DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Lercanidipine Hydrochloride and intermediates thereof, which is represented by the
following 5 structural formula-1.
Formula-1
10 Background of the Invention:
Lercanidipine, having the chemical name of 3-(1-((3,3-diphenylpropyl)(methyl)amino)-2-
methylpropan-2-yl)5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-di
carboxylate Hydrochloride belongs to the dihydropyridine, class of calcium channel blockers,
which work by relaxing and opening the blood vessels allowing the blood to circulate more
15 freely around the body. This lowers the blood pressure and allows the heart to work more
efficiently.
The drug acts more slowly than older dihydropyridines. It probably has fewer adverse effects,
but a comparatively high potential for drug interactions. Lercanidipine was developed by
Recordati first marketed in 1997 with the trade name of Zanidip for the treatment of
20 hypertension (blood pressure lowering).
The US patent No. US4705797A (herein after designated as US’797) first reported
Lercanidipine as product and process for preparation thereof. The process for preparation of
Lercanidipine was represented in scheme-I and II. The said patent has high number of steps,
low yields and not viable for commercial quantities. As per the disclosed process, there is a
25 chance for formation of more impurities, hence, the said process is time taking for industrial
production.
3
Scheme-I: The process reported in US’797.
Scheme-II:The process reported in US’797.
5
4
The US patent No. US5912351B2 reported a different process for the preparation of
lercanidipine hydrochloride using the following intermediate compound.
There are various processes reported for the preparation 5 of Lercanidipine
Hydrochloride using different solvents and reagents.
Based on draw back of the prior art processes, there is a need for providing an
improved process for the preparation of Lercanidipine Hydrochloride, which involves simple
experimental procedures, well suited to industrial production, which avoids the use of
10 column chromatography purification, and which affords high pure Lercanidipine
Hydrochloride.
The present invention provides an improved process for preparation of Lercanidipine
Hydrochloride, which is efficient, industrially viable and cost effective.
15 Brief Description :
The first aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
The second aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-3.
20 The third aspect of the present invention is to provide an improved process for the
preparation of amorphous form of Lercanidipine Hydrochloride.
Brief description of the drawings:
Figure -1: Illustrates the PXRD pattern of amorphous form of Lercanidipine Hydrochloride.
25 Figure- 2: Illustrates the IR absorption of amorphous form of Lercanidipine Hydrochloride.
Figure-3: Illustrates the PXRD pattern of Crystalline Form-I of Lercanidipine Hydrochloride.
5
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl 5 ether, ethylene
glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
10 dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; “chloro solvents” such as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol,
15 ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar
solvents” such as water or mixtures thereof. protic polar solvents like acetic acid, formic acid,
20 water;
As used herein the present invention the term “suitable base” refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
25 sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
30 and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
6
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are
selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C,
5 Raney-nickel;
The term “protecting” agent / group (PG) used in the present invention refers to a suitable
protecting reagents that are selected from di-tert-butyl dicarbonate, chlorobenzyl formate,
benzoylchloride, benzylbromide, benzylchloride, acetylchloride, fluorenyl methyloxy
carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention
10 refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammonium bromide,
tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium
chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride;
The first aspect of the present invention provides an improved process for the
15 preparation of compound of formula-1
Formula-1
20 comprising of:
a) Reacting the compound of formula-4
Formula-4
25 with methyl-3-oxobutanoate in presence of suitable base, solvent to provide compound of
formula-4a, in-situ
7
Formula-4a
further reacting with methyl-3-oxo butanoate in presence of suitable reagent in suitable
solvent to get compound of formula-5,
5
Formula-5
b) reacting the compound of formula-5 in presence of suitable reagent, solvent to provide
compound of formula-6, optionally purifying the compound of formula-6 in suitable solvent,
10
Formula-6
c) reacting the compound obtained in step-b) with compound of formula-3,
15
Formula-3
in presence of suitable reagent, solvent to provide compound of formula-1.
