Claims:1) A process for preparation of Nebivolol or its pharmaceutically acceptable salt of Formula – IV, which comprises;
a) adding an agent to mixture of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran and (R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula–V to form azeotrope;
b) isolating diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran of Formula–V-A from the azeotrope and obtaining R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula – V-B; and
c) converting the (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran of Formula–V-A and R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula–V-B into Nebivolol or its pharmaceutically acceptable salt of Formula – IV.
2) The process as claimed in claim 1, wherein the agent is selected from a group consisting of glycols, sulfolenes, nitrobenzene, biphenyl, diphenylether, acetophenone and hydrocarbons.
3) The process as claimed in claim 2, wherein the hydrocarbon solvent is aromatic hydrocarbon, open chain hydrocarbon or cyclic hydrocarbon.
4) The process as claimed in claim 3, where in the open chain hydrocarbon is selected from a group consisting of decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, Dimethylundecane, Trimethyldecane, Ethyl methyldecane, Propyldecane and butyldocosane.
5) The process as claimed in claim 3, where in the open chain hydrocarbon is n-pentadecane or n-hexadecane.
6) The process as claimed in claim 1, where in the azeotrope formation is carried out under vacuum.
7) The process as claimed in claim 1, wherein the step c further comprises;
a) reacting the (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran Formula–V-A with benzyl amine to obtain [R*(S*)]-6-fluoro-3,4-dihydro-[a]-[[(phenylmethyl)-amino]methyl]-2H-1-benzopyan-2-methanol of Formula–VI;
b) reacting the [R*(S*)]-6-fluoro-3,4-dihydro-[a]-[[(phenylmethyl)-amino] methyl]-2H-1-benzopyan-2-methanol of Formula – VI with (R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula–V-B to obtain [2S*[1R*,5R*(R*)] a,a’-[[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] of Formula–VII; and
c) converting the [2S*[1R*,5R*(R*)] a,a’-[[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] of Formula–VII into Nebivolol or pharmaceutically acceptable salt of Formula-IV.
, Description:Related application:
This is an application for patent of addition to the co-pending application of PCT/IN2016/0050144 dated 18th May 2016, which is filed based on the complete application, 1978/MUM/2015 filed on 19/05/2015.

Field of the invention:
The present invention relates to a new process for preparation of Nebivolol or it’s pharmaceutically acceptable salt. More particularly, the invention relates to an improved economical process for the preparation of intermediate, 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II, converting the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II into mixture of [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran and [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of Formula-V and separation of diastereomers of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran by forming azeotrope.

Background of Invention:
Nebivolol is chemically known as (±)(aR*,a'R*,2R*,2'S*)-a,a'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanol] having Formula.

The Nebivolol structure has four stereogenic centers, which are indicated as 1, 2, 3 and 4. Nebivolol is a mixture of equal amounts of two enantiomers having (S,R,R,R) and (R,S,S,S) configuration.

Nebivolol is useful in the treatment and prevention of coronary vascular disorders.

Nebivolol is first disclosed in U.S Patent no. 4,654,362. This patent discloses a process for preparing Nebivolol using a key intermediate, 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II.

In the ‘362 patent, 6-Fluoro-4-oxo-4H-chromene-2-carboxylic acid is reduced with hydrogen in presence of 10% Pd/C catalyst to obtain 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid. The 6- fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid is esterified with ethanolic HCl to obtain corresponding ethyl ester of 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid which is reduced with sodium dihydro-bis(2-methoxyethoxy)aluminate (also known as vitride) in benzene at reflux conditions to obtain (6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol, which is further reacted with oxalyl chloride in a mixture of dichloromethane and dimethyl sulfoxide at -60°C to obtain6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde.This carboxaldehyde is further reacted with trimethylsulfoxonium iodide to obtain mixture of RS/SR & RR/SS of 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran. The stereoisomers are separated by chromatorgraphy into two racemic mixtures (R,S)-, (S,R)-epoxides (Mixture A) and (S,S)-, (R,R)-epoxides (Mixture B). The separated isomers are further converted into Nebivolol.

However this process involves corrosive chemicals such as oxalylchloride and chromatography method is involved to separate the isomers. The chromatography method is not industrially feasible and economically unviable.

Later publication, WO 2006/025070 describes an improved process for Nebivolol synthesis wherein the diasteomeric mixture of RS/SR & RR/SS of 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran are separated into the known mixture And mixture B by using column chromatography.

