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 CONVERSION OF (2R)-6-FLUORO-2-[(2S)-OXIRAN-2-YL]-3,4-DIHYDRO-2H-CHROMENETO(2R)-6-FLUORO-2-[(2R)-OXIRAN-2-YL]-3,4-DIHYDRO-2H-CHROMENE
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LTD.
(b) NATIONALITY : An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej-Dholka Road, Bhat, Ahmedabad -
38221 O.Gujarat, India,
3. 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 start from next page)

FIELD OF THE INVENTION
The present invention relates to a novel process for the conversion of (2R)-6-f!uoro-2-I(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) to (2R)-6-f!uoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B). The compound of formulae lll-A and lll-B are key intermediates for preparing Nebivolol.

BACKGROUND OF THE INVENTION
Nebivolol, chemically known as (±) - [2R*[1S*, 5S*(S*)]] - a,a'- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] is an important antihypertensive agent and depicted by formula I:

The Nebivolol structure has four stereogenic centers, which are indicated as 1, 2, 3 and 4. Nebivolol is a mixture of equal amounts of 2 enantiomers having (S,R,R,R) and (R,S,S,S) configuration.
The process for preparing Nebivolol is disclosed in U.S Patent no. 4,654,362, wherein formula III is a racemic mixture which is separated by column chromatography into diastereomeric isomer of formulae lll-A and lll-B. Formula lll-A is obtained from the first fraction and formula lll-B is obtained from the second fraction. Formula lll-A is then reacted with benzylamine to obtain compound of formula IV which on further reaction with compound of formula lll-B gives compound of formula V. Compound of formula V is then converted to compound of formula ! as depicted in scheme I:

According to this process, the compound of formulae lll-A and Ifl-B are obtained in ratio of 66:34 w/w when separated from their diastereomeric mixture of formula III by column chromatography. Compound of formulae lll-A and lll-B react in equimolar amounts to form compound of formula V. As the amount of compound of formula lll-A is higher then the compound of formula lll-B (ratio 66:34 w/w), substantial portion of formula lll-A remains unused.
The present invention provides a novel process for the conversion of (2R)-6-fluoro-2-[{2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) to (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula ill-B) which can be used efficiently in the preparation of Nebivolol to enhance the yield of Nebivolol, resulting the process cost effective and industrially viable.
OBJECT OF THE INVENTION
The object of the present invention is to provide a novel process for the conversion of (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) into (2R)-6-f!uoro-2-[(2R)-oxiran-2-yi]-3,4-dihydro-2H-chromene (formula lll-B) for further utilized in the process for the preparation of Nebivolol.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for conversion of (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula Ili-A) into (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) and process for the preparation of Nebivolol.


In accordance with the scheme II, the process for the conversion of 2(R)-6-fluoro-2-[(2S)-oxiran-2-yl]-314-dihydro-2H-chromene (formula III-A) into (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) comprising foilowing steps:
a. reacting the 2(R)-6-fluoro-2-[(2S)-oxiran-2-yi]-3,4-dihydro-2H-chromene (formula lll-A)
with an alkali metal salt in an acid to give a corresponding terminal OH protected 6-fluoro-
chroman-2-yl intermediate.
b. reacting the intermediate 6-fluoro-chroman-2-yl compound with hydroxy protecting
reagent to give the corresponding diol protected 6-fluoro-chroman-2-yl compound
c. reacting the diol protected 6-fluoro-chroman-2-yl compound with a base in an organic
solvent for epoxy formation to give (2R)-6-fluoro-2-[(2R)-oxiran-2-ylj-3,4-dihydro-2H-
chromene (formula lll-B)
The process according to present invention is depicted in following scheme II:

In accordance with the present invention as depicted in above scheme II, the detail process of preparation of (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) comprising the steps of:
A. reacting compound of formula lll-A with alkali metal salt in acid to give corresponding
(2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) of formula VI;
B. reacting the compound of formula VI with hydroxy protecting reagent (P) using a
base to obtain corresponding diol protected (2S)-2-(6-f!uoro-3,4-dihydro-2H-
chromen-2-yl) of formula VII;
C. reacting the compound of formula VII with the base in an organic solvent for epoxy
formation to obtain (2R)-6-fluoro-2-[(2R)-oxiran-2-yl] chromane (formula-!U-B).

