964
J.-F. Ciou et al. / Process Biochemistry 46 (2011) 960–965
and (SS), and hence XR and XS, were solved using a fourth-order
Runge–Kutta method. Typical experimental data in agreements
with the theoretical predictions are illustrated in Fig. 2.
(Si)0
initial concentration, i = R or S for (R)- or (S)-enantiomer
(mM)
absolute temperature (K)
T
Vi
Xi, Xt
initial rate, i = R or S for (R)- or (S)-enantiomer (mM/h)
enantiomer conversion defined as [1 − (Si)/(Si)0], i = R or
S; racemate conversion defined as (XR + XS)/2
enthalpy difference between transition and ground
states, i = R or S (kJ/mol)
4.4. Prodrug synthesis
ꢀHi
ꢀSi
A typical example for the alcoholytic resolution has been
described in Section 2.4, in which 60.6% molar yield of pure
(R)-flurbiprofenyl 2,3-dibromo-1-propyl ester was obtained and
confirmed from NMR and HPLC spectra after the reactive extrac-
tion via 0.1 M NaOH solution. The optically pure (R)-flurbiprofenyl
2,3-bisnitrooxypropyl ester prodrug was then synthesized in
acetonitrile, recovered via extraction and solvent evaporation, con-
firmed from the NMR and HPLC spectra, and gave 79.9% molar yield.
entropy difference between transition and ground states,
i = R or S (J/mol K)
ꢀꢀG
ꢀꢀH
ꢀꢀS
defined as (ꢀꢀH − TꢀꢀS) (kJ/mol)
defined as (ꢀHR − ꢀHS) (kJ/mol)
defined as (ꢀSR − ꢀSS) (J/mol K)
Appendix B. Supplementary data
5. Conclusions
Supplementary data associated with this article can be found, in
A CALB-catalyzed alcoholysis of (R,S)-flurbiprofenyl azolide
in anhydrous MTBE was developed for the preparation of
(R)-flurbiprofenyl ester, (S)-flurbiprofenyl azolide, and hence (S)-
flurbiprofen via reactive extraction. By varying the leaving azole
moiety and alcohol as an acyl acceptor, (R,S)-flurbiprofenyl 4-
bromopyrazolide and 2,3-dibromo-1-propanol were selected as
the best substrates at 45 ◦C, and led to excellent enantioselec-
tivity (VR/VS = 200.3) with high specific activity. A decrease of
temperature might result in enhancements of the enzyme enan-
tioselectivity but not specific activity.
A thermodynamic analysis indicated that changing of the leav-
ing azole caused minor effects on varying −ꢀꢀH and −ꢀꢀS for
the transition states of both enantiomers. Yet in comparison with
the alcoholysis of (R,S)-naproxenyl 1,2,4-triaozlide by methanol,
the changing sign of −ꢀꢀS was advantageous for giving the excel-
lent enantioselectivity at 45 ◦C, where both −ꢀꢀH and −ꢀꢀS gave
equal contributions to −ꢀꢀG = 14.03 kJ/mol. A thorough kinetic
analysis for the alcoholysis at the best reaction condition was
performed, with which the kinetic constants were estimated and
successfully employed for modeling the time-course conversions
for both enantiomers. The optically pure (R)-flurbiprofenyl 2,3-
dibromo-1-propyl ester, obtained via reactive extraction after the
alcoholytic resolution, was separated and employed for synthe-
sizing the desired (R)-flurbiprofenyl 2,3-bisnitrooxypropyl ester
prodrug.
References
[1] Sih CJ, Gu QM, Fulling G, Wu SH, Reddy DR. The use of microbial enzymes
for the synthesis of optically active pharmaceuticals. Dev Ind Microbiol
1998;29:221–9.
[2] Chang CS, Tsai SW, Lin CN. Enzymatic resolution of (R,S)-2-arylpropionic acids
thioesters by Candida rugosa lipase-catalyzed thiotransesterification or hydrol-
ysis in organic solvents. Tetrahedron: Asymmetry 1998;9:2799–807.
[3] Ng IS, Tsai SW. Partially purified Carica papaya lipase: a versatile biocatalyst for
the hydrolytic resolution of (R,S)-2-arylpropionic thioesters in water-saturated
organic solvents. Biotechnol Bioeng 2005;91:106–13.
[4] Chen CC, Tsai SW, Villeneuve P. Enantioselective hydrolysis of (R,S)-naproxen
2,2,2-trifluoroethyl ester in water-saturated solvents via lipases from Car-
ica pentagona Heilborn and Carica papaya. J Mol Catal B: Enzym 2005;34:
51–7.
