DESC:FIELD OF THE INVENTION
The present invention provides a process for the preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene useful in preparation of Nebivolol.

BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) an intermediate for preparing Nebivolol (Formula-2). 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) is mixture of (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (Formula-1a) and (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (Formula-1b).


European Patent 0145067 (Janssen Pharmaceutica NV) discloses a process of preparing Nebivolol, which comprises synthesizing diastereoisomeric mixtures of chromene derivatives in accordance with the synthetic scheme-1 depicted as below:

Scheme-1: Preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene from ethyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate

Ethyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate (Formula-3), prepared by the esterification of the corresponding acid, is reduced with sodium dihydro bis-(2-methoxyethoxy)-aluminate to give corresponding primary alcohol of Formula-4. The alcohol is further reacted with oxalyl chloride and triethylamine at -60oC to give corresponding racemic aldehyde of Formula-5. The racemic aldehyde is then converted to epoxide (Formula-1) as a mixture of (R,S), (S,R), (R,R) and (S,S) stereoisomers using NaH (Sodium hydride), TMSI (Trimethyl sulfoxinium Iodide) and DMSO (Di-methyl sulfoxide). This process involves three steps in the preparation of formula-1.

European patent EP0334429 (Janssen Pharmaceutica NV) describes a process for preparation of single optical isomers (R,S,S,S) and (S,R,R,R) of Nebivolol. The said process is directed to preparation of 6-fluoro chromene carboxylic acid into single enantiomers by treatment with (+)-dehydroabiethylamine. The single enantiomers are converted into their corresponding epoxides resulting in a mixture of two diastereomers. The following synthetic scheme-2 describes the process.

Scheme-2: Preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene from 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid

Main draw back of the reaction is use of hazardous materials i.e. Potassium tertiary butoxide
IN2703CHE2008 discloses a preparation of 6-Fluoro-3,4-dihydro-2-oxiranyl-2H-benzopyran (Formula-1) from 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (Formula-5) by using Trimethyl sulfoxonium iodide in DMSO and Potassium tertiary butoxide as depicted in Scheme-3.

Scheme-3: Preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene from 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde

The known processes use sodium hydride or potassium tert. Butoxide as a base used for conversion of aldehyde to Epoxide. There exists a need for developing a method for the synthesis of diastereomeric mixture of expoxide having mole ratio of 2:1 and eliminating the use of sodium hydride, potassium tertiary butoxide.

SUMMARY OF THE INVENTION
A main object of present invention is to provide a process for the preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (formula-1) with mole ratio of 2:1.
Yet another object of the present invention is to provide a process for the preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene with reduced level of impurity.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of 6-Fluoro-2-oxiranyl-chroman with as desired yield and purity. The reaction step according to present invention involves synthesis of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) as depicted in scheme-4 :

Scheme-4: Preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) from 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde

The process for preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene from 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde. The 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) is prepared by reaction of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde in presence of Trimethyl sulfoxonium halide, Inorganic base as reagents and an organic solvent. The inorganic base used for the preparation is selected from potassium t- Butoxide, sodium hydride and Sodium methoxide, the preferably base is Sodium methoxide. The trimethyl sulfoxonium halide is selected from trimethyl sulfoxonium bromide, trimethyl sulfoxonium chloride, trimethyl sulfoxonium iodide preferably is trimethyl sulfoxonium iodide. Dimethyl sulfoxide or tertiary butanol is used as a organic solvent, preferably dimethyl sulfoxide.

The present invention is further illustrated by following non-limiting scope of the invention.

