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Preparation method of caspofungin

A caspofungin and dripping technology, applied in the direction of peptides, etc., can solve problems such as long time and affecting product production efficiency, and achieve the effects of increasing yield, facilitating quality control, and reducing production costs

Active Publication Date: 2016-03-30
成都摩尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, in terms of yield, purity, stability and three wastes, the disclosed method is not the best method for industrial production
For example, in the reaction process of intermediates and ethylenediamine, it is often necessary to slowly add ethylenediamine dropwise, so that the reaction time reaches more than 40 hours, which seriously affects the production efficiency of the product
[0007] For example, in the published Chinese patent CN201010538951.6, it is disclosed that the reduced amine group of compound 4 is reacted with ethylenediamine to obtain caspofungin, and the reaction time between the amine group and ethylenediamine is 24h to 48h. longer

Method used

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  • Preparation method of caspofungin
  • Preparation method of caspofungin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] A kind of preparation method of caspofungin, its synthetic process is:

[0029]

[0030] Specifically include the following steps:

[0031] (1) Add 1 mol neomocontin B 0 After dissolving 2mol phenylboronic acid in 300ml acetonitrile, cool down to -45°C; add 3mol thiophenol and stir to mix evenly, add dropwise 2mol trifluoromethanesulfonic acid, control the temperature below -35°C to pneumocantine B 0 The content is lower than 5%, that is, the reaction is terminated. After the reaction was terminated, sodium acetate acetonitrile aqueous solution was added dropwise, and the volume ratio of acetonitrile and water in the sodium acetate acetonitrile aqueous solution was 4:1. After the dropwise addition, the solution is nearly neutral, and the pH value can be adjusted to about 6.5. Continue to stir, then perform low-temperature filtration, wash the filter cake with pure water until the solution is nearly neutral, and dry after washing to obtain the intermediate MD-I; th...

Embodiment 2

[0035] A preparation method of caspofungin, comprising the following steps:

[0036] (1) Add 1 mol neomocontin B 0 After dissolving 3mol phenylboronic acid in 400ml acetonitrile, cool down to -42°C; add 4mol thiophenol and stir to mix evenly, add 1.5mol trifluoromethanesulfonic acid dropwise, control the temperature below -35°C to pneumocantine B 0 The content is lower than 3%, that is, the reaction is terminated. After the reaction was terminated, sodium acetate acetonitrile aqueous solution was added dropwise, and the volume ratio of acetonitrile and water in the sodium acetate acetonitrile aqueous solution was 4:1. After the dropwise addition, the solution is nearly neutral, and the pH value can be adjusted to about 7. Continue to stir, then perform low-temperature filtration, wash the filter cake with pure water until the solution is nearly neutral, and dry after washing to obtain the intermediate MD-I; the yield is 98.1%.

[0037] (2) Add the dried intermediate MD-I an...

Embodiment 3

[0040] A preparation method of caspofungin, comprising the following steps:

[0041] (1) Add 1 mol neomocontin B 0 After dissolving 3mol phenylboronic acid in 400ml acetonitrile, cool down to -42°C; add 4mol thiophenol and stir to mix evenly, add 2mol trifluoromethanesulfonic acid dropwise, control the temperature below -40°C to pneumocantine B 0The content is 5%, that is, the reaction is terminated. After the reaction was terminated, sodium acetate acetonitrile aqueous solution was added dropwise, and the volume ratio of acetonitrile and water in the sodium acetate acetonitrile aqueous solution was 4:1. After the dropwise addition, the solution is nearly neutral, and the pH value can be adjusted to about 6. Continue to stir, then perform low-temperature filtration, wash the filter cake with pure water until the solution is nearly neutral, and dry after washing to obtain the intermediate MD-I; the yield is 98.3%.

[0042] (2) Add the dried intermediate MD-I and 6mol phenylb...

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Abstract

The invention discloses a preparation method of caspofungin. The preparation method comprises steps as follows: pneumocandin B0 and phenylboronic acid are dissolved in acetonitrile, thiophenol is added, the mixture is stirred and uniformly mixed, trifluoromethane sulfonic acid is added dropwise, and an intermediate MD-I is obtained; the intermediate MD-I and phenylboronic acid are added to an anhydrous tetrahydrofuran solution, mixed and dissolved, BSTFA (bis-trimethylsilyl-trifluoroacetamide) is added under protection of nitrogen, the mixture continues to have a reaction, a borane-tetrahydrofuran solution is added dropwise, the mixture has a reaction, tetrahydrofuran is removed through reduced pressure distillation, and an intermediate MD-II is prepared after a product is separated; the intermediate MD-II is dissolved in methanol, the mixture is cooled under the protection of nitrogen, ethylene diamine is added until the mixture reacts sufficiently, and caspofungin is obtained after freezing drying. The new preparation method of caspofungin has the advantages as follows: the route is short, the reaction condition is mild, post-processing is simple, the yield is remarkably improved by comparison with that in the prior art, the total synthesis time can be remarkably shortened, the operative difficulty index and requirements for equipment are reduced to a certain extent, and the production cost is remarkably reduced.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of caspofungin. Background technique [0002] Caspofungin acetate is an echinocandin antifungal drug whose mechanism of action is to prevent the formation of fungal cell walls. Caspofungin can be used in the treatment of neutropenia, suspected fungal infection in febrile patients, and in the treatment of invasive aspergillosis refractory or intolerable to other treatments. Caspofungin is effective against Aspergillus (including Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, A. Candida, Candida guillimonia, Candida kactii, Candida krusei, Candida lipolytica, Candida portuguese, Candida parapsilosis, Candida plicata and C tropicalis) have in vitro activity. Caspofungin acetate can inhibit the synthesis of β(1,3)-D-glucan in the cell wall of many filamentous fungi and yeast; P(1,3)-D-glucan does not exist in mammalian cells suga...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56
CPCC07K7/56
Inventor 贺正全田单
Owner 成都摩尔生物医药有限公司
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