FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES , 2003
PROVISIONAL / COMPLETE SPECIFICATION.
(See sectionIO RULE 13]
1. Title of the invention : This invention relates to " a process for purification of amlodipine besylate in an aqueous medium devoid of alcoholic solvents to avoid tranesterification."
2. We, M/s. J. B. CHEMICALS a PHARMACEUTICALS LIMITED, an Indian Company, having its Registered Office at Neelam Centre, B' Wing, 4th floor, Hind Cycle Road, Worli, Mumbai 400 030, Maharashtra, India.
3. The following specification particularly describes and ascertains
the nature of this invention and the manner in which it is to be performed.
Dated this 23rd day of November 2006.
J.B.CHEMICALS a PHARMACEUTICALS LTD.
SHIRISH BHAGWANLAL MODY DIRECTOR.
To:
The Controller of Patents
The Patent Office
Mumbai.

Field of the Invention
The present invention in general relates to a process for preparing Amlodipine Besylate. In particular, the present invention relates to a process for purification of amlodipine besylate in an aqueous medium devoid of alcoholic solvents to avoid tranesterification.
Background of the Invention
The preparation of Amlodipine Besylate is disclosed in EP 0089167 as a novel substance useful as antihypertensive and antiishemic agent and also as an efficient blocking calcium canals. According to EP 0089167 disclosure amlodipine can be prepared by the removal of amino protecting group from the precursor of amlodipine, that is, 1, 4-dihydro derivative, wherein the 2-standing amino group is protected by selected protecting groups. In one of exemplified examples, the amino group is protected by benzyl group, wherein the latter is removed by catalytic hydrogenation with Pd charcoal in suitable solvents such as methanol. In another example, the protecting group is a phthalimido group, wherein the phthaloyl moiety of this group is removed by primary amine such as methyl amine or hydrazine hydrate in a solvent such as ethanol or with alkali metal hydroxides such as potassium hydroxide, followed by the reaction with any mineral acids such as hydrochloric acid or sulfuric acid in presence of tetrahydrofuran and water at room temperature or elevated temperature.
In EP 0244944, amlodipine besylate is prepared by reacting amlodipine in its free base form with benzenesulfonic acid or ammonium benzenesulfonate in an inert solvent such as industrial methanol at a temperature of 5°C. This salt is particularly preferred for preparing amlodipine pharmaceutical dosage forms due to good water solubility, high stability, non-hygroscopicity and comparatively good properties for manufacturing.
According to the GB 2188630 there is provided a method to produce amlodipine salt by means of the reaction of amlodipine base with the solution of benzene sulfonic acid and or its ammonium salt using some inert solvent like ethyl alcohol, denatured methyl alcohol. The
- 1 -

method has disadvantageous using solvents like PMA contain moisture which can hydrolyze and cause instability of the product.
In EP 0599220, amlodipine besylate is prepared by reacting amlodipine precursor, that is, 3-ethyl 5-methyl (+/-)2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate obtained via Hantzsch method with benzenesulfonic acid in methanol or water-methanol medium at a temperature between 20° C and reflux temperature, followed by isolation and purification if amlodipine besylate. The process is characterized by good overall yields of desired chemical compound, avoidance of work with some toxic and cancerous chemicals, disclosed in the EP 0089167. According to the disclosure of the EP 0599229, amlodipine base is generally not obtained by the process of substance converting.
US 20050137405 is directed to a method to produce high purity amlodipine maleate salts and emphasis on amlodipine phthalloyl quality below 1.0% or 0.5% by HPLC. According to the disclosure, transesterification impurity side product is generated during the deprotection step or any later processing step. The possibility is further increased, either by the disclosed process or the prior methods, when an alcoholic solvent such as ethanol, isopropyl alcohol, methanol, etc. is used. Transesterification reactions may appear in whatever production step in the production of phthalimido amlodipine.
PCT publication no WO 06/003672 discloses the preparation of Amlodipine base via purification of phthalimido Amlodipine in binary solvent system such as chlorinated hydrocarbons and hexane usually binary systems are not preferred in large scale synthesis. Subsequently phthalimido Amlodipine converting into Amlodipine Base using alcohol base solvent at final step may leads to transesterification impurity.
-2-

