An efficient and telescopic process for valsartan, an angiotensin II Receptor Blocker

Article abstract of DOI:10.1021/op3000306

An efficient, telescopic, and scalable process for an antihypertensive drug substance, valsartan with an overall yield of 58%, and ～99.9% purity is described. A simple, and safe process is developed for the recovery of tributyltin chloride from the tributyltin hydroxide, byproduct formed in the tetrazole ring construction, and reused in the synthesis of valsartan.

Full text of DOI:10.1021/op3000306

Article
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An Efficient and Telescopic Process for Valsartan, an Angiotensin II
Receptor Blocker†
Sampath Aalla,‡ Goverdhan Gilla,‡ Yakambram Bojja,‡ Raghupathi Reddy Anumula,‡
Prabhakar Reddy Vummenthala,§,* and Pratap Reddy Padi⊥
‡Research and Development, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Survey No.’s 42, 45, 46, and 54,
Bachupally, Qutubullapur, Ranga Reddy District-500 072, Andhra Pradesh, India
§Department of Chemistry, University College of Science, Osmania University, Hyderabad-500 007, Andhra Pradesh, India
⊥Research and Development, Macleods Pharmaceuticals Limited, G-2, Mahakali Caves Road, Shanthi Nagar, Andheri (E), Mumbai -
400 093, Maharashtra, India
ABSTRACT: An efficient, telescopic, and scalable process for an antihypertensive drug substance, valsartan with an overall yield
of 58%, and ∼99.9% purity is described. A simple, and safe process is developed for the recovery of tributyltin chloride from the
tributyltin hydroxide, byproduct formed in the tetrazole ring construction, and reused in the synthesis of valsartan.
the handling risk as tributyltin chloride has powerful odor,
causes rashes when absorbed from the skin, and is toxic.8 In
view of high volume requirement, huge revenues associated
with this molecule, and disadvantages from the reported
processes, there arises a need to develop an efficient and
scalable process for valsartan, meeting with all the regulatory
aspects.
Construction of a tetrazole ring in the synthesis of valsartan
involves the reaction of tributyltin azide and nitrile compound
followed by deprotection of the tributyltin-protected tetrazole
moiety. Removal of the tributyltin protection from the tetrazole
ring can be achieved by treatment with sodium hydroxide,9
wherein tributyltin hydroxide would be obtained as a
byproduct. Basic hydrolysis using sodium hydroxide would
generate sodium azide, if the unreacted tin azide is present in
the reaction mixture. Sodium azide is not explosive and
decomposes in a more controlled way upon heating, releasing
nitrogen gas.10 It was envisioned that, the thus obtained
tributyltin hydroxide can be recycled as tributyltin chloride,
which can be reused in the tetrazole ring construction. To the
best of our knowledge such an approach has hitherto not been
reported. Herein we describe an efficient, telescopic, and
scalable process for valsartan from the commercially available
starting materials.
INTRODUCTION
■
The angiotensin II (AT-II) receptor blockers (ARBs) represent
a newer class of antihypertensive agents. AT-II, formed in the
blood by the action of angiotensin converting enzyme (ACE),
is a very potent vasoconstrictive and volume-retaining
hormone, which plays a critical role in the regulation of
blood pressure.1,2 ARBs are safe, and effective agents for the
treatment of hypertension, anxiety, glaucoma, and heart failure,
either alone or in conjunction with hydrochlorothiazide.3
Valsartan 1 (brand name, Diovan) dilates blood vessels and
reduces blood pressure by blocking the action of AT-II. Due to
the superior efficacy, protection, tolerability, and patient
compliance valsartan has become a leading antihypertension
drug in the class of ARBs. Soon after its introduction in 1996,
the demand for valsartan rapidly increased. A recent study
revealed Diovan was prescribed more than 12 million times in
the United States, and global sales were approximately $ 6.0
billion. A study released by the Journal of Clinical Investigation
found some efficacy of valsartan in the treatment, and
prevention of Alzheimer’s disease (in a mouse model) although
such use is considered to be highly experimental.4
Reports are available in the literature regarding the various
routes, methodologies, and processes that have been adopted
for the preparation of valsartan.5 These processes have
restricted application in the industry because of less overall
yield, cumbersome workup process, difficult post-treatment and
recovery of excessive organotin reagent. Recently, Wang et al.6
developed an improved synthesis of valsartan, involving
recovery of tributyltin chloride via tributyltin fluoride by
treating with sodium fluoride. However, this process is also
encumbered by some disadvantages such as (a) treatment with
hydrochloric acid poses safety issues as it generates hydrazoic
acid from the unreacted azide present in the reaction mixture.
