New and improved manufacturing process for valsartan

Article abstract of DOI:10.1021/op9000912

A new and improved industrially viable manufacturing process for valsartan, an antihypertension drug, is described.

Full text of DOI:10.1021/op9000912

Organic Process Research & Development 2009, 13, 1185–1189
New and Improved Manufacturing Process for Valsartan
Senthil Kumar .N,† Shankar B. Reddy,*,† Brajesh Kumar Sinha,† Kagga Mukkanti,‡ and Ramesh Dandala†
Chemical Research and DeVelopment, APL Research Centre, Aurobindo Pharma Ltd., Bachupally, Hyderabad - 500072, India,
and Centre for Pharmaceutical Science, Jawaharlal Nehru Technological UniVersity, Kukatpally, Hyderabad - 500072, India
Scheme 1. Reported route Ia and IIb for valsartan
Abstract:
A new and improved industrially viable manufacturing process
for valsartan, an antihypertension drug, is described.
Introduction
The renin/angiotensin system (RAS) produces angiotensin
II (A-II), a very potent vasoconstrictive and volume-retaining
hormone, which plays a critical role in the regulation of blood
pressure.1,2 Prevention of the formation A-II, via inhibition of
angiotension converting enzyme (ACE),3 has confirmed the
therapeutic benefit of inhibiting the RAS in hypertension and
congestive heart failure. Valsartan 1, commonly known as
(N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]-
methyl]-L-valine), is an orally active specific A-II receptor
antagonist used as a hypotensive drug.4 A-II receptor antagonists
are safe and effective agents for the treatment of hypertension,
anxiety, glaucoma, and heart failure, either alone or in conjunc-
tion with hydrochlorothiazide.5
Valsartan has been proposed as an alternative to the more
traditional angiotensin-converting enzyme inhibitors because it
selectively blocks the angiotensin type 1 (AT1) receptor.6
Valsartan is marketed as the free acid under the name Diovan.
Several processes for the preparation of valsartan 1 have been
reported in the literature.7a-d One of the syntheses (Scheme 1)
involves reaction of 4-bromomethyl-2′-cyanobiphenyl 2 with
L-valine methyl ester hydrochloride 3 to produce 4. Compound
4 was converted into 5 by reacting with valeryl chloride in the
presence of base and then cyclizing with tri-n-butyltinazide to
form 6. Compound 6 on hydrolysis under alkaline conditions
gave 1.
a Reagents and conditions: (a) N,N-Diisopropylethylamine, CH2Cl2, 72%. (b)
Valeryl chloride, triethylamine, CH2Cl2, 92%. (c) Tributyltin azide. 62%, (d)
NaOH, methanol, 50%. b Reagents and conditions: (a) 1,4-Dioxane, reflux, 3 h,
67%, (b) N,N-diisopropylethylamine, valeryl chloride, CH2Cl2, 25 °C, 81%. (c)
1,4-Dioxane, 1 N HCl, 60 °C, 2 h, 90%. (d) Pd/C, H2, methanol, 24 h, 60%.
* Corresponding author. Telephone: 91-40-23040261. Fax: 91-40-23042932.
E-mail: crd@aurobindo.com.
† APL Research Centre, Aurobindo Pharma Ltd.
‡ JNT University.
Problems associated with this synthetic process have been
(a) the use of highly toxic tri-n-butyltinazide in the conversion
of compound 5 to compound 68,9 at the penultimate stage of
valsartan synthesis, (b) contamination of final product with
traces of toxic tin metal, (c) racemisation of valsartan up to
15% during hydrolysis under basic conditions,10 and (d) low
purity and low yield of valsartan. To achieve acceptable purity,
chiral purity and acceptable limit of tin as per ICH guidelines
to meet the pharmaceutical compositions, a series of purifica-
tions are being demanded, resulting in low yield.
(1) Duncia, J. V.; Chiu, A. T.; Carini, D. J.; Gregory, G. B.; Johnson,
A. L.; Price, W. A.; Wells, G. J.; Wong, P. C.; Calabrese, J. C.;
Timmermans, P. B. M. W. M. J. Med. Chem. 1990, 33, 1312.