20
8
Formula-1
d) optionally purifying the compound of formula-1 with suitable solvent to provide
amorphous form of lercanidipine hydrochloride.
5
wherein in step-a) “suitable base” refer as “organic bases” such as like dimethylamine,
diethylamine, diisopropyl amine, triethylamine, pyridine, piperidine, 4-dimethyl amino
pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof; the suitable solvent is
selected from hydrocarbon solvents like toluene, benzene, xylene; protic polar solvents are
like acetic acid, formic acid, water; alcoholic solvents are like methanol, 10 ethanol, isopropanol;
suitable reagents such as like ammonium acetate, ammonia, ammonium carbonate,
ammonium chloride, ammonium formate. Suitable temperature :0-100°C,
wherein in step-b) suitable base is selected from alkali metal hydroxides such as sodium
15 hydroxide, potassium hydroxide, lithium hydroxide and the like; suitable acid is selected
from hydrohloric acid, hydrobromic acid. The suitable solvent is selected from alcohol
solvents like methanol, ethanol, isopropanol; hydrocarbon solvents like toluene, benzene,
xylene; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ether
solvents such as diethyl ether, tetrahydrofuran, dioxane; work up acidification using with an
20 suitable acid, such as aq. HCl, HCl (g), acetic acid, citiric acid, the pH range 0-6.5; suitable
temperature 0-100°C;
wherein in step-c) suitable reagent selected from thionyl chloride, CDI, methylchloroformate,
ethylchloroformate;
25 wherein in step-c, d) the suitable solvent is hydrocarbon solvents such as n-hexane, n-heptane,
toluene, pentane, ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, nbutyl
acetate and the like; polar-aprotic solvents such as dimethylacetamide (DMA),
9
dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and
the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbontetra
chloride and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, phenol, or glycerol and the like; polar solvents such as water or mixtures thereof;
suitable base like inorganic base such as alkali metal carbonates 5 like sodium carbonate,
potassium carbonate, lithium carbonate; HCl (g) in alcohol solvents, ester solvent, ketone
solvent, ether solvent, or aqueous HCl; The pH range: 0 - 6.5;
The preferred embodiment of the present invention provides an improved process for the
10 preparation of compound of formula-1
Formula-1
15 comprising of:
a)Reacting the compound of formula-4
Formula-4
20 with methyl-3-oxobutanoate in presence of piperidine in acetic acid to provide compound of
formula-4a, further reacting in-situ
Formula-4a
with methyl-3-oxo butanoate, ammonium acetate in water to get compound of formula-5,
10
Formula-5
b)hydrolysing the compound of formula-5 with sodium hydroxide in methanol, toluene to
provide 5 compound of formula-6,
Formula-6
c)reacting the compound obtained in step-b) with compound of formula-3,
10
Formula-3
in presence of thionyl chloride, in dichloromethane followed by acidification with Con.HCl
15 to provide compound of formula-1.
Formula-1
11
The second aspect of the present invention provides an improved process for
the preparation of compound of formula-3,
Formula-3
5 comprising of:
a) Reacting the compound of formula-2
Formula-2
with 1-chloro-2-methylpropan-2-ol in presence of suitable base to produce compound of
10 formula-3,
Formula-3
wherein in step-a) the suitable base is selected from inorganic base, like sodium hydroxide,
potassium hydroxide, lithium hydroxide; sodium carbonate, potassium carbonate, suitable
15 temperature 10-100°C.
The preferred embodiment of the present invention provides an improved
process for the preparation of compound of formula-3,
Formula-3
20 comprising of:
a) Reacting the compound of formula-2
12
Formula-2
with 1-chloro-2-methylpropan-2-ol in presence of sodium hydroxide at 60-70°C to produce
compound of formula-3
5
Formula-3
The third aspect of the present invention provides an improved process for the
preparation of amorphous form of Lercanidipine hydrochloride.
