FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
“PROCESS FOR PREPARATION OF LERCANIDIPINE”
Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having
its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in
which it is to be performed.
2
FIELD OF THE INVENTION
[0001] The present invention relates to process for the preparation of lercanidipine
or salt thereof.
BACKGROUND OF THE INVENTION
[0002] Lercanidipine hydrochloride, also known as 1,4-dihydro-2,6-dimethyl-4-(3-
nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-
1,1-dimethylethylmethyl ester hydrochloride, is represented by the structure of
Formula I.
(I)
[0003] Lercanidipine hydrochloride is a synthetic antihypertensive calcium
channel blocker sold under the brand names Lercadip, Lerdip, Lerzam, Zanedip,
and Zanidip®. Lercanidipine hydrochloride is a dihydropyridine calcium channel
blocker used for the treatment of hypertension.
SUMMARY OF THE INVENTION
[0004] The present invention provides a process for the preparation of
lercanidipine, a compound of formula I or a salt thereof,
I
3
comprising:
a) reacting a compound of formula IV with methyl-3-amino but-2-enoate, a
compound of formula V to obtain a compound of formula II

IV V; and
b) reacting a compound of formula II with a compound of formula III

II III
to obtain lercanidipine or a salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] Figure 1 is a characteristic 1HNMR of compound of formula IV as obtained
in Example 2.
[0006] Figure 2 is a characteristic 1HNMR of 2-chloro-1,1-dimethyl ethyl-3-
oxobutanoate, a compound VIII as obtained in Example 1.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention provides a process for the preparation of lercanidipine,
a compound of formula I or a salt thereof
4
I
comprising:
a) reacting a compound of formula IV with methyl-3-amino but-2-enoate, a
compound of formula V to obtain a compound of formula II

IV V; and
b) reacting a compound of formula II with a compound of formula III

II III
to obtain lercanidipine or a salt thereof.
[0008] In one embodiment, the compound of formula II is obtained by a process
comprising reacting the compound of formula IV with methyl-3-amino but-2-
enoate, the compound of formula V wherein the reaction may be carried out in
presence of a solvent.
[0009] The solvent may be selected from the group consisting of esters such as
methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate
5
and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane
and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether,
tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone,
methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl
alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tertbutyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane,
chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl
acetamide; water; or mixtures thereof.
[0010] In one embodiment, the reaction is carried out at a temperature ranging from
about 0ᵒC to about reflux temperature of the solvent.
[0011] In another embodiment, the compound of formula IV is obtained by a
process, comprising:
(bi) reacting methyl acetoacetate, compound of formula VI with 1-chloro-2-
methylpropan-2-ol compound of formula VII to obtain 2-chloro-1,1-dimethyl ethyl3-oxobutanoate, compound of formula VIII.

VI VII VIII; and
(bii) reacting the compound of formula VIII with nitrobenzaldehyde to obtain the
compound of formula IV.
[0012] In (bi) methyl acetoacetate, the compound of formula VI is reacted with 1-
chloro-2-methylpropan-2-ol, the compound of formula VII to obtain 2-chloro-1,1-
dimethyl ethyl-3-oxobutanoate, the compound of formula VIII in the presence of a
solvent and a suitable reagent.
[0013] The reaction may be carried out in the presence of a solvent selected from
the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate,
isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as n-heptane,
toluene, xylene, cyclohexane, chlorobenzene, heptane, hexane and the like; ethers
6
such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran,
dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl
ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl
alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol,
pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform,
ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or
mixtures thereof.
[0014] The suitable reagent may be selected from the group consisting of dimethyl
aminopyridine, acetic acid, formic acid, sulphuric acid, p-toluene sulphonic acid,
ambarlyst resin.
[0015] In one embodiment, the reaction is carried out at a temperature ranging from
about 0°C to about reflux temperature of the solvent.
[0016] In (bii), 2-chloro-1,1-dimethyl ethyl-3-oxobutanoate, the compound of
formula VIII is reacted with nitrobenzaldehyde to obtain the compound of formula
IV in the presence of a suitable solvent and reagent.
[0017] The reaction may be carried out in the presence of a solvent selected from
the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate,
isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene,
xylene, cyclohexane, chlorobenzene, heptane, hexane and the like; ethers such as
diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane
and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone
and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl
alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol,
pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform,
ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or
mixtures thereof.
[0018] The suitable reagent may be selected from the group consisting of dimethyl
amino pyridine, acetic acid, piperidine, HCl gas in non protic solvent.
[0019] In one embodiment, the reaction is carried out at a temperature ranging from
about 0°C to about reflux temperature of the solvent.
7
[0020] In one embodiment, the present invention provides a process for the
preparation of lercanidpine or salt thereof comprising :
(ci) reacting methyl acetoacetate, compound of formula VI with 1-chloro-2-
methylpropan-2-ol compound of formula VII to obtain 2-chloro-1,1-dimethyl ethyl3-oxobutanoate, compound of formula VIII,

