CN115521316A

CN115521316A - Preparation method of nucleoside compound or intermediate thereof and nucleoside compound intermediate

Info

Publication number: CN115521316A
Application number: CN202211165527.0A
Authority: CN
Inventors: 郑龙生; 李硕; 刘新军; 李官官; 韩魁元; 肖利侠; 张静
Original assignee: Shenzhen Antai Weishengwu Pharmaceutical Co ltd
Current assignee: Shenzhen Antai Weishengwu Pharmaceutical Co ltd
Priority date: 2022-09-23
Filing date: 2022-09-23
Publication date: 2022-12-27
Anticipated expiration: 2042-09-23
Also published as: CN115521316B

Abstract

The invention provides a preparation method of a nucleoside compound or an intermediate thereof and an intermediate of the nucleoside compound, belonging to the field of medicines. The preparation method has the advantages of high product yield, simple operation, short reaction time, low cost, industrial production and the like. The intermediate of the nucleoside compound can be used for preparing the nucleoside compound.

Description

Preparation method of nucleoside compound or intermediate thereof and nucleoside compound intermediate

Technical Field

The invention belongs to the field of medicines, and particularly relates to a preparation method of a nucleoside compound or an intermediate thereof and an intermediate of the nucleoside compound.

Background

Reddesivir (Remdesivir) is a derivative of the above-mentioned pyrrolotriazine, and is an RNA-dependent RNA polymerase (RdRp) inhibitor, which can inhibit viral nucleic acid replication and thus achieve antiviral effects. Despite its excellent clinical efficacy, reidesciclovir has limited application and accessibility due to its more complex prodrug form, long synthetic steps (J.Med.chem.2017, 60, 1648-1661), expensive price and the need for intravenous injection.

Chinese patent application CN113735862A modifies main metabolite GS-441524 of Redcisvir according to the structure of Redcisvir, and develops a series of novel carbon-nucleoside small molecule drugs, such as ATV006 and ATV014. The compound effectively improves the bioavailability of the Reidcisvir, optimizes the pharmacokinetic property and the drug property of the compound, and more importantly, the compound can effectively infect the current variant strains including Deltay and Ormcken strains in vivo and in vitro (Liu C., et al, science relative Medicine, 2022).

However, for the synthesis of novel carbon-nucleoside small molecule drugs such as ATV006 and ATV014, the prior art still has the problems of low yield, complicated operation, long preparation time and the like, for example, in chinese patent application CN113735862A, the yield of ATV006 prepared from compound GS-441524 is only 44.7%, and the yield of ATV014 prepared from compound GS-441524 is only 41.8%; starting from compound 5, it took 30.5 hours to prepare ATV006 or ATV014.

SARS-CoV-2 continues to spread and mutate over the course of more than two years since its discovery, and the virus will most likely exist in a form coexisting with humans. In order to meet the requirements of subsequent clinical research and human anti-SARS-CoV-2, the research on the scale preparation processes of ATV006 and ATV014 and the like is of great significance. Therefore, rapid development and optimization of a synthetic route for efficient, high-yield, low-cost, industrially applicable compounds such as ATV006 and ATV014 is currently an important task for synthesizing and producing the above drugs.

Disclosure of Invention

In order to solve the above problems, the present invention provides the following technical solutions.

In a first aspect, the present invention provides a process for the preparation of a compound of formula B.

A method for preparing a compound of formula B, comprising:

reacting a compound shown as a formula A with a compound shown as a formula F in a solvent in the presence of a catalyst to obtain a compound shown as a formula B;

wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

In some embodiments, the catalyst is selected from at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, concentrated hydrochloric acid.

In some embodiments, the solvent comprises at least one of dichloromethane, 1, 2-dichloroethane.

In some embodiments, the molar ratio of the catalyst to the compound of formula a fed is 0.1. In some embodiments, the molar ratio of the catalyst to the compound of formula a fed is 0.5. In some embodiments, the molar ratio of the catalyst to the compound of formula a fed is 0.1, 0.5. In some preferred embodiments, the molar ratio of the catalyst to the compound represented by formula a is 1.0 to 1.0.

In some embodiments, the molar ratio of the compound of formula F to the compound of formula a is 3. In some embodiments, the molar ratio of the compound of formula F to the compound of formula a fed is 3.

In some embodiments, the reaction temperature of the reaction is from-10 ℃ to 30 ℃. In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 25 ℃.

In some embodiments, the reaction time for the reaction is 3 hours to 10 hours. In some embodiments, the reaction time for the reaction is 4 hours to 8 hours. In some embodiments, the reaction time for the reaction is 5 hours to 7 hours.

In some embodiments, the C ₁ -C ₁₀ The alkyl group comprising C ₁ Alkyl radical, C ₂ Alkyl radical, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl radical, C ₆ Alkyl radical, C ₇ Alkyl radical, C ₈ Alkyl radical, C ₉ Alkyl or C ₁₀ An alkyl group.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl radicals including C ₃ Cycloalkyl radical, C ₄ Cycloalkyl radical, C ₅ Cycloalkyl radical, C ₆ Cycloalkyl radical, C ₇ Cycloalkyl, C ₈ Cycloalkyl radical, C ₉ Cycloalkyl, C ₁₀ Cycloalkyl radical, C ₁₁ Cycloalkyl or C ₁₂ A cycloalkyl group.

In some embodiments, the C ₁ -C ₁₀ The alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl or n-octyl. In some embodiments, the C ₃ -C ₁₂ Cycloalkyl includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane.

In some embodiments, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane. In some embodiments, the aryl group comprises phenyl or tolyl.

In a second aspect, the present invention provides a method for preparing a compound of formula C.

A method for preparing a compound of formula C, comprising:

reacting the compound shown in the formula B with alkali in a solvent to obtain a compound shown in a formula C; wherein the compound shown in the formula B is prepared by the preparation method of the compound shown in the formula B in the first aspect.

In some embodiments, the base comprises at least one of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, tripotassium phosphate; sodium carbonate is preferred.

In some embodiments, the solvent comprises at least one of tetrahydrofuran, methanol, ethanol, isopropanol, preferably methanol or ethanol.

In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 30 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 15 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 25 ℃.

In some embodiments, the C ₁ -C ₁₀ The alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl or n-octyl.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.

In some embodiments, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane. In some casesIn an embodiment, the aryl group comprises phenyl or tolyl.

In a third aspect, the invention provides a process for preparing a compound of formula D.

A method for preparing a compound of formula D, comprising:

reacting a compound shown as a formula A with a compound shown as a formula F or a compound shown as a formula G in a solvent in the presence of a catalyst and a compound shown as a formula H to obtain a compound shown as a formula D;

wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ² at least one selected from chlorine and bromine atoms.

In some embodiments, the molar ratio of the catalyst to the compound of formula a fed is from 0.1 to 1.0, preferably from 1.0 to 2.0.

In some embodiments, the ratio of the charged volume of the compound of formula H to the charged molar amount of the compound of formula a is 1ml to 11mmol.

In some embodiments, the compound of formula F or the compound of formula G is fed in a molar ratio to the compound of formula a of 3.

In some embodiments, the reaction temperature of the reaction is from-10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 20 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 15 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 10 ℃. In some embodiments, the reaction temperature of the reaction is 0 ℃,1 ℃,2 ℃,3 ℃,4 ℃,5 ℃,6 ℃,7 ℃,8 ℃,9 ℃ or 10 ℃.

