6.0 eq), and TsOH·H2O (28.5 g, 150 mmol, 1.5 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 8–10 hours until the reaction was complete. Then, n-heptane (80 mL) was added and stirred for 2 hours. The mixture was filtered, and the filter cake was collected. The filter cake was mixed with a mixture of saturated sodium bicarbonate aqueous solution (200 mL) and dichloromethane (200 mL). The pH of the aqueous phase was adjusted to 8–9 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and then separated. The aqueous phase was extracted once with DCM (120 mL), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried over sodium sulfate, and the filtrate was concentrated under reduced pressure and dried to give compound F01 (pale yellow to off-white solid, 20.5 g, 57% yield, 97% yield). A suitable amount of the obtained compound F01 was analyzed by mass spectrometry, and the result was: MS (ESI): 358.2 [MH]. - .

[0342] Example 39: Preparation method of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-5-cyano-3,4-dihydroxytetrahydrofuran-2-)methyl isobutyrate (J01(ATV006))

[0343]

[0344] a) Preparation of compound E02: Compound D02 (37.5 g, 100 mmol, 1.0 eq), 2,2-dimethoxypropane (62 g, 600 mmol, 6.0 eq) and TsOH·H2O (1.9 g, 10 mmol, 0.1 eq) were mixed with dichloromethane (200 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, triethylamine (2 mL, 15 mmol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 200 mL of DCM and then washed with saturated sodium chloride aqueous solution. The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated to obtain compound E02 (39.5 g, 95% yield).

[0345] b) Preparation of compound H01: A DCM solution (150 mL) of compound E02 (37.4 g, 90 mmol, 1.0 eq), isobutyric acid (9.6 g, 108 mmol, 1.2 eq), DMAP (4-dimethylaminopyridine) (5.4 g, 45 mmol, 0.5 eq) and DCC (24 g, 117 mmol, 1.3 eq) was mixed with DCM (300 mL) and reacted at 5 °C to 10 °C for 5 h. After the reaction was completed, 20% citric acid aqueous solution (50 mL) was added and stirred for 10 min. The byproduct DCU was removed by suction filtration and the filtrate was allowed to stand and separate into layers. The organic phase was separated and washed with 20% citric acid aqueous solution (100 mL × 2), saturated sodium carbonate solution (100 mL × 1), water (100 mL × 1), and saturated sodium chloride aqueous solution (100 mL × 1). It was then dried with sodium sulfate, filtered, and dried to obtain compound H01 (white solid), which was directly used in the next reaction.

[0346] c) Preparation of compound J01 (ATV006): Compound H01 obtained in step b), 6N HCl (300 mL, 1.8 mol) and THF (tetrahydrofuran) (300 mL) were mixed and reacted at 0 °C for 7 h. After the reaction was completed, the pH was adjusted to 7-8 with sodium bicarbonate, THF was removed by vacuum distillation, and the mixture was extracted with ethyl acetate (300 mL × 2). The ethyl acetate layers were combined, washed with water (150 mL), washed with saturated sodium chloride water (150 mL), dried with magnesium sulfate, filtered, and dried to obtain 30 g of crude product. The crude product was subjected to column chromatography (dichloromethane:methanol (V:V) = 40:1) to obtain compound J01 (ATV006) (26.3 g, combined with step b), yield 81%, purity: 99.7%).

[0347] Example 40: Preparation Method II of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-5-cyano-3,4-dihydroxytetrahydrofuran-2-)methyl isobutyrate (J01(ATV006))

[0348]

