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Purification process for Oseltamivir Phosphate

A technology of oseltamivir phosphate and purification method, which is applied in the field of purification of oseltamivir phosphate, can solve the problems of increased reaction steps, undisclosed final product purification method, and difficulty in achieving the quality of finished products, and achieves simple operation and high product quality. The effect of stability and easy access to raw materials

Inactive Publication Date: 2009-01-14
SHANGHAI ZHONGXI SUNVE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when route 2 is used to prepare the compound of formula I, due to the increase in the number of reaction steps, impurities of similar structure to the finished product produced in each step of the reaction are brought in, making it difficult for the quality of the finished product to reach the standards stipulated in foreign pharmacopoeias.
Organic process Research & Development 2004, 8.86 reported the non-azide preparation method of oseltamivir phosphate, that is, ethyl (3R, 4R, 5S)-4-N-acetylamino-5-N, N-dialyl Amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (compound II) was used as the starting material to obtain compound I after hydrogenolysis and salification, but the final product was not disclosed. Purification method

Method used

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  • Purification process for Oseltamivir Phosphate
  • Purification process for Oseltamivir Phosphate
  • Purification process for Oseltamivir Phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Under nitrogen protection, ethyl (3R, 4R, 5S)-4-N-acetylamino-5-N, N-bisallylamino-3-(1-ethylpropoxy)- 12 grams of 1-cyclohexene-1-carboxylic acid, 5 grams of 1,3-dimethylbarbital, 0.3 grams of triphenylphosphine, 0.07 grams of palladium acetate and 55 grams of absolute ethanol, stirring and heating to 35 ° C React for 2 hours. Then the hydrogenolysis reaction solution was added dropwise to another reaction kettle containing 3.5 grams of phosphoric acid and 36.5 grams of absolute ethanol at 50°C, stirred and reacted for 2 hours, cooled to -17°C to -18°C, and waited for complete crystallization ,filter. Wash 20 g x 3 with acetone in turn; wash 20 g x 3 with n-heptane, and dry to obtain crude oseltamivir phosphate.

Embodiment 2

[0022] Put 12.5 g of crude oseltamivir phosphate obtained in Example 1 and 270 g of absolute ethanol into the refining kettle, heat to 60°C, add 1 g of activated carbon, continue heating to about 80°C, and decolorize and reflux for 60 minutes. Filtrate while hot, and the filtrate is cooled to precipitate crystals, and placed in the refrigerator overnight. The next day, it was filtered and dried to obtain 11.2 grams of oseltamivir phosphate finished product. The purity (content HPLC) is 99.7712%, the largest single impurity is 0.0843%, the total impurity is 0.2248%, and the total yield is 89.15%.

Embodiment 3

[0024] Put 12.5 g of crude oseltamivir phosphate obtained in Example 1 and 80 g of anhydrous methanol into the refining kettle, heat to 50°C, add 1 g of activated carbon, continue heating to about 60°C, and decolorize and reflux for 45 minutes. Filtrate while hot, and the filtrate is cooled to precipitate crystals, and placed in the refrigerator overnight. The next day, it was filtered and dried to obtain 10.5 grams of oseltamivir phosphate finished product. The purity (content HPLC) is 99.6684%, the largest single impurity is 0.0837%, the total impurity is 0.3316%, and the total yield is 83.6%.

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Abstract

The invention relates to a purification method of Oseltamivir phosphate, and the method is to recrystallize an Oseltamivir phosphate crude product acquired by a non-sodium azide process with water, alcohol or an aqueous solution of alcohol for obtaining the Oseltamivir phosphate with the purity higher than 99.0 percent, the maximum single impurity less than 0.1 percent, and the total impurities less than 1.0 percent. The method has advantages of simple operation, high purity of products, stable quality and high overall yield, and is particularly applied to the industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a purification method of oseltamivir phosphate. Background technique [0002] [0003] The compound of formula I is (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate (1 : 1), also known as oseltamivir phosphate (OseltamivirPhosphate), is a neuraminidase inhibitor. It mainly acts on all links of influenza virus infection and prevents the replication of all clinically relevant influenza virus A strains or B strains. It is an antiviral drug used to treat type A or type B influenza. [0004] There are many reports on the synthesis of the compound of formula I, wherein there are mainly two synthetic routes using shikimic acid as the starting material: [0005] Route 1: Sodium Azide Route [0006] [0007] [0008] Route 2: non-sodium azide route [0009] [0010] Comparing the above two synthetic methods,...

Claims

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Application Information

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IPC IPC(8): C07C233/52C07C231/24
Inventor 陈海荣
Owner SHANGHAI ZHONGXI SUNVE PHARMA
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