Title of Invention	IMPROVED PROCESS FOR PREPARATION OF AMLODIPINE SALTS
Abstract	1 A process for preparation of a compound of formula (I) where X represents maleate, mesylate, besylate, malate or fumarate anion by subjecting a compound of formula (II) to a deprotection reaction and isolating the salt in pure form without isolating the Amlodipine free base

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "IMPROVED PROCESS FOR PREPARATION OF AMLODIPINE SALTS" (a) CIPLALTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: TECHNICAL FIELD The invention relates to an improved process of preparation of amlodipine salts. Amlodipine is chemically described as 2-[2-(amino ethoxy) methyl]-4-(2-chlorophenyl)-3-ethoxy carbonyl-5-methoxy carbonyl-6-methyl-l, 4-dihydropyridine (I). where X represents maleate, mesylate ,besylate, fumarate or malate anions and is useful in the treatment of hypertension and angina. BACKGROUND AND PRIOR ART A number of patents describe the synthesis of amlodipine and its salts, namely the maleate, mesylate, besylate, fumarate and malate salts. Patent No. US 4,430,333 describe process for preparation of amlodipine salts and pharmaceutical compositions thereof for treating hypertension and ischaemia in animals. Patent No. US 5,389,654 reported a novel process for preparation of amlodipine mono benzene sulfonate. The said process comprises of reacting amlodipine with benzene sulfonic acid in methanolic or an aqueous methanolic medium at temperature from 20° C to reflux. Patent No. US 4,879,303 describe improved pharmaceutical salts of amlodipine, particularly the-besylate salt and pharmaceutical composition thereof in the form of tablet and capsule. This patent discloses single crystalline anhydrous besylate salt of amlodipine non-hygroscopic which is prepared by combining either benzene sulfonic acid or ammonium benzene sulfonate with slurry of amlodipine free base in industrial methylated spirit. EP 1,287,826 filed by Pfizer claimed a process for preparing free base amlodipine as well as -—its—besylate-Safts. These amlodipine free base as well as its salts are used to prepare medicament for the treatment of ischaemic heart disease or hypertension. GB2,188,630 reported improved besylate salts of amlodipine and pharmaceutical composition"thereof for anti-ischaemic and anti-hypertensive agent in the form of tablet. Patent number US 6,600,047 discloses the process for making amlodipine maleate which comprises of reacting amlodipine or an acid addition salt thereof with maleic acid. Also purification method for the same is reported in this patent. CSIR's patent US 6,608,206 describes a process for S (-) amlodipine salts such as besylate, I succinate, maleate, oxalate and tosylate in presence of an organic solvent and at room temperature. Acid to amlodipine is used in the ratio of 1:1 and water to solvent ratio used is Patent number US 6,518,288 claims amlodipine hemifumerate and crystalline salts thereof and process for the same. WO02,053,135 discloses pharmaceutical tablet composition comprising of an effective amount of amlodipine free base in crystalline form I and II with pharmaceutical^ acceptable, excipients. They also claimed the process for preparation of amlodipine free base and its method of crystallization for Form I and II. The said process comprising of deprotecting an N-protected amlodipine and precipitating amlodipine free base and isolation of the same. W003,004,025 describe a process for highly pure amlodipine benzene sulfonate salt and use of this salt to prepare medicament in the form of tablet for the treatment of heart disease or hypertension. Patent application number US 20020,068,831 discloses process for preparation of intermediates of amlodipine such as ethyl-3-amino-4-(2-(phthalimido)ethoxy)crotonate. Another application number US 20020,143,046 describe process for making amlodipine derivatives and precursor thereof. Pharmaceutically acceptable acid addition salts produced in this patent application are amlodipine maleate, mesylate or besylate. US2003 0,022,922 describes a process for preparation of crystalline amlodipine free base of Form I and II with particle size of at least 100 micron which is used to prepare the formulation in oral dosage form such as tablet with less stickiness and punch residue. Latest patent application in US20030,139,455 discloses process for preparation of crystalline amlodipine besylate hydrate (ie. Monohydrate and dihydrate) and amlodipine besylate anhydrates.