Synthesis of Rofecoxib, (MK 0966, Vioxx 4-(4′-Methylsulfonylphenyl)-3-phenyl-2(5H)-furanone), a selective and orally active inhibitor of cyclooxygenase-2

Article abstract of DOI:10.1055/s-2001-17519

The synthesis of Vioxx (Rofecoxib, MK 966, 4-(4′methylsulfonylphenyl)-3-phenyl-2(5H)-furanone), a newly FDA approved inhibitor of cyclooxygenase-2, is described.

Full text of DOI:10.1055/s-2001-17519

1
778
SHORT PAPER
®
Synthesis of Rofecoxib, (MK 0966, Vioxx 4-(4¢-Methylsulfonylphenyl)-3-
Phenyl-2(5H)-Furanone), a Selective and Orally Active Inhibitor of
Cyclooxygenase-2
S
M
ynthesis of Rofecoxib
i
,
a
Sel
c
O
h
rally
A
ctive
e
Inhibitor
o
l
f
Cyclooxyge
T
nase-2 hérien,* Jacques Yves Gauthier, Yves Leblanc, Serge Léger, Hélène Perrier, Petpiboon Prasit, Zhaoyin
Wang
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire - Dorval, Québec, Canada H9R 4P8
Fax +1(514)4284939; E-mail: Michel_Therien@Merck.com
Received 26 January 2001; revised 2 May 2001
The original synthesis of Rofecoxib, as described here, is
®
Abstract: The synthesis of Vioxx (Rofecoxib, MK 966, 4-(4’me-
straightforward and highly applicable to large scale pro-
thylsulfonylphenyl)-3-phenyl-2(5H)-furanone), a newly FDA ap-
proved inhibitor of cyclooxygenase-2, is described.
4
duction. Recently, Fallis published on the preparation of
dialkyl butenolides by magnesium mediated carbometal-
lation of phenylpropargyl alcohol, and applied this meth-
odology to synthesize Rofecoxib.
Keywords: lactones, sulfones, anti-inflammatory drugs
5
Recently, Vioxx® (Rofecoxib, MK 966) has been ap-
As illustrated in the Scheme, acetophenone 3 was pre-
pared according to the literature, by Friedel–Crafts acyla-
tion of thioanisole. Oxidation of 3 with MMPP
magnesium monoperoxyphthalate hexahydrate) afforded
sulfone 4, which was reacted with bromine in chloroform
at –5 °C in the presence of a trace amount of AlCl to give
proved, in the United States and several other countries,
for use in humans as an anti-inflammatory, to relieve the
signs and symptoms of osteoarthritis, for the treatment of
acute pain, and for the treatment of primary dismenorrhea.
It is a member of a new class of compounds called COX-
(
3
6
5
. Bromoketone 5 was then coupled and cyclized in a 2-
2
inhibitors, due to their ability to selectively inhibit the
step, one-pot procedure with phenylacetic acid. Firstly, a
mixture of bromoacetophenone 5 and phenylacetic acid in
acetonitrile was treated with triethylamine at r.t. to pro-
vide the ester intermediate, subsequent cooling to 0 °C
and addition of DBU effected the cyclization to provide
the final product 1.
action of the cyclooxygenase-2 (COX-2) enzyme, which
is implicated in pain and inflammation. Traditional non-
steroidal anti-inflammatory drugs (NSAID’s) act by1
blocking the action of both COX-2 and COX-1 enzymes,
where the COX-1 enzyme is responsible for maintaining
normal GI function. Being a selective inhibitor of the
COX-2, Vioxx® is effective against pain and inflamma- Alternatively, the synthetic sequence can be carried out on
2
tion with significantly reduced risk of severe GI toxicity the sulfide, i.e., the bromination (87%), esterification, and
3
associated with nonselective NSAID’s; it is the only cyclization (50%, one-pot) are done on the thiomethyl
COX-2 inhibitor approved in the United States for the compound, with subsequent oxidation (86%) at the last
treatment of pain.
step to provide the final compound in good yield also.
In this paper, we wish to describe the synthesis of Rofe- In conclusion, a highly efficient synthesis of the COX-2
coxib 1 [4-(4¢-methylsulfonylphenyl)-3-phenyl-2(5H)- inhibitor Rofecoxib has been described.
furanone], a tricyclic compound with a butenolide moiety
as a central ring. Though the structure and synthesis are
relatively simple, we felt that in view of the importance of
this compound, it is imperative to describe its preparation.