Example-1: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (Formula-5).
Methyl 6-Fluoro-3,4-dihydro-2H-chromene-2-carboxylate (50gm, 0.238 moles) is added to dichloromethane (500ml) under nitrogen atmosphere and cooled at -78?C. 70% vitride solution in toluene (86.7g) is mixed with the solution of vitride isopropyl alcohol (12.6ml) at 0-5?C. This mixture is added in reaction mass at -73 to -78?C. Isopropyl alcohol (22.9ml) is addedinto reaction mass and allow to stir. The reaction mixture is quenched with aqueous hydrochloride solution. Organic layer separated at room temperature and aqueous layer is washed with dichloromethane. Organic layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (Formula-5) is washed with purified water and dried over sodium sulphate. HPLC purity- Formula-5:- 85.94%; Formula-4:- 11.08%; Formula-3:- 0.06%.

Example-2: Synthesis of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) using potassium t- Butoxide.
In a round bottom flask Trimethyl sulfoxonium Iodide (44.5g) is charged with dimethylsulfoxide under nitrogen atmosphere. Potassium t- Butoxide (22.7g) is added and the mixture is stirred at room temperature. Cool the reaction mass.
A solution of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (36.84g,) in dichloromethane is added to at temperature of below 15?C. The reaction mass is stirred. The reaction mass is quenched with mixture of crushed ice and purified water (240g: 240g) and further stirred. The reaction mixture is allowed to separate the layer. Aqueous layer extract with dichloromethane. Combine both layer and wash with purified water. Organic layer is dried over sodium sulfate and Distilled out using dichloromethane at 40-45?C. Degas oily mass at 55-60?C under vacuum.
Formula-1: Oily Mass weight 45.65g. HPLC purity- Formula-1a - 38.32%, Formula-1b - 20.72%, substituted alcohol of Formula-4:- 11.93%. Weight (100% basis HPLC purity) – Formula-1a - 17.5g, Formula-1b - 9.5g

Example-3: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (Formula-5).
A solution of Methyl 6-Fluoro-3,4-dihydro-2H-chromene-2-carboxylate (50gm, 0.238 moles) is prepared using dichloromethane (500ml) under nitrogen atmosphere and cooled to -78?C. In another flask Toluene (100ml) is added in 70% vitride solution in toluene (86.7g) under nitrogen atmosphere and cooled to 0-5?C.
In this solution of vitride in isopropyl alcohol (12.6ml) is added slowly at 0-5?C. This vitride-isopropyl alcohol solution is added to the reaction mass in 3-4 Hrs. Reaction mass is stirred and then again isopropyl alcohol is added. Reaction mass is then quenched with 15% aqueous hydrochloride solution at -73 to -78?C. Water is added. Organic layer separated and aqueous layer is washed with Dichloromethane. Final organic layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with purified water and dried over sodium sulphate. HPLC purity- Formula-5:- 81.61%; Formula-4:-13.89% ; Formula-3:- 0.09%.

Example-4: Synthesis of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) using potassium t- Butoxide.
A round bottom flask Trimethyl sulfoxonium Iodide (44.5g) is charged with dimethylsulfoxide (255ml) under nitrogen atmosphere. To the mixture potassium t- butoxide (22.7g) is added and the mixture is stir at room temperature. Cool the reaction mass at 10-15?C. A solution of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (34.98g) in dichloromethane is addedfollowed by stirring the reaction mass and quench in to mixture of crushed ice and purified water. Stir the reaction mass for 0.5 hr and separate the layer. Aq.layer extract with MDC. Combine both Organic layer and wash with purified water. Organic layer dried over sodium sulfate and Distilled out Dichloromethane and Degas oily mass under vacuum. Formula-1 is Oily Mass weight 44.63g.

Example-5: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (Formula-5).
A solution of Methyl 6-Fluoro-3,4-dihydro-2H-chromene-2-carboxylate (25gm, 0.119 moles) in dichloromethane (250ml) is prepared under nitrogen atmosphere and cooled to -78?C. In another flask Toluene (50ml) is added in 70% vitride solution in toluene under nitrogen atmosphere and cooled to 0-5oC. In this solution of Vitride, isopropyl alcohol (6.3ml) is added slowly. This vitride-isopropyl alcohol solution is added in reaction mass at -73 to -78?C followed by stirring the reaction mass. Isopropyl alcohol is added. Reaction mass is then quenched with 15% aqueous hydrochloric acid solution. Water is added. Organic layer is separated at room temperature and aqueous layer is washed with Dichloromethane. Final organic layer containing methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with purified water and dried over sodium sulphate.

