Title of Invention

PROCESS FOR PREPARATION OF PHENOXYPROPANOL AMINES

Abstract

The present invention describes an improved method for the preparation of l-[4-{2-(cyclopropylmethoxy)ethyl}phenoxy]-3-[(l-methylethyl)amino]-2-propanol of Formula-I and its pharmaceutically acceptable salt, which comprises reacting 4 - [ 2 -(Cyclopropylmethoxy) ethyl] phenol with epichlorohydrin in presence of mild base and polar protic solvent to isolate 1 - {4 - [2 - (cyclopropylmethoxy)ethyl] - phenoxy} - 2, 3 - epoxy propane, which is further reacted with isopropyl amine to get betaxolol formula I. 15 18 JUL 2008

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) l.TITLE OF THE INVENTION: 'Process for preparation of phenoxypropanol amines" 2. APPLICANT: (a) NAME: M/S. INDOCO REMEDIES LIMITED. (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956. (c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098. Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification particularly describes the invention and the manner in which it is to be performed. Field of the invention: The present invention relates to an improved process for the preparation of 1 - [4 - {2 -(cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol and its pharmaceutical acceptable salts. Background and prior art: The compound 1 - [4 - {2 - (cyclopropylmethoxy)ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol of Formula - I having international non proprietary name betaxolol is a useful cardioselective p - adrenoceptor antagonist for the treatment of chronic cardiovascular diseases like glaucoma. U.S. Patent No. 4252984 to Manoury et al describes the process for preparing betaxolol starting from ethyl 2 - (4 - hydroxyphenyl). acetate (Formula - II), wherein phenolic hydroxy group of ester is protected by benzylation followed by reduction of the ester using lithium aluminium hydride and tetrahydrofuran to get 2-(4-benzyloxyphenyl)-ethanol (Formula - III). The compound of Formula - III on reaction with cyclopropylmethyl halide in the presence of strong base sodium hydride and solvent dimethyl formamide results in 4 [2 - (cyclopropylmethoxy) - ethyl] - 1 - benzyloxy benzene (Formula - IV). The compound of Formula - IV is deprotected and then reacted with epichlorohydrin in sodium hydroxide and water to isolate 1 - {4 - [2 -(cyclopropylmethoxy)ethyl] - phenoxy} - 2, 3 - epoxy propane (Formula - V) which is purified using column chromatography. The compound of Formula - V is reacted with isopropyl amine in excess in the absence of solvent to get betaxolol free base of Formula- 2 I, which is converted to hydrochloride salt by reacting with hydrochloric acid in acetone to isolate 1 - [4 - {2 - (cyclopropylmethoxy)ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol hydrochloride of Formula -1. The reaction sequence is as given in scheme - 1. Scheme - 1 Formula -1 Formula - V Formula - IV The above patent requires handling of hazardous and moisture sensitive reducing agent such as lithium aluminium hydride and hazardous base sodium hydride in alkylation stage. The epoxy compound needs purification employing column chromatography. In the final stage it uses large excess of isopropyl amine in turn making the process non -operator friendly and economically unviable. Another U.S. Patent No. 4760182 to Ippolito et al, discloses the process for preparing betaxolol hydrochloride by reacting 4 - hydroxy- phenyl ethanol (Formula - II) with a base to form phenoxide ion, which is further reacted with epichlorohydrin in the presence 3 of base potassium carbonate and acetonitrile to get 1 - [4 - (2 - hydroxyethyl) phenoxy]-2,3-epoxypropane (Formula - VI). The compound of Formula - VI is then reacted with isopropyl amine to isolate the intermediate 1 - [4 - (2 - hydroxyethyl) phenoxy] - 3 - [(1 - methylethyl) amino] -2 - propanol (Formula - VII), which is reacted with benzaldehyde in presence of toluene to yield 2 - phenyl - 3 - isopropyl - 5 - [4 - {(2 - hydroxyethyl) phenoxy} methyl] oxazolidine (Formula - VIII). The compound of Formula - VIII is alkylated with chloromethyl cyclopropane in presence of base potassium tertiary butoxide and solvent dimethyl sulfoxide to yield 2 - phenyl - 3 - isopropyl - 5 - [[4 - {(2 -cyclopropyl methoxy) ethyl} phenoxy] methyl] oxazolidine (Formula - IX), which on deprotection using hydrochloric acid yields betaxolol hydrochloride. The reaction sequence is as given in scheme - 2. Scheme - 2 OH Formula - Formula - VI Formula - VII Formula -I Formula - IX Formula-VIII The above patent requires the protection of hydroxy and amino group before alkylation of the alcoholic -OH followed by deprotection resulting in increased number of steps. The use of costly polar aprotic solvent acetonitrile for epoxide formation which has stringent limit as per ICH guidelines makes the process uneconomical and unviable. 