The detailed process of scheme III for the conversion of (2R)-6-fluoro~2-[(2S)-oxiran-
The detail process of the present invention is depicted in following scheme III:

2-yl]-3,4-dihydro-2H-chromene (formula lll-A) to (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula Ul-B) is involving the protection of hydroxy! group comprising the reaction of compound of formula IV with hydroxyl protecting agent. The details stepwise process is explained as under:
Step A: The compound of formula lll-A is reacted at 90-95°C with alkali metal salt in acid. The reaction mass was cooled to room temperature, diluted with water followed by addition of water immiscible organic solvent. The layers were separated and washed with aqueous NaHC03. The reaction mass was dried to obtain (2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl acetate of formula VI.
The alkali metal salt is selected from sodium acetate, lithium acetate, potassium acetate and like. The preferable alkali metal salt is sodium acetate.
The acid used for the preparation of compound of formula VI is selected from organic or inorganic acid. The acid is further selected from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesu!fonic acid, and the like. Particularly preferred are acetic acid, citric acid, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, tartaric acids and the like. The acetic acid is most preferred for the conversion of (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) to (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B)
The water immiscible organic solvent is selected from dichloromethane, 1,2 dichioroethane; aromatic hydrocarbons such as benzene, toluene, xylene; alicyclic solvents such as cyclohexane; esters such as ethyl acetate, butyl acetate; ethers such as diethyl ether, diisopropyl ether, 2-methylTHF, methyl tert. butyl ether; benzotrifluoride; alkanes such as hexane, heptane and like. The preferable solvent is dichloromethane.
Step B: The compound of formula VI was reacted at 40-45°C with hydroxy protecting reagent (P) using a base. The reaction mixture was cooled; water immiscible organic solvent was added and stirred. The layers were separated and washed with acid and water. The reaction mass was dried to obtain diol protected (2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) of formula VII.
The hydroxy protecting reagent (P) is selected from aryl sulphonyl chloride, alkyl sulphonyl chloride, alkyl, allyl or aryl acid chloride, /-Butyldimethylsilyl, f-Butyldiphenylsilyl, Pivaloyl chloride, acetyl, Methoxymethyl, Tetrahydropyranyl and like. The aryl sulphonyl chloride (P") is preferred wherein p-tosyl chloride is used in step B for the preparation of compound of formula VII.

