Vol. 26, No. 20 (2014)
Synthesis and Characterization of Sitafloxacin 7051
1
Compound 6 (sitafloxacin): H NMR δ: 0.84 (m, 2H,
), 0.95 (m, 1H, CH ), 1.20 (m, 1H, CH ), 1.40 (m, H, CH),
.66 (m, H, CH), 3.23 (d, J = 10 Hz, 1H, CH ), 3.54 (m, H,
CH), 3.72 (d, J = 11.6 Hz, 1H, CH ), 4.33 (m, H, CH), 4.38
m, H, CH ), 4.47 (m, H, CH ), 5.13 (d, J = 63.9 Hz, 1H, CH),
.90 (d, J = 13.4 Hz, 1H, ArH), 8.24 (m, 2H, NH ), 8.81 (d, J
3.3 Hz, 1H, CH); C NMR δ: 5.96, 14.81, 16.51, 16.59,
presence of sodium hydrogen, in under the condition of free
hydrochloric acid ester base and (S)-N-((oxoboryl) methylene)-
5-azaspiro[2,4]heptan-7-amine condensation and then reacted
with sulfonyl chloride, finally in the presence of three trifluoro-
acetic acid deprotection method under highly sitaflo-xacin
compared. Reduction in (S)-N-((oxoboryl) methylene)-5-
azaspiro[2,4]heptan-7-amine condensation generated with
fluorine condensation 5 with impurities. From cost conside-
rations, because the process of main cost in (1R, 2S)-(-)-cis-
1-amino-2-fluorine cyclopropane p-toluene sulfonate and (S)-
N-((oxoboryl) methylene)-5-azaspiro[2,4]heptan-7-amine.
Using the method of using chlorinated good products as
intermediates, than the first and (1R, 2S)-(-)-cis-1-amino-2-
fluorine cyclopropane p-toluene sulfonate and (s)-(-)-7-tert
butoxycarbonylamino-5-aza spiro[2.4] heptane condensation
condensation with sulfonyl chloride chlorine than, in the same
number of products can be reduced in the two intermediate
consumption, cost savings and to obtain a crude product are
easy to be purified, the highly purity of sitafloxacin finished.
CH
2
2
2
1
2
2
(
2
2
7
2
1
3
=
2
5
1
1
3
4
5.16, 25.20, 42.14, 42.21, 56.69, 56.74, 56.80, 56.88, 57.19,
7.25, 73.06, 73.85, 108.52, 110.99, 111.18, 114.91, 122.0,
-1
22.06, 139.37, 142.15, 142.25, 154.51; IR (νmax, cm ): 821,
039, 1345, 1184, 1452, 1576, 1530, 1609, 1384, 2991, 2890,
-
O-1) ,
068, 3046, 3440; MS m/z: 436.84, 408.1 (M-1.5 H
2
+
+
10.0 (M-1.5 H
2
O + 1) , 432.0 (M-1.5 H
·1.5H O:C 52.19, H 4.81, N 9.61; Found
C 52.08, H 4.90, N 9.68.
2
O + Na) ;Anal. Calcd
for C19
H
18ClF
2
N
3
O
3
2
RESULTS AND DISCUSSION
In this paper, ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-
oxopropanoate as the starting material, reacted with triethyl-
orthoformate and (1R, 2S)-(-)-cis-1,2-fluorine cyclopropane
amino - p-toluene sulfonic acid salt by condensation under
sodium hydrogen condition. Subsequence take place hydro-
lysis of ester because of hydrochloric acid, reacted with (S)-
N-((oxoboryl) methylene)-5-azaspiro[2,4]heptan-7-amine by
condensation. In the end taken off the protection base give to
target product sitafloxacin.
REFERENCES
1
2
.
.
K. Sato, K. Hoshino, M. Tanaka, I. Hayakawa andY. Osada, Antimicrob.
Agents Chemother., 36, 1491 (1992).
R. Nakajima, A. Kitamura, K. Someya, M. Tanaka and K. Sato,
Antimicrob. Agents Chemother., 39, 1517 (1995).
3. N. Shetty andA.P.R. Wilson, J. Antimicrob. Chemother., 46, 633 (2000).
4
.
Y. Kimura, S. Atarashi, K. Kawakami, K. Sato and I. Hayakawa, J.
Med. Chem., 37, 3344 (1994).
Conclusion
5
6
.
.
J. Matsuo, Y. Tani and Y. Hayakawa, Chem. Lett., 33, 464 (2004).
Y. Yao, W. Fan, W. Li, X. Ma, L. Zhu, X. Xie and Z. Zhang, J. Org.
Chem., 76, 2807 (2011).
The synthesis method as 3 position of the chlorinated inter-
mediates as starting materials. With the traditional ethyl 3-(3-
chloro-2,4,5-trifluorophenyl)-3-oxopropanoate as starting
materials and original formic acid ethyl ester three conden-
sation and then the (1R, 2S)-(-)-cis-1-amino-2-fluorine cyclo-
propane p-toluene sulphonate condensation, cyclization in the
7
8
.
.
J. Yukimoto, T. Ehata and T. Tojo, Preparation of 2-Fluorocylo Propane-
methanol and 2-Fluorocyclopropane Carboxylic Acid, JP 07 109 237,
(
1995).
K. Satoh, A.Imura, A.Miyadera, K.Kanai and Y.Yukimoto, Chem.
Pharm. Bull. (Tokyo), 46, 587 (1998).