A synthesis of licofelone using Fenton's reagent

Article abstract of DOI:10.1016/j.tetlet.2008.06.078

An efficient synthesis of licofelone, an anti-inflammatory drug currently undergoing phase-III clinical studies, based on Fenton-type radical alkylation of 2,3-dihydro-1H-pyrrolizine 3 with iodoacetonitrile or iodoacetates is reported. The iodoacetates can be replaced by NaI and by the corresponding bromoacetate.

Full text of DOI:10.1016/j.tetlet.2008.06.078

Tetrahedron Letters 49 (2008) 5316–5318
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A synthesis of licofelone using Fenton’s reagent
*
ˇ
´
ˇ
ˇ
Stanislav Rádl , Josef Cerny, Ondrej Klecán, Jan Stach, Lukáš Placek, Zuzana Mandelová
Zentiva, U kabelovny 130, 102 37 Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of licofelone, an anti-inflammatory drug currently undergoing phase-III clinical
studies, based on Fenton-type radical alkylation of 2,3-dihydro-1H-pyrrolizine 3 with iodoacetonitrile
or iodoacetates is reported. The iodoacetates can be replaced by NaI and by the corresponding
bromoacetate.
Received 28 April 2008
Revised 9 June 2008
Accepted 17 June 2008
Available online 21 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Licofelone
Fenton’s reagent
Radical reaction
Licofelone esters
Licofelone nitrile
Licofelone amide
Spectral characterization
Licofelone (ML3000),1 a dual cyclooxygenase/5-lipoxygenase
inhibitor developed by Merckle, is the first member of a new class
of analgesic and anti-inflammatory drugs currently undergoing
phase-III clinical studies for treatment of osteoarthritis.2
oxo group of 5 by classical Wolff–Kishner reduction3–5 or by its
modification using NaBH3CN reduction of the corresponding p-tol-
uenesulfonyl hydrazide.9 The latter methodology can also be used
for the reduction of the corresponding ethyl ester leading to 4a.8 In
order to circumvent using hydrazine derivatives, we decided to de-
velop a new methodology for the transformation of 3 into licofe-
lone which would be suitable for industrial application.
Our attempts at both electrophilic alkylation using Lewis acids
(BF3ÁEt2O, MgBr2, AlCl3) and nucleophilic alkylation (NaH, BuLi,
LDA) of 3 with ethyl bromoacetate failed, as did initial attempts
at radical alkylation with ethyl iodoacetate using AIBN and tribu-
tyltin hydride, tris(trimethylsilyl)silane or N-ethylpiperidine
hypo-phosphite.
Surprisingly, we found that the reaction was successful using
Fenton’s reagent.10,11 Fenton’s reagent is a solution of hydrogen
peroxide and a Fe2+ salt, typically ferrous sulfate. It is used as a
powerful source of radicals and is often applied for hydroxylation
of aromatic compounds,12,13 including polycyclic aromatic com-
pounds.14 It can also be used for other reactions, for example, for
the oxidation of barbituric acid to alloxane.15
Cl
N
COOH
licofelone
There are several methods for construction of the parent moiety
of the drug; it is usually formed by condensation of rather unstable
2-benzyl-4,4-dimethyl-1-pyrroline (1) with 4-chlorophenacyl bro-
mide (2) providing 2,3-dihydro-1H-pyrrolizine 3.3–5 Though a dif-
ferent synthesis of 3 based on the Suzuki cross-coupling reaction
has been published,6–8 the original method using the intermediacy
of 1 seems to be more efficient. Compound 3 when treated with
ethyl diazoacetate gives ester 4a and its hydrolysis gives licofelone.
Alternatively, compound 3 on treatment with oxalyl chloride fol-
lowed by hydrolysis gives acid 5. Wolff–Kishner reduction then
provides licofelone (Scheme 1).3–5
Torssell et al.16–20 discovered that Fenton’s reagent in the pres-
ence of DMSO generates methyl radicals, which can, under suitable
conditions, methylate reactive substrates, for example, quinones,
nitroaromatic compounds, thiophene, furan, pyridine, and quino-
line derivatives. Minisci et al.21 and Baciocchi et al.22–24 found that
the methyl radicals formed from DMSO and Fenton’s reagent in the
presence of iodo derivatives generated the corresponding alkyl
radicals, which alkylate effectively reactive pyrrole, indole, thio-
phene, or furan derivatives. This methodology was used for the
The only known methods for the transformation of 3 into licofe-
lone avoiding the use of diazoacetate are based on reduction of the
* Corresponding author. Tel./fax: +420 267243721.