The base used in step B is selected from carbonates of alkali metals such as anhydrous potassium carbonate or anhydrous sodium carbonate; organic tertiary amine triethyi amine, diisopropyl ethyl amine; pyridine; lutidines; dialkyl aniline such as dimethyl aniline, diethyl aniline, N-methyl morpholine, N-alkyl pyrrolidine, N- alkyl piperidine and like. The preferable base is pyridine.
Step C: The compound of formula VII was stirred at 10 to 70°C, preferably at 40-45°C with organic solvent using a base. The reaction mass was cooled followed by addition of ethyl acetate. The layers were separated, washed and dried to obtain (2R)-6-fluoro-2-[(2R)-oxiran-2-yl] chromane (formula-lll-B).
The base used in step C is selected from NaOH, Na2C03, KOH, K2C03l CaC03, Ca(OH)2( BaC03, Ba(OH)2l LiOH, Li2C03l CsOH, Cs2C03 and like. The preferable base is KOH and NaOH. The more preferable base is KOH.
The organic solvent used in step C is selected from dimethyl sulfoxide, dimethyl acetamide, benzotrifluoride, sulfolane, dimethyl sulfone, high boiling ethers, high boiling ai'cohoi's and Mte. The high bolling ethers /' alcohols are defined' herein as having bolling point > 100°C. The preferable solvent is dimethyl sulfoxide.
The water immiscible organic solvent used in step C is selected from benzene, toluene, dichloromethane, cyclohexane, ethyl acetate, ethylene dichloride, methyl tert. butyl ether, heptane, MIBK and like. The preferable solvent is ethyl acetate. Scheme IV
Optionally in accordance with the present invention as described in scheme II, the (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lil-B), also be prepared by alternate route for the conversion of 2R)-6-fluoro-2-((2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) wherein corresponding diol protected (2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) of formula VII is prepared by an alternate process.
The alternate process for the preparation of (2R)-6-fiuoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) comprises,
i. reacting compound of formula lll-A with alkali metal salt in acid to give corresponding
hydroxyl protected (2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) of formula VI; ii. reacting the compound of formula VI with aqueous alkali to give corresponding
ethane-1,2-diol of formula Vl-A; iii. reacting the compound of formula Vl-A with hydroxy protecting reagent (P) using a
base to give corresponding terminal hydroxy protected compound of 6-fluoro-3,4-
dihydro-2H-chromen-2-yl having formula Vl-B;

iv. reacting the compound of formula Vl-B with hydroxy protecting reagent (P) using a base to obtain give protected diol compound of 6-fluoro-3,4-dihydro-2H-chromen-2-yl having formula VII;
v. reacting the compound of formula VII with the base in an organic solvent for epoxy formation to obtain (2R)-6-fluoro-2-[(2R)-oxiran-2-yi] chromane (formula lll-B).

The compound of formula lll-A, a starting material of the present invention is obtained from 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxaldehyde by the prior art process.
The detailed process of scheme 3 for the conversion of (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) to (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-314-dihydro-2H-chromene (formula lll-B) is explained stepwise as below: Step : i : The process for the preparation of compound of formula IV is defined in the step A of Scheme III.
Step : ii : The compound of formula VI was reacted with aqueous alkali, water and refluxed. The reaction mixture was cooled followed by addition of water immiscible organic solvent, stirred and layers were seperated. The reaction mass was dried to obtain (1S)-1-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl) ethane-1, 2-diol of formula Vl-A.
The aqueous alkali used in step ii is selected from NaOH, Na2C03, KOH, K2C03, CaC03, Ca(OH)2, BaC03l Ba(OH}2, LiOH, Li2C03, CsOH, Cs2C03 and like. The preferable aqueous alkali is KOH and NaOH. The more preferable aqueous alkali is KOH.

