Oseltamivir warning structure impurity and preparation method thereof

A technology of oseltamivir and impurities, applied in the field of drug synthesis, can solve problems such as increasing the risk of safe drug use, and achieve the effect of high yield

Pending Publication Date: 2022-05-10
ZEIN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The limit of warning structural impurities in drugs is usually determined according to the maximum daily dose, generally at the ppm level. The existence of warning structural impurities greatly increases the risk of safe drug use. It is of great significance to effectively control the quality of related preparations

Method used

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  • Oseltamivir warning structure impurity and preparation method thereof
  • Oseltamivir warning structure impurity and preparation method thereof
  • Oseltamivir warning structure impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of Oseltamivir Warning Structure Impurity (I)

[0037] At room temperature, add 5.00 g of compound (II) (13.79 mmol), ethanol (50 mL) to the reaction flask, stir to dissolve, and cool to 0-10 ° C, add 1.1 g of sodium hydroxide (27.50 mmol) in 10 ml of aqueous solution, Stir overnight at 0-10°C, distill the reaction solution to dryness at 50°C under reduced pressure, add 10ml of dichloromethane and 10ml of water to the residue, add concentrated hydrochloric acid dropwise to adjust the pH=6-7, oily matter is precipitated, and the oily matter is separated Purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1 (volume ratio), and 3.23 g of oseltamivir warning structure impurity (I) was obtained with a yield of 71.1% and a purity of 99.5%.

[0038] MS [M+H]: 282.2.

[0039] 1 H-NMR (600MHz, CD 3 OD) δ0.91(t, 3H), δ0.97(t, 3H), δ1.04(s, 6H), δ1.56(m, 4H), δ2.21(d, 1H), δ2.43 (d, 1H), δ2.57(t, 2H), δ3.46(m, 1H), δ4.20(s,...

Embodiment 2

[0040] Example 2 Synthesis of oseltamivir warning structure impurity (I)

[0041] At room temperature, add 5.00g of compound (II) (13.79mmol), methanol (50mL) to the reaction flask, stir to dissolve, and cool to 0-10°C, add 1.2g of potassium hydroxide (21.43mmol) in 20ml of aqueous solution, Stir overnight at 0-10°C, distill the reaction solution to dryness at 50°C under reduced pressure, add 10ml of dichloromethane and 10ml of water to the residue, add concentrated hydrochloric acid dropwise to adjust the pH=6-7, oily matter is precipitated, and the oily matter is separated Purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1 (volume ratio), and 3.14 g of oseltamivir warning structure impurity (I) was obtained with a yield of 69.3% and a purity of 99.8%.

Embodiment 3

[0042] Example 3 The detection method of the oseltamivir warning structure impurity (I) in the product

[0043] Instruments and equipment: liquid chromatograph, electronic balance, volumetric flask

[0044] Chromatographic conditions:

[0045]

[0046]

[0047] Determination:

[0048] Blank solution: 50% acetonitrile

[0049] Reference substance solution: accurately weigh an appropriate amount of impurity (I) reference substance, dilute it with a blank solution to make about 10 μg / ml, and prepare 2 parts in parallel;

[0050] Test product solution: Accurately weigh an appropriate amount of oseltamivir test product, dilute it with a blank solution to make a 1mg / ml solution, and prepare 2 parts in parallel.

[0051] Quantitation limit: 0.05ug / ml

[0052] Detection limit: 0.017ug / ml

[0053] Sample detection result: lower than the detection limit (see the detection spectrum image 3 , Figure 4 )

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Abstract

The invention discloses an oseltamivir warning structure impurity and a preparation method thereof. The oseltamivir warning structure impurity is shown as a formula I in the specification. The preparation method disclosed by the invention is low in cost and simple and convenient to operate, can be used for large-scale synthesis, and provides a reference substance for qualitative and quantitative analysis of oseltamivir warning structure impurities, thereby laying a solid foundation for quality research of oseltamivir crude drugs and related preparations.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis and relates to a preparation method of an antiviral medicine oseltamivir impurity. Background technique [0002] Oseltamivir is a specific inhibitor of neuraminidase, which inhibits the action of neuraminidase and can inhibit the mature influenza virus from leaving the host cell, thereby inhibiting the spread of influenza virus in the human body To play a role in the treatment of influenza. Oseltamivir is a successful case of structure-based rational drug design. A large number of computer-aided drug design methods have been used in the research and development of this drug. According to the three-dimensional structure of the target enzyme, a specific drug with high efficiency and low toxicity has been designed. Potent neuraminidase inhibitor. [0003] Patent CN1759093A reports that the synthetic route of oseltamivir is as follows: [0004] [0005] Among them, the hydrolysis of c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D203/26G01N30/02G01N30/04
CPCC07D203/26G01N30/02G01N30/04G01N2030/027G01N2030/047
Inventor 肖玉梅代毅牟祥王文静罗奎李玉芳邓祥林
Owner ZEIN BIOTECHNOLOGY CO LTD
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