[0349] a) Preparation of compound F00: Compound D02 (56.3 g, 150 mmol, 1.0 eq), 2,2-dimethoxypropane (93 g, 900 mmol, 6.0 eq), and TsOH·H2O (37.1 g, 195 mmol, 1.3 eq) were mixed with dichloromethane (300 mL) and stirred at 25 °C for 3–5 hours until the reaction was complete. Then, n-heptane (120 mL) was added and stirred for 2 hours. The mixture was filtered, and the filter cake was collected. The filter cake was mixed with a mixture of saturated sodium bicarbonate aqueous solution (300 mL) and dichloromethane (300 mL). The pH of the aqueous phase was adjusted to 8–9 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and then separated. The aqueous phase was extracted once with DCM (180 mL), the organic phases were combined, the organic phases were washed with saturated sodium chloride aqueous solution (300 mL), the organic phases were dried with sodium sulfate (75 g), the filtrate was concentrated under reduced pressure and dried to give compound F00 (off-white solid, 46.7 g, 94% yield);

[0350] b) Preparation of compound G01: A DCM solution (150 mL) of compound F00 (45 g, 136 mmol), isobutyric acid (14.4 g, 163 mmol, 1.2 eq), DMAP (8.3 g, 68 mmol, 0.5 eq), and DCC (36.5 g, 177 mmol, 1.3 eq) was mixed with DCM (300 mL) and reacted at 5℃~10℃ for 5 h. After the reaction was completed, 20% citric acid aqueous solution (75 mL) was added, and the mixture was stirred for 10 min. The DCU was removed by suction filtration, and the filtrate was allowed to stand and separate into layers. The organic phase layer was separated and washed with 20% citric acid aqueous solution (150 mL × 2), saturated sodium carbonate aqueous solution (150 mL × 1), water (150 mL × 1), and saturated sodium chloride aqueous solution (150 mL × 1), respectively. The mixture was then dried with sodium sulfate, filtered, and dried to obtain compound G01 (white solid), which was directly used in the next reaction.

[0351] c) Preparation of compound J01 (ATV006): Compound G01 obtained in step b), 6N HCl (450 mL, 2.7 mol) and THF (450 mL) were mixed and reacted at 0 °C for 7 h. After the reaction was completed, the pH was adjusted to 7-8 with sodium bicarbonate solid, THF was removed by vacuum distillation, and the mixture was extracted with ethyl acetate (450 mL × 2). The ethyl acetate layers were combined, washed with water (200 mL) and saturated saline solution (200 mL) respectively, and dried with magnesium sulfate. After filtration and drying, 45 g of crude product was obtained. Column chromatography (dichloromethane:methanol (V:V) = 40:1) was performed to obtain compound J01 (ATV006) (33.1 g, combined with step b), yield 68%).

[0352] Example 41: Preparation method of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-5-cyano-3,4-dihydroxytetrahydrofuran-2-)methyl isobutyrate (J01(ATV006))

[0353]

[0354] a) Preparation of compound E02: Compound D02 (4.8 kg, 12.8 mol, 1.0 eq), 2,2-dimethoxypropane (7.9 kg, 76.8 mol, 6.0 eq), and TsOH·H2O (24.7 g, 0.13 mol, 0.1 eq) were mixed with dichloromethane (20 L) and stirred at 25 °C for 5 hours until the reaction was complete. Then, triethylamine (200 g, 1.9 mol, 0.15 eq) was added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 20 L of DCM and then washed with saturated sodium chloride aqueous solution (10 L). The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated to obtain compound E02 (5.0 kg, 94% yield).

[0355] b) Preparation of compound H01: 20 L of DCM solution of compound E02 (5.0 Kg, 12.0 mol) and DMAP (4-dimethylaminopyridine) (29.3 g, 0.24 mol, 0.02 eq) was mixed, and triethylamine (1.3 Kg, 13.2 mol, 1.1 eq) was added. The temperature was controlled at 10 ± 5 °C, and isobutyryl chloride (1.4 Kg, 13.2 mol, 1.1 eq) was added dropwise. The mixture was stirred at 20 ± 5 °C for 5 hours. After the reaction was completed, purified water (12 L) was added to wash the organic phase, and saturated sodium chloride solution (12 L) was added to wash the organic phase. The organic phase was concentrated to obtain 6.2 Kg of crude compound H01 (a light yellow oily substance), which was directly used in the next reaction.

