Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR ANTI-ALZHEMIER DRUG DONEPEZIL HYDROCHLORIDE

Abstract

The present invention relates to an improved process for the preparation of an intermediate for The preparation of Donepezil hydrochloride. The intermediate_is I-benzyl-4-[(5,6-dimethoxy- l-indanon)-2-ylidenyl]methyl piperidine has the formula I as given below Formula-I Donepezil hydrochloride which is I-benzyl-4-(5,6-dimethoxy indan-l-on-2-yl)-methyl piperidine Hydrochloride has the formula II as given below Fonnula-ll Donepezil hydrochloride is used as an anti Alzheimer's agent

Full Text

FIELD OF INVENTION The present invention relates to an improved process for the preparation of an intermediate for The preparation of Donepezil hydrochloride. The intermediate_is l-benzyl-[(5,6-dimethoxy-l-indanon)-2-ylidenyl]methyl piperidine has the formula I given below Donepezil hydrochloride which is 1 -benzyl-4-(5,6-dimethoxy indan-1 -on-2-yl)-methyl piperidine Hydrochloride has the formula II given below is an anti Alzheimer's agent The key intermediate used in the preparation of Donepezil hydrochloride, is l-benzyl-4-[(5,6- dimethoxy-l-indanon)-2"ylidenyl] methyl piperidine which has the formula (I) BACKGROUND OF INVENTION; Donepezil HCl is a memory enhancer drug useful in time treatment of Alzheimer's disease introduced by Japanese Pharmaceutical Company 'Eisai'. Its preparation was described in the patents EP 296560/ US 4895841 by tile reaction of 5,6-dimetiioxy indamine’s with l-benzyl-4-formyl piperidine in the presence of a strong base such as Lithium diisopropylamide followed by reduction of double bond. The reaction is shown in Scheme I The reaction was conducted in an argon atmosphere, and in the presence of strong base such as Lithium diisopropylamide. Diisopropylamine was added to anhydrous THF solvent, followed by addition of 1.6M solution of n-Butyl Lithium in n-Hexane at 0°C, the mixture was taken cooled to -78°C and the solution of 5,6-dimethoxy-l-indanone (formula A) in anhydrous THF and hexamethylphosphoric amide were added there to. The mixture was stirred for 15 min at -78°C and a solution of l-Benzyl-4-piperidinecarboxaldehyde (Formula B) in THF was added. Reaction mixture was slowly raised to room temperature, stirred for 2 hrs. 1% Ammonium chloride solution was added and extracted in ethyl acetate. Organic layer was washed with a saturated saline solution, dried on magnesium sulphate, and concentrated in vacuum. The resulting residue was purified by making use of a silica gel column. (Methylene chloride: Metiianol=500:l-100:l) The elute was concentrated in vacuum, and HCL salt of formula-I was prepared by using hydrochloric acid in ethyl acetate. The main drawbacks of the above said process (Shown in Scheme-I) are in the preparation of the Intermediate compound of formula-I. They are: 1. Raw materials like n-Butyl lithium, Diisopropylamine, hexamethylene phosphoric amide are relatively expensive and toxic. 2. Reaction needs anhydrous conditions, because the reagent n-Butyl lithium is highly sensitive to moisture and will decompose on exposure to moisture. So ties reaction will not proceed further. 3. The reaction needs very low temperatures of the order of -78°C which is not possible for plant scale operations. 4. Needs column chromatography for purification which is time consuming and limits the batch size. 5. Only moderate yields of intermediate of formula-I are the order of about 60% are realized. JP 11171,861 describes a process for the preparation of compound of the formula-I by using sodium ethoxide as base in Tetrahydrofuran (THF) solvent JP 11171861 describes the process for condensation of 5,6-dimethoxy-l-indanone of formula A and l-benzyl-4-piperidine carboxaldehyde formula B to yield the product formula-I in the presence of sodium metiioxide in motional in THF solvent at 17-21°C. Drawbacks of the process: i) Process involved ties use of sodium metiioxide, which is moisture sensitive reagent. ii) The solvent THF is relatively expensive and moisture sensitive. iii) Such moisture sensitive, reagents and solvents need anhydrous conditions other wise reaction does not proceed snootily and tierce is possibility of byproduct formation resulting in low yields of the desired product. Necessity of removing of above draw backs 1. Raw materials used in tike existing processes like n-Butyllithiimi, diisopropylamide, Hexamethylphosphoric amide and sodium ethoxide are relatively, expensive toxic, and moisture sensitive. Economic feasibility of these processes is questionable. 