* EP 244944, WO 02/053535 and WO 99/52873 describe a process to make amlodipine salts, namely the besylate by prior isolation of amlodipine free base. All the above patents, describe the isolation of amlodipine base after deprotection step using various deprotecting agents like monomethylamine, hydroxylamine -hydrochloride. Our process is an improved process over above reported process for amlodipine salts where . amlodipine free base isprepared and thereafter converted into the salts. Our present invention use a protected amlodipine as starting materials and convert the same into desired salt in one step in high purity and yield without isolating the free base. Summary of the Invention The present invention provides for an improved one pot process for preparation of amlodipine salts from the phthaloyl protected amlodipine (II) by a process comprising of deprotection of the phthalimido group and converting the free base thus obtained to the desired salt (I) without isolating the amlodipine free base. It was surprisingly found that this process gives yields that are at least 20% higher than the processes disclosed in the prior art patents In the newly developed process, phthaloyl amlodipine (II) is used as the starting material to prepare amlodipine (I) and its salts. Phthaloyl amlodipine (II) is treated with aqueous solutions of primary amines in water immiscible solvents such as methylene chloride, ethylene dichloride, chloroform ethyl acetate and toluene or alcoholic solutions of primary amines followed by treatment of the organic phase with suitable organic acids to give amlodipine in the form of its pharmaceutically acceptable salt. The product so obtained is purified using C-l to C-4 aliphatic alcohols, or esters or mixtures thereof to give amlodipine salt having uniform particle size, free flowing powder characteristics and low levels of impurities. Detailed Description In a preferred embodiment of the invention, a process is described for producing 2-[2-(aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine mesylate by the deprotection reaction of phthaloyl amlodipine (II) with aqueous monomethylamine in solvents selected from methylene chloride, ethylene dichloride, toluene, and chloroform, followed by treatment with methane sulfonic acid. Amlodipine mesylate thus produced may be crystallized from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(amino ethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine mesylate by the deprotection reaction of phthaloyl amlodipine (II) with methanolic monomethylamine followed by treatment with methane sulfonic acid. Amlodipine mesylate thus produced may be crystallized from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(amino ethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine besylate by the deprotection reaction of phthaloyl amlodipine (II) with aqueous monomethylamine in solvents selected from methylene chloride, ethylene dichloride, toluene, and chloroform, followed by treatment with benzene sulfonic acid. Amlodipine besylate thus produced may be crystallized from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(amino ethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine besylate by the deprotection reaction of phthaloyl amlodipine (IT) with methanolic mono methylamine followed by treatment with benzene sulfonic acid. Amlodipine besylate thus produced may be crystallized from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(amino ethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine malate by the deprotection reaction of phthaloyl amlodipine (II) with aqueous monomethylamine in solvents selected from methylene chloride, ethylene dichloride, toluene, and chloroform, followed by treatment with malic acid. Amlodipine malate thus produced may be purified from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(amino ethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine malate by the deprotection reaction of phthaloyl amlodipine (II) with methanolic monomethylamine followed by treatment with malic acid. Amlodipine malate thus produced may be purified from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine maleate by the deprotection reaction of phthaloyl amlodipine (II) with aqueous monomethylamine in solvents selected from methylene chloride, ethylene dichloride, toluene, and chloroform, followed by treatment with maleic