Example-6: Synthesis of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) using sodium methoxide.
In a round bottom flask Trimethyl sulfoxonium Iodide (22.3g) is charged in dimethylsulfoxide (128ml) under nitrogen atmosphere. Sodium methoxide (5.5g) is added to the reaction mixture and allowed to stir for 1 hr at room temperature. Cool the reaction mass 10-15?C. A solution of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (14.9g) in dichloromethane is added to reaction mixture. On addition the reaction mass is stirred. On completion quench using mixture of crushed ice and purified water. The reaction mass is allowed to separate the layer. Aqueous layer extract with dichloromethane. Combine both layer and wash with purified water. Organic layer dried over sodium sulfate and Distilled out Dichloromethane and Degas oily mass under vacuum. Formula-1 is Oily Mass, weight 20.5g. Formula-1a - 9.9g, Formula-1b- 4.7g

Example-7: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (Formula-5)
A solution of Methyl 6-Fluoro-3,4-dihydro-2H-chromene-2-carboxylate (50gm, 0.238 moles) is prepared in dichloromethane under nitrogen atmosphere and cooled to -78?C. In another flask Toluene is added in 70% vitride solution under nitrogen atmosphere and cooled.
In this solution of vitride isopropyl alcohol is added slowly. The mixture is then added in reaction mass at -73 to -78?C followed by stirring. Isopropyl alcohol is added to reaction mass and quenched with 15% aqueous hydrochloride solution. Water is added. Organic layer separated at room temperature and aqueous layer is washed with Dichloromethane. The layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with purified water and dried over sodium sulphate.

Example-8: Synthesis of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene (Formula-1) using sodium methoxide.
In a round bottom flask Trimethyl sulfoxonium Iodide (44.5g) is charged in dimethylsulfoxide (255ml) under nitrogen atmosphere. Sodium methoxide (11.0g) is added to the mixture and stirred for 1 hr. Cool the reaction mass. A solution of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde (34.7g, 80.97% HPLC purity) in dichloromethane (900ml) is added to reaction mixture followed by stirring the reaction mass. The reaction is quenched using mixture of crushed ice and purified water and allowed to separate the layer. Aqueous layer extract with dichloromethane. Combine both layer and wash with purified water (480g). Organic layer dried over sodium sulfate and Distilled out Dichloromethane and Degas oily mass under vacuum. Formula-1 is Oily Mass (weight 47.54g). HPLC purity- Formula-1a - 44.45%, Formula-1b- 22.71%, Formula-4:- 15.16%. Weight (100% basis HPLC purity) – Formula-1a- 21.1g, Formula-1b - 10.8g.

,CLAIMS:We claim,
1. A process for the preparation of 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene of formula-1 wherein:
6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is reacted with Sodium methoxide and Trimethyl sulphoxonium halide in presence of organic solvent(s),
isolation of the product followed by washing and drying to yield 6-fluoro-2-(oxiran-2-yl)-3,4-dihydro-2H-chromene.

2. The process as claimed in claim 1 wherein the trimethyl sulphoxonium halide is selected from trimethyl sulphoxonium bromide, trimethyl sulphoxonium iodide and trimethyl sulphoxonium chloride.

3. The process as claimed in claim 1 and 2 wherein the trimethyl sulphoxonium halide is trimethyl sulphoxonium iodide.

4. The process as claimed in claim 1 wherein the organic solvent is Dimethyl sulfoxide or tertiary butanol.

5. The process as claimed in claim 4 wherein the organic solvent is dimethyl sulfoxide.