1422
Vol. 50, No. 10
Yield (%)a)
Table 1. Reduction of Nimesulide and Related Compounds with NaBH4 Catalyzed by TAPFe(III)Cl under N2 Atmosphere
Run
System
NaBH4 (mmol)
Time (h)
Conversion (%)a)
1
2
3
4
5
6
7
8
9
1
200b)
200
400
24
24
12
2
12
54
76
9
23
47
68
89
95
96
98
99
1/TPPFe(III)Cl
1/TPPFe(III)Cl
1/TPPFe(III)Cl
1/TPPFe(III)Cl
1/Cl8TPPFe(III)Cl
1/Cl8Cl8TPPFe(III)Cl
4/TPPFe(III)Cl
5/TPPFe(III)Cl
800
91
1200
1000
1000
800
1
100
100
100
100
100
0.5
0.5
0.5
0.5
800
a) Based on the substrate, b) NaBH4 alone.
Table 2. The Reduction of Nimesulide with NaBH4 Catalyzed by
TAPFe(III)Cl in Presence of Added Molecular Oxygena)
5) Sarkar P., McIntosh J. M., Leavitt R., Gouthro H., J. Anal. Toxico., 21,
197—202 (1997).
6) Giachetti C., Tenconi A., Biomed. Chromatogr., 12, 50—56 (1998).
7) Mingatto F. E., Santos A. C. D., Rodrigues T., Pigoso A. A., Uyemura
S. A., Curti C., Br. J. Pharm., 131, 1154—1160 (2000).
8) Sakai S., Kojima T., Arai T., J. Chem. Soc. Dalton. Trans., 1994, 7—
11.
% Yieldb)
S. No.
Metalloporphyrin
2
3
1
2
3
TPPFe(III)Cl
Cl8TPPFe(III)Cl
Cl8Cl8TPPFe(III)Cl
20
11
10
Trace amounts
9) Sakaki S., Koga H., Tao K-I., Yamashita T., Iwashita T., Hamada T., J.
Chem. Soc. Dalton. Trans., 2000, 1015—1017.
10) Sakaki S., Mitarai S., Ohkubo K., Chem. Lett., 1991, 195—198.
11) Okamoto T., Oka S., J. Org. Chem., 49, 1589—1594 (1984).
12) Kano K., Takagi H., Takeuchi M., Hashimoto S., Chem. Lett., 1991,
519—522.
13) Santa T., Mori T., Hirobe M., Chem. Pharm. Bull., 33, 2175—2178
(1985).
14) Mori T., Santa T., Higuchi T., Mashino T., Hirobe M., Chem. Pharm.
Bull., 41, 292—295 (1993).
4.5
4.8
a) 100 eq of molecular oxygen, Sub : cat : NaBH4ϭ100 : 1 : 400 mmol after 2 h at
25 °C, b) Based on the substrate and HPLC analyses, retention time of 2 is 9.04 and 3
is 11.86.
stepwise 1eϪ or 2eϪ processes.
The reaction of 1 with NaBH4 catalyzed by TAPFe(III)Cl
in presence of molecular oxygen gives 3 along with 2. (Chart
2, Table 2) The structure of 3 was confirmed by the compari-
son of HPLC retention time with that of authentic sample as
well as by other spectroscopic data.18)
15) Data of 4-aminonimesulide (2): mp 169—171 °C; 1H-NMR (300 MHz,
CDCl3, d ppm): 2.90 (s, 3H, CH3SO2), 3.7 (br s, 2H, NH2), 6.16 (s,
1H, NH), 6.35 (s, 1H, Ar-3H), 6.40 (d, 1H, Jϭ8.45 Hz, Ar-5H), 6.99
(d, 2H, Jϭ7.35 Hz, ArЈ-2H, ArЈ-6H), 7.16 (d, 1H, Jϭ8.45 Hz, Ar-6H),
7.35 (m, 3H, ArЈ-3H, ArЈ-4H, ArЈ-5H); IR (KBr, cmϪ1): 3394, 3339,
3062, 2922, 2853, 1615, 1585, 1508, 1463, 1324, 1214, 1152, 969,
863, 797, 725, 688, 489; EI-MS (m/z): 277 (Mϩ), 206, 199, 171, 154,
99, 77, 43.
