FORM 2 THE PATENT ACT 70
(ACT 39 of 70)
COMPLETE SPECIFICATION
(SECTION 10)


AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE AND ITS PHARMACEUTICALLY ACCEPTABLE
\ SALTS

UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT MAHALAXMI CHAMBERS,
,ND
FLOOR; 22, BHULABHAIDESAI ROAD, MUMBAI- 400 026. MAHARASHTRA, INDIA.

Background of the invention: -
The invention relates to an improved process for the preparation of 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5-methyl ester and its pharmaceutically acceptable acid addition salts thereof. The 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5 methyl ester which is currently known as Amlodipine, prepared by the process of the present invention which has the formula-I is a medicine useful as (β-blocker.

I
Prior art
EP patent 089 167 and corresponding U.S.pat.No. 4,572,909 disclose a class of substituted dihydropyridine derivatives as being useful as calcium channel blockers. These patents identify that one of the most preferred compounds falling under this class is 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) l,4-dihydro-6-methyl-3,5-pyridinedicarboxyhc acid-3-ethyl 5-methyl ester (amlodipine) , has the formula-I as given above.
The maleate salt of the compound of the formula I is identified as one of the most preferred acid addition salt.
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WO patent no 02053542 which is corresponding to the US patent 2002/0086888 describes the preparation of amlodipine maleate which comprises reacting amlodipine or an acid addition salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product .It is mentioned in this patent that this process results in a product substantially free from amlodipine aspartate
Another WO patent no 02/ 053535 which is corresponding to the US patent No 2002/0143046 describes the preparation of compounds of the formula-II

Formula II
3
wherein R 2 is a C1 to C4 alkylgroup , which includes amlodipine maleate The process comprises reacting O -chloro benzaldehyde with a compound of the formula III


Subsequently, EP patent NO 244944 and corresponding U.S. pat.No. 4,879,303 were issued which were directed to the besilate (or benzene sulfonate) salt. Amlodipine of the formula I which is prepared by the reaction of amlodipine base with maleic acid in the presence of industrial methylated spirit at 5 °C.
The besilate salt is stated to provide certain advantage over the known salts including amlodipine maleate.
Various amlodipine salts were also reported in the said patent and compared for their water solubility, non-hygroscopicity, and processability for tablet formation.
EP 0089167 patent describes that phthaloyl amlodipine is stirred with 33% ethanolic methyl amine solution at room temperature for three hours, the solvent is evaporated and the residue was slurried in industrial methylated spirit then filtered, to the filtrate maleic acid is added and after stirring a precipitate was produced.
The major draw back of the process disclosed in this EP patent no 089167 is that the by-product of the reaction between phthaloyl amlodipine and methylamine i.e. the N-methyl phthalimide is not eliminated out of the reaction mixture before the formation of maleate salt, which causes isolation problem of the maleate salt and is difficult to scale up on commercial scale.
Therefore the main objective of the present invention is to provide an improved process for the preparation of amlodipine maleate i.e. 2-[(2-
4

aminoethoxy)methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5-methyl ester maleate salt of the formula I overcoming the drawbacks of the prior art processes.
Another objective of the present invention is to provide an improved process for the preparation of amlodipine maleate of the formula I on a commercial scale, which is simple and cost effective.
Still another objective of the present invention is to provide an improved process for the preparation of amlodipine maleate of the formula I wherein the process is performed without the isolation of any of its intermediates i.e. making the process a one pot reaction , thereby making the process simple and economical.
Yet another objective of the present invention is to provide an improved process for the preparation of amlodipine maleate of the formula I wherein the purification of the amlodipine maleate is effected in such a way that the impurity amlodipine aspartate in the maleate salt is not more than 0.1%.
The process of the present invention has been developed, based on our finding, due to extensive R&D carried out, that it can be prepared in four steps, namely reacting 3-ethyl 5-methyl (4RS)-4-(2-chlorophenyl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]methyl]-1,4-dihydropyridine-3,5-dicarboxylate i.e. phthloyl amlodipine with methyl amine solution to get the partially opened 5-ethyl 3-methyl (4RS)-4-(2-chlorophenyl)-2-methyl-6-[[2-[[2-(methylcarbomyl)benzoyl]amino]ethoxy] methyl]-l,4-dihydropyridine-3,5-dicarboxylate i.e. amide derivative of
5

opened phthaloyl amoldipine, which under goes rearrangement to cleave the N-methyl phthalimide part to get 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxyhc acid-3-ethyl 5 methyl ester i.e. amlodipine base in the form of a solution in the solvent used, reacting the free base with maleic acid to get the amlodipine maleate, which can be purified in a solvent to get the required purity product. The complete synthetic route is according to the present invention as explained below