10
Formula-1
Comprising of
a) Stirring the lercanidipine hydrochloride in suitable solvent at suitable temperature,
b) isolating the compound obtained in step-a) in suitable solvent to 15 get the amorphous form
of compound of formula-1,
Formula-1
13
wherein in step-a,b) suitable solvents refer as hydrocarbon solvents such as n-hexane, nheptane,
cyclohexane, petether, toluene and the like; ester solvents such as methyl acetate,
ethyl acetate, isopropyl acetate, n-butyl acetate and the like; ketone solvents such as acetone,
methyl ethyl ketone, methyl isobutyl ketone and the like; alcoholic solvents 5 such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, phenol, or glycerol, water and mixture thereof;
suitable temperature 0 to 100°C.
wherein in step-b) isolation process is by evaporation, filtration;
The preferred embodiment of the present invention provides an improved process for the
10 preparation of amorphous form of Lercanidipine hydrochloride.
comprising of;
a) Stirring the lercanidipine hydrochloride in methanol at 40-50°C,
b) evaporating the solution and stirring in ethyl acetate at 45-55°C,
c) heating the solution of step-b) at 65-75°C,
15 d) filtering the compound obtained in step-c) to get the amorphous form of compound of
formula-1a,
The present invention described as follows in a schematic representation :
14
Process for preparation of compound-3:
The process for the preparation of compound of formula-I developed 5 by the present
inventors produces highly pure compound of formula-I with good yield. All the related
substances and residual solvents are controlled well within the limits as suggested by ICH
guidelines and most of the related substances are controlled in non-detectable levels.
10 The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC.
The process described in the present invention was demonstrated in examples
15 illustrated below. These examples are provided as illustration only and therefore should not
be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-5.
20 A round bottom flask was charged with compound of formula-4 (92.2 g), methyl-3-oxo
butanoate (100 g), acetic acid (1.43 g) and piperidine (2.03 g) in toluene (100 mL) at 25-
35°C, heated to 40-45°C and stirred for 2.5 hr. The reaction mixture was further heated to 90-
100°C, added methyl 3-oxobutanoate (92.2 g) and stirred for 15 min. The reaction mixture
was cooled to 40-45 °C added a solution of ammonium acetate (61.21 g in 100 mL of water)
25 and stirred for 2.5 hr. Again, the reaction mixture was charged with methyl 3-oxobutanoate
(92.2 g) and ammonium acetate solution (15.30 g in water 30 mL) at 90-100°C, stirred for 4.5
hr. The reaction mixture was cooled to 50-55°C, charged with methanol (800 mL) and stirred at
15
same temperature for 2 hr and cooled to 25-35°C, stirred for 2.5 hr. Filtered the obtained
compound and washed with methanol (200 mL), dried to get the title compound.
Yield: 185 g
Example-2: Preparation of compound of formula-5.
A round bottom flask was charged with compound of formula-5 4 (100 g), methyl-3-oxo
butanoate (92.2 g), acetic acid (1.43 g) and piperidine (2.03 g) in toluene (100 mL) at 25-
35°C, heated to 40-45°C and stirred for 2.5 hr. The reaction mixture was further heated to 90-
100°C, charged methyl-3-oxobutanoate (92.2 g) and ammonium acetate solution (61.21 g in
100 mL of water) simultaneous and stirred for 2.5 hr. Again, the reaction mixture was charged
10 with methyl-3-oxobutanoate (15.36 g) and ammonium acetate solution (15.30 g in water 30 mL)
at 90-100°C, stirred for 4.5 hr. The reaction mixture was charged with toluene (500 mL) at 90-
100°C and stirred at same temperature for 0.5 hr and cooled to 25-35°C, stirred for 2.5 hr.
Filtered the obtained compound and washed with toluene (100 mL), dried to get the title
compound.
15 Yield: 191 g
Example-3: Preparation of compound of formula-6.
A round bottom flask was charged with water (300 mL), NaOH (94.7 g) and stirred for 15
min. Methanol (1600 mL), compound of formula-5 (100 g) were added at 25-35°C, stirred
for 30 min. The reaction mixture was heated to 65-70°C and stirred for 18 hr, cooled to 10-
20 20°C stirred for 30 min. Filtered the undissolved material, washed with methanol (100 mL).