[0356] c) Preparation of compound J01 (ATV006): Compound H01 obtained in step b), 6N HCl (38 L, 230 mol), and THF (tetrahydrofuran) (38 L) were mixed and reacted at 0 °C for 7 h. After the reaction was completed, the pH was adjusted to 7-8 with sodium bicarbonate, THF was removed by vacuum distillation, and the mixture was extracted with ethyl acetate (38 L × 2). The ethyl acetate layers were combined, washed with water (20 L), washed with saturated sodium chloride aqueous solution (20 L), and dried with magnesium sulfate. After filtration and drying, 4.2 kg of crude product was obtained. The crude product was slurried with ethanol (18 L) to obtain compound J01 (ATV006) (3.7 kg, combined with that from step b). The yield was 85%, and the purity was 99.8%. MS (ESI): 362.1 [M+H] + ; 1HNMR (600MHz, DMSO-d6) δ (ppm): 7.93 (s, 1H), 7.89 (br, 2H), 6.92 (d, J = 4.3Hz, 1H),6.81(d,J=4.3Hz,1H),6.32(d,J=5.9Hz,1H),5.38(d,J=5.7Hz,1H),4.7(t ,J=5.2Hz,1H),4.32-4.30(m,1H),4.25-4.22(m,1H),4.19-4.16(m,1H),3.98- 3.95(q,J=5.6Hz,1H),2.55-2.50(m,1H),1.06-1.05(dd,J=6.8Hz,1.8Hz,6H). 13 C NMR (150MHz, DMSO-d6) δ (ppm): 176.4, 156.1, 148.4, 124.0, 117.4, 117.0, 110.7, 101.3, 81.7, 79.5, 74.5, 70.6, 63.4, 33.6, 19.2, 19.1.

[0357] Example 42: Preparation method of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-5-cyano-3,4-dihydroxytetrahydrofuran-2-)methylcyclohexylcarboxylate (J02(ATV014))

[0358]

[0359] a) Preparation of compound E02: Compound D02 (5.3 kg, 14 mol, 1.0 eq), 2,2-dimethoxypropane (8.7 kg, 84 mol, 6.0 eq), and TsOH·H2O (0.27 kg, 1.4 mol, 0.1 eq) were mixed with dichloromethane (20 L) and stirred at 25 °C for 3–5 hours until the reaction was complete. Triethylamine (0.16 kg, 1.5 mol, 0.11 eq) was then added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in DCM (20 L), washed with saturated NaCl aqueous solution and purified water, dried with sodium sulfate, filtered, and the filtrate was concentrated to obtain compound E02 (5.6 kg, 96% yield).

[0360] b) Preparation of compound H02: An acetonitrile solution (10 L) of compound E02 (5.6 kg, 1.0 eq, 13.4 mol), DMAP (4-dimethylaminopyridine) (0.82 kg, 6.7 mol, 0.5 eq), cyclohexylcarboxylic acid (2.1 kg, 16.1 mol, 1.2 eq), and DIC (N,N-diisopropylcarbodiimide) (2.1 kg, 16.8 mol, 1.25 eq) and acetonitrile (30 L) were mixed and stirred at 5 ± 5 °C for 48 hours. After the reaction was complete, the mixture was centrifuged, and ethyl acetate (30 L) and 20% citric acid aqueous solution (30 L) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 L). The organic phases were combined, and 20% sodium carbonate aqueous solution (30 L) was added. The mixture was separated and concentrated to obtain 6.8 kg of crude compound H02 (a light yellow oily substance), which was directly used in the next reaction.

[0361] c) Preparation of compound J02 (ATV014): Compound H02 (6.8 kg) was mixed with an aqueous solution (44 L) containing 66.7% vol formic acid. The mixture was stirred at 35 ± 5 °C for 48 h. After the reaction was completed, excess formic acid was recovered by vacuum distillation. Ethyl acetate (20 L) was added to the residue, and the mixture was cooled to 5 °C–10 °C. The pH was adjusted to 7–8 with a saturated sodium carbonate aqueous solution, and the mixture was stirred for another 2 h to solidify completely. The mixture was then filtered, and the filter cake was washed with a large amount of water to obtain 10 kg of crude product with a purity of 97%. The crude product was slurried with ethanol (50 L) and stirred at 50 ± 5 °C for 5 h. The mixture was then filtered, and the filter cake was dried under vacuum at 50 °C to obtain 4.5 kg of compound J02 (ATV014) (white solid). The combined yield of steps b and c) was 84%, and the purity was 99.5%.