(2) Sealey, J. E.; Laragh, J. H.; Hypertension: Pathophysiology, Diagnosis
and Management; Laragh, J. H., Brenner, B. M., Eds.; Raven: New
York, 1990, 1287.
(3) Wyvratt, M. J.; Patchett, A. A. Med. Res. ReV. 1985, 5, 483.
(4) Buhlmayer, P.; Furet, P.; Criscione, L.; De Gasparo, M.; Whitebread,
S.; Schmidlin, T.; Lattmann, R.; Wood, J. Bioorg. Med. Chem. Lett.
1994, 4, 29.
(5) Cocolas, G. H., Delgado, J. N.; Remers, W. A., Eds. Textbook of
Organic Medicinal and Pharmaceutical Chemistry, 10th ed.; Lippin-
cott-Raven: Philadelphia, New York, 1998; p 603.
(6) Wexler, W. A.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.;
Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W. M. J. Med.
Chem. 1996, 39, 625.
Another process for preparation of valsartan by the same
authors has been described in Scheme 1. Compound 7 was
(7) (a) Buhlmayer, P.; Ostermayer, F.; Schmidlin, T. U.S. Patent 5,399,578,
1995. (b) Rukhman, I.; Dolitzky, B. Z.; Flyaks, E. U.S. Patent
7,199,144, 2007. (c) Radi, S.; Stach, J.; Dedinova, E. EP 1,622,882,2004.
(d) Cosme Gomez, A.; Paloma Nicolau, F. E. PCT WO 2008/138871,
2008.
(8) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139.
(9) Chen, Z.; Guojun, Z.; Lijing, F.; Li, Y. Synlett 2006, 477.
(10) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J.
Org. Chem. 1997, 62, 1240.
10.1021/op9000912 CCC: $40.75  2009 American Chemical Society
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Scheme 2a
a Reagents and conditions: (a) N,N-Diisopropylethylamine, DMF, 45 °C. (b) Methanol, IPA-HCl, oxalic acid, 25 °C, 3 h. (c) Na2CO3, valeryl chloride, N,N-
diisopropylethylamine, toluene, 10 °C, 5 h.
reacted with L-valine benzyl ester, 8, to produce 9, which was
further treated with valeryl chloride to yield 10. Compound 10
was treated with acid for detritylation to yield 11, which on
catalytic Pd/C hydrogenation yielded valsartan, 1.
Some of the drawbacks of the approach are (a) isolation of
intermediates as an oily mass with low quality,11 (b) debenzy-
lation of 11 with a large amount of Pd/C (∼35% w/w) at high
pressure H2 gas, (c) purification of crude valsartan. The product
synthesized by this approach required multiple purifications to
meet the regulatory requirement, resulting in a significant drop
in yield.12,13 To overcome the drawbacks, there is a need to
develop an industrially viable and safe manufacturing process
for the preparation of valsartan, 1.
15, which was debenzylated with Pd/C to afforded crude
valsartan. Although hydrogenation of 15 was successful with a
commercially viable quantity of Pd/C (10% Pd/C, 50% wet),
the crude product was contaminated with byproduct p-toluidine.
Several attempts made to remove p-toluidine from crude
valsartan, however, were unsuccessful to achieve required
quality consistently.
As the elimination of byproduct p-toluidine from 1 was
unsuccessful, an alternative commercially viable process was
developed (Scheme 4) for 1 involving an inventive hydrolysis
of 6 using barium hydroxide to achieve purity greater than
99.8% with enantiomeric purity greater than 99.8% and high
yield.
Process for N-[[2′-(1-Triphenylmethyltetrazol-5-yl)biphe-
nyl-4-yl]methyl]-L-valine Methyl Ester Oxalate (18a). Com-
pound 7 was reacted with compound 3 (Scheme 4) in the
presence of N,N-diisopropylethylamine in DMF at ambient
temperature. The product 18 was extracted with ethyl acetate
and treated with oxalic acid to form the corresponding salt as
18a. Compound 18a was isolated with purity greater than 98%
by HPLC and used in the subsequent acylation reaction. The
major impurity 21 was eliminated into the mother liquor during
isolation of 18a.
