Micafungin FR-179642 impurity (acid)
[CAS# 168110-44-9]

Identification

• Classification: API >> Synthetic anti-infective drugs >> Antifungal drugs
• Name: Micafungin FR-179642 impurity (acid)
• Synonyms: [5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-18-amino-3-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-11,20,21,25-tetrahydroxy-15-[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxyphenyl] hydrogen sulfate
• Molecular Formula: C₃₅H₅₂N₈O₂₀S
• Molecular Weight: 936.90
• CAS Registry Number: 168110-44-9
• EC Number: 801-824-0
• SMILES: C[C@H]1CN2[C@@H]([C@H]1O)C(=O)N[C@@H]([C@@H](C[C@@H](C(=O)N[C@H](C(=O)N3C[C@@H](C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C2=O)[C@@H](CC(=O)N)O)[C@@H]([C@H](C4=CC(=C(C=C4)O)OS(=O)(=O)O)O)O)O)[C@@H](C)O)N)O)O

Properties

• Solubility: Soluble (37 g/L) (25 ºC), Calc.^*
• Density: 1.75±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of refraction: 1.718 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS08 Warning
• Hazard Statements: H361
• Precautionary Statements: P201-P202-P281-P308+P313-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Reproductive toxicity	Repr.	2	H361

Discovory and Applicatios

Micafungin FR-179642 impurity (acid), with the molecular formula C₃₅H₅₂N₈O₂₀S and CAS number 168110-44-9, is a key impurity associated with micafungin, an echinocandin antifungal drug. This compound, also referred to as FR-179642, is the cyclic polypeptide nucleus of micafungin, formed during its synthesis or degradation. It is recognized in pharmaceutical chemistry for its role in quality control and impurity profiling of micafungin, which is used to treat invasive fungal infections. Its discovery and applications are well-documented in the literature, stemming from the development of echinocandin antifungals and analytical methods for drug purity.

The discovery of micafungin FR-179642 impurity (acid) is tied to the development of micafungin, a semi-synthetic lipopeptide derived from the fermentation product of Coleophoma empetri, introduced by Fujisawa Pharmaceutical (now Astellas) in the 1990s. Micafungin was approved in 2005 for treating candidemia, esophageal candidiasis, and prophylaxis of Candida infections. During its synthesis, researchers identified FR-179642 as a critical intermediate and potential impurity, formed by hydrolysis of micafungin’s side chain, specifically the 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzamide group. This hydrolysis occurs under acidic or basic conditions during fermentation, purification, or storage, yielding the cyclic polypeptide core. The impurity was characterized in the 1990s using NMR and mass spectrometry, driven by the need to ensure drug safety and efficacy under regulatory standards. Its identification built on advances in high-performance liquid chromatography (HPLC) and forced degradation studies, which revealed its presence in trace amounts in micafungin formulations.

Synthetically, FR-179642 is produced during the fermentation of Coleophoma empetri in a nutrient-rich medium with glucose and amino acids. The fungus generates pneumocandin A0, which is chemically modified to form micafungin. FR-179642, chemically 1-[(4R,5R)-4,5-dihydroxy-L-ornithine]-4-[(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]pneumocandin A0, is isolated as a by-product when the side chain is cleaved, often during purification or under hydrolytic conditions. It can also be synthesized by controlled hydrolysis of micafungin, using acidic or basic aqueous solutions to remove the lipophilic side chain, followed by extraction and purification via reverse-phase chromatography. These processes rely on established protocols in echinocandin synthesis and peptide chemistry, ensuring high purity for use as a reference standard in quality control.

The primary application of micafungin FR-179642 impurity (acid) is in pharmaceutical quality control and analytical testing. As an impurity, it is monitored to ensure micafungin meets regulatory standards set by the United States Pharmacopeia and International Council for Harmonisation (ICH). Its presence in trace amounts can contribute to hemolytic activity, potentially affecting drug safety, making its quantification critical. HPLC methods, developed by 2013, use columns like Agilent Zorbax SB-C18 to separate FR-179642 from micafungin and other impurities, achieving detection limits of 0.006–0.013% and recovery rates of 98.2–102.0%, validated for specificity, linearity, and robustness. These methods are stability-indicating, confirming FR-179642’s formation under stress conditions like acidic hydrolysis. The impurity is supplied by companies like Clearsynth and SimSon Pharma as a reference standard for method development and drug testing.

In academic research, FR-179642 is studied to understand micafungin’s degradation pathways and impurity profiles, aiding in the optimization of synthesis and storage conditions. Its structure, lacking the lipophilic side chain, provides insights into the role of the cyclic polypeptide in antifungal activity, which targets 1,3-beta-D-glucan synthase in fungal cell walls. The impurity’s significance lies in its role as a marker for ensuring micafungin’s purity and safety, reflecting progress in analytical chemistry and echinocandin development.

References

2006. Micafungin. Pharmaceutical Substances.

2013. Development and Validation of a Stability-Indicating High Performance Liquid Chromatographic (HPLC) Method for the Determination of Related Substances of Micafungin Sodium. Scientia Pharmaceutica, 81(4).
DOI: 10.3797/scipharm.1305-03

2018. Deciphering the late steps of rifamycin biosynthesis. Nature Communications, 9(1).
DOI: 10.1038/s41467-018-04772-x