[0362] Example 43: Preparation Method II of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-5-cyano-3,4-dihydroxytetrahydrofuran-2-)methylcyclohexylcarboxylate J01 (ATV006)

[0363]

[0364] a) Preparation of compound F00: Compound D02 (5.2 kg, 14 mol, 1.0 eq), 2,2-dimethoxypropane (8.7 kg, 84 mol, 6.0 eq), and TsOH·H2O (3.5 kg, 18.2 mol, 1.3 eq) were mixed with dichloromethane (20 L) and stirred at 25 °C for 3–5 hours. After the reaction was complete, n-heptane (10 L) was added and stirred for 2 hours. The mixture was filtered, and the filter cake was collected. The filter cake was mixed with a mixture of saturated sodium bicarbonate aqueous solution (20 L) and dichloromethane (20 L). The pH of the aqueous phase was adjusted to 8–9 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and then separated. The aqueous phase was extracted once with DCM (15 L), the organic phases were combined, washed with saturated NaCl aqueous solution (20 L) and purified water, the organic phase was dried with sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and dried to give compound F00 (white solid, 4.2 kg, 91% yield);

[0365] b) Preparation of compound G02: An acetonitrile solution (10 L) of compounds F00 (4.2 Kg, 12.7 mol, 1.0 eq), DMAP (0.78 Kg, 6.4 mol, 0.5 eq), cyclohexylcarboxylic acid (2.2 Kg, 16.8 mol, 1.2 eq), and DIC (2.0 Kg, 15.9 mol, 1.25 eq) was mixed with acetonitrile (30 L). The mixture was stirred at 5 ± 5 °C for 48 hours. After the reaction was completed, the mixture was centrifuged, and ethyl acetate (30 L) and 20% citric acid aqueous solution (30 L) were added. The mixture was separated, and the aqueous phase was extracted with EA (20 L). The organic phases were combined, and 20% sodium carbonate aqueous solution (30 L) was added. The mixture was separated and concentrated to obtain 5.8 Kg of crude compound G02 (a light yellow oily substance), which was directly used in the next reaction.

[0366] c) Preparation of compound J02 (ATV014): Compound G02 (5.8 kg) obtained in step b) was mixed with 66.7% formic acid (40 L) and stirred at 35 ± 5 °C for 48 h. After the reaction was completed, excess formic acid was recovered by vacuum distillation. Ethyl acetate (20 L) was added to the residue, and the temperature was lowered to 5–10 °C. The pH was adjusted to 7–8 with saturated sodium carbonate aqueous solution, and stirring was continued for 2 h to fully solidify. The residue was filtered, and the filter cake was washed with water to obtain 9 kg of crude compound J02 (ATV014) with a purity of 91%. The crude product was slurried with ethanol (50 L) and stirred at 50 ± 5 °C for 5 h. The residue was filtered, and the filter cake was dried under vacuum at 50 °C to obtain compound J02 (ATV014) (white solid, 3.5 kg, b). The combined yield of steps b and c) was 69%, and the purity was 99.3%.

[0367] Example 44: Preparation method of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-5-cyano-3,4-dihydroxytetrahydrofuran-2-)methylcyclohexylcarboxylate (J02(ATV014))

[0368]

[0369] a) Preparation of compound E02: Compound D02 (5.3 kg, 14 mol, 1.0 eq), 2,2-dimethoxypropane (8.7 kg, 84 mol, 6.0 eq), and TsOH·H2O (0.27 kg, 1.4 mol, 0.1 eq) were mixed with dichloromethane (20 L) and stirred at 25 °C for 6 hours until the reaction was complete. Triethylamine (0.16 kg, 1.5 mol, 0.11 eq) was then added, and the mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in DCM (20 L), washed with saturated NaCl aqueous solution and purified water, dried with sodium sulfate, filtered, and the filtrate was concentrated to obtain compound E02 (5.5 kg, 94% yield).

