Method for synthesizing C-nucleoside compound

Patent metadata

Field	Value
Publication number	US-12583879-B2
Application number	US-202118016172-A
Country	US
Kind code	B2
Filing date	Jul 15, 2021
Priority date	Jul 17, 2020
Publication date	Mar 24, 2026
Grant date	Mar 24, 2026

Abstract

Disclosed is a method for preparing a C-nucleoside compound represented by Formula (III) or salt thereof. The present method has a high reaction yield, is simple to operate, uses a single metal reagent, has stable reaction temperature conditions, does not require frequent changes to the reaction system during the operation process, is suitable for scale-up synthesis, is suitable for large-scale production of Remdesivir, and has low costs.

First claim

What is claimed is:

1 . A method for preparing a C-nucleoside compound represented by Formula III or salt thereof, comprising:
a) providing a compound represented by Formula II; b) in a solvent, in the presence of a secondary amine represented by Formula 4, a metal lithium reagent and 1,2-bis(chlorodimethylsilyl) ethane, allowing a compound represented by Formula 1 to react with the compound represented by Formula II to generate the C-nucleoside compound represented by Formula III,

in the compound represented by Formula 1, X is halogen;
in the secondary amine represented by Formula 4, each R is independently isopropyl, isobutyl or cyclohexyl, or two Rs together with the nitrogen atom to which they are attached form a 2,2,6,6-tetramethylpiperidine;
in the compound represented by Formula II or Formula III, R a , R b and R c are each benzyl;
in the compound represented by the Formula III, “ ” indicates that the bond is in the α configuration or the β configuration, or a mixture thereof in any ratio.

2 . The method for preparing the C-nucleoside compound according to claim 1 , wherein X is bromine or iodine.

3 . The method for preparing the C-nucleoside compound according to claim 2 , wherein X is bromine.

4 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the solvent is an organic solvent.

5 . The method for preparing the C-nucleoside compound according to claim 4 , wherein the solvent is tetrahydrofuran.

6 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the metal lithium reagent is methyllithium, n-butyllithium, tert-butyllithium, lithium diisopropylamide, or lithium bis(trimethylsilyl)amide.

7 . The method for preparing the C-nucleoside compound according to claim 6 , wherein the metal lithium reagent is n-butyllithium.

8 . The method for preparing the C-nucleoside compound according to claim 1 , wherein step b) comprises:
b1) dissolving the compound represented by Formula 1 and 1,2-bis(chlorodimethylsilyl) ethane in the solvent, and adding the secondary amine represented by Formula 4 to obtain a mixture; b2) sequentially adding the metal lithium reagent and the compound represented by Formula II to the mixture obtained in b1), and allowing the compound represented by Formula 1 to react with the compound represented by Formula II to obtain the compound represented by Formula III.

9 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the compound represented by Formula 1 is reacted with the compound represented by Formula II, and the initial concentration of the compound represented by Formula 1 is 0.06 to 0.3 mol/L.

10 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the compound represented by Formula 1 is reacted with the compound represented by Formula II at a temperature of 0° C. to −80° C.

11 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the feeding molar ratio of the compound represented by Formula 1 to the compound represented by Formula II is 1:1.5˜3.

12 . The method for preparing the C-nucleoside compound according to claim 1 , wherein step b) is carried out under anhydrous and anaerobic conditions.

13 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the reaction between the compound represented by Formula 1 and the compound represented by Formula II comprises:
under the action of the secondary amine represented by Formula 4 and the metal lithium reagent, allowing the 4-position amino group in the compound represented by Formula 1 to undergo a bis-silicon protection by using 1,2-bis(chlorodimethylsilyl) ethane to generate a compound represented by the intermediate Formula 5;

under the action of the secondary amine represented by Formula 4 and the metal lithium reagent, the compound represented by Formula 5 undergoing a lithium-halogen exchange to generate a compound represented by the intermediate Formula 6, wherein M is Li;
the compound represented by the Formula 6 undergoing an addition reaction with the compound represented by the Formula II to generate the C-nucleoside compound represented by the Formula III.

14 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the secondary amine represented by Formula 4 is diisopropylamine, diisobutylamine, dicyclohexylamine, or 2,2,6,6-tetramethylpiperidine.

15 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the feeding molar ratio of the compound represented by Formula 1 to the lithium metal reagent is 1:3.5˜4.5.

16 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the feeding molar ratio of the compound represented by Formula 1 to 1,2-bis(chlorodimethylsilyl) ethane is 1:1˜1.5.

17 . The method for preparing the C-nucleoside compound according to claim 1 , wherein the feeding molar ratio of the compound represented by Formula 1 to the secondary amine represented by Formula 4 is 1:1˜1.5.

18 . A method for preparing a C-nucleoside compound, comprising:
1) In a solvent, under the action of a secondary amine represented by Formula 4 and a metal lithium reagent, allowing the 4-position amino group in the compound represented by Formula 1 to undergo a bis-silicon protection by using 1,2-bis(chlorodimethylsilyl) ethane to generate a compound represented by the intermediate Formula 5;

2) Under the action of the secondary amine represented by Formula 4 and the metal lithium reagent, the compound represented by Formula 5 undergoing lithium-halogen exchange to generate a compound represented by the intermediate Formula 6, wherein M is Li;
3) the compound represented by Formula 6 undergoing an addition reaction with a compound represented by Formula II to generate a C-nucleoside compound represented by Formula III,
wherein, in the compound represented by Formula 1, X is halogen;
in the secondary amine represented by Formula 4, each R is independently isopropyl, isobutyl or cyclohexyl, or two Rs together with the nitrogen atom to which they are attached form a 2,2,6,6-tetramethylpiperidine;
in the compound represented by Formula II or Formula III, R a , R b and R c are each benzyl;
in the compound represented by the Formula III, “ ” indicates that the bond is in the α configuration or the β configuration, or a mixture thereof in any ratio.

Assignees

• Univ Sichuan
• Acad Of Military Medical Sciences
• Chengdu Aupone Pharmaceutical Co Ltd

Inventors

• Qin Yong
• Zhong Wu
• Xue Fei
• Liu Xiaoyu
• Wang Yu
• Zhou Xiaohan
• Liu Bo
• Wang Ke
• Yang Likai
• Zhou Ruijie
• Xiao Yaxin
• Xue Fanglin
• Zhang Minjie
• Song Hao
• Zheng Zhibing
• Li Song

Classifications

• C07F7/10

  containing nitrogen {having a Si-N linkage} · CPC title

• C07H15/18 Primary

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H1/00 Primary

  Processes for the preparation of sugar derivatives · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07H15/04

  attached to an oxygen atom of the saccharide radical · CPC title