In some embodiments, the reaction time for the reaction is 2 hours to 8 hours. In some embodiments, the reaction time for the reaction is 3 hours to 8 hours. In some embodiments, the reaction time for the reaction is 3 hours to 5 hours.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl radicals including C ₃ Cycloalkyl radical, C ₄ Cycloalkyl radical, C ₅ Cycloalkyl radical, C ₆ Cycloalkyl radical, C ₇ Cycloalkyl, C ₈ Cycloalkyl radical, C ₉ Cycloalkyl radical, C ₁₀ Cycloalkyl, C ₁₁ Cycloalkyl or C ₁₂ A cycloalkyl group.

In some embodiments, the C ₁ -C ₁₀ Alkyl includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl or n-octyl.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.

In some embodiments, the aryl group comprises phenyl or tolyl.

In some casesIn the examples, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane. In a fourth aspect, the invention provides a method for preparing a compound of formula C.

In a fourth aspect, the invention provides a method for preparing a compound of formula C.

A method for preparing a compound of formula C, comprising:

reacting the compound shown in the formula D with alkali in a solvent to obtain a compound shown in a formula C; wherein the compound shown in the formula D is prepared by the preparation method of the compound shown in the formula D in the third aspect.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl radicals including C ₃ Cycloalkyl radical, C ₄ Cycloalkyl, C ₅ Cycloalkyl radical, C ₆ Cycloalkyl, C ₇ Cycloalkyl, C ₈ Cycloalkyl radical, C ₉ Cycloalkyl, C ₁₀ Cycloalkyl radical, C ₁₁ Cycloalkyl or C ₁₂ A cycloalkyl group.

In some embodiments, the aryl group comprises phenyl or tolyl.

In some embodiments, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclo-pentaneHexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane. In a fifth aspect, the present invention provides a method for preparing a compound of formula C.

In a fifth aspect, the present invention provides a process for preparing another compound of formula C.

A process for the preparation of a compound of formula C comprising

And (3) in an inert gas atmosphere, reacting the compound shown in the formula A in a solvent in the presence of an oxidant and a buffer to obtain the compound shown in the formula C.

In some embodiments, the oxidizing agent comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or ozone.

In some embodiments, the solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, and toluene.

In some embodiments, the reaction temperature of the reaction is from 40 ℃ to 100 ℃. In some embodiments, the reaction temperature of the reaction is from 50 ℃ to 90 ℃. In some embodiments, the reaction temperature of the reaction is from 60 ℃ to 85 ℃. In some embodiments, the reaction temperature of the reaction is from 70 ℃ to 85 ℃. In some embodiments, the reaction temperature of the reaction is from 75 ℃ to 85 ℃. In some embodiments, the reaction temperature of the reaction is from 80 ℃ to 90 ℃.

In some embodiments, the buffer comprises at least one of a phosphate buffer, an acetate buffer.

In some embodiments, the buffer has a pH of 6 to 7.

In some embodiments, the buffer salt concentration in the buffer is between 0.1mol/L and 0.3mol/L.

In some embodiments, the buffer salt comprises at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate, or the buffer salt comprises at least one of sodium acetate and ammonium acetate.

In some embodiments, the ratio of the buffer feed volume to the feed molar amount of the compound represented by formula a is from 2ml to 18ml. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by formula a is 2.5ml to 18ml. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by formula a is 2.8ml. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by formula a is 2.8ml to 11mmol. In some embodiments, the ratio of the buffer feed volume to the feed molar amount of the compound of formula a is 2.8ml to 11mmol. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by formula a is 2.8ml to 11mmol. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by formula a is 2ml, 11mmol, 2.5ml, 2.8ml, 11mmol, 4ml, 11mmol, 15ml, 11mmol, 6 ml.

In some embodiments, the molar ratio of the oxidant to the compound of formula a fed is 4. In some embodiments, the molar ratio of the oxidant to the compound of formula a fed is 5. In some embodiments, the molar dosing ratio of the oxidizing agent to the compound of formula a is 4.

In some embodiments, the inert gas comprises at least one of nitrogen, helium, neon, or argon.

In a sixth aspect, the present invention provides a method for preparing a compound of formula D.

A method for preparing a compound of formula D, comprising:

reacting the compound shown as the formula C with the compound shown as the formula H in a solvent in the presence of a catalyst and a condensing agentReacting to obtain a compound shown in a formula D; wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

In some embodiments, the catalyst comprises at least one of 4-dimethylaminopyridine or 4-pyrrolidinylpyridine.

In some embodiments, the condensing agent comprises at least one of DCC (dicyclohexylcarbodiimide), DIC (N, N-diisopropylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), BOP (benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), pyBOP (1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate); DCC (dicyclohexylcarbodiimide) and DIC (N, N-diisopropylcarbodiimide) are preferred.

In some embodiments, the solvent comprises at least one of acetonitrile, dichloromethane, chloroform, or 1, 2-dichloroethane.

In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 40 ℃, preferably from 0 ℃ to 10 ℃.

In some embodiments, the C ₁ -C ₁₀ The alkyl group including C ₁ Alkyl radical, C ₂ Alkyl radical, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl radical, C ₆ Alkyl radical, C ₇ Alkyl radical, C ₈ Alkyl radical, C ₉ Alkyl or C ₁₀ An alkyl group.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl radicals including C ₃ Cycloalkyl radical, C ₄ Cycloalkyl, C ₅ Cycloalkyl radical, C ₆ Cycloalkyl radical, C ₇ Cycloalkyl, C ₈ Cycloalkyl, C ₉ Cycloalkyl, C ₁₀ Cycloalkyl radical, C ₁₁ Cycloalkyl or C ₁₂ A cycloalkyl group.

In some embodiments, the C ₁ -C ₁₀ Alkyl includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl,3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl or n-octyl.

In some embodiments, the aryl group comprises phenyl or tolyl.

In some embodiments, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane. In a sixth aspect, the present invention provides a method for preparing a compound of formula E.

In a seventh aspect, the present invention provides a process for preparing a compound of formula E.

In some embodiments of the invention, a method of making a compound of formula E comprises:

reacting a compound shown as a formula A with a compound shown as a formula F in a solvent in the presence of a catalyst and a compound shown as a formula H to obtain a compound E, wherein,

R ¹ selected from isopropyl or cyclohexyl, represented by formula HThe compound is isobutyric acid or cyclohexyl formic acid.

In some embodiments, the catalyst comprises at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, concentrated hydrochloric acid.

In some embodiments, the solvent in the reaction comprises at least one of dichloromethane, 1, 2-dichloroethane.

In some embodiments, the molar ratio of catalyst to compound of formula a charged in the reaction is from 2.5. In some embodiments, the molar ratio of the catalyst to the compound of formula a fed in the reaction is 3.2.

In some embodiments, the molar ratio of the compound of formula F to the compound of formula a fed to the reaction is from 9.

In some embodiments, the ratio of the charged volume of the compound of formula H to the charged molar amount of the compound of formula a in the reaction is 1ml to 11mmol.

In some embodiments, the reaction temperature in the reaction is from-10 ℃ to 30 ℃. In some embodiments, the reaction temperature in the reaction is from-10 ℃ to 25 ℃. In some embodiments, the reaction temperature in the reaction is from-5 ℃ to 20 ℃. In some embodiments, the reaction temperature in the reaction is from-5 ℃ to 10 ℃. In some embodiments, the reaction temperature in the reaction is from-5 ℃ to 5 ℃.

In an eighth aspect, the present invention provides a process for preparing another compound of formula E.

A method for preparing a compound of formula E, comprising:

in an inert gas atmosphere, the compound shown in the formula D is subjected to debenzylation reaction 1 in dichloromethane in the presence of Lewis acid to obtain a compound E, wherein,

R ¹ selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

carrying out debenzylation reaction 2 on the compound shown in the formula D and the compound shown in the formula F or the compound shown in the formula G in a solvent in the presence of a catalyst and the compound shown in the formula H to obtain a compound shown in the formula E; wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; r ² Selected from chlorine atoms or bromine atoms.

