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Purification method of ridecevir intermediate

A purification method, the technology of remdesivir, applied in the field of drug synthesis, to achieve the effect of high product purity, good stability and high yield

Pending Publication Date: 2022-07-01
SHANGHAI SYNCORES TECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The starting materials of this route are relatively conventional. The biggest advantage of this route is that the chirality of intermediates and API is controlled by crystallization, and no chiral preparation and separation are required. However, it is currently reported that only laboratory scale is achieved, and the intermediates of the main route are Is the reaction requires low temperature and requires column chromatography separation

Method used

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  • Purification method of ridecevir intermediate
  • Purification method of ridecevir intermediate
  • Purification method of ridecevir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Prepare the organic phase concentrate of formula I after reaction treatment or directly use the crude product solution of formula I:

[0039] Under nitrogen protection, 50 g of bromopyrazole was dissolved in 1000 ml of anhydrous THF, and 67 ml of TMSCl was added. After dripping, stir at -85°C for 10 to 20 minutes, and then start to add the THF solution of ribolactone (100g lactone dissolved in 100ml THF) dropwise. After the reaction is complete, add AcOH to quench the reaction; after returning to room temperature, Add 250ml of EA, first wash with 250ml of 16% aqueous sodium chloride solution, then wash the organic phase with 400ml of saturated aqueous sodium bicarbonate solution, and concentrate to obtain an organic phase concentrate containing formula I or directly concentrated to dryness to obtain a crude product containing formula I. (The external standard yield of the product is about 40-50%, and different batches are within this range)

Embodiment 2

[0041] The crude product containing formula I was obtained in Example 1, which was subjected to silica gel chromatography, washed with 0-50% EtOAc in n-hexane, and then placed to grow crystals to obtain seed crystals of formula I.

Embodiment 3

[0043] 150 g of the organic phase concentrate containing the formula I in Example 1 (the yield of the product external standard is about 44%) was added with 600 ml of anisole to dilute the solution. At 30°C, after adding some seed crystals and stirring for 16h, after a solid precipitated out, the temperature was lowered to -10~-5°C, and after stirring for 2~3h at the temperature, suction filtration was performed to obtain a solid, and the filter cake was rinsed with 50ml of n-heptane. The solid was dried in a blast oven at 35° C. to obtain 51.44 g of intermediate formula I, purity: 97.3%, crystallization yield: 90.3%.

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Abstract

The invention provides a purification method of a ridecevir intermediate formula I. The method comprises the following steps: adding a crystallization solvent into an organic phase concentrated solution of the formula I after reaction treatment or a crude product solution of the formula I directly to obtain a solid of the formula I; the organic phase concentrated solution or crude product solution is selected from one or any combination solution of esters, alcohols, ketones, halogenated alkanes, nitriles, ethers, alkanes or aromatic hydrocarbons in a formula I; the crystallization solvent is selected from one or any combination of anisole, n-propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and other ethers or n-heptane, n-hexane and other alkane solvents. According to the preparation method, the quality of the key intermediate of the ridecevir is effectively improved by controlling the crystallization process of the purification method, the key intermediate of the ridecevir with the purity larger than or equal to 90% is prepared, the preparation method is easy and convenient to operate, the obtained product is good in quality and high in yield, and the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a method for purifying an intermediate of Remdesivir Background technique [0002] The molecular formula of remdesivir is C 27 H 35 N 6 O 8 P, the structural formula is as follows: [0003] [0004] Remdesivir is a small-molecule monophosphoramidate prodrug of adenine nucleotide analogs (NUC inhibitors), developed by Gilead Sciences for the early treatment of Ebola virus infection. The product has not yet been approved for marketing in any country, and its effectiveness against the new coronavirus is still in Phase III clinical trials. [0005] At present, there are two main synthetic routes for Redcivir, but most of them are in the laboratory 100-gram level and have not been industrially produced. [0006] References Journal of Medicinal Chemistry (2017), 60(5), 1648-1661, the synthetic route of route one is as follows: [0007] [0008] Reagents and reaction c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 季翔刘博洋占轶鹏尹凯苏虎郭效文黄鲁宁陈茜陶安平安建国顾虹
Owner SHANGHAI SYNCORES TECH INC