FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF REBOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF REBOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of reboxetine and its pharmaceutically acceptable salts thereof. The process comprises reducing a compound of structural formula V into a compound of structural formula VI and then converting a compound of structural formula VI into reboxetine compound of structural formula I

Formula V Formula VI Formula I
Wherein P is a nitrogen protection group
BACKGROUND OF THE INVENTION
Reboxetine is chemically (R*, R*)-2-[(2-ethoxyphenoxy)-phenyl-methyl] morpholine and is known from U.S. Patent No. 4,229,449 and is represented by formula I. Chemically, reboxetine has two chiral centers and it is a racemic mixture of enantiomers, (R, R) and (S, S) in a 1:1 ratio.


Reboxetine is an antidepressant drug and is being used in the treatment of clinical depression, panic disorder and ADD/ADHD. Its mesylate (i.e. methanesulfonate) salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra.
U.S. Patent No. 4,229,449 discloses a process of preparing reboxetine compound of structural formula I by the use of a compound of structural formula II as showed below in scheme no. 1:

Scheme no. 1
The prior art process for preparing reboxetine compound of structural formula I is not commercially viable due to the low yielding and therefore there is a need in the art to develop an improved process for preparing reboxetine compound of structural formula I.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a commercial viable process for the preparation of reboxetine compound of structural formula I comprising the steps of:
a. reducing a compound of structural formula V to get a compound of structural formula VI and

Formula V Formula VI
Wherein P is a nitrogen protection group b. converting a compound of structural formula VI into reboxetine compound of structural formula I.

Formula VI Formula I
Formula V Formula VI
Wherein P is a nitrogen protection group
A second aspect of the present invention is to provide novel intermediate compounds of structural formula V and VI for the preparation of reboxetine compound of structural formula I.


Another aspect of the present invention is to provide novel intermediate compounds of structural formula VII for the preparation of reboxetine compound of structural formula I.

DETAIL DESCRIPTION OF THE INVENTION
The compound of structural formula V may be prepared by cyclizing a compound of structural formula VII.

Wherein P is a nitrogen protection group
The compound of structural formula V may be prepared by protecting a compound of structural formula IV.


Formula IV Formula V
The nitrogen protecting group may include tertiary butyloxy carbonyl or carbobenzoyloxy group.
The reduction of compound of structural formula V may be carried out by reducing agent selected from the group comprising of lithium aluminum hydride, sodium bis (2-methoxy-ethoxy) aluminium hydride (vitride) or borane.
The reduction of compound of structural formula V may be carried out in aromatic hydrocarbon solvents.
The examples of aromatic hydrocarbon solvents may include toluene, xylene, benzene, ethylbenzene, mesitylene or tetralin.
The reduction of compound of structural formula V may be carried out at a temperature in the range of -20°C to 25°C for a period of 30 minutes to 8 hours.
The compound of structural formula VI may be isolated by extracting it into water as an acid addition salt by the addition of an acid such as hydrochloric acid, neutralised by the addition of a base such as sodium hydroxide or potassium hydroxide, and then extracting by aromatic hydrocarbon solvent.
The compound of structural formula VI may be converted into reboxetine compound of structural formula I by reacting solution of a compound of structural formula VI in an aromatic hydrocarbon solvent with a concentrated hydrochloric acid for a period of 30 minutes to 4 hours.

The reboxetine compound of structural formula I may be isolated by neutralizing the reaction mixture with an aqueous solution of sodium hydroxide followed by separation organic layer.
The organic layer containing reboxetine compound of structural formula I may be washed with water, dried over anhydrous sodium sulfate followed by concentrating under reduced pressure.
The reboxetine compound of structural formula I may be dried at a temperature in the range of 40°C to 50°C under reduced pressure.
The reboxetine compound of structural formula I, obtained by following the present invention is substantially pure and having more than 99.5% purity as determined by high performance liquid chromatography technique.
The intermediate compound of structural formula V, VI or VII may include the mixture of enantiomers, (R, R) and (S, S) in a 1:1 ratio.
EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
EXAMPLE: Preparation of substantially pure reboxetine.
A solution of tert-butyl 2-((2-ethoxyphenoxy)(phenyl)methyl)-5-oxomorpholine-4-carboxylate [50gm , mixture of enantiomers, (R, R) and (S, S) in a 1:1 ratio] in toluene (750ml) was added a solution of vitride in toluene (65% wt, 500ml) at 0oC in 1 hour. The resulting reaction mixture was stirred 1 hour at 0-5°C. The reaction mixture was quenched by aqueous sodium hydroxide solution (100ml, 50% weight / volume) and then organic layer was separated, washed by aqueous sodium carbonate solution (2x100 ml, 5% weight / volume). The organic layer was

treated with aqueous hydrochloric acid (150 ml, 8% weight / volume) at 25°C for 30 minutes. The organic layer was separated and discarded and then the aqueous layer was basified by sodium hydroxide solution (10% weight / volume) up to pH 10-12 and then toluene (250ml) was added. The organic layer was separated, dried over anhydrous sodium sulphate (25gm) and then concentrated hydrochloric acid (33% weight/weight 50ml) was added dropwise at 25-30°C in 15 minutes. The resulting reaction mixture was stirred for 2 hours at 25°C-30°C. The aqueous layer was separated, basified by aqueous sodium hydroxide solution (10% weight /volume) and then toluene (250ml) was added. The organic layer was separated, dried over anhydrous sodium sulfate (25gm) and then concentrated under reduced pressure and dried at 45°C under reduced pressure to get title compound. Yield: 36.3gm Purity: 99.86% (By HPLC)

WE CLAIM:
1. A process for the preparation of reboxetine compound of structural formula I comprising the steps of:
a. reducing a compound of structural formula V to get a compound of structural formula VI and

Formula V Formula VI
Wherein P is a nitrogen protection group b. converting a compound of structural formula VI into reboxetine compound of structural formula 1.

Formula VI Formula 1

Wherein P is a nitrogen protection group
2. The process according to claim no.l wherein compound of structural formula V is prepared by cyclizing a compound of structural formula VII.

3. The process according to claim no.l wherein compound of structural formula V is prepared by protecting a compound of structural formula IV.

Formula IV Formula V
4. The process according to claim no.l wherein reduction of compound of structural formula V is carried out by reducing agent selected from the group comprising of lithium aluminum hydride, sodium bis (2-methoxy-ethoxy) aluminium hydride (vitride) or borane.
5. The process according to claim no. 1, wherein reduction of compound of structural formula V is carried out at a temperature in the range of -20°C to 25°C for a period of 30 minutes to 8 hours.
6. The process according to claim no. 1 wherein reduction of compound of structural formula V is carried out in aromatic hydrocarbon solvents selected from the group comprising of toluene, xylene, benzene, ethylbenzene, mesitylene or tetralin.
7. The process according to claim no.l wherein compound of structural formula VI is converted into reboxetine compound of structural formula I by reacting a solution of a compound of structural formula VI in aromatic hydrocarbon solvent with a concentrated hydrochloric acid for a period of 30 minutes to 4 hours.
8. The enantiomers, (R, R) and (S, S) in a 1:1 ratio of compounds of structural formula V, VI, and VII.


Formula V Formula VI Formula VII
Wherein P is a nitrogen protection group
9, A method of preparing reboxetine compound of structural formula I comprises the use of
compounds of structural formula V, VI or VII.
10. The process according to claim nos.l, 2, 3 or 8 wherein protecting group is selected from the
group comprising of tertiary butyloxy carbonyl or carbobenzoyloxy group.