In some embodiments of the invention, a method of preparing a compound of formula E comprises:

in an inert gas atmosphere, carrying out debenzylation reaction 3 on a compound shown as a formula D in a solvent in the presence of an oxidant and a buffer to obtain a compound shown as a formula E; wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

In some embodiments, the lewis acid comprises at least one of boron trichloride or boron tribromide.

In some embodiments, the oxidizing agent comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), ozone.

In some embodiments, the buffer has a pH of 6 to 7.

In some embodiments, the solvent in the debenzylation reaction 1 comprises at least one of dichloromethane, 1, 2-dichloroethane.

In some embodiments, the solvent in the debenzylation reaction 2 comprises at least one of dichloromethane, 1, 2-dichloroethane.

In some embodiments, the solvent in the debenzylation reaction 3 comprises at least one of dichloromethane, 1, 2-dichloroethane, and toluene.

In some embodiments, the charged molar ratio of lewis acid to compound represented by formula D in debenzylation reaction 1 is 2.2.

In some embodiments, the feeding molar ratio of the catalyst to the compound represented by formula D in the debenzylation reaction 2 is 1.2. In some embodiments, the feeding molar ratio of the catalyst to the compound represented by formula D in the debenzylation reaction 2 is 1.5. In some embodiments, the feeding molar ratio of the catalyst to the compound represented by formula D in the debenzylation reaction 2 is 2.0.

In some embodiments, the ratio of the charged volume of the compound of formula H in debenzylation reaction 2 to the charged molar amount of formula D is 1ml to 11mmol. In some embodiments, the ratio of the charged volume of the compound of formula H in debenzylation reaction 2 to the charged molar amount of formula D is 1.2ml to 12ml.

In some embodiments, the debenzylation reaction 2 is conducted in a molar ratio of the compound of formula F or the compound of formula G to the compound of formula D of 5. In some embodiments, the debenzylation reaction 2 is a feed molar ratio of a compound of formula F or a compound of formula G to a compound of formula D of 5.

In some embodiments, the feeding molar ratio of the oxidant to the compound represented by formula D in the debenzylation reaction 3 is 8. In some embodiments, the feeding molar ratio of the oxidant to the compound represented by formula D in the debenzylation reaction 3 is 8, 1, 9, 1, 11. In some embodiments, the feeding molar ratio of the oxidant to the compound represented by formula D in the debenzylation reaction 3 is 10.

In some embodiments, the concentration of the buffer salt in the buffer in the debenzylation reaction 3 is 0.1mol/L to 0.3mol/L.

In some embodiments, the buffer salt comprises at least one of monobasic sodium phosphate and dibasic sodium phosphate.

In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by D in the debenzylation reaction 3 is from 3ml to 18ml. In some embodiments, the ratio of the feed volume of buffer to the feed molar amount of compound represented by D in debenzylation reaction 3 is 3.5ml to 18ml. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by D in the debenzylation reaction 3 is 3.8ml to 18ml. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by D in the debenzylation reaction 3 is 3.8ml. In some embodiments, the ratio of the feed volume of the buffer to the feed molar amount of the compound represented by D in the debenzylation reaction 3 is 3 ml.

In some embodiments, the reaction temperature of the debenzylation reaction 1 is-78 ℃ to-40 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 1 is from-78 ℃ to-45 ℃. In some embodiments, the reaction temperature of debenzylation reaction 1 is from-60 ℃ to-45 ℃.

In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-10 ℃ to 30 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-5 ℃ to 20 ℃. In some embodiments, the debenzylation reaction 2 is carried out at a reaction temperature of-5 ℃ to 10 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-5 ℃ to 5 ℃.

In some embodiments, the reaction temperature of the debenzylation reaction 3 is 40 ℃ to 100 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is from 50 ℃ to 90 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is 60 ℃ to 90 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is 70 ℃ to 85 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is 80 ℃ to 90 ℃.

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl radicals including C ₃ Cycloalkyl radical, C ₄ Cycloalkyl, C ₅ Cycloalkyl radical, C ₆ Cycloalkyl, C ₇ Cycloalkyl radical, C ₈ Cycloalkyl, C ₉ Cycloalkyl radical, C ₁₀ Cycloalkyl radical, C ₁₁ Cycloalkyl or C ₁₂ A cycloalkyl group.

In some embodiments, the aryl group comprises phenyl or tolyl.

In some embodiments, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane. In some embodiments, the halogen atom is selected from a fluorine atom, a chlorine atom, or a bromine atom.

In a ninth aspect the present invention provides a compound.

A compound selected from the following structures:

In some embodiments, the C ₃ -C ₁₂ Cycloalkyl radicals including C ₃ A cycloalkyl group, a,C ₄ Cycloalkyl radical, C ₅ Cycloalkyl radical, C ₆ Cycloalkyl, C ₇ Cycloalkyl radical, C ₈ Cycloalkyl, C ₉ Cycloalkyl, C ₁₀ Cycloalkyl radical, C ₁₁ Cycloalkyl or C ₁₂ A cycloalkyl group.

In some embodiments, the aryl group comprises phenyl or tolyl.

In some embodiments, R ¹ Is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane or cyclodecane. In some embodiments, R ¹ Is methyl, 2-propyl or cyclohexane.

In some embodiments, the compound is selected from the following structures:

advantageous effects

Compared with the prior art, one embodiment of the invention has at least one of the following beneficial effects:

(1) The synthesis of compounds such as ATV006 and ATV014 from the compound formula A has the advantages of few synthesis steps, high total yield, mild reaction conditions, no need of ultralow temperature reaction, convenient operation and suitability for industrial production.

(2) In the preparation method of the compound shown in the formula B, compared with other catalysts, the catalyst provided by the invention is more beneficial to improving the yield and purity of the product, and particularly, concentrated sulfuric acid is preferably used as the catalyst.

(3) Compared with other catalysts, the catalyst provided by the invention is more beneficial to improving the yield of the compound shown in the formula D, and has unexpected technical effects.

(4) Compared with other condensing agents, the condensing agent provided by the invention is more beneficial to improving the yield of the compound shown in the formula D, and has unexpected technical effects.

(5) In the preparation method for preparing the compound shown in the formula E from the compound shown in the formula A, isobutyric acid or cyclohexanecarboxylic acid (the compound shown in the formula H) is adopted, so that the reaction route is shortened, and the operation is simplified. In addition, compared with other acids, the isobutyric acid or the cyclohexyl formic acid (the compound shown in the formula H) is adopted to be beneficial to directly generating the compound shown in the formula E, prevent the generation of mixed anhydride and different esters and be beneficial to subsequent separation and purification.

Description of the terms

Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

in the present invention, the expression "compound I" and "compound represented by formula I" means the same compound.

In the present invention, the expression "5.0eq." means "5.0 equivalent".

The "H" is a hydrogen atom, and the "D" is a deuterium atom. The "halogen atom" represents a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), an iodine atom (I), an astatine atom (At), or a mother of pear atom (Ts).

"ambient temperature" in the present invention refers to ambient temperature, and the temperature is from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to a temperature of from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" refers to 10 ℃, 15 ℃,20 ℃,25 ℃,30 ℃, 35 ℃, 40 ℃, etc.

The "Bn" group represents a benzyl group.

The term "M" denotes mol/L.

