Regioselective biomimetic oxidation of etodolac with iodosylbenzene catalyzed by halogenated and perhalogenated metalloporphyrins in dichloromethane

Article abstract of DOI:10.1248/cpb.49.1375

The biomimetic oxidation of etodolac, an anti-inflammatory drug (1)with iodosylbenzene catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides TAPFe(III)Cl (7a - e) in dichloromethane gives 4-hydroxyetodolac (6) and 4-oxoetodolac (5) regioselecti

Full text of DOI:10.1248/cpb.49.1375

October 2001
Communications to the Editor
Chem. Pharm. Bull. 49(10) 1375—1376 (2001)
1375
8
b)
Regioselective Biomimetic Oxidation of
Etodolac with Iodosylbenzene Catalyzed
by Halogenated and Perhalogenated
Metalloporphyrins in Dichloromethane
(30 : 70) gave 4-hydroxyetodolac, (1,8-diethyl-4-hydroxy-
,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid (6),
1
colourless solid, yield: 72 mg, 25.0%; mp: 178—180 °C. The
Ϫ1
appearance of IR band at 3285 cm in the IR spectra of the
product (6) indicates the presence of –OH group. The disap-
pearance of 4-H peak and appearance of 4-OH (br s) peak at
d 4.69 ppm as well as the change in multipliticity of 3-CH
Shive M. S. CHAUHAN,* Srinivas A. KANDADAI and
Bishwabhusan SAHOO
2
1
proton at d 4.09 ppm from triplet to doublet in the H-NMR
spectra confirms the formation of 6. Further, the loss of
Department of Chemistry, University of Delhi, Delhi–110 007,
India. Received May 14, 2001; accepted July 30, 2001
ϩ
1
8 mass unit (285, M ϪH O) from the parent ion peak of 6
2
confirms the formation of 6.
The reaction of 1 with iodosylbenzene catalyzed by
TPPFe(III)Cl (7a) in dichloromethane in after 2 h gives re-
gioselctively 6 in 11.3% and 5 in 5.0% yield (Chart 1). The
The biomimetic oxidation of etodolac, an anti-inflammatory
drug (1) with iodosylbenzene catalyzed by 5,10,15,20-tetraaryl-
porphyrinatoiron(III) chlorides TAPFe(III)Cl (7a—e) in di-
chloromethane gives 4-hydroxyetodolac (6) and 4-oxoetodolac
reaction of 1 with iodosylbenzene catalyzed by F TPP-
20
(
5) regioselectively in moderate yields.
Fe(III)Cl (7c) in dichloromethane after 2 h gives 6 in 31.3%
and 5 in 22.2% yield. Similarly, the oxidation of 1 with io-
dosylbenzene and perhalogenated metalloporphyrins like
Cl Cl TPPFe(III)Cl (7d) and Cl Br TPPFe(III)Cl (7e) give
Key words etodolac; halogenated and perhalogenated metalloporphyrin;
iodosylbenzene; 4-hydroxyetodolac; 4-oxoetodolac
8
8
8
8
4
1.4% of 6 and 23.6% of 5 and 40.1% of 6 and 23.2% of 5,
Etodolac, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-in- respectively. The reaction of 6 with iodosylbenzene catalyzed
dole-1-acetic acid (1) is a clinically effective antiinflamma- by Cl TPPFe(III)Cl (7b) gives 5 in 42.0% yield. Further the
8
tory agent, possesses an exceptional safety profile with re- presence of strongly coordinating axial ligands like N-
1
,2)
spect to the gastrointenstinal tract and renal function. The
major primary oxidative metabolites of 1 in man are 6-hy-
droxyetodolac (2), 7-hydroxyetodolac (3), and 8-(1Ј-hy-
droxy)etodolac (4), whereas the major metabolite in rat is 4-