2. Needs anhydrous conditions otiierwise reaction will not proceed. 3. The reaction required low temperature (-78°C) which is not possible for plant scale operations 4. Column chromatography for purification is time consuming and limits batch size. OBJECTIVES OF THE INVENTION: Accordingly, the main objective of the present invention is to provide an improved process for preparation of the key intermediate of formula-I overcoming tile drawbacks of the hitherto known processes Another objective of the present invention is to provide an improved process for preparation of the key intermediate of formula-I, which is simple and economical making use of readily available raw materials. Yet another objective of the preset invention to provide an improved process for the preparation of compound of formula-I avoiding toxic chemicals, thereby making the process safe. Still another objective of the present invention is to provide an improved process for the preparation of compound of the formula I which can be commercially employed . Still another objective of the present invention is to provide an improved process for the preparation of compound of the formula I wherein the purity of the product is 95% and tie yield 75-80%. The preferred embodiment of Ie invention involves the use of 50% of aqueous alkali metal carbonate as base and aliphatic alcohols as solvent (ROH, R= lower alkyl) Accordingly the present invention provides an improved process for tile preparation of 1-benzyl-4"[(5,6-dimethoxy-l-indanon)-2-ylidenyl ] methyl piperidine of the formidably I in the presence of aqueous alkali metal carbonate as a base in an alcoholic or equinoxes alcohol solvents at reflux temperature, end product is recovering by cooling time reaction mass to room temperature, diluting with water. Filtering the product, and crystallizing in methanol. The yield of the compound of the formula I according to the process of the present invention is found to be 75-80% The condensation reaction may be optionally conducted in the presence of phase transfer catalyst like customary ammonium salts to improve the yields fur flier (85-90%). The intermediate of formula-I, [1 -benzyl-4-[(5,6-dimethoxy-1 -emanon)-2-yUdenyl]methyl piperidine can be reduced by catalytic hydrogenation to obtain the compound of ties formula II The process of the present invention is shown in Scheme 2. The Novelty of the process is, a) Avoids toxic chemicals and relatively expensive materials b) Avoids the anhydrous conditions and low temperatures like -78° C and the process involves aqueous alcoholic media and reflux temperature. c) Involves the Simple readily available, non-toxic, less expensive raw materials. d) Avoids tie column chromatographic purification, which is time consuming and limits the batch size. Typically a mixture of 5,6-dimethoxyindanone of the formula A is condensed with l-benzyl-4-piperidine carboxaldehyde of formula B in the presence of potassium carbonate and methanol at reflux temperature for 4 hours to get tie intermediate benzylidene derivative of the formula (I) in 75% yield. The yields are fortifier improved to 85% when the reaction is optionally conducted in presence of phase transfer catalyst like tetrabutylammonium bromide. Formation of byproducts as impurities is not observed when the reaction is conducted in presence of phase transfer catalyst as mentioned. Very similar results are obtained when the reaction is conducted in presence of sodium carbonate as base and lower alcoholic solvents Use eternal, isopropanol and n-butanol eerier as such or in presence of water (0-10%). The details of the invention are given in the Examples provided below which are given to illustrate time invention only and therefore should not be construed to limit the scope of the invention Example; 1 Preparation of compound of THE formula-I [l-Benzyl-4-[(5,6-dimethoxy-l-indanone)2-yl idenyljmethyl piperidine] 5,6-dimethoxy-l-indanone (61 gms, 0.32 moles) was dissolved in methanol (610 ml) under stirring at a temperature of 45-50°C. Then, the homogenous solution was heated further to reflux temperature. 