The problem of chromatography method is solved to some extent by another patent application, US20120108826 (ZACH systems). This patent application discloses separation of the diasteomeric mixture of RS/SR & RR/SS of 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran by fractional distillation using specific column of about 1.2 meter height filled with a packing material that ensures an efficiency corresponding to 10-25 theoretical plates. However this fractional distillation is also having problems of low recovery of separated isomers due to exposing the material to higher temperature for prolonged period of time. Also constructing the specific column on commercial scale poses difficulties.

An Indian patent, ??221733, discloses reaction of (6-fluoro-3.4-dihydro-2H-chromene-2-carboxylic acid 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 O, N and S, to give (6-fluoro-3,4-dihydro-2H-chromen-2yl)methanone which is reduced using alkoxy metal hydride to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde. This process also involves multiple and lengthy processes leading to increased time cycle and production cost.

The problem of lengthy steps is solved in US6545040 patent by obtaining (+)-(S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde in a single step. The US‘040 patent discloses reaction of (+)-(S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid with [bis(2-methylpropyl)]aluminum hydride (DIBAL) in presence of 1,1'-carbonylbis[1H-imidazole] at -70°C in tetrahydrofuran solvent to obtain (+)-(S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde in 59% yield. However, this process suffers lower yield and involves operating at -70°C temperature which is not industrially viable and scalable.
An Indian patent application, 2703/CHE/2008, discloses an improved process for the preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde by reducing an ester of (6-fluoro-3.4-dihydro-2H-chromene-2-carboxylic acid using Vitride at -70°C in solvents such as toluene and xylene. The same reaction is also reported in WO2014111903, which discloses reduction of methyl ester of 6-fluoro-3.4-dihydro-2H-chromene-2-carboxylic acid using Vitride at -73°C to -78°C to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehydewith 18.5% of (6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol as impurity due to uncontrolled reduction.

From the ‘2703 and ‘903 publications, it is evident that the alcohol impurity, 6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol, is formed due to un controlled over reduction. This impurity is formed even when the reduction is performed at substantially lower temperatures between -70°C to -78°C. Thus the single step process poses dual problems of 1) conducting reaction at substantially lower temperatures between -70°C to -78°C which is not industrially feasible and the process is not scalable, and 2) formation of the alcohol impurity, 6-fluoro-3,4-dihydro-2H-chromen-2-yl)methanol, is not controlled even after conducting the reaction at -70°C to -78°C leading to yield loss, and incorporation of additional purification steps to remove the impurity, increases the production cost.

The U.S Patent 4,654,362 further discloses reaction of the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde with trimethylsulfoxonium iodide to obtain mixture of RS/SR & RR/SS of 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran. The stereoisomers are separated by chromatography into two racemic mixtures (R,S)-, (S,R)-epoxides (Mixture A) and (S,S)-, (R,R)-epoxides (Mixture B).

Therefore, the objective of the present invention is to separate diastereomers of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran and to prepare the intermediate, 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde, from esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid to overcome the problems stated above by minimizing the formation of alcohol impurity while performing the reduction reaction at optimum temperatures, thereby making the process industrially feasible and economically viable.

Summary of Invention:
The present inventors have, surprisingly, found a novel process for preparation of Nebivolol or its pharmaceutically acceptable salt which comprises preparation of intermediate, 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II, converting the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II into mixture of [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran and [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of Formula-V and separation of diastereomers of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran by forming azeotrope.

Accordingly in one aspect, the invention provides a process of preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula–II, which comprises;
reducing the esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula – I, wherein R1 denotes linear or branched (C1-C8)-alkyl, cycloalkyl, aryl; in presence of a secondary amine, with a reducing agent to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula–II. The invention is depicted in Scheme-1.

The novel process of isolation of one of the diastereomers (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran having RS/SR configuration from the mixture of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran having RS/SR and (R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran having RR/SS configuration comprises addition of an agent to the mixture to form azeotrope. Surprisingly it is found that the agent is forming azeotrope with one of the diastereomers, (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran and the azeotrope is getting distilled at much lower temperature enabling the isolation of the diasteromer from its mixture.

Accordingly, another aspect of the present invention provides a novel process for preparation of Nebivolol or its pharmaceutically acceptable salt of Formula – IV, which comprises;
a) adding an agent to mixture of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran and (R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula–V to form azeotrope;
b) isolating the diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran of Formula–V-A from the azeotrope and obtaining the R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula – V-B; and
c) converting the (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran of Formula–V-A and R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran of Formula–V-B into Nebivolol or its pharmaceutically acceptable salt of Formula – IV.