Hydrazoic acid is toxic, and extremely explosive in organic
solutions;7 (b) is highly corrosive on contact with a poisonous
byproduct, hydrofluoric acid; (c) usage of polytetrafluoro-
ethylene (PTFE) reactor to deal with the hydrofluoric acid; and
(d) fractional distillation of tributyltin chloride, which increases
RESULTS AND DISCUSSION
■
Our synthesis (Scheme 1) commenced from the commercially
available chiral pure biphenyl amino acid methyl ester 2, and
valeroyl chloride. Valeroylation of biphenyl derivative 2 using
valeroyl chloride in the presence of sodium carbonate in o-
xylene medium furnished the desired intermediate 3. The
organic layer containing the intermediate 3 as such was taken
forward to the next reaction, tetrazole formation. In our studies,
it was found that minor quantities of unreacted compound 2 if
present in the reaction mixture would participate in the
Received: February 1, 2012
Published: March 5, 2012
© 2012 American Chemical Society
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Scheme 1. Synthetic route for valsartan
subsequent reactions, and result in the desvaleroyl valsartan 1a
(Scheme 2).
Scheme 2. Synthetic route for desvaleroyl valsartan
Figure 1. Effect of tributyltin chloride and sodium azide mole ratio on
rate of reaction.
The buildup of the tetrazole ring was accomplished following
the widely practiced protocol by refluxing a mixture of nitrile
compound 3 and tributyltin azide (generated in situ from
tributyltin chloride and sodium azide) in o-xylene. During the
study, it was found that the mole ratio of tributyltin chloride
and sodium azide have significant impact on the rate of
reaction. The tetrazole formation reaction was proceeded
smoothly, and in shorter period (18 h) when 2.5 mols each of
tributyltin chloride, and sodium azide were utilized, further
increasing the mole ratio beyond this limit, proved futile as
there was no significant reduction in the reaction time (Figure
1). In addition, the levels of the impurities generated during the
reaction were increased. Thus, 2.5 mols each of tributyltin
chloride and sodium azide were ideal to result in intermediate
4.
racemization, since the ester group is connected to the chiral
center. In view of this, the hydrolysis reaction was studied
carefully. We wanted to utilize the sodium hydroxide as a base
for the deprotection of the tributyltin group and ester
hydrolysis, as it is a cheaply available base. The quantity of
base can have significant impact on the quality of hydrolyzed
product. In this regard, we explored the quantity of the sodium
hydroxide required to accomplish the complete deprotection of
tributyltin as well as ester hydrolysis. The results obtained from
the study showed that the mole ratio of the sodium hydroxide
has no influence on the racemization; however, the rate of
reaction was affected significantly (Table 1). It was found that 6
mol of sodium hydroxide was optimum to bring about an
efficient hydrolysis of ester and deprotection of the tributyltin
group (entry 3, Table 1).
At this point, it was planned to simultaneously deprotect the
tributyltin group from the tetrazole and also to hydrolyze the
ester group. Ester hydrolysis is a crucial step as it may cause
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mixture containing 5, water, and ethyl acetate with dilute
hydrochloric acid to 2.5−3.5. Initially, the valsartan free acid
was isolated from the ethyl acetate layer by cooling to 0−5 °C;
however, this process resulted in 55% yield. Optimization of the
solid isolation temperature, and time increased the yield slightly
(60%). Therefore, the further yield improvement study was
carried out by using a solvent/antisolvent technique; n-heptane
as an antisolvent provided an optimum yield of 77% with 99.9%
chemical purity, and 99.98% chiral purity at 20−25 °C.
Complete analysis of the final product showed the barium
content to be less than 5 ppm and the tin content to be less
than 1 ppm (Table 3). This process was demonstrated
successfully on a commercial scale of 150 kg of 2.
After achieving the valsartan with high quality and yield, our
focus was shifted to the toxic tin waste, tributyltin hydroxide,
generated in the tetrazole ring construction. In recent studies,
we found that the byproduct tributyltin hydroxide, formed
during the tetrazole ring construction, could be converted into
tributyltin chloride which can then be reused for the same
reaction. The o-xylene layer containing the byproduct,
tributyltin hydroxide, was treated with dilute hydrochloric
acid to regenerate the active tributyltin chloride (Scheme 3).