E-mail address: stanislav.radl@zentiva.cz (S. Rádl).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.078

S. Rádl et al. / Tetrahedron Letters 49 (2008) 5316–5318
5317
O
+
Cl
Br
Cl
N
N
1
2
3
1. (COCl)2, THF
2. H2O
N2CH2COOEt
Cl
Cl
N
N
CO2H
O
CO2Et
4a
5
1. NaOH
2. H+
N2H4, KOH
Cl
N
CO2H
licofelone
Scheme 1. Synthesis of licofelone.
alkylation of pyrrole, 1-methylpyrrole and, pyrrole-2-carboxylic
acid with iodoacetonitrile, or methyl and ethyl iodoacetate.22
For our purposes, we reacted 3 with Fenton’s reagent in combi-
nation with DMSO and ethyl iodoacetate to obtain a good yield of
product 4a. Though the best results were achieved with DMSO, the
reaction also proceeded with other sulfoxides, for example, dibutyl
sulfoxide, tetrahydrothiophene 1-oxide, methyldodecyl sulfoxide,
and methylphenyl sulfoxide (thioanisole S-oxide). However, with
these sulfoxides, the reaction rate was lower and incomplete con-
version was often achieved. In the case of methylphenyl sulfoxide,
its solution in acetonitrile or DMF was used and only low yields of
4a were obtained both due to poor conversion and due to the for-
mation of several minor by-products. We also tried to substitute
DMSO with dimethyl sulfone and methylphenyl sulfone, but no
reaction was observed. Therefore DMSO was used routinely for fur-
ther optimization of the reaction.
Next we extended our study to the use of methyl and tert-butyl
iodoacetate, as well as iodoacetonitrile with similar results ob-
tained to those with ethyl iodoacetate (see Scheme 2 and Table
1).25–27
Esters 4a and 4b were saponified easily with aqueous NaOH or
KOH at 60 °C within 1 h, while saponification of 4c was slower
requiring 10 h for complete conversion. However, good yields of
licofelone were obtained from all esters 4. Attempts to prepare
licofelone by hydrolysis of nitrile 5 failed; even vigorous hydrolysis
provided only moderate yields of the corresponding amide 6 in-
stead. Its treatment with an ethanolic solution of hydrogen chlo-
ride provided a crude mixture containing mainly ester 4a and
hydrolysis of the mixture then gave licofelone (Scheme 3). Licofe-
lone was found to be unstable and its quantitative decarboxylation
was observed by NMR after 72 h in CDCl3 at ambient temperature.
The starting iodo esters were either commercially available or
prepared from the corresponding bromo derivative and NaI in ace-
tone or acetonitrile. We found that though the bromoacetates were
not effective in the radical reaction, it was possible to use them in
the presence of NaI under similar conditions as the iodo analogs.
This fact is interesting since the reaction is performed in the pres-
ence of relatively high amounts of water. Selected examples are gi-
ven in Table 1.
i or ii
Cl
N
All compounds were identified on the basis of analytical and
spectral data (IR, UV, 1H NMR, 13C NMR, MS, HRMS).28–33 For com-
pounds 4a and 5, HMBC and HSQC NMR spectra were also studied.
CO2R
4a; R = Et
4b;
R = Me
4c; R = tert-Bu
Cl
Table 1
N
Radical alkylation of 3 using Fenton’s reagent
Product
Reagent
Conditionsa
Yield (%)
3
4a
4a
4a
4a
4b
4c
5
ICH2CO2Et
BrCH2CO2Et
ICH2CO2Et
ICH2CO2Et
BrCH2CO2Me
BrCH2CO2But
ICH2CN
DMSO
78
75
43
28
57
62
65
DMSO, NaI
THTO,b MeCN
PhS(O)Me, DMF
DMSO, NaI
DMSO, MeCN, NaI
DMSO
iii
Cl
N
CN
5
a
In all cases, Fe(II)SO4 and 30% H2O2 were used.
THTO—tetrahydrothiophene 1-oxide.
