CLIAMS:We claim;

1. An efficient, cost effective process for synthesis of intermediate 6-fluoro-2-(oxiran-2-yl) chroman useful in the preparation of nebivolol or its pharmaceutically acceptable salts thereof comprising;
i. Reacting maleic anhydride dissolved in a solvent with 4-fluoro anisole in presence of AlCl3 and refluxing the mixture, cooling and adding the mixture to cold solution of 1:15 conc. HCl –water to obtain (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I);
ii. Adding (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I) to a solution of NaHCO3, water and an organic solvent, stirring at a temperature of 40-50°C until completion of reaction, cooling, adjusting the pH of the aqueous layer to pH 1-2, filtering, washing to obtain 6-fluoro-4-oxochroman-2-carboxylic acid (II);
iii. Refluxing solution of 6-fluoro-4-oxochroman-2-carboxylic acid (II) in sulphuric acid and alcohol till TLC indicated completion of the reaction, cooling to 5°C, filtering and washing to obtain methyl 6-fluoro-4-oxochroman-2-carboxylate (III);
iv. Reducing methyl 6-fluoro-4-oxochroman-2-carboxylate (III) with NaBH4 in solvent at 0°C till completion of the reaction as indicated by TLC, adjusting pH to 2-3, washing, concentrating to obtain crude 6-fluoro-2-(hydroxymethyl)chroman-4-ol (IV); optionally dissolving the crude compound in ethereal solvent and filtering;
v. Reducing 6-fluoro-2-(hydroxymethyl)chroman-4-ol (IV) with zinc in conc. HCl in solvent at 70°C until completion of the reaction as indicated by TL, cooling, washing concentrating to obtain 6-fluorochroman-2-yl)methanol (V);
vi. Adding drop wise to the solution of 6-fluorochroman-2-yl)methanol (V), KBr and TEMPO dissolved in solvent pre prepared solution of NaOCl at 0-5°C stirring till TLC indicate completion of reaction to obtain solution of 6-fluorochroman-2-carbaldehyde (VI) in a solvent; and
vii. Adding drop wise solution of 6-fluorochroman-2-carbaldehyde (VI) of step (vi) to solution of trimethyl sulfoxonium iodide in anhydrous solvent and KOtBu at r.t., cooling the reaction mixture to 10-15°C,washing, extracting and separating and purifying using silica gel column chromatography to yield anti-isomer 6-fluoro-2-(oxiran-2-yl)chroman (VIIA) as major product along with 6-fluoro-2-(oxiran-2-yl)chroman (VIIB, syn) as minor product.

2. The process for preparation of nebivolol or its pharmaceutically acceptable salts thereof using 6-fluoro-2-(oxiran-2-yl)chroman (VIIA) of claim1, comprising;
i. Reacting 6-fluoro-2-(oxiran-2-yl)chroman (anti-isomer,VIIA) obtained above with a solution of benzyl amine in alcohol at ambient temperature until completion of the reaction as indicated by TLC, cooling the reaction mixture at 0-5°C to obtain 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol (VIII);
ii. Reacting 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol (VIII) with 6-fluoro-2-(oxiran-2-yl)chroman VII B (Syn) at a temperature in the range of 60-75°C to obtain 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) (IX); and
iii. Reducing the solution of 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) (IX) with 10% Pd/C under hydrogen atmosphere to yield 2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) base and converting to its hydrochloride salt (X).

3. The process according to any of the preceding claims, wherein the solvent is selected from polar and non-polar, protic or aprotic such as lower alcohols selected from methanol, isopropyl alcohol, butanol and the like; halogenated hydrocarbons such as dichloromethane; aliphatic and aromatic hydrocarbons such as pentane, hexane, toluene, xylene and the like; ethers selected from dimethyl ether, diethyl ether, isopropyl ether and the like.

Dated this 14th day of February, 2015

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:

“IMPROVED PROCESS FOR PREPARATION OF NEBIVOLOL”

2. APPLICANT:

(a) NAME: MAITHILI LIFE SCIENCES PVT. LTD.

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Plot No 16-31-HIG/117, KPHB Phase VI Kukatpalli,
Hyderabad- 500072, Telangana State, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

Technical field of invention:

The present invention relates to an improved, industrially feasible process for synthesis of nebivolol or its pharmaceutically acceptable salts via 6-fluoro-2-(oxiran-2-yl) chroman intermediate.