Step : iii : The compound of formula Vl-A was reacted with a base and water immiscible organic solvent. The reaction mixture was cooled; hydroxy protecting reagent (P1) was added and stirred. Layers were separated and washed with hydrochloric acid and water. The reaction mass was dried to obtain terminal hydroxy protected compound of 6-fluoro-3,4-dihydro-2H-chromen-2-yl having formula Vl-B.
The hydroxy protecting reagent (P') is selected from aryl sulphonyl chloride, alkyl sulphonyl chloride, alkyl, allyl or aryl acid chloride, f-Butyldimethylsilyl, f-ButyldiphenylsiJyi, Pivaloyl chloride, acetyl, Methoxymethyl, Tetrahydropyranyl and like. The Pivaloyl chloride is preferred as hydroxy protecting reagent for terminal protection of hydroxy group.
The base used in step iii is selected from triethyl amine, tripropylamine, pyridine, lutidines, quinoline, diisopropyl ethyl amine, dimethyl aniline, diethyl aniline and like. The preferable base is diisopropyl ethyl amine.
The water immiscible organic solvent used in step iii is selected from aromatic hydrocarbons such as benzene, toluene; alkanes such as pentane, hexane, heptane; ethers such as THF, monoglyme, 1,4-dioxane; cycloalkanes such as cyclohexane; chlorinated hydrocarbons such as chloroform, d'ichtoromethane, 1,2-d'ichloroethane and Yike. The preferable solvent is dichloromethane.
Step : iv : The compound of formula Vl-B was reacted with hydroxy protecting reagent (P") in a base and stirred. Water and water immiscible organic solvent were added to the reaction mixture. Layers were separated, washed with hydrochloric acid and water and dried to obtain diol compound of 6-fluoro-3,4-dihydro-2H-chromen-2-yl having formula VII.
The hydroxy protecting reagent (P") is selected from the group as defined above wherein the aryl sulphonyl chloride is used in step iv, preferably p-tosyl chloride.
The base used in step iv is selected from carbonates of alkali metals such as anhydrous potassium carbonate or anhydrous sodium carbonate; trialkyl amines such as triethyl amine, diisopropyl ethyl amine; pyridine, lutidines, dialkyl aniline such as dimethyl aniline, diethyl aniline, N-methyl morpholine, N-alkyl pyrrolidine, N-alkyl piperidine and like. The preferable base is pyridine. The water immiscible organic solvent used in step iv is dichloromethane.
Step : v : The compound of formula VII was reacted with a base in organic solvent and stirred. Water and water immiscible organic solvent were added to the reaction mixture. Layers were separated, washed with water and dried to obtain (2R)-6-fluoro-2-[{2R)-oxiran-2-yl] chromane (formula lll-B).
The base used in step v is selected from NaOH, Na2C03, KOH, K2C03, CaC03, Ca(OH)2l BaC03l Ba(OH)2, LiOH, Li2C03l CsOH, Cs2C03 and like. The preferable base is KOH and NaOH. The more preferable base is KOH.

The organic solvent used in step v is selected from dimethyl suffoxide, dimethyl acetamide, benzotrifluoride, sulfolane, dimethyl sulfone, high boiling ethers, high boiling alcohols and like. The high boiling ethers / alcohols are defined herein as having boiling point > 100°C. The preferable solvent is dimethyl sulfoxide.
The following key intermediates are prepared during the process for the conversion of 2(R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) into (2R)-6-f!uoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula III-B) as per present invention.

A mixture of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl acetate (isomer A) (100 gm) and acetic acid (300 ml) were stirred git 25-30°C. Sodium acetate (42.4 gm) was added and stirred for 10-15 minutes. The reaction mixture was heated at 90-95°C and stirred for 2-3 hrs at the same temperature. The reaction mixture was cooled to 25-30°C, water (500ml) was added and the reaction mixture was stirred for 25-30 minutes. Methylene dichloride (MDC) (500ml) was added to the reaction mixture and stirred for 15-20 minutes. The layers were separated and the aqueous layer was extracted with MDC (250 ml). The organic layers were combined and washed with water (500 ml x 2). The organic layer was cooled to 0-5°C and washed with cold 10% solution of NaHC03 (500ml) followed by water. The MDC layer was dried over sodium sulfate, distilled off MDC under vacuum to obtain

(2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl acetate (formula VI) as an oily compound. (Yield = 120-125 gm)
Example-2: Preparation of (2S}-2-(6- fluoro-3, 4-dihydro- 2H- chromen- 2- yl) - 2-{[(4-methyl phenyl) sulfonyl]oxy}ethyl acetate

A mixture of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl acetate (formula VI) (120gm) and pyridine (600 ml) were stirred at 20-25°C. pTsCI (269.5gm) was added and the reaction mixture was stirred at 40-45°C for 8-10 hrs. The reaction mixture was dumped into crushed ice (600 gm) and stirred for 10-15 minutes. MDC was added (600 ml) into the reaction mass at 20-25DC and stirred for 10-15 minutes. The layers were separated and the MDC layer was washed with cold water. The MDC layer was cooled to 0-5^0 and washed with 18% HCI (600ml) followed by water (600 ml). The MDC layer was dried over anhydrous sodium sulfate and distilled off under vacuum to give (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-{[(4-methyl phenyl) sulfonylpxyjethyl acetate (formula VIJ). (Yield = 175-180 gm)
Example-3: Preparation of (2R)-6-fluoro-2-[{2R)-oxiran-2-yll-3, 4-dihydro-2H-chromene:

