Synthesis and spectral characterization of related substances of lacidipine, an antihypertensive drug

Article abstract of DOI:10.1080/00397910802638560

Five related substances (impurities) were detected in lacidipine bulk drug substance by a simple high-performance liquid chromatographic method (HPLC) and were identified by liquid chromatography-mass spectrometry (LC-MS). These related substances were independently synthesized, characterized, and co-injected with the sample containing impurities.

Full text of DOI:10.1080/00397910802638560

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Synthesis and Spectral
Characterization of Related
Substances of Lacidipine, an
Antihypertensive Drug
V. V. N. K. V. Prasada Raju a b , Ganta Madhusudhan
Reddy a , Vedantham Ravindra a , Vijayavitthal T.
Mathad a , P. K. Dubey b & Padi Pratap Reddy a
a Research and Development, Integrated Product
Development , Dr. Reddy's Laboratories Ltd. ,
Hyderabad, India
b Department of Chemistry , J. N. T. University ,
Hyderabad, India
Published online: 13 May 2009.
To cite this article: V. V. N. K. V. Prasada Raju , Ganta Madhusudhan Reddy ,
Vedantham Ravindra , Vijayavitthal T. Mathad , P. K. Dubey & Padi Pratap Reddy
(2009) Synthesis and Spectral Characterization of Related Substances of Lacidipine,
an Antihypertensive Drug, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:12, 2137-2145, DOI:
10.1080/00397910802638560
To link to this article: http://dx.doi.org/10.1080/00397910802638560
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Synthetic Communications1, 39: 2137–2145, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802638560
Synthesis and Spectral Characterization of
Related Substances of Lacidipine, an
Antihypertensive Drug
V. V. N. K. V. Prasada Raju,1,2 Ganta Madhusudhan Reddy,1
Vedantham Ravindra,1 Vijayavitthal T. Mathad,1 P. K. Dubey,2
and Padi Pratap Reddy1
1Research and Development, Integrated Product Development,
Dr. Reddy’s Laboratories Ltd., Hyderabad, India
2Department of Chemistry, J. N. T. University, Hyderabad, India
Abstract: Five related substances (impurities) were detected in lacidipine bulk
drug substance by a simple high-performance liquid chromatographic method
(HPLC) and were identified by liquid chromatography–mass spectrometry (LC-
MS). These related substances were independently synthesized, characterized,
and co-injected with the sample containing impurities.
Keywords: Antihypertensive drug, lacidipine, related substances, spectral
characterization, synthesis
INTRODUCTION
Lacidipine, E-4-[2-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]-
1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester is a
calcium channel blocker developed for oral administration as an antihy-
pertensive drug and has been widely used in therapy since the early 1990s.
Received October 15, 2008.
DRL Communication No. IPDO-IPM-00147.
Address correspondence to Padi Pratap Reddy, Research and Development,
Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories
Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R. R. Dist.
500072, India. E-mail: prataprp@drreddys.com
2137

