Title of Invention

PROCESS FOR SYNTHESIS OF OPTICALLY PURE ATENOLOL

Abstract

A process for the preparation of Atenolol of high optical purity comprises steps > Resolution of 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol using unsupported or supported lipases from Pseudomonas cepacia in ionic liquid vinyl acetate system to yield chiral 1-[p-(carbamoylmethyl) phenoxy]-3-chloropropan-2-ol and l-[p-(carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane > Reaction of 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol with isopropyl amine and water to yield S-Atenolol > Reaction of l-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane with isopropyl amine, water and inorganic base to yield f?-Atenolol. > Optional recycling of the Ionic liquid and enzyme > Optional separation of the enzyme for reuse.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) 'Process for synthesis of optically pure Atenolol' The Institute of Science, 15-Madam Cama Road, Mumbai-400 032. Maharashtra, India. Indian Educational Institute. [Own and managed by State Government of Maharashtra] The following specification particularly describes the nature of this invention and the manner in which it is to be performed:- ORIGINAL 17 MAR 2004 GRANTED Field of the invention This invention relates to a process for the preparation of (S)- Atenolol of high optical purity using the resolution of the intermediate 1-[p-(carbamoylmethyl)phenoxy]-3-chloropropan-2-ol (1) in ionic liquids with vinyl acetate and enzyme. Background of the invention Atenolol (i.e.4-[2-hydroxy-3-(1 -methylethyl)amino]propoxy benzeneacetamide) is useful as a p-adrenergic blocker for treatment of hypertension and angina. Out of the two isomers R and S; S - isomer is of particular importance because of its superior pharmacological activity (Pearson, A. A. et al. J. Pharmacol. Exp. Ther. 250 (3), 759, 1989: Chem. Eng. News, 69(17), 16, 1991). It is known that optically pure Atenolol can be obtained by asymmetric synthesis; like by using multiple steps starting from D-Mannitol (Tucker, H. (JCI Ltd. Ger. Offen. 2453324; Chem. Abstr. 83, 96993, 1975), reaction of 4-hydroxy phenyl acetamide with chiral epichlorohydrin in presence of different reagents (Kitaori, K. et al. Tetrahedron, 55(50), 14381, 1999; Takehira et al. Eur. Pat. Appl. 1991) to get chiral glycidyl ether and treatment of this compound with isopropyl amine. There are several disadvantages associated with these chemical methods such as longer reaction time and high temperature that affect the enantioselectivity of the reaction. Bevinakatti et.al. ( Bevinakatti, H. S. et al. J. Org. Chem. 57, 6003, 1992) have used lipase from Pseudomonas cepacia for the synthesis of optically pure Atenolol. They state that, it was not possible to resolve the compound (1), using enzymes due to its insolubility in common organic solvents. Compound (1-A) was used for the purpose of resolution, which contains ester group in place of amide group. After resolution of this compound and treatment with isopropyl amine, the resultant compound is treated with ammonium hydroxide to obtain the desired product i.e. optically pure Atenolol. The prior art (Bevinakatti, H. S. et al. J. Org. Chem. 57, 6003, 1992) which is a cumbersome, time-consuming, multistep process, involves the resolution of intermediate (1-[p-(carbamoylmethyl)phenoxy]-2-acetoxy-3-chloropropane) from its racemic mixture using unsupported lipase in organic solvents. The in¬form of intermediate is treated with isopropylamine followed by its amidation resulting in S-atenolol. Therefore in the prior art amidation is an essential additional step performed since intermediate (1-[p-(carbamoylmethyl)phenoxy]-3-chloropropan-2-ol) is insoluble in common organic solvents. It is a longfelt need in the industry to provide a direct, convenient and environment friendly process for the synthesis of chiral Atenolol. Summary of the invention: The main objective of the invention is to provide a novel process for the preparation of