A facile, one-pot synthesis of lacidipine using in situ generation of wittig intermediates

Article abstract of DOI:10.1021/op900055u

An improved, one-pot process for the preparation of lacidipine (1) via an efficient in situ generation of Wittig intermediates is reported. Generation of ylide (4) by dehydrobromination of phosphonium salt (3) followed by in situ condensation of 4 with o-phthalaldehyde (5) to yield corresponding olefin (6) and its subsequent reaction with crotonate derivative (7) in the same pot furnished the drug substance 1 with an overall yield of about 51% over the reported yield of about 24% starting from the corresponding ylide. The present work overcomes the challenges associated with prior art processes such as chromatographic purifications, handling of unstable intermediates, and formation of byproducts as potential impurities. The interesting insights on the safety aspects of the process, drawn through calorimetric studies, rendered the successful implementation of the process at manufacturing facility.

Full text of DOI:10.1021/op900055u

Organic Process Research & Development 2009, 13, 710–715
A Facile, One-Pot Synthesis of Lacidipine Using in Situ Generation of Wittig
†
Intermediates
,‡
‡
‡
§
‡
V. V. N. K. V. Prasada Raju,* Vedantham Ravindra, Vijayavitthal T. Mathad, P. K. Dubey, and Padi Pratap Reddy
Department of Research and DeVelopment, Integrated Product DeVelopment, InnoVation Plaza, Dr. Reddy’s Laboratories Ltd.,
SurVey Nos.42, 45, 46, and 54, Bachupally, Qutubullapur, R. R. District - 500 072, A.P, India, and Department of Chemistry,
Jawaharlal Nehru Technological UniVersity, Kukatpally, Hyderabad - 500 072, Andhra Pradesh, India
Abstract:
subsequent trituration of the obtained oil with petroleum ether
gave crude lacidipine, which was crystallized to give pure 1
with an overall yield of 23.7% (starting from 4, Scheme. 1).
Alternatively, condensation of 6 and 7 in acetic acid at room
temperature followed by column chromatography purification
provided compound 1 with an overall yield of 5.4% (starting
from 4).
An improved, one-pot process for the preparation of lacidipine
(1) via an efficient in situ generation of Wittig intermediates is
reported. Generation of ylide (4) by dehydrobromination of
phosphonium salt (3) followed by in situ condensation of 4 with
o-phthalaldehyde (5) to yield corresponding olefin (6) and its
subsequent reaction with crotonate derivative (7) in the same pot
furnished the drug substance 1 with an overall yield of about 51%
over the reported yield of about 24% starting from the corre-
sponding ylide. The present work overcomes the challenges
associated with prior art processes such as chromatographic
purifications, handling of unstable intermediates, and formation
of byproducts as potential impurities. The interesting insights on
the safety aspects of the process, drawn through calorimetric
studies, rendered the successful implementation of the process at
manufacturing facility.
The challenges encountered while following this reported
process were: (a) handling of unstable Wittig intermediate 4,
(
(
b) formation of potential impurities such as vinyl benzaldehyde
6a) and dimer (6b), (c) classical problem of removing the
byproduct Ph PO (6c), (d) use of column chromatography for
3
isolation and purification, and (e) low overall yield (about 24%).
The reported procedures as described above are either lengthy
3
or used hazardous and/or relatively expensive chemicals.
Herein, we report an improved, facile, and one-pot process for
the preparation of 1 by surmounting the aforesaid challenges.
Our approach was aimed to avoid the isolation and purification
of critical intermediates 4 and 6 by designing ylide generation,
olefination, and condensation with amino crotonate 7 in single
pot. In this new process, the potential impurities, byproduct,
and unreacted intermediates are efficiently controlled through
proper understanding of process parameters responsible for
impurity formation coupled with an efficient workup process.
The process was scaled up successfully by assessing the process
safety of optimized process through reaction calorimetry.
