FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Process for preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad
- 382210, Gujraat, India
3. PREAMBLE TO THE DESCRITION
COMPLETE SPECIFICATION
The following specification particularly describes the invension and the manner in which it is to be performed.
4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION
The present invention provides a process for the preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of formula-ll, intermediate for the preparation of Nebivolol, from the mixture containing undesired isomers of Nebivolol. The compound of formula-ll is further converted into Nebivolol of formula (I).

BACKGROUND OF THE INVENTION
U.S. patent no. 4,654,362 disclosed 2,2'-iminobisethanol derivatives. The compounds are antihypertensive agents. Among them Nebivolol, chemically known as (±)-[2R*[1S*,5S*(S*)]]-α,α1-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzo-pyran-2-methanol] is the most important antihypertensive agent.
Nebivolol, is a mixture of equal amounts of compound of formula (IA) and its enantiomer i.e. compound of formula (IB)

Nebivolol is administered as tablets which contains Nebivolol as an enantiomeric mixture of SRRR-Nebivolol (dextro d-Nebivolol) and RSSS-Nebivolol (levo l-Nebivolol).
Nebivolol contains four asymmetric centers, and therefore 16 stereo isomers are theoretically possible. However, because of the particular constitution of the structures and configurations of the stereo isomers (e.g., axial symmetry), only 10 stereo isomers (6 diastereomers: 4 dl forms and 2 meso forms) is formed.
Literature reports several processes for the preparation of Nebivolol (racemic mixture of enantiomers SRRR-Nebivolol and RSSS-Nebivolol).
Methods for preparation of Nebivolol are disclosed in US4654362 and US6545040. US4654362 describes a process for the conversion of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (II) into isomeric mixtures of 6-fluoro-3, 4-dihydro-2-oxiranyl-

2H-1-benzopyran (III). The mixture of oxiranes represented by the formula (III) are separated by column chromatography to obtain A-isomer of (III) (i.e., Ill-A) from the first fraction and B-isomer of (III) (i.e., lll-B) from the second fraction.
The A-isomer of (III) is then treated with benzylamine to obtain the compound-IV of scheme-l, which is reacted with compound III (B) in presence of oxalic acid to obtain the oxalate salt of benzylated Nebivolol. Furthermore the oxalate salt as obtained has to be treated with an alkali to obtain the free benzylated Nebivolol base (V), (Scheme-l).

Thus, as seen from Scheme I, the reaction between Intermediate-IV and (lll-B) involves purification by column chromatography, and subsequent treatment with oxalic acid to form the oxalate salt. Treatment with oxalic acid results in the separation of the undesired (RSRR+SRSS) diastereomers from the desired (RSSS+SRRR) isomers, due to the difference in solubility's between the desired and the undesired isomers. Further, the oxalic

acid salt has to be converted to the free benzylated nebivolol base by treatment with an alkali. The multiple steps in the process make it cumbersome and lead to increase in utilities and in the manufacturing time cycle of the active pharmaceutical ingredient. Moreover the purity of the free benzylated nebivolol base is also found to be relatively low.
U. S. patent no. 6545040 discloses a process for the preparation of RSSS isomer and SRRR isomer of Nebivolol independently. The said process for the preparation of RSSS nebivolol involves the use of hazardous reagents like thionyl chloride, sodium hydride and 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 -phenathrenemethanamine [(+)-dehydro abiethylamine] and utilities like column chromatography and low temperatures. The processes also involve a large number of steps thereby increasing time required to complete the production cycle, rendering the process commercially expensive.
Furthermore, U.S. patent No. 5,759,580 describes a process for obtaining Nebivolol hydrochloride from a mixture containing the desired (RSSS+SRRR) Nebivolol base contaminated by the undesired (RSRR+SRSS) diastereomers, using ethanol as both, reaction solvent as well as crystallization solvent. The process involves the use of impure Nebivolol base as the starting material containing different isomeric impurities, and thereby results in a low yield (6.6%) of the desired isomers (having the SRRR- and the RSSS-configuration) of Nebivolol hydrochloride.
In order to be viable for commercial manufacturing, such a process needs recycling of the undesired isomeric mixture of nebivolol.
We have surprisingly found a process for conversion of undesired isomeric mixture of Nebivolol to 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde of formula-ll, key intermediate for preparing Nebivolol.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a process for conversion of undesired isomeric mixture of Nebivolol to 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde of formula-ll, key intermediate for the preparation of Nebivolol.
Yet another object of the invention is to reduce the cost of nebivolol production by converting undesired nebivolol isomers to 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde which is useful intermediate for preparation of nebivolol.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a synthesis of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxa!dehyde from Nebivolol. Herein after Nebivolol term is used in place of a single stereoisomer or a mixture or combination 6f any no of isomers, more specifically from all