2138
V. V. N. K. V. P. Raju et al.
Besides its antihypertensive effect, lacidipine has also shown
anti-atherosclerotic, antioxidant,[1–6] and antibacterial activity on 389
Gram-positive and Gram-negative bacterial strains.[7] Lacidipine belongs
to the dihydropyridine class, and its structure is characterized by the presence
of a cinnamate moiety. The active trans form is used in therapy.[1,2,8,9]
The presence of impurities in an active pharmaceutical ingredient
(API) can have a significant impact on the quality and safety of the drug
products. International Conference on Harmonization (ICH) guidelines
recommend identifying and characterizing all impurities present in APIs
at a level of ꢀ0.10%.[10] These impurities are required in pure form to
check the analytical performance characteristics such as specificity, linear-
ity, range, accuracy, precision, limit of detection (LOD), limit of quantifi-
cation (LOQ), robustness, system suitability testing, and relative retention
factor.[11] Furthermore, related substances are also used to check the accu-
racy of the analytical method of the API. In our current investigation, we
identified five impurities in the lacidipine bulk drug substance. Their
detection, synthesis, and characterization is described in this article.
Following are the five related substances identified in our lacidipine
(1) manufacturing process: 4-[4-(2-tert-butoxycarbonylvinyl)phenyl]-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (para-
lacidipine,
(2),
4-[3-(2-tert-butoxycarbonylvinyl)phenyl]-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, meta-lacidipine (3),
3-[2-(2-tert-butoxycarbonylvinyl)phenyl]acrylic acid tert-butyl ester (dimer,
(4), 4-(2-carboxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid diethyl ester, lacidipine acid, (5), and 4-[2-(2-tert-butoxy-
carbonylvinyl)phenyl]-3,6-dimethyl-1,4-dihydropyridine-2,5-dicarboxylic
acid diethyl ester, regio-isomer, (6). Although these related substances
were reported by us earlier as process-related impurities,[12] we have taken
up the synthesis and characterization of these related substances in our
current investigation.
RESULTS AND DISCUSSION
Lacidipine (1) was synthesized by following the known synthetic sequence
(Scheme 1). A key intermediate, tert-butoxycarbonylmethyltriphenyl
phosphonium bromide (9), was obtained by reacting tert-butylbromo
acetate (8) with triphenylphosphine (7). Condensation of compound 9
with o-phthalaldehyde (10) and subsequent reaction of the resulting
(E)-3-(2-formylphenyl)-2-propenoic acid, 1,1-dimethyl ethyl ester (11),
with ethyl-3-aminocrotonate (12) furnished the desired lacidipine.
Lacidipine para-isomer (2) is the regio-isomer of lacidipine 1. The pre-
sence of p-phthalaldehyde (13) in the starting material, o-phthalaldehyde

Synthesis of Lacidipine Related Substances
2139
Scheme 1. Synthetic scheme of lacidipine.
(10), leads to the formation of 2. Compound 2 was independently prepared
using p-phthalaldehyde (13) (Scheme 2). Infrared (IR), 1H NMR, and mass
spectral (MS) data of the prepared compound 2 are identical with those of
a sample isolated from lacidipine API.
Lacidipine meta-isomer 3 is the impurity resulted from meta-
phthalaldehyde (15), which is a contaminant in o-phthalaldehyde (10).
Lacidipine meta-isomer 3 was independently prepared (Scheme 3) follow-
ing the synthetic scheme analogous to that of lacidipine (Scheme 1). This
1
compound was found to be identical (vide IR, H NMR, and MS) with
the impurity 4 associated with lacidipine 1.
Scheme 2. Synthetic scheme of para-lacidipine.

2140
V. V. N. K. V. P. Raju et al.
Scheme 3. Synthetic scheme of meta-lacidipine.
Scheme 4. Synthetic scheme of dimer impurity.
Scheme 5. Synthetic scheme of lacidipine acid.
Scheme 6. Synthetic scheme of regio-isomer.