[0370] b) Preparation of compound H02: A 20 L solution of compound E02 (5.5 Kg, 13 mol, 1.0 eq), DMAP (4-dimethylaminopyridine) (31.8 g, 0.26 mol, 0.02 eq), and triethylamine (1.44 Kg, 14.4 mol, 1.1 eq) in dichloromethane was prepared at 10 ± 5 °C. Cyclohexylformyl chloride (2.15 Kg, 1.05 eq, 14.7 mol) was added dropwise over 0.5 hours. The mixture was stirred at 20 ± 5 °C for 5 hours until the reaction was complete. The mixture was then washed with 10 L of purified water and 10 L of saturated sodium chloride solution. The organic phase was concentrated to obtain 7.0 Kg of crude compound H02 (a light yellow oily substance), which was directly used in the next reaction.

[0371] c) Preparation of compound J02 (ATV014): Compound H02 (7.0 kg) was mixed with an aqueous solution (44 L) containing 66.7% vol formic acid. The mixture was stirred at 35 ± 5 °C for 48 h. After the reaction was completed, excess formic acid was recovered by vacuum distillation. Ethyl acetate (20 L) was added to the residue, and the temperature was lowered to 5 °C to 10 °C. The pH was adjusted to 7 to 8 with a saturated sodium carbonate aqueous solution, and the mixture was stirred for another 2 h to fully solidify. The mixture was then filtered, and the filter cake was washed with a large amount of water to obtain 10 kg of crude product with a purity of 98%. The crude product was slurried with ethanol (50 L) and stirred at 50 ± 5 °C for 5 h. The mixture was then filtered, and the filter cake was dried under vacuum at 50 °C to obtain 4.8 kg of compound J02 (ATV014) (white solid). The combined yield of steps b and c) was 92%, and the purity was 99.8%. A suitable amount of compound J02 (ATV014) was analyzed by mass spectrometry and proton NMR. The results were: MS (ESI): 402.2 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.86 (br, 1H), 6.92 (d, J = 4.5Hz, 1H), 6.81 (d, J = 4 .5Hz,1H),6.33(d,J=5.9Hz,1H),5.38(d,J=5.9Hz,1H),4.70(t,J=5.3Hz,1H),4.32-4.29(dd ,J=12.2Hz,2.6Hz,1H),4.24-4.21(m,1H),4.16-4.13(dd,J=12.3Hz,4.8Hz,1H),3.98-3.95( q,J=5.9Hz,1H),2.26-2.22(m,1H),1.75-1.72(m,2H),1.64-1.56(m,3H),1.30-1.12(m,5H). 13 C NMR(150MHz,DMSO-d6)δ(ppm):175.34,156.06,148.4,124.0,117.4,117.0,1 10.7,101.2,81.7,79.4,74.5,70.6,63.0,42.6,29.0,28.9,25.7,25.2,25.1.

[0372] Example 45: Preparation method of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxono-4-carboxynitrile (F00)

[0373]

[0374] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydrofuran-2-carboxynitrile (S4) (100 kg, 178 mol) was mixed with dichloromethane (520 kg, 5.2 w / w), and triethylamine (24.3 kg, 240.3 mol, 1.35 eq) was added. The mixture was cooled to -5 °C and then... Add pentanoyl chloride (24.7 kg, 204.7 mol, 1.15 eq), stir, and react at 30 °C for 6 hours. Add 1N dilute hydrochloric acid prepared with concentrated hydrochloric acid (11 kg, 0.11 w / w), stir, separate the liquid and liquid phases, wash the organic phase with saturated aqueous solution of sodium bicarbonate (15 kg, 0.15 w / w), wash with saturated aqueous solution of sodium chloride, concentrate under reduced pressure to obtain a concentrated solution of compound CO2 (115 kg, 178 mol), which can be directly used for subsequent reactions.