Introduction
(E)-4-[2-[3-(1,1-Dimethylethoxy)-3-oxo-1-propenyl]phenyl]-
1
,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl
1
ester (lacidipine, 1), a vascular-selective calcium antagonist
with a potent and long-lasting antihypertensive activity is
marketed under the brand names, Lacipil and Motens. The first
2
3
4
reported synthesis of 1 involved the reaction of ylide 4 with
o-phthalaldehyde 5 in dichloromethane to give crude olefin 6
as yellow oil, which was purified by column chromatography
using petroleum ether and diethyl ether before it was reacted
with amino crotonate 7 in ethanol in the presence of trifluoro-
acetic acid at -10 °C for 1.5 h. Quenching the mass into an
aqueous solution of sodium bicarbonate and extracting 1 in tert-
butyl methyl ether, concentration of the organic layer, and
Results and Discussion
Identification of Challenges in the Process Development
of 1 Using the Reported Synthesis (Scheme 1). Phosphonium
5
bromide (3) when treated with an aqueous solution of sodium
hydroxide, underwent rapid dehydrobromination to yield ylide
4
along with the formation of impurities due to its instability
under the reaction conditions. It was also observed that
subsequent reaction of 4 with 5 led to the predominant formation
of decarboxylated impurity 3a, which in turn will further react
with 5, resulting in vinylbenzaldehye (6a) as an impurity.
Formation of dimer 6b is attributed to a lack of chemoselectivity
as there are two equivalent formyl groups present in o-
phthalaldehyde 5. The dimer impurity 6b was independently
synthesized by reacting 5 with an excess of 3 in the presence
of sodium hydroxide using dichloromethane or 1,4-dioxane as
†
Dr. Reddy’s Communication no. IPDO IPM-00171.
To whom correspondence should be addressed. E-mail: prasadvvnkv@
*
drreddys.com. Fax: 914044346840. Telephone: 9989997170.
‡
Dr. Reddy’s Laboratories Ltd.
Jawaharlal Nehru Technological University.
§
(
1) (a) Tcherdakoff, P.; Mallion, J. M. J. CardioVasc. Pharmacol. 1995,
2
5, S27. (b) Lee, C. R.; Bryson, H. M. Drugs 1994, 48, 274. (c)
McCormack, P. L.; Wagstaff, A. J. Drugs 2003, 63, 2327. (d) Haller,
H.; Cosentino, F.; Liischer, T. F. Drugs RD 2002, 3, 311.
2) See http://thomsonpharma.com/copyright.
3) (a) Claudio Semeraro, B.; Dino Micheli, M.; Daniele, P.; Giovanni,
G.; Allan, D. B. DE Patent 3529997, 1986; U.S. Patent 4,801,599,
(
(
1
989. (b) Safar, M.; Bons, J.; Georges, D.; Cournot, A.; Duchier, J.
Clin. Pharmacol. Ther. 1989, 46, 94. (c) Claudio Semeraro, B.; Dino
Micheli, M.; Daniele, P.; Giovanni, G.; Allan, D. B. GB Patent
(5) (a) Niedercorn, F.; Ledon, H.; Tkatchenko, I. New J. Chem. 1988,
12, 897. (b) Cabral dos Santos, L.; Bahlaouan, Z.; El Kassimi, K.;
Troufflard, C.; Hendra, F.; Delarue Cochin, S.; Zahouily, M.; Cave,
C.; Joseph, D. Heterocycles 2007, 73, 751. (c) Maaryanoff, B. E.;
Reitz, A. B. Chem. ReV. 1989, 89, 863.
2
164336 A, 1986.
(
4) (a) Miyano, M.; Dorn, C. R. J. Org. Chem. 1972, 37, 1818. (b) Hamper,
B. C. J. Org. Chem. 1988, 53, 5558.
7
10
•
Vol. 13, No. 4, 2009 / Organic Process Research & Development
10.1021/op900055u CCC: $40.75  2009 American Chemical Society
Published on Web 05/19/2009

Scheme 1. Synthetic scheme for lacidipine (1)
Scheme 2. Formation of impurities 6a, 6b, and 6c
Scheme 3. Formation of impurities 1a, 1b, 1c, and 1d
6
7
a solvent. The synthesized sample of 6b was characterized
impurities of lacidipine in British Pharmacopoeia, whereas 1d
using spectroscopic analysis and was found to be identical with
the impurity isolated from the reaction of 4 with 5 (Scheme 2).
Reaction of benzaldehyde derivative 6 with aminocrotonate
was a new impurity, whose formation may be attributed to the
lack of regioselectivity during the reaction (Scheme 3). Interest-
ingly, compound 1 obtained from the condensation of 6 with 7
in acetic acid at 25-30 °C, was found to contain the major
amount of 1d, while the same reaction performed in ethanol in
the presence of trifluoroacetic acid led to a very smaller amount
7
following the known process led to the formation of another
set of impurities characterized as ethyl methyl carboxylate (1a),
pyridine dicarboxylate (1b), z-isomer (1c) and regio isomer
6
(
1d). Impurities 1a, 1b, and 1c were earlier reported as
(
7) British Pharmacopoeia; Stationery Office: London, 2003; Vol. II.
