Title of Invention	PROCESS FOR THE PREPARATION OF PURE AMLODIPINE
Abstract	The present invention relates to an improved process for the preparation of pue amlodipine via the effective purification of phthalimido (3-ethyl-5-methy 2-[(2-phthalimido ethoxy) mathy1]-4-(2-chloropheny)-1,4-dihydro-6mathy1-3,5-dicarboxylate).

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Field of the Invention The present invention relates to a novel process for the preparation of Amlodipine via the effective purification of phthalimido amlodipine. Background of the Invention: 3-Ethyl 5-methyl 2-[(2-phthalimidoethoxy) methyl]-4-(2-chlorophenyl)4,4-dihydro-6-methyl-3,5-pyridine dicarboxylate (herein after called as phthalimido amlodipine) has the following structure is an intermediate for the preparation of amlodipine, an active pharmaceutical ingredient, useful for treating cardiovascular diseases such as stenocardia, hypertension and congestive cardioplegia Particularly useful forms of amlodipine salts in human medicine are maleate, benzenesulfonate( besylate). European patent No 89,167 (equivalent U S patent No 4,572,909) discloses the preparation of phthalimido amlodipine and its conversion to amlodipine, its different pharmaceutical^ acceptable salt forms. In particular, amlodipine maleate salt was disclosed as being preferred salt than other pharmaceutically acceptable acid addition salts. European Patent No 244,944 (Equivalent U S patent No 4,879,303) discloses the benzenesulphonate (besylate) salt of amlodipine is the most preferred salt being its good formulation properties and disclosed the process for the preparation of amlodipine besylate by reaction of amlodipine base with benzene sulphonic acid in methanol. European Patent No. 89,167 discloses the preparation of phthalimido amlodipine by the reaction of ethyl4-[2-(phthalimido)ethoxy]acetoacetate with 2-chlorobenzaldehyde and methyl 3-amino crotonate in iso-propanol at reflux temperature for about 21 hrs followed by evaporation of iso-propanol, treating the residue with acetic acid overnight at RT affords the phthalimido amlodipine which upon reaction with methyl amine in ethanol followed by removal of solvent affords the amlodipine which is directly converted to maleate salt in methanol. The purity of the obtained maleate salt and the amlodipine was not disclosed. PCT Publication No WO 02/53535 discloses the preparation of phthalimido amlodipine by reaction of 4-[2-(phthalimido) ethoxy] acetoacetate with 2-chloro benzaldehyde in iso-propanol at temperature 35 - 40°C in presence of piperidine as catalyst followed by acidification with acetic acid, cooling to 0 - 5°C, separation of the organic layer, evaporation of solvent and isolation of the intermediate ethyl-2-(2-chlorobenzylidene)-4-[2-(phthalimido)ethoxy] acetoacetate which upon reaction with methyl 3-aminocrotonate in iso-propanol followed by removal of solvent and treating with acetic acid overnight affords the phthalimido amlodipine. The phthalimido amlodipine prepared as above is reacted with aqueous methylamine followed by extraction with an organic solvent. Separation of organic layer followed by evaporation until the precipitation occurs. The precipitated solid dissolved in ethanol and converted to pharmaceutically acceptable salts by reaction with suitable acids (Maleic acid). The prior art methods for preparation of phthalimido amlodipine suffers from the drawbacks of either with low purity or the use of extensive work-up, proceeds in two stages which requires the more processing time, usage of number of solvents. Further its conversion to amlodipine employs the extraction with organic solvent, evaporation till precipitation and then dissolving into a suitable alcohol then conversion to amlodipine salts. In this method the obtained amlodipine base or its salts may not be with good enough purity. To get the pure amlodipine base or its salts, it requires the further purification, which results lengthy process, loss in the yield thereby increasing the production cost. In view of the above problems