[0375] Under a nitrogen atmosphere, the concentrated CO2 solution (115 kg, 178 mol) was mixed with dichloromethane (1035 kg, 9 w / w), cooled to -78 °C, and a 1 M dichloromethane solution of boron trichloride (712 L, 712 mol, 4.0 eq.) was added. The mixture was reacted at -50 °C for 2 h. Methanol (85.1 kg, 0.74 w / w) was added, followed by triethylamine (207 kg, 2045 mol, 11.5 eq.) to quench the reaction. The mixture was then heated to room temperature, concentrated under reduced pressure, dissolved in tetrahydrofuran (575 kg, 5.0 w / w), and then tert-butyl methyl ether (805 kg, 7 w / w). The mixture was centrifuged, and the filtrate was collected. After concentration under reduced pressure, a concentrated DO2 solution (66.8 kg, 178 mol) was obtained, which was directly used in the next reaction.

[0376] Add 2,2-dimethoxypropane (115 kg, 1104 mol, 6.2 eq.) and acetone (801.6 kg, 12 w / w) to the concentrated solution of the above compound DO2 (66.8 kg, 178 mol), cool to 0 °C, and add concentrated sulfuric acid (29.4 kg, 300 mol, 1.7 eq.) dropwise, keeping the temperature below 20 °C. After the addition is complete, continue the reaction until the endpoint, and quench the reaction by adding saturated sodium bicarbonate solution. A total of 1736 kg of ethyl acetate (26 w / w) was added and extracted three times, retaining the organic phase (containing compound E02). 28% ammonia water (83.5 kg, 668 mol, 3.75 eq.) was added to the organic phase, and after reacting for 2 hours, the mixture was separated, retaining the organic phase. The organic phase was washed with purified water until neutral, concentrated under reduced pressure to 1 / 6 volume, and then n-heptane (200.4 kg, 3 w / w) was added to induce crystallization. After centrifugation, the filter cake was washed with n-heptane / ethyl acetate (6:1, v / v), dried, and compound F00 (50.1 kg, total yield 85%) was obtained.

[0377] Conclusion: As can be seen from the above examples:

[0378] (1) In this invention, trifluoroacetyl is used as the protecting group of the amino group. Although S1 and S1-2 can successfully acylate the amino group in a suitable yield, the reactivity is poor in the subsequent coupling reaction and the purified target product B04 is not obtained. Starting from S4, the upper trifluoroacetyl group also fails to obtain the clean target product CO4.

[0379] (2) In this invention, the reaction using acetyl as an amino protecting group has a moderate yield in the coupling step to generate BO1.

[0380] (3) In this invention, the reaction using benzoyl as the amino protecting group has good yield in the processes of amidation, coupling, cyanation, debenzylation, 2',3'-diol protection and 5'-hydroxy esterification.

[0381] (4) In this invention, compared with other protecting groups (such as trifluoroacetyl or acetyl), the reaction using pivaloyl as the amino protecting group has a higher yield and higher purity; compared with other protecting groups (such as benzoyl), the reaction using pivaloyl as the amino protecting group is easier to remove during deprotection, and the deprotection reaction yield and purity are higher. Therefore, in this invention, the use of pivaloyl amino protecting group is the preferred amino protecting group and process strategy.