An "alkyl" group is a hydrocarbon containing an n-carbon atom, a secondary carbon atom, a tertiary carbon atom, or a ring carbon atom. For example, the alkyl group can have 1 to 10 carbon atoms (i.e., C) ₁ -C ₁₀ Alkyl or C ₁ Alkyl radical, C ₂ Alkyl radical, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl radical, C ₆ Alkyl radical, C ₇ Alkyl radical, C ₈ Alkyl radical, C ₉ Alkyl or C ₁₀ Alkyl), 1 to 8 carbon atoms (i.e., C) ₁ -C ₈ Alkyl) or 1 to 6 carbon atoms (i.e., C) ₁ -C ₆ Alkyl groups). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et-CH) ₂ CH ₃ ) 1-propyl (i-Pr, i-propyl, -CH) ₂ CH ₂ CH ₃ ) 2-propyl (i-Pr, i-propyl, -CH (CH) ₃ ) ₂ ) 1-butyl (n-Bu, n-butyl, -CH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) ₂ CH(CH ₃ ) ₂ ) 2-butyl (s-Bu, s-butyl, -CH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) ₃ ) ₃ ) 1-pentyl (n-pentyl, -CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) 1-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH)) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ And n-octyl (- (CH) ₂ ) ₇ CH ₃ )。

"alkenyl" is intended to include groups having at least one site of unsaturation, i.e., carbon-carbon sp ² A normal carbon atom, a secondary carbon atom, a tertiary carbon atom, or a hydrocarbon of a ring carbon atom of a double bond. For example, the alkenyl group may have 2 to 10 carbon atoms (C) ₂ -C ₁₀ Alkenyl), 2 to 12 carbon atoms (C) ₂ -C ₁₂ Alkenyl) or 2 to 6 carbon atoms (C) ₂ -C ₆ Alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH = CH) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ ) Cyclopentenyl (-C) ₅ H ₇ ) And 5-hexenyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH＝CH ₂ )。

An "alkynyl" group is a carbon atom containing at least one site of unsaturation, i.e., a carbon-carbon sp triple bondA hydrocarbon of a child, secondary carbon atom, tertiary carbon atom or ring carbon atom. For example, the alkynyl group may have 2 to 10 carbon atoms (C) ₂ -C ₁₀ Alkynyl), 2 to 12 carbon atoms (C) ₂ -C ₁₂ Alkynyl) or 2 to 6 carbon atoms (C) ₂ -C ₆ Alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C = CH), propargyl (-CH) ₂ C = CH), and the like.

"aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, the aryl group may have 6 to 20 carbon atoms (e.g., 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms), 6 to 14 carbon atoms, or 6 to 10 carbon atoms (e.g., 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms). Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, and the like.

"arylalkyl" refers to a radical in which a carbon atom (typically terminal or sp) is bonded ³ Carbon atom) is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl, and the like. Arylalkyl groups can include 7 to 20 carbon atoms, for example, the alkyl portion is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

The term "substituted" as used in reference to alkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, and the like is substituted C ₁ -C ₁₀ Alkyl group "," substituted C ₆ -C ₂₀ Aryl group, substituted arylalkyl group, and substituted C ₁ -C ₂₀ Heterocycle "and" substituted carbocyclyl "each mean C wherein one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent ₁ -C ₁₀ Alkyl radical, C ₆ -C ₂₀ Aryl, arylalkyl, C ₁ -C ₂₀ Heterocycle, carbocyclyl. Unless otherwise indicated, when the term "substituted" is used in conjunction with a group having two or more moieties capable of substitution, such as arylalkyl, the substituent may be attached to the aryl moiety, the alkyl moiety, or both.

The term "prodrug" as used herein refers to any compound that, when administered to a biological system, produces a drug, i.e., an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. Prodrugs are thus covalently modified analogs or latent forms of therapeutically active compounds.

As used herein, "heterocycle" or "heterocyclyl" includes by way of example and not limitation those heterocycles described in: paquette, leo a.: principles of Modern Heterocyclic Chemistry (w.a. Benjamin, new York, 1968), in particular chapters 1, 3,4, 6, 7 and 9: the Chemistry of Heterocyclic Compounds, A Series of monograms ^ (John Wiley & Sons, new York,1950 to now), especially volumes 13, 14, 16, 19 and 28 and J.Am.chem.Soc. (1960) 82:5566. in a particular embodiment of the invention, "heterocycle" includes "carbocycle" as defined herein, wherein one or more (e.g. 1,2, 3 or 4) carbon atoms have been replaced by a heteroatom (e.g. O, N or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyl groups include, for example, heterocyclic groups substituted with any of the substituents disclosed herein including carbonyl.

Examples of heterocycles include by way of example and not by way of limitation, pyridyl, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothienyl, thiooxidated tetrahydrothienyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuran, thianaphthyl, indolyl, indolinyl, quinolyl, isoquinolyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolyl, azocine (azocane) yl, triazinyl, 6H-1,2, 5-thiadiazinyl, 2H,6H-1,5, 2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, thioxanthyl, thioxanyl, thioxadinyl, pyrrolyl, pyrrolinyl, pyrazolyl, and imidazolyl, 2-pyrrolidinonyl a phenazinyl group, a 2H-pyrrolyl group, an isothiazolyl group, an isoxazolyl group, a pyrazinyl group, a pyridazinyl group, an indolizinyl group, an isoindolyl group, a 3H-indolyl group, an IH-indazolyl group, a purinyl group, a 4H-quinolizinyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a pteridinyl group, a 4 aH-carbazolyl group, a β -carbolinyl group, a phenanthridinyl group, an acridinyl group, a pyrimidinyl group, a phenanthrolinyl group, a phenazinyl group, a phenothiazinyl group, a furazanyl group, a phenoxazinyl group, an isochroman group, a chromanyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperazinyl group, an indolinyl group, an isoindolinyl group, a quinuclidinyl group, a morpholinyl group, an oxazolidinyl group, a benzotriazolyl group, a benzisoxazolyl group, hydroxyindolizinyl group, oxindolyl group, benzoxazolinyl group, isatinoyl and bis-tetrahydrofuranyl.

"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 "heterocyclyl" including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furyl, thienyl, benzofuryl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazolyl, and the like.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition or one or more symptoms thereof to which the term applies. The term "treatment" as used herein refers to a therapeutic action, such as "treating" is defined immediately above.

The compounds described by formula I may have a chiral center, for example a chiral carbon. The compounds of formula I thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds of the present invention include optical isomers enriched or resolved at any or all of the asymmetric chiral atoms. In other words, the chiral centers analogous to the description are provided as chiral isomers or as racemic mixtures. Mixtures of racemic and diastereomeric isomers, as well as isolated or synthetic individual optical isomers substantially free of their enantiomeric or diastereomeric partners, are within the scope of the invention. Racemic mixtures are separated into their individual, essentially optically pure isomers by well-known techniques, such as, for example, separation of diastereomeric salts with optically active auxiliaries (e.g. acids or bases) followed by conversion back into the optically active substance. In many cases, the desired optical isomer is synthesized by stereospecific reactions starting from the appropriate stereoisomer of the desired starting material.

Whenever a compound described herein is substituted with more than one of the same named group (e.g., "R" or "R") ¹ ") it is to be understood that these groups may be the same or different, i.e., each group is independently selected.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below to further explain the present invention in detail.

The reagents used in the invention are either commercially available or can be prepared by the methods described herein.

