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Process and intermediates for the synthesis of caspofungin

A technology for compounds and acid addition salts, applied in the field of preparing these intermediates, can solve problems such as not using known methods

Inactive Publication Date: 2008-11-12
SANDOZ AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, the known methods are not optimal for industrial production in terms of yield, purity, stability, and amount of by-products

Method used

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  • Process and intermediates for the synthesis of caspofungin
  • Process and intermediates for the synthesis of caspofungin
  • Process and intermediates for the synthesis of caspofungin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0172]

[0173] The compound of formula VI can be isolated from the reaction mixture by, for example, chromatography using RP-18 material followed by lyophilization of the enriched fraction. For chromatography, a mixture of acetic acid and acetonitrile may be used, wherein the ratio of acetic acid to acetonitrile is from about 60:40 to about 80:20, such as about 70:30, such as 75:25. The amorphous compound of formula VI can then be dissolved in an organic solvent, for example an alcohol such as methanol or ethanol, in the presence of acetic acid. By adding an anti-solvent, such as an ester, such as C of acetic acid 1 -C 4 Alkyl esters, such as ethyl acetate, can crystallize the monoacetate salt of the compound of formula VI. In addition, crystallization effectively removes impurities such as the C-35 epimer (homotyrosine moiety), which are difficult or impossible to remove economically by chromatography.

[0174] As described herein, compounds of formula II are intermedi...

Embodiment 1

[0191] Embodiment 1: the preparation of formula IV compound

[0192] Pneumocandin B 0 (10.2g) was dissolved in a mixture of dry 1-methyl-2-pyrrolidone (90ml) and dry N,N-dimethylformamide (10ml). The pale yellow solution was cooled to -20°C, and cyanuric chloride (4.2 g) was added in one portion. The mixture was stirred at -20°C until 98% conversion was reached (HPLC, ca. 3.5 hours). Water (100ml) was added over 10 minutes and the mixture was allowed to warm to ambient temperature.

[0193] The crude mixture was slowly poured into vigorously stirred water (1400ml). The suspension was aged for 2h, then filtered. The product was washed thoroughly with water and dried under vacuum. This material (9.3 g) was used in the next reaction without further purification.

Embodiment 2

[0194] Embodiment 2: the preparation of formula IV compound

[0195] Pneumocandin B 0 (10.0g) was dissolved in dry N,N-dimethylformamide (100ml). The water content of the solution was measured and adjusted to about 0.15%. The solution was cooled to -20°C, and cyanuric chloride (4.2 g) was added in one portion. The mixture was stirred at -20°C until 97% conversion was achieved (HPLC, ca. 1.0 hr). Water (100ml) was added over 10 minutes and the mixture was allowed to warm to ambient temperature.

[0196] The crude mixture was slowly poured into vigorously stirred water (1400ml). The suspension was aged for 2h, then filtered. The product was washed thoroughly with water and dried under vacuum. This material (8.2 g) was used in the next reaction without further purification.

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Abstract

The present invention relates to novel processes for preparing certain aza cyclohexapeptide compounds, e.g. caspofungin, novel intermediates used in said processes and a process for preparing said intermediates. In particular, the intermediates have formula (II), wherein X is amino or substituted amino, and contains a cyano / nitrile functionality.

Description

technical field [0001] This invention relates to novel processes for the preparation of certain azacyclic hexapeptides, novel intermediates for use in these processes and processes for the preparation of these intermediates. Background technique [0002] The azacyclic hexapeptides represented by formula I as defined below are macrocyclic acylpeptides belonging to the echinocandins class, which are used for the treatment of systemic fungal infections, especially caused by Candida, Those caused by Aspergillus, Histoplasma, Coccidioides and Blastomyces. They have also been found to be useful in the treatment and prophylaxis of infections caused by Pneumocystis carinii, which are often found in immunocompromised patients such as those with AIDS. Pneumocandins are a subclass of echinocandins that are naturally produced by the fungus Glarea lozoyensis. Their isolation, structural elucidation and biological evaluation are reported by Schmatz et al. in Cutaneous Antifungal Agents ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56C07K1/113
CPCA61K38/00C07K7/56A61P31/10C07K1/113
Inventor J·卢德谢尔I·马赫尔O·施托姆S·贝特尔
Owner SANDOZ AG
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