[5] Chang CS, Tsai SW, Kuo J. Lipase-catalyzed dynamic resolution of naproxen
2,2,2-trifluoroethyl thioester by hydrolysis in isooctane. Biotechnol Bioeng
1999;64:120–6.
[6] Lin CN, Tsai SW. Dynamic resolution of suprofen thioester via coupled triocty-
lamine and lipase catalysis. Biotechnol Bioeng 2000;69:31–8.
[7] Xin JY, Li SB, Xu Y, Chui JR, Xia CG. Dynamic enzymatic resolution of
naproxen methyl ester in a membrane bioreactor. J Chem Technol Biotechnol
2001;76:579–85.
[8] Chen CY, Cheng YC, Tsai SW. Lipase-catalyzed dynamic kinetic resolu-
tion of (R,S)-fenoprofen thioester in isooctane. J Chem Technol Biotechnol
2002;77:699–705.
[9] Wang LW, Cheng YC, Tsai SW. Process modeling of lipase-catalyzed dynamic
kinetic resolution of (R,S)-suprofen 2,2,2-trifluoroethyl thioester in a hollow
fiber membrane. Bioprocess Biosyst Eng 2004;27:39–49.
[10] Fazlena H, Kamaruddin AH, Zulkali MMD. Dynamic kinetic resolution: alter-
native approach in optimizing S-ibuprofen production. Bioprocess Biosyst Eng
2006;28:227–33.
[11] Weder JE, Dillon CT, Hambley TW, Kennedy BJ, Lay PA, Biffin JR, et al. Copper
complexes of non-steroidal anti-inflammatory drugs: An opportunity yet to be
realized. Coord Chem Rev 2002;232:95–126.
Acknowledgement
[12] Abdel-Tawab M, Zettl H, Schubert-Zsilavecz M. Nonsteroidal anti-
The financial support of NSC 99-2221-E-182-028 from National
Science Council is appreciated.
inflammatory drugs:
a critical review on current concepts applied to
reduce gastrointestinal toxicity. Curr Med Chem 2009;16:2042–63.
[13] Halen PK, Murumkar PR, Giridhar R, Yadav MR. Prodrug designing of NSAIDs.
Mini-Rev Med Chem 2009;9:124–39.
[14] Stefano F, Distrutti E. Cyclo-oxygenase (COX) inhibiting nitric oxide donat-
ing (CINODs) drugs: a review of their current status. Curr Top Med Chem
2007;7:277–82.
Appendix A. Nomenclature
[15] Fiorucci S, Santucci L, Distrutti E. NSAIDs, coxibs, CINOD and H2S-releasing
NSAIDs: what lies beyond the horizon. Dig Liver Dis 2007;39:1043–51.
[16] Koc E, Kucukguzel SG. Medicinal chemistry and anti-inflammatory activity of
nitric oxide-releasing NSAID drugs. Mini-Rev Med Chem 2009;9:611–9.
[17] Wallace JL, Viappiani S, Bolla M. Cyclo-oxygenase-inhibiting nitric oxide dona-
tors for osteoarthritis. Trends Pharmacol Sci 2009;30:112–7.
[18] Kolluri SK, Corr M, James SY, Bernasconi M, Lu D, Liu W, Cottam HB, Leoni LM,
Carson DA, Zhang XK. The R-enantiomer of the nonsteroidal antiinflammatory
drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis.
PNAS 2005;102:2525–30.
ees
E
(Et)
G
enantiomeric excesses for the substrate
enantiomeric ratio, defined as k2RKmS/k2SKmR
enzyme concentration (mg/mL)
parameter defined in Eq. (3)
kinetic constants, i = R or S for (R)- or (S)-enantiomer
(mmol/g h)
k2i, k4i
KI
inhibition constant (mM)
[19] Jin H, Wang Z, Liu L, Gao L, Sun L, Li X, et al. R-Flurbiprofen reverses mul-
tidrug resistance, proliferation and metastasis in gastric cancer cells by p75NTR
induction. Mol Pharm 2010;7:156–68.
Kmi, Km3i kinetic constants, i = R or S for (R)- or (S)-enantiomer
(mM)
[20] Weggen S, Rogers M, Eriksen J. NSAIDs: small molecules for prevention of
Alzheimer’s disease or precursors for future drug development? Trends Phar-
macol Sci 2007;28:536–43.
[21] Hirohata M, Ono K, Yamada M. Non-steroidal anti-inflammatory drugs as anti-
amyloidogenic compounds. Curr Pharm Des 2008;14:3280–94.
(M)
(M)0
(Si)
alcohol concentration (mM)
initial alcohol concentration (mM)
substrate concentration, i = R or
enantiomer (mM)
S
for (R)- or (S)-