Title of Invention

AN IMPROVED PROCESS FOR MANUFACTURE OF ATENOLOL

Abstract

1. A process for the preparation of atenolol, comprising the steps of: a) coupling of chloromethyl benzene (XX) with isopropyl amine to give N-benzyl-N-isopropyl amine, b) reacting N-benzyl-N-isopropylamine (XXII) with epichlorohydrin (III-A), c) converting the halohydrin (XXIII-A) in the presence of a base to the epoxide, d) reacting the salt of phenyl acetamide (XXV) with the halohydrin (XXIII A) or the epoxide (XXIV-A) in the presence of a base and e) debenzylating the N-benzylated atenolol (XXVI-A) to racemic atenolol (I-A).

Full Text

2 DEC 2005 FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR MANUFACTURE OF ATENOLOL" 2. APPLICANT (S) (a) NAME (b) NATIONALITY (c) ADDRESS EMCURE PHARMACEUTICALS LTD. India R&D Centre II, 12/2, F-II Block, MIDC, Pimpri, Pune-411018 Maharashtra, India GRANTED ORIGINAL 2-12-2005 FIELD OF THE INVENTION This relates to an improved method for the manufacture of atenolol of high purity substantially free from impurities. BACKGROUND OF THE INVENTION Beta-adrenergic antagonists referred to as beta-blockers are a class of compounds, which are employed for management of angina pectoris, hypertension and arrhythmia. The primary function of the beta-blockers is to reduce the frequency of the anginal episodes and raise the anginal threshold by attenuating the chronotropic and inotropic responses to adrenergic stimulation. Racemic atenolol known chemically as 4-[2-hydroxy-3- [(1-methyl ethyl)amino]propoxy] benzene acetamide and represented by formula (I-A), belongs to the class of beta blockers, which exerts its physiological action by blocking the beta-receptors in the body and exists as a racemic mixture of (R) and (S) optical isomers due to the presence of an asymmetric centre at the hydroxy-bonded carbon of the 1-aryloxy-3-aminopropan-2-ol moiety. (I-A) (l-B) (l-C) It is quite well known that the hypotensive activity of racemic atenolol resides in the (S)-isomer (I-B) of atenolol while the (R)-isomer of formula (I-C) is devoid of hypotensive activity. Further, the (S)-isomer has an additional advantage that it is found to avoid the occasional side effect of a lowered heart rate sometimes encountered with the racemic mixture of atenolol of formula (I-A). There are several methods reported in prior art for preparation of both racemic atenolol (I-A) and its optically active isomers (S)-atenolol (I-B) and (R)-atenolol (I-C). US 3 663 607 (assigned to Imperial Chemical Industries) discloses a process as summarized in Scheme-I for preparation of racemic atenolol which comprises reaction of a phenolic compound of formula (II) with epichlorohydrin of formula (III-A) in presence of a catalytic amount of piperidine at a temperature of 95-100°C for several hours to obtain glycidyl ether (IV), which on subsequent reaction with a lower alkyl amine like isopropylamine gives atenolol of formula (I-A). Scheme-I: Method as disclosed in US 3 663 607 for preparation of atenolol. US 4 182 911 (assigned to Imperial Chemical Industries) discloses a method for preparation of optically active (S)-atenolol as summarized in Scheme- II. This method has several disadvantages, which limits its scope on an industrial scale, they are: a) multiple steps are required to obtain compound (VI) from D-mannitol, which increases the time-cycle for each run, b) the starting compound (VI) has a secondary as well as a primary hydroxy group and during conversion of the primary hydroxy group of compound (VI) to compound of formula (VIII) the carbamoylmethyl group of compound (VII) reacts with the functional group (Z) thus giving rise to impurities which decreases the yield of atenolol considerably, c) further, the intermediate, glycidyl ether (VIII) thus obtained has a lower optical purity (80% ee). US 5 223 646 (assigned to Daiso Company Ltd) describes a process for preparation of optically active atenolol intermediate i.e. optically active glycidyl ether (VIII) by reaction of phenol and epichlorohydrin in a water-miscible solvent or water in a temperature range between 0°C and 35°C. The optically active glycidyl intermediate (VIII) thus obtained has a lower purity between 90 and 96% which on subsequent reaction with isopropyl amine gives (S)-atenolol having a lower optical purity between 93-94%. In addition, this patent also discloses a purification method utilizing a Bronsted acid such as an inorganic acid or organic acid. The inorganic acids are selected from hydrogen halides, sulfuric acid, and phosphoric acid while the organic acids are selected from a mono- or di-carboxylic acid like formic acid, acetic acid, organic sulphonic acid like methanesulfonic acid, para toluenesulfonic acid or phenol, which may be used alone or in combination thereof. (S)-atenolol is converted to its acid addition salt by heating in an