Synthesis of Lacidipine Related Substances
2141
Dimer impurity 4 is a carryover by-product resulting from the
condensation of two equivalents of tert-butoxycarbonylmethyltriphenyl
phosphonium bromide (9) with o-phthalaldehyde (10). This compound
was prepared by reacting o-phthalaldehyde (10) with large excess of tert-
butoxy carbonyl methyltriphenyl phosphonium bromide (9) in the presence
of sodium hydroxide using 1,4-dioxane as solvent (Scheme 4). Mass spectrum
of 4 showed the protonated molecular ion at m=z 330.8 and sodium adduct at
m=z 353.2. IR spectrum displayed carbonyl stretching at 1707 cmꢁ1, and 1H
NMR displayed two multiplets at d 7.34–7.36 and 7.53–7.55 ppm for the
aromatic protons. Two doublets at d 7.93 and d 6.26 ppm correspond to
olefinic protons. Methyl group protons appeared as a singlet at d 1.54. The
ratio of protons in this symmetrical molecule is 2:1:1:9.
Lacidipine acid 5 is the process impurity resulting from the con-
tamination of 2-formylbenzoic acid (17) in o-phthalaldehyde (10). It
was prepared (Scheme 5) in one step by condensing 2-formylbenzoic acid
(17) with 3 equiv. of ethyl-3-aminocrotonate (12). EI-MS showed peaks
at m=z 374.5 (Mþ þ 1) and 369.2 (Mþ þ Na); IR spectrum displayed
peaks corresponding to carboxylic (1665 cmꢁ1), ester (1741 cmꢁ1), and
1
NH (3423 cmꢁ1) functions. In the H NMR spectrum, a broad singlet
at d 9.05 ppm corresponds to acid proton (ꢁCOOH). Three multiplets
at d 7.59–7.68, 7.48–7.57, and 7.27–7.31 ppm and a double doublet at d
7.88 ppm are due to aromatic protons. Although NH appeared as broad
singlet at d 5.08 ppm, a singlet at d 2.16 ppm corresponded to six methyl
protons on the 1,4-dihydropyridine ring. A triplet at d 0.7 ppm (3H) and
quartet at d 3.76 (2H) corresponded to ethyl ester protons.
Impurity 6 is the regio-isomer of lacidipine formed as the by-product
in the synthesis of lacidipine, and it was prepared (Scheme 6) as a major
compound from the reaction of (E)-3-(2-formylphenyl)-2-propenoic acid,
1,1-dimethyl ethyl ester (11), with 3 equiv. of ethyl-3-aminocrotonate (12).
The protonated molecular ion of 6 appeared at m=z 456, and the IR spec-
trum displayed carbonyl (1709 cmꢁ1) and NH (3327 cmꢁ1) absorptions.
1H NMR spectral data of compound 6 are similar to those of lacidipine 1.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Varian Mercury Plus and Gemini
2000 at 400 MHz and 200 MHz, respectively. The IR spectra were recorded in
the solid sate as KBr dispersion medium using a Perkin-Elmer Spectrum One
FT-IR spectrophotometer. The mass analysis was performed on an AB-4000
Q-trap LC-MS=MS mass spectrometer. Melting points were determined on a
Polmon digital capillary melting-point apparatus, MP96, and are uncor-
rected. The solvents and reagents were used without further purification.

2142
V. V. N. K. V. P. Raju et al.
4-[4-(2-tert-Butoxycarbonylvinyl)phenyl]-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylic acid diethyl ester
(para-Lacidipine, 2)
(E)-tert-Butyl-3-(4-formylphenyl)acrylate (14)
Sodium hydroxide solution (13.6 g in 20 mL of water) was added to the
solution of 9 (24 g, 52 mmol) and tert-phthalaldehyde (13, 10 g, 73 mmol)
in DCM (100 mL), at 0–5ꢂC for 15 min. After the completion of reaction
(vide thin-layer chromatography, TLC), the organic layer was separated,
dried over sodium sulfate, concentrated under vacuum, and taken into
cyclohexane (50 mL). The undissolved solid was removed by filtration at
0ꢂC. The filtrate was concentrated under vaccum to provide crude com-
pound 14 (11.6 g, 95%), which was used as such in the next stage.
4-[4-(2-tert-Butoxycarbonylvinyl)phenyl]-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylic acid diethyl ester (2)
A solution of ethyl-3-aminocrotonate (12, 16.6 g, 129 mmol) in isopropyl
alcohol (50 mL) was added to the mixture of 14 (10.0 g, 43 mmol) and tri-
flouroacetic acid (9.8 g, 86 mmol) in isopropyl alcohol (50 mL) at ꢁ5 to
ꢁ 10ꢂC for 30 min. The reaction was maintained at the same temperature
for 1 h. After the completion of the reaction (vide TLC), the reaction mass
was quenched with a solution of piperidine (10.4 g, 122 mmol) in water
(130 mL) and extracted with ethyl acetate (2 ꢃ 75 mL). The combined
organic layer was washed with water (100 mL), dried over sodium sulfate,
and distilled under reduced pressure. The product was isolated from
n-hexane (60 mL) and dried at 65ꢂC for 2 h 30 min to proviþde 2 (17.0 g,
87%). Mp 183–185ꢂC; HPLC purity 99.8%; mass: 456.4 (M þH), 478.3
(MþþNa); IR (KBr, cmꢁ1): 3371 (NH), 1697, 1655, 1634 (C ¼ O ester);
1H NMR (400MHz, CDCl3): d 7.52 (d, J ¼ 16 Hz, 1H), 7.35 (d, J ¼ 8.4 Hz,
Hz, 1H), 7.27 (t, J ¼ 8.4Hz, 3H), 6.28 (d, J¼ 16Hz, 1H), 5.78 (s, NH), 4.99
(s,1H), 4.04–4.12 (m, 4H), 2.33 (s, 6H), 1.52 (s, 9H), 1.19–1.22 (m, 6H).
4-[3-(2-tert-Butoxycarbonylvinyl)phenyl]-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylic acid diethyl ester
(meta-Lacidipine, 3)
(E)-tert-Butyl-3-(3-formylphenyl)acrylate (17)
Sodium hydroxide solution (13.2 g in 20 mL of water) was added to the
solution of 9 (25 g, 54 mmol) and iso-phthalaldehyde (15, 10.2 g, 76 mmol)