16) Data of 4-nitrosonimesulide (4): It is synthesized by potassium dichro-
mate oxidation of 5 at 0 °C. mp 111—113 °C; 1H-NMR (300 MHz,
CDCl3, d ppm): 3.21 (s, 3H, CH3SO2), 6.79 (s, 1H, NH), 7.07 (d, 2H,
Jϭ7.2 Hz, ArЈ-2H, ArЈ-6H), 7.46 (m, 3H, ArЈ-3H, ArЈ-4H, ArЈ-5H),
7.66 (s, 1H, Ar-3H), 7.78 (d, 1H, Jϭ9.0 Hz, Ar-6H), 8.01 (d, 1H, Jϭ
9.0 Hz, Ar-5H); IR (KBr, cmϪ1): 3369, 3015, 2958, 2862, 1627, 1566,
1518, 1493, 1404, 1289, 1145, 1020, 887, 786, 745, 645, 524; EI-MS
(m/z): 292 (Mϩ), 262, 247, 187, 172, 154, 99, 77, 43.
The low catalytic activity of TPPFe(III)Cl with molecular
oxygen in presence of reductant NaBH4 is due to formation
of m-oxo dimer,19) whereas the high-valent iron-oxo interme-
diates formed from the halogenated and perhalogenated
iron(III)porphyrin with molecular oxygen under reduc-
tive conditions are responsible for aromatic hydroxyla-
tion.11,12,20,21) The presence of molecular oxygen has remark-
ably effected the reduction of 1. As the amount of oxygen
bubbled into the reaction mixture is increased, the yield of 2
is further decreased even with 1200 mmol of NaBH4. The de-
tailed study on the oxidation of 1 with monooxygen donors
catalyzed by metalloporphyrins will be published elsewhere.
In conclusion, the reduction of nimesulide 1 with cy-
tochrome P450-NAD(P)H model system (TAPFe(III)Cl-
NaBH4) under anaerobic conditions gives exclusively reduc-
tive metabolite 2 whereas the oxidative metabolite 3 has also
been formed along with 2 under aerobic conditions.
17) Data of 4-hydroxylamine nimesulide (5): It is synthesized from 1
under mild and neutral conditions using Zn and NH4Cl. mp 163—
167 °C; 1H-NMR (300 MHz, DMSO-d6,
d ppm): 2.86 (s, 3H,
CH3SO2), 4.78 (s, 2H, NHSO2 and OH), 6.14 (d, 1H, Jϭ2.2 Hz, Ar-
3H), 6.34 (dd, 1H, Jϭ8.53 Hz, Jϭ2.2 Hz, Ar-5H), 7.01 (d, 2H, Jϭ
7.83 Hz, ArЈ-2H, ArЈ-6H), 7.05 (d, 1H, Jϭ8.53 Hz, Ar-6H), 7.11 (t,
1H, Jϭ7.83 Hz, AArЈ-4H), 7.35 (t, 2H, Jϭ7.83 Hz, ArЈ-3H, ArЈ-5H),
8.47 (s, 1H, NHOH); IR (KBr, cmϪ1): 3412, 3352, 3028, 2949, 1619,
1578, 1515, 1478, 1401, 1311, 1267, 1150, 1079, 971, 856, 802, 741,
680; EI-MS (m/z): 294 (Mϩ), 262, 247, 183, 168, 91, 77, 57, 41.
18) Data of 4Ј-hydroxynimesulide (3): mp 124—126 °C; 1H-NMR (300
MHz, CDCl3, d ppm): 2.93 (s, 3H, CH3SO2), 6.7 (s, 1H, NH), 7.07 (d,
2H, Jϭ7.47 Hz, ArЈ-3H, ArЈ-5H), 7.23 (d, 2H, Jϭ7.47 Hz, ArЈ-2H,
ArЈ-6H), 7.34 (d, 1H, Jϭ8.5 Hz, Ar-6H), 7.46 (s, 1H, Ar-3H), 7.59 (d,
1H, Jϭ8.5 Hz, Ar-5H); IR (KBr, cmϪ1): 3482, 3286, 2924, 2854,
1591, 1519, 1342, 1215, 1153, 1078, 973, 908, 802, 469; EI-MS (m/z):
324 (Mϩ), 307, 275, 256, 223, 204, 154, 149, 123, 89, 71, 57, 41.
19) Ellis P. E., Jr., Lyons J. E., Coord. Chem. Rev., 105, 181—193 (1990).
20) Grinstaff M. W., Hill M. G., Birnbaum E. R., Schaefer W. P., Labinger
J. A., Gray H. B., Inorg. Chem., 34, 4896—4902 (1995).
Acknowledgements The authors are thankful to Council of Scientific
and Industrial Research (CSIR) and University Grants Commission (UGC),
New Delhi, India, for financial support.
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