50% aqueous potassium carbonate solution (Potassium Carbonate 305 gms, 2.20 moleswater305 ml) was added to the reaction mass drop-wise during a period in the range of 30-40 minutes. After 20 minutes of stirring, l-benzyl-4-piperidine carboxaldehyde (83.08 g, 0.409 moles) was added drop-wise to the above reaction mass. The pale brown colour suspension is maintained at batik temperature of 75°C for a period of 2.5 hrs. Reaction mass was tie cooled to room temperature and diluted with DM water (640 ml) extracted wilh CH2CI2 (600 ml x 2). Combined organic layer was washed with DM water (600 ml x 2). Organic layer was dried on sodium sulphate. The solvent was evaporated under reduced pressure to afford brown coloured shod. The sour was recrystallized in CH2CI2/IPE to yield cream coloured solid .m Wt. of the product: 92 gms [77%] Melting point: 170-174*'C The H^NMR data of this product is in agreement with literature H^NMR data. Example; 2 Preparation of compound of formula-I [l-Benzyl-4-[(5,6-dimethoxy-l-indanone)2-yl idenyl]methyl piperidine] 5,6-dimetiioxy-l-indanone (50 gms, 0.26 moles) was dissolved in isopropyl alcohol (500 ml) under stirring at a temperature in the range of 50-55'*C. Then the homogenous solution was heated to reflux temperature. 50% aqueous potassium carbonate solution (Potassium Carbonate 250gms, 1.80 moles DM water 250 ml) was added to the reaction mass drop-wise during a period of 30-40 minutes. After 20 minutes of stirring, l-benzyl-4-piperidine carboxaldehyde (68.03 g, 0.33 moles) was added drop-wise to above reaction mass. The reaction mixture was maintained at same temperature for 2.5 hrs. Reaction mass was cooled to room temperature and diluted wittier DM water (525 ml) extracted with CH2CI2 (500 ml x 2). Combined organic layer was washed with DM water (500 ml x 2). Organic layer was dried on sodium sulphate. Distilled off solvent and the residue was recrystallized from methylene chloride / isopropyl ether Wt. of the product: 69 gms [70%] Melting point: 170-175°C Example; 3 Preparation of compound of formula-l [l-Belize-[(5,6-dimethoxy-l-indanone) 2-yl indenyl]methyl piperidine] 5,6-dimethoxy-l-indanone (25 gms, 0.13 moles) was dissolved in eternal (250 ml) under stirring at 55°C. Then tiie solution was heated to reflux temperature. 50% aqueous sodium carbonate solution (sodium Carbonate 95.5 gms, 0.90 moles water 191 ml) was added to the reaction mass drop-wise during 30-40 minutes. After 20 minutes of stirring, l-benzyl-4-piperidine carboxaldehyde (34.02 g, 0.167 moles) was added drop-wise to above reaction mass. The reaction mass maintained at same temperature for 2.5 hrs. Reaction mass was cooled to room temperature, diluted wittier DM water (262 ml) product was filtered. The filtered product is dried in oven at 80-90°C for 2 hrs then crystallized from motional Wt. of the product: 36 gms [73%] Melting point: 17M74°C Advantages of tile Present Invention: i) Process is greatly simplified and employs readily available raw materials ii) Process is economically viable and cost effective. iii) Formation of impurities is almost negligible. iv) Process does not need column chromatography for pxmfication making it economical, v) Uses of toxic chemicals are not involved making the process safe. vi) Yields are consistently high (75-90%.) vii) The process can be used for manufacture on commercial scale We Claim 1. An improved process for the preparation of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidenyl]methyl piperidine of the formula I which is an important intermediate for the preparation of DonepezilHCl having &e formula II which comprises condensing 5,6-dimetiioxy indamines of the formula (A) with l-benzyl-4-piperidine carboxaldehyde of tie formula (B) in Ih presence of aqueous alkali metal carbonate as a base in an alcoholic or aqueous alcoholic solvents at reflux temperature, followed by cooling the reaction mass to room temperature, diluting with water, filtering the product and crystallizing from solvents hake methanol 2 An improved process as claimed in claim 1 wherein the base used is selected Alkali, or Alkali earth metal carbonates. 3 An improved process as claimed in claims 1 & 2 wherein the condensation reaction is conducted in the presence of phase transfer catalyst. 4 An improved process as claimed in claim 3 wherein the phase transfer catalyst used is selected from quaternary ammonium salts such as tetrabutylammonium bromide. 5 An improved process for the preparation of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2- indenyl] methyl piperidine of the formula I substantially as herein described with reference to tile Examples.

Documents:

922-1.jpg

922-2.jpg

922-che-2004 abstract.jpg 1.jpg

922-che-2004 abstract.jpg 2.jpg

922-che-2004-abstract.pdf

922-che-2004-claims.pdf

922-che-2004-correspondnece-others.pdf

922-che-2004-correspondnece-po.pdf

922-che-2004-description(complete).pdf

922-che-2004-description(provisional).pdf

922-che-2004-form 1.pdf

922-che-2004-form 18.pdf

922-che-2004-form 5.pdf