Table 1. Optimization of sodium hydroxide mole ratio (m/r)
in the hydrolysis reaction
purity by HPLC (%)
entry
NaOH (m/r)
chemical
chiral
time (h)
yield (%)
1
2
3
4
4.0
5.0
94.0
95.0
97.1
95.3
96.3
96.8
96.7
96.9
30
25
12
9
71
82
85
85
6.0
10.0
After fixing the sodium hydroxide mole ratio, another key
process parameter, reaction temperature, was studied. The
hydrolysis reaction was carried out at different temperatures,
and the results clearly indicated that the rate of reaction and the
chemical and chiral purities were significantly influenced by the
temperature. The rate of reaction was increased by increasing
the temperature, whereas the chemical and chiral purities
decreased. The optimum reaction temperature for the
hydrolysis reaction was found to be 10−15 °C (Table 2).
Table 2. Study of temperature in the hydrolysis reaction
purity by HPLC (%)
entry
temp (°C)
chemical
chiral
time (h)
yield (%)
Scheme 3. Conversion of tributyltin hydroxide into
tributyltin chloride
1
2
3
4
0−5
97.8
97.7
97.1
95.5
97.7
97.8
96.7
92.0
30
18
12
8
77
84
85
84
10−15
25−35
50−55
Therefore, deprotection of the tributyltin group and the ester
hydrolysis with sodium hydroxide furnished the crude valsartan
as the sodium salt, which solubilized in the aqueous layer, and
the byproduct, tributyltin hydroxide (TBTOH), was a
suspension in the o-xylene layer. It was observed that tributyltin
hydroxide was sparingly soluble in the aqueous layer containing
the valsartan sodium salt. To make the aqueous layer
completely free from this inorganic impurity, the pH of the
aqueous layer was adjusted to 6.5−7.0 using dilute hydrochloric
acid, and the aqueous layer was then washed with dichloro-
methane. Subsequently, the aqueous layer pH was adjusted to
3−4, and the resulting valsartan free acid was extracted into the
ethyl acetate. The chemical and chiral purities of the valsartan
free acid were found to be 97.7% and 97.8%, respectively. In
order to enhance the purity, the ethyl acetate layer containing
the valsartan crude was treated with barium hydroxide
octahydrate in the water medium to furnish the valsartan
barium salt 5. The valsartan barium salt that precipitated from
the reaction mixture was isolated and displayed an enhance-
ment in chemical purity to 99.6% and in chiral purity to 99.8%
with an overall yield of 75% (after four chemical reactions,
conversion of 2 → 5).
The o-xylene layer containing the recovered tributyltin
chloride as such was efficiently reused in the construction of
tetrazole ring. Adopting this methodology, the recovery and
reuse of tributyltin chloride was demonstrated at a scale of 150
kg of 2.
CONCLUSION
■
An efficient, telescopic, and scalable process has been
developed for synthesis of valsartan with an overall yield of
58%. The drug substance, valsartan synthesized through this
protocol complied with all the regulatory requirements. The
byproduct, tributyltin hydroxide, formed during the tetrazole
ring construction was recycled as tributyltin chloride and reused
in the same reaction, which enabled us to develop an
environmentally friendly process. The process described in
this article has certain advantages over the reported processes.
EXPERIMENTAL SECTION
A liquid chromatograph equipped with variable wavelength UV
detector and integrator was used in recording HPLC
■
The release of the valsartan free acid 1 from the highly pure
valsartan barium salt 5 was achieved by adjusting the pH of the
Table 3. Quality data of valsartan
a
purity by HPLC (%)
chiral
RS by GC (%)
c
b
entry
chemical
1a
n-heptane EA
Sn (ppm)
Ba (ppm)
yield (%)
d
1
2
3
99.91
99.92
99.89
99.95
99.98
99.99
ND
ND
ND
3245
2243
1938
ND
ND
ND
<1.0
<1.0
<1.0
<5.0
<5.0
<5.0
57.7
58.3
58.1
a
b
c
d
RS = Residual solvents. Overall yield. EA = ethyl acetate. ND = not detected.