still there is a requirement to get a pure phthalimido amlodipine and its use for the preparation of amlodipine, and its pharmaceutically acceptable salts with high purity. Summary of the invention: The main object of the present invention is to provide a process for the purification of phthalimido amlodipine and its use for the preparation of amlodipine and its pharmaceutically acceptable salts. Another object of the invention is to provide a process for the preparation of amlodipine and its pharmaceutically acceptable salts with high purity. Thus according to the present invention the 4-[2-(phthalimido) ethoxy] acetoacetate is reacted with 2-chlorobenzaldehyde, methyl 3-aminocrotonate in iso-propanol at reflux temperature followed by removal of solvent and treating with acetic acid at RT for overnight affords the phthalimido amlodipine, purified by dissolving in halogenated hydrocarbons, removal of insolubles, gradual addition of aliphatic hydrocarbons precipitates the phthalimido amlodipine in sufficient pure which upon reaction with methylamine in ethanol followed by quenching into hot water affords the pure, crystalline amlodipine which can be converted into its pharmaceutically acceptable salts with high purity i.e. all individual impurities below 0.1%. Detailed description of the Invention The essential features of the present invention consists of: - Purification of phthalimido amlodipine by dissolving it in a solvent(s), - Removal of insoluble matter - Slow addition of second solvent(s) to the clear solution - Mixing of the reaction mass for some time - Further slow addition of second solvent(s) - Mixing the reaction mass at selective temperature for some more time to complete the crystallization of the phthalimido amlodipine - Isolation and drying of the pure Phthalimido amlodipine - Reaction of phthalimido amlodipine with methyl amine in ethanol - Precipitation and Isolation of amlodipine base by quenching the reaction mass in hot water at selective temperature - Isolation and drying of amlodipine base - Optionally converting the amlodipine base thus obtained into its pharmaceutically acceptable salts The precipitated and isolated Amlodipine base is identified by its characteristic X-ray diffraction pattern; IR spectrum and melting range confirmed as polymorphic Form-I. The Phthalimido amlodipine used as starting material is prepared as follows. 4-[2-(phthalimido) ethoxy] acetoacetate is suspended in iso-propanol reacted with 2-chloro benzaldehyde and molar excess equivalents of methyl 3-aminocrotonate, preferably 1.5 mole equivalents to 3.0 mole equivalents wrt to 4-[2-(phthalimido) ethoxy] acetoacetate at temperature above 40°C, preferably about 70°C to about 83°C for about 12 hrs to 24 hrs. After the completion of reaction the iso-propanol was distilled off under vacuum. The residue is treated with acetic acid at RT for about 16 to 24 hrs crystallizes the crude phthalimido amlodipine. The phthalimido amlodipine thus obtained is purified by dissolving in 1 to 6 volumes and more preferably 1 to 3 volumes of the solvent(s), preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride, chloroform, tetrachloroethane, followed by removal of insoluble matter. To the clear filtrate slow addition of 1 to 20 volumes of second solvent(s) preferably a hydrocarbon like n-hexane, n-heptane, methyl cyclohexane, cyclohexane, n-pentane to the clear solution in lot wise over a period of 1 to 6hrs. Mixing the reaction mass for about 30 min to 3 hrs at temperature about 30°C to about 50°C, cooling and mixing the reaction mass to low temperature preferably to about 10°C to about 30°C for about lhr to about 5 hrs. Isolation and drying of the crystallized pure phthalimido amlodipine. The Phthalimido amlodipine upon reaction with methylamine in ethanol at reflux temperature followed by slow transferring of the reaction mass into water at selective temperature preferably at about 45°C to about 65°C precipitates the amlodipine base which can be converted into its pharmaceutically acceptable salts by conventional methods