8) Reaction completion was monitored by thin layer chromatography for
the absence of corresponding phosphonium salt and ylide (ap-
proximately 0.2 and 0.1 retention factors, respectively, using 15%
methanol in chloroform as mobile phase).
(
(
6) Prasada Raju, V. V. N. K. V.; Madhusudhan Reddy, G.; Ravindra,
V.; Vijayavitthal, T. M.; Dubey, P. K.; Pratap Reddy, P. Synth.
Commun. 2009, 39, 2137.
Vol. 13, No. 4, 2009 / Organic Process Research & Development
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711

Scheme 4. Synthesis of phoshoniumbromide (3)
8
Table 1. Effect of reaction time on the formation of
TLC . After completion of the reaction, the organic layer was
impurity 3a
concentrated, and the resultant crude was treated with n-heptane.
The byproduct (triphenylphosphine oxide, 6c) separated in
n-heptane was removed by filtration, and the filtrate was
concentrated to get the olefin 6 as syrup. This syrup was diluted
with isopropanol, a solution of 7 in isopropanol and trifluoro-
acetic acid were added successively at -10 °C, and the reaction
mass was stirred at -10 °C until reaction completion, monitored
by TLC. Reaction mass was quenched over sodium bicarbonate
solution, and the product was extracted with ethylacetate at pH
reaction time (h)
3a (%) by HPLC
3
6
2
8
4
0.720
0.900
1.640
2.540
2.890
1
1
2
Table 2. Effect of temperature on impurity 1d
°Ca
b
entry
1d (%)
7
.0-8.0. Finally, the organic layer was concentrated, and
1
2
3
4
5
-15 to -10
-10 to -5
-5 to 0
0.49
0.50
0.62
9.8
product 1 was isolated in the pure form from isopropyl alcohol.
In this reaction, the mole ratio of compounds 3 and 5 and
also the reaction temperature were key factors in influencing
chemoselectivity. Thus, the mole ratio of 1:1.4 with respect to
compounds 3 and 5 and the reaction temperature of -5 to 0
0 to 5
25 to 35
30.4
a
Reaction temperature. b Regioimpurity by HPLC.
°
C were found to be ideal in achieving a high degree of
chemoselectivity, minimizing the formation of impurity 6b in
the reaction.
of 1d. This observation revealed the importance of both Lewis
acid and temperature to control regioisomer 1d in the disclosed
process.
Also, the quantity of NaOH had a profound effect on reaction
completion and in the removal of unreacted 5 in view of its
high solubility in alkali. Duration of NaOH addition to a mixture
of 3 and 5 under controlled temperature to facilitate the tandem
reaction in the reaction pot was also a critical parameter in the
process.
Having understood the challenges associated with the
reported process, our quest towards designing the process
comprises (a) preparing phosphoniumbromide salt 3 in pure
form, (b) avoiding isolation of unstable ylide 4, (c) designing
the reaction in a single pot, wherein generation of 4 and its
subsequent reaction with the carbonyl compound 5 happen in
a tandem manner to provide 6, and (d) developing a workup
process to eliminate critical impurities in 6 before it is condensed
with 7 in the same pot to furnish substantially pure 1.
Process for the Preparation of 3. Our first attempt was
aimed to establish a suitable process for the preparation of key
starting material 3. The process for the preparation of 3 involved
the reaction of triphenylphosphine with ter-butylbromoacetate
Further challenge was to remove the byproduct 6c formed
9
during Wittig olefination.
The difference between the solubilities of 6 and 6c in heptane
was exploited to obtain compound 6 free from 6c. Thus, the
syrup containing 6 and byproduct 6c was taken in heptane at
ambient temperature, and undissolved 6c was removed by
filtration, and the filtrate was concentrated to get pure 6.
In the condensation reaction of olefin 6 with amino crotonate
7
to provide lacidipine 1, reaction medium and temperature have
(2) in toluene at 60-65 °C for 4-5 h. Usual workup followed
significant impact on the purity of 1. Solvent-screening studies
indicated that isopropanol was an ideal solvent to access 1 with
better purity. Content of impurity 1d increased with reaction
temperature (Table 2), and it was about 30% at 35 °C. Based
on optimization studies, -10 to -5 °C reaction temperature, 3
mol equiv of 7, and 2.25 mol equiv of trifluoroacetic acid (TFA)
were finalized for this stage.
