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Synthetic method of C-nucleoside compound

A technology of nucleoside compounds and compounds, applied in chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., can solve the problems of difficult scale-up production, cumbersome operation, and high cost

Active Publication Date: 2020-10-20
SICHUAN UNIV +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Aiming at the problems of low yield, cumbersome operation, high cost and difficulty in scale-up production of the first-step addition reaction of remdesivir reported in the past, a more concise and efficient synthetic method was developed to prepare its chiral synthetic intermediate C-nucleoside Compound (3) is extremely important, and the new method developed will help reduce the cost of drug production, thereby solving the problem of drug accessibility, and meeting the clinical application of remdesivir’s potential anti-SARS-CoV-2 virus infection

Method used

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  • Synthetic method of C-nucleoside compound
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  • Synthetic method of C-nucleoside compound

Examples

Experimental program
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Effect test

Embodiment 1

[0075] The synthesis of the chiral C-nucleoside compound shown in embodiment 1 formula 3

[0076]

[0077] Under anhydrous and oxygen-free conditions, after dissolving compound 1a (10.0g, 46.94mmol) and 1,2-bis(chlorodimethylsilyl)ethane (11.1g, 51.63mmol) in THF (100mL), add Diisopropylamine represented by Formula 4 (7.3 mL, 51.63 mmol). The reaction solution was sequentially added with n-butyllithium (81 mL, 201.8 mmol) and a THF solution (50 mL) of ribonolactone (39.3 g, 93.88 mmol) shown in formula 2 at -78°C. After the reaction solution was reacted at -78°C for 2 hours, citric acid aqueous solution (1M, 200mL) was added to quench the reaction. After the reaction solution returned to room temperature, the aqueous layer was extracted with ethyl acetate (3×200mL), the organic layers were combined, and water ( 1×250mL), saturated NaHCO 3 solution (1×250 mL), washed with saturated NaCl solution (1×250 mL). The organic layer was dried over anhydrous magnesium sulfate, fil...

Embodiment 2

[0079] According to the method described in Example 1, with the ribonolactone shown in compound 1a and formula 2 as substrates, the synthesis of chiral C-nucleoside compounds shown in the following formula 3 for different secondary amines shown in formula 4 The rates were compared and the data obtained are shown in the table below.

[0080]

[0081]

Embodiment 3

[0083] According to the method described in Example 1, compound 1a is reacted on a scale of 10 grams, and other reaction conditions are constant, only the concentration of compound 1a in the reaction solution and the equivalent number of ribonactone shown in formula 2 are changed, and the realized formula The data obtained for the synthesis yield of the chiral C-nucleoside compound shown in 3 are shown in the table below.

[0084]

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Abstract

The invention discloses a method for preparing a C-nucleoside compound shown as a formula III or a salt thereof. The method has the advantages of high reaction yield, simple operation, single used metal reagent, stable reaction temperature condition, no need of frequently changing the reaction system in the operation process, suitableness for scale-up synthesis, suitableness for large-scale production of remdesivir, and low cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing a chiral intermediate C-nucleoside compound of Remdesivir. Background technique [0002] The unique effect of nucleoside analogs on viruses, a variety of small molecule nucleoside analogs such as favipiravir (Favipiravir), brincidofovir (brofovir dipivoxil) and galidesivir (Galidevir) have been found in The clinical stage showed certain antiviral activity. After screening a large number of nucleoside analogues, Gilead found that remdesivir (Redcivir) is effective against Ebola virus, respiratory syncytial virus, coronavirus, Nipah virus and Hendra ( Hendra) virus, etc. have shown good inhibitory activity, and also showed high antiviral activity against coronavirus SARS-CoV-2. Phase III clinical trials for the treatment of SARS-CoV-2 virus infection are currently being carried out in China, Europe and the United States. In the existing reports on the synth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H15/10C07H15/04C07H1/00C07F7/10
CPCC07H15/18C07H15/10C07H15/04C07H1/00C07F7/10C07D487/04Y02P20/55
Inventor 秦勇钟武薛斐刘小宇王雨周骁汉刘波王科杨立开周瑞捷肖雅心薛芳琳张敏杰宋颢郑志兵李松
Owner SICHUAN UNIV
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