FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION (See section 10)
A process for the preparation of 6-fluoro-3,4-dihydro-2H-chrornene-
2-carbaldehyde
CADILA PHARMACEUTICALS LIMITED
"Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad - 382210,
Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde which is a useful intermediate in the synthesis of (D,L) Nebivoiol or its pharmaceutical acceptable salts thereof.
BACKGROUND OF THE INVENTION
Synthesis of (D,L) Nebivoiol or its pharmaceutical acceptable salts thereof involves the use of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde a useful intermediate which is depicted as structural formula-1.

US 4,654,432 discloses a process for synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 from 6-Fluoro-4-oxo-4H-chromene-2-carboxylic acid of Formula-5, as depicted in synthetic scheme-1. The 6-fluoro-4-oxo-4H-chromene-2-carboxylic acid of Formula-5 is hydrogenated by using 10% Pd/C catalyst at normal pressure and room temperature to obtain 6-fluoro-3,4-dihydro-2H-chroinene-2-carboxylic acid of Formula-4. The 6-fluoro-3,4-dihydro-2H-chromene-2-carboxy[ic acid of Formula-4 is esterified with ethanolic HCI to corresponding ethyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 which is reduced with sodium dihydro-bis(2-methoxyethoxy)aluminate (known as vitride) in a mixture of toluene and benzene to obtain (6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol of Formula-2 which in turn is oxidized by treatment with oxalyl chloride in a mixture of dichloromethane and dimethyl sulfoxide at -60°C to 6-fluoro-3,4-dihydro-2H-chromene-2-carba!dehyde of Formula-1. Scheme-1:

EP0334429B1 discloses a process for the preparation of specifically the RSSS isomer of nebivoiol independently. The said process for the independent preparation of RSSS nebivoiol involves synthesis of (+)-{S)-6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde as an intermediate compound. The said process 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-climethyl-7-(1-methylethyl-1-prienathrene-methanamine[(+)-dehydroabiethy)amine] and utilities like column chromatography and low temperatures. The processes also involve a large number of steps thereby increasing utilities, manpower and time required to complete the production cycle, rendering the process cumbersome and commercially expensive. Scheme-2:

Indian granted patent IN221733 patent involves the synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 from (6-fluoro-3,4-dihydro-2H-chromen-2-yl)(piperidin-1-yl)methanone of Formula-4A by using alkoxy metallic hydride. The intermediate of Formula-4A was synthesized from reaction of 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid of Formula-4 with an acid activating agent, and an amine RR'NH, wherein R and R' are independently H, alkyl or aryl, optionally joined together with or without a heteroatom selected from 0, N and S, to give (6-fluoro-3,4-dihydro-2H-chromen-2-yl)(piperidin-1-yl)methanone of Formula-4A. Scheme-3:

Indian patent application IN2703CHE2008 involves the improved process for the preparation of Nebivolol intermediate. The patent application involves conversion of methyl, ethyl and propyl chroman ester to aldehyde by using Vitride as a reducing agent at -70°C in different solvents like toluene, xylene, cyclic ethers like THF, ethers particularly alkyl ethers either open chain such as ethylene glycol, dimethyl ether, tert.butylether, butyl methyl ether and the like or mixture thereof.
Scheme-4:


In our study of prior art processes for the preparation of 6-Fluoro-3,4-dihydro 2H-chromene-2-carbafdehyde compound we have observed that the reaction of compound of formula-3 of Scheme-4, there is formation of large amounts of (6-Fluoro-3,4-dihydro-2H-chromene-2-yl)-methanol which is an impurity and results in lowering of desired compound thus there is an unmet need for the modification of the reaction conditions to increase in selectivity of desired compound formation, thus improving the yields.
The prior art process still has drawback to give the desired yield of 6-Ruoro-3,4-dihydro 2H-chromene-2-carbaldehyde. The vitride as an active reducing agent is also resulting the formation of corresponding alcohol. There is an unmet need to modify the reaction conditions to reduce the impurity levels and increase the yield and purity of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1.
SUMMARY OF THE INVENTION
In a preferred embodiment, the present invention provides a process for the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde.
In another embodiment, the present invention provides process for the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaIdehyde of Formula-1 from methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 using Sodium bis(2-methoxyethoxy)aluminium dihydride (known as Vitride) as a reducing agent in presence of an alcohol and other organic solvents.
In yet another embodiment, the process for the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde using vitride in presence of alcohol and other organic solvent which results product with high yield and purity when compared to disclosed known processes.
DETAILED DESCRIPTION OF THE INVENTION
The present invention according to the preferred embodiment provides a process for the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of formula-1, The process according to present invention results a cost effective preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of formula-1 wherein the product is resulting high yield and purity when compared to known processes.
The process for preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde, comprises:
esterification of 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid of formula-4 to give
methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of formula-3;