Furthermore, for an in situ process, carryover of earlier stage
raw materials, reagents, intermediates, byproducts, side reaction
products, and catalysts into the isolated product is the commonly
observed phenomenon. In our process, there was the possibility
of 12 such impurities to be present in the product. Among them
two (5 and 7) were key starting materials, eight (3a, 6a, 6b,
by drying under vacuum at 65-70 °C provided compound 3
in 95% yield with 99.3% purity by HPLC. Traces of triph-
enylphosphine present in the compound 3 were efficiently
removed by toluene washings. During optimization, under abuse
studies when the reaction was maintained for more than 20 h
to evaluate the impact of reaction time, the formation of 3a
(Scheme 4) was observed (Table 1). The content of this impurity
was a function of reaction time, and preferred maintenance time
to control the formation of this impurity was 4-5 h.
Preparation of Lacidipine (1). Having pure 3 in hand, our
next endeavor was to design a robust process for lacidipine (1).
As per our design (Scheme 5), the process for the formation of
1
in a single pot was performed as follows: aqueous solution
of sodium hydroxide was added slowly to the mixture of 3 and
in dichloromethane at -5 °C, wherein generation of ylide 4
1a, 1c, 1d, 3, and 6) were process-related impurities, one (1b)
was a degradation product, and one (6c) was a byproduct. In
5
and its subsequent reaction with o-phthalaldehyde 5 in the same
pot in a tandem manner led to the formation of 6 within 30-40
min, and complete conversion of 3 and 4 was monitored by
(9) (a) Vedejs, E.; Marth, C. F.; Ruggeri, R. J. Am. Chem. Soc. 1988,
1
3
493.
10, 3940. (b) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1988, 110,
948. (c) Ward, W. J., Jr.; McEwen, W. E. J. Org. Chem. 1990, 55,
7
12
•
Vol. 13, No. 4, 2009 / Organic Process Research & Development

Scheme 5. Improved one-pot synthetic scheme for lacidipine (1)
Table 3. Measured solubility of 3, 5, and 1 in ICH class 3 solvents
solventa
IPA
cmpd
acetone
EtOAc
DMSO
EMK
tert-BuOH
EtOH
MIK
TBME
3
5
1
++++
+
+
++
+
++
++
+
+
++
+
++
++
++
+
+++
++
+
+++
++++
+
+++
++++
++
+++
++
++++
a
EtOAc ) ethylacetate, EMK ) ethylmethyl ketone, IPA ) isopropanol, tert-BuOH ) tertiary butanol, EtOH ) ethanol, MIK ) methylisobutyl ketone, TBME ) tertiary
butyl methyl ether; + ) freely soluble (1-10 times), + + ) soluble (10-30 times), + + + ) sparingly soluble (30-100 times), + + + + ) slightly soluble (100-1000
times).
Table 4. Measured solubilities of 6b, 6c, 1d and 1 in
isopropanol
cmpd
descriptiona
solubility
6
6
1
1
b
c
d
++
1 g is soluble in 30 volumes/mL
1 g is soluble in 3 volumes/mL
1 g is soluble in 60 volumes/mL
1gm is soluble in 130 volumes/mL
+
+++
++++
a
+
) freely soluble (1-10 times), + + ) soluble (10-30 times), + + + )
sparingly soluble (30-100 times), + + + + ) slightly soluble (100-1000 times).
Figure 1
the light of these observations, we have developed an appropri-
ate workup process addressing all of these impurities. The
workup process involved quenching of the reaction mass over
sodium bicarbonate solution to neutralize unreacted TFA and
adjusting the reaction mass pH to 7.0-8.0 and extracting the
pure product (1) into ethyl acetate by leaving the impurities
and unreacted 7 in the aqueous layer.
of single isolation using isopropanol in all the plant production
batches, and the results of the batches produced at various scales
are depicted in Table 5.
Process Safety Assessment by Reaction Calorimetry
(RC). There was no literature precedent to identify the hazards
associated with the manufacturing process of 1. Thus, an initial
10
reaction calorimetric study was performed in the Mettler-
In order to identify a suitable solvent for crystallization, we
have measured isothermal solubilities of compounds 3, 5, and
Toledo RC1 reaction calorimeter following the parameters of
the optimized process. The key outcomes were essentially used
for designing the plant equipment, services, and operations to
ensure scalability of the optimized process.
Reaction Calorimetry: Results and Discussion. During the
olefination reaction, after introducing both 3 and 5 in a 2 L
cylindrical reaction calorimeter equipped with an anchor having
1
in selected ICH class III solvents (Table 3) and used those
solvents for purification.
