Facile conversion of racemic ibuprofen to (S)-ibuprofen

Article abstract of DOI:10.1016/j.tetasy.2012.02.014

The methyl ester of ibuprofen was quantitatively formed by Fischer esterification and converted into (S)-ibuprofen in 94% yield with an ee of 94% under dynamic kinetic resolution conditions at pH 9.8, using Candida rugosa lipase, and 20% DMSO. The (R)-methyl ibuprofen ester was observed to racemize by chiral HPLC without the Candida rugosa lipase present. The rates of in situ racemization and enzymatic hydrolysis for the dynamic kinetic resolution were determined to be 0.026 ± 0.004 and 0.053 ± 0.004 h^-1, respectively. The rate of enzymatic hydrolysis when no DMSO was present was twice as fast but no racemization occurred. A facile purification of enriched (S)-ibuprofen was developed. Overall, 88% of racemic ibuprofen by weight was converted into (S)-ibuprofen with an ee of 99.7%.

Full text of DOI:10.1016/j.tetasy.2012.02.014

Tetrahedron: Asymmetry 23 (2012) 237–239
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Facile conversion of racemic ibuprofen to (S)-ibuprofen
⇑
David Chavez-Flores , James M. Salvador
Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 January 2012
Accepted 23 February 2012
The methyl ester of ibuprofen was quantitatively formed by Fischer esterification and converted into
(S)-ibuprofen in 94% yield with an ee of 94% under dynamic kinetic resolution conditions at pH 9.8, using
Candida rugosa lipase, and 20% DMSO. The (R)-methyl ibuprofen ester was observed to racemize by chiral
HPLC without the Candida rugosa lipase present. The rates of in situ racemization and enzymatic hydro-
lysis for the dynamic kinetic resolution were determined to be 0.026 0.004 and 0.053 0.004 hꢀ1
,
respectively. The rate of enzymatic hydrolysis when no DMSO was present was twice as fast but no race-
mization occurred. A facile purification of enriched (S)-ibuprofen was developed. Overall, 88% of racemic
ibuprofen by weight was converted into (S)-ibuprofen with an ee of 99.7%.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Noting that (R)-ibuprofen is more easily racemized in refluxing
base in the presence of dimethylsulfoxide (DMSO), and that up to
We recently described a kinetic enzymatic resolution of racemic
ibuprofen to isolate 46% (S)-ibuprofen ( -methyl-4-[isobutyl]
20% DMSO by volume neutral aqueous solutions do not hinder
Candida rugosa lipase activity but actually enhance its enantiose-
lectivity, we investigated the effect of DMSO on the dynamic ki-
netic resolution of the methyl ester of ibuprofen.9–11 The use of
DMSO to slightly increase (2%) the conversion of racemic 2-ethoxy-
ethyl ibuprofen esters into (S)-ibuprofen treated with Candida
rugosa lipase under dynamic kinetic resolution conditions has also
been reported.12,13
a
phenylacetic acid) with an enantiomeric excess (ee) of greater than
99% using untreated commercially available Candida rugosa lipase.1
This is significant because (S)-ibuprofen is 100 times more active
than its (R)-enantiomer with fewer side effects.2 The greater bioac-
tivity of the (S)-enantiomer is observed for all members of the
profen (2-arylpropionic acid) family of non-steroidal anti-inflam-
matory drugs (NSAID).3 In order to overcome the theoretical 50%
limit in the resolution of racemic drugs, herein we report the facile
conversion of racemic ibuprofen into its (S)-enantiomer via uncon-
ventional dynamic kinetic resolution conditions.4,5
The dynamic kinetic resolution of profens involves the in situ
racemization of profen esters in the presence of an enolizing base
and a hydrolyzing enzyme in order to drive the equilibrium to iso-
late mostly (S)-profens (Fig. 1). The literature describes several
examples of profen esters converted to greater than 50% of (S)-pro-
fens using encapsulation or membranes in order to protect the activ-
ity of the hydrolyzing enzyme (mostly Candida rugosa lipase) and a
biphasic hydrocarbon/aqueous system.6,7 The base can be dissolved
in either the polar or non-polar layer. The esters vary from the
simple methyl ester of naproxen [2-(6-methoxynaphthalen-2-yl)
propanoic acid], to the thioesters of fenoprofen [2-(3-phenoxyphe-
nyl)propanoic acid], naproxen, and suprofen [2-[4-(2-thienylcar-
bonyl)phenyl]propanoic acid] which attempt to mimic the
mechanism of the epimerase that is found in the human body.8
OH
y
enzyme
water
y
Ar
Ar
R
Ar
R
O
O
O
- H
+ H
- H
+ H
y = O, S
y
Ar
R
O
Figure 1. Dynamic kinetic resolution of racemic profen esters.
2. Results and discussion
Without DMSO, under alkaline buffer conditions, no in situ
racemization of the methyl ibuprofen ester occurred but most of
the (S)-methyl ibuprofen ester was enzymatically hydrolyzed in
less than 24 h.14 With a base and DMSO, but no lipase, the methyl
ester of (R)-ibuprofen was observed to completely racemize in
5 days by chiral HPLC. With DMSO and a base, but before adding
⇑
Corresponding author. Tel.: +1 915 239 0673.
E-mail
addresses:
dabidcha@hotmail.com,
dchavez3@miners.utep.com
(D. Chavez-Flores), jsal@utep.edu (J.M. Salvador).
Tel.: +1 915 747 5704.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.014