optically pure isomer of the drug Atenolol. Another objective of the invention is to provide a process for resolution of 1-[p-(carbamoylmethyl)phenoxy]-3-chloropropan-2-ol (1) using enzyme and vinyl acetate in ionic liquids. It is yet another objective of the invention to explore the possibility of recycling of solvent 'ionic liquid' as well as enzyme catalyst. The present invention achieves the resolution of this intermediate in combination with vinyl acetate and ionic liquid using lipase Pseudomonas cepacia supported (PS-C and PS-D) as well as unsupported. The essential feature of this invention is the novel use of (1-[p-(carbamoylmethyl)phenoxy]-3-chloropropan-2-ol) and the resolution of its R & S -isomers using ionic liquids and supported/unsupported lipases from Pseudomonas cepacia and its direct conversion to R/S-atenolol, thereby avoiding multiple steps as taught in the prior art. This invention exploits the use of ionic liquids and \ — •- ■ " ' \ (supported/unsupported) for resolution of intermediate (1-[p- (carbamoylmethyl)phenoxy]-3-chloropropan-2-ol). Thus in accordance with this invention: >Intermediate (1) is prepared from 4-hydroxy phenyl acetamide, using procedure described by Bevinakatti et al. > Intermediate compound (1) is resolved by lipase from Pseudomonas cepacia (unsupported as well as supported) in ionic liquid - vinyl acetate system to give chiral alcohol (2)and ester (3). > Ionic liquid and enzyme both were recycled and reused. > Treatment of (2) with isopropyl amine and water gives S-Atenolol and treatment of (3) with isopropyl amine, water and NaOH gives R-Atenolol. Detailed description of the invention: The process for producing optically active Atenolol comprises of preparation of intermediate (1) and its resolution using ionic liquid (hydrophobic ionic liquid such 1-butyl-3-methylimidazolium hexafluorophosphate or hydrophilic ionic liquid such as 1-butyl-3-methylimidazolium tetraffuoroborate) -vinyl acetate system (in the ratio of about 2:1 to about 5:1 preferably of 3:1) with supported and unsupported lipase from Pseudomonas cepacia (11,000 units To about 13,500 units). In the present invention lipase supported on celite, (lipase PS-C) or on diatomaceous earth (PS-D) or unsupported (PS) from Pseudomonas cepacia is obtained from Amano Pharmaceuticals, Japan. .The supported and unsupported lipases from Pseudomonas cepacia used in the present invention are commercial product of Amano Pharmaceuticals, Japan. The resultant chiral alcohol 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan- 2-ol (2) and ester 1-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3- chloropropane (3) are separated by column chromatography. R/S Atenolol is obtained by treatment of these compounds with isopropyl amine. 4-hydroxy phenyl acetamide is treated with epichlorohydrin in presence of base (aq. NaOH) at room temperature for 48 hrs. Mixture of the products; 1- [p-(carbamoylmethyl)phenoxy]-2-3-epoxypropane and 1-[p- (carbamoylmethyl)phenoxy]-3-chloropropan-2-ol is obtained. This mixture is filtered and resultant solid is dried under vacuum. This solid mixture is suspended in methanol and dry HCI gas is passed through this suspension for one hour under cold conditions. Methanol is evaporated and resultant solid is recrystallised from chloroform to obtain pure (1); 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol. This compound (1) is resolved by taking it in ionic liquid-vinyl acetate system (in the ratio of about 2:1 to about 5:1 preferably of 3:1) and by using lipase PS/PS-C/PS-D (11,000 units To about 13,500 units); the reaction mixture is stirred at room temperature (at temperatures in the range 27 °C to 40 °C)\till 50 % conversion is reached. The resultant products (2) 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol and (3) 1-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane are separated by column chromatography. Ionic liquid and enzyme both were recycled without considerable loss in their properties. (2) is treated with isopropyl