In a preferred embodiment, the agents are suitable solvents which are immiscible with OXI and having higher boiling points may be used to form azeotrope with the diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopranof Formula–V-A.

In another preferred embodiment, suitable solvents are hydrocarbons include aromatic or aliphatic hydrocarbons. The aliphatic hydrocarbons are having 10-20 carbon atoms include open chain hydrocarbons like decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, Dimethylundecane, Trimethyldecane, Ethyl methyldecane, Propyldecane, butyldocosane and cyclic hydrocarbons like 1-methyl-2-pentyl cyclohexane. However, preferred solvent is n-penta decane or n-hexadecane.

Brief description of the drawings:
Figure 1 shows schematic drawing of the system displaying separation of OXI-A and OXI-B by azeotropic distillation.

Description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

Abbreviations:
OXI : 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran (Mixture of RS/SR & RR/SS)
OXI-A :(R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran, OR [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of and (Mixture of RS &SR)
OXI-B :(R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran OR [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran(Mixture of RR &SS)

Azeotrope:
An azeotrope or a constant boiling mixture is a mixture of two or more liquids whose proportions cannot be altered by simple distillation. This happens because, when an azeotrope is boiled, the vapour has the same proportions of constituents as the unboiled mixture.

The present invention provides an improved economical process to prepare Nebivolol or it’s pharmaceutically acceptable salts.

Accordingly in one aspect, the invention provides a process of preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula–II, which comprises;
reducing the esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula – I, wherein R1 denotes linear or branched (C1-C8)-alkyl, cycloalkyl, aryl; in presence of a secondary amine, with a reducing agent to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula–II.

The invention is depicted in Scheme-1.

Scheme-1

The secondary amines may be open chain (R2R3NH) or a cyclic amine which may be pyrrolidine (five membered) or six membered ring of Formula-III;

Pyrrolidine Formula-III
wherein, R2 and R3 denote independently linear or branched (C1-C8)-alkyl, cycloalkyl, phenyl and benzyl; X denotes O or N-R4 ; and R4 denotes H, linear or branched (C1-C8)-alkyl, cycloalkyl, phenyl or benzyl. However, dipropyl amine and n-methyl aniline are preferred from open chain secondary amines. Morpholine and N-methyl piperazine are preferred from cyclic six membered ring of formula-III.

The reducing agents include, but not limited, to metal hydrides such as lithium aluminium hydride and sodium borohydride; alkyl aluminium hydrides such as diisobutyl aluminum hydride (DIBAL), or alkoxy aluminium hydrides such as sodium bis(2-methoxyethoxy)aluminium hydride (it is also called Vitride), lithium diethoxyaluminiumdihydride and lithium tri-tert-butoxyaluminium hydride. However Vitride is preferred reagent from alkoxy aluminium hydrides.

In a preferred embodiment, the esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula – I, wherein R1 denotes methyl or ethyl, are reduced with Vitride in presence of a morpholine or N-methyl piperazine.

According to the present invention, the reducing agent and the secondary amine are separately mixed in a suitable solvent to form a mixture or complex. Then the mixture/complex is reacted with the esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula–I to obtain the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula–II. Typically the reducing agent is taken in a solvent, cooled the mixture to about 10°C under nitrogen followed by addition of secondary amine at the same temperature. After addition of the amine, the mixture is equilibrated for another 15 to 30 minutes. Then the mixture of reducing agent-secondary amine is added into ester of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula–I for completing reduction reaction.

The reduction reaction may be performed in suitable solvents. Suitable solvents for conducting reduction reaction include, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, nitriles, ethers etc. Chlorinated hydrocarbons preferably include methylenedichloride, ethylenedichloride, chloroform, carbon tetrachloride. Nitrile solvents include acetonitrile and propionitrile. Aromatic hydrocarbons preferably selected from benzene, toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane etc. Ethers include tetrahydrofuran, diisopropyl ether or diethyl ether. However, most preferred solvents are toluene, xylene or tetrahydrofuran.

In another preferred embodiment, the reduction reaction is conducted typically from -25°C to 10°C temperature. However, the preferred temperature range varies between -15°C to 0°C temperature. Molar ratio of secondary amine may be used in the range of 1 mole to 4 moles relative to esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula – I. However, the preferred range is 1.5 to 1.7 moles. Alkoxy aluminium hydrides may be used in the range of 1 to 2 moles relative to esters of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid of Formula – I. However, the preferred range of alkoxy aluminium hydrides is 1.3 to 1.5 moles.