Detailed description of the present invention
Accordingly the present invention provides an improved process for the preparation of 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5 methyl ester of the formula-I

I and its pharmaceutically acceptable acid addition salt thereof which
comprises
(i) Reacting 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-
methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine with
methylamine solution in a polar solvent in the presence of water immiscible solvent and stirring the reaction mixture thoroughly.
(ii) Adding water to the reaction mixture and separating the solvent layer from the aqueous layer to remove the N-methyl phthalimide, byproduct.
(in) Washing the organic layer with water to remove the left over of N-methyl phthalimide, by product followed by drying the organic layer with anhydrous sodium sulfate to get the free base of amlodipine in the organic solvent.
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(iv)Adding the required quantity (based on molar equivalent) of maleic acid to the resultant base to get the amlodipine maleate and if desired.
(v) Converting the amlodipine base into its pharmaceuticaUy acceptable salts by conventional methods
The process of the present invention has the advantage that the by product (N-methyl phthalimide) formed during the reaction is eliminated during water washing as a water immiscible solvent is used in the reaction, this enables a reasonably pure amlodipine base in a organic solvent and then the required salt is prepared without the isolation of free base.
The polar solvent used in step (i) may preferably be alcohol based and more preferably methanol, ethanol or isopropanol . The water immiscible solvent such as hydrocarbon, chlorinated hydrocarbon, esters, ether may also be used
The stirring in the step (i) may be effected for a period in the range of 6-10 hrs. The reaction is monitored with the help of HPLC system and with the help of same system the quantity of base present in the reaction mixture is determined and then the calculated quantity of molar equivalent maleic acid is used for the preparation of maleate.
In a preferred embodiment of the invention the amlodipine maleate formed may be filtered, washed with solvent and dried. The amlodipine maleate
8

formed may also be further purified by recrystalisation from an alcoholic solvent preferably alcohol based and more preferably methanol.
In another preferred embodiment of the invention the amlodipine base formed may be converted into its pharmaceutically acceptable salts by adding the required quantity (based on molar equivalent) of acid to the resultant base .The acid used may be selected from maleic acid, benzene sulphonic acid, methane sulphonic acid, succinic acid and the like. The salts obtained are maleate, besilate, mesilate, succinate, and the like. The base and the salts obtained may then be purified, if required, by recrystalisation from an alchoholic solvent. The alchoholic solvent such as methanol, ethanol, isopropanol etc. may be used for this purpose
The details of the process of the present invention are given in the Examples given below which are provided solely for the purposes of illustration and therefore should not be construed to limit the scope of the present invention
9

Example 1
Preparation of 2-[(2-Aminoethoxy) methyI]-4-(2-chlorophenyI)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyI 5 methyl ester maleate salt
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-
methoxycarbonyl-6-methyl-2'(2-phthahmidoethoxy)methyl-1,4-
dihydropyridine (100 gms) was suspended in methylene chloride (500 ml)
and stirred to get a clear solution. 30% methylamine solution in methanol
(200 ml) was added to the resulting reaction mixture. The reaction mixture
was stirred for 6 hrs at ambient temperature. Water (500 ml) was added to
the reaction mixture, stirred for 15 mins and separated the layers. The
methylene chloride layer was further washed twice with water, dried over
anhydrous sodium sulphate. Maleic acid was then added to the dried layer
(the quantity of maleic acid required was calculated on the basis of the base
content in the reaction mixture estimated by HPLC method) at ambient
temperature, stired the reaction mixture for 1-2 hrs, filtered the separated
product, washed with methylene chloride (100 ml) and dried. Yield of 2-[(2-
Aminoethoxy) methyl]-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-
pyridinedicarboxylic acid-3-ethyl 5-methyl ester maleate salt was above 90% and had purity above 99%.
Example-2 :-
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (100 gms) was suspended in toluene (500 ml) and stirred. 30% methylamine solution in methanol (200 ml) was added to the resulting
10

