Method for preparing faropenem daloxate

A technology for faropenem axetil and ropenem axetil is applied in the field of preparation of faropenem axetil, and can solve the problems of inability to prepare faropenem axetil, high price of tetrabutylammonium fluoride, unattainable yield and quality, and the like. And the effect of high purity of finished product, lower cost and improved quality of finished product

Active Publication Date: 2010-11-03
NANJING HUAWE MEDICINE TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Use the preparation methods provided by the above documents to prepare this product, we found that the yield and quality of these methods are not ideal
In terms of finished product quality, HPLC (area normalization method) content is about 95%, and it is extremely difficult to further improve its quality
The reaction yield is generally about 15%, which is far from the yield reported in the literature
In addition, the product is obtained through a multi-step reaction, and the product needs to be obtained after purification by column chromatography. The tetrabutylammonium fluoride mentioned in the literature is expensive, and the industrial production cost is high
Using the above method, by reducing or increasing the reaction temperature, changing the post-treatment conditions, prolonging the reaction time and other methods, although the reaction yield and the quality of the finished product have been improved, faropenem ester that meets the medicinal quality cannot be prepared. And the yield and quality are still far from reaching the data provided by the literature

Method used

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  • Method for preparing faropenem daloxate
  • Method for preparing faropenem daloxate
  • Method for preparing faropenem daloxate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Add 570g of faropenem and 2500mL of 1,3-dimethylpropylene urea into a 10000mL three-necked bottle, stir and dissolve at room temperature, then add 260g of K 2 CO 3 , 50g 18-crown-6, 70g KI, stirred for 1 hr, cooled to 0~5°C, added dropwise 320g 4-methyl-5-chloromethyl-1,3-dioxol-2-one (DMDO-Cl), and control the reaction temperature between 0 and 5°C. After dropping, stir at the same temperature for 6hr. Add 2500 mL of ice water and 3000 mL of ethyl acetate and stir for 20 minutes, let stand, separate the organic layer, wash with 2500 mL of saturated brine, and dry over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure at 40°C. The residue was recrystallized from a mixed solution of ethyl acetate:n-hexane=2:1 to obtain 687g of faropenem ester, with a yield of 86.5%, mp: 122-125°C, [M+1] + : 398.41.

Embodiment 2

[0049] Add 50g of N-methylmorpholine, 500mL of dichloromethane, and 100mL of iodomethane into a 1000mL three-necked flask, heat up and reflux for 3 hours, then concentrate under reduced pressure to dryness to obtain a yellow N, N-dimethylmorpholine iodide solid, which is added to Add 4000mL of acetone to a 10000mL three-necked flask, add 570g of faropenem and 50g of 18-crown-6 under stirring, stir at room temperature for 30 minutes, and adjust the pH to 7.5-8.5 with N-methylmorpholine. Cool in an ice bath to 0-5°C, add 320g of DMDO-Cl dropwise, and control the reaction temperature between 0-5°C. After dropping, stir at the same temperature for 6hr. Add 3000mL of water, stir and crystallize at 0~5℃ for 4hr. The solid was collected by filtration. Vacuum-dried at 40°C to obtain the crude yellow faropenem ester, which was recrystallized with 75% aqueous methanol to obtain 670g of the finished product with a yield of 84.4%, mp: 123-125.5°C, [M+1] + : 398.41.

Embodiment 3

[0051] Add 57g of faropenem and 250mL of dimethyl sulfoxide into a 1000mL three-necked bottle, stir and dissolve at room temperature, then add 32g of NaHCO 3 , 5g 18-crown-6, 7g sodium iodide, after stirring for 3hr, under cooling, dropwise add 32g (4-methyl-5-chloromethyl-1,3-dioxol-2-one ( DMDO-Cl), control the reaction temperature between 20~25°C. After dropping, stir at the same temperature for 6hr. Add 250mL of ice water and 300mL of ethyl acetate and stir for 20 minutes, let stand, separate the organic layer, 250mL of saturated saline Wash and dry over anhydrous magnesium sulfate. Remove the desiccant by filtration, and concentrate the filtrate to dryness under reduced pressure at 40°C. The residue is recrystallized from a mixed solution of ethyl acetate:n-hexane=2:1 to obtain 66g of faropenem ester, with a yield of 83.1 %, mp: 122~125℃, [M+1] + : 398.41.

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Abstract

The invention relates to a preparation method of faropenem medoxomil, belonging to chemical synthesis technical field, which is characterized in that faropenem and 4-halogenated methyl radical-5-methyl-1, 3-dioxane cyclopentene-2-ketone, in an alkali condition and a solvent A, via a phase transfer catalyst and a reaction promoter containing iodine are synthesized to obtain faropenem medoxomil, orthe inorganic salt of faropenem medoxomil and 4-halogenated methyl radical-5-methyl-1, 3-dioxane cyclopentene-2-ketone, in a solvent B, via a phase transfer catalyst and reaction promoter containing iodine are synthesized to obtain faropenem medoxomil. The method has simple operation, mild reaction and saved cost, while the synthesized faropenem medoxomil has high yield and purity.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of faropenem. Background technique [0002] Faropenem medoxomil, the chemical name is (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (5R, 6S)-6-[(1R )-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thio-1-azabicyclo[3.2.0]hept-2-ene- 2-Carboxylate. It is the first orally administered penem antibacterial drug, and it is an oral prodrug of the new carbapenem antibiotic faropenem, which is transformed into faropenem with antibacterial activity after oral absorption. This product was developed by Suntory Company of Japan, and now authorized to Bayer Company of Germany, the research code is Bay56-6854. At present, this product has undergone phase III clinical research in Germany and the United States, and is expected to be launched in the market soon. [0003] At present, there are two methods for the preparation of faropenem ester, one of which in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/893A61P31/00
Inventor 张孝清陆宏国孙田江肖涛周斌孙益林孟霆陈国俊
Owner NANJING HUAWE MEDICINE TECH DEV
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