organic solvent like acetone and allowing it to crystallize slowly overnight. The free base of the optically pure (S)-isomer is obtained from its acid addition salt by treatment with an ion-exchange resin. This method has the disadvantage of requiring rigid reaction conditions since there is a danger of racemization of the glycidyl ether (VIII) above 35°C which lowers its optical purity. Moreover, when the reaction temperature is above 35°C, the glycidyl ether (VIII) reacts with phenol to give associated impurities, which are difficult to purify utilizing conventional methods. One can therefore easily notice that the process utilized for obtaining (S)-atenolol by this method is quite lengthy, tedious and time consuming and not suitable for manufacture on an industrial scale. US 5 290 958 (assigned to Industrial Technology Research Institute) discloses a method as described in Scheme-Ill, for preparation of racemic atenolol (I-A) which utilizes a phase transfer catalyst like a quaternary ammonium salt of high alkyl groups or tertiary ammonium salts of lower alkyl group as phase transfer catalyst (PTC), in the reaction of p-hydroxyphenyl acetamide and epichlorohydrin to yield epoxide and halohydrin intermediates. O SCHEME-MI: Method as disclosed In US 5 290 958 for the preparation of atenolol It is pertinent to note that all the above methods utilize a phenol or its derivative for preparation of atenolol and it is also worth mentioning that the product obtained by the above prior art methods generate associated impurities which are disclosed in British Pharmacopoeia 2003 Vol: 1, Page 173. The associated impurities as disclosed in Scheme-IV are 2,2'-[(l-methylethyl) iminobis (2-hydroxypropan-3,l-diyloxy-4,l-phenylene)] diacetamide (XII), 2-(4-hydroxyphenyl) acetamide (XIII), 2-[4-[[(2RS)-oxiran-2-yl]methoxy]phenyl] acetamide (XIV), 2-[4-[(2RS)-3-chloro-2-hydroxypropoxy] phenyl] acetamide (XV), 2,2'-[2-hydroxypropan-l, 3-diylbis (oxy-4, 1 phenylene)] diacetamide (XVI), 2-[4[[(2RS)-2-hydroxy-3- [(1 methylethyl) amino] propoxy] phenyl] acetic acid (XVII), 2-[4-[(2RS)-2-hydroxy-3-[(l-methylethyl)amino]propoxy] phenyl]acetonitrile (XVIII), and 2[4-[(2RS)-2,3-dihydroxypropoxy]phenyl] acetamide (XIX), which are difficult to remove utilizing conventional methods of purification and if removed significantly reduces the yield of the desired product. Regulatory authorities all over the world are becoming very stringent about the level of impurities in an approved drug. Most of the prior art methods however, do not give product conforming to pharmacopoeial specifications. Chemical and Pharmaceutical Bulletin 1997, 45(2) 412-414 discloses a method for purification of (S)-atenolol by recrystallization of the impure (S)-atenolol from an organic solvent such as methanol. This method for preparation of (S)-atenolol is not suitable for commercial purpose since the procedure is lengthy as most of the steps disclosed therein require a purification step. Chemical and Pharmaceutical Bulletin 1998, 46(3) 505-507 discloses a method for purification of (S)-atenolol which involves preparation of acid addition salts of (S)-atenolol by utilizing various acids like benzoic acid, p-toluic acid, p-toluene sulfonic acid and p-tert-butyl benzoic acid. (S)-Atenolol is obtained from these acid addition salts by treating with an ion-exchange resin. This method has the disadvantage of utilizing an acid exchange resin for liberation of atenolol from its acid addition salt. The utilization of acid exchange resins requires large investments and also the time required for purification by such a method is very long, which eventually increases the time cycle of each run and reduces the production capacity. In view of the above shortcomings, it was necessary to develop alternate synthetic routes, which would not only minimise all the impurities below pharmacopoeial limits but also give compound of formula (I-A) or (I-B) or (I-C) of high purity and with good yield. The present inventors have developed a novel synthetic route for preparing racemic atenolol (I-A), (S)-atenolol (I-B) and (R)-atenolol (I-C) starting from benzyl chloride and isopropyl amine, which not only suppresses the above impurities but also gives racemic atenolol (I-A),a(S)-atenolol (I-B) and (R)-atenolol (I-C) of high purity and substantially free from impurities. In the present invention, compounds of the formula (I-A), (I-B) or (I-C) are purified by a method, which comprises treatment of the free base of atenolol [racemic or its (S)-isomer] with an organic acid to give the respective acid addition salt, which is then further treated with an aqueous solution of an inorganic base to liberate the free amine i.e. purified atenolol [racemic or its (S)-isomer] of high purity and with good yields. The present method utilizes an inorganic base such as readily available sodium