Background and prior art:

Nebivolol which is chemically (6-Fluorochroman-2-yl)-{[2-(6-fluorochroman-2-yl)-2-hydroxy-ethyl]amino}ethanol is a ß1 receptor blocker and is useful in the treatment and prevention of coronary vascular disorders.

The structure of nebivolol has four asymmetric carbon atoms producing a mixture of 16 stereoisomers ( due to presence of asymmetry in nebivolol structure ) or 10 stereoisomers (due to presence of symmetry in nebivolol structure) which makes the synthesis of a,a'-[imino-bis (methylene)] bis [chroman-2-methanol] with desired stereochemistry challenging.

Various methods are described in the art for preparation of nebivolol and generally relate to the reaction of amino alcohol compounds with anti-epoxy compound. The processes for preparation of epoxy compound described in the literature are multistep, cumbersome and involve the use of various reagents thus making the process costly and not industrially viable.

The further strategies for preparation of nebivolol is based on the synthesis of chroman ring and stereo selective formulation of its side chain.

EP0145067 by Janssen Pharmaceutica describes a method for preparation of nebivolol comprising synthesis of diastereoisomeric mixtures of chroman epoxide derivative by the process steps shown below:

Accordingly, 6-fluoro chroman carboxylic acid ethyl ester, derived from the esterification of the corresponding acid, is reduced with sodium dihydro bis-(2-methoxyethoxy)-aluminate to primary alcohol which is further reacted with oxalyl chloride and then triethylamine at -60° C. to give corresponding racemic aldehyde. The aldehyde is converted into epoxide as a mixture of (R,S),(S,R),(R,R)and(S,S) stereoisomers which is further separated using chromatographic separation to obtain two racemic mixtures (R,S)-, (S,R)-epoxides (Mixture A) and (S,S)-, (R,R)-epoxides (Mixture B), respectively as key intermediates for preparing nebivolol.

The further patent, EP0334429 by the same Applicant describes preparation of single optical isomers (R,S,S,S) and (S,R,R,R) of nebivolol by substantially same preparation method as described in EP’067 and further comprises resolving 6-fluoro chroman carboxylic acid into single enantiomers by treatment with (+)-dehydroabiethylamine. Said single enantiomers are further separated into their corresponding epoxides resulting in a mixture of two diastereoisomers.

There are however many disadvantages in the processes described above for preparation of nebivolol such as the use of costly reagents, lengthy and cumbersome process steps, most of the process steps are carried out at very low temperatures thus requiring special equipment and the yield of the intermediates and the product are very low.

It is observed that the processes in the art require costly chromatographic separation of the diastereoisomeric mixtures obtained in the intermediate steps which are useful for the preparation of desired product.

In view of the above shortcomings, there remains a need in the art to provide an improved, cost effective, shorter synthesis for preparation of nebivolol. These and other objectives are met in the present invention by providing an improved, cost effective process for preparation of nebivolol starting from basic, safe and mild reagents and using mild reaction conditions. The invention further provides a process for synthesis of desired diastereomeric mixture of high purity from appropriate starting materials and avoiding use of costly chromatographic separation at each intermediate stage employed in the art.

Summary of the invention:

In line with the objectives, the present invention provides a short, simple, cost effective process for the synthesis of pharmaceutical active ingredient, nebivolol or its pharmaceutically acceptable salts via the preparation of pure intermediate 6-fluoro-2-(oxiran-2-yl) chroman.

In the first aspect, the present invention provides an efficient, cost effective process for synthesis of intermediate 6-fluoro-2-(oxiran-2-yl) chroman useful in the preparation of pharmaceutical active ingredient, nebivolol or its pharmaceutically acceptable salts thereof.

