Synthesis of echinocandin antifungal agent

A compound and composition technology, applied in antifungal agents, peptide/protein components, cyclic peptide components, etc., can solve the complex and difficult production of pharmaceutical grade echinocandins

Pending Publication Date: 2021-05-25
CIDARA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The production of pharmaceutical-grade echinocandins is complicated by the difficulty and expense of relying on chromatographic methods to remove structurally similar impurities produced during the commercial-scale production of these antifungal agents

Method used

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  • Synthesis of echinocandin antifungal agent
  • Synthesis of echinocandin antifungal agent
  • Synthesis of echinocandin antifungal agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1. Compound 1 was synthesized from the phenylboronic acid ester of Anifungin.

[0098] Anifungin Phenylboronate:

[0099] To a solution of anidulungin (5 g) in tetrahydrofuran (70 mL) was added a solution of phenylboronic acid (0.7 g) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated by rotary evaporation. The resulting solid was dissolved in tetrahydrofuran (60 mL) and concentrated by rotary evaporation. The resulting solid was redissolved in tetrahydrofuran (60 mL) and concentrated by rotary evaporation. The resulting solid mixture was redissolved in acetonitrile / tetrahydrofuran (30 mL / 15 mL) and concentrated by rotary evaporation. The resulting anidulungin phenyl borate solid was dried overnight in vacuo.

[0100] Choline Chloride Drying:

[0101] In a round bottom flask, choline chloride (18.6 g) was suspended in acetonitrile (150 mL) and stirred for 4 hours. The susp...

Embodiment 2

[0106] Example 2. Compound 1 was synthesized from 4-(trifluoromethyl)phenylboronate of anidulungin.

[0107] The reaction was performed on a 200 mg scale similar to the method of Example 1 except that the boronic acid was changed to 4-(trifluoromethyl)phenylboronic acid and the reaction time was 24 hours. Results: 63% Compound 1; 7.0% Compound 1 β-diastereomer.

[0108] A second conjugation experiment was performed in which 4-(trifluoromethyl)phenyl boronate was first dissolved in an acetonitrile:TFA mixture, and then a dry solution of choline chloride was added to it. After 2.5 h, the reaction mixture was diluted with water:acetonitrile (70:30) and the pH was adjusted to 2.0 by addition of ammonium hydroxide. Results: 75% Compound 1; 4.8% Compound 1 β-diastereomer.

Embodiment 3

[0109] Example 3. Compound 1 was synthesized from 2,6-dimethylphenyl borate of anidulungin.

[0110] The reaction was performed on a 200 mg scale similar to the method of Example 1 except that the boronic acid was changed to 2,6-dimethylphenylboronic acid. Results: 55% compound 1; 7.4% compound 1 β-diastereomer.

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PUM

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Abstract

The present invention relates to echinocandin cyclopeptides and to methods for preparing echinocandin cyclopeptides.

Description

Background technique [0001] The invention features methods for the synthesis of compounds useful in the treatment of fungal infections and related conditions. [0002] Fungal infections, such as those caused by Candida and Aspergillus, can be serious and life-threatening infections that represent a major public health problem, especially in highly vulnerable groups, including the elderly people, postoperative patients, critically ill patients, and other hospitalized patients with serious medical conditions. Due to the increasing resistance to existing antifungal drugs, there is an urgent need to develop new and more effective antifungal agents to treat these serious infections. Echinocandins are members of a major class of antifungal agents used to treat fungal infections. These compounds target the cell wall by preventing the production of 1,3-β-D-glucan through inhibition of the catalytic subunit of the 1,3-β-D-glucan synthase complex. [0003] While nature provides a sig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56C07K1/02A61K38/12A61P31/10
CPCA61K9/0019A61K38/00C07K7/56C07D487/14C07K7/64
Inventor D·休斯M·P·休斯R·M·休斯B·拉哈克里什南Y·博尔盖特S·麦金泰尔
Owner CIDARA THERAPEUTICS
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