Example 1 Synthesis of Compound B01{ ((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis-benzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate }:

reacting (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-carbonitrile (compound represented by formula a) (5.6 g,10mmol, 1.0eq.) was reacted with dichloromethane (28 mL), acetic anhydride (3 eq.), cooled to 0 ℃, a mixed solution of sulfuric acid (1.0 eq.) and dichloromethane (11 mL) was added dropwise, after completion of the addition, the reaction was carried out at 25 ℃ for 6 hours, the reaction mixture was cooled to 0 ℃, purified water (11 mL) was added thereto and stirred for 15 minutes, triethylamine was then added thereto to adjust the reaction solution pH =7, liquid separation was carried out, the organic phase was collected, the organic phase was washed twice with saturated brine (11 mL/time), dried over sodium sulfate, filtered, the filtrate was concentrated, and column separation (dichloromethane: ethyl acetate (V/V) = 100) was carried out to obtain compound B01 (4.2g, 78% yield). Taking a proper amount of the obtained compound B01 to detect a mass spectrum and a hydrogen spectrum, wherein the results are as follows: MS (ESI): 554.3[ M-H] ^- ； ¹ H NMR(400MHz,DMSO-d ⁶ )δ10.99(s,1H),8.38(s,1H),7.41–7.23(m,11H),7.03(d,J＝4.8Hz, 1H),4.97(d,J＝4.9Hz,1H),4.92(d,J＝11.7Hz,1H),4.82(d,J＝11.7Hz,1H),4.63–4.51(m,2H),4.50(dt, J＝5.5,2.7Hz,1H),4.30(dd,J＝12.3,3.3Hz,1H),4.19(dd,J＝12.3,5.1Hz,1H),4.12(dd,J＝6.1,4.9Hz, 1H),2.41(s,3H),1.98(s,3H).

EXAMPLE 2 Synthesis of Compound B01{ ((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bisbenzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate }:

reacting (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-carbonitrile (a compound represented by formula a) (5.6 g,10mmol, 1.0eq.) was reacted with dichloromethane (28 mL), acetic anhydride (5 eq.), cooled to 0 ℃, a mixed solution of sulfuric acid (1.5 eq.) and dichloromethane (11 mL) was added dropwise, after dropwise addition, the reaction was carried out at 25 ℃ for 10 hours, the reaction mixture was cooled to 0 ℃, purified water (11 mL) was added thereto and stirred for 15 minutes, triethylamine was added thereto to adjust the reaction mixture pH =8, liquid separation was carried out, an organic phase was collected, the organic phase was washed twice with saturated brine (11 mL/time), dried over sodium sulfate, filtered, the filtrate was concentrated, and column separation was carried out (dichloromethane: ethyl acetate: dichloromethane: 11 mL)(V/V) =100 to 70) to give compound B01 (4.6g, 84% yield). Taking a proper amount of the obtained compound B01 to detect a mass spectrum and a hydrogen spectrum, wherein the results are as follows: MS (ESI) 554.3[ 2 ], [ M ] -H] ^- ； ¹ H NMR(400MHz,DMSO-d ⁶ )δ10.99(s,1H),8.38(s,1H),7.41–7.23(m,11H), 7.03(d,J＝4.8Hz,1H),4.97(d,J＝4.9Hz,1H),4.92(d,J＝11.7Hz,1H),4.82(d,J＝11.7Hz,1H),4.63– 4.51(m,2H),4.50(dt,J＝5.5,2.7Hz,1H),4.30(dd,J＝12.3,3.3Hz,1H),4.19(dd,J＝12.3,5.1Hz,1H),4.12 (dd,J＝6.1,4.9Hz,1H),2.41(s,3H),1.98(s,3H).

Example 3: synthesis of Compound C { (2R, 3R,4R, 5R) -2- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile) }

Compound B01 (2.2g, 4 mmol) was mixed with methanol (10 mL), saturated aqueous sodium carbonate (5 mL), stirred at 25 ℃ for 1 hour, dichloromethane (10 mL) and saturated brine (5 mL) were added, stirred, subjected to liquid separation, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give Compound C (1.82g, 98% yield).

EXAMPLE 4 Synthesis of Compound D01{ ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bis-benzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate } }

Reacting (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-carbonitrile (16.8g, 30mmol, 1.0eq.) and acetic anhydride (3 eq.) were mixed, cooled to 0 ℃, added dropwise with a mixed solution of sulfuric acid (1.0 eq.) and glacial acetic acid (34 mL), reacted at 25 ℃ for 3 hours, the reaction solution was cooled to 0 ℃, added with dichloromethane (85 mL), purified water (34 mL), stirred for 15 minutes, added with triethylamine to adjust the pH of the reaction solution to =7, subjected to liquid separation, and the organic phase was collected and used as a saturated foodWashed twice with brine (34 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and purified by column separation (dichloromethane: ethyl acetate (V/V) =100 from 0 to 60) to give compound D01 (13.0 g,85% yield). Taking a proper amount of the obtained compound D01 to detect a mass spectrum and a hydrogen spectrum, wherein the result is as follows: 512.2[ m-H ]] ^- ； ¹ H NMR (400MHz,DMSO-d ⁶ )δ8.06–7.79(m,3H),7.54–7.17(m,10H),6.92(d,J＝4.6Hz,1H),6.78(d,1H),4.96 (d,J＝5.0Hz,1H),4.88(d,J＝11.7Hz,1H),4.78(d,J＝11.7Hz,1H),4.64–4.50(m,2H),4.44(td,J＝5.6, 3.3Hz,1H),4.29(dd,J＝12.3,3.4Hz,1H),4.17(dd,J＝12.3,5.3Hz,1H),4.09(t,J＝5.5Hz,1H),1.97(s, 3H).

Example 5: synthesis of Compound D01{ ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis-benzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate } }

Reacting (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-carbonitrile (16.8g, 30mmol, 1.0eq.), acetic anhydride (5 eq.) were mixed, cooled to 0 ℃, a mixed solution of sulfuric acid (1.2 eq.) and glacial acetic acid (34 mL) was added dropwise, reaction was performed at 25 ℃ for 5 hours, the reaction solution was cooled to 0 ℃, dichloromethane (85 mL) was added, purified water (34 mL) was stirred for 15 minutes, triethylamine was further added to adjust the pH =8 of the reaction solution, the organic phase was separated, collected, washed twice with saturated brine (34 mL/time), dried over sodium sulfate, filtered, the filtrate was concentrated, and purified by column separation (dichloromethane: ethyl acetate (V/V) =100 from 0 to 60), to obtain compound D01 (14.1 g,92% yield). Taking a proper amount of the obtained compound D01 to detect a mass spectrum and a hydrogen spectrum, wherein the results are as follows: 512.2[ m-H ]] ^- ； ¹ H NMR(400MHz, DMSO-d ⁶ )δ8.06–7.79(m,3H),7.54–7.17(m,10H),6.92(d,J＝4.6Hz,1H),6.78(d,1H),4.96(d,J＝5.0 Hz,1H),4.88(d,J＝11.7Hz,1H),4.78(d,J＝11.7Hz,1H),4.64–4.50(m,2H),4.44(td,J＝5.6,3.3Hz,1H), 4.29(dd,J＝12.3,3.4Hz,1H),4.17(dd,J＝12.3,5.3Hz,1H),4.09(t,J＝5.5Hz,1H),1.97(s,3H).

EXAMPLE 6 Synthesis of Compound C { (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bis (benzyloxy) -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile) }

Compound D01 (5.1g, 10mmol) was mixed with methanol (15 mL) and a saturated aqueous sodium carbonate solution (10 mL), stirred at 25 ℃ for 1 hour, dichloromethane (20 mL) and a saturated saline solution (10 mL) were added, stirred for 10 minutes, liquid separation was performed, an organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound C (4.5g, 97% yield).