acid. Amlodipine maleate thus produced may be purified from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine maleate by the deprotection reaction of phthaloyl amlodipine (II) with methanolic mono njethylamine followed by treatment with maleic acid. Amlodipine maleate thus produced may be purified from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine fumarate by the deprotection reaction of phthaloyl amlodipine (II) with aqueous monomethylamine in solvents selected from methylene chloride, ethylene dichloride, toluene, and chloroform, followed by treatment with fumaric acid. Amlodipine fumarate thus produced may be purified from suitable solvent or mixtures thereof. In another preferred embodiment of the invention, a process is described for producing 2-[2-(aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro pyridine fumarate by the deprotection reaction of phthaloyl amlodipine (II) with methanolic mono methylamine followed by treatment with fumaric acid. Amlodipine fumarate thus produced may be purified from suitable solvent or mixtures thereof The preferred solvent for the deprotection is methylene chloride. The reaction is carried out ambient temperature. After the deprotection reaction the aqueous phase containing mono methylamine is separated and the organic phase is washed with water to remove excess mono methylamine. The neutral organic layer is taken directly for salt formation or is partially replaced by another solvent before salt formation. The invention is further illustrated by the following examples The salt obtained is crystallized from C-l to C-4 alcohols or esters or mixtures thereof. Amodipine salts prepared by the process of the present invention are characterized by high purity of more than 99.7%. The product is further characterized by a very low level of the pyridine impurity (III), preferably the impurity is less than 0.1%. Examples Example 1 100 grams of phthaloyl amlodipine is stirred in a mixture of 40% aqueous monomethylamine (700 ml) and methylene chloride (500ml) at ambient temperature for 12 hours. After reaction completion, the MDC layer is separated and the organic layer is-washed with water. The MDC layer is dried over sodium sulfate and distilled to about half the original volume. Isopropyl alcohol (700 ml) is added and the distillation continued till a total volume of 600 ml is left behind. The contents are then cooled to 25 - 30°C. Benzene sulfonic acid (30 gm) is dissolved in 100 ml of isopropyl alcohol and is added to the above solution in 30 - 45 mins. at 25 - 30°C. Then the contents are stirred for 1 hour at 0 - 5 °C for 30 mins and filtered to give amlodipine besylate. Example 2 100 grams of phthaloyl amlodipine is stirred in 20% methanolic monomethylamine (1000 ml.) for 12 hours at room temperature. After reaction completion, the reaction mass is distilled to half of its original volume and 800 ml of MDC is added and further distilled till a total of 500 ml remains in the reaction flask. The MDC layer is washed with water and dried over sodium sulfate. The MDC layer is distilled to half the original volume. 800 ml isopropyl alcohol is added and further distilled till 600ml of solution is retained. The contents are then cooled to 25 - 30°C 30 gm of Benzene sulfonic acid dissolved in 100 ml of isopropyl alcohol is added to the above solution in 30 - 45 mins. at 25 - 30°C. Then the contents are stirred for 1 hour at 0 - 5 C for 30 mins. and filtered to give amlodipine besylate. This amlodipine besylate is dissolved in .300 ml of methanol at 40 - 45°C. 400 ml of isopropyl alcohol is added at 35 - 40°C. The contents are then stirred at 25 - 30°C for 1 hour, cooled and filtered. Example 3 100 grams of phthaloyl amlodipine is stirred in a mixture of 40% aqueous monomethylamine (700 ml) and methylene chloride (500ml) at ambient temperature for 12 hours. After reaction completion, the MDC layer is separated and the organic layer is washed with water. The MDC layer is dried over sodium sulfate and distilled to about half the original volume. Ethyl acetate (1000 ml) is added and the distillation continued till a total volume of 600 ml is left behind. The contents are then cooled to 25 - 30°C. Methane sulfonic acid (18 gm) is dissolved in 100 ml of ethyl acetate and is added to the above solution in 30 - 45 mins. at 20 - 25°C maintaining an inert atmosphere. Then the contents are stirred for 1 hour at 0 - 5 °C for 30 mins and filtered to give amlodipine mesylate Example 4 100 grams of phthaloyl amlodipine is stirred in 20% methanolic monomethylamine (1000 ml.) for 12 hours at room temperature. After reaction completion, the reaction mass is distilled to half of its original volume and 800 ml of MDC is added and further distilled till a total of 500 ml remains in the reaction flask. The MDC layer is washed with water and dried over sodium sulfate. The MDC layer is distilled to half the original volume. 