hydroxide for purification of atenolol instead of ion-exchange resins, which results in considerable savings thereby making the overall process cost-effective and suitable for industrial manufacture. OBJECT OF THE INVENTION An object of the present invention is to provide an improved method for preparation of racemic atenolol i.e. 4-[2-hydroxy-3- [(1-methylethyl) amino] propoxy] benzene acetamide of formula (I-A) and enantiomers thereof by a synthetic route which is distinct from prior art methods. SUMMARY OF THE INVENTION One aspect of the invention relates to an improved method for preparation of racemic atenolol of formula (I-A), (S)-atenolol of formula (I-B) and (R)-atenolol of formula (I-C) of high purity substantially free from impurities, f Another aspect of the invention relates to an improved method for preparation of racemic atenolol of formula (I-A), which comprises reaction of chloromethyl benzene (XX) and isopropyl amine (XXI) to give N-benzyl-N-isopropyl amine (XXII), which on reaction with epichlorohydrin (IIIA) gives l-[benzyl(isopropyl)amino]-3-chloropropan-2-ol of formula (XXIII-A). This compound on treatment with an inorganic base gives N-benzyl-N[(2)-oxiran-2-ylmethyl]propan-2-amine (XXIV-A), which oh reaction with the sodium salt of 2-(4-hydroxyphenyl)acetamide of formula (XXV) gives N-benzyl-2-(4-{[2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)acetamide (XXVI-A), which is then reduced to give racemic atenolol of formula (I-A). Yet another aspect of the invention relates to an improved method for preparation of (S)-atenolol of formula (I-B), which comprises reaction of chloromethyl benzene (XX) and isopropyl amine (XXI) to give N-benzyl-N-isopropyl amine (XXII) which on further reaction with S-epichlorohydrin (IIIB) gives (2S)-l-[benzyl(isopropyl)amino]-3-chloropropan-2ol of formula (XXIfl-B). This compound on treatment with an inorganic base gives N-benzyl-N[(2S)-oxirafl-2-ylmethyl]propan-2-amine (XXIV-B) which on reaction with 2-(4-hydroxyphenyl)acetamide (XXV) gives N-benzyl-2-(4-{[(2S)-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)acetamide (XXVI-B), which is then reduced to give (S)-ateno\ol of formula (I-B). A further aspect of the invention relates to an improved method for preparation of (R)-atenolol of formula (I-C), which comprises reaction of chloromethyl benzene (XX) and isopropyl amine (XXI) to give N-benzyl-N-isopropyl amine (XXII) which on further reaction with R-epichlorohydrin (HIC) gives (2R)-l-[benzyl(isopropyl)amino]-3-chloropropan-2ol of formula (XXIII-C). This compound on treatment with an inorganic base gives N-benzyl-N[(2R)-oxiran-2-ylmethyl]propan-2-amine (XXIV-C) which on reaction with 2-(4-hydroxyphenyl)acetamide (XXV) gives N-benzyl-2-(4-{[(2R)-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)acetamide (XXVI-C), which is then reduced to give (R)-atenolol of formula (I-C). Yet a further aspect of the invention relates to a method for preparing atenolol of formula either (I-A) or (I-B) or (I-C) comprising reaction of chloromethyl benzene (XX) and isopropyl amine (XXI) to give N-benzyl-N-isopropyl amine (XXII) which on further reaction with 2-{4-[(2S)-oxiran-2-ylmethoxy]phenyl}acetamide of formula (XXVII) gives N-benzyl-2-(4-{[(2R)-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)acetamide (XXVI-C), which is then reduced to give atenolol of either formula (I-A), (I-B) or (I-C). Yet a further aspect of the invention relates to a simple cost-effective method for purification of racemic atenolol (I-A), (S)-atenolol (I-B) and (R)-atenolol (I-C), which comprises treatment of atenolol [racemic or (S)-isomer or R-isomer] with an organic acid or inorganic acid to give the respective acid addition salt, which is then neutralized with an aqueous solution of an inorganic base to give atenolol of high purity substantially free from impurities. DETAILED DESCRD7TION OF THE INVENTION Atenolol (I-A), (S)-Atenolol (I-B) and (R)-Atenolol (I-C) are obtained by the method summarized in Scheme-V, Scheme-VA and Scheme-VB respectively. Further atenolol of formula (I-A), (I-B) or (I-C) can also be prepared by the method disclosed in Scheme-(V-C). Scheme-VC: Method for preparation of racemic atenolol or specifically its (R) or (S) isomers. The present invention describes a method for preparation of atenolol (as referred in Scheme V), which comprises reaction of chloromethyl benzene (XX) and isopropyl amine (XXI) to yield N-benzyl-N-isopropylamine (XXII). This intermediate on reaction with either racemic epichlorohydrin (III-A) or S-epichlorohydrin (III-B) or R-epichlorohydrin (III-C) gives halohydrin (XXIII-A or B or C) and an epoxide (XXIV-A or B or C). The molar range for epichlorohydrin is 0.25 to 5 moles. This reaction is carried out at a temperature of 40 to 70°C. The same reaction can also be performed in alcoholic solvent. The halohydrin (XXIII-A or B or C) on treatment with an inorganic base in an organic solvent is converted to epoxide (XXIV-A or B or C)). The inorganic base is selected from the group comprising of hydroxides, carbonates, bicarbonates etc. of alkali or alkaline earth metals. The preferred inorganic bases are hydroxide of alkali or alkaline earth metals. More preferably, the inorganic base is the group comprising of NaOH, KOH etc. The molar range of the inorganic base used is 1.0 to 3.5 moles. This reaction is carried out at a temperature of 30-60 °C. This compound (XXIV-A) when reacted with compound of formula (XXV) in presence of base selected from the group comprising of hydroxides, carbonates, bicarbonates etc. of alkali or alkaline earth metals gives (N)-benzylated atenolol (XXVI-A or B or C), which on reduction gives racemic atenolol (I-A) or S-atenolol (I-B) or R-atenolol. The reaction is also catalyzed using phase transfer catalyst such as tetra butyl ammonium iodide, tetra butyl ammonium bromide etc. The preferred inorganic bases are selected from the group comprising of carbonates of alkali or alkaline earth metals. More preferably, the inorganic base is K2C03, Na2C03 etc. The molar range for the inorganic base is 1 to 3 moles. This reaction is carried out at 40 -85 °C. Further, the present invention also provides a method which comprises reaction of N-benzyl-N-isopropyl amine with 2-{4-[(2)-oxiran-2-ylmethoxy] phenyl]acetamide (XXVII-A) to give N-benzylated atenolol, which on reduction with palladium on carbon in alcoholic solvent gives atenolol. The alcoholic solvent is selected from the group comprising of methanol, ethanol, n-proponol, isoproponal etc. This method as summarized in Scheme-VC can be utilized for the preparation of racemic atenolol as well as specifically for its (S) or (R) isomers utilizing the (S) or (R) respectively isomers of epichlorohydrin. The present invention is superior to prior art methods since the formation of impurities is minimal. This is due to the fact that in prior art methods the final product atenolol (I-A or I-B or I-C) obtained by reaction of glycidyl ether (VIII) with isopropyl amine (XXI) has a tendency to react further as atenolol (I-A or I-B or I-C), which has a secondary amine functional group is very likely to react again with the glycidyl ether (VIII) present in the reaction mixture to give an associated impurity (XII) as summarized in Scheme-VI, which is difficult to remove by conventional methods of purification. Scheme-VI: Impurity formed during preparation of atenolol by prior art methods. The method embodied in this invention is very unlikely to give impurity (XII) since a tertiary amine (XXIII) or (XXIV) is formed after reaction with epichlorohydrin (IIIA), (IIEB), or (m-C), which is unlikely to react further to give the associated impurity (XII) formed in prior art methods, due to the complete blocking of the nitrogen atom. The present embodiment thus provides a method for preparation of atenolol (I-A, I-B or I-C), wherein the possibility of forming associated impurities is very much reduced, hence the yields are improved and atenolol (I-A, I-B or I-C) thus obtained has better purity and is substantially free from impurities. PURIFICATION OF ATENOLOL Racemic atenolol of formula (I-A), (S)-Atenolol of formula (I-B) and (R)-atenolol of formula (I-C) obtained by various methods, as disclosed in prior art, are associated with various impurities. As already mentioned before, regulatory authorities all over the world are stringent about the associated impurities. Hence, there is a need for the purification for removal of associated impurities. The said compound is purified according to Scheme-VII, which describes a method for purification of (S)-atenolol (I-B), which is similar to that of racemic atenolol (I-A) and (R)-atenolol. Scheme-VII: Method embodied in the present invention for the purification of atenolol (l-B) Typically, (S)-atenolol (I-B) is treated with an organic or inorganic acid employing an organic solvent like a ketone at ambient temperature to give the acid addition salt (S)-Atenolol salt (XXVIII), which separates out from the mixture as a solid. The organic acids utilized for preparing the acid addition salt is selected from organic acids like acetic acid, methane sulphonic acid, benzene sulphonic acid, trifluoro acetic acid, L-tartaric acid, maleic acid, fumaric acid etc. The inorganic acids used for preparation of salt are selected from the group comprising of acids like HNO3, HO, H2SO4, HBr, etc. The acid addition salt thus prepared is dissolved in water and treated with a dilute solution of an inorganic base to get pH between 12.0 and 12.5 at which the optically pure (S)-isomer (I-B) separates out as a white solid. The inorganic base utilized for liberating the free base of atenolol from its acid addition salt is selected from