A mixture of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-{[(4-methyl phenyl) sulfonyl]oxy}ethyl acetate (formula VII) (180gm) and DMSO (900 ml) were stirred at 25-30°C. KOH (123.5 gm) was added into the reaction mixture and stirred at 40-45°C for 4-5 hrs. The reaction mixture was cooled to 25-30DC.The reaction mixture was dumped into cold water (2700 ml) at 0-5°C and stirred for 10-15 minutes. Ethyl acetate (1260 ml) was added to the reaction mixture and stirred for 15-20 minutes. The layers were separated, the aqueous layer was extracted with ethyl acetate (900 ml), washed with water (2700 ml), dried over anhydrous sodium sulfate and distilled off under vacuum to obtain (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3, 4-dihydro-2H-chromene (Isomer B). (Yield = 75-80 gm)


Exampie-4: Preparation of (1S)-1-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl) ethane-1, 2-diol (formula Vl-A):
A mixture of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl acetate (formula VI) (10 gm) and KOH solution (4.4 gm in 50 ml water) were heated at 100-105°C and stirred for 3-4 hrs. The reaction mass was cooled, MDC (50 ml) was added to the reaction mixture and stirred for. 10-15 minutes. The payers were separated, the MDC layer was dried over anhydrous sodium sulfate and MDC layer was distilled off under vacuum to obtain (1S)-1-(6-fiuoro-3, 4-dihydro-2H-chromen-2-yl) ethane-1, 2-dio! (formula Vl-A). (Yield = 7-7.5 gm)
ExampIe-5: Preparation of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl-2, 2-dimethylpropanoate (formula Vl-B):

A mixture of (1S)-1-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl) ethane-1, 2-dio! (formula Vl-A) (10 gm) and MDC (40 ml) were stirred at 25-30°C for 10-15 minutes. Diisopropyl ethylamine (DIPEA, 12.2gm) was added to the reaction mixture and cooled to 0-5°C. Pivaloyl chloride (13.5 gm) was added and the reaction mixture was stirred for 12-14 hrs. Water was added to the reaction mixture and stirred for 10-15 minutes. The layers were separated, the organic layer was washed with 2% HCI followed by water, dried over anhydrous sodium sulfate and distilled off under vacuum to obtain (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl-2, 2-dimethylpropanoate (formula Vl-B). (Yield = 10-12 gm)
Example-6: Preparation of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-tosyloxy ethyl-2, 2-dimethylpropanoate (formula VII):


A mixture of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl-2, 2-dimethylpropanoate (formula Vl-B) (6.0 gm) and pyridine (30 ml) were mixed and cooled to 10-15°C. pTsCI (11.5 gm) was added at 10-15°C and the reaction mixture was stirred for 5-6 hrs. MDC and water were added to the reaction mixture and stirred for 10-15 minutes. The layers were separated, MDC layer was washed with 6N HCI followed by water. The MDC layer was dried over anhydrous sodium sulfate and distilled off under vacuum to obtain (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-tosyloxyethyl-2, 2-dimethylpropanoate (formula VII). (Yield = 6.5-7.5 gm)
Example-7: Preparation of (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3, 4-dihydro-2H-chromene (formula II1-B):

mixture of (2S)-2-(6-fluoro-3, 4-dihydro-2H-chromen-2-yl)-2-tosyloxyethyl-2, 2-dimethylpropanoate (formula VII) (2.0 gm) and DMSO (10ml) were stirred at room temperature. KOH (1.25 gm) was added to the reaction mixture and stirred at room temperature for 5-6 hrs.
The reaction mixture was dumped into cold water followed by addition of MDC and stirred the reaction mixture for 10-15 minutes. The layers were separated; the MDC layer was washed with water, dried over anhydrous sodium sulfate and distilled off under vacuum to obtain (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3, 4-dihydro-2H-chromene (formula lll-B, Isomer B). (Yield = 0.8-1.0 gm)
Example-8: Preparation of 2-{Benzylamino)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-y))ethanoI:

