2-carba!dehyde

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of 6-fluoro-3,4-dihydro- 2H~chromene-2-carbaidehyde which is a usefui intermediate :ti the synthesis of (D, L) ebivolol or its pharmaceutical acceptable salts thereof

BACKGROUND OF THE INVENTION

Synthesis of (D, L) Nebivolol or its pharmaceutical acceptable salts thereof involves the use of 6-fiuoro-3 _i 4 -dihydrO"2H-chromene-2-c3rbaidehyde a usefui intermediate which is depicted as structural formula-l

Formula-1

US 4,654,432 discloses a process for synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2- carbaldehyde of Formuia-1 from 6-Fluoro-4-oxo-4H-chromene-2-carboxylic acid of Formuia-5, as depicted in synthetic scheme-1 . The 6-fiuoro-4-oxo-4H-chromene-2-C3rboxylic acid of Formuia-5 is hydrogenated by using 10% Pd/C catalyst at norma! pressure and room temperature to obtain 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid of Formu!a-4. The 6- fluoro-3,4-dihydro-2H-chromene~2-carboxyiic acid of Formula-4 is esterif;ed with ethanoiic HCi to corresponding ethyl 6~fluoro-3,4~dihydro~2H~chromene-2-earboxylate of Formula-3 which is reduced with sodium dihydro-bis(2-methoxyethoxy)aluninate (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 oxaiyi chloride in a mixture of dichioromethane and dimethyl sulfoxide at -60°C to 6-fjuoro-3,4-dihydro-2H-chromene-2~carbaldehyde of Formuia-1 . Scheme

{FormulH-2;

6-fluoro 4-dihydfo--2B-c i"cmene- {6-f!iiDro-3,4-<Sfy<J« -2H-onfomen- ^csrbaicehyds vijmethanol

EPQ334429B1 discloses a process for the preparation of specifically the RSSS isomer of nebivolol independently. The said process for the independent preparation of RSSS nebivolol involves synthesis of (÷)-(S)-8-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde as an intermediate compound. The said process involves the use of hazardous reagents like thlonyl chloride, sodium hydride and di-isobutyl aluminium hydride (DI 3AL), expensive optically active reagents tike ,2,3/· ,43,9, 10, 1 Oa-octahydro-1 ,4a-dimethyi-7-(1 -methylethyi- 1 -phenaihrene- methanamine[{+)-dehydroabiethylamine] and utilities like column chromatograph 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,

Indian granted patent ΙΝ221733 patent involves the synthesis of 8-iluoro-3/-dihydro- 2H-chromene-2-carbaidehyde of Formula 1 from (8-fluoro-3,4-dihydro-2H-chromen-2- yj)(piperidin-1 -yS)meihanone of Formuia~4A by using aikoxy metallic hydride. The intermediate of Formula-4A was synthesized from reaction of 8-fluoro-3.4-dihydro-2H-chromene-2-carboxy!ic acid of Formu!a- with an acid activating agent, and an amine RR'NH, wherein R and R ^' are independently H, alkyi or aryl, optionally joined together with or without a heteroatom selected from O, N and S, to give (e-fiuoro-S^-dihydro^H-chromen^-y ipiperidin-l -ylJrneihanone of Formuia-4A.

Schem©-3:

Indian patent application SN2703CHE2008 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 -7CTC in different solvents like toluene, xylene, cyclic ethers like THF, ethers particularly alkyi ethers either open chain such as ethylene glycol, dimethyl ether, iert.butyiether, butyl methyl ether and the like or mixture thereof. jcheme-4:

(FormuSs-3 (Formiiia-1 )

Ester of 6-F ^' !uora-chroman-2- 8-Fluoro-3,4-di ydro-2H- carboxviic acid chromene-2-carba!dehyde

R = Methyl, Ethyl, Propyl

In our study of prior art processes for the preparation of 6-Fluoro-3,4-dihydro 2H- chromene~2~carbaidehyde compound we have observed that the reaction of compound of formu!a-3 of Scheme-4, there is formation of large amounts of (6-Fiuoro-3,4-dihydro-2H- chromene-2-yi)-methanoS 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-Fluoro-3.4-ciihydro

2H-chromene-2-carbaloehyde. 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 8-fluoro3,4-dihydrc-2H- chromene-2-carbaidehyde of Formula-!

SUGARY OF THE INVENTION

In a preferred embodiment, the present invention provides a process for the preparation of 6-fiuoro-3,4-dihydro-2H-chromene-2-carbaidehyde.