the hydroxides, carbonates, and bicarbonates of alkali or alkaline earth metal. The preferred bases can be selected from a group comprising of NaOH, KOH, Na2C03, NaHC03, K2C03) LiOH, Ca(OH)2 etc. An advantage of the invention is that the racemic atenolol of formula (I-A), (S)-atenolol of formula (I-B) or (R)-atenolol of formula (I-C) thus obtained by the process of the invention has high purity substantially free from impurities. Yet another advantage is that the atenolol obtained is of high optical purity. This invention is described in detail here below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the invention in any matter. For preparation of Atenolol or enantiomer thereof, the synthetic strategy remains same, but for the use of appropriate enantiomer of epichlorohydrin. Example 1 Preparation of N-benzyl-N-isopropylamine of formula (XXII) Triethylamine (119.9gm) was added to isopropyl amine (XXI; 1000ml) with agitation at ambient temperature. The reaction mixture was cooled to 10-15°C and agitated for 10 mins. Chloromethyl benzene (XX; lOOgm) was added gradually at 10-15°C and the mixture agitated for 24 hrs at 10-15°C. The reaction mixture was concentrated and water (500 ml) was added to the residue. The aqueous layer was extracted with methylene dichloride (2x500ml). The organic layer was separated, dried with anhydrous sodium sulphate and concentrated under reduced pressure to give a thick oily liquid. Yield: 126.7 gin (90.5%). Example 2 Preparation of (2S)-l-[benzyt(isopropyl)aminoJ-3~chloropropan-2-ol (XXIII-B). (2S)-2-(Chloromethyl)oxirane (III-B; 310gm) was added to N-benzyl-N-isopropylamine (XXII; 100.5gm) and the reaction mixture agitated at 55-60°C for 6 hrs. The reaction mixture was concentrated and toluene (300ml) was added and again concentrated to give an oily residue of the product (2S)-l-[benzyl(isopropyl)amino]-3-chloropropan-2-ol. Yield: 158.4 gm (% Yield: 97.3). Example 3 Preparation ofN-benzyl-N-[(2S)-oxiran-2-ylmethyl]propan-2-amine (XXIV-B) (2S)-l-Benzyl(isopropyl)amino]-3-chloropropan-2-ol (2.42gm) was added to methanolic solution of KOH (1.66gm; in 25 ml methanol), and stirred till completion of reaction at 45-50°C. The reaction mixture was then concentrated and water (100ml) was added to the residue followed by addition of methylene chloride (50ml). The organic layer containing the product was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give N-benzyl-N-[(2S)-oxiran-2-ylmethyl]propan-2-amine(XXIV-B) as a thick oily liquid. Yield: 1.3gm (%Yield: 63.41) Example 4 Preparation of N-benzyl-2-(4-{[(2S)-2-hydroxy-34sopropylamino) propyljoxy/phenyl) acetamide (XXVIB). 2-(4-Hydroxyphenyl)acetamide (XXV; 0.75gm) was added to acetone (30ml) followed by addition of K2CO3 (1.035gm), and refluxed for one hour with agitation. (2S)-1-[benzyl(isopropyl)amino]-3- chloropropan-2-ol (XXIII-B; 3.626gm) was added and the reaction mixture refluxed for 48 hrs. The reaction mixture was cooled to 30°C, filtered, washed with acetone, and dried under vacuum. Yield: 1.70gms (%Yield: 96.0) Example 5 Preparation of2-(4-{[(2S)-2-hydroxy-3-(isopropylamino) propyljoxy jphenyl) acetamide S-(-)-Atenolol (IB) N-Benzyl-N-[(2S)-oxiran-2-ylmethyl]propan-2-amine 10 gm, (XXVI-B), methanol (400ml), 5%Pd/C (2gm) was charged into an autoclave and flushed with N2 gas, which was then followed by passage of H2 gas to generate a pressure of 45-50 psi. The mixture was stirred at 35-38°C for 24 hrs and filtered. The filtrate was concentrated and chilled water added to the residue to separate out a white solid, which was then filtered and dried in an oven at 55-60°C. Yield: 7.2 gms; (%Yield: 96.5). Example 6 Preparation of2-{4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl} acetamide acetate( S-(-) Atenolol Acetate Add crude S(-) 2-{4-[2-hydroxy-3-(isopropylamino)prop]oxy]phenyl} acetamide (255.Ogm) to acetone 5.1L (20 vol) with stirring. Cool the reaction mixture to 15-20°C and charge glacial acetic acid (102.0gm) within 10-15mins. Stir for 2.0 hrs at 15-20°C and filter. Wash the mixture with chilled acetone (2 vol.). Wash the wet S (-) atenolol acetate 5-7 times with acetone (7 vol.). HPLC Purity of Crude S (-) Atenolol = 97.5% HPLC Purity of S (-) Atenolol acetate = 99.58% Example 7 Preparation of (S)-Atenolol (IB) from (S)-Atenolol acetate (XXVII). Dissolve wet S (-) atenolol acetate in water (1.53L) (6.0 vol.) & adjust pH =12.5 using 30% NaOH Solution (95.0ml) at 10°C. Stir for 1.0 hour. Filter and wash with chilled water 510.0ml (2.0vol). Dry the material at 50-55°C. (70.27%) HPLC Purity of Pure S (-) Atenolol = 100.0% Example 8 Preparation of (2R)~l-[benzyl(isopropyl)amino]-3-chloropropan-2-ol (XXIII-Q In a 1-lit round bottom flask, charge N-benzyl-N-isopropylamine, (100.5 gm) and (2R)-2-(chloromethyl)oxir Example 9 Preparation of N-benzyl-2-(4-{[(2R)-2-hydroxy-3-(isopropylamino)propyl]oxy}- phenyl)acetamide (XXVI-C) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl)acetamide, 0.75gm), acetone (30ml) and stir for 15 min at 30°C. Add K2C03 1.035gm, and stir for one hr reflux temperature. Add (2R)-l-[benzyl(isopropyl)amino]-3- chloropropan-2-ol 3.626gm, maintain the reflux for 48 hrs. After 48 hrs, reaction cooled to 30°C, filtered, washed with acetone, filtrate collected, concentrated under reduced pressure. Weight of N-benzyf-2-(4-{f(2R)-2-hydroxy-3-(isopropyiamino)propyI]oxy}phenyO acetamide obtained is 1.70 gm (96.0%). Example 10 Preparation of 2-(4-{f(2R)-2-hydroxy-3-(isopropylamino) propyljoxy Jphenyl) acetamide ie. R-(+)-Atenolot (I-C) In 1-lit autoclave high pressure reactor, charge N-benzyl-N~[(2R)-oxiran-2-ylmethylJpropan-2-amine 10 gm, methanol 400 ml, 5% Pd/C 2gm, flush reactor with N2, and pressurised with H2 gas (45-50 psi). Stir the mixture at 35-38°C for 24 hrs. After 24 hrs, reaction mixture was discharged, catalyst was filtered, and filtrate was concentrated. The residue was treated with chilled water and white solid was isolated, which is dried in oven dryer at 55-60°C. Wt of 2-(4-{[(2R)-2-hydroxy-3-(isopropylamino) propyljoxy jphenyl) acetamide i.e . R-(+)-Atenolol obtained is 7.2 gm (96.5%) Example 11 Preparation of N-benzyl-2-(4-{[(2R)-2-hydroxy-3-(isopropylamino)propyl]oxy}- phenyl)acetamide (XXV7-Q In a 100ml round bottom flask, charge 2-{4-[(2R)-oxiran-2-ylmethoxy]phenyl}acetamide 5gm, methanol 50 ml, N-benzylisopropylamine 5.04 gm, reaction mixture was stirred at 60-65°C for 24 hrs. The methanol was removed from the reaction mixture by distillation under reduced pressure. To the residue Methylene dichloride 100ml was added, precipitated solid was filtered, filtrate concentrated. Thick oily liquid was obtained. Weight of N-benzyl-2-(4-{[(2R)-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)-acetamide obtained is 8.0gm (93.13%), Example 12 Preparation ofl-[benzyl(isopropyl)amino/-3-chloropropan-2-ol (XXIII-A) In a 1-lit round bottom flask, charge N-benzyl-N-isopropylamine, 100.5gm, and 2-(chloromethyl)oxirane, 310gm. Heat the reaction mixture to 55-60°C and Stir for 6 hrs at 55-60°C. Distilled off the unreacted excess of 2-(chloromethyl) oxirane (II1-A) from reaction mixture initially then toluene 300ml was added and distilled off un-reacted 2-(chloromethyl) oxirane under reduced pressure. This was repeated until complete removal of un-reacted 2-(chloromethyl)oxirane. Wt of 1-[benzyl(isopropyl)amino]-3-chloropropan~2~ol obtained is 158.4 gm (97.3%) Example 13 Preparation of N-benzyl-2-(4-{[2-hydroxy-3-(isopropylamino)propyl]oxy}- phenyl)acetamide (XXVI-A) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl)acetamide, 0.75gm, acetone (30ml) and stir for 15 min at 30°C. Add K2CO3 1.035gm, and stir for one hr at reflux temperature. Add l-[benzyl(isopropyl) amino]-3- chloropropan-2-ol, 3.626gm maintain the reflux for 48 hrs. After 48 hrs, reaction cooled to 30°C, filtered, washed with acetone, filtrate collected, concentrated under reduced pressure. Weight of N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino) propyljoxy} phenyl) acetamide obtained is J. 70 gm (96.0%) Example 14 Preparation of 2-(4-{[2-hydroxy-3-(isopropylamino) propyljoxy jphenyl) acetamide Le. Atenolol (I-A) In 1-lit autoclave, charge N-benzyl-N-[oxiran-2-ylmethyl]propan~2~amine 10 gm, , methanol 400ml, 5%Pd/C, 2gm flush reactor with N2> and pressurised with H2 gas (45-50 psi). Stir the reaction mixture at 35-38°C for 24 hrs. After 24 hrs, reaction mixture was discharged, catalyst was filtered, and filtrate was concentrated. The residue was treated with chilled water to get a white solid product, which was dried in oven dryer at 55-60°C. Wt o?2-(4-{[2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)-acetamide obtained is 7.2 gm (96.5%) Example 15 Preparation of N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)- acetamide (XXVI-A) In a 100 ml round bottom flask, charge 2-{4-[oxiran-2-ylmethoxy]phenyl}acetamide 5 gm, methanol 50 ml, N-benzylisopropylamine 5.04 gm, reaction mixture was stirred at 60-65°C for 24 hrs. After 24 hrs methanol was distilled off under reduced pressure from the reaction mixture. To the residue, Methylene dichloride 100 ml was added and precipitated solid was filtered, filtrate concentrated. Thick oily liquid was obtained. Weight of N-benzyl~2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)acetamide obtained is 8.0 gm (93.13%). Example 16 Preparation of2-{4-[(2S)-oxiran-2-ylmethoxy]phenyl}acetamide (XXVII) In a 2-lit round bottom flask, charge 2-(4-nydroxyphenyl)acetamide, lOOgm, water, 400ml and stir for half an hour. Add previously cooled NaOH solution [31.78gm + DM water 200ml], cooled to 0°C. Add (2R)-2-(chloromethyl)oxirane, 91.88gm in one hr. Reaction mixture was stirred for 25 hrs. at 0°C. After 25 hrs reaction mixture was