[0382] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing a compound of formula F00, comprising: ， Under alkaline conditions, the compound shown in formula S4 reacts with pivaloyl chloride in an organic solvent, followed by post-treatment to obtain the compound shown in formula CO2; the organic solvent in the step of obtaining the compound shown in formula CO2 includes at least one of dichloromethane and 1,2-dichloroethane; the post-treatment in the step of obtaining the compound shown in formula CO2 includes: adding an acidic aqueous solution, extraction, separation, washing the organic solvent layer, concentrating the organic solvent layer, and then directly using it for subsequent reactions. Under an inert gas atmosphere, the compound represented by formula CO2 is mixed with a Lewis acid and a solvent, and after a debenzylation reaction and post-treatment, the compound represented by formula D02 is obtained. The post-treatment in the step of obtaining the compound represented by formula D02 includes: quenching reaction, concentration, dissolution with tetrahydrofuran, addition of tert-butyl methyl ether, centrifugation, obtaining a supernatant, concentration of the obtained supernatant, and then direct use in the next reaction. In the presence of sulfuric acid, the compound shown in formula D02 reacts with 2,2-dimethoxypropane in an organic solvent. After post-treatment, the compound shown in formula E02 is obtained. Then, a base is added to carry out the reaction, and after post-treatment, the compound shown in formula F00 is obtained.

2. The preparation method according to claim 1, wherein the base in the step of obtaining the compound of formula CO2 comprises at least one selected from triethylamine, pyridine, tri-n-butylamine, diisopropylethylamine, dimethylbenzylamine, morpholine, and N-methylpiperidine; and / or The inert gas includes nitrogen or argon; and / or The Lewis acid includes at least one of boron trichloride and boron tribromide; and / or In the step of obtaining the compound represented by formula D02, the solvent is at least one of dichloromethane and 1,2-dichloromethane; and / or The organic solvent in the step of obtaining the compound of formula E02 includes at least one of acetone and dichloromethane; and / or The work-up in the step to obtain the compound of formula E02comprises: Quenching reaction, extraction, and retention of organic phase layer; and / or In the step of obtaining the compound represented by formula F00, the base includes at least one of ammonia water, ammonia methanol solution, ammonia ethanol solution, an aqueous solution of methylamine, an alcoholic solution of methylamine, or hydrazine hydrate; and / or The post-processing in the step of obtaining the compound of formula F00 includes: separation, retaining the organic phase layer, washing the organic phase layer, concentration, adding an alkane solvent to induce crystallization, centrifugation or filtration to obtain a precipitate or filter cake, washing the precipitate or filter cake with a mixed solution of n-heptane and ethyl acetate, and drying to obtain the compound of formula F00.

3. The preparation method according to claim 2, wherein the alkane solvent includes at least one of n-hexane, n-heptane, or petroleum ether.

4. The preparation method according to any one of claims 1-3, wherein in the step of obtaining the compound represented by formula CO2, the molar ratio of the base to the compound represented by formula S4 is 1.0:1.0 – 1.5:1.0; and / or In the step of obtaining the compound represented by formula C02, the molar ratio of the pentanoyl chloride to the compound represented by formula S4 is 1.0:1.0 – 1.4:1.0; and / or In the step of obtaining the compound represented by formula C02, the mass ratio of the compound represented by formula S4 to the organic solvent is 1:4 – 1:10; and / or In the step of obtaining the compound represented by formula D02, the molar ratio of the Lewis acid to the compound represented by formula CO2 is 3.1:1.0 – 5.0:1.0; and / or In the step of obtaining the compound represented by formula D02, the mass ratio of the compound represented by formula C02 to the solvent is 1:7 – 1:12; and / or In the step of obtaining the compound represented by formula E02, the molar ratio of the acid to the compound represented by formula D02 is 0.5:1.0 – 2.0:1.0; and / or In the step of obtaining the compound represented by formula E02, the molar ratio of 2,2-dimethoxypropane to the compound represented by formula D02 is 3:1 – 10:1; and / or In the step of obtaining the compound represented by formula E02, the mass ratio of the compound represented by formula D02 to the organic solvent is 1:8 – 1:15; and / or In the step of obtaining the compound represented by formula F00, the molar ratio of the base to the compound represented by formula D02 is independently 1:1 – 5:1; and / or The reaction temperature for obtaining the compound represented by formula C02 is 0°C – 40°C; and / or The reaction temperature for obtaining the compound represented by formula D02 is -78°C to -40°C; and / or The reaction temperature for obtaining the compound represented by formula E02 is 0°C – 40°C; and / or The reaction temperature for obtaining the compound represented by formula F00 is 0°C – 40°C.

Images