238
D. Chavez-Flores, J. M. Salvador / Tetrahedron: Asymmetry 23 (2012) 237–239
the lipase, the ester was observed to partially dissolve in the aque-
ous buffer, which allowed for its more effective contact with the
enolizing base. Unlike the previously reported dynamic kinetic res-
olutions of profens, a biphasic solvent system was not necessary.
Without DMSO, the enantiomeric ratio (E) for the enzymatic
hydrolysis was calculated to be 54. Assuming pseudo first-order
kinetics [time vs the natural log of the (S)-ibuprofen produced]
4.2. Analytical methods
4.2.1. Chiral high performance liquid chromatography
All reactions were monitored by chiral HPLC at room tempera-
ture with a Chiracel OJ chiral column (Diacel Chemical Industries,
Ltd.) capable of resolving racemic ibuprofen, but not the less polar
ibuprofen esters. The mobile phase used was hexanes/isopropanol
(95:5, v:v) at a flow rate of 1 mL/min. The UV detector was set at
256 nm.
the rate of enzymatic hydrolysis was about 0.098 0.001 hꢀ1
.
The rate was the same under neutral or alkaline pH conditions,
which indicates that a pH of 9.8 did not have an adverse effect
on the lipase and that, unlike previously reported dynamic kinetic
resolutions of profens, no special preparation of the lipase was
necessary.
4.3. Procedures
4.3.1. Fischer esterification of ibuprofen
‘Consecutive reactions with a reversible step’ kinetics were fit to
the conversion of the racemic methyl ibuprofen ester to (S)-ibupro-
fen under dynamic kinetic resolution conditions by the least-
squares criterion. By this model, the rate of in situ racemization be-
tween methyl ester enantiomers catalyzed by base and DMSO was
To a 100 mL round bottomed flask was added 40 mL (1 mol) of
methanol, 10 mmol of racemic ibuprofen, and 0.5 mL (9 mmol) of
concentrated H2SO4. The mixture was stirred at 40 °C. By chiral
HPLC, after 5 h, all ibuprofen was converted into the ester. The
mixture was extracted with 2 ꢁ 40 mL of hexane, and the volatiles
were removed on a rotary evaporator to give 2.2 g (10 mmol, quan-
titative) of the racemic methyl ibuprofen ester. The synthesis of the
same ester via its acyl chloride was achieved with less than quan-
titative yield.
0.026 0.004 hꢀ1, k1 and k and the rate of enzymatic hydrolysis
ꢀ1
of the (S)-methyl ibuprofen ester was 0.053 0.004 hꢀ1, k2 in Fig-
ure 2. This indicates that although the base and DMSO did not have
an effect on the enzyme separately, together the lipase activity was
reduced in half to enable the ester to be racemized.
4.3.2. Kinetic resolution of racemic methyl ibuprofen ester at
pH 9.8
3. Conclusion
To a 125 mL round bottomed flask were added 40 mL of pH 9.8
aqueous buffer (100 mL of 0.5 M NaHCO3 + 15.2 mL of 1.0 M
NaOH), 2.2 g (10 mmol) of racemic methyl ibuprofen ester, and
1.67 g of Candida rugosa lipase.15 The mixture was stirred at
40 °C and monitored by chiral HPLC for 144 h. The reaction was
acidified to pH 5 with 1 M HCl. The mixture was extracted with
2 ꢁ 40 mL of hexanes. The hexanes layers were extracted with
10 mL of 0.5 M NaOH and evaporated to give 1.19 g (5.3 mmol,
53% yield) of enriched (R)-methyl ibuprofen ester.
Combining the dynamic kinetic resolution and purification
steps, and considering that forming the racemic methyl ester is
quantitative, the overall conversion of racemic ibuprofen to pure
(S)-ibuprofen was 88%. The application of this methodology to
other profens is currently in progress.
4. Experimental
4.1. Materials
4.3.3. Racemization of (R)-methyl ibuprofen ester with DMSO
and base
To a 25 mL round bottomed flask were added 8 mL of pH 9.8
aqueous buffer, 2 mL of DMSO, and 1.1 g (5 mmol) of enriched
(R)-methyl ibuprofen ester. The mixture was stirred at 40 °C and
monitored by chiral HPLC for 144 h.
Racemic ibuprofen was isolated from inexpensive commercial
tablets (200 mg Member’s Mark, Sam’s Club). Candida rugosa lipase
(706 units/mg solid) was purchased from Sigma Chemical Com-
pany and was used without any further treatment. All other re-
agents were from commercial sources.
Figure 2. Dynamic kinetic resolution data and consecutive reactions with a reversible step simulation.

