156366-27-7Relevant academic research and scientific papers
Amlodipine benzenesulfonate: A mechanistic investigation of its industrial preparation via detritylation of N-tritylamlodipine and related NMR studies
Furlan, Borut,Grdadolnik, Simona Golic,Hocevar, Stanko,Kocjan, Darko,Levec, Janez,Maskill, Howard,Navratilova, Hana,Pospisil, Jiri,Potacek, Milan,Urleb, Uros,Zmitek, Janko
experimental part, p. 299 - 309 (2010/03/30)
Kinetics and product analysis of detritylation of N-tritylamlodipine by benzenesulfonic acid in methanol, methanol-chloroform (volume ratio 9:1), ethanol, 2-propanol, and methanol/2-propanol (mole ratio 1:1) have been investigated by HPLC; amongst these reaction conditions are ones closely similar to those of one method of manufacturing amlodipine benzenesulfonate. Kinetics of detritylation of Ntritylamlodipine have also been investigated in methanol-d4 by 1H NMR spectroscopy and the agreement with the results by HPLC is good. The rate of detritylation increases with increasing concentrations of benzenesulfonic acid, and p-methoxy-substituents in the trityl group have been shown to lead to faster reactions. In methanol, the rate is hardly affected by 10 % (vol. fraction) chloroform. These studies relate to mechanistic investigations of acid-catalysed deaminations of methoxy-substituted tritylalkylamines, and Arrhenius activation parameters (Ea and A) are similar indicating a common generic mechanism. Acid-catalysed trans-esterification has been shown by HPLC to accompany detritylation in methanol, and attendant protium-deuterium exchange in the methyl at C6 by reversible acid-catalysed iminium ion formation in the 4-aryl-1,4-dihydropyridine moiety of both N-tritylamlodipine and amlodipine has been investigated in deuteriated methanol by 1H, 13C, and 15N NMR spectroscopy.
A PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULFONATE
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Page/Page column 8-9, (2008/06/13)
The present invention relates to novel alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate, wherein alkyl represents C1C4 alkyl group, preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate in high overall yield and high purity, containing substantially less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4- dihydro-6-methyl-3,5-pyridinedicarboxylate as the single remaining impurity. No other impurities are contained in obtained pure crystalline amlodipine benzenesulfonate. Preferably, 2-chlorobenzaldehyde is contacted with ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate in an organic solvent, preferably ethanol, to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, which is converted without isolation from the reaction mixture, preferably with methyl (E)-3- aminocrotonate to form 3-ethyl 5-methyl (±)-2-[2-(N-tritylamino)ethoxymethyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate ("tritylamlodipine"), which is converted without isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, preferably ethanol, followed by isolation and purification of amlodipine benzenesulfonate. C1-C4 alkyl alcohols, especially methanol, ethanol, isopropanol and mixtures thereof, are used as an organic solvent. Amlodipine benzenesulfonate (besylate) is useful as antiishemic and antihypertensive agent.
TWO CRYSTALLINE HYDRATE FORMS OF AMLODIPINE BENZENESULFONATE OF HIGH PURITY, PROCESSES FOR THEIR PREPARATION AND USE
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Page 18; 19, (2010/02/04)
The novel crystalline amlodipine benzenesulfonate dihydrate of high purity is disclosed, as well as the process for preparation of the novel crystalline amlodipine benzenesulfonate dihydrate of high purity and the crystalline amlodipine benzenesulfonate monohydrate of high purity, suitable for the preparation of pharmaceutical formulations for the treatment of cardiac diseases or hypertension, and their use as intermediate compounds in the improved process of purification of the nonhydrate benzenesulfonate (besylate) salt of amlodipine.The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate is carried in the way that from the C1-C5 alcoholic solution of amlodipine benzenesulfonate with water while stirring at a temperature of 20°C or lower the crystals of pure amlodipine benzenesulfonate dihydrate are separated, and isolated.The process for preparation of the crystalline amlodipine benzenesulfonate monohydrate is carried in the way that from the C1-C5 alcoholic solution of amlodipine benzenesulfonate with water while stirring at a temperature of 30°C or higher the crystals of pure amlodipine benzenesulfonate monohydrate are separated, and isolated.