Results and Discussion
Initially, we attempted to produce valsartan through Scheme
2 involving new intermediate 14. Valine p-nitrobenzyl ester 12
was prepared according to the method described in the litera-
ture.14 Compound 12 was N-alkylated in the presence of base
to produce compound 13 which was subsequently detritylated
by treating with acid, and 14 was isolated as a white solid with
purity greater than 95% by HPLC.
N-Acylation of the amine function in the valine moiety of
compound 14 in the presence of base resulted in compound 15
with purity about 75% by HPLC. As expected, N-acylation
occurred at both NH functions of valine and tetrazole in
compound 14 that led to low purity of 15. Further conversion
of impure 15 to valsartan on commercial scale is not worthwhile.
This synthetic approach was unsuccessful due to the lack of
single acylation at the NH function of the valine moiety.
Alternatively, compound 13 (Scheme 3) was treated with
oxalic acid, and the corresponding oxalate salt 16 was isolated.
The NH function of the valine moiety of 16 was acylated with
valeryl chloride in the presence of N,N-diisopropylethylamine,
and compound 17 was isolated with purity greater than 95%.
Compound 17 was detritylated in mild acidic conditions to yield
Process for N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-
biphenyl]-4-yl]methyl]-L-valine Methyl Ester (6). Compound
18a was acylated with valeryl chloride in the presence of N,N-
diisopropylethylamine and detritylated with IPA-HCl in anhy-
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Scheme 3a
a Reagents and conditions: (a) Oxalic acid, ethyl acetate, 15-20 °C. (b) Aqueous Na2CO3, valeryl chloride, N,N-diisopropylethylamine, toluene. (c) IPA-HCl,
methanol. (d) Pd/C, H2, ethyl acetate.
Scheme 4. Improved route for valsartana
a Reagents and conditions: (a) N,N-diisopropylethylamine, DMF, 45-50 °C. (b) Oxalic acid, ethyl acetate, 10-15 °C, 76%. (c) Na2CO3, valeryl chloride, N,N-
diisopropylethylamine, toluene, 5-10 °C, 95%. (d) Methanol, IPA-HCl, 20-30 °C, 72%. (e) Aqueous barium hydroxide, 20-30 °C. (f) Aqueous HCl, ethyl acetate,
65%.
drous conditions to yield compound 6. A robust purification
method has been developed to remove process impurities, and
compound 6 was isolated with purity greater than 97% by
HPLC.
Process for N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-
biphenyl]-4-yl]methyl]-L-valine(1). Compound 6 can be hy-
drolysed with alkaline and alkaline earth metal hydroxides.
However, hydrolysis with bases such as lithium hydroxide,
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Table 1. Optimization of base in the hydrolysis of
1.87-1.92 (m, 1H), 3.01-3.03 (m, 1H), 3.51-3.75 (dd, 2H),
5.30 (s, 2H), 6.82-8.25 (m, 27H).
compound 6
entry
base
reaction time (h)
eea 1 (%)
N-[[2′-(1H-Tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-
valine-4-nitrobenzyl Ester Oxalate (14). Compound 13 (20
g, 0.027 mol) was added to a mixture of methanol (100 L) and
20% w/w isopropyl alcohol hydrogen chloride (0.79 g; 0.0054
mol) at 25 °C and stirred for 3 h. The reaction mass was cooled,
filtered off the solid byproduct, trityl methyl ether, and the
filtrate was concentrated. The resulting concentrated mass was
dissolved in ethyl acetate (100 mL) and treated with oxalic acid
dihydrate (3.7 g, 0.0297 mol) at 20-30 °C. The reaction mixture
was cooled to 0-5 °C, and the solid product was filtered,
washed with ethyl acetate (20 mL), and dried at 45-50 °C to
1
2
3
4
5
NaOH
LiOH
9
8
88.00
91.00
86.90
99.95
91.20
KOH
8
Ba(OH)2
Ca(OH)2
10
9
a Isolated product purity.
sodium hydroxide, potassium hydroxide, etc., resulted in
racemisation up to 15% (Table 1).