In another embodiment, the present invention provides process for the preparation of 6- fluoro-3,4-dShydro~2H-chromene-2-carbaidehyde of Formula-1 from methyl 6-f!uoro-3,4-d!hydro-

2H-chrornene-2-carboxylate of Formula-3 using Sodium bis(2-methoxyethoxy)aiuminium 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-carbalde ^' nyde 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-dShydro~2H-chromene-2-carbaldehyde of formula-1 . The process according to present Invention results a cost effective preparation of 6-fiuoro~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:

esferification of 8-fluoro~3,4-dinydro-2H-chromene~2~carboxylic acid of formuia-4 to give methyl 8-fluoro-3 _! 4-dihydro-2H-chromene-2-carboxyiate of formula-3; reduction of methyl e-fiuoro-S^-dlhydro^H-chromene^-carboxyiate of formu!a-3 to afford 6-fiuoro-3,4-dlhydro-2H-chromene-2-carba!dehyde of formu!a-1 using Sodium bis(2-methoxyethoxy)a!uminium dihydride (known as vitride) in presence of alcohol and optionally with other organic soivent(s); the resulting product is dried and purified to yield pure 6-fluoro~3,4-dihydro-2H- chromene~2-c3rbaidehyde of formuia-1.

The steps involved in synthesis of 6-fluoro-3,4-dihydro-2H-chromene-2-carbaidehyde of formuia-1 which is depicted in synthetic scheme-5 below:

5cheme~5:

6-F!uoro-3,4-dihydro-2H- methyl 6-ffuoro-3,4-dihydro- 6-F!uoro-3,4-dihydro-2H- chromene-2-carboxylic acid 2H-chromene-2-car oxy!ats chrofrsene-2-carbaidehyde

According to present invention Sodium bis{2-mefhoxyethoxy)a!uminium dihydride or Sodium dihydrido-bis(2-methoxyethoxy)aiuminate is referred as commonly known name - vitride.

The esterification of the 6-F!uoro-3,4-dihydro-2H-chromene-2-carboxySic acid of Formuia-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, H ₂ S0 ₄ and the like. Preferably methyl 6-fluoro-3,4-dihydro-2H-chromene-2-carboxy!ate of Formula-3 is prepared by reacting acid (Formuia-4) with methanol in presence of H ₂ S0 under reflux conditions. The methyl 6-fluoro-3,4-dihydro-2H-chromene-2--carboxylaie 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 8-fiuoro-3,4- dihydro-2H-chromene-2-carboxylate of Formula-3 using vitride-alcohoi as a reducing agent to give 6-fiuoro-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, isopropanoi and n-butanoi.

The use of vitride-alcohoi in place of normal vitride gives more conversion of ester to aldehyde and control over reaction proceed towards the formation of (6-fiuoro-3,4-dihydro-2H- chromen-2-yl)methanoi of Formu!a-2: (Forrrsuia~2)

(6-fluoro-3,4-dihydra-2K-chramert-2- yl);meihano!

The present invention is further illustrated by experimental details to study the use of vitride with or without using different a!cohol(s) for reduction of methyl S-fluoro~3,4~dibydro-2H- cnromene-2- carboxylate to give 6-Fluoro-3,4-dihydro-2H-chromene-2-carbaldeh de. The results are tabulated beiow:

Table-1 : Reaction of Vitride in presence of different afcoho! s)

Sr. Reducing agent according to present invention

Formula~1 % Formula-2 %

1 Vitride 78.73 18.50

2 Vitride along with Methanol 80.29 12.19

3 Vitride along with Ethanoi 86.19 1 1 .58

4 Vitride along with IPA 85.94 1 1 .08

5 Vitride along with n-Butanol 83.27 13.81

The commercially available Vitride is used in presence methyl 6-fluoro-3,4-dihydro-2H- chromene-2-carboxylate of Formuia-3, the preparation of 6-fiuoro-3,4-dihydro~2H-chromene~2- carbaidehyde of Formuia-1 is 78.73% which also results (8-fluoro-3,4-dihydro-2H-chromen--2- yi)methano! of Formula-2 is 18.50%. The Vitride in presence of alcohol results the formation of 6-fiuoro-3,4-d!hydro-2H-chromene-2--carbaidehyde of Formuia- with reduced level of (6-fiuoro- 3,4-dihydro-2H-chroman-2-yl)methanoi 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 4.8 mm), 5μ or equivalent

Detection wavelength : 210nm

Flow Rate : LOmlJminute

injection Volume : 20 J L

Oven Temoerature : 25^0

The given results demonstrates that vitride with alcohol used for conversion of methyl 8~ fiuoro-3.4-dihydro-2H-chromene-2-carboxylaie of Formuia-3 to 6-fiuoro--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-iimiiing examples.

