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A kind of preparation method of baloxavir intermediate compound

A technology of compounds and intermediates, applied in the direction of organic chemistry, etc., can solve the problems of pollution synthesis methods, dangers, etc.

Active Publication Date: 2021-05-18
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

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  • A kind of preparation method of baloxavir intermediate compound
  • A kind of preparation method of baloxavir intermediate compound
  • A kind of preparation method of baloxavir 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 present invention relates to a kind of preparation method of baloxavir intermediate compound, by 2-methyl-3-benzyloxy-4-oxo-4-hydropyran as starting material, with oxygen as oxidant, in nitrogen Oxidation reaction occurs under the oxide catalyst to generate 3-benzyloxy-4-oxo-4-hydropyran-2-formaldehyde, and then the product 3-benzyloxy-4-oxo-4-hydrogen is obtained through one-step oxidation Pyran-2-carboxylic acid methyl ester, and optimized product purification steps; the raw materials involved in the method of the present invention are cheap and easy to get, the post-processing steps are simple, will not bring additional production costs, and can greatly reduce production costs and product unit prices , which is conducive to expanding the research and development of various pharmaceutical intermediates using the above products as raw materials, and has good 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 Patents(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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