16155-08-1Relevant articles and documents
A new HPLC-UV derivatization approach for the determination of potential genotoxic benzyl halides in drug substances
Ji, Shunli,Gao, Hongbin,Xia, Xingya,Zheng, Feng
, p. 25797 - 25804 (2019/08/28)
Benzyl halides, widely used as alkylation reagents in drug synthesis, are potential genotoxic impurities (PGTIs) required to be controlled at trace levels. However, the existing analytical methods for benzyl halides often suffer from matrix interferences or low derivatization efficiency of benzyl chlorides. In this paper, a simple derivatization HPLC-UV method was developed for the analysis of these residual trace benzyl halides in drug substances. 1-(4-Nitrophenyl) piperazine (4-NPP) was selected as a new derivatization reagent because it shifted well the benzyl halides derivatives away to the near visible range (392 nm), which could minimize the matrix interferences from the drug substances and related impurities. Meanwhile, potassium iodide (KI) was used to convert the mixed benzyl halides into benzyl iodides before derivatization. The derivatization parameters were also optimized using the design of experiments (DoE) for achieving the best reaction efficiency. The results showed that the new approach had high specificity and sensitivity, and the LOQs were 7-9 μg g-1 relative to 5 mg mL-1 antipyrine and 17.5-22.5 μg g-1 relative to 2 mg mL-1 oroxylin A. The method is a valuable alternative for the determination of residual benzyl halides in the drug substances.
Synthesis of N-alkyl-N′-aryl or Alkenylpiperazines: A Copper-Catalyzed C–N Cross-Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO
Ghazanfarpour-Darjani, Majid,Barat-Seftejani, Forugh,Khalaj, Mehdi,Mousavi-Safavi, Seyed Mahmoud
, (2017/08/18)
Unsymmetrical piperazines are key constituents of many pharmaceuticals. Given that the selective introduction of an aryl and alkyl motif onto the piperazine is not always straightforward, direct arylation and alkenylation of 1,4-diaza-bicyclo[2.2.2]octane would obviate the inefficiencies associated with the preparation of these target molecules. We have utilized alkyl halides, aryl or alkenyl triflates, and 1,4-diaza-bicyclo[2.2.2]octane for the synthesis of N-alkyl-N′-aryl or alkenylpiperazines. The optimum conditions are developed using CuCl, t-BuOLi in NMP. Alkenyl triflates requires N,N′-dimethylethylenediamine and higher temperature to afford the desired cross-coupled product. Substrates bearing electron-deficient and electron-rich groups were successfully coupled under the optimum reaction conditions.
Design, synthesis and pharmacological evaluation of N-[4-(4-(alkyl/aryl/heteroaryl)-piperazin-1-yl)-phenyl]-carbamic acid ethyl ester derivatives as novel anticonvulsant agents
Kumari, Shikha,Mishra, Chandra Bhushan,Tiwari, Manisha
supporting information, p. 1092 - 1099 (2015/02/19)
A series of alkyl/aryl/heteroaryl piperazine derivatives (37-54) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h) and also delivered excellent protection in sc-PTZ test (100 mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5 mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule.