reduction of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of formula-3 to afford 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of formula-1 using Sodium bis(2-methoxyethoxy)aluminium dihydride (known as stride) in presence of alcohol and optionally with other organic solvent(s);
the resulting product is dried and purified to yield pure 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of formula-1.
The steps involved in synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of
formula-1 which is depicted in synthetic scheme-5 below:
Scheme-5:

According to present invention Sodium bis(2-methoxyethoxy)aluminium dihydride or Sodium dihydrido-bis{2-methoxyethoxy)aluminate is referred as commonly known name "vitride".
The esterification of the 6-Fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid of Formula-4 is carried out with lower alcohol in presence of a strong acid. The lower alcohol is selected from group consisting of methanol, ethanol, propanol and the acid is selected from HCI, H2SO4 and the like. Preferably methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 is prepared by reacting acid (Formula-4) with methanol in presence of H2SO4 under reflux conditions. The methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 can also be obtained by various methods know in the art. The purity of ester is 99.97 % which is measured by HPLC.
The present invention provides a process for reduction of the methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 using vitride-alcohol as a reducing agent to give 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde.The reducing agents such as vitride, DIBAL-H is known wherein vitride is preferred. Vitride is taken with alcohol and used for reduction of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 in MDC as a solvent. The alcohols used along with Vitride are selected from methanol, ethanol, isopropanol and n-butanol.
The use of vitride-alcohol in place of norma! vitride gives more conversion of ester to aldehyde and control over reaction proceed towards the formation of (6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol of Formula-2:


The present invention is further illustrated by experimental details to study the use of vitride with or without using different alcohol(s) for reduction of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate to give 6-Fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde. The results are tabulated below:
Table-1: Reaction of Vitride in presence of different alcohol(s)

Sr. No. Reducing agent according to present invention Formula-1% Formula-2 %
1 2 3 4 5 Vitride
Vitride along with Methanol Vitride along with Ethanol Vitride along with IPA Vitride along with n-Butanol 78.73 80.29 86.19 85.94 83.27 18.50 12.19 11.58 11.08 13.61
The commercially available Vitride is used in presence methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3, the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 is 78.73% which also results (6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol of Formula-2 is 18.50%. The Vitride in presence of alcohol results the formation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 with reduced level of (6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol of Formula-2
HPLC Characterization of synthesized compounds:
Inject a sample of blank (diluents), standard preparation and sample preparation into the chromatography, run and record the chromatograph and measure the responses for all the peaks. Disregards any peak due to diluent and calculate the percentage of chromatographic purity by area normalization method.
Column : Hypersil BDS Phenyl (250 X 4.6 mm), 5u or equivalent
Detection wavelength: 210nm
Flow Rate : LOmL/minute
Injection Volume : 20 μL
Oven Temperature : 25°C
The given results demonstrates that vitride with alcohol used for conversion of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 to 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 is resulting good purity and yield.

