Preparation method of ribonucleoside

A ribonucleoside formula and reagent technology, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve problems such as being unsuitable for large-scale industrial preparation, complicated post-processing processes, and long reaction steps, etc. Achieve the effect of low cost, few steps and good product quality

Pending Publication Date: 2021-11-12
SHANGHAI SYNCORES TECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The technical problem to be solved by the present invention is to overcome the defects of long reaction steps, low reaction yield, high preparation cost, complicated post-treatment process and unsuitability for industrial large-scale preparation in the existing preparation method of formula (I), And provide a kind of preparation method of one step direct synthesis formula (I) by formula (II)

Method used

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  • Preparation method of ribonucleoside
  • Preparation method of ribonucleoside
  • Preparation method of ribonucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]

[0036] Under nitrogen protection, 4-aminopyrrolo[2,1-f][1,2,4]triazine (5g), TMSCl (8.1g) and THF (150mL) were added to the three-necked flask, and the mixture was stirred at 25°C After 1 hour, the temperature was lowered to -20°C, and iPrMgCl (57 mL, 1.3M in THF solution) was slowly added dropwise, keeping the internal temperature ≤ -15°C during the dropwise addition, stirred for 1 hour after the dropwise addition, and cooled to -75°C. Slowly add LDA (18.7 mL, 2.0 M in tetrahydrofuran / n-hexane solution), keep the internal temperature ≤ -70°C during the dropwise addition, stir for 1 hour after the dropwise addition, and cool down to -70°C. Slowly add a solution of sugar lactone (Formula III) (20.3 g) in THF (25 mL) dropwise, keep the internal temperature ≤ -65°C during the dropwise addition, and stir for 1 hour after the dropwise addition is completed. After the reaction was complete, it was quenched with AcOH, washed with water, concentrated, and finally purified ...

Embodiment 2

[0038]

[0039] Under nitrogen protection, 4-aminopyrrolo[2,1-f][1,2,4]triazine (10g), TMSCl (12.5g) and Me-THF (300mL) were added to the three-necked flask, and the mixture was heated to reflux Stir for 1 hour, then cool down to -80°C, slowly add n-BuLi (60mL, 2.5M in n-hexane solution) dropwise, keep the internal temperature ≤ -75°C during the dropwise addition, stir for 10 minutes after the dropwise addition, and cool down to - 80°C. Slowly add BMDA (40mL, 2M solution in n-hexane), keep the internal temperature ≤ -75°C during the dropwise addition, stir for 1 hour after the dropwise addition, and slowly add the THF (50mL) solution of sugar lactone (Formula III) (31g) dropwise , Keep the internal temperature ≤ -65°C during the dropwise addition, keep stirring for 1 hour after the dropwise addition is completed. After the reaction was complete, it was quenched with AcOH, washed with water, concentrated, and finally purified by silica gel column to obtain the final product...

Embodiment 3

[0041]

[0042] Under nitrogen protection, 4-aminopyrrolo[2,1-f][1,2,4]triazine (50g), TMSCl (81g) and THF (1200mL) were added to the three-necked flask, and the mixture was heated to reflux and stirred for 1 hour , then lower the temperature to -75°C, slowly add n-BuLi (300mL, 2.5M in n-hexane solution) dropwise, keep the internal temperature ≤ -70°C during the dropwise addition, stir for 10 minutes after the dropwise addition, and cool down to -75°C. Slowly add LDA (190 mL, 2.0 M in tetrahydrofuran / n-hexane solution), keep the internal temperature ≤ -70°C during the dropwise addition, stir for 1 hour after the dropwise addition, and cool down to -70°C. Slowly add a THF (250 mL) solution of sugar lactone (Formula III) (170 g) dropwise, keep the internal temperature ≤ -65°C during the dropwise addition, and stir for 1 hour after the dropwise addition is complete. After the reaction was complete, it was quenched with AcOH, washed with water, concentrated, and finally recryst...

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Abstract

The invention provides a method for preparing ribonucleoside of a formula I, which comprises the following steps: forming a reaction mixture containing a deprotonation reagent, a coupling agent, a silylation reagent, a compound of a formula II and a compound of a formula III under conditions suitable for preparing the formula I, wherein a hydroxyl protecting group PG is an independent hydroxyl protecting group. According to the technical scheme provided by the invention, the defects of long reaction steps, low reaction yield, high preparation cost, complex post-treatment process and unsuitability for industrial large-scale preparation in the existing preparation method of the formula (I) are overcome, and a preparation method for directly synthesizing the formula (I) from the formula (II) in one step is provided. The method has few steps, high yield, simple and convenient operation and low cost, and the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a key intermediate of antiviral drugs. [0002] technical background [0003] Remdesivir is a nucleoside antiviral drug discovered by Gilead, which can potentially be used as a broad-spectrum anti-coronavirus drug. Remdesivir and key intermediates for preparing antiviral drugs (such as Remdesivir), the structural formula is as follows: [0004] [0005] According to the report of Gilead patent document WO2012012776A1, the synthesis of the key intermediate formula (I) is the key technical difficulty of the whole Remdesivir synthesis route. The synthetic route is as shown in the following formula: [0006] [0007] Formula (II) is brominated by NBS to obtain formula (IV), and then coupled with formula (III) at low temperature under the action of butyllithium as a coupling agent to obtain intermediate formula (I). [0008] Sinc...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07H15/18C07H23/00C07H1/00
CPCC07H15/18C07H23/00C07H1/00Y02P20/55
Inventor张一凯陶安平黄鲁宁郭效文常连举余文龙安建国顾虹
OwnerSHANGHAI SYNCORES TECH INC