The process steps comprises;
i. Reacting maleic anhydride dissolved in a solvent with 4-fluoro anisole in presence of AlCl3 and refluxing the mixture, cooling and adding the mixture to cold solution of 1:15 conc. HCl –water to obtain (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I);
ii. Adding (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I) to a solution of NaHCO3, water and an organic solvent, stirring at a temperature of 40-50°C until completion of reaction, cooling, adjusting the pH of the aqueous layer to pH 1-2, filtering, washing to obtain 6-fluoro-4-oxochroman-2-carboxylic acid (II);
iii. Refluxing solution of 6-fluoro-4-oxochroman-2-carboxylic acid (II) in sulphuric acid and alcohol till TLC indicated completion of the reaction, cooling to 5°C, filtering and washing to obtain methyl 6-fluoro-4-oxochroman-2-carboxylate (III);
iv. Reducing methyl 6-fluoro-4-oxochroman-2-carboxylate (III) with NaBH4 in solvent at 0°C till completion of the reaction as indicated by TLC, adjusting pH to 2-3, washing, concentrating to obtain crude 6-fluoro-2-(hydroxymethyl)chroman-4-ol (IV); optionally dissolving the crude compound in ethereal solvent and filtering;
v. Reducing 6-fluoro-2-(hydroxymethyl)chroman-4-ol (IV) with zinc in conc. HCl in solvent at 70°C until completion of the reaction as indicated by TL, cooling, washing concentrating to obtain 6-fluorochroman-2-yl)methanol (V);
vi. Adding drop wise to the solution of 6-fluorochroman-2-yl)methanol (V), KBr and TEMPO dissolved in solvent pre prepared solution of NaOCl at 0-5°C stirring till TLC indicate completion of reaction to obtain solution of 6-fluorochroman-2-carbaldehyde (VI) in a solvent;
vii. Adding drop wise solution of 6-fluorochroman-2-carbaldehyde (VI) of step (vi) to solution of trimethyl sulfoxonium iodide in anhydrous solvent and KOtBu at r.t., cooling the reaction mixture to 10-15°C,washing, extracting and separating and purifying using silica gel column chromatography to yield anti-isomer 6-fluoro-2-(oxiran-2-yl)chroman (VIIA) as major product along with 6-fluoro-2-(oxiran-2-yl)chroman (VIIB, syn) as minor product.

In the second aspect, the process for preparation of nebivolol or its pharmaceutically acceptable salt comprises;
i. Reacting 6-fluoro-2-(oxiran-2-yl)chroman (anti-isomer,VIIA) obtained above with a solution of benzyl amine in alcohol at ambient temperature until completion of the reaction as indicated by TLC, cooling the reaction mixture at 0-5°C to obtain 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol (VIII);
ii. Reacting 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol (VIII) with 6-fluoro-2-(oxiran-2-yl)chroman VII B (Syn) at a temperature in the range of 60-75°C to obtain 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) (IX);
iii. Reducing the solution of 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) (IX) with 10% Pd/C under hydrogen atmosphere to yield 2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) base and converting to its hydrochloride salt (X).
Abbreviations:
TEMPO: 2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl (free radical)

Detailed description of the invention:

The invention will now be described in detail with reference to various preferred and optional embodiments, so that various aspects thereof will be more fully understood and appreciated.

In a preferred aspect, the present invention relates to an improved, cost effective process for preparation of pure 6-fluoro-2-(oxiran-2-yl) chroman intermediate from simple, safe and mild reagents and mild reaction conditions which are useful for preparation of nebivolol or its pharmaceutically acceptable salts.

The process steps are as follows:
Step i: Maleic anhydride was dissolved in an organic solvent and stirred at room temperature until complete dissolution. Aluminium chloride was added lot wise over the period and the reaction mixture was heated at 50-55°C and maintained at same temperature for about an hour. To the mixture was added 4-flouro anisole slowly at 50-55°C over the period of 3-4h. Reaction mixture was further heated to 75-80°C and refluxed for another 3-5 hrs. After completion of the starting material by TLC, reaction mixture was cooled to 50-55°C and added to the cold solution (0-5°C) of conc. HCl: H2O (1:15) slowly. Resulting mixture was stirred at RT, filtered, washed with water and solvent to obtain (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I) as yellow solid.
Step ii: To a solution of NaHCO3 in water and Toluene at 40-50°C was added (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I) lot wise slowly and stirred at the same temperature for 5-6hrs. After completion of the starting material by TLC, reaction mass was cooled to 25°C and the toluene layer was separated. Aqueous layer was adjusted to pH 1-2 with con HCl. Filtered the solid and washed with water to give 6-fluoro-4-oxochroman-2-carboxylic acid (II) as off white solid.

Step iii: The solution of 6-fluoro-4-oxochroman-2-carboxylic acid (II) and sulfuric acid in lower alcohol was heated at reflux for about 5-7hrs. After completion of starting material by TLC, reaction mixture was cooled to 5°C and stirred. The solid was filtered and washed with cold solvent to give methyl 6-fluoro-4-oxochroman-2-carboxylate (III) as off white solid.