possible stereoisomers, in any proportion / ratio and is not restricted to any particular stereoisomer or stereoisomers. This synthesis is depicted as Scheme-ll.
As per prior art method when the isomeric mixture of Nebivolol is separated, the undesired isomeric mixture of Nebivolol is obtained as a waste product. In the process of the present invention, the undesired isomeric mixture of nebivolol is oxidatively cleaved to produce 6-fluoro chroman 2- carboxaldehyde which can be further used to convert to epoxide, which can be converted to Nebivolol desired isomers.
The solvent used for the reaction is selected from C1 to C4 chlorinated solvent such as , such as dichloromethane, 1,2 dichloroethane, 1,3 dichloro propane, 1,4-dichloro butane and the like, preferably dichloromethane.
The preferred reagent used for the reaction is periodic acid (HI04), or its alkali metal or alkaline earth metal salt; the salt include but does not limit to, salt such as potassium periodate (Kl04) or Sodium periodate (Nal04), preferably HI04 or Nal04 Other reagents, such as mixture of HCI04+HI04 may also be useful. Other reagents such as Mn (III) acetate, lead tetra acetate can also be used to convert Nebivolol to 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde.
After treating the aqueous solution of periodic acid or its salt with nebivolol in suitable halogenated solvent, the reaction mixture is stirred for a period, such as from about 1-24 hours at 0-150°C. The desired product is then isolated by conventional extractions and solvent removal. The solvent used is C1 to C4 chlorinated solvent, such as dichloromethane, 1,2 dichloroethane, 1,3 dichloro propane, 1,4-dichloro butane and the like, preferably dichloromethane.
The product of the present process, the 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde compound, is converted to Nebivolol using prior art process.
The isomer of Nebivolol are selected from,
1. (+)-[2R-[2R*[R*[R*(S*)]]]]-alpha1alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-
2H-1-benzopyran-2-methanol]
2. (-H2S-[2R*[R*[R*(S*)]]]]-alpha,alpha'[iminobis(methylene)]bis[6-fiuoro-3,4-dihydro-
2H-1 -benzopyran-2-methanol]
3. (+)-t2S-[2R*[S*[S*(R*)]]]]-alpha,alpha'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-
2H-1 -benzopyran-2-methahol]