16.56 kg of benzyl amine in 22.5 L IPA is taken in a reactor and stir the reaction mass. The (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) is taken in IPA and stir the reaction mixture at ambient temperature. The reaction mass is

chilled to 0-5 °C and stirred. The reaction mass is filtered and washed with I PA and dried over reduced pressure to yield 2-(Benzylamino)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol. (Yield = 6.9-7.0 kg)
Example-9: Preparation of 2-{Benzyl-[2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]-amino}-1-{6-fluoro-chroman-2-yl)-ethanol:

4 kg of (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) is taken in 10.5 L methanol is taken in a reactor and stirred. 6.2 kg of 2-(Benzylamino)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol and 15.5 L methanol is charged to reactor. The reaction mass is refluxed and maintain for over 17 hrs. 2.5 L of HCi is charged into reaction mass and stir. Solvent is removed under vacuum and degass the mass for 1 hr at 45-50°C. The reaction mass is cool at ambient temperature and 8 L of Acetonitrile is charged into reaction mass with stirring. 16.2 L of diisopropyl ether is added and stirred. The reaction mass is filtered and washed with Acetonitrile + diisopropyl ether. The product is dried hot vaccum pan to yield 2-{Benzyl-[2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]-amino}-1-(6-fluoro-chroman-2-yl)-ethanol. (Yield : 9.8-10 kg)
Example-10: Preparation of Nebivolol HCI:

18 kg of Benzyl Nebivolol of formula V, 1.8 kg PD/C are charge with 361 L methanol in the an autoclave. The reaction mass is heated to 48-52°C under 5.0-5.5 kg/cm2 hydrogen pressure. The reaction is maintained at the pressure and cooled to 35-40°C. The reaction mixture is filtered through hyfiow bed and washed with methanol.
The solvent is distilled under vacuum and IPA HCI is added and reflux for 3 hrs. Methanol is added to the reaction mass and reflux for 30 min. The solvent is atmospherically distilled until the volume of reaction mass remains 45-54 L.
The reaction mass is cool the mass to 33-35°C and stir. The reaction mass is filtered and washed with methanol. The product is dried to give wet cake which is further charged

into Methanol. The reaction mixture is heated to reflux and stired. The reaction mass is filter through hyflow bed and wash with 2 methanol
The solvent is distilled from the mass atmospherically at 65-70°C up to 3 vol. remains intact and gradually cool to 33-35°C with stirring. Filter the product and wash the cake with Methanol. The product is dried under vaccum to yield Nebivotol HCI. (Yield: 5.2-5.4 kg)
Thus, the (2R)-6-f!uoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene of formula Hl-B obtained from (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene of formula lll-A is utilized for the preparation of Nebivolol HC! to enhance the overall yield of Nebivolol, and resulting the process as cost effective and industrially viable.