VI VII VIII; and
(cii) reacting the compound of formula VIII with nitrobenzaldehyde to obtain the
compound of formula IV;
(ciii) reacting the compound of formula IV with methyl-3-amino but-2-enoate, the
compound of formula V to obtain a compound of formula II;

IV V; and
(civ) reacting the compound of formula II with a compound of formula III to obtain
lercanidipine, the compound of formula I or a salt thereof.

II III
8
[0021] In (ci), the reaction of methyl acetoacetate, the compound of formula VI
with 1-chloro-2-methylpropan-2-ol, the compound of formula VII is carried out in
n-heptane in the presence of dimethyl aminopyridine to obtain 2-chloro-1, 1-
dimethyl ethyl-3-oxobutanoate, the compound of formula VIII.
[0022] In (cii), the compound of formula VIII is reacted with nitrobenzaldehyde in
toluene in presence of acetic acid and piperidine to obtain compound of formula IV.
[0023] In (ciii) the compound of formula IV is reacted with methyl-3-amino but2-enoate compound of formula V in isopropyl alcohol to obtain the compound of
formula II.
[0024] In (civ) the compound of formula II is reacted with the compound of formula
III to obtain lercanidipine.
[0025] In another embodiment, the lercanidipine obtained may be optionally
converted into a salt.
[0026] In another embodiment, the lercanidipine obtained may be optionally
converted into its hydrochloride salt.
[0027] In another embodiment, the compound of formula II may be obtained by a
process comprising:
(di) reacting methyl acetoacetate, the compound of formula VI with nitro
benzaldehyde to obtain a compound of formula IX;
IX; and
(dii) reacting the compound of formula IX with the compound of formula VIII in
the presence of ammonium acetate OR with a compound of formula X
9

VIII X
to obtain the compound of formula II.
[0028] In another embodiment, the compound of formula II may be prepared by a
process comprising:
(ei) reacting the compound of formula IX with the 1-chloro-2-methylpropan-2-ol
compound of formula VII

IX VII
to obtain a compound of formula IV;
IV; and
(eii) reacting the compound of formula IV with methyl-3-aminocrotonoate, a
compound of formula V
10
V
to obtain a compound of formula II.
[0029] In another embodiment, the compound of formula II may be obtained by a
process comprising;
(fi) converting a compound of formula IX to a compound of formula XI
XI;
(fii) reacting the compound of formula XI with the compound of formula VII to
obtain a compound of formula XII