Step iv: Solution of methyl 6-fluoro-4-oxochroman-2-carboxylate (III) in solvent was prepared and sodium borohydride was added at 0°C slowly. The reaction mixture was stirred at same temperature for about an hour. After completion of the starting material by TLC, pH of the mixture was adjusted in the range 2-3 with 5N HCl. The solvent was removed under reduced pressure and the crude mixture was diluted with water and extracted in the solvent. The organic layer was dried on sodium sulfate and concentrated under reduced pressure to give 6-fluoro-2-(hydroxymethyl) chroman-4-ol (IV). The crude material was used for the next reaction without any further purification. Optionally, the crude was dissolved in ethereal solvent stirred for about 30 min and filtered).

Step v: To a solution of 6-fluoro-2-(hydroxymethyl)chroman-4-ol IV in conc. HCl and solvent at r.t was added zinc lot wise slowly and the temperature was raised to 70°C and maintained at same temperature until TLC indicated completion of the reaction. The reaction mixture was cooled to r.t. followed by removal of the solvent. The aqueous layer was further extracted in the solvent and the combined organic layers was washed with water and dried. The organic layer was concentrated under reduced pressure to give (6-fluorochroman-2-yl) methanol (V) which was used for the next reaction without any further purification.

Step vi. To the mixture of (6-fluorochroman-2-yl) methanol (V) dissolved in a solvent, KBr and solution of TEMPO was added pre-prepared solution of NaOCl (10-12% in water), NaHCO3 in water (80 ml) at 0-5°C drop wise. The reaction mixture was stirred at same temperature until completion of the starting material was indicated by TLC. The organic layer was separated and dried to obtain 6-fluorochroman-2-carbaldehyde (VI) which was used for the next reaction as its solution in a solvent.

Step vii: To the solution of trimethyl sulfoxonium iodide in anhydrous solvent was added a strong base such as KOtBu at r.t. under nitrogen atmosphere. The reaction mixture was stirred at same temperature for about an hour and cooled to 10°C. This was followed by addition of solution of 6-fluorochroman-2-carbaldehyde (VI), obtained in step (vi), drop wise. Reaction mixture was stirred at 10-15°C for about 30 min and allowed to stir at r.t for about an hour. Reaction mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted again in the solvent and the combined organic layers were dried and concentrated under vacuum. The crude material was purified on silica gel column chromatography to give 6-fluoro-2-(oxiran-2-yl)chroman VIIA (anti isomer) and 6-fluoro-2-(oxiran-2-yl)chroman VIIB (syn isomer).

The reaction process is shown below in Scheme 1:

In another embodiment, the so obtained 6-fluoro-2-(oxiran-2-yl)chroman VIIA was used to prepare nebivolol. The process steps are as follows:

Step i: 6-fluoro-2-(oxiran-2-yl) chroman (VIIA; anti isomer) obtained above was added to a solution of benzyl amine and stirred at 25-30°C. After completion of the starting material by TLC, reaction mixture was cooled and stirred at 0-5°C. The solid was filtered, washed to give 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol (VIII) as white solid.

Step ii: To the compound (VIII) i.e 2-(benzylamino)-1-(6-fluorochroman-2-yl) ethanol was added a solution of 6-fluoro-2-(oxiran-2-yl)chroman (VIIB) (Syn) in lower alcohol at r.t. The reaction mixture was heated at 65-70°C for 18-20hrs. After completion of the starting material by TLC, reaction mixture was cooled to r.t and conc. HCl was added. The alcohol was removed under vacuum followed by addition of a solvent and the mixture was stirred at r.t. this was followed by addition of ethereal solvent and stirred. The solid was filtered, washed to give 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) (IX) as off white solid.

Step iii: Finally, to the solution of 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) (IX) was added 10% Pd/C in solvent under hydrogen atmosphere (5-5.5 kg/cm2) at about 50°C and the mixture was stirred for 2-3hrs. After completion of the starting material by TLC, reaction mixture was cooled to r.t and hydrogen gas was released. Pd/C was filtered on celite bed and filtrate was distilled under reduced pressure. IPA.HCl (20%) mixture was added to the residue, heated and stirred at 65-70°C for about 4hrs. This was followed by addition of solvent and stirred at 65-70°C. The solvents were distilled at atmospheric pressure to maintain 60ml volume. Reaction mixture was cooled and stirred at r.t. for about 4hrs. Solid was filtered and washed to give 2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) hydrochloride (X).