The reaction mixture was charge with DM water (200 mL), toluene (200 mL) at 25-35°C for
30 min and separated the both layers. The aqueous layer was charged with toluene (200 mL)
at 25-35°C, stirred for 30 min and separated both layers. The aqueous layer pH was adjusted
to 7.0 by using 10% aq.HCl solution and stirred for 1.5 hr. Filtered the obtained solid and
25 washed with DM Water (100 mL). The obtained wet compound was purified in a mixture of
acetone, toluene and filtered the precipitate and washed with toluene to get the title
compound.
Yield: 40 g
Example-4: Preparation of compound of formula-6.
30 A round bottom flask was charged with water (250 mL), NaOH (23.1 g) and stirred for 15
16
min. Methanol (800 mL), compound of formula-5 (100 g) and toluene (150 mL) were added
at 25-35°C, stirred for 30 min. The reaction mixture was heated to 65-70°C and stirred for 18
hr. Cooled to 5-15°C and charged with water (300 mL), Con.HCl (25 mL in 25 mL of water)
stirred for 30 min. Filtered the undissolved material, washed with water (100 mL). The
filtrate solution was charged with dichloromethane (2x200 mL) 5 stirred for 20 min and
separated the layers. The aqueous layer was diluted with Con.HCl (25 mL in 25 mL of water)
about 2 hr, stirred for 30 min and maintained pH about 4 to 6. Filtered the obtained
solid,washed with water (100 mL). The wet compound was charged with methanol (100 mL),
toluene (250 mL) and water (30 mL) stirred for 45 min at 60-70°C. Cooled the reaction
10 mixture to 25-35°C, stirred for 45 min, filtered the obtained solid and washed with toluene (5
ml) and dried to get the title compound.
Yield: 41.5 g
Example-5: Preparation of compound of formula-1.
A round bottom flask was charged with compound of formula-6 (100 g), MDC (500 mL) and
15 DMF (50 mL) at 25-35°C under N2 atmosphere, stirred for 30 min. The reaction mass was
cooled to -15 to -5 °C, slowly added a solution of thionyl chloride (46.55 g in 100 mL of
MDC), stirred for 3 hr at same temperature. A solution of compound of formula-3 (89.53 g in
100 mL of MDC) was added to the above reaction mixture at same temperature and stirred
for 3 hr. The reaction mixture was gradually heated to 20-30°C, stirred for 1.5 hr, charged
20 with DM water (200 mL) and MDC (200 mL) stirred for 30 min and separated the both
layers. The organic layer was stirred with sodium carbonate solution (25 g in 250 mL of
water; 2 times ) at 20-30°C for 30 min and separated the organic layers. The combined
organic layer was washed with sodium chloride solution (20.0 g in 200 mL of water),
followed by 10% HCl (2x100 mL), water (100 mL) and separated the organic layer. The
25 organic layer was dried over sodium sulphate (20 g), charged activated carbon (10 g) and
filtered the organic layer. The organic layer was distilled off completely, charged with
dichloromethane (500 mL), ethyl acetate (400 mL) and heated to 55-65°C stirred for 30 min
and maintained the pH in between 2 to 4.0. The reaction mixture was cooled to 20-30°C,
stirred for 16 hr and charged with ethanol (100 mL) heated to 55-65°C and stirred for 1.5 hr.
30 Cooled the reaction mixture to 20-30°C, stirred for 1.5 hr, filtered the precipitate solid and
17
washed with ethyl acetate (100 mL) and dried to get crude compound.
The obtained compound was charged with ethyl acetate (525 mL) and heated to 58-68°C,
stirred for 45 min. The reaction mixture was cooled to 20-30°C, added seeding material,
stirred for 14 hr. The reaction mixture was charged with ethanol (100 mL) and heated to 55-
65°C and stirred for 2 hr. The reaction mixture was cooled to 20-5 25°C, stirred for 2 hr.