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chromatogram. Mass spectra were recorded using 4000-Q-trap
LC−MS/MS mass spectrometer. 1H NMR and 13C NMR
spectra were recorded in DMSO-d6 at 500 MHz on a Varian
Unity INOVA 500 and 400 MHz on a Mercury Plus Varian 400
MHz FT NMR spectrometer; the chemical shifts are reported
in δ (ppm) relative to TMS (δ 0.00 ppm), and DMSO-d6 (δ
39.50 ppm). IR spectra were recorded on a Perkin-Elmer FT IR
instrument (KBr pellet method). The thermal analysis was
carried out on DSC Q1000 TA. The thermogram was recorded
from 40 to 160 °C under the nitrogen flow of 50 mL/min at a
heating rate of 10 °C/min. The tin content was analyzed by an
inductively coupled plasma optical emission spectrometry
(ICP-OES) method.
130.0, 130.5, 132.2, 137.2, 138.0, 139.4, 140.6, 160.8, 173.5,
173.7, 176.6, 176.9. Mass: 436.4 (M + H)+, 458.6 (M + Na)+.
N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphen-
yl]-4-yl]methyl-L-valine (1). To a solution of 5 (35 kg, 0.061
kmol) in ethyl acetate (140 L) and water (175 L) was added a
solution of aqueous HCl (assay 33%, 14 L, 0.126 kmol) in
water (14 L), and the pH was adjusted to 2.5−3.5 at room
temperature. The organic layer was separated, and product was
extracted from the aqueous layer with ethyl acetate (35 L).
Total organic layers were combined, and the solvent was
distilled completely below 45 °C under vacuum. The residue
was cooled to room temperature and dissolved in ethyl acetate
(175 L). The resulted solution was cooled to 20−25 °C, n-
heptane (525 L) was slowly added and stirred for 2−2.5 h. The
solid was filtered and washed with n-heptane (4 L). The wet
solid was dried in FBD at 35 °C for 3−4 h, followed by 4 h at
65−70 °C to obtain 20.6 kg (77%) of the title compound.
Purity by HPLC: chemical 99.91%, chiral 99.95%. Barium
content: <5 ppm. Tin content: <1.0 ppm. Ethyl acetate: 0 ppm,
N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphen-
yl]-4-yl]methyl-L-valine Barium (5). A suspension of 2 (150
kg, 0.418 kmol) in o-xylene (450 L) was treated with a solution
of sodium carbonate (44.4 kg, 0.419 kmol) in water (450 L) at
room temperature, and layers were separated. Sodium
carbonate (44.4 kg, 0.419 kmol) was charged into the organic
layer followed by valeryl chloride (90 kg, 0.747 kmol) was
added in three equivalent lots with 1 h maintenance at room
temperature between each lot. The reaction mixture was stirred
for 2 h at room temperature, water (150 L) was charged, and
the organic layer was separated followed by washing with a
solution of aqueous HCl (assay 33%, 38 L, 0.343 kmol) in
water (338 L). To the organic layer were charged o-xylene (450
L), tributyltin chloride (340 kg, 1.044 kmol), and sodium azide
(67.8 kg, 1.043 kmol) at room temperature. The reaction
mixture was heated to 145 °C, stirred for 18 h, and then cooled
to room temperature, and the unwanted solid (sodium
chloride) filtered . The filtrate was charged into a solution of
sodium hydroxide (100.5 kg, 2.512 kmol) in water (780 L) at
10−15 °C and stirred for 18 h. The layers were separated at
25−35 °C, and the aqueous layer was washed with o-xylene (2
× 225 L). Dichloromethane (600 L) was charged into the
aqueous layer, pH was adjusted to 6.5−7.0 with a solution of
aqueous HCl (assay 33%, 150 L, 1.356 kmol) in water (150 L),
and the layers were separated. The aqueous layer was washed
with dichloromethane (2 × 400 L) and treated with charcoal
(7.5 kg) for 60 min. Ethyl acetate (450 L) was charged into the
aqueous layer, and the pH was adjusted to 3−4 with a solution
of aqueous HCl (assay 33%, 120 L, 1.085 kmol) in water (120
L). The aqueous and the organic layers were separated, and
