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Method for preparing oseltamivir phosphate

A technology of oseltamivir and palladium acetate, which is applied in the field of preparation of oseltamivir phosphate, can solve the problems of excessive residues of heavy metal elements and impurities

Active Publication Date: 2019-04-05
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The present invention provides a preparation method of oseltamivir phosphate to overcome the technical problem of excessive residual impurities of heavy metal elements in the preparation of oseltamivir phosphate in the prior art

Method used

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  • Method for preparing oseltamivir phosphate
  • Method for preparing oseltamivir phosphate
  • Method for preparing oseltamivir phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A comparative example of oseltamivir phosphate was prepared using the method disclosed in CN1759093.

[0022]

[0023] Weigh 200 g of the compound represented by formula (IV) and dissolve it in 300 ml of dichloromethane, add it dropwise to 800 ml of trifluoroacetic acid, and react for 1 h at a temperature controlled to ≤50°C. The end point was monitored by TLC, the solvent was concentrated under reduced pressure, and toluene was added to dry it up three times. Add 800ml of toluene and 800ml of purified water to the concentrated solution, stir vigorously for 30min, and separate the layers. The organic layer is quenched with 400ml×2 purified water, and the aqueous layers are combined. The aqueous layer was quenched with 200ml×2 toluene. Add 800ml of dichloromethane to the aqueous layer, and use saturated Na 2 CO 3 The aqueous solution was adjusted to pH=9.0. Let stand to layer. The aqueous layer was extracted with 400ml×3 dichloromethane. The dichloromethane laye...

Embodiment 2

[0031]

[0032] Under nitrogen protection, in a 2000ml reaction flask, add the compound represented by formula (IV) (179.5g, 0.40mol), absolute ethanol 776g, N,N-dimethylbarbituric acid (75.0g, 0.48mol) , palladium acetate (0.90g, 0.004mol), and triphenylphosphine (4.20g, 0.016mol) were added, and the temperature was controlled at 20-25°C, and the reaction was stirred for 2h. Cool down to 10-15°C, keep warm for 30 minutes, filter with suction, and concentrate the filtrate to obtain the crude product of formula (Ⅲ).

[0033] The above crude product of formula (III) was added dropwise into 800ml of trifluoroacetic acid, and reacted at a temperature of 35-40°C for 1h. The temperature of the reaction solution was controlled to be ≤50°C, the solvent was concentrated under reduced pressure, and toluene was added to dry it three times. Add 800ml of toluene and 800ml of purified water to the concentrated solution, stir vigorously for 30min, and separate the layers. The organic lay...

Embodiment 3

[0040] Reaction formula is with embodiment 2.

[0041] Under nitrogen protection, in a 1000ml reaction flask, add the compound represented by formula (IV) (44.9g, 0.10mol), absolute ethanol 194g, N,N-dimethylbarbituric acid (18.8g, 0.12mol) , palladium acetate (0.23g, 0.001mol), triphenylphosphine (1.05g, 0.004mol), after the addition is completed, the temperature is controlled at 20-25°C, and the reaction is stirred for 2h. Cool down to 10-15°C, keep warm for 30 minutes, filter with suction, and concentrate the filtrate to obtain the crude product of formula (Ⅲ).

[0042]The crude product of the above formula (III) was dissolved in 45ml of dichloromethane, added dropwise into 200ml of trifluoroacetic acid, and reacted at a temperature of 35-40°C for 2h. The temperature of the reaction solution was controlled to be ≤50°C, the solvent was concentrated under reduced pressure, and toluene was added to dry it three times. Add 200ml of toluene and 200ml of purified water to the c...

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Abstract

The invention discloses a method for preparing oseltamivir phosphate. The method includes steps of carrying out reaction on intermediates shown as a formula (IV) with palladium acetate, triphenylphosphine and N,N-dimethylbarbituricacid in solvents, and removing allyl to obtain intermediates shown as a formula (III); carrying out acid treatment on the intermediates shown as the formula (III), and removing tertiary butyl to obtain oseltamivir free alkali shown as a formula (II); carrying out reaction on the oseltamivir free alkali with phosphoric acid in solvents, and carrying out crystallization purification. An equivalence ratio of the intermediates shown as the formula (IV) to the palladium acetate to the triphenylphosphineto the N,N-dimethylbarbituricacid is 1:0.01:0.04:1.2. The method has the advantages that the residual quantities of main heavy metal such as palladium, arsenic, cadmium, cobalt, copper, mercury, lithium, nickel, lead, antimony, titanium and vanadium in the oseltamivir phosphate prepared by the aid of the method are within the limit ranges, and accordingly the ICH standards can be met.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a preparation method of oseltamivir phosphate. Background technique [0002] Oseltamivir phosphate, as the only oral neuraminidase inhibitor drug in the world, has long been recognized as one of the most effective anti-influenza drugs in the world. It can be metabolized into a neuraminidase inhibitor by the human body, thereby inhibiting the formation of new virus particles, reducing its spread in the human body, and relieving influenza symptoms. [0003] The structure of oseltamivir phosphate is shown in formula (I): [0004] [0005] At present, there are many synthetic routes of oseltamivir phosphate, which are mainly divided into azide synthetic route and non-azide synthetic route. Among them, most processes of the azide route have disadvantages such as high energy consumption, dangerous operation, and serious environmental pollution. The non-azide route ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/52C07C231/12C07C231/24
CPCC07C231/12C07C231/24C07C2601/16C07C233/52
Inventor 袁建栋刘平陈德君
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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