Filtered the precipitate solid and washed with ethyl acetate (100 mL), dried to get the title
compound.
Yield: 98 g
Example-6: Preparation of compound of formula-1 ( Lercanidipine hydrochloride)
10 A round bottom flask was charged with compound of formula-6 (100 g), MDC (600 mL) and
DMF (50 mL) at -15 to -8 °C under N2 atmosphere, stirred for 30 min. The reaction mass
was charged with a solution of thionyl chloride (46.54 g in 100 mL of MDC), stirred for 4 hr
at same temperature. A solution of compound of formula-3 (89.53 g in 100 mL of MDC) was
added to the above reaction mixture at same temperature and stirred for 3 hr. The reaction
15 mixture was gradually heated to 17-27°C, stirred for 6 hr, charged with DM water (200 mL)
and separated the layers. The organic layer was stirred with water (200 mL), sodium
carbonate solution (25 g in 250 ml of water; 2 times ) at 20-30°C for 30 min. Separated the
organic layers, the combined organic layer was washed with sodium chloride solution (20.0
gr in 200 ml of water) dried with sodium sulphate. The organic layer was charged with Conc.
20 HCl (40 mL in 200 mL of water ) and stirred for 30 min and separated the organic layer.
Again the organic layer was charged with the same amount of Con .HCl and separated the
organic layer. The combined organic layer was washed with brine solution (20 g in 200 mL),
dried over anhydrous sodium sulfate. To the organic layer cahrged with carbon (10 g) , stirred
for 30 min, filtered through hyflow, washed with dichloromethane (200 mL). The organic
25 layer was dried over sodium sulfate, evaporated the organic layer completely. Charge
methanol (100 mL) to the obtained compound and stirred for 45 min at 45-55°C, distilled off
the completely. To the obtained compound charged with ethyl acetate (50 mL), heated to 70-
75°C, stirred for 45 min and stirred for 12 hr at 20-30°C. Filtered the obtained solid and
charged with ethyl acetate (700 mL) stirred for 1.5 hr at 65-75°C. Cooled the reaction
30 mixture to 20-30°C, stirred for 2 hr and filtered the solid washed with ethyl acetate (50 mL)
18
and n-heptane (10 mL) and dried to get the title compound.
Yield: 150 g.
Example-7: Preparation of compound of formula-3.
A round bottom flask was charged with compound of formula-2 (100 g) with sodium
hydroxide (21.3 g) at 25-35°C, stirred for 15 min. 1-chloro-2-methylpropan-5 2-ol (81.90 g)
was added slowly to the above reaction mixture about 1.5 hr and heated to 60-70°C, stirred
for 8 hr. The another lot of sodium hydroxide (17.75 g) was added to the above solution and
stirred for 1.5 hr, The reaction mixture was cooled to 20 to 30°C, charged with DM water
(250 mL) and MDC (2 x250 mL), stirred for 30 min and separated the both layers. The
10 combined organic layers were charged with DM Water (200 mL), stirred for 30 min at 20-
30°C. Separated the organic layer, dried with sodium sulfate and distilled off completely
under the vacuum, dried to get the title compound.
Yield: 125 g
Example-8: Preparation of compound of formula-3.
15 A round bottom flask was charged with compound of formula-2 (100 g) with sodium
hydroxide (26.6 g, lot -1) at 25-35°C, stirred for 15 min. 1-chloro-2-methylpropan-2-ol (96.3
gr) was added slowly to the above reaction mixture about 1.5 hr and heated to 60-70°C,
stirred for 12 hr. The another lot-2 of sodium hydroxide (17.75 g) was added to the above
solution and stirred for 1.5 hr at 60-70°C. Cooled the reaction mixture to 20 to 30°C,
20 charged with DM water (250 mL) and MDC (2 x 250 mL), stirred for 30 min and separated
the layers. The combined organic layers were charged with DM Water (200 ml), stirred for 30
min at 20-30°C. Separated the organic layer, dried with sodium sulfate and distilled off
completely under the vacuum, dried to get the title compound.