oxoetodolac (5). The biomimetic oxidation of selected drugs
with monooxygen donors catalyzed by 5,10,15,20-tetraaryl-
porphyrinatoiron(III) chlorides (TAPFe(III)Cl) has been stud-
ied to understand the drug metabolism as well as to isolate
the drug metabolites and reactive intermediates in sufficient
3
—6)
amount without the use of experimental animals.
The cat-
alytic activity of metalloporphyrins can be increased either
by introduction of bulkier substituents at ortho position of
the phenyl rings or by substitution of hydrogens by halogens
of main porphyrin ring of metalloporphyrins (TAPFe(III)Cl).
Herein, we report the biomimetic oxidation of etodolac with
iodosylbenzene catalyzed by halogenated and perhalogenated
iron(III) porphyrins TAPFe(III)Cl (7a—e) in organic sol-
vents to mimic the reactions of natural cytochrome P450 en-
zyme.
Chart 1
7
)
Table 1. Biomimetic Oxidation of Etodolac (1) with Iodosylbenzene
Catalyzed 5,10,15,20-Tetraarylporphyrinatoiron(III) Chloride (7a—e) in
Iodosylbenzene (1 mmol, 220 mg) was added to a mixture Dichloromethane after 2 h
of 1 (1 mmol, 287 mg) and Cl TPPFe(III)Cl (7b) (0.01 mmol)
in dichloromethane (10 ml). The reaction mixture was stirred
8
b)
Products (% Yield)
a)
Entry
System
for 2 h at room temperature. The solvent was removed under
reduced pressure and the residue was chromatographed on
silica gel. The elution of column with petrol : chloroform
d)
6
5
1
2
3
4
5
6
7
8
9
1/PhIO/TPPFe(III)Cl
1/PhIO/TPPFe(III)Cl/NMeIm
1/PhIO/Cl TPPFe(III)Cl
1/PhIO/Cl TPPFe(III)Cl/NMeIm
6/PhIO/Cl TPPFe(III)Cl
1/PhIO/F TPPFe(III)Cl
1/PhIO/F TPPFe(III)Cl/NMeIm
1/PhIO/Cl Cl TPPFe(III)Cl
11.3
17.0
28.3 (25.0)
39.2
5.0
8
a)
(
60 : 40) gave 4-oxoetodolac
(1,8-diethyl-4-oxo-1,3,4,9-
9.4
20.8 (20.0)
28.3
c)
c)
tetrahydropyrano[3,4-b]-indole-1-acetic acid) (5), colourless
8
3
)
8
solid, yield: 60.2 mg, 20.0%, mp 200—203 °C (lit. mp
—
31.7
33.5
42.4
42.0
40.1
39.5
42.0
22.2
23.6
23.6
23.0
23.2
22.5
Ϫ1
8
2
00—202 °C). The appearance of a new band at 1732 cm
2
0
in the IR spectra of product (5) indicates the presence of new
carbonyl group along with –COOH group. The disappear-
ance of 3-H and 4-H coupling and appearance of a broad sin-
2
0
e)
8
8
1/PhIO/Cl Cl TPPFe(III)Cl/NMeIm
1/PhIO/Cl Br TPPFe(III)Cl
1/PhIO/Cl Br TPPFe(III)Cl/NMeIm
8
8
1
1
0
1
1
8
8
glet for 3-H at d 4.28 ppm in H-NMR spectrum confirms
8
8
formation of 5. Again the structure of 5 is confirmed by the
ϩ
a) Substrate : oxidant : catalyst : co-catalystϭ100 : 100 : 1 : 10. b) Yields were de-
termined by HPLC analysis (m-Bondapak) based on starting etodolac. c) Isolated
yield. d) On over-oxidation, the yield of 6 decreases and 5 increases with increase of
loss of 29 mass unit (272, M ϪC H ) and again loss of
2
5
ϩ
6
0 mass unit (M ϪCH COOH) from the parent ion peak.
2
The further elution of column with petrol : chloroform time, catalyst and oxidant. e) Two minor unidentified products were also observed.
∗
To whom correspondence should be addressed. e-mail: smschauhan@chemistry.du.ac.in © 2001 Pharmaceutical Society of Japan

