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Preparation method of baloxavir marboxil intermediate compound

A technology of compounds and intermediates, applied in the direction of organic chemistry, can solve the problems of polluting synthesis methods, dangers, etc., and achieve the effects of optimizing purification steps, reducing production costs and unit prices, good commercial value and industrial development potential

Active Publication Date: 2019-10-08
JIANGSU UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Aiming at the danger and pollution problems caused by the toxic substances used in the prior art and the problems of complex synthesis methods, a simple, low-cost, and pollution-free preparation of 3-benzyloxy-4-oxo- Method for methyl 4-hydropyran-2-carboxylate

Method used

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  • Preparation method of baloxavir marboxil intermediate compound
  • Preparation method of baloxavir marboxil intermediate compound
  • Preparation method of baloxavir marboxil intermediate compound

Examples

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Embodiment 1

[0034] A preparation method of baloxavir intermediate compound, the baloxavir intermediate compound is 3-benzyloxy-4-oxo-4-hydropyran-2-carboxylic acid methyl ester, compound 1 Express, described preparation method is as follows:

[0035]

[0036](1), add 21.6 grams (100 millimoles) compound 2 in a 500 milliliter reaction bottle with magnetic stirring bar (can be prepared in one step by cheap and easy-to-get commercial reagent luteol, see document Organic Process Research&Development, 2012, 16 (11), 1783-1786) and 250 milliliters of bromobenzene solvents, then add 0.95 grams (10 mmol) of pyridine-N-oxides, a bottle mouth is connected with a reflux condenser, and the other bottle mouth is passed into oxygen, and then Under stirring, it was raised to 160°C to reflux the solvent, and the reaction system was kept under reflux and stirred for 20 hours. After the reaction of compound 2 was completed, it was lowered to room temperature, and then the bromobenzene solvent was separa...

Embodiment 2

[0046] A kind of preparation method of baloxavir intermediate compound, described compound is 3-benzyloxy-4-oxo-4-hydropyran-2-carboxylic acid methyl ester (compound 1), described preparation method is as follows :

[0047]

[0048] (1), add 21.6 grams (100 millimoles) compound 2 and 50 milliliters of chlorobenzene solvents in a 500 milliliters reaction bottles with magnetic stirring bar, then add 0.94 grams (6 millimoles) tetramethylpiperidine nitrogen oxidation (TEMPO), one bottle mouth is connected with a reflux condenser, and the other bottle mouth is fed with oxygen, and then raised to 140°C under stirring to make the solvent reflux reaction, keep the reaction system under reflux state and stir for 48 hours, follow the reaction of compound 2 After complete, be down to room temperature, then decompression distillation separates bromobenzene solvent and obtains residual crude product, described solvent is through drying, can reuse after redistilling, and residual crude p...

Embodiment 3

[0051] A kind of preparation method of baloxavir intermediate compound, described compound is 3-benzyloxy-4-oxo-4-hydropyran-2-carboxylic acid methyl ester (compound 1), described preparation method is as follows :

[0052]

[0053] (1), add 21.6 grams (100 millimoles) compound 2 and 25 milliliters of fluorobenzene solvents in a 500 milliliters reaction bottles with magnetic stirring bar, then add 0.35 grams (3.4 millimoles) N-methylmorpholine nitrogen For oxides, one bottle mouth is connected to a reflux condenser, and the other bottle mouth is fed with oxygen, and then raised to 100 ° C under stirring to allow the solvent to reflux for reaction, and the reaction system is kept under reflux and stirred for 36 hours. After the completion of the reaction of compound 2 , down to room temperature, and then the bromobenzene solvent is separated by distillation under reduced pressure and obtains the residual crude product. The solvent is dried and can be reused after re-evaporat...

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Abstract

The invention relates to a preparation method of a baloxavir marboxil intermediate compound. The preparation method includes: using 2-methyl-3-benzyloxy-4-oxo-4-hydropyrane as the initial raw materialand oxygen as the oxidizing agent to perform oxidizing reaction under the effect of a nitric oxide catalyst to generate 3-benzyloxy-4-oxo-4-hydropyrane-2-formaldehyde, and performing further oxidization to obtain the product 3-benzyloxy-4-oxo-4-hydropyrane-2-methyl carboxylate. The preparation method has the advantages that product purification steps are optimized, the raw materials of the methodis cheap and easy to obtain, and the method is simple in post-processing steps, capable of avoiding extra production cost, capable of greatly lowering production cost and product unit price, capableof favorably promoting the researches and development of various medicine intermediates using the product as the raw material and good in commercial value and industrial development potential.

Description

technical field [0001] The invention relates to the technical field of organic synthesis of pharmaceutical intermediates, in particular to a method for preparing a baloxavir intermediate compound, namely methyl 3-benzyloxy-4-oxo-4-hydropyran-2-carboxylate . Background technique [0002] Baloxavir is a new anti-influenza drug approved by the US FDA in 2018 [WO 2017221869; AU2017282305; JP 6212678; CN 109311911;], its English name is Xofluza, or baloxavirmarboxil, is a new type of small molecule drug that can Effectively treat patients (aged ≥ 12 years) with uncomplicated acute influenza within 48 hours. The treatment effect is very obvious. According to experts, the new drug only needs 1 tablet, which is equivalent to the effect of 10 tablets of the current conventional treatment drug. Baloxavir (Young-A Heo. Baloxavir: First Global Approval [J]. Drugs, 2018, 78, 693-697.). [0003] Therefore, the demand for baloxavir will also increase, and the currently reported syntheti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/40
CPCC07D309/40
Inventor 罗世鹏陶紫薇王欣杨廷海刘维桥
Owner JIANGSU UNIV OF TECH
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