Exarnp!e-1 : Synthesis of methyl 6-fluoro-3,4-dihydro-2H-chromene-2-car oxylate of Formu!a-3:

A solution of 6-fiucro~3,4-dihydro-2H-chromene-2-carboxylic acid (l OQgro, 0,510 moles) sn methanol (500ml) is prepared in I Sir Round Bottom Flask (RBF) at Room Temperature (RT, 25-30X). 19.8 grn 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 40-45X. In the reaction mixture is added 500 ml DC and 500 ml purified water. Organic Iayer is washed with 500 ml purified water and 500 ml sodium bicarbonate solution. Organic Iayer finally washed with 500 mi purified water. Organic Iayer 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-chromerie- 2-carboxylate of Formula-3. Weight of oi!-102 gm HPLC purity- 99.97%; Yield - 98%. Example-2: Synthesis of 6-fluoro-3 _s 4 Jihydro-2H-chromene-2-carbaldehyde of Forroula-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 ⁰ 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 mi of 15% aqueous HCI solution at -73 to -78 ^U C. 250 mi water is added. Organic layer separated at RT and Aqueous Iayer is washed with 250 ml MDC. Final organic layer containing 8-fiuoro--3,4-dihydro-2H-chromene-2-carbaldehyde is washed with 375 mi purified water and dried over 20 gm sodium sulphate. HPLC purity- Formula- ^' ! :- 78.73%, Formu!a~2 18.50%; Yield-87%.

Example~3; Synthesis of 6-fiuoro-3, 4-dihydro-2H-chromene-2-carhaidehyde of Formuia-1 using Vitride in presence of SPA:

A solution of methyl 6-fiuoro-3,4-dihydro-2H-chromene-2-carboxyiate (50gm, 0,238 moles) in Methylene dichloride (MDC) (500ml) is prepared under nitrogen atmosphere and cooled to -7S°C. In another flask 100 ml Toluene is added in 86.7 gm of 70% Sodium bis(2~ meihoxyethoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere and cooled to Q~5°C. In this solution of vitride 12.63 ml of I PA is added slowly at 0-5°C. This viiride- 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 I PA at -73 to -78°C. Reaction mass then quenched with 130 ml of 15% aqueous HCI solution at -73 to ~78 ^'5 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 w th 375 mi purified water and dried over 20 gm sodium sulphate HPLC purity- Formula-1 :- 85.94%, Formuia:-2-1 1 .08%. Yield - 99.01 %.

Example-4: Synthesis of 6-fluoro~3 _s 4-dihydro-2H-chrornene-2-carbaidehyde of Formula-1 using Vitride in presence of Methanol:

A solution of methyl 6-fluoro-3,4-dihydro-2H-ehromene-2-carboxylate (15 grn., 0.071 moles) in Methylene dich!onde (MDC) (150ml) is prepared under nitrogen atmosphere and cooled to -78 ^C C. in another flask 30 ml Toluene is added in 35.28 gm of 51 .81 % Sodium bis(2- methcxye†hoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere and cooled to 0-5°C. In thss solution of vitride 2.01 ml of methanol is added slowly at 0-5C. This vithde-methano! 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 3.86 mi methanol at -73 to ~78°C. Reaction mass then quenched with 40 mi 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 1 15 mi purified water and dried over 8 gm sodium sulphate.

HPLC purity- (Formula-1 :- 80.29%, Formula-2:-12, 19%), Yield - 91 .15%.

Examp!e-5: Synthesis of G-f!uoro-3, -dihydro-2H-chromene-2-carba!dehyde of Formuia-1 using Vitride presence of Ethanol:

A solution of methyl 8-fluoro-3,4-dihydro-2H-chromene-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 .81 % Sodium bis(2- methoxyethoxy)aluminium dihydride (vitride) solution in toluene under nitrogen atmosphere and cooled to Q-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 -78°C. After the end of addition reaction mass is stirred for 0,5 hrs and then added 3.88 ml ethanol at -73 to -78°C. Reaction mass then quenched with 40 ml of 15% aqueous HCI solution at -73 to -78 ^C' C. 75 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 75 m! MDC. Final organic layer containing 6-fluoro-3,4-dihydro-2H-chromene-2-carbaldehyde is washed with 1 15 ml purified water and dried over 6 gm sodium sulphate. HPLC purity- Formula-1 88, 19%, Formula-2:- 1 1 .58% , Yield - 89.23%.