1000 ml ethyl acetate is added and further distilled till 600ml of solution is retained. The contents are then cooled to 25 - 30°C. 18 gm of methane sulfonic acid dissolved in 100 ml of ethyl acetate is added to the above solution in 30 - 45 mins. at 20 - 25°C under an inert atmosphere. Then the contents are stirred for 1 hour at 0 - 5 °C for 30 mins. and filtered to give amlodipine mesylate. This amlodipine mesylate is dissolved in 900 ml of ethyl acetate, 100 ml methanol and 10ml purified water at 40 - 45°C. The contents are then stirred at 25 - 30°C for 1 hour, cooled and filtered. Example 5 100 grams of phthaloyl amlodipine is stirred in a mixture of 40% aqueous monomethylamine (700 ml) and methylene chloride (500ml) at ambient temperature for 12 hours. After reaction completion, the MDC layer is separated and the organic layer is washed with water. The MDC layer is dried over sodium sulfate and distilled to about half the original volume. Ethyl acetate (1000 ml) is added and the distillation continued till a total volume of 600 ml is left behind. The contents are then cooled to 25 - 30°C. Malic acid (17.8g) dissolved in 50ml of methanol and is added to above solution in 30-45mins at 25-30C. Then the contents were stirred at 25-30C for lhour and filtered to give amlodipine malate Example 6 100 grams of phthaloyl amlodipine is stirred in 20% methanolic monomethylamine (1000 ml.) for 12 hours at room temperature. After reaction completion, the reaction mass is distilled to half of its original volume and 800 ml of MDC is added and further distilled till a total of 500 ml remains in the reaction flask. The MDC layer is washed with water and dried over sodium sulfate. The MDC layer is distilled to half the original volume. 1000 ml ethyl acetate is added and further distilled till 600ml of solution is retained. The contents are then cooled to 25 - 30°C. Malic acid (17.8g) dissolved in 50ml of methanol is added to above solution in 30-45mins at 25-30C. Then the contents were stirred at 25-30C for lhour and filtered to give amlodipine malate. This amlodipine malate is stirred in 900 ml of ethyl acetate and 100 ml methanol at 40 - 45°C. The contents are then stirred at 25 - 30°C for lhour filtered. WE CLAIMS: 1 A process for preparation of a compound of formula (I) where X represents maleate, mesylate, besylate, malate or fumarate anion by subjecting a compound of formula (II) to a deprotection reaction and isolating the salt in pure form without isolating the Amlodipine free base 2. A process for preparation of compound of formula I as claimed in Claim 1 wherein the deprotection reaction is carried out in presence of a aqueous solution primary amine in a water immiscible solvent 3. A process for preparation of compound of formula I as claimed in Claim 2 wherein the primary amine is monomethyl amine 4. A process for preparation of compound of formula I as claimed in claim 2 wherein the water immiscible solvent is methylene chloride, ethyl acetate, toluene or chloroform 5. A process for preparation of compound of formula I as claimed in claim 1 wherein the deprotection reaction is carried out in presence an alcoholic solution of monomethyl amine 6. A process for preparation of compound of formula I as claimed in claim 5 where in the alcohol used is selected from methanol, ethanol or isopropanol 7. A process for preparation of compound of formula I as claimed in claim 1 wherein, the salt is crystallized from Cl to C4 alcohol or esters or mixtures thereof 8. A process for preparation of compound of formula I as claimed in claim 1 to 8 wherein the compound of Formula (I) has total impurities less than 0.3% and pyridine impurity (III) less than 0.1% 9. A process for preparation of compound of Formula (I) as claimed in claim 1 substantially described herein are with reference to the foregoing examples. To The Controller of Patents The Patent Office, At Mumbai.

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