These studies revealed that, isopropanol was an apt solvent,
which was further supported by the solubility data generated
for 6b, 6c and 1d (Table 4).
On the basis of this study, the crude 1 was crystallized from
isopropanol, which involved dissolution of crude 1 in isopro-
panol at reflux followed by cooling to 0-5 °C and isolation at
the same temperature. The optimal isolation temperature was
1
05 mm diameter with 200 rpm, it became apparent from
comparison of the batch temperature profile inside the reactor
Tr) with the reactor jacket temperature profile (Tj) during
(
0-5 °C. Drug substance 1 crystallized from isopropanol was
(10) (a) Jacobsen, J. P. Thermochim. Acta 1990, 160, 13. (b) Landau, R. N.;
Williams, L. R. Chem. Eng. Prog. 1991, 87, 65. (c) Landau, R. N.;
Blackmond, D. G. Chem Eng. Prog. 1994, 43. (d) Landau, R. N.
Thermochim. Acta 1996, 289, 101.
substantially free of impurities. The levels of 12 identified and
other unidentified impurities were very much within the control
Vol. 13, No. 4, 2009 / Organic Process Research & Development
•
713

Table 5. Results of the batches at various scales
purity by HPLC (%)
batch input (kg)
1a
1aa
1ba
1ca
3ab
6ac
6bc
1dc
6cb
3b
6b
5d
7d
0
0
5
5
5
.1
.1
.0
.0
.0
99.92
99.92
99.89
99.75
99.86
0.02
0.005
0.03
0.02
0.01
0.001
0.002
ND
0.028
0.028
0.01
ND
ND
0.001
ND
ND
ND
0.024
0.092
ND
0.02
0.01
0.007
0.057
0.02
0.019
0.078
ND
0.03
0.02
0.019
0.007
ND
0.01
ND
ND
ND
ND
0.02
ND
0.005
0.01
0.04
0.02
ND
0.006
0.018
0.01
ND
ND
0.002
ND
0.03
0.07
0.05
0.01
0.002
0.08
0.07
0.008
a
estimated by HPLC method 1. b ) estimated by HPLC method 2. c ) estimated by HPLC method 3. d ) estimated by GC.
)
Figure 2
aqueous NaOH solution addition that the estimated adiabatic
temperature rise would be 55.6 °C (Figure 1) for a batch size
of 100 g of 3 and hence in case of cooling jacket failure at an
instant of time during aqueous NaOH solution addition, the
reaction mass temperature would rise to 55.6 °C from the
operating temperature (-5 °C).
Perkin-Elmer model spectrum GX series FT-IR as KBr pellet.
The H NMR spectra were recorded at 400 MHz on Varian
mercury plus 400 MHz spectrometer. The chemical shift values
were reported on δ scale in ppm with respect to TMS (δ 0.00
ppm) as an internal standard.
1
Preparation of tert-Butoxycarbonylmethyl Triphenyl
Phosphoniumbromide (3). A mixture of toluene (32 L) and
triphenylphosphine (3.2 kg, 12.1 mol) was heated to 55 °C under
nitrogen atmosphere and compound 2 (2.85 kg, 14.6 mol) was
added below 60 °C. The mixture was aged for 4 h at 65 °C,
product was separated by filtration at ambient temperature under
nitrogen atmosphere and dried at 70 °C to yield 5.28 kg
(94.63%) of the compound 3; purity by HPLC 99.31%, MR
During the condensation of compounds 6 and 7, when TFA
was added to the reaction mass, the estimated adiabatic
temperature (Tad) rise was found to be 10.17 °C for a batch
size of 75 g of 6. The most observable occurrence took place
during the workup stage. After completion of the reaction, while
adding aqueous sodium bicarbonate solution (3.75 mL per min)
to the reaction mass in isothermal mode at -10 °C, it was found
to be instantaneous with heat evolution, and reaction mass
temperature rose to 0 °C at the start of addition, as evidenced
by the significant deviation between Tr and Tj (Figure 2), while
the jacket temperature Tj dipped to -24.6 °C to maintain the
reaction temperature set point of -10 °C. U value of the reaction
mass after decomposition was found to be decreasing signifi-
cantly which was an indication of the decreasing heat transfer
capability of the reaction mass. Adiabatic temperature rise was
found to be 73 °C. Hence, in case of cooling jacket failure at
any instant of time during sodium bicarbonate solution addition,
the reaction mass temperature would rise by 73 °C from an
operating temperature of -10 °C.
