A convenient new synthesis of a Naproxen precursor

Article abstract of DOI:10.1055/s-2002-33920

A precursor of Naproxen, 2-(6-methoxy-2-naphthyl)propenoic acid was synthesized in good yield from commercially available 6-methoxy-2-naphthaldehyde in three steps. The synthesis includes an unprecedented one-step reduction of acrylic acid ethyl ester to propenoic acid ethyl ester in high yield.

Full text of DOI:10.1055/s-2002-33920

SHORT PAPER
1807
A Convenient New Synthesis of A Naproxen Precursor
A
Convenient
y
N
ew Synthe
e
sis of A N
a
d
proxen Precursor J. Mahmood, Courtney Brennan, M. Mahmun Hossain*
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Fax +1(414)2295530; E-mail: mahmun@uwm.edu
Received 9 April 2002; revised 4 June 2002
H
H
H
OH
Abstract: A precursor of Naproxen, 2-(6-methoxy-2-naphthyl)pro-
penoic acid was synthesized in good yield from commercially avail-
able 6-methoxy-2-naphthaldehyde in three steps. The synthesis
includes an unprecedented one-step reduction of acrylic acid ethyl
ester to propenoic acid ethyl ester in high yield.
.
BH3 THF
COOEt
COOEt
10 mole% piperdine
3
4
Key words: anti-inflammatory agents, Lewis acids, organometallic
reagents, catalysis, Naproxen
H
H
1. KOH, H2O
2. H3O+
COOH
The synthesis of optically active -arylpropanoic acids is
of great commercial interest as they are widely used as
non steroidal anti-inflammatory agents.1 Of these, (S)-2-
(6-methoxy-2-naphthyl)propanoic acid, commercially
known as Naproxen (2), is a highly valued anti-inflamma-
tory drug with annual sales of $600 million.2 So far, the
best method for the synthesis of (S)-Naproxen in high
yield with an excellent ee was reported by Noyori.3a The
method involved a chiral Ru catalyzed asymmetric reduc-
tion of 2-(6-methoxy-2-naphthyl)propenoic acid. Recent-
ly, Chan has patented a chiral Ru catalyst for the reduction
of 1 also in very high optical yield.3b However, the unsat-
urated acid 1 is not readily accessible. Each method re-
ported thus far either entails several steps with moderate
yields4a–c or requires CO gas under high pressure.4d Here-
in, we would like to report a new synthesis of 1 in three
simple steps from commercially available starting alde-
hyde in very good yields (Figure 1, 1).
(98%)
5
Scheme 1
H
H
COOH
COOH
MeO
MeO
1
2
Scheme 2
Figure 1
Based on our initial success, we decided to apply this
method to synthesize 2-(6-methoxy-2-naphthyl)propeno-
ic acid (1) starting from commercially available 6-meth-
oxy-2-naphthaldehyde (6). Reaction of 1 equiv of 6-
methoxy-2-naphthaldehyde (6) with 1.2 equiv of ethyldia-
zoacetate (EDA) in the presence of 10 mol% of the iron
Lewis acid [CpFe(CO)2(THF)]+ resulted in the formation
of 65% of the acrylic acid ester 7 (Scheme 2). The acrylic
acid ester 7 was then converted to the propenoic ester 8 in
75% yield by BH3 THF in the presence of 20 mol% piper-
dine and later, the ester 8 was hydrolyzed to the acid 14b in
91% yield.
Recently, we have reported the synthesis of aryl-substitut-
ed 3-hydroxyacrylic acid ester 3.5 Now, we have found
that this acid ester could be converted to propenoic acid 5
via a two step sequence (Scheme 1): first reduction by
BH3 THF in the presence of 10 mol% piperdine to prope-
noic acid ethyl ester 5, followed by hydrolysis of the ester
group. The one-step reduction of acrylic acid ester 4 to
propenoic acid ester 5 was found to be unprecedented.
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1807,1809,ftx,en;M11302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1808
S. J. Mahmood et al.
SHORT PAPER
Column chromatography was performed using silica gel (230–400
mesh). HPLC reagent grade CH2Cl2 was distilled under nitrogen
from P2O5. Technical grade pentane was stirred with sulfuric acid
overnight and then washed with sat. NaHCO3 and stored over
Na2SO4. The pentane was then distilled under nitrogen from sodi-
um. Reagent grade Et2O and THF were freshly distilled under a ni-
trogen atmosphere from sodium benzophenone ketyl. HPLC grade
MeOH was distilled under nitrogen from magnesium iodide. All
other reagents were used as supplied.