Scheme 2. Radical alkylations of 3. Reagents: (i) FeSO4/H2O2, DMSO, ICH2CO2R; (ii)
FeSO4/H2O2, DMSO, NaI, BrCH2CO2R; (iii) FeSO4/H2O2, DMSO, ICH2CN.
b

5318
S. Rádl et al. / Tetrahedron Letters 49 (2008) 5316–5318
22. Baciocchi, E.; Muraglia, E.; Sleiter, G. J. Org. Chem. 1992, 57, 6817–6820.
23. Baciocchi, E.; Muraglia, E. Tetrahedron Lett. 1993, 34, 3799–3800.
24. Baciochi, E.; Muraglia, E. Tetrahedron Lett. 1993, 34, 5015–5018.
25. General procedure for the preparation of compounds 4 using iodoacetates: A
solution of 30% aqueous hydrogen peroxide (15 mL) in DMSO (75 mL) was
added dropwise over 20 min with cooling in a cold water bath (17–19 °C) to a
stirred solution of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-
pyrrolizine (3; 15.0 g, 46.6 mmol), the appropriate iodoacetate (56.1 mmol),
and Fe(II)SO4 heptahydrate (3.0 g) in DMSO (220 mL). After 1 h, the reaction
mixture was diluted with brine (240 mL) and extracted with ethyl acetate
(200 mL, 70 mL). The combined extracts were washed with aqueous 20%
Na2S2O3 (2 Â 30 mL), dried over MgSO4, and evaporated under reduced
pressure. The obtained residue was crystallized from ethanol to afford the
desired product 4.
X = COOR
78–89%
Cl
N
COOH
licofelone
i
Cl
N
X
26. General procedure for the preparation of compounds 4 using bromoacetates: To a
stirred solution of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-
pyrrolizine (3; 15 g, 46.6 mmol), the appropriate bromoacetate (55.7 mmol),
NaI (9.45 g, 63.1 mmol), and Fe(II)SO4 heptahydrate (3.0 g) in DMSO (375 mL)
was added dropwise a solution of 30% aqueous hydrogen peroxide (15 mL) and
DMSO (75 mL) over 20 min with cooling in a cold water bath (17–19 °C). After
1 h, the reaction mixture was diluted with brine (240 mL) and extracted with
ethyl acetate (200 mL, 70 mL). The combined extracts were washed with
aqueous 20% Na2S2O3 (2 Â 30 mL), dried over MgSO4, and evaporated under
reduced pressure. The residue was crystallized from ethanol to give the desired
product 4.
4a; X = COOEt
4b;
X = COOMe
X = CN
46%
4c; X = COOtBu
5; X = CN
Cl
N
CONH2
6
Scheme 3. Saponification of esters 4 and nitrile 5. Reagents and conditions: (i)
aqueous NaOH or KOH, MeOH or EtOH, 60–70 °C.
27. Preparation of 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-
pyrrolizine-5-yl]acetonitrile (5): To a stirred solution of 6-(4-chlorophenyl)-
2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (3; 2.0 g, 6.21 mmol),
iodoacetonitrile (1.5 g, 8.98 mmol), and Fe(II)SO4 heptahydrate (0.8 g) in
DMSO (50 mL) was added dropwise aqueous 30% hydrogen peroxide (4 mL)
over 30 min with cooling in a cold water bath. After 4.5 h, the reaction mixture
was diluted with brine (200 mL) and extracted with ether. The combined
extracts were dried over MgSO4 and evaporated under reduced pressure. The
residue was crystallized from ethanol to afford 1.46 g (65%) of the desired
product 5.
In summary, we have developed an efficient synthesis of licofe-
lone, an anti-inflammatory drug currently undergoing phase-III
clinical studies, based on Fenton-type radical alkylation of com-
pound 3 with iodoacetonitrile or iodoacetates. The iodoacetates
can be replaced by NaI and the corresponding bromoacetate.
28. Data for compound 4a: mp 77–79 °C. 1H NMR (250 MHz, CDCl3): 1.28 (t, J = 7.1,
2H, CH2), 1.29 (s, 6H, 2 Â CH3), 2.85 (s, 2H, CH2), 3.51 (s, 2H, CH2), 3.75 (s, 2H,
CH2), 4.18 (q, J = 7.1, 2H, CH2), 7.02–7.27 (m, 9H, Ar). 13C NMR (62.9 MHz,
CDCl3): 14.2, 28.0, 31.6, 40.5, 43.3, 58.4, 61.0, 114.8, 117.7, 123.6, 124.6, 128.0,
128.2, 128.2, 131.5, 131.6, 134.1, 134.7, 136.0, 170.8. IR (KBr): 1733 cmÀ1
Acknowledgments
This work was supported by Zentiva Prague. The authors’
thanks are also due to Ms. Lucie Tisovská for measuring the IR
and UV spectra.
(COO). UV (EtOH), kmax (loge): 210 (4.45), 248 (4.34), 274 (4.10). HRMS m/z
calcd for C25H27ClNO2 (M+H) 408.17303, found 408.17255.
