Title of Invention	PROCESS FOR INSITU PREPARATION OF AMLODIPINE BESYLATE
Abstract	A process for the insitu preparation of amlodipine salts from pthaloyl amlodipine is depthaloylated using aqueous mono methly amine and the base produced is extracted into an organic solvent.The desird amlodipine salt is producted by directly reacting the amlodipine solution with the appropriate acid.A Co-solvent can be used to dissolve the Acid.

Full Text

Field of the invention: The present invention relates to a process for insitu preparation of Amlodipine besylate and other pharmaceutically acceptable salts without isolating the amlodipine free base. The present invention particularly describes the acid addition salts of amlodipine viz., besylate, maleate and succinate salts. Background of the invention Amlodipine besylate is a long-acting calcium channel blocker. Amlodipine besylate is chemically described as (R/S) 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-K4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate and having the structural formula (1) below. wherein, X represents besylate, maleate and succinate anion. Amlodipine is used alone or in combination with other medications to treat high blood pressure and chest pain (angina). Amlodipine belongs to a class of medications called calcium channel blockers. It lowers blood pressure by relaxing the blood vessels so the heart does not have to pump as hard. It controls chest pain by increasing the supply of blood to the heart. The Commercial product containing Amlodipine besylate is available under the Brand name NORVASC ( Pfizer Inc). Amlodipine is a generic name for 3-ethyl 5-methyl (+A)-2-(2-aminoethoxy)methyI]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, and was disclosed as a novel substance in the European Patent EP-B-00 89 167 as a useful anti ischemic and antihypertensive agent. Also, pharmaceutically acceptable amlodipine acid addition salts were described, among which, maleate salt is particularly suitable. EP0089I67 disclosed 3 synthetic routes for the preparation of amlodipine maleate ie. 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxyarbonyl-6-methyl-l,4-dihydropyridine maleate. The deprotection of the phthaloyl group is achieved by three conventional methods viz., by using ethanolic methylamine or with hydrazine hydrate or with alkali metal hydroxide followed by acid treatment. Amlodipine Base produced upon dephthaloylation was isolated, and the pharmaceutically acceptable acid addition salts were prepared. These salts are prepared by slurrying the said base in industrial methylated spirit and treating with acids. US 4879303 describe the process for the preparation of besylate salt of amlodipine and pharmaceutical compositions thereof. Amlodipine besylate was prepared by two different methods viz., treating the amlodipine base with benzene sulphonic acid and ammonium benzene sulphonate in a solvent like industrial methylated spirit, WO02053135 describes study of amlodipine free base and its crystalline forms I and II. This patent taught the deprotection step of N- protected amlodipine; obtain the free base in solid state form. The solution from which amlodipine free base precipitates out can be the solution resulting from the deprotection step; or from a different solution like extraction solvent. The purification of amlodipine from a non-aqueous solvent is also disclosed. WO02053535 describes the preparation of amlodipine maleate by treating the phthalimido amlodipine with aqueous methylamine at 25°C for 24hrs. The free base was extracted with toluene, followed by distillation of the extracted layer under vacuum until the precipitation occurred. This base was further dissolved in Ethanol and the solution was filtered and then treated with the solution of maieic acid in ethanol to precipitate the maleate salt of amlodipine. The Amlodipine free base is not isolated by filtration, but the patent describes the precipitation of Amlodipine base solution in Toluene by vacuum distiHag£i&e*followed by further dissolution of the Base in ethanol. It amounts to isolation of the base prior to treatment with Maieic acid in ethanol EP 0599220 and Vj/003/004025 disclose a process for the preparation of amlodipine benzenesulphonate by the reaction of trityl-protected amlodipine base with benzenesuiphonic acid. The product was obtained in the form of a resin and the processing thereof is extremely complicated including continuous extraction of amlodipine besylate. Additionally the product is the dihydrate of Amlodipine besylate and an additional step is required to convert it to anhydrous form. WO 03/043635 describes additional forms of Amlodipine besylate and forms like crystalline hydrates and anhydrates and amorphous forms are described. The process involves conversion of Amlodipine Besylate to different forms. This patent reports the reaction of amlodipine base with Benzene Sulfonic acid in water or water alcohol mixtures at 40°C to precipitate the hydrate or anhydrate forms of amlodipine besylate directly from the solution depending upon the conditions employed. Pharmaceutical compositions contain amlodipine besylate hydrate and anhydrate along with the excipients is disclosed. All processes described in the prior art involve isolation of Amlodipine free base by filtration or concentration / evaporation of solvent used for extraction of Amlodipine free base. Even WO 02/ 053535 describes the