A simple catalytic route to naproxen

Article abstract of DOI:10.1016/j.tetasy.2004.12.011

We report herein the asymmetric synthesis of naproxen involving catalytic enantioselective methylation for the first time. The reaction is conducted in a solid-liquid biphasic system using chiral quaternary ammonium salts.

Full text of DOI:10.1016/j.tetasy.2004.12.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 647–649
A simple catalytic route to naproxen
Sanjeev Kumar and Uma Ramachandran*
Department of Pharmaceutical Technology, National Institute of Pharmaceutical Education & Research (NIPER), Sector-67,
Mohali, Punjab 160 062, India
Received 12 October 2004; accepted 2 December 2004
Available online 22 January 2005
Abstract—We report herein the asymmetric synthesis of naproxen involving catalytic enantioselective methylation for the first time.
The reaction is conducted in a solid–liquid biphasic system using chiral quaternary ammonium salts.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral quaternary ammonium salts have been used in
asymmetric alkylations.7 In fact, the first successful
example was reported by the Merck group in the asym-
metric alkylation of a cyclic ketone intermediate leading
to the synthesis of indacrinone using N-(4-trifluorometh-
ylbenzyl)cinchoninium bromide as chiral phase-transfer
catalysts (PTC) in aqueous NaOH.8
Naproxen [(S)-2-(6-methoxy-2-naphthyl)propanoic acid]
1 is one of the most popular non-steriodal anti-
inflammatory drugs.1 It is an arylpropionic acid with a
stereogenic centre. It has been shown that the activity
of (S)-enantiomer of this class of drugs is greater than
the (R)-isomer, because it is able to form a larger num-
ber of interactions at the active site of the cyclooxygen-
ase enzyme.2 For example, the pharmacological activity
of the (S)-enantiomer of 2-(6-methoxy-2-naphthyl)prop-
anoic acid is 28 times greater than its (R)-enantiomer.2
H
H
Br
Br
R1O
R1O
N
N
OH
H
H
R
R
O
MeO
1
Methods reported for obtaining naproxen are either by
resolution3 or by asymmetric synthesis4 usually with
the use of chiral auxiliaries.5 The main disadvantages
of the above methods is the need to recycle the undesired
isomer or to recover the chiral auxiliary, respectively. A
more practical approach would be the use of a chiral
catalyst.
N
N
2
3
a) R = 9-Anthracene, R1 = Allyl.
b) R = 2-Fluorophenyl, R1 = Allyl.
R
R
Br
N
In asymmetric synthesis, alkylation of a prochiral sub-
strate is an attractive approach. Although the enantiose-
lective alkylation of arylpropionic acids has been
reported using chiral auxiliaries,6 there is none using a
catalytic method. We report herein the results of enan-
tioselective methylation using chiral quaternary ammo-
nium salts as catalysts under solid–liquid phase-
transfer conditions.
4 (R = 3,4,5-F3-Ph)
2. Results and discussion
Prochiral substrates 5a–c were prepared by esterifying 6-
methoxy-2-naphthyl acetic acid9 with different alcohols.
Our initial efforts in methylating 5a using various inor-
ganic bases like powdered NaOH, KOH and CsOH
along with tetrabutylammonium bromide in toluene at
room temperature were unsuccessful; in all the cases
the methylated product was obtained in poor yields.
Use of sodium methoxide did not improve the yield,
*
Corresponding author. Tel.: +91 172 2214682/87; fax: +91 172
2214692; e-mail: umaram54@yahoo.com
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.12.011

