J. Hong et al. / Tetrahedron Letters 50 (2009) 2525–2528
2527
O
N
O
F
Boc
N
OEt
a
Cl
+
NH
CN
O
19
10
O
O
F
OEt
b, c
Boc
1
N
N
N
CN
20
O
Scheme 4. Reagent and conditions: (a) DMP, DIPEA, 100 °C, 76%; (b) LiOH, 75%; (c)
HCl/ether, 85%.
chiral pyrrolidine N-Boc 10 to give the 7-substituted quinolone es-
ter 20 in 76% yield (Scheme 4). Hydrolysis of the ester followed by
Boc-deprotection was completed in two steps with good yield to
afford the desired final product finafloxacin hydrochloride.22
In summary, a novel convergent synthesis of finafloxacin hydro-
chloride (1, BAY35-3377) was achieved on a multi-gram scale. The
core quinolone ester unit 19 was synthesized by a new route. The
chiral N-Boc 10 was prepared and the absolute configuration was
confirmed by X-ray analysis. The isolation of the chiral amine 5a
and 5b by solvent extraction and crystallization was demonstrated
for the first time as per our knowledge.
14. (a) N-Boc 10: 1H NMR (400 MHz, CDCl3, d ppm) 1.1 (s, 3H), 3.13–3.47 (m, 3H),
3.49–3.5.3 (m, 2H), 3.62–3.67 (m, 1H), 3.71–3.3.75 (m, 1H), 3.83–3.9 (m, 1H),
4.01–4.07 (m, 1H), 4.15–4.19 (m, 1H); EIMS 229.2 (M+1).
15. Synthesis of 19: Stage 1: A solution of the acid of the corresponding ester 15
(100 g, 0.43 mol) in toluene (800 mL) was treated with SOCl2 (100 mL) and
then stirred under reflux for 3 h. The solvent was removed under reduced
pressure to dryness and azeotrop with toluene to remove excess SOCl2 to give
acid chloride 16. Then a solution of 16 in toluene (200 mL) was added into a
solution of 3-dimethylamino-acrylic acid ethyl ester (68 g, 0.47 mol) and
triethylamine (87 g, 0.86 mol) in toluene (1.0 L) at 50 °C. After completion of
addition, the reaction mixture was stirred at 70–80 °C for 4 h. Then the solvent
was removed completely to dryness under reduced pressure and redissolved in
ethyl acetate (500 mL). The solid was filtrated off and washed with ethyl
acetate. The filtrate was concentrated to dryness under reduced pressure. The
residue was purified by column to give compound 17 (107 g, 70% yield). 1H
NMR (400 MHz, CDCl3, d ppm) 1.03 (t, 3H, J = 7.2 Hz), 3.03 (s, 3H), 3.43 (s, 3H),
4.01 (q, 2H, J = 7.2 Hz), 7.4 (d, 1H, J = 8 Hz), 7.91 (s, 1H). Stage 2: A solution of
16 (100 g, 0.28 mol) in ethanol (500 mL) and ether (500 mL) was treated with
cyclopropylamine (32 g, 0.56 mol) at room temperature. After stirring for 1.5 h,
the solvent was removed under reduced pressure to give crude compound 18
which was used in next step without purification. Stage 3: A solution of 18 in
CH3CN (1.0 L) was treated with K2CO3 (193 g, 1.4 mol) at room temperature
and then heated to 70–80 °C for 1 h. The K2CO3 was filtrated off while hot. The
solvent was concentrated to half amount and standby overnight. The
precipitate was collected by filtrating to give compound 19 (83 g, 89% yield
for 2 steps). 1H NMR (400 MHz, CDCl3, d ppm) 1.03 (t, 3H, J = 7.2 Hz), 1.21–1.33
(m, 4H), 4.01 (q, 2H, J = 7.2 Hz), 4.23–4.26 (m, 1H), 8.5 (d, 1H, J = 8 Hz), 8.78 (s,
1H); EI-MS 371.1 (M+1).
16. (a) Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890; (b) Cruz, A. de la;
Elguero, J.; Goya, P.; Martinez, A.; Pfleiderer, W. Tetrahedron 1992, 48, 6135; (c)
Nolt, M. B.; Zhao, Z.; Wolkenberg, S. E. Tetrehedron Lett. 2008, 49, 3137; (d)
Wang, Z.; Vince, R. Bioorg. Med. Chem. Lett. 2008, 18, 1293.
17. (a) Chu, D. T. W.; Maleczka, R. E.; Nordeen, Carl W. J. Heterocycl. Chem. 1988, 25,
927; (b) Bouzard, D.; Cesare, P. D.; Essiz, M.; Jacquet, J. P.; Remuzon, P. J. Med.
Chem. 1989, 32, 537.
18. Sandmayer condition: A solution of CuCN (75 g, 0.84 mol) in DMSO (400 mL)
was heated to 60 °C for 1 h and then tert-butyl-nitrite (173 g, 1.7 mol) was
added at once. To this mixture, a solution of amine 14 (100 g, 0.42 mmol) in
DMSO (150 mL) was added while maintaining the reaction temperature
between 60 and 70 °C. After complete addition and stirring for additional
3 h, the reaction mixture was poured onto ice-water and was extracted with
ethyl acetate (1.0 L ꢀ 3). The combined organic layer was washed with brine.
The solvent was removed under reduced pressure. The residue was purified by
column to give cyano compound 15 (45 g, 43% yield).
19. Hogenkamp, D. J.; Johnstone, T. B. C.; Huang, J.-C.; Li, W.-Y.; Tran, M.;
Whittemore, E. R.; Bagnera, R. E.; Gee, K. W. J. Med. Chem. 2007, 50, 3369.
20. (a) Al-Hiari, Y. M.; Al-Mazari, I. S.; Shakya, A. K.; Darwish, R. M.; Abu-Dahab, R.
Molecules 2007, 12, 1240; (b) Cecchetti, V.; Parolin, C.; Moro, S.; Pecere, T.;
Filipponi, E.; Calistri, A.; Tabarrini, O.; Gatto, B.; Palumbo, M.; Fravolini, A.;
Palu, G. J. Med. Chem. 2000, 43, 3799.
Acknowledgment
The authors are thankful to Jie Sun at Shanghai Institute of Or-
ganic Chemistry for X-ray analysis of our compound and providing
the ORTEP diagram.
References and notes
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22. Synthesis of finafloxacin hydrochloride: A mixture of 10 (22.8 g, 0.1 mol) and 19
(33.4 g, 0.1 mol) and DIPEA (26 g, 0.2 mol) in DMP (100 mL) was heated to
60 °C for 6 h. The reaction mixture was cooled to room temperature and then
diluted with water. The resultant mixture was extracted with ethyl acetate
(200 mL ꢀ 3). The combined organic layer was washed with 0.5 M HCl and
brine. The solvent was evaporated under reduced pressure to give 20 (32.5 g,