D. Chavez-Flores, J. M. Salvador / Tetrahedron: Asymmetry 23 (2012) 237–239
239
4.3.4. Dynamic kinetic resolution of racemic methyl ibuprofen
ester
To a 125 mL round bottomed flask was added 32 mL of pH 9.8
Acknowledgments
We gratefully acknowledge the financial support of the Depart-
ment of Education of the State of Chihuahua (Mexico), the Depart-
ment of Chemistry of the University of Texas at El Paso, the
Graduate School and the College of Science of the University of
Texas at El Paso, the US Army Research Laboratory, the Facultad
de Ciencias Químicas de la Universidad Autónoma de Chihuahua
and US Army Research Office (W911NF0410052), and the National
Council of Science and Technology of Mexico (CONACyT).
aqueous buffer, 8 mL of DMSO, 2.2 g (10 mmol) of racemic methyl
ibuprofen ester, and 1.67 g of Candida rugosa lipase. The mixture
was stirred at 40 °C and monitored by chiral HPLC for 144 h. The
reaction was acidified to pH 5 with 1 M HCl. The mixture was ex-
tracted with 2 ꢁ 40 mL of hexane. The hexane layers were ex-
tracted with 20 mL of 0.5 M NaOH. The aqueous layer was
acidified to pH 5 with 1 M HCl and extracted with 2 ꢁ 40 mL of
hexanes. The hexanes were evaporated to give 1.94 g (9.4 mmol,
94% yield) of (S)-ibuprofen with an ee of 94%.
References
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4.3.5. Purification of enriched (S)-ibuprofen
To
a 25 mL round bottomed flask were added 2.00 g
(9.7 mmol) of pulverized enantiomerically enriched (S)-ibuprofen
(ee = 94%) and 10 mL of methanol. The flask was placed in a
water bath at 45 °C and stirred with a magnetic bar until of
the all ibuprofen had dissolved. The temperature of the water
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was gradually reduced to 0 °C overnight in
a refrigerator.
Racemic ibuprofen crystals (0.13 g, 0.66 mmol, 6.8%) were
collected by vacuum filtration and the methanol was evaporated
from the filtrate to give 1.864 g (9.0 mmol, 93%) of (S)-ibuprofen
with an ee of 99.7%. The specific rotation of this material was
½
a 2D5
ꢂ
¼ þ59:5 (c 1, ethanol 95%), indicating an ee of at least
16. Jeffrey, P.; Gjhgnj, T. G.; Bye, A.; Crewe, H. K.; Wright, P. A. J. Pharm. Pharmacol.
1991, 43, 6.
17. Snell, D.; Colby, J. Enzyme Microbial Technol. 1999, 24, 160–163.
99.2%. The melting point of 55 °C was in good agreement with
the literature value of 55.5 °C.16,17