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Preparation method of anidulafungin intermediate

A technology of anidungin and intermediates, applied in the field of drug synthesis, can solve problems such as not being suitable for industrial production, and achieve the effect of simple operation

Inactive Publication Date: 2019-05-24
南京天越星生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The preparation method of the anifungin intermediate p-pentylene terbenzoic acid in the prior art is not suitable for industrialized production

Method used

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  • Preparation method of anidulafungin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] At room temperature, add potassium carbonate (190g), water (750mL) and DMF (750mL) to the reaction flask, and add 4-iodobenzoic acid (53g), 1,4-benzenediboronic acid pinacol ester indole under stirring condition (93g) under nitrogen protection, add tetrakis (triphenylphosphine) palladium (2.7g), be heated to 60 ℃ of reaction, after reacting for 3 hours, slowly add 4-n-pentyloxy iodobenzene (62g) in the reaction system DMF (130mL) solution was added, and the reaction was continued for 4 hours. Cool the reaction solution to 5-10°C, adjust the pH of the system to 4 with 0.5M dilute hydrochloric acid under stirring, continue stirring for 1 hour, filter, wash the filter cake with water, and then wash the filter cake with alcohol, and dry to obtain p-amyl Terbenzoic acid (82 g), HPLC purity 99.9%.

Embodiment 2

[0025] At room temperature, add sodium carbonate (100g), water (500mL) and DMF (800mL) into the reaction flask, add 4-iodobenzoic acid (39g), 1,4-benzenediboronic acid pinacol ester indole under stirring condition (59g) Under the protection of nitrogen, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dioxide (2.1g), heat to 60°C for reaction, after 2.5 hours of reaction, slowly pour into the reaction system A solution of 4-n-pentyloxyiodobenzene (45 g) in DMF (100 mL) was added, and after the addition was complete, the reaction was continued for 3 hours. The reaction solution was cooled to 5-10°C, and the pH value of the system was adjusted to 4 by using 0.5M dilute hydrochloric acid under stirring conditions, and continued to stir for 0.5 hours, filtered, washed the filter cake with water and ethanol, and dried to obtain p-pentyleneterphenylcarboxylic acid (55g ), HPLC purity 99.8%.

Embodiment 3

[0027] At room temperature, add sodium carbonate (1000g), water (4L) and DMF (6L) to the reaction flask, add 4-iodobenzoic acid (390g), 1,4-benzenediboronic acid pinacol ester indole under stirring conditions (590g) under the protection of nitrogen, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dioxide (21g), heat to 60°C for reaction, after reacting for 3 hours, slowly add DMF (1 L) solution of 4-n-pentyloxyiodobenzene (450 g) was added, and the reaction was continued for 6 hours. The reaction solution was cooled to 5-10°C, and the pH value of the system was adjusted to 4 by using 0.5M dilute hydrochloric acid under the stirring condition, and the stirring was continued for 2 hours, filtered, and the filter cake was washed with water and ethanol, and dried to obtain p-pentyleneterphenylcarboxylic acid (550g ), HPLC purity 99.7%.

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an anidulafungin intermediate. The preparation method includes the steps of (1), subjecting iodobenzoic acid and 1,4-indole-dibenzoboronic acid pinacol ester to reaction in a solvent in the presence of palladium and alkali; (2), adding 4-p-(pentyloxy) iodobenzene to reaction liquid of the step (1) to obtain 4''-(pentyloxy)-[1,1':4',1''-Terphenyl]-4-carboxylic acid, namely the anidulafungin intermediate. The preparation method is easy in operation and high in yield and capable ofmeeting requirements on industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an anifungin intermediate. Background technique [0002] Anifungin is an echinocandin antifungal drug used to treat candidemia. The drug was developed by Pfizer and was approved by the FDA in 2006 for listing in the United States. Anifungin has a relatively complex structure In the industry, bio-fermentation technology is often used for synthesis, including the fermentation of Aspergillus nidulans to produce echinocandin B; then in the microbial transformation process, the deacylase produced by the fermentation of actinomycetes catalyzes echinocandin B, making echinocandin B Its side chain is broken to generate the precursor of anidungin - the echinocandin B core, and further introduce a new side chain through chemical modification on the basis of the core, that is, the pentyloxy-triphenylcarboxylic acid group, Existing documents such a...

Claims

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Application Information

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IPC IPC(8): C07C51/353C07C65/24
Inventor 吴学平李德建
Owner 南京天越星生物技术有限公司
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