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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REGIOMERS

http://www.google.com/patents/US7514563

FIG. 1 is a gHMBC spectrum of the borylation products of 4-chlorobenzonitrile. BELOW
 







FIG. 2 is a gHMBC spectrum of the borylation products of 4-bromobenzonitrile.
 






FIG. 3 is a gHMBC spectrum of the borylation product of 4-iodobenzonitrile.


 





FIG. 4 is a gHMBC spectrum of the borylation products of 4-methoxybenzonitrile.
FIG. 5 is a gHMBC spectrum of the borylation products of 4-thiomethylbenzonitrile.
FIG. 6 is a gHMBC spectrum of the borylation product of 4-dimethylaminobenzonitrile.
FIG. 7 is a gHMBC spectrum of the borylation product of methyl 4-cyanobenzoate.
FIG. 8 is a gHMBC spectrum of the borylation product of 4′-cyanoacetanilide.
FIG. 9 is a gHMBC spectrum of the borylation products of 1,5-dimethyl-2-pyrrolecarbonitrile.
FIG. 10 is a gHMBC spectrum of the borylation products of 5-methyl-2-furonitrile.



Regioisomer Assignment by NMR Spectroscopy:

From gHMBC NMR experiments, the two regioisomers for the borylation of 4-substituted benzonitriles can be distinguished unambiguously as in FIGS. 1 to 10. In isomer A, carbon atoms represented as C1 and C4 on the benzene ring, as well as C7 (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C3 is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (³J_C-H), which can be observed using gHMBC spectroscopy. In the gHMBC spectrum, carbon atoms C1 and C7 should show one cross peak each to proton H_c, whereas carbon atom C4 should show two cross peaks to protons H_a and H_b. Therefore the resulting number of cross peaks for C1, C4, and C7 should be 1, 2, and 1, respectively.
In Isomer B, carbon atoms represented as C1′, C4′, on the benzene ring, as well as C7′ (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C2′ is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (³J_C-H). In the gHMBC spectrum, carbon atoms C1′ and C7′ should show two cross peaks each, to protons H_d and H_e, whereas carbon atom C4′ should show only one cross peak to proton H_f. Therefore the resulting number of cross peaks for C1′, C4′, and C7′ should be 2, 1, and 2, respectively. Hence isomers A and B can be unambiguously assigned from gHMBC data.
For isomer A, with proton H_c unambiguously assigned by gHMBC, H_a and H_b can be assigned from their multiplicities. Proton H_a appears as a doublet, coupled to proton H_b with J≈2-3 Hz. Proton H_b appears as a doublet of doublets due to coupling to protons H_a and H_c. Carbon atoms C2, C6, and C5 were then assigned from the correlations in the gHMQC spectra. Carbon atom C7 (nitrile carbon) usually appears around δ 119. Depending on the substituent, carbon atom C1 was usually found shifted downfield around δ 130-170 (except in 4-iodobenzonitrile for which it appears around δ 100). Carbon atom C4 is shifted upfield, and was usually found around δ 100-115. Similarly, all the carbons of isomer B can be assigned.
In the five membered heterocycles, the ⁴J_H-H coupling was used together with gHMBC and NOESY1D spectroscopy to identify the major isomer. Regioisomers in the fluorine containing benzonitriles were assigned by ¹³C spectroscopy (with the help of the fact that the boron bearing carbon is not observed due to broadening from and coupling with boron). In the case of 1,3-dicyanobenzene, ¹H NMR spectroscopy was employed to assign the major and minor isomers.
Experimental Details and Spectroscopic Data EXAMPLE 1 Borylation of 4-fluorobenzonitrile

General procedure A was applied to 4-fluorobenzonitrile (242 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 8 h. The ratio of the two isomers in the crude reaction mixture by GC was 11:89. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (88.5 mg, 72%) as a white solid. The ratio of the two isomers in the isolated product by GC was 8:92. ¹³C NMR spectroscopy was used to assign the major isomer as 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. ¹H NMR (CDCl₃, 500 MHz): δ (major isomer) 8.04 (dd, ⁴J_H-F=5.4 Hz, J=2.2 Hz, 1H, H_d), 7.7 (ddd, J=8.5, 2.2 Hz, ⁴J_H-F=4.9 Hz, 1H, H_e), 7.1 (t, J=8.5 Hz, 1H, H_f), 1.32 (br s, 12H), (minor isomer) 7.67 (dd, J=8.8 Hz, ⁴J_H-F=4.9 Hz, 1H, H_c), 7.52 (dd, ³J_H-F=8.5 Hz, J=2.9 Hz, 1H, H_a), 7.17 (dt, J=8.3, 2.9 Hz, 1H, H_b) 1.34 (br s, 12H); ¹³C NMR {¹H} (CDCl₃, 125 MHz): δ (major isomer) 169.0 (d, ¹J_C-F=261.3 Hz, C1′), 141.6 (d, ³J_C-F=9.6 Hz, C3′), 137.0 (d, ³J_C-F=10.5 Hz, C5′), 117.9 (nitrile C7′), 116.7 (d, ²J_C-F=25.6 Hz, C6′), 108.2 (d, ⁴J_C-F=3.8 Hz, C4′), 84.5 (C8′), 24.7 (C9′), (minor isomer) 164.2 (d, ¹J_C-F=257.1 Hz, C1), 135.9 (d, ³J_C-F=8.8 Hz, C5), 122.8 (d, ²J_C-F=21.0 Hz, C2), 118.5 (d, ²J_C-F=22.2 Hz, C6), 118.1 (nitrile C7), 113.1 (C4), 85.1 (C8), 24.7 (C9); ¹¹B NMR (CDCl₃, 96 MHz): δ 29.92; ¹⁹F NMR (CDCl₃, 282 MHz): δ (major isomer) −92.62 (m), (minor isomer) −104.84 (m); FT-IR (neat): 3076, 2982, 2934, 2231, 1608, 1487, 1429, 1412, 1373, 1350, 1236, 1143, 1070, 964, 852, 835, 571 cm⁻¹; LRMS (% rel. int.): m/e (major isomer) 247 M⁺ (26), 232 (100), 205 (12), 188 (20), (minor isomer) 247 M⁺ (29), 232 (97), 206 (100), 189 (74), 148 (97), 121 (25); Anal. Cacld for C₁₃H₁₅BFNO₂: C, 63.20; H, 6.12; N, 5.67. Found: C, 63.52; H, 6.20; N, 5.56. HRMS Calcd for C₁₃H₁₅BFNO₂: 247.1180. Found: 247.1171.





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