in pure form. The invention can be further illustrated by a few non-limiting examples. EXAMPLE Stage-1: Preparation of phthalimido amlodipine: 2-chlorobenzaldehyde (27 g) and methyl 3-amino crotonate (64.8 g) are added to the suspension of 4-[2-(Phthalimido) ethoxy] acetoacetate (60 g) in iso-propanol (300 ml). Temperature of the reaction mass is raised and maintained for 21 hrs at reflux temperature. Distilled off the solvent under vacuum at temperature below 75°C. Washed the residue with n-Hexane and again removed the low volatiles under vacuum to get residue. Acetic acid (300 ml) is added to the residue, mixed for 22 hrs at room temperature. Crystallized Phthaliimido amlodipine is filtered and washed the wet cake with acetic acid and n-Hexane. The wet cake is again mixed with methanol (150 ml) at room temperature for about 30 min, filtered and dried at 55°C - 60°C till constant weight. The dry wt of the phthalimido amlodipine crude is 26 g (Yield: 31.7%). Stage-2: Purification of phthalimido amlodipine: Phthalimido amlodipine (25 g) prepared as above in stage-1 is dissolved in MDC (50 ml) at 30°C - 35°C. Filtered the insoluble matter. n-Hexane (50 ml) is added to the filtrate slowly over lhr at 30°C - 35°C and mixed for another 2hrs. Again n-Hexane (50 ml) is added over 1 hr at 30°C - 35°C and maintained for another 2hrs at 20°C - 25°C. The precipitated product is filtered, washed the wet cake with n-Hexane and dried at 60°C - 65°C. Dry wt of the pure phthalimido amlodipine is 21.7 g (Yield: 87%). Stage-3: Preparation of Amlodipine from phthalimido amlodipine: Pure Phthalimido amlodipine (50 g) prepared as above is suspended in ethanolic methylamine (600 ml) and maintained for 17 hrs at 28°C - 32°C. The reaction mass is slowly poured into hot water (1200 ml) held at 50°C - 55°C over 45 min and mixed for about 1 hr at 50°C - 55°C. Reaction mass is slowly cooled and maintained for about 1 hr at 20°C - 25°C The precipitated solid is filtered, washed the wet cake with water. Dried the product at 55°C - 60°C till constant weight. Dry weight of the amlodipine base is 33.0 g (Yield: 87.2%). Purity : 99.7%(by HPLC) The XRD and IR of this product is matched with the standard data available for the Form-1 We claim: 1. An improved process for the preparation of Amlodipine comprising steps: - Dissolving phthalimido Amlodipine in an organic solvent(s), - Removing the insolubles (if any) by filtration - Slowly adding the second solvent(s) to the clear filtrate - Mixing the reaction mass for 30min to 3hrs - Further adding the second solvent(s) slowly - Mixing the reaction mass at selective temperature for some more time to complete the crystallization of the phthalimido Amlodipine - Isolating and drying of the pure phthalimido Amlodipine - Reacting phthalimido Amlodipine with methyl amine in ethanol - Precipitating and isolating Amlodipine base by quenching the reaction mass in hot water at temperature - Isolating and drying the Amlodipine base 2. A process as claimed in claim 1, wherein the organic solvent is selected from methylene chloride, ethylene chloride, chloroform and tetrachloroethane 3. A process as claimed in claim 1, wherein the organic solvent(s) volume is about 1 volume to 6 volumes with respect to phthalimido Amlodipine 4. A process as claimed in claim 1, wherein the second solvent is n-Hexane, n-Heptane, cyclohexane and methyl cyclohexane 5. A process as claimed in claim 1, wherein the addition of second solvent is slowly over a period of 1 to 6 hrs 6. A process as claimed in claims 1 and 6 wherein the volume of second solvent is 1 volume to 12 volumes with respect to phthalimido Amlodipine 7. A process as claimed in claim 1, wherein the hot water temperature is 45°C to 65°C

Documents:

542-che-2003-abstract.pdf

542-che-2003-claims duplicate.pdf

542-che-2003-claims original.pdf

542-che-2003-correspondnece-others.pdf

542-che-2003-correspondnece-po.pdf

542-che-2003-description(complete) duplicate.pdf

542-che-2003-description(complete) original.pdf

542-che-2003-form 1.pdf

542-che-2003-form 3.pdf