The solvents used herein are selected from polar and non-polar, protic or aprotic such as lower alcohols selected from methanol, isopropyl alcohol, butanol and the like; halogenated hydrocarbons such as dichloromethane; aliphatic and aromatic hydrocarbons such as pentane, hexane, toluene, xylene and the like; ethers selected from dimethyl ether, diethyl ether, isopropyl ether and the like.
The process steps are indicated in Scheme 2 below:

The present invention thus provides an efficient process for preparation of pharmaceutically active ingredient nebivolol via 6-fluoro-2-(oxiran-2-yl) chroman using safe and mild reagents and reaction conditions and avoiding the need for costly chromatographic purification at each intermediate step.

In another embodiment, the present invention provides nebivolol prepared by the current process useful as anti- hypertensive agents.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the invention. The examples included herein are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

Examples:
Example 1: (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I)
To the solution of maleic anhydride (487g, 4.968 mols) in EDC (4 lit) was stirred for 1h at RT to dissolve perfectly. Aluminium chloride (1.32 kg, 9.93 mols) was added lot wise over the period of 1h 30min. Reaction mixture was heated at 50-55oC and maintained at same temperature for 1h. 4-flouro anisole (500g, 3.968 mols) was added slowly at 50-55oC over the period of 3-4h. Reaction mixture was heated to 75-80oC and refluxed for 4h. After completion of the starting material by TLC, reaction mixture was cooled to 50-55oC and added to the cold solution (0-5oC) of conc. HCl: H2O (1:15, 16 lit) slowly. Resulting mixture was stirred at r.t. for 30 min, filtered, washed with water (2 lit) and hexane (3 lit) to give (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (670g, 80%) as yellow solid.

Example 2: 6-fluoro-4-oxochroman-2-carboxylic acid (II)
To a solution of NaHCO3 (52.8g, 0.628 mols) in water (1 lit) and Toluene (500 ml) at 40-50°C was added (Z)-4-(5-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid (I) (100g, 0.476 mols) lot wise slowly and stirred at the same temperature for 5-6h. After completion of the starting material by TLC, reaction mass was cooled to 25°C and the toluene layer was separated. Aqueous layer was adjusted to pH 1-2 with conc. HCl (70 ml). Filtered the solid and washed with water (200 ml) to give 6-fluoro-4-oxochroman-2-carboxylic acid (II) (60g, 60%) as off white solid.

Example 3: Methyl 6-fluoro-4-oxochroman-2-carboxylate (III)
The solution of 6-fluoro-4-oxochroman-2-carboxylic acid (II) (100g, 0.476 mols) and sulfuric acid (10ml) in methanol (500 ml) was heated at reflux for 6h. After completion of starting material by TLC, reaction mixture was cooled to 5°C and stirred for 30 min. Filtered the solid and washed with cold methanol (10 ml) to give methyl 6-fluoro-4-oxochroman-2-carboxylate (III) (96g, 90%) as off white solid.

Example 4: 6-fluoro-2-(hydroxymethyl)chroman-4-ol (IV)
To a solution of methyl 6-fluoro-4-oxochroman-2-carboxylate (III) (100g, 0.446 mols) in methanol (500 ml) was added sodium borohydride (42g, 1.116 mols) at 0°C slowly. Reaction mixture was stirred at 0°C for 1h. After completion of the starting material by TLC, adjusted pH 2-3 with 5N HCl. Methanol was removed under reduced pressure, crude was diluted with water (1 lit) and extracted with ethyl acetate (2x200 ml). Organic layer was dried on sodium sulfate and concentrated under reduced pressure to give 6-fluoro-2-(hydroxymethyl)chroman-4-ol IV (crude, 80g, 90%). The crude material was used for the next reaction without any further purification.

Alternately, the crude product (80g) was dissolved in IPE (160 ml), stirred for 30 min and filtered to be used in the next reaction.