EXAMPLE 7 Synthesis of Compound C { (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile) }

(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-carbonitrile (compound represented by formula A) (5.6 g,10mmol, 1.0eq.) was mixed with 1, 2-dichloromethane (28 mL) under a nitrogen atmosphere, 0.1M phosphoric acid buffer (pH = 7.0) (28 mL) was added, and 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) (11.4g, 50mmol, 5eq.) was further added and heated at 80 ℃ under reflux for 8 hours. The reaction solution was cooled to 0 ℃, a saturated sodium bicarbonate solution was added, pH was adjusted to 6-7, dichloromethane (28 mL) was extracted twice, the organic phase was washed with saturated brine, the organic phase was dried over sodium sulfate, and column separation (dichloromethane: ethyl acetate (V/V) =100 from 0 to 50) was performed to purify compound C (3.2g, 68% yield).

Example 8: compound D02 (((2r, 3r,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methylcyclohexanecarboxylate) synthesis:

acetonitrile solutions (60 mL) containing compound C (11.8g, 25mmol, 1.0eq), DMAP (4-dimethylaminopyridine) (0.5 eq.), cyclohexanecarboxylic acid H01 (1.2 eq.), DIC (N, N-diisopropylcarbodiimide) (1.25 eq.) were mixed, stirred at 5 ± 5 ℃ for 24 hours, the reaction was completed, concentrated, and column-separated (dichloromethane: EA (V/V) =100, 0 to 50) to obtain compound D02 (13g, 90% yield. Taking a proper amount of the obtained compound D02 to detect a mass spectrum and a hydrogen spectrum, wherein the results are as follows: MS (ESI) 582.4[ m ] +H] ⁺ ； ¹ H NMR(400MHz,DMSO-d ⁶ )δ8.05– 7.84(m,3H),7.42–7.24(m,10H),6.92(d,J＝4.6Hz,1H),6.76(d,J＝4.5Hz,1H),4.96(d,J＝4.9Hz,1H), 4.90(d,J＝11.7Hz,1H),4.81(d,J＝11.7Hz,1H),4.59(d,J＝11.9Hz,1H),4.50(d,J＝11.9Hz,1H),4.45(dt, J＝6.4,3.9Hz,1H),4.28(dd,J＝12.4,3.3Hz,1H),4.17(dd,J＝12.4,4.4Hz,1H),4.08(dd,J＝6.4,4.9Hz, 1H),2.18(ddd,J＝14.2,9.5,3.4Hz,1H),1.74–1.50(m,5H),1.26–1.15(m,5H).

Example 9: compound D03 (((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methyl isobutyrate) synthesis:

an acetonitrile solution (60 mL) containing compound C (11.8g, 25mmol, 1.0eq.), DMAP (4-dimethylaminopyridine) (0.5 eq.), isobutyric acid H02 (1.2 eq.), DIC (N, N-diisopropylcarbodiimide) (1.25 eq.) was mixed, stirred at 5 ± 5 ℃ for 24 hours, the reaction was completed, concentrated, and column-separated (dichloromethane: EA (V/V) =100 to 50). Taking a proper amount of the obtained compound D03 to detect a mass spectrum and a hydrogen spectrum, wherein the results are as follows: MS (ESI) 540.2[ 2 ], [ M ] -H] ^- ； ¹ H NMR(400MHz,Chloroform-d)δ 7.93(s,1H),7.36–7.19(m,10H),6.96(d,J＝4.6Hz,1H),6.65(d,J＝4.6Hz,1H),5.89(s,2H),4.99–4.90 (m,2H),4.83(d,J＝12.1Hz,1H),4.63(ddd,J＝6.8,5.0,3.6Hz,1H),4.54(d,J＝11.9Hz,1H),4.43–4.26(m, 3H),3.93(dd,J＝6.8,5.1Hz,1H),2.52(dt,J＝14.0,7.0Hz,1H),1.17(d,J＝6.5Hz,3H),1.12(d,J＝6.5Hz, 3H).

Example 10: preparation of Compound E01 (method one)

Under nitrogen atmosphere, compound D02 (10mmol, 5.8g, 1.0eq.) was mixed with dichloromethane (30 mL), cooled to-78 ℃, added with a 1M dichloromethane solution of boron trichloride (22ml, 2.2eq.), -the reaction was completed at 50 ℃, added with methanol (12 mL), then added with a methanol (12 mL) solution of triethylamine (4.6 eq.), quenched, warmed to room temperature, concentrated under reduced pressure, washed with n-hexane (12 mL) for 3 times, then added with dichloromethane (12 mL), water (30 mL), stirred, left to stand, separated, collected as an organic phase layer, extracted twice with dichloromethane (12 mL) as an aqueous phase layer, combined with the organic phase layers, washed with pure water (12 mL), dried over sodium sulfate, filtered, concentrated the filtrate, and purified by column separation (dichloromethane: methanol (V/V) = 40).

Example 11: preparation of Compound E01 (method two)

Mixing a compound D02 (10mmol, 5.8g, 1.0eq.) and acetic anhydride (5 eq.) and cooling to 0 ℃, dropwise adding a mixed solution of sulfuric acid (2 eq.) and glacial acetic acid (12 mL), reacting at 25 ℃ until the raw materials are completely consumed, concentrating under reduced pressure, cooling a concentrated solution to 0 ℃, adding dichloromethane (30 mL), stirring for 15min, adding triethylamine to adjust the pH of the reaction solution to =7, separating, extracting an aqueous phase twice by dichloromethane (30 mL), collecting an organic phase, washing the organic phase twice by saturated saline (18 mL/time), drying the organic phase by sodium sulfate, filtering, concentrating a filtrate, and performing column separation (dichloromethane: methanol (V/V = 40): 1) to obtain a compound E01 (3.7g, 92% yield).

Example 12: preparation of Compound E01 (method III)

Under a nitrogen atmosphere, compound D02 (10mmol, 5.8g, 1.0eq.), 1, 2-dichloroethane (42 mL) were mixed, and 0.1M phosphoric acid buffer (pH = 7.0) (42 mL) was added, and finally 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) (10 eq.) was added, and heated at 80 ℃ for reflux for 6 hours. The reaction solution was cooled to 0 ℃, a saturated sodium bicarbonate solution was added, pH was adjusted =6, dichloromethane (30 mL) was extracted twice, the organic phase was washed with saturated brine, the organic phase was dried over sodium sulfate, and column separation (dichloromethane: methanol (V/V) = 40) was performed to purify the compound E01 (2.5g, 62% yield).

Example 13: preparation of Compound E01 (method IV)

Mixing a compound A (10mmol, 5.8g, 1.0eq.) and cyclohexyl formic anhydride (5 eq.) and cooling to 0 ℃, dropwise adding a mixed solution of sulfuric acid (1.2 eq.) and cyclohexyl formic acid (12 mL) and reacting at 25 ℃ until the raw materials are completely consumed to mainly obtain a compound D02; continuously adding cyclohexylmethyl anhydride (8 eq.), cooling to 0 ℃, dropwise adding sulfuric acid (2.0 eq.), reacting at 25 ℃ until D02 is completely consumed, concentrating under reduced pressure, cooling the concentrated solution to 0 ℃, adding dichloromethane (30 mL), stirring with purified water (18 mL) for 15min, adding triethylamine to adjust the pH of the reaction solution =7, separating, extracting the aqueous phase twice with dichloromethane (30 mL), collecting the organic phase, washing the organic phase twice with saturated brine (18 mL/time), drying the organic phase with sodium sulfate, filtering, concentrating the filtrate, and purifying by column separation (dichloromethane: methanol (V/V) = 40).