1
376
Vol. 49, No. 10
methylimidazole (NMeI) increased the yield of 6 from 11.3 References and Notes
1
)
Cayen M. N., Kraml M., Ferdinandi E. S., Gresejin E., Dvornik D.,
Drug Metab. Rev., 12, 339—362 (1981).
Humber L. G., Med. Res. Rev., 7, 1—28 (1987).
to 43.0% and 5 from 5 to 24.0%. These results were summa-
rized in Table 1. The addition of 1-methylimidazole as co-
catalyst did not induce the larger differences in product
yields, except with 7b.
Although the aromatic ring hydroxylated and 8-ethyl hy-
droxylated metabolites are known but the pyrano ring hy-
droxylated metabolite, 6 is not detected in the metabolism of
etodolac in human or rat. It is believed that 6 is a intermedi-
ate compound in the formation of another metabolite 4-urei-
doetodolac. But with chemical model systems of cytochrome
P450, unlike in vivo metabolism of etodolac, 6 is one of the
major product in moderate yields.
2
3
)
)
Higuchi T., Hirobe M., J. Mol. Catal. A: Chem., 113, 403—422 (1996).
4) Masumoto H., Takeuchi K., Ohta S., Hirobe M., Chem. Pharm. Bull.,
7, 1788—1794 (1989).
5
3
)
Chauhan S. M. S., Chemical Models of Cytochrome P450 and Flavin
Monooxygenase in Drug Metabolism, in 6th National Symposium on
Bioorganic Chemistry, IISc, Bangalore, June 6, 1997.
6
)
Yang S. J., Nam W., Inorg. Chem., 37, 606—607 (1998).
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Sharma T. K., J. Ind. Chem. Soc., 74, 199—201 (1997).
1
8
)
a) Data of 4-oxoetodolac (5): H-NMR (300 MHz, DMSO-d /TMS): d
6
0
.83 (t, Jϭ7.3 Hz, 3H), 1.34 (t, Jϭ7.3 Hz, 3H), 2.01 (m, 1H), 2.17 (m,
1
H), 2.71—3.04 (m, 4H), 3.06 (s, 2H), 4.28 (br s, 2H), 7.01 (d,
The formation of 6 may be explained by abstraction of hy-
drogen radical from the allylic 4-position of etodolac by the
high valent oxo-iron(IV) porphyrins and subsequent recom-
bination of the etodolac radical with the hydroxy radical or
hydroxy-iron(III) porphyrin present in the reaction medium.
Further the formation of 5 can also be explained as over-oxi-
dation of 6. Further the yield of 5 increases with increase of
time, catalyst and oxidant. This type of hydrogen abstraction
and recombination mechanism have been reported earlier
Jϭ9 Hz, 1H), 7.07 (t, Jϭ9 Hz, 1H), 7.36 (d, Jϭ9 Hz, 1H), 8.59 (br s,
Ϫ1
1H), 11.23 (br s, 1H); IR (KBr, cm ): 3520, 3345, 1731, 1632, 1598,
ϩ
1
2
499, 1463, 1307, 1261, 1079, 1018, 805, 675. EI-MS m/z: 301 (M ),
ϩ
ϩ
72 (M ϪC H ), 242 (M ϪCH COOH). b) Data of 4-hydroxy-
etodolac (6): H-NMR (300 MHz, DMSO-d /TMS) d ppm: 0.89 (t,
2
5
2
1
6
Jϭ7.3 Hz, 3H), 1.25 (t, Jϭ7.3 Hz, 3H), 1.90—2.13 (m, 2H), 2.64—
2.91 (m, 2H), 3.27 (m, 2H), 4.09 (d, Jϭ15 Hz, 2H), 4.30 (m, 1H), 4.
69 (s, 1H), 5.09 (d, Jϭ15 Hz, 2H), 5.78 (s, 1H), 6.94 (d, Jϭ9 Hz, 1H),
7
.06 (t, Jϭ9 Hz, 1H), 7.37 (d, Jϭ9 Hz, 1H), 8.57 (br s, 1H), 11.24
Ϫ1
(
br s, 1H); IR (KBr, cm ): 3345, 3285, 1731, 1453, 1375, 1243, 1201,
ϩ
1
118, 1087, 1018, 926, 832, 750, 680; EI-MS m/z: 303 (M ) 285
ϩ
9
—13)
with cytochrome P450 chemical model systems.
Al-
and
(M ϪH O).
2
1
4)
though the decarboxylation of indole acetic acid
9) Mansuy D., Battioni P., Battioni J. P., Eur J. Biochem., 184, 267—285
1989).
0) Chauhan S. M. S., Gupta M., Gulati A., Nizar P. N. H., Ind. J. Chem.,
5B, 1267—1270 (1996).
1
5)
(
ibuprofen with hydrogen peroxide catalyzed by iron(III)
porphyrins in aqueous and organic solvents has been
reported, we have not observed the decarboxylation of
etodolac in the above reaction conditions. Thus the above
1
3
1
1
1) Chauhan S. M. S., J. Sci. Ind. Res., 56, 311—334 (1997).
2) Lindsey J. S., Wagner R. W., J. Org. Chem., 54, 828—836 (1989).
chemical model systems i.e., halogenated and perhalogenated 13) Chauhan S. M. S., Ray PC., Bioorg. Med. Chem. Lett., 1, 601—606
(
1991).
iron(III) porphyrins (7a—e)/PhIO may be used as efficient
catalysts in the regioselective synthesis of two oxidative
metabolites from etodolac in milder conditions.
1
1
4) Chauhan S. M. S., Mohapatra P. P., Kalra B., Kohli T. S., Satapathy S.,
J. Mol. Catal. A: Chem., 113, 239—247 (1996).
5) Chauhan S. M. S., Sahoo B. B., Bioorg. Med. Chem., 7, 2629—2634
(
1999).
Acknowledgement The authors are thankful to Council of Scientific
and Industrial Research (CSIR), New Delhi, India for financial support.