Typically the reduction reaction completes in 2-3 hours to form 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde. After completion of reaction, the mass is quenched with methanol followed by dilute hydrochloric acid. Then the reaction mass is extracted with suitable solvents followed by concentration to isolate the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde.

According to another aspect, there is provided a process for preparation of Nebivolol or its pharmaceutically acceptable salts such as hydrochloride or hydrobromide salts. Accordingly the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde prepared as per the present invention mentioned above is converted into Nebivolol or its pharmaceutically acceptable salt.

Accordingly, the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde is reacted with trimethylsulfoxonium iodide in presence of base, sodium methoxide, in dimethyl sulfoxide solvent to obtain mixture of [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of formula-V-A and [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of formula-V-B.

According to another aspect, there is provided a process for preparation of Nebivolol or its pharmaceutically acceptable salt, which comprises isolation of one of the diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran having RS/SR configuration from the mixture of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopran having RS/SR and (R*)-6-Fluoro-3,4-dihydro-2-((R*)-oxiran-2-yl)-2H-benzopran having RR/SS configuration by adding an agent to form azeotrope.

In one embodiment, the agents are suitable solvents which are immiscible with OXI and having higher boiling points may be used to form azeotrope with diastereomer (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)-2H-benzopranof Formula–V-A.

The suitable solvents for forming azeotrope may include but not limited to glycols, sulfolenes, glymes, glycerol ethers, hydrocarbons, crown ethers such as 12-crown-4, nitrobenzene, biphenyl, diphenylether, acetophenone. Glycols include glycerol, monoethyleneglycol, diethyleneglycol, triethyleneglycol, 1,3-Proapnediol, 1,4-Butanediol, 1,2-Butanediol and 1,3-Butanediol. Sulfolenes include 2-sulfolene, 3-sulfolene, 3-methyl-2-sulfolene, 3-methyl-3-sulfolene, and 3-ethyl-3-sulfolene. Glymes include diglyme, triglyme, tetraglyme. Glycerol ethers include 1,2,3-trimethoxy propane, 1,2,3-triethoxy propane.

Hydrocarbons include aromatic or aliphatic hydrocarbons. The aliphatic hydrocarbons are having 10-20 carbon atoms include open chain hydrocarbons like decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, Dimethylundecane, Trimethyldecane, Ethyl methyldecane, Propyldecane, butyldocosane and cyclic hydrocarbons like 1-methyl-2-pentyl cyclohexane. However, preferred solvent is n-pentadecane or n-hexadecane.

Usually the process involves addition of agent to the OXI and heated under vacuum at about 2 torr to form azeotrope. It is surprisingly found that OXI-A isomer forms azeotrope with the agent at much lower vapor temperature of 69-70°C (when monoethyleneglycol used as agent) which is collected as distillate. The azeotrope containing two layers- top layer (agent) and bottom layer-(OXI-A rich layer) are separated, the top layer is refluxed back to the distillation flask. The azeotropic distillation is carried out till maximum OXI-A isomer is separated from OXI-B. Finally enriched OXI-B isomer retained in the distillation flask along with the agent is separated to obtain enriched OXI-B.

The [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of formula-Va (OXI-A) is reacted with benzylamine in water to obtain [R*(S*)]-6-fluoro-3,4-dihydro-[a]-[[(phenylmethyl)-amino] methyl]-2H-1-benzopyan-2-methanol of formula-VI, which is further reacted with [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of formula-Vb(OXI-B) in methanol at reflux temperature to obtain [2S*[1R*,5R*(R*)]a,a’-[[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]. The [2S*[1R*,5R*(R*)]a,a’-[[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] is debenzylated using hydrogen in presence of Pd/C catalyst in acetic acid solvent. After completion of reaction, catalyst is separated by filtration. The filtrate containing Nebivolol base is treated with acid (HX) such as hydrogen chloride gas to obtain Nebivolol hydrochloride salt in one pot.

The invention is depicted in scheme-2:

Scheme-2:

The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the claimed invention.

