Title of Invention

An improved process for the preparation of N-[2-(phthalimido) ethoxy] acetic acid

Abstract

An improved method for the preparation of [2-(phthalimido)ethoxy]-acetic acid by reacting phthalamide with methyl-2-(2'-chloroethoxy)-acetate in presence of a base in organic solvent at a temperature ranging between 100-140°C for the period from 6-8 hours, cooling to room temperature and adding organic solvent selected from toluene while stirring, adding alkali hydroxide, separating toluene layer and aquare layer containing [2-(phthalimido)ethoxy]-acetic acid followed by acidification with hydrochloric acid 5N, filtering to obtain [2-(phthalimido)ethoxy]-acetic acid.

Full Text

This invention relates to the method for the preparation of [ 2-(phthalimido)-ethoxy]acetic acid having formula (1) which is an important intermediate in the (Formula Removed) manufacture of anti-ischaemic and antihypertensive drug i.e. Amlodipine of formula. (2) (Formula Removed) 4-[2-(Phthalimido)-ethoxy]- acetic acid (1) has been hitherto obtained by condensation of N-(2-hydroxyethyl)phthalimide with methyl bromoacetate [Liu, Yu-Ying; Thorn, Edna; Liebman, Arnold A. Can. J. Chem., 56(22), 2853-5, 1978]or condensation of phthalicanhydride with 2-aminoethoxyethanol followed by oxidation [Roubini, Eli; Laufer, Ralph; Gilon, Chaim; Selinger, Zvi; Roques, Bernard P.; Chorev, Michael /. Med. Chem., 34(8), 2430-8, 1991; Griesbeck, Axel G.; Henz, Andreas; Kramer, Wolfgang; Lex, Johann; Nerowski, Frank; Oelgemoller, Michael; Peters, Karl; Peters, Eva Helv. Chim. Acta, 80(3), 912-933, 1997]. The reaction involves use of sodium hydride as base which is known to be pyroforic. The O-alkylation is carried out in anhydrous tetrahydrofuran involving stringent reaction conditions (-10°C). The present invention provides an improved and elegant process for the preparation of N-(2-phthalimido)ethoxy]-acetic acid (1) an intermediate used for the manufacture of antischaemic and antihypertensive drug i.e. Amiodipine besylate. The main object of the present invention is to prepare (2- phthalimido)ethoxy]-acetic acid of the formula 1, an intermediate in the manufacture of (Formula Removed) Antischaemic and antihypertensive drug i.e. amiodipine besylate starting from easily available raw materials like phthalimide, solvent like toluene and base like potassium carbonate. Accordingly, the present invention provides an improved method for the preparation of [2-(phthalimido)ethoxy]-acetic acid having formula (1) which comprises reacting phthalamide with methyl-2-(2'-chloroethoxy)-acetate in presence of a base in organic solvent such as herein described at a temperature ranging between 100-140°C for the period from 6-8 hours, cooling to room temperature and adding organic solvent selected from toluene while stirring, adding alkali hydroxide, separating toluene layer and aquare layer containing [2-(phthalimido)ethoxy]-acetic acid followed by acidification with hydrochloric acid 5N, filtering to obtain [2-(phthalimido)ethoxy]-acetic acid. In one of the embodiments of the present invention, the organic solvent used for the reaction is selected from hydrocarbon, amide or chlorinated hydrocarbons exemplified as toluene, dimethyl formamide or ethylene dichloride. In one of the embodiment the base used for the reaction is selected from potassium carbonate, sodium carbonate, sodium hydroxide. In another embodiment, the alkali hydroxide may be of concentration ranging between 5% to 25% Thus the main feature of the invention is the N-alkylation of phthalimide with methyl-2-chloroethoxyacetate using anhydrous potassium carbonate. The invention also provides a general methodology to prepare various alkyl- N-[2-(phthalimido)-ethoxy]-acetic acids, useful intermediates in the manufacture of novel 1,4 -dihydropyridine derivatives. The process of the present invention is described herein below with reference to examples which are illustrative only and should not be construed to limit the scope of the present invention in any manner. Examples 1 Phthalimide 100 parts (0.68 mol. part), anhydrous potassium carbonate 140 parts (1.01 mole part) were suspended in dimethyl formamide (300 parts) and heated to 50°Cwith stirring and maintained for two hrs. Methyl 2-(2'-chloroethoxy) acetate 125 parts (0.82 mol. parts) was slowly added over a period of one hr. The resulting mixture was