filtered, obtained solid was dried at 50°C. Weight of 2-{4-[(2S)-oxiran-2-ylmethoxy]phenyl}acetamide obtained is 137.08gm (73.24%) Example 17 Preparation of N-ben%yl-2-(4-{[(2S)-2-hydroxy-3-(isopropylanuno)propyl] oxy}phenyl)acetamide In a 100ml round bottom flask, charge 2-{4-[(2S)-oxiran-2-ylmethoxy]phenyl}acetamide 5gm, methanol 50ml, N-benzylisopropylamine 5.04gm, reaction mixture was stirred at 60-65°C for 43 hrs. After 43 hrs reaction mixture methanol was distilled off under reduced pressure. To the residue Methylene dichloride 100ml was added, precipitated solid was filtered, filtrate concentrated. Thick oily liquid was obtained. Weight of N-benzyl-2-(4-{[(2S)-2-nydroxy-3-(isopropylamino)propyl]ox yjphenyl) acetamide obtained is 8.0gm (93.13%) Example 18 Preparation of N-benzyl-2-(4-{[-2-hydroxy-3-(hopropylamino)propyl]oxy}phenyl)- acetamide (XXVI-A) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl) acetamide (5gm) acetone (200.0ml) and K2C03 (4.57gm). Heat at 55°C and stir for 1.0 hour at reflux temperature. Add N-benzyl-N-isopropylamino chlorohydrin (16.0 g), maintain the reflux for 15 days. Cool the reaction to 30°C, filter, wash with acetone, and collect the filtrate. The filtrate is concentrated. Add water. Adjust the pH of reaction mixture to 2.0 with hydrochloric acid & extract with dichloromethane. Adjust the pH of aqueous layer adjusted to 12.2 with 30 % sodium hydroxide & extract with dichloromethane. Concentrate the organic layer to an oily product. Weight of N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)-acetamide (XXVI-A) obtained is 8.5 gm (72.1 %). Example 19 Preparation of N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)-acetamide (XXVI-A) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl) acetamide (lOgm) acetonitrile 100ml and K2C03 (18.3 lgm), and heat to 80 °C. Stir at refluxed temperature for 1 hour. Add tetra-butyl-ammonium-idodide in catalytic amounts. Add N-benzyl-N-isopropylamino chlorohydrine (31.96gm), maintain the reflux for 28 hours. After 28 hours, cool the reaction to 30°C and filter. Collect the filtrate and concentrate under reduced pressure. Add water. The pH is adjusted to 1.5 with hydrochloric acid & extracted with dichloromethane. Adjust the pH of aqueous layer 12.2 with 30 % sodium hydroxide & extract with dichloromethane. Concentrate the organic layer to afford the oily product. Weight of N-benzyl-2-(4- {[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)-acetamide (XXVI-A) obtained is 15 gm (63.64 %). Example 20 Preparation of N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)-acetamide (XXVI-A) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl) acetamide, (5gm) acetonitrile 50ml and stir for 15 min at 30°C. Add K2C03 (9.2gm) and heat at 80 °C with stirring. Add tetra-butyl-ammonium-idodide in catalytic amounts Add N-benzyl-N-isopropylamino chlorohydrine 9(gm) and maintain the reflux for 46 hrs. Cool the reaction to 30°C, filter and wash with acetonitrile. Concentrate under reduced pressure. Add water and dichloromethane in the concentrated oil and adjust the pH 0.7 with hydrochloric acid and extract with dichloromethane. Adjust the pH of aqueous layer 12.2 with 30 % sodium hydroxide & extract with dichloromethane. Concentrate the organic layer to afford the oily product. N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino) propyljoxyjphenyl)-acetamide (XXVI-A) obtained is 11.2gm (95.07%). Example 21 Preparation of N-ben7yl-2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy}phenyl)- acetamide (XXVI-A) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl) acetamide, (5gm) acetonitrile 50ml and stir for 15 min at 28°C. Add K2C03 9.15 gm, and heat at 80 °C. Stir for 1 hour at reflux temperature. Add tetra-butyl-ammonium-idodide in catalytic amounts. Add N-benzyl-N-isopropylamino chlorohydrine (9.6gm) and maintain the reflux for 58 hrs. Cool the reaction to 30°C, filter and wash with acetonitrile. Concentrate the mixture under reduced pressure. Add water and dichloromethane in the concentrated oil and adjust the pH to 1.0 with hydrochloric acid. Extract with dichloromethane. Adjust the pH of aqueous layer to 12.2 with 30 % sodium hydroxide and extract with dichloromethane. Concentrate the organic layer to afford the oily proiuct.N-benzyl-2-(4-{[-2-hydroxy-3~ (isopropylamino)propyl]oxy}phenyl)-acetamide (XXVI-A) obtained is 11.5 gm (97.62%). Example 22 Preparation of N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino)propyl]oxy/phenyl)- acetamide (XXVI-A) In a 1-lit round bottom flask, charge 2-(4-hydroxyphenyl) acetamide, 5gm acetonitrile 50ml and stir for 15 min at 27°C. Add K2C03 (9.15 gm) and heat at 80 °C with stirring. Add tetra-butyl-ammonium-idodide in catalytic amounts. Add N-benzyl-N-isopropylamino chlorohydrine (9.6gm) and reflux for 24 hrs. Cool the reaction mixture to 30°C, filter and wash with acetonitrile. Concentrate the reaction mixture under reduced pressure. N-benzyl-2-(4-{[-2-hydroxy-3-(isopropylamino )propyl]oxy}phenyl)-acetamide (XXVI-A) obtained is 10.2 gm (86.58 %). Example 23 Preparation of N-ben%yl-N-[(2S)-oxiran-2-ylmethyl]propan-2-amine (XXIV-A) Add l-Benzyl(isopropyl)amino]-3-chloropropan-2-ol (JO.Ogm) to methanolic solution of KOH (8.192gm) in 100.0ml methanol and stirr till completion of reaction at 45-50 °C. Concentrate the reaction mixture and add water (250ml) to the residue followed by addition of methylene chloride (250ml). Dry the organic layer containing the product over anhydrous sodium sulphate and concentrate under reduced pressure to give N-benzyl-N-[(2S)-oxiran-2-ylmethyl]propan-2-amine(XXIV-A) as a thick oily liquid. Yield: 8.7gm (98%Yield) Example 24 Preparation of racemic 2-{4-(2-hydtroxy-3-(isopropylamino) propoxy)phenyl} acetamide acetate. Add crude race/w/'c2-hydroxy-3-(isopropylamino) propoxy) acetamide (25.0gm) to acetone 0.5 L (20vol) with stirring for 15minutes. Cool the reaction mixture to 15-20°C and charge glacial acetic acid lO.Ogm within 10-15 minutes. Stir the mixture for 2.0 hrs at 15-20°C. Filter and wash with chilled acetone (2 vol). Wash the wet racemic atenolol acetate 5-7 times with acetone (7 vol.). Dissolve wet racemic atenolol acetate in water 150 ml (6.0 vol.) and adjuste the pH =12.5 using 30% NaOH Solution (11.0ml) at 10°C. Stir for 1.0 hour. Filter and wash with chilled water 50.0ml (2.0vol). Dry the material at 50-55°C. Yield (75.04%) HPLC Purity of Crude Atenolol = 96.96% HPLC Purity of Atenolol acetate =99.32% HPLC Purity of Pure Atenolol = 99,77% We claim: 1. A process for the preparation of atenolol, comprising the steps of: a) coupling of chloromethyl benzene (XX) with isopropyl amine to give N-benzyl-N-isopropyl amine, b) reacting N-benzyl-N-isopropylamine (XXII) with epichlorohydrin (III-A), c) converting the halohydrin (XXIII-A) in the presence of a base to the epoxide, d) reacting the salt of phenyl acetamide (XXV) with the halohydrin (XXIII A) or the epoxide (XXIV-A) in the presence of a base and e) debenzylating the N-benzylated atenolol (XXVI-A) to racemic atenolol (I-A). 2. A process as claimed in claim 1, wherein the intermediate (XXVI-A) is formed comprising steps of: b) reacting parahydroxy phenyl acetamide (II) with epichlorohydrin (III-A), a) coupling of chloromethyl benzene (XX) with isopropyl amine to give N-benzyl-N-isopropyl amine, c) reacting the acetamide (XXVII-A) with N-benzyl-N-isopropyl amine (XXII) and d) debenzylating (XXVI-A) to yield atenolol. 3. A process as claimed in claim 1, wherein atenolol formed is (S) atenolol with proviso that epichlorohydrin used is (S)-epichlorohydrin. 4. A process as claimed in claim 1, wherein atenolol formed is (R) atenolol with proviso that epichlorohydrin used is (R)-epichlorohydrin. 5. A process as claimed in claim 1(c), wherein the base used is selected from the group comprising of hydroxides, carbonates, bicarbonates of alkali and alkaline earth metals. 6. A process as claimed in claim 1(c), wherein the base used is selected from the group comprising of hydroxides of alkali and alkaline earth metals. 7. A process as claimed in claim 1(c), wherein the base used is selected from the group comprising of KOH and NaOH. 8. A process as claimed in claim 1(d), wherein the base used is selected from the group comprising of hydroxides, carbonates, bicarbonates of alkali and alkaline earth metals. 9. A process as claimed in claim 1(d), wherein the base used is selected from the group comprising of carbonates of alkali and alkaline earth metals. 10. A process as claimed in claim 1(d), wherein the base used is selected from the group comprising of K2C03 and Na2C03. 11. A process as claimed in claim 1(d), wherein the base is used along with a phase transfer catalyst. 12. A process as claimed in claim 12, wherein the phase transfer catalyst is selected form tetra butyl ammonium iodide or tetra butyl ammonium bromide. 13. A process for preparing atenolol and optically pure atenolol substantially as described with reference to the examples. Dated this 6th day of December, 2004 [RAJESHWARI H.| OF K&S PARTNERS ATTORNEY FOR THE APPLICANT(S)

Documents:

1299-mum-2004-cancelled pages(02-12-2005).pdf

1299-mum-2004-claims(granted)-(02-12-2005).doc

1299-mum-2004-claims(granted)-(02-12-2005).pdf

1299-mum-2004-correspondence(01-04-2008).pdf

1299-mum-2004-correspondence-(ipo)-(31-05-2007).pdf

1299-mum-2004-form 1(06-12-2001).pdf

1299-mum-2004-form 18(07-07-2006).pdf

1299-mum-2004-form 2(granted)-(02-12-2005).doc

1299-mum-2004-form 2(granted)-(02-12-2005).pdf

1299-mum-2004-form 3(02-04-2008).pdf

1299-mum-2004-form 3(02-12-2003).pdf

1299-mum-2004-form 5(02-11-2008).pdf

1299-mum-2004-form 5(02-12-2005).pdf

1299-mum-2004-petition under rule 137(02-04-2008).pdf