It was found in our hands that hydrolysis of compound 6
with barium hydroxide, however, resulted in compound 1 with
less than 3% of racemisation. Further, compound 20 was
crystallized from the reaction mixture with enantiomeric purity
greater than 99.7% by HPLC. Barium hydroxide is a suitable
base to hydrolyse the compound 6 efficiently and to produce
compound 1 with minimum racemisation, which on single
crystallization resulted in compound 1 with higher purity and
enantiomeric purity and with less than 20 ppm of barium
content. This process was performed on a commercial scale of
250 kg of 7 to 1 successfully. Purity, enantiomeric purity (ee),
and overall yield of 1 are presented in Table 2.
1
yield 14. Yield 90% (14.04 g). mp 137-140 °C. H NMR
(DMSO-d6) δ: 0.86-0.95 (m, 6H), 2.01-2.08 (m, 1H),
3.27-3.29 (m, 1H), 3.67-3.90 (dd, 2H), 5.31 (s, 2H), 7.05-8.27
(m, 12H). Mass: 487.1 [M + H]+.
N-[[2′-(1-Triphenylmethyltetrazol-5-yl)biphenyl-4-
yl]methyl]-L-valine Methyl Ester Oxalate (18a). L-Valine
methyl ester hydrochloride 3 (132.2 g, 0.789 mol) was added
to a mixture of 1-triphenylmethyl-5-[4′-(bromomethyl)biphenyl-
2-yl]tetrazole 7 (400 g, 0.717 mol) and N,N-dimethylformamide
(400 mL) at 25-30 °C and stirred for 10 min. N,N-Diisopro-
pylethylamine (231.7 g, 1.79 mol) was added to the reaction
mass and heated to 45-50 °C. The resulting reaction mixture
was maintained until completion of reaction at 45-50 °C. The
reaction mass was cooled to 10-15 °C and quenched by
pouring into a mixture of ethyl acetate (2 L) and water (400
mL). The organic layer was separated and washed successively
with water (400 mL) followed by 10% w/w aqueous sodium
chloride solution (200 mL). The ethyl acetate layer was
separated and treated with oxalic acid dihydrate (99.5 g, 0.789
mol) at 10-15 °C. The reaction mixture was cooled to 0-5
°C, and the solid product was filtered, washed with ethyl acetate
(400 mL), and dried at 45-50 °C to yield 18a. Yield 76% (420
g). HPLC purity 98.14%. mp 172-176 °C. [R ]20D ) +5.3 (c
0.5% w/v in methanol). IR (cm-1): 3443 (N-H), 3186 (O-H),
1759 (CdO), 1644 (CdO). 1H NMR (DMSO-d6) δ: 0.86-0.97
(m, 6H), 1.96-2.03 (m, 1H), 3.26-3.27 (m, 1H), 3.7 (s, 3H),
3.82-3.90 (m, 2H), 6.85-7.79 (m, 23H). 13C NMR (DMSO-
d6) δ: 19.1, 19.9, 30.9, 51.4, 52.7, 66.2, 83.2, 126.6, 128.7,
129.2, 129.5, 129.7, 130.4, 131.2, 131.4, 136.4,140.4, 141.7,
142.1, 163.7, 164.4, 173.0. Anal. Calcd for C41H39N5O6: C,
70.57; H, 5.59; N, 10.03. Found: C, 71.40; H, 5.55; N, 10.00.
N-[[2′-(1-Triphenylmethyltetrazol-5yl]biphenyl-4-yl]-
methyl]-N-valeryl-L-valine Methyl Ester (19). Compound
18a (150 g, 0.215 mol) was added to a mixture of toluene (450
mL) and water (300 mL) and basified with 10% w/w aqueous
sodium carbonate solution (450 mL) at 20-30 °C. The organic
layer was separated and washed with water (150 mL) followed
by 10% w/w aqueous sodium chloride solution. The organic
Conclusion
We have provided an improved, industrially viable and safe
manufacturing process for valsartan that is substantially free
from tin and meets the regulatory norms in terms of quality
with high yield.
Experimental Section
Materials and Instruments. 1H NMR and 13C NMR spectra
were recorded on a Bruker 300 spectrometer at 300 and 75
MHz, respectively, and the chemical shifts were reported as δ
values in parts per million relative to TMS as an internal
standard. Infrared spectra were recorded in the solid state as
KBr dispersion using a Perkin-Elmer spectrophotometer. Mass
spectra were recorded on API 2000 Perkin-Elmer PE-SCIEX
mass spectrometer. The melting points were recorded on open
capillaries and are uncorrected.
