Waterless Peramivir crystal and medicament composition thereof

A technology of composition and crystal, which is applied to the crystal form of the influenza neuraminidase inhibitor anhydrous peramivir and the field of preparation of the crystal, which can solve the problems that there are no anhydrous peramivir crystals yet.

Active Publication Date: 2008-12-03
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The Chinese patent applications for peramivir include: the patent application with the application number 98812351.7 discloses the peramivir compound, the preparation method and its use, and the patent applications with the application numbers 00809622.8 and 00809654.6 disclose the preparation of peramivir Method and A, B crystal structures containing water of crystallization, but there is no report about anhydrous peramivir crystals

Method used

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  • Waterless Peramivir crystal and medicament composition thereof
  • Waterless Peramivir crystal and medicament composition thereof
  • Waterless Peramivir crystal and medicament composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Preparation of (1S, 4R) methyl 4-aminocyclopent-2-1-carboxylate tartrate

[0071] (±)-2-Azabicyclo[2.2.1]hept-5-en-3-one (100.0 g, 0.916 mol) was dissolved in methanol (83.0 g), forming a brown solution. HCl gas 37.8 g was carefully bubbled in for 20 minutes. After completion of HCl introduction, the mixture was cooled to 20 °C. Add L-tartaric acid (82.5g, 0.55mol) and water (50.0g) successively, then add triethylamine (60.0g, 0.596mol), when the pH of the solution reaches 2.0, add a small amount of L-tartaric acid (1S, 4R) Crystals of methyl 4-aminocyclopent-2-ene-1-carboxylate were used as seeds. The mixture was cooled to 22°C and filtered. The solid was washed with methanol and dried under vacuum (D 20℃ =-40.0° (c=1g / dL, H 2 O).

Embodiment 2

[0073] Preparation of (1S,4R)4-[[(1,1-methylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylic acid methyl ester

[0074] Methyl L-tartrate (1S,4R) 4-aminocyclopent-2-ene-1-carboxylate and di-tert-butyl dicarbonate (78.8 g, 0.361 mol) were suspended in 130 g of methanol. Triethylamine (80.0 g, 0.791 mol) was then added dropwise. The mixture solution was stirred for 1 hour, the solution was cooled to 5°C, and water was added. A small amount of (1S,4R) methyl 4-[[(1,1-methylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylate crystals were added as seed crystals to give a white precipitate. The mixture was stirred and filtered. The filtered solid was washed with water and dried in vacuo.

[0075] Yield: (1S,4R) 4-[[(1,1-methylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylate (79.0 g, 95.7%); mp: 51.9 -52.4°C; [α] D 20℃ =--52.0° (c=1g / dL, cHcl 3 ).

Embodiment 3

[0077] (3aR, 4R, 6S, 6aS)-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1'-ethylpropyl)-3a,5,6,6a-tetra Preparation of 2,2-dimethylethylammonium hydrogen-4H-cyclopenta[d]isoxazole-6-carboxylate

[0078] Dissolve (1S,4R)-(-)-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopent-2-ene-1-carboxylic acid methyl ester (50 g, 0.207 mol) in Toluene and triethylamine (62.9 g, 0.622 mol), and the reaction mixture was heated to 70°C. To this solution was added 2-ethyl-N-hydroxybutyrimide chloride (93.0 g, 0.622 mol) in toluene, and a white solid precipitated. After the addition was complete, the reaction mixture was stirred for an additional 5 hours. The reaction mixture was cooled, the precipitate was removed by filtration, and the filter cake was washed with toluene. The combined filtrates were treated at 15°C with a solution of sodium hydroxide (12.4g) in water (37.3g). The reaction mixture was diluted with water, the organic phase was extracted with water and the combined aqueous phases wer...

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PUM

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Abstract

The invention relates to an anhydrous peramivir crystal compound and a preparation method thereof, and further discloses a pharmaceutical composition comprising the same and the application thereof in the preparation of medicaments for treating the influenza virus and the Avian influenza virus.

Description

technical field [0001] The invention belongs to the technical field of organic medicinal chemistry, and relates to a crystal form of influenza neuraminidase inhibitor anhydrous Peramivir (Peramivir), a method for preparing the crystal, and a pharmaceutical composition containing the crystal. Background technique [0002] Influenza viruses can be divided into three serotypes according to the antigenic properties of their nucleoproteins and matrix proteins, namely influenza A, B, and C, among which influenza A viruses can infect a variety of animals, including humans, poultry, pigs, Ma et al, while B and C influenza viruses are generally more common in human infection. [0003] Avian influenza virus is one of type A (ie type A) influenza viruses. In theory, drugs used to treat and prevent influenza A in humans should be effective against bird flu. For example, the current amantadine (amantadine), rimantadine (rimantadine), zanamivir (Zanamivir, trade name Relenza) and oselta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/16C07C277/06A61K31/196A61P31/16
Inventor 陈华赵健孙继铨张村子田青松刘玉凤王伟
Owner 天津泰普制药有限公司
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