Summary of the Invention
In prior art, the preparation of Amlodipine phthalimido and Besilate salts suffers from the drawbacks with extensive work-up viz; extraction with solvents, evaporation till precipitation followed by use of alcohol. Further insitu operations of Amlodipine base which may results side products/ impurities.
In the present invention, there is no use of alcohol solvents in overall preparation of Amlodipine Besylate from its phtalloyl salt. Amlodipine base is isolated with no solvent and subsequent purification in hydrocarbons to avoid organic volatile impurities. Further Amlodipine base is converting into Amlodipine Besylate with benzene sulfonic acid in aqueous media and again purification in hot water only.
Detailed Description of the Invention
The present invention of the process provides the simple purification process of phthalimido Amlodipine and its use for the preparation of Amlodipine Besylate without using alcohol solvents or any other organic solvent(s).
In industrial production of this product, impurities/side products may appear can undergo transesterification especially when an alcohol solvent is employed as disclosed in US 20050137405. In the present embodiment there is no use of alcohol solvents in overall preparation of amlodipine besylate from its phtalloyl salt. Amlodipine base is isolated with no solvent and subsequent purification in hydrocarbons to avoid organic volatile impurities. Further Amlodipine base is converting into Amlodipine Besilate with benzene sulfonic acid in aqueous media and again purification in hot water only.
Surprisingly the process of the present invention allows for the formation of the compound in a satisfactory pure form with total impurity 0.3% even less than 0.2% based on its assay includes thin layer chromatography (TLC) and high performance liquid chromatography (HPLC).
- 3-

Thus according to present invention to produce Amlodipine Besilate, at first 1,4-dihydro pyridine prepared via Hantzsch reaction for preparing diesters with 4-[2-(phthalimido)ethoxy] acetoacetate, methyl-(E)-3-amino crotonate and 2-Chlorobenzaldehyde in alcohol at reflux temperature followed by removal of solvent and treating with acetic acid provides 2-[2-(N-phthalimido)- ethoxy methyl]-4-(2-chlorophenyl)-1,4-dihydro-6- methyl-3,5-pyridinecarboxylic acid. The Amlodipine phthalimido salt is suspended in solvent preferably a hydrocarbon, to get purified compound which upon reaction with mono methyl amine affords Amlodipine base. To remove any organic volatile impurities base is dissolved in hydrocarbon solvent like toluene, distilled and teuterated in solvent(s) preferably a hydrocarbon like n- hexane, n-heptane or benzene. The resulting Amlodipine Benzenesulfonate is prepared by the reaction of purified Amlodipine base with benzene sulphonic acid in water at 25-30° C, the resulting compound was isolated and purified into hot water afford the pure Amlodipine Besilate .
In operation, phthalimido amlodipine is isolated and dried after slurification in hexane to remove insoluble impurities followed by formation of amlodipine base in mono methyl amine. Amlodipine base crude is dissolved in a hydrocarbon such as toluene and teuterated with second hydrocarbon based solvent like n-heptane or n-hexane to obtain pure amlodipine base after isolation and drying. The purified amlodipine base is reacted with benzene sulphonic acid in water to form amlodipine besylate having high purity with impurities below 0.3%. The present process involves remote possibility of transesterification at final or previous steps since no alcohol solvent(s) are used in the any of the steps.
Below are provided the detailed examples illustrating the present invention, which is not intended to restrict the scope of the present invention.
-4-