reaction mixture. The reaction mixture was stirred for 6 hrs at ambient temperature. Water (500 ml) was added to the reaction mixture, stirred for 15 mins and separated the layers. The toluene layer was further washed twice with water, and dried over anhydrous sodium sulphate. Maleic acid was added to the dried reaction mixture (the quantity of maleic acid required was calculated on the basis of the base content in the reaction mixture estimated by HPLC method) at ambient temperature stirred for 1-2 hrs, filtered the separated product, washed with toluene (100ml) and dried. Yield of 2-[(2-Aminoethoxy) methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5 methyl ester maleate salt was above 90% and the purity was above 99%.
Example-3 ;-
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-memoxycarbonyl-6-methyl-2-(2-phmalimidoethoxy)methyl-l,4-dihydropyridine (100 gms) was suspended in ethyl acetate (500 ml). 30% methylamine solution in methanol (200 ml) was added to the resulting reaction mixture. The reaction mixture was stirred for 6 hrs at ambient temperature. Water (500 ml) was added to the reaction mixture, stired the reaction mixture for 15 mins and separated the layers. The ethyl acetate layer was further washed twice with water, dried over anhydrous sodium sulphate Maleic acid was added to the reaction mixture (the quantity of maleic acid required was calculated on the basis of the base content in the reaction mixture estimated by HPLC method) at ambient temperature. Stirred for 1-2 hrs, filtered the separated product, washed with ethyl acetate (100 ml) and dried. Yield of 2-[(2-Aminoethoxy) methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5 methyl ester maleate salt was above 90% and purity was above 99%.
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ExampIe-4
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (100 gms) was suspended in Methylene chloride (500 ml). 30% methylamine solution in methanol (200 ml) was added to the reaction mixture. The reaction mixture was stirred for 6 hrs at ambient temperature. Water (500 ml) was added to the reaction mixture, stired the reaction mixture for 15 mins and separate the layers. The methylene chloride layer was further washed twice with water, dried over anhydrous sodium sulphate. Maleic acid was added to the reaction mixture (the quantity of maleic acid required was calculated on the basis of the base content in the reaction mixture estimated by HPLC method) at ambient temperature stirred for lhrs, the solvent was evaporated to dryness and the residual product was taken up in methanol 500 ml heated to get a clear solution cooled to 0-5 °C and filtered to get 2-[(2-Aminoethoxy) methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5 methyl ester maleate salt . Yield was above 90% and purity was above 99%.
Such a procedure improves the filtration rate as compared to the processes exemplified in Examples 1,2 or 3.
Example-5 :-
Preparation of 2-[(2-Aminoethoxy) methyI]-4-(2-chlorophenyI)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5 methyl ester besilate salt
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxy carbonyl-6-memyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (100 gms) was suspended in methylene chloride (500 ml)
12

and stir to get a clear solution. 30% methylamine solution in methanol (200
ml) was added to the resulting reaction mixture. The reaction mixture was
stirred for 6 hrs at ambient temperature. Water (500 ml) was added to the
reaction mixture, stirred the reaction mixture for 15 mins and separated the
layers. The methylene chloride layer was washed twice with water, dried
over anhydrous sodium sulphate. Benzene sulphonic acid was added to the
dried layer (the quantity of Benzene sulphonic acid required was calculated
on the basis of the base content in the reaction mixture estimated by HPLC
method) at ambient temperature stirred for 1-2 hrs, filtered the product,
washed with methylene chloride 100 ml and dried. Yield of 2-[(2-
Aminoethoxy) methyl]-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-
pyridinedicarboxylic acid-3 -ethyl 5-methyl ester besilate salt was above 90% and had purity above 99%
Example-6:
-Preparation of 2-[(2-Aminoethoxy) methyl]-4-(2-chlorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyI 5 methyl ester succinate salt.
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-memoxycarbonyl-6-memyl-2-(2-phmalimidoethoxy)methyl-1,4-dihydropyridine (100 gms) was suspended in methylene chloride (500 ml) and stirred to get a clear solution. 30% methylamine solution in methanol (200 ml) was added to the resulting reaction mixture. The reaction mixture was stirred for 6 hrs at ambient temperature. Water (500 ml) was added to the reaction mixture, stirred the reaction mixture for 15 mins and separated the layers. The methylene chloride layer was washed twice with water, dried over anhydrous sodium sulphate. Succinic acid was added to the dried layer (the quantity of succinic acid required was calculated on the basis of the base
13