The present invention is further illustrated by following non-limiting examples.
Example-1: Synthesis of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3:
A solution of 6-fluoro-3,4-dihydro-2H-chronnene-2-carboxy!ic acid (100gm, 0.510 moles) in methanol (500ml) is prepared in 1ltr Round Bottom Flask (RBF) at Room Temperature (RT, 25-30°C). 19.9 gm of sulphuric acid is added and stirred reaction mass at RT (25-30°C) for 3-5 hrs. Methanol is distilled out under vacuum at 40-45°C. In the reaction mixture is added 500 ml MDC and 500 ml purified water. Organic layer is washed with 500 ml purified water and 500 ml sodium bicarbonate solution. Organic layer finally washed with 500 ml purified water. Organic layer dried over 20gm sodium sulphate. MDC is distilled under high vacuum and degas at 50°C to obtained oily mass of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3. Weight of oil-102 gm HPLC purity- 99.97%; Yield - 98%.
Example-2: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 using Vitride:
A solution of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate (50gm, 0.238 moles) in Methylene dichloride (MDC) (500ml) is prepared under nitrogen atmosphere and cooled to -78°C. In another flask 100 ml Toluene is added in 77.63 gm of 70% Sodium bis(2-methoxyethoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere. This vitride solution is added in reaction mass in 3-4 hrs at -73 to -78°C. After the end of addition reaction mass is stirred for 0.5 hrs at -73 to -78°C. Reaction mass then quenched with 130 ml of 15% aqueous HCI solution at -73 to -78°C. 250 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 250 ml MDC. Final organic layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with 375 ml purified water and dried over 20 gm sodium sulphate. HPLC purity- Formula-1:- 78.73%, Formula-2:-18.50%; Yield-87%.
Example-3: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehydo of Formula-1 using Vitride in presence of IPA:
A solution of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate (50gm, 0.238 moles) in Methylene dichloride (MDC) (500ml) is prepared under nitrogen atmosphere and cooled to -78°C. In another flask 100 ml Toluene is added in 86.7 gm of 70% Sodium bis(2-methoxyethoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere and cooled to 0-5°C. In this solution of vitride 12.63 ml of IPA is added slowly at 0-5eC. This vitride-IPA solution is added in reaction mass in 3-4 hrs at -73 to -78°C. After the end of addition reaction mass is stirred for 0.5 hrs and then added 22.97 ml IPA at -73 to -78°C. Reaction mass then quenched with 130 ml of 15% aqueous HCI solution at -73 to -78°C. 250 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 250 ml MDC. Final organic layer containing Methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed

with 375 ml purified water and dried over 20 gm sodium sulphate. HPLC purity- Formula-1:-85.94%, Formula:-2-11.08%, Yield - 99.01 %.
Example-4: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 using Vitride in presence of Methanol:
A solution of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate (15 gm, 0.0714 moles) in Methylene dichloride (MDC) (150ml) is prepared under nitrogen atmosphere and cooled to -78°C. In another flask 30 ml Toluene is added in 35.28 gm of 51.61% Sodium bis(2-methoxyethoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere and cooled to 0-5°C. In this solution of vitride 2.01 ml of methanol is added slowly at 0-5C. This vitride-methanol solution is added in reaction mass in 3-4 hrs at -73 to -78°C. After the end of addition reaction mass is stirred for 0.5 hrs and then added 3.66 ml methanol at -73 to -78°C. Reaction mass then quenched with 40 ml of 15% aqueous HCI solution at -73 to -78°C. 75 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 75ml MDC. Final organic layer containing Methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with 115 ml purified water and dried over 6 gm sodium sulphate. HPLC purity- (Formula-1:- 80.29%, Formula-2:-12.19%), Yield - 91.15%.
Example-5: Synthesis of 6-fluoro-3, 4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 using Vitride in presence of Ethanol:
A solution of methyl 6-fluoro-3,4-dihydro-2H-chrornene-2-carboxy!ate (15 gm, 0.0714 moles) in Methylene dichloride (MDC) (150ml) is prepared under nitrogen atmosphere and cooled to -78°C. In another flask 30 ml Toluene is added in 35.28 gm of 51.61% Sodium bis(2-methoxyethoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere and cooled to 0-5°C. In this solution of vitride 2.9 ml of ethanol is added slowly at 0-5°C. This vitride-ethanol solution is added in reaction mass in 3-4 hrs at -73 to -78oC. After the end of addition reaction mass is stirred for 0.5 hrs and then added 3.66 ml ethanol at -73 to -78oC. Reaction mass then quenched with 40 ml of 15% aqueous HCI solution at -73 to -78°C. 75 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 75 ml MDC. Final organic layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with 115 ml purified water and dried over 6 gm sodium sulphate. HPLC purity- Formula-1:- 86.19%, Formula-2:-11.58% , Yield - 89.23%.
Example-6: Synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 using Vitride in presence of n-Butanol:
A solution of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate (15 gm, 0.0714 moles) in Methylene dichloride (MDC) (150ml) is prepared under nitrogen atmosphere and cooled to -78°C. In another flask 30 ml Toluene is added in 35.28 gm of 51.61 % Sodium bis(2-methoxyethoxy)aluminium dihydride vitride solution in toluene under nitrogen atmosphere and cooled to 0-5oC. In this solution of vitride 4.55 ml of n-butanol is added slowly at 0-5°C. This vitride-n-butanol solution is added in reaction mass in 3-4 hrs at -73 to -78°C. After the end of