Example-1: Preparation of Methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate.
100 gm of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was charged in 500 ml of methanol under stirring and then added 2 gms of concentrated sulfuric acid at around 30°C. Then, reaction mixture was slowly heated to reflux temperature. Reaction was maintained at the reflux temperature. After reaction, methanol was distilled and product was extracted with toluene. Toluene solution was washed with 5% sodium bicarbonate solution. Toluene layer was concentrated to get 104 gm of Methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate.
Yield= 97%. Purity (GC area%)= 99.5%

Example 2: Preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (Formula-II).
206 gm of vitride (70% toluene solution) was taken in 500 ml toluene at 10°C, under nitrogen atmosphere. 69.7 gm of morpholine was added into it at the same temperature. The mixture was stirred for 15 minutes. In another flask, 100 gm of methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate was taken in 500 ml of toluene and was cooled to -10°C. Then, the above vitride+ morpholine solution was slowly added into methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate solution at about -10°C and was stirred at same temperature for 2 hrs. Reaction mass was then quenched with methanol followed by dilute hydrochloric acid, extracted with toluene and concentrated to get 84 gm of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde.
Yield= 98%, Purity= 95.8% (GC area%), Alcohol impurity = 2.8%

Example-3: Preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (Formula-II).
178 gm of vitride (70% toluene solution) was taken in 500 ml toluene at around 10°C, under nitrogen atmosphere. 69.4 gm of N-methyl piperazine was slowly added into it at the same temperature. The reaction mixture was stirred for 15 minutes. In another flask, 100 gm of Methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate was taken in 500 ml of toluene and cooled to -10°C. Then the above vitride + N-methyl piperazine solution was slowly added into the Methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate solution at about -10°C and was stirred at the same temperature for 2 hrs. Reaction mass was then quenched with methanol followed by dilute hydrochloric acid, extracted with toluene and concentrated to get 79.4gm of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde.
Yield= 92.7%, Purity= 91% (GC area%), Alcohol impurity = 1.68%

Example -4: 6-Fluoro-3,4-dihydro-2-oxiran-2-yl-2H-benzopran (Mixture of RS/SR & RR/SS) (OXI).

124.7 gm of trimethylsulfoxonium iodide was taken into 425 ml of dimethyl sulfoxide. It was cooled below 15°C and to this charged 25.5 gm of sodium methoxide and the mass was stirred at 15°C for 2 hrs. In another flask, prepared solution of 85 gm of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde in 425 ml MDC. This MDC solution was slowly added into above trimethylsulfoxonium iodide + sodium Methoxide dimethyl sulfoxide solution, while maintaining the temperature at 10 to 15°C and continued stirring for 2 hrs. The reaction mixture was then quenched into ice-cold water, aqueous layer extracted with MDC. MDC layer was washed with water and concentrated. Concentrated mass then distilled under vacuum to give 69 gm of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran as a mixture of A and B.
(Yield= 75%, HPLC assay: Formula-VA=60%, Formula-VB =29.6%)

Example-5: Separation of OXI-A (Formula-VA) & OXI-B (Formula-VB) by forming azeotrope:
Arranged azeotropic distillation using 1 liter capacity Round bottom flask (RBF), equipped with temperature pocket, 1 meter pack column (SS wire mesh rolls), column head attached to a condenser followed by Dean & Stark apparatus to get layer separation of compound of Formula-VA and monoethylene glycol in distillate.
Packed column is used to provide rectification stages for enrichment of azeotropic composition in the distillate (OXI-A + mono ethylene glycol). Provision of sufficient rectification stages ensures more pure heterogeneous azeotrope obtaining at the top.

Vacuum was applied from the top of the condenser using high vacuum pump with vacuum gauge.

The compound OXI 150 gm and Ethylene glycol 150 gm were charged in RBF. Then vacuum (~2 torr) was applied and started heating to get reflux through Dean & Stark apparatus. Layer separation was observed in Dean & Stark side arm. Top layer (Ethylene glycol layer) was refluxed back to the column and bottom layer (OXI-A rich layer) was collected at vapor temperature = 69-70°C, vacuum= 1.8-2.1 torr and Bottom (Re-boiler) temperature= 80-95°C.
Distillate (OXI-A rich) = 50 gm
(Purity by GC area%: OXI-A = 96.2% )
Bottom Residual mass : 138 gm (having two layers).
? Top layer: 21 gm; was of monoethylene glycol.
? Bottom layer: 117 gm ; OXI-B rich
(Purity of OXI-B rich layer by GC area% : OXI-B = 51.8%).

