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Method for preparing peramivir

A technology of amino and methyl carboxylate, which is applied in the direction of chemical instruments and methods, preparation of organic compounds, bulk chemical production, etc., can solve the problem of unsatisfactory purification treatment and affect the purity, yield and preparation of peramivir intermediate products Efficiency and other issues to achieve the effect of improving the preparation efficiency

Active Publication Date: 2014-01-22
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this route is not ideal in some steps and purification processes in the most critical 1,3-dipolar cycloaddition reaction, which will affect the purity, yield and preparation efficiency of peramivir and subsequent intermediate products to varying degrees

Method used

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  • Method for preparing peramivir

Examples

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preparation example Construction

[0053] The invention discloses a preparation method of peramivir, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the preparation method described herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention. Invent technology.

[0054] The 2-ethyl-N-hydroxybutyryl chloride described in the present invention can be prepared with reference to the preparation method in the patent CN1367776, and can also be prepared according to the method of the present inven...

Embodiment 1

[0059] Example 1: Preparation of PM01 ((1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid methyl ester L-tartrate)

[0060] 1. Preparation method

[0061] Put 1200g PM00 in a three-necked flask, add 3820mL of methanol, measure 785.2g of thionyl chloride, put it in a constant pressure dropping funnel, and add it dropwise to the above reaction system, control the reaction temperature at 15-30°C, and TLC after the addition is completed Detection, the reaction is complete. Methanol and acid gas were removed by rotary evaporation to give an oil. Dissolve the oil in 1920mL of methanol, control the temperature at 20-25°C, add 990.6g of L-tartaric acid and 720ml of water, add 734.6g of triethylamine dropwise, keep stirring for 0.5-1 hour after the addition is complete, and control the temperature at 20 -25°C, continue to stir for 1 hour, filter, wash the filter cake with 500ml of methanol, and dry in vacuum at 40°C for 5h to obtain 1368g of PM01. Yield 85.3%, ee ≥ 99% measured by HPL...

Embodiment 2

[0077] Example 2: PM02 ((1S,4R)-methyl-4-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopent-2-ene-1-carboxylic acid methyl ester) preparation

[0078] 1. Preparation method

[0079] Weigh 1300g PM01 and place it in a three-necked flask, add methanol 2135ml, Boc anhydride 1022g, then slowly add 1038g triethylamine dropwise, control the reaction temperature to less than 40°C, cool down to room temperature and stir for 1-2 hours after the dropwise addition is complete, TLC detection Until the reaction is complete, add 4550ml of water, add a small amount of PM02 seed crystals, stir out the solid, cool in an ice bath to 0-5°C and stir for 0.5 hours, add 2000ml of water, continue stirring for 2 hours, filter, wash the filter cake with 600ml of water, and then Washed twice with 1.5L petroleum ether, vacuum dried at 40°C for 5h to obtain 1045g PM02, yield 97.1%, HPLC measured ee≥99% (patent CN1358170 Example 3 report: yield 95.7%, purity unrecorded, by the present invention detection, i...

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Abstract

The invention relates to the field of chemical synthesis, and discloses a method for preparing peramivir. In allusion to the defects of two technical schemes of conventional patents CN1358170 and CN1367776, the method improves some steps in an amide alcoholysis opening ring reaction of 2-azabicyclo[2.2.1]hept-5-en-3-one and a 1,3-dipolar cycloaddition reaction, increases the preparation efficiency, purity and yield of the peramivir and an intermediate thereof, and has the extremely significant practical significance for industrialized production of the peramivir.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing peramivir. Background technique [0002] Peramivir (Peramivir) was developed by American Biocrystal Pharmaceutical Co., Ltd. It is another new type of neuraminidase (NA) inhibitor following the successful development of zanamivir and oseltamivir and its launch in 1999 Anti-influenza-like drugs for the treatment and prevention of influenza A and B in adults and children. [0003] The chemical name of peramivir is (1S, 2S, 3R, 4R, 1′S)-(-)-3-[(1′-acetylamino-2′-ethyl)butyl]-4-[[( Aminoimino)methyl]amino]-2-hydroxycyclopentane-1-carboxylic acid trihydrate, the chemical structural formula is as follows: [0004] [0005] Multiple groups with different polarities on the peramivir molecule respectively act on multiple active sites of the influenza virus enzymatic enzyme molecule, strongly inhibit the activity of NA, and prevent the interaction between the h...

Claims

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Application Information

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IPC IPC(8): C07C279/16C07C277/08
CPCY02P20/55
Inventor 李明杰朱全明王春艳
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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