heated to 95° and maintained for 8 hrs. The completion of the reaction was followed by disappearance of phthalimide. After completion of reaction the reaction mixture was cooled to room temperature and toluene 500 parts was added with stirring. The stirring was continued for 30 minutes, the slurry was filtered and the cake was washed with 100 parts toluene. the combined toluene filtrate was washed with water (200 parts x 2). The toluene layer was cooled (5°C) and 10% aqueous sodium hydroxide (540 parts) was slowly added with stirring and maintaining the temp, at 5°C for 30 min. Completion of hydrolysis was followed by TLC analysis of toluene layer for disappearance of methyl-N-[2-(phthalimido)ethoxy]-acetate (silica gel, ethylacetate:hexane 60:40 as eluent). The toluene layer was separated and the aqueous layer was cooled (5°C) and acidified by 5N HCl (220 parts). The slurry was further stirred at 5°Cfor two hours and filtered. The solid was washed with cold water (200 parts) dried at 60°C (hot air circulating oven) till constant weight. Yield [ 2-(phthalimido)ethoxy] acetic acid 110 parts (0.44 mole; 64%).m.p. 129-130°C *H NMR (DMSO D6)- values: 7.8 to 7.4 (4H, m); 4.05 (2H, S); 3.6 to 3.2 (4H, m) Example 2. Phthalimide 100 parts (0.68 mol. part), anhydrous potassium carbonate 140 parts (1.01 mole part) were suspended in toluene (300 parts) and heated to 50°Cwith stirring and maintained for two hrs. Methyl 2-(2'-chloroethoxy) acetate 125 parts (0.82 mol. parts) was slowly added over a period of one hr. The resulting mixture was heated to 90°C and maintained for 8 hrs. The completion of the reaction was followed by disappearance of phthalimide. After completion of reaction the reaction mixture was cooled to room temperature and toluene 500 parts was added with stirring. The stirring was continued for 30 minutes, the slurry was filtered and the cake was washed with 100 parts toluene, the combined toluene filtrate was washed with water (200 parts x 2). The toluene layer was cooled (5°C) and 10% aqueous sodium hydroxide (540 parts) was slowly added with stirring and maintaining the temp, at 5°C for 30 min. Completion of hydrolysis was followed by TLC analysis of toluene layer for disappearance of methyl-N-[2-(phthalimido)ethoxy]-acetate (silica gel, ethylacetate:hexane 60:40 as eluent). The toluene layer was separated and the aqueous layer was cooled (5°C) and acidified by 5N HCl (220 parts). The slurry was further stirred at 5°Cfor two hours and filtered. The solid was washed with cold water (200 parts) dried at 60°C (hot air circulating oven) till constant weight. Yield [2-(phthalimido)ethoxy] acetic acid 11.8 parts (0.047 mole; 6.48%).m.p. 129-130°C Advantages 1. Easily and commercially available raw materials. 2. Ease of handling of raw materials. 3. Ease in scale up and commercial production. 4. Reaction conditions are simple. We claim : 1. An improved method for the preparation of [2-(phthalimido)ethoxy]-acetic acid having formula (1) which comprises reacting phthalamide with methyl-2-(2'-chloroethoxy)-acetate in presence of a base in organic solvent such as herein described at a temperature ranging between 100-140°C for the period from 6-8 hours, cooling to room temperature and adding organic solvent selected from toluene while stirring, adding alkali hydroxide, separating toluene layer and aquare layer containing [2-(phthalimido)ethoxy]-acetic acid followed by acidification with hydrochloric acid 5N, filtering to obtain [2-(phthalimido)ethoxy]-acetic acid. 2. A process as claimed in claim 1 wherein the organic solvent used for the reaction is selected from toluene, dimethyl formamide, ethylene dichloride. 3. A process as claimed in claims 1-2 wherein the base used for the reaction is selected from potassium carbonate, sodium carbonate, sodium hydroxide. 4. A process as claimed in claims 1-3 wherein the alkali hydroxide used is 10% sodium hydroxide. 5. An improved method for the preparation of [2-(phthalimido)ethoxy]-acetic acid substantially as herein described with reference to the examples.

Documents:

65-del-2002-abstract.pdf

65-del-2002-claims.pdf

65-del-2002-complete specification (granded).pdf

65-del-2002-correspondence-others.pdf

65-del-2002-correspondence-po.pdf

65-del-2002-description (complete).pdf

65-del-2002-form-1.pdf

65-del-2002-form-13.pdf

65-del-2002-form-2.pdf

65-del-2002-form-4.pdf