Yield: 129.5 g
25 Example-9: Preparation of amorphous form of Lercanidipine hydrochloride.
A round bottom flask was charged with compound of formula-1(100 g), ethyl acetate (1L).
water (50 mL) and stirred for 30 min at 45-55°C. The reaction mixture was distilled off
completely under reduced pressure, the obtained compound was stirred in n-Heptane (200
mL) for 30 min, filtered the precipitate to get the title compound.
30 Yield: 95 gr. The obtained PXRD depicted in figure-1
19
Example-10: Preparation of amorphous form of Lercanidipine hydrochloride.
A round bottom flask was charged with compound of formula-1(100 g), acetone (1 L), water
(50 mL) and stirred for 30 min at 45-55°C. The reaction mixture was distilled off completely
under reduced pressure, the obtained compound was stirred in n-Heptane (200 mL) for 30
min, filtered the precipitate to 5 get the title compound.
Yield: 95 g
Example-11: Preparation of amorphous form of Lercanidipine hydrochloride.
A round bottom flask was charged with compound of formula-1(100 g), methanol (400 mL)
and stirred for 45 min at 40-50°C. The reaction mixture was distilled off completely, cooled
10 to 25-35°C and charged with ethyl acetate (50 mL) and stirred for 10 min. The reaction
mixture was distilled off completely and charged with ethyl acetate (500 mL), stirred for 45
min at 45-55°C. Cooled the reaction mixture to 35-45°C, charged with seeding compound
and stirred for 5 hr. The reaction mixture was heated to 65-75°C, charged with ethanol (100
mL) and stirred for 1.5 hr at same temperature. Cooled the reaction mixture to 25-35°C,
15 filtered the obtained solid washed with ethyl acetate (50 mL). The obtained wet compound
was charged with ethyl acetate (50 mL), methanol (400 mL) and stirred for 30 min at 50-
60°C, filtered through micron filtrate, washed with methanol (50 mL). The reaction mixture
was distilled off completely, charged with n-Heptane (400 ml) stirred for 30 min at 20-30°C.
Cooled the reaction mixture to 0-10°C, charged with water (600 mL) and stirred for 45 min,
20 filtered the obtained solid and washed with water (50 mL) and dried to get the title compound.
Yield: 75 g
Example-12: Preparation of Crystalline form-I of Lercanidipine hydrochloride.
A round bottom flask was charged with compound of formula-6 (100 g), MDC (500 mL) and
DMF (50 mL) at 25-35°C under N2 atmosphere, stirred for 30 min. The reaction mass was
25 cooled to -15 to -5 °C, slowly added a solution of thionyl chloride (46.55 g in 100 mL of
MDC), stirred for 3 hr at same temperature. A solution of compound of formula-3 (89.53 g in
100 mL of MDC) was added to the above reaction mixture at same temperature and stirred
for 3 hr. The reaction mixture was gradually heated to 20-30°C, stirred for 2 hr, charged with
DM water (200 mL) and MDC (200 mL) stirred for 30 min and separated the both layers.
30 The organic layer was stirred with sodium carbonate solution (25 g in 250 mL of water; 2
20
times ) at 20-30°C for 30 min. Separated the organic layers, the combined organic layer was
washed with sodium chloride solution (20.0 g in 200 mL of water) dried with sodium
sulphate. The organic layer was distilled off completely at 30-40°C under vacuum. Toluene
(50 mL) was added to the obtained compound at 30-40°C, stirred for 20 min and distilled off
completely at 55-65°C. Ethyl acetate (400 mL) was added to the obtained 5 compound, stirred
for 30 min at 55-65°C. The reaction mixture was cooled to 20-30°C, slowly added 98 ml of
isopropanol HCl upto the pH 3.5, added the seeding material and stirred for 24 hr. Filtered
the precipitate solid, wash with EtOAc (1800 mL) and dried. The obtained compound was
charged with ethanol (525 mL), heated to 60-70°C and stirred for 45 min. The reaction
10 mixture was cooled to 20-30°C, added seeding material and stirred for 36 hr. Filtered the
obtained solid, washed with ethanol (75 mL), dried to get the title compound.
