Laninamivir octanoate preparation method

A technology of miviroctate and la nina, which is applied in the field of neuraminic acid derivatives, can solve the problems of increased use of organic solvents, unsuitable for industrial production, and difficulty in purchasing raw materials, and achieves simple equipment, easy quality control, and ease of use. The effect of separation and purification

Active Publication Date: 2013-12-11
SHENZHEN NEPTUNUS PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] From routes 2 to 5, we can see that the reaction routes are very long, basically greater than 4-step reaction; the reaction conditions are severe and difficult to control; and the raw materials are not easy to purchase, such as the synthesis of starting material Ⅰ needs to go through 7-step reaction; The reported process adopts column chromatography purification method in multiple steps, the operation is complicated, the usage of organic solvent is greatly increased, and the environment is polluted; in addition, highly toxic reagents such as mercuric chloride are used in the process, which does not meet the requirements Industrial Production Requirements

Method used

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  • Laninamivir octanoate preparation method
  • Laninamivir octanoate preparation method
  • Laninamivir octanoate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation of embodiment 1 laninamivir axetil

[0035] Synthesis of formula 16 compound zanamivir methyl ester

[0036] In a 20L reactor, a suspension was prepared by mixing zanamivir (109.7g, 0.33mol) with 6.9L of methanol. Add an acidic positive resin selected from Dowex50 (H+) (55g) to the suspension, and react at room temperature for 30 hours; complete, remove the resin by filtration, wash with methanol (0.1L×2), and concentrate the filtrate to obtain an off-white solid, namely compound 16 , yield 98.1%.

[0037] Synthesis of compounds of formula 17

[0038] Mix the compound of formula 16 (103.8g, 0.30mol) and toluene (300ml) at room temperature, then add dimethyl carbonate (63.2ml) and methanol solution of sodium methoxide (0.3ml) respectively, and heat the mixture to 80°C, Reflux reaction for 5 hours; after the reaction is completed, cool down to 0°C, stir for 15 minutes, let stand to crystallize, filter, and wash with toluene (50ml×2) to obtain a light ye...

Embodiment 2

[0045] The preparation of embodiment 2 laninamivir axetil

[0046] Synthesis of the compound of formula 16

[0047] In a 20L reactor, a suspension was prepared by mixing zanamivir (36.6g, 0.11mol) with 0.92L methanol. Add an acidic positive resin selected from Bio-Rad (H+) (11.0g) to the suspension, and react at room temperature for 10 hours; complete, remove the resin by filtration, wash with methanol (30mL×2), and concentrate the filtrate to obtain an off-white solid, namely Formula 16 compound, yield 90.6%.

[0048] Synthesis of compounds of formula 17

[0049] The compound of formula 16 (34.6g, 0.10mol) was mixed with tetrahydrofuran (100ml) at room temperature, then dimethyl carbonate (9.3ml) and methanol solution of sodium methoxide (0.06ml) were added respectively, and the mixture was heated to 50°C, Reflux reaction for 4 hours; after the reaction was completed, cool down to 0°C, stir for 20 minutes, stand for crystallization, filter, wash with toluene (15ml×2), and ...

Embodiment 3

[0056] The preparation of embodiment 3 laninamivir axetil

[0057] Synthesis of the compound of formula 16

[0058] In a 20L reactor, a suspension was prepared by mixing zanamivir (54.8g, 0.16mol) with 6.94L of methanol. Add an acidic positive resin selected from Dowex50 (H+) (54.8g) to the suspension, and react at 70°C for 72 hours; after completion, remove the resin by filtration, wash with methanol (50mL×2), and concentrate the filtrate to obtain an off-white solid, the compound Formula 16 compound, yield 94.2%.

[0059] Synthesis of compounds of formula 17

[0060] Mix the compound of formula 16 (51.9g, 0.15mol) and 1,4-dioxane (150ml) at room temperature, then add dimethyl carbonate (63.2ml) and methanol solution of sodium methoxide (0.8ml) respectively. The mixed solution was heated to 100°C, and refluxed for 8 hours; after the reaction was completed, the temperature was lowered to 0°C, stirred for 15 minutes, left to stand for crystallization, filtered, washed with t...

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Abstract

The invention relates to a laninamivir octanoate preparation method, wherein the method is performed in the same reactor or a plurality of reactors in a step-by-step manner. The reaction process sequentially comprises: 1) mixing zanamivir and methanol while adding an acid cation resin, and carrying out a reaction to obtain zanamivir methyl ester; 2) carrying out a reaction of the zanamivir methyl ester and dimethyl carbonate under an alkaline condition to produce a compound represented by a formula (17); 3) carrying out a reaction of the compound represented by the formula (17) and methyl iodide under an alkaline condition to obtain a compound represented by a formula (18); 4) carrying out a reaction of the compound represented by the formula (18) and an alkali, and adopting a cation resin to adjust the pH value to the neutral state to obtain a compound represented by a formula (19); and 5) carrying out a reaction of the compound represented by a formula (19) and octanoyl chloride to obtain the target product laninamivir octanoate. The present invention provides the laninamivir octanoate preparation method, which has characteristics of simple route, low cost, low energy consumption, high product purity, and avoidance of use of hypertoxic reagents and explosive reagents.

Description

technical field [0001] The present invention relates to a method for preparing neuraminic acid derivatives with neuraminidase inhibitory activity, and to synthetic intermediates of neuraminic acid derivatives and their preparation methods. Furthermore, the present invention relates to neuraminic acid derivatives with high purity. Background technique [0002] Among many viral infectious diseases, influenza is one of the infectious diseases with the largest number of patients, the widest range of disease-causing areas and the highest fatality rate. Influenza is a respiratory infection caused by influenza virus. The outbreak of H1N1 flu in April 2009 cast a shadow over the world. It can be seen that influenza, as a viral infectious disease, not only seriously threatens public health, but also brings a heavy economic burden to the country and society. Therefore, the research and development of anti-influenza drugs has become a research hotspot. [0003] In recent years, rep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/28
Inventor 唐田彭江华吴婧李勇崔婧黄传贵王菲
Owner SHENZHEN NEPTUNUS PHARM CO LTD
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