4 U.S. Patent No. 5731463 describes the preparation of betaxolol by selective alkylation of the alcoholic hydroxy group using strong base and solvent, without protecting the phenolic hydroxy group of 4 - hydroxy phenyl ethanol. The alkylated compound is further reacted with epichlorohydrin in presence of potassium carbonate and polar aprotic solvent selected from acetonitrile or N,N - dimethylformamide to get epoxide which on subsequent reaction with isopropyl amine and further with hydrochloric acid results in betaxolol hydrochloride. The above patent uses costly solvent such as acetonitrile or N, N - dimethylformamide for epoxide formation, has stringent limit as per ICH guidelines. Excess use of isopropyl amine makes the process uneconomical for industrial use. Therefore there remains a need for an improved process for preparing betaxolol hydrochloride that eliminates or substantially reduces the impurities, avoids the use of strong base, and employs a more robust process which is convenient and cost efficient. The present inventors have come out with an improved process which ameliorates the drawbacks in the prior art for the preparation of betaxolol hydrochloride by avoiding the use of hazardous reducing agent and strong base for alkylation. The present inventors employ cost effective solvent for epoxidation reaction, which results in epoxide which is substantially devoid of impurities, avoids the use of column chromatography for purification. Further use of substantially reduced quantity of isopropyl amine makes the process robust, operator friendly and techno commercially viable for industrial production. Objective of the invention: The objective of the present invention is to provide an improved process for the preparation of 1 - [4 - {2 - (cyclopropylmethoxy) ethyl} phenoxy] - 3-[(l - methyl ethyl) amino] - 2 - propanol of Formula - I. 5 Another objective of the present invention is to provide a robust and techno commercially useful process for the preparation of 1 - [4 - {2 - (cyclopropylmethoxy) ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol of Formula -1. Yet another objective of the present invention is to avoid the use of strong base for O -alkylation. Yet another objective of the present invention is to prepare the pharmaceutically acceptable salt of 1—[4—{2 - (cyclopropylmethoxy) ethyl} phenoxy]-3-[(l-methyl ethyl) amino] -2-propanol of Formula -I. Summary of the invention: The present invention provides an improved process for the preparation of 1 - [4 - {2 -(cyclopropylmethoxy)ethyl}phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol of Formula I comprising a. reacting 2 - (4 - benzyloxy) - phenyl ethanol of formula III with cyclopropyl methyl bromide in presence of base to get l-[(benzyloxy)- 4—(2 - cyclopropyl methoxy)ethyl]benzene of Formula IV; b. debenzylating Formula IV compound with 10% Pd / C using polar solvent to get 4 - [ 2 - (Cyclopropylmethoxy) ethyl] phenol; c. reacting debenzylated compound with epichlorohydrin in presence of base and solvent C1 - C4 alcohol to isolate 1 — {4 — [2 — (cyclopropylmethoxy)ethyl] - phenoxy} - 2, 3 - epoxy propane of Formula V; d. reacting compound of Formula V with isopropyl amine in presence of water to get 1 - [4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 — [(1 - methyl ethyl) amino] - 2 - propanol (betaxolol free base) of formula I; e. reacting Betaxolol freebase of Formula - I with suitable acid to isolate pharmaceutically acceptable salt of 1 - [4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol. 6 Detailed description of the invention: The present invention describes an improved process for the preparation of 1 - [4 - {2 -(cyclopropylmethoxy) ethyl} phenoxy] -3- [(1 - methyl ethyl) amino] - 2 - propanol of Formula I. In one embodiment of the present invention 2 - (4 - benzyloxy) - phenyl ethanol of Formula-Ill on alkylation with cyclopropyl methyl bromide in presence of a base and polar aprotic solvent yields 1 - [(benzyloxy) - 4 - (2 - cyclopropyl methoxy) ethyl] benzene of Formula IV. The base for alkylation reaction is selected from metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide; the preferred base used for the alkylation is potassium hydroxide. The polar aprotic solvent is selected from the group comprising of dimethyl sulfoxide, N, N-dimethyl formamide, N, N-dimethyl acetamide or N - methyl pyrrolidine; the preferred solvent used is dimethyl sulfoxide or N, N - dimethylformamide, whereas the most preferred solvent is dimethyl sulfoxide. The compound of Formula - IV is debenzylated in presence of 10% Pd/C catalyst and in presence of methanol to get 4 -[2 - (cyclopropylmethoxy)ethyl] phenol of Formula - X. In another embodiment of the present invention the compound 4-[2-(cyclo-propylmethoxy) ethyl] phenol of Formula - X is reacted with epihalohydrin in presence of mild base and a polar protic solvent selected from C1 - C4 linear, cyclic or branched alcohol at temperature of 40°C - 90°C to yield l-{4-[2-(cyclopropylmethoxy)ethyl]-phenoxy} -2,3 - epoxy propane of Formula V. The epihalohydrin used in the reaction is selected from epichlorohydrin, epibromohydrin or epiiodohydrin. The preferred epihalohydrin used is epichlorohydrin. The mild base used for the reaction is selected from metal carbonates and metal alkoxides. The preferred base used is metal carbonate selected from sodium carbonate, potassium carbonate, lithium carbonate or cesium 7 carbonate. The most preferred base used is potassium carbonate. The suitable solvent used for the reaction include, but is not intended to be limited to C1 - C4 linear, branched or cyclic alcohol selected from methanol, ethanol, propanol, isopropyl alcohol, cyclopropanol, butanol and sec. butanol. The preferred solvent used is isopropyl alcohol. Reaction is carried out in the temperature range of 40 - 90°C; preferred range of temperature is between 70°C - 90°C, whereas the most preferred range of the temperature for the reaction is 81°C - 85°C. The compound l-{4—[2-(cycIopropylmethoxy) ethyl] - phenoxy}-2,3-epoxy propane of Formula V is subsequently reacted with isopropyl amine in presence of water to yield 1 -[4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 -propanol of formula I. The betaxolol isolated is further used to prepare the pharmaceutical acceptable salt of betaxolol. Salt is prepared by the reaction of betaxolol free base with appropriate inorganic or organic acid; here the inventors have prepared the hydrochloric salt of betaxolol by employing the process known in the art. The reaction sequence can be represented as per the scheme-3 below; Scheme - 3 8 Formula - XI Formula - Formula - V Formula -1 CX Formula - IV OH Formula - X CH3 Hydrochloride Salt of Formula -1 The following examples are intended to be illustrative of the present invention and are not to be construed as limiting. Examples: Example - 1: Preparation of 1 - [(Benzyloxy) - 4 - (2 - cyclopropyl methoxy) ethyl] benzene: In a 1.0 lit flask charged 4-benzyloxy-2-phenyl ethanol (100 gms, 0.44 moles) in dimethyl sulfoxide (300 ml). Stirred and charged powdered potassium hydroxide (61.4 9 gms, 1.1 moles). Stirred and cooled to 10 - 15°C. Charged cyclopropyl methyl bromide (71.1 gms, 0.53 moles). Raised the temperature to 25 - 30°C and maintained. After 3 hours, the reaction mass was quenched in chilled water (600 ml) maintaining temperature below 5°C. The pH of the reaction solution was adjusted with dilute (1:4) hydrochloric acid, extracted the solution with 3 x 200 ml of toluene and distilled out toluene under vacuum below 55°C. Charged petroleum ether (250 ml) to the residual mass and cooled to 0°C and maintained under stirring for 2 hours. Filtered the separated solid and washed with petroleum ether. Charcoalised the filtrate for 30 minutes and filtered through hyflow bed and distilled out solvent to get the product. Wt of the product = 90-92 gms. Example - 2: Preparation of 4 - [2 - (Cyclopropylmethoxy) ethyl] phenol: In methanol (180 ml) charged 1 - [(Benzyloxy) - 4 - (2 - cyclopropyl methoxy) ethyl] benzene (90 gms, 0.32 mole), 10% Pd/C (22 gms) in an autoclave. Flushed with nitrogen and passed 6 - 7 Kg of hydrogen and maintained under stirring at 20 - 35°C, monitored the reaction on TLC for completion. After completion of the reaction released the pressure and filtered the catalyst. The methanol was concentrated under reduced pressure to get the oily product. Wt of the product = 58-60 gms. Example - 3: Preparation of 1 - {4 - [2 - (Cyclopropylmethoxy) ethyl] - phenoxy} -2,3 - epoxy propane: In 1.0 lit flask with reflux condenser, charged 4 - [2 - (Cyclopropylmethoxy) ethyl] phenol (55 gms, 0.29 mole), anhydrous potassium carbonate (118.5 gms, 3.0 moles) and isopropyl alcohol (220 ml). The reaction mass was stirred and charged epichlorohydrin (67.2 ml, 0.73 moles) at 25 - 30°C. The temperature was raised to reflux and maintained for 3 hours. Filtered the reaction mass and washed the solid with hot