Example 14: preparation of Compound E02 (method one)

Under a nitrogen atmosphere, compound D03 (10mmol, 5.4g, 1.0eq.) was mixed with dichloromethane (27 mL), cooled to-78 ℃, 1M dichloromethane solution of boron trichloride (22ml, 2.2eq.) was added, the reaction was completed at-50 ℃, methanol (11 mL) was added, a methanol (11 mL) solution of triethylamine (4.6 eq.) was added to quench the reaction, the temperature was raised to room temperature, the mixture was concentrated under reduced pressure, n-hexane (11 mL) was added and washed 3 times, dichloromethane (11 mL) was added, purified water (30 mL) was added, the mixture was stirred, allowed to stand, separated, an organic phase layer was collected, a dichloromethane (11 mL) was added to the aqueous phase layer and extracted twice, the organic phase layers were combined, washed with pure water (11 mL), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and purified by column separation (dichloromethane: methanol (V/V) =40 1), to obtain compound E (2.3g, 65% yield).

Example 15: preparation of Compound E02 (method two)

Mixing compound D03 (10mmol, 5.4g, 1.0eq.) and acetic anhydride (5 eq.) and cooling to 0 ℃, dropwise adding a mixed solution of sulfuric acid (2 eq.) and glacial acetic acid (11 mL), reacting at 25 ℃ until the raw materials are completely consumed, concentrating under reduced pressure, cooling the concentrated solution to 0 ℃, adding dichloromethane (11 mL), stirring for 15min with purified water (30 mL), adding triethylamine to adjust the pH =7 of the reaction solution, separating, extracting the aqueous phase twice with dichloromethane (27 mL), collecting the organic phase, washing the organic phase twice with saturated brine (16 mL/time), drying the organic phase with sodium sulfate, filtering, concentrating the filtrate, and purifying by column separation (dichloromethane: methanol (V/V) = 40) to obtain compound E02 (3.2g, 88% yield).

Example 16: preparation of Compound E02 (method III)

Under a nitrogen atmosphere, compound D03 (10mmol, 5.4g, 1.0eq.), 1, 2-dichloroethane (38 mL) were mixed, and a 0.1M phosphoric acid buffer (pH = 7.0) (38 mL) was added, followed by addition of 2, 3-dichloro-5, 6-dicyanoquinone (DDQ) (10 eq.) at 80 ℃ and heating and refluxing for 6 hours. The reaction solution was cooled to 0 ℃, a saturated sodium bicarbonate solution was added, pH was adjusted to =6, dichloromethane (27 mL) was extracted twice, the organic phase was washed with saturated brine, the organic phase was dried over sodium sulfate, and column separation (dichloromethane: methanol (V/V) = 40) was performed to purify to obtain compound E02 (1.8g, 50% yield).

Example 17: preparation of Compound E02 (method IV)

Mixing compound A (10mmol, 5.6g, 1.0eq.) and isobutyric anhydride (5 eq.), cooling to 0 ℃, dropwise adding a mixed solution of sulfuric acid (1.2 eq.) and isobutyric acid (11 mL), and reacting at 25 ℃ until the raw materials are completely consumed to mainly obtain compound D03; continuing to supplement isobutyric anhydride (8 eq.), cooling to 0 ℃, dropwise adding sulfuric acid (2.0 eq.), reacting at 25 ℃ until D03 is completely consumed, concentrating under reduced pressure, cooling the concentrated solution to 0 ℃, adding dichloromethane (28 mL), stirring with purified water (17 mL) for 15min, adding triethylamine to adjust the pH of the reaction solution to =7, separating, extracting the aqueous phase twice with dichloromethane (28 mL), collecting the organic phase, washing the organic phase twice with saturated saline (17 mL/time), drying the organic phase with sodium sulfate, filtering, concentrating the filtrate, and purifying by column separation (dichloromethane: methanol (V/V) = 40) to obtain a compound E02 (2.6g, 73% yield).

Comparative example 1: synthesis of Compound B01{ ((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bisbenzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate }:

(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-carbonitrile (compound represented by formula a) (5.6 g,10mmol, 1.0eq.) was reacted with dichloromethane (28 mL), acetic anhydride (3 eq.), cooled to 0 ℃, a mixed solution of trifluoroacetic acid (1.0 eq.) and dichloromethane (11 mL) was added dropwise, reacted at 25 ℃ for 6 hours after completion of dropping, the reaction was cooled to 0 ℃, purified water (11 mL) was added and stirred for 15 minutes, triethylamine was adjusted to pH =7, the organic phase was separated, washed twice with saturated brine (11 mL 4jv), the organic phase was dried over sodium sulfate, filtered, concentrated, and column-separated (dichloromethane: ethyl acetate (V/V) = 100), and purified from 0 to 70 g, B (0.01% yield).

Comparative example 2 Synthesis of Compound D01{ ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis-benzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate } } (reaction without glacial acetic acid)

(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-carbonitrile (16.8g, 30mmol, 1.0eq.), acetic anhydride (3 eq.), cooled to 0 ℃, a mixed solution of sulfuric acid (1.0 eq.) was added dropwise, reacted at 25 ℃ for 3 hours, the reaction liquid was cooled to 0 ℃, dichloromethane (85 mL) was added, purified water (34 mL) was stirred for 15 minutes, triethylamine was added to adjust the reaction liquid pH =7, the organic phase was separated, collected, washed twice with saturated brine (34 mL/time), dried over sodium sulfate, filtered, the filtrate was concentrated, and column-separated (dichloromethane: ethyl acetate (V/V) =100 0 to 60) to obtain compound D01 (6.5g, 42% yield.

Example 18: compound D02 (((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methylcyclohexanecarboxylate) synthesis (investigation of condensing agents):

an acetonitrile solution (60 mL) containing compound C (11.8g, 25mmol, 1.0eq), DMAP (4-dimethylaminopyridine) (0.5 eq.), cyclohexanecarboxylic acid H01 (1.2 eq.), a condensing agent (1.25 eq.) shown in table 1 was mixed, stirred at 5 ± 5 ℃ for 24 hours, the reaction was completed, concentrated, and column-separated (dichloromethane: EA (V/V) =100 to 50) to purify to obtain compound D02, the results of which are shown in table 1.

Table 1: examination of condensing agent in Synthesis of Compound D02

Condensing agent	Compound D02 yield
		DCC (dicyclohexylcarbodiimide)	72％
DIC (N, N-diisopropylcarbodiimide)	90％
		EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride)	67％

Example 19: compound D02 (((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methylcyclohexanecarboxylate) synthesis (investigation of catalyst):

an acetonitrile solution (85 mL) containing compound C (11.8g, 25mmol, 1.0eq), a catalyst (0.5 eq.) shown in table 2, cyclohexanecarboxylic acid H01 (1.2 eq.), and DIC (N, N-diisopropylcarbodiimide) (1.25 eq.) was mixed, stirred at 5 ± 5 ℃ for 24 hours, the reaction was terminated, concentrated, and column-separated (dichloromethane: EA (V/V) =100 to 50) to obtain compound D02, the results of which are shown in table 2.

Table 2: examination of condensing agent in Synthesis of Compound D02

Catalyst and process for preparing same	Compound D02 yield
		DMAP (4-dimethylaminopyridine)	90％
Pyridine compound	53％
		4-pyrrolidinyl-pyridines	78％

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A method for preparing a compound of formula B, comprising:

2. The production method according to claim 1, wherein the catalyst is at least one selected from the group consisting of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, and concentrated hydrochloric acid; and/or

The solvent comprises at least one of dichloromethane and 1, 2-dichloroethane; and/or

The feeding molar ratio of the catalyst to the compound shown in the formula A is 0.1-2.0, and preferably 1.0; and/or;

and/or

The feeding molar ratio of the compound shown in the formula F to the compound shown in the formula A is 3; and/or

The reaction temperature of the reaction is-10 ℃ to 30 ℃; and/or

The reaction time of the reaction is 3 to 10 hours.