N-[[2′-(1-Triphenylmethyltetrazol-5-yl)biphenyl-4-
yl]methyl]-L-valine-4-nitrobenzyl Ester (13). L-Valine
p-nitrobenzyl ester 12 (19.2 g, 0.044 mol) was added to a
mixture of 1-triphenylmethyl-5-[4′-(bromomethyl)biphenyl-2-
yl]tetrazole 7 (25 g, 0.044 mol) and N,N-dimethylformamide
(75 mL) at 25-30 °C and stirred for 10 min. N,N-Diisopro-
pylethylamine (14.2 g, 0.11 mol) was added to the reaction mass
and heated to 45 °C. The resulting reaction mixture was
maintained until completion of reaction at 45 °C and cooled to
20-30 °C. The reaction mass was dissolved in methylene
chloride (125 mL) and washed successively with water (3 ×
100 mL). The organic layer was separated and concentrated
completely under reduced pressure to dryness to yield 13. Yield
(11) Ashok, K.; Manmohan, M. N.; Sanjay, G. B.; Dattatray, S. M.; Rahul,
S. K.; Bharat, D. S.; Larkesh, D. K. U.S. Patent Appl. Publ. U.S. 2006/
0281801, 2006.
(12) Cepanec, I.; Litvic, M.; Koretic, S.; Bartolinlic, A.; Druskovic, V.;
Sporec, A. PCT Int. Appl. WO 2005/049586, 2005.
(13) Soni, R. R.; Vasoya, S. L.; Gotikar, R. C.; Pandey A. K.; Shah, H. R.
PCT Int. Appl. WO 2007/032019, 2007.
(14) Tagami, Y.; Katsura, T.; Itaya, N. EP 985,658, 2004.
(15) Erwin, E. M. U.S. Patent 6,869,970, 2005.
1
85% (27.8 g). H NMR (DMSO-d6) δ: 0.86-0.91 (m, 6H),
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Vol. 13, No. 6, 2009 / Organic Process Research & Development

Table 2. Purity, enantiomeric purity, and overall yield of commercial batches
by HPLC (%) residual solvent (by GC, ppm)
entry cmpda 7 (kg) cmpda 1 (kg) purity
ee
ethyl acetate
methanol
barium (ppm) DSC (°C) overall yield (%)
1
2
3
250
250
250
64.80
64.05
66.20
99.86 99.92
99.82 99.90
99.85 99.95
3984
3556
2871
180
219
164
7
7
8
90.41
89.42
88.75
33.2
32.8
33.9
a cmpd ) compound.
layer was separated, dried over anhydrous sodium sulfate, and
reacted with valeryl chloride (33.7 g, 0.23 mol) in the presence
of N,N-diisopropylethylamine (55.6 g, 0.43 mol) at 0-5 °C.
The reaction mixture was stirred at 5-10 °C for 3 h and
quenched into water (150 mL). The organic layer was separated
and washed with 10% w/w sodium carbonate solution (68 mL)
followed by 10% w/w aqueous oxalic acid solution (40 mL).
The organic phase was separated and concentrated completely
under reduced pressure to dryness to yield 19 as an oily mass.
Yield 95% (141.3 g). HPLC purity 97.21%. IR (cm-1): 1743
(CdO), 1656 (CdO). 1H NMR (DMSO-d6) δ: 0.68-0.78 (m,
5H), 0.84-0.90 (m, 4H), 1.06-1.52 (m, 4H), 2.17-2.3 (m,
3H), 3.3 (s, 3H), 4.18-4.73 (m, 3H), 6.9-7.7 (m, 23H).