amine and water system in ratio 3:1 and ratio of compound (2) to this system was around 1:4 to obtain optically pure S- Atenolol and (3) is treated with isopropyl amine, water and inorganic base, such as sodium hydroxide, potassium hydroxide, potassium carbonate in ratio 3:1:1:13F and ratio of compound (3) to this system was around 1:3 to 1:6 preferably at 1:4 to obtain optically pure R-Atenolol. Both the isomers were purified by washing with cold methanol. The invention is now illustrated with non limiting examples. Example 1: preparation of intermediate 1-[p-(carbamoylmethyl)phenoxy]-3-chtoropropan-2-ol (1) from 4-hydroxyphenyl acetamide: A reaction mixture containing 5g. of 4-hydoxyphenylacetamide, 26 ml. epichlorohydrin, 0.66 g. NaOH and 10 ml. water is stirred for about 48 h at room temperature. A mixture of products 1-[p-(carbamoylmethyl)phenoxy]-2- 3-epoxypropane and 1-[p-(carbamoylmethyl)phenoxy]-3-chloropropan-2-ol is obtained as shown in schemel. This mixture is filtered and dried under vacuum. 3 g. of this mixture is taken in 50-ml. methanol and dry HCI gas is passed through this solution for about 1 h under cold conditions. Evaporation of methanol followed by recrystalisation of solid gives 3g. intermediate (1)1-[p- (carbamoylmethyl) phenoxy]-3-chloroproan-2-ol. Example 2: Resolution of intermediate (1) prepared in example 1 in ionic liquid-vinyl acetate system using supported and unsupported lipase from Pseudomonas cepacia, which is a key step of this investigation. A reaction mixture containing 1.0 g. substrate (1) in 16 ml. ionic liquid, 8 ml. vinyl acetate and lipase PS-C/PS-D/PS (13,200 units) is stirred for 90 h. at room temperature (c.a. 50% conversion). Excess of vinyl acetate is removed under reduced pressure and products (2) 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol and (3) 1-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane is extracted in diethyl ether. The solvent is removed under vacuum and these products are separated by column chromatography. The yield of (2) is 0.470 g. and (3) is 0.420 g. Example 3: This illustrates the recycling and reusability of ionic liquids as well as enzymes. The supported lipases offer the advantage of reusability over unsupported lipases. In this investigation after the reaction described in example 2, the system containing ionic liquid and enzyme is washed twice with ether. The system is made free from ether under vacuum. To this system of ionic liquid and enzyme substrate (1) and vinyl acetate was charged (addition of 10 mg. of new enzyme is necessary for desired conversion). If enzyme has to be separated, it can be separated by addition of dichloromethanaio the system of ionic liquid and enzyme and after filtration the enzyme can be preserved and reused in subsequent reactions. Example 4: Synthesis of desired isomer of 'Atenolol' from (2) obtained from example 2. The reaction mixture containing 0.2 g. of (2), isopropyl amine 2 ml. and water 0.8 ml is stirred for about 24 h. at room temperature. After reaction is over, excess of isopropyl amine is removed under reduced pressure and product is extracted in diethyl ether. Evaporation of solvent yields 0.17 g. of S- Atenolol. The product is purified by washing with minimum quantity of cold methanol. [α]D=-12.7(1,EtOH). Example 5: Synthesis of other isomer of Atenolol from compound (3) obtained in example 2. Essentially the same procedure as described in 4 is followed, except that sodium hydroxide is also used. The product is purified by washing with minimum quantity of cold methanol. [Α]D= 12.45 (1, EtOH) We claim, 1. A process for the preparation of Atenolol of high optical purity comprises steps > Resolution of 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol using unsupported or supported lipases from Pseudomonas cepacia in ionic liquid vinyl acetate system to yield chiral 1-[p-(carbamoylmethyl) phenoxy]-3-chloropropan-2-ol and l-[p-(carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane > Reaction of 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol with isopropyl amine and water to yield S-Atenolol > Reaction of l-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane with isopropyl amine, water and inorganic base to yield f?-Atenolol. > Optional recycling of the Ionic liquid and enzyme > Optional separation of the enzyme for reuse. 2. A process for the preparation of Atenolol of high optical purity as claimed in claim 1 wherein the lipases supported on materials selected from celite (PS-C) or diatomaceous earth (PS-D) is obtained from Pseudomonas cepacia. 3. A process for the preparation of Atenolol of high optical purity as claimed in claim 1 wherein the unsupported lipase (PS) is obtained from Pseudomonas cepacia. 4. A process for the preparation of Atenolol of high optical purity as claimed in claims 1-3 wherein^the intermediate 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol is resolved in steps comprising > Mixing the intermediate in hydrophobic ionic liquid such as 1- butyl-3-methylimidazolium hexafluorophosphate or in hydrophilic ionic liquid such as 1-butyl-3-methylimidazolium tetrafluoroborate and vinyl acetate system in the ratio OF 2:1 to 3:1 and lipase PS-C/PS-D/PS of 11,000 units to 13,500 units > Stirring the mixture for 90 hrs at temperature in the range 27 °C to 40 °C to obtain chiral 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol and 1-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane, after the removal of excess vinyl acetate and extraction in diethyl ether. 5. A process for the preparation of S-Atenolol of high optical purity as claimed in claims 1-4 wherein 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol is reacted with isopropyl amine/water system in ratio of 2:1 to 5:1, preferably of 3:1 and ratio of 1-[p- (carbamoylmethyl) phenoxy]-3-chloropropan-2-ol to the isopropyl/water system of 1:3 to 1:6, preferably 1:4 for a period of 16 hrs to 26 hrs, preferably for 22 hrs at about 27 °C to 40 °C, followed by removal of excess isopropyl amine on completion of the reaction and extraction of the product in diethyl ether, evaporating the solvent and purifying the product by washing with cold methanol. 6. A process for the preparation of f?-Atenolol of high optical purity as claimed in claims 1-4 wherein 1-[p- (carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane is reacted with isopropyl amine/alkali/water system in ratio of 2-5:0.8-1.5:1-2, preferably 3:1.1:1 and ratio of l-[p-(carbamoylmethyl) phenoxy]-2-acetoxy-3-chloropropane to this system of 1:3 to 1:6, preferably 1:4, for 8 hrs at abetrt-27 °C to 40 °C; followed by removal of excess isopropyl amine on completion of the reaction and extraction of the product in diethyl ether, evaporating the solvent and purifying the product by washing with cold methanol. 7. A process as claimed in claims 1 and 6 wherein the alkali is selected from sodium hydroxide, potassium hydroxide, potassium carbonate preferably sodium hydroxide. 8. A process as claimed in claims 1-4 wherein the system containing ionic liquid and enzyme is recyclable and reusable. 9. A process as claimed in claim 4 wherein the system containing ionic liquid and enzyme is washed with ether followed by freeing the system of ether to yield the recyclable and reusable ionic liquid and enzyme system. Dated this 17th day of March 2003 Applicant (The Institute of Science, Mumbai)

Documents:

828-mum-2003-cancelled pages (17-03-2004).pdf

828-mum-2003-claim(granted)-(17-3-2004).doc

828-mum-2003-claims(granted)-(17-03-2004).pdf

828-mum-2003-correspondence 1(29-08-2003).pdf

828-mum-2003-correspondence 2(19-08-2004).pdf

828-mum-2003-correspondence(ipo)-(27-06-2006).pdf

828-mum-2003-form 1(19-08-2003).pdf

828-mum-2003-form 1(29-08-2003).pdf

828-mum-2003-form 19(19-08-2003).pdf

828-mum-2003-form 2(granted)-(17-03-2004).pdf

828-mum-2003-form 2(granted)-(17-3-2004).doc

828-mum-2003-form 3(19-08-2003).pdf

828-mum-2003-form 3(29-08-2003).pdf

828-mum-2003-form 5(19-08-2003).pdf

828-mum-2003-power of attorney (19-08-2003).pdf