648
S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 16 (2005) 647–649
KOtBu, MeI,
OR
OR
OR
+
O
O
O
{QX }, 0oC
Toluene
MeO
MeO
MeO
5a-c
6
7
Scheme 1. Phase-transfer catalysed methylation of 5a–c.
however, the use of stronger bases like potassium tert-
butoxide under similar conditions gave the methylated
product in good yields.
gave the (R)-enantiomer but with decreased selectivity.
Recrystallisation of the crude product (56% ee) was tried
from different solvents like hexane, 2-propanol, n-buta-
nol and tert-butanol. Single recrystallisation from tert-
butanol yielded the product with 93% ee. Finally the
tert-butyl ester was hydrolysed with 6 M HCl to give
naproxen in 94% yield.
Switching to chiral quaternary ammonium salt, O-(9)-
allyl-N-9-anthracenylmethylcinchoninium bromide 2a
as the catalyst, substrate 5a was methylated in toluene10
at 0 ꢁC using potassium tert-butoxide as the base. Prod-
ucts 6a and 7a were obtained in 88% yield but with very
poor enantioselectivity (15%) (Scheme 1). Cyclohexyl
ester 5b and tert-butyl ester 5c were also tried as syn-
thons (Table 1).
The reaction discussed is a classical example of a solid–
liquid phase-transfer catalysed reaction, where the C–H
acidic compound is being deprotonated by the chosen
strong base generating a reactive anion in the presence
of the chiral quaternary ammonium salt.12 The ion-pair
formed by the anion thus formed with the positively
charged nitrogen of the chiral PTC results in asymmetric
induction. Though such solid–liquid phase-transfer
reactions using strong base like KOtBu have been re-
ported using chiral crown ethers or cinchona alkaloids
in Michael additions, along with its mechanism,13 to
the best of our knowledge this is the first report of it
being used in direct asymmetric alkylation.
Table 1. Methylation of esters 5a–c catalysed by 2a
Entry
Substrate (R)
Time (h)
% Eea
Yieldb (%)
1
2
3
5a (isopropyl)
5b (cyclohexyl)
5c (tert-butyl)
11
8
15
8
84
88
86
19
18
a Determined using chiral HPLC.
b Yields of isolated product.
Based on the results, tert-butyl ester 5c was chosen as
substrate for optimisation of reaction conditions. Reac-
tions were done in different solvents and various temper-
atures (Table 2, entries 1–8). Catalyst 2a gave the
highest selectivity for the desired (S)-isomer (78:22)
(Table 2, entry 5), when the methylation was done in a
mixture of toluene:dichloromethane (7:3) at ꢀ50 ꢁC.
Spiro quaternary ammonium salt (S,S)-3,4,5-trifluor-
ophenyl-NAS bromide 4 gave the product with 74%
selectivity in 72% yield.11
3. Conclusions
We have designed a new catalytic route to naproxen
involving asymmetric methylation. Prochiral ester pre-
cursors 5a–c, which can be easily prepared, are enantio-
selectively methylated using chiral quaternary
ammonium salts under solid–liquid biphasic system.
O-(9)-Allyl-N-(9-anthracenylmethyl)cinchoninium bro-
mide gave the best result.
We next tried two other chiral quaternary ammonium
salts, which are known to give good enantioselectivities
in alkylation reactions. The use of O-(9)-allyl-N-(9-anth-
racenylmethyl)cinchonidinium bromide 3a gave the (R)-
enantiomer with 80% selectivity. While the use of O-(9)-
allyl-N-(2-fluorobenzyl)cinchonidinium bromide 3b also
4. Experimental
General procedure for asymmetric methylation: To a stir-
red solution of prochiral ester 5a–c (3.67 mmol) and cat-
alyst (0.36 mmol or 0.036 mmol),14 in an appropriate
Table 2. Reaction conditions for the methylation of tert-butyl (6-methoxy-2-naphthyl) acetate 5c
Entry
Solvent
Temp (ꢁC)
Catalyst
Time (h)
Yielda (%)
% Selectivityb (S:R)
1
2
3
4
5
6
7
8
CH2Cl2
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ50
ꢀ50
ꢀ30
ꢀ40
2a
2a
2a
2a
2a
3a
3b
4
6
10
18
16
14
14
12
8
70
75
68
69
74
78
72
72
62:38
75:25
72:28
70:30
78:22
20:80
36:64
74:26
CH2Cl2/toluene (7:3)
Chlorobenzene
Anisole
CH2Cl2/toluene (7:3)
CH2Cl2/toluene (7:3)
CH2Cl2/toluene (7:3)
CH2Cl2/toluene (7:3)
a Isolated yields.
b Selectivity was determined using chiral HPLC; the absolute configuration was determined by comparison of the specific rotation and retention time
of the hydrolysed ester with (R)- and (S)-2-(6-methoxy-2-naphthyl)propanoic acid.

S. Kumar, U. Ramachandran / Tetrahedron: Asymmetry 16 (2005) 647–649
649
solvent (15 mL) was added KOtBu (0.399 g, 3.55 mmol)
at ꢀ50 ꢁC, followed by addition of methyl iodide
(2.08 g, 14.68 mmol) via syringe pump under an argon
atmosphere. The contents were stirred for 6–18 h and
the reaction then quenched by diluting with water
(5 mL). The aqueous layer was extracted with diethyl
ether (3 · 50 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by column chromato-
graphy (SiO2, hexane/ethyl acetate, 98:2), to give the
product in 68–78% yield. In case of tert-butyl ester
(5c) the methylated product (6c and 7c) was recrystal-
lised with tert-butanol to afford the product 6c with
93% ee. (Chiralcel OD-H, hexane/isopropanol 95.5:0.5,
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tR = 14.0 min, tS = 15.7 min, 0.5 mL/min, 254 nm). Mp
25
D
92–93 ꢁC (lit. mp 94–96 ꢁC).15 ½aꢁ ¼ þ24:8 (c 1,
25
CH2Cl2) {lit. ½aꢁ ¼ þ26:9 (c 1, CH2Cl2)}.15 IR (KBr)
D
m 2977, 2938, 1724, 1610, 1458, 1393, 1370, 1327, 1265,
1203, 1163, 1025, 858 cmꢀ1
.
1H NMR (CDCl3,
300 MHz) 1.38 (s, 9H), 1.52 (d, J = 7.18, 3H), 3.73 (q,
J = 7.14, 1H), 3.90 (s, 3H), 7.11–7.25 (m, 3H), 7.40
(dd, J = 2.8, 5.49, 1H), 7.64 (s, 1H), 7.69 (dd, J = 2.9,
5.66, 1H). MS (APCI): m/z (%) 286 (M+, 5), 230 (40),
185 (100).
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Acknowledgements
9. Fried J. H.; Harrison, I. T. US Pat. Appl. US 3980699,
1976.
This work was supported by funds from National Insti-
tute of Pharmaceutical Education & Research (NIPER).
We would like to thank Prof. K. P. R. Kartha for help-
ful discussions.
10. Toluene had a moisture content of 0.01–0.02%.
11. In a separate experiment 6c (98% ee) was treated with
potassium tert-butoxide at 0 to ꢀ50 ꢁC, to check for
possible racemisation in the presence of MeI and 2a.
Around 3–5% racemisation was observed in the given
experimental conditions.
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