Example 01
4-[2-(phthalimido) ethoxy] acetoacetate (155 gm), methyl-(E)-3-arm'no crotonate(164 gm) and 2-Chlorobenzaldehyde(69 gm) in 667 ml isopropyl alcohol in a temperature range between 65° to 75°C for 20 hrs. Distilled out the solvent under vacuum below 75°C.Acetic acid (686 ml) is added to the residue and maintained at 6.0 hrs to 10 hrs at 25-30° C.Precipitation is filtered off and wash the cake with acetic acid. The wet cake is suspended in 560 ml hexane at 25-30°C and stir for 1.0 Hr then filtered off and cake is washed with n-Hexane (110 ml) at 25-30°C and dry till constant weight.
Dry wt of Phthalimido Amlodipine = 65 gm (Yield -31%)
Example 02
The Phthalimido Amlodipine, 50 gm (prepared in Example-01) is added to the mono methyl amine (500 ml) and maintained for 10 hrs at 25-30°C.The reaction mass is filtered off and cake wash with water.
Example 02(A)
The wet cake is dissolved in toluene (200 ml) and stir for 30 minutes at hot conditions. Distilled
out toluene under vacuum, cool the reaction mass and add 25 ml hexane at 25-30 °C. Filtered
the cake and dry under vacuum at 60-65°C till constant weight.
Dry wt of Amlodipine Base = 35 gm (yield-92.48%)
Example 03
29 gm Amlodipine Base prepared as above was suspended in purified water. A solution of 16.53
gm benzene sulfonic acid in 33.06 ml of water was prepared and adds into above suspension
under stirring. The reaction mass was stir for 24 hrs at 25-30°C.Filtered and wash cake with
water. The product was dried at 40-45 °C under vacuum till constant weight.
Dry wt of Amlodipine Besilate (Crude) = 38.57 gm (yield-96.37%)
- 5-

Example 04
The above prepared crude Amlodipine Besilate (38.57 gm) is suspended with 578.55 ml purified
water and heat to 80-85 °C activated charcoal treatment followed by cellite filtration while
hot and re precipitated product upon cooling 5-10°C. Filtered and wet cake is dry in vacuo at
60-65°C till constant weight.
Dry wt of Amlodipine Besilate (Pure) = 30.56 gm (yield-79.23%)
m.p. - 199-200°C; Purity- 99.78 %( assay by HPLC)
The pure Amlodipine Besilate is identified by its characteristic x-ray diffraction pattern, confirmed as polymorphic Form-01). Further its characteristics are confirmed by IR spectrum and DSC (differential scanning calorimeter).
-6-

Claims
We claim
1. A process for preparation of compound of the formula

Me.Y >--.^-o"-^-' NM,SO-H
MeOOC' v-^^COOEi ^<\ "~"^/
k *^>
or its phthalloyl salt is purified in solvent(s) hydrocarbon i.e. hexane and base is isolated which is further purified in hydrocarbon(s) such as toluene , n-heptane & n-hexane.
2. The Amlodipine Base as claimed above is then converted into benzene sulfonic acid salt, wherein the converting of substance is performed in aqueous media at a temperature 40-50°C and reflux temperature followed by isolation 6t purification of compound.
3. The method according to claim 1 comp arises in that the volume of water for crystallization is about 10 volumes to 18 volumes with respect to its crude salt preferable 14 times.
4. A process as claimed in claim 1, wherein the addition of hydrocarbon based solvent(s) such as toluene, hexane & benzene; first to dissolve base and then re precipitated to get pure Amlodipine Base.
5. The use according to claim 3 where in benzene sulphonate containing overall impurities less than 0.3% and individual less than 0.1% with a pharmaceutical^ acceptable salt.
Dated this 23rd day of November, 2006.
For J.B.CHEMICALS a PHARMACEUTICALS LTD
SHIRISH BHAGWANLAL MODY DIRECTOR.

Abstract
A process for the preparation of 3-ethyl 5-methyl (+/-)2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, Amlodipine Besilate, formula (I) and its novel purification in aqueous medium to avoid transesterification.
-8-