precipitation of Amlodipine base by vacuum distillation of organic layer containing the Amlodipine base. Noxious vapours of Mono Methyl amine are produced during the processes of prior art except in the process described in WO 02/053535. All prior art processes involve additional steps like cooling, filtration, vacuum distillation leading to longer process times. It was therefore felt useful to develop an efficient industrial process for the preparation of amlodipine benzenesulfonate. The present invention is directed to prepare amlodipine and its acid addition salts in industrially viable and economically feasible manner by avoiding the drawbacks of the prior art, as described above. Objects of the invention It is an object of the invention to provide a simple insitii process for the preparation of amlodipine besylate salt with improved efficiency. Another object of the invention is to provide a process for amlodipine besylate with improved yield and with high purity. Further objective of the invention is to provide a simple insitu process for amlodipine other acid addition salts such as amlodipine maleate, and succinate. Further object of the invention is to avoid the use of methylamine directly, which produces hazardous vapors. Yet another objective is to prepare stable amlodipine besylate anhydrate. Summary of the invention The present invention discloses process for insitu preparation of amlodipine acid addition salts in anhydrated form without isolating the amlodipine base. The present invention particularly describes the acid addition salts of amlodipine viz., besylate, maleate and succinate salts. The deprotection step of phthalimido amlodipine was carried out by employing 40% aqueous monomethyl amine at a temperature range of 25 to 35°C, followed by stirring with organic solvent for 30 minutes. This organic layer was separated and washed with water followed by brine solution. Solution of benzene sulphonic acid in water / co solvent was added to the above solution and stirred for 3 hr to obtain the precipitated amlodipine besylate anhydrate salt without forming any byproducts thereby enhancing the throughput of the reaction.. The present process does not require the Amlodipine base to be precipitated before converting it to a salt. The process thus avoids the extra step like cooling, filtration, vacuum distillation etc. resulting in better recoveries of Toluene, reduction in process time etc. The amlodipine besylate salt as prepared by the above method is a highly stable anhydrate which does not absorb moisture even when exposed to high humidity of over 75% for prolonged periods. The present invention further discloses process for preparation of other amlodipine salts like amlodipine maleate and amlodipine succinate. Detailed description of the invention The present invention describes the insitu process for preparation of the amlodipine acid addition salts in anhydrate form with out isolating the amlodipine free base. The present invention particularly describes the acid addition salts of amlodipine viz., besylate, maleate and succinate salts. The preferred embodiment of the invention, a process is described for the preparation of amlodipine besylate by the deprotection reaction of phthalimido amlodipine with aqueous monomethylamine at a temperature range of 25-350C, extracted with organic solvent, followed by treatment with solution of benzene sulphonic acid to yield amlodipine besylate anhydrate. In another embodiment of the invention, a process is described for the preparation of amlodipine besylate by deprotection of phthalimido amlodipine aqueous monomethylamine at a temperature range of 25-35°C, extracted with organic solvent, followed by treatment with a clear solution of benzene sulphonic acid in acetone resulted into precipitated stable amlodipine besylate anhydrate. The organic solvent used to extract the amlodipine base from the reaction mass is selected from the// group consisting of methylenechloride, chloroform and ethylenedichloride, trichloroethyleneii tetrachloro ethane, toluene, xylene & Methyl Isobutyl Ketone. */ The co-solvent used to dissolve the benzene sulphonic acid is selected from ketonic solvent, which is selected from the group consisting of Acetone, Methyl Ethyl Ketone, Methyl Isobutyl Ketone, Cyclohexanone. The solvent preferably used is a mixture of methylenechloride and water in a ratio of from 2: 1 to 1: 2 vol/vol%. The mixture of solvent and co - solvent is in a ratio of from 2: I to 1: 2 vol/vol%. The amount of benzenesulphonic acid is at least a stoichiometric amount or a small excess of benzenesulphonic acid is to be used in the reaction and the reaction will complete within 3 to 4 hours. The product obtained in the present invention is crystalline Amlodipine besylate in an anhydrate form. So that the Amlodipine is not required to be further purified; thus saving time and energy and improving the overall economy of the amlodipine production. The above said process further used to prepare pharmaceutical^ acceptable acid addition salt of amlodipine such as hydrochloride, fumerate, maleate, mesylate and succinate thereof. All operations in the present process are carried out at temperature of 25 - 35°C. The present invention is further illustrated with the following examples. Example 1 : Preparation of amlodipine besylate anhydrate 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyi-6-methyl-2-(2-phthaIimidoethoxy) methyl-1,4-dihydropyridine (phthalimido amlodipine) (120.0 Kg) was added to a stirred 40% aqueous solution of monomethylamine (630 litres) at room temperature for 17 hours. After completion of the reaction (monitored by TLC ), methylene dichloride (720 lit.) was added to the reaction mixture and vigorously stirred for 30 min. and the free amlodipine base was allowed to go to the methylene chloride layer and the by product formed N-methyl phthalimde remained in the water layer. Then the solvent methylene chloride was separated and washed with water (630 lit), brine solution (27 Kg NaCl). Benzenesulphonic acid (48.4 Kg) in a solution of water (290 lit) was added slowly (3 hours) to the methylene chloride layer containing free base.. The whole reaction mixture was stirred vigorously for 3 hours and methylene chloride layer was separated, washed with water, brine and concentrated to give residue, which was precipitated by using ethylacetate (720 lit) to obtain amlodipine besylate salt anhydrate (96 Kg, 76%) of 99.7% purity. ~~" Example 2 : Preparation of amlodipine besylate anhydrate 50 kgs of Phthalimido amlodipine was stirred with aqueous monomethylamine (275 lit) for 17 hrs. The precipitate was extracted with toluene, washed with water and dried over Sodium Chloride. A clear solution of benzene sulphonic acid (17.5 kgs) in acetone (52.5 lit) was added to toluene solution and stirred for 5 hrs at room temperature. The resultant mass was filtered, washed with ethyl acetate. The wet material was boiled with ethyl acetate (150 lit) filtered and dried at 50 -60°C. Dry wt: 35 kgs. Purity of >99.7% Example-3: Preparation of Amlodipine Maleate. 100 kgs of Phthalimido amlodipine was stirred with 500 kgs of aqueous mono methylamine for 17 hrs. The precipitate was extracted with 1,2 - dichloromethane, washed with water and dried over Sodium Chloride.20.6 kgs of Maleic acid was added and stirred for 4 hrs at room temp. The precipitate was filtered and stirred with ethyl acetate for one hr and filtered, The product was dried at.50-60°C Dry wt: 75 kgs. Purity > 99.7% Example 4 : Preparation of amlodipine Mesylate and Succinate. The amlodipine mesylate and succinate can also be prepared by the above procedure described in the Example-2. The anhydrate salts prepared using the procedure described in example 1 & 2 above were exposed to RH of > 90% for over 24 hr. The salts did not absorb any moisture. The DSC thermograms after exposure were same as those obtained before exposure. This shows that the products obtained in Ex. 1 & 2 are true anhydrates and not anhydrates Isomorphic with the corresponding hydrated forms as described in Prior art. We claim, 1. A process for the insitu preparation of Amlodipine besylate of the formula 1 comprising; reacting phthalimido amlodipine of the formula 11 with an aqueous solution of mono methylamine; extracting the base into an organic solvent; treating immediately with benzene sulfonic acid solution prepared in a co-solvent; recovering the product amlodipine besylate by distillation of the solvent; and precipitating by treatment with Ethyl Acetate. t $ if* * § ^ wherein, X represents besylate, maleate and succinate anion. 2. The process as claimed in claims 1, wherein said organic solvent is selected from the group consisting of aliphatic chlorinated hydrocarbons such as methylenechloride, chloroform and ethylenedichloride, trichloroethylene, tetrachloro ethane and hydrocarbons such as toluene, xylene and ketones like Methyl Isobutyl Ketone. •orb t^JiStfnt wtlb 3. The process as claimed in claim 1 and 2, wherein said solvent is preferably methylene ch]orki£- 4/ The process as claimed in claim 1 wherein said co-solvent is a ketonic solvent. hfi* X5/The process as claimed in claim 1 and 4 wherein said ketonic is selected from the grou| consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone. 6. The process as claimed in any of the preceding claims wherein said reaction is carried out a 7. The process as claimed in any of the preceding claims, wherein the solvent is a mixture o v/methylenechloride and water in a ratio of from 2: 1 to 1 : 2 vol/vol%. 8. The process as claimed in any of the preceding claims, wherein the mixture of solvent and co ^/solvent is in a ratio of from 2: 1 to 1 : 2 vol/vol%. 9. The process as claimed in claim 1, wherein the amount of benzenesulphonic acid used is a least a stoichiometric amount or a small excess of benzenesulphonic acid. 10. The process as claimed in claim I, wherein said process is further used to prepar pharmaceutical^ acceptable acid addition salt of amlodipine such as amlodipine hydrochloride fumerate, maleate, mesylate and succinate thereof. 11. The Process as claimed in claim 1 wherein the crystalline Amlodipine Besylate produced is an anhydrate. 12. Pharmaceutically acceptable acid addition salt amlodipine besylate obtained by the above one-pot process is having high purity 99.9% by HPLC analysis. 13. A process for the insitu preparation of Amlodipine besylate of the formula 1 as substantially described herein particularly with reference to the examples 1 to 4.

Documents:

075-che-2005-abstract.pdf

075-che-2005-claims duplicate.pdf

075-che-2005-claims orginal.pdf

075-che-2005-correspondnece-others.pdf

075-che-2005-correspondnece-po.pdf

075-che-2005-description(complete) duplicate.pdf

075-che-2005-description(complete) original.pdf

075-che-2005-form 1.pdf

075-che-2005-form 3.pdf

075-che-2005-form 9.pdf