product was extracted from the aqueous layer with ethyl acetate
(450 L). Total organic layers were combined and washed with
water (150 L) followed by a solution of sodium chloride (22.5
g) in water (150 L). Water (900 L) was charged to the ethyl
acetate layer and stirred for 15 min, and barium hydroxide
octahydrate (165 kg, 0.523 kmol) was charged. The resultant
reaction mixture was stirred for 2−3 h at room temperature and
the precipitated solid filtered. The wet solid was washed with
ethyl acetate (150 L) and dried under vacuum at 75−80 °C to
furnish 180 kg (75%) of the title compound. Purity by HPLC:
chemical 99.6%, chiral 99.8%. IR (KBr, cm−1): 2958, 2929,
2870, 1628, 1570, 1460, 1409, 1355, 1104, 1008. 1H NMR (400
MHz, DMSO-d6): δ 0.73 (d, J = 6.8, Hz, 3H), 0.89 (t, J = 7.6
Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 1.12−1.60 (m, 4H), 1.97−
2.18 (m, 2H), 2.39−2.45 (m, 1H), 3.75, 4.47 (d, J = 10.4, 10.4
Hz, 1H), 4.52, 4.75 (d, J = 17.2, 17.2 Hz, 2H), 6.94 (d, J = 8.0
Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H),
7.28−7.38 (m, 3H), 7.52−7.58 (m, 1H). 13C NMR (125 MHz,
DMSO-d6): δ 13.8, 14.0, 19.4, 20.5, 20.8, 21.9, 22.1, 27.1, 27.3,
28.0, 33.0, 45.9, 48.2, 70.2, 125.7, 126.6, 127.5, 128.4, 128.9,
n-heptane: 3245 ppm. DSC: 99.4 °C. [α]20 = (−) 65.6 (c =
D
1% w/v in methanol). IR (KBr, cm−1): 3418, 2953, 2923, 2854,
1
1730, 1599, 1459, 1377. H NMR (400 MHz, CDCl3): δ 0.96
(d, J = 6.0 Hz, 6H), 0.99 (t, J = 6.8 Hz, 3H), 1.38−1.48 (m,
2H), 1.71−1.79 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.68−2.75
(m, 1H), 3.40 (d, J = 11.2 Hz, 1H), 4.22, 4.98 (d, J = 14.8, 14.8
Hz, 2H), 7.20 (m, 4H), 7.47 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6
Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H). 13
C
NMR (125 MHz, DMSO-d6): δ 13.7, 13.8, 18.4, 18.8, 19.4,
20.1, 21.6, 21.8, 26.8, 27.0, 27.5, 32.4, 45.4, 48.7, 62.9, 65.7,
123.5, 126.3, 126.9, 127.5, 128.3, 128.8, 130.5, 130.6, 131.0,
137.1, 137.8, 138.2, 141.2, 141.3, 154.9, 171.6, 171.9, 173.4,
173.5. Mass: 436.2 (M + H)+, 458.4 (M + Na)+. Anal. Calcd for
C24H29N5O3 (435.52): C, 66.19, H, 6.71, N, 16.08. Found: C,
66.09, H, 6.71, N, 15.76.
Tributyltin Chloride Recovery. The o-xylene layer
containing tributyltin hydroxide (1300 L, 1.044 kmol,
equivalent to 340 kg of tributyltin chloride) from the 150 kg
batch of 2 was charged into a reactor, and around 650 L of o-
xylene was distilled below 90 °C under reduced pressure. The
resultant reaction mixture was cooled to room temperature, and
water (500 L) was charged and stirred for 30 min. A solution of
aqueous HCl (33% assay, 124 L, 1.121 kmol) and water (124
L) was charged into the reaction mixture and stirred for 3 h at
room temperature. The organic layer was separated, and the
aqueous layer was washed with o-xylene (100 L). Total organic
layers were combined (695 kg, tributyltin chloride assay 43%)
to furnish 299 kg (88%) of recovered tributyltin chloride. IR
(KBr, cm−1): 2957, 2925, 2872, 2855, 1463, 1377, 1075, 876.
1H NMR (400 MHz, CDCl3): δ 0.87−0.97 (m, 9H), 1.27−1.39
(m, 12H), 1.61−1.68 (m, 6H).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vummenthalapv@yahoo.co.in. Fax: +91-40-44346285.
Telephone: +91-9849210408.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to the management of Dr. Reddy’s
Laboratories Ltd. for giving support to carry out this work.
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We are also thankful to the colleagues of analytical, and process
development departments for their cooperation.
ADDITIONAL NOTE
Dr. Reddy’s Communication no. IPDO IPM-00250.
■
†
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