-(Methylthio)acetophenone (3)5
To a cold (0–10 °C) solution of AlCl (351 g, 2.63 mol) in CHCl (2
4
3
3
L) was added acetyl chloride (205 mL, 2.88 mol) while cooling to
maintain the temperature below 10 °C. Thioanisole (2, 260 mL,
2.21 mol) was then added with cooling to maintain the temperature
O
S
below 5 °C, more CHCl (500 mL) was added to facilitate stirring;
3
O
the ice bath was removed, and the mixture stirred for 1.5 h. The mix-
ture was then cooled to below 10 °C, H O (2 L) was slowly added,
2
O
the mixture was well stirred, and the layers were separated. The or-
ganic layer was washed with H O (2 ¥ 2 L), sat. NaHCO (2 ¥ 2 L),
2
3
O
then brine, and dried (Na SO ). The solvent was evaporated and the
2 4
residue was triturated overnight in hexane (1.5 L) containing
CH Cl (150 mL). The solid was filtered and air-dried to afford
1
2
2
3
02.62 g (1.82 mol, 82%) of 3 as a light grey solid.
Figure
Mp 80.5–81.5 °C.
1
H NMR (acetone-d ): d = 7.90 (d, 2H, J = 8.5 Hz), 7.34 (d, 2H, J =
6
Synthesis 2001, No. 12, 25 09 2001. Article Identifier:
8.5 Hz), 2.55 (s, 3H), 2.53 (s, 3H).
1
©
437-210X,E;2001,0,12,1778,1779,ftx,en;M00601SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
Synthesis of Rofecoxib, a Selective and Orally Active Cyclooxygenase-2
1779
O
S
S
MMPP
S
AcCl, AlCl3
O
MeOH, CH2Cl2
4
2
O
3
O
AlCl3, Br2
CHCl3
O
S
O
O
S
HOOC
O
O
1. Et3N,
, CH3CN
Br
2
. DBU
O
O
5
1
Scheme
-(Methylsulfonyl)acetophenone (4)
4
ica gel (300 g) and the mixture was concentrated to near dryness.
The residue was applied on top of a short silica gel column and elut-
ed with 10% EtOAc–CH Cl to give 36.6 g (116 mmol, 54%) of 1.
To a solution of 4-(methylthio)acetophenone (3, 197g, 1.18 mol) in
MeOH (700 mL) and CH Cl (3.5 L) was added MMPP (881 g, 1.42
2
2
2
2
mol) over 30 min. The mixture was stirred at r.t. for 3 h, then filtered
Mp 204.7 °C.
and the filtrate was washed with sat. NaHCO (2 L) and brine (1 L).
3
–
1
IR (KBr): 1745 cm .
The aqueous layer was further extracted with CH Cl (2 L). The or-
2
2
ganic extracts were combined, dried (Na SO ), and the solvent was
1
2
4
H NMR (acetone-d ): d = 7.96 (d, 2H, J = 8.4 Hz), 7.68 (d, 2H, J =
6
evaporated under vacuum to give 4-(methylsulfonyl)acetophenone
240 g, quantitative).
8
.4 Hz), 7.42 (s, 5H), 5.37 (s, 2H), 3.15 (s, 3H).
(
1
3
C NMR (DMSO-d ): d = 172.4, 156.0, 142.0, 135.8, 129.8, 129.1,
6
Mp 131.7 °C.
1
28.9, 128.8, 128.7, 127.4, 126.9, 70.9, 43.1.
–
1
IR (KBr): 1687 cm .
+
MS (Pos ESI): [M + H] = 315.1
1
H NMR (acetone-d ): d = 8.23 (d, 2H, J = 9.5 Hz), 8.10 (d, 2H, J =
6
8
.5 Hz), 3.22 (s, 3H), 2.70 (s, 3H).
References
1
3
C NMR (acetone-d ): d = 197.0, 145.2, 141.2, 129.4, 128.0, 43.6,
6
(
1) (a) Kargmann, S.; Wong, E.; Greig, G. M.; Falgueyret, J. P.;
Cromlish, W.; Ethier, D.; Yergey, J. A.; Riendeau, D.;
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I. W.; Chan, C.-C. Inflamm. Res. 1996, 45, 68.