VII XII; and
(fiii) reacting compound of formula XII with the compound of formula VI to obtain
the compound of formula II.
[0030] In one embodiment, the present invention provides a compound of formula
IV characterised by 1HNMR having peaks at 8.23-8.26, 7.71-7.73, 7.28-7.62, 3.88,
2.42, 1.62(400MHz, CDCl3).
[0031] In one embodiment, the present invention provides a compound of formula
VIII characterised by 1HNMR having peaks at 3.74-3.76, 3.33, 2.18, 1.46
11
[0032] The examples that follow are provided to enable one skilled in the art to
practice the invention and are merely illustrative of the invention. The examples
should not be read as limiting the scope of the invention as defined in the features
and advantages.
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EXAMPLES
Example 1: Preparation of 2-chloro-1,1-dimethylethyl 3-oxobutanoate (VIII)
Methyl acetoacetate (100g) and 1-chloro-2-methylpropan-2-ol (154.4g) was added
to n-heptane (1500mL). To this mass 4-dimethyl amino pyridine (10g) was added
and heated to a temperature of about 95°C to 100°C. The reaction mass was
distilled out azeotropically for 24 hours at about 95oC to about 100oC and cooled to
60°C to 65°C. The reaction mass then filtered through and washed with n-heptane.
The filtrate was distilled under reduced pressure and degassed to get oily residue
(110g). The residue was purified by column chromatography on silica gel using nhexane: ethyl acetate mixture as eluent to obtain 2-chloro-1,1-dimethylethyl 3-
oxobutanoate as pale yellow oil (55.0g).
1H NMR (400MHz, CDCl3): δ 3.74-3.76, 3.33, 2.18, 1.46.
Example 2: Preparation of 2-chloro-1, 1-dimethylethyl -2-(3-
nitrobenzylidene)-3-oxobutanoate (IV)
3-nitrobenzaldehyde (5g), 2-chloro-1, 1-dimethylethyl 3-oxobutanoate (7g), acetic
acid (0.2g) and piperidine (0.17g) were charged to toluene (50mL) and heated to
reflux for 5 hours. After completion of reaction, the reaction mass was cooled to a
temperature of about 35°C to 40°C. The reaction mass then distilled out under
reduced pressure to get oily mass. The residue was further purified by column
chromatography on silica gel by using n-hexane: ethyl acetate mixture as eluent to
obtain 2-chloro-1,1-dimethylethyl -2-(3-nitrobenzylidene)-3-oxobutanoate as oil
(2g).
1H NMR (400MHz, CDCl3): δ 8.23-8.26, 7.71-7.73, 7.28-7.62, 3.88, 2.42, 1.62.
Example 3: Preparation of 1-chloro-2-methyl-2-propyl methyl 1,4-dihydro2,6-dimethyl-4-(3-nitrophenyl)-1-pyridine-3 ,5-dicarboxylate
2-chloro-1,1-dimethylethyl -2-(3-nitrobenzylidene)-3-oxobutanoate (0.50g),
methyl-3-aminocrotonate (0.18g) charged to isopropyl alcohol (5.0mL) and heated
to reflux for 4 hours. The reaction progress is monitored by TLC and after
completion of reaction, cooled to about 35°C to 40°C. The mass then distilled out
13
under reduced pressure to get oily mass. The residue further purified by column
chromatography on silica gel by using n-hexane: ethyl acetate mixture as eluent to
obtain, 1-chloro-2-methyl-2-propyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(3-
nitrophenyl)-1-pyridine-3 ,5-dicarboxylate as oil (0.30g).
1H NMR (400MHz, CDCl3): 8.13, 8.02-8.00, 7.65-7.67, 7.41, 6.0, 5.0, 3.78, 3.68,
2.40, 1.49
Example 4: Preparation of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid,
methyl ester (IX)
3-Nitro benzaldehyde (1g) was reacted with methyl acetoacetate (1.07g) in
presence of piperidine (0.04g) and acetic acid (0.03g) in isopropyl alcohol (4
ml) at a temperature of about 25°C to 35°C to obtain 2-[(3-
nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (1.45g). The product
was isolated by filtration.
Example 5: Preparation of 1,1-N-trimethyl-N-(3,3-diphenylpropy)-2-
aminoethyl acetoacetate