Example-S: Synthesis of 8~fluoro~3, 4-dihydro-2H~chromsene~2~carbaldehyde of Formula-1 using Vitride in presence of n-Buiano!:

A solution of methyl 6-fluoro-3,4-djhydro-2H-chromene-2-carboxylate (15 gm, 0.0714 moles) in Methylene dichloride (MDC) (150mi) is prepared under nitrogen atmosphere and cooled to -78°C. in another flask 30 ml Toluene is added in 35.28 gm of 6181 % Sodium bis(2- methoxyethoxy)a!uminium dihydride vitride solution in toluene under nitrogen atmosphere and cooled to 0-5X. In this solution of vitride 4.55 ml of n-hutanol 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-butano! at -73 io -78°C. Reaction mass then quenched with 40 mi of 15% aqueous HCi solution at -73 to -78 ^C' C, 75 ml water is added. Organic layer separated at RT and Aqueous layer is washed with 75m! DC Final organic layer containing 6-fiuoro-3,4-dihydro-2H-chroirsene-2-carbalde yde is washed with 1 15 mi purified water and dried over 6 g sodium sulphate.

HPLC purity- Formula-1 :- 83.27%, Formula-2:- 13.16%, Yield - 90.28%.

Examp!e-T: Synthesis of 6~Fiuoro-2-oxirany!-3,4-dihydro-2H~chromene (Formula-

Formuia-6B

To a solution of 101 g of trimethyisuifoxonium iodide in DMSO, potassium t-butoxide (53g) was added to obtain a clear solution. The oily material from any of examples 2 to 8, 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).

ExampIe-8: Preparation of 2- BenzyfaiT5ino)-1 -(6>ffuoro-3,4-d!hydro-2H-c romen-2- y^ethanol (Formula-?):

18.56 kg of benzyi amine in 22.5 L iPA is taken in a reactor and stir the reaction mass. The 4 gm of (2R)-6-fiuoro-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-(Ben2ylamino)-1 -(8-fSuoro-3,4-dihydro-2H-chromen-2-yi)ethanol (Formula-7 with Yield = 6.0-6.1 kg (98,38%), Example-S: Preparation of 2-{Benzyl~[2~{6~fiuoro~chroman-2~ l -hydroxy-ethyl]- amino}- 1 - 6-fiuoro-chroman-2-yI5-ethanoi (Formu a-8):

4 kg of {2R)-8-fiuoro-2-[(2R)-ox!ran-2-yl]-3^-dihydro-2H-chrorriene (formuia 6-6) is taken in 10.5 L methanoi is taken in a reactor and stirred. 6.2 kg of 2-(Benzyiamino)-1 -(8- fiuoro-3,4-dihydro-2H-chromen-2-yi)ethaROl (Formula-7) and 15.5 L methanoi is charged to reactor. The reaction mass is refiuxed and maintain for over 17 hrs. 2.5 L of HCI is charged info 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 Acefonitrile 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 Acefonit iie + diisopropyl ether. The product is dried hot vaccum pan to yield 2-{Benzyh[2~(8~fiuoro-chroman-2-yl)-2-hydroxy-ethyi1-amino}- 1 -{6- f!uoro-chroman-2-yi)- eihanol (Formula-8 with Yield : 9.8-10 kg (98.13%))

Examp e-10: Preparation of Nebtvolol HCI {Pormula~9):

Formii!a-8 FormuSa-9

18 kg of Benzyl Nebivolol of formula-8 1.8 kg PD/C are charge with 381 L methanoi in the an autoclave. The reaction mass is heated to 48~52°C under 5.0-5,5 kg/cm ² hydrogen pressure. The reaction is maintained at pressure and cooled to 35-40X. The reaction mixture is filtered through hyfiow bed and washed with methanol. The solvent is distiiied and IPA HCi is added and reflux for 3 hrs. Methanol is added to the reaction mass and reflux for 30 mln. The solvent is atmospherically distilled until the volume of reaction mass remains 45-54 L.

The reaction mass is cooi the mass to 33-35 ^c C and stir. The reaction mass is filtered and washed with methanoi. The product Nebivolol {Formuia-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 fiiter through hyfiow bed and wash with 2 methanoi The solvent is distilled from the mass atmospherically at 65-70°C up to 3 vol. remains intact and gradually cool to 33-35 ^* 0 with stirring. Filter the product and wash the cake with Methanoi. The product is dried under vaccum to yield Nebivolol HCI. (Yield: 1 1 -1 1 .2 kg, {76.7%})