+
H2N
H
OH
H
O-
O
NH
OEt
OEt
O
O
3
H
N
H
+
BH3
O
H
H
-
H
H
B
H
H
B
H
OEt
3-Hydroxy-2-Arylacrylic Acid Ethyl Ester (3)
We have reported this synthesis as well as the physical and spectro-
scopic data in an earlier publication.5a
H
OEt
O-
O
2-Phenylpropenoic Acid Ethyl Ester (4)
A sample of compound 3 (0.25 g, 1.3 mmol) was dissolved in fresh-
ly distilled THF (20 mL). Piperdine (0.013 L; 0.13 mmol) was
added to the solution. The solution was cooled to 0 °C and
BH3 THF (1.56 ml, 1.56 mmol) was added. The reaction mixture
was stirred for 20 h at 0 °C. H2O (20 mL) was added to quench the
reaction and organic compounds were extracted with Et2O (3 20
mL). The ethereal solution was passed through a silica plug and
dried (Na2SO4). The solvent was removed by rotary evaporation to
yield 2-phenylpropenoic acid ethyl ester (4).
10
9
H
H
OEt
+
BH2(OH)
+
NH
O
4
Yield: 0.216 g (86%).
1H NMR (CDCl3, 250 MHz): = 7.43–7.24 (m, 5 H), 6.34 (d, 1 H,
Scheme 3
J = 1.3 Hz), 5.88 (d, 1 H, J = 1.3 Hz), 4.28 (q, 2 H), 1.32 (t, 3 H).4d
Although we have not studied the mechanism of this one-
3-Phenylpropenoic acid (5)
step reduction, a plausible one is outlined in Scheme 3. In A sample of 4 (70 mg) was dissolved in acetone (15 mL). Aq KOH
(1 M; 0.86 mL, 0.048 g, 0.85 mmol) was added to this solution. The
mixture was allowed to stir at r.t. for 16 h. The reaction mixture was
this proposed mechanism, the -hydroxyacrylic acid ester
3 reacts with BH3 in the presence of the piperdine to pro-
extracted with Et2O. The aq layer was then acidified with dilute aq
duce the boron complex 9. An intramolecular migration of
HCl and was extracted with Et2O. The ethereal solution was washed
the hydride from the boron atom of intermediate 9 to the
with aq NaCl and dried (Na2SO4). The solvent was removed by ro-
double bond provides the enolate 10. In the presence of
protonated piperdine, the enolate 10 undergoes an elimi-
nation reaction to form the propenoic acid ester 4,
BH2(OH) and regenerates the catalyst, piperdine.
tary evaporation to get practically pure 3-phenylpropenoic acid (5).
Yield: 62 mg (98% yield).
1H NMR (CDCl3, 250 MHz): = 7.33 (m, 5 H), 6.30 (d, 1 H, J = 1.0
Hz), 5.94 (d, 1 H, J = 1.0 Hz).4d
In summary, we have reported a new method for the syn-
thesis of 2-(6-methoxy-2-naphthyl)propenoic acid, a
valuable precursor for the synthesis of (S)-Naproxen in
three simple steps from 6-methoxy-2-naphthaldehyde in
an overall yield of 45%. This method would be useful in
designing a new industrial process for synthesizing the
(S)-Naproxen. During these studies, we have developed a
new one-step reaction of converting acrylic acid ester to
propenoic acid ester. This new reaction is under investiga-
tion with other similar substrates and will be used in the
preparation of other biologically active compounds.
3-Hydroxy-2-(6-methoxy-2-naphthyl)acrylic Acid Ethyl Ester
(7)
A sample of cyclopentadienyl dicarbonyl iron Lewis acid catalyst
(0.14 g, 0.42 mmol) was dissolved in freshly distilled CH2Cl2 (16
mL) under nitrogen and 6-methoxy-2-naphthaldehyde (7) (0.77 g,
4.16 mmol) was added to it. The solution was cooled to 0 °C. A
sample of ethyldiazoacetate (0.58 mL, 4.99 mmol) was diluted with
freshly distilled CH2Cl2 (3–4 mL) and was drawn into a gas-tight
syringe. It was then added to the reaction mixture dropwise over a
period of 6–7 h via syringe pump. After the addition was complete,
the reaction mixture was stirred for another 10–12 h at 0°C. The re-
action was stopped by adding Et2O (9–10 mL), which caused the
catalyst to precipitate from the solution. Any remaining metal moi-
ety was removed by filtration through a silica plug. The solvent was
removed by rotary evaporation and the products were isolated by
column chromatography (2–10% Et2O in pentane) to get 3-hy-
droxy-2-(6-methoxy-2-naphthyl)acrylic acid ethyl ester (7).