2
6.7.
2
-Bromo-1-(4-(methylsulfonyl)phenyl)ethanone (5)
To a solution of 4-(methylsulfonyl)acetophenone (4, 174 g, 0.88
mol) in CHCl (2.5 L) at –5 °C was added AlCl (20 mg), followed
3
3
by a solution of bromine (40 mL, 0.78 mol) in CHCl (300 mL). Af-
3
(
2) (a) Chan, C.-C.; Boyce, S.; Brideau, C.; Charleson, C.;
Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A.
W.; Forrest, M. J.; Gauthier, J. Y.; Gordon, R.; Gresser, M.;
Guay, J.; Kargmann, S.; Kennedy, B.; Leblanc, Y.; Léger,
S.; Mancini, J.; O’Neill, G. P.; Ouellet, M.; Patrick, D.;
Percival, M. D.; Perrier, H.; Prasit, P.; Rodger, I. W.; Tagari,
P.; Thérien, M.; Vickers, P.; Visco, D.; Wang, Z.; Webb, J.;
Wong, E.; Xu, L.-J..; Young, R. N.; Zamboni, R.; Riendeau,
D. J. Pharmacol. Exp. Ther. 1999, 290, 551. (b) Prasit, P.;
Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson, C.;
ter completion of the reaction, H O (1.5 L) was added and the layers
2
were separated. The aqueous layer was extracted with EtOAc (1 L),
and the organic layers were combined, dried (Na SO ), and concen-
2
4
trated. The residue obtained was recrystallized in EtOAc–hexane
1:1) to give 210 g of 5 (76 mol, 86%).
(
Mp 127.5–128.5 °C.
–
1
IR (KBr): 1700 cm .
1
H NMR (acetone-d ): d = 8.28 (d, 2H, J = 8.4 Hz), 8.12 (d, 2H, J =
6
8
.4 Hz), 4.87 (s, 2H), 3.20 (s, 3H).
Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A.
W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.;
Kargmann, S.; Kennedy, B.; Leblanc, Y.; Léger, S.;
Mancini, J.; O’Neill, G. P.; Ouellet, M.; Percival, M. D.;
Perrier, H.; Riendeau, D.; Rodger, I. W.; Tagari, P.; Thérien,
M.; Vickers, P.; Wong, E.; Xu, L.-J.; Young, R. N.;
1
3
C NMR (CDCl ): d = 190.3, 144.7, 137.9, 130.0, 128.0, 44.2, 30.5.
3
4
-(4¢-Methylsulfonylphenyl)-3-phenyl-2(5H)-furanone) (1)
3
Et N (30.8 mL, 221 mmol) was slowly added with stirring to a so-
lution (25 °C) of phenyl acetic acid (27.4 g, 201 mmol) and 2-bro-
mo-1-(4-(methylsulfonyl)phenyl)ethanone (5, 60 g, 216 mmol) in
Zamboni, R. Bioorg. Med. Chem. Lett. 1999, 9, 1773.
CH CN. Stirring was continued for 20 min at 25 °C, the mixture was
3
(3) Richardson, C.; Emery, P. Drug Safety 1996, 15, 249.
cooled in an ice bath, and DBU (60.1 mL, 402 mmol) was slowly
added. Stirring was continued for 20 min at 0 °C, and the mixture
was acidified with 1 N HCl (a color change from dark brown to light
(
(
(
4) Forgione, P.; Wilson, P. D.; Fallis, A. G. Tetrahedron Lett.
000, 41, 17.
5) Cutler, R. A.; Stenger, R. J.; Suter, C. M. J. Am. Chem. Soc.
1952, 74, 5475.
6) Ducharme, Y.; Gauthier, J. Y.; Prasit, P.; Leblanc, Y.; Wang,
Z.; Léger, S.; Thérien, M. US Patent 5,474,995, 1995.
2
yellow was observed). Then, ice and H O (2.4 L) were added and
2
the stirring continued for a few minutes. The precipitate was filtered
and rinsed with H O. The crude wet solid was dissolved in CH Cl
2
2
2
(
750 mL), dried (MgSO ), and filtered. To the filtrate was added sil-
4
Synthesis 2001, No. 12, 1778–1779 ISSN 0039-7881 © Thieme Stuttgart · New York