Di-Olmesartan Medoxomil an impurity
Dimedoxomil olmesartan
Dimedoxomil Impurity (19)
Preparation of (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4-(2-hydroxypropan-2-yl)-1-((2′-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl) methyl)-1H-tetrazol-5-yl) biphenyl-4-yl) methyl)-2-propyl-1H-imidazole-5-carboxylate (19)
To a solution of 1-((2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 8 (10.0 g 0.022 mole) in acetone (100 mL) was added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (medoxomil) (6.6 g 0.044 mole), potassium carbonate (5.7 g, 0.043 mole), and tetrabutylammonium bromide (cat) at ambient temperature. The resulting mixture was heated at reflux for 12 hours. The reaction was cooled to room temperature, filtered and washed with acetone (40 mL). The combined filtrate, and washings were concentrated under reduced pressure, and the residue partitioned between ethyl acetate ( 2 × 6 0 mL) and water ( 2 × 2 0 mL). The combined ethyl acetate layer was dried over anhydrous sodium sulfate and recovered at reduced pressure to afford crude 19, which was purified by column chromatography on silica gel using 10% methanol in dichloromethane afforded solid which on recrystallisation in acetone afforded pure 19 as an off-white colored powder (14.0 g, 93%) (Scheme 6).
IR (KBr, cm−1) 3385 (O–H); 2931 (C–H); 2875 (Ar C–H); 1816.4 (Carbonate C=O); 1741.9 (Ester C=O); 1531 (Ar C=C); 1531 (Ar C–N).
1H NMR (CDCl3) 0.96 (t, 3H, CH3); 1.54 (s, 6H, 2CH3); 1.66 (m, 2H, CH2); 1.7–1.98 (s, 6H, 2CH3); 2.55 (t, 2H, CH2); 4.40 (s, 2H, CH2); 4.92 (s, 2H, CH2); 5.19 (s, 2H, CH2); 6.98 (d, 2H, Ar–H); 7.28 (dd, 2H Ar–H); 7.45–7.80 (m, 4H, Ar–H).
Mass (m/e): 671.4, mp: 126–130°C,
Elemental analysis: calculated for C34H34N6O9: C, 60.89; H, 5.11; N, 12.53; O, 21.47; found: C, 60.91; H, 5.23; N, 12.62; O, 21.52.
Unknown Impurity (19) (M/Z: 670.67)
The unknown impurity 19 has higher m/z value than that of olmesartan medoxomil and as per analysis of mass spectral data of LC-MS, presence of extra medoxomil moiety intacts with target chemical entity 1. The possibility could be the reaction of known impurity 19 with medoxomil and leads to both O and N alkylation. It was prepared by employing the same strategy (mechanistic reason), and all the spectral data confirm the structure. Chromatographic studies (HPLC) with varying the concentration of impurity are also conducted and concluded that the same impurity existed in targeted entity olmesartan medoxomil.
Journal of Chemistry Volume 2013 (2013), Article ID 516459, 8 pages http://dx.doi.org/10.1155/2013/516459
Research Article
Synthesis and Characterization of Process-Related Impurities of Antihypertensive Drug Olmesartan Medoxomil
1Department of Research and Development, Inogent Laboratories Private Limited, 28A, IDA, Nacharam, Hyderabad 500 076, India
2Centre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
2Centre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
Received 18 February 2012; Accepted 17 May 2012
Academic Editor: Andreas G. Tzakos
Copyright © 2013 G. Venkanna et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Olmesartan medoxomil (1) is the latest angiotensin receptor antagonist approved by the FDA for the treatment of hypertension. During the process development of olmesartan medoxomil, three process-related impurities were observed along with the final API. These impurities were identified as isopropyl olmesartan (12), dimedoxomil olmesartan (19), dibiphenyl olmesartan (17). The present work describes the synthesis and characterization of all these three impurities.
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