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Peramivir impurity A and impurity C, and preparation methods and application thereof

An impurity and reaction technology, applied in the field of preparation of new peramivir impurities, can solve the problems of drug resistance, affecting the effect of vaccine prevention and control, difficult to meet the demand for anti-influenza drugs, etc., and achieve the effect of safety guarantee

Inactive Publication Date: 2022-01-04
湖南凯铂生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As influenza viruses become stronger, vaccines that are effective against certain influenza viruses are ineffective against other types of influenza viruses, which affects the prevention and control of vaccines. Therefore, the control of influenza still needs to rely on effective antiviral drugs
Moreover, some drugs have developed resistance to
Recognized anti-influenza effective drugs such as "Tamiflu" brand oseltamivir capsules are resistant to drugs due to long drug use time, which is difficult to meet the global demand for anti-influenza drugs, especially the H7N9 virus has developed drug resistance to it
Third, the way of administration cannot meet the clinical needs
[0006] At present, when serious adverse reactions occur, the commonly used clinical strategy is to reduce the dosage of peramivir or suspend the use of drugs, and there is no report on how to reduce the side effects of peramivir

Method used

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  • Peramivir impurity A and impurity C, and preparation methods and application thereof
  • Peramivir impurity A and impurity C, and preparation methods and application thereof
  • Peramivir impurity A and impurity C, and preparation methods and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation of embodiment 1 impurity A

[0062] ① Preparation of 2-ethyl-N-hydroxybutyrimide chloride (compound A-2)

[0063] 3.45 g of hydroxylamine hydrochloride, 3.3 g of water, and 10.5 g of toluene were mixed, and 4.74 g of 2-ethylbutyraldehyde was added with stirring. At 10 to 25°C, 6.95 g of a 30% sodium hydroxide solution (containing 2.085 g of sodium hydroxide) was added over 1 hour. After addition, continue to stir for 1.5h. Stand to separate layers, take the upper toluene layer, directly used in the next step. Suspend 6.32 g of N-chlorosuccinimide (NCS) in 7.5 g of dimethylformamide and cool to 0-10°C. The toluene solution of the above oxime was added in 2.5 hours, and the reaction temperature did not exceed 25°C during the dropwise addition. After the addition was complete, stirring was continued for 1.5 hours. After completion of the reaction, 8.3 g of water was added, stirred for 30 minutes, and the reaction temperature was controlled not to excee...

Embodiment 2

[0074] The preparation of embodiment 2 impurity A

[0075] ① Preparation of 2-ethyl-N-hydroxybutyrimide chloride (compound A-2)

[0076] 3.5 g of hydroxylamine hydrochloride, 3.3 g of water, and 10.5 g of toluene were mixed, and 4.8 g of 2-ethylbutyraldehyde was added with stirring. At 10 to 25°C, 6.90 g of a 30% sodium hydroxide solution (containing 2.0 g of sodium hydroxide) was added over 1 hour. After addition, continue to stir for 1.5h. Leave to stand for stratification, take the upper toluene layer, and use it directly for the next step. Suspend 6.3 g of N-chlorosuccinimide (NCS) in 7.5 g of dimethylformamide and cool to 0-10°C. The toluene solution of the above oxime was added in 2.5 hours, and the reaction temperature did not exceed 25°C during the dropwise addition. After the addition was complete, stirring was continued for 1.5 hours. After completion of the reaction, 8.3 g of water was added, stirred for 30 minutes, and the reaction temperature was controlled n...

Embodiment 3

[0087] The preparation of embodiment 3 impurity C

[0088] ①(1S, 2S, 3S, 4R, 1'S)-3-[(1-amino-2'-ethyl)butyl]-4-[[(1,1-dimethylethoxy)carbonyl]amino Preparation of ]-2-hydroxycyclopentane-1-carboxylic acid methyl ester (compound C-2)

[0089] (3aR, 4R, 6R, 6aS)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1'-ethylpropyl)-3a,5,6, Dissolve 100g of 6a-tetrahydro-4H-cyclopenta[d]isoxazole-6-carboxylic acid methyl ester (compound C-1) and 30g of anhydrous nickel chloride in 300g of methanol, and cool to -10~5℃ . Dissolve 0.1 g of sodium hydroxide and 33 g of sodium borohydride in formazan (250 g, add to the reaction solution in about 1 hour, and stir the reaction solution at 0-5° C. for 60 minutes. Add 180 g of sodium nitrite, 50 g of ammonium chloride and 25% The solution formed in 60g of ammonia water and 500mL of water. Stir at room temperature for 2 hours. Suction filtration, the filtrate was extracted twice with 800g of dichloromethane, combined with the dichloromethane phase...

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Abstract

The invention discloses a peramivir impurity A and a peramivir impurity C with structures as shown in the specification. The invention also provides synthesis methods of the impurity A and the impurity C, and application of the impurity A and the impurity C as impurity reference substances in quality control of peramivir or a pharmaceutical composition thereof. The impurities can be stably prepared and supplied, and a basis is provided for related research and contrast. The peramivir impurity A and the peramivir impurity C disclosed by the invention have important significance in controlling peramivir raw material medicines and researching impurities of preparations of the peramivir raw material medicines.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to the preparation and application of a new impurity of peramivir. Background technique [0002] Peramivir is a novel cyclopentane anti-influenza virus drug targeting the surface glycoprotein neuraminidase of influenza virus, which can effectively treat influenza A and B viruses including H1N1 and H7N9 viruses. The chemical name is (1S, 2S, 3R, 4R, 1'S)-3-[(1'-acetylamino-2'-ethyl)butyl)]-4-[[(aminoimino)methyl]amino ]-2-hydroxycyclopentane-1-carboxylic acid trihydrate, the structural formula is as follows: [0003] [0004] China is a country with a high incidence of influenza. Influenza is highly contagious and spreads mainly through the respiratory tract. As influenza viruses become stronger, vaccines effective against certain influenza viruses are ineffective against other types of influenza viruses, which affects the prevention and control effect of vaccines....

Claims

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Application Information

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IPC IPC(8): C07C279/16C07C277/08A61K31/196A61P31/16G01N1/28
CPCC07C279/16C07C277/08A61K31/196A61P31/16G01N1/28C07B2200/07C07C2601/08
Inventor 罗军奇万林朱海芳
Owner 湖南凯铂生物药业有限公司
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