Synthesis of Lacidipine Related Substances
2143
in dichloromethane (100 mL) at 0–5ꢂC for 20 min. The organic layer was
separated, dried over sodium sulfate, and concentrated under vacuum.
The crude was dissolved in heptane (50 mL), and the undissolved solid
was filtered off at 25ꢂC. The filtrate was concentrated under vaccum at
60ꢂC to give compound 16 as crude material (12 g, 94%), which was used
as such in the next stage.
4-[3-(2-tert-Butoxycarbonylvinyl)phenyl]-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylic acid diethyl ester (3)
Ethyl-3-aminocrotonate (12, 16.6 g, 129 mmol) in isopropyl alcohol
(50 mL) was added to a solution of 16 (10.0 g, 43 mmol) in isopropyl alco-
hol (50 mL) at ꢁ5 to ꢁ10ꢂC for 40 min, and after that trifluoroacetic acid
(9.8 g, 86 mmol) was added slowly at ꢁ5 to ꢁ10ꢂC for 40 min. The reac-
tion was maintained at the same temperature for 30 min. The reaction
mass was quenched with a solution of piperidine (10.4 g, 122 mmol) in
water (130 mL) and extracted with ethyl acetate (1 ꢃ 100, 1 ꢃ 30 mL).
The combined organic layer was washed with water (100 mL), dried over
sodium sulfate, and distilled off under reduced pressure. Isopropyl alco-
hol (40 mL) was added to the crude, and the precipitate was collected by
vaccum filtration and dried at 65ꢂC; for 1 h 30 min to provide 3 (12 g,
61%). HPLC purity 96%; mp 157–160ꢂC; mass: 456.5 (Mþ þ H), 478.8
1
(Mþ þ Na); IR (KBr, cmꢁ1): 3377 (NH), 1702, 1682 (C¼O ester); H
NMR (400 MHz, CDCl3): d 7.53 (d, J ¼ 16 Hz, 1H), 7.39 (s, 1H), 7.30
(t, J ¼ 1.6 Hz, 1H), 7.28 (t, J ¼ 1.6 Hz, 1H), 6.29 (d, J ¼ 16 Hz, 1H),
5.76 (s, NH), 4.99 (s, 1H), 4.03–4.12 (m, 4H), 2.33 (s, 6H), 1.52 (s, 9H),
1.18–1.22 (m, 6H).
3-[2-(2-tert-Butoxycarbonylvinyl)phenyl]acrylic acid tert-butylester
(Dimer, 4)
Caustic lye (50 mL, 625 mmol, 50%) solution was added to the mixture of
o-phthalaldehyde (10, 25 g, 37 mmol) and tert-butoxycarbonylmethyltri-
phenyl phosphonium bromide (9, 85.3 g, 186 mmol) in 1,4-dioxane
(250 mL) at 20–25ꢂC for 45 min. The reaction mass was heated to 50ꢂC
and maintained for 30 min. On completion of reaction (vide TLC), the
reaction mass was cooled to 30ꢂC, and the organic layer was separated
and distilled off completely under vacuum at 50ꢂC. The solid was taken
in cyclohexane (25 mL), cooled to 0ꢂC, and filtered at 0ꢂC, and filtrate
was distilled off under vacuum at 50ꢂC. Compound 4 was isolated from
petroleum ether (50 mL) and dried at 50ꢂþC for 2 h (22 g, þ88%). HPLC
purity 98%; mp 85–90ꢂC; mass: 330.8 (M þH), 353.2 (M þNa), 683.4

