- Identification and synthesis of potential impurities of bilastine drug substance
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Bilastine is a new, well-tolerated, nonsedating H1 receptor antihistamine. Herein, we describe the synthesis of four new potential impurities of bilastine, namely 2-[4-(2-(4-(1-(2-methoxyethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl) phenyl]-2-methylpropanoic acid (2) (methoxyethyl bilastine), 2-[4-(2-(4-(1-(2-(2-ethoxyethoxy)ethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl)phenyl]-2-methyl propanoic acid (3) ((2-ethoxyethoxy)ethyl bilastine), 2-amino-2-methylpropyl 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl) piperidine-1-yl)ethyl)phenyl]-2-methyl propanoate (4) (2-amino-2-methylpropyl ester of bilastine or bilastine open-ring ester) and 2-[4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl] piperidine-1-yl) ethyl) phenyl]-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylpropanamide (5) [N-(1-hydroxy-2-methyl-2-propanyl)amide of bilastine or bilastine open-ring amide]. Each (2, 3, 4 and 5) is an observed process-related impurity with a possible significant impact on the quality of the drug product. This work is useful for generic pharmaceutical industry for making impurity reference standards. Pharmacopeia is not available for bilastine; hence, the control of these impurities in the API below the threshold level is essential as per International Conference on Harmonization (ICH) recommendations.
- Chavakula, Ramadas,Dussa, Nageshwar,Mamidi, Srinivas,Padma, M.,Panasa, Mahesh,Reddy, T. Purendar
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- TITLE: PROCESS FOR THE PREPARATION OF BILASTINE
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The present invention relates to a process for the preparation of bilastine, a compound of formula I. The present invention relates to p-xylene solvate of bilastine and process for its preparation. The present invention relates to a process for the prepar
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Paragraph 0130
(2020/05/12)
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- A process for the preparation of the compared to the russ sandbank method (by machine translation)
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The invention relates to a process for the preparation method compared to the russ sandbank, including I [...] compound added to the water, to add a phase transfer catalyst, paratoluene sulfonyl chloride and sodium hydroxide, after stirring and reacting and filtration to obtain [...] sulfonic acid ester. The sulfonic acid ester added to the water, by adding 2 - (4 - piperidinyl) 1 - H - benzimidazole and phase-transfer catalyst, adding sodium carbonate or potassium carbonate, heating suspension reaction 3 - 5 hours, filtering the obtained intermediate II is added to the strong polar non-protic solvent, by adding sodium hydroxide, phase-transfer catalyst, ethylene glycol is added to the toluene sulfonic acid ester, - 20 - 60° stirring reaction after the end of the filter and wash the obtained intermediate III. The intermediate III into the organic acid aqueous solution, refluxing 3 - 5 hours, water addition, adding alkali saturated, solution reflux 3 - 5 hours, generated in the saturated [...] does not dissolve in the alkaline solution, extraction [...]. The method of mild reaction conditions, the operation is simple, environmental protection, high yield, is suitable for industrial production. (by machine translation)
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Paragraph 0027-0031
(2019/05/11)
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- Bilastine intermediate preparation method
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The present invention relates to a Bilasiting intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole preparation method, the compound 2-{1-[4-(2-hydroxyethyl) phenyl]-1-methylethyl}-4,5-2H-4,4-dimethyl-oxazole is dissolved in an organic solvent, trifluoromethanesulfonyl chloride is dissolved, and added dropwise to the system, after the completion of the addition, triethylamine is added for heating and refluxing for 1h to obtain structure II compound 2-[4-(1-(4,4-dimethyl-2H-oxazol-2-yl)-1-methylethyl) phenyl] ethyl triflate, and the resulting compound 2-[4-(1-(4,4-dimethyl-2H-oxazol-2-yl)-1-methylethyl) phenyl] ethyl triflate is dissolved in an organic solvent, under nitrogen protection, sodium methoxide is added for reaction for 2 h, 2-(4-piperidine)-1 H-benzimidazole is added for heating and refluxing for 2h to obtain 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole.
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