N-substituted regioisomer of Besifloxacin

REGIOMER OF BESIFLOXACIN

Abstract: In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1 was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2 in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of 1H-NMR, 13C-NMR, mass spectrometry data and elemental analysis.

Structural Characterization
1H-NMR (500 MHz, DMSO-d6): δ ppm: 14.73 (H-23, s, 1H), 9.72 (H-14, s, 2H), 8.69 (H-7, s, 1H),7.79 (H-1, d, J = 13.1 Hz, 1H), 6.20 (H-11, d, J = 9.1 Hz, 1H), 4.37 (H-12 and H-19, m, 2H), 3.38(H-13, m, 2H), 3.23 (H-15, m, 1H), 3.09 (H-15, m, 1H), 2.14 (H-18, m, 1H), 1.94 (H-16 and H-18, m,2H), 1.84 (H-16 and H-17, m, 2H), 1.60 (H-17, m, 1H), 1.23 (H-20 or H-21, m, 2H), 1.03 (H-20 orH-21, m, 2H).
13C-NMR(125 MHz, DMSO-d6): δ ppm: 175.6 (C-9), 165.4 (C-22), 151.7 (C-7), 150.6 (C-2), 148.7(C-3), 139.0 (C-5), 137.3 (C-4), 117.8 (C-10), 110.3 (C-1), 107.0 (C-8), 52.9 (C-12), 50.1 (C-13), 46.2(C-15), 41.3 (C-19), 34.0 (C-18), 24.9 (C-16), 21.6 (C-17), 10.9 (C-20 or C-21).
FAB-MS, m/z = 394.1 (M+).
Elemental analysis: Calculated for C19H21ClFN3O3.HCl: C, 53.03%; H, 5.15%; N, 9.77%; found: C,52.82%; H, 5.39%; N, 9.50%.

1H-NMR (500 MHz, DMSO-d6): δ ppm: 14.73 (H-23, s, 1H), 9.72 (H-14, s, 2H), 8.69 (H-7, s, 1H), 7.79 (H-1, d, J = 13.1 Hz, 1H), 6.20 (H-11, d, J = 9.1 Hz, 1H), 4.37 (H-12 and H-19, m, 2H), 3.38 (H-13, m, 2H), 3.23 (H-15, m, 1H), 3.09 (H-15, m, 1H), 2.14 (H-18, m, 1H), 1.94 (H-16 and H-18, m,2H), 1.84 (H-16 and H-17, m, 2H), 1.60 (H-17, m, 1H), 1.23 (H-20 or H-21, m, 2H), 1.03 (H-20 orH-21, m, 2H).

 

13C-NMR(125 MHz, DMSO-d6): δ ppm: 175.6 (C-9), 165.4 (C-22), 151.7 (C-7), 150.6 (C-2), 148.7(C-3), 139.0 (C-5), 137.3 (C-4), 117.8 (C-10), 110.3 (C-1), 107.0 (C-8), 52.9 (C-12), 50.1 (C-13), 46.2(C-15), 41.3 (C-19), 34.0 (C-18), 24.9 (C-16), 21.6 (C-17), 10.9 (C-20 or C-21).

PAPER

Molbank 2013, 2013(2), M801; doi:10.3390/M801

Short Note

(R)-7-(Azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid Hydrochloride

Zhengjun Xia, Zaixin Chen *  and Shuitao Yu

 http://www.mdpi.com/1422-8599/2013/2/M801

Supplementary File 3:Support Information (PDF, 340 KB)

Download PDF [188 KB, 27 May 2013; original version 22 May 2013]

R&D Center, Jiangsu Yabang Pharmaceutical Group, Changzhou 213200, China

In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of ¹H-NMR, ¹³C-NMR, mass spectrometry data and elemental analysis

REGIOMER OF BESIFLOXACIN

BESIFLOXACIN

 

 

Zaixin Chen *
R&D Center, Jiangsu Yabang Pharmaceutical Group, Changzhou 213200, China
* Author to whom correspondence should be addressed;

E-Mail: zaixin_chen@163.com.

Zai-Xin Chen

Director of R&D Center at Jiangsu Yabang Pharmaceutical Group Co., Ltd

https://cn.linkedin.com/in/zai-xin-chen-45074179

https://www.researchgate.net/profile/Zai_Xin_Chen

Experience

Director of R&D Center

Jiangsu Yabang Pharmaceutical Group Co., Ltd

Visiting Scientist

National Research Council Canada

2002 – 2003 (1 year)

Postdoctoral Researcher

RWTH Aachen University

August 2000 – February 2002 (1 year 7 months)Aachen, Germany

Education

Chengdu University of Science and Technology

CHANGZHOU,  CHINA

Changzhou

City in China

Changzhou is a prefecture-level city in southern Jiangsu province of China. It was previously known as Yanling, Lanling, Jinling, and Wujin.Wikipedia

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Di-Olmesartan Medoxomil an impurity

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

G. Venkanna,1,2 G. Madhusudhan,1 K. Mukkanti,2 A. Sankar,1 Y. Sampath Kumar,1 and G. Venakata Narayana1

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

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.

http://www.hindawi.com/journals/jchem/2013/516459/

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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