2144
V. V. N. K. V. P. Raju et al.
(2MþþNa); IR (KBr, cmꢁ1): 1707, 1635 (C¼O ester); 1H
NMR (400 MHz, CDCl3): d 7.93 (d, J ¼ 16 Hz, 2H), 7.53–7.55 (m, 2H),
7.34–7.36 (m, 2H), 6.26 (d, J ¼ 16 Hz, 2H), 1.54 (s, 18H).
4-(2-Carboxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid diethyl ester (Lacidipine Acid, 5)
A solution of ethyl-3-aminocrotonate (12, 27 g, 209 mmol) in isopropyl
alcohol (50 mL) followed by trifluoroacetic acid (16 g, 140 mmol) was
added to a solution of 2-formylbenzoic acid (17, 10 g, 66 mmol) in isopro-
pyl alcohol (50 mL) at ꢁ5ꢂC to ꢁ10ꢂC. On completion of the reaction
(vide TLC), a solution of piperidine (21.5 g, 252 mmol) in water
(300 mL) was added at ꢁ5ꢂC to 0ꢂC for 30 min and extracted with ethy-
lacetate (1 ꢃ 100, 1 ꢃ 30 mL). The organic layer was distilled off under
reduced pressure, and compound 5 was isolated from the mixture of iso-
propyl alcohol and water (330 mL, 1:10) at 0–5ꢂC and dried under vac-
cum at 65ꢂC for 2 h (12 g, 61%). HPLC purity 93%; mp 80–85ꢂC; mass:
374.5 (Mþ þ H), 396.2 (Mþ þ Na); IR (KBr, cmꢁ1) 3423 (NH), 1741
1
(C¼O ester), 1665 (C¼ O acid), 1262, 1208 (CꢁO); H NMR (400MHz,
CDCl3): 9.05 (br, 1H), 7.88 (dd, J ¼ 8, 16.4Hz, 1H), 7.59–7.68 (m, 1H),
7.48–7.57 (m, 1H), 7.27–7.31 (m, 1H), 6.39 (s, 1H), d 5.34 (s, 1H), 5.08
(br, NH), 3.76, (q, J ¼ 6.8, 14, 4H), 2.16 (s, 6H), 0.70 (t, J ¼ 6.8, 6H).
4-[2-(2-tert-Butoxycarbonylvinyl)phenyl]-3,6-dimethyl-1,4-
dihydropyridine-2,5-dicarboxylic acid diethyl ester (Regio-isomer, 6)
Ethyl-3-aminocrotonate (12, 83.4 g, 645 mmol) in acetic acid (50 ml)
was added to a solution of 11 (50 g, 215 mmol) in acetic acid (150 mL)
at 25–30ꢂC for 30 min. The reaction was maintained at 25–30ꢂC for
2 h. On completion of the reaction (vide TLC), the reaction mass was
quenched with chilled water (250 mL) and extracted with ethylacetate
(1 ꢃ 250 mL, 1 ꢃ 125 mL). The combined organic layer was washed with
the solution of piperidine (50 g in 250 ml of water) followed by water
(100 mL) and dried over sodium sulfate, the solvent was distilled off
under vacuum, and the residue was purified by column chromatography
to furnish compound 6 (53 g, 54%). HPLC purity 99.88%; mp 148–150ꢂC;
mass 456 (Mþ þ H); IR (KBr, cmꢁ1): 3327 (NH), 1709 (C¼O Ester), 1223
1
(CꢁO); H NMR (400 MHz, CDCl3): d 8.10 (d, J ¼ 15.6 Hz, 1H), 7.20–
7.60 (m, 4H), 6.34 (d, J ¼ 16 Hz, 1H), 6.00 (s, 1H), 5.18 (br, 1H), 4.20
(q, 2H), 4.10 (q, J ¼ 7.2, 2H), 2.47 (s, 3H), 2.08 (s, 3H), 1.50 (s, 9H),
1.31 (t, J ¼ 7.2, 6H).

Synthesis of Lacidipine Related Substances
ACKNOWLEDGMENTS
2145
The authors are grateful to colleagues in the Analytical Research
Department of Integrated Product Development Organization and the
management of Dr. Reddy’s Laboratories Ltd. for providing the
necessary support.
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