N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-
4-yl]methyl]-L-valine Methyl Ester (6). Compound 19 (100
g, 0.1445 mol) was added to a mixture of methanol (1 L) and
20% w/w isopropyl alcohol hydrogen chloride (2.756 g; 0.0143
mol) at 20-30 °C and stirred for 5 h. The reaction mass was
cooled, filtered off the solid byproduct, trityl methyl ether, and
the filtrate was concentrated. The resulting concentrated mass
was dissolved in ethyl acetate (300 mL) and treated with 2%
w/w aqueous sodium carbonate solution (700 mL). The aqueous
layer was separated, the pH was adjusted to 7-8 with 10%
w/w aqueous acetic acid, and the solution was washed with
ethyl acetate (100 mL). The aqueous layer was separated and
acidified with 10% w/w aqueous acetic acid to pH 4.0 to
precipitate product. The solid product was filtered, washed with
water, and dried to yield 6. Yield 72.3% (47 g). HPLC purity
97.21%. mp 70-71 °C [lit. 70.9-73.3 °C]. 1H NMR (DMSO-
d6) δ: 0.76-0.93 (m, 9H), 1.18-1.46 (m, 4H), 2.29-2.51 (m,
3H), 3.30 (s, 3H), 4.47-4.74 (m, 3H), 6.98-7.07 (m, 4H),
7.47-7.63 (m, 4H). Mass: 450.3 (M + H)+.
and distilled completely under reduced pressure at 50-60 °C.
The resulting solid mass was recrystallized from ethyl acetate
(225 mL), filtered at -15 to -20 °C, and dried at 45-50 °C
to yield 1. Yield 65% (28.5 g). HPLC purity 99.82%, ee )
99.95%. DSC: 90.4 °C [lit. 80-95 °C]. [R ]20D ) (-) 67.9 (c
1% w/v in methanol). IR (cm-1): 3441 (N-H), 2964 (O-H),
1732 (CdO), 1603 (CdO). 1H NMR (DMSO-d6) δ: 0.69-0.94
(m, 9H), 1.08-1.21 (m, 1H), 1.27-1.56 (m, 3H), 1.97-2.11
(m, 1H), 2.16-2.50 (m, 2H), 4.06-4.62 (m, 3H), 6.99-7.21
(m, 4H), 7.52-7.71 (m, 4H), 12.67 (br, 1H), 16.20 (br, 1H).
Mass: 436.3 (M + H)+. Anal. Calcd for C24H29N5O3 (435.52):
C, 66.19; H, 6.71; N, 16.08. Found: C, 66.50; H, 6.85; N, 15.80.
13C NMR (DMSO-d6) δ: 41.6, 14.7, 19.3, 19.7, 20.3, 21.0, 22.5,
27.7, 27.9, 28.4, 33.3, 41.2, 46.3, 63.8, 66.6, 124.3, 127.1, 127.8,
128.4, 128.6, 129.2, 129.7, 131.4, 131.5, 131.9, 138.0, 138.6,
139.1, 142.1, 142.2, 155.2, 172.5, 172.8, 174.3. Barium content:
8 ppm. Ethyl acetate: 2759 ppm. Methanol: 125 ppm.
HPLC Conditions for Enantiomer Purity.
Column:
Chiralcel OD-H, 5 µ (250 mm × 4.6 mm)
UV, 220 nm
0.8 mL/min
10 µL
Detection:
Flow:
Injection volume:
Data acquisition time: 30 min
Pump mode:
isocratic
Mobile phase:
prepare a mixture of n-hexane and isopropyl
alcohol in the ratio of 850:150. To the mixture,
add 1 mL of trifluoroacetic acid and degas
Retention time of
valsartan:
∼13 min
Retention time of
enantiomer:
∼8.2 min
N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-
4-yl]methyl]-L-valine (1). Compound 6 (45 g, 0.1 mol) was
hydrolyzed with 15% w/v aqueous barium hydroxide solution
(528 mL) at 20-30 °C for 10 h. The precipitated solid was
filtered, treated with 10% w/v dilute hydrochloric acid to pH
0.5-1.5 in water, and crude valsartan was isolated. The crude
valsartan was dissolved in 2.5% w/v aqueous sodium carbonate
solution (460 mL) at 20-30 °C, acidified to pH 5.0 with 10%
w/v hydrochloric acid, and then washed with methylene chloride
(90 mL). The aqueous layer was further acidified to pH 1.0
with 10% w/v hydrochloric acid, and the product was extracted
with ethyl acetate (495 mL). The organic layer was separated
Acknowledgment
We thank the Aurobindo Pharma limited for supporting this
work. We are also thankful to colleagues at the analytical
research department and chemical research department of APL
research centre for their cooperation and fruitful discussions.
Received for review April 11, 2009.
OP9000912
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