All organometallic operations were performed under a dry nitrogen
atmosphere using standard Schlenk techniques. All of the glass
flasks were flame dried under vacuum and filled with nitrogen prior
to use. Proton and carbon spectra were obtained on a 250 MHz
NMR spectrometer. The chemical shifts ( ) are expressed in ppm
relative to tetramethylsilane and CDCl3 was used as the solvent.
Previously reported compounds were identified by comparing their
1H NMR with those of the known compounds. All new compounds
were additionally characterized by 13C NMR and elemental analy-
sis.
Yield: 65% (0.74 g).
1H NMR (CDCl3, 250 MHz): = 12.15 (d, 1 H), 7.73–7.13 (m, 6 H),
4.31 (q, 2 H), 3.96 (s, 3 H), 1.29 (t, 3 H).
13C NMR (CDCl3, 250 MHz): = 14.22, 55.38, 61.00, 105.71,
108.75, 118.97, 126.41, 127.60, 128.62, 128.87, 129.40, 129.53,
133.58, 157.84, 163.37, 171.84. Anal. Calcd for C16H16O4: C,
70.60; H, 5.90. Found: C, 70.77; H, 5.91.
Synthesis 2002, No. 13, 1807–1809 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Convenient New Synthesis of A Naproxen Precursor
1809
2-(6-Methoxy-2-naphthyl)propenoic Acid Ethyl Ester (8)
A sample of compound 6 (0.18 g, 0.67 mmol) was dissolved in
freshly distilled THF (20 mL). Piperdine (0.01 mL, 0.10 mmol) was
added to the solution. The solution was cooled to 0 °C and
BH3 THF (1.0 mL, 1.0 mmol) was added to the solution. The reac-
tion mixture was stirred for 20 h at 0 °C. H2O (20 mL) was added to
quench the reaction and organic compounds were extracted with
Et2O (3 20 mL) and the ethereal solution was dried (Na2SO4). The
solvent was removed by rotary evaporation and the products were
isolated by column chromatography (Et2O in pentane, 2–40%) to
yield 8.
1H NMR (CDCl3, 250 MHz): = 7.86–7.05 (m, 6 H), 6.41 (d, 1 H,
J = 1.3 Hz), 6.01 (d, 1 H, J = 1.3 Hz), 3.91 (s, 3 H).4b
Acknowledgement
We gratefully thank the NIH for partial support of this research. We
also thank Professor Jim Cook for helping us with the mechanism
of the reduction.
References
Yield: 0.13 g (75%).
(1) (a) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D.
G. Tetrahedron: Asymmetry 1992, 3, 163. (b) Stinson, S. C.
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R. J. Org. Chem. 1987, 52, 3174. (b) Chan, A. S. C.;
Laneman, S. A. US Patent 5198561, 1993; Chem. Abstr.
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(4) (a) Rieu, J. P.; Boucherle, A.; Cousse, H.; Mouzin, G.
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Gazz. Chim. Ital. 1989, 119, 220. (d) Scrivanti, A.;
Matteoli, U. Tetrahedron Lett. 1995, 36, 9015.
1H NMR (CDCl3, 250 MHz): = 7.86–7.13 (m, 6 H), 6.39 (d, 1 H,
J = 1.2 Hz), 5.98 (d, 1 H, J = 1.2 Hz), 4.32 (q, 2 H), 3.92 (s, 3 H),
1.33 (t, 3 H).4b
Anal. Calcd for C16H16O3: C, 74.90; H, 6.30. Found: C, 74.53; H,
6.34.
2-(6-Methoxy-2-naphthyl)propenoic Acid (1)
A sample of 8 (0.10 g, 0.40 mmol) was dissolved in acetone (15
mL). Aq KOH (1 M; 0.79 mL, 0.044 g, 0.79 mmol) was added to
this solution. The mixture was allowed to stir at r.t. for 12 h. The re-
action mixture was extracted with Et2O. The aq layer was then acid-
ified with dilute aq HCl and was extracted with Et2O. The ethereal
solution was washed with aq NaCl and dried (Na2SO4). The solvent
was removed by rotary evaporation to give practically pure 2-(6-
methoxy-2-naphthyl)propenoic acid.
(5) (a) Mahmood, S. J.; Hossain, M. M. J. Org. Chem. 1998, 63,
3333. (b) Mahmood, S. J.; McLaughlin, M.; Hossain, M. M.
Synth. Commun. 1999, 29, 2967.
Yield: 91% (0.083 g).
Synthesis 2002, No. 13, 1807–1809 ISSN 0039-7881 © Thieme Stuttgart · New York