Example-6: Distillation of OXI-B:
Above OXI-B rich bottom layer was further subjected to direct distillation under vacuum. OXI-B pure collected at pot temperature 76-82°C, vapor temperature 78-91°C and vacuum 1-1.5 torr. Distillate collected = 16.7 gm
(Purity by GC area%: OXI-B = 91.2%)

Example-7: Separation of OXI-A (Formula-VA) & OXI-B (Formula-VB) by forming azeotrope using n-pentadecane:
Arranged azeotropic distillation using 1 liter capacity Round bottom flask (RBF), equipped with temperature pocket, 1 meter pack column (SS wire mesh rolls), column head attached to Dean & Stark apparatus with reflux condenser to get layer separation of compound and n-Pentadecane in distillate. Vacuum was applied from the top of the condenser using high vacuum pump with vacuum gauge.
The compound OXI (mix) 157 gm and n-Pentadecane 157 gm were charged in RBF. Then vacuum (~1 torr) was applied and started heating to get reflux through Dean & Stark apparatus. Azeotropic mixture of OXI-A rich with n-Pentadecane got collected in Dean & Stark apparatus. Layer separation was observed in Dean & Stark side arm. Top n-Pentadecane layer was refluxed back to the column and bottom layer collected in two cuts as follows. Re-boiler temperature was 110-115°C.
? OXI-A rich cut= 58g, collected at vapor temperature~85-90°C, vacuum=0.9-1.1 torr.
(Analysis by GC area%: OXI-A= 96%, OXI-B= 2.2%, Alcohol impurity= 1.5%)
? Intercut = 60gm, collected at vapor temperature ~ 89°C-92°C, vacuum= 0.9 torr.
(Analysis by GC area%: OXI-A= 65.6%, OXI-B= 34.2%)
Intercut will be recharged back in next distillation batch.
? Residual mass was having two layers. Top layer was of n-Pentadecane and
Bottom layer OXI-B rich = 20.8 gm.
(Analysis of OXI-B rich layer by GC area%: OXI-A= 0.6%, OXI-B= 95.7%)

Example-8: Distillation of OXI-B:
Above 20.8gm of OXI-B rich bottom layer was further subjected to direct distillation under vacuum. OXI-B pure collected at vapor temperature 78-91°C and vacuum 0.9-1.0 torr.
Distillate collected = 19.6gm
(Analysis by GC area%: OXI-A= 0.9%, OXI-B= 96.4%)

Example-9: Preparation of [R*(S*)]-6-fluoro-3,4-dihydro-[a]-[[(phenylmethyl)-amino]
methyl]-2H-1-benzopyan-2-methanol (Formula-VI):
276.0 gm of benzylamine was taken in 400 ml of water at around 25 to 30°C and 100 gm of [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran was added at around 10°C. Then reaction mass was stirred at 10-15°C for 1 hr. Further temperature was raised to 30°C and stirred for 5 hrs. Then the mass was cooled to 0-5°C, filtered, washed with chilled water and dried to get 136 gm of [R*(S*)]-6-fluoro-3,4-dihydro-[a]-[[(phenylmethyl)-amino]methyl]-2H-1-benzopyan-2-methanol (Formula-VI) Yield = 87.8%, Purity= 98.2% (HPLC area%).

Example-9: Preparation of [2S*[1R*,5R*(R*)] a,a’-[[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (Formula-VII)
125 gm of [R*(S*)]-6-fluoro-3,4-dihydro-[a]-[[(phenylmethyl)amino]methyl]-2H-1-benzopyan-2-methanol (Formula-VI) was taken in 500 ml of methanol at 30°C. To this added 80.6 gm of [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran at around 30°C. The reaction mass was heated to reflux and stirred at reflux for 15 hr. Then slowly added water and stirred for 1 hr. The mass was then cooled to -5 to 0°C, stirred for 24 hrs and filtered, washed with chilled methanol and dried to get 109.5 gm of crude 2S*[1R*,5R*(R*)] a,a’-[[(phenylmethyl)imino] bis -methylene] bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]. It was then purified in methanol to get 87.7gm of 2S*[1R*,5R*(R*)] a,a’-[[(phenylmethyl)imino] bis -methylene] bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].
Yield = 42.9% Purity=99% (HPLC area%). Undesired isomer: 0.32%

Example-10: Preparation of Nebivolol.HCl (one pot method)
50 gm of [2S*[1R*,5R*(R*)] a, a’-[[(phenylmethyl)imino]bismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol and 2.5 gm of Pd/C was taken in 200 ml of acetic acid at 30°C, was hydrogenated under 5 kg/cm2 of hydrogen pressure at 30-35°C. Then filtered off catalyst and purged dry hydrogen chloride gas in the filtrate. Precipitated product was filtered, washed with acetic acid followed by methanol, filtered and dried to give 36.6 gm of Nebivolol.HCl.
Yield=83.8%. Purity= 99.8%.