Example 5: (6-fluorochroman-2-yl)methanol (V)
To a solution of 6-fluoro-2-(hydroxymethyl)chroman-4-ol (IV) (50g, 0.252 mols) in conc. HCl (500 ml) and toluene (250 ml) at RT was added zinc (82.5g, 1.26 mols) lot wise slowly, and the mass temperature was maintained at 70°C. The reaction mixture was heated at 70°C for 1h. After completion of the starting material by TLC, reaction mixture was cooled to RT and separated the toluene layer. Aqueous layer was extracted with toluene (1x 100ml). The combined organic layers were washed with water (1x 100ml) and dried on Na2SO4. Organic layer was concentrated under reduced pressure to give 6-fluorochroman-2-yl)methanol (V) (crude, 41g, 90%) and used for the next reaction without any further purification.

Example 6: 6-fluorochroman-2-carbaldehyde (VI)
To the solution of 6-fluorochroman-2-yl)methanol (V)(40g, 0.219mols), KBr (1.3g, 0.010 mols), TEMPO (500 mg) in DCM (800 ml) was added the pre prepared solution of NaOCl (29.4g, 0.395 mols, 10-12% in water), NaHCO3 (41.5g, 0.494 mols) in water (80 ml) at 0-5°C drop wise. The reaction mixture was stirred for 30 min at 0-5°C. After completion of the starting material by TLC, DCM layer was separated and dried on sodium sulfate. The 6-fluorochroman-2-carbaldehyde (VI) (DCM solution) was used for the next reaction as such.

Example 7: 6-fluoro-2-(oxiran-2-yl)chroman (Anti, VII A) and 6-fluoro-2-(oxiran-2-yl)chroman (Syn, VII B)
To the solution of trimethyl sulfoxonium iodide (48.3g, 0.219 mols) in anhydrous DMSO (240 ml) was added KOtBu (24.6g, 0.219mols) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 1h. The reaction mixture was cooled to 10°C and 6-fluorochroman-2-carbaldehyde VI (DCM solution) was added drop wise. Reaction mixture was stirred at 10-15°C for 30 min and allowed to stir at RT for 1h. Reaction mixture was diluted with water (500 ml) and separated the DCM layer. Aqueous layer was extracted again with DCM (1x100 ml). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude material was purified on silica gel column chromatography (2% EtOAc/Hexane) to give 6-fluoro-2-(oxiran-2-yl)chroman VII A (Anti isomer,16g, 37.8%) and 6-fluoro-2-(oxiran-2-yl)chroman VIIB (Syn isomer, 6g, 14.2%).
Example 8: 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol (VIII)
To a solution of benzyl amine (27g, 0.252 mols) in IPA (50 ml) was added 6-fluoro-2-(oxiran-2-yl)chroman VII A (Anti, 9.8g, 0.0504 mols) and stirred for 4h at 25-30°C. After completion of the starting material by TLC, reaction mixture was cooled and stirred for 30min at 0-5°C. The solid was filtered, washed with chilled IPA (10ml) to give 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol VIII (11.3g, 78%) as white solid.

Example 9: 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) IX
To a solution of 6-fluoro-2-(oxiran-2-yl)chroman VII B (Syn, 5.06g, 0.026 mols) in methanol (40 ml) was added 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol VIII (8g, 0.027 mols) at RT. The reaction mixture was heated at 65-70°C for 18-20h. After completion of the starting material by TLC, reaction mixture was cooled to RT and conc. HCl (3.2 ml) was added. Methanol was removed under vacuum; acetonitrile (10.5 ml) was added and stirred for 10 min at RT. Then IPE (21 ml) was added and stirring continued for 30 min. Filtered the solid and washed with mixture of acetonitrile: IPE (1:2, 15.3 ml) to give 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) IX (12.7g, 86%) as off white solid.

Example 10: 2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) hydrochloride X
The solution of 2,2'-(benzylazanediyl)bis(1-(6-fluorochroman-2-yl)ethanol) IX (20g, 0.037 mols), 10% Pd/C (2g) in methanol (500 ml) under hydrogen atmosphere (5-5.5 kg/cm2) at 50°C was stirred for 2-3h. After completion of the starting material by TLC, reaction mixture was cooled to RT and hydrogen gas was released. Pd/C was filtered on celite bed and filtrate was distilled under reduced pressure. IPA.HCl (20 ml, 20%) was added to the residue. Then heated and stirred at 65-70°C for 4h. Methanol (270 ml) was added to the reaction mixture and stirred at 65-70°C for 30 min. Solvents were distilled at atmospheric pressure to maintain 60 ml volume. Reaction mixture was cooled and stirred at RT for 4h. Solid was filtered and washed with methanol (10 ml) to give 2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) hydrochloride X (5.9g, 36%).