The obtained PXRD is similar to Crystalline form-I of Lercanidipine Hydrochloride, depicted
in figure-3.
Yield: 105 g
15 Example-13: Preparation of Crystalline form-I of Lercanidipine hydrochloride.
A round bottom flask was charged with compound of formula-1(100 g), methanol (400 mL),
and stirred for 45 min at 40-50°C. The reaction mixture was filtered through micron filter,
washed washed with methanol (50 mL). The organic layer was distilled completely, charged
with ethyl acetate (50 mL) and distilled off completely. The resulting compound was charged
20 with ethyl acetate (500 mL) and heated to 45-55°C, stirred for 45 min. Cooled the reaction
mixture to 23-33°C, stirred for 5 hr and heated to 65-75°C, charged with ethanol (100 mL)
and stirred for 1.5 hr at same temperature. The reaction mixture was cooled to 25-35°C,
filtered the obtained solid was washed with ethyl acetate (100 mL) and dried to get the title
compound.
25 Yield: 89 g ,CLAIMS:We claim
1. A process for the preparation of compound of formula-3
5 Formula-3
comprising of:
a) Reacting the compound of formula-2
Formula-2
10 with 1-chloro-2-methylpropan-2-ol in presence of suitable base without any solvent to
produce compound of formula-3, at a suitable temperature,
Formula-3
2. The process according to claim 1 wherein in step-a) the suitable base is selected from
15 inorganic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide; sodium
carnonate, potassium bicarbonate, suitable temperature 10-100°C.
3. A process for the preparation of compound of formula-3,
comprising of:
a) Reacting the compound of formula-2,
20
Formula-2
22
with 1-chloro-2-methylpropan-2-ol in presence of sodium hydroxide at 60-70°C to produce
compound of formula-3.
Formula-3
5
4. An improved process for the preparation of compound of formula-1
Formula-1
10
comprising of:
a) Reacting the compound of formula-4
Formula-4
15
with methyl-3-oxobutanoate in presence of piperidine in acetic acid to provide compound of
formula-4a, further reacting in-situ with methyl-3-oxo butanoate, ammonium acetate in water
to get compound of formula-5,
20
Formula-4a
23
Formula-5
b) hydrolysing the compound of formula-5 with sodium hydroxide in methanol, toluene to
provide 5 compound of formula-6,
Formula-6
c) reacting the compound obtained in step-b) with compound of formula-3,
10
Formula-3
in presence of thionyl chloride, in dichloromethane followed by acidification with Con.HCl
to provide compound of formula-1.
15
Formula-1
20
24
5. A process for the preparation of amorphous form of Lercanidipine hydrochloride.
5 Formula-1
comprising of ;
a) Stirring the lercanidipine hydrochloride in a suitable solvent at suitable temperature,
b) isolating the compound obtained in step-a) in suitable solvent to get the amorphous form
10 of compound of formula-1,
Formula-1
15 6. The process according to claim 5 wherein in step-a,b) suitable solvents refer as
hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petether, toluene and the
like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate
and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone
and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
20 phenol, or glycerol, water and mixture thereof; suitable temperature 0 to 100°C.
wherein in step-b) isolation process is by evaporation, filtration.
25
7. A process for the preparation of amorphous form of Lercanidipine hydrochloride.
comprising of ;
a) Stirring the lercanidipine hydrochloride in methanol at 40-50°C,
b) evaporating the solution and stirring in ethyl acetate at 45-55°C,
c) heating the solution 5 of step-b) at 65-75°C,
d) filtering the compound obtained in step-c) to get the amorphous form of compound of
formula-1a.
10
Dated this day 06- Apr-2021.
15
Authorized Signatory
(Chakilam Nagaraju)
Maithri Drugs Private Limited