1-[N-(3,3-diphenylpropyl)-N-methylamino]-2-methyl-2-propanol (1g) was
reacted with methyl acetoacetate (1.95g) in presence of dimethyl amino
pyridine (0.5%) in toluene (10ml) at reflux temperature to form 1,1-Ntrimethyl-N-(3,3-diphenylpropy)-2-aminoethyl acetoacetate. It was further
washed with acetic acid solution to form pure 1,1-N-trimethyl-N-(3,3-
diphenylpropy)-2-aminoethyl acetoacetate (0.7g).
Example 6: Preparation of 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-
pyridine dicarboxylic acid-2- [(3,3-diphenylpropyl)methylamino] -1,1-
dimethylethyl methyl ester hydrochloride.
1,1,N-trimethyl-N-(3,3-diphenylpropy)-2-aminoethyl acetoacetate (2.9 g) was
reacted with 3-nitro benzaldehyde (1.16 g) using hydrochloride gas (1.45 g) in
toluene (10.3 ml) to obtain 2-[(3-nitrophenyl)methylene]-3-oxo-butanoic acid 2-
[(3,3-Diphenylpropyl) methyl amino] -1,1-dimethylethyl ester. The obtained
14
product was reacted methyl 3-amino crotonate (0.791 g) in presence of
triethylamine (1.88 gm) in methanol (8.3 ml). On completion of reaction, the
reaction mixture was distilled to obtain product as an oil. The product was treated
with hydrochloric acid in isopropyl alcohol (2.5 g) and extracted in isopropyl
acetate. The isopropyl acetate solution was distilled to obtain a residue and the
residue dissolved in a mixture of methanol (1.45 ml) and isopropyl acetate (29
ml) to obtain 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine
dicarboxylic acid-2- [(3,3-diphenylpropyl) methylamino] -1,1-dimethylethyl
methyl ester hydrochloride (1.30 g).
Example 7: Preparation of 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-
pyridine dicarboxylic acid-2- [(3,3-diphenylpropyl)methylamino] -1,1-
dimethylethyl methyl ester hydrochloride.
1,1, N-trimethyl-N-(3,3-diphenylpropy)-2-aminoethyl acetoacetate (1.0 g) was
reacted with ammonium carbonate (0.25g) in (6.0 ml) methanol form insitu [1-[3,3-
diphenylpropyl (methyl) amino]-2-methylpropan-2-yl]-3-aminobut-2-enoate. This
was then reacted with 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid methyl
ester(IX, 6.5 gm) in isopropyl alcohol (6 ml) at reflux temperature to form 1,4-
dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-2- [(3,3-
diphenylpropyl)methylamino] -1,1-dimethylethyl methyl ester. After reaction
completion, the reaction mixture was distilled to obtain an oil. The oil was dissolved
in isopropyl acetate and reacted with hydrochloric acid in isopropyl alcohol. The
isopropyl acetate layer was concentrated under vacuum to obtain a residue. The
obtained residue was dissolved in a mixture of methanol (0.5 ml) and isopropyl
acetate (10 ml) to obtain 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-
pyridine dicarboxylic acid-2- [(3,3-diphenylpropyl)methyl amino] -1,1-
dimethylethyl methyl ester hydrochloride (1.0g).
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We Claim:
1. A process for the preparation of lercanidipine, a compound of formula I or a
I
salt thereof comprising:
a) reacting a compound of formula IV with methyl-3-amino but-2-enoate, a
compound of formula V to obtain a compound of formula II;

IV V
b) reacting a compound of formula II with a compound of formula III

II III
to obtain lercanidipine or a salt thereof.
2. The process as claimed in claim 1, wherein the compound of formula IV is
obtained by a process comprising:
16
i) reacting methyl acetoacetate, a compound of formula VI with 1-chloro-2-
methylpropan-2-ol, a compound of formula VII to obtain 2-chloro-1,1-dimethyl
ethyl-3-oxobutanoate, compound of formula VIII

VI VII VIII; and
ii) reacting the compound of formula VIII with nitrobenzaldehyde to obtain the
compound of formula IV.