content in the reaction mixture estimated by HPLC method) at ambient temperature stirred for 1-2 hrs, filtered the separated product, washed with methylene chloride 100 ml and dried. Yield of 2-[(2-Aminoethoxy) methyl]-4-(2-chloro phenyl) l,4-dihydro-6-methyl-3,5-pyridinedicarboxyhc acid-3-ethyl 5-methyl ester succinate salt is above 90% and have Purity above 99% The above product was further purified in water at higher temperature followed by recrystalisation in isopropanol.
Example-7: -
Preparation of 2-[(2-Aminoethoxy) methyl]-4-(2-chIorophenyl)l,4-dihydro-6-methyl-3,5-pyridinedicarboxyIic acid-3-ethyl 5 methyl ester mesilate salt
In a 2 lits round bottom flask 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-
methoxy carbonyl-6-methyl-2-(2-phthalimido ethoxy) methyl-1,4-
dihydropyridine (100 gms) was suspended in methylene chloride (500 ml)
and stirred to get a clear solution. 30% methylamine solution in methanol
(200 ml) was added to the resulting reaction mixture. The reaction mixture
was stirred for 6 hrs at ambient temperature. Water (500 ml) was added to
the reaction mixture, stirred the reaction mixture for 15 mins and separated
the layers. The methylene chloride layer was washed twice with water, dried
over anhydrous sodium sulphate. Methane sulphonic acid was added to the
dried layer (the quantity of methane sulphonic acid required was calculated
on the basis of the base content in the reaction mixture estimated by HPLC
method) at ambient temperature stirred for 1-2 hrs, filtered the separated
product, washed with methylene chloride 100 ml and dried. Yield of 2-[(2-
Aminoethoxy) methyl]-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-
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pyridinedicarboxylic acid-3-ethyl 5-methyl ester mesilate salt was 90% and had purity above 99%
Example-8 ;-
Purification of products obtained in Examples 1 to 4
The product obtained by the process described in the Examples 1 to 4 can be further purified by recrystallization in methanol by following the method described below
Take 100 gm of the product obtained in Example 1 in 500 ml methanol. The reaction mixture is heated to a temperature in the range of to 55-60 °C to get a solution, filter the reaction mixture to get clear solution. The reaction mixture is chilled to 0-5 °C, filter the separated solid, dried to get pure product of purity above 99% (the point in purification is to remove if any fibrous or suspended particles if present in the product. Even though the purity may not increase or decrease but it is required on the commercial scale).
Following the similar procedure the compounds prepared by the process described in Examples 2 to 4 can also be purified • Advantages of the present invention.
a. The process is a one-pot reaction, which makes it simple and
economical.
b. The purity of amlodipine maleate prepared is not less than 99% The
impurity in the amlodipine maleate prepared is not more than 0.1%.
c. The process is useful for commercial production of amlodipine
maleate.
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We Claim -
1. An improved process for the preparation of 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxyUc acid-3-ethyl 5 methyl ester of the formula I

I and pharmaceutically acceptable acid addition salt thereof, which comprises, i. reacting 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbony 1-6-
methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine with
methylamine solution in polar solvent in the presence of a water
immiscible solvent ii. Adding water to the reaction mixture and separating the solvent layer
from the aqueous layer iii. Washing the organic layer with water followed by drying with
anhydrous sodium sulfate to get the free base of amlodipine in the
organic solvent iv. Adding the required quantity (based on molar equivalent) of maleic
acid to the resultant base to get the amlodipine maleate and if desired v Converting the amlodipine base into its pharmaceutically acceptable
salts by conventional methods
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2. An improved process as claimed in claim 1 wherein the polar solvent used in step (i) is alcohol based, preferably methanol, ethanol or isopropanol.
3. An improved process as claimed in claims 1 & 2 wherein the water immiscible solvent such as hydrocarbon, chlorinated hydrocarbon, esters, ether is used.
4. An improved process as claimed in claims 1 to 3 wherein the stirring in the step (i) is effected for a period in the range of 6-10 hrs.
5. An improved process as claimed in claims 1 to 4 wherein the amlodipine maleate or the other salt formed is filtered, washed with solvent and dried.
6. An improved process as claimed in claims 1 to 5 wherein the amlodipine maleate or other salts formed is purified by recrystalisation from a solvent or a mixture of solvents.
7. An improved process as claimed in claim 6 where in the solvent used for purification is alcohol based, preferably methanol.
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8. An improved process for the preparation of 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5-methyl ester of the formula I and its pharmaceutically acceptable salts substantially as herein described with reference to the Examples 1 to 9
Dated this day of 2004

( K. SUBHARAMAN)
( COMPANY SECETARY )
UNICHEM LABORATORIES LIMITED