Two new impurities were described and determined using gradient HPLC method with UV detection in retigabine (RET). Using LC-HRMS, NMR and IR analysis the impurities were identified as RET-dimer I: diethyl {4,4'-diamino-6,6'-bis[(4-fluorobenzyl)amino]biphenyl-3,3'-diyl}biscarbamate and RET-dimer II: ethyl {2-amino-5-[{2-amino-4-[(4-fluorobenzyl) amino] phenyl} (ethoxycarbonyl) amino]-4-[(4-fluorobenzyl)amino] phenyl}carbamate. Reference standards of these impurities were synthesized followed by semipreparative HPLC purification. The mechanism of the formation of these impurities is also discussed. An HPLC method was optimized in order to separate, selectively detect and quantify all process-related impurities and degradation products of RET. The presented method, which was validated in terms of linearity, limit of detection (LOD), limit of quantification (LOQ) and selectivity is very quick (less than 11min including re-equilibration time) and therefore highly suitable for routine analysis of RET related substances as well as stability studies.
A new impurity was detected and determined using gradient ion-pair UHPLC method with UV detection in zolmitriptan (ZOL). Using MS, NMR and IR study the impurity was identified as (4S,4'S)-4,4'-(2,2'-(4-(dimethylamino)butane-1,1-diyl)bis(3-(2-(dimethylamino) ethyl)-1H-indole-5,2-diyl))bis(methylene)di(oxazolidin-2-one) (ZOL-dimer). The standard of ZOL-dimer was consequently prepared via organic synthesis followed by semipreparative HPLC purification. The UHPLC method was optimized in order to selectively detect and quantify other known and unknown process-related impurities and degradation products of ZOL as well. The presented method which was validated with respect to linearity, accuracy, precision and selectivity has an advantage of a very quick UHPLC chromatographic separation (less than 7 min including re-equilibration time) and therefore is highly suitable for routine analysis of related substances and stability studies of ZOL.
- MeSH
- hmotnostní spektrometrie metody MeSH
- kontaminace léku MeSH
- limita detekce MeSH
- magnetická rezonanční spektroskopie metody MeSH
- oxazolidinony chemie izolace a purifikace MeSH
- oxazoly izolace a purifikace MeSH
- spektrofotometrie infračervená metody MeSH
- spektrofotometrie ultrafialová metody MeSH
- techniky syntetické chemie metody MeSH
- tryptaminy chemie izolace a purifikace MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate for the synthesis of licofelone, an anti-inflammatory drug currently undergoing evaluation of the phase-III clinical studies, is described. The method is based on a novel synthesis of unstable 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole, which is then treated with 2-bromo-1-(4-chlorophenyl)ethan-1-one. 2,2-Dimethyl-5-phenylpent-4-ynal with benzylamines provides the corresponding Schiff bases. Migration of the C=N double bond in these N-(2,2-dimethyl-5-phenylpent-4-yn-1-ylidene)benzylamines into conjugation with the aromatic ring using various base/solvent systems was studied. Acid hydrolysis of the formed Schiff bases then provided 2,2-dimethyl-5-phenylpent-4-yn-1-amine and 2,2-dimethyl-5-phenylpenta-3,4-dien-1-amine; their ratio was influenced mainly by the reaction conditions. Cyclization of these amines using Ag or Au catalysts then led to 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole.
A new methodology useful for preparation of indole derivatives bearing a 2-(dialkylamino)-ethyl substituent at the 3-position has been developed. Application of this methodology to the synthesis of N,N-dimethyl-2-{5-[(1H-1,2,4-triazol-1-yl)methyl]-1H-indol-3-yl}ethan-1-amine (rizatriptan; 3) is described. The key reaction step is based on the radical cyclization of N-[4-(dimethylamino)but-2-yn-1-yl]-N-{2-iodo-4-[(1H-1,2,4-triazol-1-yl)methyl]phenyl}-acetamide (21), easily available by the Mannich reaction, and subsequent isomerization of the primarily formed methylidene derivative 22.
