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Preparation method of oseltamivir phosphate

A technology of oseltamivir phosphate and temperature control, which is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, and the preparation of cyanide reactions, etc., which can solve the research and development limitations of oseltamivir phosphate generic drugs and the inability of the original research and preparation route to be effective. Substitute, process cost and industrialization transformation competition and other issues, to achieve the effect of high total yield, mild process conditions and simple operation

Active Publication Date: 2019-12-13
BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 2) Although there are many routes for preparing oseltamivir phosphate, such as CN101801914B, CN107304171A, etc., but due to the problems of process cost and industrial transformation, it cannot compete with the original research, so the original research preparation route cannot be effectively replaced
[0008] my country is a country with a large population, and it is still in the developing stage. Due to the constraints of the original research and preparation patents, the research and development of generic oseltamivir phosphate is restricted, which seriously affects the availability of this drug for the nationals.

Method used

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  • Preparation method of oseltamivir phosphate
  • Preparation method of oseltamivir phosphate
  • Preparation method of oseltamivir phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of Example 1 Compound II

[0045]

[0046] Compound I(R 1 Methanesulfonyl, 500.0g, 1.44mol, 1.0eq.) was dissolved in 5L N,N-dimethylformamide (DMF), and cesium carbonate (1407.4g, 4.32mol, 3.0eq.) was added under stirring, and then Diallylamine ((allyl) 2 NH; 168.2g, 1.73mol, 1.2eq.), the temperature was raised to 90-100°C for 8 hours, and the reaction was complete as monitored by TLC. The reaction solution was cooled to room temperature and filtered. Add 20L of water to the filtrate for dilution, then add 5L of ethyl acetate to stir and separate the liquids, the organic phase is washed with 5% aqueous sodium chloride, then dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 479.2g of orange oil formula II (theoretical The value is 503.3g), and the yield is 95%.

[0047] 1 H NMR (CDCl 3 ,400MHz)δ6.93(m,1H),5.77-5.66(m,2H),5.18(d,2H,J=17Hz),5.06(d,2H,J=10Hz),4.22(m,2H), 4.09(m,1H),3.90(m,1H),3.39(m,1H),3.29(m,2H),2.93(...

Embodiment 2

[0050] Embodiment 2 Compound III Preparation

[0051]

[0052]Compound II (479.2g, 1.37mol, 1.0eq.) was dissolved in 4.5L of dichloromethane, the temperature was lowered to -40~-35°C under the protection of nitrogen, and triethylsilane (223.3g, 1.92mol, 1.4eq.), titanium tetrachloride (299.7g, 1.58mol, 1.15eq.) were dissolved in 1.5L dichloromethane solution, and reacted for 2 hours under temperature control and stirring, and the reaction was complete as monitored by TLC. 6L of water was added to the reaction solution with stirring, and the temperature was slowly raised to 0°C for liquid separation. The organic phase was washed successively with saturated aqueous sodium bicarbonate solution and 5% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 418.9 g (theoretical value: 481.5 g) of orange oily substance formula III, with a yield of 87% .

[0053] 1 H NMR (CDCl 3 ,400MHz)δ6.73(m,1H),5.78-5.66...

Embodiment 3

[0056] Embodiment 3 Compound IV Preparation

[0057]

[0058] Compound III (418.9g, 1.19mol, 1.0eq.) was dissolved in 1L of acetonitrile, cooled to 0°C, and a mixed solution of sulfuric acid and acetic acid (sulfuric acid: 50mL; acetic acid: 100mL) was added dropwise, and the temperature was slowly raised to 20 °C for 1 hour. TLC monitored the completion of the reaction. The reaction solution was slowly added dropwise into water at 0-5° C., then extracted twice with 2 L of ethyl acetate, and the organic phases were combined. The organic phase was washed successively with saturated aqueous sodium bicarbonate solution and 5% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 415.7 g (theoretical value 467.1 g) of orange oily substance formula IV, with a yield of 90% .

[0059] 1 H NMR (CDCl 3 ,400MHz)δ6.73(m,1H),5.78-5.66(m,2H),5.36(d,1H),5.17(d,2H,J=16.5Hz),5.08(d,2H,J=10Hz) ,4.22(m,2H),4.09(m,1...

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Abstract

The invention provides a novel preparation method of ethyl (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate, and belongs to the technical field of chemical drug synthesis. An acetamido group is introduced into the construction process of oseltamivir phosphate molecules by using a Ritter reaction. The preparation way of the initial raw material in the invention is close to the shikimic acid end of a natural product, so the novel preparation method has the advantages of mild conditions, simplicity in operation, high total yield, and suitableness for commercial production of oseltamivir phosphate bulk drugs. The method successfully avoids an original research route to overcome protection period limitation of an original research and preparation methodpatent, and can accelerate the solving of the problem of medication accessibility of the medicine in China.

Description

technical field [0001] The invention relates to the field of drug synthesis, and relates to a raw material drug oseltamivir phosphate ((3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1- The preparation method of ethyl cycloethylene-1-carboxylate phosphate). Background technique [0002] Oseltamivir phosphate is used for the treatment of influenza A and B in adults and children aged 1 and over (oseltamivir phosphate can effectively treat influenza A and B), for adults and adolescents aged 13 and over Prevention of type and B influenza. The original research company of this variety is Roche Pharmaceuticals. It was launched in the United States on October 27, 1999, and in China on September 6, 2001. The listed dosage form is capsule 30 / 45 / 70mg. Influenza A and B are infectious diseases, and oseltamivir phosphate is a specific clinical drug for such diseases. [0003] The preparation method patent CN100545145C applied by Roche Pharmaceuticals in China on March 10, 2004 ha...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/52
CPCC07C227/16C07C231/06C07C231/12C07C2601/16C07D317/68C07C233/52C07C229/48
Inventor 王辉王春娟刘芳杜保权
Owner BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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