4. (-)-[2R-[2R*[R*[S*(R*)]]]]-alpha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
5. (+)-[2S-[2R*[R-[S*(R*)]]]]-alpha,alpha [iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]
6. (-)-[2R-[2R*[S*[S*(R*)]]]]-alpha,alpha'[iminobis(methylene)]bis[6-fiuoro-3,4-dihydro-2H-1-benzopyran-2-methanol]
7. (-)-[2R-[2R*[R*[R*(R*)]]]]-alpha,alpha[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
8. (±)-[2R*[R*[S*(S*)]]]]-alpha,alpha'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]
9. (+)-[2S-[2R*[R*[R*(R*)]]]]-a!pha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
10. [2R-[2R*[S*[R*(S*)]]]]-alpha,alpha'[imnobis(methylene)]bis[6-fluo-3,4-dihydro-2H-1-benzopyran-2-methanol]
Advantages of the present invention:
[1] Isomers of Nebivolol are converted to 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde to enhance the yield of Nebivolol. [2] The process is scalable for commercial scale.
The invention is illustrated by following non-limiting examples:
Example-1 Preparation of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde:
A Nebivolol hydrochloride (5 gm) m 50 ml dichloromethane was stirred at below 15-20°C. HI04 (3.1 gm in 20 ml purified water) solution was added gradually to the reaction mass at 15-200C within one hour and raised the temperature of the reaction mass up to 25-30°C. Stirred the reaction mass for 3-4 hours at 25-30°C. Filtered the reaction mass through hyflo bed. Separated the layers and washed the dichloromethane layer with 25 ml purified water. Separated the dichloromethane layer and dried the dichloromethane layer over 1.0 g. sodium sulfate and dichloromethane layer contained the 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde.
Example-2 Preparation of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde:
Nebivolol hydrochloride (5 gm) in 50 ml dichloromethane was stirred at below 15-20°C. Nal04 (2.43 gm in 20 ml purified water) solution was added gradually to the reaction mass at 15-20°C within one hour and raised the temperature of the reaction mass up to 25-

30°C. Stirred the reaction mass for 3-4 hours at 25-30°C. Filtered the reaction mass through hyflo bed. Separated the layers and washed the dichioromethane layer with 25 ml purified water. Separated the dichioromethane layer and dried the dichioromethane layer over 1.0 g. sodium sulfate and dichioromethane layer contained the 6-fIuoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde.

We claim:
[1] A process for the conversion of isomer of Nebivolol to 6-fIuoro-3, 4-dihydro-2H-t- benzopyrari-2-carboxaldehyde comprising steps:
(a) Reacting isomer of Nebivolol in a solvent with aqueous solution of periodic acid or its salt to give 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde;
(b) Removing the solvent from step (a) to obtain 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde.
[2] The isomer of Nebivolol as claimed in claim 1 are selected from, 1. (+)-[2R-[2R*[R*[R*(S*)]]]]-alpha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 benzopyran-2-methanol]
2. (-)-[2S-[2R*[R*[R*(S*)]]]]-alpha,alpha'[iminobis(methylene)]bis[6-fluoro-3t4-dihydro-
2H-1 -benzopyran-2-methanol]
3. (+)-[2S-[2R*[S*[S*(R*)]]]3-alpha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
4. (-)-2R-[2R*[R*[S*(R*)]]]]-alpha.alpha'[iminobis(methylene)[bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]
5. (+)-[2S-[2R*[R*[S*(R*)]]]]-alpha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
6. (-H2R-[2R*[S*[S*(R*)]]]]-alpha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]
7. (-)-[2R-[2R*[R*[R*[R*)]]]]-alpha.alpha'[iminobis(methylene)[bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
8. (±)-[2R*[R*[S*(S*)]]]-alpha,alpha'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1--benzopyran-2-methanol]
9. (+)-[2S-[2R*[R*[R*(R*)]]]]-alpha,alpha,[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol]
10. [2R-[2R*[S*[R*(S*)]]]]-alpha.alpha'[iminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]
[3] The process as claimed in claim-1, wherein the solvent used in step-[a] is selected from
C1 to C4 chlorinated solvent such as dichloromethane, 1,2-dichloroethane, 1,3-dichloro
propane, 1,4-dichloro butane and like.
[4] The preferable solvent as claimed in claim-2 is dichloromethane.
[5] The process as claimed in claim-1, wherein the salt of periodic acid is alkali metal salt or
alkaline earth metal salt.
[6] The preferable salt of periodic acid as claimed in claim-4 is sodium or potassium salt.

[7] The process for the preparation of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde from isomer of Nebivolol as describes and illustrated by the examples herein.