isopropyl alcohol. The isopropyl alcohol was distilled out completely till the weight of the residue is constant. Wt of the product = 68-70 gms 10 Example - 4: Preparation of 1 - |4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] -3 - [(1 - methyl ethyl) amino] - 2 - propanol (Betaxolol free base): In a flask, charged 1 — {4 — [2 — (Cyclopropylmethoxy) ethyl] - phenoxy} - 2, 3 - epoxy propane (15 gms, 0.06 mole) followed by charging isopropyl amine (52 ml) drop wise below 0°C under stirring. The reaction mass was stirred and charged water (34 ml) drop wise below 0°C and stirring was continued at 25 — 35°C for 3 hours. The excess of isopropyl amine was distilled out under vacuum at 50°C. Charged DM water (30 ml) in the degassed mass and extracted with 2 x 30 ml dichloromethane. Washed combined dichloromethane layer with 2 x 30 ml water and distilled out solvent completely under vacuum. Charged to the residue diisopropyl ether (30 ml) and stirred to isolate solid betaxolol free base. Filtered the product and dried. Wt of the product - 11.5 gms. Example - 5: Preparation of 1 - [4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol hydrochloride: Charged betaxolol base (10 gms) in a flask containing acetone (60 ml). Stirred and cooled the reaction mass to 10 - 15 °C. Purged hydrochloric acid gas till pH of the solution becomes 2.0. Filtered the solid mass and washed with chilled acetone. Dried the product under vacuum at 55 - 60°C. Wt of the product =9.0 gms. 11 We claim, 1. A process for the preparation of 1 - [4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol of Formula - I and its pharmaceutically acceptable salt Comprising step of; a. reacting 4 - [2 - (Cyclopropylmethoxy) ethyl] phenol of Formula - X with OH Formula - X b. epihalohydrin of Formula - XI X Q Formula-XI where X = CI, Br, or I. in presence of polar protic solvent of formula 'R - OH', where 'R' is CI - C4 linear, cyclic or branched aliphatic chain. 2. The process as claimed in claim 1, wherein, a. reacting 4 - [2 - (Cyclopropylmethoxy) ethyl] phenol of Formula - X with epihalohydrin in presence of a mild base and polar protic solvent at temperature 12 of 70 - 90°C to get 1 - {4 - [2 - (Cyclopropylmethoxy) ethyl] - phenoxy} - 2, 3 - epoxy propane of Formula - V; b. reacting the Formula - V compound with isopropyl amine to give 1 - [4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol of Formula -1; C. the compound of Formula - I is further converted to its pharmaceutically acceptable salt. 3. The process as claimed in claim 1 and 2, wherein epihalohydrin used is selected from epichlorohydrin, epibromohydrin and epiiodohydrin. 4. The process as claimed in claim 1, 2 and 3, wherein the epihalohydrin used is epichlorohydrin. 5.The process as claimed in claim 2, wherein the mild base used are sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate. 6.The process as claimed in claim 5, wherein the preferred base used is potassium carbonate. 7.The process as claimed in claim 1, wherein polar protic solvent used are methanol, ethanol, propanol, isopropyl alcohol, cyclopropanol, butanol and sec. butanol. 8.The process as claimed in claim 7, wherein polar protic solvent used is isopropyl alcohol. 9.The process as claimed in claim 2, wherein the preferred temperature for the reaction is 80-90°C. 10. A process for the preparation of 4 - [2 - (Cyclopropylmethoxy) ethyl] phenol of Formula - X used as reactant in claim 1, 13 Formula - X wherein; a. reacting the compound 2 - (4 - Benzyloxy) - phenyl ethanol with cyclopropyl methyl bromide in presence of a base and solvent to get 1 - [(Benzyloxy) - 4 - (2 - cyclopropyl methoxy)ethyl]benzene of Formula - IV; b. debenzylating the compound of Formula - IV in polar solvent using metal catalyst to get 4 - [2 - (Cyclopropylmethoxy) ethyl] phenol of Formula - X. 11. The process as claimed in claim 10, wherein the base used is selected from . sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. 12. The process as claimed in claim 11, wherein the preferred base used is potassium hydroxide. 13. The process as claimed in claim 10, wherein the solvent used for the reaction is selected from Dimethyl sulfoxide, N, N - Dimethyl formamide, N, N - Dimethyl acetamide and N - methyl pyrrolidine. 14. The process as claimed in claim 1; wherein the pharmaceutically acceptable salt is hydrochloride salt of 1 - [4 - {2 - (cyclopropylmethoxy) - ethyl} phenoxy] - 3 - [(1 - methyl ethyl) amino] - 2 - propanol of Formula -1. Dated this 18th day of July 2008 Dr.P.Aruna Sree Agent for the Applicant 14

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