addition reaction mass is stirred for 0.5 hrs and then added 8.28 ml n-butanol at -73 to -78°C. Reaction mass then quenched with 40 ml of 15% aqueous HCI solution at -73 to -78°C. 75 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 75ml MDC. Final organic layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with 115 ml purified water and dried over 6 gm sodium sulphate. HPLC purity- Formula-1:- 83.27%, Formula-2:-13.16%, Yield - 90.29%.
Example-7: Synthesis of 6-Fluoro-2-oxtranyl-3,4-dihydro-2H-chromene (Formula-6)

To a solution of 101g of trimethylsulfoxonium iodide in DMSO, potassium t-butoxide (53g) was added to obtain a clear solution. The oily material from any of examples 2 to 6, dissolved in Dimethyl sulfoxide (DMSO) was added to the above reaction mass at 25°C and stirred. After completion of the reaction, the reaction mixture was quenched in cold water. The aqueous layer was extracted with ethyl acetate and washed with brine solution and concentrated under reduced pressure to yield oily liquid. The crude oily liquid was purified through column chromatography using hexane and EtOAc to obtain Epoxide 6-A (SR/RS) and Epoxide 6-B (SS/RR).
Example-8: Preparation of 2-{Benzylamino)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yljethanol (Formula-?):

16.56 kg of benzyl amine in 22.5 L IPA is taken in a reactor and stir the reaction mass. The 4 gm of (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula 6-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 IPA and dried over reduced pressure to yield 2-(Benzylamino)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol (Formula-7 with Yield = 6.0-6.1 kg (98.38%).

Example-9: Preparation of 2-{Benzyl-l2-(6-fluoro-chroman-2-yl)-2-hydroxy-ethyl]- amino}-1 -(6-fluoro-chroman-2-yl)-ethanol (Formula-8):

4 kg of (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula 6-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 (Formula-7) 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 degas 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 (Formula-8 with Yield : 9.8-10 kg (98.13%))
Example-10: Preparation of Nebivolol HCI (Formula-9):

18 kg of Benzyl Nebivolol of formula-8 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 pressure and cooled to 35-40oC. The reaction mixture is filtered through hyflow bed and washed with methanol. The solvent is distilled 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 33-35oC and stir. The reaction mass is filtered and washed with methanol. The product Nebivolol {Formula-9) is dried to give wet cake which is further charged into Methanol. The reaction mixture is heated to reflux and stirred. 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 Nebivolol HCI. (Yield: 11-11.2 kg, (76.7%))

We claim,
1. A process for the preparation of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde of Formula-1 comprising:
reduction of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate of Formula-3 using Sodium bis(2-methoxyethoxy)aluminium dihydr/de with alcohol and in presence of organic solvent(s).

wherein R represents hydrogen or (C1-C4) alkyl group,
2. The process according to claim-1, wherein the alcohol is selected from methanol, ethanol, Isopropyl alcohol and butanol or mixtures thereof.
3. The process according to claim-1, wherein the organic solvent is selected from chlorinated hydrocarbon.
4. The process according to claim-3, wherein the chlorinated hydrocarbon solvent is methylene dichloride.
5. A process for the preparation of Nebivolol or its salt comprising the process of preparing Formula-1 from Formula-3 using vitride with alcohol in organic solvent as claimed in claim-1.