We claim:
1. A process for the preparation of Nebivolo! consisting conversion of (2R)-6-fluoro-2-[(2S)-
oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) into (2R)-6-fluoro-2-[(2R)-oxiran-2-
yl]-3,4-dihydro-2H-chromene (formula lll-B) comprising,
a. reacting the 2(R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula III-
A) with an alkali metal salt in an acid to give corresponding terminal hydroxyl
protected 6-ftuoro-chroman-2-yl intermediate,
b. reacting the intermediate 6-fluoro-chroman-2-yl compound with hydroxy protecting
reagent to give the corresponding diol protected 6-fluoro-chroman-2-y! compound of
formula VII,
c. reacting the diol protected compound of formula VII with a base in an organic solvent
for epoxy formation to give (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-
chromene (formula lll-B).
2. The process as claimed in claim 1 wherein the compound of formula VII, which is
resulting (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) is
prepared by the process comprising the steps of:
i. reacting compound of formula lll-A with alkali metal salt in acid to give corresponding (2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) of formula VI;
ii. reacting the compound of formula VI with hydroxy protecting reagent using a base to obtain corresponding diol protected (2S)-2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) of formula VII.
3. The process as claimed in claim 1 wherein the compound of formula VII, which is
resulting (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-B) is
prepared by the process comprising the steps of:
i. reacting the 2(R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula
lll-A) with an alkali metal salt in an acid to give corresponding 6-fluoro-chroman-
2-yl intermediate of formula VI, ii. reacting with the compound of formula VI with aqueous alkali to give (1S)-1-(6-
fluoro-3, 4-dihydro-2H-chromen-2-yl) ethane-1, 2-diol of formula Vl-A, iii. reacting the compound of formula Vl-A with terminal hydroxy protecting reagent
using a base to obtain corresponding hydroxy protected compound of 6-fluoro-
3,4-dihydro-2H-chromen-2-yl having formula Vl-B, iv. reacting the compound of formula Vl-B with hydroxy protecting reagent using a
base to obtain give protected diol compound of 6-fluoro-3,4-dihydro-2H-chromen-
2-yl having formula VII.
4. The process as claimed in claim 1-3, wherein the alkali metal salt is selected from
sodium acetate, lithium acetate, potassium acetate and like.

5. The process as claimed in claim 1-3, wherein the acid is acetic acid.
6. The process as claimed in claim 1-3, wherein hydroxy protecting reagent is selected from p-tosyl chloride or pivaloyl chloride.
7. The process as claimed in claim 1-3, wherein the base is selected from carbonates of alkali metals such as anhydrous potassium carbonate or anhydrous sodium carbonate; organic tertiary amine triethyi amine, diisopropyl ethyl amine; pyridine; iutidines; dialkyl aniline such as dimethyl aniline, diethyl aniline, N-methyl morpholine, N-alkyl pyrrolidine, N- alky! piperidine and like.
8. The process as claimed in claim 1 step-c wherein the base used for epoxy formation is selected from NaOH, Na2C03, KOH, K2C03, CaC03l Ca(OH)2, BaC03, Ba(OH)2, LiOH, Li2C03l CsOH, Cs2C03 and like.
9. The process as claimed in claim 1 step-c, wherein the organic solvent used for expoxy formation is selected from dimethyl sulfoxide, dimethyl acetamide, benzotrifluoride, sulfolane, dimethyl sulfone, high boiling ethers, high boiling alcohols and like.
10. The process for the preparation of Nebivolol comprising conversion of 2(R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene into (2R)-6-fluoro-2-[(2R)-oxtran-2-yl]-3,4-dihydro-2H-chromene.
11. The process for the preparation of (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromenefrom 2(R)-6-fluoro-2-[(2S}-oxiran-2-y[]-3,4-dihydro-2H-chrornene.
12. The diol protected 6-fluoro-chroman-2-yl compound of formula VII,

13. The compound as claimed in claim 10 is 2,2-dimethyl-propionic acid-2-(6-f!uoro-chroman-2-yl}-2-(toluene-4-sulfonyloxy)-ethyl ester.
14. The compound as claimed in claim 10 is Acetic acid-2-(6-fluoro-chroman-2-yl)-2-(toluene-4-sulfonyloxy)-ethyl ester.
15. The hydroxyl protected 6-fluoro-chroman-2-yi intermediate as per claim 1 is 2,2-
Dimethyl-propionic acid 2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl ester or Toiuene-4-
sulfonic acid 2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl ester.