3. A method for preparing a compound of formula C, comprising:

reacting the compound shown in the formula B with alkali in a solvent to obtain a compound shown in a formula C; wherein the compound represented by the formula B is prepared by the preparation method according to any one of claims 1 to 2.

4. A method for preparing a compound of formula D, comprising:

R ² at least one selected from chlorine and bromine atoms.

5. The production method according to claim 4, wherein the catalyst is at least one selected from the group consisting of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, and concentrated hydrochloric acid; and/or

The feeding molar ratio of the catalyst to the compound shown in the formula A is 0.1-2.0, and preferably 1.0; and/or

The ratio of the charging volume of the compound shown in the formula H to the charging molar weight of the compound shown in the formula A is 1ml to 12mL; and/or

The feeding molar ratio of the compound shown in the formula F or the compound shown in the formula G to the compound shown in the formula A is 3; and/or

The reaction temperature of the reaction is-10 ℃ to 25 ℃; and/or

The reaction time of the reaction is 2 to 8 hours.

6. A method for preparing a compound of formula C, comprising:

reacting the compound shown in the formula D with alkali in a solvent to obtain a compound shown in a formula C; wherein the compound shown in the formula D is prepared according to the preparation method of any one of claims 4 to 5.

7. The production method according to claim 3 or 6, wherein the base comprises at least one of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, and tripotassium phosphate; preferably sodium carbonate; and/or

The solvent comprises at least one of tetrahydrofuran, methanol, ethanol and isopropanol, and is preferably methanol or ethanol; and/or

The reaction temperature of the reaction is 0-30 ℃.

8. A process for the preparation of a compound of formula C comprising

And in an inert gas atmosphere, reacting the compound shown in the formula A in a solvent in the presence of an oxidant and a buffer to obtain the compound shown in the formula C.

9. The method of claim 8, wherein the oxidizing agent comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or ozone; and/or

The solvent comprises at least one of dichloromethane, 1, 2-dichloroethane and toluene; and/or

The reaction temperature of the reaction is 40-100 ℃; and/or

The buffer solution comprises at least one of phosphate buffer solution and acetic acid buffer solution; and/or

The pH value of the buffer solution is 6-7; and/or

The concentration of the buffer salt in the buffer solution is 0.1 mol/L-0.3 mol/L and/or

The buffer salt comprises at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate or at least one of sodium acetate and ammonium acetate; and/or

The ratio of the charging volume of the buffer solution to the charging molar weight of the compound shown in the formula A is 2ml-18ml; and/or

The feeding molar ratio of the oxidant to the compound shown in the formula A is 4.

10. A process for the preparation of a compound of formula D comprising

Reacting the compound shown in the formula C with the compound shown in the formula H in a solvent in the presence of a catalyst and a condensing agent to obtain a compound shown in the formula D; wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

11. The method of claim 10, the catalyst comprising at least one of 4-dimethylaminopyridine or 4-pyrrolidinylpyridine; and/or

The condensing agent comprises at least one of DCC (dicyclohexylcarbodiimide), DIC (N, N-diisopropylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate); preferably DCC (dicyclohexylcarbodiimide), DIC (N, N-diisopropylcarbodiimide); and/or

The solvent comprises at least one of acetonitrile, dichloromethane, chloroform or 1, 2-dichloroethane; and/or

The reaction temperature of the reaction is-5 ℃ to 40 ℃, and preferably 0 ℃ to 10 ℃.

12. A method for preparing a compound of formula E, comprising:

reacting the compound shown in the formula A with the compound shown in the formula F in a solvent in the presence of a catalyst and the compound shown in the formula H to obtain a compound E, wherein,

R ¹ is selected from isopropyl or cyclohexyl, and the compound shown in the formula H is isobutyric acid or cyclohexyl formic acid.

13. The production method according to claim 12, wherein the catalyst comprises at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, and concentrated hydrochloric acid;

the solvent in the reaction comprises at least one of dichloromethane and 1, 2-dichloroethane; and/or

The feeding molar ratio of the catalyst to the compound shown in the formula A in the reaction is (2.5); and/or

The feeding molar ratio of the compound shown in the formula F to the compound shown in the formula A in the reaction is 9-15; and/or

The ratio of the feeding volume of the compound shown in the formula H to the feeding molar quantity of the compound shown in the formula A in the reaction is 1ml to 1mmol; and/or

The reaction temperature in the reaction is-10 ℃ to 30 ℃.

14. A method for preparing a compound of formula E, comprising:

R ¹ selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or alternatively

Carrying out debenzylation reaction 2 on the compound shown in the formula D and the compound shown in the formula F or the compound shown in the formula G in a solvent in the presence of a catalyst and the compound shown in the formula H to obtain a compound shown in the formula E; wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; r ² Selected from chlorine atom or bromine atom;

or alternatively

In an inert gas atmosphere, carrying out debenzylation reaction 3 on the compound shown in the formula D in a solvent in the presence of an oxidant and a buffer to obtain a compound shown in the formula E; wherein R is ¹ Selected from substituted or unsubstituted C ₁ -C ₁₀ Alkyl, substituted or unsubstituted C ₃ -C ₁₂ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

15. The preparation process of claim 14, the lewis acid comprising at least one of boron trichloride or boron tribromide; and/or

The catalyst comprises at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid and concentrated hydrochloric acid; and/or

The oxidant comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) and ozone; and/or

The pH value of the buffer solution is 6-7; and/or

The solvent in the debenzylation reaction 1 comprises at least one of dichloromethane and 1, 2-dichloroethane; and/or

The solvent in the debenzylation reaction 2 comprises at least one of dichloromethane and 1, 2-dichloroethane; and/or

The solvent in the debenzylation reaction 3 comprises at least one of dichloromethane, 1, 2-dichloroethane and toluene; and/or

The feeding molar ratio of the Lewis acid to the compound shown in the formula D in the debenzylation reaction 1 is (2.2); and/or

The feeding molar ratio of the catalyst to the compound shown in the formula D in the debenzylation reaction 2 is 1.2; and/or

The ratio of the feeding volume of the compound shown in the formula H in the debenzylation reaction 2 to the feeding molar weight of the compound shown in the formula D is 1ml to 2ml; and/or

The feeding molar ratio of the compound shown in the formula F or the compound shown in the formula G to the compound shown in the formula D in the debenzylation reaction 2 is 5; and/or

The feeding molar ratio of the oxidant to the compound shown in the formula D in the debenzylation reaction 3 is 8

The concentration of buffer salt in the buffer solution in the debenzylation reaction 3 is 0.1-0.3 mol/L and/or

The ratio of the feeding volume of the buffer solution in the debenzylation reaction 3 to the feeding molar weight of the compound shown in D is 3 ml-18ml; and/or

The reaction temperature of the debenzylation reaction 1 is-78 ℃ to-40 ℃; and/or

The reaction temperature of the debenzylation reaction 2 is-10 ℃ to 30 ℃; and/or

The reaction temperature of the debenzylation reaction 3 is 40-100 ℃.

16. The method according to any one of claims 1 to 15, wherein C is ₁ -C ₁₀ The alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl or n-octyl; and/or

Said C is ₃ -C ₁₂ Cycloalkyl includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane; and/or

The aryl group comprises phenyl or tolyl; and/or

The halogen atom is selected from fluorine atom, chlorine atom or bromine atom.

17. A compound selected from the following structures:

18. The compound of claim 17, said C ₁ -C ₁₀ The alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl or n-octyl; and/or

Said C is ₃ -C ₁₂ Cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane; and/or

The aryl group includes phenyl or tolyl.

19. The compound according to any one of claims 17-18, selected from the structures: