FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Process for the purification of benzyl nebivolol
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat,
Ahmedabad - 382210, Gujarat, India

PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed
4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION
The present invention relates to a commercially feasible process for the purification of benzyl nebivolol which involves the separation of RSSS/SRRR isomeric pair of benzyl nebivolol from the mixture of RSSS/SRRR and RSRR/SRSS benzyl nebivolol isomers.
BACKGROUND OF THE INVENTION
Nebivolol, (1RS, 1'RS)-1, 1'-[(2RS, 2'SR)-bis (6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-yl)]- 2,2'-iminodiethanol is a racemate composed of d-Nebivolol and l-Nebivolol with the stereochemical designations of [SRRR]-nebivolol and [RSSS]-nebivolol, respectively. Nebivolol hydrochloride is an adrenergic beta-antagonist, an antihypertensive agent, a platelet aggregation inhibitor and a vasodilating agent represented by the following structures:

Nebivolol contains four asymmetric centers, and therefore 16 stereoisomers are theoretically possible. However, because of the particular constitution of the structures and configurations of the stereoisomers only 10 stereoisomers (6 diastereomers: 4 dl forms and 2 meso forms) be formed.
U. S. Patent No. 4,654,362 discloses a non-stereoselective preparation of nebivolol stereoisomers from 2-oxiranyl-chromans. 2-oxiranyl-chromans as two diastereomeric racemates ("A form" =RS/SR and "B form" =SS/RR) are formed from the racemic aldehydes which are separated by chromatography. The A-form is then treated with benzylamine to obtain the benzylated A-form of 2-oxiranyl-chroman, which is then reacted with the B-form to obtain N-benzyl protected nebivolol. The protecting group is removed in the final step by catalytic hydrogenation to obtain nebivolol base. The said

patent does not provide description of a workup procedure, separation of stereoisomers or yields for the benzyl nebivolol.
U.S. Patent No. 6,545,040 discloses a process for stereoselective synthesis of RSSS and SRRR nebivolol isomers independently by using enantiopure intermediates. The said process for the preparation of independent isomers involves the use of hazardous reagents like di-isobutyl aluminium hydride (DIBAL), expensive optically active reagents like (+)-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1 -methylethyl-1 -phenathrene methan-amine [(+)-dehydroabietylamine]. It is a multistep process which is commercially unattractive.
U. S. Patent No. 5,759,580 describes a process for the separation of RSSS/SRRR isomers of nebivolol hydrochloride from mixture of RSSS/SRRR and RSRR/SRSS isomers wherein nebivolol hydrochloride salts are formed in ethanol and then re-crystallized from ethanol. The yield of the process is as low as 6.6%.
PCT publication WO2007/083318 discloses the purification process of benzyl nebivolol in ether to obtain RSSS/SRRR isomeric pair of benzyl nebivolol.
There is an unmet need to provide industrially viable process for the purification of benzyl nebivolol, an intermediate of nebivolol with high yield.
OBJECT OF THE INVENTION
The object of the present invention is to provide a process for the purification of benzyl nebivolol which involves the separation of RSSS/SRRR isomeric pair of benzyl nebivolol from the mixture of RSSS/SRRR and RSRR/SRSS benzyl nebivolol isomers.
SUMMARY OF THE INVENTION
A process for the purification of benzyl nebivolol which involves separating RSSS/SRRR isomeric pair of benzyl nebivolol from the mixture of RSSS/SRRR and RSRR/SRSS isomers of benzyl nebivolol by suspending or dissolving the said mixture in an alcohol and then isolating solid to obtain RSSS/SRRR isomers of benzyl nebivolol.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the purification of benzyl nebivolol which involves the separation of RSSS/SRRR isomeric pair of benzyl nebivolol from the mixture of RSSS/SRRR and RSRR/SRSS isomers of benzyl nebivolol, comprising the steps of:
(a) suspending or dissolving the mixture of RSSS/SRRR and RSRR/SRSS
isomers of benzyl nebivolol in an alcohol; and
(b) isolating solid to obtain RSSS/SRRR isomeric pair of benzyl nebivolol.

Alcohol used is selected from the group of C1 to C4 alcohols such as methanol, ethanol, propanol, 2-propanol (IPA), n-butanol, 2-butanol, isobutanol, tert-butanol or mixtures thereof.
Isolation is done by cooling, drying, adding an anti-solvent or seeding; preferably by cooling.
Isolation by cooling is done below 45°C.
■ The present invention provides benzyl nebivolol having high enatiomeric purity and yield of RSSS/SRRR isomeric pair.
The present invention is further illustrated by following non-limiting examples.
Example 1: Purification of benzyl nebivolol
The crude benzyl nebivolol (25 gm) was stirred with IPA (125 ml) at 80-85°C for about 2 hours, cooled to 25-30°C and stirred at same temperature for about 10-12 hours, the precipitated solid was filtered, washed with IPA (25 ml) and dried at about 50-55°C for about 5-6 hrs to give purified benzyl nebivolol. (Yield= 92%)

We claim:
1. A process for the purification of benzyl nebivolol which involves separating
RSSS/SRRR isomeric pair of benzyl nebivolol comprising the steps of:
(i) suspending or dissolving the mixture of RSSS/SRRR and RSRR/SRSS
isomers of benzyl nebivolol in an alcohol; and
(ii) isolating solid to obtain RSSS/SRRR isomeric pairs of benzyl nebivolol.
2. The process as claimed in claim 1, wherein the C1 to C4 alcohol is selected from methanol, ethanol, propanol, 2-propanol, n-butanol, isobutanol and tert-butanol or mixture thereof.
3. The process as claimed in claim 2, wherein the preferred C1 to C4 alcohol is 2-propanol.
4. The process as claimed in claim 1, wherein isolation is carried out by cooling, drying, adding an anti-solvent or seeding.
5. The process as claimed in claim 4, wherein isolation is carried out by cooling.
6. The process as claimed in claim 5, wherein isolation is carried out by cooling below 45°C.