-1
172-174 °C. IR (νmax, cm ) 3052, 3006, 2877, 2831, 2761,
1
1723, 1587, 1436, 1371, 1138, 1112, 833, 808; H NMR
(CDCl
(s, 9 H).
Preparation of Diethyl (E)-4-{2-[(tert-Butoxycarbonyl)vi-
3
, 400 MHz) δ: 7.75-7.9 (m, 15 H), 3.38 (d, 2 H), 1.18
nyl]phenyl}-1,4-dihydro-2,6-dimethyl pyridine-3,5-dicar-
boxylate (1). Caustic soda flakes (2.65 kg, 66.25 mol) were
dissolved in water (5 L), and this alkaline solution was cooled
to ambient temperature and added to a mixture of methylene
chloride (20 L), 3 (5 kg, 13.25 mol), and 5 (2.05 kg, 15.29
mol) at -5 °C over a period of 90 min. The reaction mass was
aged for about 60 min for completion of the reaction. The
organic layer was separated at 30 °C and concentrated under
atmospheric pressure until the temperature reached to 55 °C.
Then n-heptane (35 L) was added to the mass slowly at 55 °C
for 40 min. The solvent was stripped off under vacuum below
70 °C, and byproduct 6b was removed by filtration at ambient
temperature after aging for 2 h at the same temperature. Filtrate
was concentrated under vacuum below 70 °C, and product was
diluted with isopropanol (12.5 L) and cooled to -10 °C.
7 (4.25 kg, 32.92 mol) was dissolved in isopropanol (12.5
L) and cooled to 25 °C. This compound solution was added to
Out of three in situ additions and decomposition reactions,
it was therefore important to ensure a maximum cooling
capacity requirement in the decomposition step, and this process
safety assessment data served as the basis for safe scale-up
design and successful execution for the optimized process at
plant scale.
Experimental Section
The ESI mass spectrum was recorded on 4000-Q-trap LC-
mass spectrometer. The FT-IR spectrum was recorded on
7
14
•
Vol. 13, No. 4, 2009 / Organic Process Research & Development

6
at -10 °C in 45 min. TFA (2.8 kg, 22.47 mol) was added at
10 °C in 1 h. Reaction mass was maintained at -10 °C for
in situ generation of the ylide 4 and subsequent condensation
with carbonyl compound 5 in a tandem manner in one pot.
Thorough understanding of the process parameters coupled with
integrated calorimetric approach ensured successful scale-up of
the optimized process.
-
the completion of the reaction. Sodium bicarbonate (2.6 kg,
0.95 mol) was dissolved in water (50 L), and this solution
was added to the reaction mass at 0 °C over a period of about
5 min until the pH reached 7.0-8.0, and then ethylacetate (25
3
4
L) was charged. Layers were separated at 30 °C, the aqueous
layer was extracted with ethylacetate (12.5 L), and the combined
organic layers were concentrated at atmospheric pressure until
reaction mass temperature reached 88 °C. Isopropanol (6.3 L)
was charged, and the mixture was heated to 75 °C to get a
clear solution. Solution was cooled to 0-5 °C, and the product
was filtered and dried to furnish pure lacidipine, 1 (2.6 kg,
Acknowledgment
We thank the management of the Dr.Reddy’s Laboratories
Ltd. for supporting this work. Co-operation from the colleagues
from analytical research and development is highly appreciated.
5
2.2%) with 99.8% purity by HPLC which melts at 174 °C.
-1
IR (νmax, cm ) 3350, 2980, 2934, 1703, 1676, 1452, 1369,
Supporting Information Available
1
1
(
311, 1193, 832, 745; H NMR (DMSO-d
s, 1 H), 5.20 (s, 1 H), 7.58 (d, 1 H), 7.32 (t, 1 H), 7.12 (t, 1
H), 7.32 (d, 1 H), 3.77 (m, 2 H), 1.05 (t, 3 H), 2.25 (s, 3 H),
.38 (d, 1 H), 6.32 (d, 1 H), 1.49 (s, 3 H).
6
, 200 MHz) δ: 8.82
Further experimental details and additional information on
the work. This material is available free of charge via the
Internet at http://pubs.acs.org.
8
Conclusion
In conclusion, an improved, cost-viable, and plant-friendly
process was developed for the synthesis of lacidipine, 1, through
Received for review March 11, 2009.
OP900055U
Vol. 13, No. 4, 2009 / Organic Process Research & Development
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