29. Data for compound 4b: mp 166–168 °C. 1H NMR (250 MHz, CDCl3): 1.29 (s, 6H,
2 Â CH3), 2.84 (s, 2H, CH2), 3.53 (s, 2H, CH2), 3.72 (s, 3H, CH3), 3.73 (s, 2H, CH2),
7.02–7.27 (m, 9H, Ar). 13C NMR (62.9 MHz, CDCl3): 28.0, 31.3, 40.5, 43.3, 52.1,
58.8, 114.8, 117.5, 123.7, 124.7, 128.0, 128.2, 128.3, 131.6, 131.7, 134.2, 134.6,
References and notes
135.9, 171.2. IR (KBr): 1734 cmÀ1 (COO). UV (EtOH), kmax (log
e): 208 (4.48),
246 (4.32). HRMS m/z calcd for
394.15671.
C24H25ClNO2 (M+H) 394.15738, found
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445–461.
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30. Data for compound 4c: mp 165–167 °C. 1H NMR (250 MHz, CDCl3): 1.29 (s, 6H,
2 Â CH3), 1.46 (s, 9H, t-Bu), 2.84 (s, 2H, CH2), 3.41 (s, 2H, CH2), 3.75 (s, 2H, CH2),
7.03–7.26 (m, 9H, Ar). 13C NMR (62.9 MHz, CDCl3): 28.1, 28.2, 33.0, 40.7, 43.5,
58.5, 81.3, 114.8, 118.5, 123.6, 124.7, 128.1, 128.3, 128.4, 131.7, 131.8, 134.1,
135.0, 136.3, 170.3. IR (KBr): 1726 cmÀ1 (COO). UV (EtOH), kmax (log
e): 206
(4.52), 248 (4.35), 276 (4.18). HRMS m/z calcd for
436.19651, found 436.20374.
C27H31ClNO2 (M+H)
31. Data for compound 5: mp 144–146 °C. 1H NMR (250 MHz, CDCl3): 1.33 (s, 6H,
2 Â CH3), 2.85 (s, 2H, CH2), 3.62 (s, 2H, CH2), 3.84 (s, 2H, CH2), 7.00–7.31 (m, 9H,
Ar). 13C NMR (62.9 MHz, CDCl3): 14.5, 28.0, 40.4, 43.6, 58.3, 112.5, 115.4, 116.7,
124.2, 125.1, 128.1 (2 Â CHAr), 128.7, 131.4, 132.3, 133.7, 135.2, 135.3. IR (KBr):
2245 cmÀ1 (CN). UV (EtOH), kmax (log
e): 208 (4.47), 246 (4.33). HRMS m/z calcd
for C23H22ClN2 (M+H) 361.14715, found 361.14664.
32. Data for compound 6: mp 230–232 °C. 1H NMR (250 MHz, CDCl3): 1.29 (s, 6H,
2 Â CH3), 2.85 (s, 2H, CH2), 3.49 (s, 2H, CH2), 3.71 (s, 2H, CH2), 5.64 (br d,
J = 61.5 Hz, 2H, CONH2), 7.02–7.28 (m, 9H, Ar). 13C NMR (62.9 MHz, CDCl3):
27.9, 33.1, 40.6, 43.4, 58.1, 115.2, 118.5, 123.7, 124.9, 128.1 (2 Â CHAr), 128.6,
131.3, 132.0, 134.4, 134.6, 135.6, 172.6. IR (KBr): 1654 cmÀ1 (CONH2). UV
(EtOH), kmax (log
e): 208 (4.50), 248 (4.33), 276 (4.17). HRMS m/z calcd for
C
23H24ClN2O (M+H) 379.15771, found 379.15744.
33. Data for licofelone: mp 156–157 °C. 1H NMR (250 MHz, CDCl3): 1.29 (s, 6H,
2 Â CH3), 2.86 (s, 2H, CH2), 3.58 (s, 2H, CH2), 3.78 (s, 2H, CH2), 7.00–7.30 (m, 9H,
Ar). 13C NMR (62.9 MHz, CDCl3): 28.0, 31.3, 40.5, 43.3, 58.4, 115.0, 116.7, 124.1,
124.8, 128.0, 128.1, 128.2, 128.4, 131.6, 131.8, 134.4, 135.8, 177.2. IR (KBr):
18. Torssell, K. Tetrahedron 1970, 26, 2759–2773.
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21. Minisci, F.; Vismara, E.; Fontana, F. J. Org. Chem. 1989, 54, 5224–5227.
1721 cmÀ1 (COOH). UV (EtOH), kmax (log
e): 208 (4.49), 248 (4.33), 278 (4.17).
HRMS m/z calcd for C23H23ClNO2 (M+H) 380.14173, found 380.14117.